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Sample records for oral morphine tablets

  1. Effect of filtration on morphine and particle content of injections prepared from slow-release oral morphine tablets

    PubMed Central

    2009-01-01

    Background Injections of mixtures prepared from crushed tablets contain insoluble particles which can cause embolisms and other complications. Although many particles can be removed by filtration, many injecting drug users do not filter due to availability, cost or performance of filters, and also due to concerns that some of the dose will be lost. Methods Injection solutions were prepared from slow-release morphine tablets (MS Contin®) replicating methods used by injecting drug users. Contaminating particles were counted by microscopy and morphine content analysed by liquid chromatography before and after filtration. Results Unfiltered tablet extracts contained tens of millions of particles with a range in sizes from < 5 μm to > 400 μm. Cigarette filters removed most of the larger particles (> 50 μm) but the smaller particles remained. Commercial syringe filters (0.45 and 0.22 μm) produced a dramatic reduction in particles but tended to block unless used after a cigarette filter. Morphine was retained by all filters but could be recovered by following the filtration with one or two 1 ml washes. The combined use of a cigarette filter then 0.22 μm filter, with rinses, enabled recovery of 90% of the extracted morphine in a solution which was essentially free of tablet-derived particles. Conclusions Apart from overdose and addiction itself, the harmful consequences of injecting morphine tablets come from the insoluble particles from the tablets and microbial contamination. These harmful components can be substantially reduced by passing the injection through a sterilizing (0.22 μm) filter. To prevent the filter from blocking, a preliminary coarse filter (such as a cigarette filter) should be used first. The filters retain some of the dose, but this can be recovered by following filtration with one or two rinses with 1 ml water. Although filtration can reduce the non-pharmacological harmful consequences of injecting tablets, this remains an unsafe practice due

  2. Morphine

    MedlinePlus

    Morphine is used to relieve moderate to severe pain. Morphine extended-release tablets and capsules are only used ... controlled by the use of other pain medications. Morphine extended-release tablets and capsules should not be ...

  3. Possible Neonatal Herpes Simplex Virus (HSV) Acquired Postpartum from Maternal Oral HSV Reactivation after Neuraxial Morphine.

    PubMed

    De Guzman, M Cecilia; Chawla, Rupesh; Duttchen, Kaylene

    2014-05-01

    In this report, we describe a case of a neonatal oral herpes simplex virus (HSV) infection possibly acquired from a mother who had oral HSV reactivation in association with neuraxial morphine. Neuraxial morphine is commonly administered for postpartum analgesia after cesarean delivery. While there is evidence that neuraxial morphine increases the risks of oral HSV reactivation in parturients, there has been no report of neonatal HSV infection directly acquired from a mother who had HSV recurrence from neuraxial morphine.

  4. [Cost-effective analysis of rotation from sustained-release morphine tablet to transdermal fentanyl of matrix type or sustained-release oxycodone tablet].

    PubMed

    Ise, Yuya; Wako, Tetsuya; Miura, Yoshihiko; Katayama, Shirou; Shimizu, Hisanori

    2009-12-01

    The present study was undertaken to determine the pharmacoeconomics of switching from sustained-release morphine tablet to matrix type (MT) of transdermal fontanel or sustained-release Oxycodone tablet. Cost-effective analysis was performed using a simulation model along with decision analysis. The analysis was done from the payer's perspective. The cost-effective ratio/patient of transdermal MT fontanel (22, 539 yen)was lower than that of sustained -release Oxycodone tablet (23, 630 yen), although a sensitivity analysis could not indicate that this result was reliable. These results suggest the possibility that transdermal MT fontanel was much less expensive than a sustained-release Oxycodone tablet.

  5. The determination of morphine in urine and oral fluid following ingestion of poppy seeds.

    PubMed

    Rohrig, Timothy P; Moore, Christine

    2003-10-01

    In workplace drug-testing programs, the use of heroin, morphine, and codeine is currently determined by the analysis of urine specimens. It has been shown that ingestion of poppy seeds can cause a positive test result for morphine. In an attempt to differentiate positive results caused by poppy seed ingestion from those caused by heroin or morphine abuse, the screening cutoff concentration for urine opiates in the federal workplace drug-testing program was raised to 2000 ng/mL from 300 ng/mL. Currently, oral fluid is under consideration as a possible alternative to urine for drug testing. The suggested cutoff for oral fluid morphine is 40 ng/mL; however, the effect of poppy seed ingestion on morphine concentrations in this specimen type has not been widely investigated. Volunteers at two separate sites ingested commercially available poppy seeds and/or poppy seed bagels. Oral fluid and urine samples were collected at both sites. Oral fluid samples were collected for 24 h; urine was collected for 2 days. The samples were analyzed for the presence of codeine and morphine using gas chromatography-mass spectrometry. Morphine concentrations greater than the suggested cutoff concentrations were detected in oral fluid up to 1 h and in urine for up to 8 h. This study has demonstrated that a positive result for morphine in oral fluid may be due to the ingestion of poppy seeds.

  6. [Fast-disintegration oral tablets having sustained release property].

    PubMed

    Jin, Yi; Ohkuma, Hideki; Wang, Hua; Natsume, Hideshi; Sugibayashi, Kenji; Morimoto, Yasunori

    2002-11-01

    Fast-disintegrating (FD) tablets containing nicorandil-loaded dry emulsions were prepared and their controlled-release properties were examined and compared with the plain FD tablets (FD tablets without dry emulsions) and commercial tablets. The dry emulsions were prepared with myristyl alcohol and stearyl alcohol and their property was modified by mixing the ratio of the two alcohols. Disintegration time of the prepared FD tablets was sufficiently fast (i.e., 12 to 23 s). In vitro release of nicorandil from the FD tablets containing the dry emulsions was sustained over 6 h, while that from plain FD and commercial tablets was complete within 5 min. In vivo absorption of nicorandil from the tablets was evaluated by oral administration in beagle dogs. FD tablets containing dry emulsions showed a similar AUC, lower Cmax, and delayed Tmax compared to the plain FD and commercial tablets. These results suggest that the dry emulsion-loaded FD tablets can be utilized to improve the sustained-release property of active drugs.

  7. Morphine and Codeine in Oral Fluid after Controlled Poppy Seed Administration

    PubMed Central

    Concheiro, Marta; Newmeyer, Matthew N.; da Costa, Jose Luiz; Flegel, Ron; Gorelick, David A.; Huestis, Marilyn A.

    2014-01-01

    Opiates are an important drug class in drug testing programs. Ingestion of poppy seeds containing morphine and codeine can yield positive opiate tests and mislead result interpretation in forensic and clinical settings. Multiple publications evaluated urine opiate concentrations following poppy seed ingestion, but only 2 addressed oral fluid (OF) results; neither provided the ingested morphine and codeine dosage. We administered two 45g raw poppy seed doses, each containing 15.7mg morphine and 3.1mg codeine, 8h apart to 17 healthy adults. All OF specimens were screened by on-site OF immunoassay Draeger DrugTest 5000, and confirmed with OF collected with Oral-Eze® device and quantified by liquid chromatography tandem mass spectrometry (1μg/L morphine and codeine limits of quantification). Specimens (n=459) were collected before and up to 32h after the first dose. All specimens screened positive 0.5h after dosing and remained positive for 0.5-13h at Draeger 20μg/L morphine cutoff. Maximum OF morphine and codeine concentrations (Cmax) were 177 and 32.6μg/L, with times to Cmax (Tmax) of 0.5-1h and 0.5-2.5h post-dose, respectively. Windows of detection after the second dose extended at least 24h for morphine and to 18h for codeine. After both doses, the last morphine positive OF result was 1h with 40μg/L 2004 proposed US Substance Abuse and Mental Health Services Administration cutoff, and 0.5h with 95μg/L cutoff, recently recommended by the Driving Under the Influence of Drugs and Medicines project. Positive OF morphine results are possible 0.5-1h after ingestion of 15.7mg of morphine in raw poppy seeds, depending upon the cutoff employed. PMID:25345619

  8. Discovering novel carriers for oral insulin tablets: a pharmacoinformatics approach.

    PubMed

    Seenivasagam, R; Hemavathi, K; Sivakumar, G; Niranjan, Vidya

    2013-01-01

    Insulin is used medically to treat Type 1 diabetes mellitus most commonly injected subcutaneously for human beings. The realisation that insulin injections have become a part of life can be extremely harrowing for many diabetic patients. Using insulin therapeutically is not a new practice, but still delivery methods to make the process more bearable have not gained widespread prominence as of yet. Oral delivery of insulin in tablet form has always been a significant challenge for pharmaceutical researchers. This study is a prospect of oral insulin tablet through pharmacoinformatics approach.

  9. Focused review: neuraxial morphine and oral herpes reactivation in the obstetric population.

    PubMed

    Bauchat, Jeanette R

    2010-11-01

    Neuraxial morphine administration is a common strategy for providing postcesarean delivery analgesia. Morphine delivered via this route increases the risk of herpes labialis (oral herpes) reactivation, a disease common in women of childbearing age. A primary concern is risk of transmission to the neonate from maternal reactivation. The benefits to the mother of this form of analgesia outweigh the risk of neonatal herpes acquired postpartum from maternal recurrence because serious neonatal morbidity from recurrent herpes has not been described.

  10. Ginger Orally Disintegrating Tablets to Improve Swallowing in Older People.

    PubMed

    Hirata, Ayumu; Funato, Hiroki; Nakai, Megumi; Iizuka, Michiro; Abe, Noriaki; Yagi, Yusuke; Shiraishi, Hisashi; Jobu, Kohei; Yokota, Junko; Hirose, Kahori; Hyodo, Masamitsu; Miyamura, Mitsuhiko

    2016-01-01

    We previously prepared and pharmaceutically evaluated ginger orally disintegrating (OD) tablets, optimized the base formulation, and carried out a clinical trial in healthy adults in their 20 s and 50s to measure their effect on salivary substance P (SP) level and improved swallowing function. In this study, we conducted clinical trials using the ginger OD tablets in older people to clinically evaluate the improvements in swallowing function resulting from the functional components of the tablet. The ginger OD tablets were prepared by mixing the excipients with the same amount of mannitol and sucrose to a concentration of 1% ginger. Eighteen healthy older adult volunteers aged 63 to 90 were included in the swallowing function test. Saliva was collected before and 15 min after administration of the placebo and ginger OD tablets. Swallowing endoscopy was performed by an otolaryngologist before administration and 15 min after administration of the ginger OD tablets. A scoring method was used to evaluate the endoscopic swallowing. Fifteen minutes after taking the ginger OD tablets, the salivary SP amount was significantly higher than prior to ingestion or after taking the placebo (p<0.05). Among 10 subjects, one scored 1-3 using the four evaluation criteria. Overall, no aspiration occurred and a significant improvement in the swallowing function score was observed (p<0.05) after taking the ginger OD tablets. Our findings showed that the ginger OD tablets increased the salivary SP amount and improved swallowing function in older people with appreciably reduced swallowing function.

  11. Fexofenadine in pediatrics: oral tablet and suspension formulations.

    PubMed

    Mansfield, Lyndon E

    2008-02-01

    Allergic rhinitis is a common chronic condition in children. Oral antihistamines are a first-line treatment option in allergic rhinitis and different formulations are available to aid administration to children. The tablet formulation of the second-generation antihistamine fexofenadine has established efficacy and safety in both adults and children. To aid administration in young children, a new oral suspension formulation of fexofenadine has been developed, indicated for the relief of seasonal allergic rhinitis symptoms in children aged 2-11 years and for uncomplicated skin manifestations of chronic idiopathic urticaria in children aged 6 months-11 years. Clinical studies have shown the oral suspension to have both bioequivalence with the 30 mg tablet formulation and a favorable safety and tolerability profile.

  12. Effects of maternal oral administration of morphine sulfate on developing rat fetal cerebrum: a morphometrical evaluation.

    PubMed

    Sadraie, Seyed Homayoon; Kaka, Gholam Reza; Sahraei, Hedayat; Dashtnavard, Hosein; Bahadoran, Hosein; Mofid, Mahmood; Nasab, Hossein Mahdavi; Jafari, Fatemeh

    2008-12-15

    Intrauterine morphine exposure is a risk factor for neurological and behavioral deficit in children, although the precise underlying biological correlate for this is unclear. Female pregnant rats were orally treated with 0.1 mg/ml of morphine solution on the 21st day of gestation. Pregnant rats were killed on the 21st day of gestation and their fetuses were taken out and evaluated for growth and cerebral development. The fetuses were fixed and followed by dehydration through graded ethanol solutions and were then embedded and their heads were coronally sectioned through the frontal cerebral cortex. Quantitative computer-assisted morphometric study was done on the frontal cerebral cortex (FCC) which consists of cortical plate (CP), intermediate (migratory) zone (IZ) and matrix (proliferative) zone (MZ) in the rat embryos. The results showed that morphine exposure caused a significant reduction of fetal weight and crown-to-rump length in morphine exposure group. The present study showed that animals with intrauterine morphine exposure, induced by a period of reduced placental blood flow during the second week of pregnancy, demonstrate reduced both cortical thickness and the numbers of neurons in the developing fetal frontal cerebral cortex (FCC). Histomorphometric evaluation revealed that the thickness of the CP was significantly decreased in the morphine-exposed embryos. In addition, neuronal counting showed that cell proliferation in the CP was suppressed after morphine administration and that the migration of neurons from the matrix zone (MZ) to the cortex was decelerated. In conclusion, these results showed that morphine exposure during the second week of pregnancy could affect brain development in a way, which could lead to neurological and behavioral deficits in the postnatal animal.

  13. Morphine and codeine in oral fluid after controlled poppy seed administration.

    PubMed

    Concheiro, Marta; Newmeyer, Matthew N; da Costa, Jose Luiz; Flegel, Ron; Gorelick, David A; Huestis, Marilyn A

    2015-07-01

    Opiates are an important drug class in drug testing programmes. Ingestion of poppy seeds containing morphine and codeine can yield positive opiate tests and mislead result interpretation in forensic and clinical settings. Multiple publications evaluated urine opiate concentrations following poppy seed ingestion, but only two addressed oral fluid (OF) results; neither provided the ingested morphine and codeine dosage. We administered two 45 g raw poppy seed doses, each containing 15.7 mg morphine and 3.1 mg codeine, 8 h apart to 17 healthy adults. All OF specimens were screened by on-site OF immunoassay Draeger DrugTest 5000, and confirmed with OF collected with Oral-Eze® device and quantified by liquid chromatography-tandem mass spectrometry (1 µg/L morphine and codeine limits of quantification). Specimens (n = 459) were collected before and up to 32 h after the first dose. All specimens screened positive 0.5 h after dosing and remained positive for 0.5-13 h at Draeger 20 µg/L morphine cut-off. Maximum OF morphine and codeine concentrations (Cmax ) were 177 and 32.6 µg/L, with times to Cmax (Tmax ) of 0.5-1 h and 0.5-2.5 h post-dose, respectively. Windows of detection after the second dose extended at least 24 h for morphine and to 18 h for codeine. After both doses, the last morphine positive OF result was 1 h with 40 µg/L 2004 proposed US Substance Abuse and Mental Health Services Administration cut-off, and 0.5 h with 95 µg/L cut-off, recently recommended by the Driving under the Influence of Drugs and Medicines project. Positive OF morphine results are possible 0.5-1 h after ingestion of 15.7 mg of morphine in raw poppy seeds, depending on the cut-off employed.

  14. Ingestibility and Formulation Quality of Lansoprazole Orally Disintegrating Tablets

    PubMed Central

    Matsui, Megumi; Nakamura, Katsuki; Kasai, Ryoya

    2016-01-01

    Objectives. We evaluated the ingestibility and formulation quality of one branded (formulation A) and five generic (formulations B, C, D, E, and F) lansoprazole orally disintegrating (OD) tablets. Methods. Ingestibility, including the oral disintegrating time, taste, mouth feeling, and palatability, was examined by sensory testing in healthy subjects. Formulation qualities, including salivary stability, gastric acid resistance, and intestinal dissolution behavior, were examined. Results and Discussion. The oral disintegration time of formulation F (52 s) was significantly longer than that of other formulations (32–37 s). More than 90% of subjects did not experience bitterness with formulations A, E, and F, whereas 50% of subjects felt rough and powdery sensations with formulations B, C, and D. More than 80% of subjects suggested that formulations A, E, and F had good palatability. Ingestibility was different between formulations. OD tablets consist of enteric granules containing lansoprazole, which is unstable in gastric acid. Enteric granules of each formulation were stable in artificial saliva and gastric juice. No differences were observed in dissolution behaviors among the formulations, indicating that the formulation quality of the formulations was almost equivalent. Conclusions. This study provides useful information for selecting branded or generic lansoprazole OD tablets for individualized treatments. PMID:28044122

  15. Design, Formulation, and Physicochemical Evaluation of Montelukast Orally Disintegrating Tablet

    PubMed Central

    Aslani, Abolfazl; Beigi, Maryam

    2016-01-01

    Background: Orally disintegrating tablets (ODTs) are a modern form of tablets that when placed in the oral cavity, disperses rapidly. These tablets have advantages, particularly good applications for children and old patients who have a complication in chewing or swallowing solid dosage forms. The aim of this study was to design, formulate, and evaluate the physicochemical properties of 5 mg montelukast ODTs for the prevention of asthma and seasonal allergies. Methods: Formulations were prepared with different amounts of super disintegrating agents and effervescent bases as disintegrant agents. Flowability and compressibility of mixed powders were evaluated. The prepared formulations were tested for hardness, thickness, friability, weight variation, drug content, wetting time, disintegration time, dissolution study, and moisture uptake studies. Results: The compressibility index and angle of repose were in the range of 15.87%–23.43% and 32.93–34.65, respectively. Hardness, thickness, friability, wetting time, and content uniformity of formulations were in the range of 33.7–37.1 N, 3.00–3.81 mm, 0.27%–0.43%, 31–50 s and 96.28%–99.90%, respectively. Disintegration time of the tablets prepared with super disintegrating agents, effervescent bases, and combination of two were in the range of 30–50, more than 60 and 20–36 s, respectively. Conclusions: Mixture of powders and tablets passed all the specified tests. The results showed formulations prepared by super disintegrating agents and super disintegrating agents with effervescent bases had shorter disintegration time compared to formulations with effervescent bases alone. PMID:27857833

  16. Within-subject comparison of the psychopharmacological profiles of oral oxycodone and oral morphine in non-drug-abusing volunteers

    PubMed Central

    Lichtor, Stephanie A.

    2008-01-01

    Rationale Nonmedical use and abuse of prescription opioids is a significant problem in the USA. Little attention has been paid to assessing the relative psychopharmacological profile (including abuse liability-related effects) of specific prescription opioids. Objectives The aim of this study is to directly compare the psychopharmacological profile of two oral opioids within the same subject. Methods A randomized, placebo-controlled, crossover study was done in which 20 non-drug-abusing volunteers ingested 10 and 20 mg of oxycodone, 30 and 60 mg of morphine, and placebo in separate sessions. Drug doses were equated on an objective measure of opiate effects: miosis. Subjective, psychomotor, reinforcing, and physiological effects of the opioids were assessed. Results In general, the two opioids at equimiotic doses produced similar prototypic opiate-like effects and psychomotor impairment of similar magnitude. However, several effects were found only with 20 mg oxycodone. Both drugs produced abuse liability-related subjective effects but also dysphoric effects, particularly with 60 mg morphine. Neither drug at either dose functioned as a reinforcer, as measured by the Multiple Choice Procedure. Relative potency ratios indicated an average oxycodone:morphine ratio of 1:3. Conclusions The psychopharmacological profile of oxycodone and morphine at equimiotic doses had many similarities; however, differences were found in producing abuse liability-related and dysphoric effects. In the medical community, it is commonly accepted that oral oxycodone is 1.5 to 2 times as potent as oral morphine in producing analgesia; using this ratio, although patients may experience similar degrees of pain relief, those receiving oxycodone may be experiencing stronger and potentially different psychopharmacological effects. PMID:17899018

  17. Formulation of multiparticulate systems as lyophilised orally disintegrating tablets.

    PubMed

    Alhusban, Farhan; Perrie, Yvonne; Mohammed, Afzal R

    2011-11-01

    The current study aimed to exploit the electrostatic associative interaction between carrageenan and gelatin to optimise a formulation of lyophilised orally disintegrating tablets (ODTs) suitable for multiparticulate delivery. A central composite face centred (CCF) design was applied to study the influence of formulation variables (gelatin, carrageenan and alanine concentrations) on the crucial responses of the formulation (disintegration time, hardness, viscosity and pH). The disintegration time and viscosity were controlled by the associative interaction between gelatin and carrageenan upon hydration which forms a strong complex that increases the viscosity of the stock solution and forms tablet with higher resistant to disintegration in aqueous medium. Therefore, the levels of carrageenan, gelatin and their interaction in the formulation were the significant factors. In terms of hardness, increasing gelatin and alanine concentration was the most effective way to improve tablet hardness. Accordingly, optimum concentrations of these excipients were needed to find the best balance that fulfilled all formulation requirements. The revised model showed high degree of predictability and optimisation reliability and therefore was successful in developing an ODT formulation with optimised properties that were able deliver enteric coated multiparticulates of omeprazole without compromising their functionality.

  18. Development of sildenafil-loaded orally disintegrating tablet with new lactate salt.

    PubMed

    Jung, Si-Young; Kim, Dong-Wuk; Seo, Youn Gee; Woo, Jong Soo; Yong, Chul Soon; Choi, Han-Gon

    2012-05-01

    To develop a sildenafil lactate-loaded orally disintegrating tablet with a faster drug effect onset and immediate action of erection, the orally disintegrating tablets were prepared with various amounts of menthol and colloidal silica using the direct compression technique followed by vacuum drying. Their tablet properties such as friability, hardness, wetting time and disintegration time were investigated. The oral bioavailability of sildenafil in the orally disintegrating tablet was then compared with the sildenafil citrate-loaded commercial tablet (Viagra(®)) in rabbits. Sildenafil lactate was a new salt form with more improved solubility and alleviated bitterness compared with commercial salt, sildenafil citrate. As the amount of menthol in the orally disintegrating tablet increased, the friability increased and hardness decreased, resulting in a shorter wetting time and disintegration time. Colloidal silica did the opposite. The sildenafil lactate-loaded orally disintegrating tablet prepared with 45 mg/tab of menthol and 1.5 mg/tab of colloidal silica gave a hardness of 3-4 KP, friability less than 0.5% and disintegration time less than 30 s, suggesting that it was a practical and commercial product with good tablet property and excellent efficacy. Furthermore, it gave higher AUC and C(max), and shorter T(max) values than did the commercial tablet, indicating that it improved the oral bioavailability of sildenafil in rabbits compared with the commercial tablet. Thus, the sildenafil lactate-loaded orally disintegrating tablet might induce a fast onset of action and immediate erection compared with the sildenafil citrate-loaded commercial tablet.

  19. 77 FR 1695 - Determination That AVALIDE (Hydrochlorothiazide and Irbesartan), Oral Tablets, 25 Milligrams/300...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-11

    ... and irbesartan), oral tablets, 25 milligrams (mg)/300 mg and 12.5 mg/75 mg, were not withdrawn from... new drug applications (ANDAs) for hydrochlorothiazide and irbesartan, oral tablets, 25 mg/300 mg and 12.5 mg/75 mg, if all other legal and regulatory requirements are met. FOR FURTHER...

  20. Randomised crossover trial of transdermal fentanyl and sustained release oral morphine for treating chronic non-cancer pain

    PubMed Central

    Allan, Laurie; Hays, Helen; Jensen, Niels-Henrik; de Waroux, Bernard Le Polain; Bolt, Michiel; Donald, Royden; Kalso, Eija

    2001-01-01

    Objectives To compare patients' preference for transdermal fentanyl or sustained release oral morphine, their level of pain control, and their quality of life after treatment. Design Randomised, multicentre, international, open label, crossover trial. Setting 35 centres in Belgium, Canada, Denmark, Finland, the United Kingdom, the Netherlands, and South Africa. Participants 256 patients (aged 26-82 years) with chronic non-cancer pain who had been treated with opioids. Main outcome measures Patients' preference for transdermal fentanyl or sustained release oral morphine, pain control, quality of life, and safety assessments. Results Of 212 patients, 138 (65%) preferred transdermal fentanyl, whereas 59 (28%) preferred sustained release oral morphine and 15 (7%) expressed no preference. Better pain relief was the main reason for preference for fentanyl given by 35% of patients. More patients considered pain control as being “good” or “very good” with fentanyl than with morphine (35% v 23%, P=0.002). These results were reflected in both patients' and investigators' opinions on the global efficacy of transdermal fentanyl. Patients receiving fentanyl had on average higher quality of life scores than those receiving morphine. The incidence of adverse events was similar in both treatment groups; however, more patients experienced constipation with morphine than with fentanyl (48% v 29%, P<0.001). Overall, 41% of patients experienced mild or moderate cutaneous problems associated with wearing the transdermal fentanyl patch, and more patients withdrew because of adverse events during treatment with fentanyl than with morphine (10% v 5%). However, within the subgroup of patients naive to both fentanyl and morphine, similar numbers of patients withdrew owing to adverse effects (11% v 10%, respectively). Conclusion Transdermal fentanyl was preferred to sustained release oral morphine by patients with chronic non-cancer pain previously treated with opioids. The main

  1. Formulation study for orally disintegrating tablet using partly pregelatinized starch binder.

    PubMed

    Mimura, Kazuki; Kanada, Ken; Uchida, Shinya; Yamada, Masaki; Namiki, Noriyuki

    2011-01-01

    In this study, we aimed to design orally disintegrating tablets by employing a formulation design approach that enables the production of such tablets in the same facilities used for the production of solid dosage forms on an industrial scale. First, we examined the relationships between the types of binders used in the tablets and the properties of orally disintegrating tablets prepared by the wet granulation method. Results revealed that partly pregelatinized starch is a relatively suitable binder for orally disintegrating tablets as it also serves as a disintegrant. Next, we employed a central composite design for 2 factors, namely, corn starch and partly pregelatinized starch, in order to design granules suited for orally disintegrating tablets composed of D-mannitol, corn starch or partly pregelatinized starch. The effects of these 2 factors on 3 types of responses, namely, 50% granule size, compressing index and disintegrating index, were analyzed with a software package, and responses to changes in the factors were predicted. This study investigated the effects of binder type and binder content in orally disintegrating tablets, and provided evidence that the binder exerts a strong influence on tablet properties, and is therefore an important component of orally disintegrating tablets.

  2. [Impact of slow-release oral morphine on drug abusing habits in Austria].

    PubMed

    Beer, Beate; Rabl, Walter; Libiseller, Kathrin; Giacomuzzi, Salvatore; Riemer, Yvonne; Pavlic, Marion

    2010-01-01

    A well-established possibility to treat opiate addiction is the participation in opiate maintenance treatment programmes. For this purpose the opioids methadone and buprenorphine have been evaluated and are used nowadays in many countries. However, since 1998 also the use of slow-release oral morphine (SROM) has been legally permitted in Austria. Our data show that these morphine preparations are frequently abused and are dominating the black market in the meantime. Especially the intravenous consumption of SROM goes along with highly dangerous side effects that exceed the risks of needle sharing alone. Special galenics are supposed to ensure a 24 h effect of the otherwise quickly metabolised morphine. If dissolved and injected, insoluble contents such as talcum cause microembolisms, leading to severe damages of the inner organs. Furthermore, SROM, i.e. a drug prescribed by physicians, has been proved to be the main responsible substance in most drug related deaths since its permission and has nearly replaced heroin. Forensic physicians play a major role in the profound examination of these cases, including extensive toxicological analyses and interpretation of results. For instance, a differentiation between a recent morphine and heroin consumption is certainly possible, provided appropriate methods are used. A reliable estimation of the current situation of drug abusing habits is a premise for adequate therapeutic offers and preventive measures. Thus, well-founded and comparable data have to be collected. To facilitate data report a standardized report form has been developed that includes an obligatory statement regarding morphine or heroin consumption. This should help to enlighten the ongoing discussion on the role of SRM in drug abuse cases. Our results indicate that the prescription of SROM in opiate maintenance therapy has to be handled very strictly and should be reserved for special patients only. A slackening of the Austrian law concerning SROM is

  3. The technologies used for developing orally disintegrating tablets: a review.

    PubMed

    Badgujar, Bhatu P; Mundada, Atish S

    2011-06-01

    Orally disintegrating tablets (ODTs), also known as fast melts, quick melts, fast disintegrating and orodispersible systems, have the unique property of disintegrating in the mouth in seconds without chewing and the need of water and are thus assumed to improve patient compliance. Conventional methods like direct compression, wet granulation, moulding, spray-drying, freeze-drying and sublimation were used to prepare ODTs. New advanced technologies like Orasolv®, Durasolv®, Wowtab®, Flashtab®, Zydis®, Flashdose®, Oraquick®, Lyoc®, Advatab®, Frosta®, Quick-Disc® and Nanomelt® have been introduced by some pharmaceutical companies for the production of ODTs. The main objective of this review is to give a comprehensive insight into conventional and recent technologies used for the preparation of ODTs.

  4. Opioid-induced myoclonus and hyperalgesia following a short course of low-dose oral morphine

    PubMed Central

    Woodward, Owen Bleddyn; Naraen, Sangeeta; Naraen, Akriti

    2016-01-01

    A 76-year-old man was admitted to hospital with a right-sided fractured neck of femur requiring repair via a cemented hemiarthroplasty. Intraoperatively he received 10 mg of intravenous morphine. Post-operatively he received a short course of low-dose oral opioids and subsequently developed myoclonic jerks and hyperalgesia. The opioids were discontinued and both adverse effects resolved. This case report discusses the concurrent development of myoclonus and hyperalgesia following a low dose of opioids and explores possible management options. PMID:28386402

  5. Enhanced oral bioavailability of felodipine by novel solid self-microemulsifying tablets.

    PubMed

    Jing, Boyu; Wang, Zhiyuan; Yang, Rui; Zheng, Xia; Zhao, Jia; Tang, Si; He, Zhonggui

    2016-01-01

    The novel self-microemulsifying (SME) tablets were developed to enhance the oral bioavailability of a poor water-soluble drug felodipine (FDP). Firstly, FDP was dissolved in the optimized liquid self-microemusifying drug delivery systems (SMEDDS) containing Miglyol® 812, Cremophor® RH 40, Tween 80 and Transcutol® P, and the mixture was solidified with porous silicon dioxide and crospovidone as adsorbents. Then after combining the solidified powders with other excipients, the solid SME tablets were prepared by wet granulation-compression method. The prepared tablets possessed satisfactory characterization; the droplet size of the SME tablets following self-emulsification in water was nearly equivalent to the liquid SMEDDS (68.4 ± 14.0 and 64.4 ± 12.0 nm); differential scanning calorimetry (DSC) and powder X-ray diffractometry (PXRD) analysis demonstrated that FDP in SME tablets had undergone a polymorphism transition from a crystal form to an amorphous state, which was further confirmed by transmission electron microscopy (TEM). A similar dissolution performance of SME tablets and liquid SMEDDS was also obtained under the sink condition (85% within 10 min), both significantly higher than commercial tablets. The oral bioavailability was evaluated for the SME tablets, liquid SMEDDS and commercial conventional tablets in the fasted beagle dogs. The AUC of FDP from the SME tablets was about 2-fold greater than that of conventional tablets, but no significant difference was found when compared with the liquid SMEDDS. Accordingly, these preliminary results suggest that this formulation approach offers a useful large-scale producing method to prepare the solid SME tablets from the liquid SMEDDS for oral bioavailability equivalent enhancement of poorly soluble FDP.

  6. Formulation and Taste Masking of Ranitidine Orally Disintegrating Tablet

    PubMed Central

    Hesari, Zahra; Shafiee, Akram; Hooshfar, Shirin; Mobarra, Naser; Mortazavi, Seyed Alireza

    2016-01-01

    Orally Disintegrating Tablets (ODT) have the advantages of both solid dosage form specially the stability and ease of handling and liquid dosage forms including ease of swallowing and pre-gastric absorption. We focused on taste masking and formulation of ranitidine ODT which disintegrates rapidly in the mouth within 60 sec using super-disintegrants, special polymers, water soluble and even insoluble excipients, sweeteners and essence. Various formulations were designed and made in four series. The amount of ranitidine in each formulation was 150 mg, and the final weight of tablets was around 500 mg. Prepared formulations were evaluated in terms of several physicochemical tests including powder/granule flowability, appearance, thickness, uniformity of weight, hardness, friability and disintegration time. Several taste masking techniques were investigated in each series of formulation, in order to cover the bitter taste of wranitidine. These included the addition of sweetener, granulation, solid dispersion with soluble and insoluble agents and complex formation with cellulose derivatives. The best formulation(s) in each group was/were chosen for taste evaluations with the help of 10 volunteers. Finally, formulation F14 was selected as the ultimate formulation, based on its better taste and shorter disintegration time (around 5 seconds). Formulation F14 contained Na CMC, avicel, Na starch glycolate, xylitol, saccharin, Na benzoate and menthol. The chosen formulation successfully passed the complementary evaluations such as assay of active ingredient and dissolution time. Na CMC was found to be acceptable in terms of decreasing disintegration time and enhanced taste masking potential and can be used in further ODT formulations. PMID:28243264

  7. The influence of formulation and manufacturing process parameters on the characteristics of lyophilized orally disintegrating tablets.

    PubMed

    Jones, Rhys J; Rajabi-Siahboomi, Ali; Levina, Marina; Perrie, Yvonne; Mohammed, Afzal R

    2011-07-20

    Gelatin is a principal excipient used as a binder in the formulation of lyophilized orally disintegrating tablets. The current study focuses on exploiting the physicochemical properties of gelatin by varying formulation parameters to determine their influence on orally disintegrating tablet (ODT) characteristics. Process parameters, namely pH and ionic strength of the formulations, and ball milling were investigated to observe their effects on excipient characteristics and tablet formation. The properties and characteristics of the formulations and tablets which were investigated included: glass transition temperature, wettability, porosity, mechanical properties, disintegration time, morphology of the internal structure of the freeze-dried tablets, and drug dissolution. The results from the pH study revealed that adjusting the pH of the formulation away from the isoelectric point of gelatin, resulted in an improvement in tablet disintegration time possibly due to increase in gelatin swelling resulting in greater tablet porosity. The results from the ionic strength study revealed that the inclusion of sodium chloride influenced tablet porosity, tablet morphology and the glass transition temperature of the formulations. Data from the milling study showed that milling the excipients influenced formulation characteristics, namely wettability and powder porosity. The study concludes that alterations of simple parameters such as pH and salt concentration have a significant influence on formulation of ODT.

  8. Evaluation of coprocessed disintegrants produced from tapioca starch and mannitol in orally disintegrating paracetamol tablet.

    PubMed

    Adeoye, Oluwatomide; Alebiowu, Gbenga

    2014-01-01

    The study evaluated two novel coprocessed excipients (with two methods) as disintegrants in an orally disintegrating paracetamol tablet formulation. The tablets produced were assessed for mechanical properties with the use of friability and tensile strength while the release properties were assessed with wetting time, water absorption ratio, disintegration time and dissolution profile. The results obtained showed that the methods of coprocessing and disintegrant incorporation influenced the activities of the disintegrants. The novel disintegrant enhanced the mechanical properties of the tablets containing them as shown by lower friability and higher tensile strength of the tablets. The result further showed that the rate and amount of water absorbed, type of disintegrant and the method of disintegrant incorporation influenced the total amount of paracetamol released. The study concluded that the novel disintegrants will be effective in the formulation of orally disintegrating paracetamol tablets.

  9. Proniosomal oral tablets for controlled delivery and enhanced pharmacokinetic properties of acemetacin.

    PubMed

    Shehata, Tamer M; Abdallah, Marwa H; Ibrahim, Mahmoud Mokhtar

    2015-04-01

    Free-flowing proniosomal powders of acemetacin (AC) were prepared using the slurry method and maltodextrin as carrier. Positively charged proniosomes composed of 70:20:10 of Span 60/cholesterol (Chol)/stearylamine (SA), respectively, were successively compressed into tablets using direct compression method. The tablets were characterized for weight variability, friability, hardness, drug content uniformity, and dissolution properties. The in vivo evaluation of the prepared proniosomes (powder or tablet forms) after oral administration was investigated by the determination of AC and its active metabolite indomethacin (IND) in the blood of albino rabbits. Results indicated that the increase of Chol from 10% to 20% markedly reduced the efflux of the drug. Further Chol addition from 30% to 50% led to increased AC release rates. The proniosome tablets of AC showed greater hardness and disintegration time and less friability than AC plain tablets. The dissolution of proniosomal tablets indicated a lower drug release percentage compared to powdered proniosomes and AC plain tablets. The mean pharmacokinetic parameters of AC and IND from different formulations indicated increased t 1/2 and area under the curve (AUC) of both AC and IND for proniosomal tablets compared with both proniosomal powders and AC plain tablets. This study suggested the formulation of AC proniosomal powder into tablets to control and extend its pharmacologic effects.

  10. A new formulation for orally disintegrating tablets using a suspension spray-coating method.

    PubMed

    Okuda, Y; Irisawa, Y; Okimoto, K; Osawa, T; Yamashita, S

    2009-12-01

    The aim of this study was to design a new orally disintegrating tablet (ODT) that has high tablet hardness and a fast oral disintegration rate using a new preparation method. To obtain rapid disintegration granules (RDGs), a saccharide, such as trehalose, mannitol, or lactose, was spray-coated with a suspension of corn starch using a fluidized-bed granulator (suspension method). As an additional disintegrant, crospovidone, light anhydrous silicic acid, or hydroxypropyl starch was also included in the suspension. The RDGs obtained possessed extremely large surface areas, narrow particle size distribution, and numerous micro-pores. When tabletting these RDGs, it was found that the RDGs increased tablet hardness by decreasing plastic deformation and increasing the contact frequency between granules. In all tablets, a linear relationship was observed between tablet hardness and oral disintegration time. From each linear correlation line, a slope (D/H value) and an intercept (D/H(0) value) were calculated. Tablets with small D/H and D/H(0) values could disintegrate immediately in the oral cavity regardless of the tablet hardness and were considered to be appropriate for ODTs. Therefore, these values were used as key parameters to select better ODTs. Of all the RDGs prepared in this study, mannitol spray-coated with a suspension of corn starch and crospovidone (2.5:1 w/w ratio) showed most appropriate properties for ODTs; fast in vivo oral disintegration time, and high tablet hardness. In conclusion, this simple method to prepare superior formulations for new ODTs was established by spray-coating mannitol with a suspension of appropriate disintegrants.

  11. Oral heroin in opioid-dependent patients: pharmacokinetic comparison of immediate and extended release tablets.

    PubMed

    Perger, Ludwig; Rentsch, Katharina M; Kullak-Ublick, Gerd A; Verotta, Davide; Fattinger, Karin

    2009-03-02

    In diacetylmorphine prescription programs for heavily dependent addicts, diacetylmorphine is usually administered intravenously, but this may not be possible due to venosclerosis or when heroin abuse had occurred via non-intravenous routes. Since up to 25% of patients administer diacetylmorphine orally, we characterised morphine absorption after single oral doses of immediate and extended release diacetylmorphine in 8 opioid addicts. Plasma concentrations were determined by liquid chromatography-mass spectrometry. Non-compartmental methods and deconvolution were applied for data analysis. Mean (+/-S.D.) immediate and extended release doses were 719+/-297 and 956+/-404 mg, with high absolute morphine bioavailabilities of 56-61%, respectively. Immediate release diacetylmorphine caused rapid morphine absorption, peaking at 10-15 min. Morphine absorption was considerably slower and more sustained for extended release diacetylmorphine, with only approximately 30% of maximal immediate release absorption being reached after 10 min and maintained for 3-4h, with no relevant food interaction. The relative extended to immediate release bioavailability was calculated to be 86% by non-compartmental analysis and 93% by deconvolution analysis. Thus, immediate and extended release diacetylmorphine produce the intended morphine exposures. Both are suitable for substitution treatments. Similar doses can be applied if used in combination or sequentially.

  12. Preparation and evaluation of swelling induced-orally disintegrating tablets by microwave irradiation.

    PubMed

    Sano, Syusuke; Iwao, Yasunori; Kimura, Susumu; Itai, Shigeru

    2011-09-15

    A major challenge in the development of orally disintegrating tablets (ODTs) is to achieve a good balance between tablet hardness and disintegration time. In this study, an advanced method was demonstrated to improve these opposing properties in a molded tablet using a one-step procedure that exploits the swelling induced by microwave treatment. Wet molded tablets consisting of the delta form of mannitol and silicon dioxide were prepared and microwave-heated to generate water vapor inside the tablets. This induced either swelling or shrinking of tablets, in the extent of each being dependent on tablet formulation and manufacturing conditions. A two-level full factorial design method was used to evaluate the effects of several variables in formulation and manufacturing conditions on the tablet properties, hardness, disintegration time and change in shape. The variables investigated in this study were: ratio of silicon dioxide in formulation, water volume added in granulation, ratio of water absorbed by silicon dioxide prior to granulation, and microwave irradiation time. Swelling of tablet by microwave irradiation was observed in the batches with high ratio of silicon dioxide and low levels of water volume. The disintegration time was clearly shortened by induction of the swelling, while tablet hardness increased. We demonstrated that the water vapor generated by microwave irradiation promoted a change in the crystalline form of mannitol from delta to beta, and that this may have contributed to an increase in tablet hardness. Additionally, it was found that new solid bridges were formed between the granules in the tablet via the pathway from dissolution of mannitol in water vapor to congelation, resulting in an increase in tablet hardness. Thus, both tablet hardness and disintegration properties of the molded tablets were improved by the proposed one-step method and the appropriate ranges for variables are indicated. In addition, multiple regression modeling was

  13. Efficacy of oral powder compared with chewable tablets for lanthanum carbonate administration in hemodialysis patients.

    PubMed

    Sakurada, Tsutomu; Oishi, Daisuke; Shibagaki, Yugo; Yasuda, Takashi; Kimura, Kenjiro

    2013-10-01

    Lanthanum carbonate (LC) has been administered in a chewable tablet form for patients with hyperphosphatemia undergoing dialysis. However, some patients have difficulty chewing the tablets. LC oral powder has recently been released in Japan. The purpose of this study was to clarify the efficacy of LC oral powder form compared with that of chewable tablet form. The efficacy and safety of LC oral powder was retrospectively assessed in hemodialysis patients who switched from chewable tablet form to oral powder form without dose modification. Thirty-six patients (mean age, 66.8 ± 10.5 years; male, 64%; 39% with diabetes; mean duration of dialysis treatment, 99.2 ± 95.6 months) were enrolled in this study between June and July of 2012. Changes in clinical data and adverse events after the switch to oral powder form were investigated. The average dose of LC was 1180 ± 520 mg/day. Serum phosphorus levels were significantly decreased after the switch from chewable tablet form to oral powder form (5.3 ± 1.7 mg/dL at baseline vs. 4.9 ± 1.2 mg/dL at after 1 month after, P = 0.038). In contrast, no significant differences were observed in serum calcium and parathyroid hormone levels. Furthermore, no significant differences were evident in weight gain after the switch to oral powder form (2.5 ± 1.2 kg at baseline vs. 2.4 ± 1.1 kg at 1 month after the switch, P = 0.29). No serious adverse events were recorded. Our results suggest that LC is more effective in oral powder form than chewable tablet form for hemodialysis patients.

  14. Development and evaluation of cetirizine HCl taste-masked oral disintegrating tablets.

    PubMed

    Douroumis, Dionysios Dennis; Gryczke, Andreas; Schminke, Silke

    2011-03-01

    The purpose of the current study was to mask the taste of cetirizine HCl and to incorporate the granules produced in oral disintegrating tablets (ODT). The bitter, active substance was coated by fluidized bed coating using Eudragit® RL30-D at levels between 15% and 40% w/w. The ODTs were developed by varying the ratio of superdisintegrants such as sodium croscarmellose, crospovidone grades and low substituted hydroxypropyl cellulose (L-HPC). A direct compression process was used to compress the ODTs under various compaction forces to optimize tablet robustness. The properties of the compressed tablets including porosity, hardness, friability and dissolution profiles were further investigated. The in vitro and in vivo evaluation of the tablet disintegration times showed almost identical rapid disintegration below 10 s at the optimal levels of each superdisintegrant. Finally, the taste and sensory evaluation in human volunteers demonstrated excellence in masking the bitter active and tablet palatability.

  15. Long-Term High-dose Oral Morphine in Phantom Limb Pain with No Addiction Risk

    PubMed Central

    Kumar, Vinod; Garg, Rakesh; Bharati, Sachidanand Jee; Gupta, Nishkarsh; Bhatanagar, Sushma; Mishra, Seema; Balhara, Yatan Pal Singh

    2015-01-01

    Chronic phantom limb pain (PLP) is a type of neuropathic pain, which is located in the missing/amputated limb. Phantom pain is difficult to treat as the exact basis of pain mechanism is still unknown. Various methods of treatment for PLP have been described, including pharmacological (NSAIDs, opioids, antiepileptic, antidepressants) and non-pharmacological (TENS, sympathectomy, deep brain stimulation and motor cortex stimulation). Opioids are used for the treatment of neuropathic pain and dose of opioid is determined based on its effect and thus there is no defined ceiling dose for opioids. We report a case where a patient receiving high-dose oral morphine for chronic cancer pain did not demonstrate signs of addiction. PMID:25709194

  16. Orally disintegrating films and mini-tablets-innovative dosage forms of choice for pediatric use.

    PubMed

    Preis, Maren

    2015-04-01

    Oral drug delivery is a non-invasive and therefore a very convenient route of administration. Orally disintegrating dosage forms, like soluble films and (mini-)tablets, appear promising for use in the pediatric population. New guidance for the development of pediatric medicines has been published, which provides considerations on how pediatric products should be designed. However, most of the considerations leave a lot of room for interpretations. Bearing in mind the different aspects discussed in the latest guideline, the use of orally disintegrating films and tablets, in particular, small-sized tablets, is discussed and reflected upon by providing evidence from the scientific literature. The available dosage forms for children are various and examples of currently licensed products for use in the pediatric population were compiled. Aspects such as the appropriateness for pediatrics, the choice of excipients, the opportunities for modified drug release preparations or fixed-dose combinations, the acceptability and palatability, and also limitations were discussed with respect to the new dosage forms of orally disintegrating films and mini-tablets. This paper points out that innovation in pediatric medicines are planned and should be encouraged; however, supported by the regulatory guidance, only general considerations are provided. Nevertheless, the guideline summarizes multiple points to consider during the development of medicines for pediatric use. Considering the scientific evidence and the regulatory guidance, orally disintegrating dosage forms, like soluble films and (mini-)tablets, offer an innovative solution for pediatric drug delivery.

  17. Development of oral dispersible tablets containing prednisolone nanoparticles for the management of pediatric asthma.

    PubMed

    Chen, Yi-Dan; Liang, Zhong-Yuan; Cen, Yan-Yan; Zhang, He; Han, Mei-Gui; Tian, Yun-Qiao; Zhang, Jie; Li, Shu-Jun; Yang, Da-Sheng

    2015-01-01

    The purpose of the present study was to develop oral dispersible tablets containing prednisolone (PDS)-loaded chitosan nanoparticles using microcrystalline cellulose (MCC 101), lactose, and croscarmellose sodium (CCS). The PDS-loaded chitosan nanoparticles were formulated by ionotropic external gelation technique in order to enhance the solubility of PDS in salivary pH. Prepared nanoparticles were used for the development of oral fast disintegrating tablets by direct compression method. The prepared tablets were evaluated for disintegration time (DT), in vitro drug release (DR), thickness, weight variation, drug content uniformity, friability, and hardness. The effect of concentrations of the dependent variables (MCC, lactose, CCS) on DT and in vitro DR was studied. Fast disintegrating tablets of PDS can be prepared by using MCC, CCS, and lactose with enhanced solubility of PDS. The minimum DT was found to be 15 seconds, and the maximum DR within 30 minutes was 98.50%. All independent variables selected for the study were statistically significant. Oral fast disintegrating tablets containing PDS nanoparticles could be the better choice for the pediatric patients that would result in better patient compliance. From this study, it can be concluded that fast disintegrating tablets could be a potential drug delivery technology for the management of asthma in pediatrics.

  18. Development of oral dispersible tablets containing prednisolone nanoparticles for the management of pediatric asthma

    PubMed Central

    Chen, Yi-Dan; Liang, Zhong-Yuan; Cen, Yan-Yan; Zhang, He; Han, Mei-Gui; Tian, Yun-Qiao; Zhang, Jie; Li, Shu-Jun; Yang, Da-Sheng

    2015-01-01

    The purpose of the present study was to develop oral dispersible tablets containing prednisolone (PDS)-loaded chitosan nanoparticles using microcrystalline cellulose (MCC 101), lactose, and croscarmellose sodium (CCS). The PDS-loaded chitosan nanoparticles were formulated by ionotropic external gelation technique in order to enhance the solubility of PDS in salivary pH. Prepared nanoparticles were used for the development of oral fast disintegrating tablets by direct compression method. The prepared tablets were evaluated for disintegration time (DT), in vitro drug release (DR), thickness, weight variation, drug content uniformity, friability, and hardness. The effect of concentrations of the dependent variables (MCC, lactose, CCS) on DT and in vitro DR was studied. Fast disintegrating tablets of PDS can be prepared by using MCC, CCS, and lactose with enhanced solubility of PDS. The minimum DT was found to be 15 seconds, and the maximum DR within 30 minutes was 98.50%. All independent variables selected for the study were statistically significant. Oral fast disintegrating tablets containing PDS nanoparticles could be the better choice for the pediatric patients that would result in better patient compliance. From this study, it can be concluded that fast disintegrating tablets could be a potential drug delivery technology for the management of asthma in pediatrics. PMID:26640367

  19. Pharmacokinetics of desmopressin administered as tablet and oral lyophilisate formulation in children with monosymptomatic nocturnal enuresis.

    PubMed

    De Bruyne, Pauline; De Guchtenaere, Ann; Van Herzeele, Charlotte; Raes, Ann; Dehoorne, Jo; Hoebeke, Piet; Van Laecke, Erik; Vande Walle, Johan

    2014-02-01

    Desmopressin 120 μg oral lyophilisate and 200 μg tablet are considered bioequivalent, based on extrapolation of studies in a limited number of adults and on one dose-finding study of desmopressin oral lyophilisate in children. However, no comparative pharmacokinetic study in children was executed confirming this statement. No data are available on the influence of food intake on the bioavailability of desmopressin tablet in a pediatric setting, although studies in adults have documented that food intake results in a significantly lower desmopressin plasma concentration. In this study, we analyzed plasma concentrations of desmopressin oral lyophilisate and tablet with concomitant food intake. Twenty-three children with monosymptomatic nocturnal enuresis (mean age, 12.7 years) were recruited. Two tests were performed on two separate days in identical conditions with a standardized food and fluid intake. Desmopressin was administered as desmopressin tablet or desmopressin oral lyophilisate immediately after a meal. Desmopressin plasma concentration was measured at 1 h, 2 h, and 6 h postdosing. No significant difference in plasma concentration of 120 μg desmopressin oral lyophilisate and 200 μg tablet was demonstrated, even with concomitant food intake. A significant difference in variability was found, identifying a smaller variance for desmopressin oral lyophilisate plasma concentrations at all time points. This study demonstrates comparable plasma levels for desmopressin oral lyophilisate, despite the lower dose. The dosage for desmopressin oral lyophilisate is more predictable due to the significantly smaller variance. Therefore, desmopressin oral lyophilisate seems more suitable, especially in the younger age group for which time interval between dinner and drug administration is limited.

  20. Effect of powder characteristics on oral tablet disintegration.

    PubMed

    Yamamoto, Yoshihisa; Fujii, Makiko; Watanabe, Ken-ichi; Tsukamoto, Masashi; Shibata, Yusuke; Kondoh, Masuo; Watanabe, Yoshiteru

    2009-01-05

    This report describes an investigation of the factors affecting disintegration time in the mouth (DTM) of rapidly disintegrating tablets. The relation between DTM and stationary time of upper punch displacement (STP) was examined using a tableting process analyzer (TabAll). Results indicated that the bulk density of mixed excipient powder used for tablet preparation affects both DTM and STP. As the value of bulk density increased, STP became longer and DTM shorter. The results of a combination of granules and powder with or without a drug showed liner relation between apparent volume (reciprocal of bulk density) and DTM (r(2)=0.7332). For a DTM less than 60 s, a formulation with a bulk density greater 0.5 g/mL should be chosen with a compression force of 5 kN. The hardness of tablets could be greater than 3 kg if at least one high-compressibility excipient was used in the formulation.

  1. The intravenous to oral relative milligram potency ratio of morphine during chronic dosing in cancer pain.

    PubMed

    Lasheen, Wael; Walsh, Declan; Mahmoud, Fade; Sarhill, Nabeel; Rivera, Nilo; Davis, Mellar; Lagman, Ruth; Legrand, Susan

    2010-01-01

    Morphine (M) is the opioid analgesic of choice for severe cancer pain. The IV to PO M equipotent switch ratio (CR) is controversial. We designed this prospective observational cohort to confirm the efficacy and safety of M IV to PO CR of 1:3. Consecutive cancer patients admitted to an inpatient palliative medicine unit were screened for inclusion. Pain was managed by palliative medicine specialists. They were blinded to the patient data collected, and the calculated CR. The switch was considered successful if the following criteria were met: (1) Pain adequately controlled: pain rated as none or mild (2) Number of RD less than 4 (for non incident pain) per 24 hours (3) No limiting side effects. We used Day 3 ATC M dose for CR calculations. The major outcome measures were the IV : PO CR ratio, morphine doses (mg/day), pain severity, number of PRN doses, and day 1 and day 3side effects. Descriptive statistics were used to report mean, median, standard deviation and range of different variables. Two hundred and fifty six consecutive admissions were screened, and 106 were eligible for the study. Sixty two underwent a successful M route switch and were included in this analysis. A ratio of 1:3 was safely implemented over a wide M dose range. About 80% were successfully switched with a calculated CR of 1:3. 20% required an oral M dose adjustment after route switch either to better pain control or reduce side effects with a resultant higher (e.g. 1:4) or lower (e.g. 1:2) calculated potency ratios respectively. A potency ratio of 1:3 was safe as evaluated by common M side-effects, the dose also easy to calculate. The 1: 3 M IV to PO relative milligram potency ratio appears correct and practical for most patients over a wide M dose range.

  2. Preparation and evaluation of orally rapidly disintegrating tablets containing taste-masked particles using one-step dry-coated tablets technology.

    PubMed

    Kondo, Keita; Niwa, Toshiyuki; Ozeki, Yuichi; Ando, Masaki; Danjo, Kazumi

    2011-01-01

    In this study, in order to address the problems with manufacturing orally rapidly disintegrating tablets (ODT) containing functional (taste masking or controlled release) coated particles, such as the low compactability of coated particles and the rupture of coated membrane during compression, a novel ODT containing taste-masked coated particles (TMP) in the center of the tablets were prepared using one-step dry-coated tablets (OSDrC) technology. As a reference, physical-mixture tablets (PM) were prepared by a conventional tableting method, and the properties of the tablets and the effect of compression on the characteristics of TMP were evaluated. OSDrC was found to have higher tensile strength and far lower friability than PM, but the oral disintegration time of OSDrC is slightly longer than that of PM following high compression pressure. Consequently, OSDrC approaches the target tablet properties of ODT, whereas PM does not. The deformation of TMP in OSDrC due to compression is slight, and the release rate of acetaminophen (AAP) from OSDrC is the same as from TMP. However, TMP on the surface of PM are considerably deformed, and the release rate of AAP from PM is faster than from TMP. These findings suggest that OSDrC technology is a useful approach for preparing ODT containing functional coated particles. Furthermore, we demonstrate that the elastic recovery of tablets can affect differences in the properties of OSDrC, PM and placebo tablets (PC).

  3. Formulation and Characterization of Oral Mucoadhesive Chlorhexidine Tablets Using Cordia myxa Mucilage

    PubMed Central

    Moghimipour, Eskandar; Aghel, Nasrin; Adelpour, Akram

    2012-01-01

    Background The dilution and rapid elimination of topically applied drugs due to the flushing action of saliva is a major difficulty in the effort to eradicate infections of oral cavity. Utilization a proper delivery system for incorporation of drugs has a major impact on drug delivery and such a system should be formulated for prolonged drug retention in oral cavity. Objectives The aim of the present study was the use of mucilage of Cordia myxa as a mucoadhesive material in production of chlorhexidine buccal tablets and its substitution for synthetic polymers such as HPMC. Materials and Methods The influence of mucilage concentration on the physicochemical responses (hardness, friability, disintegration time, dissolution, swelling, and muco-adhesiveness strength) was studied and swelling of mucilage and HPMC were compared. The evaluated responses included pharmacopoeial characteristics of tablets, the force needed to separate tablets from mucosa, and the amount of water absorbed by tablets. Results In comparison to HPMC, the rise of mucilage concentration in the formulations increased disintegration time, drug dissolution rate, and reduced MDT. Also, compared to 30% HPMC, muco-adhesiveness strength of buccal tablets containing 20% mucilage was significantly higher. Conclusions It can be concluded that the presence of Cordia myxa powdered mucilage may significantly affect the tablet characteristics, and increasing in muco-adhesiveness may be achieved by using 20% w/w mucilage. PMID:24624170

  4. Stability of cilazapril in pediatric oral suspensions prepared from commercially available tablet dosage forms.

    PubMed

    Stanisz, Beata J; Paszun, Sylwia K; Zalewska, Anna

    2014-01-01

    Abstract: Cilazapril is a drug commonly used in management of heart failure in pediatric population. On pharmaceutical market it is available only in inconvenient for pediatric use tablet dosage forms. Until now, no oral liquid formulation containing cilazapril has been evaluated. Therefore, the aim of this study was to prepare easy to made and palatable 1 mg/mL oral liquid formulation with cilazapril (with consideration of original and generic cilazapril tablet and different packages) and subsequent investigation of physicochemical stability of these suspensions. Formulations were compounded using cilazapril obtained from original or generic cilazapril marketed tablet formulations and Ora-Blend" suspending agent. Stability of prepared suspensions stored in closed amber glass or amber plastic PET bottles in the temperature of 298 K was estimated throughout 28 day shelf-life period. Chemical stability was assessed by HPLC cilazapril stability indicating method. Physical stability was evaluated by appearance, taste, smell, pH and theological assessments. Cilazapril oral suspensions at concentration of 1 mg/mL demonstrated satisfactory stability over 28 day long storage at room temperature. Cilazapril concentrations remained within acceptable limit (+/- 10%) stored in closed amber bottles made of glass or PET material. Moreover, suspensions physical properties remained unaffected. Cilazapril - Ora-Blend* pediatric oral liquid is easy to made, palatable and stable when stored at room temperature for 28 days. Stability of cilazapril oral liquid remains unchanged while using cilazapril tablets produced by different manufacturers and bottles made of amber glass or PET material.

  5. Risperidone oral disintegrating mini-tablets: A robust-product for pediatrics.

    PubMed

    El-Say, Khalid M; Ahmed, Tarek A; Abdelbary, Maged F; Ali, Bahaa E; Aljaeid, Bader M; Zidan, Ahmed S

    2015-12-01

    This study was aimed at developing risperidone oral disintegrating mini-tablets (OD-mini-tablets) as age-appropriate formulations and to assess their suitability for infants and pediatric use. An experimental Box-Behnken design was applied to assure high quality of the OD-mini-tablets and reduce product variability. The design was employed to understand the influence of the critical excipient combinations on the production of OD-mini-tablets and thus guarantee the feasibility of obtaining products with dosage form uniformity. The variables selected were mannitol percent in Avicel (X1), swelling pressure of the superdisintegrant (X2), and the surface area of Aerosil as a glidant (X3). Risperidone-excipient compatibilities were investigated using FTIR and the spectra did not display any interaction. Fifteen formulations were prepared and evaluated for pre- and post-compression characteristics. The prepared OD-mini-tablet batches were also assessed for disintegration in simulated salivary fluid (SSF, pH 6.2) and in reconstituted skimmed milk. The optimized formula fulfilled the requirements for crushing strength of 5 kN with minimal friability, disintegration times of 8.4 and 53.7 s in SSF and skimmed milk, respectively. This study therefore proposes the risperidone OD-mini-tablet formula having robust mechanical properties, uniform and precise dosing of medication with short disintegration time suitable for pediatric use.

  6. Design and evaluation of microwave-treated orally disintegrating tablets containing polymeric disintegrant and mannitol.

    PubMed

    Sano, Syusuke; Iwao, Yasunori; Noguchi, Shuji; Kimura, Susumu; Itai, Shigeru

    2013-05-01

    Microwave (MW) treatment was used to develop a formulation process for the preparation of wet molded orally disintegrating tablets (ODTs) consisting of mannitol and polymeric disintegrant with improved hardness and disintegration properties. The wet molded tablets were prepared in accordance with the conventional methods and subsequently heated by MW irradiation to induce the swelling of the tablet. Croscarmellose sodium, crospovidone, and low-substituted hydroxypropylcellulose (L-HPC) were evaluated for their use with this technology. NBD-020, which is a grade of L-HPC, provided the better hardness and disintegration results. In addition, the crystalline forms of mannitol impacted on hardness and disintegration properties of the ODT upon MW irradiation. The effects of the disintegrant ratio, δ and β crystalline mannitol ratio, amount of water, and compression force on the ODT properties were evaluated using the design of experiment method. MW-induced swelling was enhanced by an increase in the disintegrant ratio. Although the hardness of the tablet increased following MW treatment, the disintegration time became less than that of the MW-untreated tablets as the β-mannitol ratios increased. Taken together, the results indicated that the polymeric disintegrant greatly improved the properties of the molded tablets in combination with MW treatment.

  7. Hair testing in postmortem diagnosis of substance abuse: An unusual case of slow-release oral morphine abuse in an adolescent.

    PubMed

    Baillif-Couniou, Valérie; Kintz, Pascal; Sastre, Caroline; Pok, Phak-Rop Pos; Chèze, Marjorie; Pépin, Gilbert; Leonetti, Georges; Pelissier-Alicot, Anne-Laure

    2015-11-01

    Morphine sulfate misuse is essentially observed among regular heroin injectors. To our knowledge, primary addiction to morphine sulfate is exceptional, especially among young adolescents. A 13-year-old girl, with no history of addiction, was found dead with three empty blisters of Skenan(®) LP 30 mg at her side. Opiates were detected in biological fluids and hair by chromatographic methods. Blood analyses confirmed morphine overdose (free morphine: 428 ng/mL; total morphine: 584 ng/mL) and segmental hair analysis confirmed regular exposure over several months (maximum morphine concentration 250 pg/mg). Suspecting the victim's mother of recreational use of Skenan(®), the magistrate ordered analysis of her hair, with negative results. From an epidemiological viewpoint, this case of oral morphine sulfate abuse in an adolescent with no previous history suggests the emergence of a new trend of morphine sulfate consumption. From a toxicological viewpoint, it demonstrates the value of hair testing, which documented the victim's regular exposure and made an important contribution to the police investigation.

  8. Review of the new delayed-release oral tablet and intravenous dosage forms of posaconazole.

    PubMed

    Guarascio, Anthony J; Slain, Douglas

    2015-02-01

    The triazole antifungal posaconazole was first approved as an oral suspension formulation. Despite pharmacokinetic target attainment and clinical efficacy in premarketing trials, postmarketing analyses indicated unpredictable bioavailability resulting in subtherapeutic concentrations and reports of breakthrough fungal infections. The newly approved posaconazole delayed-release tablet and intravenous formulations display more consistent bioavailability in the presence of concomitant disease states, medications, and dietary considerations that classically alter drug concentrations of the oral suspension. Both the delayed-release tablet and intravenous formulation display a similar adverse-effect profile to the oral suspension. The posaconazole delayed-release oral tablet is not significantly affected by gastric acid suppression therapy, and the intravenous dosage form provides an option for patients who are intubated or unable to tolerate oral medications. Pharmacoeconomic considerations, particularly with intravenous posaconazole, will likely play a role in dosage form selection and frequency of use. Due to sustained, higher drug concentrations, the new posaconazole formulations hold promise for greater efficacy in antifungal prophylaxis and bring opportunity for further study in the treatment of invasive mycoses.

  9. Formulation of cyclodextrin inclusion complex-based orally disintegrating tablet of eslicarbazepine acetate for improved oral bioavailability.

    PubMed

    Desai, Samixa; Poddar, Aditi; Sawant, Krutika

    2016-01-01

    The present investigation was aimed towards developing a beta-cyclodextrin (β-CD) solid dispersion (SD) based orally disintegrating tablet (ODT) of eslicarbazepine acetate (ESL), for improving the dissolution and providing fast onset of anti-epileptic action. Optimum ratio of ESL and β-CD was determined by Job's plot. Thereafter, solid dispersions were prepared by solvent evaporation method and evaluated for yield, assay, Differential scanning calorimetry (DSC), Fourier transform infra red spectroscopy (FTIR), X-ray diffraction (XRD), and in vitro dissolution. Optimized SD was compressed into ODT by direct compression using super disintegrants and evaluated for wetting time, drug content, in vitro drug release and in vivo studies. The results of DSC, FTIR and XRD analysis supported the formation of inclusion complex. An improved dissolution with 99.95 ± 2.80% drug release in 60 min was observed in comparison to 24.85 ± 2.96% release from a plain drug suspension. Tablets with crosspovidone as a super disintegrant showed the least disintegration time of 24.66 ± 1.52 s and higher in vitro drug release against marketed tablets. In vivo studies indicated that the formulated tablets had 2 times higher bioavailability than marketed tablets. Thus, the developed β-CD-ESL SD-ODT could provide faster onset of action and higher bioavailability, which would be beneficial in case of epileptic seizures.

  10. Improved anticoagulant effect of fucosylated chondroitin sulfate orally administered as gastro-resistant tablets.

    PubMed

    Fonseca, Roberto J C; Sucupira, Isabela D; Oliveira, Stephan Nicollas M C G; Santos, Gustavo R C; Mourão, Paulo A S

    2017-04-03

    Fucosylated chondroitin sulfate (FucCS) is a potent anticoagulant polysaccharide extracted from sea cucumber. Its anticoagulant activity is attributed to the presence of unique branches of sulfated fucose. Although this glycosaminoglycan exerts an antithrombotic effect following oral administration, high doses are necessary to achieve the maximum effect. The diminished activity of FucCS following oral administration is likely due to its degradation in the gastrointestinal tract and its limited ability to cross the intestinal cell membranes. The latter aspect is particularly difficult to overcome. However, gastro-resistant tablet formulation may help limit the degradation of FucCS in the gastrointestinal tract. In the present work, we found that the oral administration of FucCS as gastro-resistant tablets produces a more potent and prolonged anticoagulant effect compared with its administration as an aqueous solution, with no significant changes in the bleeding tendency or arterial blood pressure. Experiments using animal models of arterial thrombosis initiated by endothelial injury demonstrated that FucCS delivered as gastro-protective tablets produced a potent antithrombotic effect, whereas its aqueous solution was ineffective. However, there was no significant difference between the effects of FucCS delivered as gastro-resistant tablets or as aqueous solution in a venous thrombosis model, likely due to the high dose of thromboplastin used. New oral anticoagulants tested in these experimental models for comparison showed significantly increased bleeding tendencies. Our study provides a framework for developing effective oral anticoagulants based on sulfated polysaccharides from marine organisms. The present results suggest that FucCS is a promising oral anticoagulant.

  11. PREPARATION AND CHARACTERIZATION OF ORALLY DISINTEGRATING LORATADINE TABLETS MANUFACTURED WITH CO-PROCESSED MIXTURES.

    PubMed

    Amelian, Aleksandra; Szekalska, Marta; Wilczewska, Agnieszka Zofia; Basa, Anna; Winnicka, Katarzyna

    2016-01-01

    The aim of this study was to develop orally disintegrated tablets (ODT) with loratadine using Parteck ODT and Ludiflash--new commercially available tableting excipients based on co-processed mannitol. ODT containing loratadine were prepared with 3% addition of various superdisintegrants (AcDiSol, Kollidon CL-F and Kollidon CL-SF) by direct compression method. Obtained tablets were characterized for friability, pore structure, and wetting and disintegration time measured by four independents methods. In order to identify possible interactions between loratadine and the excipients, differential scanning calorimetry was used. The results showed that all formulated ODT were characterized by appropriate mechanical properties (friability < 1%), the uniform content of the drug substance and pleasant mouth feeling. Disintegration time below 30 s was observed in formulations with crospovidones as disintegrant.

  12. Localization of fluconazole in oral cavity by preferential coating of buccoadhesive tablet for treatment of oral thrush

    PubMed Central

    Pathak, Kamla; Sharma, Vijay; Akhtar, Nida; Rastogi, Pragya

    2016-01-01

    Background: The present research work was aimed at localization of fluconazole in the oral cavity by preferential coating of buccoadhesive tablet for the treatment of oral thrush. Materials and Methods: In order to achieve the aim, buccoadhesive tablets were optimized using 32 full factorial design to study the influence of varying content of chitosan and carbopol 934P (input variables) on the responses. Results: Perturbation plots revealed high sensitivity of the input variables to ex vivo mucoadhesion force and percent cumulative drug release (CDR) whereas the ex vivo mucoadhesion time was less sensitive to the input variables. Based on the highest desirability factor of 0.693 the formulation F9 was identified as the optimized formulation and was preferentially coated with ethyl cellulose (3% w/v) on one tablet face to get F9C. In reference to F9, F9C showed superior mucoadhesive features (P < 0.05) but the % CDR was comparable (f2 = 50.80). The preferential coating (F9C, Jss = 0.812 μg/cm2/h) limited the permeation of fluconazole across goat buccal mucosa by almost half the value of F9 (Jss = 1.34 μg/cm2/h) that could serve as an advantage in establishing high local concentration of drug in the oral cavity, thereby facilitating faster attainment of minimum inhibitory concentration. Scanning electron microscopy and histological analysis established nonirritant potential. The developed formulation was stable and demonstrated antifungal activity against Candida albicans. Conclusion: Thus it can be concluded that preferentially coated buccoadhesive tablets of fluconazole might be considered as a precise approach to localize the drug delivery in oral cavity. PMID:27051630

  13. Use of medicated drops and oral tablets in glaucoma treatment.

    PubMed

    Greenwell, C; Spillman, D

    1996-04-01

    This paper addresses the many forms of treatment for glaucoma. We studied particularly the topical drops and oral medications that are most frequently prescribed by ophthalmologists, specifically examining the reasons for the side effects experienced by certain patients taking topical drops and oral medications. Some of the side effects and interactions are discussed, and the importance of proper procedure for application of topical eye drops is stressed. Finally, we emphasize that proper drug usage is critical to the well being of the patient.

  14. Bioequivalence study with lapatinib powder for oral suspension and the original tablet formulation in cancer patients.

    PubMed

    Koch, Kevin M; Ferron-Brady, Geraldine; Lemmon, Colleen; Cartee, Leanne; Hollyfield, Hedy; D'Amelio, Anthony M; Piepszak, Alexandra; Swaby, Ramona F; Curran, David; Arya, Niki

    2015-01-01

    Lapatinib is approved for use in various therapeutic combinations for treating metastatic breast cancers that over-express HER2. To deliver the approved doses, up to six large tablets need to be ingested with the current 250-mg tablets. For ease of ingestion, a powder for oral suspension was developed. This study was an open-label, randomized, adaptive design, two-period crossover bioequivalence study of the powder for suspension relative to the commercial tablet at steady state following once daily dosing for 7 days in patients with advanced cancer. To minimize the number of cancer patients required for a pivotal bioequivalence study (144 in this case), a four-stage adaptive group sequential design with interim analyses after every 36 subjects was implemented to allow for early termination. Bioequivalence for the oral suspension relative to the commercial tablet was demonstrated in both the first (and only) interim analysis and the final analysis, as the 90% confidence intervals for the treatment comparison ratios for both AUC0-24 and Cmax were contained within the acceptance criteria (0.80, 1.25). Additionally, there was no statistical difference in tlag or tmax , suggesting no difference in the absorption rate between treatments. There were no unexpected safety findings during this study.

