The goals of these studies were to prepare bleomycin (BLM) A(2)-poly(lactic-co-glycolic acid) (PLGA) microspheres and to investigate their in vitro release, pharmacokinetics, pharmacodynamics, and toxicology of this product. Long-acting BLM A(2)-PLGA microspheres were prepared using multiple emulsion solvent evaporation, and the related characteristics of the microspheres were investigated. The prepared microspheres were administered to dogs via intramuscular injection. The plasma concentration of BLM A(2) in dogs was detected using liquid chromatography-mass spectrometry. The pharmacodynamics of BLM A(2)-PLGA microspheres were investigated in a golden hamster model. The acute and chronic toxicities were investigated in a rat model. The inductive effects of BLM microspheres versus a conventional formulation on pulmonary injuries were compared in a mouse model. BLM A(2)-PLGA microspheres were released stably over 20 days and exhibited a significant inhibition of oral squamous carcinoma. The acute toxicity study suggested that doses up to 128 mg/kg were acceptable, and the chronic toxicity study showed no significant chronic toxicity. The study in mice showed less pulmonary toxicity with BLM microsphere formulation compared with the conventional formulation. As a novel microsphere drug formulation, BLM A(2)-PLGA microspheres showed a significant slow-release effect. These data may provide a new clinical medication option for patients with oral cancer. PMID:21344412
Zhang, Haifeng; Gao, Yang; Lv, Wei; Jiao, Chengfeng; Duan, Minghua; Liu, Huaiyu; Han, Bing
This study optimized conditions for preparing and characterizing gelatin surface modified poly (lactic-co-glycolic acid) (PLGA)\\u000a copolymer microspheres and determined this systems interaction with fibronectin. Some gelatin microspheres have an affinity\\u000a for fibronectin-bearing surfaces; these miscrospheres exploit the interaction between gelatin and fibronectin. PLGA copolymer\\u000a microspheres were selected because they have reproducible and slowrelease characteristics in vivo. The PLGA microspheres were
M. Jamie Tsung; Diane J. Burgess
RGD peptide was conjugated to hollow microspheres to develop PLGA ultrasound contrast agents that enhance ultrasound imaging. The microcapsules were coated with an RGD peptide that targets integrins specific to angiogenesis, ?v?3 and ?v?5. The microcapsules were then bound to rat neuroblastoma cells in vitro within 6 hours. The RGD peptide modified microcapsules makes them ideal candidates for targeted therapeutic
Justin D. Lathia; Dalia El-Sherif; N. O. Dhoot; M. A. Wheatley
Objective This multisite randomized trial addressed risks and benefits of staying on long-acting injectable haloperidol or fluphenazine versus switching to long-acting injectable risperidone microspheres. Method From December 2004 until March 2008, adult outpatients with a SCID diagnosis of schizophrenia or schizoaffective disorder who were taking haloperidol decanoate (n=40) or fluphenazine decanoate (n=22) were randomly assigned to Stay on current long-acting injectable medication or Switch to risperidone microspheres and followed for 6 months under study protocol and an additional 6 months naturalistic follow-up. Kaplan-Meier and Cox regression analyses were used to examine the primary outcome, time-to-treatment-discontinuation, and random regression models were used to examine secondary outcomes. Results Groups did not differ in time-to-treatment-discontinuation through 6 months of protocol-driven treatment. When the 6 month naturalistic follow-up period was included, time-to-treatment-discontinuation was significantly shorter for individuals assigned to Switch than for individuals assigned to Stay (10% of Stayers discontinued versus 31% of Switchers; p =.01). Groups did not differ with respect to psychopathology, hospitalizations, sexual side effects, new-onset TD, or new onset EPS. However, those randomized to Switch to long-acting injectable risperidone microspheres had greater increases in body mass (increase of 1.0 BMI versus decrease of ?0.3 BMI ; p=.00) and prolactin (maximum increase to 23.4 ng/ml versus decrease to 15.2 ng/ml, p=.01) compared to those randomized to Stay. Conclusion Switching from haloperidol decanoate or fluphenazine decanoate to risperidone microspheres resulted in more frequent treatment discontinuation as well as significant weight gain and increases in prolactin.
Covell, Nancy H; McEvoy, Joseph P.; Schooler, Nina R.; Stroup, T. Scott; Jackson, Carlos; Rojas, Ingrid; Essock, Susan M.
Purpose Heparin immobilized porous poly(d,l-lactic-co-glycolic acid) (PLGA) microspheres were prepared for sustained release of basic fibroblast growth factor (bFGF) to induce angiogenesis.Materials and Methods Porous PLGA microspheres having primary amine groups on the surface were prepared using an oil-in-water (O\\/W) single emulsion method using Pluronic F-127 as an extractable porogen. Heparin was surface immobilized via covalent conjugation. bFGF was loaded into the
Hyun Jung Chung; Hong Kee Kim; Jun Jin Yoon; Tae Gwan Park
Porous scaffolds that can prolong the release of bioactive factors are urgently required in bone tissue engineering. In this study, PLGA/gelatin composite microspheres (PGMs) were carefully designed and prepared by entrapping poly(L: -lactide-co-glycolide) (PLGA) microspheres (PMs) in gelatin matrix. By mixing PGMs with PLGA solution directly, drug-loaded PLGA/carbonated hydroxyapatite (HAp)/PGMs composite scaffolds were successfully fabricated. In vitro release of fluorescein isothiocyanate-dextran (FD70S) as a model drug from the scaffolds as well as PMs and PGMs was studied by immersing samples in phosphate buffered saline (pH = 7.4) at 37°C for 32 days. Compared with PMs, PGMs and PLGA/HAp/PGMs scaffolds exhibited slow and steady release behavior with constant release rate and insignificantly original burst release. The swelling of PGMs, diffusion of drugs, and degradation of polymer dominated the release behaviors synergistically. The PLGA/HAp/PGMs scaffold offers a novel option for sequential or simultaneous release of several drugs in terms of bone regeneration. PMID:22095448
Tang, Gongwen; Zhang, Hong; Zhao, Yunhui; Li, Xiao; Yuan, Xiaoyan; Wang, Min
Mesoporous bioactive glass (MBG) and composite microspheres with MBG particles embedded in biodegradable poly(D,L-lactide-co-glycolide) (PLGA) matrix have been prepared and used to load gentamicin (GS). The in vitro drug release experiments from both MBG and composite microspheres were conducted in distilled water and phosphate buffered saline (PBS) solution at 37 degrees C for more than 30 days. In both water and PBS, GS release from the MBG was very fast with about 60 wt % of the loaded drug released in the first 24 h, and more than 80 wt % released in two days. MBG/PLGA composite microspheres showed an initial release of about 33 wt % in the first day, and 48 wt % in 2 days, and a subsequent sustained release lasting for more than 4 weeks in PBS. MBG/PLGA composite microspheres may be used as an alternative drug release system, especially as a bone void filler for bone repair due to their combined advantages of sustained release of antibiotics and apatite-forming ability. PMID:18777577
Li, Xia; Wang, Xiupeng; Zhang, Lingxia; Chen, Hangrong; Shi, Jianlin
Calcium phosphate cements (CPCs) are frequently used as bone substitute material. Despite their superior clinical handling and excellent biocompatibility, they exhibit poor degradability, which limits bone ingrowth into the implant. Microspheres were prepared from poly(d,l-lactic-co-glycolic acid) (PLGA) and included in injectable CPCs as porogens in order to enhance its macroporosity after the polymeric microspheres had degraded. Upon degradation of the PLGA microspheres, acid is produced that enhances the dissolution rate of the CPC. However, the effect of the characteristics of PLGA microspheres on the degradation rate of CPCs has never been studied before. Therefore, the purpose of the current study was to investigate the dependence of CPC degradation on the chemical and morphological characteristics of incorporated PLGA microspheres. With respect to the chemical characteristics of the PLGA microspheres, the effects of both PLGA molecular weight (5, 17 and 44kDa) and end-group functionalization (acid-terminated or end-capped) were studied. In addition, two types of PLGA microspheres, differing in morphology (hollow vs. dense), were tested. The results revealed that, although both chemical parameters clearly affected the polymer degradation rate when embedded as hollow microspheres in CPC, the PLGA and CPC degradation rates were mainly dependent on the end-group functionalization. Moreover, it was concluded that dense microspheres were more efficient porogens than hollow ones by increasing the CPC macroporosity during in vitro incubation. By combining all test parameters, it was concluded that dense PLGA microspheres consisting of acid-terminated PLGA of 17kDa exhibited the highest and fastest acid-producing capacity and correspondingly the highest and fastest amount of porosity. In conclusion, the data presented here indicate that the combination of dense, acid-terminated PLGA microspheres with CPC emerges as a successful combination to achieve enhanced apatitic CPC degradation. PMID:21689794
Félix Lanao, R P; Leeuwenburgh, S C G; Wolke, J G C; Jansen, J A
A water-soluble anthracycline antibiotic drug (daunorubicin, DNR) was loaded into oxidized porous silicon (pSiO2) microparticles and then encapsulated with a layer of polymer (poly lactide-co-glycolide, PLGA) to investigate their synergistic effects in control of DNR release. Similarly fabricated PLGA-DNR microspheres without pSiO2, and pSiO2 microparticles without PLGA were used as control particles. The composite microparticles synthesized by a solid-in-oil-in-water emulsion method have mean diameters of 52.33±16.37?m for PLGA-pSiO2_21/40-DNR and the mean diameter of 49.31±8.87?m for PLGA-pSiO2_6/20-DNR. The mean size, 26.00±8?m, of PLGA-DNR was significantly smaller, compared with the other two (P<0.0001). Optical microscopy revealed that PLGA-pSiO2-DNR microspheres contained multiple pSiO2 particles. In vitro release experiments determined that control PLGA-DNR microspheres completely released DNR within 38days and control pSiO2-DNR microparticles (with no PLGA coating) released DNR within 14days, while the PLGA-pSiO2-DNR microspheres released DNR for 74days. Temporal release profiles of DNR from PLGA-pSiO2 composite particles indicated that both PLGA and pSiO2 contribute to the sustained release of the payload. The PLGA-pSiO2 composite displayed a more constant rate of DNR release than the pSiO2 control formulation, and displayed a significantly slower release of DNR than either the PLGA or pSiO2 formulations. We conclude that this system may be useful in managing unwanted ocular proliferation when formulated with antiproliferation compounds such as DNR. PMID:24793657
Nan, Kaihui; Ma, Feiyan; Hou, Huiyuan; Freeman, William R; Sailor, Michael J; Cheng, Lingyun
Dissolution of protein macromolecules from poly(lactic-co-glycolic acid) (PLGA) particles is a complex process and still not fully understood. As such, there are difficulties in obtaining a predictive model that could be of fundamental significance in design, development, and optimization for medical applications and toxicity evaluation of PLGA-based multiparticulate dosage form. In the present study, two models with comparable goodness of fit were proposed for the prediction of the macromolecule dissolution profile from PLGA micro- and nanoparticles. In both cases, heuristic techniques, such as artificial neural networks (ANNs), feature selection, and genetic programming were employed. Feature selection provided by fscaret package and sensitivity analysis performed by ANNs reduced the original input vector from a total of 300 input variables to 21, 17, 16, and eleven; to achieve a better insight into generalization error, two cut-off points for every method was proposed. The best ANNs model results were obtained by monotone multi-layer perceptron neural network (MON-MLP) networks with a root-mean-square error (RMSE) of 15.4, and the input vector consisted of eleven inputs. The complicated classical equation derived from a database consisting of 17 inputs was able to yield a better generalization error (RMSE) of 14.3. The equation was characterized by four parameters, thus feasible (applicable) to standard nonlinear regression techniques. Heuristic modeling led to the ANN model describing macromolecules release profiles from PLGA microspheres with good predictive efficiency. Moreover genetic programming technique resulted in classical equation with comparable predictability to the ANN model.
Szlek, Jakub; Paclawski, Adam; Lau, Raymond; Jachowicz, Renata; Mendyk, Aleksander
Pulmonary drug delivery has become a promising route in the treatment of lung diseases because of better local retention and lower systemic penetration. In this study, etoposide-loaded poly(lactic-co-glycolic acid) (PLGA) microspheres were designed with potential pulmonary delivery properties. The microspheres were prepared via improved emulsion-solvent evaporation method. Physicochemical characteristics, micromeritics properties and in vitro drug release behavior of the microspheres were then evaluated. Results showed that etoposide-loaded PLGA microspheres were spherical in shape with smooth surface with size (11.8 ± 1.25) ?m. Particles remained stable without any changing in size and morphology after dried by the freeze-drying method. Etoposide was loaded into PLGA microspheres in an amorphous state with high drug loading ((7.7 ± 0.3)%) and encapsulation efficiency ((84.2 ± 2.9)%). Results of micromeritics properties also demonstrated that etoposide-loaded PLGA microspheres were very suitable for pulmonary delivery. In addition, in vitro drug release study indicated a sustained release profile fitted with the Ritger-Peppas equation for up to 20 days. In conclusion, the etoposide-loaded PLGA microspheres were promising for pulmonary delivery, and etoposide could be sustained released from the PLGA microspheres. PMID:24107001
Feng, Ruihua; Zhang, Zhiyue; Li, Zhongwen; Huang, Guihua
Herein, we describe the detailed development of a simple and effective method to microencapsulate vaccine antigens in poly(lactic-co-glycolic acid) (PLGA) by simple mixing of preformed active self-microencapsulating (SM) PLGA microspheres in a low concentration aqueous antigen solution at modest temperature (10-38 °C). Co-encapsulating protein-sorbing vaccine adjuvants and polymer plasticizers were used to “actively” load the protein in the polymer pores and facilitate polymer self-healing at temperature > hydrated polymer glass transition temperature, respectively. The microsphere formulation parameters and loading conditions to provide optimal active self-healing microencapsulation of vaccine antigen in PLGA was investigated. Active self-healing encapsulation of two vaccine antigens, ovalbumin and tetanus toxoid (TT), in PLGA microspheres was adjusted by preparing blank microspheres containing different vaccine adjuvant (aluminum hydroxide (Al(OH)3) or calcium phosphate). Active loading of vaccine antigen in Al(OH)3-PLGA microspheres was found to: a) increase proportionally with an increasing loading of Al(OH)3 (0.88-3 wt%) and addition of porosigen, b) decrease when the inner Al(OH)3/trehalose phase to 1 mL outer oil phase and size of microspheres was respectively > 0.2 mL and 63 ?m, and c) change negligibly by PLGA concentration and initial incubation (loading) temperature. Encapsulation of protein sorbing Al(OH)3 in PLGA microspheres resulted in suppression of self-healing of PLGA pores, which was then overcome by improving polymer chain mobility, which in turn was accomplished by coincorporating hydrophobic plasticizers in PLGA. Active self-healing microencapsulation of manufacturing process-labile TT in PLGA was found to: a) obviate micronization- and organic solvent-induced TT degradation, b) improve antigen loading (1.4-1.8 wt% TT) and encapsulation efficiency (~ 97%), c) provide nearly homogeneous distribution and stabilization of antigen in polymer, and d) provide improved in vitro controlled release of antigenic TT.
Desai, Kashappa-Goud H.; Schwendeman, Steven P.
Herein, we describe the detailed development of a simple and effective method to microencapsulate vaccine antigens in poly(lactic-co-glycolic acid) (PLGA) by simple mixing of preformed active self-microencapsulating (SM) PLGA microspheres in a low concentration aqueous antigen solution at modest temperature (10-38 °C). Co-encapsulating protein-sorbing vaccine adjuvants and polymer plasticizers were used to "actively" load the protein in the polymer pores and facilitate polymer self-healing at a temperature>the hydrated polymer glass transition temperature, respectively. The microsphere formulation parameters and loading conditions to provide optimal active self-healing microencapsulation of vaccine antigens in PLGA was investigated. Active self-healing encapsulation of two antigens, ovalbumin and tetanus toxoid (TT), in PLGA microspheres was adjusted by preparing blank microspheres containing different vaccine adjuvants (aluminum hydroxide (Al(OH)?) or calcium phosphate). Active loading of vaccine antigen in Al(OH)?-PLGA microspheres was found to: a) increase with an increasing loading of Al(OH)? (0.88-3 wt.%) and addition of porosigen, b) decrease when the inner Al(OH)?/trehalose phase to 1 mL outer oil phase and size of microspheres was respectively >0.2 mL and 63 ?m, and c) change negligibly by PLGA concentration and initial incubation (loading) temperature. Encapsulation of protein sorbing Al(OH)? in PLGA microspheres resulted in suppression of self-healing of PLGA pores, which was then overcome by improving polymer chain mobility, which in turn was accomplished by coincorporating hydrophobic plasticizers in PLGA. Active self-healing microencapsulation of manufacturing process-labile TT in PLGA was found to: a) obviate micronization- and organic solvent-induced TT degradation, b) improve antigen loading (1.4-1.8 wt.% TT) and encapsulation efficiency (~97%), c) provide nearly homogeneous distribution and stabilization of antigen in polymer, and d) provide improved in vitro controlled release of antigenic TT. PMID:23103983
Desai, Kashappa-Goud H; Schwendeman, Steven P
Purpose To investigate the effect of ?-irradiation of poly(lactic-co-glycolic acid) (PLGA)/Al(OH)3/0 or 5 wt% diethyl phthalate (DEP) microspheres for active self-healing encapsulation of vaccine antigens. Methods Microspheres were irradiated with 60Co at 2.5 and 1.8 MRad and 0.37 and 0.20 MRad/h. Encapsulation of tetanus toxoid (TT) was achieved by mixing Al(OH)3-PLGA microspheres with TT solution at 10-38°C. Electron paramagnetic resonance (EPR) spectroscopy was used to examine free radical formation. Glass transition temperature (Tg) and molecular weight of PLGA was measured by differential scanning calorimetry and gel permeation chromatography, respectively. Loading and release of TT were examined by modified Bradford, amino acid analysis, and ELISA assays. Results EPR spectroscopy results indicated absence of free radicals in PLGA microspheres after ?-irradiation. Antigen-sorbing capacity, encapsulation efficiency, and Tg of the polymer were also not adversely affected. When DEP-loaded microspheres were irradiated at 0.2 MRad/h, some PLGA pores healed during irradiation and PLGA healing during encapsulation was suppressed. The molecular weight of PLGA was slightly reduced when DEP-loaded microspheres were irradiated at the same dose rate. These trends were not observed at 0.37 MRad/h. Gamma irradiation slightly increased TT initial burst release. Apart from the slightly higher polymer molecular weight decline caused by higher irradiation dose in case of DEP-loaded microspheres, the small increase in total irradiation dose from 1.8 to 2.5 MRad had insignificant effect on the polymer and microspheres properties analyzed. Conclusion Gamma irradiation is a plausible approach to provide a terminally sterilized, self-healing encapsulation PLGA excipient for vaccine delivery.
Desai, Kashappa-Goud H.; Kadous, Samer; Schwendeman, Steven P.
Drug delivery systems involving the use of polymers are widely studied and discovery of biocompatible polymers has become the focus of research in this area. Psoralen loaded poly(dl-lactide-co-glycolide) (PLGA) microspheres to be used in PUVA therapy (psoralen and UVA irradiation (ultraviolet A, 320–400nm) of psoriasis were identified in paraffin sections by histological analysis. The psoralen loaded PLGA microspheres were prepared
Anderson J. Gomes; Claure N. Lunardi; Laurelúcia O. Lunardi; Dimitrius L. Pitol; Antonio Eduardo H. Machado
A translymphatic drug delivery system which incorporates poly-lactide-co-glycolide–paclitaxel (PLGA–PTX) or PLGA–rhodamine microspheres into gelatin sponge matrix is described. The system combines the sustained release properties of PLGA–PTX with the structural advantages of gelatin matrix that can be implanted directly to the lymphatic site for both therapeutic and prophylactic purposes. The PLGA microspheres were prepared using spray drying technique. The particles
Jiang Liu; Dale Meisner; Elizabeth Kwong; Xiao Y. Wu; Michael R. Johnston
Alginate-chitosan-PLGA composite microspheres encapsulating outer membrane protein antigen of Aeromonas hydrophila as an antigen carrier was explored for the first time in a fish model. This composite microsphere showed distinct advantages over the conventional PLGA microparticles in aspects of the high encapsulation efficiency due to the protein-friendly microenvironment created by the hydrophilic alginate-chitosan cores of the composite microspheres, preventing initial burst release and the elimination of lyophilizing process. The antibody responses significantly increased and persist up to 9 weeks in composite microspheres unlike that PLGA microsphere, native OMP and FIA adjuvant. Moreover, several innate immune parameters as respiratory burst, lysozyme and complement activity were significantly increased in both composite and PLGA microspheres up to 9 weeks than other treated groups. It also gives protection from A. hydrophila infection and brought some hope, for its application in replacement with conventional PLGA microparticle for antigen delivery in fish. PMID:23823131
Behera, Truptimayee; Swain, Priyabrat
Objective To investigate the effects of BCNU/PLGA microspheres on tumor growth, apoptosis and chemotherapy resistance in a C57BL/6 mice orthotopic brain glioma model using GL261 cell line. Methods BCNU/PLGA sustained-release microspheres were prepared by the water-in-oil-in-water emulsion technique. GL261 cells were intracranially injected into C57BL/6 mouse by using the stereotactic technology. A total of 60 tumor-bearing mice were randomly and equally divided into three groups: untreated control, PLGA treated, BCNU/PLGA treated. Magnetic resonance imaging (MRI) was taken to evaluate tumor volume. BCNU/PLGA sustained-release wafers were implanted in the treatment group two weeks after inoculation. Survival time and quality were observed. Specimens were harvested, and immunohistochemical staining was used to check the expression of Bax, Bcl-2, and O6-methylguanine-DNA methyltransferase (MGMT). Statistical methods was used for analysis of relevant data. Results BCNU/PLGA sustained-release wafers were fabricated and implanted successfully. There is statistical difference of survival time between the BCNU/PLGA treated group and control groups (P<0.05). MRI scan showed inhibitory effect of BCNU/PLGA on tumor growth. Compared to the group A and B, BCNU/PLGA decreased the expression of apoptosis related gene Bcl-2 (P<0.05), but did not elevate the expression level of Bax (P>0.05), with the ratio of Bax/Bcl-2 increased. For MGMT protein expression, no statistically significant change was found in treated group (P>0.05). Conclusions Local implantation of BCNU/PLGA microspheres improved the survival quality and time of GL261 glioma-bearing mice significantly, inhibited the tumor proliferation, induced more cell apoptosis, and did not increase the chemotherapy resistance.
Zhu, Tongming; Shen, Yiwen; Tang, Qisheng; Chen, Luping; Gao, Huasong
Antibodies (Abs) require the development of stable formulations and specific delivery strategies given their susceptibility to a variety of physical and chemical degradation pathways. In this study, the encapsulation of an antibody into polylactide-co-glycolide (PLGA) based microspheres was explored to obtain a controlled-release of the incorporated drug. In order to avoid stability issues, a solid-in-oil-in-water (s/o/w) method was preferred. The solid phase was made of anti-TNF alpha monoclonal antibody (MAb) spray-dried microparticles, and the PLGA microspheres were produced using two different polymers (i.e., Resomer(®) RG505 and Resomer(®) RG755S). The stability of the MAb incorporated into the microspheres was investigated under three conditions (5±3°C, 25±2°C/60% RH and 40±2°C/75% RH) for 12 weeks. During this stability study, it was demonstrated that the MAb loaded PLGA microspheres were stable when stored at 5±3°C and that the Resomer(®) RG755S, composed of 75%(w/w) lactic acid as PLGA, was preferred to preserve the stability of the system. Storage at temperatures higher than 5°C led to antibody stability issues such as aggregation, fragmentation and loss of activity. The release profiles were also altered. Physical ageing of the system associated with changes in the glass transition temperature and enthalpy of relaxation was noticed during the storage of the MAb loaded PLGA microspheres. PMID:24792974
Marquette, S; Peerboom, C; Yates, A; Denis, L; Langer, I; Amighi, K; Goole, J
Drug delivery systems based on polymer microspheres have received considerable attention. Ceftiofur sodium and ceftiofur hydrochloride is widely used for the treatment of bacterial diseases in animals but the delivery in vivo has not been reported. In this paper, we report the synthesis of microspheres from gelatin and PLGA, two kinds of typical natural and artificial materials, for loading ceftiofur and the in vivo investigation of the pharmacokinetics in beagle dogs. By controlling the synthesis parameters, gelatin and PLGA microspheres with diameter between 5 and 35 microns were obtained. Assay procedures based on high performance liquid chromatography were evaluated and confirmed. The dogs were randomly divided into three groups, i.e., control group, gelatin group, and PLGA group and administrated via intravenous injection. Plasma concentrations of ceftiofur over time were measured and analyzed. Results indicate that the main kinetic parameters do not show significant difference for the gelatin group and control group, but the area under the curve, plasma half-life, apparent volume of distribution, and clearance ratio of PLGA group show significant difference from the gelatin group and the control group. The PLGA microspheres show a low area under the curve but long time release. PMID:23354736
Hao, Zhihui; Wang, Leilei; Xiao, Kefeng; Zhao, Yongda; Zou, Ming; Zhang, Qidi; Ding, Zhaopeng; Yang, Fenfang; Qu, Baohan
Purpose To test the potential of water-soluble divalent cationic salts to inhibit acylation of octreotide encapsulated in poly(D,L-lactic-co-glycolic\\u000a acid)-star (PLGA) microspheres.\\u000a \\u000a \\u000a \\u000a Methods The divalent cationic salts, calcium chloride and manganese chloride, previously shown to disrupt peptide sorption, were introduced\\u000a in PLGA microspheres prepared by the double emulsion-solvent evaporation method. Peptide stability was monitored by reversed-phase\\u000a high performance liquid chromatography (RP-HPLC) and identified
Ying Zhang; Andreas M. Sophocleous; Steven P. Schwendeman
Uniform hollow superparamagnetic poly(lactic-co-glycolic acid) (PLGA)/Fe3O4 composite microspheres composed of an inner cavity, PLGA inner shell and Fe3O4 outer shell have been synthesized by a modified oil-in-water (O/W) emulsion-solvent evaporation method using Fe3O4 nanoparticles as a particulate emulsifier. The obtained composite microspheres with an average diameter of 2.5 ?m showed excellent monodispersity and stability in aqueous medium, strong magnetic responsiveness, high magnetite content (>68%), high saturation magnetization (58 emu g-1) and high efficiency in lysozyme adsorption.
Yang, Qi; Wu, Yao; Lan, Fang; Ma, Shaohua; Xie, Liqin; He, Bin; Gu, Zhongwei
Serratiopeptidase-loaded poly (D,L-lactic-co-glycolic acid) (PLGA) microspheres were prepared using the modified double emulsion method. The effect of polymer concentration and external aqueous phase volume on microsphere size and entrapment efficiency was studied by 3(2) full factorial experiments. The results of analysis of variance test for measured responses indicated the test's significance (P < 0.05). The contribution of PLGA concentration on microsphere size and percentage yield was found to be higher than that of external aqueous phase volume, which produced a significant effect on entrapment efficiency. Microspheres demonstrated spherical particles in the size range of 19.08-41.14 microm and entrapment efficiency between 15.37 and 79.86%. The formulation using a medium level of polymer and a low level of external aqueous phase (PLGA: 300 mg; EAP: 100 mL) showed maximum entrapment (75.86 +/- 2.31%). The in vitro release profile of all formulations demonstrated a similar sustained release showing an initial burst followed by diffusion. The bioactivity of the peptide remained intact after microencapsulation as assayed by in vitro proteolytic activity. Response surface graphs are presented to examine the effects of independent variables on the responses studied. In conclusion, controlled-release serratiopeptidase-loaded PLGA microspheres demonstrating maximum entrapment were successfully prepared by an experimental design methodology with a minimum number of runs, representing an economical approach. PMID:19634349
Singh, Deependra; Dixit, V K; Saraf, Swarnlata; Saraf, S
In the present study, Poly (D,L-lactide-co-glycolide) microspheres (PLGA MSs) were prepared for delivering a novel oligopeptide derived from rhBMP-2 (Peptide-24). Hydroxypropyl-?-cyclodextrin (HP-?-CD) and Bovine serum albumin (BSA) were used as stabilizers for retaining bioactivity of the oligopeptide. The morphology, diameter, drugloading rates and encapsulation rates of the PLGA MSs were detected and compared. The PLGA MSs were incubated for 3 and 30 days respectively to obtain the release supernatant containing Peptide-24. The structure and bioactivity of released Peptide-24 from PLGA MSs were evaluated through physicochemical detections and cell culture. The structure integrity of the Peptide-24 was confirmed by Far-UV circular dichroism and matrix-assisted laser desorption/ionization time-of-flight Mass Spectrometer (MALDI-TOF-MS) analysis. The interaction between PLGA matrix and loaded Peptide- 24 was verified through Raman. The results showed that the diameter of PLGA MSs was from 8.62 to 15.34 ?m, the loading rate was 0.7-0.8%, and the encapsulation rate was 69.3-85.3%. The released Peptide-24 from PLGA MSs was proved to retain original bioactivity by the cellular activity and alkaline phosphatase (ALP) test. HP-?-CD is a kind of excellent stabilizer for retaining the bioactivity of Peptide-24 in PLGA MSs. PMID:23227911
Wang, Mingbo; Guo, Xiaodong; Tan, Rongwei; She, Zhending; Feng, Qingling
Recently we identified in Brugia malayi adult worm extract (BmA) a pro-inflammatory 54-68kDa SDS-PAGE resolved fraction F6 that protects the host from the parasite via Th1/Th2 type responses. We are currently investigating F6 as a potential source of vaccine candidate(s) and the present study is aimed at investigating the suitability of poly(d,l)-lactide-co-glycolide microspheres (PLGA-Ms) as immunoadjuvant for the antigen administration in a single dose. PLGA-Ms were prepared aseptically by a modified double emulsion (w/o/w) solvent evaporation technique and their size, shape, antigen adsorption efficiency, in-process stability, and antigen release were characterized. Swiss mice were immunized by a single subcutaneous administration of BmA and F6 adsorbed on PLGA-Ms (lactide:glycolide ratios 50:50 and 75:25) and the immune responses were compared with administration of 1 or 2 doses of plain BmA and F6. Specific IgG, IgG1, IgG2a, IgG2b, IgE levels in serum, cellular-proliferative response and release of IFN-?, TNF-? and nitric oxide from the cells of immunized host in response to the antigens/LPS/Con A challenge and antibody-dependant cellular cytotoxicity (ADCC) to parasite life stages were determined. The average size of PLGA-Ms 50:50 was smaller than the size of PLGA-Ms 75:25 and the % antigen adsorption efficiency of PLGA-Ms 50:50 was greater than PLGA-Ms 75:25. Single shot injection of PLGA-Ms 50:50/75:25-BmA/F6 produced better and stronger IgG, IgG1/IgG2a and cell-mediated immune responses than even two injections of plain BmA or F6. Further, PLGA-Ms 50:50-F6 produced stronger responses than PLGA-Ms 50:50-BmA. Anti-PLGA-Ms 50:50-F6 antibodies elicited higher ADCC response to infective larval and microfilarial stages of the parasite than anti-PLGA-Ms 75:25-F6 antibodies. The findings demonstrate that PLGA-Ms 50:50 is an excellent adjuvant for use with F6 in a single administration. This is the first ever report on PLGA as immunoadjuvant for filarial antigens. PMID:23827312
Saini, Vinay; Verma, Shiv Kumar; Murthy, P Kalpana; Kohli, Dharmveer
To decrease the initial burst release of protein entrapped in PLGA microspheres, bovine serum albumin was entrapped into microspheres and a one-step modified method was evaluated. Low level of alginate was added into the internal aqueous phase with protein together; meanwhile calcium chloride and chitosan were put into the external, and all the other processes kept unvaried. After modification, the initial release was inhibited markedly, and the entrapment efficiency was increased slightly, while the particle size remained unaltered. An attracting result is that almost all the little pores at the surface of microspheres had been closed with the modification one under SEM. PMID:20067365
Zheng, Caihong; Liang, Wenquan
The purpose of this study was to investigate the effect of 2 additives, poly(ethylene glycol (PEG) 1000 and 1,2,3-tridecanoyl\\u000a glycerol (tricaprin), on the physico-chemical characteristics and in vitro release of a model protein, bovine serum albumin\\u000a (BSA), form poly(D,L-lactic-co-glycolic acid) (PLGA) microspheres. BSA-loaded microspheres were prepared by the double emulsion\\u000a solvent evaporation method. Additives were incorporated into microspheres to modify
Feirong Kang; Jagdish Singh
Lysozyme was encapsulated within biodegradable poly(D, L-lactide-co-glycolide) microspheres by a double emulsion solvent evaporation method for studying its release mechanism associated with protein stability problems. When urea, a protein unfolding agent, was added into the incubation medium lysozyme release rate from the microspheres increased with the increase in urea concentration. The enhanced lysozyme release was attributed to the suppression of protein aggregation, to the facilitated diffusion of unfolded lysozyme by an efficient reptile motion of unfolded protein molecules through porous channels in microspheres, and to the largely decreased extent of nonspecific protein adsorption onto the enlarged surface area of degrading polymer microspheres in the presence of urea. Encapsulating lysozyme in an unfolded form within PLGA microspheres was attempted by using urea as an excipient. This new urea-based formulation exhibited a more sustained lysozyme release profile than the control formulation, and released lysozyme from the microspheres showed a much less amount of lysozyme dimer population while maintaining a correct conformation after refolding in the incubation medium. This study provides new insights for the formulation of protein encapsulated PLGA microspheres. PMID:10992231
Nam, Y S; Song, S H; Choi, J Y; Park, T G
5-Fluorouracil (5FU) was successfully entrapped within poly(lactide-co-glycolide) (PLGA) and hydroyapatite (HA) composite microspheres using the emulsification/solvent extraction technique. The effects of HA to PLGA ratio, solvent ratio as well as polymer inherent viscosity (IV) on encapsulation efficiency were investigated. The degradation and drug release rates of the microspheres were studied for 5 weeks in vitro in phosphate buffered solution of pH 7.4 at 37 °C. The drug release profile followed a biphasic pattern with a small initial burst followed by a zero-order release for up to 35 days. The initial burst release decreased with increasing HA content. The potential of HA in limiting the initial burst release makes the incorporation of HA into PLGA microspheres advantageous since it reduces the risk of drug overdose from high initial bursts. The linear sustained drug release profile over the course of 5 weeks makes these 5-FU-loaded HA/PLGA composite microparticles a promising delivery system for the controlled release of chemotherapy drugs in the treatment of cancer. PMID:22843166
Lin, Yuting; Li, Yan; Ooi, Chui Ping
PLGA microspheres are attractive DNA delivery vehicles due to their controlled release capabilities. One major problem with PLGA microspheres is that they develop an acidic microclimate as the polymer degrades, lowering the intraparticle pH, and potentially damaging the DNA. Antacids have recently shown promise in buffering this acidic microclimate and enhancing protein stability. We manufactured uniform plasmid DNA-encapsulating PLGA microspheres of two sizes (47, 80 ?m diameter) and antacid concentrations (0, 3% Mg(OH)2). Microspheres with antacid had a homogeneous surface coverage of small pores, which resulted in a significant reduction of the burst effect. The 47 ?m microspheres exhibited complete release of plasmid DNA over the course of two months. Incomplete release was observed from 80 ?m spheres, though microspheres with 3% Mg(OH)2 showed a higher cumulative release, suggesting that the antacid at least partially aids in increasing the stability of DNA. SEM was used to visualize the surface pore evolution and cross-sectional microsphere structure over time. Subsequent image analysis was used to quantify the increase of surface pore sizes. Cross-sectional images showed increasing internal degradation and erosion, which resulted in a hollowing-out of microspheres. Our studies show that the incorporation of antacid into the microsphere structure has potential in addressing some of the major problems associated with DNA encapsulation and release in PLGA microspheres.
Varde, Neelesh K.; Pack, Daniel W.
Surface-modified dl-lactide\\/glycolide copolymer (PLGA) microspheres with chitosan (CS) were developed for nasal immunization using recombinant Hepatitis B (HBsAg) surface protein for the induction of humoral, cellular and mucosal immunity. Modified PLGA microspheres were characterized in vitro for their size, shape, entrapment efficiency and zeta potential. The nasal clearance rate was evaluated by gamma scintigraphy in rabbits. The antigen integrity, in
K. S. Jaganathan; Suresh P. Vyas
Surface-modified DL-lactide/glycolide copolymer (PLGA) microspheres with chitosan (CS) were developed for nasal immunization using recombinant Hepatitis B (HBsAg) surface protein for the induction of humoral, cellular and mucosal immunity. Modified PLGA microspheres were characterized in vitro for their size, shape, entrapment efficiency and zeta potential. The nasal clearance rate was evaluated by gamma scintigraphy in rabbits. The antigen integrity, in vitro release and its stability at 37 degrees C were also evaluated. The designed cationic microspheres possessed 27.2 mV zeta potential and an average size less than 10 microm with antigen loading efficiency of 80+/-5%. However, zeta potential of unmodified PLGA microspheres was measured to be negative (-8.7 mV). The modified PLGA microspheres showed the lowest nasal clearance rate when compared with unmodified PLGA microspheres and lactose powder. The antigen integrity was retained intact in encapsulated form as well as on release. The immune-stimulating activity was studied by measuring anti-HBsAg titre, secretory IgA level in serum, vaginal, nasal and salivary secretions (mucosal secretions) and cytokine level (interleukin-2 (IL-2) and interferon-gamma (IFN-gamma)) in spleen homogenates following nasal administration of modified PLGA microspheres in Balb/c mice and compared with alum-HBsAg vaccine injected subcutaneously. The serum anti-HBsAg titre obtained after nasal administration of modified PLGA microspheres was comparable with titre recorded after alum-HBsAg was administered subcutaneously. Moreover, alum-HBsAg vaccine did not elicit sIgA in mucosal secretions as it was induced and measured in the case of nasal administration of modified PLGA microspheres. Similarly, there was no cellular response (cytokine level) in case of alum-HBsAg vaccine. Modified PLGA microspheres (cationic microspheres) thus produced humoral (both systemic and mucosal) and cellular immune responses upon nasal administration. These data demonstrate high potential of modified PLGA microspheres for their use as a carrier adjuvant for nasal subunit vaccines. PMID:16446012
Jaganathan, K S; Vyas, Suresh P
Our previous results on the phagocytic activity of alveolar macrophages (M?s) toward poly(lactic-co-glycolic) acid microspheres (PLGA MS) loaded with the anti-tuberculosis agent rifampicin (R-PLGA MS) suggest that the phagocytosis of R-PLGA MS enhances the phagocytic activity of M? cells. To confirm this possibility, we examined the effect of phagocytosis of R-PLGA MS and polystyrene latex (PSL) MS on the phagocytic uptake of fluorescent PSL (F-PSL) MS by cells of the rat alveolar macrophage cell line NR8383 at 37°C. Phagocytic activity was examined in terms of the population of M? cells that had phagocytosed MS (N(total)) and the total number of MS phagocytosed (n(total)) by counting the phagocytic M? cells and the MS ingested in optical microscopic fields. Phagocytosis of R-PLGA MS enhanced about 1.5 times the values of N(total) and n(total) of the phagocytosis of F-PSL MS under the conditions where the phagocytosis of F-PSL MS did not attain the saturated level. In contrast, the phagocytosis of PSL MS did not enhance the phagocytic activity of M? cells toward F-PSL MS. In conclusion, R-PLGA MS are favorable for drug delivery of anti-tuberculosis agents into alveolar M?s due to their ability to up-regulate the phagocytosis of MS. PMID:21700434
Hirota, Keiji; Hasegawa, Taizo; Nakajima, Takehisa; Makino, Kimiko; Terada, Hiroshi
Controlled-release drug delivery systems based on biodegradable polymers have been extensively evaluated for use in localized drug delivery. In the present study, intralesionally injectable poly (lactide-co-glycolide) (PLGA) microspheres for controlled release of terbinafine hydrochloride (TH) was developed for treating fungal toe/finger nail infections. TH-PLGA microspheres were formulated using O/W emulsification and modified solvent extraction/evaporation technique. Microspheres were evaluated for particle size and size distribution, encapsulation efficiency, surface, and morphology. The in vitro drug release profile was studied in aqueous media as well as in 1% agar gel. Microspheres system was also evaluated in excised cadaver toe model, and extent of TH accumulation in nail bed, nail plate, and nail matrix was measured at different time points. Microspheres were found to provide consistent and sustained TH release. Intralesional administration of controlled-release microspheres can be a potential alternative mode of treating fungus-infected toe and/or finger nails. PMID:24497012
Angamuthu, Muralikrishnan; Nanjappa, Shivakumar H; Raman, Vijayasankar; Jo, Seongbong; Cegu, Phaniraj; Murthy, S Narasimha
Blank and bovine serum albumin (BSA)-loaded microspheres based on poly(lactic-acid-alt-glycolic acid) (D,L-PLGA50) and poly(epsilon-caprolactone)-b-poly(lactic-acid-alt-glycolic acid) (PCL-b-D,L-PLGA50) were successfully fabricated using water-in-oil-in-water (w/o/w) double-emulsion extraction/evaporation technique. In vitro degradation of the blank microspheres was characterized by techniques including nuclear magnetic resonance (1H NMR), gel permeation chromatography (GPC), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). The PCL-b-D,L-PLGA50 copolymer (Mn: number-average molecular weight, Mw: weight-average molecular weight, Mn=44800, Mw/Mn=MWD=1.24, epsilon-caprolactone (CL) %=20.4% in molar ratio) had similar rate of molecular weight reduction compared with the D,L-PLGA50 copolymer before 5 weeks of in vitro degradation. The BSA % loading efficiency of microspheres was mainly controlled by both block copolymer composition and macromolecular architecture, while the sequence structure and the molecular weight of copolymer had no apparent effect on it. Significantly, The PCL-b-D,L-PLGA50 copolymer microspheres showed good release profiles with a nearly constant release during 20-110 days. PMID:16005093
Dong, Chang-Ming; Guo, Ying-Zhi; Qiu, Kun-Yuan; Gu, Zhong-Wei; Feng, Xin-De
Monodisperse PLGA-alginate core-shell microspheres with controlled size and homogeneous shells were first fabricated using capillary microfluidic devices for the purpose of controlling drug release kinetics. Sizes of PLGA cores were readily controlled by the geometries of microfluidic devices and the fluid flow rates. PLGA microspheres with sizes ranging from 15 to 50?m were fabricated to investigate the influence of the core size on the release kinetics. Rifampicin was loaded into both monodisperse PLGA microspheres and PLGA-alginate core-shell microspheres as a model drug for the release kinetics studies. The in vitro release of rifampicin showed that the PLGA core of all sizes exhibited sigmoid release patterns, although smaller PLGA cores had a higher release rate and a shorter lag phase. The shell could modulate the drug release kinetics as a buffer layer and a near-zero-order release pattern was observed when the drug release rate of the PLGA core was high enough. The biocompatibility of PLGA-alginate core-shell microspheres was assessed by MTT assay on L929 mouse fibroblasts cell line and no obvious cytotoxicity was found. This technique provides a convenient method to control the drug release kinetics of the PLGA microsphere by delicately controlling the microstructures. The obtained monodisperse PLGA-alginate core-shell microspheres with monodisperse size and homogeneous shells could be a promising device for controlled drug release. PMID:23535235
Wu, Jun; Kong, Tiantian; Yeung, Kelvin Wai Kwok; Shum, Ho Cheung; Cheung, Kenneth Man Chee; Wang, Liqiu; To, Michael Kai Tsun
Statins are used clinically for reduction of cholesterol synthesis to prevent cardiovascular disease. Previous in vitro and in vivo studies have shown that statins stimulate bone formation. However, orally administered statins may be degraded during first-pass metabolism in the liver. This study aimed to prevent this degradation by developing a locally administered formulation of simvastatin that is encapsulated in poly(lactic-co-glycolic acid)/hydroxyapatite (SIM/PLGA/HAp) microspheres with controlled-release properties. The effect of this formulation of simvastatin on bone repair was tested using a mouse model of gap fracture bridging with a graft of necrotic bone. The simvastatin released over 12 days from 3 mg and 5 mg of SIM/PLGA/HAp was 0.03–1.6 ?g/day and 0.05–2.6 ?g/day, respectively. SIM/PLGA/HAp significantly stimulated callus formation around the repaired area and increased neovascularization and cell ingrowth in the grafted necrotic bone at week 2 after surgery. At week 4, both 3 mg and 5 mg of SIM/PLGA/HAp increased neovascularization, but only 5 mg SIM/PLGA/HAp enhanced cell ingrowth into the necrotic bone. The low dose of simvastatin released from SIM/PLGA/HAp enhanced initial callus formation, neovascularization, and cell ingrowth in the grafted bone, indicating that SIM/PLGA/HAp facilitates bone regeneration. We suggest that SIM/PLGA/HAp should be developed as an osteoinductive agent to treat osteonecrosis or in combination with an osteoconductive scaffold to treat severe bone defects.