  15. Orally Administered Nano-curcumin to Attenuate Morphine Tolerance: Comparison between Negatively Charged PLGA and Partially and Fully PEGylated Nanoparticles

    PubMed Central

    Shen, Hao; Hu, Xiaoyu; Szymusiak, Magdalena; Wang, Zaijie Jim; Liu, Ying

    2014-01-01

    We have formulated hydrophobic curcurmin [1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] into stable nanoparticle suspensions (nano-curcumin) to overcome its relatively low bioavailability, high rate of metabolism and rapid elimination and clearance from the body. Employing the curcumin nanoformulations as the platform, we discovered that curcumin has the potential to alleviate morphine tolerance. The two types of stable polymeric nanoparticles - poly(lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol)-b-poly(lactic acid) (PEG-b-PLA) - and the hybrid of the two were generated using flash nanoprecipitation integrated with spray drying. The optimized formulations have high drug loading (>45%), small particles size with narrow distribution, and controlled surface properties. Mice behavioral studies (tail-flick and hot-plate tests) were conducted to verify the effects of nano-curcumin on attenuating morphine tolerance. Significant analgesia was observed in mice during both tail-flick and hot-plate tests using orally administrated nano-curcumin following subcutaneous injections of morphine. However, unformulated curcumin at the same dose showed no effect. Compared with PEGylated nano-curcumin, negatively charged PLGA nanoparticles showed better functionality. PMID:24195658

  16. Orally administered nanocurcumin to attenuate morphine tolerance: comparison between negatively charged PLGA and partially and fully PEGylated nanoparticles.

    PubMed

    Shen, Hao; Hu, Xiaoyu; Szymusiak, Magdalena; Wang, Zaijie Jim; Liu, Ying

    2013-12-02

    We have formulated hydrophobic curcurmin [1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] into stable nanoparticle suspensions (nanocurcumin) to overcome its relatively low bioavailability, high rate of metabolism, and rapid elimination and clearance from the body. Employing the curcumin nanoformulations as the platform, we discovered that curcumin has the potential to alleviate morphine tolerance. The two types of stable polymeric nanoparticles, poly(lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol)-b-poly(lactic acid) (PEG-b-PLA), and the hybrid of the two were generated using flash nanoprecipitation integrated with spray drying. The optimized formulations have high drug loading (>45%), small particles size with narrow distribution, and controlled surface properties. Mice behavioral studies (tail-flick and hot-plate tests) were conducted to verify the effects of nanocurcumin on attenuating morphine tolerance. Significant analgesia was observed in mice during both tail-flick and hot-plate tests using orally administered nanocurcumin following subcutaneous injections of morphine. However, unformulated curcumin at the same dose showed no effect. Compared with PEGylated nanocurcumin, negatively charged PLGA nanoparticles showed better functionality.

  17. The efficacy and safety of clotrimazole vaginal tablet vs. oral fluconazole in treating severe vulvovaginal candidiasis.

    PubMed

    Zhou, Xiaofang; Li, Ting; Fan, Shangrong; Zhu, Yuxia; Liu, Xiaoping; Guo, Xuedong; Liang, Yiheng

    2016-07-01

    To compare the efficacy and safety of two doses of clotrimazole vaginal tablet 500 mg with two doses of oral fluconazole 150 mg in treating severe vulvovaginal candidiasis (SVVC), 240 consecutive patients with SVVC were studied at the Department of Obstetrics and Gynaecology of Peking University Shenzhen Hospital between June 2014, and September 2015. Patients were randomly assigned in a 1 : 1 ratio to receive treatment with either two doses of clotrimazole vaginal tablet or two doses of oral fluconazole. The clinical cure rates in the clotrimazole group and the fluconazole group at days 7-14 follow-up were 88.7% (102/115) and 89.1% (98/110) respectively; the clinical cure rates at days 30-35 in the two groups were 71.9% (82/114) and 78.0% (85/109) respectively. The mycological cure rates at days 7-14 follow-up in the two groups were 78.3% (90/115) and 73.6% (81/110) respectively. The mycological cure rates of the patients at days 30-35 in the two groups were 54.4% (62/114) and 56.0% (61/109) respectively (P > 0.05). The adverse events of clotrimazole were mainly local. This study demonstrated that two doses of clotrimazole vaginal tablet 500 mg were as effective as two doses of oral fluconazole 150 mg in the treatment of patients with SVVC and could be an appropriate treatment for this disorder.

  18. Meloxicam taste-masked oral disintegrating tablet with dissolution enhanced by ion exchange resins and cyclodextrin.

    PubMed

    Samprasit, Wipada; Akkaramongkolporn, Prasert; Ngawhirunpat, Tanasait; Rojanarata, Theerasak; Opanasopit, Praneet

    2013-09-01

    The purpose of this study was to develop taste-masked oral disintegrating tablets (ODTs) using the combination of ion exchange resin and cyclodextrin, to mask the bitter taste and enhance drug dissolution. Meloxicam (MX) was selected as a model drug with poor water solubility and a bitter taste. Formulations containing various forms of MX (free drug, MX-loaded resin or resinate, complexes of MX and 2-hydroxypropyl-β-cyclodextrin (HPβCD) or MX/HPβCD complexes, and a mixture of resinate and MX/HPβCD complexes) were made and tablets were prepared by direct compression. The ODTs were evaluated for weight variation, thickness, diameter, hardness, friability, disintegration time, wetting time, MX content, MX release, degree of bitter taste, and stability. The results showed that thickness, diameter, weight, and friability did not differ significantly for all of these formulations. The tablet hardness was approximately 3 kg/in.(2), and the friability was less than 1%. Tablets formulated with resinate and the mixture of resinate and MX/HPβCD complexes disintegrated rapidly within 60 s, which is the acceptable limit for ODTs. These results corresponded to the in vivo disintegration and wetting times. However, only tablets containing the mixture of resinate and MX/HPβCD complexes provided complete MX dissolution and successfully masked the bitter taste of MX. In addition, this tablet was stable at least 6 months. The results from this study suggest that the appropriate combination of ion exchange resin and cyclodextrin could be used in ODTs to mask the bitter taste of drug and enhance the dissolution of drugs that are weakly soluble in water.

  19. Miconazole nitrate oral disintegrating tablets: in vivo performance and stability study.

    PubMed

    Ahmed, Tarek A; El-Say, Khalid M; Mahmoud, Maged F; Samy, Ahmed M; Badawi, Alia A

    2012-09-01

    The interest in and need for formulating miconazole nitrate (MN), a broad-spectrum antifungal, as an oral disintegrating tablet for treatment of some forms of candidiasis have increased. Formulation of MN in this dosage form will be more advantageous, producing dual effect: local in the buccal cavity and systemic with rapid absorption. Four formulations were prepared utilizing the foam granulation technique. The prepared tablets were characterized by measuring the weight uniformity, thickness, tensile strength, friability, and drug content. In addition, tablet disintegration time, in vitro dissolution, and in vivo disintegration time were also evaluated. Stability testing for the prepared tablets under stress and accelerated conditions in two different packs were investigated. Each pack was incubated at two different elevated temperature and relative humidity (RH), namely 40 ± 2°C/75 ± 5% RH and 50 ± 2°C/75 ± 5% RH. The purpose of the study is to monitor any degradation reactions which will help to predict the shelf life of the product under the defined storage conditions. Finally, in vivo study was performed on the most stable formula to determine its pharmacokinetic parameters. The results revealed that all the prepared tablets showed acceptable tablet characteristics and were stable under the tested conditions. The most stable formula was that containing magnesium stearate as lubricant, hydrophobic Aerosil R972 as glidant, low urea content, mannitol/microcrystalline cellulose ratio 2:1, and 9% Plasdone XL100 as superdisintegrant. The in vivo results revealed that the tested formula showed rapid absorption compared to the physical blend (t (max) were 1 and 4 h, respectively), while the extent of absorption was almost the same.

  20. A Novel Multilayered Multidisk Oral Tablet for Chronotherapeutic Drug Delivery

    PubMed Central

    Khan, Zaheeda; Choonara, Yahya E.; du Toit, Lisa C.; Ndesendo, Valence M. K.; Pillay, Viness

    2013-01-01

    A Multilayered Multidisk Tablet (MLMDT) comprising two drug-loaded disks enveloped by three drug-free barrier layers was developed for use in chronotherapeutic disorders, employing two model drugs, theophylline and diltiazem HCl. The MLMDT was designed to achieve two pulses of drug release separated by a lag phase. The polymer disk comprised hydroxyethylcellulose (HEC) and ethylcellulose (EC) granulated using an aqueous dispersion of EC. The polymeric barrier layers constituted a combination of pectin/Avicel (PBL) (1st barrier layer) and hydroxypropylmethylcellulose (HPMC) (HBL1 and HBL2) as the 2nd and 3rd barrier layers, respectively. Sodium bicarbonate was incorporated into the diltiazem-containing formulation for delayed drug release. Erosion and swelling studies confirmed the manner in which the drug was released with theophylline formulations exhibiting a maximum swelling of 97% and diltiazem containing formulations with a maximum swelling of 119%. FTIR spectra displayed no interactions between drugs and polymers. Molecular mechanics simulations were undertaken to predict the possible orientation of the polymer morphologies most likely affecting the MLMDT performance. The MLMDT provided two pulses of drug release, separated by a lag phase, and additionally it displayed desirable friability, hardness, and uniformity of mass indicating a stable formulation that may be a desirable candidate for chronotherapeutic drug delivery. PMID:24024200

  1. Formulation and characterisation of a buccoadhesive erodible tablet for the treatment of oral lesions.

    PubMed

    Ali, J; Khar, R K; Ahuja, A

    1998-05-01

    Buccoadhesive erodible tablets of trimcinolone acetonide were prepared using different bioadhesive polymers along with excipients like mannitol and PEG-6000. In vitro release characteristics were evaluated using a 'flow-thru assembly' which simulated the conditions of the human buccal cavity. The bioadhesive performance and the surface pH of the tablets was satisfactory. The optimized formulation containing 8.0 mg of triamcinolone acetonide, 2.5 mg of mannitol, 7.5 mg of PEG-6000, 2.0 mg of magnesium stearate along with carbopol-934P (CP-934P) and sodium carboxy methyl cellulose-DVP (SCMC-DVP) in the ratio of 1:4 was found to release the drug for a period of over 8 h without getting dislodged. Maximum in vitro drug release was found to be 79.08% in 8 h study. In vivo evaluation of placebo buccoadhesive tablets revealed adequate comfort, taste, non-irritancy during the period of study. None of the volunteers reported severe dry mouth/severe salivation or heaviness at the place of attachment. A linear and positive correlation was found between in vitro and in vivo mean adhesion time. The buccoadhesive tablet eroded completely after 8 h leaving no exhausted device to be removed. This formulation has potential clinical usefulness for the treatment of oral lesions.

  2. Orally disintegrating tablet of novel salt of antiepileptic drug: formulation strategy and evaluation.

    PubMed

    Rahman, Ziyaur; Siddiqui, Akhtar; Khan, Mansoor A

    2013-11-01

    The aim of present research was to design and evaluate orally disintegrating tablet (ODT) of novel lamotrigine-cyclamate salt. Box-Behnken response surface methodology was selected to design the optimized formulation. The independent factors selected were tablet hardness (X1), disintegrant (X2) and lubricant (X3) levels, and responses chosen were disintegration time (DT, Y1), friability (Y2), T50 (Y3), and T90 (Y4). The tablets were also characterized for drug uniformity by near infrared chemical imaging (NIR-CI) and taste masking evaluation by electronic tongue. All the selected independent variables were statistically (p<0.05) effect the Y1 while Y2, Y3, and Y4 affected only by X2. The optimized ODT was found to meet the regulatory requirement of DT and friability specification. The NIR-CI images indicated uniform distribution of active and inactive ingredients within the tablets. The electronic tongue results were analyzed by principle component analysis (PCA). It indicated that novel salt of lamotrigine and its ODT formulation have a taste similar to cyclamic acid which is indicated by close proximity on PCA score plot, lower Euclidean distance, and high discrimination index values. Furthermore, these parameters were very close to ODT placebo formulation. On the other hand, lamotrigine, its ODT, and placebo formulation were far from each other. In summary, lamotrigine salt provides another avenue for pediatric friendly formulation for children and will enhance patience compliance.

  3. Selection of generic preparations of famotidine orally disintegrating tablets for use in unit-dose packages.

    PubMed

    Yamazaki, N; Iizuka, R; Miyazawa, S; Wada, Y; Shimokawa, K; Ishii, F

    2012-10-01

    Changes in the hardness, dissolution, and the disintegration time of brand name and generic preparations (6 preparations) of famotidine orally disintegrating tablets were investigated. Tablets had been stored in a thermo-hygrostat-controlled environment set to simulate the home conditions of patients up to 8 weeks after unit-dose packaging. Among the tablets in unit-dose packaging prepared immediately after blister packs (BP) were opened, one generic had decreased hardness to less than 2.0 kg after 1 week, 55.1% of its initial hardness value, and a shorter disintegration time of about 1/5 of its initial disintegration time. Generics met the standard for dissolution 8 weeks after unit-dose packaging. The decrease in hardness after unit-dose packaging is presumed to be associated with additives, and particularly the types and amounts of binding agents, but evidence of this association was lacking. The hardness noted in drug interview forms (IFs) and the state of sales of bulk tablet packages must be determined to facilitate the selection of generics that remain hard even after unit-dose packaging.

  4. Impact of active ingredients on the swelling properties of orally disintegrating tablets prepared by microwave treatment.

    PubMed

    Sano, Syusuke; Iwao, Yasunori; Kimura, Susumu; Noguchi, Shuji; Itai, Shigeru

    2014-07-01

    The impact of different active pharmaceutical ingredients (APIs) loading on the properties of orally disintegrating tablets (ODTs) prepared according to our previously reported microwave (MW) treatment process was evaluated using famotidine (FAM), acetaminophen (AAP), and ibuprofen (IBU). None of the APIs interrupted the tablet swelling during the MW treatment and the tablet hardness were improved by more than 20 N. MW treatment, however, led to a significant increase in the disintegration time of the ODTs containing IBU, but it had no impact on that of the ODTs containing FAM or AAP. This increased disintegration time of the ODTs containing IBU was attributed to the relatively low melting point of IBU (Tm=76 °C), with the IBU particles melting during the MW treatment to form agglomerates, which interrupted the penetration of water into the tablets and delayed their disintegration. The effects of the MW treatment on the chemical stability and dissolution properties of ODTs were also evaluated. The results revealed that MW treatment did not promote the degradations of FAM and AAP or delay their release from the ODTs, while dissolution of the ODTs containing IBU delayed by MW treatment. Based on these results, the MW method would be applicable to the preparation of ODTs containing APIs with melting points higher than 110 °C.

  5. [Technical scheme of real-time evaluation of traditional Chinese medicine orally disintegrating tablets].

    PubMed

    Qin, Dong; Chen, Xu-dong; Feng, Liang; Gu, Jun-fei; Yuan, Jia-rui; Jia, Xiao-bin

    2014-12-01

    Orally disintegrating tablets (ODT), a kind of new solid tablet that rapidly disintegrates to work in the mouth, has became the hot form of new drug research in recent years with many advantages, such as the convenient taking, a widely applicable people, fast acting, high bioavailability, good compliance, and so on. ODT has been widely used in chemical medicines, while the application of it in traditional Chinese medicines (TCMs) is still in the stage of development The development of TCMs ODT provides a new direction for the research of Chinese medicine new dosage, accelerates the pace of connecting to the world and modernization of Chinese medicine. This dosage has a broad market prospect, and its quality control and assessment standards, taste, the disintegration time in vitro and evaluation method are the key factors that affect the industrialization, standardization of Chinese medicine ODT. Therefore, this paper reviewed the characteristics, preparation, taste masking technology and quality evaluation with new technology of ODT. Meantime, numerous application examples of ODT used in traditional Chinese medicine were described. We expect to provide the reference and utilization for the development of traditional Chinese medicine orally disinteeratine tablets.

  6. A new modified wetting test and an alternative disintegration test for orally disintegrating tablets.

    PubMed

    Hooper, Patrick; Lasher, Jason; Alexander, Kenneth S; Baki, Gabriella

    2016-02-20

    Industrial manufacturing of solid oral dosage forms require quality tests, such as friability, hardness, and disintegration. The United States Pharmacopeia (USP) disintegration test uses 900mL of water. However, recent studies of orally disintegrating tablets (ODTs) have shown that this volume does not accurately portray the oral environment. In our study, various tests were conducted with a more moderate amount of water that accurately resembles the oral environment. A simulated wetting test was performed to calculate the water absorption ratio. Results showed that wetting was comparable to disintegration. Although the wetting test worked for most types of ODTs, it had limitations that produced inaccurate results. This led to the use of a modified shaking water bath test. This test was found to work for all types of ODT products and was not subject to the limitations of the wetting test. The shake test could provide disintegration times rather than water permeation times; however, it could not be used to calculate the water absorption ratio. A strong correlation was observed between the standardized shake test and the USP disintegration times for the tablets. This shake test could be used during the development stages and quality tests for ODTs with relative ease.

  7. Pharmacokinetic evaluation of an oral tablet form of low-molecular-weight heparin and deoxycholic acid conjugate as a novel oral anticoagulant.

    PubMed

    Park, J W; Jeon, O C; Kim, S K; Al-Hilal, T A; Lim, K-M; Moon, H T; Kim, C Y; Byun, Y

    2011-06-01

    This study was designed to develop a solid oral dosage form of deoxycholic acid (DOCA)-conjugated low-molecular-weight heparin (LMWH) and to evaluate its oral absorption, distribution, and metabolic stability for the prospect of providing an orally bioavailable LMWH. The LMWH derivative (LHD) was synthesised and then formulated with solubilisers and other pharmaceutical excipients to form a solid tablet. Its absorption and distribution after oral administration were evaluated in mice, rats, and monkeys. The in vitro metabolic stability of LHD was examined by liver microsome assays. More than 80% of LHD was released from the tablet within 60 minutes, guaranteeing rapid tablet disintegration after oral administration. Oral bioavailability of LHD in mice, rats and monkeys were 16.1 ± 3.0, 15.6 ± 6.1, and 15.8 ± 2.5%, respectively. After the oral administration of 131I-tyramine-LHD, most of the absorbed drug remained in the blood circulation and was eliminated mainly through the kidneys. LHD was hardly metabolised by the liver microsomes and showed a stable metabolic pattern similar to that of LMWH. In a rat thrombosis model, 10 mg/kg of orally administered LHD reduced thrombus formation by 60.8%, which was comparable to the anti-thrombotic effect of the subcutaneously injected LMWH (100 IU/kg). Solid tablets of LHD exhibited high oral absorption and statistically significant therapeutic effects in preventing venous thromboembolism. Accordingly, LHD tablets are expected to satisfy the unmet medical need for an oral heparin-based anticoagulant as an alternative to injectable heparin and oral warfarin.

  8. Bioequivalence of ondansetron oral soluble film 8 mg (ZUPLENZ) and ondansetron orally disintegrating tablets 8 mg (ZOFRAN) in healthy adults.

    PubMed

    Dadey, Eric

    2015-01-01

    Oral formulations of ondansetron are used to prevent nausea and vomiting associated with chemotherapy, radiotherapy, and surgery. An oral soluble film formulation of ondansetron (OND OSF) was developed using MonoSol Rx's proprietary PharmFilm technology and was formulated to dissolve rapidly on the tongue, without the need for water. This product provides an oral antiemetic treatment option for patients who experience difficulty swallowing. The purpose of this study was to compare the bioequivalence of OND OSF 8 mg (ZUPLENZ, Monosol Rx, Warren, NJ) with ondansetron orally disintegrating tablets (OND ODT) 8 mg (ZOFRAN, GlaxoSmithKline, Research Triangle Park). In 3 individual open-label, randomized studies, healthy adult subjects received a single dose of OND OSF 8 mg and a single dose of OND ODT 8 mg, under fasted conditions (study 1, n = 48), fed conditions (study 2, n = 48), and fasted with and without water (study 3, n = 18). Each dosing period was followed by a 3- or 7-day washout period. Ondansetron pharmacokinetics were assessed predose to 24 hours postdose for the single 8-mg doses of OND OSF and OND ODT. All analyses were conducted on natural log-transformed pharmacokinetic parameters for OND OSF and OND ODT. Under both fasted and fed conditions, the 90% confidence interval for the comparisons of OND OSF and OND ODT plasma ondansetron area under the curve from time 0 to the last measured concentration (AUC0-t), area under the concentration vs. time curve from time 0 to infinity (AUC0-∞), and maximum plasma concentration (Cmax) were within the 80%-125% range, indicating bioequivalence between the formulations. With features designed to make it portable and easy to take, OND OSF 8 mg provides an alternative treatment option, particularly for patients with dysphagia and others who find it difficult to take oral tablets.

  9. Formulation design for orally disintegrating tablets containing enteric-coated particles.

    PubMed

    Okuda, Yutaka; Okamoto, Yasunobu; Irisawa, Yosuke; Okimoto, Kazuto; Osawa, Takashi; Yamashita, Shinji

    2014-01-01

    The purpose of this study was to investigate the applicability of our newly developed technology (RACTAB® technology) for preparing orally disintegrating tablets (ODTs) containing enteric-coated particles. Tamsulosin hydrochloride (TAM) was used as a model drug contained in the enteric-coated particles. Enteric-coated particles containing TAM (ECP-T) were prepared by spray coating a mixture of TAM with controlled-release materials. ECP-T was then mixed with rapidly disintegrating granules (RDGs), which were prepared using the suspension spray-coating method, and was tableted to form ODTs (ODTRAC). ODTRAC was evaluated for its hardness, thickness, internal structure (X-ray-CT scanning), functional properties (controlled-release profile), and in vivo disintegration time. Since RDGs with micronized ethylcellulose (MEC) increased tablet hardness by increasing the contact frequency between granules, ODTRAC containing ECP-T exhibited high hardness (>50 N) and low friability (<0.5%) with a relatively low compression force. After tableting, the structure of ECP-T in ODTRAC remained intact and no damage was observed on the surface. ECP-T recovered from ODTRAC showed the same dissolution profile of TAM in Japanese Pharmacopoeia (JP) 1st and JP 2nd media as that of intact ECP-T, which indicated that the tableting process did not affect the acid-resistibility of the particle. In addition, ODTRAC rapidly disintegrated in vivo (< 30 s), even at a high compression force (at 9 kN). These findings clearly suggest that RACTAB® technology is a useful approach to prepare ODTs containing enteric-coated particles.

  10. Design, development, and optimization of orally disintegrating tablets of etoricoxib using vacuum-drying approach.

    PubMed

    Patel, Dharmesh; Shah, Mohit; Shah, Sunny; Shah, Tejal; Amin, Avani

    2008-01-01

    Etoricoxib is a cyclooxygenase 2 (COX-2) inhibitor that selectively inhibits the COX-2 enzyme and decreases the incidences of side effects associated with these agents. It is commonly prescribed for acute pain, gouty arthritis, and rheumatoid arthritis. Conventional tablets of etoricoxib are not capable of rapid action, which is required for faster drug effect onset and immediate relief from pain. Thus, the aim of the present investigation is to formulate orally disintegrating tablets (ODTs) of etoricoxib. A combination of the superdisintegrants with a sublimation technique was used to prepare the tablets. Tablets were prepared using a direct compression method employing superdisintegrants such as low substituted hydroxylpropyl methyl cellulose (L-HPMC), low substituted hydroxyl-propyl cellulose (L-HPC), crospovidone, croscarmellose sodium, and sodium starch glycolate. Tablets of etoricoxib prepared using L-HPC exhibited the least friability and disintegration time (approximately 65 s). To decrease the disintegration time further, a sublimation technique was used along with the superdisintegrants for the preparation of ODTs. The use of sublimating agents including camphor, menthol, and thymol was explored. The addition of camphor lowered the disintegration time (approximately 30 s) further, but the percent friability was increased. A 3(2) full factorial design was employed to study the joint influence of the amount of superdisintegrant (L-HPC) and the amount of sublimating agent (camphor) on the percent of friability and the disintegration time. The results of multiple linear regression analysis revealed that for obtaining an effective ODT of etoricoxib, higher percentages of L-HPC and camphor should be used. Checkpoint batches were prepared to validate the evolved mathematical model. A response surface plot is also presented to graphically represent the effect of the independent variables on the percent of friability and the disintegration time. The approach using

  11. Sleep and GABA levels in the oral part of rat pontine reticular formation are decreased by local and systemic administration of morphine.

    PubMed

    Watson, C J; Lydic, R; Baghdoyan, H A

    2007-01-05

    Morphine, a mu-opioid receptor agonist, is a commonly prescribed treatment for pain. Although highly efficacious, morphine has many unwanted side effects including disruption of sleep and obtundation of wakefulness. One mechanism by which morphine alters sleep and wakefulness may be by modulating GABAergic signaling in brain regions regulating arousal, including the pontine reticular nucleus, oral part (PnO). This study used in vivo microdialysis in unanesthetized Sprague-Dawley rat to test the hypothesis that mu-opioid receptors modulate PnO GABA levels. Validation of the high performance liquid chromatographic technique used to quantify GABA was obtained by dialyzing the PnO (n=4 rats) with the GABA reuptake inhibitor nipecotic acid (500 microM). Nipecotic acid caused a 185+/-20% increase in PnO GABA levels, confirming chromatographic detection of GABA and demonstrating the existence of functional GABA transporters in rat PnO. Morphine caused a concentration-dependent decrease in PnO GABA levels (n=25 rats). Coadministration of morphine (100 microM) with naloxone (1 microM), a mu-opioid receptor antagonist, blocked the morphine-induced decrease in PnO GABA levels (n=5 rats). These results show for the first time that mu-opioid receptors in rat PnO modulate GABA levels. A second group of rats (n=6) was used to test the hypothesis that systemically administered morphine also decreases PnO GABA levels. I.v. morphine caused a significant (P<0.05) decrease (19%) in PnO GABA levels relative to control i.v. infusions of saline. Finally, microinjections followed by 2 h recordings of electroencephalogram and electromyogram tested the hypothesis that PnO morphine administration disrupts sleep (n=8 rats). Morphine significantly (P<0.05) increased the percent of time spent in wakefulness (65%) and significantly (P<0.05) decreased the percent of rapid eye movement (REM) sleep (-53%) and non-REM sleep (-69%). The neurochemical and behavioral data suggest that morphine may

  12. Pharmacokinetics of cimetidine in dogs after oral administration of cimetidine tablets.

    PubMed

    Le Traon, G; Burgaud, S; Horspool, L J I

    2009-06-01

    Long-term oral treatment with cimetidine is recommended to reduce vomiting in dogs with chronic gastritis. Despite this, few studies have specifically examined the plasma disposition and pharmacokinetics of cimetidine in dogs, particularly following repeated oral administration. The pharmacokinetics of cimetidine following oral administration as tablets was investigated in healthy dogs. Cimetidine was absorbed rapidly post-treatment (t(max) = 0.5 h). A mean absolute bioavailability of 75% was calculated following a single oral administration of 5 mg cimetidine/kg body weight. After intravenous administration, a plasma half-life of 1.6 h was calculated. Repeated oral administration at the recommended dose rate and regime (5 mg/kg body weight three times daily) for 30 consecutive days did not lead to any accumulation of cimetidine in plasma. Food intake concomitant with oral administration of cimetidine delayed (t(max) = 2.25 h) and decreased the rate and extent of absorption (AUC) by about 40%. Cimetidine was well absorbed in fasted dogs. Administration of food decreased the bioavailability of cimetidine by 40%. Cimetidine does not accumulate over time in plasma when administered long term to dogs.

  13. Bioequivalence of 2 Formulations of Sildenafil Oral Soluble Film 100 mg and Sildenafil Citrate (Viagra) 100 mg Oral Tablets in Healthy Male Volunteers.

    PubMed

    Dadey, Eric

    2015-07-04

    Sildenafil citrate tablets (VIAGRA; Pfizer Inc) have been used since 1998 as an oral therapy for the treatment of erectile dysfunction. However, in some cases, patients may have difficulty in swallowing tablets, and the need to use water to aid in the oral administration of the tablets has the potential to interrupt the sexual encounter, reduce spontaneity, and therefore decrease the quality of the experience. Two oral soluble film (OSF) formulations of sildenafil were developed using MonoSol Rx's proprietary PharmFilm technology. Both films were formulated to dissolve rapidly on the tongue, thereby releasing the drug into the oral cavity, whereupon it is swallowed without the use of water. From a patient perspective, it is anticipated that the film formulations of sildenafil citrate will provide a more compliant and discreet dosage form. The purpose of this clinical study was to compare the bioequivalence of the 2 sildenafil OSF 100 mg formulations (MonoSol Rx, LLC) with the sildenafil citrate 100 mg tablets. The design was a single-dose, randomized, open-label, 3-period, 6-sequence, 3-treatment, single-center, crossover study conducted in 18 healthy, nonsmoking male volunteers under fasting conditions, with each treatment period separated by a 7-day washout period. Plasma sildenafil concentrations were measured predose and then periodically to 24 hours after dosing. The 90% confidence intervals for plasma sildenafil AUC0-t, AUC0-∞, and Cmax for both sildenafil OSF formulations as compared with sildenafil citrate tablets were all within the 80%-125% range, indicating bioequivalence of both film formulations to sildenafil citrate tablets. Overall, the demonstrated bioequivalence coupled with the performance advantages of an OSF dosage form (ie, rapid dissolution in the mouth, can be taken without water, and can be dosed discreetly) suggest that the sildenafil OSF may provide an attractive alternative to sildenafil citrate oral tablets.

  14. Pharmacology and toxicology of an oral tablet whole cells inactivated cholera vaccine in Sprague Dawley rats.

    PubMed

    López, Yulieé; Infante, Juan Francisco; Sifontes, Sergio; Díaz, Daiyana; Pérez, Viviana; Año, Gemma; Hernández, Tamara; Fernández, Sonsire; Castaño, Jorge Luis; Cedré, Bárbara; Oliva, Reynaldo; García, Luis; Solís, Rosa L; Talavera, Arturo

    2011-04-27

    Here we further investigate the pharmacological and toxicological properties of a cholera vaccine based on inactivated whole cells presented in either enteric coated (COA) or uncoated (U/C) tablet formulation from Vibrio cholerae C7258 strain. Tablets were dispersed in 2mL drinking water and administered orally to Sprague Dawley rats distributed in five groups (I COA7, II U/C7 immunized at 0, 7, 69days and III COA14, IV U/C14 immunized at 0, 14, 69days and V control group). Serum vibriocidal antibody response was measured after the administration of two doses with an interval of 7-14days. To further investigate the toxicological aspects a third dose was applied 10 weeks after the initial one. Animals were observed daily and water and food consumption was measured every other day. Periodic blood extractions were performed for hematology, biochemistry, and the titer of serum vibriocidal antibodies was determined. Anatomopathological analysis was performed at days 3 or 14 after the third dose. Results from clinical observations, as well as from water and food consumption and body weigh indicated no toxicity of the vaccine product. Meanwhile, no biological differences were found among different groups in hematological, hemo-chemistry, and anatomopathological studies. Moreover, enteric coated and uncoated tablets against human cholera were found to induce an immune response in rats.

  15. Morphine Injection

    MedlinePlus

    Morphine injection is used to relieve moderate to severe pain. Morphine is in a class of medications called opiate ( ... Morphine injection comes as a solution (liquid) to inject intramuscularly (into a muscle) or intravenously (into a ...

  16. Morphine overdose

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/002502.htm Morphine overdose To use the sharing features on this page, please enable JavaScript. Morphine is a very strong painkiller. Morphine overdose occurs ...

  17. Morphine Rectal

    MedlinePlus

    Rectal morphine is used to relieve moderate to severe pain. Morphine is in a class of medications called opiate ( ... Rectal morphine comes as a suppository to insert in the rectum. It is usually inserted every 4 hours. Use ...

  18. Maltodextrin: a novel excipient used in sugar-based orally disintegrating tablets and phase transition process.

    PubMed

    Elnaggar, Yosra Shaaban R; El-Massik, Magda A; Abdallah, Ossama Y; Ebian, Abd Elazim R

    2010-06-01

    The recent challenge in orally disintegrating tablets (ODT) manufacturing encompasses the compromise between instantaneous disintegration, sufficient hardness, and standard processing equipment. The current investigation constitutes one attempt to fulfill this challenge. Maltodextrin, in the present work, was utilized as a novel excipient to prepare ODT of meclizine. Tablets were prepared by both direct compression and wet granulation techniques. The effect of maltodextrin concentrations on ODT characteristics--manifested as hardness and disintegration time--was studied. The effect of conditioning (40 degrees C and 75% relative humidity) as a post-compression treatment on ODT characteristics was also assessed. Furthermore, maltodextrin-pronounced hardening effect was investigated using differential scanning calorimetry (DSC) and X-ray analysis. Results revealed that in both techniques, rapid disintegration (30-40 s) would be achieved on the cost of tablet hardness (about 1 kg). Post-compression conditioning of tablets resulted in an increase in hardness (3 kg), while keeping rapid disintegration (30-40 s) according to guidance of the FDA for ODT. However, direct compression-conditioning technique exhibited drawbacks of long conditioning time and appearance of the so-called patch effect. These problems were, yet, absent in wet granulation-conditioning technique. DSC and X-ray analysis suggested involvement of glass-elastic deformation in maltodextrin hardening effect. High-performance liquid chromatography analysis of meclizine ODT suggested no degradation of the drug by the applied conditions of temperature and humidity. Overall results proposed that maltodextrin is a promising saccharide for production of ODT with accepted hardness-disintegration time compromise, utilizing standard processing equipment and phenomena of phase transition.

  19. Effect of the type of lubricant on the characteristics of orally disintegrating tablets manufactured using the phase transition of sugar alcohol.

    PubMed

    Kuno, Yoshio; Kojima, Masazumi; Nakagami, Hiroaki; Yonemochi, Etsuo; Terada, Katsuhide

    2008-08-01

    The aim of this study was to evaluate the effect of lubricants on the characteristics of orally disintegrating (OD) tablets manufactured using the phase transition of sugar alcohol. OD tablets were produced by directly compressing a mixture containing lactose-xylitol granules, disintegrant, glidant and lubricant, and subsequent heating. The effect of the type of lubricant on the tablet characteristics was evaluated using magnesium stearate (Mg-St), sodium stearyl fumarate (SSF), and talc as lubricants. The hardness of the tablets increased to ca. 6kp as a result of heating, regardless of the kind of lubricant. The oral disintegration time of the tablets containing Mg-St or SSF increased with an increase in the hardness. In contrast, the oral disintegration time of the tablets containing talc was not changed despite of an increase in hardness. The water absorption rate of the tablets containing talc was much faster than that of the tablets containing other lubricants. The surface free energy measurement showed that the polarity of the tablet components containing talc was remarkably increased by heating. The water absorption rate of the tablets containing talc was also increased by heating. These results indicate that a more hydrophilic surface might be attained by heating the talc. Consequently, talc was demonstrated to be the most desirable lubricant for the preparation of OD tablets based on the principle of the phase transition of sugar alcohol.

  20. [Pharmacokinetics of scopolamine hydrobromide oral disintegrative microencapsule tablets in Beagle dogs determined with LC-MS/MS].

    PubMed

    Xia, Tian; Liu, De-Ding; Shi, Li-Fu; Hu, Jin-Hong

    2011-08-01

    The study aims to elucidate the characteristics of pharmacokinetics of scopolamine hydrobromide oral disintegrative microencapsule tablets in healthy Beagle dogs. Chromatographic separation was performed on a C18 column (100 mm x 3.0 mm, 3.5 microm) with methanol - 2 mmol x L(-1) ammonium formate (25 : 75) as the mobile phase. A trip-quadrupole tandem mass spectrum with the electrospray ionization (ESI) source was applied and positive ion multiple reaction monitoring mode was operated. Six Beagle dogs were randomly devided into two groups. They received oral single dose of scopolamine hydrobromide oral disintegrative microencapsule tablets 0.6 mg (test tablet) or scopolamine hydrobromide normal tablets (reference tablet). Plasma samples were collected at designed time. Plasma concentration of scopolamine hydrobromide was determined by LC-MS/MS and pharmacokinetic parameters were calculated. The pharmacokinetic parameters of test tablet vs reference tablet were as follows: C(max): (8.16 +/- 0.67) ng x mL(-1) vs (3.54 +/- 0.64) ng x mL(-1); t1/2: (2.83 +/- 0.45) h vs (3.85 +/- 0.82) h; t(max): (1.25 +/- 0.27) h vs (0.42 +/- 0.09) h; AUC(0-12h): (25.06 +/- 3.75) h x ng x mL(-1) vs (9.59 +/- 1.02) h x ng x mL(-1); AUC(0-infinity): (26.30 +/- 3.92) h x ng x mL(-1) vs (10.80 +/- 1.45) h x ng x mL(-1); MRT(0-12h): (3.38 +/- 0.34) h vs (3.86 +/- 0.26) h; MRT(0-infinity): (3.98 +/- 0.63) h vs (5.37 +/- 1.00) h. The absorption rate and AUC of test tablet is different from that of reference tablet. The bioavailability of test tablet is better than those of reference tablet.

  1. Concentrations of Morphine and Codeine in Paired Oral Fluid and Urine Specimens Following Ingestion of a Poppy Seed Roll and Raw Poppy Seeds

    PubMed Central

    Samano, Kimberly L.; Clouette, Randal E.; Rowland, Barbara J.; Sample, R.H. Barry

    2015-01-01

    Interpretation of opiate drug test results can be challenging due to casual dietary consumption of poppy seeds, which may contain variable opiate content. Opiate concentrations in paired oral fluid (OF), collected with the Oral-Eze® Oral Fluid Collection System, and urine were analyzed after ingestion of poppy seeds from the same source, consumed raw or contained in a roll. In Part 1, 12 individuals consumed equal portions of a poppy seed roll. For Part 2, the same individuals consumed an equivalent quantity of raw poppy seeds, containing ∼3.2 mg of morphine and 0.6 mg of codeine. Specimens were analyzed both by enzyme immunoassay (opiates) and by GC–MS (morphine/codeine). Urinary morphine was between 155–1,408 (roll) and 294–4,213 ng/mL (raw), measured at 2, 4, 6 and 20 h post-ingestion. Urinary codeine concentrations between 140–194 (roll) and 121–664 ng/mL (raw) were observed up to 6 h post-ingestion. Following consumption of raw poppy seeds, OF specimens were positive, above LOQ, from 0.25 to 3.0 h with morphine ranging from 7 to 600 ng/mL and codeine from 8 to 112 ng/mL. After poppy seed roll consumption, morphine concentrations of 7–143 ng/mL were observed up to 1.5 h with codeine detected in only 5.5% of OF specimens and ranging from 8 to 28 ng/mL. Combined with the existing poppy seed literature, these results support previous findings and provide guidance for interpretation of OF opiate testing. PMID:26378141

  2. Concentrations of Morphine and Codeine in Paired Oral Fluid and Urine Specimens Following Ingestion of a Poppy Seed Roll and Raw Poppy Seeds.

    PubMed

    Samano, Kimberly L; Clouette, Randal E; Rowland, Barbara J; Sample, R H Barry

    2015-10-01

    Interpretation of opiate drug test results can be challenging due to casual dietary consumption of poppy seeds, which may contain variable opiate content. Opiate concentrations in paired oral fluid (OF), collected with the Oral-Eze(®) Oral Fluid Collection System, and urine were analyzed after ingestion of poppy seeds from the same source, consumed raw or contained in a roll. In Part 1, 12 individuals consumed equal portions of a poppy seed roll. For Part 2, the same individuals consumed an equivalent quantity of raw poppy seeds, containing ∼3.2 mg of morphine and 0.6 mg of codeine. Specimens were analyzed both by enzyme immunoassay (opiates) and by GC-MS (morphine/codeine). Urinary morphine was between 155-1,408 (roll) and 294-4,213 ng/mL (raw), measured at 2, 4, 6 and 20 h post-ingestion. Urinary codeine concentrations between 140-194 (roll) and 121-664 ng/mL (raw) were observed up to 6 h post-ingestion. Following consumption of raw poppy seeds, OF specimens were positive, above LOQ, from 0.25 to 3.0 h with morphine ranging from 7 to 600 ng/mL and codeine from 8 to 112 ng/mL. After poppy seed roll consumption, morphine concentrations of 7-143 ng/mL were observed up to 1.5 h with codeine detected in only 5.5% of OF specimens and ranging from 8 to 28 ng/mL. Combined with the existing poppy seed literature, these results support previous findings and provide guidance for interpretation of OF opiate testing.

  3. Retrospective Comparison of Posaconazole Levels in Patients Taking the Delayed-Release Tablet versus the Oral Suspension.

    PubMed

    Durani, Urshila; Tosh, Pritish K; Barreto, Jason N; Estes, Lynn L; Jannetto, Paul J; Tande, Aaron J

    2015-08-01

    While posaconazole prophylaxis decreases the risk of invasive fungal infection compared to fluconazole, low bioavailability of the oral-suspension formulation limits its efficacy. A new delayed-release tablet formulation demonstrated an improved pharmacokinetic profile in healthy volunteers. However, serum levels for the two formulations have not been compared in clinical practice. This study compared achievement of therapeutic posaconazole levels in patients taking the delayed-release tablet to those taking the oral suspension. This retrospective cohort study included 93 patients initiated on posaconazole between 2012 and 2014 and had at least one serum posaconazole level measured. The primary measure was the proportion of patients achieving an initial therapeutic level (>700 ng/ml). An initial therapeutic posaconazole level was seen in 29 of 32 (91%) patients receiving tablets and 37 of 61 (61%) patients receiving suspension (P = 0.003). Among patients with a steady-state level measured 5 to 14 days after initiation, a therapeutic level was observed in 18 of 20 (90%) patients receiving tablets and 25 of 43 (58%) patients receiving suspension (P = 0.01). In these patients, the median posaconazole level of the tablet cohort (1655 ng/ml) was twice that of the suspension cohort (798 ng/ml) (P = 0.004). In this cohort study, the improved bioavailability of delayed-release posaconazole tablets translates into a significantly higher proportion of patients achieving therapeutic serum levels than in the cohort receiving the oral suspension. The results of this study strongly support the use of delayed-release tablets over suspension in patients at risk for invasive fungal infection.

  4. Comparative efficacy of patient-controlled administration of morphine, hydromorphone, or sufentanil for the treatment of oral mucositis pain following bone marrow transplantation.

    PubMed

    Coda, B A; O'Sullivan, B; Donaldson, G; Bohl, S; Chapman, C R; Shen, D D

    1997-09-01

    A total of 119 bone marrow transplant patients suffering from oral mucositis pain were enrolled in a randomized, double-blind, parallel-group trial comparing the efficacy of patient-controlled analgesia with morphine, hydromorphone and sufentanil. Patient ratings of pain and side-effects on visual analog scales were gathered daily from the start of patient-controlled analgesia (PCA) therapy until the discontinuation of opioid treatment either because of resolution of oral mucositis pain, intolerable side-effects, inadequate pain control, or complications related to transplantation. Of the 119 enrolled subjects, 100 met the evaluable criteria of developing oral mucositis and remaining on the study for at least 2 days. Multivariate analysis of the outcome measures indicated that the analgesia achieved in all three opioid groups was nearly equivalent, while measures of side-effects, especially for the combination of sedation, sleep and mood disturbances, were statistically lower in the morphine group than in hydromorphone or sufentanil groups. Patients in the hydromorphone group exhibited the most variability in pain control. Event analysis also indicated significant differences in time to treatment failure between the three groups, with the morphine arm exhibiting clear superiority. The proportion of patients discontinued because of inadequate pain relief was much higher in the sufentanil group (7/36) as compared to the hydromorphone (0/34) or the morphine group (1/30). The daily opioid consumption pattern showed a continual dose escalation during the first week of therapy for all groups, coincident with worsening mucositis. Morphine consumption reached a plateau by day 5, whereas hydromorphone and sufentanil consumption continued to rise until days 7 and 9, respectively. Sufentanil dose requirement increased by approximately 10-fold compared to morphine and hydromorphone, whose requirements increased only 5-fold, suggesting the possibility of development of acute

  5. Formulation and Evaluation of a Novel Matrix-Type Orally Disintegrating Ibuprofen Tablet

    PubMed Central

    Tayebi, Hoda; Mortazavi, Seyed Alireza

    2011-01-01

    Orally disintegrating tablets (ODTs) are capable of turning quickly into a liquid dosage form in contact with the saliva, thus possessing the advantages of both the solid dosage forms particularly stability and liquid dosage forms specially ease of swallowing and pre-gastric absorption of drug. The aim of this study was to prepare a novel matrix-type buccal fast disintegrating ibuprofen tablet formulation using special polymers, water soluble excipients, super-disintegrants and quickly soluble granules. For this purpose different tablet formulations of ibuprofen were prepared. The amount of ibuprofen in each formulation was 100 mg. Eight groups of formulation were prepared (A-H series), accounting for a total number of 45 formulations. Formulations prepared were examined in terms of different physicochemical tests including powder/granule flowability, appearance, thickness, uniformity of weight, hardness, friability and disintegration time. Results of formulation F22a (in series F), was found to be acceptable, making it the chosen formulation for further studies. Then, by adding various flavorants and sweeteners to this formulation, complementary series of formulations, named G and H, were prepared. Following the comparison of their taste with each other through asking 10 volunteers, the most suitable formulation regarding the taste, being formulation F22s, was chosen as the ultimate formulation. This formulation had PVP, ibuprofen and croscarmellose as the intra-granular components and xylitol and saccharin as the extra-granular ingredients. Formulation F22s was found to be acceptable in terms of physicochemical tests conducted, showing quick disintegration within the buccal cavity, appropriate hardness and rather low friability. Hence formulation F22s was selected as the final formulation. PMID:24250378

  6. Evidence-Based Nanoscopic and Molecular Framework for Excipient Functionality in Compressed Orally Disintegrating Tablets

    PubMed Central

    Al-khattawi, Ali; Alyami, Hamad; Townsend, Bill; Ma, Xianghong; Mohammed, Afzal R.

    2014-01-01

    The work investigates the adhesive/cohesive molecular and physical interactions together with nanoscopic features of commonly used orally disintegrating tablet (ODT) excipients microcrystalline cellulose (MCC) and D-mannitol. This helps to elucidate the underlying physico-chemical and mechanical mechanisms responsible for powder densification and optimum product functionality. Atomic force microscopy (AFM) contact mode analysis was performed to measure nano-adhesion forces and surface energies between excipient-drug particles (6-10 different particles per each pair). Moreover, surface topography images (100 nm2–10 µm2) and roughness data were acquired from AFM tapping mode. AFM data were related to ODT macro/microscopic properties obtained from SEM, FTIR, XRD, thermal analysis using DSC and TGA, disintegration testing, Heckel and tabletability profiles. The study results showed a good association between the adhesive molecular and physical forces of paired particles and the resultant densification mechanisms responsible for mechanical strength of tablets. MCC micro roughness was 3 times that of D-mannitol which explains the high hardness of MCC ODTs due to mechanical interlocking. Hydrogen bonding between MCC particles could not be established from both AFM and FTIR solid state investigation. On the contrary, D-mannitol produced fragile ODTs due to fragmentation of surface crystallites during compression attained from its weak crystal structure. Furthermore, AFM analysis has shown the presence of extensive micro fibril structures inhabiting nano pores which further supports the use of MCC as a disintegrant. Overall, excipients (and model drugs) showed mechanistic behaviour on the nano/micro scale that could be related to the functionality of materials on the macro scale. PMID:25025427

  7. Oral Morphine Pharmacokinetic in Obesity: The Role of P-Glycoprotein, MRP2, MRP3, UGT2B7, and CYP3A4 Jejunal Contents and Obesity-Associated Biomarkers.

    PubMed

    Lloret-Linares, Célia; Miyauchi, Eisuke; Luo, Huilong; Labat, Laurence; Bouillot, Jean-Luc; Poitou, Christine; Oppert, Jean-Michel; Laplanche, Jean-Louis; Mouly, Stéphane; Scherrmann, Jean-Michel; Uchida, Yasuo; Tachikawa, Masanori; Terasaki, Tetsuya; Bergmann, Jean-François; Declèves, Xavier

    2016-03-07

    The objective of our work was to study the association between the jejunal expression levels of P-gp, MRP2, MRP3, UGT2B7, CYP3A4, the ABCB1 c.3435C > T polymorphism, and several obesity-associated biomarkers, as well as oral morphine and glucuronides pharmacokinetics in a population of morbidly obese subjects. The pharmacokinetics of oral morphine (30 mg) and its glucuronides was performed in obese patients candidate to bariatric surgery. A fragment of jejunal mucosa was preserved during surgery. Subjects were genotyped for the ABCB1 single nucleotide polymorphism (SNP) c.3435C > T. The subjects were 6 males and 23 females, with a mean body mass index of 44.8 (35.4-61.9) kg/m(2). The metabolic ratios AUC0-inf M3G/morphine and AUC0-inf M6G/morphine were highly correlated (rs = 0.8, p < 0.0001) and were 73.2 ± 24.6 (34.7-137.7) and 10.9 ± 4.1 (3.8-20.6). The pharmacokinetic parameters of morphine and its glucuronides were not associated with the jejunal contents of P-gp, CYP3A4, MRP2, and MRP3. The jejunal content of UGT2B7 was positively associated with morphine AUC0-inf (rs = 0.4, p = 0.03). Adiponectin was inversely correlated with morphine Cmax (rs = -0.44, p = 0.03). None of the factors studied was associated with morphine metabolic ratios. The interindividual variability in the jejunal content of drug transporters and metabolizing enzymes, the ABCB1 gene polymorphism, and the low-grade inflammation did not explain the variability in morphine and glucuronide exposure. High morphine metabolic ratio argued for an increased morphine glucuronidation in morbidly obese patients.

  8. Effect of granule properties on rough mouth feel and palatability of orally disintegrating tablets.

    PubMed

    Kimura, Shin-Ichiro; Uchida, Shinya; Kanada, Ken; Namiki, Noriyuki

    2015-04-30

    In this study, we evaluated the palatability of orally disintegrating tablets (ODTs) containing core granules with different particle sizes, coating, and types of materials using visual analog scales (VAS). Tableting the core granules into ODTs reduced rough mouth feel and improved overall palatability compared to the ingestion of core granules alone. Moreover, the evaluation performed immediately after spitting out ODTs demonstrated differences in rough mouth feel between ODTs containing placebo and core granules. Rough mouth feel was found to be significantly more intense with core granules with particle sizes ≥ 200 μm. Since ODTs may contain taste-masked particles, palatability of ODTs containing coated core granules was also evaluated. Although coating with polymers impairs palatability, it was improved by coating the outer layer with d-mannitol. The effects on palatability of materials constituting core granules were also evaluated, with reduced rough mouth feel observed with core granules composed of water-soluble additives. Based on these data, receiver operating characteristic analysis was performed to determine the threshold VAS scores at which the subjects felt roughness and discomfort. In addition, the threshold particle size of the core granule contained within the ODT required for feeling roughness was determined to be 244 μm. This study elucidated the effect of the properties of masking particles on the rough mouth feel and palatability of ODTs.

  9. Preparation and evaluation of an orally fast disintegrating tablet formulation containing a hydrophobic drug.

    PubMed

    Comoglu, Tansel; Unal, Burcu

    2015-01-01

    Orally fast disintegrating tablets (FDTs or ODTs) have received ever-increasing demand during the last decade, and the field has become a rapidly growing area in the pharmaceutical industry. Upon introduction into the mouth, these tablets dissolve or disintegrate in the mouth in the absence of additional water for easy administration of active pharmaceutical ingredients. Although the FDT area has passed its infancy, as shown by a large number of commercial products on the market, there are still many aspects to improve in the FDT formulations. Despite advances in the FDT technologies, formulation of hydrophobic drugs is still a challenge, especially when the amount of drug is high. In this study, a new solution is being developed to incorporate higher doses of a model hydrophobic drug; meloxicam, without affecting the fast disintegrating properties of the formulation. In order to enhance the solubilization of meloxicam in FDT formulations, β cyclodextrin inclusion complex of the drug is prepared and FDTs containing meloxicam--β cyclodextrin inclusion complex (F1 A and F2 A) were compared and evaluated with the FDTs containing pure meloxicam (F1 and F2) by means of in vitro quality control tests.

  10. Self-Nanoemulsifying Lyophilized Tablets for Flash Oral Transmucosal Delivery of Vitamin K: Development and Clinical Evaluation.

    PubMed

    El-Say, Khalid M; Ahmed, Tarek A; Ahmed, Osama A A; Hosny, Khaled M; Abd-Allah, Fathy I

    2017-01-10

    Owing to limited solubility, vitamin K undergoes low bioavailability with large inter-individual variability after oral administration. This article aimed to prepare self-nanoemulsifying lyophilized tablets (SNELTs) for the flash oral transmucosal delivery of vitamin K. Twenty-one formulae of vitamin K self-nanoemulsifying drug delivery systems (SNEDDS) were prepared using different concentrations of vitamin K, Labrasol, and Transcutol according to mixture design. The SNEDDS was loaded on porous carriers and formulated as lyophilized tablets. The release profile and the pharmacokinetic parameters of vitamin K SNELTs were evaluated in comparison with commercial tablets and ampoules on human volunteers. Results revealed that the optimized SNEDDS showed the smallest and most stable nanoemulsion globules. SNELTs were prepared successfully and showed substantial superiority drug release compared with the commercial tablets. Interestingly, SNELTs enhanced both rate and extent of vitamin K absorption as well as relative bioavailability (169.67%) in healthy subjects compared with the commercial tablets. SNELTs revealed promising no significant difference in the area under the curve compared with the commercial intramuscular injection. SNELTs enhanced dissolution and bioavailability that expected to have the strong impact on the efficiency of vitamin K in the prophylaxis and treatment of bleeding disorders in patients with hepatic dysfunction.

  11. Mucoadhesive elementary osmotic pump tablets of trimetazidine for controlled drug delivery and reduced variability in oral bioavailability.

    PubMed

    Alam, Naushad; Beg, Sarwar; Rizwan, Mohammad; Ahmad, Akifa; Ahmad, Farhan Jalees; Ali, Asgar; Aqil, Mohammad

    2015-04-01

    The objectives of this work was preparation and evaluation of the mucoadhesive elementary osmotic pump tablets of trimetazidine hydrochloride to achieve desired controlled release action and augmentation of oral drug absorption. The drug-loaded core tablets were prepared employing the suitable tableting excipients and coated with polymeric blend of ethyl cellulose and hydroxypropyl methylethylcellulose E5 (4:1). The prepared tablets were characterized for various quality control tests and in vitro drug release. Evaluation of drug release kinetics through model fitting suggested the Fickian mechanism of drug release, which was regulated by osmosis and diffusion as the predominant mechanism. Evaluation of mucoadhesion property using texture analyzer suggested good mucoadhesion potential of the developed osmotic systems. Solid state characterization using Fourier-transform infrared spectroscopy, differential scanning calorimetry and powder X-ray diffraction spectroscopy confirmed the absence of any physiochemical incompatibilities between drug and excipients. Scanning electron microscopy analysis showed the smooth surface appearance of the coated tablets with intact polymeric membrane without any fracture. In vivo pharmacokinetic studies in rabbits revealed 3.01-fold enhancement in the oral bioavailability vis-à-vis the marketed formulation (Vastarel MR®). These studies successfully demonstrate the bioavailability enhancement potential of the mucoadhesive elementary osmotic pumps as novel therapeutic systems for other drugs too.

  12. [Dose-finding for treatment with a transdermal fentanyl patch : Titration with oral transmucosal fentanyl citrate and morphine sulfate].

    PubMed

    Mücke, M; Conrad, R; Marinova, M; Cuhls, H; Elsner, F; Rolke, R; Radbruch, L

    2016-12-01

    To date, no studies investigating titration with oral transmucosal fentanyl for the dose-finding of transdermal fentanyl treatment have been published. In an open randomized study 60 patients with chronic malignant (n = 39) or nonmalignant pain (n = 21), who required opioid therapy according to step three of the guidelines of the World Health Organization (WHO), were investigated. In two groups of 30 patients each titration with immediate release morphine (IRM) or oral transmucosal fentanyl citrate (OTFC) was undertaken. For measurement purposes the Brief Pain Inventory (BPI) and Minimal Documentation System (MIDOS) were used. After a 24-h titration phase, in which patients documented the intensity of pain, nausea, and tiredness, treatment with transdermal fentanyl was evaluated over a 10-day period by means of the necessary dose adaptation (responder ≤ 1 dose adaptation; conversion formula 1:1 [OTFC group] vs 100:1 [IRM group]).The pain reduction over the first 24 h (titration phase) did not differ significantly between the groups. The number of responders (17 OTFC vs. 21 IRM) over the 10-day period did not show any difference either. In both groups there was a significant reduction in pain intensity (p < 0.001). Over the course of the study, there were significantly more drop-outs because of adverse effects in the OTFC group than in the IRM group (8 vs 1, p = 0.028).Oral transmucosal fentanyl citrate can be applied for the titration of transdermal fentanyl, but it does not show any clinically relevant advantage. For example, the risk of side effects-induced drop-outs was greater in the present study. Whether the unnecessary opioid switching to treat chronic pain and breakthrough pain is advantageous with regard to minimizing conversion errors cannot be definitively answered within the scope of this study.

  13. A three-layer guar gum matrix tablet for oral controlled delivery of highly soluble metoprolol tartrate.

    PubMed

    Krishnaiah, Y S R; Karthikeyan, R S; Satyanarayana, V

    2002-07-25

    The objective of the study is to design oral controlled drug delivery systems for highly water-soluble drugs using guar gum as a carrier in the form of a three-layer matrix tablet. Metoprolol tartrate was chosen as a model drug because of its high water solubility. Matrix tablets containing either 30 (M1), 40 (M2) or 50% (M3) of guar gum were prepared by wet granulation technique using starch paste as a binder. Three-layer matrix tablets of metoprolol tartrate were prepared by compressing on both sides of guar gum matrix tablet granules of metoprolol tartrate M1, M2 or M3 with either 50 (TL1M1, TL1M2 or TL1M3) or 75 mg (TL2M1, TL2M2 or TL2M3) of guar gum granules as release retardant layers. Both the matrix and three-layer matrix tablets were evaluated for hardness, thickness, drug content uniformity, and subjected to in vitro drug release studies. The amount of metoprolol tartrate released from the matrix and three-layer matrix tablets at different time intervals was estimated by using a HPLC method. Matrix tablets of metoprolol tartrate were unable to provide the required drug release rate. However, the three-layer guar gum matrix tablets (TL2M3) provided the required release rate on par with the theoretical release rate for metoprolol tartrate formulations meant for twice daily administration. The three-layer guar gum matrix tablet (TL2M3) showed no change either in physical appearance, drug content or in dissolution pattern after storage at 40 degrees C/75% RH for 6 months. The FT-IR study did not show any possibility of metoprolol tartrate/guar gum interaction with the formulation excipients used in the study. The results indicated that guar gum, in the form of three-layer matrix tablets, is a potential carrier in the design of oral controlled drug delivery systems for highly water-soluble drugs such as metoprolol tartrate.

  14. Fentanyl Sublingual Tablets Versus Subcutaneous Morphine for the Management of Severe Cancer Pain Episodes in Patients Receiving Opioid Treatment: A Double-Blind, Randomized, Noninferiority Trial.

    PubMed

    Zecca, Ernesto; Brunelli, Cinzia; Centurioni, Fabio; Manzoni, Andrea; Pigni, Alessandra; Caraceni, Augusto

    2017-03-01

    Purpose Fentanyl sublingual tablets (FST) are a potentially useful alternative to parenteral opioids such as subcutaneous morphine (SCM) to treat severe cancer pain episodes. No direct comparison between FST and SCM is available. The aim of this study was to test noninferiority of FST versus SCM during the first 30 min postadministration. Methods Patients receiving stable opioid therapy and experiencing a severe pain episode were randomly assigned to either 100 µg FST or 5 mg SCM in a double-blind, double-dummy trial. Average pain intensity (PI) assessed on a 0 to 10 numerical rating scale at 10, 20, and 30 min postadministration was the main end point. Analysis of covariance, adjusted by baseline PI, was the main analysis. The noninferiority margin (NIm) for the between-group difference was set at -0.6, that is, equal to one third of the minimum clinically important PI difference of two points. Results A total of 114 patients were randomly assigned to either FST (n = 58) or SCM (n = 56). One patient (in the FST group) withdrew consent before drug administration and was excluded from analysis. Baseline mean PIs were 7.5 in both groups; mean average PIs assessed at 10, 20, and 30 min postadministration were 5.0 and 4.5 for FST and SCM, respectively, with the 95% CI of the between-group difference including the NIm (-0.49; 95% CI, -1.10 to 0.09). Patients taking FST received a second drug dose after 30 min more frequently than did patients taking SCM (51% v 37%, respectively; risk difference, -13%; 95% CI, -30% to 3%). Both treatments were well tolerated, with average follow-up adverse event scores below the response of "A Little." Ninety-three percent of patients preferred the sublingual administration. Conclusion This trial did not show noninferiority of FST versus SCM within the chosen NIm. Both treatments were safe, and patients preferred the sublingual route of administration. FST provides analgesia with modest to moderate increased risk of lower efficacy

  15. Effect of food on the comparative pharmacokinetics of modified-release morphine tablet formulations: Oramorph SR and MST Continus

    PubMed Central

    DRAKE, J.; KIRKPATRICK, C. T.; ALIYAR, C. A.; CRAWFORD, F. E.; GIBSON, P.; HORTH, C. E.

    1996-01-01

    The relative bioavailability and pharmacokinetic profiles of Oramorph SR (OSR) and MST Continus (MST), were evaluated by a randomized, four-way cross-over study in 24 healthy, male volunteers given single oral (30 mg) doses whilst fasting or after a high-fat breakfast. Mean Cmax, tmax, AUC(0,24h), AUC and tlag were significantly greater in fed compared with fasting subjects. Overall relative bioavailability of the two formulations (log AUC), was within the acceptable 80–125% limits for bioequivalence both fed and fasting. Mean fasting Cmax for OSR was greater than MST (P<0.05) but there was no difference between formulations in mean fed Cmax. No statistically significant difference between OSR and MST was found for other parameters nor in the incidence of adverse events. These results suggest that OSR and MST are bioequivalent and that if patients were to transfer between formulations, dosage adjustment would be unnecessary, irrespective of their meal schedules or food intake. PMID:8735684

  16. Oral liquid L-thyroxine (L-t4) may be better absorbed compared to L-T4 tablets following bariatric surgery.

    PubMed

    Pirola, Ilenia; Formenti, Anna M; Gandossi, Elena; Mittempergher, Francesco; Casella, Claudio; Agosti, Barbara; Cappelli, Carlo

    2013-09-01

    Drug malabsorption is a potential concern after bariatric surgery. We present four case reports of hypothyroid patients who were well replaced with thyroxine tablets to euthyroid thyrotropin (TSH) levels prior to Roux-en-Y gastric bypass surgery. These patients developed elevated TSH levels after the surgery, the TSH responded reversibly to switching from treatment with oral tablets to a liquid formulation.

  17. Formulation and In-vitro Evaluation of Orally Disintegrating Tablets of Olanzapine-2-Hydroxypropyl-β-Cyclodextrin Inclusion Complex

    PubMed Central

    Ajit Shankarrao, Kulkarni; Dhairysheel Mahadeo, Ghadge; Pankaj Balavantrao, Kokate

    2010-01-01

    The aim of this study was to design orally disintegrating tablets of Olanzapine and to complex Olanzapine with 2-hydroxypropyl-β- cyclodextrin with special emphasis on disintegration and dissolution studies. Phase solubility studies demonstrated the formation of 1:1 molar inclusion complex by kneading method. Tablets were prepared by using superdisintegrants namely, sodium starch glycolate, croscarmellose sodium, crospovidone, tulsion 339, and indion 414. Complex was characterized using infrared spectroscopy, drug content estimation, saturated solubility study, diffrerential scanning calorimetry and X-ray diffractometry. 5% w/w croscarmellose sodium showed the minimum disintegration time 39 ± 1.76 sec and in-vitro drug release 99.19 ± 0.18% within 6 min. In general, solubility of Olanzapine can be improved by complexing with 2-hydroxypropyl-β- cyclodextrin. Croscarmellose sodium can be used for faster disintegration of tablets. PMID:24381598

  18. Lessons learned from the development of oral calcitonin: the first tablet formulation of a protein in phase III clinical trials.

    PubMed

    Karsdal, M A; Henriksen, K; Bay-Jensen, A C; Molloy, B; Arnold, M; John, M R; Byrjalsen, I; Azria, M; Riis, B J; Qvist, P; Christiansen, C

    2011-04-01

    Oral delivery of proteins has been hampered by an array of difficulties. However, promising novel oral delivery systems have been developed. 5-CNAC, formulated with the peptide salmon calcitonin, is in phase III clinical trials for the treatment of osteoporosis or osteoarthritis and could become the first marketed oral peptide. This article reviews key findings and implications from studies undertaken to date with this oral formulation. Findings include these: (1) the optimal calcitonin tablet dose is 0.8 mg; (2) 0.8 mg of oral calcitonin is rapidly absorbed, reaching maximum concentration in 15 to 30 minutes, and is eliminated from plasma with a short half-life-9 to 15 minutes; (3) the 0.8-mg tablet is more highly absorbed than the marketed nasal formulation, with biomarker levels indicating significantly greater efficacy in suppression of bone resorption; (4) drug absorption is increased with dosing at least 10 minutes before a meal rather than postprandially and also with 50 mL of water; (5) the optimal timing of dosing for osteoporosis therapy is in the evening to mitigate the circadian peak in bone resorption; and (6) the oral formulations of synthetic and recombinant calcitonin have similar pharmacokinetic and pharmacodynamic properties. These key findings may aid researchers in the development of other oral formulations.

  19. One Month of Oral Morphine Decreases Gray Matter Volume in the Right Amygdala of Individuals with Low Back Pain: Confirmation of Previously Reported Magnetic Resonance Imaging Results

    PubMed Central

    Chu, Larry F.; Stringer, Elizabeth Ann; Baker, Katharine S.; Sayyid, Zahra N.; Sun, John; Campbell, Kelsey A.; Younger, Jarred W.

    2016-01-01

    Objective. Prolonged exposure to opioids is known to produce neuroplastic changes in animals; however, few studies have investigated the effects of short-term prescription opioid use in humans. A previous study from our laboratory demonstrated a dosage-correlated volumetric decrease in the right amygdala of participants administered oral morphine daily for 1 month. The purpose of this current study was to replicate and extend the initial findings. Methods. Twenty-one participants with chronic low back pain were enrolled in this double-blind, placebo-controlled study. Participants were randomized to receive daily morphine (n = 11) or a matched placebo (n = 10) for 1 month. High-resolution anatomical images were acquired immediately before and after the treatment administration period. Morphological gray matter changes were investigated using tensor-based morphometry, and significant regions were subsequently tested for correlation with morphine dosage. Results. Decreased gray matter volume was observed in several reward- and pain-related regions in the morphine group, including the bilateral amygdala, left inferior orbitofrontal cortex, and bilateral pre-supplementary motor areas. Morphine administration was also associated with significant gray matter increases in cingulate regions, including the mid cingulate, dorsal anterior cingulate, and ventral posterior cingulate. Conclusions. Many of the volumetric increases and decreases overlapped spatially with the previously reported changes. Individuals taking placebo for 1 month showed neither gray matter increases nor decreases. The results corroborate previous reports that rapid alterations occur in reward-related networks following short-term prescription opioid use. PMID:26814280

  20. Formulation strategy and evaluation of nanocrystal piroxicam orally disintegrating tablets manufacturing by freeze-drying.

    PubMed

    Lai, Francesco; Pini, Elena; Corrias, Francesco; Perricci, Jacopo; Manconi, Maria; Fadda, Anna Maria; Sinico, Chiara

    2014-06-05

    Piroxicam (PRX) is a non-steroidal anti-inflammatory drug characterized by a poor water solubility and consequently by a low oral bioavailability. In this work, different nanocrystal orally disintegrating tablets (ODT) were prepared to enhance piroxicam dissolution rate and saturation solubility. PRX nanocrystals were prepared by means of high pressure homogenization technique using poloxamer 188 as stabilizer. Three different ODTs were prepared with the same nanosuspension using different excipients in order to study their effect on the PRX dissolution properties. PRX nanocrystal size and zeta potential were determined by photon correlation spectroscopy. Additional characterization of PRX nanocrystal ODT was carried out by infrared spectroscopy, X-ray powder diffractometry, differential scanning calorimetry. Dissolution study was performed in distilled water (pH 5.5) and compared with PRX coarse suspension ODT, PRX/poloxamer 188 physical mixture, bulk PRX samples and a PRX commercial ODT. All PRX nanocrystal ODT formulations showed a higher drug dissolution rate than coarse PRX ODT. PRX nanocrystal ODT prepared using gelatin or croscarmellose as excipient showed a higher PRX dissolution rate compared with the commercial formulation and ODT prepared using xanthan gum. Overall results confirmed that improved PRX dissolution rate is due to the increased surface-to-volume ratio due to the nanosized drug particle but also revealed the important role of different excipients used.

  1. In vivo evaluation of thiolated chitosan tablets for oral insulin delivery.

    PubMed

    Millotti, Gioconda; Laffleur, Flavia; Perera, Glen; Vigl, Claudia; Pickl, Karin; Sinner, Frank; Bernkop-Schnürch, Andreas

    2014-10-01

    Chitosan-6-mercaptonicotinic acid (chitosan-6-MNA) is a thiolated chitosan with strong mucoadhesive properties and a pH-independent reactivity. This study aimed to evaluate the in vivo potential for the oral delivery of insulin. The comparison of the nonconjugated chitosan and chitosan-6-MNA was performed on several studies such as mucoadhesion, release, and in vivo studies. Thiolated chitosan formulations were both about 80-fold more mucoadhesive compared with unmodified ones. The thiolated chitosan tablets showed a sustained release for 5 h for the polymer of 20 kDa and 8 h for the polymer of 400 kDa. Human insulin was quantified in rats' plasma by means of ELISA specific for human insulin with no cross-reactivity with the endogenous insulin. In vivo results showed thiolation having a tremendous impact on the absorption of insulin. The absolute bioavailabilities were 0.73% for chitosan-6-MNA of 20 kDa and 0.62% for chitosan-6-MNA 400 kDa. The areas under the concentration-time curves (AUC) of chitosan-6-MNA formulations compared with unmodified chitosan were 4.8-fold improved for the polymer of 20 kDa and 21.02-fold improved for the polymer of 400 kDa. The improvement in the AUC with regard to the most promising aliphatic thiomer was up to 6.8-fold. Therefore, chitosan-6-MNA represents a promising excipient for the oral delivery of insulin.

  2. A dual strategy to improve psychotic patients' compliance using sustained release quetiapine oral disintegrating tablets.

    PubMed

    Refaat, Ahmed; Sokar, Magda; Ismail, Fatma; Boraei, Nabila

    2016-12-01

    Quetiapine (QT) is a short acting atypical antipsychotic drug effective in schizophrenia and bipolar disorder. This study aims at designing a novel dosage form of sustained release taste-masked QT orally disintegrating tablets (ODTs) based on solid lipid micro-pellets (SLMPs). QT SLMPs were prepared using the hot melt extrusion technique and utilizing three lipid carriers: Compritol, Precirol and white beeswax either alone or in mixtures. They showed sustained QT release and a taste masking effect. The selected QT SLMP was further blended with an aqueous solution containing polyvinylpyrollidone (2.5 %), croscarmellose sodium (2 %) and mannitol (50 %); it was then lyophilized into ODT in a mass ratio of 1:2, respectively. ODTs containing QT SLMPs showed: average wetting time (40.92 s), average oral disintegration time (21.49 s), average hardness (16.85 N) and also imparted suitable viscosity to suspend pellets during the lyophilization process. In conclusion, lyophilization is a promising technique for the formulation of multiparticulate systems into ODTs.

  3. A novel spray-dried nanoparticles-in-microparticles system for formulating scopolamine hydrobromide into orally disintegrating tablets.

    PubMed

    Li, Feng-Qian; Yan, Cheng; Bi, Juan; Lv, Wei-Lin; Ji, Rui-Rui; Chen, Xu; Su, Jia-Can; Hu, Jin-Hong

    2011-01-01

    Scopolamine hydrobromide (SH)-loaded microparticles were prepared from a colloidal fluid containing ionotropic-gelated chitosan nanoparticles using a spray-drying method. The spray-dried microparticles were then formulated into orally disintegrating tablets (ODTs) using a wet granulation tablet formation process. A drug entrapment efficiency of about 90% (w/w) and loading capacity of 20% (w/w) were achieved for the microparticles, which ranged from 2 μm to 8 μm in diameter. Results of disintegration tests showed that the formulated ODTs could be completely dissolved within 45 seconds. Drug dissolution profiles suggested that SH is released more slowly from tablets made using the microencapsulation process compared with tablets containing SH that is free or in the form of nanoparticles. The time it took for 90% of the drug to be released increased significantly from 3 minutes for conventional ODTs to 90 minutes for ODTs with crosslinked microparticles. Compared with ODTs made with noncrosslinked microparticles, it was thus possible to achieve an even lower drug release rate using tablets with appropriate chitosan crosslinking. Results obtained indicate that the development of new ODTs designed with crosslinked microparticles might be a rational way to overcome the unwanted taste of conventional ODTs and the side effects related to SH's intrinsic characteristics.

  4. Comparative Study Between Different Ready-Made Orally Disintegrating Platforms for the Formulation of Sumatriptan Succinate Sublingual Tablets.

    PubMed

    Tayel, Saadya A; El Nabarawi, Mohamed A; Amin, Maha M; AbouGhaly, Mohamed H H

    2017-02-01

    Sumatriptan succinate (SS) is a selective serotonin receptor agonist used for the treatment of migraine attacks, suffering from extensive first-pass metabolism and low oral bioavailability (∼14%). The aim of this work is to compare the performance of different ready-made co-processed platforms (Pharmaburst®, Prosolv ODT®, Starlac®, Pearlitol Flash®, or Ludiflash®) in the formulation of SS sublingual orodispersible tablets (ODTs) using direct compression technique. The prepared SS ODT formulae were evaluated regarding hardness, friability, simulated wetting time, and in vitro disintegration and dissolution tests. Different mucoadhesive polymers-HPMC K4M, Carbopol®, chitosan, or Polyox®-were tested aiming to increase the residence time in the sublingual area. A pharmacokinetic study on healthy human volunteers was performed, using LC/MS/MS assay, to compare the optimum sublingual formula (Ph25/HPMC) with the conventional oral tablet Imitrex®. Results showed that tablets prepared using Pharmaburst® had significantly (p < 0.05) the lowest simulated wetting and in vitro disintegration times of 17.17 and 23.50 s, respectively, with Q 5 min of 83.62%. HPMC showed a significant (p < 0.05) increase in the residence time from 48.44 to 183.76 s. The relative bioavailability was found to be equal to 132.34% relative to the oral tablet Imitrex®. In conclusion, Pharmaburst® was chosen as the optimum ready-made co-processed platform that can be successfully used in the preparation of SS sublingual tablets for the rapid relief of migraine attacks.

  5. Effect of a high-fat meal on the pharmacokinetics of 300-milligram posaconazole in a solid oral tablet formulation.

    PubMed

    Kersemaekers, Wendy M; Dogterom, Peter; Xu, Jialin; Marcantonio, Eugene E; de Greef, Rik; Waskin, Hetty; van Iersel, Marlou L P S

    2015-01-01

    Posaconazole in oral suspension must be taken multiple times a day with food (preferably a high-fat meal) to ensure adequate exposure among patients. We evaluated the effect of food on the bioavailability of a new delayed-release tablet formulation of posaconazole at the proposed clinical dose of 300 mg once daily in a randomized, open-label, single-dose, two-period crossover study with 18 healthy volunteers. When a single 300-mg dose of posaconazole in tablet form (3 tablets × 100 mg) was administered with a high-fat meal, the posaconazole area under the concentration-time curve from 0 to 72 h (AUC0-72) and maximum concentration in plasma (Cmax) increased 51% and 16%, respectively, compared to those after administration in the fasted state. The median time to Cmax (Tmax) shifted from 5 h in the fasted state to 6 h under fed conditions. No serious adverse events were reported, and no subject discontinued the study due to an adverse event. Six of the 18 subjects reported at least one clinical adverse event; all of these events were mild and short lasting. The results of this study demonstrate that a high-fat meal only modestly increases the mean posaconazole exposure (AUC), ∼1.5-fold, after administration of posaconazole tablets, in contrast to the 4-fold increase in AUC observed previously for a posaconazole oral suspension given with a high-fat meal.

  6. Desmopressin orally disintegrating tablet in Japanese patients with central diabetes insipidus: a retrospective study of switching from intranasal desmopressin.

    PubMed

    Murakami, Takaaki; Hatoko, Tomonobu; Nambu, Takuo; Matsuda, Yuki; Matsuo, Koji; Yonemitsu, Shin; Muro, Seiji; Oki, Shogo

    2014-01-01

    Central diabetes insipidus (CDI) is a rare disease characterized by polyuria and polydipsia. Patients with CDI have been successfully treated with desmopressin administered either by intranasal instillation or oral tablets. Recently, a desmopressin orally disintegrating tablet (ODT) was approved as the first oral desmopressin tablet for CDI treatment in Japan. We conducted a retrospective single-center study of 15 Japanese CDI patients treated with desmopressin ODT therapy, which aimed to evaluate the efficacy and safety of switching to desmopressin ODT and to analyze the clinical factors that affect the desmopressin ODT dose in Japanese patients. The daily mean dose of desmopressin ODT was 104 ± 46.30 μg and the mean ratio of oral to nasal desmopressin dose was 17.0 ± 7.6, both of which are considerably smaller than those of previous dose-titration study. Moreover, the nasal spray group needed significantly smaller ratios of nasal to oral desmopressin than the nasal drop group (11.7 ± 6.5 vs 21.0 ± 5.5, p = 0.02). The ratio of oral to nasal desmopressin dose had a significant inverse correlation with the required nasal desmopressin dose. Multiple regression analysis demonstrated the ratios of nasal to oral desmopressin dose depended on intranasal formulations. In conclusion, desmopressin ODT was safe and effective in the treatment of Japanese adult CDI patients. When switching to ODT, we should care about the possibility that patients require smaller ODT doses than what was initially expected based on previously published data and also nasal formulations in terms of their differences of expected switching ratio.

  7. Development of Oral Flexible Tablet (OFT) Formulation for Pediatric and Geriatric Patients: a Novel Age-Appropriate Formulation Platform.

    PubMed

    Chandrasekaran, Prabagaran; Kandasamy, Ruckmani

    2016-12-05

    Development of palatable formulations for pediatric and geriatric patients involves various challenges. However, an innovative development with beneficial characteristics of marketed formulations in a single formulation platform was attempted. The goal of this research was to develop solid oral flexible tablets (OFTs) as a platform for pediatrics and geriatrics as oral delivery is the most convenient and widely used mode of drug administration. For this purpose, a flexible tablet formulation using cetirizine hydrochloride as model stability labile class 1 and 3 drug as per the Biopharmaceutical Classification System was developed. Betadex, Eudragit E100, and polacrilex resin were evaluated as taste masking agents. Development work focused on excipient selection, formulation processing, characterization methods, stability, and palatability testing. Formulation with a cetirizine-to-polacrilex ratio of 1:2 to 1:3 showed robust physical strength with friability of 0.1% (w/w), rapid in vitro dispersion within 30 s in 2-6 ml of water, and 0.2% of total organic and elemental impurities. Polacrilex resin formulation shows immediate drug release within 30 min in gastric media, better taste masking, and acceptable stability. Hence, it is concluded that ion exchange resins can be appropriately used to develop taste-masked, rapidly dispersible, and stable tablet formulations with tailored drug release suitable for pediatrics and geriatrics. Flexible formulations can be consumed as swallowable, orally disintegrating, chewable, and as dispersible tablets. Flexibility in dose administration would improve compliance in pediatrics and geriatrics. This drug development approach using ion exchange resins can be a platform for formulating solid oral flexible drug products with low to medium doses.

  8. Influence of non-water-soluble placebo pellets of different sizes on the characteristics of orally disintegrating tablets manufactured by freeze-drying.

    PubMed

    Stange, Ulrike; Führling, Christian; Gieseler, Henning

    2013-06-01

    The present study describes the development of an orally disintegrating tablet containing a non-water-soluble drug delivery system. A model system was applied to evaluate the effect of different-sized particles on tablet characteristics. Cellets were incorporated into tablets prepared by freeze-drying from a 100 mg/mL mannitol or sucrose solution. Particle size distributions were 200-355 µm for Cellets 200 (C200) and 500-710 µm for Cellets 500 (C500). An examination of the tablets revealed that the particles could not be sufficiently embedded in mannitol because of its crystalline nature. The tablet hardness was also inadequate. In contrast, the hardness of sucrose tablets was increased by the addition of Cellets 500. Therefore, the sucrose-based formulation was studied further. Binders [hydroxyethylstarch, sodium alginate, methylcellulose (MC), and gelatin] were added in different concentrations, and tablets were made either with or without placebo pellets. A positive effect of the Cellets on the hardness of tablets was identified. Furthermore, disintegration time could be clearly reduced by Cellets for tablets made from 100 mg/mL sucrose with addition of 10 mg/mL MC, 20 or 40 mg/mL gelatin. The freeze-dried tablet index revealed that the formulations of sucrose with 50 mg/mL hydroxyethylstarch or 20 mg/mL gelatin were particularly advantageous.

  9. Combination effect of physical and gustatory taste masking for propiverine hydrochloride orally disintegrating tablets on palatability.

    PubMed

    Matsui, Rakan; Uchida, Shinya; Namiki, Noriyuki

    2015-01-01

    Orally disintegrating tablets (ODTs) containing propiverine hydrochloride (which is extremely bitter and leaves a feeling of numbness in the mouth) were prepared with a combined use of physical and organoleptic taste masking. Propiverine-loaded masking particles (PLMPs) were prepared with different amounts of gastric-soluble coatings as physical masking. ODTs without organoleptic masking were prepared by mixing each group of PLMPs with Ludiflash®, crospovidone, and magnesium stearate. ODTs with organoleptic masking were also prepared by addition of L-menthol, aspartame, thaumatin, and cinnamon. Fifteen-minute dissolution of propiverine in solutions with pH 1.2 was ≥ 85% for all ODTs, whereas that in pH 6.8 solutions was ≤ 85% and increased with physical masking. A single blind randomized crossover trial was conducted. Ten healthy volunteers were asked to quantify the bitterness, numbness, and overall palatability using a 100-mm visual analog scale (VAS) at the period of disintegration as well as 1 and 5 min later. VAS scores of bitterness, numbness, and overall palatability improved along with increasing amounts of physical masking, and the effects persisted for 5 min. VAS scores for numbness increased over time regardless of the amount of physical masking. Bitterness, numbness, and overall palatability were significantly improved by organoleptic masking if the amount of physical masking was small. Combined use of physical and organoleptic masking is useful for improving palatability of ODTs containing propiverine.

  10. Utilization of posaconazole oral suspension or delayed-released tablet salvage treatment for invasive fungal infection.

    PubMed

    Kim, Jong Hun; Benefield, Russell J; Ditolla, Kali

    2016-11-01

    Posaconazole may be useful for salvage treatment (ST) for invasive fungal infections (IFIs). The aim of this study was to evaluate the efficacy of posaconazole ST with either posaconazole oral suspension (SUS) or delayed-released tablet (TAB) in patients with IFI. A retrospective review of patients who received posaconazole ST for IFI at the University of Utah Health Sciences Center between December 2007 and March 2014 was conducted. A total of 14 episodes of posaconazole ST for proven (9 episodes) and probable (5 episodes) IFI were identified in 14 patients. The median age was 54 years and the majority of patients (64.3%) had underlying haematological diseases. Posaconazole SUS and TAB were used in 11 episodes and 3 episodes respectively. The duration of posaconazole ST ranged from 28 to 370 days with a median of 65 days. Posaconazole ST with TAB achieved favourable serum posaconazole trough concentrations (median 1.4 μg mL(-1) ) compared to posaconazole SUS (median 1.0 μg mL(-1) ). The overall clinical success rate with posaconazole ST was 71.4% (10 of 14 episodes). One patient died of progression of IFI. Adverse events were noted in two patients. Posaconazole SUS or TAB may be used effectively for IFI ST.

  11. Orally disintegrating vardenafil tablets for the treatment of erectile dysfunction: efficacy, safety, and patient acceptability

    PubMed Central

    Green, Roger; Hicks, Rodney W

    2011-01-01

    Background: Erectile dysfunction (ED) is a well-documented medical condition that is expected to increase significantly over the next several decades, especially as men live longer and the prevalence of diabetes and cardiovascular diseases increase. Pharmacology agents are often the first line treatment approach. Newer solid dosage forms, known as orally disintegrating tablets (ODT), are now available as one treatment option. Objectives: To review the drug delivery mechanisms of ODTs in general and to review safety and efficacy of vardenafil ODT (a PDE-5 inhibitor) as a treatment option for management of ED. Method: Literature reviews were performed of pharmaceutical dosage forms and the POTENT I (n = 358 subjects) and POTENT II (n = 337 subjects) studies that investigated vardenafil ODT. Results: Vardenafil ODT has been successfully used in multiple age groups and in multiple settings with men from various ethnic backgrounds. Efficacy of vardenafil ODT, as measured using the International Index of Erectile Function (IIEF-EF) and from the Sexual Encounter Profile (SEP) was significantly greater than placebo (P < 0.0001) at 12 weeks. Safety profiles were similar to film-coated dosage forms with no patient deaths reported. Conclusion: Vardenafil ODT offers a convenient, ready-to-use approach for combating ED. Safety concerns are similar to other PDE-5 inhibitors and practitioners should counsel patients accordingly. PMID:21573049

  12. The MERITO Study: a multicentre trial of the analgesic effect and tolerability of normal-release oral morphine during 'titration phase' in patients with cancer pain.

    PubMed

    De Conno, F; Ripamonti, C; Fagnoni, E; Brunelli, C; Luzzani, M; Maltoni, M; Arcuri, E; Bertetto, O

    2008-04-01

    Adequate and rapid pain control is one of the main goals of cancer pain treatment. The objective of this study was to assess the effect and tolerability of oral normal-release morphine during the initial phase of treatment in patients with moderate-to-severe cancer pain. Consecutive patients naïve to strong opioids received normal-release morphine 5 or 10 mg every 4 h during the titration phase (first 5 days), depending on previous analgesic therapy. Pain intensity was assessed using an 11-point Numerical Rating Scale (0-10), and data were recorded in a patient-compiled diary. The primary endpoint was the proportion of time with pain control (a reduction of at least 50% with respect to the baseline pain score) during the titration phase. A total of 159 consecutive patients (102 men; mean age 65 years) with cancer-related pain were enrolled. Pain control was observed for 75% (95% CI 70-80) of the follow-up period in the intent-to-treat population. Overall, 50% and 75% of patients achieved pain control within 8 and 24 h after starting normal-release morphine therapy respectively. The mean pain score was 7.63 points at baseline, and decreased to 2.43 and 1.67 points (both P<0.001) at days 3 and 5 respectively. The most commonly reported adverse events were somnolence (24% of patients), constipation (22%), vomiting (13%), nausea (10%) and confusion (7%). Normal-release morphine results in rapid and satisfactory pain control, and is well tolerated, during the strong-opioid titration phase in patients with moderate-to-severe cancer pain.

  13. High-Amylose Sodium Carboxymethyl Starch Matrices: Development and Characterization of Tramadol Hydrochloride Sustained-Release Tablets for Oral Administration

    PubMed Central

    Nabais, Teresa; Leclair, Grégoire

    2014-01-01

    Substituted amylose (SA) polymers were produced from high-amylose corn starch by etherification of its hydroxyl groups with chloroacetate. Amorphous high-amylose sodium carboxymethyl starch (HASCA), the resulting SA polymer, was spray-dried to obtain an excipient (SD HASCA) with optimal binding and sustained-release (SR) properties. Tablets containing different percentages of SD HASCA and tramadol hydrochloride were produced by direct compression and evaluated for dissolution. Once-daily and twice-daily SD HASCA tablets containing two common dosages of tramadol hydrochloride (100 mg and 200 mg), a freely water-soluble drug, were successfully developed. These SR formulations presented high crushing forces, which facilitate further tablet processing and handling. When exposed to both a pH gradient simulating the pH variations through the gastrointestinal tract and a 40% ethanol medium, a very rigid gel formed progressively at the surface of the tablets providing controlled drug-release properties. These properties indicated that SD HASCA was a promising and robust excipient for oral, sustained drug-release, which may possibly minimize the likelihood of dose dumping and consequent adverse effects, even in the case of coadministration with alcohol. PMID:25006518

  14. Influence of Prosolv and Prosolv:Mannitol 200 direct compression fillers on the physicomechanical properties of atorvastatin oral dispersible tablets.

    PubMed

    Gowda, Veeran; Pabari, Ritesh M; Kelly, John G; Ramtoola, Zebunnissa

    2015-06-01

    The objective of the present study was to evaluate the influence of Prosolv® and Prosolv®: Mannitol 200 direct compression (DC) fillers on the physicomechanical characteristics of oral dispersible tablets (ODTs) of crystalline atorvastatin calcium. ODTs were formulated by DC and were analyzed for weight uniformity, hardness, friability, drug content, disintegration and dissolution. Three disintegration time (DT) test methods; European Pharmacopoeia (EP) method for conventional tablets (Method 1), a modification of this method (Method 2) and the EP method for oral lyophilisates (Method 3) were compared as part of this study. All ODTs showed low weight variation of <2.5%. Prosolv® only ODTs showed the highest tablet hardness of ∼ 73 N, hardness decreased with increasing mannitol content. Friability of all formulations was <1% although friability of Prosolv®:Mannitol ODTs was higher than for pure Prosolv®. DT of all ODTs was <30 s. Method 2 showed the fastest DT. Method 3 was non-discriminatory giving a DT of 13-15 s for all formulations. Atorvastatin dissolution from all ODTs was >60% within 5 min despite the drug being crystalline. Prosolv® and Prosolv®:Mannitol-based ODTs are suitable for ODT formulations by DC to give ODTs with high mechanical strength, rapid disintegration and dissolution.

  15. Enhancement of the Oral Bioavailability of Fexofenadine Hydrochloride via Cremophor® El-Based Liquisolid Tablets

    PubMed Central

    Yehia, Soad Ali; El-Ridi, Mohamed Shafik; Tadros, Mina Ibrahim; El-Sherif, Nolwa Gamal

    2015-01-01

    Purpose: The current work aimed to develop promising Fexofenadine hydrochloride (FXD) liquisolid tablets able to increase its oral bioavailability and shorten time to reach maximum plasma concentrations (Tmax). Methods: Eighteen liquisolid powders were developed based on 3 variables; (i) vehicle type [Propylene glycol (PG) or Cremophor® EL (CR)], (ii) carrier [Avicel® PH102] to coat [Aerosil® 200] ratio (15, 20, 25) and (iii) FXD concentration in vehicle (30, 35, 40 %, w/w). Pre-compression studies involved identification of physicochemical interactions and FXD crystallinity (FT-IR, DSC, XRD), topographic visualization (SEM) and estimation of flow properties (angle of repose, Carr’s index, Hausner’s ratio). CR-based liquisolid powders were compressed as liquisolid tablets (LST 9 – 18) and evaluated for weight-variation, drug-content, friability-percentage, disintegration-time and drug-release. The pharmacokinetics of LST-18 was evaluated in healthy volunteers relative to Allegra® tablets. Results: Pre-compression studies confirmed FXD dispersion in vehicles, conversion to amorphous form and formation of liquisolid powders. CR-based liquisolid powders showed acceptable-to-good flow properties suitable for compaction. CR-based LSTs had appropriate physicochemical properties and short disintegration times. Release profile of LST-18 showed a complete drug release within 5 min. Conclusion: LST-18 succeeded in increasing oral FXD bioavailability by 62% and reducing Tmax to 2.16 h. PMID:26819931

  16. Day-to-day variations during clinical drug monitoring of morphine, morphine-3-glucuronide and morphine-6-glucuronide serum concentrations in cancer patients. A prospective observational study

    PubMed Central

    Klepstad, Pål; Hilton, Priscilla; Moen, Jorunn; Kaasa, Stein; Borchgrevink, Petter C; Zahlsen, Kolbjørn; Dale, Ola

    2004-01-01

    Background The feasibility of drug monitoring of serum concentrations of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) during chronic morphine therapy is not established. One important factor relevant to drug monitoring is to what extent morphine, M6G and M3G serum concentrations fluctuate during stable morphine treatment. Methods We included twenty-nine patients admitted to a palliative care unit receiving oral morphine (n = 19) or continuous subcutaneous (sc) morphine infusions (n = 10). Serum concentrations of morphine, M6G and M3G were obtained at the same time on four consecutive days. If readmitted, the patients were followed for another trial period. Day-to-day variations in serum concentrations and ratios were determined by estimating the percent coefficient of variation (CV = (mean/SD) ×100). Results The patients' median morphine doses were 90 (range; 20–1460) mg/24 h and 135 (range; 30–440) mg/24 h during oral and sc administration, respectively. Intraindividual fluctuations of serum concentrations estimated by median coefficients of day-to-day variation were in the oral group for morphine 46%, for M6G 25% and for M3G 18%. The median coefficients of variation were lower in patients receiving continuous sc morphine infusions (morphine 10%, M6G 13%, M3G 9%). Conclusion These findings indicate that serum concentrations of morphine and morphine metabolites fluctuate. The fluctuations found in our study are not explained by changes in morphine doses, administration of other drugs or by time for collection of blood samples. As expected the day-to-day variation was lower in patients receiving continuous sc morphine infusions compared with patients receiving oral morphine. PMID:15461818

  17. [Effect of xuebijing oral effervescent tablet on endotoxin induced fever and disseminated intravascular coagulation rabbit model].

    PubMed

    Guo, Shan-Shan; Gao, Ying-Jie; Tian, Xue-Chuan; Jin, Ya-Hong; Liu, Fang-Zhou; Cui, Xiao-Lan

    2013-08-01

    In order to discover the mechanism of Xuebijing oral effervescent tablet (XBJOET) to treat infectious diseases, the effect of XBJOET on endotoxin induced rabbit fever and disseminated intravascular coagulation (DIC) was investigated. Auricle microcirculation in rabbit was detected by laser speckle blood perfusion imager system; coagulation function was measured by coagulation analyzer, fibrinolytic system was quantified by Elisa assay and micro thrombosis in tissues was observed with HE staining under light microscope. The results demonstrated that the body temperature of rabbit decreased significantly at 1-3 h after administration with 4.8, 2.4 and 1.2 g x kg(-1) XBJOET to endotoxin induced DIC rabbit model, the auricle microcirculation blood flow in model group (54.45 +/- 14.53) PU was lower than that in control group (77.18 +/- 12.32) PU. The auricle microcirculation blood flow increased markedly and there was significant difference between model group and 1.2 g x kg(-1) XBJOET group. There was significant difference between model group and control group in the content of PAI1 and FIB. The PAI1 levels in model and control groups were (30.48 +/- 2.46) ng x mL(-1) and (20.93 +/- 3.25) ng x mL(-1), respectively. The FIB levels in model and control group were (3.34 +/- 1.09) g x L(-1) and (4.84 +/- 1.10) g x L(-1), respectively. The content of PAI1 in rabbit plasma decreased notably, there were significant differences between model group and 4.8, 2.4 g x kg(-1) XBJOET groups. On the contrary the content of FIB increased. XBJOET possessed pharmacological activities of curing infectious fever and DIC, the mechanism of which is related to amelioration of microcirculation disturbance, inhibition of fibrinolytic system activation and coagulation and micro thrombosis elimination.

  18. Pharmacokinetics and pharmacodynamics of an orally disintegrating tablet formulation of dexlansoprazole

    PubMed Central

    Kukulka, Michael; Nudurupati, Sai; Perez, Maria Claudia

    2016-01-01

    Background: The pharmacokinetics and pharmacodynamics of a novel orally disintegrating tablet (ODT) formulation of delayed-release dexlansoprazole 30 mg was evaluated versus the dexlansoprazole 30 mg capsule in this phase I, open-label, multiple-dose, randomized, two-period crossover study. Methods: Healthy adults received daily doses of 30 mg dexlansoprazole ODT or 30 mg dexlansoprazole delayed-release capsule for 5 days during two treatment periods, separated by a 7-day washout interval. Blood samples for dexlansoprazole plasma concentrations and intragastric pH measurements were collected through 24 hours postdose on days 1 and 5 of each period. Results: Bioequivalence between the 30 mg ODT and 30 mg capsule dosage forms was demonstrated by the primary endpoints of dexlansoprazole peak concentration (Cmax) and systemic exposure (AUC) values contained within the prespecified 90% confidence interval (CI) range of 0.80–1.25. Additional primary endpoints of intragastric mean pH values and percentage of time with pH > 4 over the 24-hour postdose interval were equivalent for dexlansoprazole ODT and dexlansoprazole capsule. Treatment-emergent adverse events were reported in 23% and 28% of participants receiving the ODT and capsule formulations, respectively. Headache was the most common adverse event in both treatment regimens (5.8% with ODT and 6.0% with capsule). Conclusions: Administration of dexlansoprazole 30 mg ODT or 30 mg capsule provided equivalent plasma exposure when either was administered as a single dose or as once daily doses for 5 days. Pharmacodynamic equivalence between the two formulations was demonstrated by similar intragastric pH parameters on both day 1 and day 5. No effect of day on dexlansoprazole pharmacokinetics was observed. Dexlansoprazole ODT and dexlansoprazole capsule were both well tolerated. PMID:27803731

  19. The effect of sucralfate tablets vs. suspension on oral doxycycline absorption in dogs.

    PubMed

    KuKanich, K; KuKanich, B

    2015-04-01

    The purpose of this study was to determine the effect of concurrent sucralfate (tablet or suspension) on doxycycline pharmacokinetics and to determine the effects of delaying sucralfate by 2 h on doxycycline absorption. Five dogs were included in a crossover study receiving: doxycycline alone; doxycycline concurrently with sucralfate tablet; doxycycline followed 2 h by sucralfate tablet; doxycycline concurrently with sucralfate suspension; and doxycycline followed 2 h by sucralfate suspension. Doxycycline plasma concentrations were evaluated with liquid chromatography with mass spectrometry. No interaction was seen when sucralfate was administered as a tablet. Sucralfate tablet fragments were frequently observed in some dogs' feces. The area under the curve (AUC) and maximum plasma concentration (CMAX ) were significantly lower (P < 0.001) in the concurrent sucralfate suspension group (AUC 7.2 h·μg/mL, CMAX 0.43 μg/mL) than with doxycycline alone (AUC 36.0 h·μg/mL, CMAX 2.53 μg/mL) resulting in a relative bioavailability of 20%. Delaying sucralfate suspension by 2 h after doxycycline administration resulted in no difference in doxycycline absorption as compared with doxycycline administration alone with a relative bioavailability of 74%. The lack of an interaction with sucralfate tablets suggests sucralfate should be administered as a suspension rather than tablet in dogs.

  20. Preparation of Orally Disintegrating Tablets Containing Powdered Tea Leaves with Enriched Levels of Bioactive Compounds by Means of Microwave Irradiation Technique.

    PubMed

    Tanaka, Hironori; Iwao, Yasunori; Izumikawa, Masahiro; Sano, Syusuke; Ishida, Hitoshi; Noguchi, Shuji; Itai, Shigeru

    2016-01-01

    In the present study, a microwave treatment process has been applied to prepare orally disintegrating tablets (ODTs) containing powdered tea leaves with enriched levels of the anti-inflammatory compounds such as chafuroside A (CFA) and chafuroside B (CFB). The use of distilled water as the adsorbed and granulation solvents in this preparation process afforded tablets with a long disintegration time (more than 120 s). The CFA and CFB contents of these tablets did not also change after 4 min of microwave irradiation due to the tablet temperature, which only increased to 100°C. In contrast, the tablet temperature increased up to 140°C after 3 min of microwave irradiation when a 1.68 M Na2HPO4 solution instead of distilled water. Notably, the disintegration time of these tablets was considerably improved (less than 20 s) compared with the microwave-untreated tablets, and there were 7- and 11-fold increases in their CFA and CFB contents. In addition, the operational conditions for the preparation of the tablets were optimized by face-centered composite design based on the following criteria: tablet hardness greater than 13 N, disintegration time less than 30 s and friability less than 0.5%. The requirements translated into X1 (the amount of granulation solvent), X2 (tableting pressure) and X3 (content of the powdered tea leaves) values of 45%, 0.43 kN and 32%, respectively, and the ODTs containing powdered tea leaves prepared under these optimized conditions were found to show excellent tablet properties and contain enriched levels of CFA and CFB.

  1. Amoxicillin tablets for oral suspension in the treatment of acute otitis media: a new formulation with improved convenience.

    PubMed

    Dhaon, Nitin A

    2004-01-01

    Acute otitis media (AOM) is the most common cause of pediatric office visits in the United States and the most frequent bacterial infection in children. Antimicrobials are often prescribed and amoxicillin continues to be the first-line treatment for AOM. Recently, amoxicillin tablets that disperse in water to form an oral suspension have become available in the United States for the treatment of AOM. This formulation retains the efficacy, safety, and tolerability features of conventional amoxicillin formulations while providing the additional potential benefits of improved portability, patient convenience and compliance, and dosing accuracy.

  2. Formulation and Bioequivalence of Two Valsartan Tablets After a Single Oral Administration

    PubMed Central

    Zaid, Abdel Naser; Cortesi, Rita; Qaddomi, Aiman; Khammash, Saed

    2011-01-01

    The aim of this study is to assess the quality of Valzan® tablet (160 mg, valsartan immediate release test formulation) by comparing its pharmacokinetic parameters with Diovan® tablet (160 mg, valsartan reference formulation). Valzan® tablets were prepared according to a dry granulation method (roll compaction). To assess the bioequivalence of Valzan® tablets a randomized, two-way, crossover, bioequivalence study was performed in 24 healthy male volunteers. The selected volunteers were divided into two groups of 12 subjects. One group was treated with the reference formulation (Diovan®) and the other one with the generic Valzan®, with a cross-over after the drug washout period of 14 days. Blood samples were collected at fixed time intervals and valsartan concentrations were determined by a validated HPLC assay method. The pharmacokinetic parameters AUC0–48, AUC0–∞, Cmax, Tmax, Ke and T1/2 were determined for both the tablets and were compared statistically to evaluate the bioequivalence between the two brands of valsartan, using the statistical model recommended by the FDA. The analysis of variance (ANOVA) did not show any significant difference between the two formulations and 90% confidence intervals (CI) fell within the acceptable range for bioequivalence. Based on this statistical evaluation it was concluded that the test tablets (Valzan®) is well formulated, since it exhibits pharmacokinetic profile comparable to the reference brand Diovan®. PMID:21617777

  3. Development and Efficacy Assessment of an Enteric Coated Porous Tablet Loaded With F4 Fimbriae for Oral Vaccination of Piglets against F4+ Escherichia coli Infections.

    PubMed

    Srivastava, Atul; Gowda, D V; Madhunapantula, SubbaRao V; Siddaramaiah

    2016-01-01

    Enterotoxigenic Escherichia coli (ETEC) infection is one of the major causes contributing to the development of diarrhoea and mortality in new born, suckling and newly weaned piglets. To date, no preventive/treatment strategy showed promising results, which could be due to the lack of potent vaccines, and/or due to the development of resistance of ETEC to antibiotics. Therefore, in the present investigation, a novel porous sodium alginate (SA) tablet formulation loaded with F4 fimbriae antigen was developed and tested for efficacy against ETEC infections in piglet models. Precompression parameters of the powder mixes and post compression parameters of tablets have been evaluated and results were found to be satisfactory. Loading of F4 fimbrial antigens into the tablets was achieved by inducing pores in the tablets via the sublimation of camphor followed by incubation with purified F4 fimbriae. The loaded tablets have been coated with Eudragit L100 to protect the F4 fimbriae from (a) highly acidic gastric environment; (b) proteolytic cleavage by pepsin; and (c) to promote subsequent release in the intestine. Evaluation of developed F4 fimbrial tablets in a Pig model demonstrated induction of mucosal immunity, and a significant reduction of F4+ E. coli in faeces. Therefore, F4 fimbriae loaded porous tablets could be a novel oral vaccination candidate to induce mucosal and systemic immunity against ETEC infections.

  4. Differential pharmacokinetics and the brain distribution of morphine and ephedrine constitutional isomers in rats after oral administration with Keke capsule using rapid-resolution LC-MS/MS.

    PubMed

    Song, Yonggui; Su, Dan; Lu, Tulin; Mao, Chunqin; Ji, De; Liu, Yali; Wei, Binbin; Fan, Ronghua

    2014-02-01

    Opioid and ephedra alkaloids known as the active ingredients for Keke capsule, which is used to treat coughs and bronchial asthma, could have potential adverse effects on the central nervous system. Therefore, an efficient, sensitive rapid-resolution LC-MS/MS method for the simultaneous determination of morphine, ephedrine, and pseudoephedrine in rat plasma and brain tissue homogenate has been developed. The method was validated in the plasma and brain tissue samples, showed good linearity over a wide concentration range (r(2) > 0.99). The intra- and interday assay variability was less than 15% for all analytes, and the accuracy was between -8.8 and 5.7%. The study provided the pharmacokinetics profiles and the brain regional distribution of the three active alkaloids after oral administration of Keke capsule. The results also indicated that significant difference in pharmacokinetics parameters of the epimers was observed between ephedrine and pseudoephedrine.

  5. Development and characterisation of sustained release solid dispersion oral tablets containing the poorly water soluble drug disulfiram.

    PubMed

    Shergill, Mandip; Patel, Mina; Khan, Siraj; Bashir, Ayesha; McConville, Christopher

    2016-01-30

    Administration of drugs via the oral route is the most common and preferred route due to its ease of administration, cost-effectiveness and flexibility in design. However, if the drug being administered has limited aqueous solubility it can result in poor bioavailability. Furthermore, the low pH of the stomach as well as enzymatic activity can result in drugs delivered via the oral route being rapidly metabolised and degraded. Here we demonstrate the development and characterisation of sustained release solid dispersion oral tablets, containing the poorly water-soluble drug disulfiram (DSF). The tablets, which are manufactured from two different polymers (Kolliphor(®) P 188 and P 237) specifically designed for the manufacture of solid dispersions and two different polymers (Kollidon(®) SR and HPMC) specifically designed to provide sustained release, can enhance the solubility of DSF, sustain its release, while protecting it from degradation in simulated gastric fluid (SGF). The paper demonstrates that when using the hot melt method at 80°C the DSF loading capacity of the Kolliphor(®) P 188 and P 237 polymers is approximately 43 and 46% respectively, with the DSF completely in an amorphous state. The addition of 80% Kollidon(®) SR to the formulation completely protected the DSF in SGF for up to 70 min with 16% degradation after 120 min, while 75% degradation occurred after 120 min with the addition of 80% HPMC. The release rate of DSF can be manipulated by both the loading and type of sustained release polymer used, with HPMC providing for a much faster release rate compared to Kollidon(®) SR.

  6. Optimization of acyclovir oral tablets based on gastroretention technology: factorial design analysis and physicochemical characterization studies.

    PubMed

    El Gamal, Safaa S; Naggar, Viviane F; Allam, Ahmed N

    2011-07-01

    The purpose of this research was to prepare a floating drug delivery system of acyclovir. Floating matrix tablets of acyclovir were developed to prolong gastric residence time and increase its bioavailability. The tablets were prepared by direct compression technique, using polymers such as hydroxypropylmethylcellulose 4000, Compritol 888. Sodium bicarbonate was used as a gas-generating agent. A 3² factorial design using the Design Expert Software (version 7.1.6) was applied to optimize the drug release profile systematically. The amounts of hydroxypropylmethylcellulose 4000 (X₁) and Compritol 888 (X₂) were selected as independent variables and the percentage drug released in 1 (Q₁), 6 (Q₆), and 12 (Q₁₂) h as dependent variables. The results of factorial design indicated that a high level of both hydroxypropylmethylcellulose 4000 (X₁) and Compritol 888 (X₂) favors the preparation of floating controlled-release of acyclovir tablets. Also, a good correlation was observed between predicted and actual values of the dependent variables chosen for the study. By fitting the data into zero-order, first-order, and Higuchi models, we concluded that the release followed Higuchi diffusion kinetics. Storage of the prepared formulations at 40°C/75% relative humidity for 3 months showed no significant change in drug release profiles and buoyancy of the floating tablets. We can conclude that a combination of hydroxypropylmethylcellulose 4000, Compritol 888, and sodium bicarbonate can be used to increase the gastric residence time of the dosage form up to 12 h. These floating tablets seem to be a promising gastroretentive drug delivery system.

  7. Development and optimization of a meloxicam/β-cyclodextrin complex for orally disintegrating tablet using statistical analysis.

    PubMed

    Ainurofiq, Ahmad; Choiri, Syaiful

    2016-12-08

    The purpose of this research was to develop an inclusion complex of meloxicam (MEL)/β-cyclodextrin (β-CD) incorporated into an orally disintegrating tablet (ODT), using statistical analysis to optimize the ODT formulation based on a quality by design (QbD) approach. MEL/β-CD complexation was performed by kneading, co-precipitation and spray drying methods under different molar ratios. Fourier transform infrared spectroscopy, X-ray diffraction and thermal analysis were utilized to evaluate the complexes. A central composite design (α = 2) was applied to optimize and assess the influence of Primojel, Primellose and crushing strength (CS) as independent variables on tablet friability, disintegration behavior, wicking properties and drug release. The spray drying method induced formation of an amorphous complex and enhanced solubility and drug release of MEL. Furthermore, a QbD-based statistical analysis was successfully utilized to optimize the ODT formulation. Primojel, Primellose and CS showed unique main effects and interactions at different levels. CS was the dominant factor, affecting friability, disintegration behavior and drug release, while wicking properties were affected by Primojel and its interaction with Primellose. Therefore, according to the overlay plot, CS was dominant factor in determining the optimum region based on a QbD approach.

  8. Formulation and evaluation of a montelukast sodium orally disintegrating tablet with a similar dissolution profile as the marketed product.

    PubMed

    Chen, Yong; Feng, Tingting; Li, Yong; Du, Bin; Weng, Weiyu

    2017-03-01

    A major challenge of orally disintegrating tablet (ODT) development is predicting its bioequivalence to its corresponding marketed product. Therefore, comparing ODT dissolution profiles to those of the corresponding marketed product is very important. The objective of this study was to develop a 5.2-mg montelukast sodium (MS) ODT with a similar dissolution profile to that of the marketed chewable tablet. Dissolution profiles were examined in different media to screen each formulation. We found that MS dissolution from ODTs in acidic medium heavily depended on manufacturing methods. All MS ODTs prepared using direct compression rapidly disintegrated in acidic medium. However, dispersed MS powders aggregated into sticky masses, resulting in slow dissolution. In contrast, MS ODTs prepared using wet granulation had much faster dissolution rates in acidic medium with no obvious aggregation. Additionally, the optimized formulation, prepared using wet granulation, displayed similar dissolution profiles to the marketed reference in all four types of media examined (f2 > 50). The in vitro disintegration time of the optimized ODT was 9.5 ± 2.4 s, which meets FDA requirements. In conclusion, the wet granulation preparation method of MS ODTs resulted in a product with equivalent dissolution profiles as those of the marketed product.

  9. Enteric-coated tablet of risedronate sodium in combination with phytic acid, a natural chelating agent, for improved oral bioavailability.

    PubMed

    Kim, Jeong S; Jang, Sun W; Son, Miwon; Kim, Byoung M; Kang, Myung J

    2016-01-20

    The oral bioavailability (BA) of risedronate sodium (RS), an antiresorptive agent, is less than 1% due to its low membrane permeability as well as the formation of non-absorbable complexes with multivalent cations such as calcium ion (Ca(2+)) in the gastrointestinal tract. In the present study, to increase oral BA of the bisphosphonate, a novel enteric-coated tablet (ECT) dosage form of RS in combination with phytic acid (IP6), a natural chelating agent recognized as safe, was formulated. The chelating behavior of IP6 against Ca(2+), including a stability constant for complex formulation was characterized using the continuous variation method. Subsequently, in vitro dissolution profile and in vivo pharmacokinetic profile of the novel ECT were evaluated comparatively with that of the marketed product (Altevia, Sanofi, US), an ECT containing ethylenediaminetetraacetic acid (EDTA) as a chelating agent, in beagle dogs. The logarithm of stability constant for Ca(2+)-IP6 complex, an equilibrium constant approximating the strength of the interaction between two chemicals to form complex, was 19.05, which was 3.9-fold (p<0.05) and 1.7-fold (p<0.05) higher than those of Ca(2+)-RS and Ca(2+)-EDTA complexes. The release profile of RS from both enteric-coated dosage forms was equivalent, regardless of the type of chelating agent. An in vivo absorption study in beagle dogs revealed that the maximum plasma concentration and area under the curve of RS after oral administration of IP6-containing ECT were approximately 7.9- (p<0.05) and 5.0-fold (p<0.05) higher than those of the marketed product at the same dose (35mg as RS). Therefore, our study demonstrates the potential usefulness of the ECT system in combination with IP6 for an oral therapy with the bisphosphonate for improved BA.

  10. Risperidone solid dispersion for orally disintegrating tablet: its formulation design and non-destructive methods of evaluation.

    PubMed

    Rahman, Ziyaur; Zidan, Ahmed S; Khan, Mansoor A

    2010-11-15

    The focus of present investigation was to assess the utility of non-destructive techniques in the evaluation of risperidone solid dispersions (SD) with methyl-β-cyclodextrin (MBCD) and subsequent incorporation of the SD into orally disintegrating tablets (ODT) for a faster release of risperidone. The SD was prepared by a solvent evaporation method and evaluated by scanning electron microscopy (SEM), Fourier transform infrared (FTIR), near infrared spectroscopy (NIR), NIR-chemical imaging (NIR-CI), powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). DSC and XRD analysis indicated that crystallinity of SD has reduced significantly. FTIR showed no interaction between risperidone and MBCD. Partial least square (PLS) was applied to the NIR data for the construction of chemometric models to determine both components of the SD. Good correlations were obtained for calibration and prediction as indicated by correlation coefficients >0.9965. The model was more accurate and less biased in predicting the MBCD than risperidone as indicated by its lower mean accuracy and mean bias values. SD-3 (risperidone:MBCD, 1:3) was incorporated into ODT tablets containing diluent (D-mannitol, FlowLac(®) 100 or galenIQ™-721) and superdisintegrant (Kollidon(®) CL-SF, Ac-Di-Sol or sodium starch glycolate). Disintegration time, T(50) and T(90) were decreased in the formulations containing mannitol and Kollidon(®) CL-SF, but increased with galenIQ™-721 and sodium starch glycolate, respectively. NIR-CI images confirmed the homogeneity of SD and ODT formulations.

  11. Bioavailability of a dexlansoprazole delayed-release orally disintegrating tablet: effects of food and mode of administration

    PubMed Central

    Kukulka, Michael; Nudurupati, Sai; Perez, Maria Claudia

    2017-01-01

    Background Dexlansoprazole is a proton pump inhibitor (PPI) approved for use in dual delayed-release capsule and orally disintegrating tablet (ODT) formulations. Aim To assess effects of food, water, and route of administration on the bioavailability of dexlansoprazole 30-mg ODT. Methods Two separate open-label, phase 1, single-dose crossover studies were conducted in healthy adults. In study 1, pharmacokinetic parameters were analyzed in participants receiving dexlansoprazole ODT in a fed or fasted state with and without water. In study 2, the bioavailability of dexlansoprazole after administration via oral syringe or nasogastric (NG) tube, or after swallowing intact with water was compared to ODT administration in the fasted state, swallowed without water. Blood samples for determining dexlansoprazole plasma concentrations and pharmacokinetic parameter estimates were collected before and after dosing. Results Equivalent values for area under the plasma concentration–time curve (AUC) were observed in the fed and fasted states, but the maximum observed plasma concentration (Cmax) was 38% lower in the fed state; therefore, bioequivalence was not achieved. A water rinse following standard ODT administration decreased dexlansoprazole bioavailability, with lower Cmax and AUC values than when ODT was administered without a water rinse. Bioequivalence was demonstrated when comparing the alternative routes of administration, including via oral syringe or NG tube with standard ODT administration. Unlike with a water rinse, bioequivalence to standard ODT administration (i.e., without water) was demonstrated when swallowing the ODT intact with water. Rates of adverse events were comparable irrespective of administration route in the fasted state (6.7%–9.3%) and were 12% higher in the fed state than in the fasted state. Conclusion The AUC from the dexlansoprazole ODT was equivalent when administered in the fed and fasted states. Equivalent systemic exposure to

  12. The effect of morbid obesity on morphine glucuronidation.

    PubMed

    Lloret-Linares, Celia; Luo, Huilong; Rouquette, Alexandra; Labat, Laurence; Poitou, Christine; Tordjman, Joan; Bouillot, Jean-Luc; Mouly, Stéphane; Scherrmann, Jean-Michel; Bergmann, Jean-François; Declèves, Xavier

    2017-04-01

    The purpose of the present work was to study the change in morphine metabolic ratio in obese subjects before and after Roux-en-Y Gastric Bypass (RYGB) and to identify clinical and/or biological factors associated with this change. The pharmacokinetics (PK) of oral morphine (30mg), morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) was performed in patients before (n=25; mean BMI=43.2 (35.4-61.9)kg/m(2)), 7-15days (n=16) and 6 months after RYGB (n=19; mean BMI=32.3 (25.4-46.0)kg/m(2)). Morphine Cmax and AUC0-inf were significantly increased and morphine Tmax significantly shortened at 6 months after RYGB compared with preoperative data, indicating an important increase in the rate and extent of morphine absorption. The morphine metabolic ratio 0-inf M3G+M6G/Morphine, decreased significantly from the preoperative to 6 months postoperative period with an average of -26% (range -74%; +21%; p=0.004), but not in the immediate post-operative period. The change in morphine metabolic ratio was associated with a change in BMI, fat mass in kg, and triglyceride levels (rho=0.5, p≤0.04). The degree of change in several markers of low-grade inflammation, or the level of liver steatosis and fibrosis before surgery, was not associated with the change in morphine metabolic ratios. Our findings indicate that RYGB-induced weight loss significantly decreases morphine metabolic ratio, arguing for an effect of morbid obesity on glucuronidation. With glucuronide exposure at 6 months similar to preoperative values, a higher morphine AUC0-inf should encourage reducing morphine dosage in patients undergoing RYGB and chronically receiving immediate-release oral morphine.

  13. The Efficacy and Safety of Miconazole Nitrate Mucoadhesive Tablets versus Itraconazole Capsules in the Treatment of Oral Candidiasis: An Open-Label, Randomized, Multicenter Trial

    PubMed Central

    Liu, Yang; Han, Ying; Lin, Mei; Wang, Wenmei; Guan, Xiaobing; Zhu, Shengrong; Zhang, Handong; Wang, Qintao; Chou, Lihong; Zhu, Xinghao; Hua, Hong

    2016-01-01

    Background Oral candidiasis (OC) is a common oral fungal infection. Recently, miconazole mucoadhesive tablets have been gaining attention for OC treatment. Despite trials in patients with human immunodeficiency virus and cancer, evidence of its application in the large-scale, general population with OC is lacking. This study aimed to evaluate the efficacy and safety of miconazole nitrate mucoadhesive tablets in comparison with itraconazole capsules for OC treatment. Methods The study was a randomized, open-label, parallel-armed, multicenter clinical trial. Totally, 343 patients diagnosed with OC, who met the inclusion criteria, were randomly assigned to either a treatment group that received miconazole nitrate mucoadhesive tablets (10 mg) once daily or a control group that received itraconazole capsules (100 mg QD) for 2 weeks, and were followed up for 2 weeks. The clinical cure, improvement of clinical symptoms/signs, mycologic cure, and safety were evaluated. Results The mucoadhesive tablets (n = 171) did not show inferiority to itraconazole (n = 172) in the treatment of OC. At the end of the 14-day treatment, the clinical cure rates were 45.29% and 41.76% in the miconazole and itraconazole groups, respectively (P = 0.3472). At the end of the 14-day follow-up, the clinical cure rates were 51.18% and 41.76% in the miconazole and itraconazole groups, respectively (P = 0.0329). Adverse events occurred in 53 subjects (33 in the miconazole group and 20 in the itraconazole group). There was no statistical difference in the safety profile between miconazole and itraconazole (P = 0.0533). Thrombocytopenic purpura, although rare, occurred in one patient in the miconazole group and was considered a drug-related, severe adverse event. Conclusion Miconazole nitrate mucoadhesive tablets may be as effective as systemic itraconazole capsule for OC treatment. Physicians should be cautious about thrombocytopenic purpura occurring as a rare and serious adverse event of miconazole

  14. Comparative Studies on the Dissolution Profiles of Oral Ibuprofen Suspension and Commercial Tablets using Biopharmaceutical Classification System Criteria

    PubMed Central

    Rivera-Leyva, J. C.; García-Flores, M.; Valladares-Méndez, A.; Orozco-Castellanos, L. M.; Martínez-Alfaro, M.

    2012-01-01

    In vitro dissolution studies for solid oral dosage forms have recently widened the scope to a variety of special dosage forms such as suspensions. For class II drugs, like Ibuprofen, it is very important to have discriminative methods for different formulations in physiological conditions of the gastrointestinal tract, which will identify different problems that compromise the drug bioavailability. In the present work, two agitation speeds have been performed in order to study ibuprofen suspension dissolution. The suspensions have been characterised relatively to particle size, density and solubility. The dissolution study was conducted using the following media: buffer pH 7.2, pH 6.8, 4.5 and 0.1 M HCl. For quantitative analysis, the UV/Vis spectrophotometry was used because this methodology had been adequately validated. The results show that 50 rpm was the adequate condition to discriminate the dissolution profile. The suspension kinetic release was found to be dependent on pH and was different compared to tablet release profile at the same experimental conditions. The ibuprofen release at pH 1.0 was the slowest. PMID:23626386

  15. Pharmaceutical development of an oral tablet formulation containing a spray dried amorphous solid dispersion of docetaxel or paclitaxel.

    PubMed

    Sawicki, Emilia; Beijnen, Jos H; Schellens, Jan H M; Nuijen, Bastiaan

    2016-09-25

    Previously, it was shown in Phase I clinical trials that solubility-limited oral absorption of docetaxel and paclitaxel can be drastically improved with a freeze dried solid dispersion (fdSD). These formulations, however, are unfavorable for further clinical research because of limitations in amorphicity of SD and scalability of the production process. To resolve this, a spray drying method for an SD (spSD) containing docetaxel or paclitaxel and subsequently drug products were developed. Highest saturation solubility (Smax), precipitation onset time (Tprecip), amorphicity, purity, residual solvents, yield/efficiency and powder flow of spSDs were studied. Drug products were monitored for purity/content and dissolution during 24 months at +15-25°C. Docetaxel spSD Smax was equal to that of fdSD but Tprecip was 3 times longer. Paclitaxel spSD Smax was 30% increased but Tprecip was equal to fdSD. spSDs were fully amorphous, >99% pure, <5% residual solvents, mean batch yield was 100g and 84%. spSDs had poor powder flow characteristics, which could not be resolved by changing settings, but by using 75% lactose as diluent. The drug product was a tablet with docetaxel or paclitaxel spSD and was stable for at least 24 months. Spray drying is feasible for the production of SD of docetaxel or paclitaxel for upcoming clinical trials.

  16. Combined Effect of Synthetic and Natural Polymers in Preparation of Cetirizine Hydrochloride Oral Disintegrating Tablets: Optimization by Central Composite Design

    PubMed Central

    2017-01-01

    Our aim was to employ experimental design to formulate and optimize cetirizine hydrochloride oral disintegrating tablets (ODTs) by direct compression technique, using the mutual effect of synthetic croscarmellose sodium (CCS) and natural Hibiscus rosa-sinensis mucilage (HRM) as disintegrants in the formulation. Central composite design (CCD) was applied to optimize the influence of three levels each of CCS (X 1) and HRM (X 2) concentrations (independent variables) for investigated responses: disintegration time (DT) (Y 1), % friability (F) (Y 2), and % cumulative drug release (DR) (Y 3) (dependent variables). This face-centered second-order model's reliability was verified by the probability and adequate precision values from the analysis of variance, while the significant factor effects influencing the studied responses were identified using multiple linear regression analysis. Perturbation and response surface plots were interpreted to evaluate the responses' sensitivity towards the variables. During optimization, the concentrations of the processed factors were evaluated, and the resulting values were in good agreement with predicted estimates endorsing the validity. Spectral study by Fourier Transform Infrared Spectroscopy (FTIR) and thermograms from Differential Scanning Calorimetry (DSC) demonstrated the drug-excipients compatibility of the optimized formulation. The optimized formulation has concentrations of 9.05 mg and 16.04 mg of CCS and HRM each, respectively, and the model predicted DT of 13.271 sec, F of 0.498, and DR of 99.768%. PMID:28154771

  17. The practical approach to the evaluation of methods used to determine the disintegration time of orally disintegrating tablets (ODTs)

    PubMed Central

    Brniak, Witold; Jachowicz, Renata; Pelka, Przemyslaw

    2015-01-01

    Even that orodispersible tablets (ODTs) have been successfully used in therapy for more than 20 years, there is still no compendial method of their disintegration time evaluation other than the pharmacopoeial disintegration test conducted in 800–900 mL of distilled water. Therefore, several alternative tests more relevant to in vivo conditions were described by different researchers. The aim of this study was to compare these methods and correlate them with in vivo results. Six series of ODTs were prepared by direct compression. Their mechanical properties and disintegration times were measured with pharmacopoeial and alternative methods and compared with the in vivo results. The highest correlation with oral disintegration time was found in the case of own-construction apparatus with additional weight and the employment of the method proposed by Narazaki et al. The correlation coefficients were 0.9994 (p < 0.001), and 0.9907 (p < 0.001) respectively. The pharmacopoeial method correlated with the in vivo data much worse (r = 0.8925, p < 0.05). These results have shown that development of novel biorelevant methods of ODT’s disintegration time determination is eligible and scientifically justified. PMID:27134547

  18. Mefenamic acid taste-masked oral disintegrating tablets with enhanced solubility via molecular interaction produced by hot melt extrusion technology

    PubMed Central

    Alshehri, Sultan M.; Park, Jun-Bom; Alsulays, Bader B.; Tiwari, Roshan V.; Almutairy, Bjad; Alshetaili, Abdullah S.; Morott, Joseph; Shah, Sejal; Kulkarni, Vijay; Majumdar, Soumyajit; Martin, Scott T.; Mishra, Sanjay; Wang, Lijia; Repka, Michael A.

    2015-01-01

    The objective of this study was to enhance the solubility as well as to mask the intensely bitter taste of the poorly soluble drug, Mefenamic acid (MA). The taste masking and solubility of the drug was improved by using Eudragit® E PO in different ratios via hot melt extrusion (HME), solid dispersion technology. Differential scanning calorimetry (DSC) studies demonstrated that MA and E PO were completely miscible up to 40% drug loads. Powder X-ray diffraction analysis indicated that MA was converted to its amorphous phase in all of the formulations. Additionally, FT-IR analysis indicated hydrogen bonding between the drug and the carrier up to 25% of drug loading. SEM images indicated aggregation of MA at over 30% of drug loading. Based on the FT-IR, SEM and dissolution results for the extrudates, two optimized formulations (20% and 25% drug loads) were selected to formulate the orally disintegrating tablets (ODTs). ODTs were successfully prepared with excellent friability and rapid disintegration time in addition to having the desired taste-masking effect. All of the extruded formulations and the ODTs were found to be physically and chemically stable over a period of 6 months at 40°C/75% RH and 12 months at 25°C/60% RH, respectively. PMID:25914727

  19. Evaluation of the palatabilities in 10 different famotidine orally disintegrating tablets by combination of disintegration device and taste sensor.

    PubMed

    Yoshida, Miyako; Hazekawa, Mai; Haraguchi, Tamami; Uchida, Takahiro

    2015-01-01

    The purpose of this study was to evaluate the palatabilities of the original and nine generic versions of famotidine orally disintegrating tablets (FODTs) by means of disintegration times and bitterness intensities determined using in combination disintegration device and taste sensor comparison of human gustatory sensation tests. The disintegration times were determined using a new disintegration testing equipment for ODTs, the OD-mate and bitterness intensities were determined using the SA501C taste-sensing system. The disintegration time and bitterness of each FODT was evaluated in gustatory sensation tests. There was a good correlation between the disintegration times of 10 FODTs estimated in human gustatory testing and those found using the OD-mate. The bitterness intensities of FODTs at 10, 20 and 30 s after starting the disintegration using the OD-mate and the values determined by the taste sensor were highly correlated with the bitterness intensities determined in gustatory sensation testing. A combination of the OD-mate and the SA501C was capable of predicting the palatabilities, disintegration properties and bitterness intensity of FODTs.

  20. Preliminary buprenorphine sublingual tablet pharmacokinetic data in plasma, oral fluid and sweat during treatment of opioid-dependent pregnant women

    PubMed Central

    Concheiro, Marta; Jones, Hendreé E.; Johnson, Rolley E.; Choo, Robin; Huestis, Marilyn A.

    2011-01-01

    Background Buprenorphine is currently under investigation as a pharmacotherapy to treat pregnant women for opioid dependence. This research evaluates buprenorphine (BUP), norbuprenophine (NBUP), buprenorphine-glucuronide (BUP-Gluc) and norbuprenorphine-glucuronide (NBUP-Gluc) pharmacokinetics after high dose (14–20 mg) BUP sublingual tablet administration in three opioid-dependent pregnant women. Methods Oral fluid and sweat specimens were collected in addition to plasma specimens for 24 h during gestation weeks 28 or 29 and 34, and 2 months after delivery. Tmax was not affected by pregnancy; however, BUP and NBUP Cmax and AUC0–24h tended to be lower during pregnancy compared to postpartum levels. Results Statistically significant but weak positive correlations were found for BUP plasma and OF concentrations, and BUP/NBUP ratios in plasma and OF. Conclusion Statistically significant negative correlations were observed for times of specimen collection and BUP and NBUP OF/plasma ratios. BUP-Gluc and NBUP-Gluc were detected in only 5% of OF specimens. In sweat, BUP and NBUP were detected in only 4 of 25 (12 or 24 h) specimens in low concentrations (<2.4 ng/patch). These preliminary data describe BUP and metabolite pharmacokinetics in pregnant women and suggest that, like methadone, upward dose adjustments may be needed with advancing gestation. PMID:21860340

  1. Enhancement of Solubility of Lamotrigine by Solid Dispersion and Development of Orally Disintegrating Tablets Using 32 Full Factorial Design

    PubMed Central

    Singh, Jatinderpal; Garg, Rajeev; Gupta, Ghanshyam Das

    2015-01-01

    Present investigation deals with the preparation and evaluation of orally disintegrating tablets (ODTs) of lamotrigine using β-cyclodextrin and PVP-K30 as polymers for the preparation of solid dispersion which help in enhancement of aqueous solubility of this BCS CLASS-II drug and sodium starch glycolate (SSG) and crospovidone as a superdisintegrating agent, to reduce disintegration time. The ODTs were prepared by direct compression method. Nine formulations were developed with different ratios of superdisintegrating agents. All the formulations were evaluated for disintegration time, weight variation, hardness, friability, drug content uniformity, wetting time, and in vitro drug release study. In vitro drug release study was performed using United States Pharmacopoeia (USP) type 2 dissolution test apparatus employing paddle stirrer at 50 rpm using 900 mL of 0.1 N HCl maintained at 37°C ± 0.5°C as the dissolution medium. On the basis of evaluation parameters formulations were prepared using β-CD 1 : 1 solid dispersion. Then 32 full factorial design was applied using SSG and crospovidone in different ratios suggested by using design expert 8.0.7.1 and optimized formulation was prepared using amount of SSG and crospovidone as suggested by the software. The optimized formulation prepared had disintegrating time of 15 s, wetting time of 24 s, and % friability of 0.55. PMID:26634173

  2. Abuse Potential with Oral Route of Administration of a Hydrocodone Extended-Release Tablet Formulated with Abuse-Deterrence Technology in Nondependent, Recreational Opioid Users

    PubMed Central

    Darwish, Mona; Ma, Yuju; Tracewell, William; Robertson, Philmore; Webster, Lynn R.

    2017-01-01

    Objective. To compare the oral abuse potential of hydrocodone extended-release (ER) tablet developed with CIMA® Abuse-Deterrence Technology with that of hydrocodone immediate release (IR). Design. Randomized, double-blind, placebo-controlled, crossover study. Setting and Patients. One study site in the United States; adult nondependent, recreational opioid users. Methods. After confirming their ability to tolerate and discriminate hydrocodone IR 45 mg from placebo, eligible participants were randomized to receive each of the following oral treatments once: finely crushed placebo, hydrocodone IR 45-mg powder, intact hydrocodone ER 45-mg tablet, and finely crushed hydrocodone ER 45-mg tablet. Primary pharmacodynamic measure was “at the moment” drug liking. Secondary measures included overall drug liking, drug effects (e.g., balance, positive, negative, sedative), pupillometry, pharmacokinetics, and safety. Results. Mean maximum effect (Emax) for “at the moment” drug liking was significantly lower for intact (53.9) and finely crushed hydrocodone ER (66.9) vs. hydrocodone IR (85.2; P < 0.001). Drug liking for intact hydrocodone ER was comparable to placebo (Emax: 53.9 vs. 53.2). Secondary measures were consistent with these results, indicating that positive, negative, and sedative drug effects were diminished with intact and crushed hydrocodone ER tablet vs. hydrocodone IR. The 72-hour plasma concentration-time profile for each treatment mimicked its respective “at the moment” drug-liking-over-time profile. Incidence of adverse events was lower with intact hydrocodone ER (53%) vs. hydrocodone IR (79%) and finely crushed hydrocodone ER (73%). Conclusions. The oral abuse potential of hydrocodone ER (intact and finely crushed) was significantly lower than hydrocodone IR in healthy, nondependent, recreational opioid users. Hydrocodone ER was generally well tolerated. PMID:27330154

  3. 21 CFR 520.2150a - Stanozolol tablets.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...) Administered orally to cats and small breeds of dogs, 1/2 to 1 tablet twice daily for several weeks; to large breeds of dogs, 1 to 2 tablets twice daily for several weeks. The tablets may be crushed and...

  4. 21 CFR 520.2150a - Stanozolol tablets.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ...) Administered orally to cats and small breeds of dogs, 1/2 to 1 tablet twice daily for several weeks; to large breeds of dogs, 1 to 2 tablets twice daily for several weeks. The tablets may be crushed and...

  5. 21 CFR 520.2150a - Stanozolol tablets.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ...) Administered orally to cats and small breeds of dogs, 1/2 to 1 tablet twice daily for several weeks; to large breeds of dogs, 1 to 2 tablets twice daily for several weeks. The tablets may be crushed and...

  6. An integrated, quality by design (QbD) approach for design, development and optimization of orally disintegrating tablet formulation of carbamazepine.

    PubMed

    Mishra, Saurabh M; Rohera, Bhagwan D

    2016-06-27

    The objective of the present study was to design and develop a formulation for orally disintegrating tablets (ODTs) of carbamazepine using quality by design principles. The target product profile (TPP) and quality target product profile (QTPP) of ODTs were identified. Risk assessment was carried out by leveraging prior knowledge and experience to define the criticality of factors based on their impact by Ishikawa fishbone diagram and preliminary hazard analysis tool. Box-Behnken response surface methodology was used to study the effect of critical factors on various attributes of ODTs. The independent factors selected were compression pressure (X1), concentration of sublimating agent (volatile material) (X2), disintegrant concentration (X3) and the responses were tablet crushing strength, tablet porosity, disintegration time, water absorption time, tablet friability and drug dissolution. ANOVA and lack of fit test illustrated that selected independent variables had significant effect on the response variables, and excellent correlation was observed between actual and predicted values. Optimization by desirability function indicated that compression pressure, X1 (1534 lbs), ammonium bicarbonate concentration, X2 (7.68%) and Kollidon(®) CL-SF concentration, X3 (6%) were optimum to prepare ODT formulation of carbamazepine of desired attributes complying with QTPP. Thus, in the present study, a high level of assurance was established for ODT product quality and performance.

  7. Mice with neuropathic pain exhibit morphine tolerance due to a decrease in the morphine concentration in the brain.

    PubMed

    Ochiai, Wataru; Kaneta, Mitsumasa; Nagae, Marina; Yuzuhara, Ami; Li, Xin; Suzuki, Haruka; Hanagata, Mika; Kitaoka, Satoshi; Suto, Wataru; Kusunoki, Yoshiki; Kon, Risako; Miyashita, Kazuhiko; Masukawa, Daiki; Ikarashi, Nobutomo; Narita, Minoru; Suzuki, Tsutomu; Sugiyama, Kiyoshi

    2016-09-20

    The chronic administration of morphine to patients with neuropathic pain results in the development of a gradual tolerance to morphine. Although the detailed mechanism of this effect has not yet been elucidated, one of the known causes is a decrease in μ-opioid receptor function with regard to the active metabolite of morphine, M-6-G(morphine-6-glucuronide), in the ventrotegmental area of the midbrain. In this study, the relationship between the concentration of morphine in the brain and its analgesic effect was examined after the administration of morphine in the presence of neuropathic pain. Morphine was orally administered to mice with neuropathic pain, and the relationship between morphine's analgesic effect and its concentration in the brain was analysed. In addition, the expression levels of the conjugation enzyme, UGT2B (uridine diphosphate glucuronosyltransferase), which has morphine as its substrate, and P-gp, which is a transporter involved in morphine excretion, were examined. In mice with neuropathic pain, the concentration of morphine in the brain was significantly decreased, and a correlation was found between this decrease and the decrease in the analgesic effect. It was considered possible that this decrease in the brain morphine concentration may be due to an increase in the expression level of P-gp in the small intestine and to an increase in the expression level and binding activity of UGT2B in the liver. The results of this study suggest the possibility that a sufficient analgesic effect may not be obtained when morphine is administered in the presence of neuropathic pain due to a decrease in the total amount of morphine and M-6-G that reach the brain.

  8. The Effects of Screw Configuration and Polymeric Carriers on Hot-Melt Extruded Taste-Masked Formulations Incorporated into Orally Disintegrating Tablets

    PubMed Central

    Morott, Joseph T.; Pimparade, Manjeet; Park, Jun-Bom; Worley, Chelsea P.; Majumdar, Soumyajit; Lian, Zhuoyang; Pinto, Elanor; Bi, Yunxia; Durig, Thomas; Repka, Michael A.

    2015-01-01

    The primary aim of this research was to produce successfully taste masked formulations of Sildenafil Citrate (SC) using hot-melt extrusion (HME) technology. Multiple screw configurations and polymeric carriers were evaluated for their effects on taste masking efficiency, which was assessed by both E-tongue analysis and in vitro dissolution in simulated salivary fluid (SSF, pH 6.8 artificial saliva). The screw configurations were further assessed for their effects on the morphology of the API using PXRD, FT-IR and mid-infrared chemical imaging. It was determined that the screw configuration had a profound effect on the taste masking efficiency of the formulations as a result of altering the physical state of the API. Selected extruded formulations using ethylcellulose (EC) with a pore former were further formulated into orally disintegrating tablets (ODTs), which were optimized by varying the grade and percentage of the superdisintegrant used. An optimized disintegration time of approximately 8 seconds was achieved. The final ODT formulation exhibited excellent taste masking properties with over 85% drug release in gastric media as well as physical tablet properties. Interestingly, friability, which tends to be a common concern when formulating ODTs, was well within the acceptable limits (<1%) for common tablets. PMID:25410968

  9. Improvement of Meloxicam Solubility Using a β-Cyclodextrin Complex Prepared via the Kneading Method and Incorporated into an Orally Disintegrating Tablet

    PubMed Central

    Ainurofiq, Ahmad; Choiri, Syaiful; Azhari, Muhamad Ali; Siagian, Chaterin Romauli; Suryadi, Bambang Budi; Prihapsara, Fea; Rohmani, Sholichah

    2016-01-01

    Purpose: The aim of this research was to formulate and develop an orally disintegrating tablet (ODT) that incorporated a MEL/β-CD complex, using a quality by design (QbD) approach to enhance solubility and drug release. Methods: Multiple regression linear analysis was conducted to develop the kneading process and ODT formulation. Mixing time and amount of solvent were used as independent variables in kneading process optimisation, while the superdisintegrants were used to obtain the desired formulation. Fourier transform infrared spectroscopy and differential scanning calorimetry were performed for complex characterization. Results: MEL/β-CD complexation was successful in enhancing MEL solubility. The results suggest that increasing the amount of solvent and mixing time enhances drug loading and drug release. However, increased solvent amounts present the problem of removing the solvent. Primojel and Polyplasdone had a significant effect on the water wicking and tablet disintegration process (p<0.05), although Polyplasdone negatively affected tablet hardness. Both an optimized KN process and ODT formulation were obtained using a QbD approach. Conclusion: Incorporation of the MEL/β-CD complex during ODT formulation using the QbD approach serves as a model for ODT product development, with optimal product performance based on the specification of quality target product profiles. To understand more specific phenomena, one point in the middle of the design for each factor should be added to more powerfully estimate this effect and avoid the lack of estimate due to an inadequate equation. PMID:27766224

  10. Tablet and oral liquid L-thyroxine formulation in the treatment of naïve hypothyroid patients with Helicobacter pylori infection.