Tai, I-Chun; Fu, Yin-Chih; Wang, Chih-Kuang; Chang, Je-Ken; Ho, Mei-Ling
Statins are used clinically for reduction of cholesterol synthesis to prevent cardiovascular disease. Previous in vitro and in vivo studies have shown that statins stimulate bone formation. However, orally administered statins may be degraded during first-pass metabolism in the liver. This study aimed to prevent this degradation by developing a locally administered formulation of simvastatin that is encapsulated in poly(lactic-co-glycolic acid)/hydroxyapatite (SIM/PLGA/HAp) microspheres with controlled-release properties. The effect of this formulation of simvastatin on bone repair was tested using a mouse model of gap fracture bridging with a graft of necrotic bone. The simvastatin released over 12 days from 3 mg and 5 mg of SIM/PLGA/HAp was 0.03-1.6 ?g/day and 0.05-2.6 ?g/day, respectively. SIM/PLGA/HAp significantly stimulated callus formation around the repaired area and increased neovascularization and cell ingrowth in the grafted necrotic bone at week 2 after surgery. At week 4, both 3 mg and 5 mg of SIM/PLGA/HAp increased neovascularization, but only 5 mg SIM/PLGA/HAp enhanced cell ingrowth into the necrotic bone. The low dose of simvastatin released from SIM/PLGA/HAp enhanced initial callus formation, neovascularization, and cell ingrowth in the grafted bone, indicating that SIM/PLGA/HAp facilitates bone regeneration. We suggest that SIM/PLGA/HAp should be developed as an osteoinductive agent to treat osteonecrosis or in combination with an osteoconductive scaffold to treat severe bone defects. PMID:24143094
Tai, I-Chun; Fu, Yin-Chih; Wang, Chih-Kuang; Chang, Je-Ken; Ho, Mei-Ling
The purpose of this study was to characterize the phase separation behavior of fusidic acid (FA) and rifampicin (RIF) in poly(d,l-lactic acid-co-glycolic acid) (PLGA) using a model microsphere formulation. To accomplish this, microspheres containing 20% FA with 0%, 5%, 10%, 20%, and 30% RIF and 20% RIF with 30%, 20% 10%, 5%, and 0% FA were prepared by solvent evaporation. Drug-polymer and drug-drug compatibility and miscibility were characterized using laser confocal microscopy, Raman spectroscopy, XRPD, DSC, and real-time video recordings of single-microsphere formation. The encapsulation of FA and RIF alone, or in combination, results in a liquid-liquid phase separation of solvent-and-drug-rich microdomains that are excluded from the polymer bulk during microsphere hardening, resulting in amorphous spherical drug-rich domains within the polymer bulk and on the microsphere surface. FA and RIF phase separate from PLGA at relative droplet volumes of 0.311 ± 0.014 and 0.194 ± 0.000, respectively, predictive of the incompatibility of each drug and PLGA. When coloaded, FA and RIF phase separate in a single event at the relative droplet volume 0.251 ± 0.002, intermediate between each of the monoloaded formulations and dependent on the relative contribution of FA or RIF. The release of FA and RIF from phase-separated microspheres was characterized exclusively by a burst release and was dependent on the phase exclusion of surface drug-rich domains. Phase separation results in coalescence of drug-rich microdroplets and polymer phase exclusion, and it is dependent on the compatibility between FA and RIF and PLGA. FA and RIF are mutually miscible in all proportions as an amorphous glass, and they phase separate from the polymer as such. These drug-rich domains were excluded to the surface of the microspheres, and subsequent release of both drugs from the microspheres was rapid and reflected this surface location. PMID:22482935
Gilchrist, Samuel E; Rickard, Deborah L; Letchford, Kevin; Needham, David; Burt, Helen M
Drug release from implant surfaces is an effective approach to impart biological activities, (e.g., antimicrobial and osteogenic properties) to bone implants. Coatings of polylactide-based polymer are a candidate for this purpose, but a continuous (fully covering) coating may be non-optimal for implant-bone fixation. This study reports a simple room-temperature method for attaching poly (lactide-co-glycolide) (PLGA) microspheres to titanium (Ti) surfaces. Microspheres were prepared with polyvinyl alcohol (PVA) or polyvinylpyrrolidone (PVP) as the emulsifier. Microspheres were attached to Ti discs by pipetting as a suspension onto the surfaces followed by vacuum drying. After immersion in shaking water bath for 14 d, a substantial proportion of the microspheres remained attached to the discs. In contrast, if the vacuum-drying procedure was omitted, only a small fraction of the microspheres remained attached to the discs after immersion for only 5 min. Microspheres containing triclosan (a broad-spectrum antibiotic) were attached by porous-surfaced Ti discs. In vitro experiments showed that the microsphere-carrying discs were able to kill Staphylococcus aureus and Escherichia Coli, and support the adhesion and growth of primary rat osteoblasts. This simple method may offer a flexible technique for bone implant-based drug release.
Xiao, Dongqin; Liu, Qing; Wang, Dongwei; Xie, Tao; Guo, Tailin; Duan, Ke; Weng, Jie
Nutrient depletion within three-dimensional (3D) scaffolds is one of the major hurdles in the use of this technology to grow cells for applications in tissue engineering. In order to help in addressing it, we herein propose to use the controlled release of encapsulated nutrients within polymer microspheres into chitosan-based 3D scaffolds, wherein the microspheres are embedded. This method has allowed maintaining a stable concentration of nutrients within the scaffolds over the long term. The polymer microspheres were prepared using multiple emulsions (w/o/w), in which bovine serum albumin (BSA) and poly (lactic-co-glycolic) acid (PLGA) were regarded as the protein pattern and the exoperidium material, respectively. These were then mixed with a chitosan solution in order to form the scaffolds by cryo-desiccation. The release of BSA, entrapped within the embedded microspheres, was monitored with time using a BCA kit. The morphology and structure of the PLGA microspheres containing BSA before and after embedding within the scaffold were observed under a scanning electron microscope (SEM). These had a round shape with diameters in the range of 27-55 ?m, whereas the chitosan-based scaffolds had a uniform porous structure with the microspheres uniformly dispersed within their 3D structure and without any morphological change. In addition, the porosity, water absorption and degradation rate at 37 °C in an aqueous environment of 1% chitosan-based scaffolds were (92.99±2.51) %, (89.66±0.66) % and (73.77±3.21) %, respectively. The studies of BSA release from the embedded microspheres have shown a sustained and cumulative tendency with little initial burst, with (20.24±0.83) % of the initial amount released after 168 h (an average rate of 0.12%/h). The protein concentration within the chitosan-based scaffolds after 168 h was found to be (11.44±1.81)×10(-2) mg/mL. This novel chitosan-based scaffold embedded with PLGA microspheres has proven to be a promising technique for the development of new and improved tissue engineering scaffolds. PMID:23827602
Song, Kedong; Liu, Yingchao; Macedo, Hugo M; Jiang, Lili; Li, Chao; Mei, Guanyu; Liu, Tianqing
The drug release and degradation behavior of two double-walled microsphere formulations consisting of a doxorubicin loaded poly(D,L-lactic-co-glycolic acid) (PLGA) core (~46 kDa) surrounded by a poly(D,L-lactic acid) (PDLLA) shell layer (~55 and 116 kDa) were examined. It was postulated that different molecular weights of the shell layer could modulate the erosion of the outer coating and limit the occurrence of water penetration into the inner drug-loaded core on various time scales, and therefore control the drug release from the microspheres. For both microsphere formulations, the drug release profiles were observed to be similar. The degradation of the microspheres was monitored for a period of about nine weeks and analyzed using scanning electron microscopy, laser scanning confocal microscopy, and gel permeation chromatography. Interestingly, both microsphere formulations exhibited occurrence of bulk erosion of PDLLA on a similar time scale despite different PDLLA molecular weights forming the shell layer. The shell layer of the double-walled microspheres served as an effective diffusion barrier during the initial lag phase period and controlled the release rate of the hydrophilic drug independent of the molecular weight of the shell layer.
Xu, Qingxing; Chin, Shi En; Wang, Chi-Hwa; Pack, Daniel W.
In this study, we investigated the effects of temozolomide (TMZ)/Poly (lactide-co-glycolide)(PLGA)/nano-hydroxyapatite microspheres on the behavior of U87 glioma cells. The microspheres were fabricated by the "Solid/Water/Oil" method, and they were characterized by using X-Ray diffraction, scanning electron microscopy and differential scanning calorimetry. The proliferation, apoptosis and invasion of glioma cells were evaluated by MTT, flow cytometry assay and Transwell assay. The presence of the key invasive gene, ?(V)?3 integrin, was detected by the RT-PCR and Western blot method. It was found that the temozolomide/PLGA/nano-hydroxyapatite microspheres have a significantly diminished initial burst of drug release, compared to the TMZ laden PLGA microspheres. Our results suggest they can significantly inhibit the proliferation and invasion of glioma cells, and induce their apoptosis. Additionally, ?(V)?3 integrin was also reduced by the microspheres. These data suggest that by inhibiting the biological behavior of glioma cells in vitro, the newly designed temozolomide/PLGA/nano-hydroxyapatite microspheres, as controlled drug release carriers, have promising potential in treating glioma. PMID:22312307
Zhang, Dongyong; Tian, Ang; Xue, Xiangxin; Wang, Mei; Qiu, Bo; Wu, Anhua
In this study, we investigated the effects of temozolomide (TMZ)/Poly (lactide-co-glycolide)(PLGA)/nano-hydroxyapatite microspheres on the behavior of U87 glioma cells. The microspheres were fabricated by the “Solid/Water/Oil” method, and they were characterized by using X-Ray diffraction, scanning electron microscopy and differential scanning calorimetry. The proliferation, apoptosis and invasion of glioma cells were evaluated by MTT, flow cytometry assay and Transwell assay. The presence of the key invasive gene, ?V?3 integrin, was detected by the RT-PCR and Western blot method. It was found that the temozolomide/PLGA/nano-hydroxyapatite microspheres have a significantly diminished initial burst of drug release, compared to the TMZ laden PLGA microspheres. Our results suggest they can significantly inhibit the proliferation and invasion of glioma cells, and induce their apoptosis. Additionally, ?V?3 integrin was also reduced by the microspheres. These data suggest that by inhibiting the biological behavior of glioma cells in vitro, the newly designed temozolomide/PLGA/nano-hydroxyapatite microspheres, as controlled drug release carriers, have promising potential in treating glioma.
Zhang, Dongyong; Tian, Ang; Xue, Xiangxin; Wang, Mei; Qiu, Bo; Wu, Anhua
Dexamethasone loaded poly(lactic-co-glycolic acid) (PLGA) microsphere/PVA hydrogel composites have been investigated as an outer drug-eluting coating for implantable devices such as glucose sensors to counter negative tissue responses to implants. The objective of this study was to develop a discriminatory, accelerated in vitro release testing method for this drug-eluting coating using United States Pharmacopeia (USP) apparatus 4. Polymer degradation and drug release kinetics were investigated under "real-time" and accelerated conditions (i.e. extreme pH, hydro-alcoholic solutions and elevated temperatures). Compared to "real-time" conditions, the initial burst and lag phases were similar using hydro-alcoholic solutions and extreme pH conditions, while the secondary apparent zero-order release phase was slightly accelerated. Elevated temperatures resulted in a significant acceleration of dexamethasone release. The accelerated release data were able to predict "real-time" release when applying the Arrhenius equation. Microsphere batches with faster and slower release profiles were investigated under "real-time" and elevated temperature (60°C) conditions to determine the discriminatory ability of the method. The results demonstrated both the feasibility and the discriminatory ability of this USP apparatus 4 method for in vitro release testing of drug loaded PLGA microsphere/PVA hydrogel composites. This method may be appropriate for similar drug/device combination products and drug delivery systems. PMID:22016033
Shen, Jie; Burgess, Diane J
Purpose Green fluorescent protein (GFP) encoding adenovirus (ADV) was surface modified with polyethylene glycol (PEG) for microencapsulation\\u000a within poly(lactic-co-glycolic acid) (PLGA) microspheres with the aim of improving stability and gene transfection activity.\\u000a \\u000a \\u000a \\u000a Methods A series of PEGylated ADV (PEG-ADV) with different PEG seeding densities on the viral surface was prepared and the GFP expression\\u000a efficiency of each PEG-ADV in the series determined.
Hyejung Mok; Ji Won Park; Tae Gwan Park
The primary goal of this study was to evaluate the feasibility of using anti-vascular endothelial growth factor receptor 2 (VEGFR2)-conjugated poly(lactic-co-glycolic acid) (PLGA) microspheres as an x-ray phase contrast agent to assess the VEGFR2 expression in cell cultures. The cell lines, mouse LLC (Lewis lung carcinoma) and HUVEC (human umbilical vein endothelial cell), were selected for cell adhesion studies. The bound PLGA microspheres were found to better adhere to LLC cells or HUVECs than unbound ones. Absorption and phase contrast images of PLGA microspheres were acquired and compared in vitro. Phase contrast imaging (PCI) greatly improves the detection of the microspheres as compared to absorption contrast imaging. The cells incubated with PLGA microspheres were imaged by PCI, which provided clear 3D visualization of the beads, indicating the feasibility of using PLGA microspheres as a contrast agent for phase contrast CT. In addition, the microspheres could be clearly distinguished from the wall of the vessel on phase contrast CT images. Therefore, the approach holds promise for assessing the VEGFR2 expression on endothelial cells of tumor-associated vessels. We conclude that PLGA microsphere-based PCI of the VEGFR2 expression might be a novel, promising biomarker for future studies of tumor angiogenesis.
Tang, Rongbiao; Chai, Wei-Min; Ying, Weihai; Yang, Guo-Yuan; Xie, Honglan; Liu, Hui-Qiang; Chen, Ke-Min
A controlled drug release system based on the injectable PLGA microspheres loaded with gestodene and ethinyl estradiol was prepared and evaluated for the feasibility of monthly synchronic delivery of the two hormonal contraceptives. The scanning electron microscopy, light-scattering analyzer and gel permeation chromatography were used to study the morphology, particle size and molecular weight of the polymer microspheres, respectively. HPLC was utilized to determine the drug loading and the drug released, while a LC-MS-MS system was employed to analyze the plasma drug concentration. Result indicated that the PLGA particles obtained were spherical and appropriate in size. The formulation was stable during the test period. In vitro drug release from the microspheres for both drugs was sustained for about 30 days mostly by the diffusion mechanism. The plasma drug concentration-time profiles of the drug-loaded microspheres were relatively smooth after subcutaneous injection to rats for about 1-month, compared with that for drug suspension. In vitro and in vivo correlation was established. One of the most important facts is the synchronicity of the two contraceptives both in the release kinetics in vitro and the pharmacokinetic behaviors in vivo. Therefore, the synchronic delivery of two contraceptives is achieved for about 1 month by using the injectable PLGA-based microspheres. PMID:18539353
Sun, Yi; Wang, Jiancheng; Zhang, Xuan; Zhang, Zhijun; Zheng, Yan; Chen, Dawei; Zhang, Qiang
Cathelicidin-BF-30 (BF-30), a water-soluble peptide isolated from the snake venom of Bungarus fasciatus containing 30 amino acid residues, was incorporated in poly(D,L-lactide-co-glycolide) (PLGA) 75?25 microspheres (MS) prepared by a water in oil in water W/O/W emulsification solvent extraction method. The aim of this work was to investigate the stability of BF-30 after encapsulation. D-trehalose was used as an excipient to stabilize the peptide. The MS obtained were mostly under 2 µm in size and the encapsulation efficiency was 88.50±1.29%. The secondary structure of the peptide released in vitro was determined to be nearly the same as the native peptide using Circular Dichroism (CD). The ability of BF-30 to inhibit the growth of Escherichia coli was also maintained. The cellular relative growth and hemolysis rates were 92.16±3.55% and 3.52±0.45% respectively.
Li, Hongli; Yuan, Mingwei; Yuan, Minglong
Lysozyme, as a model protein, was precipitated through the formation of protein-Zn complex to micronize for subsequent encapsulation within poly (lactic-co-glycolic acid) (PLGA) microspheres. Various parameters, including pH, type and concentration of added salts and protein concentration, were modified to optimize the yield of protein complexation and precipitation. The resulting protein particles (lysozyme-Zn complex as a freshly prepared suspension or a freeze-dried solid) were then loaded into PLGA (Resomer® 503H) microspheres, using a double emulsion technique and microspheres encapsulation efficiency and their sizes were determined. It was observed that salt type could significantly influence the magnitude of protein complexation. At the same conditions, zinc chloride was found to be more successful in producing pelletizable lysozyme. Generally, higher concentrations of protein solution led also to the higher yields of complexation and at the optimum conditions, the percentage of pelletizable lysozyme reached to 80%. Taking advantage of this procedure, a modified technique for preparation of protein-loaded PLGA microspheres was established, although it is also expected that this technique increases the protein drugs stabilization during the encapsulation process.
Nafissi Varcheh, Nastaran; Luginbuehl, Vera; Aboofazeli, Reza; Peter Merkle, Hans
An increasing number of drugs are needing improved formulations to optimize patient compliance because of their short half-lives in blood. Sustained-release formulations of drugs are often required for long-term efficacy, and microspheres are among the most popular ones. When drugs are encapsulated into microsphere formulations, different methods of preparation need to be used according to specific clinical requirements and the differing physicochemical characteristics of individual drugs. In this work, we developed a novel method for sustained-release drug delivery using a water-in-oil-in-hydrophilic oil-in-water (w/o/oh/w) emulsion to encapsulate a drug into poly(lactic-co-glycolic acid) (PLGA) microspheres. Different effects were achieved by varying the proportions and concentrations of hydrophilic oil and PLGA. Scanning electron and optical microscopic images showed the surfaces of the microspheres to be smooth and that their morphology was spherical. Microspheres prepared using the w/o/oh/w emulsion were able to load protein efficiently and had sustained-release properties. These results indicate that the above-mentioned method might be useful for developing sustained-release microsphere formulations in the future.
Hong, Xiaoyun; Wei, Liangming; Ma, Liuqing; Chen, Yinghui; Liu, Zhenguo; Yuan, Weien
We prepared monodisperse poly(lactide-co-glycolide) (PLGA) microspheres containing blue dextran (BLD)--a hydrophilic drug--by membrane emulsification technique. The effects of electrolyte addition to the w(2) phase and significance of the droplet size ratio between primary (w(1)/o) and secondary (w(1)/o/w(2)) emulsions during the preparation of these microspheres was examined. The droplet size ratio was evaluated from the effect of stirring rate of the homogenizer when preparing the primary emulsion. The drug loading efficiency of BLD in these microspheres increased with stirring rate. It increased to approximately 90% when 2.0% NaCl was added to the w(2) phase. Drug release from these microspheres was slower than that when they were prepared without electrolyte addition. Despite the very high efficiency drug release was gradual because BLD was distributed at the microspheres core. Relatively monodisperse hydrophilic-drug-containing PLGA microspheres with controlled drug loading efficiency and drug release behavior were prepared. PMID:20221788
Ito, Fuminori; Fujimori, Hiroyuki; Honnami, Hiroyuki; Kawakami, Hiroyoshi; Kanamura, Kiyoshi; Makino, Kimiko
Infection and epithelial downgrowth are two major problems with maxillofacial transcutaneous implants, and both are mainly due to lack of stable closure of soft tissues at transcutaneous sites. Fibroblasts have been shown to play a key role in the formation of biological seals. In this work, titanium (Ti) model surfaces were coated with mussel adhesive proteins (MAPs) utilizing its unique adhesion ability on diverse inorganic and organic surfaces in wet environments. Prepared basic fibroblast growth factor (bFGF)-poly(lactic-co-glycolic acid) (PLGA) microspheres can be easily synthesized and combined onto MAPs-coated Ti surfaces, due to the negative surface charges of microspheres in aqueous solution, which is in contrast to the positive charges of MAPs. Titanium model surfaces were divided into three groups. Group A: MAPs/bFGF-PLGA microspheres composite-coated Ti surfaces. Group B: MAPs-coated Ti surfaces. Group C: uncoated Ti surfaces. The effects of coated Ti surfaces on adhesion of fibroblasts, cytoskeletal organization, proliferation, and extracellular matrix (ECM)-related gene expressions were examined. The results revealed increased adhesion (P < 0.05), enhanced actin cytoskeletal organization, and up-regulated ECM-related gene expressions in groups A and B compared with group C. Increased proliferation of fibroblasts during five days of incubation was observed in group A compared with groups B and C (P < 0.05). Collectively, the results from this in vitro study demonstrated that MAPs/bFGF-PLGA microspheres composite-coated Ti surfaces had the ability to increase fibroblast functionality. In addition, MAPs/bFGF-PLGA microsphere composite-coated Ti surfaces should be studied further as a method of promoting formation of stable biological seals around transcutaneous sites. PMID:24739496
Wang, Zhongshan; Wu, Guofeng; Bai, Shizhu; Feng, Zhihong; Dong, Yan; Zhou, Jian; Qin, Haiyan; Zhao, Yimin
Hyaluronic acid (HA) was used as an internal phase additive to improve the loading efficiency of ofloxacin, a hydrophilic drug encapsulated by hydrophobic polylactic-co-glycolic acid (PLGA) materials, through a double emulsion (water-in-oil-in-water) solvent extraction/evaporation method. Results from laser distribution analysis show that polyelectrolyte additives have low impact on the average particle size and distribution of the microspheres. The negatively charged HA increases the drug loading efficiency as well as the amount of HA in microspheres. Burst release can be observed in the groups with the polyelectrolyte additives. The release rate decreases with the amount of HA inside the microspheres in all negatively charged polyelectrolyte-added microsphere groups. PMID:24211960
Wu, Gang; Chen, Long; Li, Hong; Wang, Ying-jun
We prepared monodisperse poly(lactide-co-glycolide) (PLGA) microspheres containing blue dextran (BLD)—a hydrophilic drug—by membrane emulsification technique. The\\u000a effects of electrolyte addition to the w2 phase and significance of the droplet size ratio between primary (w1\\/o) and secondary (w1\\/o\\/w2) emulsions during the preparation of these microspheres was examined. The droplet size ratio was evaluated from the effect\\u000a of stirring rate of the
Fuminori Ito; Hiroyuki Fujimori; Hiroyuki Honnami; Hiroyoshi Kawakami; Kiyoshi Kanamura; Kimiko Makino
The purpose of this research was to develop a topical microsphere delivery system in a thermosensitive 20% poloxamer 407 gel (Pluronic F127) to control release of KSL-W, a cationic antimicrobial decapeptide, for a period of 4–7 days for potential application in combat related injuries. KSL-W loaded microsphere formulations were prepared by a solvent extraction-evaporation method (water-oil-water), with poly (D,L-lactic-co-glycolic acid) (PLGA) (50?:?50, low-weight, and hydrophilic end) as the polymeric system. After optimization of the process, three formulations (A, B, and C) were prepared with different organic to water ratio of the primary emulsion while maintaining other components and manufacturing parameters constant. Formulations were characterized for surface morphology, porous nature, drug loading, in vitro drug release, and antimicrobial activity. Microspheres containing 20% peptide with porous surfaces and internal structure were prepared in satisfactory yields and in sizes varying from 25 to 50??m. Gels of 20% Pluronic F127, which were liquid at or below 24.6°C and formed transparent films at body temperature, were used as carriers for the microspheres. Rheological studies showed a gelation temperature of 24.6°C for the 20% Pluronic F127 gel alone. Gelation temperature and viscosity of formulations A, B, and C as a function of temperature were very close to those of the carrier. A Franz diffusion cell system was used to study the release of peptide from the microspheres suspended in both, phosphate-buffered saline (PBS) and a 20% Pluronic F127 gel. In vitro release of greater than 50% peptide was found in all formulations in both PBS and the gel, and in one formulation there was a release of 75% in both PBS and the gel. Fractions collected from the release process were also tested for bactericidal activity against Staphylococcus epidermidis using the broth microdilution method and found to provide effective antimicrobial activity to warrant consideration and testing in animal wound models for treating combat-related injuries.
Machado, H. A.; Abercrombie, J. J.; You, T.; DeLuca, P. P.; Leung, K. P.
This study aimed to demonstrate that microspheres, used as delivery vehicle of DNA-Hsp65/TDM [plasmid DNA encoding heat shock protein 65 (Hsp65) coencapsulated with trehalose dimycolate (TDM) into PLGA microspheres], are widely spread among several organs after intramuscular administration in BALB/c mice. In general, we showed that these particles were phagocytosed by antigen presenting cells, such as macrophages and dendritic cells. Besides, it was demonstrated herein that draining lymph node cells presented a significant increase in the number of cells expressing costimulatory molecules (CD80 and CD86) and MHC class II, and also that the administration of the DNA-Hsp65/TDM and vector/TDM formulations resulted in the up-regulation of CD80, CD86 and MHC class II expression when compared to control formulations (vector/TDM and empty). Regarding the intracellular trafficking we observed that following phagocytosis, the microspheres were not found in the late endosomes and/or lysosomes, until 15 days after internalization, and we suggest that these constructions were hydrolysed in early compartments. Overall, these data expand our knowledge on PLGA [poly (lactic-co-glycolic acid)] microspheres as gene carriers in vaccination strategies, as well as open perspectives for their potential use in clinical practice. PMID:17880727
Trombone, Ana Paula F; Silva, Celio L; Almeida, Luciana P; Rosada, Rogerio S; Lima, Karla M; Oliver, Constance; Jamur, Maria C; Coelho-Castelo, Arlete A M
Presently available marketed alum adsorbed hepatitis B vaccine used for prophylactic immunization, can effectively elicit humoral immunity but is poor inducer of cell-mediated immunity (CMI). Besides, conventional alum-adjuvant vaccines require multiple injections to achieve long-lasting protective immune responses. Therefore, as a result of insufficient immunization, infections are still the leading killer among diseases. The present investigation was therefore, aimed at developing "single-shot" HBsAg adsorbed microspheres of poly (DL)-lactide-co-glycolide (PLGA) (L/G 50:50 and 75:25) and their capability to stimulate the cell mediated immune response against hepatitis B surface antigen. These microspheres were characterized in vitro for their size, shape polydispersity index, percentage HBsAg adsorption efficiency and in vitro release profile. The immune-stimulating activities were also studied following subcutaneous injection of HBsAg adsorbed PLGA microspheres (single-dose on day 0) and compared with alum adsorbed vaccines (two-doses on 0 and 28 days) in Balb/c mice. Specific cell-mediated immune responses such as lymphocyte transformation assay (stimulation-index) including release of interferon-gamma (IFN-?), interleukin-2 (IL-2) and nitric-oxide were determined. Cellular responses in case of alum adsorb HBsAg vaccine was very low. These studies demonstrate the potential of cationic polymeric microspheres based vaccine in stimulating cell mediated immune response along with humoral response against hepatitis B. PMID:21291968
Saini, Vinay; Jain, Vikas; Sudheesh, M S; Jaganathan, K S; Murthy, P K; Kohli, D V
Potent immunoadjuvants are needed to elicit responses following mucosal delivery. PLGA (poly[D,L-lactic-co-glycolic acid]) nanospheres, Quillaja saponin (QS) and cross-linked dextran microspheres (CDM) as drug delivery and absorption enhancer adjuvants were evaluated. PLGA nanospheres were prepared by solvent evaporation method. Particulate characteristics of nanospheres were studied by optical and scanning electron microscopes and dynamic light scattering technique. The mean diameter of nanospheres encapsulated with TT and TT?+?QS determined as 425 and 390?nm. Loadings of TT and QS were 30?±?1.9% and 23?±?2.8%. Nanospheres encapsulated with TT or QS were intranasally administered to rabbits, three times in two-week intervals and the serum IgG and nasal lavage IgA titers were determined by ELISA. The serum IgG titer induced with (TT)(PLGA) nanospheres was higher than TT solution (P?0.001). IgG titers induced with (TT?+?QS)(PLGA) was higher than (TT)(PLGA) (P?0.0001). When (TT)(PLGA) and (TT?+?QS)(PLGA) nanospheres were mixed with CDM, higher IgG titers were induced (P?0.001). The highest mucosal sIgA titers were seen in animals immunized with (TT?+?QS)(PLGA)?+?CDM. Co-encapsulation of QS and TT in PLGA nanospheres increased sIgA titers. In conclusion, the highest immune responses were observed by concomitant use of three adjuvants. PMID:20082579
Mohaghegh, Maliheh; Tafaghodi, Mohsen
Despite the widespread role of transforming growth factor-?3 (TGF?3) in wound healing and tissue regeneration, its long-term controlled release has not been demonstrated. Here, we report microencapsulation of TGF?3 in poly-d-l-lactic-co-glycolic acid (PLGA) microspheres and determine its bioactivity. The release profiles of PLGA-encapsulated TGF?3 with 50:50 and 75:25 PLA:PGA ratios differed throughout the experimental period. To compare sterilization modalities of microspheres, bFGF was encapsulated in 50:50 PLGA microspheres and subjected to ethylene oxide (EO) gas, radiofrequency glow discharge (RFGD), or ultraviolet (UV) light. The release of bFGF was significantly attenuated by UV light, but not significantly altered by either EO or RFGD. To verify its bioactivity, TGF?3 (1.35 ng/mL) was control-released to the culture of human mesenchymal stem cells (hMSC) under induced osteogenic differentiation. Alkaline phosphatase staining intensity was markedly reduced 1 week after exposing hMSC-derived osteogenic cells to TGF?3. This was confirmed by lower alkaline phosphatase activity (2.25 ± 0.57 mU/mL/ng DNA) than controls (TGF?3-free) at 5.8 ± 0.9 mU/mL/ng DNA (p < 0.05). Control-released TGF?3 bioactivity was further confirmed by lack of significant differences in alkaline phosphatase upon direct addition of 1.35 ng/mL TGF?3 to cell culture (p > 0.05). These findings provide baseline data for potential uses of microencapsulated TGF?3 in wound healing and tissue-engineering applications.
MOIOLI, EDUARDO K.; HONG, LIU; GUARDADO, JESSE; CLARK, PAUL A.; MAO, JEREMY J.
Double-walled microspheres trapping gentamicin sulphate were prepared from poly( L-lactic acid) (PLLA) and poly( L-lactic-co-glycolic acid) (PLGA) as a delivery system for highly hydrophilic antibiotics. The surface and cross-section morphology of the microspheres were characterized by SEM and FTIR. The diameters of the microspheres were ranging from about 50 ?m to 700 ?m. A low initial burst was achieved. The encapsulation efficiency was more than 70% and the cumulative drug release was about 40% for 30 days. The results indicated that the double-walled microspheres were able to achieve higher encapsulation efficiency and lower initial burst for highly water-soluble drugs.
Tan, Hongxiang; Ye, Jiandong
The secondary structure of a staphylokinase variant (K35R, DGR) encapsulated in poly (lactic-co-glycolic acid) (PLGA) microspheres was quantitatively examined by Fourier transform infrared (FTIR) spectroscopy. Resolution enhancement technique and Fourier deconvolution were combined with band with curve-fitting procedures to quantitate the spectral information from the amide I bands. Nine component bands were found under the broad, nearly featureless amide I bands and assigned to alpha-helix, beta-sheet, turn and irregular (random) structures. The changes of bands at 1 651 and 1 623 cm(-1) after encapsulation were discussed. PMID:17020023
He, Jin-Tian; Wang, Gai-Zhen; Song, Hou-Yan
Acetylcholinesterase inhibitors (AChEIs), including Huperzine A (HupA), have been the mainstay of treatment for Alzheimer's disease (AD). However, AChEIs can cause gastrointestinal side effects, which has been related to the high Cmax and short tmax after oral administration. Clinical trials have verified that extended-release formulation with lower Cmax and prolonged tmax, such as rivastigmine patch, could perform a similar efficacy with significantly improved tolerability compared with the oral formulations. In this study, we developed an extended-release microspheres formulation of HupA (called as HAM) with poly(lactide-co-glycolide) (PLGA) as drug carrier. HAM has showed the loading rate as 1.35% (w/w) and yielded 42% with mean particle size at 72.6 ?m. In vitro and in vivo pharmacokinetics studies have showed that HAM produced a relatively smooth and continuous drug concentration in 14 days. Furthermore, in vivo pharmacokinetics data have demonstrated that the Cmax was lower and the tmax was considerably later in single intramuscular administration of HAM (1,000 ?g/kg) than the counterparts in single intragastric administration of HAT (75 ?g/kg/d). Meanwhile, HAM has performed a continuous inhibition to brain AChE activity in normal rats and improvement of memory deficit in A?1-40 i.c.v. infused AD rat model for 14 days. The results have suggested that HAM has performed good extended-release properties and good prolonged pharmacological efficacy in vivo in the 2-week period, and could exert a similar efficacy with significantly lowered gastrointestinal side effects as compared with oral formulation. PMID:23455202
Ye, Liang; Fu, Fenghua; Liu, Wanhui; Sun, Kaoxiang; Li, Youxin; He, Jie; Yu, Xin; Yu, Pengfei; Tian, Jingwei
A biocompatible moist system was developed for effective and complete wound healing. Optimized PLGA microspheres of gentamicin (GM) and serratiopeptidase (STP) were incorporated into PVA-gelatin slurry and casted into films to prepare multiphase hydrogel. The prepared system was characterized by in vitro and in vivo studies. Results revealed the uniform dispersion of microspheres in three-dimensional matrix of the hydrogel. The in vitro release data showed a typical biphasic release pattern. All parameters such as wound contraction, tensile strength, histopathological and biochemical parameters were observed significant (p 0.05) in comparison to the control group. Results suggested an accelerated re-epithelialization with minimum disturbance of wound bed. PMID:22540900
Singh, Deependra; Singh, Manju Rawat
The aim of this work was to produce insulin-loaded microspheres allowing the preservation of peptide stability during both particle processing and insulin release. Our strategy was to combine the concepts of using surfactants to improve insulin stability while optimising overall microsphere characteristics such as size, morphology, peptide loading and release. Bovine insulin was encapsulated within poly(lactide-co-glycolide) (PLGA 50:50, Resomer RG504H)
G. De Rosa; R. Iommelli; M. I. La Rotonda; A. Miro; F. Quaglia
The purpose of this research effort was to evaluate in vivo a newly developed dexamethasone/PLGA microsphere system designed to suppress the inflammatory tissue response to an implanted device, in this case a biosensor. The microspheres were prepared using an oil/water (O/W) emulsion technique. The microsphere system was composed of drug-loaded microspheres (including newly formulated and predegraded microspheres) and free dexamethasone. The combination of the drug and drug-loaded microspheres provided burst release of dexamethasone followed by continuous release from days 2-14. Continuous release to at least 30 days was achieved by mixing predegraded and newly formulated microspheres. The ability of our mixed microsphere system to control tissue reactions to an implant then was tested in vivo using cotton thread sutures to induce inflammation subcutaneously in Sprague-Dawley rats. Two different in vivo studies were performed, the first to find the dosage level of dexamethasone that effectively would suppress the acute inflammatory reaction and the second to show how effective the dexamethasone delivered by PLGA microspheres was in suppressing chronic inflammatory response to an implant. The first in vivo study showed that 0.1 to 0.8 mg of dexamethasone at the site minimized the acute inflammatory reaction. The second in vivo study showed that our mixed microsphere system suppressed the inflammatory response to an implanted suture for at least 1 month. This study has proven the viability of microsphere delivery of an anti-inflammatory to control the inflammatory reaction at an implant site. PMID:12007197
Hickey, T; Kreutzer, D; Burgess, D J; Moussy, F
This study describes the influence of preparation temperature on the various characteristics and release profiles of poly(DL-lactide-co-glycolide) (PLGA) microspheres. The bovine serum albumin (BSA)-loaded microspheres were prepared using the water-in-oil-in-water (w/o/w) technique with poly(vinyl alcohol) as surfactant in the external aqueous phase. We have varied the preparation temperature to observe its effect on microsphere characteristics such as the microsphere shrinking rate during formation, particle size, density, surface and internal morphology, BSA encapsulation efficiency, BSA initial release, microsphere degradation and BSA in vitro release behaviour. During fabrication, a low preparation temperature of 5 degrees C gives the fastest initial but the slowest overall shrinking rate. Microspheres formed at high temperatures of 38 degrees C and 42 degrees C on the other hand have the lowest initial yet the highest overall shrinking rate. Subsequently, microsphere mean size increases and the particle size distribution widens with increase in the preparation temperature. Although all the microspheres have a porous surface as well as internal structure, microspheres fabricated at high temperatures have a uniform internal pore distribution and a very thin dense skin layer, while microspheres fabricated at lower temperatures have a thicker but porous skin layer and bigger pores in the middle of the sphere. Microspheres formed at 33 degrees C are found to give the highest initial burst release. In terms of in vitro release, microspheres fabricated at low temperatures (5 degrees C, 15 degrees C and 22 degrees C) exhibit similar, steady rates. Microspheres formed at higher temperatures however give very low release rates after their initial release. The results obtained suggest that preparation temperature significantly affects microsphere formation, resulting in their structural and protein release profile differences. These differences ultimately work together to affect the initial release and overall release patterns of the microspheres. PMID:11018548
Yang, Y Y; Chia, H H; Chung, T S
Calcium phosphate cement (CPC) is a highly promising bone substitute and an excellent carrier for delivering growth factors. Yet, the lack of macro-porosity and osteoinductive ability, limit its use. This study is aimed at developing a novel biodegradable biomaterial for bone repair with both highly osteoconductive and osteoinductive properties. RhBMP-2 loaded PLGA microspheres were incorporated into rhBMP-2/CPC for macropores for bone ingrowth. The compressive strength, crystallinity, microscopic structure, and bioactivity of the composites were investigated. The results showed that with the incorporation of rhBMP-2 loaded PLGA microspheres, the compressive strength was decreased from (29.48+/-6.42) MPa to (8.26+/-3.58) MPa. X-ray diffraction revealed that the crystallinity pattern of HA formed by CPC had no significant change. Inside the composite, the microspheres distributed homogeneously and contacted intimately with the HA matrix, as observed by scanning electron microscopy (SEM). When the PLGA microspheres dissolved after having been emerged in PBS for 56 days, macropores were created within the CPC. The rhBMP-2/PLGA/CPC composite, showing a 4.9% initial release of rhBMP-2 in 24 h, followed by a prolonged release for 28 days, should have a greater amount of rhBMP-2 released compared to the CPC delivery system. When rabbit marrow stromal cells were cocultured with the composite, the alkaline phosphatase (ALP) and osteocalcin (OC) showed a dose response to the rhBMP-2 released from the composite, indicating that the activity of rhBMP-2 was retained. This study shows that the new composite reveals more rhBMP-2 release and osteogenic activity. This novel BMP/PLGA/CPC composite could be a promising synthetic bone graft in craniofacial and orthopedic repairs. PMID:17701313
Fei, Zhengqi; Hu, Yunyu; Wu, Daocheng; Wu, Hong; Lu, Rong; Bai, Jianping; Song, Hongxun
Using poly(lactide-co-glycolide) (PLGA) particles for drug encapsulation and delivery has recently gained considerable popularity for a number of reasons. An advantage in one sense, but a drawback of PLGA use in another, is that drug delivery systems made of this material can provide a wide range of dissolution profiles, due to their internal structure and properties related to particles' manufacture. The advantages of enriching particulate drug design experimentation with computer models, are evident with simulations used to predict and optimize design, as well as indicate choice of best manufacturing parameters. In the present work, we seek to understand the phenomena observed for PLGA micro- and nanospheres, through Cellular Automata (CA) agent-based Monte Carlo (MC) models. Systems are studied both over large temporal scales (capturing slow erosion of PLGA) and for various spatial configurations (capturing initial as well as dynamic morphology). The major strength of this multi-agent approach is to observe dissolution directly, by monitoring the emergent behaviour: the dissolution profile manifested, as a sphere erodes. Different problematic aspects of the modelling process are discussed in details in this paper. The models were tested on experimental data from literature, demonstrating very good performance. Quantitative discussion is provided throughout the text in order to make a demonstration of the use in practice of the proposed model. PMID:18436414
Barat, Ana; Crane, Martin; Ruskin, Heather J
Purpose To investigate the in vitro release of octreotide acetate, a somatostatin agonist, from microspheres based on a hydrophilic polyester, poly(D,L-lactide-co-hydroxymethyl\\u000a glycolide) (PLHMGA).\\u000a \\u000a \\u000a \\u000a \\u000a Methods Spherical and non-porous octreotide-loaded PLHMGA microspheres (12 to 16 ?m) and loading efficiency of 60–70% were prepared\\u000a by a solvent evaporation. Octreotide release profiles were compared with commercial PLGA formulation (Sandostatin LAR®); possible peptide modification with lactic, glycolic and
Amir H. Ghassemi; Mies J. van Steenbergen; Arjan Barendregt; Herre Talsma; Robbert J. Kok; Cornelus F. van Nostrum; Daan J. A. Crommelin; Wim E. Hennink
Purpose The objective of this study was to manufacture paclitaxel (PTX) loaded polymeric microspheres, that were surface conjugated\\u000a with antibodies to vascular endothelial growth factor receptor 2 (anti-VEGFR2), for systemic targeting to angiogenic sites\\u000a in prostate tumors.\\u000a \\u000a \\u000a \\u000a Methods Microspheres were manufactured in the 1–3 ?m size range from poly (l-lactic acid) (PLLA) or poly (lactide-co-glycolide) (PLGA)\\u000a by a modified solvent evaporation method using
Jianjun Lu; John K. Jackson; Martin E. Gleave; Helen M. Burt
The aim of this work was to produce insulin-loaded microspheres allowing the preservation of peptide stability during both particle processing and insulin release. Our strategy was to combine the concepts of using surfactants to improve insulin stability while optimising overall microsphere characteristics such as size, morphology, peptide loading and release. Bovine insulin was encapsulated within poly(lactide-co-glycolide) (PLGA 50:50, Resomer RG504H) microspheres by the multiple emulsion-solvent evaporation technique. Microspheres were prepared by adding to the primary emulsion three non-ionic surfactants, poloxamer 188, polysorbate 20 and sorbitan monooleate 80, at different concentrations (1.5 and 3. 0% w/v). The presence of surfactants was found to decrease the mean diameter and to affect the morphology of the microspheres. Insulin encapsulation efficiency was reduced in the presence of surfactants and especially for sorbitan monooleate 80, in a concentration-dependent mode. The influence of the surfactants on the interactions between insulin and PLGA together with the primary emulsion stability were found to be the major determinants of insulin encapsulation. The release of insulin from microspheres was biphasic, showing an initial burst effect followed by a near zero-order release for all the batches prepared. The initial burst was related to the presence of insulin molecules located onto or near to the microsphere surface. In the presence of surfactants, a faster insulin release with respect to microspheres encapsulating insulin alone was observed. Insulin stability within microspheres after processing, storage and release was evaluated by reversed phase- and size-exclusion-HPLC. The analysis of microsphere content after processing and 6 months of storage showed that insulin did not undergo any chemical modification within microspheres. On the contrary, during the period of sustained release insulin was transformed in a high-molecular weight product, the amount of which was related to the surfactant used. In conclusion, polysorbate 20 at 3% w/v concentration was the most effective in giving regular shaped particles with both good insulin loading and slow release, and limiting insulin modification within microspheres. PMID:11064135
Rosa, G D; Iommelli, R; La Rotonda, M I; Miro, A; Quaglia, F
Poly(lactic-co-glycolic acid) microspheres loaded with imatinib mesylate has been developed as a new therapeutic strategy to prevent craniopharyngioma recurrence. Microspheres composed of different lactic/glycolic acid ratios, molecular weights and drug compositions were synthesized and loaded with imatinib mesylate by modified double-emulsion/solvent evaporation technique and subsequently characterized by particle-size distribution, scanning electron microscopy, encapsulation efficiency and in vitro drug release. Inhibitory potential of imatinib containing microspheres on tumor neovascularization was investigated on craniopharyngioma tumor samples by rat cornea angiogenesis assay. Results showed that microspheres in different LA:GA ratios [LA:GA 50:50 (G50), 75:25 (G25), 85:15 (G15)] considerably reduced neovascularization induced by recurrent tumor samples in an in vivo angiogenesis assay (P < 0.01). Our data indicate that local delivery of imatinib mesylate to the post-surgical tumoral cavity using biodegradable microspheres may be a promising biologically selective approach to prevent the recurrence of craniopharyngiomas, via inhibition of neovascularization. PMID:23053813
Karal-Yilmaz, Oksan; Ozkan, Abdulkadir; Akgun, Emel; Kukut, Manolya; Baysal, Kemal; Avsar, Timucin; Kilic, Turker
We report on the development of a modified solvent removal method for the encapsulation of hydrophilic drugs within poly(lactic-co-glycolic acid) (PLGA). Using a water/oil/oil double emulsion, hydrophilic doxycycline was encapsulated within PLGA spheres with particle diameters ranging from approximately 600?nm to 19?µm. Encapsulation efficiencies of up to 74% were achieved for theoretical loadings from 1% to 10% (w/w), with biphasic release over 85 days with nearly complete release at the end of this time course. About 1% salt was added to the formulations to examine its effects on doxycycline release; salt modulated release only by increasing the magnitude of initial release without altering kinetics. Fourier transform infrared spectroscopy indicated no characteristic differences between doxycycline-loaded and control spheres. Differential scanning calorimetry and X-ray diffraction suggest that there may be a molecular dispersion of the doxycycline within the spheres and the doxycycline may be in an amorphous state, which could explain the slow, prolonged release of the drug. PMID:22263669
Patel, Roshni S; Cho, Daniel Y; Tian, Cheng; Chang, Amy; Estrellas, Kenneth M; Lavin, Danya; Furtado, Stacia; Mathiowitz, Edith
Methylprednisolone (MP) released by poly(d,l-lactide-co-glycolide) microspheres (PLGA MS) was monitored in plasma after intra-articular (i.a.) administration into rat joint. A validated LC-ESI-MS/MS method was used to quantify the plasmatic concentrations of MP. The calculated pharmacokinetic parameters were compared to those obtained after the i.a. administration of a commercially available suspension of MP acetate (MPA). Different pharmacokinetic profiles were observed in the two formulations, and a lower peak level (C(max) = 13.7 ± 4.3 ng · mL(-1)) and AUC(0-72 h) (198 ± 45 ng · mL(-1) · h) were observed for MP-PLGA MS than MPA (C(max) = 18.4 ± 2.7 ng · mL(-1)) and AUC(0-72 h) (943 ± 249 ng · mL(-1) · h). The administration of MP-PLGA MS resulted in a rapid increase in the MP concentration at 30 min, with a t(max) at 0.8 ± 0.3 h. Instead, for the MPA suspension the t(max) was 32.0 ± 13.9 h. These differences were indirectly confirmed by the evaluation of the extra-articular effects, namely, carrageenan-induced paw edema, since MP-PLGA MS showed a lower anti-inflammatory activity than MPA. PMID:21850665
Panusa, Alessia; Selmin, Francesca; Rossoni, Giuseppe; Carini, Marina; Cilurzo, Francesco; Aldini, Giancarlo
We evaluated the influence of ligand grafting on the rate and intensity of uptake of poly(d,l-lactide-co-glycolide) microparticles by alveolar macrophages. Microspheres with a mean diameter of 2.5?m were obtained by spray drying. Three ligands (WGA, an RGD containing peptide and mannose-PEG3-NH2) and a cationic molecule (PLL) were covalently grafted on the particle surface using the carbodiimide method. Their grafting efficiency
Nolwenn Brandhonneur; François Chevanne; Véronique Vié; Benoît Frisch; Roselyne Primault; Marie-Frédérique Le Potier; Pascal Le Corre
The aim of the present study was to investigate the morphology and function of a drug eluting metallic porous surface produced by the immobilization of poly lactide-co-glycolide microspheres bearing dexamethasone onto plasma electrolytically oxidized Ti–6Al–7Nb medical alloy. Spheres of 20 ?m diameter were produced by an oil-in-water emulsion/solvent evaporation method and thermally immobilized onto titanium discs. The scanning electron microscopy investigations revealed that the size distribution and morphology of the attached spheres had not changed significantly. The drug release profiles following degradation in phosphate buffered saline for 1000 h showed that, upon immobilisation, the spheres maintained a sustained release, with a triphasic profile similar to the non-attached system. The only significant change was an increased release rate during the first 100 h. This difference was attributed to the effect of thermal attachment of the spheres to the surface.