    PubMed

    Ribichini, Danilo; Fiorini, Giulia; Repaci, Andrea; Castelli, Valentina; Gatta, Luigi; Vaira, Dino; Pasquali, Renato

    2016-11-15

    To compare the clinical efficacy of tablet and oral liquid L-thyroxine (LT4) formulation in naïve hypothyroid subjects with Helicobacter pylori infection. Forty-seven adult naïve hypothyroid subjects with dyspeptic symptoms were investigated with upper endoscopy and divided into: 28 patients with Helicobacter pylori infection (Group A); 15 patients without gastric alterations (group B); 4 patients with autoimmune gastritis were excluded from the study. Subjects were randomly treated with a same dose of LT4 tablet (TAB) or oral liquid formulation (SOL), for 9 months on group A and 6 months on group B. Helicobacter pylori infection was eradicated after 3 months of LT4 treatment. On group A, after 3 months (before Helicobacter pylori eradication), subjects treated with SOL showed a greater thyroid-stimulating hormone reduction (ΔTSH3-0: TAB = -4.1 ± 4.6 mU/L; SOL = -7.7 ± 2.5 mU/L; p = 0.029) and a greater homogeneity in the thyroid-stimulating hormone values (TSH3mo: TAB = 5.7 ± 4.9 mU/L; SOL = 4.1 ± 2.0 mU/L; p = 0.025), compared to LT4 tablet. At 9 months (after 6 months of Helicobacter pylori eradication) mean thyroid-stimulating hormone values were lower in subjects treated with LT4 tablet (TSH9mo: TAB = 1.8 ± 1.2 mU/L; SOL = 3.2 ± 1.7 mU/L; p = 0.006). On group B no difference were observed, at each time point, in the mean thyroid-stimulating hormone values and thyroid-stimulating hormone variations between two LT4 formulations. LT4 liquid formulation may produce a better clinical response compared to the tablet formulation in hypothyroid subjects with Helicobacter pylori infection.

  11. Pharmacokinetic Comparative Study of Gastrodin and Rhynchophylline after Oral Administration of Different Prescriptions of Yizhi Tablets in Rats by an HPLC-ESI/MS Method

    PubMed Central

    Ge, Zhaohui; Liang, Qionglin; Wang, Yiming; Luo, Guoan

    2014-01-01

    Pharmacokinetic characters of rhynchophylline (RIN), gastrodin (GAS), and gastrodigenin (p-hydroxybenzyl alcohol, HBA) were investigated after oral administration of different prescriptions of Yizhi: Yizhi tablets or effective parts of tianma (total saponins from Gastrodiae, EPT) and gouteng (rhynchophylla alkaloids, EPG). At different predetermined time points after administration, the concentrations of GAS, HBA, and RIN in rat plasma were determined by an HPLC-ESI/MS method, and the main pharmacokinetic parameters were investigated. The results showed that the pharmacokinetic parameters Cmax and AUC0–∞ (P < 0.05) were dramatically different after oral administration of different prescriptions of Yizhi. The data indicated that the pharmacokinetic processes of GAS, HBA, and RIN in rats would interact with each other or be affected by other components in Yizhi. The rationality of the compatibility of Uncaria and Gastrodia elata as a classic “herb pair” has been verified from the pharmacokinetic viewpoint. PMID:25610474

  12. Oral Doxycycline in the Management of Acne Vulgaris: Current Perspectives on Clinical Use and Recent Findings with a New Double-scored Small Tablet Formulation.

    PubMed

    Del Rosso, James Q

    2015-05-01

    Oral antibiotics have been used for the treatment of acne vulgaris for six decades. Among dermatologists, tetracyclines represent at least three-fourths of the oral antibiotics prescribed in clinical practice. Unlike other specialties, antibiotic use in dermatology is predominantly for the treatment of noninfectious disorders, such as acne vulgaris and rosacea, which usually involves prolonged therapy over several weeks to months as compared to short courses used to treat cutaneous infections. At the present time, doxycycline and minocycline are the most commonly prescribed tetracyclines in dermatology, used primarily for treatment of acne vulgaris with a long overall favorable track record of effectiveness and safety. Although both are commonly used, doxycycline may be chosen by clinicians more readily as there is a lower risk of rare yet potentially serious adverse reactions, although doxycycline does warrant preventative measures to reduce the risks of esophagitis and phototoxicity reactions. This article reviews data with a new double-scored small 150mg tablet of doxycycline hyclate that has proven functional scoring, exhibits bioavailability similar to enteric-coated doxycycline, and has been shown to be associated with a low potential for gastrointestinal adverse reactions very comparable to what is achieved with enteric-coated tablets.

  13. Low-dose oral immunization with lyophilized tissue of herbicide-resistant lettuce expressing hepatitis B surface antigen for prototype plant-derived vaccine tablet formulation.

    PubMed

    Pniewski, Tomasz; Kapusta, Józef; Bociąg, Piotr; Wojciechowicz, Jacek; Kostrzak, Anna; Gdula, Michał; Fedorowicz-Strońska, Olga; Wójcik, Piotr; Otta, Halina; Samardakiewicz, Sławomir; Wolko, Bogdan; Płucienniczak, Andrzej

    2011-05-01

    Efficient immunization against hepatitis B virus (HBV) and other pathogens with plant-based oral vaccines requires appropriate plant expressors and the optimization of vaccine compositions and administration protocols. Previous immunization studies were mainly based on a combination of the injection of a small surface antigen of HBV (S-HBsAg) and the feeding with raw tissue containing the antigen, supplemented with an adjuvant, and coming from plants conferring resistance to kanamycin. The objective of this study was to develop a prototype oral vaccine formula suitable for human immunization. Herbicide-resistant lettuce was engineered, stably expressing through progeny generation micrograms of S-HBsAg per g of fresh weight and formed into virus-like particles (VLPs). Lyophilized tissue containing a relatively low, 100-ng VLP-assembled antigen dose, administered only orally to mice with a long, 60-day interval between prime and boost immunizations and without exogenous adjuvant, elicited mucosal and systemic humoral anti-HBs responses at the nominally protective level. Lyophilized tissue was converted into tablets, which preserved S-HBsAg content for at least one year of room temperature storage. The results of the study provide indications on immunization methodology using a durable, efficacious, and convenient plant-derived prototype oral vaccine against hepatitis B.

  14. 21 CFR 520.1310 - Marbofloxacin tablets.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Marbofloxacin tablets. 520.1310 Section 520.1310... DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1310 Marbofloxacin tablets. (a) Specifications. Each tablet contains 25, 50, 100, or 200 milligrams (mg) marbofloxacin....

  15. 21 CFR 520.812 - Enrofloxacin tablets.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Enrofloxacin tablets. 520.812 Section 520.812 Food... DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.812 Enrofloxacin tablets. (a) Specifications. Each tablet contains either 22.7, 68.0, or 136.0 milligrams of enrofloxacin. (b) Sponsor. See...

  16. 21 CFR 520.1870 - Praziquantel tablets.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... section. (c) Conditions of use—(1) Dogs—(i) Amount. 5 pounds (lb) and under, 1/2 tablet (17 mg); 6 to 10... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Praziquantel tablets. 520.1870 Section 520.1870... DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1870 Praziquantel tablets....

  17. 21 CFR 520.1451 - Moxidectin tablets.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Moxidectin tablets. 520.1451 Section 520.1451 Food... DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1451 Moxidectin tablets. (a) Specifications. Each tablet contains 30, 68, or 136 micrograms of moxidectin. (b) Sponsor. See No. 000856...

  18. 21 CFR 520.455 - Clomipramine tablets.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Clomipramine tablets. 520.455 Section 520.455 Food... DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.455 Clomipramine tablets. (a) Specifications. Each tablet contains 5, 20, 40, or 80 milligrams (mg) clomipramine hydrochloride. (b)...

  19. 21 CFR 520.816 - Epsiprantel tablets.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Epsiprantel tablets. 520.816 Section 520.816 Food... DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.816 Epsiprantel tablets. (a) Specifications. Each tablet contains either 12.5, 25, 50, or 100 milligrams of epsiprantel. (b) Sponsor. See...

  20. 21 CFR 520.1870 - Praziquantel tablets.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... section. (c) Conditions of use—(1) Dogs—(i) Amount. 5 pounds (lb) and under, 1/2 tablet (17 mg); 6 to 10... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Praziquantel tablets. 520.1870 Section 520.1870... DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1870 Praziquantel tablets....

  1. 21 CFR 520.455 - Clomipramine tablets.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Clomipramine tablets. 520.455 Section 520.455 Food... DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.455 Clomipramine tablets. (a) Specifications. Each tablet contains 5, 20, 40, or 80 milligrams (mg) clomipramine hydrochloride. (b)...

  2. 21 CFR 520.816 - Epsiprantel tablets.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Epsiprantel tablets. 520.816 Section 520.816 Food... DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.816 Epsiprantel tablets. (a) Specifications. Each tablet contains either 12.5, 25, 50, or 100 milligrams of epsiprantel. (b) Sponsor. See...

  3. 21 CFR 520.816 - Epsiprantel tablets.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Epsiprantel tablets. 520.816 Section 520.816 Food... DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.816 Epsiprantel tablets. (a) Specifications. Each tablet contains either 12.5, 25, 50, or 100 milligrams of epsiprantel. (b) Sponsor. See...

  4. 21 CFR 520.812 - Enrofloxacin tablets.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Enrofloxacin tablets. 520.812 Section 520.812 Food... DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.812 Enrofloxacin tablets. (a) Specifications. Each tablet contains either 22.7, 68.0, or 136.0 milligrams of enrofloxacin. (b) Sponsor. See...

  5. 21 CFR 520.1310 - Marbofloxacin tablets.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Marbofloxacin tablets. 520.1310 Section 520.1310... DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1310 Marbofloxacin tablets. (a) Specifications. Each tablet contains 25, 50, 100, or 200 milligrams (mg) marbofloxacin....

  6. 21 CFR 520.455 - Clomipramine tablets.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Clomipramine tablets. 520.455 Section 520.455 Food... DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.455 Clomipramine tablets. (a) Specifications. Each tablet contains 5, 20, 40, or 80 milligrams (mg) clomipramine hydrochloride. (b)...

  7. 21 CFR 520.1310 - Marbofloxacin tablets.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Marbofloxacin tablets. 520.1310 Section 520.1310... DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1310 Marbofloxacin tablets. (a) Specifications. Each tablet contains 25, 50, 100, or 200 milligrams (mg) marbofloxacin....

  8. 21 CFR 520.455 - Clomipramine tablets.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Clomipramine tablets. 520.455 Section 520.455 Food... DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.455 Clomipramine tablets. (a) Specifications. Each tablet contains 5, 20, 40, or 80 milligrams (mg) clomipramine hydrochloride. (b)...

  9. 21 CFR 520.1870 - Praziquantel tablets.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... section. (c) Conditions of use—(1) Dogs—(i) Amount. 5 pounds (lb) and under, 1/2 tablet (17 mg); 6 to 10... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Praziquantel tablets. 520.1870 Section 520.1870... DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1870 Praziquantel tablets....

  10. Development of Extended-Release Oral Flexible Tablet (ER-OFT) Formulation for Pediatric and Geriatric Compliance: an Age-Appropriate Formulation.

    PubMed

    Chandrasekaran, Prabagaran; Kandasamy, Ruckmani

    2017-01-30

    Development of age-appropriate formulation suitable for pediatric and geriatric patients involves various challenges. The objective of this research was to develop extended-release oral flexible tablet (ER-OFT) formulation using carbamazepine (CBZ) as model drug for pediatric and geriatric compliance. ER-microparticles of carbamazepine, a BCS class 2, and narrow therapeutic index (NTI) drug, were prepared using ethyl cellulose as matrixing polymer and hypromellose as hydrophilic pore former. Microparticles were prepared using high-shear granulator fitted with an atomizing spray system. Granulation of carbamazepine and ethyl cellulose (EC-FP) with ethanolic binder solution resulted in ER-microparticles with extended-release >16 h. Release kinetics of ER microparticles showed Higuchi model by drug diffusion and erosion. Korsemeyer-peppas release exponent "n" value 0.42 suggested Fickian diffusion. ER-OFT was prepared by blending of ER-microparticles with water-insoluble compressible aid and disintegrating agent. ER-OFT was characterized for performance characteristics and elemental impurities. As the polymer content in formulation was <10%, the size of ER-OFT was smaller compared to marketed ER-formulations. ER-OFT showed in vitro disintegration time of <30 s as per USP and dispersion time of ∼60 to 180 s in 5 to 10 mL of water. Drug release profiles of ER-microparticles and ER-OFT were comparable as f2 values were >50. In vitro dissolution of ER-OFT was comparable to the marketed ER formulation in the pH range of GIT. ER-OFT can be orally swallowed, orally disintegrating, and used as dispersible tablets. Compared to non-disintegrating type ER-formulations, ER-OFT would provide uniform drug release in GIT with low within-subject variability an essential criterion for NTI drug.

  11. Postoperative intravenous morphine titration.

    PubMed

    Aubrun, F; Mazoit, J-X; Riou, B

    2012-02-01

    Relief of acute pain during the immediate postoperative period is an important task for anaesthetists. Morphine is widely used to control moderate-to-severe postoperative pain and the use of small i.v. boluses of morphine in the post-anaesthesia care unit allows a rapid titration of the dose needed for adequate pain relief. The essential principle of a titration regimen must be to adapt the morphine dose to the pain level. Although morphine would not appear to be the most appropriate choice for achieving rapid pain relief, this is the sole opioid assessed in many studies of immediate postoperative pain management using titration. More than 90% of the patients have pain relief using a protocol of morphine titration and the mean dose required to obtain pain relief is 12 (7) mg, after a median of four boluses. Sedation is frequent during i.v. morphine titration and should be considered as a morphine-related adverse event and not evidence of pain relief. The incidence of ventilatory depression is very low when the criteria to limit the dose of i.v. morphine are enforced. Morphine titration can be used with caution in elderly patients, in children, or in obese patients. In practice, i.v. morphine titration allows the physician to meet the needs of individual patients rapidly and limits the risk of overdose making this method the first step in postoperative pain management.

  12. Evaluation of who oral rehydration solution (ORS) and salt tablets in resuscitating adult patients with burns covering more than 15% of total body surface area (TBSA)

    PubMed Central

    Moghazy, A.M.; Adly, O.A.; Elbadawy, M.A.; Hashem, R.E.

    2016-01-01

    Summary Intra-venous (IV) burn resuscitation is effective; nevertheless it has its disadvantages. WHO Oral Rehydration Solution (ORS) has shown high effectiveness in treating dehydration. WHO-ORS, with salt supplement, seems to be suitable for burn resuscitation, where IV resuscitation is not available, feasible or possible. The objective of the study was to evaluate acute phase efficacy and safety, as well as limitations and complications of burn resuscitation using WHO-ORS and salt tablets. This randomized controlled clinical trial was conducted in the Burn Unit, Suez Canal University Hospital, Ismailia, Egypt. The study group was given WHO-ORS (15% of body weight/day) with one salt tablet (5gm) per liter according to Sørensen’s formula. The control group was given IV fluids according to the Parkland formula. Patients’ vital signs and urine output were monitored for 72 hours after starting resuscitation. Both groups were comparable regarding age, sex, and percentage, etiology and degree of burns. For all assessed parameters, there were no major significant differences between the study group (10 cases) and control group (20 cases). Even where there was a significant difference, apart from blood pressure in the first hour of the first day, the study group never crossed safe limits for pulse, systolic blood pressure, urine output, respiratory rate and conscious level. WHO-ORS with 5gm salt tablets, given according to Sørenson’s formula, is a safe and efficient alternative for IV resuscitation. It could even be a substitute, particularly in low resource settings and fire disasters. PMID:27857652

  13. 21 CFR 520.1284 - Sodium liothyronine tablets.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Sodium liothyronine tablets. 520.1284 Section 520...) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1284 Sodium liothyronine tablets. (a) Specifications. Sodium liothyronine tablets consist of tablets intended for...

  14. 21 CFR 520.1284 - Sodium liothyronine tablets.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Sodium liothyronine tablets. 520.1284 Section 520...) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1284 Sodium liothyronine tablets. (a) Specifications. Sodium liothyronine tablets consist of tablets intended for...

  15. 21 CFR 520.1284 - Sodium liothyronine tablets.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Sodium liothyronine tablets. 520.1284 Section 520...) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1284 Sodium liothyronine tablets. (a) Specifications. Sodium liothyronine tablets consist of tablets intended for...

  16. High-performance column liquid chromatographic method for the simultaneous determination of buclizine, tryptophan, pyridoxine, and cyanocobalamin in tablets and oral suspension.

    PubMed

    Kuminek, Gislaine; Stulzer, Hellen K; Tagliari, Monika P; Oliveira, Paulo R; Bernardi, Larissa S; Rauber, Gabriela S; Cardoso, Simone G

    2011-01-01

    An HPLC method was developed and validated for the simultaneous determination of buclizine, tryptophan, pyridoxine, and cyanocobalamin in pharmaceutical formulations. The chromatographic separation was carried out on an RP-C18 column using a mobile phase gradient of methanol, 0.015 M phosphate buffer (pH 3.0), and 0.03 M phosphoric acid at a flow rate of 1.0 mL/min and UV detection at 230, 280, and 360 nm, respectively, for buclizine, tryptophan, pyridoxine, and cyanocobalamin. The method validation yielded good results with respect to linearity (r>0.999), specificity, precision, accuracy, and robustness. The RSD values for intraday and interday precision were below 1.82 and 0.63%, respectively, and recoveries ranged from 98.11 to 101.95%. The method was successfully applied for the QC analysis of buclizine, tryptophan, pyridoxine, and cyanocobalamin in tablets and oral suspension.

  17. Urinary excretion of morphine and codeine following the administration of single and multiple doses of opium preparations prescribed in Taiwan as "brown mixture".

    PubMed

    Liu, Hsiu-Chuan; Ho, Hsiu-O; Liu, Ray H; Yeh, Geng-Cheng; Lin, Dong-Liang

    2006-05-01

    Parallel to the "poppy-seed defense" strategy commonly reported in the United States, donors of urine samples tested positive for opiates in Taiwan often claimed the consumption of Brown Mixture (BM) as the source of the observed morphine and codeine. Because BM contains opium powder (10.0-10.5% morphine), opium tincture (0.9-1.1% morphine), or camphorated opium tincture (0.045-0.055% morphine) and is a popular remedy, and heroin use is considered a serious criminal act, the claim of BM use has to be adequately addressed. In this study, BM from seven different manufacturers (5 tablets and 2 solutions) and urine samples from alleged heroin users and volunteers with various ingestion patterns and were analyzed for their morphine and codeine contents. The analytical procedure included hydrolysis, trimethylsilylation, and gas chromatography-mass spectrometry analysis. The contents of morphine and codeine in the tablets were found to be very consistent, but with significant differences in the two BM solutions. Morphine concentrations found in urine specimens collected from volunteers ingesting BM tablets (or solutions) were always < 4000 ng/mL. The following morphine-to-codeine ([M]/[C]) ratios were observed for urine specimens with morphine concentration > or = 300 ng/mL: (A) < 3.0 for volunteers ingesting BM solution and (B) > 3.0 (mostly > 5.0) for volunteers ingesting BM tablets and alleged heroin users. It appeared that (A) BM ingestion (tablet or solution) was unlikely to result in a morphine concentration > 4000 ng/mL; and (B) [M]/[C] ratio might not be an effective parameter to differentiate heroin use from BM tablet ingestion.

  18. 21 CFR 520.2150b - Stanozolol chewable tablets.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... treatment in dogs. (2) Administered orally to small breeds of dogs, 1/2 to 1 tablet twice daily for several weeks; to large breeds of dogs, 1 to 2 tablets twice daily for several weeks. (3) Federal law...

  19. 21 CFR 520.2150b - Stanozolol chewable tablets.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... treatment in dogs. (2) Administered orally to small breeds of dogs, 1/2 to 1 tablet twice daily for several weeks; to large breeds of dogs, 1 to 2 tablets twice daily for several weeks. (3) Federal law...

  20. 21 CFR 520.2150b - Stanozolol chewable tablets.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... treatment in dogs. (2) Administered orally to small breeds of dogs, 1/2 to 1 tablet twice daily for several weeks; to large breeds of dogs, 1 to 2 tablets twice daily for several weeks. (3) Federal law...

  1. 21 CFR 520.2150b - Stanozolol chewable tablets.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... treatment in dogs. (2) Administered orally to small breeds of dogs, 1/2 to 1 tablet twice daily for several weeks; to large breeds of dogs, 1 to 2 tablets twice daily for several weeks. (3) Federal law...

  2. Review of bilayer tablet technology.

    PubMed

    Abebe, Admassu; Akseli, Ilgaz; Sprockel, Omar; Kottala, Niranjan; Cuitiño, Alberto M

    2014-01-30

    Therapeutic strategies based on oral delivery of bilayer (and multilayer) tablets are gaining more acceptance among brand and generic products due to a confluence of factors including advanced delivery strategies, patient compliance and combination therapy. Successful manufacturing of these ever more complex systems needs to overcome a series of challenges from formulation design to tablet press monitoring and control. This article provides an overview of the state-of-the-art of bilayer tablet technology, highlighting the main benefits of this type of oral dosage forms while providing a description of current challenges and advances toward improving manufacturing practices and product quality. Several aspects relevant to bilayer tablet manufacturing are addressed including material properties, lubrication, layer ordering, layer thickness, layer weight control, as well as first and final compression forces. A section is also devoted to bilayer tablet characterization that present additional complexities associated with interfaces between layers. The available features of the manufacturing equipment for bilayer tablet production are also described indicating the different strategies for sensing and controls offered by bilayer tablet press manufacturers. Finally, a roadmap for bilayer tablet manufacturing is advanced as a guideline to formulation design and selection of process parameters and equipment.

  3. Part IV: effects of zolmitriptan orally disintegrating tablet on migraine symptoms and ability to perform normal activities: a post-marketing surveillance study in Germany.

    PubMed

    Diener, Hans-Christoph; Gendolla, Astrid

    2005-01-01

    Zolmitriptan has been developed in an orally disintegrating tablet (ODT) formulation that rapidly dissolves on the tongue and can be taken quickly, conveniently and discreetly without fluid intake. In this 3-month, non-comparative, observational, post-marketing surveillance (PMS) study, 5,570 physicians prescribed the zolmitriptan 2.5 mg ODT for 16,261 patients with migraine. Of the 14,543 patients who were evaluable for efficacy analysis, 94% had reduced headache intensity within 2 hours of taking zolmitriptan 2.5 mg ODT for the first attack. Improvements were reported within 30 minutes in 35% of patients and within 15 minutes in 7% of patients. Non-headache migraine symptoms and normal daily activities improved for the majority of patients within 2 hours of taking zolmitriptan ODT. Ninety-one percent of patients required only a single dose of zolmitriptan 2.5 mg ODT to treat each attack. Ninety-two percent of patients considered zolmitriptan ODT as having very good or good efficacy and 96% said that tolerability was very good or good. This study also demonstrated that 94% of patients would be willing to continue to use zolmitriptan ODT in the future and 81% of patients considered that being able to take the ODT without water was important or very import ant. In summary, zolmitriptan ODT has demonstrated high efficacy and excellent tolerability. In addition, patients found zolmitriptan ODT to be convenient and easy to use, and were willing to continue using the product. Following placebo-controlled studies, these PMS results provide insight into the use of zolmitriptan ODT in a setting more representative of real life than randomised clinical trials, further demonstrating that it provides a reliable and convenient alternative to conventional tablets.

  4. Fixed-dose combination orally disintegrating tablets to treat cardiovascular disease: formulation, in vitro characterization and physiologically based pharmacokinetic modeling to assess bioavailability

    PubMed Central

    Dennison, Thomas J; Smith, Julian C; Badhan, Raj K; Mohammed, Afzal R

    2017-01-01

    Cardiovascular disease (CVD) is the leading cause of death among men and women worldwide. In CVD, hypertension and dyslipidemia commonly coexist and are managed through coadministration of amlodipine and atorvastatin, respectively. The case for fixed-dose combination (FDC) oral dosage forms and orally disintegrating tablet (ODT) technology to enhance outcomes and compliance is strong. This work follows the development and characterization of single and FDC ODTs containing amlodipine and atorvastatin, followed by bioequivalence comparison between these single and FDC formulations, using in vitro dissolution and Caco-2 apparent permeability (Papp) and in silico physiologically based pharmacokinetic modeling approaches. ODTs containing amlodipine (5 mg) and atorvastatin (10 mg) either alone or in combination rapidly disintegrated (<30 s) while displaying a radial crushing strength in excess of 100 N and friability ≤1%. In vitro dissolution test was performed in fasted and fed-state simulated intestinal fluid (FeSSIF) and analyzed using high-performance liquid chromatography. Dissolution profiles for single and FDC ODTs were compared using US FDA recommended difference (f1) and similarity (f2) factor testing for bioequivalence. In all cases, there was no difference in active pharmaceutical ingredient dissolution between single or FDC ODTs, with the exception of amlodipine in FeSSIF. Pharmacokinetic clinical trial simulations were conducted using Simcyp (Version 14), incorporating Papp and dissolution data. Simulated clinical trials in healthy volunteers showed no difference in bioavailability based on pharmacokinetic parameters between single and combination doses with either active pharmaceutical ingredient. An increase in Cmax and AUC for atorvastatin in fed subjects was attributed to extended transit along the gut lumen and reduced atorvastatin metabolism due to lower CYP3A4 expression at more distal small intestine absorption sites. The results demonstrated

  5. Fixed-dose combination orally disintegrating tablets to treat cardiovascular disease: formulation, in vitro characterization and physiologically based pharmacokinetic modeling to assess bioavailability.

    PubMed

    Dennison, Thomas J; Smith, Julian C; Badhan, Raj K; Mohammed, Afzal R

    2017-01-01

    Cardiovascular disease (CVD) is the leading cause of death among men and women worldwide. In CVD, hypertension and dyslipidemia commonly coexist and are managed through coadministration of amlodipine and atorvastatin, respectively. The case for fixed-dose combination (FDC) oral dosage forms and orally disintegrating tablet (ODT) technology to enhance outcomes and compliance is strong. This work follows the development and characterization of single and FDC ODTs containing amlodipine and atorvastatin, followed by bioequivalence comparison between these single and FDC formulations, using in vitro dissolution and Caco-2 apparent permeability (Papp) and in silico physiologically based pharmacokinetic modeling approaches. ODTs containing amlodipine (5 mg) and atorvastatin (10 mg) either alone or in combination rapidly disintegrated (<30 s) while displaying a radial crushing strength in excess of 100 N and friability ≤1%. In vitro dissolution test was performed in fasted and fed-state simulated intestinal fluid (FeSSIF) and analyzed using high-performance liquid chromatography. Dissolution profiles for single and FDC ODTs were compared using US FDA recommended difference (f1) and similarity (f2) factor testing for bioequivalence. In all cases, there was no difference in active pharmaceutical ingredient dissolution between single or FDC ODTs, with the exception of amlodipine in FeSSIF. Pharmacokinetic clinical trial simulations were conducted using Simcyp (Version 14), incorporating Papp and dissolution data. Simulated clinical trials in healthy volunteers showed no difference in bioavailability based on pharmacokinetic parameters between single and combination doses with either active pharmaceutical ingredient. An increase in Cmax and AUC for atorvastatin in fed subjects was attributed to extended transit along the gut lumen and reduced atorvastatin metabolism due to lower CYP3A4 expression at more distal small intestine absorption sites. The results demonstrated

  6. Evaluation of tilidine for morphine-like subjective effects and euphoria.

    PubMed

    Jasinski, D R; Preston, K L

    1986-11-01

    Tilidine is an opioid analgesic that has been abused predominantly by the oral route. Studies of parenterally administered tilidine in animals did not clearly indicate a dependence potential of the morphine type. In this study we examined the abuse potential of orally and parenterally administered tilidine in humans. Both orally and intramuscularly given tilidine produced miosis and morphine-like subjective effects in non-dependent subjects. Oral tilidine was 1/8-1/10 as potent and intramuscular tilidine was 1/22 as potent as parenteral morphine in producing morphine-like subjective and miotic effects. Intramuscular tilidine suppressed and did not precipitate signs of abstinence in morphine-dependent subjects. However, intramuscularly given tilidine produced toxic effects not seen with morphine. Meperidine, codeine and d-propoxyphene produced morphine-like subjective and miotic effects, but also produced toxic effects at the highest doses tested. The results suggest that tilidine has a potential to be abused, that this potential is less than that of parenteral morphine and that tilidine is more likely to be abused orally than by the intramuscular route.

  7. Insulin availability from mucoadhesive tablets.

    PubMed

    Pluta, J; Haznar, D; Suszka-Switek, A; Ryszka, F

    2008-09-01

    The widespread implementation of peptides as drugs encounters numerous obstacles, the main being invasive and inconvenient parenteral administration. Oral transmucosal administration is one of the possible alternatives, valuable for its noninvasiveness and easy accessibility. The aim of our study was to determine the implementation possibilities of mucoadhesive tablets prepared on a methylcellulose and sodium alginate basis with an addition of absorption-modifying hyaluronic acid, as carriers for peptides destined for oral transmucosal administration. Two series of 50 mg tablets containing 5mg of insulin were prepared for the study. The first series contained methylcellulose, hyaluronic acid and mannitol, while the second series' formulation included sodium alginate, hyaluronic acid and mannitol. Carried out study confirmed that insulin administration in the form of mucoadhesive tablets lowers blood glucose levels in rabbits. Better effects were reached in vivo in the case of MC-based tablets, for which stronger and longer glycemia lowering was achieved.

  8. Fentanyl buccal tablet for the treatment of cancer-related breakthrough pain.

    PubMed

    Mercadante, Sebastiano

    2015-01-01

    Fentanyl buccal tablet (FBT) (FENTORA) is indicated for the management of breakthrough pain (BTP) in patients with cancer pain and who are tolerant to ≥60 mg of oral morphine equivalents, at least with the current availability of the minimal strength of 100 μg. FBT uses the OraVescent technology to further increase the rate and extent of absorption of fentanyl. Short-term, randomized, controlled, clinical studies of FBT in patients with cancer pain have shown the efficacy of FBT in the management of breakthrough cancer pain. The efficacy was also confirmed in long-term studies on the safety and tolerability of FBT. It has been recommended that administration should be tailored to the patient's individual requirement, through dose titration starting from the lowest dose to find the effective dose. However, recent studies have demonstrated that predictable doses calculated from the basal opioid regimen are safe and more effective than doses achieved after dose titration.

  9. Efficacy and safety of desmopressin orally disintegrating tablet in patients with central diabetes insipidus: results of a multicenter open-label dose-titration study.

    PubMed

    Arima, Hiroshi; Oiso, Yutaka; Juul, Kristian Vinter; Nørgaard, Jens Peter

    2013-01-01

    Central diabetes insipidus (CDI) is associated with arginine vasopressin (AVP) deficiency with resultant polyuria and polydipsia. Intranasal desmopressin provides physiological replacement but oral formulations are preferred for their ease of administration. This study aimed to demonstrate the efficacy and safety of desmopressin orally disintegrating tablet (ODT) in the treatment of Japanese patients with CDI, and confirm that antidiuresis is maintained on switching from intranasal desmopressin to desmopressin ODT. A total of 20 patients aged 6-75 years with CDI were included in this 4-week multicenter, open-label study. Following observation, patients switched from intranasal desmopressin to desmopressin ODT with titration to optimal dose over ≤5 days at the study site. Following three consecutive doses with stable patient fluid balance, patients were discharged with visits at Weeks 2 and 4. Following titration from intranasal desmopressin to ODT, the mean 24-hour urine volume was unchanged, indicating similar antidiuresis with both formulations. The proportion of patients with endpoint measurements (urine osmolality, 24-hour urine volume, hourly diuresis rate and urine-specific gravity) within normal range at Days 1-2 (intranasal desmopressin) and Week 4 (desmopressin ODT) was similar. The mean daily dose ratio of intranasal desmopressin to desmopressin ODT (Week 4) was 1:24 but a wide range was observed across individuals to maintain adequate antidiuretic effect. Hyponatraemia was generally mild and managed by dose titration. Desmopressin ODT achieved sufficient antidiuretic control compared to intranasal therapy and was well tolerated over long-term treatment. The wide range of intranasal:ODT dose ratios underline the importance of individual titration.

  10. Enhancement of Solubility of Lamotrigine by Solid Dispersion and Development of Orally Disintegrating Tablets Using 3(2) Full Factorial Design.

    PubMed

    Singh, Jatinderpal; Garg, Rajeev; Gupta, Ghanshyam Das

    2015-01-01

    Present investigation deals with the preparation and evaluation of orally disintegrating tablets (ODTs) of lamotrigine using β-cyclodextrin and PVP-K30 as polymers for the preparation of solid dispersion which help in enhancement of aqueous solubility of this BCS CLASS-II drug and sodium starch glycolate (SSG) and crospovidone as a superdisintegrating agent, to reduce disintegration time. The ODTs were prepared by direct compression method. Nine formulations were developed with different ratios of superdisintegrating agents. All the formulations were evaluated for disintegration time, weight variation, hardness, friability, drug content uniformity, wetting time, and in vitro drug release study. In vitro drug release study was performed using United States Pharmacopoeia (USP) type 2 dissolution test apparatus employing paddle stirrer at 50 rpm using 900 mL of 0.1 N HCl maintained at 37°C ± 0.5°C as the dissolution medium. On the basis of evaluation parameters formulations were prepared using β-CD 1 : 1 solid dispersion. Then 3(2) full factorial design was applied using SSG and crospovidone in different ratios suggested by using design expert 8.0.7.1 and optimized formulation was prepared using amount of SSG and crospovidone as suggested by the software. The optimized formulation prepared had disintegrating time of 15 s, wetting time of 24 s, and % friability of 0.55.

  11. Taste-masking effect of physical and organoleptic methods on peppermint-scented orally disintegrating tablet of famotidine based on suspension spray-coating method.

    PubMed

    Sugiura, Takeshi; Uchida, Shinya; Namiki, Noriyuki

    2012-01-01

    Orally disintegrating tablets (ODTs) are useful for improving benefits for patients of various ages. Masking the unpleasant taste of a drug is an important factor in the compliance of patients who take ODTs. We evaluated the taste acceptability effects of various taste-masking methods on bitter famotidine ODTs as a clinical pharmacological study. The following methods were tested to compare taste-masking effects: physical masking by spray-coating famotidine with ethyl cellulose versus organoleptic masking with added sweetener and flavor. The ODT samples were prepared as single or combinations of each taste-masking method using a novel suspension spray-coating method including a placebo. A total of 31 healthy volunteers were enrolled in this randomized, double-blind study and asked to score their bitterness, sweetness and total palate impressions by 100 mm visual analogue scale (VAS). VAS scores were significantly improved by the physical and organoleptic methods as compared to without taste-masked ODTs. Furthermore, the combination of both taste-masking methods was most effective for improving palatability and VAS scores were similar to those of placebo ODTs. The results of this study suggest that different taste-masking mechanisms function cooperatively.

  12. LC-MS/MS determination and urinary excretion study of seven alkaloids in healthy Chinese volunteers after oral administration of Shuanghua Baihe tablets.

    PubMed

    Cheng, Minlu; Liu, Ruijuan; Wu, Yao; Gu, Pan; Zheng, Lu; Liu, Yujie; Ma, Pengcheng; Ding, Li

    2016-01-25

    An LC-MS/MS method was developed and validated for the simultaneous determination of magnoflorine, berberrubine, jatrorrhizine, coptisine, epiberberine, palmatine and berberine in human urine. The sample preparation procedure involved the four-fold dilution of the urine samples with acetonitrile/water (1:3, v/v). The chromatographic separation was achieved on a Hedera ODS-2 column under gradient elution at a flow rate of 0.4 mL/min with acetonitrile and water containing 0.5% formic acid as the mobile phase. The mass detection was performed in the positive mode. Calibration curves of the seven alkaloids showed good linearity (correlation coefficients>0.9973) over their concentration ranges. To meet the requirements of urinary excretion study for each alkaloid in human, the lower limit of quantification was set at different values from 0.05063 ng/mL to 2.034 ng/mL for the seven alkaloids, respectively. The intra- and inter-batch precision and accuracy were all within ± 15%. No matrix effect was observed for the analytes. The validated method was applied to the excretion study for the seven alkaloids in healthy Chinese volunteers after oral administration of Shuanghua Baihe tablets. The average 72 h cumulative urinary excretion of magnoflorine, berberrubine, jatrorrhizine, coptisine, epiberberine, palmatine and berberine accounted for 1.81%, 0.27%, 0.29%, 0.046%, 0.027%, 0.010% and 0.021% of the respective administered dose.

  13. 21 CFR 520.804 - Enalapril tablets.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Enalapril tablets. 520.804 Section 520.804 Food... DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.804 Enalapril tablets. (a) Specifications. Each tablet contains either 1.0, 2.5, 5.0, 10.0, or 20.0 milligrams of enalapril maleate....

  14. 21 CFR 520.804 - Enalapril tablets.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Enalapril tablets. 520.804 Section 520.804 Food... DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.804 Enalapril tablets. (a) Specifications. Each tablet contains either 1.0, 2.5, 5.0, 10.0, or 20.0 milligrams of enalapril maleate....

  15. Benefit–risk assessment of paliperidone oral extended-release tablet versus monthly injectable for maintenance treatment of schizophrenia

    PubMed Central

    Markowitz, Michael; Turkoz, Ibrahim; Fu, Dong-Jing; Gopal, Srihari; Alphs, Larry

    2016-01-01

    The purpose of this study was to conduct a post-hoc benefit–risk assessment of paliperidone palmitate once-monthly (PP1M) injectable versus oral paliperidone extended-release (ER) in schizophrenia maintenance treatment. The Benefit–Risk Action Team framework was used to structure the analysis based on patient-level data from two similar, double-blind, placebo-controlled relapse studies. Efficacy outcomes were relapse, psychiatric hospitalization, Clinical Global Impression–Severity scale, Personal and Social Performance (PSP) scale, and Positive and Negative Syndrome Scale (PANSS). Safety outcomes were extrapyramidal symptom–related adverse events, weight gain, prolactin-related adverse events, somnolence, orthostatic hypotension, anticholinergic use, fasting plasma glucose, and total cholesterol/high–density lipoprotein. For the first 8 weeks of maintenance treatment, most efficacy outcomes significantly favored PP1M compared with paliperidone ER. Per 1000 patients, there would be 165, 115, 85, and 53 fewer cases of PSP worsening, relapse, PANSS worsening, and hospitalizations, respectively. For the first 40 weeks, PSP worsening significantly favored PP1M (140 fewer cases). Relapse, PANSS, hospitalizations, and Clinical Global Impression–Severity scale showed a consistent pattern favoring PP1M but were not significant. Safety outcomes for both 8-week and 40-week periods demonstrated no statistically significant differences between groups. These analyses suggest a benefit–risk profile favoring PP1M over oral paliperidone ER throughout 40 weeks of treatment, particularly in early treatment. PMID:27434314

  16. 21 CFR 520.1380 - Methocarbamol tablets.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Methocarbamol tablets. 520.1380 Section 520.1380... DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1380 Methocarbamol tablets. (a) Chemical name. 3-(O-Methoxyphenoxy)-1,2-propanediol 1-carbamate. (b) Specifications. Each...

  17. 21 CFR 520.1380 - Methocarbamol tablets.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Methocarbamol tablets. 520.1380 Section 520.1380... DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1380 Methocarbamol tablets. (a) Chemical name. 3-(O-Methoxyphenoxy)-1,2-propanediol 1-carbamate. (b) Specifications. Each...

  18. 21 CFR 520.581 - Dichlorophene tablets.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    .... (2) Indications for use. It is used as an aid in the removal of tapeworms (Taenia pisiformis and... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Dichlorophene tablets. 520.581 Section 520.581... DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.581 Dichlorophene tablets....

  19. 21 CFR 520.2330 - Sulfisoxazole tablets.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... No. 000856 in § 510.600(c) of this chapter. (c) Conditions of use—(1) Amount. Administer one tablet... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Sulfisoxazole tablets. 520.2330 Section 520.2330... DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.2330 Sulfisoxazole...

  20. 21 CFR 520.581 - Dichlorophene tablets.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ...) Indications for use. It is used as an aid in the removal of tapeworms (Taenia pisiformis and Dipylidium... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Dichlorophene tablets. 520.581 Section 520.581... DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.581 Dichlorophene tablets....

  1. 21 CFR 520.1380 - Methocarbamol tablets.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Methocarbamol tablets. 520.1380 Section 520.1380... DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1380 Methocarbamol tablets. (a) Chemical name. 3-(O-Methoxyphenoxy)-1,2-propanediol 1-carbamate. (b) Specifications. Each...

  2. 21 CFR 520.2330 - Sulfisoxazole tablets.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... No. 000856 in § 510.600(c) of this chapter. (c) Conditions of use—(1) Amount. Administer one tablet... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Sulfisoxazole tablets. 520.2330 Section 520.2330... DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.2330 Sulfisoxazole...

  3. 21 CFR 520.2330 - Sulfisoxazole tablets.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... No. 000856 in § 510.600(c) of this chapter. (c) Conditions of use—(1) Amount. Administer one tablet... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Sulfisoxazole tablets. 520.2330 Section 520.2330... DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.2330 Sulfisoxazole...

  4. 21 CFR 520.1380 - Methocarbamol tablets.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Methocarbamol tablets. 520.1380 Section 520.1380... DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1380 Methocarbamol tablets. (a) Chemical name. 3-(O-Methoxyphenoxy)-1,2-propanediol 1-carbamate. (b) Specifications. Each...

  5. 21 CFR 520.581 - Dichlorophene tablets.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    .... (2) Indications for use. It is used as an aid in the removal of tapeworms (Taenia pisiformis and... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Dichlorophene tablets. 520.581 Section 520.581... DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.581 Dichlorophene tablets....

  6. 21 CFR 520.1380 - Methocarbamol tablets.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Methocarbamol tablets. 520.1380 Section 520.1380... DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1380 Methocarbamol tablets. (a) Chemical name. 3-(O-Methoxyphenoxy)-1,2-propanediol 1-carbamate. (b) Specifications. Each...

  7. 21 CFR 520.2330 - Sulfisoxazole tablets.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... No. 000856 in § 510.600(c) of this chapter. (c) Conditions of use—(1) Amount. Administer one tablet... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Sulfisoxazole tablets. 520.2330 Section 520.2330... DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.2330 Sulfisoxazole...

  8. 21 CFR 520.581 - Dichlorophene tablets.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    .... (2) Indications for use. It is used as an aid in the removal of tapeworms (Taenia pisiformis and... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Dichlorophene tablets. 520.581 Section 520.581... DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.581 Dichlorophene tablets....

  9. 21 CFR 520.812 - Enrofloxacin tablets.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Enrofloxacin tablets. 520.812 Section 520.812 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.812 Enrofloxacin tablets....

  10. 21 CFR 520.804 - Enalapril tablets.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Enalapril tablets. 520.804 Section 520.804 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.804 Enalapril tablets....

  11. 21 CFR 520.581 - Dichlorophene tablets.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Dichlorophene tablets. 520.581 Section 520.581 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.581 Dichlorophene tablets....

  12. 21 CFR 520.455 - Clomipramine tablets.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Clomipramine tablets. 520.455 Section 520.455 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.455 Clomipramine tablets....

  13. 21 CFR 520.312 - Carnidazole tablets.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Carnidazole tablets. 520.312 Section 520.312 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.312 Carnidazole tablets....

  14. 21 CFR 520.370 - Cefpodoxime tablets.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Cefpodoxime tablets. 520.370 Section 520.370 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.370 Cefpodoxime tablets....

  15. 21 CFR 520.2362 - Thenium closylate tablets.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...) Conditions of use. (1) The tablets are administered orally to dogs as a single day treatment of canine... Uncinaria stenocephala (hookworms). Dogs weighing 10 pounds and over are administered 1 tablet as a single dose. Dogs weighing 5 to 10 pounds are administered one-half tablet twice during a single day....

  16. 21 CFR 520.2362 - Thenium closylate tablets.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ...) Conditions of use. (1) The tablets are administered orally to dogs as a single day treatment of canine... Uncinaria stenocephala (hookworms). Dogs weighing 10 pounds and over are administered 1 tablet as a single dose. Dogs weighing 5 to 10 pounds are administered one-half tablet twice during a single day....

  17. 21 CFR 520.1696d - Penicillin V tablets.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Penicillin V tablets. 520.1696d Section 520.1696d... DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1696d Penicillin V tablets. (a) Specifications. Each tablet contains penicillin V potassium equivalent to 125 milligrams...

  18. 21 CFR 520.1696d - Penicillin V tablets.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Penicillin V tablets. 520.1696d Section 520.1696d... DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1696d Penicillin V tablets. (a) Specifications. Each tablet contains penicillin V potassium equivalent to 125 milligrams...

  19. 21 CFR 520.863 - Ethylisobutrazine hydrochloride tablets.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Ethylisobutrazine hydrochloride tablets. 520.863... Ethylisobutrazine hydrochloride tablets. (a) Specifications. Each tablet contains either 10 milligrams or 50.... (c) Conditions of use. (1) It is administered orally to dogs as a tranquilizer.1 1 These...

  20. 21 CFR 520.2362 - Thenium closylate tablets.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ...) Conditions of use. (1) The tablets are administered orally to dogs as a single day treatment of canine... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Thenium closylate tablets. 520.2362 Section 520... tablets. (a) Chemical name....

  1. 21 CFR 520.2123a - Spectinomycin tablets.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Spectinomycin tablets. 520.2123a Section 520.2123a... DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.2123a Spectinomycin tablets. (a) Specifications. Each tablet contains spectinomycin dihydrochloride pentahydrate equivalent to...

  2. 21 CFR 520.863 - Ethylisobutrazine hydrochloride tablets.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Ethylisobutrazine hydrochloride tablets. 520.863... Ethylisobutrazine hydrochloride tablets. (a) Specifications. Each tablet contains either 10 milligrams or 50.... (c) Conditions of use. (1) It is administered orally to dogs as a tranquilizer.1 1 These...

  3. 21 CFR 520.863 - Ethylisobutrazine hydrochloride tablets.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Ethylisobutrazine hydrochloride tablets. 520.863... Ethylisobutrazine hydrochloride tablets. (a) Specifications. Each tablet contains either 10 milligrams or 50.... (c) Conditions of use. (1) It is administered orally to dogs as a tranquilizer.1 1 These...

  4. 21 CFR 520.863 - Ethylisobutrazine hydrochloride tablets.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Ethylisobutrazine hydrochloride tablets. 520.863... Ethylisobutrazine hydrochloride tablets. (a) Specifications. Each tablet contains either 10 milligrams or 50.... (c) Conditions of use. (1) It is administered orally to dogs as a tranquilizer.1 1 These...

  5. 21 CFR 520.2362 - Thenium closylate tablets.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ...) Conditions of use. (1) The tablets are administered orally to dogs as a single day treatment of canine... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Thenium closylate tablets. 520.2362 Section 520... tablets. (a) Chemical name....

  6. 21 CFR 520.2123a - Spectinomycin tablets.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Spectinomycin tablets. 520.2123a Section 520.2123a... DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.2123a Spectinomycin tablets. (a) Specifications. Each tablet contains spectinomycin dihydrochloride pentahydrate equivalent to...

  7. 21 CFR 520.863 - Ethylisobutrazine hydrochloride tablets.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Ethylisobutrazine hydrochloride tablets. 520.863... Ethylisobutrazine hydrochloride tablets. (a) Specifications. Each tablet contains either 10 milligrams or 50.... (c) Conditions of use. (1) It is administered orally to dogs as a tranquilizer.1 1 These...

  8. 21 CFR 520.2362 - Thenium closylate tablets.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ...) Conditions of use. (1) The tablets are administered orally to dogs as a single day treatment of canine... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Thenium closylate tablets. 520.2362 Section 520... tablets. (a) Chemical name....

  9. 21 CFR 520.784 - Doxylamine succinate tablets.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Doxylamine succinate tablets. 520.784 Section 520...) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.784 Doxylamine succinate tablets. (a) Specifications. The drug is in tablet form and contains doxylamine succinate as...

  10. 21 CFR 520.784 - Doxylamine succinate tablets.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Doxylamine succinate tablets. 520.784 Section 520...) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.784 Doxylamine succinate tablets. (a) Specifications. The drug is in tablet form and contains doxylamine succinate as...

  11. 21 CFR 520.784 - Doxylamine succinate tablets.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Doxylamine succinate tablets. 520.784 Section 520...) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.784 Doxylamine succinate tablets. (a) Specifications. The drug is in tablet form and contains doxylamine succinate as...

  12. 21 CFR 520.1157 - Iodinated casein tablets.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Iodinated casein tablets. 520.1157 Section 520...) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1157 Iodinated casein tablets. (a) Specifications. Each 1-gram tablet contains 25 milligrams of iodinated casein. (b)...

  13. 21 CFR 520.1157 - Iodinated casein tablets.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Iodinated casein tablets. 520.1157 Section 520...) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1157 Iodinated casein tablets. (a) Specifications. Each 1-gram tablet contains 25 milligrams of iodinated casein. (b)...

  14. 21 CFR 520.784 - Doxylamine succinate tablets.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Doxylamine succinate tablets. 520.784 Section 520...) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.784 Doxylamine succinate tablets. (a) Specifications. The drug is in tablet form and contains doxylamine succinate as...

  15. 21 CFR 520.1331 - Meclofenamic acid tablets.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Meclofenamic acid tablets. 520.1331 Section 520...) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1331 Meclofenamic acid tablets. (a) Specifications. Each tablet contains either 10 or 20 milligrams of meclofenamic acid....

  16. 21 CFR 520.1331 - Meclofenamic acid tablets.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Meclofenamic acid tablets. 520.1331 Section 520...) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1331 Meclofenamic acid tablets. (a) Specifications. Each tablet contains either 10 or 20 milligrams of meclofenamic acid....

  17. 21 CFR 520.1331 - Meclofenamic acid tablets.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Meclofenamic acid tablets. 520.1331 Section 520...) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1331 Meclofenamic acid tablets. (a) Specifications. Each tablet contains either 10 or 20 milligrams of meclofenamic acid....

  18. 21 CFR 520.1331 - Meclofenamic acid tablets.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Meclofenamic acid tablets. 520.1331 Section 520...) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1331 Meclofenamic acid tablets. (a) Specifications. Each tablet contains either 10 or 20 milligrams of meclofenamic acid....

  19. Bioavailability, safety, and pharmacodynamics of delayed-release dexlansoprazole administered as two 30 mg orally disintegrating tablets or one 60 mg capsule

    PubMed Central

    Kukulka, Michael; Nudurupati, Sai; Perez, Maria Claudia

    2016-01-01

    Background: Dual delayed-release dexlansoprazole is approved for use in adults as a 30 mg orally disintegrating tablet (ODT) or as 30 mg and 60 mg capsules. The pharmacokinetics, pharmacodynamics, and safety profile of two dexlansoprazole 30 mg ODTs were compared with one dexlansoprazole 60 mg capsule in this randomized, phase I, open-label, single-center, multiple-dose, two-period crossover study. Methods: Participants were randomized in one of two treatment sequences, each comprised two 5-day treatment periods during which two dexlansoprazole 30 mg ODTs or one 60 mg capsule was administered once daily. Pharmacokinetic parameters and the mean intragastric pH profile for the 24-hour period after dosing on days 1 and 5 were described. Adverse events were monitored during study duration and followed up with a phone call 5–10 days after the last dose of study drug. Results: On day 1, peak observed plasma concentration (Cmax) values were similar between two 30 mg ODTs (1047 ng/ml) and one 60 mg capsule (1164 ng/ml). Systemic exposure, measured by the area under the plasma concentration–time curve (AUC), was approximately 25% lower after ODT administration. On day 5, mean pH after daily doses of two 30 mg ODT or one 60 mg capsule was 4.33 and 4.36, respectively; both regimens maintained intragastric pH above 4.0 for 60% of the 24-hour period. Headache was the most commonly reported adverse event (observed in 19.2% of participants); no adverse events leading to study withdrawal occurred. Conclusions: While systemic exposure (AUC) was 25% lower with ODT, peak concentrations (Cmax) after administration of two dexlansoprazole 30 mg ODTs and one 60 mg capsule were similar. The 24-hour intragastric pH control after administration of two dexlansoprazole 30 mg ODTs was equivalent to one dexlansoprazole 60 mg capsule. Both ODT and capsule were well tolerated. PMID:27803732

  20. Tablet Weaving

    ERIC Educational Resources Information Center

    Kren, Margo

    1976-01-01

    Article described a weaving technique called tablet weaving, an ancient textile process that provides opportunity for making a variety of items, such as guitar straps, belts, and decorative bands. (Author/RK)

  1. Investigation of the Bioequivalence of Rosuvastatin 20 mg Tablets after a Single Oral Administration in Mediterranean Arabs Using a Validated LC-MS/MS Method

    PubMed Central

    Zaid, Abdel Naser; Al Ramahi, Rowa; Cortesi, Rita; Mousa, Ayman; Jaradat, Nidal; Ghazal, Nadia; Bustami, Rana

    2016-01-01

    There is a wide inter-individual response to statin therapy including rosuvastatin calcium (RC), and it has been hypothesized that genetic differences may contribute to these variations. In fact, several studies have shown that pharmacokinetic (PK) parameters for RC are affected by race. The aim of this study is to demonstrate the interchangeability between two generic RC 20 mg film-coated tablets under fasting conditions among Mediterranean Arabs and to compare the pharmacokinetic results with Asian and Caucasian subjects from other studies. A single oral RC 20 mg dose, randomized, open-label, two-way crossover design study was conducted in 30 healthy Mediterranean Arab volunteers. Blood samples were collected prior to dosing and over a 72-h period. Concentrations in plasma were quantified using a validated liquid chromatography tandem mass spectrometry method. Twenty-six volunteers completed the study. Statistical comparison of the main PK parameters showed no significant difference between the generic and branded products. The point estimates (ratios of geometric mean %) were 107.73 (96.57–120.17), 103.61 (94.03–114.16), and 104.23 (94.84–114.54) for peak plasma concentration (Cmax), Area Under the Curve (AUC)0→last, and AUC0→∞, respectively. The 90% confidence intervals were within the pre-defined limits of 80%–125% as specified by the Food and Drug Administration and European Medicines Agency for bioequivalence studies. Both formulations were well-tolerated and no serious adverse events were reported. The PK results (AUC0→last and Cmax) were close to those of the Caucasian subjects. This study showed that the test and reference products met the regulatory criteria for bioequivalence following a 20 mg oral dose of RC under fasting conditions. Both formulations also showed comparable safety results. The PK results of the test and reference in the study subjects fall within the acceptable interval of 80%–125% and they were very close to the

  2. Investigation of the Bioequivalence of Rosuvastatin 20 mg Tablets after a Single Oral Administration in Mediterranean Arabs Using a Validated LC-MS/MS Method.

    PubMed

    Zaid, Abdel Naser; Al Ramahi, Rowa; Cortesi, Rita; Mousa, Ayman; Jaradat, Nidal; Ghazal, Nadia; Bustami, Rana

    2016-06-30

    There is a wide inter-individual response to statin therapy including rosuvastatin calcium (RC), and it has been hypothesized that genetic differences may contribute to these variations. In fact, several studies have shown that pharmacokinetic (PK) parameters for RC are affected by race. The aim of this study is to demonstrate the interchangeability between two generic RC 20 mg film-coated tablets under fasting conditions among Mediterranean Arabs and to compare the pharmacokinetic results with Asian and Caucasian subjects from other studies. A single oral RC 20 mg dose, randomized, open-label, two-way crossover design study was conducted in 30 healthy Mediterranean Arab volunteers. Blood samples were collected prior to dosing and over a 72-h period. Concentrations in plasma were quantified using a validated liquid chromatography tandem mass spectrometry method. Twenty-six volunteers completed the study. Statistical comparison of the main PK parameters showed no significant difference between the generic and branded products. The point estimates (ratios of geometric mean %) were 107.73 (96.57-120.17), 103.61 (94.03-114.16), and 104.23 (94.84-114.54) for peak plasma concentration (Cmax), Area Under the Curve (AUC)0→last, and AUC0→∞, respectively. The 90% confidence intervals were within the pre-defined limits of 80%-125% as specified by the Food and Drug Administration and European Medicines Agency for bioequivalence studies. Both formulations were well-tolerated and no serious adverse events were reported. The PK results (AUC0→last and Cmax) were close to those of the Caucasian subjects. This study showed that the test and reference products met the regulatory criteria for bioequivalence following a 20 mg oral dose of RC under fasting conditions. Both formulations also showed comparable safety results. The PK results of the test and reference in the study subjects fall within the acceptable interval of 80%-125% and they were very close to the results among

  3. Influence of the coating thickness and type of oral delivery system (tablets, pellets) on the stability towards degradation by neutron irradiation. Validation of neutron activation III.

    PubMed

    Waaler, T; Sande, S A; Müller, B W; Schüller Lisether, G

    1999-03-01

    Enteric coated dexchlorpheniramine maleate (DCPA) tablets and pellets with varying coating thickness were subjected to several in vitro tests after irradiation by thermal neutrons in a flux of 1. 1 x 10(13) n cm-2 s-1 for 2, 4 or 15 min. The appearance of the tablet formulation changed extensively after exposure of the tablets to pile radiation. The irradiation caused the film to loosen from the surface of the core, indicating the generation of gases during the irradiation process. Already after irradiating the tablets for 2 min the disintegration and dissolution behaviour were significantly changed. The extent of tablet damage increased with increasing time of exposure and increasing thickness of the coating. Compared with the tablet formulation, the cores could resist a larger amount of irradiation since dissolution behaviour of the cores was only affected after 15 min of irradiation. This indicates that the irradiation procedure initially affects the coating of the formulation. Although the dissolution behaviour of the pellet formulations changed significantly after the irradiation procedure, the changes were too small to be attributed exclusively to radiation damage.

  4. Increased calcium/calmodulin-dependent protein kinase II activity by morphine-sensitization in rat hippocampus.

    PubMed

    Kadivar, Mehdi; Farahmandfar, Maryam; Ranjbar, Faezeh Esmaeli; Zarrindast, Mohammad-Reza

    2014-07-01

    Repeated exposure to drugs of abuse, such as morphine, elicits a progressive enhancement of drug-induced behavioral responses, a phenomenon termed behavioral sensitization. These changes in behavior may reflect long-lasting changes in some of the important molecules involved in memory processing such as calcium/calmodulin-dependent protein kinase II (CaMKII). In the present study, we investigated the effect of morphine sensitization on mRNA expression of α and β isoforms and activity of CaMKII in the hippocampus of male rats. Animals were treated for 3 days with saline or morphine (20mg/kg) and following a washout period of 5 days, a challenge dose of morphine (5mg/kg) were administered. The results indicate that morphine administration in pre-treated animals produces behavioral sensitization, as determined by significant increase in locomotion and oral stereotypy behavior. In addition, repeated morphine treatment increased mRNA expression of both α and β isoforms of CaMKII in the hippocampus. The present study also showed that induction of morphine sensitization significantly increased both Ca2+/calmodulin-independent and Ca2+/calmodulin-dependent activities of CaMK II in the rat hippocampus. However, acute administration of morphine (5mg/kg) did not alter either α and β CaMKII mRNA expression or CaMKII activity in the hippocampus. The stimulation effects of morphine sensitization on mRNA expression and activity of CaMKII were completely abolished by administration of naloxone, 30min prior to s.c. injections of morphine (20mg/kg/day×3 days). Our data demonstrated that induction of morphine sensitization could effectively modulate the activity and the mRNA expression of CaMKII in the hippocampus and this effect of morphine was exerted by the activation of opioid receptors.

  5. [Study of Preparation and Utility of Suppository Containing Carbamazepine Tablet for Hospital Use in Rabbits].

    PubMed

    Murata, Isamu; Arai, Narutoshi; Fukushima, Aishi; Saito, Astuko; Inoue, Yutaka; Kimura, Masayuki; Kanamoto, Ikuo

    2015-01-01

    Cancer patients often report a decreased quality of life due to cancer-related pain, especially neuropathic pain, which is difficult to manage and often develops resistance to morphine. Thus a supplementary analgesic can play an important role in the treatment of cancer-related pain. Carbamazepine (CBZ), for example, can be effective, but only if the patient can take medication orally because it is limited to oral administration. In this study we investigated the efficacy of a suppository containing CBZ tablet in hospital preparations. We selected a base for the suppository of either polyethylene glycol (P), Witepsol VOSCO(®) H-15 (H), or Witepsol VOSCO(®) S-55 (S). Six to eight in vitro and in vivo groups were divided randomly based on route of administration and treatment: intravenous (i.v.), per os (p.o.), and intrarectal administration (i.r.) (composed of CBZ powder and tablet formulations, CBZp and CBZt) prepared in either a base of P, H, or S (CBZp/P, CBZp/H, CBZp/S, CBZt/P, CBZt/H, and CBZt/S). The hardness levels of the CBZt suppository group were significantly lower than the CBZp suppository group. The drug release profiles of the CBZt suppository group were high in order of P, H, and S; there were no significant differences between these groups and the CBZp suppository group. The maximum drug concentration time levels of the CBZt suppository group significantly increased compared with the p.o. group. These two groups had equivalent maximum drug concentration and bioavailability levels. These results suggest that a suppository containing CBZ tablet can be useful for hospital preparations.

  6. Pooled post hoc analysis of population pharmacokinetics of oxycodone and acetaminophen following a single oral dose of biphasic immediate-release/extended-release oxycodone/acetaminophen tablets.

    PubMed

    Franke, Ryan M; Morton, Terri; Devarakonda, Krishna

    2015-01-01

    This analysis evaluated the single-dose population pharmacokinetics (PK) of biphasic immediate-release (IR)/extended-release (ER) oxycodone (OC)/acetaminophen (APAP) 7.5/325 mg tablets administered under fasted conditions and the effects of a meal on their single-dose population PK. Data were pooled from four randomized, single-dose crossover trials enrolling healthy adult (18-55 years old) participants (three trials) and nondependent recreational users of prescription opioids (one trial) with a body weight of ≥59 kg. Participants received IR/ER OC/APAP 7.5/325 mg tablets in single doses of 7.5/325 mg (one tablet), 15/650 mg (two tablets), or 30/1,300 mg (four tablets) under fasted or fed conditions. Six variables were examined: sex, race, age, weight, height, and body mass index. Single-dose population PK was analyzed using first-order conditional estimation methods. A total of 151 participants were included in the analysis under fasted conditions, and 31 participants were included in the fed analysis. Under fasted conditions, a 10% change in body weight was accompanied by ~7.5% change in total body clearance (CL/F) and volume of distribution (V/F) of OC and APAP. Black participants had 17.3% lower CL/F and a 16.9% lower V/F of OC compared with white participants. Under fed conditions, the absorption rate constant of OC and APAP decreased significantly, although there was no effect on CL/F and V/F. Considering that the recommended dose for IR/ER OC/APAP 7.5/325 mg tablets is two tablets every 12 hours, adjustments of <50% are not clinically relevant. Dose adjustment may be necessary for large deviations from average body weight, but the small PK effects associated with race and consumption of a meal are not clinically relevant.

  7. Pooled post hoc analysis of population pharmacokinetics of oxycodone and acetaminophen following a single oral dose of biphasic immediate-release/extended-release oxycodone/acetaminophen tablets

    PubMed Central

    Franke, Ryan M; Morton, Terri; Devarakonda, Krishna

    2015-01-01

    This analysis evaluated the single-dose population pharmacokinetics (PK) of biphasic immediate-release (IR)/extended-release (ER) oxycodone (OC)/acetaminophen (APAP) 7.5/325 mg tablets administered under fasted conditions and the effects of a meal on their single-dose population PK. Data were pooled from four randomized, single-dose crossover trials enrolling healthy adult (18–55 years old) participants (three trials) and nondependent recreational users of prescription opioids (one trial) with a body weight of ≥59 kg. Participants received IR/ER OC/APAP 7.5/325 mg tablets in single doses of 7.5/325 mg (one tablet), 15/650 mg (two tablets), or 30/1,300 mg (four tablets) under fasted or fed conditions. Six variables were examined: sex, race, age, weight, height, and body mass index. Single-dose population PK was analyzed using first-order conditional estimation methods. A total of 151 participants were included in the analysis under fasted conditions, and 31 participants were included in the fed analysis. Under fasted conditions, a 10% change in body weight was accompanied by ~7.5% change in total body clearance (CL/F) and volume of distribution (V/F) of OC and APAP. Black participants had 17.3% lower CL/F and a 16.9% lower V/F of OC compared with white participants. Under fed conditions, the absorption rate constant of OC and APAP decreased significantly, although there was no effect on CL/F and V/F. Considering that the recommended dose for IR/ER OC/APAP 7.5/325 mg tablets is two tablets every 12 hours, adjustments of <50% are not clinically relevant. Dose adjustment may be necessary for large deviations from average body weight, but the small PK effects associated with race and consumption of a meal are not clinically relevant. PMID:26316698

  8. Wuchereria bancrofti antigenemia clearance among Myanmar migrants after biannual mass treatments with diethylcarbamazine, 300 mg oral-dose FILADEC tablet, in Southern Thailand.

    PubMed

    Koyadun, Surachart; Bhumiratana, Adisak; Prikchu, Pathomporn

    2003-12-01

    Using qualitative ICT Filariasis and quantitative Og4C3 ELISA, we assessed a long-term macrofilaricidal effect of two-year biannual mass treatments with a 300 mg oral-dose FILADEC tablet, a reformulation of 6 mg/kg diethylcarbamazine (DEC), on clearance of the Wuchereria bancrofti adult worm circulating filarial antigens (CFA) in Myanmar migrants, at risk of emergence of imported bancroftian filariasis in Southern Thailand. Of the 34 antigenemic Myanmar index cases of varying initial CFA levels, who were initially screened out with the ICT Filariasis, 13 index cases were follow-up treated and monitored at the DEC post treatments, 6, 12, and 18 months. At the 18-month post treatment, residual antigenemias (%) in 4 of 5 index cases (group 1) with high antigen titers (99.7-181.6 x 10(3) AU/ml) were 54.44%, 33.58%, 27.43%, and 9.97%. Significant decreases of the CFA levels in only 3 out of 5 index cases were affected by the response to DEC treatments (p < 0.007). The treatment effects on clearance of the CFA in 8 index cases (group II) with low antigen titers (15.4-37.2 x 10(3) AU/ml) were shown for at least 6 months post DEC treatment and hence had 100% efficacy in the first 6 months of the first year of year round treatment. Group I, was more likely to show an increase of the DEC efficacy after the first 6 months of the second year round treatment, but there was no statistically significant difference (p = 0.063). We reemphasized that, for use in the national program to eliminate lymphatic filariasis (PELF) in Thailand, such a DEC regimen had a macrofilaricidal effect on antigenemia clearance, and confirmed its value in evaluating response to the treatment and monitoring the long-term efficacy of the DEC regimen in W. bancrofti adult worm burden reductions in Myanmar migrants on a wide scale.

  9. 21 CFR 520.816 - Epsiprantel tablets.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.816 Epsiprantel tablets. (a... of feline cestodes D. caninum and T. taeniaeformis. (3) Limitations. For oral use only as a...

  10. 21 CFR 520.531 - Cythioate tablets.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ...) Limitations. For oral use in dogs only. Do not use in greyhounds or in animals that are pregnant, sick, under... and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.531 Cythioate tablets. (a)...

  11. 21 CFR 520.816 - Epsiprantel tablets.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.816 Epsiprantel tablets. (a... of feline cestodes D. caninum and T. taeniaeformis. (3) Limitations. For oral use only as a...

  12. 21 CFR 520.531 - Cythioate tablets.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.531 Cythioate tablets. (a) (b...) Limitations. For oral use in dogs only. Do not use in greyhounds or in animals that are pregnant, sick,...

  13. The effect of gut microbiome on tolerance to morphine mediated antinociception in mice.

    PubMed

    Kang, Minho; Mischel, Ryan A; Bhave, Sukhada; Komla, Essie; Cho, Alvin; Huang, Charity; Dewey, William L; Akbarali, Hamid I

    2017-02-17

    There is growing appreciation for the importance of gastrointestinal microbiota in many physiological and pathophysiological processes. While morphine and other narcotics are the most widely prescribed therapy for moderate to severe pain clinically, they have been noted to alter microbial composition and promote bacterial translocation to other tissues. Here we examined the pharmacodynamic properties of chronic morphine in mice following bacterial depletion with oral gavage of an antibiotic cocktail (ABX). ABX significantly reduced gut bacteria and prevented chronic morphine induced increases in gut permeability, colonic mucosal destruction, and colonic IL-1β expression. In addition, ABX prevented the development of antinociceptive tolerance to chronic morphine in both the tail-immersion and acetic acid stretch assays. Morphine tolerance was also reduced by oral vancomycin that has 0% bioavailability. These findings were recapitulated in primary afferent neurons isolated from dorsal root ganglia (DRG) innervating the lower gastrointestinal tract, wherein in-vivo administration of ABX prevented tolerance to morphine-induced hypoexcitability. Finally, though ABX repeatedly demonstrated an ability to prevent tolerance, we show that it did not alter susceptibility to precipitation of withdrawal by naloxone. Collectively, these finding indicate that the gastrointestinal microbiome is an important modulator of physiological responses induced by chronic morphine administration.

  14. The effect of gut microbiome on tolerance to morphine mediated antinociception in mice

    PubMed Central

    Kang, Minho; Mischel, Ryan A.; Bhave, Sukhada; Komla, Essie; Cho, Alvin; Huang, Charity; Dewey, William L.; Akbarali, Hamid I.

    2017-01-01

    There is growing appreciation for the importance of gastrointestinal microbiota in many physiological and pathophysiological processes. While morphine and other narcotics are the most widely prescribed therapy for moderate to severe pain clinically, they have been noted to alter microbial composition and promote bacterial translocation to other tissues. Here we examined the pharmacodynamic properties of chronic morphine in mice following bacterial depletion with oral gavage of an antibiotic cocktail (ABX). ABX significantly reduced gut bacteria and prevented chronic morphine induced increases in gut permeability, colonic mucosal destruction, and colonic IL-1β expression. In addition, ABX prevented the development of antinociceptive tolerance to chronic morphine in both the tail-immersion and acetic acid stretch assays. Morphine tolerance was also reduced by oral vancomycin that has 0% bioavailability. These findings were recapitulated in primary afferent neurons isolated from dorsal root ganglia (DRG) innervating the lower gastrointestinal tract, wherein in-vivo administration of ABX prevented tolerance to morphine-induced hypoexcitability. Finally, though ABX repeatedly demonstrated an ability to prevent tolerance, we show that it did not alter susceptibility to precipitation of withdrawal by naloxone. Collectively, these finding indicate that the gastrointestinal microbiome is an important modulator of physiological responses induced by chronic morphine administration. PMID:28211545

  15. Role of various natural, synthetic and semi-synthetic polymers on drug release kinetics of losartan potassium oral controlled release tablets

    PubMed Central

    Jayasree, J.; Sivaneswari, S.; Hemalatha, G.; Preethi, N.; Mounika, B.; Murthy, S. Vasudeva

    2014-01-01

    Objective: The objective of the present work was to formulate and to characterize controlled release matrix tablets of losartan potassium in order to improve bioavailability and to minimize the frequency of administration and increase the patient compliance. Materials and Methods: Losartan potassium controlled release matrix tablets were prepared by direct compression technique by the use of different natural, synthetic and semisynthetic polymers such as gum copal, gum acacia, hydroxypropyl methyl cellulose K100 (HPMC K100), eudragit RL 100 and carboxy methyl ethyl cellulose (CMEC) individually and also in combination. Studies were carried out to study the influence of type of polymer on drug release rate. All the formulations were subjected to physiochemical characterization such as weight variation, hardness, thickness, friability, drug content, and swelling index. In vitro dissolution studies were carried out simulated gastric fluid (pH 1.2) for first 2 h and followed by simulated intestinal fluid (pH 6.8) up to 24 h, and obtained dissolution data were fitted to in vitro release kinetic equations in order to know the order of kinetics and mechanism of drug release. Results and Discussion: Results of physiochemical characterization of losartan potassium matrix tablets were within acceptable limits. Formulation containing HPMC K100 and CMEC achieved the desired drug release profile up to 24 h followed zero order kinetics, release pattern dominated by Korsmeyer — Peppas model and mechanism of drug release by nonfickian diffusion. The good correlation obtained from Hixson-Crowell model indicates that changes in surface area of the tablet also influences the drug release. Conclusion: Based on the results, losartan potassium controlled release matrix tablets prepared by employing HPMC K100 and CMEC can attain the desired drug release up to 24 h, which results in maintaining steady state concentration and improving bioavailability. PMID:25426439

  16. Comparative efficacy of a spot-on formulation containing emodepside and praziquantel (Profender ®, Bayer) and praziquantel and pyrantel oral tablets (Drontal ® for Cats) against experimental Ancylostoma ceylanicum infections in cats.