Fratila-Apachitei, L. E.; Necula, B. S.; Apachitei, I.; Witkamp, G. J.; Duszczyk, J.
Abstract Developing a highly effective and lung-targeted local drug delivery carrier with low irritancy may be critical for improving treatment of lung cancer. Using soluble excipients as microspheres (MS) matrix, respirable MS embedding chitosan-coated poly(d,l-lactide-co-glycolide) nanoparticles (CNP-MS) for 2-methoxyestradiol (2-ME) were designed, which could avoid macrophage phagocytosis to achieve the targeted delivery of these drugs. 2-ME CNP-MS were prepared by spray-drying and characterized by morphology, redispersability, fine particle fraction (FPF) and drug release. Cytotoxicity, and lung deposition and histological examination were investigated. Results showed that 2-ME CNP-MS were spherical with a rough surfaces, exhibiting good redispersability, a high respirable fraction and sustained release characteristics. CNP-MS markedly enhanced the cytotoxicity of 2-ME by approximately 8.8-fold and 3.65-fold on SPC-A1 cells compared to solution and NP, respectively. After pulmonary administration, 2-ME CNP were distributed in rat lungs and for 10?mg of 2-ME CNP-MS, haematoxylin and eosin staining showed no obvious difference compared to the untreated control group. Therefore, CNP-MS revealed suitable features for local lung delivery and significantly enhanced cytotoxicity of 2-ME without obvious inflammation in lungs of rats, suggesting that 2-ME CNP-MS have great potential as an inhalation agent for targeted, highly effective and safe treatment of lung cancer. PMID:24417740
Guo, XinHong; Zhang, XinXin; Ye, Ling; Zhang, Ying; Ding, Rui; Hao, YongWei; Zhao, YaLin; Zhang, ZhenZhong; Zhang, Yun
Bony defects have been three-dimensionally (3D) created in many clinical circumstances; however, many defects cannot be reconstructed because most of the current bony substitutes cannot provide the necessary exact 3D structure. Therefore, to overcome this limitation, a 3D scaffold with embedded growth factor-delivering microspheres was developed by solid free-form fabrication (SFF) technology using computer-aided design/manufacturing (CAD/CAM). In this study, BMP-2-loaded poly(DL-lactic-co-glycolic acid) (PLGA) microspheres were incorporated into a 3D scaffold that was fabricated using a microstereolithography (MSTL) system with a suspension of microspheres and a poly(propylene fumarate) (PPF)/diethyl fumarate (DEF) photopolymer. By measuring release profiles in vitro, we verified that the fabricated microsphere-containing 3D scaffold could gradually release growth factor. The effects of BMP-2 were also assessed in vitro by observing cell differentiation using MC3T3-E1 pre-osteoblasts. Finally, we confirmed that SFF scaffolds created by MSTL were superior to traditional scaffolds produced using a particulate leaching/gas foaming method. In addition, based on in vivo tests, the scaffolds that released BMP-2 promoted bone formation. Based on these results, we concluded that our 3D scaffold might be a useful tool for enhancing reconstruction quality in many complex bony defects that should be reconstructed using a customized 3D scaffold. PMID:20933279
Lee, Jin Woo; Kang, Kyung Shin; Lee, Seung Ho; Kim, Jun-Young; Lee, Bu-Kyu; Cho, Dong-Woo
Diabetic foot ulcers (DFUs) represent a major clinical challenge in the ageing population. To address this problem, rhEGF-loaded Poly-Lactic-co-Glycolic-Acid (PLGA)-Alginate microspheres (MS) were prepared by a modified w/o/w-double-emulsion/solvent evaporation method. Different formulations were evaluated with the aim of optimising MSs properties by adding NaCl to the surfactant solution and/or the solvent removal phase and adding alginate as a second polymer. The characterisation of the developed MS showed that alginate incorporation increased the encapsulation efficiency (EE) and NaCl besides increasing the EE also became the particle surface smooth and regular. Once the MS were optimised, the target loading of rhEGF was increased to 1% (PLGA-Alginate MS), and particles were sterilised by gamma radiation to provide the correct dosage for in vivo studies. In vitro cell culture assays demonstrated that neither the microencapsulation nor the sterilisation process affected rhEGF bioactivity or rhEGF wound contraction. Finally, the MS were evaluated in vivo for treatment of the full-thickness wound model in diabetised Wistar rats. rhEGF MS treated animals showed a statistically significant decrease of the wound area by days 7 and 11, a complete re-epithelisation by day 11 and an earlier resolution of the inflammatory process. Overall, these findings demonstrate the promising potential of rhEGF-loaded MS (PLGA-Alginate MS) to promote faster and more effective wound healing, and suggest its possible application in DFU treatment. PMID:23872142
Gainza, Garazi; Aguirre, José Javier; Pedraz, José Luis; Hernández, Rosa María; Igartua, Manoli
The purpose of this study was to investigate in vitro release property of mono-PEGylated growth hormone-releasing peptide-6 (GHRP-6) microspheres. The microspheres encapsulating native GHRP-6 or mono-PEG-GHRP-6 were prepared using the single oil-in-water emulsion solvent evaporation method. In vitro release study was performed in 0.1 M phosphate buffer, pH 7.4, containing 0.02% Tween 80 and sodium azide at 37 or 55
Eun Ji Park; Dong Hee Na; Kang Choon Lee
Engineering strategies to control vascular endothelial growth factor stability and levels in a collagen matrix for angiogenesis: the role of heparin sodium salt and the PLGA-based microsphere approach.
New vessel formation is the result of the complex orchestration of various elements, such as cells, signalling molecules and extracellular matrix (ECM). In order to establish the suitable conditions for an effective cell response, the influence of vascular endothelial growth factor (VEGF) complexation with heparin sodium salt (Hp) on its pro-angiogenic activity has been evaluated by an in vitro capillary-like tube formation assay. VEGF with or without Hp was embedded into collagen gels, and the activated matrices were characterized in terms of VEGF activity and release kinetics. Taking into account the crucial role of Hp in VEGF stability and activity, VEGF/Hp complex was then encapsulated into microspheres based on poly(lactide-co-glycolide) (PLGA), and microsphere properties, VEGF/Hp release kinetics and VEGF in vitro activity over time were evaluated. Integrated microsphere/collagen matrices were developed in order to provide a continuous release of active VEGF/Hp inside the matrix but also a VEGF gradient at the boundary, which is an essential condition for endothelial cell attraction and scaffold invasion. The results confirmed a strong influence of Hp on VEGF configuration and, consequently, on its activity, while the encapsulation of VEGF/Hp complex in PLGA-microspheres guaranteed a sustained release of active VEGF for more than 30days. This paper confirms the importance of VEGF stability and signal presentation to cells for an effective proangiogenic activity and highlights how the combination of two stabilizing approaches, namely VEGF/Hp complexation and entrapment within PLGA-based microspheres, may be a very effective strategy to achieve this goal. PMID:23523534
d'Angelo, Ivana; Oliviero, Olimpia; Ungaro, Francesca; Quaglia, Fabiana; Netti, Paolo Antonio
This study tests the hypothesis that large porous poly (lactic-co-glycolic acid) (PLGA) microparticles modified with polyethyleneimine (PEI) are viable carriers for pulmonary delivery of prostaglandin E(1) (PGE(1)) used in the treatment of pulmonary arterial hypertension (PAH), a pulmonary vascular disorder. The particles were prepared by a double-emulsion solvent evaporation method with PEI-25 kDa in the internal aqueous phase to produce an osmotic pressure gradient. Polyvinyl alcohol (PVA) was used for external coating of the particles. The particles were examined for morphology, size, aerodynamic diameter, surface area, pore volume and in-vitro release profiles. Particles with optimal properties for inhalation were tested for in-vivo pulmonary absorption, metabolic stability in rat lung homogenates, and acute toxicity in rat bronchoalveolar lavage fluid and respiratory epithelial cells, Calu-3. The micromeritic data indicated that the PEI-modified particles of PGE(1) are optimal for inhalation. Incorporation of PEI in the formulations resulted in an increased entrapment efficiency - 83.26 ± 3.04% for particles with 1% PVA and 95.48 ± 0.46% for particles with 2% PVA. The amount of cumulative drug released into the simulated interstitial lung fluid was between 50.8 ± 0.76% and 55.36 ± 0.06%. A remarkable extension of the circulation half-life up to 6.0-6.5h was observed when the formulations were administered via the lungs. The metabolic stability and toxicity studies showed that the optimized formulations were stable at physiological conditions and relatively safe to the lungs and respiratory epithelium. Overall, this study demonstrates that large porous inhalable polymeric microparticles can be a feasible option for non-invasive and controlled release of PGE(1) for treatment of PAH. PMID:21530623
Gupta, Vivek; Ahsan, Fakhrul
Vital information on a person's physical condition can be obtained by identifying and counting the population of T-cells and B-cells, lymphocytes of the same shape and size that help the immune system protect the body from the invasion of disease. The late Dr. Alan Rembaum developed a method for identifying the cells. The method involved tagging the T-cells and B-cells with microspheres of different fluorescent color. Microspheres, which have fluorescent dye embedded in them, are chemically treated so that they can link with antibodies. With the help of a complex antibody/antigen reaction, the microspheres bind themselves to specific 'targets,' in this case the T-cells or B-cells. Each group of cells can then be analyzed by a photoelectronic instrument at different wavelengths emitted by the fluorescent dyes. Same concept was applied to the separation of cancer cells from normal cells. Microspheres were also used to conduct many other research projects. Under a patent license Magsphere, Inc. is producing a wide spectrum of microspheres on a large scale and selling them worldwide for various applications.
This study tests the feasibility of large porous particles as long-acting carriers for pulmonary delivery of low molecular weight heparin (LMWH). Microspheres were prepared with a biodegradable polymer, poly(lactic-co-glycolic acid) (PLGA), by a double-emulsion–solvent-evaporation technique. The drug entrapment efficiencies of the microspheres were increased by modifying them with three different additives—polyethyleneimine (PEI), Span 60 and stearylamine. The resulting microspheres were evaluated for morphology, size, zeta potential, density, in vitro drug-release properties, cytotoxicity, and for pulmonary absorption in vivo. Scanning electron microscopic examination suggests that the porosity of the particles increased with the increase in aqueous volume fraction. The amount of aqueous volume fraction and the type of core-modifying agent added to the aqueous interior had varying degrees of effect on the size, density and aerodynamic diameter of the particles. When PEI was incorporated in the internal aqueous phase, the entrapment efficiency was increased from 16.22±1.32% to 54.82±2.79%. The amount of drug released in the initial burst phase and the release-rate constant for the core-modified microspheres were greater than those for the plain microspheres. After pulmonary administration, the half-life of the drug from the PEI- and stearylamine-modified microspheres was increased by 5- to 6-fold compared to the drug entrapped in plain microspheres. The viability of Calu-3 cells was not adversely affected when incubated with the microspheres. Overall, the data presented here suggest that the newly developed porous microspheres of LMWH have the potential to be used in a form deliverable by dry-powder inhaler as an alternative to multiple parenteral administrations of LMWH.
Rawat, Amit; Majumder, Quamrul H.; Ahsan, Fakhrul
Bony defects have been three-dimensionally (3D) created in many clinical circumstances; however, many defects cannot be reconstructed because most of the current bony substitutes cannot provide the necessary exact 3D structure. Therefore, to overcome this limitation, a 3D scaffold with embedded growth factor-delivering microspheres was developed by solid free-form fabrication (SFF) technology using computer-aided design\\/manufacturing (CAD\\/CAM). In this study, BMP-2-loaded
Jin Woo Lee; Kyung Shin Kang; Seung Ho Lee; Jun-Young Kim; Bu-Kyu Lee; Dong-Woo Cho
Controlled-release formulations based on poly(lactic) (PLA) and poly(lactic\\/glycolic) acid (PLGA) microspheres containing tetanus vaccine were designed. The polymers forming the microspheres were L-PLA of different molecular weights and DL-PLGA, 50:50. These microspheres were prepared by two solvent elimination procedures, both using a double emulsion, and were characterized for size, morphology, and toxoid release kinetics. The influence of formulation variables such
Maria J. Alonso; Smadar Cohen; Tae G. Park; Rajesh K. Gupta; George R. Siber; Robert Langer
National rates of unintended births are a major public health concern. The availability of highly effective long-acting contraceptives has prompted some public officials to promote the coercive use of these methods to reduce such problems as intergenerational poverty and child abuse. Broad-brush public policies that require long-term contraceptive use are unethical. However, persuasion to use these methods can be appropriate. One place for exerting ethically justified influence is in family planning counseling. The dominant nondirective counseling model, which excludes the possibility of vigorous persuasion, is overly rigid. Family planning professionals should develop practice protocols that permit and guide the exercise of directive counseling to use long-acting contraception.
Moskowitz, E; Jennings, B
Antipsychotic drugs have been used to treat patients with schizophrenia and other psychotic disorders. Long-acting injectable antipsychotic drugs are useful for improving medication compliance with a better therapeutic option to treat patients who lack insight or adhere poorly to oral medication. Several long-acting injectable antipsychotic drugs are clinically available. Haloperidol decanoate and fluphenazine decanoate are first-generation depot drugs, but the use of these medicines has declined since the advent of second-generation depot agents, such as long-acting risperidone, paliperidone palmitate, and olanzapine pamoate. The second-generation depot drugs are better tolerated and have fewer adverse neurological side effects. Long-acting injectable risperidone, the first depot formulation of an atypical antipsychotic drug, was prepared by encapsulating risperidone into biodegradable microspheres. Paliperidone palmitate is an aqueous suspension of nanocrystal molecules, and olanzapine pamoate is a microcrystalline salt of olanzapine and pamoic acid suspended in aqueous solution. This review summarizes the characteristics and recent research of formulations of each long-acting injectable antipsychotic drug. PMID:23543652
Park, Eun Ji; Amatya, Sarmila; Kim, Myung Sun; Park, Jong Hoon; Seol, Eunyoung; Lee, Heeyong; Shin, Young-Hee; Na, Dong Hee
Biodegradable polymer/ceramic composite scaffold could overcome limitations of biodegradable polymers or ceramics for bone regeneration. Injectable scaffold has raised great interest for bone regeneration in vivo, since it allows one for easy filling of irregularly shaped bone defects and implantation of osteogenic cells through minimally invasive surgical procedures The purpose of this study was to determine whether apatite-coated poly(lactic-co-glycolic acid) (PLGA) microspheres could be used as an injectable scaffold to regenerate bone in vivo. Apatite-coated PLGA microspheres were fabricated by incubating PLGA microspheres in simulated body fluid. The apatite that coated the PLGA microsphere surfaces was similar to apatite in natural bone, as demonstrated by scanning electron microscopy, X-ray diffraction spectra, energy-dispersive spectroscopy, and Fourier transformed-infrared spectroscopy analyses. Rat osteoblasts were mixed with apatite-coated PLGA microspheres and injected immediately into subcutaneous sites of athymic mice. Osteoblast transplantation with plain PLGA microspheres served as a control. Histological analysis of the implants at 6 weeks with hematoxylin and eosin staining, Masson's trichrome staining, and von Kossa staining revealed much better regeneration of bone in the apatite-coated PLGA microsphere group than the plain PLGA microsphere group. The new bone formation area and the calcium content of the implants were significantly higher in the apatite-coated PLGA microsphere group than in the plain PLGA microsphere group. This study demonstrates the feasibility of using apatite-coated PLGA microspheres as an injectable scaffold for in vivo bone tissue engineering. This scaffold may be useful for bone regeneration through minimally invasive surgical procedures in orthopedic applications. PMID:17896763
Kang, Sun-Woong; Yang, Hee Seok; Seo, Sang-Woo; Han, Dong Keun; Kim, Byung-Soo
In this study, ionic immobilization of dexamethasone (DEX)-loaded poly(lactic-co-glycolic acid) (PLGA) microspheres was performed on the hydroxyapatite (HAp) scaffold surfaces. It was hypothesized that in vivo bone regeneration could be enhanced with HAp scaffolds containing DEX-loaded PLGA microspheres compared to the use of HAp scaffolds alone. In vitro drug release from the encapsulated microspheres was measured prior to the implantation
Jun Sik Son; Mark Appleford; Joo L. Ong; Joseph C. Wenke; Jong Min Kim; Seok Hwa Choi; Daniel S. Oh
In this study a novel kind of porous poly(l-glutamic acid) (PLGA)/chitosan polyelectrolyte complex (PEC) microsphere was developed through electrostatic interaction between PLGA and chitosan. By adjusting the formula parameters chitosan microspheres with an average pore size of 47.5 ± 5.4 ?m were first developed at a concentration of 2 wt.% and freeze temperature of -20 °C. For self-assembly of the PEC microspheres porous chitosan microspheres were then incubated in PLGA solution at 37 °C. Due to electrostatic interaction a large amount of PLGA (110.3 ?g mg(-1)) was homogeneously absorbed within the chitosan microspheres. The developed PEC microspheres retained their original size, pore diameters and interconnected porous structure. Fourier transform infrared spectroscopy, thermal gravimetric analysis and zeta potential analysis revealed that the PEC microspheres were successfully prepared through electrostatic interaction. Compared with microspheres fabricated from chitosan, the porous PEC microspheres were shown to efficiently promote chondrocyte attachment and proliferation. After injection subcutaneously for 8 weeks PEC microspheres loaded with chondrocytes were found to produce significant more cartilaginous matrix than chitosan microspheres. These results indicate that these novel fabricated porous PLGA/chitosan PEC microspheres could be used as injectable cell carriers for cartilage tissue engineering. PMID:24025620
Fang, Jianjun; Zhang, Yun; Yan, Shifeng; Liu, Zhiwen; He, Shiming; Cui, Lei; Yin, Jingbo
In this study, ionic immobilization of dexamethasone (DEX)-loaded poly(lactic-co-glycolic acid) (PLGA) microspheres was performed on the hydroxyapatite (HAp) scaffold surfaces. It was hypothesized that in vivo bone regeneration could be enhanced with HAp scaffolds containing DEX-loaded PLGA microspheres compared to the use of HAp scaffolds alone. In vitro drug release from the encapsulated microspheres was measured prior to the implantation in the femur defects of beagle dogs. It was observed that porous, interconnected HAp scaffolds as well as DEX-loaded PLGA microspheres were successfully fabricated in this study. Additionally, PEI was successfully coated on PLGA microsphere surfaces, resulting in a net positive-charged surface. With such modification of the PLGA microsphere surfaces, DEX-loaded PLGA microspheres were immobilized on the negatively charged HAp scaffold surfaces. Release profile of DEX over a 4week immersion study indicated an initial burst release followed by a sustained release. In vivo evaluation of the defects filled with DEX-loaded HAp scaffolds indicated enhanced volume and quality of new bone formation when compared to defects that were either unfilled or filled with HAp scaffolds alone. This innovative platform for bioactive molecule delivery more potently induced osteogenesis in vivo, which may be exploited in implantable bone graft substitutes for stem cell therapy or improved in vivo performance. It was thus concluded that various bioactive molecules for bone regeneration might be efficiently incorporated with calcium phosphate-based bioceramics using biodegradable polymeric microspheres. PMID:21420453
Son, Jun Sik; Appleford, Mark; Ong, Joo L; Wenke, Joseph C; Kim, Jong Min; Choi, Seok Hwa; Oh, Daniel S
Despite their widespread use, long acting antipsychotics, are often regarded with prejudice, due to fears of punishment, control and insufficient evolution towards psychosocial development of psychotic patients raised by their improper utilization. Another major shortcoming of long-acting antipsychotics is the impossibility of altering their dosage if side-effects appear. However, long-acting antipsychotics proved effective in schizophrenia and other severe psychotic disorders as a consequence of stable dose administration, leading to reduction of relapses and increased treatment adherence. Therapeutic opportunities have also risen after introduction of newer long acting second generation antipsychotics in recent years. Newer long-acting antipsychotics were developed to tackle the need for pharmacotherapy enhancing adherence in integrated rehabilitation programmes. This review is an outline of the development and introduction of older and newer long-acting antipsychotics in the treatment of schizophrenia and other psychoses, with considerations on past and present pharmacological and therapeutic issues. PMID:23343446
De Risio, Alessandro; Lang, Antonella P
Oral and long-acting risperidone has been shown to be effective for acute and maintenance treatment of patients with schizoaffective disorders. The present analysis investigated the efficacy and tolerability of direct transition from other antipsychotics to risperidone long-acting injectable in patients with schizoaffective disorder.Patients aged ? 18 years with schizoaffective disorder (DSM-IV), who required a change of medication, received risperidone long-acting
A. Mohl; K. Westlye; S. Opjordsmoen; A. Lex; A. Schreiner; M. Benoit; P. Bräunig; R. Medori
There are now long-acting versions of six antipsychotic drugs on the U.S. market, and with them, five unique combinations of molecular form and delivery strategy long-acting-injectable-antipsychotics (LAIAs) show evidence of reduced relapses of schizophrenia, but their introduction has been slow, taking at least nine years after the approval of each oral drug. Oily solutions of lipophilic prodrugs were the first to enter the LAIA market, but they relied on esterification of a hydroxyl handle that was lost with the emergence of the atypical antipsychotics. A review of the literature and patents shows that companies tested many different approaches before reaching the currently marketed versions, including aqueous suspensions of poorly soluble salts, polymeric microspheres, and new approaches to making prodrugs. Yet, very little has been published to support faster development of safe long-acting injectables (LAIs). This review introduces some of the critical considerations in creating an LAI; then it analyzes the existing products and discusses areas where further research is needed. The available literature suggests that lipophilic prodrugs may be inherently safer than poorly soluble salts as LAIs. Other areas needing additional study include (1) the range of physical properties acceptable for LAIs and the effect of prodrug tail length in achieving them, and (2) the role of physiological responses at the injection site in the release of drug from a depot. PMID:24679167
Remenar, Julius F
Bone tissue engineering is an alternative approach to bone grafts. In our study we aim to develop a composite scaffold for bone regeneration made of doped zirconium oxide (ZrO2) conjugated with poly(lactic-co-glycolic acid) (PLGA) particles for the delivery of growth factors. In this composite, the PLGA microspheres are designed to release a crucial growth factor for bone formation, bone morphogenetic protein-2 (BMP2). We found that by changing the polymer's molecular weight and composition, we could control microsphere loading, release and size. The BMP2 released from PLGA microspheres retained its biological activity and increased osteoblastic marker expression in human mesenchymal stem cells (hMSCs). Uncapped PLGA microspheres were conjugated to ZrO2 scaffolds using carbodiimide chemistry, and the composite scaffold was shown to support hMSCs growth. We also demonstrated that human umbilical vein endothelial cells (HUVECs) can be co-cultured with hMSCs on the ZrO2 scaffold for future vascularization of the scaffold. The ZrO2 composite scaffold could serve as a bone substitute for bone grafting applications with the added ability of releasing different growth factors needed for bone regeneration. PMID:23893013
Lupu-Haber, Yael; Pinkas, Oded; Boehm, Stefanie; Scheper, Thomas; Kasper, Cornelia; Machluf, Marcelle
Purpose: To study the effect of encapsulation of recombinant adenovirus type 5 encoding ?-galactosidase (Ad5-?gal) in poly (D,L- lactic-co-glycolic acid) (PLGA) microspheres on viral delivery to professional antigen presenting cells (APCs) in vitro, viral dissemination in vivo, and induction of protective immune responses in vivo. Methods: PLGA microspheres containing Ad5-?gal were prepared by a double emulsion solvent evaporation method. Encapsulation
Daqing Wang; Ommoleila Molavi; M. E. Christine; Praveen Elamanchili; Glen S. Kwon; John Samuel
Poly(lactide-co-glycolide) (PLGA) has most often been employed for the controlled release of protein formulations because of its safety profile with non-toxic degradation products. Nevertheless, such formulations have been plagued by a local acidic microenvironment and protein-polymer interactions, which result in chemical and physical denaturation of loaded proteins and often unfavorable release profiles. This study investigated the pH change of inner PLGA microsphere (MS) using charged (PLGA)n-b-branched polyethyleneimine (bPEI) micelles. The designed micelles can be transformed into either micelle or reverse micelle (RM) depending on the solvent and RM can form microspheres. In addition, (PLGA)n-b-bPEI can be modified into (PLGA)n-b-(carboxylated bPEI) via carboxylation of the primary amines. Cationic micelle (CM) or anionic micelle (AM) were complexed with counter-charged proteins leading to nanosized particles (approximately 100 nm). In the micelle/protein complexes, the micelles mostly maintained their proton buffering capacity, and consequently, prevented or delayed the typical decrease in pH caused by degradation of PLGA in aqueous solution. Reconstitutable micelle/protein complexes allowed for increased and fine-tuned protein loading (~20 wt% when using CM1 (CM prepared from PLGA36kDa-b-bPEI25kDa)/insulin complexes) in PLGA MS. In CM2 (CM prepared from (PLGA36kDa)2-b-bPEI25kDa)/insulin (4 of weight ratio (WR) of micelle to protein; WR4)-loaded PLGA MS, CM2 strongly prevented the micellar nanoenvironmental pH (pH 6.6 within 5 days and then approximately pH 8.5) to be acidified in PLGA MS for 9 weeks, unlike CM2-free PLGA MS. In conclusion, our findings propose that the proton buffering capacity and protein loading in PLGA MS can be tuned by controlling the complexation ratios of micelles and proteins, polymeric architectures of (PLGA)n-b-bPEI copolymers and WR of micelle/protein complexes and PLGA (or RM).
Kang, Han Chang; Lee, Ji Eun; Bae, You Han
1 The whole blood concentrations of propranolol have been compared, over a 48 h period, in twelve healthy male volunteers dosed with a 160 mg long-acting capsule formulation (LA, United Kingdom patent application No. 23114/77) and three standard tablet regimens; 160 mg once a day (CP160), 80 mg twice a day (CP80) and 40 mg four times a day (CP40). 2 The mean peak blood level for the long-acting formulation was significantly lower than that obtained with the 160 mg standard tablet. However, from 12 h on the mean levels for the long-acting formulation were higher. 3 The mean peak blood level for the long-acting formulation was significantly lower than that obtained with the 80 mg twice a day regimen and this difference was maintained up to 24 h. Thereafter, however, the situation was reversed. 4 The mean blood levels between 12 and 15 h were lower for the long-acting formulation when compared with the 40 mg four times a day regimen. At all other times, however, the observed levels were very similar. 5 The profiles achieved with the long-acting formulation in two separate studies were almost identical over a 48 h period. 6 The percentage reductions in exercise heart rate over the 3-24 h post dosing period were similar for the long-acting formulation and the two standard regimens studied (i.e. CP40 and CP80) when compared with placebo. 7 In the 2 h post dosing period the 80 mg twice a day regimen produced a significant reduction in the post-exercise systolic blood pressure when compared with the long-acting formulation.
McAinsh, J.; Baber, N. S.; Smith, R.; Young, J.
The aim of this study was to use CO2 at sub-critical pressures as a tool to sinter 3D, macroporous, microsphere-based scaffolds for bone and cartilage tissue engineering. Porous scaffolds composed of ~200 ?m microspheres of either poly(lactic-co-glycolic acid) (PLGA) or polycaprolactone (PCL) were prepared using dense phase CO2 sintering, which were seeded with rat bone marrow mesenchymal stromal cells (rBMSCs), and exposed to either osteogenic (PLGA, PCL) or chondrogenic (PLGA) conditions for 6 weeks. Under osteogenic conditions, the PLGA constructs produced over an order of magnitude more calcium than the PCL constructs, whereas the PCL constructs had far superior mechanical and structural integrity (125 times stiffer than PLGA constructs) at week 6, along with twice the cell content of the PLGA constructs. Chondrogenic cell performance was limited in PLGA constructs, perhaps as a result of the polymer degradation rate being too high. The current study represents the first long-term culture of CO2-sintered microsphere-based scaffolds, and has established important thermodynamic differences in sintering between the selected formulations of PLGA and PCL, with the former requiring adjustment of pressure only, and the latter requiring the adjustment of both pressure and temperature. Based on more straightforward sintering conditions and more favorable cell performance, PLGA may be the material of choice for microspheres in a CO2 sintering application, although a different PLGA formulation with the encapsulation of growth factors, extracellular matrix-derived nanoparticles, and/or buffers in the microspheres may be advantageous for achieving a more superior cell performance than observed here. PMID:24094202
Bhamidipati, Manjari; Sridharan, BanuPriya; Scurto, Aaron M; Detamore, Michael S
The objectives of this study were to prepare the amifostine polylactide-co-glycolide (PLGA) microsphere and investigate its irradiation protective to mouse through oral administration. Amifostine-loaded PLGA microsphere was formulated using a modified double emulsion-solvent evaporation technique. The microsphere particle was spherical with a mean diameter of 2.8 ± 0.1 ?m. Release data of amifostine PLGA microsphere was tested in phosphate-buffered saline at 37°C using a dialysis method and its release profiles was biphasic, showing a relatively large burst effect (50%) over the first 6 h, followed by a slower release phase, which sustained with 80% amifostine released in 48 h and almost 100% release till 6 days (144 h). A diffusion-controlled release model (Higuchi equation, R² = 0.9725) was obtained for amifostine releasing from PLGA microsphere. The radiation experiment was performed by applied cobalt-60 ?-radiation source. One hour before ?-radiation exposure, the mouse was orally given free amifostine and PLGA microsphere, respectively. The irradiation effects, such as blood cell concentration, superoxidase dismutase (SOD) activity and malondialdehyde (MDA) level were monitored. The results indicated that amifostine PLGA microsphere was more irradiation protective to mouse than that of free amifostine under the same oral administration route. PMID:21721846
Lu, Ting-Li; Sun, Wei-guang; Zhao, Wen; Chen, Tao
Purpose of review Long-acting antiretroviral (ARV) drugs may improve adherence to therapy and extend opportunities for therapeutic or prophylactic intervention to underserved patient populations. This review focuses on recent advances in the development of small molecule long-acting injectable ARV agents. Recent findings The need for combination ART and physicochemical and dosing limitations of current ARV drugs impede attempts to redevelop them as long-acting injectable formulations. However, the intrinsic properties of rilpivirine, a nonnucleoside reverse transcriptase inhibitor, and GSK1265744, an HIV-1 integrase strand transfer inhibitor, have enabled crystalline nanoparticle formulations to progress to clinical trials. Summary Investigational long-acting injectable nanoformulations of rilpivirine and GSK1265744 are clinical-stage development candidates. Complementary pharmacologic properties of both agents – different mechanisms of action, resistance profiles, metabolic pathways, lack of drug interactions and low daily oral doses – offer the potential for combination use. Phase I studies of the pharmacokinetics and safety of each long-acting formulation alone and in combination indicate that a monthly dosing regimen is possible for HIV treatment. An ongoing phase IIb trial of oral GSK1265744 and oral rilpivirine is evaluating this two-drug regimen for maintenance of virologic suppression; results will inform future studies using the injectable formulations. Additional preclinical and clinical studies indicate a potential use of each agent for HIV pre-exposure prophylaxis.
Spreen, William R.; Margolis, David A.; Pottage, John C.
In order to study the mechanism of initial burst release from drug-loaded poly(d,l-lactide-co-glycolide) (PLGA) microspheres, a model peptide, octreotide acetate, was encapsulated in PLGA 50\\/50 (Mw?50,000) microspheres using a double emulsion–solvent evaporation method. A simple and accurate continuous monitoring system was developed to obtain a detailed release profile. After different incubation times in the release medium, the morphology and permeability
Juan Wang; Barbara M. Wang; Steven P. Schwendeman
A 4-week sustained release risperidone biodegradable poly(D,L-lactide-co-glycolide) (PLGA) microsphere for the therapy of schizophrenia, the effects of formulation parameters on encapsulation efficiency and release behavior were studied. The risperidone PLGA microspheres were prepared by O/W solvent evaporation method and characterized by HPLC, SEM, laser particle size analysis, GC and HPLC-MS. The results indicated that the morphology of the risperidone PLGA microspheres presented a spherical shape with smooth surface, the particle size was distributed from 32 to 92 microm and the drug encapsulation efficiency was influenced by homogeneous rotation speed, intrinsic viscosity, carboxylic terminal group, the polymer concentration in the oil phase and the molecular weight of the polymer. These changes were also reflected in drug release. When the Mw of the polymers increased from ca. 28000 to ca. 90000, the initial burst release of risperidone PLGA microspheres decreased from 13 to 0.8% and the sustained-release could be extended to 4 weeks. Pharmacokinetic study on beagle dogs showed that the 4-week sustained release profile of the risperidone loaded microspheres prepared with 75253A was verified. The PLGA 75253A and 75255A show the potential as excipients for the monthly sustained release risperidone PLGA microspheres due to higher encapsulation efficiency and almost zero-order release kinetics of release profile. PMID:19881277
Su, Zhengxing; Sun, Fengying; Shi, Yanan; Jiang, Chaojun; Meng, Qingfan; Teng, Lirong; Li, Youxin
We synthesize drug-loaded poly (lactic-co-glycolic acid) (PLGA) microspheres for image-guided combinatory epigenetic therapy in MCF-10A human mammary epithelial cells. LY294002 and Nile Red are encapsulated in microspheres for sustained drug release and fluorescence microscopic imaging. Drug-loaded microspheres target MCF-10A cells through a three-step binding process involving biotinylated antibody, streptavidin, and biotinylated microspheres. LY294002 loaded microspheres and 5-Aza-2-deoxycytidine are applied to MCF-10A cells for combinatory PI3K?AKT inhibition and deoxyribonucleic acid (DNA) demethylation. Our study implies the technical potential of disease targeting and image-guided combinatory epigenetic therapy using drug-loaded multifunctional biodegradable PLGA microspheres. PMID:21361663
Xu, Ronald X; Xu, Jeff S; Zuo, Tao; Shen, Rulong; Huang, Tim H; Tweedle, Michael F
Surface-modified dl-lactide\\/glycolide copolymer (PLGA) nanospheres with chitosan (CS) were prepared by the emulsion solvent diffusion method for pulmonary delivery of peptide, i.e., elcatonin. The nanosphere suspension was successfully aerosolized with a nebulizer similar to the drug solution, whereas the microsphere suspensions could not be aerosolized. After pulmonary administration, CS-modified PLGA nanospheres were more slowly eliminated from the lungs than unmodified
Hiromitsu Yamamoto; Yoshio Kuno; Shohei Sugimoto; Hirofumi Takeuchi; Yoshiaki Kawashima
Inhalable highly porous large PLGA microparticles with incorporated doxorubicin and surface-attached with TRAIL (TRAIL/Dox PLGA MP) were fabricated using a w/o/w double emulsification method using ammonium bicarbonate as a gas-foaming agent for the treatment of lung cancer. The TRAIL/Dox PLGA MP produced were highly porous and 11.5 ± 0.4 ?m in diameter, and the loading efficiencies of Dox and TRAIL were 86.5 ± 6.5% and 91.8 ± 2.4%, respectively. TRAIL and doxorubicin were gradually released by TRAIL/Dox PLGA over 7 days, and pulmonary administration resulted in the deposition of TRAIL/Dox PLGA MP in mouse lungs, and they remained in situ for up to a week. The anti-tumor efficacy of pulmonary administered TRAIL/Dox PLGA MP was evaluated in a BALB/c nu/nu mice mouse model of H226 cell metastasis. Tumors in H226-implanted mice treated with TRAIL/Dox PLGA MP were markedly smaller and fewer in number than mice treated with TRAIL or Dox PLGA MP alone. Furthermore, this improved performance was found to be due to the synergistic apoptotic effects of the two drugs. We believe that TRAIL/Dox PLGA MP offer a promise of a sustained-release, long-acting, inhalable anti-lung cancer agent. Furthermore, the synergism observed between TRAIL and doxorubicin suggests that the doxorubicin dosage could be substantially reduced and its side effects minimized. PMID:23755831
Kim, Insoo; Byeon, Hyeong Jun; Kim, Tae Hyung; Lee, Eun Seong; Oh, Kyung Taek; Shin, Beom Soo; Lee, Kang Choon; Youn, Yu Seok
\\u000a Long-acting injectable antipsychotic medication or depots are an important element in the treatment of schizophrenia. Before\\u000a assessing the pros and cons of such treatment and determining whether it has a significant impact on outcome over and above\\u000a oral medication, it may be useful to consider where the idea of depot injections came from. There is surely a history behind\\u000a this
Anthony S. David; Ayana Gibbs; Maxine X. Patel
New long-acting medications for attention-deficit\\/hyperactivity disorder (ADHD) have become available, which combine certain\\u000a advantages over conventional short-acting drugs with higher acquisition costs. Choices between these drugs should thus be\\u000a driven by their clinical profiles and by an acceptable balance of increased costs and additional benefits. Accordingly, the\\u000a notion of relative cost-effectiveness should be central to recommendations about the use of
A systematic review of published and unpublished data on the use of long-acting medications in ADHD and hyperkinetic disorder\\u000a is reported, giving effect sizes and numbers-to-treat for extended-release stimulant preparations and atomoxetine (ATX). A\\u000a panel of experts from several European countries used the review to make recommendations about the use of these drugs in practice,\\u000a and conclusions are reported: (1)
Tobias Banaschewski; David Coghill; Paramala Santosh; Alessandro Zuddas; Philip Asherson; Jan Buitelaar; Marina Danckaerts; Manfred Döpfner; Stephen V. Faraone; Aribert Rothenberger; Joseph Sergeant; Hans-Christoph Steinhausen; Edmund J. S. Sonuga-Barke; Eric Taylor
Background: In Sweden, risperidone long-acting injectable (RLAI) is generally used in a population of schizophrenia patients who are at a high risk of being non-compliant. However, RLAI might also be suitable for use in the general schizophrenia population. Objectives: To analyse the clinical and economic effects of RLAI in the Swedish treatment practice using a discrete-event simulation (DES) model. Treatment
Marja Hensen; Bart Heeg; Mickael Löthgren; Ben van Hout
An important step in simplifying asthma and chronic obstructive pulmonary disease (COPD) management and improving adherence with prescribed therapy is to reduce the dose frequency to the minimum necessary to maintain disease control. Therefore, the incorporation of once-daily dose administration is an important strategy to improve adherence and is a regimen preferred by most patients, which may also lead to enhancement of compliance, and may have advantages leading to improved overall clinical outcomes. Once-daily ?2-agonists or ultra long-acting ?2-agonists (LABAs) such as carmoterol, indacaterol, GSK-159797, GSK-597901, GSK-159802, GSK-642444 and GSK-678007 are under development for the treatment of asthma and COPD. Also some new long-acting antimuscarinic agents (LAMAs) such as aclidinium, LAS-35201, GSK656398, GSK233705, NVA-237 (glycopyrrolate) and OrM3 are under development. In any case, the current opinion is that it will be advantageous to develop inhalers containing combination of several classes of long-acting bronchodilator drugs in an attempt to simplify treatment regimens as much as possible. Consequently, several options for once-daily dual-action ultra LABA+LAMA combination products are currently being evaluated. A different approach is to have a dimer molecule in which both pharmacologies are present (these molecules are known as M3 antagonist-?2 agonist (MABA) bronchodilators). The advent of a successful MABA product will revolutionize the field and open the door for a new range of combination products.
Cazzola, M; Matera, M G
Abstract Objectives: Unplanned pregnancy is a public health problem in the United States, including in rural areas. Primary care physicians are the main providers of health care to women in rural areas and are uniquely positioned to help reduce unplanned pregnancy in rural women. This study documents provision of contraception by rural primary care physicians, focusing on the most effective, long acting methods, intrauterine devices (IUDs) and contraceptive implants. Methods: We surveyed all primary care physicians practicing in rural areas of Illinois and Wisconsin. Bivariate analysis was performed using chi squared and Fisher's exact test, and multivariable analysis was performed with logistic regression to determine factors associated with provision. Results: The response rate was 862 out of 2312 physicians (37%). Nine percent of respondents place implants and 35% place IUDs. Eighty-seven percent of physicians had not had training in implant placement, and 41% had not had training in IUD placement. In multivariable analysis, factors associated with placement of long acting contraception include provision of maternity care, and female gender of the physician. The most common reasons for not providing the methods were lack of training and perceived low demand from patients. Conclusions: Many rural primary care providers do not place long acting contraceptive devices due to lack of training. Female physicians and those providing maternity care are the most likely to place these devices. Increased training for primary care physicians both during and after residency would help increase access to these options for women in rural areas. PMID:24443930
Lunde, Britt; Smith, Paul; Grewal, Manpreet; Kumaraswami, Tara; Cowett, Allison; Harwood, Bryna
The depot antipsychotics are synthesized by esterification of the active drug to a long chain fatty acid and the resultant compound is then dissolved in a vegetable oil, with the exception of some molecules of new generation characterized by microcrystalline technologies. The absorption rate constant is slower than the elimination rate constant and therefore, the depot antipsychotics exhibit 'flip-flop' kinetics where the time to steady-state is a function of the absorption rate, and the concentration at steady-state is a function of the elimination rate The pharmacokinetics of depot antipsychotic medications are such that an intramuscular injection given at intervals of from 1 to 4 weeks will produce adequate plasma concentrations that are sufficient to prevent relapse over the dosage interval. Such medication is useful in patients who do not reliably take their oral medication. The pharmacokinetics and clinical actions of various depot formulations of antipsychotic drugs have been extensively studied. The clinical pharmacokinetics of the depot antipsychotics for which plasma level studies are available (i.e. fluphenazine enanthate and decanoate, haloperidol decanoate, bromperidol decanoate, clopenthixol decanoate, flupenthixol decanoate, perphenazine onanthat, pipotiazine undecylenate, pipotiazine palmitate, fluspirilene, Long-acting injectable risperidone, olanzapine pamoate, paliperidone palmitate, Long-acting iloperidone, Long-acting injectable aripiprazole) are reviewed. The proper study of these agents has been handicapped until recently by the necessity of accurately measuring subnanomolar concentrations in plasma. Their kinetic properties, the relationship of plasma concentrations to clinical effects, and conversion from oral to injectable therapy are discussed. PMID:23343447
Spanarello, Stefano; La Ferla, Teresa
Abstract Objective: The objective of this study was to fabricate double-walled poly(lactide-co-glycolide) (PLGA) microspheres to increase encapsulation efficiency and avoid rapid release of hydrophilic drugs such as meglumine antimoniate. Methods: In this study, double-walled and one-layered microspheres of PLGA were prepared using the emulsion solvent evaporation technique to better control the release of a hydrophilic drug, meglumine antimoniate (Glucantime®), which is the first choice treatment of cutaneous leishmaniasis. The effect of hydrophobic coating on microspheres' size, morphology, encapsulation efficiency and drug release characteristics was evaluated. Furthermore, the presence of antimony in meglumine antimoniate made it possible to observe the drug distribution within the microspheres' cross section by means of energy dispersive X-ray spectroscopy. Results: Drug distribution images confirmed accumulation of the drug within the inner core of double-walled microspheres. In addition, these microspheres encapsulated the drug more efficiently up to 87% and demonstrated reduced initial burst and prolonged release compared to one-layered microspheres. These superiorities make double-walled microspheres an optimum candidate for sustained delivery of hydrophilic drugs. Conclusion: Double-walled microspheres provide some advantages over traditional microspheres overcoming most of their limitations. Double-walled microspheres were found to be more efficient than their corresponding one-layered microspheres in terms of encapsulation efficiencies and release characteristics. PMID:23594302
Navaei, Ali; Rasoolian, Morteza; Momeni, Arash; Emami, Shahriar; Rafienia, Mohammad
Olanzapine long acting injection has joined risperidone and paliperidone as the second generation long acting antipsychotic injection options for treatment of patients with schizophrenia. Long acting injections are important alternatives to oral medications for patients who have difficulty adhering to daily or multiple daily medication administrations, yet may be underutilized or not well understood. Patient perceptions, adherence, and preferences are important issues for health care providers to address when discussing treatment options with their patients. Reviewed here are overall patient and health care provider attitudes and perceptions regarding long acting injections and the details of olanzapine long acting injectable, the newest agent, and how it will fit in the marketplace. In addition, efficacy, safety, dosing and use data regarding this newest long acting agent are reviewed and compared to other available long acting agents.
Wehring, Heidi J.; Thedford, Sheryl; Koola, Maju; Kelly, Deanna L.
Olanzapine long acting injection has joined risperidone and paliperidone as the second generation long acting antipsychotic injection options for treatment of patients with schizophrenia. Long acting injections are important alternatives to oral medications for patients who have difficulty adhering to daily or multiple daily medication administrations, yet may be underutilized or not well understood. Patient perceptions, adherence, and preferences are important issues for health care providers to address when discussing treatment options with their patients. Reviewed here are overall patient and health care provider attitudes and perceptions regarding long acting injections and the details of olanzapine long acting injectable, the newest agent, and how it will fit in the marketplace. In addition, efficacy, safety, dosing and use data regarding this newest long acting agent are reviewed and compared to other available long acting agents. PMID:23293546
Wehring, Heidi J; Thedford, Sheryl; Koola, Maju; Kelly, Deanna L
An ovalbumin (OVA) peptide, consisting of residues 323–339, was incorporated into poly(d,l lactic-co-glycolic acid) (PLGA) microspheres and administered to mice. It was hypothesized that microencapsulation of the peptide in PLGA microspheres would avoid the need for traditional adjuvants and bias the immune response towards a type 1 T helper (Th1) response. An immunomodulator, monophosphoryl lipid A (MPLA), was incorporated into
K. D Newman; J Samuel; G Kwon
The influence of a tertiary amine, namely risperidone (pKa?=?7.9) on the degradation of poly(D, L lactide-co-glycolide) (PLGA) microspheres was elucidated. Risperidone and blank microspheres were fabricated at two lactide/glycolide ratios, 65:35 and 85:15. The microspheres were characterized for drug loading by high-performance liquid chromatography, particle size by laser diffractometry, and surface morphology by scanning electron microscopy. Polymer degradation studies were carried out with drug-loaded microspheres and blank microspheres in presence of free risperidone in 0.02 M PBS containing 0.02% Tween®80 at 37°C. Molecular weight was monitored by gel permeation chromatography. Risperidone and blank microspheres had similar size distribution and were spherical with a relatively nonporous smooth surface. The presence of risperidone within the microspheres enhanced the hydrolytic degradation in both polymeric matrices with faster degradation occurring in 65:35 PLGA. The molecular weight decreased according to pseudo-first-order kinetics for all the formulations. During the degradation study, the surface morphology of drug-loaded microspheres was affected by the presence of risperidone and resulted in shriveled microspheres in which there appeared to be an intrabatch variation with the larger microspheres being less shriveled than the smaller ones. When blank microspheres were incubated in free risperidone solutions, a concentration-dependent effect on the development of surface porosity could be observed. Risperidone accelerates the hydrolytic degradation of PLGA, presumably within the microenvironment of the drug-loaded particles, and this phenomenon must be taken into consideration in designing PLGA dosage forms of tertiary amine drugs. PMID:23090111
Selmin, Francesca; Blasi, Paolo; DeLuca, Patrick P
Stable polymeric microspheres capable of controlled release of tetanus toxoid (TT) for periods ranging from days to over months were developed. TT was stabilized, encapsulated in microspheres prepared from poly(D,L)-lactide-co-glycolide (PLGA) and chitosan by using protein stabilizer (trehalose) and its immune response was compared. The influence of co-encapsulated protein stabilizer on tetanus toxoid's stability and release from the microspheres was studied. The protein stabilizer (trehalose) prevented structural losses and aggregation of microencapsulated TT. To neutralize the acids liberated by the biodegradable lactic/glycolic acid-based polymer, we also co-incorporated into the polymer an antacid, (Mg(OH)2), which neutralized the acidity during degradation of the polymer and also prevented TT structural losses and aggregation. The in vitro release experiments with PLGA and chitosan microspheres were performed and the release of TT was increased up to 80-90%. The antigen integrity was investigated by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) followed by coomassie brilliant blue staining. The SDS-PAGE analysis confirmed that antigen integrity was not affected by the encapsulation procedure. In addition, the immunogenicity of PLGA and chitosan microspheres based single dose vaccine was evaluated in guinea pigs and compared with multiple doses of alum adsorbed TT. Results indicated that a single injection of PLGA and chitosan microspheres containing TT could maintain the antibody response at a level comparable to the booster injections of conventional alum adsorbed vaccines. The both PLGA and chitosan based stable vaccine formulations produced an equal immune response. Hence chitosan can be used to replace the expensive polymer PLGA. This approach should have potential application in the field of vaccine delivery. PMID:15814228
Jaganathan, K S; Rao, Y U B; Singh, Paramjit; Prabakaran, D; Gupta, Swati; Jain, Anubhav; Vyas, Suresh P
All patients with type 1 diabetes and significant numbers of those with type 2 diabetes are treated with insulin. Nonadherence to insulin regimen can impact glycaemic control. Insulin degludec is a new generation, ultra-long-acting basal insulin that forms soluble multihexamers at the injection site that slowly release insulin degludec monomers into the circulation giving a prolonged duration of action. Insulin degludec may provide a safe and convenient dosing option for patients who require some flexibility in adhering to an insulin regimen according to their lifestyle or circumstances. In this review we focus on the early phases of insulin degludec development.
Atkin, Stephen L.
All patients with type 1 diabetes and significant numbers of those with type 2 diabetes are treated with insulin. Nonadherence to insulin regimen can impact glycaemic control. Insulin degludec is a new generation, ultra-long-acting basal insulin that forms soluble multihexamers at the injection site that slowly release insulin degludec monomers into the circulation giving a prolonged duration of action. Insulin degludec may provide a safe and convenient dosing option for patients who require some flexibility in adhering to an insulin regimen according to their lifestyle or circumstances. In this review we focus on the early phases of insulin degludec development. PMID:23148194
Wakil, Ammar; Atkin, Stephen L
Two commercially available long-acting oxytetracycline hydrochloride formulations (Primamycin LA (Pfizer) and Terralent 20%\\u000a LA (?.E. Ulagay)) were administered by the intramuscular route to 20 clinically healthy sheep at a dose of 20 mg\\/kg. The study\\u000a was performed in a two-period crossover design. Plasma samples were analysed by high-pressure liquid chromatography. The mean\\u000a maximum concentrations (C\\u000a max) was 8.00 2.05??g\\/mland 8.61
N. Ozdemir; M. Y?ld?r?m
Poly(lactic-co-glycolic acid) (PLGA) and/or poly(lactic-acid) (PLA) microspheres are important drug delivery systems. This study investigated eye biocompatibility and safety of PLGA/PLA microspheres through intravitreal injection in rabbits. Normal New Zealand rabbits were randomly selected and received intravitreal administration of different doses (low, medium, or high) of PLGA/PLA microspheres and erythropoietin-loaded PLGA/PLA microspheres. The animals were clinically examined and sacrificed at 1, 2, 4, 8, and 12 weeks postadministration, and retinal tissues were prepared for analysis. Retinal reactions to the microspheres were evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end staining and glial fibrillary acidic protein immunohistochemistry. Retinal structure changes were assessed by hematoxylin and eosin staining and transmission electron microscopy. Finally, retinal function influences were explored by the electroretinography test. Terminal deoxynucleotidyl transferase-mediated dUTP nick end staining revealed no apoptotic cells in the injected retinas; immunohistochemistry did not detect any increased glial fibrillary acidic protein expression. Hematoxylin and eosin staining and transmission electron microscopy revealed no micro- or ultrastructure changes in the retinas at different time points postintravitreal injection. The electroretinography test showed no significant influence of scotopic or photopic amplitudes. The results demonstrated that PLGA/PLA microspheres did not cause retinal histological changes or functional damage and were biocompatible and safe enough for intravitreal injection in rabbits for controlled drug delivery.
Rong, Xianfang; Yuan, Weien; Lu, Yi; Mo, Xiaofen
Antipsychotic medications are important for the successful management of schizophrenia. Continuous treatment with medication is superior in relapse prevention and non-adherence to antipsychotic medication is associated with a poor clinical outcome. Long-acting injectable antipsychotics (LAIs) that can guarantee adherence to a treatment regimen could be a useful treatment option. With the introduction of second-generation atypical antipsychotics-long acting injection (SGA-LAI), the risks for extrapyramidal adverse events are decreased. The indications for SGA-LAI have been extended from chronic, stabilized patients to acute psychotic patients. Some studies investigated the use of LAI in first-episode schizophrenia patients and raised the possibility of prescribing LAI as a treatment option. However, there is still limited research using LAI in first-episode schizophrenia. More well-designed, randomized, controlled clinical trials using SGA-LAIs in first episode schizophrenia are needed. Additionally, studies on side effects of SGA-LAI in long-term use are required prior to recommending LAI for patients with first episode schizophrenia.
In this study, we have optimized different formulations of DNA encapsulated into PLGA microspheres by correlating the protocol of preparation and the molecular weight and composition of the polymer, with the main characteristics of these systems in order to design an efficient non-viral gene delivery vector. For that, we prepared poly(d,l-lactic-co-glycolic acid) (PLGA) microparticles with an optimized water–oil–water double emulsion
Sonsoles Díez; Conchita Tros de Ilarduya
Across the world rates of unintended pregnancy are high. Unintended pregnancy not only results in substantial costs to health services, it can lead to personal distress for women experiencing this. Whilst a large number of unintended pregnancies occur in those not using any method of contraception, a proportion occur in women using a contraceptive method incorrectly or inconsistently. Long acting reversible methods of contraception such as the IUD, IUS, contraceptive implant and contraceptive injectables are the most effective methods of contraception. In spite of this, they are under-utilized by women in developed countries. Educating women and health professionals, and dispelling myths about these methods may improve their acceptability. Furthermore, facilitating uptake by ensuring that a range of contraceptive providers are trained and able to provide to women without undue delay, particularly in the immediate post abortion and postpartum period, may also be effective strategies to improve uptake, and prevent more unintended pregnancies. PMID:23689167
Michie, L; Cameron, S T
Long-acting reversible contraception (LARC) includes intrauterine devices (IUDs) and the subdermal implant. These methods are the most effective reversible methods of contraception, and have the additional advantages of being long-lasting, convenient, well liked by users and cost effective. Compared with other user-dependent methods that increase the risk of noncompliance-related method failure, LARC methods can bring ‘typical use’ failure rates more in line with ‘perfect use’ failure rates. LARC methods are ‘forgettable’; they are not dependent on compliance with a pill-taking regimen, remembering to change a patch or ring, or coming back to the clinician for an injection. LARC method failure rates rival that of tubal sterilization at <1% for IUDs and the subdermal implant. For these reasons, we believe that IUDs and implants should be offered as first-line contraception for most women. This article provides a review of the LARC methods that are currently available in the US, including their effectiveness, advantages, disadvantages and contraindications. Additionally, we dispel myths and misconceptions regarding IUDs, and address the barriers to LARC use.
Stoddard, Amy; McNicholas, Colleen; Peipert, Jeffrey F.
Bronchodilator drugs are the foundation for the treatment of chronic obstructive pulmonary disease. The principal inhaled bronchodilator treatments used are ?(2) -agonists and anticholinergics, either alone or in combination. Currently available ?(2) -agonists are of either short duration and used multiple times/day, or of long duration, which requires twice-daily administration. Indacaterol is considered an ultra-long-acting ?(2) -agonist and was recently approved for use in the United States. Its duration of action is approximately 24 hours, allowing for once-daily administration. Cough was the most commonly reported adverse effect with use of indacaterol. Cough usually occurred within 15 seconds of inhalation of the drug, lasted around 6 seconds, was not associated with bronchospasm, and did not cause discontinuation of the drug. Otherwise, the drug's safety profile was similar to that of other bronchodilators. Based on similar improvement in spirometric measurements compared with other bronchodilator drugs and the convenience of its once-daily dosing, indacaterol may be beneficial in the management of mild-to-moderate chronic obstructive pulmonary disease, either alone or in combination with anticholinergic drugs administered once/day. PMID:22499359
Ray, Shaunta' M; McMillen, James C; Treadway, Sarah A; Helmer, Robert S; Franks, Andrea S
A major source of limitation to the real effectiveness of antipsychotics is the high rate of patient nonadherence or, more frequently, partial adherence. Using long-acting injectable (LAI) formulations is likely to reduce the impact of such adherence problems. Conversely, the use of LAIs in Canada remains low relative to many other jurisdictions. Based on effectiveness data from randomized control trials and other, less rigorous, studies, as well as our 2 qualitative studies exploring numerous issues around the use of LAIs, including their low use, we put forward 10 different recommendations for consideration by clinicians. These are also based on the experience of many clinicians and clinician scientists. These recommendations address mostly clinical challenges associated with the use of LAIs. Their application in clinical settings is illustrated in our report through several case examples highlighting the large variation across patients and different phases of illness. It is recommended that LAIs should be considered as a treatment option for psychotic disorders across all phases, including the first 2 to 5 critical years. PMID:23945065
Malla, Ashok; Tibbo, Phil; Chue, Pierre; Levy, Emmanuelle; Manchanda, Rahul; Teehan, Michael; Williams, Richard; Iyer, Srividya; Roy, Marc-André
In situ gelling systems are very attractive for pharmaceutical applications due to their biodegradability and simple manufacturing processes. The synthesis and characterization of thermosensitive poly(D,L-lactic-co-glycolic acid) (PLGA)-polyethylene glycol (PEG)-PLGA triblock copolymers as in situ gelling matrices were investigated in this study as a drug delivery system. Ring-opening polymerization using microwave irradiation was utilized as a novel technique, and the results were compared with those using a conventional method of polymerization. The phase transition temperature and the critical micelle concentration (CMC) of the copolymer solutions were determined by differential scanning calorimetry and spectrophotometry, respectively. The size of the micelles was determined with a light scattering method. In vitro drug release studies were carried out using naltrexone hydrochloride and vitamin B12 as model drugs. The rate and yield of the copolymerization process via microwave irradiation were higher than those of the conventional method. The copolymer structure and concentration played critical roles in controlling the sol-gel transition temperature, the CMC, and the size of the nanomicelles in the copolymer solutions. The rate of drug release could be modulated by the molecular weight of the drugs, the concentration of the copolymers, and their structures in the formulations. The amount of release versus time followed zero-order release kinetics for vitamin B12 over 25 days, in contrast to the Higuchi modeling for naltrexone hydrochloride over a period of 17 days. In conclusion, PLGA-PEG1500-PLGA with a lactide-to-glycolide ratio of 5:1 is an ideal system for the long-acting, controlled release of naltrexone hydrochloride and vitamin B12. PMID:22528547
Khodaverdi, Elham; Tekie, Farnaz Sadat Mirzazadeh; Mohajeri, Seyed Ahmad; Ganji, Fariba; Zohuri, Gholamhossein; Hadizadeh, Farzin
This paper describes an investigation of the use of poly(lactic\\/glycolic acid) polymers for long-term delivery of high molecular weight, water-soluble proteins. Poly(lactic\\/glycolic acid) (PLGA) microspheres, containing (fluorescein isothiocyanate)-labeled bovine serum albumin and (fluorescein isothiocyanate)-labeled horseradish peroxidase, were prepared by a modified solvent evaporation method using a double emulsion. The microspheres were spherical with diameters of 55–95 µm and encapsulated more
Smadar Cohen; Toshio Yoshioka; Melissa Lucarelli; Lena H. Hwang; Robert Langer
The entrapment of a protein in porous poly(d,l-lactide-co-glycolide) (PLGA) microspheres is demonstrated through the closure of their outer surface pores for sustained delivery of the protein. The porous PLGA microspheres with less than 10 ?m in size are prepared by electrospraying. Aqueous solutions containing fluorescein isothiocyanate-dextran or bovine serum albumin (BSA) are penetrated into the inner pores as a result of vacuum treatment, and the outer surface pores of the porous PLGA microspheres are then closed using a solvent (dimethyl sulfoxide) to ensure entrapment of the macromolecules. Confocal microscopy images confirm the presence of a large amount of the macromolecules inside the porous structure. Circular dichroism spectroscopy and release analysis reveal that BSA is entrapped without denaturation and released in a sustained manner for a period of over 2 months, respectively. PMID:24700776
Paik, Dong-Hyun; Choi, Sung-Wook
Almost half of the pregnancies in the United States are unintended. Currently available contraceptive methods are highly efficacious, but the most commonly used methods rely on patients for appropriate use. There has been a push to advocate for long-acting reversible contraceptives (LARCs) as first-line methods because they are placed by medical professionals and are the most effective form of reversible contraception available. There are four LARCs currently available in the United States: the Copper T intrauterine device, two forms of the levonorgestrel intrauterine system, and the etonogestrel subdermal implant. Once inserted, they can be left in place for 3-10 years, depending on the device. Some of these devices have been available for a number of years, but their use is limited in the United States due to controversies and misconceptions. A MEDLINE search from 1990-2012 was conducted to identify articles describing the use of LARCs in populations with limited data, including postpartum women, adolescents and nulliparous women, and women with sexually transmitted infections, including human immunodeficiency virus (HIV). Health care provider safety concerns surrounding intrauterine device (IUD) expulsions and infection are issues for use in adolescents and nulliparous women. Concern regarding IUD expulsion in the postpartum population questions the benefit of immediate versus delayed insertion, and the progestin effect in the levonorgestrel IUD and etonogestrel implant is of theoretic concern for breastfeeding women. In women with HIV, concerns have been raised about increased viral shedding with the IUD and drug interactions with the progestin methods. Many misconceptions surrounding LARCs are unfounded, but individual risk factors may leave LARC users at risk of unintended pregnancy if not addressed properly. PMID:24130075
Prescott, Gina M; Matthews, Christina M
Primary care physicians, pediatricians, and psychiatrists account for approximately 80 percent of attention deficit hyperactivity disorder (ADHD) treatments prescribed in the United States. Selection of short-acting versus long-acting ADHD treatment varies by specialty with long-acting agents representing 56 percent of primary care prescriptions, 64 percent of psychiatrist prescriptions, and 79 percent of pediatric prescriptions. There appears to be a correlation between short-acting versus long-acting treatment selection and age, with long-acting agents accounting for 78 percent of prescriptions for pediatric patients (age 0–17) but only 49 percent of prescriptions for adults (patients aged 18+). A discussion of data is included.
Cascade, Elisa; Kalali, Amir H.; Weisler, Richard H.
Microspheres of acrolein homopolymers and copolymer with hydrophillic comonomers such as methacrylic acid and/or hydroxyethylmethacrylate are prepared by cobalt gamma irradiation of dilute aqueous solutions of the monomers in presence of suspending agents, especially alkyl sulfates such as sodium dodecyl sulfate. Amine or hydroxyl modification is achieved by forming adducts with diamines or alkanol amines. Carboxyl modification is effected by oxidation with peroxides. Pharmaceuticals or other aldehyde reactive materials can be coupled to the microspheres. The microspheres directly form antibody adducts without agglomeration.
Rembaum, Alan (Inventor)
Microspheres of acrolein homopolymers and copolymer with hydrophillic comonomers such as methacrylic acid and/or hydroxyethylmethacrylate are prepared by cobalt gamma irradiation of dilute aqueous solutions of the monomers in presence of suspending agents, especially alkyl sulfates such as sodium dodecyl sulfate. Amine or hydroxyl modification is achieved by forming adducts with diamines or alkanol amines. Carboxyl modification is effected by oxidation with peroxides. Pharmaceuticals or other aldehyde reactive materials can be coupled to the microspheres. The microspheres directly form antibody adducts without agglomeration.
Rembaum, Alan (Inventor)
Microspheres of acrolein homopolymers and co-polymer with hydrophillic comonomers such as methacrylic acid and/or hydroxyethylmethacrylate are prepared by cobalt gamma irradiation of dilute aqueous solutions of the monomers in presence of suspending agents, especially alkyl sulfates such as sodium dodecyl sulfate. Amine or hydroxyl modification is achieved by forming adducts with diamines or alkanol amines. Carboxyl modification is effected by oxidation with peroxides. Pharmaceuticals or other aldehyde reactive materials can be coupled to the microspheres. The microspheres directly form antibody adducts without agglomeration.
Rembaum, Alan (Inventor)
In this paper, we present the first report about constructing a scaffold-like delivery system with poly (lactic-co-glycolic) (PLGA) microspheres on micro-arc oxidation titanium (MAO-Ti). The results show that this system could be stable on the porous MAO-Ti surface up for 6 weeks. Not only the system could control the release of model protein BSA, but also the MAO film could regulate the pH value of the solution which would decrease by the degradation of PLGA microspheres. In addition, compared to MAO-Ti, this system loaded with BSA could improve the proliferation of HBMSCs after 3 or 7 days culture.
Wang, Lin; Zheng, Huade; Du, Chang; Shi, Zhifeng; Ren, Li; Wang, Yingjun
The aim of this study was to prepare biodegradable sustained release magnetite microspheres sized between 1 to 2 ?m. The microspheres with or without magnetic materials were prepared by a W/O/W double emulsion solvent evaporation technique using poly(lactide-co-glycolide) (PLGA) as the biodegradable matrix forming polymer. Effects of manufacturing and formulation variables on particle size were investigated with non-magnetic microspheres. Microsphere size could be controlled by modification of homogenization speed, PLGA concentration in the oil phase, oil phase volume, solvent composition, and polyvinyl alcohol (PVA) concentration in the outer water phase. Most influential were the agitation velocity and all parameters that influence the kinematic viscosity of oil and outer water phase, specifically the type and concentration of the oil phase. The magnetic component yielding homogeneous magnetic microspheres consisted of magnetite nanoparticles of 8 nm diameter stabilized with a polyethylene glycole/polyacrylic acid (PEG/PAA) coating and a saturation magnetization of 47.8 emu/g. Non-magnetic and magnetic microspheres had very similar size, morphology, and size distribution, as shown by scanning electron microscopy. The optimized conditions yielded microspheres with 13.7 weight% of magnetite and an average diameter of 1.37 ?m. Such biodegradable magnetic microspheres seem appropriate for vascular administration followed by magnetic drug targeting.
Zhao, Hong; Gagnon, Jeffrey; Hafeli, Urs O
Recently three groups of rifampicin (RIF)-loaded microparticles (MPs), consisting of chitosan (CHT), PLGA and PLGA\\/CHT mixtures, were assessed in terms of RIF-loading and retention during nebulisation. The CHT-coated PLGA MPs were found to exhibit high RIF-loading ability together with nebulisation ability, stability, and mucoadhesive properties. All MP types had comparable toxicity towards alveolar cells which was significantly lower than that
Maria Letizia Manca; Giuseppe Loy; Marco Zaru; Anna Maria Fadda; Sophia G. Antimisiaris
OBJECTIVETo evaluate the efficacy and safety of a long acting somatostatin analogue in a subset of patients with refractory rheumatoid arthritis (RA).METHODSTen patients with active, refractory RA, who had failed to respond to at least four disease modifying antirheumatic drugs (DMARDs), were treated with monthly intramuscular injections of 20 mg of a long acting preparation of octreotide (Sandostatin-LAR) for three
D Paran; O Elkayam; A Mayo; H Paran; M Amit; M Yaron; D Caspi
Microspheres have been developed as drug carriers in controlled drug delivery systems for years. In our present study, near infrared spectroscopy (NIRS) is applied to analyze the particle size and drug loading rate in risperidone poly(d,l-lactide-co-glycolide) (PLGA) microspheres. Various batches of risperidone PLGA microspheres were designed and prepared successfully. The particle size and drug-loading rate of all the samples were determined by a laser diffraction particle size analyzer and high performance liquid chromatography (HPLC) system. Monte Carlo algorithm combined with partial least squares (MCPLS) method was applied to identify the outliers and choose the numbers of calibration set. Furthermore, a series of preprocessing methods were performed to remove signal noise in NIR spectra. Moving window PLS and radical basis function neural network (RBFNN) methods were employed to establish calibration model. Our data demonstrated that PLS-developed model was only suitable for drug loading analysis in risperidone PLGA microspheres. Comparatively, RBFNN-based predictive models possess better fitting quality, predictive effect, and stability for both drug loading rate and particle size analysis. The correlation coefficients of calibration set (Rc(2)) were 0.935 and 0.880, respectively. The performance of optimum RBFNN models was confirmed by independent verification test with 15 samples. Collectively, our method is successfully performed to monitor drug-loading rate and particle size during risperidone PLGA microspheres preparation. PMID:24954726
Song, Jia; Xie, Jing; Li, Chenliang; Lu, Jia-Hui; Meng, Qing-Fan; Yang, Zhaogang; Lee, Robert J; Wang, Di; Teng, Le-Sheng
Expansion of long-acting gas bubbles used in vitreoretinal surgery may lead to increased intraocular pressure and central retinal artery occlusion. To further understand the principles controlling the expansion of long-acting gases, we compared the expansion of perfluoropropane gas bubbles with that of sulfur hexafluoride gas bubbles in an in vitro model, as well as in rabbits. We found that perfluoropropane bubbles expand more rapidly and to a greater extent than do sulfur hexafluoride bubbles in the first 24 hours. The early rate of expansion of a long-acting gas is largely dependent on convection of the surrounding fluid and is independent of the type of long-acting gas. Early postoperative monitoring of intraocular pressure is, therefore, equally important when using any long-acting gas. PMID:4004624
Crittenden, J J; de Juan, E; Tiedeman, J
To demonstrate the effect of formulation conditions on the controlled release of protein from poly(lactide-co-glycolide) (PLGA) microspheres for use as a parenteral drug carrier, ovalbumin (OVA) microspheres were prepared using the W/O/W multiple emulsion solvent evaporation and extraction method. Methylene chloride or ethyl acetate was applied as an organic phase and poly(vinyl alcohol) as a secondary emulsion stabilizer. Low loading efficiencies of less than 20% were observed and the in vitro release of OVA showed a burst effect in all batches of different microspheres, followed by a gradual release over the next 6 weeks. Formulation processes affected the size and morphology, drug content, and the controlled release of OVA from PLGA microspheres. PMID:10976588
Cho, S W; Song, S H; Choi, Y W
To preserve the positive effect of collagen on tissue regeneration and to locally deliver low molecular weight compounds for an extended time period, a composite for parenteral application was devised based on a collagen sponge with gentamicin-loaded PLGA microparticles incorporated. Antibiotic liberation from the particles was sustained over 1 week by blending two PLGA polymers. Homogenous incorporation of the microspheres in the porous carrier could be realized by lyophilization of a particle suspension in the aqueous collagen preparation. Particle loss upon incubation was reduced with higher collagen concentration enabling local particle retention after application. Lower freezing rate and longer exposure of the PLGA microparticles to the acidic collagen dispersion at temperatures below the glass transition temperature resulted in an increase of the gentamicin burst. The final implant containing both nonencapsulated gentamicin and an equivalent amount incorporated in the microparticles reflected the microbiological demands and exhibited liberation of a high gentamicin dose initially and subsequently extended antibiotic liberation for about one week. PMID:14603500
Schlapp, Monika; Friess, Wolfgang
The main challenge in the oral delivery of protein drugs is to enhance their oral bioavailability. Herein, we report the uniform-sized liposphere prepared by premix membrane emulsification combined with W1/O/W2 double-emulsion method as a potential oral carrier for proteins. The protein-loaded liposphere was composed of a hydrophobic poly (d, l-lactide-co-glycolide) (PLGA) core and the lipid molecules self-assembled at the interface of W1/O and O/W2. During the preparation, the protein structure was effectively maintained. Compared with PLGA microsphere, the liposphere achieved a higher loading capacity (LC, 20.18%), entrapment efficiency (EE, 90.82%) and a lower initial burst (24.73%). Importantly, the lipospheres also showed high transcytotic efficiency with human microfold cell (M cell) model, leading to a potential enhancement of intestinal absorption. This result, together with the above studies supported that the PLGA-lipid liposphere could be a promising platform for enhancing the proteins oral bioavailability. PMID:24698146
Ma, Tongtong; Wang, Lianyan; Tingyuanyang; Wang, Dong; Ma, Guanghui; Wang, Siling
Many research groups are investigating degradable magnetic particles for magnetic resonance imaging (MRI) contrast agents and as carriers for magnetic drug guidance. These particles are composite materials with a degradable polymer matrix and iron oxide nanoparticles for magnetic properties. The degradable polymer matrix acts to provide colloidal stability and, for drug delivery applications, provides a reservoir for the storage and release of drugs. Natural polymers, like albumin and dextran, which degrade by the action of enzymes; have been used for the polymer matrix. Iron oxide nanoparticles are used for magnetic properties since they can be digested in vivo and have low toxicities. Polylactic acid (PLA) and its copolymers with polyglycolic acid (PLGA) are versatile polymers that degrade by simple hydrolysis without the aid of enzymes. Microspheres are easily formed using the solvent extraction/evaporation method and a wide range of drugs can be encapsulated in them. Magnetic PLGA microspheres suitable for applications were synthesized for the first time in this dissertation. This was accomplished by coating iron oxide nanoparticles with oleic acid to make them dispersible in the organic solvents used in the extraction/evaporation microsphere preparation method. In addition to the magnetic PLGA microspheres, a novel all-aqueous method for preparing crosslinked dextran magnetic microspheres was developed in this dissertation. This method uses free radical polymerization for crosslinking and does not require the use of flammable and harmful solvents. For efficient MRI contrast and magnetic drug guidance, maximized iron oxide content of microspheres is desirable. The two different microsphere preparation methods were optimized for iron oxide content. The effect of iron oxide content on microsphere size and morphology was studied. In addition, an in vitro circulation model was used to evaluate the ability of magnetic microspheres to be guided at physiologic blood flow velocities. The MRI contrast effect was studied as a function of microsphere concentration.
Leamy, Patrick J.
Staphylococcus aureus is an important cause of nosocomial and community-acquired infections in humans and animals, as well as the cause of mastitis in dairy cattle. Vaccines aimed at preventing S. aureus infection in bovine mastitis have been studied for many years, but have so far been unsuccessful due to the complexity of the bacteria, and the lack of suitable vaccine delivery vehicles. The current study developed an Escherichia coli protein expression system that produced a recombinant staphylococcal enterotoxin A (rSEA) encapsulated into biodegradable microparticles generated by polylactic-co-glycolic acid (PLGA) dissolved in methylene chloride and stabilized with polyvinyl acetate. Antigen loading and surface properties of the microparticles were investigated to optimize particle preparation protocols. The prepared PLGA-rSEA microspheres had a diameter of approximately 5 ?m with a smooth and regular surface. The immunogenicity of the PLGA-rSEA vaccine was assessed using mice as an animal model and showed that the vaccine induced a strong humoral immune response and increased the percent survival of challenged mice and bacterial clearance. Histological analysis showed moderate impairment caused by the pathogen upon challenge afforded by immunization with PLGA-rSEA microspheres. Antibody titer in the sera of mice immunized with PLGA-rSEA microparticles was higher than in vaccinated mice with rSEA. In conclusion, the PLGA-rSEA microparticle vaccine developed here could potentially be used as a vaccine against enterotoxigenic S. aureus. PMID:22429499
Chen, Liben; Li, Shuang; Wang, Zhengfang; Chang, Ruilong; Su, Jingliang; Han, Bo
Long-acting injectable (depot) antipsychotics are one approach in the management of individuals with schizophrenia. Since the introduction of risperidone long-acting injection in 2003, three additional second-generation antipsychotics have become available in a long-acting injectable formulation: paliperidone, olanzapine and aripiprazole. Although these different depot options can help with adherence and thus encourage better treatment outcomes, they differ in terms of specific indications, approved injection sites, needle gauge, injection volume, injection interval, requirements for oral supplementation, availability of prefilled syringes, storage needs and postinjection observation period, as well as potential drug-drug interactions and commonly encountered adverse reactions. After a review of the evidence base, guidance is offered on the appropriate selection among the long-acting injectable formulations of both first and second-generation antipsychotics. PMID:23898849
Abstract Background. COPD is the fourth leading cause of death in the world. In the case of exacerbations or persistent symptoms, regular treatment with long-acting bronchodilators is recommended to control the symptoms, reduce exacerbations and improve health status. Objectives. To describe patterns of drug utilization among patients diagnosed with COPD, to measure continuity with long-acting bronchodilators, to identify determinants of not receiving long-acting therapy continuously. Methods. We identified a cohort of patients discharged from hospital with diagnosis of COPD between 2006 and 2008. Patients were observed for a two-year follow-up period, starting from the day of discharge. Follow-up was segmented in six-month periods, in order to dynamically evaluate prescription patterns of Long-Acting Beta-Agonists (LABA), tiotropium, and inhaled corticosteroids. Patients with prescriptions for LABA and/or tiotropium in each of the six-month periods were defined as "continuously treated with long-acting bronchodilators." The degree of drug treatment coverage was measured through the Medication Possession Ratio (MPR). Logistic regression was performed to identify determinants of not receiving long-acting bronchodilators continuously. Results. A total of 11,452 patients diagnosed with COPD were enrolled. Only 34.8% received long-acting bronchodilators continuously. The MPR was greater than 75% in 19.6% of cases. Among the determinants of not receiving long-acting bronchodilators continuously, older age and co-morbidities played an important role. Conclusions. In clinical practice, the COPD pharmacotherapy is not consistent with clinical guidelines. Medical education is needed to disseminate evidence-based prescribing patterns for COPD, and to raise awareness among physicians and patients on the health benefits of an appropriate pharmacological treatment. PMID:24090036
Di Martino, Mirko; Agabiti, Nera; Bauleo, Lisa; Kirchmayer, Ursula; Cascini, Silvia; Pistelli, Riccardo; Colamesta, Vittoria; Patorno, Elisabetta; Pinnarelli, Luigi; Fusco, Danilo; Perucci, Carlo Alberto; Davoli, Marina
This work was aimed at studying enzyme prolidase stability and its interactions with the reagents and the process conditions involved in preparation, by an emulsification process, of prolidase loaded poly(lactide-co-glycolide) (PLGA) microparticulate systems. Enzyme stability was tested with respect to contact with methylene chloride, ethyl acetate, PLGA polymers, and several agents used as emulsifiers such as polyvinyl alcohol (PVA), polyvinyl pyrolidone (PVP), carboxymethyl cellulose (CMC) and sodium oleate (NaOl). Enzyme stability to temperature and mechanical stirring was also evaluated. Prolidase-loaded PLGA microspheres were prepared and evaluated in terms of protein activity. The results obtained showed that the prolidase-loaded PLGA microspheres can be prepared only upon enzyme stabilization by addition of both BSA and MnCl(2) into its TRIS solution. Methylene chloride was the suitable organic solvent to be used in the double emulsion process, together with PVA as dispersing agent in the outer aqueous phase. Low temperatures during the emulsification step and very short process times are recommended, in order to maintain enzyme activity at its maximum. In these conditions spherical microspheres were obtained, releasing active prolidase for up to 15 days. PMID:12433302
Perugini, P; Genta, I; Pavanetto, F; Modena, T; Maculotti, K; Conti, B
The current availability of a long-acting injectable formulation of risperidone and the potential future availability of long-acting formulations of other atypical antipsychotics (such as paliperidone) should prompt a reconsideration of at what stage in the treatment of schizophrenia such long-acting agents should be introduced. At present, long-acting formulations, particularly of conventional antipsychotics (depots), are usually reserved for patients with chronic schizophrenia who are at high-risk of noncompliance. Recent and increasing data from other patient groups, such as those with first-episode psychosis, suggest that long-acting risperidone is associated with good efficacy and tolerability leading to high patient acceptance, and treatment continuation rates that are greater than with oral antipsychotics. The benefits of an atypical antipsychotic coupled with the assurance of medication delivery in the form of a long-acting injection imply that these novel formulations should be considered in first-episode patients, for whom optimal outcome is frequently compromised by early treatment discontinuation and poor adherence. PMID:17521224
Chue, Pierre; Emsley, Robin
Combinations of two long-acting bronchodilators and long-acting bronchodilators with inhaled corticosteroids (ICS) are recommended therapies in the management of chronic obstructive pulmonary disease (COPD). Three fixed-dose combination products have recently been approved for the treatment of COPD (the long-acting ?2-agonist plus long-acting muscarinic antagonist [LABA/LAMA] combinations glycopyrronium/indacaterol [QVA149] and umeclidinium/vilanterol, and the LABA/ICS fluticasone furoate/vilanterol), with others currently in late-stage development. LABA/LAMA and LABA/ICS combination therapies demonstrate positive effects on both lung function and patient-reported outcomes, with significant improvements observed with LABA/LAMA combinations compared with placebo, each component alone and other comparators in current use. No new safety concerns have been observed with combinations of long-acting bronchodilators. Combinations of two long-acting bronchodilators represent a new and convenient treatment option in COPD. This review summarizes published efficacy and safety data from clinical trials of both LABA/LAMA and novel LABA/ICS combinations in patients with COPD. PMID:24802656
Bateman, Eric D; Mahler, Donald A; Vogelmeier, Claus F; Wedzicha, Jadwiga A; Patalano, Francesco; Banerji, Donald
Latex particles with attached antibodies have potential biochemical and environmental applications. Human red blood cells and lymphocytes have been labeled with fluorescent microspheres by either direct or indirect immunological technique. Immunolatex spheres can also be used for detecting and localizing specific cell surface receptors. Hormones and toxins may also be bondable.