    PubMed

    Taweethavonsawat, Piyanan; Chungpivat, Sudchit; Watanapongchati, Supoj; Traub, Rebecca J; Schaper, Roland

    2013-01-16

    Ancylostoma ceylanicum is a common zoonotic hookworm of dogs and cats throughout Asia and has also been reported to occur within the Australasian region. The aim of this study to was to determine the efficacy of a spot-on formulation containing emodepside and praziquantel (Profender(®), Bayer) and praziquantel and pyrantel oral tablets (Drontal(®) for Cats, Bayer) against experimental A. ceylanicum infections in cats. Twenty-four kittens were each subcutaneously injected with 100 infective third-stage larvae of A. ceylanicum. Kittens were stratified by egg count and randomly allocated equally into control and two treatment groups. The first group were treated with emodepside 2.1%/praziquantel 8.6% (Profender®, Bayer) at the recommended label dose. The second group was treated with 80 mg pyrantel and 20mg praziquantel (Drontal(®) for Cats, Bayer) at the recommended label dose. The kittens in the control group were not treated. Egg counts were performed daily until the end of the study period and compared for the treated and control groups. No eggs were detected in the treated group of kittens within 4 days of treatment and faecal samples from this group remained negative throughout the rest of the study, resulting in a treatment efficacy (egg reduction) of 100% (P<0.0001). The egg counts remained high (993 ± 666 epg) in the untreated control group for the rest of the study period. This study demonstrated that both combination products containing topical emodepside/praziquantel (Profender(®), Bayer) and praziquantel/pyrantel oral tablets (Drontal(®) for Cats, Bayer) given at the recommended dose is highly effective against infection with A. ceylanicum in cats.

  17. Tablet Use within Medicine

    ERIC Educational Resources Information Center

    Hogue, Rebecca J.

    2013-01-01

    This paper discusses the scholarly literature related to tablet computer use in medicine. Forty-four research-based articles were examined for emerging categories and themes. The most studied uses for tablet computers include: patients using tablets to complete diagnostic survey instruments, medical professionals using tablet computers to view…

  18. Lubrication in tablet formulations.

    PubMed

    Wang, Jennifer; Wen, Hong; Desai, Divyakant

    2010-05-01

    Theoretical aspects and practical considerations of lubrication in tablet compression are reviewed in this paper. Properties of the materials that are often used as lubricants, such as magnesium stearate, in tablet dosage form are summarized. The manufacturing process factors that may affect tablet lubrication are discussed. As important as the lubricants in tablet formulations are, their presence can cause some changes to the tablet physical and chemical properties. Furthermore, a detailed review is provided on the methodologies used to characterize lubrication process during tablet compression with relevant process analytical technologies. Finally, the Quality-by-Design considerations for tablet formulation and process development in terms of lubrication are discussed.

  19. 21 CFR 520.2150a - Stanozolol tablets.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... chapter. (c) Conditions of use. (1) Used as an anabolic steroid treatment in dogs and cats. (2... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Stanozolol tablets. 520.2150a Section 520.2150a... DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.2150a Stanozolol tablets....

  20. Miconazole mucoadhesive tablet for oropharyngeal candidiasis

    PubMed Central

    Lalla, Rajesh V; Bensadoun, René-Jean

    2011-01-01

    Oropharyngeal candidiasis is a commonly encountered problem in daily clinical practice. Topical therapies for oropharyngeal candidiasis are considered preferable to systemic therapies in most patient populations. However, traditional topical therapies have limitations including short contact time with the oral mucosa and the need for multiple doses each day. Miconazole mucoadhesive tablet has recently been approved in Europe (Loramyc®) and the USA (Oravig™) for the treatment of oropharyngeal candidiasis. This tablet adheres to the oral mucosa and provides sustained local release of miconazole over a period of several hours with just one daily application. This article reviews the pharmacology, safety and efficacy of this novel agent. PMID:21171872

  1. Evaluation of the ease of taking mini-tablets compared with other tablet formulations in healthy volunteers.

    PubMed

    Hayakawa, Yoshiyuki; Uchida, Shinya; Namiki, Noriyuki

    2016-03-10

    "Mini-tablets" (MTs) are tablets of diameter≤3mm and have been widely studied and developed. However, reports comparing MTs with other tablet formulations are few. We wished to evaluate the ease of taking a MT quantitatively in comparison with an orally disintegrating mini-tablet (ODMT), conventional tablet (CT) and conventional orally disintegrating tablet (ODT). Four types of tablets were prepared. We prepared tablets of two diameters (3mm for MTs and ODMTs vs. 8mm for CTs and ODTs) and two formulations (MTs and CTs vs. ODMTs and ODTs). Our randomized crossover trial in 18 healthy volunteers (8 men and 10 women; mean age, 22.5years) indicated that the visual analog scale (VAS) score for the ease and amount of water required for intake of MTs was significantly lower than those of CTs. An ODMT required the least amount of water and smallest VAS score for the ease of taking a tablet. Our results showed that the advantage of MTs with regard to the ease of taking and decreased amount of water required was exerted for a unit of dosing comprising <5 tablets. These data suggested the usefulness of MTs and the importance of the number of MTs for comfortable consumption by patients.

  2. EDX-Element Analysis of the In Vitro Effect of Fluoride Oral Hygiene Tablets on Artificial Caries Lesion Formation and Remineralization in Human Enamel.

    PubMed

    Eggerath, J; Kremniczky, T; Gaengler, P; Arnold, W H

    2011-01-01

    Aim of this in-vitro-study was to assess the remineralization potential of a tooth cleaning tablet with different fluoride content quantitatively using EDX analysis.Twenty three caries free impacted third molars were examined; enamel surfaces were wax coated leaving two 3x4mm windows for exposure to demineralization/remineralization cycles. The teeth were randomly assigned to 4 groups of 5 control and 6 experimental teeth each. Demineralization by standardized HEC-gel, pH 4.7 at 37°C for 72h, was alternated by rinsing in remineralization solution, pH 7.0 at 37°C for 72h, total challenge time 432h. The negative control group N was treated during remineralization cycles with saline; positive control group P was treated with remineralization solution; experimental group D1 was exposed to remineralization solution containing Denttabs(®)-tablets with 1450 ppm F; experimental group D2 was exposed to remineralization solution and Denttabs(®)-tablets with 4350 ppm F. Each tooth was cut into serial sections and analyzed by scanning electron microscopy with EDX element analysis for assessment of the different zones of the lesions in 3 representative sections. Statistical analysis was based on the AVOVA test for repeated measurements and post hoc Bonferroni adjustment. The results showed a significantly higher Ca and P content in the body of the lesion in both fluoride treated groups compared to the controls. It can be concluded that higher concentrations of NaF may be more effective in remineralization of early advanced caries lesions.

  3. Miconazole mucoadhesive buccal tablet in high-dose therapy with autologous stem cell transplantation (HDT/ASCT)-induced mucositis.

    PubMed

    Orvain, C; Moles-Moreau, M P; François, S; Mercier, M; Moal, F; Hamel, J F; Parot-Schinkel, E; Ifrah, N; Hunault-Berger, M; Tanguy-Schmidt, A

    2015-02-01

    Oral mucositis is a major cause of morbidity in high-dose therapy/autologous stem cell transplantation (HDT/ASCT), where microbial colonization has an important pathological implication. In this study, we evaluated the impact of miconazole mucoadhesive buccal tablet (MBT) on mucositis-related complications. During two consecutive 34-month periods, patients treated with HDT/ASCT in our hematology department received either miconazole MBT (60 patients) or conventional oral amphotericin B suspensions three times a day (44 patients) in order to prevent or decrease chemotherapy-induced mucositis. The use of miconazole MBT is associated with less infectious complications as indicated by shorter antibiotic use (7.8 vs. 12.3 days; p < 0.0001), shorter intravenous antifungal use (1.4 vs. 3.6 days; p = 0.02), and a trend towards less yeast contamination in stool samples. Less patients required any analgesic drugs during hospitalization in the miconazole MBT group (18 vs. 7 %; p = 0.09). Indirect indicators of chemotherapy-induced mucositis (duration of hospitalization, morphine use) were in favor of miconazole MBT in patients with multiple myeloma (MM) but not for those with lymphoma. This study suggests that miconazole MBT provides a valid alternative to oral amphotericin B suspensions in regards to mucositis-related complications. A prospective and randomized study is warranted to establish the definite role of miconazole MBT.

  4. 21 CFR 520.2123a - Spectinomycin tablets.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    .... (a) Specifications. Each tablet contains spectinomycin dihydrochloride pentahydrate equivalent to 100... use in dogs—(1) Amount. Administer orally to provide 10 mg per pound (lb) of body weight twice...

  5. 21 CFR 520.2150a - Stanozolol tablets.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... chapter. (c) Conditions of use. (1) Used as an anabolic steroid treatment in dogs and cats. (2) Administered orally to cats and small breeds of dogs, 1/2 to 1 tablet twice daily for several weeks; to...

  6. Neuroexcitatory effects of morphine and hydromorphone: evidence implicating the 3-glucuronide metabolites.

    PubMed

    Smith, M T

    2000-07-01

    1. Morphine is recommended by the World Health Organization as the drug of choice for the management of moderate to severe cancer pain. 2. Education of health professionals in the past decade has resulted in a large increase in the prescribing of opioids, such as morphine, and in the magnitude of the doses administered, resulting in an improvement in the quality of pain relief available for many cancer patients. 3. However, the reported incidence of neuroexcitatory side effects (allodynia, myoclonus, seizures) in patients administered large doses of systemic morphine or its structural analogue, hydromorphone (HMOR), has also increased. 4. Clinically, increasing the magnitude of the morphine or HMOR dose administered to patients already exhibiting neuroexcitatory opioid related side effects, results in an exacerbation rather than an attenuation of the excitatory behaviours. 5. In contrast, cessation of the opioid or rotation to a structurally dissimilar opioid (e.g. from morphine/HMOR to methadone or fentanyl), usually results in a restoration of analgesia and resolution of the neuroexcitatory opioid side effects over a period of hours to days. 6. To explain the clinical success of 'opioid rotation', it is essential to understand the in vivo metabolic fate of morphine and HMOR. 7. Following systemic administration, morphine and HMOR are metabolized primarily to the corresponding 3-glucuronide metabolites, morphine-3-glucuronide (M3G) and hydromorphone-3-glucuronide (H3G), which are not only devoid of analgesic activity but evoke a range of dose-dependent excitatory behaviours, including allodynia, myoclonus and seizures, following intracerebroventricular (i.c.v.) administration to rats. 8. Several studies have shown that, following chronic oral or subcutaneous morphine administration to patients with cancer pain, the cerebrospinal fluid (CSF) concentrations of M3G exceed those of morphine and morphine-6-glucuronide (analgesically active morphine metabolite) by

  7. Morphine metabolism in the naturally morphine-tolerant afghan pika: a preliminary study.

    PubMed

    Coimbra-Farges, R; Puget, A; Monsarrat, B; Moisand, C; Meunier, J C

    1990-01-01

    The afghan pika (Ochotona rufescens), a lagomorph which is naturally tolerant to the analgesic action of morphine, metabolizes morphine into morphine 3-glucuronide apparently faster than does the rabbit, another lagomorph which is however normally responsive to morphine. In the two species, following morphine administration, another unidentified component appears very soon (5 min) in pika blood plasma and much later (60 min) in rabbit blood plasma. This unknown component which appears not to be morphine derived might be involved in the natural resistance of the Afghan pika to morphine.

  8. Morphine, morphine-6-glucuronide and morphine-3-glucuronide pharmacokinetics in newborn infants receiving diamorphine infusions.

    PubMed

    Barrett, D A; Barker, D P; Rutter, N; Pawula, M; Shaw, P N

    1996-06-01

    1. The pharmacokinetics of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) were studied in 19 ventilated newborn infants (24-41 weeks gestation) who were given a loading dose of 50 micrograms kg-1 or 200 micrograms kg-1 of diamorphine followed by an intravenous infusion of 15 micrograms kg-1 h-1 of diamorphine. Plasma concentrations of morphine, M3G and M6G were measured during the accrual to steady-state and at steady state of the diamorphine infusion. 2. Following both the 50 micrograms kg-1 or 200 micrograms kg-1 loading doses the mean steady-state plasma concentration (+/- s.d.) of morphine, M3G and M6G were 86 +/- 52 ng ml-1, 703 +/- 400 ng ml-1 and 48 +/- 28 ng ml-1 respectively and morphine clearance was found to be 4.6 +/- 3.2 ml min-1 kg-1. 3. M3G formation clearance was estimated to be 2.5 +/- 1.8 ml min-1 kg-1, and the formation clearance of M6G was estimated to be 0.46 +/- 0.32 ml min-1 kg-1. 4. M3G metabolite clearance was 0.46 +/- 0.60 ml min-1 kg-1, the elimination half-life was 11.1 +/- 11.3 h and the volume of distribution was 0.55 +/- 1.13 l kg-1. M6G metabolite clearance was 0.71 +/- 0.36 ml min-1 kg-1, the elimination half-life was 18.2 +/- 13.6 h and the volume of distribution was 1.03 +/- 0.88 l kg-1. 5. No significant effect of the loading dose (50 micrograms kg-1 or 200 micrograms kg-1) on the plasma morphine or metabolite concentrations or their derived pharmacokinetic parameters was found. 6. We were unable to identify correlations between gestational age of the infants and any of the determined pharmacokinetic parameters. 7. M3G: morphine and M6G: morphine steady-state plasma concentration ratios were 11.0 +/- 10.8 and 0.8 +/- 0.8, respectively. 8. The metabolism of morphine in neonates, in terms of the respective contributions of each glucuronide pathway, was similar to that in adults.

  9. Morphine-Induced Constipation Develops With Increased Aquaporin-3 Expression in the Colon via Increased Serotonin Secretion.

    PubMed

    Kon, Risako; Ikarashi, Nobutomo; Hayakawa, Akio; Haga, Yusuke; Fueki, Aika; Kusunoki, Yoshiki; Tajima, Masataka; Ochiai, Wataru; Machida, Yoshiaki; Sugiyama, Kiyoshi

    2015-06-01

    Aquaporin-3 (AQP3) is a water channel that is predominantly expressed in the colon, where it plays a critical role in the regulation of fecal water content. This study investigated the role of AQP3 in the colon in morphine-induced constipation. AQP3 expression levels in the colon were analyzed after oral morphine administration to rats. The degree of constipation was analyzed after the combined administration of HgCl(2) (AQP3 inhibitor) or fluoxetine (5-HT reuptake transporter [SERT] inhibitor) and morphine. The mechanism by which morphine increased AQP3 expression was examined in HT-29 cells. AQP3 expression levels in rat colon were increased during morphine-induced constipation. The combination of HgCl(2) and morphine improved morphine-induced constipation. Treatment with morphine in HT-29 cells did not change AQP3 expression. However, 5-HT treatment significantly increased the AQP3 expression level and the nuclear translocation of peroxisome proliferator-activated receptor gamma (PPARγ) 1 h after treatment. Pretreatment with fluoxetine significantly suppressed these increases. Fluoxetine pretreatment suppressed the development of morphine-induced constipation and the associated increase in AQP3 expression in the colon. The results suggest that morphine increases the AQP3 expression level in the colon, which promotes water absorption from the luminal side to the vascular side and causes constipation. This study also showed that morphine-induced 5-HT secreted from the colon was taken into cells by SERT and activated PPARγ, which subsequently increased AQP3 expression levels.

  10. Speed of kill efficacy and efficacy of flavored spinosad tablets administered orally to cats in a simulated home environment for the treatment and prevention of cat flea (Ctenocephalides felis) infestations.

    PubMed

    Snyder, Daniel E; Meyer, Katherine A; Wiseman, Scott; Trout, Candace M; Young, David R

    2013-09-23

    The efficacy of spinosad against adult fleas (Ctenocephalides felis) on cats was evaluated in two separate controlled, blinded studies-one to determine flea knockdown and speed of flea kill (SOFK) on experimentally infested cats, another to assess the ability of spinosad to prevent flea infestations in a simulated home environment (SHE) study design. In each study, pre-treatment live flea counts were used as a blocking factor to randomize cats to treatment, and treated in the fed state, with flavored tablets containing either no active ingredient (control) or spinosad (50-100mg/kg in the SOFK study; 50-75 mg/kg body weight in the SHE study). In the SOFK study, 6 cats per group were infested with unfed adult fleas on Day -1. Groups 1-5 received control tablets; groups 6-10 received spinosad tablets. Flea counts were conducted at 0.5, 2, 4, 8 and 24h post-dosing. In the SHE study, 12 flea-free cats per group, treated on Days 0, 30 and 60, were maintained in solid-sided cages with solid carpeted floors. Each cat was infested on Days 1, 7 and 14 with 100 unfed adult fleas. Individual flea comb counts were performed on Days 3, 9, 16, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84, 91 and 95. After each count, except Day 95, up to 300 live fleas were replaced on each cat. To augment flea challenge, the carpeted area in each cage was sprinkled weekly with larval flea growth media (dried blood, yeast). In the SOFK study, reductions in mean flea counts in the spinosad groups were observed at all post-treatment assessments, beginning at 0.5h post-infestation with significant differences (p<0.0001) from vehicle-treated cats from 2h post-treatment when efficacy was >90%, through the final flea counts 24h post-infestation when no fleas were found on spinosad treated cats. In the SHE study, GM post-treatment flea counts in the control group ranged between 38.9 and 107.0 (arithmetic means 58.8-118.1); no live fleas were combed from spinosad-treated cats (100% effectiveness) at any time

  11. [High expectation for combination tablets for diabetes treatment].

    PubMed

    Uchida, Daigaku

    2012-09-01

    Recently, a combination therapy of several oral agents has been more common for antihyperglycemic therapy and four kinds of combination tablets are available in Japan. Any combination tablet is not allowed for the initial treatment but very useful for a numbers of patients who are already taking two-drug combinations and in stable condition to reduce the number of tablets. Additionally, a combination tablet is also beneficial for patients who are in inadequate glycemic control with a single agent to gain the better glucose lowing effectiveness with a single tablet of dual agents. For a favorable treatment outcome of chronic diseases, it is very important for physicians to enhance drug adherence rate of patients and utilize combination tablets more.

  12. Minocycline suppresses morphine-induced respiratory depression, suppresses morphine-induced reward, and enhances systemic morphine-induced analgesia

    PubMed Central

    Hutchinson, Mark R.; Northcutt, Alexis L.; Chao, Lindsey W.; Kearney, Jeffrey J.; Zhang, Yingning; Berkelhammer, Debra L.; Loram, Lisa C.; Rozeske, Robert R.; Bland, Sondra T.; Maier, Steven F.; Gleeson, Todd T.; Watkins, Linda R.

    2008-01-01

    Recent data suggest that opioids can activate immune-like cells of the central nervous system (glia). This opioid-induced glial activation is associated with decreased analgesia, owing to the release of proinflammatory mediators. Here we examine in rats whether the putative microglial inhibitor, minocycline, may affect morphine-induced respiratory depression and/or morphine-induced reward (conditioned place preference). Systemic co-administration of minocycline significantly attenuated morphine-induced reductions in tidal volume, minute volume, inspiratory force and expiratory force, but did not affect morphine-induced reductions in respiratory rate. Minocycline attenuation of respiratory depression was also paralleled with significant attenuation by minocycline of morphine-induced reductions in blood oxygen saturation. Minocycline also attenuated morphine conditioned place preference. Minocycline did not simply reduce all actions of morphine, as morphine analgesia was significantly potentiated by minocycline co-administration. Lastly, morphine dose-dependently increased cyclooxygenase-1 gene expression in a rat microglial cell line, an effect that was dose-dependently blocked by minocycline. Together, these data support that morphine can directly activate microglia in a minocycline-suppressible manner and suggest a pivotal role for minocycline-sensitive processes in the mechanisms of morphine-induced respiration depression, reward, and pain modulation. PMID:18706994

  13. 21 CFR 520.812 - Enrofloxacin tablets.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.812 Enrofloxacin tablets. (a... pregnant cats has not been established. Federal law restricts this drug to use by or on the order of...

  14. 21 CFR 520.1616 - Orbifloxacin tablets.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1616 Orbifloxacin tablets. (a... kilogram body weight once daily. (2) Indications for use. For management of diseases associated...

  15. 21 CFR 520.1451 - Moxidectin tablets.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1451 Moxidectin tablets. (a... Dirofilaria immitis and the subsequent development of canine heartworm disease. (3) Limitations. Use...

  16. 21 CFR 520.1451 - Moxidectin tablets.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1451 Moxidectin tablets. (a... Dirofilaria immitis and the subsequent development of canine heartworm disease. (3) Limitations. Use...

  17. 21 CFR 520.1616 - Orbifloxacin tablets.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1616 Orbifloxacin tablets. (a... kilogram body weight once daily. (2) Indications for use. For management of diseases associated...

  18. 21 CFR 520.1616 - Orbifloxacin tablets.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1616 Orbifloxacin tablets. (a... kilogram body weight once daily. (2) Indications for use. For management of diseases associated...

  19. 21 CFR 520.1451 - Moxidectin tablets.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1451 Moxidectin tablets. (a... Dirofilaria immitis and the subsequent development of canine heartworm disease. (3) Limitations. Use...

  20. 21 CFR 520.1451 - Moxidectin tablets.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1451 Moxidectin tablets. (a... Dirofilaria immitis and the subsequent development of canine heartworm disease. (3) Limitations. Use...

  1. 21 CFR 520.1616 - Orbifloxacin tablets.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1616 Orbifloxacin tablets. (a... kilogram body weight once daily. (2) Indications for use. For management of diseases associated...

  2. 21 CFR 520.1900 - Primidone tablets.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1900 Primidone tablets. (a... convulsions, viral encephalitis, distemper, and hardpad disease that occurs as a clinically...

  3. A Single-Dose, Single-Period Pharmacokinetic Assessment of an Extended-Release Orally Disintegrating Tablet of Methylphenidate in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder

    PubMed Central

    Childress, Ann; Newcorn, Jeffrey; Stark, Jeffrey G.; McMahen, Russ; Tengler, Mark

    2016-01-01

    Abstract Objective: To determine the pharmacokinetic (PK) profile of a proprietary formulation of methylphenidate (MPH) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) in a phase 1 study. Methylphenidate extended-release orally disintegrating tablets (MPH XR-ODTs) combine two technologies in a single-tablet formulation—an extended-release profile that was designed for once-daily dosing in an ODT that does not require water or chewing for ingestion. Methods: This was a single-dose, open-label, single-period, single-treatment study, in which 32 children with ADHD who were receiving MPH in doses of 40 or 60 mg before beginning the study each received a 60-mg dose (2 × 30 mg) of MPH XR-ODT. The following plasma PK parameters of MPH were determined for participants grouped by age (6–7, 8–9, 10–12, and 13–17 years old): maximum concentration (Cmax), time to maximum concentration (Tmax), elimination half-life (T½), area under the curve from 0 hours to infinity (AUCinf), oral clearance (CL/F), and volume of distribution in the terminal phase (Vz/F). Safety and tolerability were also assessed. Results: A total of 32 participants received the study drug. For all participants, plasma concentration–time profiles of MPH exhibited a broad peak after administration of MPH XR-ODT through ∼8 hours, indicating extended release from the formulation, followed by an apparent first-order elimination phase. As age increased, MPH exposure decreased and mean estimates of CL/F increased; however, weight-normalized CL/F values were comparable across age groups. Similarly, mean estimates of Vz/F increased with age, but weight-normalization decreased differences across age groups, with the exception of the youngest age group, which had higher values. All adverse events (AEs) were mild. Conclusion: This XR-ODT formulation of MPH demonstrated weight-normalized clearance rates that were consistent across all age groups, a PK profile

  4. Morphine induces albuminuria by compromising podocyte integrity.

    PubMed

    Lan, Xiqian; Rai, Partab; Chandel, Nirupama; Cheng, Kang; Lederman, Rivka; Saleem, Moin A; Mathieson, Peter W; Husain, Mohammad; Crosson, John T; Gupta, Kalpna; Malhotra, Ashwani; Singhal, Pravin C

    2013-01-01

    Morphine has been reported to accelerate the progression of chronic kidney disease. However, whether morphine affects slit diaphragm (SD), the major constituent of glomerular filtration barrier, is still unclear. In the present study, we examined the effect of morphine on glomerular filtration barrier in general and podocyte integrity in particular. Mice were administered either normal saline or morphine for 72 h, then urine samples were collected and kidneys were subsequently isolated for immunohistochemical studies and Western blot. For in vitro studies, human podocytes were treated with morphine and then probed for the molecular markers of slit diaphragm. Morphine-receiving mice displayed a significant increase in albuminuria and showed effacement of podocyte foot processes. In both in vivo and in vitro studies, the expression of synaptopodin, a molecular marker for podocyte integrity, and the slit diaphragm constituting molecules (SDCM), such as nephrin, podocin, and CD2-associated protein (CD2AP), were decreased in morphine-treated podocytes. In vitro studies indicated that morphine modulated podocyte expression of SDCM through opiate mu (MOR) and kappa (KOR) receptors. Since morphine also enhanced podocyte oxidative stress, the latter seems to contribute to decreased SDCM expression. In addition, AKT, p38, and JNK pathways were involved in morphine-induced down regulation of SDCM in human podocytes. These findings demonstrate that morphine has the potential to alter the glomerular filtration barrier by compromising the integrity of podocytes.

  5. Morphine or oxycodone in cancer pain?

    PubMed

    Heiskanen, T E; Ruismäki, P M; Seppälä, T A; Kalso, E A

    2000-01-01

    Oxycodone is an opioid analgesic that closely resembles morphine. Oxymorphone, the active metabolite of oxycodone, is formed in a reaction catalyzed by CYP2D6, which is under polymorphic genetic control. The role of oxymorphone in the analgesic effect of oxycodone is not yet clear. In this study, controlled-release (CR) oxycodone and morphine were examined in cancer pain. CR oxycodone and morphine were administered to 45 adult patients with stable pain for 3-6 days after open-label titration in a randomized, double-blind, cross-over trial. Twenty patients were evaluable. Both opioids provided adequate analgesia. The variation in plasma morphine concentrations was higher than that of oxycodone, consistent with the lower bioavailability of morphine. Liver dysfunction affected selectively either oxycodone or morphine metabolism. Three patients with markedly aberrant plasma opioid concentrations are presented. Significant individual variation in morphine and oxycodone metabolism may account for abnormal responses during treatment of chronic cancer pain.

  6. [Modern polymers in matrix tablets technology].

    PubMed

    Zimmer, Łukasz; Kasperek, Regina; Poleszak, Ewa

    2014-01-01

    Matrix tablets are the most popular method of oral drug administration, and polymeric materials have been used broadly in matrix formulations to modify and modulate drug release rate. The main goal of the system is to extend drug release profiles to maintain a constant in vivo plasma drug concentration and a consistent pharmacological effect. Polymeric matrix tablets offer a great potential as oral controlled drug delivery systems. Cellulose derivatives, like hydroxypropyl methylcellulose (HPMC) are often used as matrix formers. However, also other types of polymers can be used for this purpose including: Kollidon SR, acrylic acid polymers such as Eudragits and Carbopols. Nevertheless, polymers of natural origin like: carragens, chitosan and alginates widely used in the food and cosmetics industry are now coming to the fore of pharmaceutical research and are used in matrix tablets technology. Modern polymers allow to obtain matrix tablets by 3D printing, which enables to develop new formulation types. In this paper, the polymers used in matrix tablets technology and examples of their applications were described.

  7. Simultaneous quantification of chlorogenic acid and taurocholic acid in human plasma by LC-MS/MS and its application to a pharmacokinetic study after oral administration of Shuanghua Baihe tablets.

    PubMed

    Gu, Pan; Liu, Rui-Juan; Cheng, Min-Lu; Wu, Yao; Zheng, Lu; Liu, Yu-Jie; Ma, Peng-Cheng; Ding, Li

    2016-04-01

    An LC-MS/MS method was developed and validated for the simultaneous quantification of chlorogenic acid (CGA) and taurocholic acid (TCA) in human plasma using hydrochlorothiazide as the internal standard. The chromatographic separation was achieved on a Hedera ODS-2 column with a gradient elution using 10 mmol·L(-1) of ammonium acetate buffer solution containing 0.5% of formic acid - acetonitrile as mobile phase at a flow rate of 300 μL·min(-1). The detection was performed on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring in negative ESI mode. The method was fully validated over the concentration ranges of 0.1-10 ng·mL(-1) for CGA and 2-150 ng·mL(-1) for TCA. It was successfully applied to a pharmacokinetic study of CGA and TCA in healthy Chinese volunteers after oral administration of Shuanghua Baihe tablets (SBTs). In the single-dose study, the maximum plasma concentration (Cmax), time to reach Cmax (Tmax) and elimination half-life (t1/2) of CGA were (0.763 8 ± 0.542 0) ng·mL(-1), (1.0 ± 0.5) h, and (1.3 ± 0.6) h, respectively. In the multiple-dose study, the Cmax, Tmax and t1/2 of CGA were (0.663 7 ± 0.583 3) ng·mL(-1), (1.1 ± 0.5) h, and (1.4 ± 0.7) h, respectively. For TCA, no significant characteristic increasing plasma TCA concentration-time curve was found in the volunteers after oral administration of SBTs, indicating its complicated process in vivo as an endogenous ingredient.

  8. Simultaneous determination of four phenolic acids and seven alkaloids in rat plasma after oral administration of traditional Chinese medicinal preparation Jinqi Jiangtang Tablet by LC-ESI-MS/MS.

    PubMed

    Chang, Yan-xu; Ge, Ai-hua; Yu, Xie-an; Jiao, Xiu-cheng; Li, Jin; He, Jun; Tian, Ji; Liu, Wei; Azietaku, John Teye; Zhang, Bo-li; Gao, Xiu-mei

    2016-01-05

    A rapid, sensitive and selective high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous determination of four phenolic acids (neochlorogenic acid, chlorogenic acid, cryptochlorogenic acid and ferulic acid) and seven alkaloids (berberine, epiberberine, coptisine, magnoflorine, berberubine, palmatine and jatrorrhizine) in rat plasma. After mixing with the internal standards tetrahydropalmatine (IS1) and rosmarinic acid (IS2), plasma samples were pretreated by protein precipitation using acetonitrile. The HPLC analysis was performed on an Agilent Eclipse plus C18 (4.6 mm×100 mm, 1.8 μm) column with mobile phase consisting of 0.1% formic acid aqueous solution and acetonitrile at a flow rate of 0.3 mL min(-1). The detection was accomplished for the analytes and internal standards using positive electrospray ionization for the alkaloids and negative electrospray ionization for the phenolic acids in multiple-reaction monitoring mode. The method showed a good linearity over a wide concentration range (r(2)>0.99). The lower limit of quantification of seven alkaloids was lower than 2 ng mL(-1) and that of four phenolic acids was less than 20 ng mL(-1). The developed method was applied to the pharmacokinetic study of 11 components after oral administration of traditional Chinese medicinal preparation Jinqi Jiangtang Tablet in rats.

  9. Tolerability of up to 200 days of prophylaxis with valganciclovir oral solution and/or film-coated tablets in pediatric kidney transplant recipients at risk of cytomegalovirus disease.

    PubMed

    Varela-Fascinetto, G; Benchimol, C; Reyes-Acevedo, R; Genevray, M; Bradley, D; Ives, J; Silva, H T

    2017-02-01

    This multicenter, open-label study evaluated the tolerability of extended prophylaxis with valganciclovir in pediatric kidney transplant recipients at risk of CMV disease. Fifty-six patients aged 4 months to 16 years received once-daily valganciclovir oral solution and/or tablets, dosed by BSA and renal function, for up to 200 days. The most common AEs on treatment were upper respiratory tract infection (33.9%), urinary tract infection (33.9%), diarrhea (32.1%), leukopenia (25.0%), neutropenia (23.2%), and headache (21.4%). There were fewer AEs during days 101-228 vs days 1-100. Twenty-seven patients (48.2%) had treatment-related AEs during valganciclovir treatment, most commonly leukopenia (21.4%), neutropenia (19.6%), anemia (7.1%), and tremor (5.4%). Treatment-related serious AEs were reported for nine patients (16.1%) and six withdrew due to AEs. Viremia was centrally confirmed in 10 patients; there was no confirmed CMV disease. One patient tested positive for a resistance mutation (UL97 L595F). Biopsy-proven acute rejection occurred in six patients (10.7%), but no graft loss or deaths occurred. In conclusion, up to 200 days of valganciclovir prophylaxis in pediatric kidney allograft recipients showed a safety profile consistent with that established in adult transplant patients.

  10. Preparation of highly porous gastroretentive metformin tablets using a sublimation method.

    PubMed

    Oh, Tack-Oon; Kim, Ju-Young; Ha, Jung-Myung; Chi, Sang-Cheol; Rhee, Yun-Seok; Park, Chun-Woong; Park, Eun-Seok

    2013-04-01

    The present investigation is aimed to formulate floating gastroretentive tablets containing metformin using a sublimation material. In this study, the release of the drug from a matrix tablet was highly dependent on the polymer concentrations. In all formulations, initial rapid drug release was observed, possibly due to the properties of the drug and polymer. The effect of the amount of PEO on swelling and eroding of the tablets was determined. The water-uptake and erosion behavior of the gastroretentive (GR) tablets were highly dependent on the amount of PEO. The water-uptake increased with increasing PEO concentration in the tablet matrix. The weight loss from tablets decreased with increasing amounts of PEO. Camphor was used as the sublimation material to prepare GR tablets that are low-density and easily floatable. Camphor was changed to pores in the tablet during the sublimation process. SEM revealed that the GR tablets have a highly porous morphology. Floating properties of tablets and tablet density were affected by the sublimation of camphor. Prepared floating gastroretentive tablets floated for over 24 h and had no floating lag time. However, as the amount of camphor in the tablet matrix increased, the crushing strength of the tablet decreased after sublimation. Release profiles of the drug from the GR tablets were not affected by tablet density or porosity. In pharmacokinetic studies, the mean plasma concentration of the GR tablets after oral administration was greater than the concentration of glucophase XR. Also, the mean AUC(0-∞) values for the GR tablets were significantly greater than the plasma concentrations of glucophase XR.

  11. Non-destructive acoustic defect detection in drug tablets.

    PubMed

    Akseli, Ilgaz; Mani, Girindra N; Cetinkaya, Cetin

    2008-08-06

    For physical defect detection in drug tablets, a non-destructive and non-contact technique based on air coupled excitation and interferometric detection is presented. Physical properties and mechanical integrity of drug tablets can often affect their therapeutic and structural functions. The monitoring for defects and the characterization of tablet mechanical properties therefore have been of practical interest for solid oral dosage forms. The presented monitoring approach is based on the analysis of the transient vibrational responses of an acoustically excited tablet in both in temporal and spectral domains. The pulsed acoustic field exciting the tablet is generated by an air-coupled transducer. Using a laser vibrometer, the out-of-plane vibrational transient response of the tablet is detected and acquired in a non-contact manner. The physical state of the tablet is evaluated based on the spectral properties of these transient responses. In the current study, the effectiveness of three types of simple similarity measures is evaluated for their potential uses as defect detection norms, and for their potential use in quantifying the extent of tablet defect is discussed. It is found that these quantities can not only be used for identification of defective tablets, but could also provide a measure for the extent of the damage.

  12. Morphine, morphine-6-glucuronide and morphine-3-glucuronide pharmacokinetics in newborn infants receiving diamorphine infusions

    PubMed Central

    BARRETT, D. A.; BARKER, D. P.; RUTTER, N.; PAWULA, M.; SHAW, P. N.

    1996-01-01

    1The pharmacokinetics of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) were studied in 19 ventilated newborn infants(24–41 weeks gestation) who were given a loading dose of 50 μg kg−1 or 200 μg kg−1 of diamorphine followed by an intravenous infusion of 15 μg kg−1 h−1 of diamorphine. Plasma concentrations of morphine, M3G and M6G were measured during the accrual to steady-state and at steady state of the diamorphine infusion. 2Following both the 50 μg kg−1 or 200 μg kg−1 loading doses the mean steady-state plasma concentration (±s.d.) of morphine, M3G and M6G were 86±52 ng ml−1, 703±400 ng ml−1 and 48±28 ng ml−1 respectively and morphine clearance was found to be 4.6±3.2 ml min−1 kg−1. 3M3G formation clearance was estimated to be 2.5±1.8 ml min−1 kg−1, and the formation clearance of M6G was estimated to be 0.46±0.32 ml min−1 kg−1. 4M3G metabolite clearance was 0.46±0.60 ml min−1 kg−1, the elimination half-life was 11.1±11.3 h and the volume of distribution was 0.55±1.13 l kg−1. M6G metabolite clearance was 0.71±0.36 ml min−1 kg−1, the elimination half-life was 18.2±13.6 h and the volume of distribution was 1.03±0.88 l kg−1. 5No significant effect of the loading dose (50 μg kg−1 or 200 μg kg−1) on the plasma morphine or metabolite concentrations or their derived pharmacokinetic parameters was found. 6We were unable to identify correlations between gestational age of the infants and any of the determined pharmacokinetic parameters. 7M3G:morphine and M6G:morphine steady-state plasma concentration ratios were 11.0±10.8 and 0.8±0.8, respectively. 8The metabolism of morphine in neonates, in terms of the respective contributions of each glucuronide pathway, was similar to that in adults. PMID:8799518

  13. 21 CFR 520.62 - Aminopentamide hydrogen sulphate tablets.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... Section 520.62 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.62... mydriasis. (2) Dosage is administered by oral tablet every 8 to 12 hours, as follows: Weight of animal...

  14. A paper-based lateral flow assay for morphine.

    PubMed

    Teerinen, Tuija; Lappalainen, Timo; Erho, Tomi

    2014-09-01

    Morphine was used as a model analyte to examine the possibility of using cellulose, physically modified by papermaking and converting techniques, as a capillary matrix in a lateral flow type of diagnostic assay. This research was directed toward low-cost, disposable, and portable paper-based diagnostics, with the aim of addressing the analytical performance of paper as a substrate in the analysis for drugs of abuse. Antibody Fab fragments were used as sensing molecules, and gold nanoparticle detection was employed. Inkjet printing was used to pattern sensing biomolecules as detection zones on paper. To validate the usefulness of paper as a diagnostic platform, the principle of a direct sandwich assay, based on immunocomplex formation between morphine and the anti-morphine Fab fragment and detection of the formed immunocomplex by another Fab fragment, was implemented. Results were compared with that achieved by using nitrocellulose as a reference material. Possible interfering from the sample matrix on assay quality was investigated with spiked oral fluid samples. Under optimized conditions, a visually assessed limit of detection for the sandwich assay was 1 ng/mL, indicating that the paper-based test devices developed in this work can perform screening for drugs of abuse and can fulfill the requirement for a sensitive assay in diagnostically relevant ranges.

  15. Preparation and pharmaceutical evaluation of acetaminophen nano-fiber tablets: Application of a solvent-based electrospinning method for tableting.

    PubMed

    Hamori, Mami; Nagano, Kana; Kakimoto, Sayaka; Naruhashi, Kazumasa; Kiriyama, Akiko; Nishimura, Asako; Shibata, Nobuhito

    2016-03-01

    In this study, we developed nano-fiber-based tablets with acetaminophen (AAP; LogPow=0.51) for controlled-release delivery systems and evaluated in vitro drug dissolution and in vivo pharmacokinetics in rats. Nano-fibers made from methacrylic acid copolymer S (MAC; EUDRAGIT S100) and containing AAP were prepared using a solvent-based electrospinning (ES) method. In vitro dissolution rate profiles of AAP showed tableting pressure-dependent decreases and pH-dependent increases. The results of tablet tracking by X-ray irradiation showed tablets based on MAC nano-fibers did not disintegrate in the upper intestinal lumen and had the properties of a long-term-acting tablet. In addition, the in vitro release profiles of AAP from nano-fiber tablets prepared by dissolving MAC with AAP (NFT), nano-fiber tablets prepared by adsorbing AAP to drug-free MAC nano-fibers (NFTadso), and tablets prepared by adsorbing half the amount of AAP to MAC nano-fibers containing the remaining amount of AAP (NFThalf) showed independent controlled-release aspects of AAP compared with physical mixture tablets (PMT). In vivo pharmacokinetic studies in rats after intraduodenal administration of 14 mg/rat AAP in NFT, NFTadso, and NFThalf demonstrated that all these tablets based on MAC nano-fibers showed sustained-release profiles compared with PMT, and showed ultra-sustained release properties for AAP. These new tablets based on MAC nano-fibers did not disintegrate in the intestine in the lower pH region, and the tablets could regulate the release of AAP in a pH-dependent manner. The ES method is a useful technique to prepare nano-fibers and showed promising results as an oral delivery system for sustained-release regulation.

  16. Socially induced morphine pseudosensitization in adolescent mice.

    PubMed

    Hodgson, Stephen R; Hofford, Rebecca S; Roberts, Kris W; Wellman, Paul J; Eitan, Shoshana

    2010-03-01

    Given that social influences are among the strongest predictors of adolescents' drug use, this study examined the effect of social interaction on morphine-induced hyperlocomotion in both adolescent and adult mice. Three experimental groups of adolescent and adult male mice were examined (i) morphine-treated mice (twice daily, 10-40 mg/kg, subcutaneous), (ii) saline-injected mice housed together with the morphine-treated mice ('saline cage-mates'), and (iii) saline-injected mice housed physically and visually separated from the morphine-treated mice ('saline alone'). After the treatment period, mice were tested individually for their locomotor response to 10 mg/kg morphine (subcutaneous). Adolescent saline cage-mates, though administered morphine for the very first time, exhibited an enhanced hyperlocomotion response similar to the locomotor sensitization response exhibited by the morphine-treated mice. This was not observed in adults. In adults, there were no significant differences in morphine-induced hyperlocomotion between saline alone and saline cage-mates. As expected, morphine-treated adults and adolescents both exhibited locomotor sensitization. These results show a vulnerability to social influences in adolescent mice, which does not exist in adult mice.

  17. Immunoregulatory effects of morphine on human lymphocytes.

    PubMed Central

    Nair, M P; Schwartz, S A; Polasani, R; Hou, J; Sweet, A; Chadha, K C

    1997-01-01

    It is now well established that parenteral drug abuse is a significant risk factor for contracting human immunodeficiency virus type 1 (HIV-1) infection and subsequently developing AIDS. Earlier studies have shown that morphine can modulate various immune responses and therefore support the premise that morphine is a cofactor in susceptibility to and progression of HIV infection. Dysregulation of interferon (IFN) production, nonspecific apoptosis of T cells, and the immune response to soluble HIV gene products have been associated with potential mechanisms of pathogenesis in HIV disease. The present study was undertaken to examine the immunomodulatory role of morphine on HIV protein-induced lymphocyte proliferative responses, Sendai and Newcastle disease virus-induced alpha IFN (IFN-alpha) and IFN-beta production by lymphocytes and fibroblast cells, respectively, and induction of apoptosis of normal lymphocytes in vitro. Our results demonstrate that HIV protein-induced human lymphocyte proliferative responses were significantly inhibited by morphine in a dose-dependent manner. Furthermore, morphine significantly inhibited both IFN-alpha and IFN-beta production by normal lymphocytes and fibroblasts but induced apoptosis of normal lymphocytes. Inhibition of IFN-alpha production by morphine could be reversed by the opiate receptor antagonist naloxone. This suggests that the immunomodulatory effects of morphine are mediated through the opioid receptor. These studies support a role of morphine as a cofactor in the pathogenesis of HIV infection and describe some of the possible pathologic mechanisms which underlie the immunoregulatory effects of morphine. PMID:9067644

  18. The Trouble with Tablets.

    PubMed

    Espinoza, Kathy

    2015-09-01

    The biggest recommendation is to get your tablet screen up. This can be done by using a case or a tablet stand. Avoid using the tablet on your lap because posture follows vision. If you must use it on your lap, try placing it on a pillow to raise its height and reduce dangerous neck flexion. Whenever possible, set the tablet on a table rather than holding it with your hands because hands and forearms fatigue quickly. Consider finding an external keyboard that can be separated from the tablet screen. This way, you can set the tablet on a higher surface to elevate the screen and have a lower keyboard to eliminate some of the wrist extension when keying.

  19. The Environmental footprint of morphine: a life cycle assessment from opium poppy farming to the packaged drug

    PubMed Central

    McAlister, Scott; Ou, Yanjun; Neff, Elise; Hapgood, Karen; Story, David; Mealey, Philip; McGain, Forbes

    2016-01-01

    Objective To examine the environmental life cycle from poppy farming through to production of 100 mg in 100 mL of intravenous morphine (standard infusion bag). Design ‘Cradle-to-grave’ process-based life cycle assessment (observational). Settings Australian opium poppy farms, and facilities for pelletising, manufacturing morphine, and sterilising and packaging bags of morphine. Main outcome measures The environmental effects (eg, CO2 equivalent (‘CO2 e’) emissions and water use) of producing 100 mg of morphine. All aspects of morphine production from poppy farming, pelletising, bulk morphine manufacture through to final formulation. Industry-sourced and inventory-sourced databases were used for most inputs. Results Morphine sulfate (100 mg in 100 mL) had a climate change effect of 204 g CO2 e (95% CI 189 to 280 g CO2 e), approximating the CO2 e emissions of driving an average car 1 km. Water use was 7.8 L (95% CI 6.7– to 9.0 L), primarily stemming from farming (6.7 L). All other environmental effects were minor and several orders of magnitude less than CO2 e emissions and water use. Almost 90% of CO2 e emissions occurred during the final stages of 100 mg of morphine manufacture. Morphine's packaging contributed 95 g CO2 e, which accounted for 46% of the total CO2 e (95% CI 82 to 155 g CO2 e). Mixing, filling and sterilisation of 100 mg morphine bags added a further 86 g CO2 e, which accounted for 42% (95% CI 80 to 92 g CO2 e). Poppy farming (6 g CO2 e, 3%), pelletising and manufacturing (18 g CO2 e, 9%) made smaller contributions to CO2 emissions. Conclusions The environmental effects of growing opium poppies and manufacturing bulk morphine were small. The final stages of morphine production, particularly sterilisation and packaging, contributed to almost 90% of morphine's carbon footprint. Focused measures to improve the energy efficiency and sources for drug sterilisation and packaging could be explored as these are

  20. Novel approach of aceclofenac fast dissolving tablet.

    PubMed

    Dave, Vivek; Yadav, Sachdev; Sharma, Swapnil; Vishwakarma, Pushpendra; Ali, Nasir

    2015-01-01

    Fast disintegrating tablets (FDTs) have received ever increasing demand during the last decade, and the field has become a hastily growing area in the pharmaceutical industry. Upon introduction into the mouth, these tablets dissolve or disintegrate in the mouth in the absence of additional water for easy administration of active pharmaceutical ingredients. Aceclofenac, an NSAID, has been recommended orally for the treatment of bone and connective tissue disorder and thus the formulation of the same resulted in development of several FDT technologies. The present aim is to formulate a tablet which disintegrate and dissolve rapidly and give its rapid onset of action: analgesic, antipyretic and anti-inflammatory action. Besides, the conventional tablets also show poor patient compliance an attempt had been made to formulate for FDT of aceclofenac by using various super disintegrants like sodium starch glycolate, croscarmellose sodium and crosspovidone (polyplasdone XL) and PEG 6000 followed by novel technique. The tablets were evaluated for friability, hardness, weight variation, disintegration time, wetting time, in vitro dissolution studies and drug content studies. It was concluded that the batch which was prepared by using combination of crosspovidone and sodium starch glycolate as a super disintegrant shows excellent disintegration time, enhance dissolution rate, taste masking and hence lead to improve efficacy and bioavailability of drug.

  1. Urinary concentrations of morphine and codeine after consumption of poppy seeds.

    PubMed

    Thevis, Mario; Opfermann, Georg; Schänzer, Wilhelm

    2003-01-01

    A quantitative analysis of morphine and codeine in human urine was performed after oral intake of cakes containing commercially available poppy seeds in order to estimate the possibility of positive doping results. Therefore, eight products from different manufacturers (poppy seeds or baking mixtures) and origin were obtained and analyzed by gas chromatography-mass spectrometry for the presence of the alkaloids. One selected batch of poppy seeds was used as an ingredient in a typical cake and was the object of an excretion study with nine volunteers. After application, several urine specimens contained morphine with concentrations higher than 1 microg/mL, and peak values of approximately 10.0 microg/mL were detected. Because the International Olympic Committee set a cutoff limit for morphine at 1 microg/mL, high-performance athletes could possibly test positive in doping control after consumption of products containing poppy seeds.

  2. Differences in morphine-induced antinociception in male and female offspring born of morphine exposed mothers

    PubMed Central

    Biglarnia, Masoomeh; Karami, Manizheh; Hafshejani, Zahra Khodabakhshi

    2013-01-01

    Objective: Antinociceptive effect of morphine in offspring born of mothers that received saline or morphine during the gestation period was investigated. Materials and Methods: Wistar rats (200-250 g) received saline, morphine 0.5 mg/kg or 5 mg/kg during gestation days 14-16. All pups after weaning were isolated treatment/sex dependently and were allowed to fully mature. The antinociceptive effect of morphine was assessed in formalin test. Morphine (0.5-7.5 mg/kg) or saline (1 ml/kg) was injected intraperitoneally 10 min before formalin (50 μl of 2.5% solution in right hind-paw). Results: Male offspring born of saline-treated mothers were less morphine-sensitive than females. On the contrary, male offspring exposed prenatally to morphine (5 mg/kg) were more sensitive to morphine-induced antinociceptive response in formalin test. However, no difference in antinociceptive effect was observed amongst offspring of either sex born of mothers treated with morphine 0.5 mg/kg, identifying a lower dose effect of the opioid. Conclusion: The exposure to morphine during the developmental period may result in altered development of tolerance to morphine and thus involved in drug abuse. PMID:23833363

  3. Can personality traits and gender predict the response to morphine? An experimental cold pain study.

    PubMed

    Pud, Dorit; Yarnitsky, David; Sprecher, Elliot; Rogowski, Zeev; Adler, Rivka; Eisenberg, Elon

    2006-02-01

    The aim of the present study was to examine the possible role of personality traits, in accordance with Cloninger's theory, and gender, in the variability of responsiveness to opioids. Specifically, it was intended to test whether or not the three personality dimensions - harm avoidance (HA), reward dependence (RD) and novelty seeking (NS) - as suggested by Cloninger, can predict inter-personal differences in responsiveness to morphine after exposure to experimental cold pain. Thirty-four healthy volunteers (15 females, 19 males) were given the cold pressor test (CPT). Pain threshold, tolerance, and magnitude (VAS) were measured before and after (six measures, 30 min apart) the administration of either 0.5 mg/kg oral morphine sulphate (n=21) or 0.33 mg/kg oral active placebo (diphenhydramine) (n=13) in a randomized, double blind design. Assessment of the three personality traits, according to Cloninger's Tridimensional Personality Questionnaire, was performed before the CPT. A high HA score (but not RD, NS, or baseline values of the three pain parameters) predicted a significantly larger pain relief following the administration of morphine sulphate (but not of the placebo). Women exhibited a larger response in response to both treatments, as indicated by a significantly increased threshold and tolerance following morphine sulphate as well as significantly increased tolerance and decreased magnitude following placebo administration. The present study confirms the existence of individual differences in response to analgesic treatment. It suggests that high HA personality trait is associated with better responsiveness to morphine treatment, and that females respond better than men to both morphine and placebo.

  4. Comparison of efficacy of intra-articular morphine and steroid in patients with knee osteoarthritis

    PubMed Central

    Beyaz, Serbülent Gökhan

    2012-01-01

    Introduction: Primary therapeutic aim in treatment of osteoarthritis of the knee is to relieve the pain of osteoarthritis. The aim of this study was to compare the efficacy of intra-articular triamcinolone with intra-articular morphine in pain relief due to osteoarthritis of the knee in the elderly population. Materials and Methods: Patients between 50 and 80 years of age were randomized into three groups. Group M received morphine plus bupivacaine intra-articularly, Group T received triamcinolone plus bupivacaine intra-articularly, and Group C received saline plus bupivacaine intra-articularly. Patients were evaluated before injection and in 2nd, 4th, 6th, and 12th weeks after injection. First-line supplementary analgesic was oral paracetamol 1500 mg/day. If analgesia was insufficient with paracetamol, oral dexketoprofen trometamol 50 mg/day was recommended to patients. Results: After the intra-articular injection, there was statistically significant decrease in visual analog scale (VAS) scores in Groups M and T, when compared to Group C. The decrease of VAS scores seen at the first 2 weeks continued steadily up to the end of 12th week. There was a significant decrease in Groups M and T in the WOMAC scores, when compared to Group C. There was no significant difference in the WOMAC scores between morphine and steroid groups. Significantly less supplementary analgesics was used in the morphine and steroid groups. Conclusion: Intra-articular morphine was as effective as intra-articular triamcinolone for analgesia in patients with osteoarthritis knee. Intra-articular morphine is possibly a better option than intra-articular steroid as it has lesser side effects. PMID:23225932

  5. Using Raman spectroscopy in tablet moisture surface analysis: tablet surface markers.

    PubMed

    Atef, Eman; Chauhan, Harsh; Ceresia, Michelle; Pidgeon, Charles

    2010-12-01

    A method was developed to monitor the hydration of a tablet surface using chemical functional groups able to bind atmospheric water through H-bonding. In this study, generic oral dissolving loratadine tablets were used. These tablets have relatively high mannitol and lactose concentrations. Both mannitol and lactose have C-OH alcohol functional groups, several of which are potentially available for H-bonding with atmospheric water. The Raman intensity of the alcohol functional groups decreases upon hydration. This observation can be used to indirectly monitor water adsorbed to tablet surfaces at the alcohol sites. The hydration assay is based on the change in the Raman peak intensity of the alcohol C-OH stretching at 875.5 cm(-1). Consequently the decrease in the Raman intensity of this vibration can be used to monitor water adsorption. The Raman measurement of tablet surface water was compared to the direct moisture measurement method using a microbalance. The Raman spectroscopy is used to monitor the water that is specifically bound to the C-OH alcohol functional groups available for hydration. The microbalance was used to monitor the tablets' weight change during water adsorption and desorption. The distribution of the ratio of the Raman intensity of C-OH peak at 875.5 cm(-1) divided by the intensity of loratadine's C-Cl peak at 712.6 cm(-1) was experimentally determined to be a Gaussian distribution with a mean of 3.22+/-0.277. Raman analysis indicates that there is both tightly and loosely bound water at the tablet surface. This can be a useful technique with regard to inspecting and controlling the tablet drying process.

  6. Delay of Morphine Tolerance by Palmitoylethanolamide

    PubMed Central

    Di Cesare Mannelli, Lorenzo; Corti, Francesca; Micheli, Laura; Zanardelli, Matteo; Ghelardini, Carla

    2015-01-01

    In spite of the potency and efficacy of morphine, its clinical application for chronic persistent pain is limited by the development of tolerance to the antinociceptive effect. The cellular and molecular mechanisms underlying morphine tolerance are complex and still unclear. Recently, the activation of glial cells and the release of glia-derived proinflammatory mediators have been suggested to play a role in the phenomenon. N-Palmitoylethanolamine (PEA) is an endogenous compound with antinociceptive effects able to reduce the glial activation. On this basis, 30 mg kg−1 PEA was subcutaneously daily administered in morphine treated rats (10 mg kg−1 intraperitoneally, daily). PEA treatment significantly attenuated the development of tolerance doubling the number of days of morphine antinociceptive efficacy in comparison to the vehicle + morphine group. PEA prevented both microglia and astrocyte cell number increase induced by morphine in the dorsal horn; on the contrary, the morphine-dependent increase of spinal TNF-α levels was not modified by PEA. Nevertheless, the immunohistochemical analysis revealed significantly higher TNF-α immunoreactivity in astrocytes of PEA-protected rats suggesting a PEA-mediated decrease of cytokine release from astrocyte. PEA intervenes in the nervous alterations that lead to the lack of morphine antinociceptive effects; a possible application of this endogenous compound in opioid-based therapies is suggested. PMID:25874232

  7. Delay of morphine tolerance by palmitoylethanolamide.

    PubMed

    Di Cesare Mannelli, Lorenzo; Corti, Francesca; Micheli, Laura; Zanardelli, Matteo; Ghelardini, Carla

    2015-01-01

    In spite of the potency and efficacy of morphine, its clinical application for chronic persistent pain is limited by the development of tolerance to the antinociceptive effect. The cellular and molecular mechanisms underlying morphine tolerance are complex and still unclear. Recently, the activation of glial cells and the release of glia-derived proinflammatory mediators have been suggested to play a role in the phenomenon. N-palmitoylethanolamine (PEA) is an endogenous compound with antinociceptive effects able to reduce the glial activation. On this basis, 30 mg kg(-1) PEA was subcutaneously daily administered in morphine treated rats (10 mg kg(-1) intraperitoneally, daily). PEA treatment significantly attenuated the development of tolerance doubling the number of days of morphine antinociceptive efficacy in comparison to the vehicle + morphine group. PEA prevented both microglia and astrocyte cell number increase induced by morphine in the dorsal horn; on the contrary, the morphine-dependent increase of spinal TNF-α levels was not modified by PEA. Nevertheless, the immunohistochemical analysis revealed significantly higher TNF-α immunoreactivity in astrocytes of PEA-protected rats suggesting a PEA-mediated decrease of cytokine release from astrocyte. PEA intervenes in the nervous alterations that lead to the lack of morphine antinociceptive effects; a possible application of this endogenous compound in opioid-based therapies is suggested.

  8. Wettability studies of morphine sulfate powders.

    PubMed

    Prestidge, C A; Tsatouhas, G

    2000-04-05

    A capillary penetration technique was used to determine the wettability of morphine sulfate powders by a range of wetting and partially wetting liquids. Wetting rates were found to be dependent on both the properties of the wetting liquid and the morphine sulfate batch. A number of liquids were established as perfectly wetting, and the critical surface tension for morphine sulfate wetting was estimated to be approximately 40 mN m(-1). Effective capillary radii for packed beds of morphine sulfate powders were determined in the range 0.3-0.6 microm; these are compared with particle size, shape and surface area data. From the Washburn approach, the advancing water-particle contact angles for the different morphine sulfate samples were determined to be in the range 57-79 degrees, with errors less than +/-3 degrees. Sessile drop measurements on the same samples were unable to determine reproducible equilibrium contact angles and could not differentiate between the batches. The role of surface chemistry, crystal morphology and crystal structure in controlling morphine sulfate powder wettability was explored by X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM) and X-ray diffraction. Contact angles were shown to correlate with both the aspect ratio of the morphine sulfate crystals and the nitrogen-to-oxygen surface atomic concentration ratio, determined by SEM and XPS, respectively. The relative exposure of different crystal faces is considered to play an important role in controlling the wettability of morphine sulfate powders.

  9. Brain Reward Circuits in Morphine Addiction

    PubMed Central

    Kim, Juhwan; Ham, Suji; Hong, Heeok; Moon, Changjong; Im, Heh-In

    2016-01-01

    Morphine is the most potent analgesic for chronic pain, but its clinical use has been limited by the opiate’s innate tendency to produce tolerance, severe withdrawal symptoms and rewarding properties with a high risk of relapse. To understand the addictive properties of morphine, past studies have focused on relevant molecular and cellular changes in the brain, highlighting the functional roles of reward-related brain regions. Given the accumulated findings, a recent, emerging trend in morphine research is that of examining the dynamics of neuronal interactions in brain reward circuits under the influence of morphine action. In this review, we highlight recent findings on the roles of several reward circuits involved in morphine addiction based on pharmacological, molecular and physiological evidences. PMID:27506251

  10. 21 CFR 862.3640 - Morphine test system.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Morphine test system. 862.3640 Section 862.3640....3640 Morphine test system. (a) Identification. A morphine test system is a device intended to measure morphine, an addictive narcotic pain-relieving drug, and its analogs in serum, urine, and gastric...

  11. 21 CFR 862.3640 - Morphine test system.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Morphine test system. 862.3640 Section 862.3640....3640 Morphine test system. (a) Identification. A morphine test system is a device intended to measure morphine, an addictive narcotic pain-relieving drug, and its analogs in serum, urine, and gastric...

  12. 21 CFR 862.3640 - Morphine test system.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Morphine test system. 862.3640 Section 862.3640....3640 Morphine test system. (a) Identification. A morphine test system is a device intended to measure morphine, an addictive narcotic pain-relieving drug, and its analogs in serum, urine, and gastric...

  13. 21 CFR 862.3640 - Morphine test system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Morphine test system. 862.3640 Section 862.3640....3640 Morphine test system. (a) Identification. A morphine test system is a device intended to measure morphine, an addictive narcotic pain-relieving drug, and its analogs in serum, urine, and gastric...

  14. 21 CFR 862.3640 - Morphine test system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Morphine test system. 862.3640 Section 862.3640....3640 Morphine test system. (a) Identification. A morphine test system is a device intended to measure morphine, an addictive narcotic pain-relieving drug, and its analogs in serum, urine, and gastric...

  15. Toxicological analysis in rats subjected to heroin and morphine overdose.

    PubMed

    Strandberg, Joakim J; Kugelberg, Fredrik C; Alkass, Kanar; Gustavsson, Anna; Zahlsen, Kolbjørn; Spigset, Olav; Druid, Henrik

    2006-09-30

    In heroin overdose deaths the blood morphine concentration varies substantially. To explore possible pharmacokinetic explanations for variable sensitivity to opiate toxicity we studied mortality and drug concentrations in male Sprague-Dawley rats. Groups of rats were injected intravenously (i.v.) with heroin, 21.5 mg/kg, or morphine, 223 mg/kg, causing a 60-80% mortality among drug-naïve rats. Additional groups of rats were pre-treated with morphine for 14 days, with or without 1 week of subsequent abstinence. Brain, lung and blood samples were analyzed for 6-acetylmorphine, morphine, morphine-3-glucuronide and morphine-6-glucuronide. i.v. morphine administration to drug-naïve rats resulted in both rapid and delayed deaths. The brain morphine concentration conformed to an exponential elimination curve in all samples, ruling out accumulation of morphine as an explanation for delayed deaths. This study found no support for formation of toxic concentration of morphine-6-glucuronide. Spontaneous death among both heroin and morphine rats occurred at fairly uniform brain morphine concentrations. Morphine pre-treatment significantly reduced mortality upon i.v. morphine injection, but the protective effect was less evident upon i.v. heroin challenge. The morphine pre-treatment still afforded some protection after 1 week of abstinence among rats receiving i.v. morphine, whereas rats given i.v. heroin showed similar death rate as drug-naïve rats.

  16. Inhibition of morphine metabolism by ketamine.

    PubMed

    Qi, Xiaoxin; Evans, Allan M; Wang, Jiping; Miners, John O; Upton, Richard N; Milne, Robert W

    2010-05-01

    Clinical observation of a synergistic effect of ketamine on morphine analgesia remains controversial. Although a pharmacodynamic basis for an interaction has been explored in animal and clinical studies, the possibility of a pharmacokinetic mechanism has not been investigated. Whereas both morphine and morphine-6-glucuronide are effective analgesics, morphine-3-glucuronide (M3G) lacks activity. Thus, changes in the metabolism and disposition of morphine may result in an altered response. First, we investigated the interaction between morphine and ketamine in the isolated perfused rat liver preparation. The clearance of morphine was decreased from 16.8 +/- 4.6 ml/min in the control period to 7.7 +/- 2.8 ml/min in the ketamine-treatment period, with the formation clearance of M3G decreasing from 8.0 +/- 4.1 ml/min to 2.1 +/- 1.1 ml/min. Fractional conversion of morphine to M3G was significantly decreased from 0.46 +/- 0.17 in the control period to 0.28 +/- 0.14 upon the addition of ketamine. The possible mechanism of the interaction was further investigated in vitro with rat liver microsomes as the enzyme source. The formation of M3G followed single-enzyme Michaelis-Menten kinetics, with a mean apparent K(m) of 2.18 +/- 0.45 mM and V(max) of 8.67 +/- 0.59 nmol/min/mg. Ketamine inhibited morphine 3-glucuronidation noncompetitively, with a mean K(i) value of 33.3 +/- 7.9 microM. The results demonstrate that ketamine inhibits the glucuronidation of morphine in a rat model.

  17. RACK1 affects morphine reward via BDNF.

    PubMed

    Wan, Lihong; Xie, Yizhou; Su, Lan; Liu, Yanyou; Wang, Yuhui; Wang, Zhengrong

    2011-10-06

    Chronic morphine addiction may trigger functional changes in the mesolimbic dopamine system, which is believed to be the neurobiological substrate of opiate addiction. Brain derived neurotrophic factor (BDNF) has been implicated in addiction-related pathology in animal studies. Our previous studies have shown that RACK1 is involved in morphine reward in mice. The recent research indicates nuclear RACK1 by localizing at the promoter IV region of the BDNF gene and the subsequent chromatin modifications leads to the activation of the promoter and transcription of BDNF. The present study was designed to investigate if shRACK1 (a short hairpin RNA of RACK1) could reverse the mice's behavioral responses to morphine and BDNF expression in hippocampus and prefrontal cortex. No significant changes were observed in vehicle-infused mice which received no morphine treatment (CONC) and shRACK1-infused mice which received no morphine treatment (CONR), whereas vehicle-infused mice preceded the morphine injection (MIC) showed increased BDNF expression in hippocampus and prefrontal cortex, as compared to vehicle-infused mice which received no morphine treatment (CONC). Intracerebroventricular shRACK1 treatment reversed these, and in fact, ShRACK1-infused mice preceded the morphine injection (MIR) showed reduced BDNF expression in hippocampus and prefrontal cortex, as compared to MIC. In the conditioned place preference (CPP) test, inactivating RACK1 markedly reduces morphine-induced conditioned place preference. Non-specific changes in CPP could not account for these effects since general CPP of shRACK1- and vehicle-infused animals was not different. Combined behavioral and molecular approaches have support the possibility that the RACK1-BDNF system plays an important role in the response to morphine-induced reward.

  18. Development of fast disintegrating compressed tablets using amino acid as disintegration accelerator: evaluation of wetting and disintegration of tablet on the basis of surface free energy.

    PubMed

    Fukami, Jinichi; Ozawa, Asuka; Yoshihashi, Yasuo; Yonemochi, Etsuo; Terada, Katsuhide

    2005-12-01

    A fast disintegrating compressed tablet was formulated using amino acids, such as L-lysine HCl, L-alanine, glycine and L-tyrosine as disintegration accelerator. The tablets having the hardness of about 4 kgf were prepared and the effect of amino acids on the wetting time and disintegration time in the oral cavity of tablets was examined on the basis of surface free energy of amino acids. The wetting time of the tablets increased in the order of L-lysine HCl, L-alanine, glycine and L-tyrosine, whereas the disintegration time in the oral cavity of the tablets increased in the order of L-alanine, glycine, L-lysine HCl and L-tyrosine. These behaviors were well analyzed by the introduction of surface free energy. When the polar component of amino acid was large value or the dispersion component was small value, faster wetting of tablet was observed. When the dispersion component of amino acid was large value or the dispersion component was small value, faster disintegration of tablet was observed, expect of L-tyrosine tablet. The fast disintegration of tablets was explained by the theory presented by Matsumaru.

  19. Excretion of codeine and morphine following ingestion of poppy seeds.

    PubMed

    Struempler, R E

    1987-01-01

    After the ingestion of three poppy-seed bagels, the following codeine and morphine concentrations were determined in the urine: 214 ng/mL codeine and 2797 ng/mL morphine at 3 h, and 16 ng/mL codeine and 676 ng/mL morphine at 22 h. This work indicates that a positive finding of codeine or morphine in the urine of an individual does not necessarily indicate heroin, morphine, or codeine use.

  20. Calcification prevention tablets

    NASA Technical Reports Server (NTRS)

    Lindsay, Geoffrey A.; Hasting, Michael A.; Gustavson, Michael A.

    1991-01-01

    Citric acid tablets, which slowly release citric acid when flushed with water, are under development by the Navy for calcification prevention. The citric acid dissolves calcium carbonate deposits and chelates the calcium. For use in urinals, a dispenser is not required because the tablets are non-toxic and safe to handle. The tablets are placed in the bottom of the urinal, and are consumed in several hundred flushes (the release rate can be tailored by adjusting the formulation). All of the ingredients are environmentally biodegradable. Mass production of the tablets on commercial tableting machines was demonstrated. The tablets are inexpensive (about 75 cents apiece). Incidences of clogged pipes and urinals were greatly decreased in long term shipboard tests. The corrosion rate of sewage collection pipe (90/10 Cu/Ni) in citric acid solution in the laboratory is several mils per year at conditions typically found in traps under the urinals. The only shipboard corrosion seen to date is of the yellow brass urinal tail pieces. While this is acceptable, the search for a nontoxic corrosion inhibitor is underway. The shelf life of the tablets is at least one year if stored at 50 percent relative humidity, and longer if stored in sealed plastic buckets.

  1. Photoaffinity labeling of opioid receptor with morphine-7,8-oxide (morphine epoxide)

    SciTech Connect

    Takayanagi, I.; Shibata, R.; Miyata, N.; Hirobe, M.

    1982-05-01

    The opioid receptor mediating inhibitory action of morphine in the electrically stimulated guinea pig ileum was irreversibly photoinactivated by morphine epoxide (3 X 10(-6) M). Morphine epoxide (up to 3 X 10(-5) M) did not influence the responses of rat vas deferens (epsilon-receptor) or rabbit vas deferens (kappa-receptor) to electrical stimulation. Effective concentrations of morphine epoxide were much lower in the guinea pig ileum (mu-receptor) than in the mouse vas deference (delta-receptor). The inhibitory action of (Met)-enkephalin on the twitch responses of the rat vas deferens and mouse vas deferens to electrical stimulation were not influenced after irradiation in the presence of morphine epoxide (3 X 10(-6) M). Therefore, morphine epoxide is probably a useful probe for photoaffinity labeling of the mu-receptor in vitro.

  2. Efficacy, Safety, and Tolerability of an Extended-Release Orally Disintegrating Methylphenidate Tablet in Children 6–12 Years of Age with Attention-Deficit/Hyperactivity Disorder in the Laboratory Classroom Setting

    PubMed Central

    Childress, Ann C.; Kollins, Scott H.; Cutler, Andrew J.; Marraffino, Andrea; Sikes, Carolyn R.