Background The aim of this study was to prepare poly(d,l-lactide-co-glycolide) (PLGA) microspherical implants containing teicoplanin (TCP) using a double emulsion solvent evaporation method\\u000a and to evaluate its efficacy for the local treatment of chronic osteomyelitis.\\u000a \\u000a \\u000a \\u000a Methods The particle size and distribution, morphological characteristics, thermal behaviour, drug content, encapsulation efficiency\\u000a and in vitro release assessments of the formulations were carried out. Sterile TCP–PLGA
Zafer Orhan; Erdal Cevher; Ayca Y?ld?z; Rengin Ah?skal?; Demet Sensoy; Lütfiye Mülaz?mo?lu
The successful design and development of pharmaceutical drug-polymer composites requires detailed information about the phase behavior of the drug-polymer binary system. This study presents an extended investigation of the phase equilibrium established between the chiral anti-inflammatory drug Ketoprofen (KET) and the bio-compatible and biodegradable polymer poly(lactic-co-glycolic) acid 5050 (PLGA). Equilibration experiments were carried out in aqueous suspensions of KET crystals together with PLGA in the form of spherical amorphous nanoparticles obtained by supercritical fluid extraction of emulsions (SFEE). The influence of temperature was studied in the range between 0°C and 50°C, while the effect of KET chirality was investigated by using two different crystalline forms of KET, namely enantiopure S-KET and a racemic compound, RS-KET, in equilibration experiments. It was found that the level of KET established in PLGA at equilibrium increases with temperature, e.g. from 6.9 wt.% at 20°C to 25.8 wt.% at 40°C for the case of S-KET. At each temperature level, the solubility of KET in PLGA was lower for equilibration with RS-KET, significantly higher for equilibration with S-KET, and the highest for simultaneous equilibration with both crystalline species. Experimental solubility data of KET in PLGA were also described in a model based on the Sanchez-Lacombe equation of state. For experiments carried out at 10°C or below, an equilibrium state could not be reached even after a prolonged equilibration period, presumably because the polymer phase had undergone a transition into the glassy state. For this temperature range, where an experimental equilibration is not any more possible, the model may be used to estimate the solubility of KET in PLGA by extrapolation. PMID:20728513
Kluge, Johannes; Mazzotti, Marco; Muhrer, Gerhard
Peptide or protein degradation often occurs when water flows into the dosage form. The aim of this study was to investigate the effect of water on exenatide acylation in poly(lactide-co-glycolide) (PLGA) microspheres. Exenatide-loaded PLGA microspheres were incubated at different relative humidities (RH) as well as in solutions of different pH for 20 days. The stability of exenatide was monitored using HPLC and HPLC-MS analysis. The alteration of exenatide conformation caused by water was investigated by FT-IR spectroscopy. Exenatide and glycolide were incubated in DMSO-water solutions to verify the effect of exenatide conformation state on the peptide acylation. Exenatide was relatively stable in microspheres at lower RH, and the absorbed water could act as a plasticizer and thus promote the peptide acylation by PLGA. However, when the microspheres were incubated at 100% RH, the excessively absorbed water could cause conformation recovery of exenatide and play an inhibitory effect on acylation. The formation of acylated exenatide incubated in acetate buffer saline of pH 6.0 was more than that of pH 4.5 and 3.0. Stability studies of exenatide in glycolide solutions showed that exenatide in nonnative monomer state was easier to be acylated by eletrophiles than that in aggregation state. PMID:23872225
Liang, Rongcai; Li, Xiang; Shi, Yanan; Wang, Aiping; Sun, Kaoxiang; Liu, Wanhui; Li, Youxin
Negatively charged poly(lactic-co-glycolic acid) (PLGA) microspheres with an encapsulated hydrophilic antibiotic (amoxicillin) have been prepared by the solid-in-oil-in-water (s/o/w) method using the anionic surfactant, sodium dodecyl sulfate (SDS). Drug encapsulation efficiency is over 40%. Successful coating of hydroxyapatite (HA) on these negatively charged PLGA microspheres has been achieved by a dual constant composition method in 3-6 h. The HA-coated PLGA microspheres (HPLG) have been characterised by zeta-potential and particle size measurements and the coating has been confirmed to be calcium deficient HA by analysis of X-ray diffraction, Fourier transform infrared spectroscopy and wavelength dispersive spectroscopy. The morphology of HPLG was studied by scanning electron microscopy, and cross sections of HPLG microspheres were prepared and imaged using focused ion beam microscopy. In-vitro drug release experiments in PBS (pH7.4) showed a sustained release profile for at least 31 days with little initial burst release. It shows a triphasic drug release profile commonly observed for biodegradable polymers. PMID:18325617
Xu, Qingguo; Czernuszka, Jan T
Interferon alpha-2b (IFN?-2b) is an important immune regulator used widely in clinic. However, frequent subcutaneous injection and substantial toxicity decrease patients' compliance. So, drug delivery with more precisely controlled drug release is urgent for IFN?-2b. Microsphere is a promising sustained drug delivery system, which has been studied widely for delivery of proteins. However, it was found difficult to keep proteins' activity and guarantee complete release. In this study, we solidified IFN?-2b as microparticles firstly by co-lyophilizing it with gelatin and ZnSO(4). Microspheres were then prepared. The preparing procedure and formulation were optimized with encapsulation efficiency and in vitro release as main parameters. Finally, the microspheres were prepared by S/O/W method with microparticle size about 5 ?m and PEGT/PBT-PLGA (9:1, w/w) as matrix material. The diameter of microspheres was 28.94 ?m, the encapsulation efficiency was 86.01%, the burst release was 16.69%, the cumulative release was 83.06% at 23th day, and IFN?-2b was released from microspheres with a zero-order profile. These microspheres also demonstrated sustained and steady release for about 13 days in rats. In conclusion, the procedure and formulation used in this study were supposed to be successful to keep IFN?-2b active and released constantly and completely. PMID:21419205
Li, Zhiping; Li, Lin; Liu, Yan; Zhang, Hui; Li, Xueru; Luo, Fang; Mei, Xingguo
Poly(ethylene glycol) methacrylate (PEGMA) hydrolyzable microspheres intended for biomedical applications were readily prepared from poly(lactide-co-glycolide) (PLGA)-poly(ethylene glycol) (PEG)-PLGA crosslinker and PEGMA as a monomer using a suspension polymerization process. Additional co-monomers, methacrylic acid and 2-methylene-1,3-dioxepane (MDO), were incorporated into the initial formulation to improve the properties of the microspheres. All synthesized microspheres were spherical in shape, calibrated in the 300-500 ?m range, swelled in phosphate-buffered saline (PBS) and easily injectable through a microcatheter. Hydrolytic degradation experiments performed in PBS at 37 °C showed that all of the formulations tested were totally degraded in less than 2 days. The resulting degradation products were a mixture of low-molecular-weight compounds (PEG, lactic and glycolic acids) and water-soluble polymethacrylate chains having molecular weights below the threshold for renal filtration of 50 kg mol(-1) for the microspheres containing MDO. Both the microspheres and the degradation products were determined to exhibit minimal cytotoxicity against L929 fibroblasts. Additionally, in vivo implantation in a subcutaneous rabbit model supported the in vitro results of a rapid degradation rate of microspheres and provided only a mild and transient inflammatory reaction comparable to that of the control group. PMID:24321348
Louguet, Stéphanie; Verret, Valentin; Bédouet, Laurent; Servais, Emeline; Pascale, Florentina; Wassef, Michel; Labarre, Denis; Laurent, Alexandre; Moine, Laurence
Recombinant human bone morphogenetic protein-2 (rhBMP-2) is a critical regulator of osteogenic capacity that is commonly used in bone grafts. The effectiveness of rhBMP-2 may be reduced as it can become unstable and degraded after injection into the body. Microspheres are considered appropriate vehicles for the sustained release of proteins in vivo. In this study, rhBMP-2 microspheres were manufactured using the water-in-oil-in-water (W/O/W) double-emulsion solvent-extraction technique by encapsulation in poly(lactic-co-glycolic) acid (PLGA). The microspheres were then embedded in two hydrogels made of either poloxamer 407 hydrogel or chitosan thioglycolic acid (CS-TA). The encapsulation efficiency and in vitro release of rhBMP-2 were examined and compared with the control release system (rhBMP-2 microspheres alone). The rhBMP-2 microspheres in the CS-TA hydrogel showed the lowest burst release (about 40% in the first 8h) among the three groups. The mechanisms may be the high viscosity of CS-TA hydrogel and the sustained release characteristics of CS-TA itself. The CS-TA hydrogel combined with PLGA microspheres can efficiently encapsulate rhBMP-2, control the burst release at early time points, and provide sustained release in vitro. It may be an appropriate rhBMP-2 vehicle for bone regeneration. PMID:22570935
Fu, Yangmu; Du, Lina; Wang, Qi; Liao, Weixiong; Jin, Yiguang; Dong, Anjie; Chen, Chen; Li, Zhongli
In tissue engineering, the recapitulation of natural sequences of signaling molecules, such as growth factors, as occurring in the native extracellular matrix (ECM), is fundamental to support the stepwise process of tissue regeneration. Among the manifold of tissue engineering strategies, a promising one is based on the creation of the chrono-programmed presentation of different signaling proteins. This approach is based upon the integration of biodegradable microspheres, loaded with suitable protein molecules, within scaffolds made of collagen and, in case, hyaluronic acid, which are two of the fundamental ECM constituents. However, for the design of bioactivated gel-like scaffolds the determination of release kinetics must be performed directly within the tissue engineering template. In this work, biodegradable poly(lactic-co-glycolic)acid (PLGA) microspheres were produced by the multiple emulsion-solvent evaporation technique and loaded with rhodamine-labelled bovine serum albumin (BSA-Rhod), a fluorescent model protein. The microdevices were dispersed in collagen gels and collagen-hyaluronic acid (HA) semi-interpenetrating networks (semi-IPNs). BSA-Rhod release kinetics were studied directly on single microspheres through confocal laser scanning microscopy (CLSM). To thoroughly investigate the mechanisms governing protein release from PLGA microspheres in gels, BSA-Rhod diffusion in gels was determined by fluorescence correlation spectroscopy (FCS), and water transport through the microsphere bulk was determined by dynamic vapor sorption (DVS). Moreover, the decrease of PLGA molecular weight and glass transition temperature (T(g)) were determined by gel permeation chromatography (GPC) and differential scanning calorimetry (DSC), respectively. Results indicate that protein release kinetics and delivery onset strongly depend on the complex interplay between protein transport through the PLGA matrix and in the collagen-based release media, and water sequestration within the scaffolds, related to the scaffold hydrophilicity, which is dictated by HA content. The proper manipulation of all these features may thus allow the obtainment of a fine control over protein sequential delivery and release kinetics within tissue-engineering scaffolds. PMID:19449203
Biondi, Marco; Indolfi, Laura; Ungaro, Francesca; Quaglia, Fabiana; La Rotonda, Maria Immacolata; Netti, Paolo A
The purpose of this research was to study the chemical reactivity of a somatostatin analogue octreotide acetate, formulated\\u000a in microspheres with polymers of varying molecular weight and co-monomer ratio under in vitro testing conditions. Poly(D,L-lactide-co-glycolide)\\u000a (PLGA) and poly(D,L-lactide) (PLA) microspheres were prepared by a solvent extraction\\/evaporation method. The microspheres\\u000a were characterized for drug load, impurity content, and particle size. Further,
Santos B. Murty; Jack Goodman; B. C. Thanoo; Patrick P. DeLuca
Mixtures of fast-acting and long-acting insulins were administered nasally to anesthetized, hyperglycemic rats in the presence and absence of tetradecyl-?-D-maltoside (TDM). The fast-acting analogs, aspart insulin, lispro insulin, and glulisine insulin, were all rapidly absorbed from the nose when applied individually with 0.125% TDM (Tmax = 15 minutes). One long-acting insulin analog, glargine insulin, was also absorbed from the nose when applied individually in the presence of 0.125% TDM (Tmax = 60 minutes). The other long-acting insulin analog, detemir insulin, was not soluble when formulated with 0.125% TDM. A series of mixtures (1:1) of the three rapid-acting insulins and long-acting glargine insulin were formulated with 0.125% TDM and applied nasally. The pharmacokinetic and pharmacodynamic profiles of the insulin mixtures reflected the additive contributions of both the rapid-acting and the long-acting insulin. These results support the possibility of formulating certain insulin mixtures in tandem to provide nasal insulin products that match the needs of patients with diabetes mellitus better than those currently available.
Pillion, Dennis J.; Fyrberg, Michael D.; Meezan, Elias
Background: Long-acting injectable antipsychotics may improve medication adherence, thereby improving overall treatment effectiveness. This study aimed to evaluate the effectiveness, safety, and tolerability of risperidone long-acting injection in schizophrenic patients switched from oral antipsychotic medication. Methods: In a 12-month, multicenter, open-label, noncomparative study, symptomatically stable patients on oral antipsychotic medication with poor treatment adherence during the previous 12 months received intramuscular injections of risperidone long-acting injection (25 mg starting dose) every 2 weeks. The primary endpoint was the change in Positive and Negative Syndrome Scale (PANSS) total score. Results: Of the 60 patients who were screened, 53 received at least one injection (safety population), and 51 provided at least one postbaseline assessment. Mean PANSS total scores improved significantly throughout the study and at endpoint. Significant improvements were also observed in Clinical Global Impression of Severity, Personal and Social Performance, and Drug Attitude Inventory scales. Risperidone long-acting injection was safe and well-tolerated. Severity of movement disorders on the Extrapyramidal Symptom Rating Scale was reduced significantly. The most frequently reported adverse events were insomnia (22.6%), increased prolactin (17.0%), and weight gain (13.2%). Conclusion: Risperidone long-acting injection was associated with significant symptomatic improvements in stable patients with schizophrenia following a switch from previous antipsychotic medications.
Louza, Mario Rodrigues; Elkis, Helio; Ruschel, Sandra; de Oliveira, Irismar Reis; Bressan, Rodrigo Affonseca; Belmonte-de-Abreu, Paulo; Grabowski, Hamilton; Appolinario, Jose Carlos
Objective: To review and comment on the long-acting medications presently marketed in Canada for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in terms of design, composition, mode of action and efficacy including other long-acting products that are not yet available in Canada. Method: A literature review was conducted using MEDLINE, PsycInfo, CINAHL, and PubMed with additional information gathered from other sources. Results: The American Academy of Pediatrics (AAP), the American Academy of Child and Adolescent Psychiatry (AACAP) and the Canadian Attention Deficit Hyperactivity Disorder Resource Alliance (CADDRA) while endorsing the stimulants as first line medications to treat ADHD also recommended the use of long-acting once-a-day medication for better efficacy, convenience and adherence. Most studies rated the controlled release and the immediate release medications as similar in efficacy. However, long-acting medication was shown to be superior in terms of remission rates. Conclusion: When a child is receiving a long-acting medication for treatment of ADHD, he may feel less stigmatized, is more likely to be adherent and achieve remission. A child in remission can benefit from other treatment modalities thus improving long-term prognosis.
Hosenbocus, Sheik; Chahal, Raj
The aim of this study was to evaluate the effects of preparation method and the type of surfactant on the properties of cephalexin (CPX) microspheres in order to obtain delivery systems suitable for the treatment of dairy mastitis. Microspheres were obtained using various preparation conditions and their physicochemical characteristics such as size, loading efficiency, morphology, and drug crystallinity were investigated. Antibacterial activity of microspheres from the optimum preparation condition was also studied. CPX microspheres were prepared by two different W/O/W emulsion solvent evaporation methods using PLGA as a matrix forming polymer. Several types of surfactants including nonionic, cationic, and anionic at different concentrations were used for preparation of the particles. The type and concentration of surfactant did neither affect the size nor morphology of the microspheres but showed a pronounced effect on the CPX encapsulation efficiency. It was found that Tween 80 showed the highest drug encapsulation efficiency (66.5%). Results from X-ray diffraction diffractograms and differential scanning calorimetry thermograms indicated that CPX entrapped in these microparticles was amorphous. Assessment of antibacterial activity showed that the obtained CPX microspheres exhibited good inhibition with minimum inhibitory concentration and minimum bactericidal concentration values of 128 µg/mL and 2,048 mg/mL against Staphylococcus aureus ATCC 25923, 512 µg/mL and 4,096 mg/mL against Escherichia coli ATCC 25922, respectively.
Chaisri, Wasana; Hennink, Wim E.; Ampasavate, Chadarat
The optimized preparation of Poly-(lactide-co-glycolic acid) (PLGA) nanospheres containing ubiquinone (UQ) for cosmetic products was pursued. By investigating various conditions for the preparation of UQ/PLGA nanospheres such as the molecular weight of PLGA, PLGA concentration, and UQ concentration, UQ/PLGA nanospheres with increased stability and slower drug release at a higher drug loading efficiency were prepared. Permeation tests on the prepared nanospheres using iontophoresis via electric dermal administration on membrane filters (200?nm pore size) and hairless mouse skin samples were also carried out. After iontophoresis, the nanospheres choked the membrane filter and remained on the horny layer of the hairless mouse skin, even after washing. Therefore, the prepared UQ/PLGA nanospheres and the established iontophoresis technique with the PLGA nanospheres in the present study can be applied to the future development of cosmetics. PMID:22725249
Ito, Fuminori; Takahashi, Tadahito; Kanamura, Kiyoshi; Kawakami, Hiroyoshi
Various types of rifampicin (RIF)-loaded microparticles were compared for their stability during nebulization. Poly(lactide-co-glycolide) (PLGA), chitosan (CHT) and PLGA\\/CHT microparticles (MPs) were prepared by emulsion or precipitation techniques. MPs ability to be nebulized (NE%) as well as stability during freeze-drying or\\/and nebulization (NEED%), were evaluated after RIF extraction from MPs and determination by light spectroscopy. MP mean diameters and ?-potential
Maria-Letizia Manca; Spyridon Mourtas; Vassileios Dracopoulos; Anna Maria Fadda; Sophia G. Antimisiaris
Initiation of effective topical therapy as early as possible within the disease course is associated with improved patient experiences and better therapeutic outcomes in most dermatological diseases. Additionally, patient adherence is associated with better outcomes and lower long-term treatment costs, while poor adherence is directly linked to poor treatment results and patient dissatisfaction. Local cutaneous irritation associated with topical drug formulations has been an historical challenge to therapy initiation and adherence. Retinoids and benzoyl peroxide—essential elements of topical acne treatment—are two of the drugs most commonly associated with application-site adverse events. Novel approaches to product formulation incorporating microsphere technology may improve treatment tolerability, encourage adherence, and contribute to better long-term therapeutic outcomes. Microsphere technology eliminates the rapid delivery of high concentrations of active drug to the application site and instead facilitates controlled release of potentially irritating drugs. It is associated with improved treatment outcomes and minimal irritation. Microsphere formulations of topical tretinoin and benzoyl peroxide currently on the market have demonstrated good efficacy and tolerability and are expected to encourage adherence and long-term therapeutic benefit.
Bone regeneration is a complex process that involves multiple cell types, growth factors (GFs) and cytokines. A synergistic contribution of various GFs and a crosstalk between their signalling pathways was suggested as determinative for the overall osteogenic outcome. The purpose of this work was to develop a brushite-PLGA system, which controls the release rate of the integrated growth factors (GFs) to enhance bone formation. The brushite cement implants were prepared by mixing a phosphate solid phase with an acid liquid phase. PDGF (250 ng) and TGF-?1 (100 ng) were incorporated into the liquid phase. PLGA microsphere-encapsulated VEGF (350 ng) was pre-blended with the solid phase. VEGF, PDGF and TGF-?1 release kinetics and tissue distributions were determined using iodinated ((125)I) GFs. In vivo results showed that PDGF and TGF-?1 were delivered more rapidly from these systems implanted in an intramedullary defect in rabbit femurs than VEGF. The three GFs released from the brushite-PLGA system remained located around the implantation site (5 cm) with negligible systemic exposure. Bone peak concentrations of approximately 4 ng/g and 1.5 ng/g of PDGF and TGF-?1, respectively were achieved on day 3. Thereafter, PDGF and TGF-?1 concentrations stayed above 1 ng/g during the first week. The scaffolds also provided a VEGF peak concentration of nearly 6 ng/g on day 7 and a local concentration of approximately 1.5 ng/g during at least 4 weeks. Four weeks post implantation bone formation was considerably enhanced with the brushite-PLGA system loaded with each of the three GFs separately as well as with the combination of PDGF and VEGF. The addition of TGF-?1 did not further improve the outcome. In conclusion, the herein presented brushite-PLGA system effectively controlled the release kinetics and localisation of the three GFs within the defect site resulting in markedly enhanced bone regeneration. PMID:22035848
Reyes, Ricardo; De la Riva, Beatriz; Delgado, Araceli; Hernández, Antonio; Sánchez, Esther; Évora, Carmen
Objective: This study compares 3 cohorts of patients with schizophrenia before, during, and after initiating treatment with fluphenazine decanoate (FD), haloperidol decanoate (HD), or long-acting injectable risperidone (LAR). Methods: Administrative data are analyzed from California Medicaid (Medi-Cal) beneficiaries with schizophrenia who initiated FD, HD, or LAR treatment. Patients were required to have been continuously enrolled in Medi-Cal for 180 days before and 180 days after the start of the new episode of long-acting antipsychotic therapy. Results: There were few demographic and clinical differences among patients initiating FD, HD, and LAR. During the 180 days before starting long-acting injections, most patients initiating FD (53.5%), HD (58.5%), and LAR (61.2%) received oral antipsychotic medications for <80% of the days in this period (medication possession ratio: <0.80). The mean duration of depot treatment episodes was 58.3 days (SD = 53.6) for FD, 71.7 days (SD = 56.4) for HD, and 60.6 days (SD = 48.8) for LAR (F = 18.3, df = 2, 2694, P < .0001, HD > FD). Few patients who started on FD (5.4%), HD (9.7%), or LAR (2.6%) continued for at least 180 days. Most patients in each group (FD [77.4%], HD [78.9%], and LAR [75.5%]) received oral antipsychotic medications during the 45 days after discontinuing long-acting injections. Coprescription with antidepressants, mood stabilizers, and benzodiazepines was common. Conclusions: Patients treated with long-acting antipsychotic injections tend to have complex pharmacological regimens and recent medication nonadherence. A great majority of patients initiating long-acting antipsychotic medications discontinue use within the first few months of treatment.
Olfson, Mark; Marcus, Steven C.; Ascher-Svanum, Haya
Many pharmacological approaches have been used in managing substance use disorders. Conventional pharmacological agents have relatively short durations of action which make them vulnerable to non-adherence and relapse to substance use disorder. To overcome this problem, long-acting preparations have been developed with the aim of reducing the frequency of use and hence improving adherence. This review takes a broad overview of the long-acting preparations available for the management of substance use disorders. The pharmacology, advantages and disadvantages of these preparations are discussed. Many of these preparations hold promise for improving patient outcomes.
Hegde, Aditya; Singh, Shubh Mohan; Sarkar, Siddharth
Dengue virus results in dengue fever or severe dengue hemorrhagic fever/dengue shock syndrome in humans. The purpose of this work was to develop an effective antidengue virus delivery system, by designing poly (dl-lactic-co-glycolic) acid/polyethylene glycol (PLGA/PEG) microspheres using a double-emulsion solvent extraction method, for vaccination therapy based on locally and continuously sustained biological activity. Nonstructural protein 1 (NS1) in deoxyribonucleic acid (DNA) vaccine-loaded PLGA/PEG microspheres exhibited a high loading capacity (4.5% w/w), yield (85.2%), and entrapment efficiency (39%), the mean particle size 4.8 ?m, and a controlled in vitro release profile with a low initial burst (18.5%), lag time (4 days), and continued released protein over 70 days. The distribution of protein on the microspheres surface, outer layer, and core were 3.0%, 28.5%, and 60.7%, respectively. A release rate was noticed to be 1.07 ?g protein/mg microspheres/day of protein release, maintained for 42 days. The cumulative release amount at Days 1, 28, and 42 was 18.5, 53.7, and 62.66 ?g protein/mg microspheres, respectively. The dengue virus challenge in mice test, in which mice received one dose of 20 ?g NS1 protein content of microspheres, in comparison with NS1 protein in Al(OH)3 or PBS solution, was evaluated after intramuscular immunization of BALB/c mice. The study results show that the greatest survival was observed in the group of mice immunized with NS1 protein-loaded PLGA/PEG microspheres (100%). In vivo vaccination studies also demonstrated that NS1 protein-loaded PLGA/PEG microspheres had a protective ability; its steady-state immune protection in rat plasma changed from 4,443 ± 1,384 pg/mL to 10,697 ± 3,197 pg/mL, which was 2.5-fold higher than that observed for dengue virus in Al(OH)3 at 21 days. These findings strongly suggest that NS1 protein-loaded PLGA/PEG microspheres offer a new therapeutic strategy in optimizing the vaccine incorporation and delivery properties of these potential vaccine targeting carriers. PMID:23990724
Huang, Shih-shiung; Li, I-Hsun; Hong, Po-da; Yeh, Ming-kung
A novel method has been developed to protect Recombinant Human Growth Hormone (rhGH) in poly (lactic-co-glycolic acid) (PLGA) microspheres using an aqueous phase/aqueous phase emulsion and S/O/W multi-emulsion method. This method develops a novel rhGH sustained-release system, which is based on the combination of rhGH-loaded dextran microparticles and PLGA microspheres. The process to fabricate rhGH-loaded dextran microparticles involves an aqueous phase/aqueous phase emulsion system formed at the reduced temperature. RhGH was first dissolved in water together with dextran and polyethylene glycol, followed by stirring at the speed of 2000rpm for 20-30s at 0°C, and then a freezing process could enable the dextran phase to separate from the continuous PEG phase and rhGH could preferentially be loaded with dextran. The sample after freezing and phase separation was then lyophilized to powder and washed with dichloromethane to remove the PEG. Once loaded in the dextran microparticles (1-4?m in diameter), rhGH gained resistance to interface tensions and was encapsulated into PLGA microspheres without aggregation thereafter. RhGH released from PLGA microspheres was in a sustained manner with minimal burst and maximally reduced incomplete release in vitro. Single subcutaneous injection of rhGH-loaded PLGA microspheres to rats resulted in a stable plasma concentration for 30days avoiding the drug concentration fluctuations after multiple injections of protein solutions. In a hypophysectomized rat model, the IGF-1 and bodyweight results showed that there were higher than the levels obtained for the sustained release formulation by W/O/W for 40days. These results suggest that the microsphere delivery system had the potential to be an injectable depot for sustained-release of the biocompatible protein of rhGH. PMID:24907681
Kang, Jian; Wu, Fei; Cai, Yunpeng; Xu, Mingxin; He, Mu; Yuan, Weien
A method and apparatus for radiographic characterization of small hollow spherical members (microspheres), constructed of either optically transparent or opaque materials. The apparatus involves a microsphere manipulator which holds a batch of microspheres between two parallel thin plastic films for contact microradiographic characterization or projection microradiography thereof. One plastic film is translated to relative to and parallel to the other to roll the microspheres through any desired angle to allow different views of the microspheres.
Singleton, Russell M. (Livermore, CA)
Substrates, particularly inert synthetic organic resin beads (10) or sheet (12) such as polystyrene are coated with a covalently bound layer (24) of polyacrolein by irradiation a solution (14) of acrolein or other aldehyde with high intensity radiation. Individual microspheres (22) are formed which attach to the surface to form the aldehyde containing layer (24). The aldehyde groups can be converted to other functional groups by reaction with materials such as hydroxylamine. Adducts of proteins such as antibodies or enzymes can be formed by direct reaction with the surface aldehyde groups.
Rembaum, Alan (Inventor); Yen, Richard C. K. (Inventor)
Context: In clinical practice, patients with acromegaly may be switched from therapy with long-acting somatostatin analogs to pegvisomant. The effect of changing therapies on glucose homeostasis and safety has not been reported. Objectives: The objectives of this study were to monitor changes in IGF-I levels, glycemic control, and safety, particularly liver function and tumor size. Design: This was a multicenter,
Ariel L. Barkan; Pia Burman; David R. Clemmons; William M. Drake; Robert F. Gagel; Philip E. Harris
PurposeAlthough treatment advances have improved outcomes in schizophrenia, definitions of remission and recovery are still evolving. Recently proposed criteria for remission (mild or less on multiple core-symptom ratings for at least 6 months) have been applied to a 1-year study of long-acting risperidone injection.
Robert A. Lasser; Cynthia A. Bossie; Georges M. Gharabawi; John M. Kane
Long-acting steroids (LAS) are widely used to treat various inflammatory diseases and allergies. They have many adverse effects including the inhibition of the hypothalamopituitary axis that can last several months. LAS are also strong immunosuppressors and can result in severe opportunistic infections and immunodeficiency-related malignancies. However, the time needed for immune recovery after withdrawal of LAS is unknown. Here we
D. Nassar; N. E. C. Schartz; C. Bouché; A. Lévy; D. Kerob; F. Agbalika; M. Lafaurie; C. Lebbé
Previously, we developed an apatite-coated non-porous poly(lactic-co-glycolic acid) (PLGA) microsphere (ANPM) as an injectable bone substitute. We hypothesized that an apatite-coated porous PLGA microsphere (APPM) would have enhanced osteogenic potential compared to that of an ANPM. To test the hypothesis, critical-sized bone defects were made in mouse calvaria, and APPMs and ANPMs were implanted in the defects for 8 weeks. New bone formed around both types of bone substitutes implanted in mouse calvarial defects. Importantly, the portion of bone-like tissue area in the implant cross-sectional area was significantly higher in the APPM group than in the ANPM group (36.9% versus 14.6%, P < 0.001). Fluorochrome-labeling analysis showed that bone regeneration occurred in the pores of implanted APPMs. The results show that APPM may be useful as a bone substitute in orthopedic applications. PMID:20338097
Lee, Tae-Jin; Kang, Sun-Woong; Bhang, Suk Ho; Kang, Jin Muk; Kim, Byung-Soo
Background Little is known about the comparative effectiveness of atypical antipsychotics in long-acting injection formulation. Due to the absence of head-to-head studies comparing olanzapine long-acting injection and risperidone long-acting injection, this study was intended to make exploratory, indirect, cross-study comparisons between the long-acting formulations of these two atypical antipsychotics in their effectiveness in treating patients with schizophrenia. Methods Indirect, cross-study comparisons between olanzapine long-acting injection and risperidone long-acting injection used 12-month treatment-completion rates, because discontinuation of an antipsychotic for any cause is a recognized proxy measure of the medication’s effectiveness in treating schizophrenia. Following a systematic review of the literature, two indirect comparisons were conducted using open-label, single-cohort studies in which subjects were stabilized on an antipsychotic medication before depot initiation. The first analysis compared olanzapine long-acting injection (one study) with pooled data from nine identified risperidone long-acting injection studies. The second analysis was a “sensitivity analysis,” using only the most similar studies, one for olanzapine long-acting injection and one for risperidone long-acting injection, which shared near-identical study designs and involved study cohorts with near-identical patient characteristics. Pearson Chi-square tests assessed group differences on treatment-completion rates. Results Comparison of olanzapine long-acting injection data (931 patients) with the pooled data from the nine risperidone long-acting injection studies (3950 patients) provided almost identical 12-month treatment-completion rates (72.7% versus 72.4%; P = 0.87). When the two most similar studies were compared, the 12-month completion rate for olanzapine long-acting injection was significantly higher than for risperidone long-acting injection (81.3% versus 47.0%; P < 0.001). However, any conclusions drawn from this comparison may be limited by differences in the studies’ geographic catchment areas. Conclusion Using treatment-completion rates as a proxy measure of medication effectiveness, olanzapine long-acting injection did not differ significantly from risperidone long-acting injection when including all eligible studies. However, the findings of this exploratory analysis should be interpreted with caution, considering the methodological limitations of these indirect, cross-study comparisons.
Ascher-Svanum, Haya; Montgomery, William S; McDonnell, David P; Coleman, Kristina A; Feldman, Peter D
Despite current guidelines and the range of available treatments, over a half of patients with asthma continue to suffer from poor symptomatic control and remain at risk of future worsening. Although a number of non-pharmacological measures are crucial for good clinical management of asthma, new therapeutic controller medications will have a role in the future management of the disease. Several long-acting anticholinergic bronchodilators are under investigation or are available for the treatment of respiratory diseases, including tiotropium bromide, aclidinium bromide, glycopyrronium bromide, glycopyrrolate and umeclidinium bromide, although none is yet licensed for the treatment of asthma. A recent Phase III investigation demonstrated that the once-daily long-acting anticholinergic bronchodilator tiotropium bromide improves lung function and reduces the risk of exacerbation in patients with symptomatic asthma, despite the use of inhaled corticosteroids (ICS) and long-acting ?2-agonists (LABAs). This has prompted the question of what the rationale is for long-acting anticholinergic bronchodilators in asthma. Bronchial smooth muscle contraction is the primary cause of reversible airway narrowing in asthma, and the baseline level of contraction is predominantly set by the level of 'cholinergic tone'. Patients with asthma have increased bronchial smooth muscle tone and mucus hypersecretion, possibly as a result of elevated cholinergic activity, which anticholinergic compounds are known to reduce. Further, anticholinergic compounds may also have anti-inflammatory properties. Thus, evidence suggests that long-acting anticholinergic bronchodilators might offer benefits for the maintenance of asthma control, such as in patients failing to gain control on ICS and a LABA, or those with frequent exacerbations. PMID:25030457
Price, David; Fromer, Leonard; Kaplan, Alan; van der Molen, Thys; Román-Rodríguez, Miguel
Background Risperidone long-acting injectable was previously approved for treatment of schizophrenia as biweekly injections in the gluteal muscle only. We present data on local injection-site tolerability and safety of risperidone long-acting injectable and comparability of systemic exposure of deltoid versus gluteal injections. Methods Risperidone long-acting injectable was administered in an open-label, single-dose, two-way crossover study, with patients randomized to receive either 25mg gluteal/37.5mg deltoid crossover in two treatment periods or 50mg gluteal/50mg deltoid injections crossover; each treatment period was separated by an 85-day observation period (Study 1) and an open-label, multiple-dose study (4 sequential 37.5mg or 50mg deltoid injections every 2 weeks) (Study 2). The pharmacokinetic results from both the studies have already been published. Results In Study 1 (n=170), the majority of patients had no local injection-site findings, based on investigator and patient-rated evaluations. In Study 2 (n=53), seven of the 51 patients who received at least two deltoid injections discontinued (primary endpoint). However, none of the discontinuations were due to injection-site related reasons. The 90-percent upper confidence limit of the true proportion of injection-site issue withdrawals was 5.7 percent. No moderate or severe injection-site reactions were reported. Conclusion Intramuscular injections via the deltoid and gluteal sites are equivalent routes of administration of risperidone long-acting injectable with respect to local injection-site tolerability. The overall safety and tolerability profile of risperidone long-acting injectable was comparable when administered as an intramuscular injection in the deltoid (37.5mg and 50mg) and gluteal (25mg and 50mg) sites.
Quiroz, Jorge A.; Rusch, Sarah; Thyssen, An; Kushner, Stuart
Herein, we envisage the possibility of preparing stable cationic poly(lactic-co-glycolic acid) (PLGA) microspheres encapsulating the iron oxide nanoparticles (IONPs; 8-12 nm). The IONPs are incorporated into PLGA in organic phase followed by microsphere formation and chitosan coating in aqueous medium via nano-emulsion technique. The average size of the microspheres, as determined by dynamic light scattering are about 310 nm, while the zeta potential for the composite remains near 35 mV at pH 4.0. These microspheres are electrophoretically deposited onto indium tin oxide (ITO)-coated glass substrate used as cathode and parallel platinum plate as the counter electrode. This platform is utilized to fabricate a DNA biosensor, by immobilizing a probe sequence specific to Escherichia coli. The bioelectrode shows a surface-controlled electrode reaction with the electron transfer coefficient (?) of 0.64 and charge transfer rate constant (ks) of 61.73 s-1. Under the optimal conditions, this biosensor shows a detection limit of 8.7 × 10-14 M and is found to retain about 81% of the initial activity after 9 cycles of use.Herein, we envisage the possibility of preparing stable cationic poly(lactic-co-glycolic acid) (PLGA) microspheres encapsulating the iron oxide nanoparticles (IONPs; 8-12 nm). The IONPs are incorporated into PLGA in organic phase followed by microsphere formation and chitosan coating in aqueous medium via nano-emulsion technique. The average size of the microspheres, as determined by dynamic light scattering are about 310 nm, while the zeta potential for the composite remains near 35 mV at pH 4.0. These microspheres are electrophoretically deposited onto indium tin oxide (ITO)-coated glass substrate used as cathode and parallel platinum plate as the counter electrode. This platform is utilized to fabricate a DNA biosensor, by immobilizing a probe sequence specific to Escherichia coli. The bioelectrode shows a surface-controlled electrode reaction with the electron transfer coefficient (?) of 0.64 and charge transfer rate constant (ks) of 61.73 s-1. Under the optimal conditions, this biosensor shows a detection limit of 8.7 × 10-14 M and is found to retain about 81% of the initial activity after 9 cycles of use. Electronic supplementary information (ESI) available. See DOI: 10.1039/c3nr34355c
Pandey, Chandra Mouli; Sharma, Aditya; Sumana, Gajjala; Tiwari, Ida; Malhotra, Bansi Dhar
The majority of bioengineering strategies to promote peripheral nerve regeneration after injury have focused on therapies to bridge large nerve defects while fewer therapies are being developed to treat other nerve injuries, such as nerve transection. We constructed delivery systems using fibrin gels containing either free GDNF or polylactide-glycolic acid (PLGA) microspheres with GDNF to treat delayed nerve repair, where ELISA verified GDNF release. We determined the formulation of microspheres containing GDNF that optimized nerve regeneration and functional recovery in a rat model of delayed nerve repair. Experimental groups underwent delayed nerve repair and treatment with GDNF microspheres in fibrin glue at the repair site or control treatments (empty microspheres or free GDNF without microspheres). Contractile muscle force, muscle mass, and MUNE were measured 12 weeks following treatment, where GDNF microspheres (2 weeks formulation) were superior compared to either no GDNF or short-term release of free GDNF to nerve. Nerve histology distal to the repair site demonstrated increased axon counts and fiber diameters due to GDNF microspheres (2 weeks formulation). GDNF microspheres partially reversed the deleterious effects of chronic nerve injury, and recovery was slightly favored with the 2 weeks formulation compared to the 4 weeks formulation. PMID:23239194
Wood, Matthew D; Gordon, Tessa; Kemp, Stephen W P; Liu, Edward H; Kim, Howard; Shoichet, Molly S; Borschel, Gregory H
In this study, we have optimized different formulations of DNA encapsulated into PLGA microspheres by correlating the protocol of preparation and the molecular weight and composition of the polymer, with the main characteristics of these systems in order to design an efficient non-viral gene delivery vector. For that, we prepared poly(D,L-lactic-co-glycolic acid) (PLGA) microparticles with an optimized water-oil-water double emulsion process, by using several types of polymers (RG502, RG503, RG504, RG502H and RG752), and characterized in terms of size, zeta potential, encapsulation efficiency (EE%), morphology, DNA conformation, release kinetics, plasmid integrity and erosion. The size of the particles ranged between 0.7 and 5.7 microm depending on the protocol of formulation and the molecular mass of the polymer used. The microspheres prepared by using in their formulation polymers of high molecular weight (RG503 and RG504) were bigger in size than in the case of using a lower molecular weight polymer (RG502). The EE (%) of plasmid DNA increased with increasing the molecular mass of the polymer and by using the most hydrophilic polymer RG502H, which contains terminal acidic groups in its structure. The plasmid could be encapsulated without compromising its structural and functional integrity. Also a protective effect of PLGA on endonuclease digestion is observed. Plasmid DNA release from microspheres composed of low molecular weight or hydrophilic polymers, like RG502H, was faster than from particles containing high molecular weight or hydrophobic polymers. These PLGA microspheres could be an alternative to the viral vectors used in gene therapy, given that may be used to deliver genes and other bioactive molecules, either very rapidly or in a controlled manner. PMID:16697172
Díez, Sonsoles; Tros de Ilarduya, Conchita
Petroleum pitch carbon microspheres were prepared by flash heating emulsified pitch and carbonizing the resulting microspheres in an inert atmosphere. Microsphere composites were obtained from a mixture of microspheres and tetraester precursor pyrrone powder. Scanning electron micrographs of the composite showed that it was an aggregate of microspheres bonded together by the pyrrone at the sphere contact points, with voids in and among the microspheres. Physical, thermal, and sorption properties of the composite are described. Composite applications could include use as a honeycomb filler in elevated-temperature load-bearing sandwich boards or in patient-treatment tables for radiation treatment of tumors.
Price, H. L.; Nelson, J. B.
A concentric delivery system, composed of the three biomaterials SPU, PLGA, and ?TCP (segmented polyurethane, poly[lactic-co-glycolic acid], and ?-tricalcium phosphate) was fabricated as an external, porous ring of ?TCP with a pasty core of a new SPU, mixed with PLGA microspheres. The regenerative effects of two distinct doses of either immediately available or continuously released rhBMP-2 were evaluated in an 8mm, critical calvaria defect in rats. Protein dose and release kinetics affected material resorption rates and the progression of the regeneration process. Groups treated with the empty system alone or in conjunction with free rhBMP-2 did not respond. By contrast, after 12 weeks, approximately 20% and 60% of the defects implanted with systems loaded with 1.6 ?g and 6.5 ?g rhBMP-2, respectively were healed, with all the growth factor being released in the course of 6 weeks. The NMR, FTIR, GPC, DSC, and histological analyses showed that PLGA microsphere degradation occurred independently of the regenerative process. However, the resorption rate of the SPU and ?TCP did depend on the regeneration process, which was governed by dose and release rate of rhBMP-2. Furthermore, the biocompatibility and high capacity of adaptation to the defect convert the herein proposed, new SPU polymer into a potential material for applications in tissue engineering and regenerative medicine. PMID:23797057
Rodríguez-Évora, M; Delgado, A; Reyes, R; Hernández-Daranas, A; Soriano, I; San Román, J; Evora, C
Intravenous regional anesthesia is a widely used technique for brief surgical interventions, primarily on the upper limbs and less frequently, on the lower limbs. It began being used at the beginning of the 20th century, when Bier injected procaine as a local anesthetic. The technique to accomplish anesthesia has not changed much since then, although different drugs, particularly long-acting local anesthetics, such as ropivacaine and levobupivacaine in low concentrations, were introduced. Additionally, drugs like opioids, muscle relaxants, paracetamol, neostigmine, magnesium, ketamine, clonidine, and ketorolac, have all been investigated as adjuncts to intravenous regional anesthesia, and were found to be fairly useful in terms of an increased onset of operative anesthesia and longer lasting perioperative analgesia. The present article provides an overview of current knowledge with emphasis on long-acting local anesthetic drugs. PMID:24156887
Atanassoff, P G; Lobato, A; Aguilar, J L
The introduction of long-acting injectable atypical antipsychotics has ensured adherence to treatment in patients with low awareness of the disorder, with an acceptable rate of side effects. In the case of long acting olanzapine injection in particular, has particular relevance the existence of a special side-effect called post-injection syndrome. This rare side effect consisting in the presence of symptoms of olanzapine overdose after intramuscular administration of medication has led to restrictions on the use of the drug and the need for patient observation for three hours after each injection. We report a case of postinjection syndrome, to our knowledge, the first in Spain since the commercialization of Zypadhera. As in most cases described in the literature have symptoms of overdosage of olanzapine (dysarthria, sedation, fatigue, etc.) that are selflimiting without any therapeutic measure and are accompanied by supratherapeutic plasma levels of olanzapine. PMID:23440537
Duran-Sindreu, Santiago F; Grasa-Bello, Eva; Corripio-Collado, Illuminada; Sauras-Quetcuti, Rosa B; Keymer-Gausset, Alejandro; Roldán-Bejarano, Alexandra; Alonso-Solís, Anna; Figueras-Vilalta, María; Álvarez-Martínez, Enric
Nitroglycerin (NTG) spray and sublingual tablets rapidly relieve an established attack of angina, and their infrequent use is not associated with the development of tolerance. Although, following a suitable nitrate-free interval, the first dose of oral, long-acting nitrates produces significant hemodynamic effects, increases angina free walking, and decreases exercise-induced ischemia, during continued long-term therapy tolerance limits their usefulness. Appropriate dosing
Udho Thadani; Raymond J. Lipicky
The role of inhaled beta-2 agonists in the management of asthma has changed significantly over the last several years. This review outlines the most recent understanding of the pathophysiology of asthma and the studies that define the roles that both short- and long-acting beta-2 agonists play in therapy for this disease. A concentration on the clinical pharmacology and genetic implications for clinical use of this class of drugs in accordance with the national and international guidelines are described.
Kelly, H. William; Harkins, Michelle S.; Boushey, Homer
OBJECTIVES:The aim of this study was to assess the effects of the long-acting release (LAR) depot octreotide preparation Sandostatin LAR Depot on stool water and electrolyte losses, fecal fat excretion, and GI transit in patients with short bowel syndrome.METHODS:We performed a 15-wk, prospective, open-label study of intramuscular (i.m.) Sandostatin LAR Depot, 20 mg, at 0, 3, 7, and 11 wk.
Vandana Nehra; Michael Camilleri; Duane Burton; LaVonne Oenning; Darlene G. Kelly
Background\\/Aims: The aim of the study was to evaluate the efficacy and safety of lanreotide prolonged release (PR) 30 mg (long-acting lanreotide) in girls with constitutional tall stature (CTS). Methods: This open label prospective study included 35 girls (mean age 12.6 years) with CTS and a predicted adult height of >180 cm. Intramuscular injections of lanreotide PR 30 mg were
Jean-Claude Carel; Joëlle Blumberg; Muriel Bougeard-Julien; Pierre Rochiccioli; Jean-Louis Chaussain; Maïthé Tauber
Patients with first-episode schizophrenia frequently relapse during the first years of the illness. This may be associated with clinical deterioration. It is important to prevent relapses in first-episode schizophrenia. We examine whether risperidone long-acting injection (RLAI) could effectively act to prevent relapse in first-episode schizophrenia. We conducted a prospective, naturalistic, controlled, and open-label study over 2 years in 50 patients with
Borah Kim; Sang-Hyuk Lee; Tae Kyou Choi; ShinYoung Suh; Yong Woo Kim; EunHee Lee; Ki Hwan Yook
Background Nocturnal hypoglycemia may be the most common type of hypoglycemia in individuals with diabetes using insulin and is particularly worrisome because it often goes undetected and may lead to unconsciousness and even death in severe cases. Objectives The prevalence, causes, and consequences of nocturnal hypoglycemia as well as detection and prevention strategies are reviewed, including the use of long-acting insulin analogs, which offer more physiologic and predictable time-action profiles than traditional human basal insulin. Data Sources A total of 307 publications (151 PubMed; 104 Adis; 52 BIOSIS) were reviewed. Review Methods Relevant trials were found by searching for “(detemir OR glargine) AND nocturnal AND (hypoglycemia OR hypoglycaemia) AND diabetes.” To capture trials that may not have specified “nocturnal” in the title or abstract text but still reported nocturnal hypoglycemia data, a supplemental search of PubMed using “(detemir OR glargine) AND (nocturnal OR hypoglycemia OR hypoglycaemia) AND diabetes” was undertaken. Results A review of these trials found that patients with type 1 and type 2 diabetes mellitus have a lower risk for nocturnal hypoglycemia when receiving long-acting insulin analogs (insulin detemir or insulin glargine), provided that glycemic control is comparable to that provided by traditional human basal insulin. Long-acting insulin analogs may be the best option to provide basal insulin coverage in patients who do not choose or require continuous subcutaneous insulin infusion. Conclusions Randomized clinical trials suggest that the long-acting insulin analogs are associated with a lower risk for nocturnal hypoglycemia than neutral protamine Hagedorn without sacrificing glycemic control.
Brunton, Stephen A.
Although long-acting injectable risperidone (LAIR) has been hypothesized to improve medication adherence compared to oral\\u000a medications, data from real-world practice have yet to be presented on time to treatment discontinuation. Records of all new\\u000a prescriptions for antipsychotic medication during the first 2 months of FY 2006 for VA patients diagnosed with schizophrenia\\u000a (N = 11,821) were examined and duration of treatment with LAIR
Somaia Mohamed; Robert Rosenheck; Ilan Harpaz-Rotem; Douglas Leslie; Michael J. Sernyak
Objective: Non-concordance with pharmacotherapy is common in psychiatric patients. Long-acting injectable atypical antipsychotic (LAI AA) medication may improve adherence but patients and clinicians may be reluctant to consider this alternative. This paper describes the application of Motivational Interviewing (MI) to the commencement of LAI AA.Method: We developed a workshop applying the principles of MI to address medication adherence through the
Steve Kisely; Loys Ligate; Marc-André Roy; Terri Lavery
We evaluated the usefulness of a treatment manual to facilitate the use of long-acting injectable risperidone in community\\u000a mental health centers (CMHCs) during an open-label observational study. Perceived clinical utility and clinician adherence\\u000a to the manual were evaluated. Patient adherence to treatment satisfaction, Clinical Global Impression of Severity (CGI-S)\\u000a and the Schizophrenia Quality-of-Life Scale (SQLS) were assessed. Mean score for
John P. Docherty; Robert Jones; Ibrahim Turkoz; Robert A. Lasser; Mary Kujawa
The addition of an inhaled long-acting b2-agonist (LABA) to an inhaled corticosteroid (ICS) gives optimal control of asthma in most patients and two fixed combination inhalers (salmeterol\\/fluticasone and formoterol\\/budesonide) are increas- ingly used as a convenient controller in patients with persistent asthma. There is a strong scientific rationale for the combination of these two drug classes. ICS suppress the chronic
P. J. Barnes
The objective was to evaluate long-acting moxidectin (Cydectin® 2% LA for sheep) against trichostrongylids in sheep. We performed a blocked, parallel, controlled clinical trial. We included 45 ewe-lambs, allocated into treated (n=30, 1.0mg moxidectin per kg bw, subcutaneously at base of ear on D 0) or controls (n=15). Animals had been naturally infected (pre-treatment geometric mean epg counts: 233 and
E. Papadopoulos; I. A. Fragkou; V. S. Mavrogianni; D. A. Gougoulis; D. C. Orfanou; E. Gallidis; S. Ptochos; I. A. Taitzoglou; L. Parker; G. C. Fthenakis
This open-label, rater-blinded, parallel-group study was designed to evaluate noninferiority of paliperidone palmitate (PP), a once-monthly injectable atypical antipsychotic, to once-biweekly risperidone long-acting injectable (RIS-LAI) in adult Chinese patients with acute schizophrenia. Eligible Chinese adults (N=452) with schizophrenia were randomized (1:1) to either PP (N=229; deltoid injections on day 1 [150mg eq.] and day 8 [100mg eq.]; then once-monthly deltoid
Huafang Li; Qing Rui; Xiaoping Ning; Haiyan Xu; Niufan Gu
Hypertension is a global condition affecting billions worldwide. It is a significant contributor to cardiovascular events, cardiac death and kidney disease. A number of medication classes exist to aid healthcare providers and their patients in controlling hypertension. Nifedipine, a dihydropyridine calcium channel blocker, was once one of the most widely used medications for hypertension, but safety and tolerability concerns along with the introduction of new classes of antihypertensive medications and an increasing pool of data showing mortality benefit of other classes caused nifedipine to fall out of favor. More recently, long-acting formulations were developed and made available to clinicians. These newer formulations were designed to address many of the concerns raised by earlier formulations of nifedipine. Numerous clinical trials have been conducted comparing long-acting nifedipine to many of the more commonly prescribed antihypertensive medications. This review will address the pharmacology, pharmacokinetics and the available clinical trial data on long-acting nifedipine and summarize its role in the management of hypertension.