    2017-01-01

    Abstract Objective: Methylphenidate extended-release orally disintegrating tablets (MPH XR-ODTs) represent a new technology for MPH delivery. ODTs disintegrate in the mouth without water and provide a pharmacokinetic profile that is consistent with once-daily dosing. This study sought to determine the efficacy, safety, and tolerability of this novel MPH XR-ODT formulation in school-age children with attention-deficit/hyperactivity disorder (ADHD) in a laboratory classroom setting. Methods: Children aged 6–12 years with ADHD (n = 87) were enrolled in this randomized, multicenter, double-blind, placebo-controlled, parallel, laboratory classroom study. The MPH XR-ODT dose was titrated to an optimized dose during a 4-week open-label period and maintained on that dose for 1 week. Participants (n = 85) were then randomized to receive their optimized dose of MPH XR-ODT or placebo once daily for 1 week (double blind), culminating in a laboratory classroom testing day. Efficacy was evaluated using the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Attention, Deportment, and Combined scores along with Permanent Product Measure of Performance (PERMP; Attempted and Correct) assessments. Onset and duration of drug action were also evaluated as key secondary endpoints. Safety assessments included adverse events (AEs), physical examinations, electrocardiograms (ECGs), and the Columbia Suicide Severity Rating Scale (C-SSRS). Results: The average SKAMP-Combined score on the classroom study day was significantly better for the MPH XR-ODT group (n = 43) than for the placebo group (n = 39; p < 0.0001). The effect was evident at 1 hour and lasted through 12 hours postdose. The average SKAMP-Attention, SKAMP-Deportment, PERMP-A, and PERMP-C scores were indicative of significantly greater ADHD symptom control for the MPH XR-ODT group. The most common AEs reported were decreased appetite, upper abdominal pain, headache, insomnia, upper respiratory tract

  3. Investigation of pharmacokinetic data of hypericin, pseudohypericin, hyperforin and the flavonoids quercetin and isorhamnetin revealed from single and multiple oral dose studies with a hypericum extract containing tablet in healthy male volunteers.

    PubMed

    Schulz, Hans-Ulrich; Schürer, Michael; Bässler, Dagmar; Weiser, Dieter

    2005-01-01

    Hypericins, hyperforin and flavonoids are discussed as the main components contributing to the antidepressant action of St. John's wort (Hypericum perforatum). Therefore, the objective of the two open phase I clinical trials was to obtain pharmacokinetic data of these constituents from a hypericum extract containing tablet: hypericin, pseudohypericin, hyperforin, the flavonoid aglycone quercetin, and its methylated form isorhamnetin. Each trial included 18 healthy male volunteers who received the test preparation, containing 900 mg dry extract of St John's wort (STW 3-VI, Laif 900), either as a single oral dose or as a multiple once daily dose over a period of 14 days. Concentration/time curves were determined for the five constituents, for 48 h after single dosing and for 24 h on day 14 at the end of 2 weeks of continuous daily dosing. After single dose intake, the key pharmacokinetic parameters were determined as follows: Hypericin: Area under the curve (AUC(0-infinity)) = 78.33 h x ng/ml, maximum plasma concentration (Cmax) = 3.8 ng/ml, time to reach Cmax (tmax) = 7.9 h, and elimination half-life (t1/2) = 18.71 h; pseudohypericin: AUC(0-infinity) = 97.28 h x ng/ml, Cmax = 10.2 ng/ml, tmax = 2.7 h, t1/2 = 17.19 h; hyperforin: AUC(0-infinity) = 1550.4 h x ng/ml, Cmax = 122.0 ng/ml, tmax = 4.5 h, t1/2 = 17.47 h. Quercetin and isorhamnetin showed two peaks of maximum plasma concentration separated by about 3-3.5 h. Quercetin: AUC(0-infinity) = 417.38 h x ng/ml, Cmax (1) = 89.5 ng/ml, tmax (1) = 1.0 h, Cma (2) = 79.1 ng/ml, tmax (2) = 4.4 h, t1/2 = 2.6 h; isorhamnetin: AUC(0-infinity) = 155.72 h x ng/ml, Cmax (1) = 12.5 ng/ml, tmax (1) = 1.4 h, Cmax (2) = 14.6 ng/ml, tmax (2) = 4.5 h, t1/2 = 5.61 h. Under steady state conditions reached during multiple dose administration similar results were obtained. Further pharmacokinetic characteristics calculated from the obtained data were the mean residence time (MRT), the lag-time, the peak-trough fluctuation (PTF), the

  4. Intrathecal PLC(β3) oligodeoxynucleotides antisense potentiates acute morphine efficacy and attenuates chronic morphine tolerance.

    PubMed

    Quanhong, Zhou; Ying, Xue; Moxi, Chen; Tao, Xu; Jing, Wang; Xin, Zhang; Li, Wang; Derong, Cui; Xiaoli, Zhang; Wei, Jiang

    2012-09-07

    Morphine is a mainstay for chronic pain treatment, but its efficacy has been hampered by physical tolerance. The underlying mechanism for chronic morphine induced tolerance is complicated and not well understood. PLC(β3) is regarded as an important factor in the morphine tolerance signal pathway. In this study, we determined intrathecal (i.t.) administration of an antisense oligodeoxynucleotide (ODN) of PLC(β3) could quicken the on-set antinociceptive efficacy of acute morphine treatment and prolong the maximum effect up to 4h. The antisense could also attenuate the development of morphine-induced tolerance and left shift the ED50 after 7 day of coadministration with morphine. These results probably were contributed by the PLC(β3) antisense ODN as they successfully knocked down protein expression levels and reduced activity of PLC(β3) in spinal cord in rats. The mismatch group had no such effects. The results confirmed the important involvement of PLC(β3) in both acute morphine efficacy and chronic morphine tolerance at spinal level in rats. This study may provide an idea for producing a novel adjuvant for morphine treatment.

  5. Formulation and Evaluation of Omeprazole Tablets for Duodenal Ulcer

    PubMed Central

    Choudhury, A.; Das, S.; Bahadur, S.; Saha, S.; Roy, A.

    2010-01-01

    Omeprazole pellets containing mucoadhesive tablets were developed by direct punch method. Three mucoadhesive polymers namely hydroxypropylemethylcellulose K4M, sodium carboxy methylcellulose, carbopol-934P and ethyl cellulose were used for preparation of tablets which intended for prolong action may be due to the attachment with intestinal mucosa for relief from active duodenal ulcer. Mucoadhesive tablets were coated with respective polymer and coated with Eudragit L100 to fabricate enteric coated tablets. The prepared tablets were evaluated for different physical parameters and dissolution study were performed in three dissolution mediums like 0.1N hydrochloric acid for 2h, pH 6.5 and pH 7.8 phosphate buffer solution for 12hr. Sodium carboxymethylcellulose showed above 95% release within 10 h where as carbopol-934P showed slow release about 88% to 92% over a period of 12 h. having excellent mucoadhesive strength but ethyl cellulose containing tablets showed less than 65% release. The release mechanism of all formulation was diffusion controlled confirmed from Higuchi’s plot. Thus, the present study concluded that, carbopol-934P containing mucoadhesive tablets of omeprazole pellets can be used for local action in the ulcer disease as well as for oral controlled release drug delivery. PMID:21218061

  6. Comparison of mirtazapine, gabapentin and ondansetron to prevent intrathecal morphine-induced pruritus

    PubMed Central

    Akhan, Ayse; Subasi, Ferhunde Dilek; Bosna, Gulsen; Ekinci, Osman; Pamuk, Hakan; Batan, Siddika; Ateser, Rezzan Yagmur; Turan, Gulden

    2016-01-01

    OBJECTIVE: Antagonism of the central nervous system inhibitor neurotransmitter gamma-Aminobutyric acid (GABA) or serotonergic system activation is an important factor in the pathogenesis of intrathecal morphine-induced pruritus. This study tested the hypothesis that preoperative use of ondansetron, gabapentin or mirtazapine can prevent morphine-induced pruritus. METHODS: We randomly allocated 80 patients of American Society of Anesthesiology (ASA) classification I and II physical status who were to undergo unilateral inguinal hernia or pilonidal sinus operations under spinal anesthesia into 4 equal groups. The first 3 groups received oral doses of 30 mg mirtazapine, 8 mg ondansetron, and 1200 mg gabapentin at 2 hours, 10 minutes, and 1 hour before surgery, respectively, and the fourth group was given a placebo. All patients received intrathecal injection of 15 mg of 0.5% hyperbaric bupivacaine and 0.2 mg morphine. Pruritus was evaluated at 0, 3, 6, 9, 12, and 24 hours after intrathecal morphine administration, and details of presence, onset time, duration, localization, and severity of pruritus were recorded. RESULTS: Incidence of pruritus was significantly more frequent in the placebo group compared to ondansetron, gabapentin, and mirtazapine groups (70%, 55%, 35%, and 35%, respectively). In general, onset of pruritus was between 2 and 6 hours after intrathecal morphine injection; however, onset in the gabapentin group (mean±SD: 4.75±2.7 hours; p=0.019) was delayed compared to other groups. It was observed that pruritus persisted relatively longer in the ondansetron and placebo groups (mean±SD: 6±3.08; 5.82±2.96 hours, respectively; p=0.047). No statistical determination was made regarding location of pruritus. Severity of pruritus was greater in the placebo group (p=0.0001). Necessity for antipruritic treatment was not statistically significantly different between groups. CONCLUSION: Incidence and severity of intrathecal morphine-induced pruritus decreased

  7. Fast disintegrating tablets: Opportunity in drug delivery system

    PubMed Central

    Parkash, Ved; Maan, Saurabh; Deepika; Yadav, Shiv Kumar; Hemlata; Jogpal, Vikas

    2011-01-01

    Fast disintegrating tablets (FDTs) have received ever-increasing demand during the last decade, and the field has become a rapidly growing area in the pharmaceutical industry. Oral drug delivery remains the preferred route for administration of various drugs. Recent developments in the technology have prompted scientists to develop FDTs with improved patient compliance and convenience. Upon introduction into the mouth, these tablets dissolve or disintegrate in the mouth in the absence of additional water for easy administration of active pharmaceutical ingredients. The popularity and usefulness of the formulation resulted in development of several FDT technologies. FDTs are solid unit dosage forms, which disintegrate or dissolve rapidly in the mouth without chewing and water. FDTs or orally disintegrating tablets provide an advantage particularly for pediatric and geriatric populations who have difficulty in swallowing conventional tablets and capsules. This review describes various formulations and technologies developed to achieve fast dissolution/dispersion of tablets in the oral cavity. In particular, this review describes in detail FDT technologies based on lyophilization, molding, sublimation, and compaction, as well as approaches to enhancing the FDT properties, such as spray drying and use of disintegrants. In addition, taste-masking technologies, experimental measurements of disintegration times, and dissolution are also discussed. PMID:22247889

  8. Is intramuscular morphine satisfying frontline medical personnels’ requirement for battlefield analgesia in Helmand Province, Afghanistan? A questionnaire study

    PubMed Central

    Gibson, Lorna M; Claydon, Michael A

    2015-01-01

    Background: All deployed British Army personnel carry intramuscular (IM) morphine auto-injectors to treat battlefield casualties. No other nation supplies parenteral opiate analgesia on individual issue. Studies highlight this agent’s inefficacy and safety issues, but are limited by a relative lack of inclusion of frontline personnel. We aimed to determine the opinions of frontline medical personnel on current battlefield analgesia. Methods: We surveyed 88 British Army frontline medical personnel (medical officers (n = 12), nurses (n = 7), combat medical technicians (CMTs) (n = 67), paramedics (n = 1) and health-care assistants (n = 1)) upon completion of a six-month deployment (September 2011 to April 2012) to Helmand Province, Afghanistan, using Likert scale questions on the efficacy of battlefield analgesia, complications of IM morphine, safety of morphine auto-injectors and its suitability for treating child casualties. Results: A total of 88/88 questionnaires were returned. Of these, 61/88 had treated casualties on the battlefield, 26/86 agreed that current battlefield analgesia is effective, 80/87 agreed that a more potent analgesic with a faster onset than IM morphine is desirable in the first hour following injury, 47/65 CMTs agreed that they can manage complications of current battlefield analgesia and 53/86 respondents correctly disagreed that current battlefield analgesia is suitable for child casualties. The potential for accidental self-injection was reported. Conclusions: A more potent, faster onset analgesic than IM morphine is desirable in the first hour following injury. Pre-deployment training should emphasise management of complications of opiate analgesics and treatment of child casualties. Oral transmucosal fentanyl citrate is now being issued to all frontline medical personnel. IM morphine will remain on individual issue to all deployed soldiers for environments where an oral agent is not suitable, for example, chemical, biological

  9. Morphine metabolism in human skin microsomes.

    PubMed

    Heilmann, S; Küchler, S; Schäfer-Korting, M

    2012-01-01

    For patients with severe skin wounds, topically applied morphine is an option to induce efficient analgesia due to the presence of opioid receptors in the skin. However, for topical administration it is important to know whether the substance is biotransformed in the skin as this can eventually reduce the concentration of the active agent considerably. We use skin microsomes to elucidate the impact of skin metabolism on the activity of topically applied morphine. We are able to demonstrate that morphine is only glucuronidated in traces, indicating that the biotransformation in the skin can be neglected when morphine is applied topically. Hence, there is no need to take biotransformation into account when setting up the treatment regimen.

  10. Morphine metabolism, transport and brain disposition.

    PubMed

    De Gregori, Simona; De Gregori, Manuela; Ranzani, Guglielmina Nadia; Allegri, Massimo; Minella, Cristina; Regazzi, Mario

    2012-03-01

    The chemical structures of morphine and its metabolites are closely related to the clinical effects of drugs (analgesia and side-effects) and to their capability to cross the Blood Brain Barrier (BBB). Morphine-6-glucuronide (M6G) and Morphine-3-glucuronide (M3G) are both highly hydrophilic, but only M6G can penetrate the BBB; accordingly, M6G is considered a more attractive analgesic than the parent drug and the M3G. Several hypotheses have been made to explain these differences. In this review we will discuss recent advances in the field, considering brain disposition of M6G, UDP-glucoronosyltransferases (UGT) involved in morphine metabolism, UGT interindividual variability and transport proteins.

  11. A highly toxic morphine-3-glucuronide derivative.

    PubMed

    Salvatella, Mariona; Arsequell, Gemma; Valencia, Gregorio; Rodríguez, Raquel E

    2004-02-23

    By the coupling of octylamine to the uronic acid function of morphine-3-glucuronide (M3G) a new glycoconjugate (morphine-3-octylglucuronamide, M3GOAM) was prepared. When assayed in both rats and mice up to ng/kg (i.p.) doses none of the animals survived. The aliphatic octyl chain may be the lethal factor since a closely related derivative (M3GNH2), was not toxic and showed similar opioid antagonist properties than naloxone.

  12. Intrathecal injection of morphine for obstetric analgesia.

    PubMed

    Baraka, A; Noueihid, R; Hajj, S

    1981-02-01

    Intrathecal injection of morphine was used to provide obstetric analgesia in 20 primiparous women in labor. When the cervix was at least 3 cm dilated, morphine, 1 or 2 mg, was injected intrathecally. In all parturients, labor pains were completely relieved after 15-60 min and analgesia lasted as long as eight to 11 hours. The analgesia was not associated with any alteration of pin-prick sensation or motor power, and there was no change in the arterial blood pressure or heart rate. All infants were delivered vaginally by use of episiotomy annd a low forceps, except two infants of mothers in the 2 mg of morphine group who needed cesarean section. During the second stage of labor, analgesia was supplemented by lidocaine, 2 per cent, using local perineal infiltration in 14 parturients and pudendal block in two parturients, and by epidural block in four parturients. Nineteen of the 20 newborns cried immediately at birth, and had Apgar scores o 7-9 at 1 min and 8-10 at 5 min. During the first 24 hours of life, the neurobehavioral responses of all newborns were scored as normal. Systemic maternal side effects such as somnolence, nausea, vomiting, and itching occurred in a high proportion of the parturients. However, in the majority of cases, these side effects were mild. Only two parturients of the 2 mg morphine group complained of marked somnolence, itching, and vomiting, which persisted post partum; these were effectively reversed by the specific antagonist naloxone. The analgesic effect of intrathecal morphine can be attributed to its action on the opiate receptors in the substantia gelatinosa of the dorsal horn of the spinal cord. However, supraspinal effects of morphine cannot be excluded. The low lipid solubility of morphine can explain its slow onset and prolonged duration of action. Also, this will result in minimal systemic absorption of morphine, which protects the fetus and results in selective maternal analgesia.

  13. Comparison of a drug versus money and drug versus drug self-administration choice procedure with oxycodone and morphine in opioid addicts.

    PubMed

    Comer, Sandra D; Metz, Verena E; Cooper, Ziva D; Kowalczyk, William J; Jones, Jermaine D; Sullivan, Maria A; Manubay, Jeanne M; Vosburg, Suzanne K; Smith, Mary E; Peyser, Deena; Saccone, Phillip A

    2013-09-01

    This double-blind, placebo-controlled study investigated the effects of oral morphine (0, 45, 135 mg/70 kg) and oral oxycodone (0, 15, 45 mg/70 kg) on buprenorphine-maintained opioid addicts. As a 3: 1 morphine : oxycodone oral dose ratio yielded equivalent subjective and physiological effects in nondependent individuals, this ratio was used in the present study. Two self-administration laboratory procedures - that is, a drug versus money and a drug versus drug procedure - were assessed. Study participants (N=12) lived in the hospital and were maintained on 4 mg/day sublingual buprenorphine. When participants chose between drug and money, money was preferred over all drug doses; only high-dose oxycodone was self-administered more than placebo. When participants chose between drug and drug, both drugs were chosen more than placebo, high doses of each drug were chosen over low doses, and high-dose oxycodone was preferred over high-dose morphine. The subjective, performance-impairing, and miotic effects of high-dose oxycodone were generally greater than those of high-dose morphine. The study demonstrated that a 3: 1 oral dose ratio of morphine : oxycodone was not equipotent in buprenorphine-dependent individuals. Both self-administration procedures were effective for assessing the relative reinforcing effects of drugs; preference for one procedure should be driven by the specific research question of interest.

  14. Morphine: a protective or destructive role in neurons?

    PubMed

    Zhang, Yan; Chen, Qiuyue; Yu, Long-Chuan

    2008-12-01

    Morphine has received intensive research interest for a long time. However, until recently, the protective versus destructive roles of morphine in the neuronal system have not been studied. There is evidence suggesting that morphine induces apoptotic cell death in neuronal and glial cells, whereas controversial studies support a neuroprotective role for morphine. The exact mechanisms for both protective and destructive pathways are not clear and are still under investigation. Improved understanding of morphine neuroprotection and neurotoxicity will be helpful to control morphine side effects in medical applications and to identify new targets for potential therapies and prevention strategies to opioid addiction.

  15. A new tablet brittleness index.

    PubMed

    Gong, Xingchu; Sun, Changquan Calvin

    2015-06-01

    Brittleness is one of the important material properties that influences the success or failure of powder compaction. We have discovered that the reciprocal of diametrical elastic strain at fracture is the most suitable tablet brittleness indices (TBIs) for quantifying brittleness of pharmaceutical tablets. The new strain based TBI is supported by both theoretical considerations and a systematic statistical analysis of friability data. It is sufficiently sensitive to changes in both tablet compositions and compaction parameters. For all tested materials, it correctly shows that tablet brittleness increases with increasing tablet porosity for the same powder. In addition, TBI increases with increasing content of a brittle excipient, lactose monohydrate, in the mixtures with a plastic excipient, microcrystalline cellulose. A probability map for achieving less than 1% tablet friability at various combinations of tablet tensile strength and TBI was constructed. Data from marketed tablets validate this probability map and a TBI value of 150 is recommended as the upper limit for pharmaceutical tablets. This TBI can be calculated from the data routinely obtained during tablet diametrical breaking test, which is commonly performed for assessing tablet mechanical strength. Therefore, it is ready for adoption for quantifying tablet brittleness to guide tablet formulation development since it does not require additional experimental work.

  16. A morphine conjugate vaccine attenuates the behavioral effects of morphine in rats

    PubMed Central

    Kosten, Therese A.; Shen, Xiaoyun Y.; O'Malley, Patrick W.; Kinsey, Berma M.; Lykissa, Ernest D.; Orson, Frank M.; Kosten, Thomas R.

    2013-01-01

    Vaccines for opioid dependence may provide a treatment that would reduce or slow the distribution of the drug to brain, thus reducing the drug's reinforcing effects. We tested whether a conjugate vaccine against morphine (keyhole limpet hemocyanin-6-succinylmorphine; KLH-6-SM) administered to rats would produce antibodies and show specificity for morphine or other heroin metabolites. The functional effects of the vaccine were tested with antinociceptive and conditioned place preference (CPP) tests. Rats were either vaccinated with KLH-6-SM and received two boosts 3 and 16 weeks later or served as controls and received KLH alone. Anti-morphine antibodies were produced in vaccinated rats; levels increased and were sustained at moderate levels through 24 weeks. Antibody binding was inhibited by free morphine and other heroin metabolites as demonstrated by competitive inhibition ELISA. Vaccinated rats showed reduced morphine CPP, tested during weeks 4 to 6, and decreased antinociceptive responses to morphine, tested at week 7. Brain morphine levels, assessed using gas-chromatography coupled to mass spectrometry (GC–MS) on samples obtained at 26 weeks, were significantly lower in vaccinated rats. This suggests that morphine entry into the brain was reduced or slowed. These results provide support for KLH-6-SM as a candidate vaccine for opioid dependence. PMID:23739535

  17. A morphine conjugate vaccine attenuates the behavioral effects of morphine in rats.

    PubMed

    Kosten, Therese A; Shen, Xiaoyun Y; O'Malley, Patrick W; Kinsey, Berma M; Lykissa, Ernest D; Orson, Frank M; Kosten, Thomas R

    2013-08-01

    Vaccines for opioid dependence may provide a treatment that would reduce or slow the distribution of the drug to brain, thus reducing the drug's reinforcing effects. We tested whether a conjugate vaccine against morphine (keyhole limpet hemocyanin-6-succinylmorphine; KLH-6-SM) administered to rats would produce antibodies and show specificity for morphine or other heroin metabolites. The functional effects of the vaccine were tested with antinociceptive and conditioned place preference (CPP) tests. Rats were either vaccinated with KLH-6-SM and received two boosts 3 and 16 weeks later or served as controls and received KLH alone. Anti-morphine antibodies were produced in vaccinated rats; levels increased and were sustained at moderate levels through 24 weeks. Antibody binding was inhibited by free morphine and other heroin metabolites as demonstrated by competitive inhibition ELISA. Vaccinated rats showed reduced morphine CPP, tested during weeks 4 to 6, and decreased antinociceptive responses to morphine, tested at week 7. Brain morphine levels, assessed using gas-chromatography coupled to mass spectrometry (GC-MS) on samples obtained at 26 weeks, were significantly lower in vaccinated rats. This suggests that morphine entry into the brain was reduced or slowed. These results provide support for KLH-6-SM as a candidate vaccine for opioid dependence.

  18. Thalidomide Promotes Morphine Efficacy and Prevents Morphine-Induced Tolerance in Rats with Diabetic Neuropathy.

    PubMed

    Zhao, Jianhui; Wang, Hong; Song, Tieying; Yang, Yunliang; Gu, Kunfeng; Ma, Pengyu; Zhang, Zaiwang; Shen, Limin; Liu, Jiabao; Wang, Wenli

    2016-12-01

    Opioid analgesics have less efficacy in diabetic neuropathy treatment, and tolerance often occurs after chronic usage. Given that thalidomide can potentiate the morphine efficacy in diabetic neuropathy treatment, we investigated the effects of intrathecal administrations of thalidomide on morphine tolerance during the treatment of diabetic neuropathy. We found that intrathecal administrations of thalidomide (25 mg/kg/ml) potentiated the analgesic effects of morphine on mechanical hyperalgesia and prevented the development of morphine tolerance. While this treatment regimen did not alter the protein levels of μ-opioid receptor (MOR) in the spinal cord of diabetic rats, chronic morphine treatment robustly increased MOR binding density in the synaptic plasma membranes fraction, but decreased it in the microsomal fraction. Furthermore, thalidomide was able to reverse the distribution of MOR altered by chronic morphine treatment. Finally, STZ-induced diabetes promoted PKC activation and enhanced TNFα level in the spinal cord, which were attenuated by intrathecal administrations of thalidomide. Taken together, these results suggested that thalidomide may potentiate morphine efficacy on diabetic neuropathy and prevent the development of morphine tolerance by suppressing PKC activation and TNFα level in the spinal cord.

  19. Morphine and codeine concentrations in human urine following controlled poppy seeds administration of known opiate content.

    PubMed

    Smith, Michael L; Nichols, Daniel C; Underwood, Paula; Fuller, Zachary; Moser, Matthew A; LoDico, Charles; Gorelick, David A; Newmeyer, Matthew N; Concheiro, Marta; Huestis, Marilyn A

    2014-08-01

    Opiates are an important component for drug testing due to their high abuse potential. Proper urine opiate interpretation includes ruling out poppy seed ingestion; however, detailed elimination studies after controlled poppy seed administration with known morphine and codeine doses are not available. Therefore, we investigated urine opiate pharmacokinetics after controlled oral administration of uncooked poppy seeds with known morphine and codeine content. Participants were administered two 45 g oral poppy seed doses 8 h apart, each containing 15.7 mg morphine and 3mg codeine. Urine was collected ad libitum up to 32 h after the first dose. Specimens were analyzed with the Roche Opiates II immunoassay at 2000 and 300 μg/L cutoffs, and the ThermoFisher CEDIA(®) heroin metabolite (6-acetylmorphine, 6-AM) and Lin-Zhi 6-AM immunoassays with 10 μg/L cutoffs to determine if poppy seed ingestion could produce positive results in these heroin marker assays. In addition, all specimens were quantified for morphine and codeine by GC/MS. Participants (N=22) provided 391 urine specimens over 32 h following dosing; 26.6% and 83.4% were positive for morphine at 2000 and 300 μg/L GC/MS cutoffs, respectively. For the 19 subjects who completed the study, morphine concentrations ranged from <300 to 7522 μg/L with a median peak concentration of 5239 μg/L. The median first morphine-positive urine sample at 2000 μg/L cutoff concentration occurred at 6.6 h (1.2-12.1), with the last positive from 2.6 to 18 h after the second dose. No specimens were positive for codeine at a cutoff concentration of 2000 μg/L, but 20.2% exceeded 300 μg/L, with peak concentrations of 658 μg/L (284-1540). The Roche Opiates II immunoassay had efficiencies greater than 96% for the 2000 and 300 μg/L cutoffs. The CEDIA 6-AM immunoassay had a specificity of 91%, while the Lin-Zhi assay had no false positive results. These data provide valuable information for interpreting urine opiate results.

  20. Morphine and Codeine Concentrations in Human Urine following Controlled Poppy Seeds Administration of Known Opiate Content

    PubMed Central

    Smith, Michael L.; Nichols, Daniel C.; Underwood, Paula; Fuller, Zachary; Moser, Matthew A.; LoDico, Charles; Gorelick, David A.; Newmeyer, Matthew N.; Concheiro, Marta; Huestis, Marilyn A.

    2014-01-01

    Opiates are an important component for drug testing due to their high abuse potential. Proper urine opiate interpretation includes ruling out poppy seed ingestion; however, detailed elimination studies after controlled poppy seed administration with known morphine and codeine doses are not available. Therefore, we investigated urine opiate pharmacokinetics after controlled oral administration of uncooked poppy seeds with known morphine and codeine content. Participants were administered two 45g oral poppy seed doses 8h apart, each containing 15.7mg morphine and 3mg codeine. Urine was collected ad libitum up to 32h after the first dose. Specimens were analyzed with the Roche Opiates II immunoassay at 2,000 and 300μg/L cutoffs, and the ThermoFisher CEDIA® Heroin Metabolite (6-acetylmorphine, 6AM) and Lin-Zhi 6AM immunoassays with 10μg/L cutoffs to determine if poppy seed ingestion could produce positive results in these heroin marker assays. In addition, all specimens were quantified for morphine and codeine by GC/MS. Participants (N=22) provided 391 urine specimens over 32h following dosing; 26.6% and 83.4% were positive for morphine at 2,000 and 300μg/L GC/MS cutoffs, respectively. For the 19 subjects who completed the study, morphine concentrations ranged from <300 to 7,522μg/L with a median peak concentration of 5,239μg/L. The median first morphine-positive urine sample at 2,000μg/L cutoff concentration occurred at 6.6h (1.2-12.1), with the last positive from 2.6 to 18h after the second dose. No specimens were positive for codeine at a cutoff concentration of 2,000μg/L, but 20.2% exceeded 300μg/L, with peak concentrations of 658 μg/L (284-1540). The Roche Opiates II immunoassay had efficiencies greater than 96% for the 2000 and 300μg/L cutoffs. The CEDIA 6AM immunoassay had a specificity of 91%, while the Lin-Zhi assay had no false positive results. These data provide valuable information for interpreting urine opiate results. PMID:24887324

  1. 21 CFR 520.2582 - Triflupromazine hydrochloride tablets.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Triflupromazine hydrochloride tablets. 520.2582 Section 520.2582 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS §...

  2. 21 CFR 520.1341 - Megestrol acetate tablets.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Megestrol acetate tablets. 520.1341 Section 520.1341 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1341 Megestrol...

  3. 21 CFR 520.2582 - Triflupromazine hydrochloride tablets.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Triflupromazine hydrochloride tablets. 520.2582 Section 520.2582 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS §...

  4. 21 CFR 520.1341 - Megestrol acetate tablets.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Megestrol acetate tablets. 520.1341 Section 520.1341 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1341 Megestrol...

  5. 21 CFR 520.1284 - Sodium liothyronine tablets.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Sodium liothyronine tablets. 520.1284 Section 520.1284 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1284...

  6. 21 CFR 520.1341 - Megestrol acetate tablets.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Megestrol acetate tablets. 520.1341 Section 520.1341 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1341 Megestrol...

  7. 21 CFR 520.2582 - Triflupromazine hydrochloride tablets.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Triflupromazine hydrochloride tablets. 520.2582 Section 520.2582 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS §...

  8. 21 CFR 520.2582 - Triflupromazine hydrochloride tablets.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Triflupromazine hydrochloride tablets. 520.2582 Section 520.2582 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS §...

  9. 21 CFR 520.1341 - Megestrol acetate tablets.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Megestrol acetate tablets. 520.1341 Section 520.1341 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1341 Megestrol...

  10. 21 CFR 520.1284 - Sodium liothyronine tablets.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Sodium liothyronine tablets. 520.1284 Section 520.1284 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1284...

  11. 21 CFR 520.2582 - Triflupromazine hydrochloride tablets.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Triflupromazine hydrochloride tablets. 520.2582 Section 520.2582 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS §...

  12. 21 CFR 520.2098 - Selegiline hydrochloride tablets.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.2098 Selegiline... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Selegiline hydrochloride tablets. 520.2098 Section... selegiline hydrochloride. (b) Sponsor. See No. 000069 in § 510.600(c) of this chapter. (c) (d) Conditions...

  13. 21 CFR 520.434 - Chlorphenesin carbamate tablets.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Chlorphenesin carbamate tablets. 520.434 Section 520.434 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS §...

  14. 21 CFR 520.82a - Aminopropazine fumarate tablets.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Aminopropazine fumarate tablets. 520.82a Section 520.82a Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS §...

  15. Inhibition of the development of morphine tolerance by a potent dual mu-delta-opioid antagonist, H-Dmt-Tic-Lys-NH-CH2-Ph.

    PubMed

    Jinsmaa, Yunden; Marczak, Ewa D; Balboni, Gianfranco; Salvadori, Severo; Lazarus, Lawrence H

    2008-10-01

    Three analogues of the dual mu-/delta-antagonist, H-Dmt-Tic-R-NH-CH2-Ph (R = 1, Lys-Z; 2, Lys-Ac; 3, Lys) were examined in vivo: 1 and 2 exhibited weak bioactivity, while 3 injected intracerebroventricularly was a potent dual antagonist for morphine- and deltorphin C-induced antinociception comparable to naltrindole (delta-antagonist), but 93% as effective as naloxone (nonspecific opioid receptor antagonist) and 4% as active as CTOP, a mu antagonist. Subcutaneous or oral administration of 3 antagonized morphine-induced antinociception indicating passage across epithelial and blood-brain barriers. Mice pretreated with 3 before morphine did not develop morphine tolerance indicative of a potential clinical role to inhibit development of drug tolerance.

  16. Pleiotrophin modulates morphine withdrawal but has no effects on morphine-conditioned place preference.

    PubMed

    Gramage, Esther; Vicente-Rodríguez, Marta; Herradón, Gonzalo

    2015-09-14

    Pleiotrophin (PTN) is a neurotrophic factor with important functions in addiction and neurodegenerative disorders. Morphine administration induces an increase in the expression of PTN and Midkine (MK), the only other member of this family of cytokines, in brain areas related with the addictive effects of drug of abuse, like the Ventral Tegmental Area or the hippocampus. In spite of previous studies showing that PTN modulates amphetamine and ethanol rewarding effects, and that PTN is involved in morphine-induced analgesia, it was still unknown if the rewarding effects of morphine may be regulated by endogenous PTN. Thus, we aim to study the role of PTN in the reward and physical dependence induced by morphine. We used the Conditioned Place Preference (CPP) paradigm in PTN genetically deficient (PTN-/-) and wild type (WT) mice to assess the rewarding effects of morphine in absence of endogenous PTN. Second, to study if PTN may be involved in morphine physical dependence, naloxone-precipitated withdrawal syndrome was induced in PTN-/- and WT morphine dependent mice. Although the increase in the time spent in the morphine-paired compartment after conditioning tended to be more pronounced in PTN-/- mice, statistical significance was not achieved. The data suggest that PTN does not exert an important role in morphine reward. However, our results clearly indicate that PTN-/- mice develop a more severe withdrawal syndrome than WT mice, characterized as a significant increase in the time standing and in the total incidences of forepaw licking, forepaw tremors, wet dog shake and writhing. The data presented here suggest that PTN is a novel genetic factor that plays a role in morphine withdrawal syndrome.

  17. Interactions between morphine and the morphine-glucuronides measured by conditioned place preference and locomotor activity.

    PubMed

    Vindenes, Vigdis; Ripel, Ase; Handal, Marte; Boix, Fernando; Mørland, Jørg

    2009-07-01

    After intake of heroin or morphine, active metabolites are formed in the body. The two most important morphine metabolites are morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G). M6G and M3G are present for longer time periods and in higher concentrations than the parent drug, but their potential contribution to reward and to development of dependence and addiction is not clear. We tested the effects of morphine and M6G separately (doses of 10, 20, 30 and 50 micromol/kg), administered together, and also in combination with with 200 microm l/kg M3G in male C57BL/6J-Bom mice. M3G in doses of 50, 100, 200, 300 and 400 micromol/kg were also tested alone. We evaluated the rewarding effects in a conditioning place preference (CPP) model and the psychomotor stimulating effects by recording locomotor activity. Mice were subjected to three consecutive conditioning days with drugs or saline before testing. Changes in locomotor activity from conditioning day one to day three were also compared to the expression of CPP on the test day. This study revealed that coadministration of morphine and M6G induced CPP of similar magnitude to the sum of equimolar doses of these compounds alone, and different ratios of the two drugs did not affect the results. M3G did not cause CPP and reduced the CPP induced by both morphine and M6G when coadministered with these drugs. Morphine induced locomotor activity was reduced by coadministration of M3G, but this was not seen when M3G was co-injected with M6G. The changes in locomotor activity during the conditioning periods did not correlated with the expression of CPP. This study revealed that the morphine-glucuronides in different and complex ways can influence the pharmacological effects of psychomotor activation and reward observed after intake of morphine.

  18. Differential effects of acute morphine, and chronic morphine-withdrawal on obsessive-compulsive behavior: inhibitory influence of CRF receptor antagonists on chronic morphine-withdrawal.

    PubMed

    Umathe, S N; Mundhada, Y R; Bhutada, P S

    2012-10-01

    Recent studies have provided convincing evidences for co-morbidity between opioid addiction and obsessive-compulsive disorder (OCD), and the involvement of the corticotrophin-releasing factor (CRF) in the effects of morphine-withdrawal. Some scanty evidences also point towards the role of CRF in OCD and related disorders. But, no evidence indicated the role of CRF in morphine withdrawal associated obsessive-compulsive behavior (OCB). Therefore, the present study investigated the role of CRF in morphine-withdrawal induced OCB in mice. Marble-burying behavior in mice was used to assess OCB as this model has good predictive and face validity. The results revealed that acute morphine dose dependently attenuated the marble burying behavior, whereas withdrawal of chronic morphine was associated with significant rise in marble burying behavior. This indicates the differential effect of acute morphine and chronic morphine-withdrawal on OCB. Further, acute treatment with CRF receptor antagonists like antalarmin (2 and 4 μg/mouse, i.c.v.) or astressin-2B (3 and 10 nmol/mouse, i.c.v.) dose dependently attenuated the peak morphine-withdrawal induced increase in marble burying behavior. Moreover, concomitant treatment with antalarmin (4 μg/mouse, i.c.v.) or astressin-2B (10 nmol/mouse, i.c.v.) along with morphine blocked the morphine-withdrawal associated exacerbation of OCB. These results indicate that OCB associated with morphine withdrawal state is partly mediated by the activation of central CRF receptors.

  19. Morphine as a Potential Oxidative Stress-Causing Agent.

    PubMed

    Skrabalova, Jitka; Drastichova, Zdenka; Novotny, Jiri

    2013-11-01

    Morphine exhibits important pharmacological effects for which it has been used in medical practice for quite a long time. However, it has a high addictive potential and can be abused. Long-term use of this drug can be connected with some pathological consequences including neurotoxicity and neuronal dysfunction, hepatotoxicity, kidney dysfunction, oxidative stress and apoptosis. Therefore, most studies examining the impact of morphine have been aimed at determining the effects induced by chronic morphine exposure in the brain, liver, cardiovascular system and macrophages. It appears that different tissues may respond to morphine diversely and are distinctly susceptible to oxidative stress and subsequent oxidative damage of biomolecules. Importantly, production of reactive oxygen/nitrogen species induced by morphine, which have been observed under different experimental conditions, can contribute to some pathological processes, degenerative diseases and organ dysfunctions occurring in morphine abusers or morphine-treated patients. This review attempts to provide insights into the possible relationship between morphine actions and oxidative stress.

  20. The Use of D-Optimal Mixture Design in Optimizing Development of Okara Tablet Formulation as a Dietary Supplement.

    PubMed

    Zen, Nur Izzati Mohamad; Abd Gani, Siti Salwa; Shamsudin, Rosnah; Masoumi, Hamid Reza Fard

    2015-01-01

    The usage of soy is increasing year by year. It increases the problem of financial crisis due to the limited sources of soybeans. Therefore, production of oral tablets containing the nutritious leftover of soymilk production, called okara, as the main ingredient was investigated. The okara tablets were produced using the direct compression method. The percentage of okara, guar gum, microcrystalline cellulose (Avicel PH-101), and maltodextrin influenced tablets' hardness and friability which are analyzed using a D-optimal mixture design. Composition of Avicel PH-101 had positive effects for both hardness and friability tests of the tablets. Maltodextrin and okara composition had a significant positive effect on tablets' hardness, but not on percentage of friability of tablets. However, guar gum had a negative effect on both physical tests. The optimum tablet formulation was obtained: 47.0% of okara, 2.0% of guar gum, 35.0% of Avicel PH-101, and 14.0% of maltodextrin.

  1. The Use of D-Optimal Mixture Design in Optimizing Development of Okara Tablet Formulation as a Dietary Supplement

    PubMed Central

    Mohamad Zen, Nur Izzati; Abd Gani, Siti Salwa; Shamsudin, Rosnah; Fard Masoumi, Hamid Reza

    2015-01-01

    The usage of soy is increasing year by year. It increases the problem of financial crisis due to the limited sources of soybeans. Therefore, production of oral tablets containing the nutritious leftover of soymilk production, called okara, as the main ingredient was investigated. The okara tablets were produced using the direct compression method. The percentage of okara, guar gum, microcrystalline cellulose (Avicel PH-101), and maltodextrin influenced tablets' hardness and friability which are analyzed using a D-optimal mixture design. Composition of Avicel PH-101 had positive effects for both hardness and friability tests of the tablets. Maltodextrin and okara composition had a significant positive effect on tablets' hardness, but not on percentage of friability of tablets. However, guar gum had a negative effect on both physical tests. The optimum tablet formulation was obtained: 47.0% of okara, 2.0% of guar gum, 35.0% of Avicel PH-101, and 14.0% of maltodextrin. PMID:26171418

  2. In vivo bioavailability studies of sumatriptan succinate buccal tablets

    PubMed Central

    Shivanand, K; Raju, SA; Nizamuddin, S; Jayakar, B

    2011-01-01

    Back ground and the purpose of study Sumatriptan succinate is a Serotonin 5- HT1 receptor agonist, used in treatment of migraine. It is absorbed rapidly but incompletely when given orally and undergoes first-pass metabolism, resulting in a low absolute bioavailability of about 15%. The aim of this work was to design mucoadhesive bilayered buccal tablets of sumatriptan succinate to improve its bioavailability. Methods Mucoadhesive polymers carbopol 934 (Carbopol), HPMC K4M, HPMC K15M along with ethyl cellulose as an impermeable backing layer were used for the preparation of mucoadhesive bilayered tablets. In vivo bioavailability studies was also conducted in rabbits for optimized formulation using oral solution of sumatriptan succinate as standard. Results Bilayered buccal tablets (BBT) containing the mixture of Carbopol and HPMC K4M in the ratio 1:1 (T1) had the maximum percentage of in vitro drug release within 6 hrs. The optimized formulation (T1) followed non-Fickian release mechanism. The percentage relative bioavailability of sumatriptan succinate from selected bilayered buccal tablets (T1) was found to be 140.78%. Conclusions Bilayered buccal tablets of sumatriptan succinate was successfully prepared with improved bioavailability. PMID:22615661

  3. A specific immunoassay for the determination of morphine and its glucuronides in human blood.

    PubMed

    Beike, J; Blaschke, G; Mertz, A; Köhler, H; Brinkmann, B

    1998-01-01

    The development of specific antisera for immunochemical determination of morphine, morphine-3-glucuronide and morphine-6-glucuronide is described. Morphine was N-demethylated to normorphine and N-alkylated to give N-aminopropyl-normorphine as hapten for antisera against morphine. As haptens for antisera against morphine-3-glucuronide and morphine-6-glucuronide, N-aminopropyl-nor-morphine was glucuronidated in position 3 or 6 respectively. Each of these three haptens were coupled to BSA employing the glutaraldehyde method to obtain three different immunogens. Immunisation of rabbits with these conjugates gave anti-morphine, anti-morphine-3-glucuronide and anti-morphine-6-glucuronide antisera, which were tested in a competitive, heterogeneous radioimmunoassay. Tracers for this radioimmunoassay procedure were synthesised by substitution of morphine and morphine-6-glucuronide in position 2 with 125I and indirect iodination of the morphine-3-glucuronide hapten according to the method of Bolton and Hunter. The resulting antisera show very specific reactions with morphine, morphine-3-glucuronide and morphine-6-glucuronide. Cross reactivities of each antiserum with structurally related opiates and opioides are very low. The cross reactivities of the anti-morphine antiserum against morphine-3-glucuronide, morphine-6-glucuronide, codeine, codeine-6-glucuronide or dihydrocodeine were less than 0.3%, the anti-morphine-3-glucuronide antiserum against morphine, morphine-6-glucuronide, codeine, codeine-6-glucuronide or dihydrocodeine less than 0.1% and the anti-morphine-6-glucuronide antiserum against morphine, morphine-3-glucuronide, codeine or dihydrocodeine less than 0.1%, against codeine-6-glucuronide less than 2.3%. The determination of morphine, morphine-3-glucuronide and morphine-6-glucuronide in blood samples (limit of detection= 3, 1, 0.5 ng/g) of nine cases of fatal heroin overdose with this radioimmunoassay method and the comparison with a GC/MS method is described.

  4. A Randomized Controlled Trial on the Effect of Tapentadol and Morphine on Conditioned Pain Modulation in Healthy Volunteers

    PubMed Central

    Martini, Chris; van Velzen, Monique; Drewes, Asbjørn; Aarts, Leon; Dahan, Albert; Niesters, Marieke

    2015-01-01

    Background Modulatory descending pathways, originating at supraspinal sites that converge at dorsal horn neurons, influence pain perception in humans. Defects in descending pain control are linked to chronic pain states and its restoration may be a valuable analgesic tool. Conditioned pain modulation (CPM) is a surrogate marker of descending inhibition that reduces the perception of pain from a primary test stimulus during application of a conditioning stimulus. Here the effects of the analgesics tapentadol, a combined mu-opioid receptor agonist and noradrenaline reuptake inhibitor, and morphine, a strong mu-opioid receptor agonist, were tested on CPM in a randomized, double-blind, placebo-controlled crossover trial in 12 healthy pain-free volunteers, to understand possible differences in mechanism of action between these opioids. Methods and Results On three occasions CPM responses were obtained 60-90 and 120-150 min following intake of tapentadol (100 mg immediate release tablet), morphine (40 mg immediate release tablet) or placebo. At both time points, CPM was detectable after treatment with placebo and tapentadol (peak pain ratings reduced by 20-30% after application of the conditioning stimulus) but not after morphine. Compared to placebo morphine displayed significantly less CPM: mean treatment difference 18.2% (95% CI 3.4 to 32.9%) at 60-90 min after drug intake and 19.5% (95% CI 5.7 to 33.2%) at 120-150 min after drug intake (p = 0.001). No difference in CPM between placebo and tapentadol was detected: mean treatment difference 1.5% (95% CI -11.6 to 14.6%) at 60-90 min after drug intake and 1.5% (95% CI -16.0 to 18.9%) at 120-150 min after drug intake (p = 0.60). Conclusions Our data show that in volunteers morphine affects CPM, while tapentadol was without effect despite identical experimental conditions. These data confirm that tapentadol’s main mechanism of action is distinct from that of morphine and likely related to the effect of adrenergic

  5. A Bacoside containing Bacopa monnieri extract reduces both morphine hyperactivity plus the elevated striatal dopamine and serotonin turnover.

    PubMed

    Rauf, Khalid; Subhan, Fazal; Sewell, Robert D E

    2012-05-01

    Bacopa monnieri (BM) has been used in Ayurvedic medicine as a nootropic, anxiolytic, antiepileptic and antidepressant. An n-butanol extract of the plant (nBt-ext BM) was analysed and found to contain Bacoside A (Bacoside A3, Bacopaside II and Bacopasaponin C). The effects of the BM extract were then studied on morphine-induced hyperactivity as well as dopamine and serotonin turnover in the striatum since these parameters have a role in opioid sensitivity and dependence. Mice were pretreated with saline or nBt-ext BM (5, 10 and 15 mg/kg, orally), 60 min before morphine administration and locomotor activity was subsequently recorded. Immediately after testing, striatal tissues were analysed for dopamine (DA), serotonin (5HT) and their metabolites using HPLC coupled with electrochemical detection. The results indicated that nBt-ext BM significantly (p < 0.001) decreased locomotor activity in both the saline and morphine treated groups. Additionally, nBt-ext BM significantly lowered morphine-induced dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindole acetic acid (5-H1AA) upsurges in the striatum but failed to affect DA, 5-HT and their metabolites in the saline treated group. These findings suggest that nBt-ext BM has an antidopaminergic/serotonergic effect and may have potential beneficial effects in the treatment of morphine dependence.

  6. Sensitivity changes after morphine treatment in the mouse uterus.

    PubMed

    Contreras, E; Tamayo, L; Juica, S

    1982-01-01

    The addition of morphine to a bath containing the vas deferens from chronically morphinized mice induces a facilitatory effect on noradrenaline contractile responses. This facilitatory effect of morphine has been thought to be a dependence-like effect. In the present work the possibility that a pretreatment with morphine might induce a similar effect on the contractile responses of the mouse uterus to acetylcholine and serotonin was examined. The acute effect of morphine on the uteri of untreated mice consisted in an attenuation of the responses to both substances, whereas a long term pretreatment with morphine induced a supersensitivity state. Tolerance to the depressant action of morphine on the contractile responses induced by the stimulating compounds was also observed. Acute morphine in the uteri from morphinized mice did not induce a facilitatory effect on acetylcholine or serotonin responses. Naloxone did not modify the effects of morphine in the naive or chronically treated mice. The supersensitivity state and the intensity of tolerance were unaffected by changes in the concentration of calcium in the bath medium. Caffeine or theophylline decreased the tolerance observed in the uterus from chronically morphinized mice. The attenuation of tolerance suggests that methylxanthines induce effects opposed to those of chronic morphine in the calcium distribution within the cell.

  7. The Role of GABAB Receptors in Morphine Self-Administration

    PubMed Central

    Ramshini, Effat; Alaei, Hojjatallah; Reisi, Parham; Alaei, Samaneh; Shahidani, Somaye

    2013-01-01

    Background: There is only little information about the effects of GABA receptors agonist and antagonist on morphine self-administration. Present study was designed to assess role of GABAB receptors in the regulation of morphine-reinforced self-administration. Methods: This study was performed in four groups of rats: (1) Saline group, which received saline in the self-administration session. (2) Morphine group, which received morphine in saline solution in the self-administration session. (3) Baclofen + Morphine group, which received both baclofen 20 min before self- administration test and morphine in the self-administration session. (4) Phaclofen + Morphine group, which received both phaclofen 20 min before self- administration test and morphine in the self-administration session. The number of lever pressing and self-infusion were recorded. Results: Morphine significantly increased the number of active lever pressing dose dependently in self-administration session in comparative with saline group. Administration of baclofen, 20 min before morphine self-administration produced significant decrease in the initiation of morphine self-administration during all session. Conversely, pre-treatment of phaclofen increased the number of active lever pressing and self-infusion in this test. Conclusion: Our results indicated a short-term treatment by baclofen, reduced morphine-maintenance response in a dose-dependent manner, suggesting that GABAB receptor agonists could be useful for reversing the neuroadaptations related to opiates. PMID:23542877

  8. A dual action of valproic acid upon morphine analgesia and morphine withdrawal.

    PubMed

    Tamayo, L; Contreras, E

    1983-01-01

    Effects of valproic acid administration on morphine analgesia and on morphine tolerance and dependence were investigated in mice. Valproate increased the reaction time to thermal stimulation in naive animals. This effect was additive with morphine when valproate was administered shortly before the analgesic. However, an antagonism was observed if a 4-hour period elapsed between valproate and morphine administration. When administered to mice receiving a sustained release preparation of morphine, valproate antagonized the development of tolerance to morphine. Valproate elicited a dual action on the abstinence signs observed after naloxone administration in morphine-treated mice. The effect consisted in a reduction of abstinence behavior if the anticonvulsant was administered a few minutes before naloxone; the same treatment increased the severity of the abstinence behavior when valproate was injected 1 h before the precipitating dose of naloxone. In this latter schedule, concomitant administration of gamma-vinyl-GABA failed to reduce the severity of the convulsions observed during the abstinence syndrome. These results suggest that valproate is metabolized to a compound responsible for decreased analgesia and intensified withdrawal signs.

  9. The effect of different durations of morphine exposure on mesencephalic dopaminergic neurons in morphine dependent rats.

    PubMed

    Shi, Weibo; Ma, Chunling; Qi, Qian; Liu, Lizhe; Bi, Haitao; Cong, Bin; Li, Yingmin

    2015-12-01

    Mesencephalic dopaminergic neurons are heavily involved in the development of drug dependence. Thyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis, plays an important role in the survival of dopaminergic neurons. Therefore, this study investigated TH changes in dopaminergic neurons of the ventral tegmental area (VTA) and substantia nigra (SN), as well as the morphine effects on dopaminergic neurons induced by different durations of morphine dependence. Models of morphine dependence were established in rats, and paraffin-embedded sections, immunohistochemistry and western blotting were used to observe the changes in the expression of TH protein. Fluoro-Jade B staining was used to detect degeneration and necrosis, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling (TUNEL) detected the apoptosis of mesencephalic dopaminergic nerve cells. Immunohistochemistry and western blotting showed that the number of TH positive cells and the protein levels in the VTA and SN were significantly decreased in the rats with a long period of morphine dependency. With prolonged morphine exposure, the dopaminergic nerve cells in the VTA and SN showed degeneration and necrosis, while apoptotic cells were not observed. The number of VTA and SN dopaminergic nerve cells decreased with increasing periods of morphine dependence, which was most likely attributable to the degeneration and necrosis of nerve cells induced by morphine toxicity.

  10. A randomised comparison of increase in serum 25-hydroxyvitamin D concentration after 4 weeks of daily oral intake of 10 microg cholecalciferol from multivitamin tablets or fish oil capsules in healthy young adults.

    PubMed

    Holvik, Kristin; Madar, Ahmed A; Meyer, Haakon E; Lofthus, Cathrine M; Stene, Lars C

    2007-09-01

    Many types of vitamin supplements are available on the market, but little is known about whether cholecalciferol obtained from fat-containing capsules differs in bioavailability from that of solid tablets. Our objective was to test whether 4 weeks of daily supplementation with 10 mug cholecalciferol given as a fish oil capsule produces a larger increase in serum 25-hydroxyvitamin D (s-25(OH)D) concentration compared with the same dose of cholecalciferol given as a multivitamin tablet. A total of seventy-four healthy subjects aged 19-49 years were initially included and fifty-five of these completed the study and fulfilled the inclusion criteria. After completing a self-administered questionnaire about diet and sunshine exposure and having a non-fasting venous blood sample drawn, participants were randomised to receive daily multivitamin tablets (n 28) or fish oil capsules (n 27), each containing equal doses of cholecalciferol. A second blood sample was drawn after 28 d. Mean baseline s-25(OH)D was 40.3 (sd 22.0) nmol/l in the multivitamin group and 48.5 (24.8) nmol/l in the fish oil group. When controlling for baseline s-25(OH)D, mean 4-week increase in s-25(OH)D was 35.8 (95 % CI 30.9, 40.8) nmol/l in the multivitamin group and 32.3 (95 % CI 27.3, 37.4) nmol/l in the fish oil group; the mean difference was 3.5 (95 % CI - 3.6, 10.6) nmol/l (P = 0.33). The results were unaltered by statistical adjustment for BMI, ethnic background, age and sex. We conclude that fish oil capsules and multivitamin tablets containing 10 microg cholecalciferol administered over a 4-week period produced a similar mean increase in s-25(OH)D concentration.

  11. Obtaining fast dissolving disintegrating tablets with different doses of melatonin.

    PubMed

    Muñoz, H; Castan, H; Clares, B; Ruiz, M A

    2014-06-05

    Fast dissolving disintegrating tablets (FDDTs) containing different dosages of melatonin have been manufactured for administration to a specific target population: pediatric patients, having potential difficulties taking other oral forms. The lower dosages (3 and 5mg) are intended for epileptic children, migraine prevention, neurodevelopmental disability, sleep disorders and blindness. Dosages of 10 and 60 mg are intended for Duchenne muscular dystrophy. Two FDDT groups have been designed, one which has excipients for direct compression and others having direct compression and effervescent excipients. Tablets have been produced having disintegration times of less than 25s and with friability and hardness values that require no special storage or packaging conditions.

  12. Tianeptine reduces morphine antinociceptive tolerance and physical dependence.

    PubMed

    Chu, Chin-Chen; Shieh, Ja-Ping; Shui, Hao-Ai; Chen, Jen-Yin; Hsing, Chung-Hsi; Tzeng, Jann-Inn; Wang, Jhi-Joung; Ho, Shung-Tai

    2010-09-01

    Long-term use of morphine can cause neuronal dystrophic changes in specific areas of the brain. These changes may underlie the mechanism for developing morphine antinociceptive tolerance and physical dependence. We evaluated the effect of tianeptine, an antidepressant with prominent neuroprotective and neuroplastic properties, on the development of morphine antinociceptive tolerance and physical dependence. Male C57BL/6 mice were rendered tolerant to or dependent on morphine by subcutaneously injecting them with morphine (10 mg/kg) and intraperitoneally with saline or tianeptine (1, 3, or 5 mg/kg) twice daily for 6 days. The mice were given a daily tail-flick test 1 h after the first morphine injection to evaluate the development of their tolerance to morphine antinociception. To evaluate their physical dependence on morphine, 3 h after the final morphine injection on day 6, naloxone-HCl-precipitated (2 mg/kg, intraperitoneally) withdrawal symptoms were counted for 30 min, and body weight was checked 1 h after the naloxone injection. Tianeptine per se produced no antinociception, neither did it modify the antinociception produced by morphine, nor did it evoke the behavioral responses different from those in the saline controls. The combination of tianeptine with morphine significantly reduced the development of morphine antinociceptive tolerance and suppressed the incidence of naloxone-precipitated withdrawal symptoms. We conclude that tianeptine is an effective inhibitor of morphine-induced antinociceptive tolerance and physical dependence in mice. Our results would imply that comedication with tianeptine and morphine might benefit those who need long-term morphine treatment.

  13. CES 2011: Tablet Crazy

    ERIC Educational Resources Information Center

    Rapp, David

    2011-01-01

    Ereaders are so last year. Tablets were the watchword at this year's annual Consumer Electronics Show (CES) in Las Vegas, January 6-9. This year, the show set new records, with some 2700 companies from around the world exhibiting at the multiple exhibition halls and 30,000 attendees gawking at the products. What did they see? There were still some…

  14. [Sanhuang tablets research].

    PubMed

    Liu, Cui-zhe; Chen, Da-wei

    2007-09-01

    Sanhuang tablets is one of common traditional Chinese patent preparation, it has effects of clear fever, detoxifcation, dispel inflammation, purgation. It was contained in the ministerial standards of Ministry of Health in 1997, and was contained in Chinese pharmacopoeia version 1 of 2000 and 2005. Its improvement of dosage form, preparation technique, quality analysis, pharmacology and clinical usage were reviewed in this paper.

  15. Effects of morphine in the isolated mouse urinary bladder.

    PubMed

    Acevedo, C G; Tamayo, L; Contreras, E

    1986-01-01

    Acute morphine increased the responses to acetylcholine of the isolated mouse urinary bladder. A chronic morphine treatment did not change the responses of the urinary bladder to acetylcholine or ATP. The acute administration of morphine did not modify the contractile response to ATP in the urinary bladders from untreated or chronically morphine treated mice. Methadone and ketocyclazocine decreased the responses to the electrical stimulation of the urinary bladder. These depressant effects were not modified by naloxone. The results suggest the nonexistence of opiate receptors in the mouse urinary bladder and the lack of direct effects of morphine on the neuroeffector junction.

  16. Disturbed patterns of behaviour in morphine tolerant and abstinent rats

    PubMed Central

    Kumar, R.; Mitchell, E.; Stolerman, I. P.

    1971-01-01

    1. Eating, drinking and spontaneous motor activity were studied in rats receiving large daily doses of morphine. These forms of behaviour were largely suppressed when the rats were made abstinent and were restored when morphine was given again. 2. Compensation for depressions of behaviour during abstinence did not seem sufficient to account for all the stimulant effects of morphine in tolerant rats. Morphine also had slight stimulant actions in non-tolerant rats. 3. In tolerant rats, the repeated pairing of the effects of morphine with the re-emergence of behaviour such as eating and drinking may intensify the rewarding value of the drug. PMID:5105387

  17. Improving the hardness of dry granulated tablets containing sodium lauryl sulfate.

    PubMed

    Moore, Francis; Okelo, Geoffrey; Colón, Ivelisse; Kushner, Joseph

    2010-11-15

    The impact of the addition of a wetting agent, the surfactant sodium lauryl sulfate (SLS), on the tablet hardness of a dry granulated, solid oral dosage form was investigated. In three batches, SLS was added concurrently with: (1) a poorly soluble, highly hydrophobic active pharmaceutical ingredient (API) and the other excipients prior to the initial blending step, (2) magnesium stearate prior to roller compaction, or (3) magnesium stearate prior to tableting. A fourth batch, which did not contain SLS, served as a control. The maximum hardness of 100 mg, 1/4″-SRC tablets for the four batches--SLS added initially, prior to roller compaction, prior to tableting, and no SLS--were 61±3, 71±3, 89±5, and 86±3N, respectively, suggesting reduced processing of SLS improves tablet hardness by ∼50%. Dissolution of the tablets in 900 ml of simulated gastric fluid with paddles at 75 rpm showed that: (1) there was no impact on the insertion point of SLS into the process on API dissolution, and (2) that the presence of SLS improved dissolution by 5% compared to the control tablets. Adding SLS just prior to tableting can improve tablet hardness and yield similar dissolution performance relative to SLS addition prior to the initial blending step.

  18. Synthetic substances with morphine-like effect

    PubMed Central

    Eddy, Nathan B.; Halbach, H.; Braenden, Olav J.

    1957-01-01

    A review of effects in man of morphine-like drugs which have been brought under international narcotics control is presented in the form of individual monographs. These are based on controlled observations with quantitative data and significant reports of results obtained in medical practice. In a summarizing section, the drugs are compared with respect to effectiveness, side-effects and addiction liability. Morphine-like drugs of natural and synthetic origin now cover a wide range of potency (analgesic, antitussive), not necessarily paralleled by incidence of side-effects or addiction liability. PMID:13511135

  19. Calcium channel antagonists increase morphine-induced analgesia and antagonize morphine tolerance.

    PubMed

    Contreras, E; Tamayo, L; Amigo, M

    1988-04-13

    The influence of calcium channel blockers on morphine-induced analgesia and on tolerance to the chronic administration of the opiate was investigated in mice. The effects of a test dose of morphine were significantly increased by the administration of diltiazem, flunarizine, nicardipine and verapamil. In contrast, nifedipine induced an antagonistic effect. The calcium channel antagonists did not change the reaction time to thermal stimulation in mice (hot plate test). The administration of nifedipine, flunarizine and verapamil reduced the intensity of the tolerance induced by a single dose of morphine administered in a slow release preparation. Diltiazem induced a non-significant decrease of the process. The present results are in accordance with the known interaction of acute and chronic morphine administration with the intracellular calcium concentration in neurones of the central nervous system.

  20. Practical limitations of tableting indices.

    PubMed

    Kuppuswamy, R; Anderson, S R; Hoag, S W; Augsburger, L L

    2001-11-01

    The purpose of this study was to utilize tableting indices to distinguish between materials with varying degrees of compactibility by establishing a quantitative relationship between indices and compactibility. Compactibility in this study is restricted to tablet strength and friability alone. Nine mixtures with varying degrees of compactibility were tableted and the tensile strength and friability of the tablets were determined. The tableting indices of these mixtures were determined using an Instron Universal testing machine. An artificial neural network program was used to establish a quantitative relationship between indices and tablet strength and friability. Six new powders were used to validate the models describing the relationship between indices and tablet strength and friability. These powders were compressed into tablets and their strength and friability were determined. Their indices were also determined. The established models were used to predict tablet strength and friability from index values. The predicted values were compared with the experimentally determined values. There was little correlation between the predicted and experimentally determined values for tablet strength and friability. It was also found that materials or mixtures having almost similar indices had remarkably different compactibilities. It was concluded that models created to predict compactibility using one set of materials may not be able to successfully predict the compactibility of a new material. This calls into question the practicality of indices.

  1. Dysregulation of dopaminergic regulatory mechanisms in the mesolimbic pathway induced by morphine and morphine withdrawal.

    PubMed

    García-Pérez, Daniel; López-Bellido, Roger; Rodríguez, Raquel E; Laorden, M Luisa; Núñez, Cristina; Milanés, M Victoria

    2015-07-01

    Dopamine (DA) is thought to represent a teaching signal and has been implicated in the induction of addictive behaviours. Previously, it has been proposed that the transcription factors Nurr1 and Pitx3, which are critical for transcription of a set of genes involved in DA metabolism in the mesolimbic pathway, are associated with addiction pathology. The aim of our study was to investigate abnormalities in the mesolimbic pathway associated with morphine dependence and withdrawal. Using quantitative real-time PCR, immunofluorescence, HPLC and Western blotting, here we studied the effects of single morphine administration, morphine dependence and morphine withdrawal on Nurr1 and Pitx3 expression as well as on the DA marker tyrosine hydroxylase (TH) and the turnover of DA in the ventral tegmental area (VTA) and/or nucleus accumbens. We showed that the three experimental conditions caused induction of Nurr1 and Pitx3 in the VTA, which correlated with changes in TH expression during chronic morphine administration. Present data also confirmed the colocalization of Nurr1 and Pitx3 with TH-positive neurons in the posterior VTA. Furthermore, during morphine dependence, Nurr1 was detected in the nucleus compartment of VTA TH-positive neurons, whereas Pitx3 was strongly detected in the nucleus of TH-positive neurons after single morphine administration and during morphine withdrawal. The number of TH neurons, number of Nurr1 or Pitx3-positive cells, and the number of TH neurons expressing Nurr1 or Pitx3 were not modified in the subpopulations of DA neurons. Present data provide novel insight into the potential correlation between Nurr1 and Pitx3 and DA neurons plasticity during opiate addiction in the mesolimbic pathway.

  2. Intrathecal combination of ziconotide and morphine for refractory cancer pain: a rapidly acting and effective choice.

    PubMed

    Alicino, Ilaria; Giglio, Mariateresa; Manca, Fabio; Bruno, Francesco; Puntillo, Filomena

    2012-01-01

    Ziconotide is a nonopioid intrathecal analgesic drug used to manage moderate to severe chronic pain. The aim of this work is to assess the safety and efficacy of intrathecal (IT) combination of ziconotide and morphine in malignant pain refractory to high doses of oral opioids. Patients with malignant pain refractory to high oral opioids doses with a mean visual analogue scale of pain intensity (VASPI) score of ≥ 70 mm were enrolled. An IT combination therapy was administered: Ziconotide was started at a dose of 2.4 μg/day, followed by increases of 1.2 μg/day at intervals of at least 7 days, and an initial IT daily dose of morphine was calculated based on its oral daily dose. Percentage change in VASPI scores from baseline was calculated at 2 days, at 7 days, and weekly until the first 28 days. The mean percentage change of VASPI score from baseline was used for efficacy assessment. Safety was monitored based on adverse events and routine laboratory values. Twenty patients were enrolled, with a mean daily VASPI score at rest of 90±7. All had a disseminated cancer with bone metastases involving the spine. The percentage changes in VASPI mean scores from baseline to 2 days, 7 days, and 28 days were 39±13% (95% confidence interval [CI]=13.61-64.49, P<.001), 51±12% (95% CI=27.56-74.56, P<.001), and 62±13% (95% CI=36.03-87.89%, P<.001), respectively. Four patients experienced mild adverse events related to the study drugs. In conclusion, an IT combination of low doses of ziconotide and morphine allows safe and rapid control of oral opioid-refractory malignant pain.

  3. Pediatric drugs--a review of commercially available oral formulations.

    PubMed

    Strickley, Robert G; Iwata, Quynh; Wu, Sylvia; Dahl, Terrence C

    2008-05-01

    Pediatric oral formulations can be quite scientifically challenging to develop and the prerequisites for both a measurable dosage form to administer based upon bodyweight, and also taste-masking are two of the challenges unique for pediatric oral formulations. The physicochemical and organoleptic properties of the active drug substance such as solubility, chemical stability, and taste along with the intended dose can determine which formulations are feasible to develop. Oral pediatric formulations are available in 17 different varieties and can be either a ready-to-use formulation such as a solution, syrup, suspension, tablet, scored tablet, chewable tablet, orally disintegrating tablet, or thin strip, or can also be a formulation that requires manipulation such as a powder for constitution to a suspension, tablet for constitution to a suspension, powder for constitution to a solution, drops for reconstitution to a suspension, concentrated solution for dilution, effervescent tablet, bulk oral granules, bulk oral powder, or solid in a capsule to mix with food or drink. Recently there has been an increase in pediatric formulation development inspired by increased regulatory incentives. The intent of this review is to educate the reader on the various types of formulations administered orally to pediatrics, the rationale in deciding which type of formulation to develop, the excipients used, development challenges, the in-use handling of oral pediatric formulations, and the regulatory incentives.

  4. Time Dependent Antinociceptive Effects of Morphine and Tramadol in the Hot Plate Test: Using Different Methods of Drug Administration in Female Rats

    PubMed Central

    Gholami, Morteza; Saboory, Ehsan; Mehraban, Sogol; Niakani, Afsaneh; Banihabib, Nafiseh; Azad, Mohamad-Reza; Fereidoni, Javid

    2015-01-01

    Morphine and tramadol which have analgesic effects can be administered acutely or chronically. This study tried to investigate the effect of these drugs at various times by using different methods of administration (intraperitoneal, oral, acute and chronic). Sixty adult female rats were divided into six groups. They received saline, morphine or tramadol (20 to 125 mg/Kg) daily for 15 days. A hot plate test was performed for the rats at the 1st, 8th and 15th days. After drug withdrawal, the hot plate test was repeated at the 17th, 19th, and 22nd days. There was a significant correlation between the day, drug, group, and their interaction (P<0.001). At 1st day (d1), both morphine, and tramadol caused an increase in the hot plate time comparing to the saline groups (P<0.001), while there was no correlation between drug administration methods of morphine and/or tramadol. At the 8th day (d8), morphine and tramadol led to the most powerful analgesic effect comparing to the other experimental days (P<0.001). At the 15th day (d15), their effects diminished comparing to the d8. After drug withdrawal, analgesic effect of morphine, and tramadol disappeared. It can be concluded that the analgesic effect of morphine and tramadol increases with the repeated use of them. Thereafter, it may gradually decrease and reach to a level compatible to d1. The present data also indicated that although the analgesic effect of morphine and tramadol is dose-and-time dependent, but chronic exposure to them may not lead to altered nociceptive responses later in life. PMID:25561936

  5. Optical properties of aqueous morphine solutions

    NASA Astrophysics Data System (ADS)

    Kuznetsov, Pavel E.; Gracheva, Anna A.; Zlobin, Vladimir A.; Nazarov, Georgy V.; Kuznetsova, Nina B.; Rogacheva, Svetlana M.

    2003-10-01

    We have studied morphine action on mobility and structure of water by means of fluorescent investigations and light scattering analysis. Wave-like concentration dependences have been plotted in the both cases. Theoretical description of the discovered effect has been made based on the formalism of N.N.Bogolubov.