Snider, Morgan E; Nuzum, Donald S; Veverka, Angie
This study describes disposition of long-acting moxifloxacin and conventional formulations of moxifloxacin in sheep after intravenous administration in five male sheep. Long acting moxifloxacin solution (10% moxifloxacin in solution with L-arginine, N-butyl alcohol, and benzyl alcohol) and conventional moxifloxacin (10%) were injected in jugular vein. Blood samples were collected from contralateral jugular vein in test tubes containing 30–50?IU heparin (anticoagulant) periodically from 0.083 to 72?h of drug administration. Drug concentrations in plasma were determined using High-Performance Liquid Chromatography (HPLC) with fluorescence detector. The mobile phase consisted of a mixture of buffer (10?gm of tetrabutyl ammonium hydrogen sulphate per liter-deionised water) and acetonitrile (80?:?20). The buffer was 0.067M of disodium hydrogen phosphate with pH of 7.5. The flow rate was 1?mL·min?1 at ambient temperature. The effluent was monitored at 296?nm excitation and 504?nm emissions wavelength. HPLC with fluorescence detector method for plasma moxifloxacin assay was standardized with specific modification for plasma of sheep in the present study. After single-dose intravenous administration of long acting moxifloxacin the plasma concentration of 0.016 ± 0.001??g·mL?1 was maintained for up to 72?h. Conventional formulation of moxifloxacin remained in body for up to 24?h of drug administration with the level of 0.015 ± 0.005 ?g·mL?1.
Modi, C. M.; Mody, S. K.; Modi, F. D.; Patel, H. B.
The prescribed use of methylphenidate in the treatment of attention deficit hyperactivity disorder (ADHD) is widespread. The intranasal and parenteral abuse of methylphenidate (Ritalin) among teenagers is becoming increasingly more common, and deaths have been reported. Newer medical treatment options of long-acting stimulants offer effective treatment with a lower risk of abuse potential. We describe a case of a 17-year-old girl who had attempted suicide by ingesting 270 mg of Concerta. During the third years of treatment with Concerta, parents of patient reported that the patient had a depressive mood in the last week, and had attempted suicide with five tablets of Concerta 54 mg. She was sent to a local hospital with a diagnosis of long-acting methylphenidate overdose. All of vital and laboratory findings were normal except heart rate, which was 132 beats/min. Since more than 3 h have elapsed after the time of ingestion, activated charcoal administration was not carried out at the hospital. She was only observed for 12 h at the emergency department and later discharged from the hospital. While long-acting stimulants offer lower risk of abuse, their greater availability increases the likelihood of ingestion of this nature. Education of clinicians and families to be aware of this risk should reduce the frequency of this complication of treatment. PMID:21432595
Ozdemir, Esra; Karaman, Mehmet Goksin; Yurteri, Nihal; Erdogan, Ayten
Injectable biomaterials alone may alter local tissue responses, including inflammatory cascades and matrix production (e.g., stimulatory dermal fillers are used as volumizing agents that induce collagen production). To expand upon the available material compositions and timing of presentation, a tunable hyaluronic acid (HA) and poly(lactide-co-glycolide) (PLGA) microsphere composite system was formulated and assessed in subcutaneous and cardiac tissues. HA functionalized with hydroxyethyl methacrylate (HeMA) was used as a precursor to injectable and degradable hydrogels that carry PLGA microspheres (~50 m diameter) to tissues, where the HA hydrogel degradation (~20 or 70 days) and quantity of PLGA microspheres (0–300 mg/ml) are readily varied. When implanted subcutaneously, faster hydrogel degradation and more microspheres (e.g., 75mg/mL) generally induced more rapid tissue and cellular interactions and a greater macrophage response. In cardiac applications, tissue bulking may be useful to alter stress profiles and to stabilize the tissue after infarction, limiting left ventricular (LV) remodeling. When fast degrading HeMA-HA hydrogels containing 75 mg/mL microspheres were injected into infarcted tissue in sheep, LV dilation was limited and the thickness of the myocardial wall and the presence of vessels in the apical infarct region were increased ~35% and ~60%, respectively, compared to empty hydrogels. Both groups decreased volume changes and infarct areas at 8 weeks, compared to untreated controls. This work illustrates the importance of material design in expanding the application of tissue bulking composites to a range of biomedical applications.
Tous, Elena; Weber, Heather M.; Lee, Myung Han; Koomalsingh, Kevin J.; Shuto, Takashi; Kondo, Norihiro; Gorman, Joseph H.; Lee, Daeyeon; Gorman, Robert C.; Burdick, Jason A.
Objective: To evaluate the long-term results of the use of nerve growth factor (NGF)-loaded poly-D, L-lactide-co-glycolide (PLGA) microspheres for improve nerve regeneration with small gap tubulization. Methods: NGF microspheres were prepared by a modified W/O/W emulsion solvent evaporation method. Forty-eight male SD rats were separated into 4 groups and received a chitin conduit to bridge a sciatic nerve injury left a 2 mm gap. Saline (Group A), 20 ng/ml NGF solution (Group B), blank PLGA microspheres (Group C), or 40 ng/ml NGF-loaded microspheres (Group D) was injected in the gap. Each group had two study endpoints, 3 months subgroup and 1 year subgroup. Results: The myelinated fiber count at 2 mm distal to the conduit at 1 year was slightly less than at 3 months in all groups (P>0.05). However, the maturity of the myelinated nerves at 1 year was obviously improved. The fiber count, myelin sheath thickness, axon area of NGF microsphere group were significantly higher than the saline groups at 3 months (P=0.05, P<0.05, and P<0.05, respectively). The SFI was significantly improved in NGF microspheres group compared to the saline group and NGF solution group at 1 year (P<0.05, and P<0.05, respectively). Conclusions: The results demonstrated that the release of NGF microspheres in small gap tubulization benefit on peripheral nerve injury facilitated nerve regeneration histologically, especially for the maturity of early regenerative nerve fibers and also had an effect on functional recovery in the long term.
Wang, Zhenwei; Han, Na; Wang, Jiancheng; Zheng, Hua; Peng, Jianping; Kou, Yuhui; Xu, Chungui; An, Shuai; Yin, Xiaofeng; Zhang, Peixun; Jiang, Baoguo
A water-soluble antioxidant (ascorbic acid, vitamin C) was encapsulated together with poly(l-glutamic acid)-capped silver nanoparticles (AgNpPGA) within a poly(lactide-co-glycolide) (PLGA) polymeric matrix and their synergistic effects were studied. The PLGA/AgNpPGA/ascorbic acid particles synthesized by a physicochemical method with solvent/non-solvent systems are spherical, have a mean diameter of 775 nm and a narrow size distribution with a polydispersity index of 0.158. The encapsulation efficiency of AgNpPGA/ascorbic acid within PLGA was determined to be >90%. The entire amount of encapsulated ascorbic acid was released in 68 days, and the entire amount of AgNpPGAs was released in 87 days of degradation. The influence of PLGA/AgNpPGA/ascorbic acid on cell viability, generation of reactive oxygen species (ROS) in HepG2 cells, as well as antimicrobial activity against seven different pathogens was investigated. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay indicated good biocompatibility of these PLGA/AgNpPGA/ascorbic acid particles. We measured the kinetics of ROS formation in HepG2 cells by a DCFH-DA assay, and found that PLGA/AgNpPGA/ascorbic acid caused a significant decrease in DCF fluorescence intensity, which was 2-fold lower than that in control cells after a 5h exposure. This indicates that the PLGA/AgNpPGA/ascorbic acid microspheres either act as scavengers of intracellular ROS and/or reduce their formation. Also, the results of antimicrobial activity of PLGA/AgNpPGA/ascorbic acid obtained by the broth microdilution method showed superior and extended activity of these particles. The samples were characterized using Fourier transform infrared spectroscopy, field-emission scanning electron microscopy, transmission electron microscopy, zeta potential and particle size analysis. This paper presents a new approach to the treatment of infection that at the same time offers a very pronounced antioxidant effect. PMID:23988864
Stevanovi?, Magdalena; Bra?ko, Ines; Milenkovi?, Marina; Filipovi?, Nenad; Nuni?, Jana; Filipi?, Metka; Uskokovi?, Dragan P
Transforming growth factor-beta1 (TGF-beta1) is of great relevance to cartilage development and regeneration. A delivery system for controlled release of growth factors such as TGF-beta1 may be therapeutic for cartilage repair. We have encapsulated TGF-beta1 into poly(DL-lactide-co-glycolide) (PLGA) microspheres, and subsequently incorporated the microspheres into biodegradable hydrogels. The hydrogels are poly(ethylene glycol) based, and the degradation rate of the hydrogels is controlled by the non-toxic cross-linking reagent, genipin. Release kinetics of TGF-beta1 were assessed using ELISA and the bioactivity of the released TGF-beta1 was evaluated using a mink lung cell growth inhibition assay. The controlled release of TGF-beta1 encapsulated within microspheres embedded in scaffolds is better controlled when compared to delivery from microspheres alone. ELISA results indicated that TGF-beta1 was released over 21 days from the delivery system, and the burst release was decreased when the microspheres were embedded in the hydrogels. The concentration of TGF-beta1 released from the gels can be controlled by both the mass of microspheres embedded in the gel, and by the concentration of genipin. Additionally, the scaffold permits containment and conformation of the spheres to the defect shape. Based on these in vitro observations, we predict that we can develop a microsphere-loaded hydrogel for controlled release of TGF-beta1 to a cartilage wound site. PMID:16140372
DeFail, Alicia J; Chu, Constance R; Izzo, Nicholas; Marra, Kacey G
Problem Greater understanding is needed related to qualitatively-assessed pregnancy intentions and rapid subsequent pregnancies among adolescent and adult mothers. Methods 4-site prospective study of 227 adolescent and adult mothers. Data analyzed to understand the relationship between pregnancy intentions, adolescent status, and use of long-acting contraceptives and rapid subsequent pregnancy. Findings The findings from this study provide evidence of the importance of goal-oriented pregnancy intentions, long-acting contraceptive use, and older age in delaying a second pregnancy. Conclusion Findings reveal the need for clinician awareness of the qualitative pregnancy intentions of young women and potential desired use of long-acting contraceptives.
Waggoner, Miranda R.; Lanzi, Robin Gaines; Klerman, Lorraine V.
Cost is a major barrier to adolescents' ability to obtain long-acting reversible contraception (LARC). By reviewing the available literature on this issue, we provide a framework to understand how insurance coverage, out-of-pocket expenses, parental involvement, and recent pregnancy can impact access. We provide examples of cost-free access to LARC for adolescents, such as the Contraceptive CHOICE Project. Universal coverage for contraception, without cost-sharing, could increase use of LARC among adolescents resulting in fewer unintended pregnancies, improved health outcomes, and considerable cost savings to the healthcare system. PMID:23535059
Eisenberg, David; McNicholas, Colleen; Peipert, Jeffrey F
Long-acting reversible contraception (LARC)—intrauterine devices and the contraceptive implant—are safe and appropriate contraceptive methods for most women and adolescents. The LARC methods are top-tier contraceptives based on effectiveness, with pregnancy rates of less than 1% per year for perfect use and typical use. These contraceptives have the highest rates of satisfaction and continuation of all reversible contraceptives. Adolescents are at high risk of unintended pregnancy and may benefit from increased access to LARC methods. PMID:22996129
This article summarizes the literature regarding the epidemiology and prevention of unintended pregnancy in the United States. Because of the Affordable Care Act and its accompanying contraceptive provision, there is a need for more primary care clinicians to provide family planning services. Office-based interventions to incorporate family planning services in primary care are presented, including clinical tools and electronic health record use. Special attention is paid to long-acting reversible contraceptive methods (the subdermal implant and intrauterine devices); these highly effective and safe methods have the greatest potential to decrease the rate of unintended pregnancy, but have been underused. PMID:24830607
Pickle, Sarah; Wu, Justine; Burbank-Schmitt, Edith
The Food and Drug Administration (FDA) is requiring manufacturers of long-acting and extended-release opioids to have a class-wide Risk Evaluation and Mitigation Strategy (REMS). The comprehensive risk management plan will include training for prescribers on the appropriate and safe use of these pain medications. The letter dated April 19, 2011 from FDA to manufacturers outlining the REMS requirements describes voluntary training that should be certified education "where practicable." The current report includes data from a recent comprehensive study of healthcare professionals and patients and highlights key insights that can guide the development of the opioid REMS training. PMID:22941848
Nicholson, Susan C; Evanyo, Kimberly; Salinas, Gregory D; Roepke, Nancy; Burton, B Stephen; Susalka, Debi
The long-acting neuroleptics perphenazine enanthate and pipothiazine palmitate were found to be effective for the long-term tranquilization of newly-captured and captive impala (Aepyceros melampus). Perphenazine enanthate (1.5 to 5.7 mg kg-1) produced a favourable state of tranquilization with a maximum effect lasting up to 7 d. Pipothiazine palmitate (4.5 mg kg-1) produced tranquilization lasting 16 d. The animals accepted humans inside their pens, at a distance of 0.5 to 4 m, without showing any excitement. No untoward side-effects were observed. PMID:2577291
Gandini, G C; Ebedes, H; Burroughs, R E
Accelerated in vitro release testing methodology has been developed as an indicator of product performance to be used as a discriminatory quality control (QC) technique for the release of clinical and commercial batches of biodegradable microspheres. While product performance of biodegradable microspheres can be verified by in vivo and/or in vitro experiments, such evaluation can be particularly challenging because of slow polymer degradation, resulting in extended study times, labor, and expense. Three batches of Leuprolide poly(lactic-co-glycolic acid) (PLGA) microspheres having varying morphology (process variants having different particle size and specific surface area) were manufactured by the solvent extraction/evaporation technique. Tests involving in vitro release, polymer degradation and hydration of the microspheres were performed on the three batches at 55°C. In vitro peptide release at 55°C was analyzed using a previously derived modification of the Weibull function termed the modified Weibull equation (MWE). Experimental observations and data analysis confirm excellent reproducibility studies within and between batches of the microsphere formulations demonstrating the predictability of the accelerated experiments at 55°C. The accelerated test method was also successfully able to distinguish the in vitro product performance between the three batches having varying morphology (process variants), indicating that it is a suitable QC tool to discriminate product or process variants in clinical or commercial batches of microspheres. Additionally, data analysis utilized the MWE to further quantify the differences obtained from the accelerated in vitro product performance test between process variants, thereby enhancing the discriminatory power of the accelerated methodology at 55°C. PMID:24519488
D'Souza, Susan; Faraj, Jabar A; Dorati, Rossella; DeLuca, Patrick P
Electrospinning is a promising approach to create nanofiber structures that are capable of supporting adhesion and guiding extension of neurons for nerve regeneration. Concurrently, electrical stimulation of neurons in the absence of topographical features also has been shown to guide axonal extension. Therefore, the goal of this study was to form electrically conductive nanofiber structures and to examine the combined effect of nanofiber structures and electrical stimulation. Conductive meshes were produced by growing polypyrrole (PPy) on random and aligned electrospun poly(lactic-co-glycolic acid) (PLGA) nanofibers, as confirmed by scanning electron micrographs and X-ray photon spectroscopy. PPy-PLGA electrospun meshes supported the growth and differentiation of rat pheochromocytoma 12 (PC12) cells and hippocampal neurons comparable to non-coated PLGA control meshes, suggesting that PPy-PLGA may be suitable as conductive nanofibers for neuronal tissue scaffolds. Electrical stimulation studies showed that PC12 cells, stimulated with a potential of 10 mV/cm on PPy-PLGA scaffolds, exhibited 40–50% longer neurites and 40–90% more neurite formation compared to unstimulated cells on the same scaffolds. In addition, stimulation of the cells on aligned PPy-PLGA fibers resulted in longer neurites and more neurite-bearing cells than stimulation on random PPy-PLGA fibers, suggesting a combined effect of electrical stimulation and topographical guidance and the potential use of these scaffolds for neural tissue applications.
Lee, Jae Young; Bashur, Chris A.; Goldstein, Aaron S.; Schmidt, Christine E.
PURPOSE. To develop a controlled-drug delivery system for the long-term inhibition of vascular endothelial growth factor (VEGF) and its mediated responses. METHODS. Poly(lactic-co-glycolic)acid (PLGA) microspheres containing anti-VEGF RNA aptamer (EYE001) formulations in the solid-state were developed by an oil-in-oil solvent evapora- tion process. In vitro experiments were performed to charac- terize the release profiles. Stability and bioactivity of the re-
Karen G. Carrasquillo; Joseph A. Ricker; Ioannis K. Rigas; Joan W. Miller; Evangelos S. Gragoudas; Anthony P. Adamis
Between 5 and 10% of the European population suffers from diabetes, and its prevalence is constantly rising, in Austria like in other countries. The main goals in the treatment of diabetes mellitus are the prevention of complications and organ damage, the prevention of severe hypo- and hyperglycaemia and the preservation of quality of life. Many patients with type 2 diabetes become insulin-dependent in the course of their disease. The application of a long acting insulin or insulin analogue is the simplest way of initiating an insulin therapy and is in accordance with current guidelines. Current scientific evidence shows that the use of long acting insulin analogues for type 2 diabetes; which can no longer be sufficiently controlled with oral antidiabetic agents, is simple, safe and efficacious. Thus, this treatment option should be available without any restrictions to physicians and patients in order to facilitate the beginning of an insulin regime. This position paper summarises up the current evidence concerning this subject. PMID:19657612
Ludvik, Bernhard; Brath, Helmut; Wascher, Thomas; Toplak, Hermann
Background Adolescent women have a high risk of unintended pregnancy. Currently, there are little data about their choice to initiate long-acting reversible contraception (LARC). Study Design We evaluated the association of age and preference for a LARC vs. a non-LARC method among adolescent participants in the Contraceptive CHOICE Project, comparing those aged 14–17 years to adolescents aged 18–20 years. We then analyzed the association between age and choice of the implant vs. the intrauterine device (IUD) among adolescents. Results Of the 5086 women enrolled, 70% (n=3557) of participants chose a LARC method. Among adolescents aged 14–20 years, 69% of 14–17-year-olds chose LARC, while 61% of 18–20-year-olds chose LARC (relative risk 1.16, 95% confidence interval 1.03–1.30). Among adolescents choosing a LARC method, 63% (n=93/148) of the 14–17-year-olds chose the implant, whereas 71% (n=364/510) of the 18–20-year-olds chose the IUD. Conclusion Long-acting reversible contraception use is clearly acceptable and common among adolescents enrolled in the Contraceptive CHOICE Project, with the younger group being most interested in the implant.
Mestad, Renee; Secura, Gina; Allsworth, Jenifer E; Madden, Tessa; Zhao, Qiuhong; Peipert, Jeffrey F
Carbamazepine (CBZ) is the gold standard antiepileptic drug (AED) for focal onset seizures. Despite CBZ being the benchmark AED, with readily available therapeutic drug monitoring, patients presenting with recurrent secondarily generalized tonic-clonic (or cluster) seizures or generalized tonic-clonic status epilepticus (SE) are primarily treated with other long-acting agents. The aim of the study was to examine the potential use of rectal (PR) CBZ as alternative long-acting treatment to parenteral AEDs following the termination of cluster seizures or SE with acute intravenous therapies. Oral CBZ syrup was given PR using 400-mg equivalent aliquots. Serum CBZ levels were requested after administration to confirm achievement of minimum therapeutic levels (total CBZ>20?mol·L(-1)). Where levels were subtherapeutic, the procedure was repeated using 400-mg CBZ bolus aliquots until therapeutic levels were achieved. Seven patients received PR CBZ to manage cluster seizures or SE following the initial termination of acute seizures with IV therapies including benzodiazepines. Six patients had no prior history of seizures, and 1 patient with a prior history was not taking AED therapy at the time of presentation. All patients subsequently remained seizure-free, and therapeutic CBZ levels were achieved in 6 of the 7 subjects within 5-10h of initial CBZ dosing. In conclusion, the present study reports 7 patients who were safely and effectively treated with PR CBZ, which proved to be a viable and safe alternative to parenteral AEDs for maintenance of seizure freedom. PMID:24333499
Patel, Vishal; Cordato, Dennis J; Malkan, Ashish; Beran, Roy G
Antipsychotics are the mainstay of the long-term treatment of patients with schizophrenia. In this context, the evidence also supports the effectiveness of long-acting injections (LAIs) or depots of antipsychotics regarding their relapse-preventing properties. When a LAI formulation of risperidone was launched as the first second-generation depot, there was a renaissance of interest in these formulations. In the meantime, olanzapine, paliperidone, and aripiprazole have been approved by regulatory authorities as LAIs in various countries. All studies using the new-generation depots have shown a clear advantage over placebo regarding relapse prevention and symptom reduction. Safety profiles of the long-acting compounds are comparable to their oral formulations with the exception of olanzapine pamoate injections, which can sometimes lead to a post-injection delirium. Despite the fact that many treatment guidelines recommend LAI antipsychotics as an important treatment option for the long-term management of schizophrenia, they are still most frequently used in chronically ill patients with considerable compliance problems. It is imperative to overcome this indication bias in order to be able to utilize all available treatment options in the long-term management of schizophrenia. There is little evidence on comparisons between LAIs and their oral mother compounds, and even less concerning effectiveness comparisons between different depots. The purpose of this manuscript is to review the recent clinical evidence on new-generation depot antipsychotics. PMID:23780619
Rauch, Anna-Sophia; Fleischhacker, W Wolfgang
For over 40 years, antipsychotic drugs have been used as long-term maintenance treatment to control symptoms and reduce relapse rates in patients with schizophrenia. 'First-generation' oral agents such as haloperidol and chlorpromazine are associated with high levels of unwanted neurological effects and poor rates of patient adherence.1,2 Long-acting ('depot') injections of antipsychotics were developed to try to improve adherence. 'Second-generation' antipsychotic agents (also known as atypical antipsychotics) were introduced into clinical practice over 16 years ago. Although these agents have a lower propensity to cause extrapyramidal side effects, they are associated with a range of other unwanted effects (e.g. weight gain and its sequelae).1,3,4 Initially, second-generation agents were only available as orally administered medicines. Three long-acting injectable formulations of second-generation antipsychotics are now available in the UK: olanzapine embonate injection (ZypAdhera), paliperidone injection (Xeplion) and risperidone injection (Risperdal Consta). In this article we review the evidence for these agents and discuss the practical implications of their use. PMID:22966099
The management of schizophrenia remains a clinical challenge, despite improvements in drug therapy, the availability of psychosocial treatments and family and community interventions. High rates of impaired adherence play a substantive role in promoting poor outcomes. Long-acting injectable (LAI) antipsychotics have been developed with the aim of enhancing treatment adherence and improving the long-term treatment outcomes of schizophrenia. Second-generation LAIs combine the favourable features of an atypical antipsychotic with the improved pharmacokinetic profile of a long-acting formulation (e.g., improved bioavailability and assured medication delivery). Therefore, LAI antipsychotics may have clinical utility as a potential treatment strategy in many patients. Second-generation LAIs minimise the risk of relapse, improve global outcomes, and may contribute to helping patients improve their level of recovery. Given the relatively recent introduction of these agents, and the promising results of current clinical trials it is anticipated that future well conducted studies will lend support to the more widespread use of these agents in a broader range of patients. PMID:23680996
Lambert, Timothy J
Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation and debilitating symptoms. For patients with moderate-to-severe COPD, long-acting bronchodilators are the mainstay of therapy; as symptoms progress, guidelines recommend combining bronchodilators from different classes to improve efficacy. Inhaled long-acting ?2-agonists (LABAs) have been licensed for the treatment of COPD since the late 1990s and include formoterol and salmeterol.
Donald P Tashkin; Leonardo M Fabbri
The efficacy and tolerability of risperidone long-acting injectable were investigated in patients with schizophrenia or other psychotic disorders who had previously been symptomatically stable on olanzapine treatment. Patients received risperidone long-acting injectable, 25mg, by intramuscular injection every 2 weeks; the dose could be increased to 37.5 or 50 mg if necessary. Patients were transferred directly from their previous medication to
M. Gastpar; M. Masiak; M. A. Latif; S. Frazzingaro; R. Medori; E.-R. Lombertie
Biofouling and tissue inflammation present major challenges toward the realization of long-term implantable glucose sensors. Following sensor implantation, proteins and cells adsorb on sensor surfaces to not only inhibit glucose flux but also signal a cascade of inflammatory events that eventually lead to permeability-reducing fibrotic encapsulation. The use of drug-eluting hydrogels as outer sensor coatings has shown considerable promise to mitigate these problems via the localized delivery of tissue response modifiers to suppress inflammation and fibrosis, along with reducing protein and cell absorption. Biodegradable poly (lactic-co-glycolic) acid (PLGA) microspheres, encapsulated within a poly (vinyl alcohol) (PVA) hydrogel matrix, present a model coating where the localized delivery of the potent anti-inflammatory drug dexamethasone has been shown to suppress inflammation over a period of 1-3 months. Here, it is shown that the degradation of the PLGA microspheres provides an auxiliary venue to offset the negative effects of protein adsorption. This was realized by: (1) the creation of fresh porosity within the PVA hydrogel following microsphere degradation (which is sustained until the complete microsphere degradation) and (2) rigidification of the PVA hydrogel to prevent its complete collapse onto the newly created void space. Incubation of the coated sensors in phosphate buffered saline (PBS) led to a monotonic increase in glucose permeability (50%), with a corresponding enhancement in sensor sensitivity over a 1 month period. Incubation in serum resulted in biofouling and consequent clogging of the hydrogel microporosity. This, however, was partially offset by the generated macroscopic porosity following microsphere degradation. As a result of this, a 2-fold recovery in sensor sensitivity for devices with microsphere/hydrogel composite coatings was observed as opposed to similar devices with blank hydrogel coatings. These findings suggest that the use of macroscopic porosity can reduce sensitivity drifts resulting from biofouling, and this can be achieved synergistically with current efforts to mitigate negative tissue responses through localized and sustained drug delivery. PMID:23039161
Vaddiraju, S; Wang, Y; Qiang, L; Burgess, D J; Papadimitrakopoulos, F
Poly (lactic-co-glycolic acid) (PLGA) is one of the most effective biodegradable polymeric nanoparticles (NPs). It has been approved by the US FDA to use in drug delivery systems due to controlled and sustained- release properties, low toxicity, and biocompatibility with tissue and cells. In the present review, the structure and properties of PLGA copolymers synthesized by ring-opening polymerization of DL-lactide and glicolide were characterized using 1H nuclear magnetic resonance spectroscopy, gel permeation chromatography, Fourier transform infrared spectroscopy and differential scanning calorimetry. Methods of preparation and characterization, various surface modifications, encapsulation of diverse anticancer drugs, active or passive tumor targeting and different release mechanisms of PLGA nanoparticles are discussed. Increasing experience in the application of PLGA nanoparticles has provided a promising future for use of these nanoparticles in cancer treatment, with high efficacy and few side effects. PMID:24568455
Sadat Tabatabaei Mirakabad, Fatemeh; Nejati-Koshki, Kazem; Akbarzadeh, Abolfazl; Yamchi, Mohammad Rahmati; Milani, Mortaza; Zarghami, Nosratollah; Zeighamian, Vahideh; Rahimzadeh, Amirbahman; Alimohammadi, Somayeh; Hanifehpour, Younes; Joo, Sang Woo
Patients with schizophrenia who have been nonadherent to oral antipsychotics may experience better outcomes with long-acting injectable (LAI) antipsychotics. Studies have shown that LAI medications help prevent relapse and rehospitalization in schizophrenia. Despite the evidence that they are beneficial, LAI antipsychotics continue to be underutilized in the United States, partly due to organizational barriers such as concerns about the time and effort related to their use, the costs, and misunderstanding and overall lack of experience on the part of medical staff and patients alike. Doctors and the entire treatment team should become educated on the use and benefits of LAI medications, which they can then impart to their patients and their families, and create treatment plans for the betterment of the patients. PMID:25004193
Kane, John M
Purpose To identify provider and practice characteristics associated with long-acting reversible contraception (LARC – progesterone contraceptive implants or IUDs [intrauterine devices]) provision among adolescent health care providers. Methods We analyzed physician characteristics and self-reported provision of LARC using chi-square analyses. Multivariate logistic regressions identified factors predicting provision of any form of LARC, as well as progesterone contraceptive implants or IUDs specifically. Results In logistic regressions, residency training in obstetrics/gynecology or family medicine (rather than internal medicine/pediatrics) was the strongest predictor of LARC provision, particularly for IUDs. Practicing in suburban (rather than urban) and hospital-based (rather than private) settings was associated with lower and higher likelihoods of providing LARC respectively. Conclusions Exposure to procedural women’s health training was the strongest predictor LARC provision. Increasing the number of providers offering this type of contraception may have broad reaching consequences for adolescent pregnancy prevention, and may be most easily accomplished via contraceptive implants.
Greenberg, Katherine Blumoff; Makino, Kevin K; Coles, Mandy S
A series of potent ?2-adrenoceptor agonists incorporating a biarylamine secondary binding group was identified. The previously reported milveterol (5), identified by a multivalent approach and containing a typical ?2-agonist primary binding group linked via a phenethylamine linker to a hydrophilic secondary binding group, served as an initiation point. A more hydrophobic set of secondary binding groups was explored, prepared rapidly from a common intermediate by Buchwald-Hartwig amination. TD-5471 (25), a potent and selective full agonist of the human ?2-adrenoceptor, was identified as the most promising agent. It is potent, with slow onset in an in vitro guinea pig trachea model and shows a dose-dependent and long duration of action in an in vivo guinea pig model of bronchoprotection. TD-5471 is structurally differentiated from milveterol and its long duration of action is consistent with a correlation with hydrophobicity observed in other long-acting ?2-agonist discovery programs. PMID:24813741
Jacobsen, John R; Aggen, James B; Church, Timothy J; Klein, Uwe; Pfeiffer, Juergen W; Pulido-Rios, Teresa M; Thomas, G Roger; Yu, Cecile; Moran, Edmund J
Insulin overdose can cause harm due to hypoglycaemia, effects on electrolytes and acute hepatic injury. The established long-acting insulin analogue preparations (detemir and glargine) can present specific management problems because, in overdose, their effects are extremely prolonged, often lasting 48-96 hours. The primary treatment is continuous intravenous 10% or 20% glucose infusion with frequent capillary blood glucose monitoring. Surgical excision of the insulin injection site has been used successfully, even days after the overdose occurred. Once the effects of overdose have receded, diabetes treatment must be restarted with care, especially in patients with type 1 diabetes. Monitoring serum insulin concentration has been successfully used to predict when the effects of the overdose will cease. PMID:24098877
Eldred, A E; Mustafa, O G; Hunt, K F; Whitelaw, B C
Schizophrenia is a chronic, severe and recurrent brain disorder that requires continuous, long-term treatment with antipsychotic medication to minimize relapse and provide clinical benefit to patients. For patients with schizophrenia, non-adherence to medication is a major risk factor for relapse and re-hospitalization. Long-acting injectable formulations of second-generation antipsychotics (SGAs-LAIs) provide constant medication delivery and the potential for improved adherence. Currently, three drugs are available for the treatment of schizophrenia, risperidone longacting injectable, olanzapine pamoate and paliperidone palmitate. Several studies have also demonstrated efficacy and safety of such drugs in patients with acute schizophrenia. In the present paper the literature on LAI atypical antipsychotics will be reviewed and practical advice will be given concerning the use of these drugs in the clinical practice. PMID:23343445
De Berardis, Domenico; Marini, Stefano; Carano, Alessandro; Lang, Antonella Padovan; Cavuto, Marilde; Piersanti, Monica; Fornaro, Michele; Perna, Giampaolo; Valchera, Alessandro; Mazza, Monica; Iasevoli, Felice; Martinotti, Giovanni; Di Giannantonio, Massimo
Depot formulations are not widely used in everyday practice. This study aimed to assess psychiatrists' attitudes toward the use of long-acting injectable (LAI) antipsychotics in schizophrenia. We interviewed 113 French psychiatrists about the factors that influenced their prescription of LAI antipsychotics. Multidimensional and cluster analyses were used to detect correlations. The most important factor against the use of LAI antipsychotics is a sufficient estimated compliance with the oral formulation. For first-generation LAI, the main factor is the risk for extrapyramidal symptoms; and for second-generation LAI, it is the unavailability of the equivalent oral formulation. Four factors incite the psychiatrists to prescribe LAI. Two different clusters of patients can also be identified. Most factors influencing the clinicians' attitudes toward the use of LAI antipsychotics are shared in many countries. Conversely, some attitudes related to organizational aspects, particularly the relevance of health care costs, may vary from one country to another. PMID:23817151
Samalin, Ludovic; Charpeaud, Thomas; Blanc, Olivier; Heres, Stephan; Llorca, Pierre-Michel
The past several years have seen an expansion in contraception options. Emerging data support the use of long-acting reversible contraception (LARC) such as the intrauterine device and subdermal implant as the most effective methods of contraception with the highest continuation rates and very high levels of patient satisfaction. In addition, the appropriate target population for the use of the intrauterine device now includes nulliparous women and adolescents. When a patient considers initiating a new contraceptive method, it is important to consider the characteristics of each method, including the side effects, effectiveness, and patient acceptability. Additionally, medical comorbidities must also be evaluated prior to choosing a method. In this article, we provide a brief overview of available reversible contraceptive methods, with an emphasis on LARC.
Mestad, Renee E.; Kenerson, Jessica; Peipert, Jeffrey F.
Diabetes mellitus is a growing public health concern in the US and worldwide. Insulin therapy is the cornerstone of diabetes therapy, and the use of basal insulins will increase as clinicians strive to help their patients reach glycemic goals. Basal insulins have been continually improved upon over the years, and the long-acting basal insulin analogs, glargine and detemir, have many pharmacokinetic and pharmacodynamic advantages over neutral protamine Hagedorn insulin, namely, less variable absorption profiles, a less pronounced peak in effect, and a longer duration of action. Overall, glargine and detemir do not differ greatly in their safety and efficacy profiles. Major differences between the two include lower within-subject variability, lower risk of hypoglycemia, and a weight-sparing effect with insulin detemir. This review summarizes data from the key pharmacokinetic and pharmacodynamic studies, as well as clinical and observational studies to elucidate the role of each basal insulin analog in therapy.
Poon, Kitty; King, Allen B
Objective To investigate a possible increased risk observed in tiotropium clinical trials of stroke and other adverse events. Design New users of long-acting anticholinergic therapy (tiotropium HandiHaler®) were compared with new users of long-acting ?-agonist (LABA) monotherapy, and propensity scores were used to control confounding. Setting UK healthcare system general practitioner electronic medical record database. Participants 10?840 patients newly prescribed tiotropium (n=4767) or LABA (n=6073), at least 40?years old, and not having asthma as their only respiratory illness. Primary and secondary outcome measures Incidence rates of total stroke, myocardial infarction, angina and other adverse events. Results Tiotropium was associated with increased rates of stroke (HR=1.49, 95% CI 0.91 to 2.45), angina (HR=1.38, 95% CI 0.88 to 2.16) and myocardial infarction (HR=1.26, 95% CI 0.72 to 2.21). Groups had similar rates of chronic obstructive pulmonary disease exacerbation (HR=0.95, 95% CI 0.80 to 1.12) and pneumonia (HR=0.96, 95% CI 0.58 to 1.58). Tiotropium was associated with a lower rate of total mortality (HR=0.70, 95% CI 0.56 to 0.89) and asthma exacerbations (HR=0.46, 95% CI 0.36 to 0.57) than users of LABA. Conclusion Small increased risks of serious ischaemic cardiovascular events have been reported with inhaled anticholinergic medication from randomised and nonrandomized studies of ipratropium, tiotropium HandiHaler® and tiotropium Respimat®. Additional research is needed to understand the full extent of cardiovascular effects of inhaled anticholinergic medications and the patients who may be most susceptible.
Wentworth, Charles; Lanes, Stephan
To develop the long acting nifedipine oral delivery with bioavailability enhancement, a nifedipine dry elixir (NDE) containing nifedipine ethanol solution in dextrin shell was prepared using a spray-dryer, and then coated nifedipine dry elixir (CNDE) was prepared by coating NDE with Eudragit acrylic resin. The physical characteristics and bioavailability of NDE and CNDE were evaluated, and then compared to those of nifedipine powder. NDE and CNDE, which were spherical in shape, had about 6.64 and 8.68-8.75 ?m of geometric mean diameters, respectively. The amount of nifedipine dissolved from NDE for 60 min increased about 7- and 40-fold compared to nifedipine powder in pH 1.2 simulated gastric fluid and pH 6.8 simulated intestinal fluid, respectively. Nifedipine released from CNDE was retarded in both dissolution media compared with that from NDE. After oral administration of NDE, the C(max) and AUC(0?8h) of nifedipine in rat increased about 13- and 7-fold, respectively, and the Tmax of nifedipine was reduced significantly compared with those after oral administration of nifedipine powder alone. The AUC(0?8h) and T(max) of nifedipine in CNDE increased markedly and the C(max) of nifedipine in CNDE was significantly reduced compared to those in NDE. It is concluded that CNDE, which could lower the initial burst-out plasma concentration and maintain the plasma level of nifedipine over a longer period with bioavailability enhancement, might be one of potential alternatives to the marketed long acting oral delivery system for nifedipine. PMID:22076771
Choi, Jae-Yoon; Jin, Su-Eon; Park, Youmie; Lee, Hyo-Jong; Park, Yohan; Maeng, Han-Joo; Kim, Chong-Kook
We use hydrophobic poly(lactic-co-glycolic) acid (PLGA) to encapsulate hydrophilic ofloxacin to form drug loading microspheres. Hyaluronic acid (HA) and polylysine (Pls) were used as internal phase additives to see their influences on the drug loading and releasing. Double emulsion (water-in-oil-in-water) solvent extraction/evaporation method was used for the purpose. Particle size analysis display that the polyelectrolytes have low impact on the microsphere average size and distribution. Scanning electron microscope (SEM) pictures show the wrinkled surface resulted by the internal microcavity of the microspheres. Microspheres with HA inside have higher drug loading amounts than microspheres with Pls inside. The loading drug amounts of the microspheres increase with the HA amounts inside, while decreasing with the Pls amounts inside. All the polyelectrolytes adding groups have burst release observed in experiments. The microspheres with Pls internal phase have faster release rate than the HA groups. Among the same polyelectrolyte internal phase groups, the release rate increases with the amounts increasing when Pls is inside, while it decreases with the amounts increasing when HA is inside.
Chen, Long; Li, Hong; Deng, Chun-Ling; Chen, Xiao-Feng
We use hydrophobic poly(lactic-co-glycolic) acid (PLGA) to encapsulate hydrophilic ofloxacin to form drug loading microspheres. Hyaluronic acid (HA) and polylysine (Pls) were used as internal phase additives to see their influences on the drug loading and releasing. Double emulsion (water-in-oil-in-water) solvent extraction/evaporation method was used for the purpose. Particle size analysis display that the polyelectrolytes have low impact on the microsphere average size and distribution. Scanning electron microscope (SEM) pictures show the wrinkled surface resulted by the internal microcavity of the microspheres. Microspheres with HA inside have higher drug loading amounts than microspheres with Pls inside. The loading drug amounts of the microspheres increase with the HA amounts inside, while decreasing with the Pls amounts inside. All the polyelectrolytes adding groups have burst release observed in experiments. The microspheres with Pls internal phase have faster release rate than the HA groups. Among the same polyelectrolyte internal phase groups, the release rate increases with the amounts increasing when Pls is inside, while it decreases with the amounts increasing when HA is inside. PMID:24707480
Wu, Gang; Chen, Long; Li, Hong; Deng, Chun-Ling; Chen, Xiao-Feng
The literature of metabolism in proteinoids and proteinoid microspheres is reviewed and criticized from a biochemical and experimental point of view. Closely related literature is also reviewed in order to understand the function of proteinoids and proteinoid microspheres. Proteinoids or proteinoid microspheres have many activities. Esterolyis, decarboxylation, amination, deamination, and oxidoreduction are catabolic enzyme activities. The formation of ATP, peptides or oligonucleotides is synthetic enzyme activities. Additional activities are hormonal and inhibitory. Selective formation of peptides is an activity of nucleoproteinoid microspheres; these are a model for ribosomes. Mechanisms of peptide and oligonucleotide syntheses from amino acids and nucleotide triphosphate by proteinoid microspheres are tentatively proposed as an integrative consequence of reviewing the literature.
Nakashima, T.; Fox, S. W. (Principal Investigator)
The literature of metabolism in proteinoids and proteinoid microspheres is reviewed and criticized from a biochemical and experimental point of view. Closely related literature is also reviewed in order to understand the function of proteinoids and proteinoid microspheres. Proteinoids or proteinoid microspheres have many activities. Esterolysis, decarboxylation, amination, deamination, and oxidoreduction are catabolic enzyme activities. The formation of ATP, peptides or oligonucleotides is synthetic enzyme activities. Additional activities are hormonal and inhibitory. Selective formation of peptides is an activity of nucleoproteinoid microspheres; these are a model for ribosomes. Mechanisms of peptide and oligonucleotide syntheses from amino acids and nucleotide triphosphate by proteinoid microspheres are tentatively proposed as an integrative consequence of reviewing the literature.