  6. Intrathecal Morphine Plus General Anesthesia in Cardiac Surgery: Effects on Pulmonary Function, Postoperative Analgesia, and Plasma Morphine Concentration

    PubMed Central

    dos Santos, Luciana Moraes; Santos, Verônica Cavani Jorge; Santos, Silvia Regina Cavani Jorge; Malbouisson, Luiz Marcelo Sá; Carmona, Maria José Carvalho

    2009-01-01

    OBJECTIVES: To evaluate the effects of intrathecal morphine on pulmonary function, analgesia, and morphine plasma concentrations after cardiac surgery. INTRODUCTION: Lung dysfunction increases morbidity and mortality after cardiac surgery. Regional analgesia may improve pulmonary outcomes by reducing pain, but the occurrence of this benefit remains controversial. METHODS: Forty-two patients were randomized for general anesthesia (control group n=22) or 400 μg of intrathecal morphine followed by general anesthesia (morphine group n=20). Postoperative analgesia was accomplished with an intravenous, patient-controlled morphine pump. Blood gas measurements, forced vital capacity (FVC), forced expiratory volume (FEV), and FVC/FEV ratio were obtained preoperatively, as well as on the first and second postoperative days. Pain at rest, profound inspiration, amount of coughing, morphine solicitation, consumption, and plasma morphine concentration were evaluated for 36 hours postoperatively. Statistical analyses were performed using the repeated measures ANOVA or Mann-Whiney tests (*p<0.05). RESULTS: Both groups experienced reduced FVC postoperatively (3.24 L to 1.38 L in control group; 2.72 L to 1.18 L in morphine FEV1 (p=0.085), group), with no significant decreases observed between groups. The two groups also exhibited similar results for FEV1/FVC (p=0.68) and PaO2/FiO2 ratio (p=0.08). The morphine group reported less pain intensity (evaluated using a visual numeric scale), especially when coughing (18 hours postoperatively: control group= 4.73 and morphine group= 1.80, p=0.001). Cumulative morphine consumption was reduced after 18 hours in the morphine group (control group= 20.14 and morphine group= 14.20 mg, p=0.037). The plasma morphine concentration was also reduced in the morphine group 24 hours after surgery (control group= 15.87 ng.mL−1 and morphine group= 4.08 ng.mL−1, p=0.029). CONCLUSIONS: Intrathecal morphine administration did not significantly alter

  7. Formulation and evaluation of sublingual tablets containing Sumatriptan succinate

    PubMed Central

    Prajapati, Shailesh T; Patel, Parth B; Patel, Chhagan N

    2012-01-01

    Objective: Sumatriptan succinate is a selective 5-hydroxytryptamine-1 receptor agonist effective in the acute treatment of migraine headaches, having low bioavailability of about 15% orally due to first-pass metabolism. The purpose of this research was to mask the intensely bitter taste of Sumatriptan succinate and to formulate fast-acting, taste-masked sublingual tablet formulation. Materials and Methods: Taste masking was performed by solid dispersion method with mannitol and ion exchange with Kyron T 114 because it releases the drug in salivary pH. The resultant batches were evaluated for in-vivo taste masking as well compatability study (Fourier transform infrared (FTIR) and differential scanning calorimetry (DSC)). For a better feel in the mouth, menthol and sweetener Na saccharine were added to the tablet formulation. The tablets were prepared by direct compression and evaluated for weight variation, thickness, friability, drug content, hardness, disintegration time, wetting time, in vitro drug release, and in vitro permeation study. Results and Discussion: Optimized batches disintegrated in vitro within 28-34 s. Maximum drug release could be achieved with in 10 min for the solid dispersion batches and 14-15 min for the ion-exchange batches with Kyron T 114. The optimized tablet formulation showed better taste and the formulated sublingual tablets may act as a potential alternate for the Sumatriptan succinate oral tablet. Conclusion: Sumatriptan succinate can be successfully taste-masked by both the solid dispersion method using mannitol by the melting method and Ion exchange resin with Kyron T114. It was also concluded that prepared formulation improve bioavailability by prevention of first pass metabolism. PMID:23373008

  8. Comparison of a drug versus money and drug versus drug self-administration choice procedure with oxycodone and morphine in opioid addicts

    PubMed Central

    Comer, Sandra D; Metz, Verena E; Cooper, Ziva D; Kowalczyk, William J; Jones, Jermaine D; Sullivan, Maria A; Manubay, Jeanne M; Vosburg, Suzanne K; Smith, Mary E; Peyser, Deena; Saccone, Phillip A

    2014-01-01

    This double-blind, placebo-controlled study investigated effects of oral morphine (0, 45, 135 mg/70kg) and oral oxycodone (0, 15, 45 mg/70kg) in buprenorphine-maintained opioid addicts. Since a 3:1 morphine:oxycodone dose ratio had yielded equivalent subjective and physiological effects in non-dependent individuals, this ratio was used in the present study. Two self-administration laboratory procedures, i.e. a drug vs. money and a drug vs. drug procedure, were assessed. Study participants (N=12) lived in the hospital and were maintained on 4 mg/day sublingual buprenorphine. When participants chose between drug and money, money was preferred over all drug doses; only high-dose oxycodone was self-administered more than placebo. When participants chose between drug and drug, both drugs were chosen more than placebo, high doses of each drug were chosen over low doses, and high-dose oxycodone was preferred over high-dose morphine. The subjective, performance-impairing, and miotic effects of high-dose oxycodone were generally greater compared to high-dose morphine. The study demonstrated that a 3:1 dose ratio of morphine:oxycodone was not equipotent in buprenorphine-dependent subjects. Both self-administration procedures were effective for assessing the relative reinforcing effects of drugs; preference for one procedure should be driven by the specific research question of interest. PMID:23839029

  9. Oral contraceptives.

    PubMed

    Maclennan, A H

    1987-12-01

    Over 60 million women use highly efficient and safe modern combined oral contraceptives (OCs) every day. A women who takes the oral contraceptive for 5 years before the age of 30 will actually live 12 days longer, although a woman taking the pill for the 1st time for 5 years after the age of 30 will have her life span reduced on the average by 80 days. OC related morbidity and mortality mostly occur in women over 35 who smoke. Combined low dose OCs are safe for women who do not smoke, at least to 45 years of age and probably to the menopause. The prescription of OCs is also safe to the young adolescent. The pill does not interfere with maturation of the hypothalamic-pituitary ovarian axis and does not increase the incidence of amenorrhoea, oligomenorrhoea or infertility in later life. Patients with contraindications to estrogen therapy are excluded from OC use (history of thromboembolism, major heart disease, liver disease, breast cancer). Low-dose (30-35 mcg estrogen-containing monophasic or triphasic) pills are recommended. Combined oral contraceptives contain either ethinyl estradiol (1.7 to 2 times more potent) or mestranol. After absorption the progestagens, norethisterone acetate, ethynodiol diacetate and lynoestrenol are all metabolized to norethisterone. The progestagen-only pill has about a 2% failure rate and poorer cycle control than the combined pill, but it lacks estrogenic, progestagenic and androgenic side effects. This pill is suitable for the lactating mother, for smokers over 35, for hypertensive patients, and for those with a history of thrombosis. The efficacy of the progestagen-only pill is restored in 3 days of pill taking. Postcoital contraception is an alternative: treatment can be given for at least 72 hours after intercourse. The Yuzpe method calls for the patient to take 2 combined oral contraceptive tablets containing levonorgestrel and ethinyl estradiol (Eugynon or Ovral) followed by a further 2 tablets 12 hours later. This regimen

  10. Sex differences in locomotor effects of morphine in the rat

    PubMed Central

    Craft, Rebecca M.; Clark, James L.; Hart, Stephen P.; Pinckney, Megan K.

    2007-01-01

    Sex differences in reinforcing, analgesic and other effects of opioids have been demonstrated; however, the extent to which sex differences in motoric effects of opioids contribute to apparent sex differences in their primary effects is not known. The goal of this study was to compare the effects of the prototypic mu opioid agonist morphine on locomotor activity in male vs. female rats. Saline or morphine (1-10 mg/kg) was administered s.c. to adult Sprague-Dawley rats, which were placed into a photobeam apparatus for 3-5 hr to measure activity. Modulation of morphine's effects by gonadal hormones and by handling (either during the test session or for 4 days before the test session) were examined. Morphine initially suppressed and later increased locomotor activity in both sexes relative to their saline-injected controls, but males were more sensitive than females to the initial locomotor suppressant effect of morphine. Intermittent, brief handling during the 3-hr test session blunted morphine-induced locomotor activation in both sexes. Females in proestrus were the most sensitive to morphine's locomotor-stimulant effect, with females in estrus showing the least response to morphine. Gonadectomized (GDX) males with or without testosterone were equally sensitive to morphine's effects, whereas GDX females treated with estradiol showed a blunted response to morphine's effects, similar to intact females in estrus. Brief handling on each of 4 consecutive days pre-test attenuated morphine's locomotor suppressant effect in males but had no effect in females, thereby eliminating the sex difference. These data suggest that sex differences in morphine's effects on locomotor activity can be attributed to gonadal hormones in females, and to differential stress-induced modulation of morphine's effects in males vs. females. PMID:17217999

  11. Intravaginal prostaglandin E2 for cervical ripening and induction of labour. A comparison of gel and tablets.

    PubMed

    Davey, D A; Dommisse, J; MacNab, M

    1980-09-27

    Prostaglandin E2 (PGE2) 4,5 mg in the form of either 0,5 mg oral tablets or tylose gel, was inserted intravaginally to induce labour in 11 pairs of patients with an unripe cervix. Labour commenced spontaneously in 68% of the patients and there was no difference in efficacy or complications between the tablets and the gel. PGE2 in tylose gel was originally introduced as the optimal preparation, but is not readily available. PGE2 oral tablets, inserted vaginally, although not ideal, are available and are as effective. The use of intravaginal PGE2 for induction of labour is a significant advance in obstetric practice.

  12. Controlled release tablet formulation containing natural Δ(9)-tetrahydrocannabinol.

    PubMed

    Punyamurthula, Nagendra S; Hingorani, Tushar; Adelli, Goutham; Gul, Waseem; ElSohly, Mahmoud A; Repka, Michael A; Majumdar, Soumyajit

    2016-01-01

    Cannabinoids are increasingly being used in the treatment of chemotherapy-induced nausea and vomiting (CINV) because of their action on the cannabinoid receptors, CB1 and CB2. The currently marketed capsule formulations (sesame oil based and crystalline powder) are required to be administered frequently to maintain therapeutic levels, which leads to non-compliance. In the present study, oral controlled release tablet formulations of Δ(9)-tetrahydrocannabinol (THC) were prepared using the lipids Precirol® and Compritol®. Release profiles using THC-lipid matrices and/or with the lipids in the external phase (blend) were evaluated. The effect of directly compressible diluents lactose mixture (Ludipress®), dicalcium phosphate anhydrous (Emcompress®) and microcrystalline cellulose (Avicel® 102) on tablet characteristics and in vitro drug release was also investigated. Further, in vitro THC release in the presence of a lipase inhibitor, Pluronic® F68, was also studied. A 24 h zero-order THC release profile was obtained with a combination of Precirol® and Compritol® in the compression blend. Addition of Pluronic® F68 did not alter THC release in vitro. These optimized tablets were chemically and physically stable for 3 months, the last time point tested, at 25 °C/60% RH. The overall results demonstrate the feasibility of preparing oral THC tablets for once a day administration which can improve CINV management.

  13. Controlled release camptothecin tablets based on pluronic and poly(acrylic acid) copolymer. Effect of fabrication technique on drug stability, tablet structure, and release mode.

    PubMed

    Bromberg, Lev; Hatton, T Alan; Barreiro-Iglesias, Rafael; Alvarez-Lorenzo, Carmen; Concheiro, Angel

    2007-06-01

    Poly(ethylene oxide)-b-poly(propylene oxide)-b-(polyethylene oxide)-g-poly(acrylic acid), a graft-comb copolymer of Pluronic 127 and poly(acrylic acid) (Pluronic-PAA), was explored as an excipient for tablet dosage form of camptothecin (CPT). The tablets were prepared by either direct compression of the drug-polymer physical blend, suspension in ethanol followed by evaporation, or compression after kneading and characterized with respect to their physical structures, drug stability, and release behavior. Porosity and water uptake rate were strongly dependent on the fabrication procedure, ranking in the order: direct compression of physical blend > compression after suspension/evaporation in ethanol > compression after kneading. Tablets prepared by compression of physical blends swelled in water with a rapid surface gel layer formation that impeded swelling and disintegration of the tablets core. These tablets were able to sustain the CPT release for a period of time longer than those observed with the tablets made by either suspension/evaporation or kneading, which disintegrated within a few minutes. Despite the tablet disintegration, the CPT release was impeded for at least 6 hr, which was attributed to the ability of the Pluronic-PAA copolymers to form micellar aggregates at the hydrated surface of the particles. Physical mixing did not alter the fraction of CPT being in the pharmaceutically active lactone form, whilst the preparation of the tablets by the other two methods caused a significant reduction in the lactone form content. Tablets prepared from the physical blends demonstrated CPT release rates increasing with the pH due to the PAA ionization leading to the increase in the rate and extent of the tablet swelling. The results obtained demonstrate the potential of the Pluronic-PAA copolymers for the oral administration of chemotherapeutic agents.

  14. Regulation of dopaminergic markers expression in response to acute and chronic morphine and to morphine withdrawal.

    PubMed

    García-Pérez, Daniel; Núñez, Cristina; Laorden, M Luisa; Milanés, M Victoria

    2016-03-01

    Dopamine (DA) is thought to represent a teaching signal and has been implicated in the induction of addictive behaviours. Dysfunction of DA homeostasis leading to high or low DA levels is causally linked to addiction. Previously, it has been proposed that the transcription factors Nurr1 and Pitx3, which are critical for transcription of a set of genes involved in DA metabolism in the mesolimbic pathway, are associated with addiction pathology. Using quantitative real-time polymerase chain reaction, immunofluorescence and Western blotting, we studied the effects of single morphine administration, morphine dependence and withdrawal on the DA markers DA transporters (DAT), vesicular monoamine transporters (VMAT2) and DA 2 receptor subtype (DRD2), DA 1 receptor subtype as well as tyrosine hydroxylase (TH) in the ventral tegmental area (VTA) and/or nucleus accumbens (NAc). In addition, Nurr1 and Pitx3 expression was also measured. Present data showed a high degree of colocalization of Nurr1 and Pitx3 with TH(+) neurons in the VTA. We found that the increased Nurr1 and/or Pitx3 levels during morphine dependence and in morphine-withdrawn rats were associated to an increase of DAT, VMAT2 and DRD2. Altogether, present data indicate that morphine dependence and withdrawal induced consistent alterations of most of the DA markers, which was correlated with transcription factors involved in the maintenance of DA neurons in drug-reward pathways, suggesting that Nurr1 and Pitx3 regulation might be associated with controlling adaptation to chronic morphine and to morphine withdrawal-induced alterations of DA neurons activity in the mesolimbic pathway.

  15. Development of a novel tablet machine for a tiny amount of powder and evaluation of capping tendency.

    PubMed

    Nakamura, Hideya; Sugino, Yui; Iwasaki, Tomohiro; Watano, Satoru

    2011-01-01

    A novel single punch tablet machine was developed for a tiny amount of powder sample. This tablet machine mainly consists of upper and lower punches, single die, and conical powder feeder equipped with micro-vibrators. By using the powder feeder, mass of discharged powder can be maintained constant even if a tiny amount of powder having poor flowability is used. Motions of both upper and lower punches can be set arbitrarily. Thus, this machine enables us to prepare tablets with a tiny amount of powder sample under the same compression mechanism as conventional rotary tablet machines. Performance of the developed tablet machine was evaluated in a continuous direct tableting using a model powder with poor flowability. Thirty-four tablets (195 mg×34) having acceptable properties can be successfully prepared using no more than 10.0 g of a powder sample. We then proposed a novel in-die evaluation method of capping tendency. A new phase diagram consisting of the elastic recovery energy and the plastic deformation energy was proposed. These energies were calculated from a force-displacement profile, continuously monitored by the developed tablet machine. The results indicate that by using the new diagram the capping tendency of tablets prepared from various model powders can be well discriminated. The developed tablet machine and proposed evaluation method can contribute to a significant cost reduction and speeding up of formulation studies of oral dosage form.

  16. Novel levocetirizine HCl tablets with enhanced palatability: synergistic effect of combining taste modifiers and effervescence technique

    PubMed Central

    Labib, Gihan S

    2015-01-01

    Objectives Levocetirizine HCl, a second-generation piperazine derivative and H1-selective antihistaminic agent, possesses few side effects. The first objective of the study was to compare and evaluate the taste-masking effect of different ratios of 2-hydroxypropyl-β-cyclodextrin and mannitol on levocetirizine HCl using an inclusion complex and solid dispersion, respectively. The second objective was to study the possibility of preparing and evaluating effervescent tablets from the best-chosen taste-masked blends for the purpose of their use either as orodispersible tablets or as water-soluble effervescent tablets, according to patients’ will. Materials and methods Prepared taste-masked blends were prepared and subjected to palatability, Fourier-transform infrared spectroscopy, and differential scanning calorimetry studies. Tablets containing different percentages of effervescent mixtures were prepared by direct compression on the selected taste-modified blends. Evaluation tests were conducted, including flowability and compressibility on the precompressed blends and hardness, friability, wetting time, effervescent time, in vitro, in vivo disintegration time, and in vitro dissolution study on the compressed tablets. Formulated tablets were evaluated and compared to marketed orodispersible tablets for mouth feel and palatability. Results All prepared tablets showed convenient physical and palatability properties compared to the selected brand. The in vitro drug-release study revealed fast release of levocetirizine HCl within 5 minutes from all prepared tablets. Conclusion Levocetirizine HCl effervescent tablets are likely to increase patient compliance with drug administration. Moreover, the use of these effervescent tablets in an orodispersible dosage form can improve oral drug bioavailability and act as an attractive pediatric dosage form. PMID:26379426

  17. Evaluation of enteric-coated tablets as a whole cell inactivated vaccine candidate against Vibrio cholerae.

    PubMed

    Fernández, Sonsire; Año, Gemma; Castaño, Jorge; Pino, Yadira; Uribarri, Evangelina; Riverón, Luis A; Cedré, Bárbara; Valmaseda, Tania; Falero, Gustavo; Pérez, José L; Infante, Juan F; García, Luis G; Solís, Rosa L; Sierra, Gustavo; Talavera, Arturo

    2013-01-01

    A vaccine candidate against cholera was developed in the form of oral tablets to avoid difficulties during application exhibited by current whole cell inactivated cholera vaccines. In this study, enteric-coated tablets were used to improve the protection of the active compound from gastric acidity. Tablets containing heat-killed whole cells of Vibrio cholerae strain C7258 as the active pharmaceutical compound was enteric-coated with the polymer Kollicoat(®) MAE-100P, which protected them efficiently from acidity when a disintegration test was carried out. Enzyme-linked immunosorbent assay (ELISA) anti-lipopolysaccharide (LPS) inhibition test and Western blot assay revealed the presence of V. cholerae antigens as LPS, mannose-sensitive haemagglutinin (MSHA) and outer membrane protein U (Omp U) in enteric-coated tablets. Immunogenicity studies (ELISA and vibriocidal test) carried out by intraduodenal administration in rabbits showed that the coating process of tablets did not affect the immunogenicity of V. cholerae-inactivated cells. In addition, no differences were observed in the immune response elicited by enteric-coated or uncoated tablets, particularly because the animal model and immunization route used did not allow discriminating between acid resistances of both tablets formulations in vivo. Clinical studies with volunteers will be required to elucidate this aspect, but the results suggest the possibility of using enteric-coated tablets as a final pharmaceutical product for a cholera vaccine.

  18. Acute Morphine, Chronic Morphine, and Morphine Withdrawal Differently Affect Pleiotrophin, Midkine, and Receptor Protein Tyrosine Phosphatase β/ζ Regulation in the Ventral Tegmental Area.

    PubMed

    García-Pérez, Daniel; Laorden, M Luisa; Milanés, M Victoria

    2017-01-01

    Pleiotrophin (PTN) and midkine (MK) are secreted growth factors and cytokines, proposed to be significant neuromodulators with multiple neuronal functions. PTN and MK are generally related with cell proliferation, growth, and differentiation by acting through different receptors. PTN or MK, signaling through receptor protein tyrosine phosphatase β/ζ (RPTPβ/ζ), lead to the activation of extracellular signal-regulated kinases (ERKs) and thymoma viral proto-oncogene (Akt), which induce morphological changes and modulate addictive behaviors. Besides, there is increasing evidence that during the development of drug addiction, astrocytes contribute to the synaptic plasticity by synthesizing and releasing substances such as cytokines. In the present work, we studied the effect of acute morphine, chronic morphine, and morphine withdrawal on PTN, MK, and RPTPβ/ζ expression and on their signaling pathways in the ventral tegmental area (VTA). Present results indicated that PTN, MK, and RPTPβ/ζ levels increased after acute morphine injection, returned to basal levels during chronic opioid treatment, and were upregulated again during morphine withdrawal. We also observed an activation of astrocytes after acute morphine injection and during opiate dependence and withdrawal. In addition, immunofluorescence analysis revealed that PTN, but not MK, was overexpressed in astrocytes and that dopaminergic neurons expressed RPTPβ/ζ. Interestingly, p-ERK 1/2 levels during chronic morphine and morphine withdrawal correlated RPTPβ/ζ expression. All these observations suggest that the neuroprotective and behavioral adaptations that occur during opiate addiction could be, at least partly, mediated by these cytokines.

  19. Assessing Student Writing on Tablets

    ERIC Educational Resources Information Center

    Davis, Laurie Laughlin; Orr, Aline; Kong, Xiaojing; Lin, Chow-Hong

    2015-01-01

    There is increasing expectation that schools should be able to use tablets for a range of instructional and assessment purposes. This article considers the comparability of student writing on tablets and laptops to ensure that writing assessment is conducted in a way that is fair to all students. Data were collected from a sample of 826 students…

  20. Tablet PCs: The Write Approach

    ERIC Educational Resources Information Center

    Milner, Jacob

    2006-01-01

    This article discusses the transforming effects of tablet PCs in the classroom. As 1-to-1 computing becomes the goal on K-12 campuses, school districts are turning to this newer, pen-based technology. Saint Mary's School's new Lenovo ThinkPad X41 tablet PCs had transformed the way Saint Mary's teachers did their jobs. Teachers created outlines for…

  1. Metabolism and pharmacokinetics of morphine in neonates: A review

    PubMed Central

    Pacifici, Gian Maria

    2016-01-01

    Morphine is an agonist of the µ and k receptors, whose activation results in analgesia. Morphine-like agonists act through the µ opioid receptors to cause pain relief, sedation, euphoria and respiratory depression. Morphine is glucuronidated and sulfated at positions 3 and 6; the plasma concentration ratios correlate positively with birth weight, which probably reflects increased liver weight with increasing birth weight. Moreover, morphine clearance correlates positively with gestational age and birth weight. Steady-state morphine plasma concentrations are achieved after 24-48 hours of infusion, but the glucuronide metabolite plasma concentrations do not reach steady state before 60 hours. The morphine-3-glucuronide metabolite has lower clearance, a shorter half-life and a smaller distribution volume compared with the morphine-6 metabolite, which is the most active morphine-like agonist. Ordinary doses cause constipation, urinary retention and respiratory depression. Neonatal pain relief may require a blood level of approximately 120 ng/ml, whereas lower levels (20-40 ng/ml) seem adequate for children. A bibliographic search was performed using the PubMed database and the keywords “morphine metabolism neonate” and “morphine pharmacokinetics neonate”. The initial and final cutoff points were January 1990 and September 2015, respectively. The results indicate that morphine is extensively glucuronidated and sulfated at positions 3 and 6, and that the glucuronidation rate is lower in younger neonates compared with older infants. Although much is known about morphine in neonates, further research will be required to ensure that recommended therapeutic doses for analgesia in neonates are evidence based. PMID:27626479

  2. Persistent hiccup associated with intrathecal morphine infusion pump therapy.

    PubMed

    Ruan, Xiulu; Couch, John Patrick; Shah, Rinoo; Wang, Frank; Liu, Hai Nan

    2007-12-01

    Intraspinal drug-delivery therapy has been increasingly used in patients with intractable nonmalignant pain syndromes during the past two decades. Morphine, the only FDA-approved opioid for intrathecal administration, has been the principle agent for such therapy. Although intrathecal morphine infusion can produce profound spinal analgesia, it may also cause some untoward side effects. We describe the first case of persistent hiccup caused by intrathecal morphine infusion therapy.

  3. Effect of delta 9-tetrahydrocannabinol on the morphine-induced hyperactivity of mice.

    PubMed

    Ulkü, E; Ayhan, I H; Tulunay, F C; Uran, B; Kaymakçalan, S

    1980-01-01

    The effect of delta 9-tetrahydrocannabinol (THC) on the locomotor activity-stimulating action of morphine has been investigated in mice. THC (10 mg/kg) has been found to potentiate morphine-induced hyperactivity. On the other hand, the stimulating action of morphine on motor activity strongly diminished in mice rendered tolerant by the implantation of a morphine pellet. The pretreatment of morphine-tolerant mice with the same dose of THC did not change the effect of morphine on the motor activity. These results suggest that tolerance also developed to the potentiating action of THC on morphine-induced hyperactivity during the development of tolerance to this action of morphine.

  4. The effect of morphine consumption on plasma corticosteron concentration and placenta development in pregnant rats

    PubMed Central

    Kazemi, Masoomeh; Sahraei, Hedayat; Azarnia, Mahnaz; Dehghani, Leila; Bahadoran, Hossein; Tekieh, Elaheh

    2011-01-01

    Background: Previous studies have shown that morphine consumption during pregnancy may delay embryo development or cause abnormal nervous system function. Objective: The present study focused on the effect of maternal morphine consumption on development of placenta and blood corticosteron concentration in addictive pregnant mothers. Materials and Methods: 24 female rats, 170-200g weight, were used. The experimental groups after pregnancy received an oral dose of 0.05 mg/ml of morphine by tap water while the control group received only tap water. On 10th and 14th day of pregnancy, rats were anesthetized and placenta removed surgically, 1ml blood was collected from each pregnant mother from retro-orbital sinus, the concentration of blood corticosteron was determined by corticosteron Elisa kit after centrifugation. The fixed tissue was processed, sectioned and stained with hematoxylin and eosin. Placenta was studied microscopically according to the thickness of layers, area of blood cisterns, and the number of cells. Results: Comparing the plasma corticosteron concentration of the treatment and the control groups, not only a severe increase in the treatment group was detected, but also the thickness of maternal and embryonic portions of the placenta at day 10th and 14th of gestation was different significantly (p≤0.05). Furthermore, an increase in number of cells in maternal and embryonic portion of placenta and a decrease in blood cistern area were demonstrated in both the experimental and the control groups. Conclusion: The effects of morphine, including an increase in blood concentration of corticosteron, in dependent pregnant mothers were seen. Development of placenta in the experimental group was delayed. PMID:25587250

  5. Morphine in the treatment of acute pulmonary oedema--Why?

    PubMed

    Ellingsrud, C; Agewall, S

    2016-01-01

    Morphine has for a long time, been used in patients with acute pulmonary oedema due to its anticipated anxiolytic and vasodilatory properties, however a discussion about the benefits and risks has been raised recently. A literature search in Medline and Embase using the keywords "pulmonary oedema" OR "lung oedema" OR "acute heart failure" AND "morphine" was performed. A certain vasodilation has been described after morphine administration, but the evidence for this mechanism is relatively poor and morphine-induced anxiolysis may possibly be the most important factor of morphine in pulmonary oedema and therefore some authors have suggested benzodiazepines as an alternative treatment. Respiratory depression seems to be a less relevant clinical problem according to the literature, whereas vomiting is common, which may cause aspiration. In the largest outcome study, based on the ADHERE registry, morphine given in acute decompensated heart failure was an independent predictor of increased hospital mortality, with an odds ratio of 4.8 (95% CI: 4.52-5.18, p<0.001). Other, smaller studies have shown a significant association between morphine administration and mortality, which was lost after adjusting for confounding factors. Morphine is still used for pulmonary oedema in spite of poor scientific background data. A randomised, controlled study is necessary in order to determine the effect--and especially the risk--when using morphine for pulmonary oedema. Since the positive effects are not sufficiently documented, and since the risk for increased mortality cannot be ruled out, one can advocate that the use should be avoided.

  6. Effect of morphine on PC12 cells with molecular radar

    NASA Astrophysics Data System (ADS)

    Shi, Chen; Yu, Xiaoli; Lu, Jiuyi; Zhang, Chunyang; Jin, Lei; Ma, Hui; Zhang, Dacheng; Chen, Die Yan

    2000-10-01

    Molecular Radar (MR) is a new method to detect biological processes in living cells at the level of molecular, it is also the newest means to get intracellular information. In this paper we study the effect of morphine on PC12 cells using MR. The results show that the effect of morphine on PC12 cells is time- and concentration-dependent. Morphine treating for short time induces the increase and fluctuation of intracellular (CA2+), while morphine treating for long time induces chromatin condensation, loss of mitochondria membrane potential apoptosis.

  7. Attitudes of Polish physicians and medical students toward breaking bad news, euthanasia and morphine administration in cancer patients.

    PubMed

    Leppert, Wojciech; Majkowicz, Mikolaj; Forycka, Maria

    2013-12-01

    Medical students and physicians should possess basic knowledge concerning medical ethics and palliative care. The aim of the study was to explore the knowledge on the end-of-life ethics and palliative care in third-year medical students and physicians during internal medicine specialty training and their attitude towards breaking bad news and euthanasia. A voluntary and anonymous questionnaire survey with the participation of 401 students and 217 physicians filled after lectures concerning ethics for medical students and after palliative medicine course for physicians during internal medicine specialty training. A total of 28 % students and 24 % physicians (p = 0.282) were ready to reveal full information to advanced cancer patients. A total of 82 % of students and 90 % of physicians (p = 0.008) would not practice euthanasia; 67 % of students and 75 % of physicians (p = 0.039) were opponents of euthanasia legalisation. A total of 70 % doctors and 23 % students indicated oral as the most preferable route of morphine administration. A total of 74 % physicians and 43 % students stated that there is no maximal dose of morphine; 64 % of doctors and 6 % of students indicated constipation as a constant adverse effect of morphine. Breaking bad news is a significant difficulty for both students and physicians. There is a small percentage of those tending to practice euthanasia and bigger accepting its legalisation with fewer physicians than students. In contrast to medical students, the majority of physicians have knowledge concerning chronic morphine use in the treatment of cancer patients.

  8. Orodispersible tablets: A new trend in drug delivery

    PubMed Central

    Dey, Paramita; Maiti, Sabyasachi

    2010-01-01

    The most common and preferred route of drug administration is through the oral route. Orodispersible tablets are gaining importance among novel oral drug-delivery system as they have improved patient compliance and have some additional advantages compared to other oral formulation. They are also solid unit dosage forms, which disintegrate in the mouth within a minute in the presence of saliva due to super disintegrants in the formulation. Thus this type of drug delivery helps a proper peroral administration in pediatric and geriatric population where swallowing is a matter of trouble. Various scientists have prepared orodispersible tablets by following various methods. However, the most common method of preparation is the compression method. Other special methods are molding, melt granulation, phase-transition process, sublimation, freeze-drying, spray-drying, and effervescent method. Since these tablets dissolve directly in the mouth, so, their taste is also an important factor. Various approaches have been taken in order to mask the bitter taste of the drug. A number of scientists have explored several drugs in this field. Like all other solid dosage forms, they are also evaluated in the field of hardness, friability, wetting time, moisture uptake, disintegration test, and dissolution test. PMID:22096326

  9. Revisiting tolerance from the endogenous morphine perspective.

    PubMed

    Stefano, George B; Kream, Richard M; Esch, Tobias

    2009-09-01

    Tolerance represents a dynamic mechanism that can be used to temper various regulatory processes regardless of whether they mediate excitation or inhibition. Tolerance operationally directs state-dependent attenuation of the action of endogenous and exogenous morphine. For example, tolerance ensures that immuno-inhibition induced by morphine does not compromise a requisite functional system over an extended period of time. In the nervous system, tolerance to inhibitory action insures that excitatory tone is resumed. Thus, desensitization sets in and allows various essential processes to be operational once again. Clearly, the temporal rebound of diverse immune and nervous processes involved with opiate actions provides a self-contained operational mechanism to ensure survival of the organism. Furthermore, love and/or pleasure, and satiety, are complex neurobiological phenomena linked to limbic brain reward circuitry. These processes are critically dependent on oxytocin, vasopressin, dopamine, endogenous morphine and serotoninergic signaling. Naturally rewarding and/or pleasurable activities are usually governed by beneficial biological behaviors like eating, sex, and reproduction. It is our contention that critically important tolerance mechanisms extend to behaviors mediated by CNS reward systems. In other words, we become satisfied with sex, food, pleasure for the moment and disinterest creeps in until the "urges" return.

  10. Biomarkers of morphine tolerance and dependence are prevented by morphine-induced endocytosis of a mutant μ-opioid receptor

    PubMed Central

    He, Li; Kim, Joseph A.; Whistler, Jennifer L.

    2009-01-01

    Growing evidence shows that trafficking of the μ-opioid receptor (MOR) is a critical process in functional recovery from desensitization following activation and plays important roles in morphine tolerance and dependence largely because of the failure of morphine to promote such trafficking. However, morphine tolerance and dependence are believed to be mediated by multiple mechanisms, including well-documented biochemical changes in cAMP activity, N-methyl-d-aspartate receptors (NMDARs), glucocorticoid receptors (GRs), and c-fos. Here, we assess the consequences of promoting morphine-induced endocytosis on these biochemical changes utilizing a knock-in mouse model, RMOR, in which MORs undergo morphine-induced endocytosis. Chronic morphine treatment of wild-type (WT) mice promoted superactivation of adenylyl cyclase, alterations in NMDARs, and up-regulation of GR and c-fos in distinct brain regions. Notably, none of these biochemical changes occurred in the RMOR-knock-in mice. Together, these data demonstrate that morphine tolerance and dependence are mediated by multiple biochemical mechanisms and that MOR endocytosis plays a critical role in each of these mechanisms.—He, L., Kim, J. A., Whistler, J. L. Biomarkers of morphine tolerance and dependence are prevented by morphine-induced endocytosis of a mutant μ-opioid receptor. PMID:19679639

  11. Effect of Food Thickener on the Inhibitory Effect of Mitiglinide Tablets on Post-prandial Elevation of Blood Glucose Levels.

    PubMed

    Tomita, Takashi; Goto, Hidekazu; Sumiya, Kenji; Yoshida, Tadashi; Tanaka, Katsuya; Kudo, Kenzo; Kohda, Yukinao

    2017-03-07

    The aim of this study was to examine the effect of food thickener on the pharmacodynamics of mitiglinide (MGN), a drug belonging to a class of rapid-acting insulin secretagogues. First, MGN tablets were coated by immersion in a xanthan gum-based food-thickening agent. This treatment was shown to delay disintegration rates of MGN tablets in vitro. The pharmacodynamics of MGN after ingestion of a single oral dose of an MGN tablet, with or without food thickener immersion, were then examined in an open-label crossover study comprising 5 healthy participants. It was observed that after administration of 75 g of oral glucose, the area under the blood glucose concentration-time curve was larger for treatment with MGN tablets that had been immersed in the food thickener than for nonimmersed tablets. The maximum blood glucose level was also higher in treatments with MGN tablets that had been immersed in food thickener. The extended time of higher glucose levels associated with thickener-immersed MGN tablets given to human volunteers may be associated with the reduced disintegration rates of immersed MGN tablets as observed in the in vitro experiment. Overall, our study suggests that commercially available food thickeners influence the pharmacodynamics of MGN and that their use should therefore be carefully assessed and monitored in certain clinical situations.

  12. [Analgesics; the use of aspirin in dogs; effects of tablet type and food intake on plasma salicylate level].

    PubMed

    Nap, R C; Breen, D J; Lam, T J; Peters, I O; Willemsen, A; De Bruyne, J J

    1993-07-15

    Administration of acetylsalicylic acid (aspirin) in the dog may cause gastric mucosal damage. Enteric-coated tablets protect the canine stomach during oral aspirin medication. A therapeutic plasma salicylate concentration can be attained using enteric-coated aspirin tablets at a dosage of 25 mg/kg TID. In a series 4 of experiments using adult beagle and large mixed breed dogs and two types enteric-coated tablets, the influence of food intake on the plasma salicylate concentration was studied. Tablets were administered with 8h intervals and food intake was either once daily or three time daily with 8h intervals. Plasma salicylate concentrations were also studied during fasting. It is concluded that, when using enteric-coated tablets, the plasma salicylate concentration in the dog after oral medication is strongly influenced by the aspirin dosage, the tablet type and the feeding pattern. Large enteric-coated tablets may accumulate in the stomach over several days and are not suitable for use in the dog. The gastric accumulation is caused by the enteric-coating of the large tablets and not by the aspirin medication.

  13. Study of the clomipramine-morphine interaction in the forced swimming test in mice.

    PubMed

    Eschalier, A; Fialip, J; Varoquaux, O; Makambila, M C

    1987-01-01

    Tricyclic antidepressant-morphine interactions have been extensively studied on pain tests but less often on tests predictive of antidepressant activity. The effects of clomipramine (CMI) and morphine were tested on the forced swimming test in mice after pretreatment with CMI, morphine or saline. Like CMI, though less so, morphine was significantly active. Morphine pretreatment partially inhibited the effect of CMI irrespective of the morphine pretreatment dose, but reduction of morphine activity by CMI was non-significant. Acquired tolerance to morphine occurred, but not to CMI. The mechanisms at work were discussed. CMI and desmethylclomipramine (DCMI) plasma levels remained the same after morphine pretreatment, ruling out a pharmacokinetic mechanism. The interaction implied involvement of opiate systems. CMI might have been acting on two different opiate receptor populations, one sensitive to morphine pretreatment, the other not. The mechanism of this action seems to be different from that of morphine.

  14. Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction: the randomized, double-blind, placebo-controlled IMPRESSION trial

    PubMed Central

    Kubica, Jacek; Adamski, Piotr; Ostrowska, Małgorzata; Sikora, Joanna; Kubica, Julia Maria; Sroka, Wiktor Dariusz; Stankowska, Katarzyna; Buszko, Katarzyna; Navarese, Eliano Pio; Jilma, Bernd; Siller-Matula, Jolanta Maria; Marszałł, Michał Piotr; Rość, Danuta; Koziński, Marek

    2016-01-01

    Aims The currently available data indicate a drug–drug interaction between morphine and oral P2Y12 receptor inhibitors, when administered together. The aim of this trial was to assess the influence of infused morphine on pharmacokinetics and pharmacodynamics of ticagrelor and its active metabolite (AR-C124910XX) in patients with acute myocardial infarction. Methods and results In a single-centre, randomized, double-blind trial, patients were assigned in a 1:1 ratio to receive intravenously either morphine (5 mg) or placebo, followed by a 180 mg loading dose of ticagrelor. Pharmacokinetics was determined with liquid chromatography tandem mass spectrometry and ticagrelor antiplatelet effects were measured with up to three different platelet function tests: vasodilator-stimulated phosphoprotein phosphorylation assay, multiple electrode aggregometry and VerifyNow. The pharmacokinetic and pharmacodynamic assessment was performed in 70 patients (35 in each study group). Morphine lowered the total exposure to ticagrelor and its active metabolite by 36% (AUC(0–12): 6307 vs. 9791 ng h/mL; P = 0.003), and 37% (AUC(0–12): 1503 vs. 2388 ng h/mL; P = 0.008), respectively, with a concomitant delay in maximal plasma concentration of ticagrelor (4 vs. 2 h; P = 0.004). Multiple regression analysis showed that lower AUC(0–12) values for ticagrelor were independently associated with the administration of morphine (P = 0.004) and the presence of ST-segment elevation myocardial infarction (P = 0.014). All three methods of platelet reactivity assessment showed a stronger antiplatelet effect in the placebo group and a greater prevalence of high platelet reactivity in patients receiving morphine. Conclusions Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction. ClinicalTrials.gov Identifier: NCT02217878. PMID:26491112

  15. Methadone Reverses Analgesic Tolerance Induced by Morphine Pretreatment

    PubMed Central

    Posa, Luca; Accarie, Alison; Marie, Nicolas

    2016-01-01

    Background: Opiates such as morphine are the most powerful analgesics, but their protracted use is restrained by the development of tolerance to analgesic effects. Recent works suggest that tolerance to morphine might be due to its inability to promote mu opioid receptor endocytosis, and the co-injection of morphine with a mu opioid receptor internalizing agonist like [D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin reduces tolerance to morphine. So far, no studies have been conducted to evaluate the ability of methadone to reduce morphine tolerance in morphine-pretreated animals, a treatment sequence that could be encountered in opiate rotation protocol. We investigated the ability of methadone (a mu opioid receptor internalizing agonist used in therapy) to reverse morphine tolerance and the associated cellular mechanisms in the periaqueductal gray matter, a region involved in pain control. Methods: We measured analgesic response following a challenge dose of morphine in the hot plate test and investigated regulation of mu opioid receptor (coupling and endocytosis) and some cellular mechanisms involved in tolerance such as adenylate cyclase superactivation and changes in N-methyl-d-aspartate receptor subunits expression and phosphorylation state. Results: A chronic treatment with morphine promoted tolerance to its analgesic effects and was associated with a lack of mu opioid receptor endocytosis, adenylate cyclase overshoot, NR2A and NR2B downregulation, and phosphorylation of NR1. We reported that a methadone treatment in morphine-treated mice reversed morphine tolerance to analgesia by promoting mu opioid receptor endocytosis and blocking cellular mechanisms of tolerance. Conclusions: Our data might lead to rational strategies to tackle opiate tolerance in the frame of opiate rotation. PMID:26390873

  16. Morphine, but not trauma, sensitizes to systemic Acinetobacter baumannii infection.

    PubMed

    Breslow, Jessica M; Monroy, M Alexandra; Daly, John M; Meissler, Joseph J; Gaughan, John; Adler, Martin W; Eisenstein, Toby K

    2011-12-01

    Acinetobacter baumannii is an important nosocomial pathogen in civilian intensive care units. Recently the incidence has increased in wounded military personnel. Morphine is documented in numerous animal studies to be immunosuppressive and to sensitize to infection. The hypotheses were tested that morphine, administered for analgesia in the battlefield, predisposes to Acinetobacter infection, and that the opioid may have an additive or synergistic effect with trauma. To test these hypotheses, an intraperitoneal infection model was established in mice using several Acinetobacter strains. Morphine administered for 48 h by implantation of a slow-release morphine pellet increased mortality compared to animals receiving a placebo pellet, an effect that was blocked by the mu-opioid receptor antagonist, naltrexone. Acinetobacter burdens in the blood, spleens, livers, and lungs of morphine-treated mice, were significantly higher than those in placebo-treated animals, confirming that mortality was due to potentiated growth of the bacteria. There were also elevated levels of pro-inflammatory cytokines in morphine-treated versus placebo-treated mice. Morphine caused a reduction in the total number of cells in the peritoneal cavity, a decrease in the percentage and total numbers of neutrophils, and a decrease in the total number of macrophages. Morphine treatment also suppressed levels of the neutrophil-inducing molecules, IL-17A and KC/CXCL1. However, IL-17A(-/-) mice given morphine were not sensitized to Acintobacter infection to a greater degree than similarly treated wild-type mice. Trauma alone did not sensitize to Acinetobacter infection, and there was no additive effect between morphine and trauma. These results support the hypothesis that morphine potentiates Acinetobacter infection.

  17. Biotransformation and pharmacokinetics of ethylmorphine after a single oral dose.

    PubMed Central

    Aasmundstad, T A; Xu, B Q; Johansson, I; Ripel, A; Bjørneboe, A; Christophersen, A S; Bodd, E; Mørland, J

    1995-01-01

    1. The pharmacokinetics of ethylmorphine after administration of a single dose of the cough mixture Cosylan were investigated in 10 healthy subjects. 2. The median urinary recovery of ethylmorphine and measured metabolites was 77% over 48 h. The median tmax of unchanged ethylmorphine was 45 min, and the terminal elimination t1/2 was 2 h. Ethylmorphine-6-glucuronide was found to be the major metabolite. 3. Two subjects had significantly lower urinary recovery (0.48 h) of morphine and morphine-glucuronides than the remainder. Furthermore, these two had urinary metabolic ratios (MRO) and partial metabolic clearances (CLmO) for O-deethylation of ethylmorphine tentatively classifying them phenotypically as poor metabolisers of the debrisoquine/sparteine type. 4. Genotyping for cytochrome P450 (CYP) 2D6 alleles revealed five homozygote (wt/wt) and five heterozygote subjects. Two subjects phenotypically classified as poor metabolisers were genotypically CYP2D6A/wt and CYP2D6D/wt, respectively. 5. Serum and urine samples taken more than 8 and 24 h after administration of ethyl-morphine respectively, contained morphine and morphine-glucuronides, but no ethylmorphine, ethylmorphine-6-glucuronide or (serum only) norethylmorphine. Norethylmorphine could be detected after hydrolysis of urine samples in all subjects. The urinary recovery of the active metabolites morphine and morphine-6-glucuronide after administration of ethylmorphine varied by a factor of 9 between individuals. 6. The wide variation in recovery of morphine and morphine-glucuronides after oral administration of ethylmorphine could not be explained simply by a difference in CYP2D6 genotype. Constitutional variation in other enzymatic pathways involved in ethylmorphine metabolism is probably crucial. Ratios of morphine to parent drug cannot be used to distinguish the source of morphine after administration of ethylmorphine. Norethylmorphine should be included in urine assays for opiates in forensic toxicology

  18. 21 CFR 520.1870 - Praziquantel tablets.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...) Specifications. Each tablet contains: (1) 34 milligrams (mg) praziquantel. (2) 11.5 or 23 mg praziquantel. (b... section. (c) Conditions of use—(1) Dogs—(i) Amount. 5 pounds (lb) and under, 1/2 tablet (17 mg); 6 to 10 lb, 1 tablet (34 mg); 11 to 15 lb, 1 1/2 tablets (51 mg); 16 to 30 lb, 2 tablets (68 mg); 31 to 45...

  19. 21 CFR 520.1870 - Praziquantel tablets.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ...) Specifications. Each tablet contains: (1) 34 milligrams (mg) praziquantel. (2) 11.5 or 23 mg praziquantel. (b... section. (c) Conditions of use—(1) Dogs—(i) Amount. 5 pounds (lb) and under, 1/2 tablet (17 mg); 6 to 10 lb, 1 tablet (34 mg); 11 to 15 lb, 1 1/2 tablets (51 mg); 16 to 30 lb, 2 tablets (68 mg); 31 to 45...

  20. A Traditional Chinese Medicine Xiao-Ai-Tong Suppresses Pain through Modulation of Cytokines and Prevents Adverse Reactions of Morphine Treatment in Bone Cancer Pain Patients.

    PubMed

    Cong, Yan; Sun, Kefu; He, Xueming; Li, Jinxuan; Dong, Yanbin; Zheng, Bin; Tan, Xiao; Song, Xue-Jun

    2015-01-01

    Treating cancer pain continues to possess a major challenge. Here, we report that a traditional Chinese medicine Xiao-Ai-Tong (XAT) can effectively suppress pain and adverse reactions following morphine treatment in patients with bone cancer pain. Visual Analogue Scale (VAS) and Quality of Life Questionnaire (EORTC QLQ-C30) were used for patient's self-evaluation of pain intensity and evaluating changes of adverse reactions including constipation, nausea, fatigue, and anorexia, respectively, before and after treatment prescriptions. The clinical trials showed that repetitive oral administration of XAT (200 mL, bid, for 7 consecutive days) alone greatly reduced cancer pain. Repetitive treatment with a combination of XAT and morphine (20 mg and 30 mg, resp.) produced significant synergistic analgesic effects. Meanwhile, XAT greatly reduced the adverse reactions associated with cancer and/or morphine treatment. In addition, XAT treatment significantly reduced the proinflammatory cytokines interleukin-1β and tumor necrosis factor-α and increased the endogenous anti-inflammatory cytokine interleukin-10 in blood. These findings demonstrate that XAT can effectively reduce bone cancer pain probably mediated by the cytokine mechanisms, facilitate analgesic effect of morphine, and prevent or reduce the associated adverse reactions, supporting a use of XAT, alone or with morphine, in treating bone cancer pain in clinic.

  1. A Traditional Chinese Medicine Xiao-Ai-Tong Suppresses Pain through Modulation of Cytokines and Prevents Adverse Reactions of Morphine Treatment in Bone Cancer Pain Patients

    PubMed Central

    Cong, Yan; Sun, Kefu; He, Xueming; Li, Jinxuan; Dong, Yanbin; Zheng, Bin; Tan, Xiao; Song, Xue-Jun

    2015-01-01

    Treating cancer pain continues to possess a major challenge. Here, we report that a traditional Chinese medicine Xiao-Ai-Tong (XAT) can effectively suppress pain and adverse reactions following morphine treatment in patients with bone cancer pain. Visual Analogue Scale (VAS) and Quality of Life Questionnaire (EORTC QLQ-C30) were used for patient's self-evaluation of pain intensity and evaluating changes of adverse reactions including constipation, nausea, fatigue, and anorexia, respectively, before and after treatment prescriptions. The clinical trials showed that repetitive oral administration of XAT (200 mL, bid, for 7 consecutive days) alone greatly reduced cancer pain. Repetitive treatment with a combination of XAT and morphine (20 mg and 30 mg, resp.) produced significant synergistic analgesic effects. Meanwhile, XAT greatly reduced the adverse reactions associated with cancer and/or morphine treatment. In addition, XAT treatment significantly reduced the proinflammatory cytokines interleukin-1β and tumor necrosis factor-α and increased the endogenous anti-inflammatory cytokine interleukin-10 in blood. These findings demonstrate that XAT can effectively reduce bone cancer pain probably mediated by the cytokine mechanisms, facilitate analgesic effect of morphine, and prevent or reduce the associated adverse reactions, supporting a use of XAT, alone or with morphine, in treating bone cancer pain in clinic. PMID:26617438

  2. The facts that the physical-chemical properties of modern tablets distinguish them from natural food lumps

    NASA Astrophysics Data System (ADS)

    Urakov, A.; Urakova, N.; Reshetnikov, A.; Kopylov, M.; Kasatkin, A.; Baymurzin, D.; Gabdrafikov, R.

    2017-02-01

    It was found that pharmaceutical companies produce drugs in tablet form, physical or physical-chemical properties that are radically different from those of the properties of natural food lumps, in that adult converts food in our mouth before swallowing. It was shown that the conventional shape, color, size, volume, specific gravity, hardness, osmotic and acid activity of modern tablets impair the physical and physicochemical properties of the liquid contents of the stomach is much stronger than such “building” materials, such as chalk, clay, sand, river pebbles and gravel. The results showed, that the value of the specific hardness, deforming tablets, can distinguish modern tablets from each other by more than 5000 times. Therefore, introduction tablets inside without information of ability injuring their action leads to the fact that soft and “unsalted” tablets almost nothing damage, and too “salty” and solid tablets damage the gums, lips, tongue, teeth and dental structures. To reduce the traumatic action tablets offered standardize osmoticity, corrosion and hardness within the range of safe values for soft and hard tissues of the oral cavity and improve standard introduction of tablets in the mouth.

  3. Glyburide/metformin tablets: a new therapeutic option for the management of Type 2 diabetes.

    PubMed

    Dailey, George E

    2003-08-01

    Oral antidiabetic combination therapy is a proven means of establishing glycaemic control in the hyperglycaemic, Type 2 diabetic patient, but co-administering two oral antidiabetic agents separately may hinder compliance with therapy. A new single-tablet of glyburide/metformin combination therapy (Glucovance), Bristol-Myers Squibb, Inc.) has recently been developed, which addresses the primary defects of Type 2 diabetes: beta-cell dysfunction and insulin resistance. The glyburide/metformin tablet, taken with meals, is designed to optimise the absorption of glyburide and to address the postprandial glucose rise. Glyburide/metformin tablets are more effective in controlling fasting and postprandial glycaemia than its component monotherapies, at lower doses of metformin and glyburide compared with monotherapy because of the synergy between its glyburide and metformin components. Moreover, a double-blind study showed that glyburide/metformin tablets are more effective than a free combination of glyburide co-administered with metformin in controlling postprandial glucose. Retrospective analyses suggested that glyburide/metformin tablets control glycated haemoglobin (A1C) more effectively than a free combination of glyburide co-administered with metformin, at lower mean doses of glyburide and metformin. The incidence of side effects is lower than separate component therapy for any given A1C. Glyburide/metformin tablets are an effective option for optimising the control of blood glucose in Type 2 diabetic patients and appear to enhance adherence to therapy.

  4. Glucuronidation in the chimpanzee (Pan troglodytes): studies with acetaminophen, oestradiol and morphine.

    PubMed

    Wong, H; Grace, J E; Wright, M R; Browning, M R; Grossman, S J; Bai, S A; Christ, D D

    2006-12-01

    The chimpanzee has recently been characterized as a surrogate for oxidative drug metabolism in humans and as a pharmacokinetic model for the selection of drug candidates. In the current study, the glucuronidation of acetaminophen, morphine and oestradiol was evaluated in the chimpanzee to extend the characterization of this important animal model. Following oral administration of acetaminophen (600 mg) to chimpanzees (n=2), pharmacokinetics were comparable with previously reported human values, namely mean oral clearance 0.91 vs. 0.62+/-0.05 l h-1 kg-1, apparent volume of distribution 2.29 vs. 1.65+/-0.25 l kg-1, and half-life 1.86 vs. 1.89+/-7h, for chimpanzee vs. human, respectively. Urinary excretions (percentage of dose) of acetaminophen, acetaminophen glucuronide and acetaminophen sulfate were also similar between chimpanzees and humans, namely 2.3 vs. 5.0, 63.1 vs. 54.7, and 25.0 vs. 32.3%, respectively. Acetaminophen, oestradiol and morphine glucuronide formation kinetics were investigated using chimpanzee (n=2) and pooled human liver microsomes (n=10). V(max) (app) and K(m)(app) (or S(50)(app)) for acetaminophen glucuronide, morphine 3- and 6-glucuronide, and oestradiol 3- and 17-glucuronide formation were comparable in both species. Eadie-Hofstee plots of oestradiol 3-glucuronide formation in chimpanzee microsomes were characteristic of autoactivation kinetics. Western immunoblot analysis of chimpanzee liver microsomes revealed a single immunoreactive band when probed with anti-human UGT1A1, anti-human UGT1A6, and anti-human UGT2B7. Taken collectively, these data demonstrate similar glucuronidation characteristics in chimpanzees and humans.

  5. CB1 antagonism: interference with affective properties of acute naloxone-precipitated morphine withdrawal in rats

    PubMed Central

    Wills, Kiri L.; Vemuri, Kiran; Kalmar, Alana; Lee, Alan; Limebeer, Cheryl L.; Makriyannis, Alexandros

    2014-01-01

    Rationale Modulation of the endocannabinoid system has been found to interfere with opiate withdrawal. The potential of activation and blockade of the endocannabinoid system to prevent the aversive-affective state of naloxone-precipitated morphine withdrawal (MWD) was investigated in a one-trial conditioned place aversion (CPA) paradigm. Objective CPA provides a sensitive measure of the motivational effects of acute MWD. The potential of the fatty acid amide hydrolase (FAAH) inhibitors, URB597 and PF-3845, the CB1 antagonist/inverse agonist, AM251, and the neutral CB1 antagonists, AM4113 and AM6527 (oral), to interfere with establishment of a MWD-induced CPA was investigated. As well, the potential of AM251 and AM4113 to interfere with reinstatement of a previously established MWD-induced CPA was investigated. Materials and methods Using a one-trial place conditioning paradigm, rats were administered naloxone (1 mg/kg, subcutaneous (sc)) 24 h after receiving a high dose of morphine (20 mg/kg, sc) and were placed on the conditioning floor. To determine the effect of each pretreatment drug on the establishment of the MWD-induced CPA, URB597 (0.3 mg/kg, intraperitoneally (ip)), PF-3845 (10 mg/kg, ip), AM251 (1 or 2.5 mg/kg, ip), AM4113 (1 or 2.5 mg/kg, ip), and AM6527 (5 mg/kg, oral) were administered prior to conditioning. Results AM251 (2.5, but not 1 mg/k), AM4113, and AM6527, but not URB597 or PF-3845, interfered with the establishment of the MWD-induced CPA. AM251 and AM4113 did not prevent reinstatement of the CPA. Conclusions Neutral antagonism of the CB1 receptor reduces the aversive affective properties of morphine withdrawal. PMID:24770676

  6. Plasma-mediated release of morphine from synthesized prodrugs.

    PubMed

    Thomas, Thommey P; Huang, Baohua; Desai, Ankur; Zong, Hong; Cheng, Xue-Min; Kotlyar, Alina; Leroueil, Pascale R; Dunham, Thomas; van der Spek, Abraham; Ward, Brent B; Baker, James R

    2010-11-01

    Two morphine prodrugs ('PDA' and 'PDB') were synthesized and the kinetics of esterase-mediated morphine release from these prodrugs were determined when incubated with plasma from different animal species. Morphine was rapidly released from PDA by all species plasma with the maximum reached within 5-10min; the released morphine was biologically active as determined by an in vitro cAMP assay. The morphine was released from PDB at a slower and species-dependent rate (mouse>rat>guinea pig>human). Morphine's release from PDB appeared to be mediated by carboxyl esterases as the release was inhibited by the carboxyl esterase inhibitor benzil. PDA nor PDB induce cytotoxicity in the neuronal cell lines SK-NSH and SH-SY5Y. The carboxyl and amino functional moieties present on the linker portions of PDA and PDB, respectively, may facilitate their conjugation to nanoparticles to tailor morphine pharmacokinetics and specific targeting. These studies suggest the potential clinical utility of these prodrugs for morphine release at desired rates by administration of their mixture at selected ratios.

  7. Morphine as a Potential Oxidative Stress-Causing Agent

    PubMed Central

    Skrabalova, Jitka; Drastichova, Zdenka; Novotny, Jiri

    2013-01-01

    Morphine exhibits important pharmacological effects for which it has been used in medical practice for quite a long time. However, it has a high addictive potential and can be abused. Long-term use of this drug can be connected with some pathological consequences including neurotoxicity and neuronal dysfunction, hepatotoxicity, kidney dysfunction, oxidative stress and apoptosis. Therefore, most studies examining the impact of morphine have been aimed at determining the effects induced by chronic morphine exposure in the brain, liver, cardiovascular system and macrophages. It appears that different tissues may respond to morphine diversely and are distinctly susceptible to oxidative stress and subsequent oxidative damage of biomolecules. Importantly, production of reactive oxygen/nitrogen species induced by morphine, which have been observed under different experimental conditions, can contribute to some pathological processes, degenerative diseases and organ dysfunctions occurring in morphine abusers or morphine-treated patients. This review attempts to provide insights into the possible relationship between morphine actions and oxidative stress. PMID:24376392

  8. Effects of denervation on the sensitizing effect to noradrenaline induced by morphine in the vas deferens of mice treated chronically with morphine.

    PubMed

    Contreras, E; Tamayo, L; Gaete, S; Juica, S

    1982-08-01

    The acute administration of morphine to the isolated vas deferens from mice chronically exposed to this analgesic, induced a facilitatory effect on the responses of the muscle to exogenous noradrenaline. It has been suggested that this sensitizing property of morphine might reflect a dependence-like state of the vas deferens. In the present paper, the capability of met- and leu-enkephalin to substitute for morphine was studied, as well as the influence of innervation on the apparent dependence state. The contractile responses to noradrenaline and to acetylcholine were increased after the administration of morphine to the bath containing a denervated vas deferences, prepared from chronically morphinized mice. Morphine administration facilitated noradrenaline- but not acetylcholine-induced contractile effects in vas deferens isolated from mice which had been chronically treated with either morphine or morphine plus guanethidine. The presence of met- or leu-enkephalin in the isolated vas deferens from chronically morphinized mice (either intact, denervated or treated with guanethidine) failed to sensitize contractile responses to noradrenaline or acetylcholine. It is concluded that (a) the sensitizing effect induced by morphine in the vas deferens from mice chronically treated with morphine is specific for the adrenergic neurotransmitter; (b) the effect of morphine is not mimicked by opiate peptides; and (c) denervation of the vas deferens of mice treated chronically with morphine does not suppress the noradrenaline-sensitizing property of morphine.

  9. Attenuation by dextromethorphan on the higher liability to morphine-induced reward, caused by prenatal exposure of morphine in rat offspring.

    PubMed

    Wu, Ling-Yi; Chen, Jain-Fang; Tao, Pao-Luh; Huang, Eagle Yi-Kung

    2009-11-25

    Co-administration of dextromethorphan (DM) with morphine during pregnancy and throughout lactation has been found to reduce morphine physical dependence and tolerance in rat offspring. No evidence was presented, however, for the effect of DM co-administered with morphine during pregnancy on morphine-induced reward and behavioral sensitization (possibly related to the potential to induce morphine addiction) in morphine-exposed offspring. Conditioned place preference and locomotor activity tests revealed that the p60 male offspring of chronic morphine-treated female rats were more vulnerable to morphine-induced reward and behavioral sensitization. The administration of a low dose of morphine (1 mg/kg, i.p.) in these male offspring also increased the dopamine and serotonin turnover rates in the nucleus accumbens, which implied that they were more sensitive to morphine. Co-administration of DM with morphine in the dams prevented this adverse effect of morphine in the offspring rats. Thus, DM may possibly have a great potential in the prevention of higher vulnerability to psychological dependence of morphine in the offspring of morphine-addicted mothers.

  10. In vitro morphine metabolism by rat microglia.

    PubMed

    Togna, Anna Rita; Antonilli, Letizia; Dovizio, Melania; Salemme, Adele; De Carolis, Lorenza; Togna, Giuseppina I; Patrignani, Paola; Nencini, Paolo

    2013-12-01

    Morphine is mainly transformed to morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in the liver. Glucuronidation is also performed by rat brain homogenates and UDP-glucuronosyltransferases (UGTs) are present in the brain. Here we investigated the possibility that microglia transforms morphine into its metabolites M3G and M6G. Primary cultures of neonatal rat microglia were incubated for different intervals of time in basal conditions or with different concentrations of morphine. The following measures were performed on these cultures and/or in the medium: (i) morphine as well as M3G and M6G concentrations; (ii) levels of mRNA coding for UGT1A1, UGT1A6, UGT1A7, and UGT2B1 as well as their protein levels; (iii) released prostaglandin (PG)E2 and nitrite concentrations. Results show that in basal conditions morphine and M3G are produced by microglia; accordingly, these cells expressed UGT1A1, UGT1A6 and UGT1A7, but not UGT2B1. When cultures were exposed to different concentrations of exogenous morphine, M6G was also synthesized. This shift in the glucuronidation was associated with variations in the expression of UGT isozymes. In particular, UGT1A7 expression was rapidly upregulated and this event was translated into enhanced protein levels of UGT1A7; lesser effects were exerted on UGT1A1 and UGT1A6. Upon prolonged exposure to morphine, microglial cell UGT expression returned to baseline conditions or even to reduced levels of expression. Morphine exposure did not affect the synthesis of both PGE2 and nitrites, ruling out a generalized priming of microglia by morphine. In conclusion, this study suggests that morphine glucuronides found in the cerebrospinal liquor upon peripheral morphine administration may at least in part be brain-born, reconciling the conceptual gap between the high hydrophilic features of morphine glucuronides and their presence beyond the blood-brain barrier.

  11. Development and evaluation of glyburide fast dissolving tablets using solid dispersion technique.

    PubMed

    Valleri, M; Mura, P; Maestrelli, F; Cirri, M; Ballerini, R

    2004-05-01

    Glyburide is a poorly water-soluble oral hypoglycemic agent, with problems of variable bioavailability and bio-inequivalence related to its poor water-solubility. This work investigated the possibility of developing glyburide tablets, allowing fast, reproducible, and complete drug dissolution, by using drug solid dispersion in polyethylene glycol. Phase-solubility studies were performed to investigate the drug-carrier interactions in solution, whereas differential scanning calorimetry, X-ray powder diffraction, and infrared spectroscopy were used to characterize the solid state of solid dispersions. The effects of several variables related to both solid dispersion preparation (cofusion or coevaporation technique, drug-to-carrier ratio, polyethylene glycol molecular weight) and tablet production (direct compression or previous wet-granulation, tablet hardness, drug, and solid dispersion particle size) on drug dissolution behavior were investigated. Tablets obtained by direct compression, with a hardness of 7-9 Kp, and containing larger sized solid dispersions (20-35 mesh, i.e., 850-500 microm) of micronized glyburide in polyethylene glycol 6000 prepared by the cofusion method gave the best results, with a 135% increase in drug dissolution efficiency at 60 min in comparison with a reference tablet formulation containing the pure micronized drug. Moreover, the glyburide dissolution profile from the newly developed tablets was clearly better than those from various commercial tablets at the same drug dosage.

  12. Esomeprazole immediate release tablets: Gastric mucosa ex vivo permeation, absorption and antisecretory activity in conscious rats.

    PubMed

    Benetti, Camillo; Flammini, Lisa; Vivo, Valentina; Colombo, Paolo; Colombo, Gaia; Elviri, Lisa; Scarpignato, Carmelo; Buttini, Francesca; Bettini, Ruggero; Barocelli, Elisabetta; Rossi, Alessandra

    2016-10-10

    The aim of this work was to study the esomeprazole activity on the control of gastric secretion after administration of a novel immediate release tablet. The ex vivo permeation of esomeprazole across porcine gastric mucosa from immediate release tablets, containing sodium carbonate or magnesium oxide as alkalinizing agents, was firstly assessed. Pharmacokinetics and pharmacodynamics studies in conscious rats following the administration of immediate release tablets with sodium carbonate, in comparison with delayed-release tablets having the same formula, were also conducted. The results showed an important effect of sodium carbonate and magnesium oxide on the drug release, on the ex vivo trans-mucosal transport and the stability in acid environment. In particular, the presence of sodium carbonate in esomeprazole tablet formulation provided the maximum increase of the drug in vitro transport across the mucosa. Then, the absorption and the antisecretory activity of this proton pump inhibitor orally administered in rats as immediate release tablets containing Na2CO3, was superior but not significantly different compared to delayed-release tablets having the same formula. In the adopted animal model, an activity of esomeprazole from immediate release alkaline formulation was seen also in presence of partial gastric absorption allowing inhibition of proton pumps reached via systemic circulation. This esomeprazole immediate release formulation could be used for the on-demand treatment of acid-related disorders such as gastro-esophageal reflux disease.

  13. Formulation Development and Characterization of Meclizine Hydrochloride Sublimated Fast Dissolving Tablets.

    PubMed

    Vemula, Sateesh Kumar; Vangala, Mohan

    2014-01-01

    The intention of present research is to formulate and develop the meclizine hydrochloride fast dissolving tablets using sublimation method to enhance the dissolution rate. In this study an attempt was made to fasten the drug release from the oral tablets by incorporating the superdisintegrants and camphor as sublimating agent. The prepared fast dissolving tablets were subjected to precompression properties and characterized for hardness, weight variation, friability, wetting time, water absorption ratio, and disintegration time. From in vitro release studies, the formulation F9 exhibited fast release profile of about 98.61% in 30 min, and disintegration time 47 sec when compared with other formulations. The percent drug release in 30 min (Q 30) and initial dissolution rate for formulation F9 was 98.61 ± 0.25%, 3.29%/min. These were very much higher compared to marketed tablets (65.43 ± 0.57%, 2.18%/min). The dissolution efficiency was found to be 63.37 and it is increased by 1.4-fold with F9 FDT tablets compared to marketed tablets. Differential scanning calorimetry and Fourier transform infrared spectroscopy studies revealed that there was no possibility of interactions. Thus the development of meclizine hydrochloride fast dissolving tablets by sublimation method is a suitable approach to improve the dissolution rate.

  14. Formulation Development and Characterization of Meclizine Hydrochloride Sublimated Fast Dissolving Tablets

    PubMed Central

    Vangala, Mohan

    2014-01-01

    The intention of present research is to formulate and develop the meclizine hydrochloride fast dissolving tablets using sublimation method to enhance the dissolution rate. In this study an attempt was made to fasten the drug release from the oral tablets by incorporating the superdisintegrants and camphor as sublimating agent. The prepared fast dissolving tablets were subjected to precompression properties and characterized for hardness, weight variation, friability, wetting time, water absorption ratio, and disintegration time. From in vitro release studies, the formulation F9 exhibited fast release profile of about 98.61% in 30 min, and disintegration time 47 sec when compared with other formulations. The percent drug release in 30 min (Q30) and initial dissolution rate for formulation F9 was 98.61 ± 0.25%, 3.29%/min. These were very much higher compared to marketed tablets (65.43 ± 0.57%, 2.18%/min). The dissolution efficiency was found to be 63.37 and it is increased by 1.4-fold with F9 FDT tablets compared to marketed tablets. Differential scanning calorimetry and Fourier transform infrared spectroscopy studies revealed that there was no possibility of interactions. Thus the development of meclizine hydrochloride fast dissolving tablets by sublimation method is a suitable approach to improve the dissolution rate. PMID:27355021

  15. In vitro and in vivo evaluation of a fast-disintegrating lyophilized dry emulsion tablet containing griseofulvin.

    PubMed

    Ahmed, Iman Saad; Aboul-Einien, Mona Hassan

    2007-09-01

    Development of a fast-disintegrating lyophilized dry emulsion (LDE) tablet that enhanced the in vitro dissolution and in vivo absorption of griseofulvin (GF) is presented. The LDE tablets were prepared by freeze-drying o/w emulsions of GF, a drug for which bioavailability is known to be enhanced by fat co-administration. Oil-in-water emulsions were prepared using a gelatin solution (2%, w/v) as the water phase and medium chain triglycerides (Miglyol) or sesame oil as the oil phase. In addition, different emulsifiers were evaluated. The influence of formulation parameters on the disintegration and in vitro dissolution of GF from LDE tablets along with other tablet characteristics were investigated. A significant influence of the emulsifier type on the tablet disintegration time was seen (p<0.01). Results obtained from dissolution studies showed that LDE tablets of GF improved the dissolution rate of the drug compared to the plain drug. The extent of absorption of GF from a selected LDE tablet formulation as compared to an immediate release conventional tablet as reference after single oral dose (125mg) administration was determined in four healthy subjects using a randomized crossover design. In this study, the rate of absorption of GF from LDE tablet was faster than that from the reference tablet and had significantly higher (p=0.02) peak plasma concentration (more than three times higher) and shortened time to C(max) by 4h (p=0.014). The extent of absorption expressed by AUC was 85% larger as compared to the commercial tablet. Stability results, after 6 months storage of LDE tablets at 25 degrees C and 60% relative humidity, showed a slight increase in disintegration time and residual moisture content, while results from dissolution studies showed slightly slower initial drug release.

  16. Morphine and Codeine in Biological Fluids: Approaches to Source Differentiation.

    PubMed

    ElSohly, M A; Jones, A B

    1989-06-01

    Heroin, morphine, and codeine are among the most abused opiate analgesics today. Analysis of individuals' urines for morphine and codeine is sued as an indication of prior ingestion of these dugs. Poppy seeds and products containing poppy seeds are found to have small amounts of morphine and codeine (usually less than 200 µg morphine/g seeds and much less codeine), which is enough to produce a positive urine test for opiates. This manuscript reviews current data on the analysis of various poppy seed products and urine specimens from individuals ingesting these products. A brief review of the metabolism and elimination of these drugs is presented, with general guidelines for differentiation of poppy seed use versus condone, morphine, or heroin abuse.

  17. FDA-Approved Natural Polymers for Fast Dissolving Tablets.

    PubMed

    Alam, Md Tausif; Parvez, Nayyar; Sharma, Pramod Kumar

    2014-01-01

    Oral route is the most preferred route for administration of different drugs because it is regarded as safest, most convenient, and economical route. Fast disintegrating tablets are very popular nowadays as they get dissolved or facilely disintegrated in mouth within few seconds of administration without the need of water. The disadvantages of conventional dosage form, especially dysphagia (arduousness in swallowing), in pediatric and geriatric patients have been overcome by fast dissolving tablets. Natural materials have advantages over synthetic ones since they are chemically inert, non-toxic, less expensive, biodegradable and widely available. Natural polymers like locust bean gum, banana powder, mango peel pectin, Mangifera indica gum, and Hibiscus rosa-sinenses mucilage ameliorate the properties of tablet and utilized as binder, diluent, and superdisintegrants increase the solubility of poorly water soluble drug, decrease the disintegration time, and provide nutritional supplement. Natural polymers are obtained from the natural origin and they are cost efficacious, nontoxic, biodegradable, eco-friendly, devoid of any side effect, renewable, and provide nutritional supplement. It is proved from the studies that natural polymers are more safe and efficacious than the synthetic polymers. The aim of the present article is to study the FDA-approved natural polymers utilized in fast dissolving tablets.