Nakashima, T.; Fox, S. W. (Principal Investigator)
Nanogels are promising carriers for the delivery of anti-cancer drugs for cancer therapy. We report in this study on a Janus nanogel system formed by mixing a prodrug of Taxol (PEGylated Taxol) and a copolymer of PLGA-PEG-PLGA. The Janus nanogels have good stability over months in aqueous solutions and the freeze-dried powder of nanogels can be re-dispersed instantly in aqueous solutions. The Janus nanogels show an enhanced inhibition effect on tumor growth in a mice breast cancer model probably due to the enhanced uptake of the nano-sized materials by the EPR effect. What is more, the nanogels can also serve as physical carriers to co-deliver other anti-cancer drugs such as doxorubicin to further improve the anti-cancer efficacy. The results obtained from H&E staining and TUNEL assay also support the observation of tumor growth inhibition. These results suggest the potential of this novel delivery system for cancer therapy.Nanogels are promising carriers for the delivery of anti-cancer drugs for cancer therapy. We report in this study on a Janus nanogel system formed by mixing a prodrug of Taxol (PEGylated Taxol) and a copolymer of PLGA-PEG-PLGA. The Janus nanogels have good stability over months in aqueous solutions and the freeze-dried powder of nanogels can be re-dispersed instantly in aqueous solutions. The Janus nanogels show an enhanced inhibition effect on tumor growth in a mice breast cancer model probably due to the enhanced uptake of the nano-sized materials by the EPR effect. What is more, the nanogels can also serve as physical carriers to co-deliver other anti-cancer drugs such as doxorubicin to further improve the anti-cancer efficacy. The results obtained from H&E staining and TUNEL assay also support the observation of tumor growth inhibition. These results suggest the potential of this novel delivery system for cancer therapy. Electronic supplementary information (ESI) available: Synthesis and characterization of compounds, dynamic time sweep, H&E result and body weight change of mice. See DOI: 10.1039/c3nr02937a
Wei, Jun; Wang, Huaimin; Zhu, Meifeng; Ding, Dan; Li, Dongxia; Yin, Zhinan; Wang, Lianyong; Yang, Zhimou
Nitroglycerin (NTG) spray and sublingual tablets rapidly relieve an established attack of angina, and their infrequent use is not associated with the development of tolerance. Although, following a suitable nitrate-free interval, the first dose of oral, long-acting nitrates produces significant hemodynamic effects, increases angina free walking, and decreases exercise-induced ischemia, during continued long-term therapy tolerance limits their usefulness. Appropriate dosing regimens of controlled-release formulations of isosorbide dinitrate (ISDN) and controlled-release NTG during long-term therapy have not been established. Use of immediate-release formulation of 15-120 mg of ISDN in a qid regimen lead to a marked reduction in the size and duration of antianginal effects compared to the initial dose. Asymmetric tid therapy with 30 mg of ISDN (7 a.m., 1 p.m., and 6 p.m.) is also associated with the development of partial tolerance and appears to provide antianginal prophylaxis for only a period of 6 hours each day. Asymmetric bid therapy with ISDN at 7 a.m. and noon may give sustained effect but is supported by only a single, small study that did not examine effectiveness after the noon dose in long-term use. Isosorbide-5-mononitrate (IS-5-MN) has been the subject of more recent studies than other nitrates because of attempts to bring a number of products into the U.S. market. IS-5-MN in qid, tid, and standard bid (8 a.m. and 8 p.m.) dosing regimens produce tolerance. Asymmetric regimens of immediate-release IS-5-MN (10 and 20 mg) given bid (once in the morning and again 7 hours later) decrease the development of tolerance compared to symmetric regimens and produce an increased exercise duration after each dose of the day; the 20 mg bid dosing is more effective. Similarly, once-daily 120 and 240 mg controlled-release IS-5-MN does not produce tolerance and gives a sustained increase in daytime exercise duration. Both asymmetric bid immediate-release and once-daily controlled-release IS-5-MN preparations do not produce deterioration in exercise performance prior to the administration of the medication in the morning (i.e., no zero-hour effect). Further studies are needed to establish useful dosing regimens for ISDN, for controlled-release ISDN, and for controlled-release nitroglycerin. None of the dosing regimens of any oral, long-acting nitrate (including IS-5-MN) provide 24 hour antianginal and antiischemic effects.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:7848896
Thadani, U; Lipicky, R J
Although the effectiveness of medication in the treatment of anorexia nervosa is uncertain, atypical antipsychotics such as olanzapine and risperidone have been used empirically for decades. we describe the case of a 10-year-old boy with anorexia nervosa in whom remarkable improvement was seen following the administration of risperidone or risperidone long-acting injection and deterioration when these agents were ceased. Because this is, to the best of our knowledge, the first report describing the usefulness of risperidone long-acting injection for adolescent anorexia nervosa.
Iga, Junichi; Ohmori, Tetsuro
Although the effectiveness of medication in the treatment of anorexia nervosa is uncertain, atypical antipsychotics such as olanzapine and risperidone have been used empirically for decades. we describe the case of a 10-year-old boy with anorexia nervosa in whom remarkable improvement was seen following the administration of risperidone or risperidone long-acting injection and deterioration when these agents were ceased. Because this is, to the best of our knowledge, the first report describing the usefulness of risperidone long-acting injection for adolescent anorexia nervosa. PMID:24851123
Umehara, Hidehiro; Iga, Junichi; Ohmori, Tetsuro
Objective: Olanzapine long-acting injection depot (OLAI) has been licensed in the UK since 2008. As a result of the recognition during clinical trials that in 0.07% of injections there may be inadvertent intravenous administration leading to post-injection delirium/sedation syndrome (PDSS), the licence mandates a 3 h observation after each injection and accompaniment of the patient to their final destination. The administration of OLAI may thus necessitate organization of local service provisions. We report on how a single healthcare facility in Northern Ireland has treated three initial patients and present a brief case series on these patients and their clinical outcomes. Methods: In the first three patients with schizophrenia to receive OLAI, the clinical notes were retrospectively examined to provide clinical data. Results: All three patients had acceptable clinical outcomes showing sustained clinical improvement and have continued on OLAI for over 1 year. Observation has been undertaken within an existing daycare unit staffed by nursing staff and occupational therapists for 3 h after each injection. No issues have emerged from the use of this service that has also provided educational and psycho-educational programmes for the patients. No cases of post-injection delirium/sedation syndrome were reported. There have been no additional cost implications. Conclusions: In patients for whom OLAI may be clinically indicated, the utilization of an existing service to provide the 3 h of observation after each injection may represent a solution with a cost-neutral outcome.
Doxorubicin (DOX) is a broad spectrum antineoplastic drug widely used in the treatment of several hematogenous and solid human malignancies. Despite its excellent clinical efficacy as a chemotherapeutic agent, its therapeutic usage has been restricted due to its cardiotoxicity. Phosphodiesterase-5 (PDE-5) inhibitors or erectile dysfunction drugs including sildenafil, have been shown to have powerful cardioprotective effect against injuries under a variety of experimental situations including ischemia/reperfusion injury, myocardial infarction and DOX-induced cardiomyopathy. We studied the effect of – tadalafil, a long acting PDE-5 inhibitor in preventing damage in the heart with DOX treatment. Our results showed that tadalafil improved left ventricular function and survival by attenuating DOX-induced apoptosis and cardiac oxidative stress without interfering with the anti-tumor efficacy of DOX in both in vitro and in vivo tumor models. Herein, we present an overview of our study, and consider the potential mechanisms by which tadalafil, at therapeutically relevant concentrations mediate beneficial cardioprotective effects in DOX cardiotoxicity. Based on our current and previously published studies, we propose that the class of PDE-5 inhibitors can represent a novel approach which can be exploited for achieving therapeutic benefit in the treatment of DOX-induced cardiotoxicity in patients.
Koka, Saisudha; Kukreja, Rakesh C.
The main purpose of this study was to develop and compare the pharmacokinetic behavior of two paliperidone palmitate (PP) nanosuspensions with different particle size after intramuscular (i.m.) administration. PP nanosuspensions were prepared by wet media milling method and the mean particle size of nanosuspension was controlled as 1041±6nm (A) and 505±9nm (B), respectively. The morphology of nanosuspensions was observed by scanning electron microscope (SEM). Differential scanning calorimeter (DSC) and powder X-ray diffraction (PXRD) confirmed the crystallinity of PP in nanosuspensions. The physical and chemical stabilities of nanosuspensions A and B were investigated by particle analyzer and HPLC after storage for 2 months at 25°C, 4°C and mechanical shaking condition. No obvious change in particle size and chemical degradation of drug were observed. Following single-dose i.m. administration to beagle dogs, the release of paliperidone lasted for nearly 1 month. The Tmax of nanosuspensions A and B was 6 (d) and 10 (d). The AUC0-t and Cmax of nanosuspensions A was 2.0-fold and 1.8-fold higher than nanosuspensions B (p<0.05). The results demonstrated that PP nanosuspensions formulation had long-acting effect. Nanosuspension A with a larger particle size performed better than nanosuspension B. As a result, it is important to design appropriate particle size of nanosuspensions for i.m. administration in order to produce larger therapeutic effect. PMID:24882037
Leng, Donglei; Chen, Hongming; Li, Guangjing; Guo, Mengran; Zhu, Zhaolu; Xu, Lu; Wang, Yongjun
The effects of long-acting somatostatin analogues, angiopeptin (AGP) and Sandostatin (SMS), on the early decline in the lens content of glutathione (GSH), ATP and NADPH and increase in sorbitol were studied in STZ diabetic rats, and comparison was made with the effect of insulin. Three factors prompted this study: (i) the known increase in IGF-1 in ocular tissue in diabetes and antagonistic effect of somatostatins, (ii) the known effect of IGF-1 in increasing lens aldose reductase and (iii) the lack of effect of somatostatins on diabetic hyperglycaemia, the latter enabling a differentiation to be made between effects of hyperglycaemia per se and site(s) of IGF-1/somatostatins. All four metabolites studied showed a significant restoration towards the normal control level after 7 days of treatment with AGP and SMS, and AGP was more effective on levels of GSH and ATP. A significant correlation was found between GSH and ATP across all groups at 7 days treatment. The redox state changes in diabetes include both NADP+/NADPH and NAD+/NADH in the conversion of glucose to sorbitol and via sorbitol dehydrogenase to fructose with a linked decrease in ATP formation via NAD+/NADH regulation of the glycolytic pathway. The interlinked network of change includes the requirement for ATP in the synthesis of GSH. The present study points to possible loci of action of somatostatins in improving metabolic parameters in the diabetic rat lens via effects on aldose reductase and/or glucose transport at GLUT 3. PMID:24602114
Kunjara, Sirilaksana; Greenbaum, A Leslie; Sochor, Milena; Flyvbjerg, Allan; Grønbaek, Henning; McLean, Patricia
Insulin treatment in type 1 and type 2 diabetes (T1D and T2D) is highly efficacious, but in practice, non-adherence and ineffective dose titration limit its effectiveness. Barriers to more effective insulin treatment are numerous, including hypoglycaemia, fear of hypoglycaemia and concern about weight gain. The regular treatment timing needed with conventional basal insulins [neutral protamine Hagedorn (NPH) insulin and the first-generation analogues glargine and detemir] may also make adherence to these treatments problematic for many patients. Indeed, surveys indicate that the rigidity of this schedule induces some patients with T1D and T2D to omit insulin doses. Degludec is a novel, ultra-long-acting basal insulin analogue that is as effective as insulin glargine, but significantly reduces patients' risk of nocturnal hypoglycaemia. Because of its peakless, extended and highly predictable glucose-lowering effect, once-daily dosing on a flexible schedule may be feasible with degludec. Studies testing this possibility suggest that degludec tolerates day-to-day variation in dose timing while maintaining full efficacy and low risk of nocturnal hypoglycaemia. Degludec would appear to be an appropriate choice for patients being considered for a basal analogue, and it may be particularly well suited to patients with unpredictable social or work schedules, those who travel frequently and those who find rigid scheduling of their insulin injections a burden or barrier to regular treatment. PMID:23577589
Josse, R G; Woo, V
To develop the long acting nifedipine oral delivery with enhanced bioavailability, nifedipine-loaded gelatin microcapsule containing nifedipine and ethanol in gelatin shell was prepared using a spray-dryer, and then coated microcapsule was prepared by coating the gelatin microcapsule with Eudragit acrylic resin. The dissolution test and the bioavailability of the coated microcapsule in rats were evaluated compared to nifedipine powder. The amount of nifedipine dissolved from gelatin microcapsule for 30 min increased about 5-fold compared to nifedipine powder in pH 1.2 simulated gastric fluid. Nifedipine released from the coated microcapsule was retarded in pH 1.2 simulated gastric fluid compared with that from gelatin microcapsule. Furthermore, the coated gelatin microcapsule maintained the plasma level of nifedipine over 4 h and gave significantly higher AUC of nifedipine than nifedipine powder. Thus, the Eudragit-coated gelatin microcapsule, which could maintain the plasma level of nifedipine over a longer period without the initial burst-out plasma concentration, is a preferable delivery system for poorly water-soluble nifedipine. PMID:19183885
Li, Dong Xun; Kim, Jong Oh; Oh, Dong Hoon; Lee, Won Seok; Hong, Myung Ja; Kang, Jin Yang; Choi, Jong Seo; Woo, Jong Soo; Yong, Chul Soon; Choi, Han-Gon
Abstract Objectives To identify factors involved in women's decisions to choose particular contraceptive methods and more specifically, incentives and disincentives to use three long-acting reversible contraceptive (LARC) methods: injectables, implants, and intrauterine devices/systems (IUDs/IUSs). Methods A total of 502 women aged 18 to 30 completed a cross-sectional online questionnaire. Results The three most important factors in choosing a contraceptive method were: high efficacy at preventing pregnancy, protection against sexually transmitted infections, and non-interference with sexual intercourse. The most common incentives for LARC use were the high efficacy and long duration of action. Disincentives included the possibility of irregular bleeding and concerns about effects on fertility; fear of needles and pain was a particular disincentive for IUD/IUS use. Only 93 (18%) of the participants reported ever having used a LARC. Conclusions Reported disincentives to LARC use (e.g., concern about effects on future fertility) indicated that many young women hold inaccurate beliefs about these methods. The relatively high proportions of women who held neutral attitudes about LARCs (21-40%, depending on the method) highlight the importance of education and contraceptive counselling to improve knowledge about the advantages of these methods. Chinese Abstract ?LARC???/(IUDs / IUSs)? 50218?30? ???LARC??IUDs / IUSs ?93?18%?LARC? LARC???LARCs?21-40%?,?? PMID:24882426
Bracken, Jennifer; Graham, Cynthia A
Fixed-dose combinations of inhaled corticosteroids (ICSs) and long-acting ?2-agonists (LABAs) have been used to manage asthma for several years. They are the preferred therapy option for patients who do not achieve optimal control of their asthma with low-dose ICS monotherapy. In Europe, four ICS/LABA products are commercially available for asthma maintenance therapy (fluticasone propionate/formoterol fumarate, fluticasone propionate/salmeterol xinafoate, budesonide/formoterol fumarate and beclometasone dipropionate/formoterol fumarate), and other combinations are likely to be developed over the next few years (e.g. mometasone/formoterol fumarate, fluticasone furoate/vilanterol, mometasone/indacaterol). Data from randomized, controlled, clinical trials do not demonstrate a clear overall efficacy difference among ICS/LABA combinations approved for asthma therapy. Conversely, pharmacological data indicate that there may be certain advantages to using one ICS or LABA over another because of the specific pharmacodynamic and pharmacokinetic profiles associated with particular treatments. This review article summarizes the pharmacological characteristics oft he various ICSs and LABAs available for the treatment of asthma, including the potential for ICS and LABA synergy, and gives an insight into the rationale for the development of the latest ICS/LABA combination approved for asthma maintenance therapy. PMID:23273165
Tamm, Michael; Richards, David H; Beghé, Bianca; Fabbri, Leonardo
Two commercially available long-acting oxytetracycline (OTC-LA) formulations were administered by intramuscular injection in 2 groups of 10 clinically healthy pigs at the recommended dose level of 20 mg/kg. Plasma concentrations were analysed by high-performance liquid chromatography (HPLC) of a period of 0 to 84 h. The limit of quantification of the assay was 0.125 microgram/ml. The comparison of the CMAX did not reveal any significant differences (4.45 +/- 1.30 and 4.40 +/- 0.9 micrograms/ml). The results were similar for the TMAX (3.60 +/- 1.58 and 4.00 +/- 2.67 h). The areas under the curve were also similar. The AUC0-84 h results were respectively 92.8 +/- 14.1 and 96.3 +/- 11.3 mg.h/l and the AUC0-infinity results were 99.5 +/- 14.7 and 106.7 +/- 15.4 mg.h/l. No significant difference was found. This may be considered as a preliminary study to demonstrate the bioequivalence of the 2 preparations. On the basis of the statistical analysis of the results obtained, a cross-over study using 2 groups of 20 animals is theoretically necessary for such a demonstration. PMID:8087147
Archimbault, P; Navetat, H; Vidal, R; Douin, M J; Mignot, A
Background: Long-acting therapy in laboratory animals offers advantages over the current practice of 2-3 daily drug injections. Yet little is known about the disintegration of biodegradable drug implants in rodents. Objective: Compare bioavailability of buprenorphine with the biodegradation of lipid-encapsulated subcutaneous drug pellets. Methods: Pharmacokinetic and histopathology studies were conducted in BALB/c female mice implanted with cholesterol-buprenorphine drug pellets. Results: Drug levels are below the level of detection (0.5 ng/mL plasma) within 4-5 days of implant. However, necroscopy revealed that interstitial tissues begin to seal implants within a week. Visual inspection of the implant site revealed no evidence of inflammation or edema associated with the cholesterol-drug residue. Chemical analyses demonstrated that the residues contained 10-13% of the initial opiate dose for at least two weeks post implant. Discussion: The results demonstrate that biodegradable scaffolds can become sequestered in the subcutaneous space. Conclusion: Drug implants can retain significant and unintended reservoirs of drugs.
Guarnieri, Michael; Tyler, Betty M.; DeTolla, Louis; Zhao, Ming; Kobrin, Barry
4 years of experience with the TCu 220C (901 women; 28,071 woman months of use) - a long-acting multisleeved copper IUD - are analyzed. Event rates were calculated by life-table analysis with a computer program on an IBM 370/148-OS/VS1. Net cumulative rates at 4 years were as follows: pregnancy 3.3, expulsion 5.2, removal for bleeding, pain and other medical reasons 7.7, and 4.3 respectively. The incidence of pregnancy, expulsions, and removal for bleeding/pain decreases with time. Parity influences the performance of the TCu 220C. It seems to affect the pregnancy rate only marginally, but the expulsion and removal rates (for bleeding, pain, or other medical reasons) are higher in the nulliparae, and the same trends appear to be present for women of lower age groups. The IUD insertion technique seems to be important when determining the effectiveness of the method. The expulsion rate is significantly higher when the push-in technique (without sounding) is used, and the same tendency is present for pregnancies and removals for bleeding/pain, albeit to a lesser degree. Refraining from sounding the uterus and pushing-in the TCu 220C introduces the risk of not inserting the IUD high enough into the uterine cavity and therefore increases the risk of expulsion. PMID:12335870
Thiery, M; Van Der Pas, H; Van Kets, H; Boogers, W; Haspels, A; Amy J-j
David Bromham's editorial on contraceptive implants ignores the wider issues to voice concern that trial by media could limit contraceptive choice by jeopardising research into new methods. However, it is more beneficial to the public for points of conflict to be debated openly. Furthermore, the impetus for research into new contraceptive technology is driven by profit and political motives and is only marginally affected by the media. Implanted contraceptives may increase the choice of contraceptive methods, but they put control of fertility increasingly into the hands of the medical profession. Herein lies their greatest problem: their potential to increase providers' control over clients' choice. There is the danger that certain groups of women may be targeted for their use: in the United States the coercive use of Norplant for mothers receiving welfare benefit has been suggested. Long acting contraceptives are a contraceptive of choice only when they are available without pressure, as part of a wider menu; when instant removal on request is guaranteed; and when there is an open and free flow of information and opinions between users, health professionals, and special interest groups. Images p1394-a
Thompson, M. S.
Clinical and psychosocial deterioration associated with schizophrenia occurs within the first few years following the onset of the illness. Therefore, to improve the long-term prognosis, it is important to provide schizophrenia patients with intensive treatment following their first episode. Relapse is highly associated with partial medication adherence or nonadherence in patients with first-episode schizophrenia. Recent studies suggest that long-acting injectable (LAI) antipsychotics compared with oral antipsychotics are more effective for medication adherence and relapse prevention. Moreover, some clinical guidelines for the treatment of schizophrenia suggested that LAI antipsychotics should be considered when patients are nonadherent “at any stage.” Decreased compliance is a common cause of relapse during the initial stages of the disease. Therefore, LAI antipsychotics should be highly considered when treating patients with first-episode schizophrenia. In the present paper, clinical trial data and current guidelines on the use of LAI antipsychotics for first-episode schizophrenia are discussed as well as the pros and cons of this treatment option.
Kim, Borah; Lee, Sang-Hyuk; Yang, Yen Kuang; Park, Jong-Il; Chung, Young-Chul
Medication nonadherence has been associated with persistence of psychotic symptoms, relapse, and hospitalization in patients with schizophrenia. Patients with untreated psychosis are significantly less likely to achieve remission, whereas antipsychotic drug adherence has been associated with recovery. As such, adherence to antipsychotic drug treatment is a key issue for nurses and treatment team members caring for patients who typically are on chronic, progressive disease course. Long-acting injectable (LAI) anti-psychotic drugs, developed to improve adherence and provide and alternative antipsychotic drug treatment fro schizophrenia, have been associated with improved treatment outcomes including reduction of relapse rates approximately 30% and reduction in hospitalizations. However, LAI antipsychotic drugs remain underutilized in the United States despite a growing body of literature supporting positive outcomes of LAI versus oral antipsychotic drugs. Mental health nurses are in a key position to support improved adherence inpatients with schizophrenia through use of practical educational strategies that help patients, family members, and health care providers better understand and manage treatment. PMID:23547305
Kirk Morton, N; Zubek, Donna
The single dose pharmacokinetic profiles of long-acting injectable (LAI) risperidone and oral risperidone were extrapolated to steady-state. Plasma concentrations of the active moiety (unchanged risperidone + 9-hydroxy-risperidone) were measured by radioimmunoassay up to 72 h after a single oral 1 mg dose of risperidone in healthy volunteers (n = 12), and up to 84 days after a single intramuscular injection of 50 mg LAI risperidone in schizophrenic patients (n = 26). These data were projected to multiple dose regimens (4 mg/day for the oral formulation and 50 mg every 2 weeks for LAI formulation) using the software package WinNonlin, and average steady-state pharmacokinetic profiles were predicted. The most interesting results, obtained at steady-state, were a lower predicted peak plasma level (46 vs. 62 ng/ml) and a lower predicted degree of fluctuation between Cssmax and Cssmin (53 vs 145%) with LAI compared to oral administration, which is in line with actual steady state data on LAI risperidone. In conclusion, the pharmacokinetic profile of LAI risperidone administered every 2 weeks ensures a steady-state profile with concentrations falling in the interval observed with an equivalent oral dose but with lower and less fluctuations (i.e. 1/2 weeks vs 1/day). PMID:16598965
Mannaert, E; Vermeulen, A; Remmerie, B; Bouhours, P; Levron, J C
Recombinant human interferon-? (rhIFN-?) exhibits a potent antiviral activity. Because of poor pharmacokinetics (PK) of rhIFN-?, frequent dosing of rhIFN-? is necessitated to achieve the sustained antiviral efficacy. PEGylation can efficiently improve the PK of rhIFN-? while substantially decrease its bioactivity. The structure, antiviral activity and PK of the PEGylated rhIFN-? were measured to establish their relationship with PEGylation sites, polyethylene glycol (PEG) mass and PEG structure. Accordingly, N-terminus and the lysine residues were selected as the PEGylation sites. PEGs with Mw of 20kDa and 40kDa were used to investigate the effect of PEG mass. Linear and branched PEGs were used to investigate the effect of PEG structure. PEGylation decreased the antiviral activity of rhIFN-? and improved its PK. The PEGylation sites determine the bioactivity of the PEGylated rhIFN-? and the conjugated PEG mass determines the PK. N-terminally PEGylated rhIFN-? with 40kDa linear PEG maintains 21.7% of the rhIFN-? antiviral activity with a half-life of 139.6h. Thus, N-terminally PEGylated rhIFN-? with linear 40kDa PEG is a potential antiviral agent for long-acting treatment of the viral diseases. PMID:24936771
Yu, Weili; Yu, Changming; Wu, Ling; Fang, Ting; Qiu, Rui; Zhang, Jinlong; Yu, Ting; Fu, Ling; Chen, Wei; Hu, Tao
Acetylcholine (neuronal and non-neuronal origin) regulates bronchoconstriction, and mucus secretion. It has an inflammatory effect by inducing attraction, survival and cytokine release from inflammatory cells. Muscarinic receptors throughout the bronchial tree are mainly restricted to muscarinic M1, M2 and M3 receptors. Three long-acting muscarinic receptor antagonists (LAMAs) were approved for the treatment of chronic obstructive pulmonary disease (COPD) in Europe: once-daily tiotropium bromide; once-daily glycopyrronium bromide; and twice-daily aclidinium bromide. All have higher selectivity for M3 receptors than for M2 receptors, and dissociate more slowly from the M3 receptors than they do from the M2 receptors. Some LAMAs showed anti-inflammatory effects [inhibition of neutrophil chemotactic activity and migration of alveolar neutrophils, decrease of several cytokines in the bronchoalveolar lavage (BAL) including interleukin (IL)-6, tumor necrosis factor (TNF)-? and leukotriene (LT)B4] and antiremodeling effects (inhibition of mucus gland hypertrophy and decrease in MUC5AC-positive goblet cell number, decrease in MUC5AC overexpression). In the clinic, LAMAs showed a significant improvement of forced expiratory volume in 1 second (FEV1), quality of life, dyspnea and reduced the number of exacerbations in COPD and more recently in asthma. This review will focus on the three LAMAs approved in Europe in the treatment of chronic airway diseases. PMID:24587893
Alagha, Khuder; Palot, Alain; Sofalvi, Tunde; Pahus, Laurie; Gouitaa, Marion; Tummino, Celine; Martinez, Stephanie; Charpin, Denis; Bourdin, Arnaud; Chanez, Pascal
Paliperidone palmitate (PP) is a recently introduced long-acting atypical, or second-generation, antipsychotic. Published data on PP are currently limited to controlled trials and case reports. In this observational study, we followed up 200 consecutive patients prescribed PP in normal practice. After 1 year, 65% of patients were still receiving PP. The number of admissions to hospital in the year following PP initiation was 0.49/patient compared with 0.69/patient/year, 3 years before initiation (P=0.0001). The mean number of bed days fell from 38.78 to 23.09/patient/year over the corresponding period (P=0.0001). The median number of bed days 3 years before PP initiation was 21.50/year and in the year following PP initiation, it was 0. Outcomes were numerically but not statistically better in those continuing PP than in those who ceased PP within a year of initiation. PP was effective and well-tolerated and, given its positive effect on hospital bed days, broadly cost-effective.
Corifollitropin alfa is being developed by Schering-Plough Corp as an injectable, long-acting follicle-stimulating hormone (FSH) agonist for the treatment of infertility. A single dose of corifollitropin alfa could initiate and sustain multifollicular growth in patients undergoing controlled ovarian stimulation, such as during in vitro fertilization or intracytoplasmic sperm injection. The agent comprises an alpha-subunit, which is identical to that of FSH, and a beta-subunit, which is produced by the fusion of the C-terminal peptide from the beta-subunit of chorionic gonadotropin to the beta-subunit of FSH. Corifollitropin alfa has a longer half-life compared with FSH and thus requires less frequent dosing. The drug was well tolerated and does not appear to be associated with any serious adverse events or the formation of antibodies. The initial results from a large, phase III, double-blind clinical trial indicated that the ongoing pregnancy rate achieved with corifollitropin alfa treatment was high and similar to the rate established with daily treatment of recombinant FSH. The number of oocytes retrieved following the administration of corifollitropin alfa was slightly higher compared with the number observed with daily recombinant FSH treatment. Thus, corifollitropin alfa has the potential to serve as a viable fertility agent and to gain a place in the infertility market. PMID:19337959
Loutradis, Dimitris; Drakakis, Petros; Vlismas, Antonis; Antsaklis, Aristidis
Nanogels are promising carriers for the delivery of anti-cancer drugs for cancer therapy. We report in this study on a Janus nanogel system formed by mixing a prodrug of Taxol (PEGylated Taxol) and a copolymer of PLGA-PEG-PLGA. The Janus nanogels have good stability over months in aqueous solutions and the freeze-dried powder of nanogels can be re-dispersed instantly in aqueous solutions. The Janus nanogels show an enhanced inhibition effect on tumor growth in a mice breast cancer model probably due to the enhanced uptake of the nano-sized materials by the EPR effect. What is more, the nanogels can also serve as physical carriers to co-deliver other anti-cancer drugs such as doxorubicin to further improve the anti-cancer efficacy. The results obtained from H&E staining and TUNEL assay also support the observation of tumor growth inhibition. These results suggest the potential of this novel delivery system for cancer therapy. PMID:23982346
Wei, Jun; Wang, Huaimin; Zhu, Meifeng; Ding, Dan; Li, Dongxia; Yin, Zhinan; Wang, Lianyong; Yang, Zhimou
The effect of processing techniques on the molecular weight of the polymer in biodegradable microspheres of poly(dl-lactic acid) (PLA) and poly(dl-lactic-co-glycolic acid) (PLGA) was investigated. Multiphase microspheres were produced by conventional agitation, potentiometric dispersion, or sonication. Gel permeation chromatography was used to determine the molecular weight of the polymer before and after processing. Polymer in microspheres of PLA produced by sonication experienced a 21% decrease in molecular weight of the polymer after 90 s of sonication, while microspheres made by potentiometric dispersion or mechanical agitation exhibited insignificant changes in molecular weight. Microspheres produced by potentiometric dispersion were found to have a more narrow particle size distribution compared to the other methods. A decrease in the internal diameter of the infusion tube used to produce multiphase microspheres by the potentiometric dispersion method was found to decrease the mean particle size of the resultant microspheres. Two surfactants were investigated at varied levels for utilization in the continuous phase, and particle size analysis revealed that increased surfactant levels caused an increase in the mean particle size of microspheres containing BSA produced by potentiometric dispersion. This phenomenon was attributed to an increase in conductivity of the continuous phase as the surfactant level was increased. PMID:8933352
O'Donnell, P B; McGinity, J W
A new method for preparing protein-loaded biodegradable microspheres by a process involving solid-in-oil-in-water (S/O/W) emulsion was established using poly(ethylene glycol) (PEG). In the first step, a protein solution was lyophilized with PEG, which resulted in the formation of spherical protein microparticles, less than 5 microm in diameter, dispersed in a continuous PEG phase. This process was well explained by the aqueous phase separation phenomenon induced by freezing-condensation. Since this lyophilizate could be directly dispersed in an organic phase containing biodegradable polymer by dissolving PEG with methylene chloride, a conventional in-water drying method could be adopted in the second step. Through this S/O/W emulsion process, horseradish peroxidase was effectively entrapped into monolithic-type microspheres of poly(DL-lactic-co-glycolic acid) (PLGA), without significant loss of activity. Bovine superoxide dismutase (bSOD), as another model protein, could be encapsulated into reservoir-type microspheres by the 'polymer-alloys method' using both poly(DL-lactic acid) (PLA) and PLGA. The initial release of bSOD from this reservoir-type microsphere was efficiently reduced. Further, the bSOD release kinetics could be suitably modified by adjusting the loading amounts of PEG or polymer composition. In this study, the multi-functional nature of PEG was successfully utilized in the preparation and designing of protein-loaded microspheres. PMID:11102683
Morita, T; Sakamura, Y; Horikiri, Y; Suzuki, T; Yoshino, H
Purpose: To compare human urothelial and smooth muscle cells attachment and proliferation using three different matrices; poly lactic-co-glycolic acid (PLGA), PLGA/collagen and human amniotic membrane (hAM). Materials and Methods: Human urothelial and smooth muscle cells were cultured and examined for expression of urothelium (pancytokeratin and uroplakin III) and smooth muscle cells [desmin and alpha smooth muscle actin (?-SMA)] markers. Cells were cultured on three scaffolds; PLGA, PLGA/collagen and hAM. Thereafter, they were analyzed for cell growth on days 1, 3, 7, 14 and 21 after seeding by 3-(4, 5-dimethylthiazole-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Scaffolds were fixed and processed for hematoxylin and eosin (H&E) staining and immunohistochemistry against their cell specific markers after 7 and 14 days of culture. Results: MTT assay results revealed that collagen has improved cell attachment features of PLGA and led to significant increase of MTT signal in PLGA/collagen compared to PLGA (P < .001) and hAM (P < .001). hAM was a weaker matrix for both cell types as demonstrated in MTT assay and scanning electron microscope (SEM) images. SEM micrographs showed normal phenotype and distribution on PLGA and PLGA/collagen. In the same line, cells formed a well-developed layer either on PLGA or PLGA/collagen, which maintained expression of their corresponding markers. Conclusion: Our findings demonstrated significant improvement of cell attachment and growth achieved by collagen coating (PLGA/collagen) compared to PLGA and hAM. hAM despite of its natural entity was a weaker matrix for bladder engineering purposes. PMID:25015608
Sharifiaghdas, Farzaneh; Naji, Mohammad; Sarhangnejad, Reza; Rajabi-Zeleti, Sareh; Mirzadeh, Hamid; Zandi, Mojgan; Saeed, Mahdi
The importance of in vitro degradation of poly(lactide)\\/poly(lactide-co-glycolide) (PLA\\/PLGA) microspheres and of the concomitant in vitro release of a natural and a synthetic antigen for eliciting immune response was studied in mice. A variety of PLAs and PLGAs differing in molecular weight (Mw of 14–130 kDa) and in polymer composition (lactic\\/glycolic acid ratio of 100:00, 75:25, and 50:50) were examined
Claudio Thomasin; Giampietro Corradin; Ying Men; Hans P. Merkle; Bruno Gander
The surface and internal morphology, drug distribution and release kinetics at 22°C of polyesters such as PCL (polycaprolactone) and PLGA (poly(dl-lactic-co-glycolic acid)) 65:35 microspheres containing BSA (bovine serum albumin) have been investigated in order to understand the relationship amongst morphology, drug distribution and in vitro release profiles and to develop controlled release devices for marine fishes in tropical area. CLSM
Yi-Yan Yang; Tai-Shung Chung; Ngee Ping Ng
Background Nanotechnology has received great attention since a decade for the treatment of different varieties of cancer. However, there is a limited data available on the cytotoxic potential of Temozolomide (TMZ) formulations. In the current research work, an attempt has been made to understand the anti-metastatic effect of the drug after loading into PLGA nanoparticles against C6 glioma cells. Nanoparticles were prepared using solvent diffusion method and were characterized for size and morphology. Diffusion of the drug from the nanoparticles was studied by dialysis method. The designed nanoparticles were also assessed for cellular uptake using confocal microscopy and flow cytometry. Results PLGA nanoparticles caused a sustained release of the drug and showed a higher cellular uptake. The drug formulations also affected the cellular proliferation and motility. Conclusion PLGA coated nanoparticles prolong the activity of the loaded drug while retaining the anti-metastatic activity.
One of the persistent challenges confronting tissue engineering is the lack of intrinsic microvessels for the transportation of nutrients and metabolites. An artificial microvascular system could be a feasible solution to this problem. In this study, the femtosecond laser ablation technique was implemented for the fabrication of pillared microvessel scaffolds of polylactic-co-glycolic acid (PLGA). This novel scaffold facilitates implementation of the conventional cell seeding process. The progress of cell growth can be observed in vitro by optical microscopy. The problems of becoming milky or completely opaque with the conventional PLGA scaffold after cell seeding can be resolved. In this study, PLGA microvessel scaffolds consisting of 47 ?m × 80 ?m pillared branches were produced. Results of cell culturing of bovine endothelial cells demonstrate that the cells adhere well and grow to surround each branch of the proposed pillared microvessel networks.
Wang, Hsiao-Wei; Cheng, Chung-Wei; Li, Ching-Wen; Chang, Han-Wei; Wu, Ping-Han; Wang, Gou-Jen
Curcumin-loaded PLGA microcapsules are fabricated by a liquid-driving coaxial flow focusing device. In the process, a stable coaxial cone-jet configuration is formed under the action of a coflowing liquid stream and the coaxial liquid jet eventually breaks up into microcapsules because of flow instability. This process can be well controlled by adjusting the flow rates of three phases including the driving PVA water solution, the outer PLGA ethyl acetate solution and the inner curcumin propylene glycol solution. Confocal and SEM imaging methods clearly indicate the core-shell structure of the resultant microcapsules. The encapsulation rate of curcumin in PLGA is measured to be more than 70%, which is much higher than the tranditional methods such as emulsion. The size distribution of resultant microcapsules under different conditions is presented and compared. An in vitro release simulation platform is further developed to verify the feasibility and reliability of the method.
Lei, Fan; Si, Ting; Luo, Xisheng; Xu, Ronald X.
Although various types of treatment of hepatocellular carcinoma (HCC) have been tried, the prognosis remains dismal, especially in patients with advanced stage of the disease. Somatostatin analogues exert antitumor effects. HCC have been shown to exhibit somatostatin receptors. The present randomized placebo-controlled study aimed at examining the efficacy of long-acting octreotide (Sandostatin LAR) for the treatment of advanced HCC. Seventy
Man-Fung Yuen; Ronnie Tung-Ping Poon; Ching-Lung Lai; Sheung-Tat Fan; Chung-Mau Lo; Ka-Wah Wong; Wai Man Wong; Benjamin Chun-Yu Wong
Paliperidone palmitate is a long-acting injectable antipsychotic agent. This 13-week, multicenter, randomized (1 : 1 : 1 : 1), double-blind, parallel-group study evaluated the efficacy, safety, and tolerability of fixed 25, 50, and 100 milligram equivalent (mg equiv.) doses of paliperidone palmitate vs placebo administered as gluteal injections on days 1 and 8, then every 4 weeks (days 36 and
Henry A Nasrallah; Srihari Gopal; Cristiana Gassmann-Mayer; Jorge A Quiroz; Pilar Lim; Mariëlle Eerdekens; Eric Yuen; David Hough
A 27 month old girl with congenital microvillus atrophy received two courses of SMS 201-995, a synthetic long acting analogue of native somatostatin, in an attempt to decrease profuse secretory diarrhoea. During the first trial at 13 months of age fluid and electrolytes administered by parenteral infusion were decreased as measured by water and faecal electrolyte losses. During the second
R T Couper; A Berzen; G Berall; P M Sherman
A study was conducted under a common protocol in Wisconsin and Wyoming, USA, to evaluate therapeutic and persistent efficacy of two long-acting injectable formulations of moxidectin against lice populations infesting cattle. At each site, 30 beef calves were blocked into groups of three based on naturally acquired Linognathus vituli populations, then randomly assigned to treatments within blocks. Treatments, injected subcutaneously
R. M Cleale; J. E Lloyd; L. L Smith; M. A Grubbs; S. T Grubbs; R Kumar; D. M Amodie
Proteinoid microspheres with stable internal compartments and internal structure are made from acidic proteinoid and basic proteinoid with calcium. The populations of microspheres are characterized by a wide diversity of structure. A model of primitive intracellular communication is suggested by the observed movement of internal particles between compartments of a multicompartmentalized unit. Differential response to pH change and to temperature change has been demonstrated within one population and suggests one mode of adaptive selection among primordial cell populations.
Brooke, S.; Fox, S. W.
The inflammatory response plays a pivotal role in propagating injury of intracerebral hemorrhage (ICH). Glucagon-like-peptide-1 (GLP-1) is a hormone with antidiabetic effect and may also have antiinflammatory properties. Despite consensus that the glucoregulatory action is mediated by the GLP-1 receptor (GLP-1R), mechanisms in the brain remain unclear. We investigated the effect of a long-acting GLP-1 analog, liraglutide, and its truncated metabolite, GLP-1(9-36)a from dipeptidyl peptidase-4 (DPP-4) cleavage in ICH-induced brain injury. Primary outcomes were cerebral edema formation, neurobehavior, and inflammatory parameters. GLP-1(9-36)a, GLP-1R inhibitor, adenosine monophosphate-activated protein kinase (AMPK) phosphorylation inhibitor and DPP-4 inhibitor were administered to examine the mechanisms of action. Liraglutide suppressed neuroinflammation, prevented brain edema and neurologic deficit following ICH, which were partially reversed by GLP-1R inhibitor and AMPK phosphorylation inhibitor. Liraglutide-mediated AMPK phosphorylation was unaffected by GLP-1R inhibitor, and was found to be induced by GLP-1(9-36)a. GLP-1(9-36)a showed salutary effects on primary outcomes that were reversed by AMPK phosphorylation inhibitor but not by GLP-1R inhibitor. Liraglutide and DPP-4 inhibitor co-administration reversed liraglutide-mediated AMPK phosphorylation and antiinflammatory effects. Liraglutide exerted duals actions and the antiinflammatory effects are partially mediated by its metabolite in a phosphorylated AMPK-dependent manner. Therapies that inhibit GLP-1 degradation may weaken the metabolite-mediated effects.
Hou, Jack; Manaenko, Anatol; Hakon, Jakob; Hansen-Schwartz, Jacob; Tang, Jiping; Zhang, John H
Large surveillance studies or phase IV clinical studies of long-acting ?-agonists (LABA) compared with placebo in asthma patients using variable (from nil to regular) doses of inhaled corticosteroids (ICS) have raised the issue of mortality risk in patients with asthma taking regular LABA. There have been a number of meta-analyses and systematic reviews that have examined the risk of LABA in asthma patients, and the general conclusion is that LABA added to ICS reduces asthma-related hospitalizations compared with ICS alone and there is no statistical increase in mortality. However, LABA without ICS do increase mortality risk in asthma. All reviews and analyses show a greater number of LABA deaths, but not all are statistically significant. A recent meta-analysis found LABA with concomitant ICS had a higher mortality rate in asthma than ICS alone. The flaw in the study is the higher doses of ICS in the control arms, but the implicit message remains: the essential need for enough ICS to control airway inflammation. We suggest that the pragmatic solution is to have LABA only available in the same device as ICS for asthma treatment. We do not think that a study comparing the safety of LABA plus ICS versus ICS alone in asthma is necessary. If such a study is conducted, the measurement of morbidity from increased doses of ICS is an essential design consideration. Furthermore, the critical focus in asthma management should not be forgotten - education of health professionals and the community of the critical role of ICS, and the need for good communication between health professionals and the asthma patient to facilitate good asthma control. The same arguments apply to the asthma-with-chronic obstructive pulmonary disease overlap syndrome in older patients. There is an urgent need to provide medical practitioners with the capability to diagnose the overlap syndrome. PMID:22035511
Mysore, Satya; Ruffin, Richard E
Study objective To describe and explore provider- and patient-level perspectives regarding long-acting reversible contraception (LARC) for teens and young adults (ages 16-24). Methods Data collection occurred between June – December 2011. We first conducted telephone interviews with administrative directors at 20 publicly funded facilities that provide family planning services. At six of these sites, we conducted a total of six focus group discussions (FGDs) with facility staff and forty-eight in-depth interviews (IDIs) with facility clients ages 16-24. Results Staff in the FGDs did not generally equate being a teen with ineligibility for IUDs. In contrast to staff, one quarter of the young women did perceive young age as rendering them ineligible. Clients and staff agreed that the “forgettable” nature of the methods and their duration were some of LARC’s most significant advantages. They also agreed that fear of pain associated with both insertion and removal and negative side effects were disadvantages. Some aspects of IUDs and implants were perceived as advantages by some clients but disadvantages by others. Common challenges to providing LARC-specific services to younger patients included extra time required to counsel young patients about LARC methods, outdated clinic policies requiring multiple visits to obtain IUDs, and a perceived higher removal rate among young women. The most commonly cited strategy for addressing many of these challenges was securing supplementary funding to support the provision of these services to young patients. Conclusion Incorporating young women’s perspectives on LARC methods into publicly funded family planning facilities’ efforts to provide these methods to a younger population may increase their use among young women.
Kavanaugh, Megan L.; Frohwirth, Lori; Jerman, Jenna; Popkin, Ronna; Ethier, Kathleen
Unintended pregnancy remains a significant global public health problem; 41% of all pregnancies worldwide in 2008 were unintended. The unintended pregnancy rate is greater in less developed regions (57 per 1000 women aged 15-44 years) than in more developed regions (42 per 1000), with the United States a notable exception at a rate of 52 per 1000 women. Among US women, nearly half of unintended pregnancies are due to incorrect or inconsistent use of a contraceptive method. Long-acting reversible contraception (LARC) includes the intrauterine device and subdermal implant and offers the potential to address the problem of unintended pregnancy. LARC is extremely safe and over 99% effective at preventing pregnancy. In real-world tests LARC methods were over 20 times more effective at preventing unintended pregnancy (HRadj=21.8, 95% confidence interval, 13.7 to 34.9) compared to the contraceptive pill, patch, or ring. Despite their level of effectiveness, less than 15% of contracepting women worldwide use LARC. LARC are only infrequently contraindicated, even among younger and nulliparous women. Instead education, access, and cost are the primary barriers. In a US study of nearly 10000 women aged 14-45 years, when the three barriers were removed 75% of study participants chose a LARC method. As a result, the study reported an 80% reduction in teen births and 75% reduction in abortions among women in the cohort compared to national statistics. If we are serious about reducing unintended pregnancy, we need to be serious about increasing the use of methods that we know work. Greater LARC use and continuation has been proven to effectively reduce unintended pregnancy, including abortion and teen pregnancy. PMID:23689169
PURPOSE Although the US adolescent pregnancy rate is high, use of the most effective reversible contraceptives—intrauterine devices (IUDs) and implantable contraception—is low. Increasing use of long-acting reversible contraception (LARC) could decrease adolescent pregnancy rates. We explored New York City primary care physicians’ experiences, attitudes, and beliefs about counseling and provision of LARC to adolescents. METHODS We conducted in-depth telephone interviews with 28 family physicians, pediatricians, and obstetrician-gynecologists using an interview guide based on an implementation science theoretical framework. After an iterative coding and analytic process, findings were interpreted using the capability (knowledge and skills), opportunity (environmental factors), and motivation (attitudes and beliefs) conceptual model of behavior change. RESULTS Enablers to IUD counseling and provision include knowledge that nulliparous adolescents are appropriate IUD candidates (capability) and opportunity factors, such as (1) a clinical environment supportive of adolescent contraception, (2) IUD availability in clinic, and (3) the ability to insert IUDs or easy access to an someone who can. Factors enabling motivation include belief in the overall positive consequences of IUD use; this is particularly influenced by a physicians’ perception of adolescents’ risk of pregnancy and sexually transmitted disease. Physicians rarely counsel about implantable contraception because of knowledge gaps (capability) and limited access to the device (opportunity). CONCLUSION Knowledge, skills, clinical environment, and physician attitudes, all influence the likelihood a physician will counsel or insert LARC for adolescents. Interventions to increase adolescents’ access to LARC in primary care must be tailored to individual clinical practice sites and practicing physicians, the methods must be made more affordable, and residency programs should offer up-to-date, evidence-based teaching.