  18. FDA-Approved Natural Polymers for Fast Dissolving Tablets

    PubMed Central

    Alam, Md Tausif; Parvez, Nayyar; Sharma, Pramod Kumar

    2014-01-01

    Oral route is the most preferred route for administration of different drugs because it is regarded as safest, most convenient, and economical route. Fast disintegrating tablets are very popular nowadays as they get dissolved or facilely disintegrated in mouth within few seconds of administration without the need of water. The disadvantages of conventional dosage form, especially dysphagia (arduousness in swallowing), in pediatric and geriatric patients have been overcome by fast dissolving tablets. Natural materials have advantages over synthetic ones since they are chemically inert, non-toxic, less expensive, biodegradable and widely available. Natural polymers like locust bean gum, banana powder, mango peel pectin, Mangifera indica gum, and Hibiscus rosa-sinenses mucilage ameliorate the properties of tablet and utilized as binder, diluent, and superdisintegrants increase the solubility of poorly water soluble drug, decrease the disintegration time, and provide nutritional supplement. Natural polymers are obtained from the natural origin and they are cost efficacious, nontoxic, biodegradable, eco-friendly, devoid of any side effect, renewable, and provide nutritional supplement. It is proved from the studies that natural polymers are more safe and efficacious than the synthetic polymers. The aim of the present article is to study the FDA-approved natural polymers utilized in fast dissolving tablets. PMID:26556207

  19. Formulation, Characterization and Physicochemical Evaluation of Ranitidine Effervescent Tablets

    PubMed Central

    Aslani, Abolfazl; Jahangiri, Hajar

    2013-01-01

    Purpose: The aim of this study was to design, formulate and physicochemically evaluate effervescent ranitidine hydrochloride (HCl) tablets since they are easily administered while the elderly and children sometimes have difficulties in swallowing oral dosage forms. Methods: Effervescent ranitidine HCl tablets were prepared in a dosage of 300 mg by fusion and direct compression methods. The powder blend and granule mixture were evaluated for various pre-compression characteristics, such as angle of repose, compressibility index, mean particle size and Hausner's ratio. The tablets were evaluated for post-compression features including weight variation, hardness, friability, drug content, dissolution time, carbon dioxide content, effervescence time, pH, content uniformity and water content. Effervescent systems with appropriate pre and post-compression qualities dissolved rapidly in water were selected as the best formulations. Results: The results showed that the flowability of fusion method is more than that of direct compression and the F5 and F6 formulations of 300 mg tablets were selected as the best formulations because of their physicochemical characteristics. Conclusion: In this study, citric acid, sodium bicarbonate and sweeteners (including mannitol, sucrose and aspartame) were selected. Aspartame, mint and orange flavors were more effective for masking the bitter taste of ranitidine. The fusion method is the best alternative in terms of physicochemical and physical properties. PMID:24312854

  20. Postmortem redistribution of the heroin metabolites morphine and morphine-3-glucuronide in rabbits over 24 h.

    PubMed

    Maskell, Peter D; Albeishy, Mohammed; De Paoli, Giorgia; Wilson, Nathan E; Seetohul, L Nitin

    2016-03-01

    The interpretation of postmortem drug levels is complicated by changes in drug blood levels in the postmortem period, a phenomena known as postmortem drug redistribution. We investigated the postmortem redistribution of the heroin metabolites morphine and morphine-3-glucuronide in a rabbit model. Heroin (1 mg/kg) was injected into anesthetised rabbit; after 1 h, an auricular vein blood sample was taken and the rabbit was euthanised. Following death rabbits were placed in a supine position at room temperature and divided into three groups namely (1) immediate autopsy, (2) autopsy after 30 minutes and (3) autopsy 24 h after death. Various samples which included femoral blood, cardiac blood, lung, liver, kidney, vitreous humour, subcutaneous and abdominal fat, liver, bone marrow and skeletal muscle were taken. The samples were analysed with a validated LC-MS/MS method. It was observed that within minutes there was a significant increase in free morphine postmortem femoral blood concentration compared to the antemortem sample (0.01 ± 0.01 to 0.05 ± 0.02 mg/L).Various other changes in free morphine and metabolite concentrations were observed during the course of the experiment in various tissues. Principal component analysis was used to investigate possible correlations between free morphine in the various samples. Some correlations were observed but gave poor predictions (>20 % error) when back calculating. The results suggest that rabbits are a good model for further studies of postmortem redistribution but that further study and understanding of the phenomena is required before accurate predictions of the blood concentration at the time of death are possible.

  1. Bioequivalence study of two formulations of enalapril, at a single oral dose of 20 mg (tablets): A randomized, two-way, open-label, crossover study in healthy volunteers

    PubMed Central

    Portolés, Antonio; Terleira, Ana; Almeida, Susana; García-Arenillas, Mar; Caturla, Mari-Cruz; Filipe, August; Vargas, Emilio

    2004-01-01

    Background: Enalapril maleate is the monoethyl ester prodrug of enalapril- at, an angiotensin-converting enzyme inhibitor indicated in the management of essential and renovascular hypertension, and in the treatment of congestive heart failure and in asymptomatic patients with left ventricular dysfunction and an ejection fraction of ≥35%. Enalapril has little pharmacologic activity until hydrolyzed in vivo to enalaprilat. Objective: The aim of the present study was to compare the bioavailability and tolerability of 2 commercial brands (test and reference formulations) of enalapril tablets (20 mg), described as the rate and extent of absorption of the active moiety, to assess their bioequivalence. Methods: This single-dose, randomized, 2-way, open-label, crossover study in healthy volunteers aged 18 to 40 years was conducted at the Clinical Pharmacology Study Unit, Hospital Clínico San Carlos (Madrid, Spain). Subjects were randomized to receive (under fasting conditions) either the test or reference formulation of enalapril (20-mg tablet) at study period 1 and the opposite formulation at study period 2. Study periods were separated by a washout period of at least 7 days. During each study period, 15 plasma extractions were made to determine enalapril and enalaprilat plasma concentrations and to calculate the pharmacokinetic (PK) properties (maximal plasma drug concentration [Cmax], time to Cmax [Tmax], area under the plasma concentration-time curve [AUC] to the last measurable concentration [AUCt], AUC from time 0 to infinity [AUC0−∞], mean residence time, and elimination half-life [tl2]) of both. Physical examination, subject interview, laboratory analyses, electrocardiogram, and blood pressure (BP) were used to assess tolerability. Results: Twenty-four subjects were included in the study (12 men, 12 women; mean [SD] age, 22.8 [2.2] years [range, 19–30 years]). Of these, 1 subject (4.2%) withdrew from the study for personal reasons; thus, PK and statistical

  2. Solid dispersion tablets of breviscapine with polyvinylpyrrolidone K30 for improved dissolution and bioavailability to commercial breviscapine tablets in beagle dogs.

    PubMed

    Cong, Wenjuan; Shen, Lan; Xu, Desheng; Zhao, Lijie; Ruan, Kefeng; Feng, Yi

    2014-09-01

    Breviscapine, one of cardiovascular drugs extracted from a Chinese herb Erigeron breviscapinus, has been frequently used to treat cardiovascular diseases such as hypertension, angina pectoris, coronary heart disease and stroke. However, its poor water solubility and low bioavailability in vivo severely restrict the clinical application. To overcome these drawbacks, breviscapine solid dispersion tablets consisting of breviscapine, polyvinylpyrrolidone K30 (PVP K30), microcrystalline cellulose and crospovidone were appropriately prepared. In vitro dissolution profiles showed that breviscapine released percentage of solid dispersion tablets reached 90 %, whereas it was only 40 % for commercial breviscapine tablets. Comparative pharmacokinetic study between solid dispersion tablets and commercial products was investigated on the normal beagle dogs after oral administration. Results showed that the bioavailability of breviscapine was greatly increased by 3.45-fold for solid dispersion tablets. The greatly improved dissolution rate and bioavailability might be attributed to intermolecular hydrogen bonding reactions between PVP K30 and scutellarin. These findings suggest that our solid dispersion tablets can greatly improve the bioavailability as well as the dissolution rate of breviscapine.

  3. Synthesis of morphine alkaloids and derivatives.

    PubMed

    Rinner, Uwe; Hudlicky, Tomas

    2012-01-01

    This review summarizes recent developments in the total synthesis of morphine alkaloids and some of the semisynthetic derivatives. The literature is covered for the period of 5 years after the publication of the last review in 2005. The syntheses that appeared in this period are covered in detail and are placed in the context of all syntheses of opiate alkaloids since the original one published by Gates in 1952. The introduction covers the historical aspects of total synthesis of these alkaloids. The synthesis of some of the medicinally useful derivatives is reviewed in the last section along with some of the methodology required for their preparation.

  4. Bioavailability of an extemporaneous suspension of propafenone made from tablets.

    PubMed

    Olguín, Hugo Juárez; Pérez, Carmen Flores; Pérez, Janett Flores; Mendiola, Blanca Ramírez; Portugal, Miriam Carrasco; Chávez, Jesús Bobadilla

    2006-07-01

    Propafenone is an effective antiarrhythmic agent used in children, while in Mexico no specific formulation for children is available, which causes errors in adequate dosage. The aim of this study was to determine the bioavailability of a suspension prepared extemporaneously using commercial tablets of propafenone. The bioavailability was determined in two groups of rabbits (n = 8): the first group received a single intravenous dose of 2 mg/kg of propafenone; the second was orally administered an extemporaneous suspension of propafenone prepared from commercial tablets. Blood samples were drawn at several times during the next 24 h and analysed by HPLC to determine drug levels. The extemporaneous suspension was tested previously with satisfactory results regarding physicochemical and microbiologic stability. The area under the curve (AUC) for the i.v. route was 5600.6 ng/ml.h and for oral administration the AUC was 3327.6 ng/ml.h. The bioavailability was calculated at 59.41%. These results are consistent with previous reports for solid dosage forms. The propafenone suspension prepared extemporaneously using commercial tablets is bioavailable using an animal model; nevertheless, it is necessary to carry out human studies either in volunteers or in patients to confirm these results.

  5. A mechanism of action for morphine-induced immunosuppression: corticosterone mediates morphine-induced suppression of natural killer cell activity.

    PubMed

    Freier, D O; Fuchs, B A

    1994-09-01

    Morphine is a drug of abuse with an ability to down-regulate immune responsiveness that could have potentially serious consequences in both heroin addicts and in the clinical environment. The exact mechanism of action by which morphine induces immunosuppression has yet to be clearly determined. A direct mechanism of action is suggested to operate through lymphocyte opiate receptors, but the nature of such receptors is still in question. The alternative, an indirect mechanism of action is proposed to be mediated by two possible pathways, hypothalamic-pituitary-adrenal axis activation with increased production of adrenal corticosteroids, or activation of the sympathetic nervous system and concomitant catecholamine release. Natural killer (NK) cell activity was used to determine potential indirect mechanisms of action for morphine. NK activity in the B6C3F1 mouse was suppressed between 12 and 48 hr after implantation of 75 mg timed-release morphine pellets. Morphine suppressed NK activity in a dose-responsive manner. The opiate antagonists naloxone and naltrexone completely blocked morphine-induced suppression of NK activity, whereas naloxone methiodide, a congener that crosses the blood-brain barrier much more slowly than naloxone, produced very little blockade. Implantation of the 75-mg morphine pellets produced a significant elevation in serum corticosterone levels. In vitro exposure to corticosterone is known to suppress NK activity directly, whereas in vitro morphine was unable to alter directly NK activity. The glucocorticoid receptor antagonist Roussel-Uclaf 38486 blocked morphine-induced suppression of NK activity in a dose-responsive fashion. Naltrexone (10-mg pellet) antagonized the morphine-induced elevation in serum corticosterone.(ABSTRACT TRUNCATED AT 250 WORDS)

  6. A blinded randomised placebo-controlled trial investigating the efficacy of morphine analgesia for procedural pain in infants: Trial protocol

    PubMed Central

    2016-01-01

    Infant pain has both immediate and long-term negative consequences, yet in clinical practice it is often undertreated. To date, few pain-relieving drugs have been tested in infants. Morphine is a potent analgesic that provides effective pain relief in adults, but there is inconclusive evidence for its effectiveness in infants. The purpose of this study is to establish whether oral morphine provides effective analgesia for procedural pain in infants. A blinded, placebo-controlled, parallel-group randomized, phase II, clinical trial will be undertaken to determine whether morphine sulphate administered orally prior to clinically-required retinopathy of prematurity (ROP) screening and heel lancing provides effective analgesia. 
156 infants between 34 and 42 weeks’ gestational age who require a clinical heel lance and ROP screening on the same test occasion will be included in the trial. Infants will be randomised to receive either a single dose of morphine sulphate (100 μg/kg) or placebo. Each infant will be monitored for 48 hours and safety data will be collected during the 24 hours following drug administration. The primary outcome will be the Premature Infant Pain Profile–revised (PIPP-R) score 30 seconds after ROP screening. The co-primary outcome will be the magnitude of nociceptive-specific brain activity evoked by a clinically-required heel lance. Infant clinical stability will be assessed by comparing the number of episodes of bradycardia, tachycardia, desaturation and apnoea, and changes in respiratory support requirements in the 24-hour periods before and after the clinical intervention. In addition, drug safety will be assessed by considering the occurrence of apnoeic and hypotensive episodes requiring intervention in the 24-hour period following drug administration. This study has been published as an Accepted Protocol Summary by The Lancet. PMID:28066825

  7. Preparation of fluconazole buccal tablet and influence of formulation expedients on its properties.

    PubMed

    Mohamed, Saifulla P; Muzzammil, Shariff; Pramod, Kumar T M

    2011-04-01

    The aim of present study was to prepare buccal tablets of fluconazole for oral candidiasis. The dosage forms were designed to release the drug above the minimum inhibitory concentration for prolonged period of time so as to reduce the frequency of administration and to overcome the side effects of systemic treatment. The buccal tablets were prepared by using Carbopol 71G and Noveon AA-1 by direct compression method. Microcrystalline cellulose was used as the filler and its effect was also studied. The prepared dosage forms were evaluated for physicochemical properties, in vitro release studies and mucoadhesive properties using sheep buccal mucosa as a model tissue. Tablets containing 50% of polymers (Carbopol & Noveon) were found to be the best with moderate swelling along with favorable bioadhesion force, residence time and in vitro drug release. The in vitro drug release studies revealed that drug released for 8 h, which in turn may reduce dosing frequency and improved patient compliance in oral candidiasis patients.

  8. Interaction between halothane and morphine on isolated heart muscle.

    PubMed

    Laorden, M L; Hernandez, J; Carceles, M D; Miralles, F S; Puig, M M

    1990-01-17

    The present study describes the effects of halothane on morphine activity in the isolated left atria of the rat. Concentration-response curves were obtained for the negative inotropic effects of morphine on electrically stimulated left atria. Morphine significantly decreased the contractile force, with an inhibitory concentration 16 (IC16) of 3.130.698 +/- 22.5 X 10(-9) M. The opiate agonist was more potent in reserpinized rats, causing a consistent negative inotropic action over a wide range (10(-8)-10(-4) M) or morphine concentrations. The IC16 of morphine was significantly (P less than 0.001) decreased in the presence of 1.5% v/v halothane. The administration of L-naloxone (3 X 10(-7)-10(-6) M) but not D-naloxone (10(-6) M) antagonized the inhibitory effects of morphine in the presence of halothane. These results demonstrate that halothane increases the potency of morphine on the isolated left atria and suggest that this effect is mediated by opioid receptors.

  9. Postnatal Morphine Administration Alters Hippocampal Development in Rats

    PubMed Central

    Traudt, Christopher M.; Tkac, Ivan; Ennis, Kathleen M.; Sutton, Leah M.; Mammel, Daniel M.; Rao, Raghavendra

    2011-01-01

    Morphine is frequently used as an analgesic and sedative in preterm infants. Adult rats exposed to morphine have altered hippocampal neurochemical profile and decreased neurogenesis in the dentate gyrus of the hippocampus. To evaluate whether neonatal rats are similarly affected, rat pups were injected twice daily with 2 mg/kg of morphine or normal saline from postnatal days 3 to 7. On postnatal day 8, the hippocampal neurochemical profile was determined using in vivo 1H NMR spectroscopy. The mRNA and protein concentrations of specific analytes were measured in hippocampus, and cell division in dentate gyrus was assessed using bromodeoxyuridine. The concentrations of γ-aminobutyric acid (GABA), taurine and myo-insotol were decreased, while glutathione, phosphoethanolamine and choline-containing compounds concentrations were increased in morphine-exposed rats relative to control rats. Morphine decreased glutamic acid decarboxylase enzyme levels and myelin basic protein mRNA expression in the hippocampus. Bromodeoxyuridine labeling in the dentate gyrus was decreased by 60-70% in morphine-exposed rats. These results suggest that recurrent morphine administration during brain development alters hippocampal structure. PMID:21971612

  10. Caerulein and morphine: an attempt to differentiate their antinociceptive effects.

    PubMed

    Zetler, G

    1982-01-01

    The antinociceptive effect in mice (hot-plate test) of caerulein (0.15 mg/kg s.c.) was many times more resistant to naloxone than that of morphine (2 mg/kg s.c., equipotent with the caerulein dose). The ED50 (mg/kg s.c.) of naloxone (given simultaneously with an agonist) was with morphine 0.01 and with caerulein 0.07. When administered intravenously after the agonist, the ED50 (mg/kg i.v.) against morphine was 0.012 and that against caerulein was 0.62. In either type of experiment the dose-response lines of naloxone against caerulein were very shallow as compared with those against morphine. A caerulein dose of 5 micrograms/kg enhanced the antinociceptive effect of morphine only when given before morphine, but not when given after it. The limited additivity of the effects together with the different susceptibility to naloxone of the antinociceptive actions indirectly suggest that caerulein and morphine do not share the same mechanism of action. Palpebral ptosis occurred only after caerulein and was completely resistant to naloxone 8 mg/kg s.c.

  11. Postnatal morphine administration alters hippocampal development in rats.

    PubMed

    Traudt, Christopher M; Tkac, Ivan; Ennis, Kathleen M; Sutton, Leah M; Mammel, Daniel M; Rao, Raghavendra

    2012-01-01

    Morphine is frequently used as an analgesic and sedative in preterm infants. Adult rats exposed to morphine have an altered hippocampal neurochemical profile and decreased neurogenesis in the dentate gyrus of the hippocampus. To evaluate whether neonatal rats are similarly affected, rat pups were injected twice daily with 2 mg/kg morphine or normal saline from postnatal days 3 to 7. On postnatal day 8, the hippocampal neurochemical profile was determined using in vivo (1)H NMR spectroscopy. The mRNA and protein concentrations of specific analytes were measured in hippocampus, and cell division in dentate gyrus was assessed using bromodeoxyuridine. The concentrations of γ-aminobutyric acid (GABA), taurine, and myo-insotol were decreased, whereas concentrations of glutathione, phosphoethanolamine, and choline-containing compounds were increased in morphine-exposed rats relative to control rats. Morphine decreased glutamic acid decarboxylase enzyme levels and myelin basic protein mRNA expression in the hippocampus. Bromodeoxyuridine labeling in the dentate gyrus was decreased by 60-70% in morphine-exposed rats. These results suggest that recurrent morphine administration during brain development alters hippocampal structure.

  12. Morphine tolerance offers protection from radiogenic performance deficits

    SciTech Connect

    Mickley, G.A.; Stevens, K.E.; Burrows, J.M.; White, G.A.; Gibbs, G.L.

    1983-02-01

    When rats are exposed to a sufficiently large dose of ionizing radiation they exhibit lethargy, hypokinesia, and deficits in performance. These and other behavioral changes parallel those often observed in this species after a large dose of morphine. Since the release of endogenous opiates has been implicated in some stress reactions, we sought to determine if they might play a part in radiogenic behavioral deficits. Rats were trained to criterion on a signaled avoidance task. Some subjects were then implanted with a pellet containing 75 mg of morphine. Other animals received placebo implants. Over a number of days, morphine tolerance was evaluated by measurement of body temperature changes. Prior to 2500 rad /sup 60/Co exposure or sham irradiation, morphine (or placebo) pellets were removed. Twenty-four hours later rats were retested to assess their performance on the avoidance task. Morphine-tolerant subjects performed significantly better than the irradiated placebo-implanted group and no differently than morphine-tolerant/sham-irradiated animals. Morphine tolerance seems to provide a degree of behavioral radiation resistance. These data are consistent with the hypothesis that endogenous opiate hyperexcretion may play some part in the behavioral deficits often observed after irradiation.

  13. Morphine upregulates functional expression of neurokinin-1 receptor in neurons.

    PubMed

    Wan, Qi; Douglas, Steven D; Wang, Xu; Kolson, Dennis L; O'Donnell, Lauren A; Ho, Wen-Zhe

    2006-11-15

    Neuronkinin-1 receptor (NK-1R), the neuropeptide substance P (SP) preferring receptor, is highly expressed in areas of the central nervous system (CNS) that are especially implicated in depression, anxiety, and stress. Repeated exposure to opioids may sensitize neuronal systems involved in stress response. We examined the effects of morphine, the principal metabolite of heroin, on the functional expression of NK-1R in the cortical neurons. NK-1R and mu-opioid receptor (MOR) are co-expressed in the cortical neurons. Morphine enhanced NK-1R expression in the cortical neurons at both the mRNA and protein levels. The upregulated NK-1R by morphine had functional activity, because morphine-treated cortical neurons had greater SP-induced Ca(2+) mobilization than untreated neurons. Blocking opioid receptors on the cortical neurons by naltrexone or CTAP (a mu-opioid receptor antagonist) abolished the morphine action. Investigation of the mechanism(s) responsible for the morphine action showed that morphine activated NK-1R promoter and induced the phosphorylation of p38 MAPK protein in the cortical neurons. These in vitro data provide a plausible cellular mechanism for opioid-mediated neurological disorders.

  14. Morphine-induced anxiolytic-like effect in morphine-sensitized mice: involvement of ventral hippocampal nicotinic acetylcholine receptors.

    PubMed

    Rezayof, Ameneh; Assadpour, Sara; Alijanpour, Sakineh

    2013-01-01

    In the present study, the effects of repeated intra-ventral hippocampal (intra-VH) microinjections of nicotinic acetylcholine receptor agonist or antagonist on morphine-induced anxiolytic-like behavior were investigated in morphine-sensitized mice using elevated plus-maze. Intraperitoneal (i.p.) administration of different doses of morphine (5, 7.5 and 10mg/kg) increased the percentage of open arm time (%OAT), open arm entries (%OAE), but not locomotor activity, indicating an anxiolytic-like response to morphine. The maximum response was obtained by 7.5mg/kg of the opioid. The anxiety-like behavior which was induced by a lower dose of morphine (5mg/kg) was significantly increased in mice that had previously received once daily injections of morphine (10 and 20mg/kg, i.p.) for 3 days. It should be considered that this treatment also increased locomotor activity in morphine-sensitized mice. Furthermore, the response to an ineffective dose of morphine (5mg/kg, i.p.) in the EPM was significantly increased in the animals that had previously received nicotine for 3 days (0.1, 0.3, 0.5 and 0.7 μg/mouse; intra-VH), 5 min prior to the injections of morphine (5mg/kg/day × 3 days; i.p.). On the other hand, the increase of morphine-induced anxiolytic-like effect in animals that had previously received the 3-day morphine (20mg/kg) was dose dependently suppressed by once daily injections of mecamylamine (0.5, 1 and 2 μg/mouse/day × 3 days; intra-VH). It is important to note that repeated intra-VH administrations of the same doses of nicotine or mecamylamine alone caused no significant change in morphine (5mg/kg)-induced anxiety-like parameters in the EPM. In conclusion, it seems that morphine sensitization affects the anxiety-like behavior in the EPM and the cholinergic system in the ventral hippocampus, via nicotinic receptors, may play an important role in this effect.

  15. 76 FR 51037 - Determination That Halflytely and Bisacodyl Tablets Bowel Prep Kit (Containing Two Bisacodyl...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-17

    ... (polyethylene glycol (PEG) 3350, sodium chloride, sodium bicarbonate, and potassium chloride for oral solution... applications (ANDAs) for bowel prep kits containing PEG-3350, sodium chloride, sodium bicarbonate, and... Bisacodyl Tablets Bowel Prep Kit (PEG- 3350, sodium chloride, sodium bicarbonate, and potassium chloride...

  16. 21 CFR 520.82b - Aminopropazine fumarate, neomycin sulfate tablets.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Aminopropazine fumarate, neomycin sulfate tablets. 520.82b Section 520.82b Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS §...

  17. 21 CFR 520.310 - Caramiphen ethanedisulfonate and ammonium chloride tablets.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Caramiphen ethanedisulfonate and ammonium chloride tablets. 520.310 Section 520.310 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL...

  18. Clinical pharmacokinetics of an amorphous solid dispersion tablet of elacridar.

    PubMed

    Sawicki, Emilia; Verheijen, Remy B; Huitema, Alwin D R; van Tellingen, Olaf; Schellens, Jan H M; Nuijen, Bastiaan; Beijnen, Jos H; Steeghs, Neeltje

    2017-02-01

    Elacridar is an inhibitor of the permeability glycoprotein (P-gp) and the breast cancer resistance protein (BCRP) and is a promising absorption enhancer of drugs that are substrates of these drug-efflux transporters. However, elacridar is practically insoluble in water, resulting in low bioavailability which currently limits its clinical application. We evaluated the in vitro dissolution and clinical pharmacokinetics of a novel amorphous solid dispersion (ASD) tablet containing elacridar. The dissolution from ASD tablets was compared to that from a crystalline powder mixture in a USP type II dissolution apparatus. The pharmacokinetics of the ASD tablet were evaluated in an exploratory clinical study at oral doses of 25, 250, or 1000 mg in 12 healthy volunteers. A target Cmax was set at ≥ 200 ng/mL based on previous clinical data. The in vitro dissolution from the ASD tablet was 16.9 ± 3.7 times higher compared to that from a crystalline powder mixture. Cmax and AUC0-∞ increased linearly with dose over the explored range. The target Cmax of ≥ 200 ng/mL was achieved at the 1000-mg dose level. At this dose, the Cmax and AUC0-∞ were 326 ± 67 ng/mL and 13.4 ± 8.6 · 10(3) ng · h/mL, respectively. In summary, the ASD tablet was well tolerated, resulted in relevant pharmacokinetic exposure, and can be used for proof-of-concept clinical studies.

  19. Stress antagonizes morphine-induced analgesia in rats

    NASA Technical Reports Server (NTRS)

    Vernikos, J.; Shannon, L.; Heybach, J. P.

    1981-01-01

    Exposure to restraint stress resulted in antagonism of the analgesic effect of administered morphine in adult male rats. This antagonism of morphine-induced analgesia by restraint stress was not affected by adrenalectomy one day prior to testing, suggesting that stress-induced secretion of corticosteroids is not critical to this antagonism. In addition, parenteral administration of exogenous adrenocorticotropin (ACTH) mimicked the effect of stress in antagonizing morphine's analgesic efficacy. The hypothesis that ACTH is an endogenous opiate antagonist involved in modulating pain sensitivity is supported.

  20. Recent Advances in the Synthesis of Morphine and Related Alkaloids

    NASA Astrophysics Data System (ADS)

    Chida, Noritaka

    Morphine, an alkaloid isolated from the opium poppy, has been widely used as an analgesic, and has been a fascinating synthetic target of organic chemists. After the first total synthesis reported in 1952, a number of synthetic studies toward morphine have been reported, and findings obtained in such studies have greatly contributed to the progress of synthetic organic chemistry as well as medicinal chemistry. This review provides an overview of recent studies toward the total synthesis of morphine and related alkaloids. Work reported in the literature since 2004 will be reviewed.

  1. Cholescintigraphy in acute cholecystitis: use of intravenous morphine

    SciTech Connect

    Choy, D.; Shi, E.C.; McLean, R.G.; Hoschl, R.; Murray, I.P.C.; Ham, J.M.

    1984-04-01

    Conventional cholescintigraphy (60 patients) and a modified protocol (59 patients) were compared in 74 females and 45 males with acute cholecystitis. In the modified protocol, intravenous morphine was administered whenever the gallbladder was not seen 40 minutes after injection of Tc-99m-pyroxylidene-glutamate. Accuracy was 98% with morphine, compared with 88% for the conventional protocol; specificity improved from 83% to 100% with no loss of sensitivity. Low doses of morphine are well tolerated and can result in a highly accurate diagnosis of acute cholecystitis without the need for delayed imaging.

  2. Effects of morphine and naloxone on feline colonic transit

    SciTech Connect

    Krevsky, B.; Libster, B.; Maurer, A.H.; Chase, B.J.; Fisher, R.S.

    1989-01-01

    The effects of endogenous and exogenous opioid substances on feline colonic transit were evaluated using colonic transit scintigraphy. Naloxone accelerated emptying of the cecum and ascending colon, and filling of the transverse colon. Endogenous opioid peptides thus appear to play a significant role in the regulation of colonic transit. At a moderate dose of morphine cecum and ascending colon transit was accelerated, while at a larger dose morphine had no effect. Since naloxone, a relatively nonspecific opioid antagonist, and morphine, a principally mu opioid receptor agonist, both accelerate proximal colonic transit, a decelerating role for at least one of the other opioid receptors is inferred.

  3. Morphine-Stimulated Nitric Oxide Release in Rabbit Aqueous Humor

    PubMed Central

    Dortch-Carnes, Juanita; Russell, Karen

    2007-01-01

    Recent studies in our laboratory have demonstrated a role of nitric oxide (NO) in morphine-induced reduction of intraocular pressure (IOP) and pupil diameter (PD) in the New Zealand white (NZW) rabbit. The present study was designed to determine the effect of morphine on NO release in the aqueous humor of NZW rabbits, as this effect could be associated with morphine-mediated changes in aqueous humor dynamics and iris function. Dark adapted NZW rabbits were treated as follows: 1) treatment with morphine (10, 33 or 100 μg, 5 min); 2) treatment with morphine or endomorphin-1 for 5, 15 or 30 min; 3) pretreatment with naloxone (100 μg), L-NAME (125 μg) or reduced glutathione (GSH, 100 μg) for 30 minutes, followed by treatment with morphine (100 μg, 5 min). After the various treatment regimens, aqueous humor samples were obtained by paracenthesis and immediately assayed for nitrates and nitrites (an index of NO production), using a microplate assay kit. Morphine caused a dose-dependent increase in the levels of NO in aqueous humor after 5 min of treatment with each dose. Rabbits treated with endomorphin-1 (100 μg) had no significant change in NO levels in aqueous at any point in the time course. Aqueous samples from rabbits treated with morphine (100 μg) for 5 minutes increased from 29.84 ± 2.39 μM (control) to 183.94 ± 23.48 μM (treated). The increase in NO levels by morphine (100 μg, 5 min) was completely inhibited in the presence of naloxone (100 μg), L-NAME (125 μg) or GSH (100 μg). These results indicate that morphine-induced increase in NO production in aqueous humor is a transient response that is linked to activation of mu opioid receptors. Data obtained suggest that morphine-stimulated changes in ocular hydrodynamics and iris function are due, in part, to increased release of NO in aqueous humor. In addition, the sensitivity of the response to L-NAME and GSH suggests that morphine-induced release of nitric oxide into aqueous humor is mediated by

  4. Next generation effects of female adolescent morphine exposure: sex-specific alterations in response to acute morphine emerge before puberty.

    PubMed

    Vassoler, Fair M; Johnson-Collins, Nicole L; Carini, Lindsay M; Byrnes, Elizabeth M

    2014-04-01

    Prescription opiate use by adolescent girls has increased significantly in the past decade. Preclinical studies using rats report alterations in morphine sensitivity in the adult offspring of adolescent morphine-exposed females (MOR-F1) when compared with the offspring of adolescent saline-exposed females (SAL-F1). To begin to elucidate the development of these next generation modifications, the present study examined the effects of acute morphine administration on sedation and corticosterone secretion in prepubescent SAL-F1 and MOR-F1 male and female rats. In addition, alterations in proopiomelanocortin (POMC) gene expression in the arcuate nucleus, as well as in tyrosine hydroxylase (TH) and μ-opioid receptor (OPRM1) gene expressions in the ventral tegmental area, were analyzed using quantitative PCR, to determine whether differential regulation of these genes was correlated with the observed behavioral and/or endocrine effects. Increased morphine-induced sedation, coupled with an attenuation of morphine-induced corticosterone secretion, was observed in MOR-F1 males. Significant alterations in both POMC and OPRM1 gene expressions were also observed in MOR-F1 males, with no change in TH mRNA expression. Overall, these data suggest that the transgenerational effects of adolescent morphine exposure can be discerned before pubertal development and are more pronounced in males, and suggest dysregulation of the hypothalamic-pituitary-adrenal axis in the offspring of adolescent morphine-exposed females.

  5. Prediction of dissolution profiles by non-destructive near infrared spectroscopy in tablets subjected to different levels of strain.

    PubMed

    Hernandez, Eduardo; Pawar, Pallavi; Keyvan, Golshid; Wang, Yifan; Velez, Natasha; Callegari, Gerardo; Cuitino, Alberto; Michniak-Kohn, Bozena; Muzzio, Fernando J; Romañach, Rodolfo J

    2016-01-05

    This study describes how the strain on formulation components affects dissolution and how near infrared spectroscopy can be used to predict dissolution. Strain (exposure to shear stress) applied during powder mixing affects the interaction between formulation components. Particles experience shear strain when they move relative to each other in a process affecting the properties of the final product. This stress affects the dissolution of oral solid dosages forms. However, dissolution testing destroys the entire tablet, making it impossible to further evaluate tablet properties when an out of specification result is obtained. Thus, a nondestructive technique such as near infrared spectroscopy is desirable to predict dissolution. The aim of this study was to predict dissolution on tablets with different levels of strain (shear) using near infrared spectroscopy in combination with multivariate data analysis. Shear was induced using a modified Couette cell on the powder mixture and tablets from these mixtures were produced using a tablet press emulator. Tablets produced with different strain levels were measured using near infrared spectroscopy. Spectra were obtained in diffuse reflectance mode and pretreated with baseline correction to maintain the physical and chemical information of the tablets. Dissolution profiles were obtained using USP Apparatus 2 as a reference method. Principal component analysis was used to study the sources of variation in the spectra obtained. Partial least squares 2 was used to predict dissolution on tablets with different levels of strain.

  6. Tablets of pre-liposomes govern in situ formation of liposomes: concept and potential of the novel drug delivery system.

    PubMed

    Vanić, Željka; Planinšek, Odon; Škalko-Basnet, Nataša; Tho, Ingunn

    2014-10-01

    The purpose of this study was to develop a novel drug delivery system for challenging drugs with potential for scale-up manufacturing and controlled release of incorporated drug. Pre-liposomes powder containing metronidazole, lecithin and mannitol, prepared by spray-drying, was mixed with different tableting excipients (microcrystalline cellulose, lactose monohydrate, mannitol, dibasic calcium phosphate, pregelatinized starch, pectin or chitosan) and compressed into tablets. The delivery system was characterized with respect to (i) dry powder characteristics, (ii) mechanical tablet properties and drug release, and (iii) liposomal characteristics. The pre-liposomes powder was free-flowing, and tablets of similarly high qualities as tablets made of physical mixtures were prepared with all excipients. Liposomes were formed in situ upon tablet disintegration, dissolution or erosion depending on the type of tablet excipient used. The liposomal characteristics and drug release were found to depend on the tablet excipient. The new delivery system offers a unique synergy between the ability of liposomes to encapsulate and protect drugs and increased stability provided by compressed formulations. It can be adjusted for drug administration via various routes, e.g. oral, buccal and vaginal.

  7. Galileo's Telescopy and Jupiter's Tablet

    NASA Astrophysics Data System (ADS)

    Usher, P. D.

    2003-12-01

    A previous paper (BAAS 33:4, 1363, 2001) reported on the dramatic scene in Shakespeare's Cymbeline that features the descent of the deity Jupiter. The paper suggested that the four ghosts circling the sleeping Posthumus denote the four Galilean moons of Jupiter. The god Jupiter commands the ghosts to lay a tablet upon the prone Posthumus, but says that its value should not be overestimated. When Posthumus wakens he notices the tablet, which he calls a "book." Not only has the deity's "tablet" become the earthling's "book," but it appears that the book has covers which Posthumus evidently recognizes because without even opening the book he ascribes two further properties to it: rarity, and the very property that Jupiter had earlier attributed, viz. that one must not read too much into it. The mystery deepens when the Jovian gift undergoes a second metamorphosis, to "label." With the help of the OED, the potentially disparate terms "tablet," "book," and "label," may be explained by terms appropriate either to supernatural or worldly beings. "Tablet" may recognize the Mosaic artifact, whereas "book" and "label" are probably mundane references to Galileo's Sidereus Nuncius which appeared shortly before Cymbeline. The message of the Olympian god indicates therefore that the book is unique even as its contents have limited value. The first property celebrates the fact that Galileo's book is the first of its kind, and the second advises that all results except the discovery of Jupiter's moons have been reported earlier, in Hamlet.

  8. Characterization of omega-3 tablets.

    PubMed

    Vestland, Tina Lien; Jacobsen, Øyvind; Sande, Sverre Arne; Myrset, Astrid Hilde; Klaveness, Jo

    2016-04-15

    Omega-3 nutraceuticals are extensively used as health supplements worldwide. Various administration forms for delivery of omega-3 are available. However, the niche omega-3 tablets have so far remained unexplored. In this work tablets containing 25-40% (w/w) omega-3 oil as triglycerides or ethyl esters were prepared utilizing a direct compaction grade powder with β-cyclodextrin as encapsulating agent. It was found that powders with up to 35% (w/w) triglyceride oil and 30% (w/w) ethyl ester oil, respectively, can be directly compressed into tablets of excellent quality. Physical properties of omega-3 containing powders and tablets are described. The powder X-ray diffractograms of the powders and crushed tablets show evidence of the formation of new crystalline phases not present in β-cyclodextrin. In addition, (1)H NMR data suggest that the ethyl esters form inclusion complexes with β-cyclodextrin. Compaction of other, commercially available, omega-3 powders was performed as a comparison and deemed unsuccessful.

  9. Trans fat intake across gestation and lactation increases morphine preference in females but not in male rats: Behavioral and biochemical parameters.

    PubMed

    Roversi, Karine; Pase, Camila Simonetti; Roversi, Katiane; Vey, Luciana Taschetto; Dias, Verônica Tironi; Metz, Vinícia Garzella; Burger, Marilise Escobar

    2016-10-05

    The abuse of morphine has risen considerably in recent years, mainly due to the increase of its prescription in clinical medicine. Also, increased consumption of processed foods, rich in trans fatty acids (TFA), has caused concerns about human health. Thus, the aim of our study was to determine whether trans fat consumption in the perinatal period may affect preference for morphine in adolescent female and male rats. Dams were orally supplemented with water (C-control) or hydrogenated vegetable fat (HVF-rich in TFA) during gestation and lactation periods. On post-natal day 43, pups were exposed to morphine (4mg/kg i.p., for 4 days) and assessed in the conditioned place preference paradigm. Anxiety-like symptoms were assessed, and oxidative status of the brain was estimated by reactive species (RS) generation. Female rats with HVF supplementation showed increased morphine preference and less anxiety-like symptoms. Additionally, both male and female rats from HVF-supplementation showed increased RS generation in the ventral tegmental area, whose level was similar in morphine-conditioned female rats. RS generation was increased in the hippocampus of morphine-conditioned female rats, regardless of the supplementation of their dams. We may infer that gender is a predictive factor to opioid preference, since adolescent female rats showed more susceptibility to addiction than males. Furthermore, trans fat consumption across the perinatal period is able to modify parameters of opioid preference in female rats, possibly due to TFA incorporation in phospholipid membranes, modifying the endogenous opioid system and the oxidative status in brain areas related to drug addiction.

  10. Detection of morphine-3-sulfate and morphine-6-sulfate in human urine and plasma, and formation in liver cytosol

    PubMed Central

    Andersson, Maria; Björkhem-Bergman, Linda; Ekström, Lena; Bergqvist, Lena; Lagercrantz, Hugo; Rane, Anders; Beck, Olof

    2014-01-01

    Morphine is still the mainstay in treatment of severe pain and is metabolized in the liver mainly by glucuronidation, partly to the pharmacologically active morphine-6-glucuronide (M6G). The sulfation pathway has attracted much less attention but may also form active metabolites. The aim of the present study was to study two sulfate metabolites of morphine in humans. Urine and plasma from newborns, adult heroin addicts, and terminal cancer patients was analyzed for the presence of morphine-3-sulfate (M3S) and morphine-6-sulfate (M6S) by a new liquid chromatography – tandem mass spectrometry (LC-MS/MS) method. In addition, morphine sulfation was studied in vitro in human liver cytosol preparations. M3S was present in urine and plasma from all study groups although at lower concentrations than morphine-3-glucuronide (M3G). The plasma M3S/M3G ratio was 30 times higher in newborns than in adults indicating that the relative sulfation is more important at early stage of life. M6S was measurable in only one plasma sample from a newborn patient, and in one of the urine sample from the drug testing group. The incubation of morphine with liver cytosol extracts resulted in approximately equal rate of formation of both M3S and M6S. In conclusion, sulfation of morphine is catalyzed in human liver but this minor metabolic pathway probably lacks clinical significance. The M6S metabolite is formed at a low rate, making it undetectable in most individuals. PMID:25505615

  11. Comparative study of epidural application of morphine versus gelfoam soaked in morphine for lumbar laminectomy

    PubMed Central

    Kundra, Sandeep; Gupta, Vishnu; Bansal, Hanish; Grewal, Anju; Katyal, Sunil; Choudhary, Ashwini Kumar

    2014-01-01

    Background: Epidural application of morphine has been used for postoperative analgesia following spine surgery but short duration of action of single application limits its widespread use. Materials and Methods: One hundred and fifty patients undergoing lumbar laminectomy were randomly allocated to two groups of 75 patients each. Anesthetic technique was standardized in both the groups. In Group I, at the completion of laminectomy, a 5 × 1-cm strip of gelfoam soaked in 5 mg morphine (1 mg/ml) was contoured to be placed in the epidural space whereas, in group II, gelfoam soaked in saline was placed in the epidural space and 5 mg morphine (1mg/ml) was instilled over the intact epidural space. Analgesic consumption for 48 hours, time-of first analgesic request, time of ambulation, time of discharge from post anesthesia care unit (PACU) and hospital and adverse effects were recorded. The data was analyzed using appropriate statistical tests. Results: Mean analgesic consumption in 48 hours was significantly less in group I (8.47 ± 3.674 mg) as compared to group II (24.80 ± 6.009 mg). Supplemental analgesia was requested at 30.03 ± 6.796 hours in Group I, vs 10.25 ± 2.243 in group II (P < 0.001). Group I patients were discharged earlier from PACU as compared to group II (P < 0.001) though time of discharge from hospital was similar in both the groups. There were no major adverse effects except pruritis, which was observed in 30.6% patients in group I and 37.3% in group II (statistically insignificant (P > 0.01)). Conclusion: Epidural application of morphine soaked in gelfoam is an effective method for prolonging the postoperative analgesia after spine surgery. PMID:24574593

  12. Mathematics Instruction and the Tablet PC

    ERIC Educational Resources Information Center

    Fister, K. Renee; McCarthy, Maeve L.

    2008-01-01

    The use of tablet PCs in teaching is a relatively new phenomenon. A cross between a notebook computer and a personal digital assistant (PDA), the tablet PC has all of the features of a notebook with the additional capability that the screen can also be used for input. Tablet PCs are usually equipped with a stylus that allows the user to write on…

  13. Scaffolding Equals Success in Teaching Tablet PCs

    ERIC Educational Resources Information Center

    Dickerson, Jeremy; Williams, Scott; Browning, J. B.

    2009-01-01

    After many years of using the mouse and keyboard as the primary means of computer input, people are seeing a strong surge into a new generation of input technologies such as tablet PCs. As more professionals adopt tablet PCs for use in the workplace, there is a subsequent increased demand for tablet PC instruction in the classroom. Examples of…

  14. 21 CFR 520.2088 - Roxarsone tablets.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    .... Withdraw 5 days before slaughter. Use as sole source of organic arsenic. (b)(1) Specifications. Each tablet... information. (5) Conditions of use—(i) Swine—(a) Amount. 1 tablet (400 milligrams) per gallon of drinking... slaughter. Use as sole source of organic arsenic. (ii) (c)(1) Specifications. Each tablet contains...

  15. 21 CFR 520.2088 - Roxarsone tablets.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    .... Withdraw 5 days before slaughter. Use as sole source of organic arsenic. (b)(1) Specifications. Each tablet... information. (5) Conditions of use—(i) Swine—(a) Amount. 1 tablet (400 milligrams) per gallon of drinking... slaughter. Use as sole source of organic arsenic. (ii) (c)(1) Specifications. Each tablet contains...

  16. 21 CFR 520.1900 - Primidone tablets.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ...(c) of this chapter for use of 250 milligram tablets; see No. 000856 in § 510.600(c) of this chapter for use of 50 and 250 milligram tablets. (c) Conditions of use in dogs—(1) Amount. Twenty-five... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Primidone tablets. 520.1900 Section 520.1900...

  17. 21 CFR 520.1900 - Primidone tablets.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ...(c) of this chapter for use of 250 milligram tablets; see No. 000856 in § 510.600(c) of this chapter for use of 50 and 250 milligram tablets. (c) Conditions of use in dogs—(1) Amount. Twenty-five... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Primidone tablets. 520.1900 Section 520.1900...

  18. 21 CFR 520.1900 - Primidone tablets.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ...(c) of this chapter for use of 250 milligram tablets; see No. 000856 in § 510.600(c) of this chapter for use of 50 and 250 milligram tablets. (c) Conditions of use in dogs—(1) Amount. Twenty-five... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Primidone tablets. 520.1900 Section 520.1900...

  19. Principles of Tablet Computing for Educators

    ERIC Educational Resources Information Center

    Katzan, Harry, Jr.

    2015-01-01

    In the study of modern technology for the 21st century, one of the most popular subjects is tablet computing. Tablet computers are now used in business, government, education, and the personal lives of practically everyone--at least, it seems that way. As of October 2013, Apple has sold 170 million iPads. The success of tablets is enormous and has…

  20. Touch Screen Tablets and Emergent Literacy

    ERIC Educational Resources Information Center

    Neumann, Michelle M.; Neumann, David L.

    2014-01-01

    The use of touch screen tablets by young children is increasing in the home and in early childhood settings. The simple tactile interface and finger-based operating features of tablets may facilitate preschoolers' use of tablet application software and support their educational development in domains such as literacy. This article reviews…

  1. PolyMorphine: an innovative biodegradable polymer drug for extended pain relief

    PubMed Central

    Rosario-Meléndez, Roselin; Harris, Carolyn L.; Delgado-Rivera, Roberto; Yu, Lei; Uhrich, Kathryn E.

    2012-01-01

    Morphine, a potent narcotic analgesic used for the treatment of acute and chronic pain, was chemically incorporated into a poly(anhydride-ester) backbone. The polymer termed “PolyMorphine”, was designed to degrade hydrolytically releasing morphine in a controlled manner to ultimately provide analgesia for an extended time period. PolyMorphine was synthesized via melt-condensation polymerization and its structure was characterized using proton and carbon nuclear magnetic resonance spectroscopies, and infrared spectroscopy. The weight-average molecular weight and the thermal properties were determined. The hydrolytic degradation pathway of the polymer was determined by in vitro studies, showing that free morphine is released. In vitro cytocompatibility studies demonstrated that PolyMorphine is non-cytotoxic towards fibroblasts. In vivo studies using mice showed that PolyMorphine provides analgesia for 3 days, 20 times the analgesic window of free morphine. The animals retained full responsiveness to morphine after being subjected to an acute morphine challenge. PMID:22877734

  2. Expression of spinal cord GABA transporter 1 in morphine-tolerant male Wistar rats.

    PubMed

    Shokoofeh, Siroosi; Homa, Manaheji; Leila, Dargahi; Samira, Daniali

    2015-11-15

    Chronic morphine exposure produces morphine tolerance. One of the mechanisms of morphine tolerance involves γ-aminobutric acid (GABA), whose level is regulated by GABA transporter 1 (GAT-1). The aim of this study was to investigate the expression of GAT-1 in the spinal cord during morphine treatment. Morphine was administrated to rats via drinking water for 21 days. On day 21, a single dose of morphine (10mg/kg) was injected, followed by the administration of 5% formalin after 30 min. Expression of GAT-1 in the lumbar spinal cord during morphine treatment was analyzed by Western blotting and immunohistochemistry assay. In another set of experiments, a morphine-tolerant group was treated with a GAT-1 inhibitor, ethyl nipecotate (60 mg/kg), 5 min prior to the formalin test. To assess a possible analgesic effect of the GAT-1 inhibitor, a non-tolerant group was injected only with ethyl nipecotate 5 min prior to the formalin test. Our results indicated that a chronic consumption of morphine led to morphine tolerance. Morphine tolerance was also concomitant with GAT-1 up-regulation in the lumbar spinal cord. The GAT-1 inhibitor ethyl nipecotate improved the antinociceptive effect of morphine in the morphine-tolerant group. Ethyl nipecotate also had an antinociceptive effect on the non-tolerant group. Thus, our data suggest that GAT-1 overexpression in the spinal cord plays an important role in morphine tolerance.

  3. Hydroxyl radical-mediated conversion of morphine to morphinone.

    PubMed

    Kumagai, Y; Ikeda, Y; Toki, S

    1992-05-01

    1. The hydroxyl radical-mediated conversion of morphine to morphinone (MO) was examined as an alternative to the enzymic reaction. 2. Hydroxyl radicals were generated by autoxidation of ascorbate in the presence of iron and EDTA. This system oxidized morphine to MO which was identified by h.p.l.c. and t.l.c. The reaction was dependent on the concentration of added Fe2+ and required the addition of ascorbate when Fe3+ was used. 3. Catalase inhibited production of MO whereas superoxide dismutase (SOD) had no effect. Addition of a large amount of H2O2 to the system resulted in a significant decrease in production of MO. No MO production was initiated by H2O2 itself. The oxidation of morphine was inhibited by typical hydroxyl radical-scavenging agents. These results indicate that morphine undergoes oxidation to MO by hydroxyl radical.

  4. [Detection of morphine after ingestion of poppy seeds].

    PubMed

    Angelo, H R; Kaa, E

    1993-12-06

    The aim of this study was to investigate whether morphine can be detected in urine after the ingestion of poppy seeds bought in Denmark. Morphine and codeine were determined in 10 different poppy seed specimens bought in Denmark. Ten and 25 g of the specimens containing the highest amount of morphine and codeine were consumed by respectively six and seven volunteers. Urine samples were collected for analysis at intervals up to 24 h. All samples were found positive by radioimmunoassay up to 24 h after ingestion. Using the less sensitive thin layer chromatography method, one of six and two of seven were positive, two to four hours after intake of respectively 10 and 25 g of the specimens. We conclude that the detection of morphine in urine does not necessarily indicate an illegal drug use.

  5. Relative analgesic potencies of morphine and hydromorphone in postoperative pain.

    PubMed

    Mahler, D L; Forrest, W H

    1975-05-01

    Because of discrepancies in the estimates of the relative analgesic potencies of hydromorphone and morphine, the drugs were compared in two four-point, double-blind bioassays. In the first study, hydromorphone, 1 and 2 mg, was compared with morphine, 5 and 10 mg, in 31 postoperative patients; in the second, hydromorphone, 0.5 and 1 mg, was compared with morphine, 5 and 10 mg, in 112 postoperative patients. Subjective responses to nurse-observer questions were used to quantitate analgesia for postoperative pain. Hydromorphone is more potent than commonly believed: approximately 0.9 to 1.2 mg is equianalgesic with 10 mg of morphine, with a similar incidence of side effects.

  6. Esophageal transit of risedronate cellulose-coated tablet and gelatin capsule formulations.

    PubMed

    Perkins, A C; Wilson, C G; Frier, M; Vincent, R M; Blackshaw, P E; Dansereau, R J; Juhlin, K D; Bekker, P J; Spiller, R C

    1999-09-20

    Risedronate sodium is an orally active antiresorptive agent and a member of the pyridinyl class of bisphosphonates. It has been approved for the treatment of Paget's disease of the bone and is under development as a chronic therapy for the treatment and prevention of osteoporosis. A novel cellulose film-coated tablet formulation was developed to optimize esophageal transit of this bisphosphonate. The aim of the present study was to compare the esophageal transit of the film-coated tablet formulation of risedronate with its original gelatin capsule dose form. A total of 25 elderly, healthy volunteers (mean 66 years), who were dysphagia-free, participated in this randomized cross-over study. On separate occasions, volunteers swallowed radiolabeled placebo formulations with 50 ml water. Dynamic images with participants in a sitting position were recorded for 10 min using a gamma camera. Scintigraphic imaging showed a delay in esophageal transit (greater than 15 s) in 28% of patients in the capsule group but in none of the tablet group (P<0.05). The mean transit times of the capsules and tablets were 23.8 and 3.3 s, respectively. Esophageal transit of film-coated tablets was faster than gelatin capsules, suggesting that film-coated tablets would be the appropriate formulation for all pivotal trials with risedronate and for subsequent commercialization.

  7. Bioequivalence study of 400 and 100 mg imatinib film-coated tablets in healthy volunteers.

    PubMed

    Ostrowicz, Andrzej; Mikołajczak, Przemysław L; Wierzbicka, Marzena; Boguradzki, Piotr

    2014-01-01

    The aim of the study was to investigate the bioavailability of a generic product of 100 mg and 400 mg imatinib film-coated tablets (test) as compared to that of a branded product (reference) at the same strength to determine bioequivalence. The secondary objective of the study was to evaluate tolerability of both products. An open-label, randomized, crossover, two-period, single-dose, comparative study was conducted in 43 (Imatynib-Biofarm 100 mg film-coated tablet) and in 42 (Imatynib-Biofarm 400 mg film-coated tablet), brand name Imatenil, Caucasian healthy volunteers in fed conditions. A single oral dose administration of the test or reference product was separated by 14-day washout period. The imatinib and its metabolite N-desmethyl imatinib concentrations were determined using a validated LC MS/MS method. The results of the single-dose study in healthy volunteers indicated that the film-coated tablets of Imatynib-Biofarm 100 mg and 400 mg film-coated tablets manufactured by Biofarm Sp. z o.o. (test products) are bioequivalent to those of Glivec 100 mg and 400 mg film-coated tablets manufactured by Novartis Pharma GmbH (reference products). Both products in the two doses of imatinib were well tolerated.

  8. Development and Characterization of Novel Floating-Mucoadhesive Tablets Bearing Venlafaxine Hydrochloride

    PubMed Central

    Misra, Raghvendra

    2016-01-01

    The present investigation is concerned about the development of floating bioadhesive drug delivery system of venlafaxine hydrochloride which after oral administration exhibits a unique combination of floating and bioadhesion to prolong gastric residence time and increase drug bioavailability within the stomach. The floating bioadhesive tablets were prepared by the wet granulation method using different ratios of hydroxypropyl methyl cellulose (HPMC K4MCR) and Carbopol 934PNF as polymers. Sodium bicarbonate (NaHCO3) and citric acid were used as gas (CO2) generating agents. Tablets were characterized for floating properties, in vitro drug release, detachment force, and swelling index. The concentration of hydroxypropyl methyl cellulose and Carbopol 934PNF significantly affects the in vitro drug release, floating properties, detachment force, and swelling properties of the tablets. The optimized formulation showed the floating lag time 72 ± 2.49 seconds and duration of floating 24.50 ± 0.74 hr. The in vitro release studies and floating behavior were studied in simulated gastric fluid (SGF) at pH 1.2. Different drug release kinetics models were also applied. The in vitro drug release from tablets was sufficiently sustained (more than 18 hr) and the Fickian transports of the drug from the tablets were confirmed. The radiological evidence suggests that the tablets remained buoyant and altered position in the stomach of albino rabbit and mean gastric residence time was prolonged (more than > 6 hr). PMID:27274884

  9. Development and Characterization of Novel Floating-Mucoadhesive Tablets Bearing Venlafaxine Hydrochloride.

    PubMed

    Misra, Raghvendra; Bhardwaj, Peeyush

    2016-01-01

    The present investigation is concerned about the development of floating bioadhesive drug delivery system of venlafaxine hydrochloride which after oral administration exhibits a unique combination of floating and bioadhesion to prolong gastric residence time and increase drug bioavailability within the stomach. The floating bioadhesive tablets were prepared by the wet granulation method using different ratios of hydroxypropyl methyl cellulose (HPMC K4MCR) and Carbopol 934PNF as polymers. Sodium bicarbonate (NaHCO3) and citric acid were used as gas (CO2) generating agents. Tablets were characterized for floating properties, in vitro drug release, detachment force, and swelling index. The concentration of hydroxypropyl methyl cellulose and Carbopol 934PNF significantly affects the in vitro drug release, floating properties, detachment force, and swelling properties of the tablets. The optimized formulation showed the floating lag time 72 ± 2.49 seconds and duration of floating 24.50 ± 0.74 hr. The in vitro release studies and floating behavior were studied in simulated gastric fluid (SGF) at pH 1.2. Different drug release kinetics models were also applied. The in vitro drug release from tablets was sufficiently sustained (more than 18 hr) and the Fickian transports of the drug from the tablets were confirmed. The radiological evidence suggests that the tablets remained buoyant and altered position in the stomach of albino rabbit and mean gastric residence time was prolonged (more than > 6 hr).

  10. Quantitative analysis of visible surface defect risk in tablets during film coating using terahertz pulsed imaging.

    PubMed

    Niwa, Masahiro; Hiraishi, Yasuhiro

    2014-01-30

    Tablets are the most common form of solid oral dosage produced by pharmaceutical industries. There are several challenges to successful and consistent tablet manufacturing. One well-known quality issue is visible surface defects, which generally occur due to insufficient physical strength, causing breakage or abrasion during processing, packaging, or shipping. Techniques that allow quantitative evaluation of surface strength and the risk of surface defect would greatly aid in quality control. Here terahertz pulsed imaging (TPI) was employed to evaluate the surface properties of core tablets with visible surface defects of varying severity after film coating. Other analytical methods, such as tensile strength measurements, friability testing, and scanning electron microscopy (SEM), were used to validate TPI results. Tensile strength and friability provided no information on visible surface defect risk, whereas the TPI-derived unique parameter terahertz electric field peak strength (TEFPS) provided spatial distribution of surface density/roughness information on core tablets, which helped in estimating tablet abrasion risk prior to film coating and predicting the location of the defects. TPI also revealed the relationship between surface strength and blending condition and is a nondestructive, quantitative approach to aid formulation development and quality control that can reduce visible surface defect risk in tablets.

  11. Predictive model for tensile strength of pharmaceutical tablets based on local hardness measurements.

    PubMed

    Juban, Audrey; Nouguier-Lehon, Cécile; Briancon, Stéphanie; Hoc, Thierry; Puel, François

    2015-07-25

    In the pharmaceutical field, tablets are the most common dosage forms for oral administration. During the manufacture of tablets, measures are taken to assure that they possess a suitable mechanical strength to avoid crumbling or breaking when handling while ensuring disintegration after administration. Accordingly, the tensile strength is an essential parameter to consider. In the present study, microscopic hardness and macroscopic tensile strength of binary tablets made from microcrystalline cellulose and caffeine in various proportions were measured. A relationship between these two mechanical properties was found for binary mixture. The proposed model was based on two physical measurements easily reachable: hardness and tablet density. Constants were determined from the two extreme compositions of this given system. This model was validated with experimental results, and a comparison was made with the one developed by Wu et al. (2005). Both models are relevant for this studied system. Nonetheless, with this model, the tablet tensile strength can be connected with a tablet characteristic at microscopic scale in which porosity is not needed.

  12. In vivo absorption comparison of nanotechnology-based silybin tablets with its water-soluble derivative.

    PubMed

    Xu, Di; Ni, Rui; Sun, Wei; Li, Luk Chiu; Mao, Shirui

    2015-04-01

    In this study, the in vivo oral absorption of a nanocrystal tablet formulation of a BCS II poorly water-soluble drug was compared with that of its water-soluble salt form. Silybin is used as the model drug, and its nanosuspension was prepared by high-pressure homogenization. Effect of process and formulation parameters on properties of the nansuspensions was investigated. Dried powder of the nanosuspension was prepared by spray drying and used for preparing tablets. A pharmacokinetic study was performed in Beagle dogs to compare the absorption for tablets of silybin nanocrystals and silybin meglumine. In vivo absorption of nanocrystal silybin tablet in Beagle dogs was determined. X-ray powder diffraction results indicated that silybin existed in a crystalline state after homogenization. In vivo absorption study in rats showed that the peroral absorption of silybin was enhanced remarkably by decreasing particle size. In vivo absorption of nanocrystal silybin tablet in Beagle dogs was comparable with that of the commercially available tablet of the water-soluble salt form of silybin. In conclusion, it is possible to increase the bioavailability of poorly soluble drugs by preparing its water-soluble derivative.

  13. Spray drying of a poorly water-soluble drug nanosuspension for tablet preparation: formulation and process optimization with bioavailability evaluation.

    PubMed

    Sun, Wei; Ni, Rui; Zhang, Xin; Li, Luk Chiu; Mao, Shirui

    2015-06-01

    Spray drying experiments of an itraconazole nanosuspension were conducted to generate a dry nanocrystal powder which was subsequently formulated into a tablet formulation for direct compression. The nanosuspension was prepared by high pressure homogenization and characterized for particle-size distribution and surface morphology. A central composite statistical design approach was applied to identify the optimal drug-to-excipient ratio and spray drying temperature. It was demonstrated that the spray drying of a nanosuspension with a mannitol-to-drug mass ratio of 4.5 and at an inlet temperature of 120 °C resulted in a dry powder with the smallest increase in particle size as compared with that of the nanosuspension. X-ray diffraction results indicated that the crystalline structure of the drug was not altered during the spray-drying process. The tablet formulation was identified by determining the micromeritic properties such as flowability and compressibility of the powder mixtures composed of the spray dried nanocrystal powder and other commonly used direct compression excipients. The dissolution rate of the nanocrystal tablets was significantly enhanced and was found to be comparable to that of the marketed Sporanox®. No statistically significant difference in oral absorption between the nanocrystal tablets and Sporanox® capsules was found. In conclusion, the nanosuspension approach is feasible to improve the oral absorption of a BCS Class II drug in a tablet formulation and capable of achieving oral bioavailability equivalent to other well established oral absorption enhancement method.

  14. Decreased AMPA GluR2, but not GluR3, mRNA expression in rat amygdala and dorsal hippocampus following morphine-induced behavioural sensitization.

    PubMed

    Sepehrizadeh, Zargham; Bahrololoumi Shapourabadi, Mina; Ahmadi, Shamseddin; Hashemi Bozchlou, Saeed; Zarrindast, Mohammad-Reza; Sahebgharani, Mousa

    2008-11-01

    1. Repeated administration of psychostimulants and micro-opioid receptor agonists elicits a progressive enhancement of drug-induced behavioural responses, a phenomenon termed behavioural sensitization. These changes in behaviour may reflect plastic changes requiring regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptor function. 2. In the present study, rats were treated for 7 days with saline or morphine (10 mg/kg). After a washout period of either 24 h or 7 days, locomotion, oral stereotypy and state-dependent memory in a passive avoidance test were measured in the presence or absence of 6-cyano-7-nitroquinoxaline-2,3-dione disodium salt (CNQX; 3 mg/kg), an AMPA receptor antagonist. In order to evaluate the mechanism underlying the behavioural responses, quantitative real-time reverse transcription-polymerase chain reaction was used to evaluate mRNA expression of the AMPA receptor subunits GluR2 and GluR3 in the striatum, prefrontal cortex, hippocampus, hypothalamus and amygdala of animals treated repeatedly with morphine. 3. The results indicate that repeated morphine treatment followed by 7 days (but not 24 h) washout produces behavioural sensitization, as determined by locomotion, oral stereotypy and state-dependent memory. Blockade of AMPA receptors with CNQX on the test day did not alter these behavioural responses. In addition, repeated morphine treatment followed by 7 days (but not 24 h) washout decreased GluR2 mRNA expression in both the amygdala (by 50%) and hippocampus (by 35%). Repeated morphine treatment did not alter GluR3 mRNA expression in any brain area assessed. 4. These data imply that AMPA receptors are involved in the development (but not expression) phase of behavioural sensitization. The decreases in GluR2 mRNA expression in the amygdala and hippocampus may result in the formation of calcium-permeable AMPA receptors, which are believed to play an important role in behavioural sensitization.

  15. Nano-reservoir Bioadhesive Tablets Enhance Protein Drug Permeability Across the Small Intestine.

    PubMed

    Yin, Lifang; Wang, Yong; Wang, Cuifeng; Feng, Min

    2017-01-23

    Most therapeutic proteins are classified as class III drugs according to the Biopharmaceutical Classification System means that the low permeability across the intestinal epithelium is the rate-limited step for their oral absorption. Cationic chitosan nanoparticles have been found to open the tight junctions between epithelial cells. On the other hand, bioadhesive delivery devices could prolong the gastrointestinal residence time. In the present study, we developed a novel nano-reservoir bioadhesive tablets that combining the advantages of cationic nanoparticles and bioadhesive delivery devices anticipated achieving effective transport of sufficient protein drugs across the intestinal epithelium. The nano-reservoir in bioadhesive tablets was composed of chitosan nanoparticles (CS-NPs) loading a model protein drug bovine serum albumin (BSA). The formula of bioadhesive tablets was optimized by using rotatable central composite design and response surface methodology. The nano-reservoir, BSA-loaded CS-NPs, had an average particle diameter of 312.5 ± 12.89 nm and zeta-potential value of 26.76 ± 3.56 mV. Carboxymethyl chitosan added to the formula significantly ameliorated the tight junction damage of the Caco-2 cell monolayer induced by CS-NPs, meanwhile maintained the high transport efficiency of BSA. Permeability study exhibited that these nano-reservoir bioadhesive tablets combining the advantages of cationic nanoparticles and bioadhesive tablets significantly enhanced BSA transport through rabbit small intestine in comparison with either conventional bioadhesive tablets or CS-NPs. Therefore, these nano-reservoir bioadhesive tablets provided a great potential dosage form design for the oral delivery of protein drugs.

  16. A Comparison of Morphine Delivery in Neonatal Opioid Withdrawal

    PubMed Central

    Chisamore, Brian; Labana, Safaa; Blitz, Sandra; Ordean, Alice

    2016-01-01

    Current estimates of the prevalence of opioid withdrawal in newborns from the 2012 Better Outcomes Registry and Network Ontario reveal that more than 4 births per 1000 display recognizable symptoms of neonatal abstinence syndrome (NAS). With a growing consensus surrounding aspects of newborn opioid withdrawal care, clinicians might agree that all infants exposed to maternal opioids require supportive observation and care to ensure appropriate adaptation and growth in the newborn period and, likewise, that there exists a smaller percentage of newborns who require additional pharmacotherapy. However, due to the dearth of comparative studies of NAS tools, there remains a lack of evidence to support the use of a specific NAS method of scoring or treatment. Two types of NAS treatment protocols currently in use include a symptom-only versus weight-based protocols. Our Neonatal Intensive Care Unit (NICU) has used both models. A formal structured NAS tool and weight-based morphine delivery system began in our NICU in 1999. We audited all newborns with known exposure to maternal opioids in our NICU from the years 2000 to 2014. The Finnegan scoring tool was used throughout all years of the chart audit. Modifications made to the Finnegan scoring tool from the MOTHER study were adapted for use in our NICU at the same time as adopting the Johns Hopkins model of symptom-only based morphine delivery in 2006. The objective of this comparative study using a retrospective chart audit is to compare length of stay (LOS) and total accumulative morphine dose across these two morphine delivery protocols. Our audit revealed that there were a significantly higher proportion of newborns in the symptom-only model that received morphine and, perhaps accordingly, also had a significantly higher LOS compared to those in the weight-based model. Comparing only those infants who did receive morphine, the comparative total accumulative dose of morphine and LOS were not significantly different

  17. Plasma-Mediated Release of Morphine from Synthesized Prodrugs

    DTIC Science & Technology

    2013-01-01

    plasma half-life (1-3 h) associated with a correspondingly limited duration of analgesic effect.2 Under certain circumstances, longer-acting morphine...subjected to UPLC. ANDM allows both deproteinization as well as the release of protein -bound MP.11 -Figure 2- Baseline UPLC values of ANDM treated...blood coagulation proteins nor the added anticoagulant in the plasma samples influence the hydrolytic process. The released morphine was tested for

  18. Ovarian steroids and modulation of morphine-induced analgesia and catalepsy in female rats.

    PubMed

    Banerjee, P; Chatterjee, T K; Ghosh, J J

    1983-12-23

    The influence of ovarian steroids on modulation of antinociceptive and cataleptic responses to morphine in female rats was evaluated. The sensitivity of the animals to morphine varied at different stages of the estrous cycle. The responses of postpartum and ovariectomized rats to morphine was attenuated. The test doses of estradiol-17 beta or progesterone, either alone or in combination, did not alter this attenuated morphine sensitivity. Testosterone, however, sensitized post-partum as well as ovariectomized rats to morphine. Unlike progesterone, 17-alpha-hydroxy progesterone antagonized testosterone. Collectively these data implicate ovarian testosterone as a physiological modulator of actions of morphine in female rats.

  19. Impacts of morphine addiction on spermatogenesis in rats

    PubMed Central

    Takzare, Nasrin; Samizadeh, Esmaeil; Shoar, Saeed; Majidi Zolbin, Masoumeh; Naderan, Mohammad; Lashkari, Ali; Bakhtiarian, Azam

    2016-01-01

    Background: There are numerous investigations on wide range of issues that disrupt regulatory spermatogenesis, individuals who are exposed to drug abuse faced infertility and immature spermatogenesis. Objective: The aim of this study was to evaluate the addiction effects of morphine and its derivatives on rats spermatogenesis. Materials and Methods: 40 male Wistar rats were randomly divided into 5 equal groups, which were exposed either with intravenous morphine, naloxone, naloxone and morphine, sham (with normal saline injection) and a control group without infusion. Spermatogenesis was assessed after three months via histological sections with hematoxylin and eosin staining, using a light microscope based on measurement of spermatogonia, spermatocyte, spermatid, and spermatozoa. Results: Those rats that received opioids had changes in spermatogenesis function. The population of spermatogenesis cycle cells at spermatogonia, spermatocyte, spermatid, and spermatozoa stages was significantly decreased in those rats that received opioid in comparison to the control group (p<0.05). Histological studies revealed that changes in different groups of opioid application might affect sperm formation. Sperm count in morphine group was (0±0) and in naloxone group, naloxone+morphine, sham and control were 235±3.77, 220±3.81, 247.12±6.10 and 250±6.54, respectively (p<0.001). Conclusion: Morphine could affect all spermatogenesis stages. PMID:27326414

  20. Sustained Morphine Administration Induces TRPM8-Dependent Cold Hyperalgesia.

    PubMed

    Gong, Kerui; Jasmin, Luc

    2017-02-01

    It is not uncommon for patients chronically treated with opioids to exhibit opioid-induced hyperalgesia, and this has been widely reported clinically and experimentally. The molecular substrate for this hyperalgesia is multifaceted, and associated with a complex neural reorganization even in the periphery. For instance, we have recently shown that chronic morphine-induced heat hyperalgesia is associated with an increased expression of GluN2B containing N-methyl-D-aspartate receptors, as well as of the neuronal excitatory amino acid transporter 3/excitatory amino acid carrier 1, in small-diameter primary sensory neurons only. Cold allodynia is also a common complaint of patients chronically treated with opioids, yet its molecular mechanisms remain to be understood. Here we present evidence that the cold sensor TRPM8 channel is involved in opioid-induced hyperalgesia. After 7 days of morphine administration, we observed an upregulation of TRPM8 channels using patch clamp recording on sensory neurons and Western blot analysis on dorsal root ganglia. The selective TRPM8 antagonist RQ-00203078 blocked cold hyperalgesia in morphine-treated rats. Also, TRPM8 knockout mice failed to develop cold hyperalgesia after chronic administration of morphine. Our results show that chronic morphine upregulates TRPM8 channels, which is in contrast with the previous finding that acute morphine triggers TRPM8 internalization.