Rubin, Susan E.; Davis, Katie; McKee, M. Diane
A recent meta-analysis showed that long-acting injectable (LAI) antipsychotics were not superior to oral antipsychotics for preventing relapse in patients with schizophrenia. We therefore designed a treatment strategy combining risperidone LAI and COMPASS (COMprehensive Psycho-educational Approach and Scheme Set), an original psychoeducational program supporting treatment with risperidone LAI and evaluating subjective treatment satisfaction, transition of symptoms, and effectiveness in preventing symptomatic relapse. The aim of this study was to examine whether addition of COMPASS to risperidone LAI was more effective in preventing relapse in schizophrenia patients than risperidone LAI alone, with the latter group consisting of patients enrolled in a Phase III trial of risperidone LAI in Japan. Patients were followed up for 6 months, with COMPASS continuously implemented from the transition to the observation phase. The primary efficacy measurements were relapse rate (rates of rehospitalization and discontinuation due to inefficacy). Secondary efficacy measurements were the Brief Psychiatric Rating Scale (BPRS) and Global Assessment of Functioning (GAF) scores. Of the 96 patients originally enrolled, 19 (19.8%) were discontinued from all causes. During the 6-month study period, ten of the 96 patients (10.4%) relapsed, compared with a 12.2% relapse rate in patients enrolled in a Phase III trial of risperidone LAI in Japan. Patients showed significant improvements in BPRS total scores (P = 0.0031), BPRS positive (P = 0.0451), BRPS negative (P < 0.0001), and general subscale scores (P = 0.0031), and GAF (P < 0.0001) from baseline to 6 months. In conclusion, the lower relapse rate observed in patients treated with COMPASS plus risperidone LAI than in patients treated with risperidone LAI alone suggests that COMPASS may have benefits in the treatment of schizophrenia, indicating a need for randomized, controlled trials in larger numbers of patients.
Zhao, Yueren; Kishi, Taro; Iwata, Nakao; Ikeda, Manabu
The next-generation human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase inhibitor rilpivirine (TMC278) was administered in rats and dogs as single intramuscular (IM) or subcutaneous (SC) injections, formulated as a 200-nm nanosuspension. The plasma pharmacokinetics, injection site concentrations, disposition to lymphoid tissues, and tolerability were evaluated in support of its potential use as a once-monthly antiretroviral agent in humans. Rilpivirine plasma concentration-time profiles showed sustained and dose-proportional release over 2 months in rats and over 6 months in dogs. The absolute bioavailability approached 100%, indicating a complete release from the depot, in spite of rilpivirine concentrations still being high at the injection site(s) 3 months after administration in dogs. For both species, IM administration was associated with higher initial peak plasma concentrations and a more rapid washout than SC administration, which resulted in a stable plasma-concentration profile over at least 6 weeks in dogs. The rilpivirine concentrations in the lymph nodes draining the IM injection site exceeded the plasma concentrations by over 100-fold 1 month after administration, while the concentrations in the lymphoid tissues decreased to 3- to 6-fold the plasma concentrations beyond 3 months. These observations suggest uptake of nanoparticles by macrophages, which generates secondary depots in these lymph nodes. Both SC and IM injections were generally well tolerated and safe, with observations of a transient inflammatory response at the injection site. The findings support clinical investigations of rilpivirine nanosuspension as a long-acting formulation to improve adherence during antiretroviral therapy and for preexposure prophylaxis.
van ?t Klooster, Gerben; Hoeben, Eva; Borghys, Herman; Looszova, Adriana; Bouche, Marie-Paule; van Velsen, Frans; Baert, Lieven
The treatment of cocaine addiction remains a challenge. The dopamine replacement approach in cocaine addiction involves the use of a competing dopaminergic agonist that might suppress withdrawal and drug craving in abstinent individuals. Although it has long been postulated that such an approach may be therapeutically successful, preclinical or clinical evidence showing its effectiveness to prevent relapse is scant. We used in rats a procedure that involved substitution of the N-substituted benztropine analog 3?-[bis(4'-fluorophenyl)methoxy]-tropane (AHN-1055), a long-acting dopamine uptake inhibitor (DUI), for cocaine. Maintenance treatment was self-administered. After extinction, reinstatement of drug seeking was induced by cocaine priming. We measured the contents of brain-derived neurotrophic factor (BDNF), c-Fos and Fas-associated death domain (FADD) proteins in the medial prefrontal cortex (mPFC) following reinstatement. DUI, but not amphetamine, substitution led to extinction of active lever presses, as did saline substitution. DUI substitution significantly reduced cocaine-induced reinstatement of drug-seeking behavior, which was strongly elicited after saline substitution. Rats passively yoked to DUI also showed reduced cocaine-primed reinstatement. Reductions in drug seeking during reinstatement were matched by downward shifts in the contents of BDNF, c-Fos and FADD proteins in the mPFC, which were elevated in relapsing rats. These data indicate that DUI substitution not only leads to extinction of self-administration behavior but also prevents reinstatement of drug seeking induced by cocaine re-exposure. Thus, DUI substitution therapy using compounds with low abuse potential, even if received passively in the context previously paired with drug taking, may provide an effective treatment for stimulant addiction. PMID:22741574
Velázquez-Sánchez, Clara; Ferragud, Antonio; Ramos-Miguel, Alfredo; García-Sevilla, Jesús A; Canales, Juan J
Background: Antipsychotic long-acting injections (LAIs) reduce covert nonadherence with medication in the clinical management of psychotic disorders. However, they are variably utilised by clinicians, especially in the long term. Factors including poor knowledge, stigma and perceived coercion can all adversely influence LAI utilisation. Previous research has emanated almost exclusively from developed countries. This study explores the knowledge and attitudes of psychiatrists and trainees in Nigeria towards LAIs. Methods: A cross-sectional study was undertaken among mental health professionals in Nigeria using a pre-existing questionnaire. Results: Participant psychiatrists (n = 128) expressed positive attitudes towards LAIs. Their knowledge concerning LAIs and its side effects was fair. The participants reported that nearly half (41.7%) of their patients with a psychotic illness were on LAIs. Those who reported a high prescribing rate for LAIs (>40%) were more likely to endorse more positive ‘patient-centred attitudes’ (p < 0.04). In contrast to previous reports, psychiatrists reported that patients were less likely to feel ashamed when on LAIs, though most endorsed the statement that force was required during LAI administration. Conclusion: The desirability of treatment by injections differs in Africa in comparison to Western cultures, possibly due to the increased potency that injections are perceived to have. This is perhaps evidenced by high rates reported for use of LAIs. Nigerian psychiatrists had positive attitudes to LAIs but their knowledge, particularly regarding side effects, was fair and needs to be improved. Providing information to patients prior to antipsychotic treatment may enhance informed consent in a country where medical paternalism is still relatively strong.
Omoaregba, Joyce O.; Okonoda, Kingsley M.; Otefe, Edebi U.; Patel, Maxine X.
Based on its ideal PK/PD ratios, doxycycline hyclate (DOX-h), a time-dependant antibacterial, is ideally expected to achieve sustained plasma drug concentrations at or slightly above the MIC level for as long as possible between dosing intervals. Pursuing this end, a poloxamer-based matrix was used to produce a 10% long-acting injectable preparation (DOX-h-LA) and its serum concentrations vs. time profile investigated after its injection to pigs in the pericaudal s.c. by parallel design. Results were compared with the forced oral bolus dose and i.v. pharmacokinetics of DOX-h. For this study, 12 recently weaned pigs per group were included in this trial, and a dose of 20 mg/kg was injected in all cases. DOX-h-LA showed the greatest values for bioavailability (115.38%); maximum serum concentration (Cmax) value was 1.5 ± 0.2 with a time to reach Cmax of 3.41 ± 0.04 h and an elimination rate constant of 70.93 ± 0.87( ) h. Considering minimum effective serum concentration of 0.5 ?g/mL, a dose interval of at least 5 days can be achieved for DOX-h-LA, whereas p.o. and i.v. dosing of DOX-h may only last 11 and 15 h, respectively. Pigs were slaughtered on day 30 after this trial, and no visible remnants of the preparation were detected neither fibrosis was observed after a thorough macroscopic and histopathological analysis. PMID:23866042
Gutiérrez, L; Ocampo, L; Espinosa, F; Sumano, H
Recent asthma recommendations advocate the use of long-acting beta-agonists (LABAs) in uncontrolled asthma, but also stress the importance of stepping down this therapy once asthma control has been achieved. The objective of this study was to evaluate downtitration of LABA therapy in pediatric patients who are well-controlled on combination-inhaled corticosteroid (ICS)/LABA therapy. Clinical and physiologic outcomes were studied in children with moderate-to-severe persistent asthma after switching from combination (ICS/LABA) to monotherapy with ICS. Of the 54 patients, 34 (63%) were determined to have stable asthma after the switch, with a mean followup of 10.7 weeks. Twenty (37%) had loss of asthma control leading to addition of leukotriene receptor antagonists, increased ICS, or restarting LABA. There were 2 exacerbations requiring treatment with systemic steroids. In patients with loss of control, there was a statistically significant decline in FEV1 (?8% versus ?1.9%, P = 0.03) and asthma control test (?3.2 versus ?0.5, P = 0.03). This did not approach significance for FEF25-75%, exhaled nitric oxide, lung volumes or airway reactivity. No demographic, asthma control measures, or lung function variables predicted loss of control. Pediatric patients with moderate-to-severe persistent asthma who discontinue LABA therapy have a 37% chance of losing asthma control resulting in augmented maintenance therapies. Recent recommendations of discontinuing LABA therapy as soon as control is achieved should be evaluated in a prospective long-term study.
R. O'Hagan, Adrian; Morton, Ronald; Eid, Nemr
Compliance is a critical issue across all chronic conditions, including schizophrenia. Compliance is not an all-or-nothing phenomenon, with a continuum from taking all medications as prescribed to partial compliance to complete noncompliance. Partial compliance is a serious problem that may result in abrupt dose changes leading to unanticipated adverse effects and can demoralize the patient. Further, there is a nearly 5-fold increase in the risk of relapse in first-episode patients when antipsychotic drug treatment is discontinued. Taken together, these data indicate that it is critical to ensure continuous delivery of antipsychotic treatment. Atypical antipsychotic medications were expected to result in better adherence, primarily because of the anticipated improved efficacy and safety profile. However, atypical agents have poor adherence, irrespective of the type of atypical medication, making it difficult to predict which patients are taking their oral medications. Long-acting injectable (LAI) agents may minimize the fluctuations in peak and overall plasma levels compared with oral agents, indicating they may allow more consistent and predictable administration. Based on clinical experience in my practice, several important observations regarding LAI use in patients with schizophrenia have been identified. First, there are potential advantages to using LAIs, including assistance in understanding reasons for poor response, the possibility of eliminating daily pill ingestion, and the elimination of the abrupt loss of medication coverage. There are also several potential obstacles to the use of LAIs, including a lack of infrastructure for the delivery and disposal of syringes and the ease of use with the oral agents. Several strategies can be used to increase patient willingness to initiate and continue LAI therapy. Strategies to improve acceptance involve presenting the option with enthusiasm, ensuring proper goal setting, educating the patient that this treatment is not equivalent to emergency injections, and repeatedly recommending LAI therapy. Adherence can be improved by ensuring samples are available in the clinical setting at all times. PMID:24919169
Bera, Rimal B
Paliperidone palmitate (PP) is a recently (USA) approved injectable new-generation antipsychotic. This 53-wk, Phase-III double-blind study was designed to assess the non-inferiority of PP to risperidone long-acting injectable (RIS-LAI) in schizophrenia treatment. Acutely symptomatic patients (n=749), with a Positive and Negative Syndrome Scale (PANSS) total score between 60 and 120 were randomly allocated to gluteal injections of either (a) PP: 50 mg eq. on days 1 and 8, and flexible dosing [25-100 mg eq. (i.e. 39-156 mg USA dosing)] once-monthly; or (b) RIS-LAI: bi-weekly injections of 25 mg on days 8 and 22, and flexible dosing (25-50 mg) starting from day 36, with allowed oral supplementation. Patients (n=747) were 59% men, 92% white, mean (s.d.) age of 41 (11.95) yr and 45% (n=339) completed the study. Mean (s.d.) change from baseline to endpoint in PANSS total score was: -11.6 (21.22) PP; and -14.4 (19.76) RIS-LAI (per-protocol analysis set, primary measure); least-squares means difference was -2.6 (95% CI -5.84 to 0.61), with a prespecified 5-point non-inferiority margin. PP's suboptimal dosing regimen (<150 mg eq. initial dose) resulted in lower median plasma levels of the active moiety in PP-treated vs. RIS-LAI-treated patients. Insomnia was the most common treatment-emergent adverse event, with a similar incidence in both groups (15%). PP did not demonstrate comparable efficacy to RIS-LAI, which may be attributable to the initiation dosing strategy employed. Tolerability of both treatments was comparable to previous studies, with no new safety signals detected. PMID:21777507
Fleischhacker, W Wolfgang; Gopal, Srihari; Lane, Rosanne; Gassmann-Mayer, Cristiana; Lim, Pilar; Hough, David; Remmerie, Bart; Eerdekens, Marielle
Aims Long-acting natriuretic peptide (LANP) is one of the peptide hormones in atrial natriuretic peptide (ANP) pro-hormone. Low levels of natriuretic peptide may lead to reduced lipolysis and excessive weight gain in obese patients. The aim of this study was to investigate the relationship between fasting serum LANP level and the metabolic syndrome (MetS) among congestive heart failure (CHF) patients. Methods Fasting blood samples were obtained from 186 patients with normal renal function in cardiac clinic outpatients. CHF defined by the American College of Cardiology Foundation and the American Heart Association 2005 Guidelines. MetS and its components were defined using diagnostic criteria from the International Diabetes Federation. Results Ninety-eight patients (52.7%) had CHF. There was a tendency of increased fasting LANP levels as the NYHA CHF functional classes increased (p?=?0.002). Forty-six of the CHF patients (46.9%) had MetS. Fasting LANP level negatively correlated with MetS among CHF patients (p?0.001). Univariate linear regression analysis showed that BUN (p?=?0.026) positively correlated with fasting serum LANP levels, while body weight (p?=?0.009), BMI (p?=?0.004), homeostasis model assessment of insulin resistance (HOMA-IR; p?=?0.024) and HOMA-? (p?=?0.001) negatively correlated with fasting serum LANP levels among the CHF patients. Multivariate forward stepwise linear regression analysis of the significant variables showed that the HOMA-? (R2 change?=?0.292, p?0.001) and HOMA-IR (R2 change?=?0.081, p?=?0.019) were independent predictors of fasting serum LANP levels in CHF patients. Conclusions LANP level is significantly reduced in CHF patients affected by MetS. HOMA-? and HOMA-IR were independent predictors of serum LANP levels in CHF patients.
Olanzapine pamoate (olanzapine long-acting injection [OLAI]; Zypadhera®; Zyprexa® Relprevv™) is the intramuscular depot formulation of the atypical antipsychotic olanzapine. In two pivotal, double-blind clinical trials of 8 or 24 weeks' duration, the efficacy of recommended dosages of OLAI injected every 2 or 4 weeks (without oral supplementation) was greater than that of placebo in improving symptoms in acutely ill patients with schizophrenia, and generally similar to that of continuing oral olanzapine in preventing psychotic exacerbations in patients with schizophrenia whose symptoms had previously been stabilized on oral olanzapine. The effectiveness of OLAI in the maintenance treatment of schizophrenia was also demonstrated in an (ongoing) open-label extension study in which the all-cause discontinuation rate was 34.3% after 18 months. OLAI is generally well tolerated. It has an adverse event profile similar to that of oral olanzapine, with the exception of adverse events related to the intramuscular route of administration; these include a manageable post-injection syndrome, which occurred in <0.1% of injections in clinical trials. The possibility of a post-injection syndrome event requires a risk management plan (RMP) to be adopted that includes observation by appropriately qualified personnel in a healthcare facility for at least 3 hours post-injection. With its potential to improve adherence to medication, and thereby treatment outcomes, OLAI is a useful addition to the pharmacological options available for the maintenance therapy of schizophrenia. Given its benefit/risk profile, OLAI appears most suited for patients who, despite responding well to oral olanzapine, have difficulties remaining adherent to this form of medication, provided they can comply with the conditions of the RMP. PMID:21080745
Frampton, James E
Long-acting injectable nanoformulated antiretroviral therapy (nanoART) was developed with the explicit goal of improving medicine compliance and for drug targeting of viral tissue reservoirs. Prior nanoART studies completed in humanized virus-infected mice demonstrated sustained antiretroviral responses. However, the pharmacokinetics (PK) and tissue distribution of nanoART were not characterized. To this end, the PK and tissue distribution of nanoformulated atazanavir (ATV) and ritonavir (RTV) injected subcutaneously or intramuscularly in mice and monkeys were evaluated. Fourteen days after injection, ATV and RTV levels were up to 13-, 41-, and 4,500-fold higher than those resulting from native-drug administration in plasma, tissues, and at the site of injection, respectively. At nanoART doses of 10, 50, 100, and 250 mg/kg of body weight, relationships of more- and less-than-proportional increases in plasma and tissue levels with dose increases were demonstrated with ATV and RTV. Multiple-dose regimens showed serum and tissue concentrations up to 270-fold higher than native-drug concentrations throughout 8 weeks of study. Importantly, nanoART was localized in nonlysosomal compartments in tissue macrophages, creating intracellular depot sites. Reflective data were obtained in representative rhesus macaque studies. We conclude that nanoART demonstrates blood and tissue antiretroviral drug levels that are enhanced compared to those of native drugs. The sustained and enhanced PK profile of nanoART is, at least in part, the result of the sustained release of ATV and RTV from tissue macrophases and at the site of injection.
Gautam, Nagsen; Roy, Upal; Balkundi, Shantanu; Puligujja, Pavan; Guo, Dongwei; Smith, Nathan; Liu, Xin-Ming; Lamberty, Benjamin; Morsey, Brenda; Fox, Howard S.; McMillan, JoEllyn; Gendelman, Howard E.
A meta-analysis of randomized controlled trials (RCT) was performed to evaluate the efficacy and safety of long-acting non-ergot dopamine agonists (NEDA) versus placebo in Parkinson's disease (PD). A comprehensive literature search up to February 2013 was performed, and the weighted mean differences (WMD) and relative risks (RR) with 95% confidence intervals (CI) were calculated. Nine RCT (n=2857) which assessed the rotigotine transdermal patch, extended-release pramipexole, and ropinirole prolonged-release, were included. Compared with placebo, long-acting NEDA achieved greater improvements in Unified Parkinson's Disease Rating Scale activities of daily living (ADL) score (WMD -1.77, 95% CI -2.13 to -1.41), motor score (WMD -4.18, 95% CI -4.94 to -3.43) and the ADL and motor subtotal score (WMD -5.12, 95% CI -6.16 to -4.07), as well as a reduction in "off" time (WMD -1.29, 95% CI -1.64 to -0.93) and an increase in "on" time without troublesome dyskinesia (WMD 1.55, 95% CI 1.06 to 2.04). Compared with placebo, long-acting NEDA were associated with a higher risk of nausea, but no difference was found in headache incidence. Higher risks of dizziness, somnolence, constipation, vomiting, and insomnia were only found in early PD while higher risks of dyskinesia and hallucination were only found in advanced PD. The results of our meta-analysis showed that the use of long-acting NEDA can reduce the symptoms of PD patients. However, long-acting NEDA were also associated with a higher incidence of adverse events, especially in early PD patients, compared with placebo. PMID:24786715
Zhou, Chang-Qing; Zhang, Jiang-Wei; Wang, Min; Peng, Guo-Guang
Short-acting calcium antagonists have a deleterious effect on the prognosis for patients with myocardial ischemia, possibly caused by overactivation of sympathetic nerves due to vasodilatation, negative inotropism, or coronary steal. However, there is considerable debate about whether long-acting calcium antagonists as well as the short-acting calcium antagonists have the same effect. Barnidipine-HCl is a newly-developed calcium antagonist with 1:2 short- and long-acting particles. This study evaluated the changes of autonomic tone due to barnidipine. Both the short- and long-acting effect of the calcium antagonist was evaluated. Eleven patients with primary hypertension underwent 24-hour ambulatory electrocardiogram and blood pressure monitoring before and after the treatment with barnidipine. Heart rate and blood pressure were compared before and after the medication. Heart rate variability was analyzed with a Marquette 8000/T. High frequency power (HF), as a parameter of vagal tone, and the ratio to low frequency power (LF), as a parameter of sympathetic tone, were obtained. Twenty-four-hour average blood pressure decreased significantly during the day, but nocturnal hypotension was not observed. Heart rate did not increase. HF decreased at the peak of the short- and long-acting components. LF/HF increased at the peak of the short-acting component. Short-acting particles of barnidipine had a deleterious effect on the autonomic tone, that is overactivation of sympathetic tone and suppression of vagal tone. Long-acting particles of barnidipine suppressed the vagal tone. These findings suggest that short-acting calcium antagonists may cause arrhythmia or deterioration of coronary ischemia. PMID:9253691
Soejima, K; Akaishi, M; Oyamada, K; Mitamura, H; Ogawa, S
Three types of nanoparticle formulation from biodegradable PLGA-TPGS random copolymer were developed in this research for oral administration of anticancer drugs, which include DMAB-modified PLGA nanoparticles, unmodified PLGA-TPGS nanoparticles and DMAB-modified PLGA-TPGS nanoparticles. Firstly, the PLGA-TPGS random copolymer was synthesized and characterized. DMAB was used to increase retention time at the cell surface, thus increasing the chances of particle uptake and improving oral drug bioavailability. Nanoparticles were found to be of spherical shape with an average particle diameter of around 250 nm. The surface charge of PLGA-TPGS nanoparticles was changed to positive after DMAB modification. The results also showed that the DMAB-modified PLGA-TPGS nanoparticles have significantly higher level of the cellular uptake than that of DMAB-modified PLGA nanoparticles and unmodified PLGA-TPGS nanoparticles. In vitro, cytotoxicity experiment showed advantages of the DMAB-modified PLGA-TPGS nanoparticle formulation over commercial Taxotere® in terms of cytotoxicity against MCF-7 cells. In conclusion, oral chemotherapy by DMAB-modified PLGA-TPGS nanoparticle formulation is an attractive and promising treatment option for patients.
Novel nanofibers from blends of polylactic-co-glycolic acid (PLGA) and chitosan have been produced through an emulsion electrospinning process. The spinning solution employed polyvinyl alcohol (PVA) as the emulsifier. PVA was extracted from the electrospun nanofibers, resulting in a final scaffold consisting of a blend of PLGA and chitosan. The fraction of chitosan in the final electrospun mat was adjusted from 0 to 33%. Analyses by scanning and transmission electron microscopy show uniform nanofibers with homogenous distribution of PLGA and chitosan in their cross section. Infrared spectroscopy verifies that electrospun mats contain both PLGA and chitosan. Moreover, contact angle measurements show that the electrospun PLGA/chitosan mats are more hydrophilic than electrospun mats of pure PLGA. Tensile strengths of 4.94 MPa and 4.21 MPa for PLGA/chitosan in dry and wet conditions, respectively, illustrate that the polyblend mats of PLGA/chitosan are strong enough for many biomedical applications. Cell culture studies suggest that PLGA/chitosan nanofibers promote fibroblast attachment and proliferation compared to PLGA membranes. It can be assumed that the nanofibrous composite scaffold of PLGA/chitosan could be potentially used for skin tissue reconstruction. PMID:24689041
Ajalloueian, Fatemeh; Tavanai, Hossein; Hilborn, Jöns; Donzel-Gargand, Olivier; Leifer, Klaus; Wickham, Abeni; Arpanaei, Ayyoob
In the paper, we begin by describing polyethylene glycol-poly lactic acid-co-glycolic acid (PEG-PLGA) which was chosen as a typical model copolymer for the construction of nano-sized drug delivery systems and also the types of PEG-PLGA copolymers that were eluted. Following this we examine the structure-influenced drug delivery applications including nanoparticles, micelles and hydrogels. After that, the preparation methods for nano-sized delivery systems are presented. In addition, the drug loading mode of PEG-PLGA micelles is divided into three aspects. Finally, the drug release profiles of PEG-PLGA micelles, both in terms of their in vitro and in vivo characteristics, are represented. PEG-PLGA copolymers are very suitable for the construction of micelles as carriers for insoluble drugs. This article reviews the structure and the different structure-influenced applications of PEG-PLGA copolymers, concentrating on the application of PEG-PLGA micelles. PMID:24675377
Zhang, Keru; Tang, Xing; Zhang, Juan; Lu, Wei; Lin, Xia; Zhang, Yu; Tian, Bin; Yang, Hua; He, Haibing
In the present article a facile synthesis of cerium oxide nanoparticles (CNPs) encapsulated in PLGA microparticles is reported. The release kinetics of the CNPs from the PLGA matrix was investigated under acidic, basic and near-neutral pH. A diffusion model was applied to determine the diffusivity of the CNPs from the PLGA matrix. The morphology of the degraded PLGA particles was characterized by high resolution SEM. Superoxide dismutase (SOD) mimetic activity was retained in released CNPs for a longer period of time (?90 days) under different pH. PLGA encapsulated CNP showed excellent biocompatibility. This study demonstrates a potential strategy to deliver CNPs using biodegradable PLGA that ensures a slow release of the CNPs over a long period of time. Thus, the synthesized PLGA encapsulated CNPs could find potential applications in tissue engineering like bone remodelling and regeneration, and protection from disorders caused by neurodegeneration. PMID:22419352
Singh, Virendra; Singh, Sanjay; Das, Soumen; Kumar, Amit; Self, William T; Seal, Sudipta
In this research, two simple fabrication methods to fabricate orderly nanostructured PLGA scaffolds using anodic aluminum oxide (AAO) template were conducted. In the vacuum air-extraction approach, the PLGA solution was cast on an AAO template first. The vacuum air-extraction process was then applied to suck the semi-congealed PLGA into the nanopores of the AAO template to form a bamboo sprouts array of PLGA. The surface roughness of the nanostructured scaffolds, ranging from 20 nm to 76 nm, can be controlled by the sucking time of the vacuum air-extraction process. In the replica molding approach, the PLGA solution was cast on the orderly scraggy barrier-layer surface of an AAO membrane to fabricate a PLGA scaffold of concave nanostructure. Cell culture experiments using the bovine endothelial cells (BEC) demonstrated that the nanostructured PLGA membrane can increase the cell growing rate, especially for the bamboo sprouts array scaffolds with smaller surface roughness. PMID:19365732
Wang, Gou-Jen; Lin, Yan-Cheng; Li, Ching-Wen; Hsueh, Cheng-Chih; Hsu, Shan-Hui; Hung, Huey-Shan
Ceramic microspheres were prepared by using Chinese bauxite as raw materials through the centrifugal spray drying method.\\u000a The control technology of microsphere size, degree of sphericity was researched. The ceramic microspheres were sintered by\\u000a a double sintering process. The microstructure and composition of ceramic microsphere were investigated by X-ray diffraction\\u000a (XRD), scanning electron microscopy (SEM) and X-ray energy spectroscopy. The
Xiaosu Cheng; Pingan Liu; Xiuyan Li; Anze Shui; Lingke Zeng
In the present article a facile synthesis of cerium oxide nanoparticles (CNPs) encapsulated in PLGA microparticles is reported. The release kinetics of the CNPs from the PLGA matrix was investigated under acidic, basic and near-neutral pH. A diffusion model was applied to determine the diffusivity of the CNPs from the PLGA matrix. The morphology of the degraded PLGA particles was characterized by high resolution SEM. Superoxide dismutase (SOD) mimetic activity was retained in released CNPs for a longer period of time (~90 days) under different pH. PLGA encapsulated CNP showed excellent biocompatibility. This study demonstrates a potential strategy to deliver CNPs using biodegradable PLGA that ensures a slow release of the CNPs over a long period of time. Thus, the synthesized PLGA encapsulated CNPs could find potential applications in tissue engineering like bone remodelling and regeneration, and protection from disorders caused by neurodegeneration.In the present article a facile synthesis of cerium oxide nanoparticles (CNPs) encapsulated in PLGA microparticles is reported. The release kinetics of the CNPs from the PLGA matrix was investigated under acidic, basic and near-neutral pH. A diffusion model was applied to determine the diffusivity of the CNPs from the PLGA matrix. The morphology of the degraded PLGA particles was characterized by high resolution SEM. Superoxide dismutase (SOD) mimetic activity was retained in released CNPs for a longer period of time (~90 days) under different pH. PLGA encapsulated CNP showed excellent biocompatibility. This study demonstrates a potential strategy to deliver CNPs using biodegradable PLGA that ensures a slow release of the CNPs over a long period of time. Thus, the synthesized PLGA encapsulated CNPs could find potential applications in tissue engineering like bone remodelling and regeneration, and protection from disorders caused by neurodegeneration. Electronic supplementary information (ESI) available. See DOI: 10.1039/c2nr12131j
Singh, Virendra; Singh, Sanjay; Das, Soumen; Kumar, Amit; Self, William T.; Seal, Sudipta
1 Plasma levels of propranolol were measured at intervals after the oral administration of 160 mg propranolol and 160 mg L.A. propranolol in ten subjects who received both drugs on separate occasions. 2 Mean peak plasma concentration of propranolol occurred 2 h after propranolol and 10 h after the L.A. formulation; the peak concentration with the former was four times that with the latter. At 24 h the plasma level was significantly higher after L.A. propranolol. 3 Observations were made in nine healthy volunteers who exercised before and at intervals after the oral administration of 160 mg propranolol and 160 mg L.A. propranolol. 4 Propranolol produced a maximum reduction (27.84 ± 2.4%) in the exercise tachycardia at 3 h and L.A. propranolol a maximum reduction (22.00 ± 1.73%) at 6 h. The effects at 24 h were 9.24 ± 1.55 and 16.79 ± 2.16% respectively. 5 Five subjects were given 160 mg propranolol as a single dose daily for 8 days and on a separate occasion similar treatment with L.A. propranolol. Subjects were exercised and blood samples were taken before and 3 h after each dose on days 1 to 5 and on day 8. 6 The reduction in the exercise tachycardia 3 h after propranolol ranged from 33.0 to 36.9% and 24 h after propranolol from 12.2 to 20.8%. The corresponding values after L.A. propranolol were 26.8 and 31.4 (3 h values) and 20.4 and 25.0 (trough values). 7 The trough plasma levels of propranolol during administration of propranolol ranged from 10.2 to 19.4 ng/ml and peak values from 202.2 to 245.0 ng/ml. The corresponding values after L.A. propranolol were 12.5 to 17.5 (trough values) and 18.4 to 50.0 (peak values) ng/ml. 8 These observations show that the new long acting formulation of propranolol produces a significant reduction of an exercise tachycardia throughout a 24 h period without a very high initial effect during single and multiple dosing. This formulation should be suitable for once a day administration.
Leahey, W. J.; Neill, J. D.; Varma, M. P. S.; Shanks, R. G.
Background. Antipsychotic medications are the key of the treatment in schizophrenia, and a large body of data confirms the value of ongoing and continuous antipsychotic pharmacotherapy in controlling symptoms and preventing relapse. Even so medication non-adherence in patients with schizophrenia continues to be a significant problem and threatens successful treatment outcomes. Estimates is ranging from 40% to 90%. The introduction of the long acting injectable antipsychotics (LAI) had as its primary objective to overcome the poor adherence. Aim. This review focuses on the role of LAI in the treatment of schizophrenia, particularly on new generation antipsychotics. The existing literature, with an emphasis on clinical evidence, is assessed. Both advantages and limitations are discussed. Results. Clinical evidence suggest that treatment with LAI is associated with a better outcome, both global and as a reduced number of rehospitalization, and better adherence. The LAI ensure a better bioavailability, more predictable correlation between drug dose and plasma concentrations, a better pharmacokinetic profile allowing the prescription of lower doses and less risk of side effects. First generation antipsychotic LAI (FGA-LAI) share with their equivalent oral compounds an increased susceptibility to induce extrapyramidal symptoms and tardive dyskinesia, with minor differences between the compounds. The second-generation LAI (SGA-LAI), as their oral formulations, compared to first generation antipsychotics, have the advantage of not causing movement disorders, but their use is complicated by the delayed release (risperidone) and the risk of the syndrome post-injection (olanzapine) and the high cost (paliperidone). Discussion and conclusions. Despite identified advantages, LAIs are not used as widely as might be expected. It would seem that clinicians are at least partly responsible for this, influenced by our own misperceptions (e.g., that LAIs are not acceptable to patients) and misinformation (e.g., increate side effect risk). Current guidelines on the treatment of schizophrenia recommend the use of LAI in patients who have demonstrated non-adherence or recurrent relapses related to poor or no adherence and underline the importance of patient preference. The prescription of LAI will increase in coming years as more number of LAI will be available and the increasing use of compulsory community treatment may contribute to this. PMID:25000887
Graffino, Marco; Montemagni, Cristiana; Mingrone, Cinzia; Rocca, Paola
This open-label, rater-blinded, parallel-group study was designed to evaluate noninferiority of paliperidone palmitate (PP), a once-monthly injectable atypical antipsychotic, to once-biweekly risperidone long-acting injectable (RIS-LAI) in adult Chinese patients with acute schizophrenia. Eligible Chinese adults (N=452) with schizophrenia were randomized (1:1) to either PP (N=229; deltoid injections on day 1 [150 mg eq.] and day 8 [100 mg eq.]; then once-monthly deltoid or gluteal injections, flexibly dosed [50, 100, or 150 mg eq.]), or RIS-LAI (N=223; once-biweekly gluteal injections, flexibly dosed [25, 37.5 or 50 mg]). RIS-LAI-treated patients received oral risperidone supplementation (1-6 mg/day) at initiation and with RIS-LAI dose increases. Mean (SD) Positive and Negative Syndrome Scale (PANSS) total score at baseline was 83.2 (12.44). Mean (SD) change from baseline to endpoint in PANSS total scores (primary efficacy measure) was: -23.6 (16.28) for PP group and -26.9 (15.43) for RIS-LAI group. PP was noninferior to RIS-LAI (least squares mean difference [95% CI]: -2.3 [-5.20; 0.63]; predetermined non-inferiority margin: -5.5). Mean (SD) change from baseline to endpoint in Clinical Global Impression-Severity scale score was: -1.5 (1.24; PP group), -1.7 (1.16; RIS-LAI group) and in Personal and Social Performance Scale scores was: 16.8 (14.76; PP group), 18.6 (13.92; RIS-LAI group). The incidence of treatment-emergent adverse events (TEAEs) was similar between the two groups (73% [PP]; 75% [RIS-LAI]). The most common TEAEs were akathisia, tremor, and insomnia. The study demonstrated the noninferiority of PP (50-150 mg eq., flexibly dosed, without oral paliperidone supplementation) to risperidone-LAI (25-50 mg, flexibly dosed, with oral risperidone supplementation) for the treatment of acute schizophrenia in adult Chinese patients. PP injections were generally tolerable, and no new safety signals were detected in this population. PMID:21315787
Li, Huafang; Rui, Qing; Ning, Xiaoping; Xu, Haiyan; Gu, Niufan
The use of coated microsphere fuels has been suggested for the Savannah River Plant's (SRP) operating reactors as well as for the Low-Temperature Heavy-Water (LTHW) New Production Reactor (NPR). A program is underway to examine the feasibility of incorporating coated microsphere fuels into the well developed powder metallurgy (PM) fuel fabrication process. The coated microspheres were developed for use in
Specific targeting of tissues and/or cells is essential for any type of drug delivery system because this determines the efficacy and side effects of the drug. Poly lactic-co-glycolic acids (PLGA) have long been used as biomaterials for drug delivery due to their excellent biocompatibility and biodegradability. Direct visualization of PLGA particles is feasible even within tissues, and cell specificity of the drug delivery system is normally assessed by using labeled particles. However, particle labeling alone does not address factors such as the release and distribution of the drug. Thus, it is desirable to set up a simulation system of drug release and distribution in vivo. In the present study, we aimed to establish a method to simulate drug distribution in PLGA drug delivery by using Hoechst 33342 as an imitating drug. Our approach enabled us to identify, isolate, and characterize cells exposed to Hoechst 33342 and to deduce the concentration of this fluorescent dye around both targeted and nontargeted cells. We believe that the method described herein will provide essential information regarding the specificity of cell targeting in any type of PLGA drug delivery system.
Sasaki, Kaori; Igarashi, Martha; Hinata, Manami; Komori, Yuna
Many drug delivery systems have indicated improvement in delivery of various drug molecules and among these biodegradable and biocompatible polymers such as poly(D,L-lactide-co-glycolide) (PLGA) have been shown to enhance intracellular uptake of drug candidates when formulated as nanoparticles. PLGA nanoparticles were prepared by means of a double emulsion solvent evaporation technique and evaluated in terms of size, encapsulation efficiency, surface charge, isoniazid release and in vitro transport. The nanoparticles have an average size of 237 nm and were previously shown to be distributed in several tissues after oral administration without triggering an immune response. This study focussed on the in vitro permeation of the PLGA nanoparticles across different membranes and showed that although Rhodamine 6G-labelled nanoparticles are efficiently delivered across the intestinal epithelium, its epithelial permeability changes when a drug such as isoniazid is encapsulated. Future studies should focus on ways to optimise PLGA nanoparticle delivery when a drug such as isoniazid is encapsulated for instance by coating with polymers such as polyethylene glycol. PMID:22812395
Nkabinde, Lindiwe A; Shoba-Zikhali, Lungile N N; Semete-Makokotlela, Boitumelo; Kalombo, Lonji; Swai, Hulda S; Hayeshi, Rose; Naicker, Brendon; Hillie, Thembela K; Hamman, Josias H
Biodegradable Poly(lactic-co-glycolic acid; PLGA), microspheres encapsulating the angiogenic protein recombinant human vascular endothelial growth factor (rhVEGF) were formed to achieve VEGF release in a sustained manner. These microspheres are a promising delivery system which can be used for therapeutic angiogenesis. The PLGA microspheres incorporating two different initial loading amounts of rhVEGF have been prepared by a modified water-in-oil-in-water (w/o/w) double emulsion/solvent evaporation technique. The microspheres have been characterized by particle size distribution, environmental scanning electron microscopy (ESEM), light microscopy, encapsulation efficiency and their degradation was studied in vitro. The rhVEGF released from microspheres was quantified by the competitive enzyme-linked immunosorbent assay (ELISA) and human umbilical vein endothelial cell (HUVEC) proliferation assay was used to assess biological activity of the released VEGF. The microspheres were spherical with diameters of 10-60?µm and the encapsulation efficiency was between 46% and 60%. The release kinetics of rhVEGF was studied for two different amounts: 5?µg VEGF (V5) and 50?µg VEGF (V50) per 500?mg starting polymer. The total protein (VEGF:BSA) release increased up to 4 weeks for two rhVEGF concentrations. The ELISA results showed that the burst release for V5 and V50 microspheres were 4 and 27?ng/mL, respectively. For V5, the microspheres showed an initial burst release, followed by a higher steady-state release until 14 days. VEGF release increased up to 2 weeks for V50 microsphere. HUVEC proliferation assay showed that endothelial cells responded to bioactive VEGF by proliferating and migrating. PMID:21171816
Karal-Y?lmaz, Ok?an; Serhatl?, Müge; Baysal, Kemal; Baysal, Bahattin M
Octreotide (octreotide-acetate, Sandostatin®) is a somatostatin analogue, used in long-term treatment of acromegaly. The present study describes the absorption profile in rabbits of octreotide after release from the long-acting formulation OncoLAR (denoted as octreotide-LAR). In a first experiment, the disposition kinetics of octreotide was studied for 24 h in six rabbits after intravenous (i.v.) injection of 0.025 mg of a
E. Comets; F. Mentré; F. Nimmerfall; R. Kawai; I. Mueller; P. Marbach; J. Vonderscher
Long-acting parenteral formulations of antiretrovirals could facilitate maintenance and prophylactic treatment in HIV. Using the poorly water- and oil-soluble non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC278 (rilpivirine) as base or hydrochloride (HCl), nanosuspensions were prepared by wet milling (Elan NanoCrystal® technology) in an aqueous carrier. Laser diffraction showed that the average particles size were (1) close to the targeted size proportionality
Lieven Baert; Gerben van ‘t Klooster; Willy Dries; Marc François; Alfons Wouters; Esther Basstanie; Koen Iterbeke; Fred Stappers; Paul Stevens; Laurent Schueller; Pieter Van Remoortere; Guenter Kraus; Piet Wigerinck; Jan Rosier
The effectiveness, safety and production-enhancing benefit (improved weight gains) of moxidectin long-acting injection given subcutaneously in the ear at the rates of 0.75, 1.0 and 1.5mg\\/kg bw were evaluated in three studies under common protocol. The only adverse reaction to treatment was a mild (<2 tablespoons in volume), and for the most part transient (<28 days for the treatment rate
T. A. Yazwinski; J. C. Williams; L. L. Smith; C. Tucker; A. F. Loyacano; A. DeRosa; P. Peterson; D. J. Bruer; R. L. Delay
Two field trials were carried out in successive years at the Ngong Veterinary Farm, Kenya, in which young cattle, previously unexposed to tick-borne diseases, were introduced into an area with endemic East Coast fever while protected by a series of injections of a long-acting oxytetracycline. In 1984, 12 animals which received injections of 20 mg\\/kg of the drug on days
RS Chumo; AD Irvin; SP Morzaria; J Katende; RE Purnell
This 13-week double-blind study was designed to assess noninferiority of the recently approved (in the U.S.) injectable atypical antipsychotic paliperidone palmitate (PP) versus risperidone long-acting injectable (RIS-LAI) in adult patients with schizophrenia. Patients (N=1220) were randomized (1:1) to either a) PP: deltoid injections on day 1 (150mgeq.), day 8 (100mgeq.), and once-monthly flexible dosing as deltoid or gluteal injections on
Gahan Pandina; Srihari Gopal; Cristiana Gassmann-Mayer; David Hough; Bart Remmerie; George Simpson
Objective Treatment of schizophrenia in patients with comorbid substance use (alcohol/illicit drug use, abuse or dependence) presents challenges for public health systems. Substance use in people with schizophrenia is up to four times greater than the general population and is associated with medication nonadherence and poor outcomes. Therefore, continuous antipsychotic treatment in this population may pose more of a challenge than for those with schizophrenia alone. Many clinical trials and treatment recommendations in schizophrenia do not take into consideration substance use as people with comorbid substance use have typically been excluded from most antipsychotic trials. Nonetheless, antipsychotic treatment appears to be as efficacious in this population, although treatment discontinuation remains high. The objective of this review was to highlight the importance and utility of considering long-acting injectable antipsychotics for patients with schizophrenia and comorbid substance use. Methods We did a literature search using PubMed with key words schizophrenia and substance use/abuse/dependence, nonadherence, antipsychotics, long acting injectables, relapse, and psychosocial interventions. We limited our search to human studies published in English and 4,971 articles were identified. We focused on clinical trials, case reports, case series, reviews and meta-analyses resulting in 125 articles from 1975-2011. Results Our review suggests the potential role of long-acting injectables for people with comorbid substance use and schizophrenia in leading to improvements in psychopathology, relapse prevention, fewer rehospitalizations, and better outcomes. Conclusions While more research is needed, long-acting antipsychotics should be considered an important option in the management of people with schizophrenia and comorbid substance use.
Koola, Maju Mathew; Wehring, Heidi J.; Kelly, Deanna L.
In animal health care, current therapeutic regimens for severe external infections require repeated instillations of antibiotic eye drop solutions. The aim of this work is to drastically decrease the frequency of instillations by developing a long-acting ophthalmic insert.Ophthalmic inserts based on mixtures of hydroxypropyl cellulose, ethyl cellulose, poly(acrylic) acid and 25.0% (w\\/w) of gentamicin sulfate either combined with cellulose acetate
Florian Gurtler; Vassilios Kaltsatos; Bernard Boisramé; Robert Gurny
Background Oxycodone controlled release (CR) and oxymorphone extended release (ER) are frequently prescribed long-acting opioids, which are approved for twice-daily dosing. The US Food and Drug Administration approved a reformulated crush-resistant version of oxycodone CR in April 2010. Objective To compare the daily average consumption (DACON) for oxycodone CR and for oxymorphone ER before and after the introduction of the reformulated, crush-resistant version of oxycodone CR. Methods This was a retrospective claims database analysis using pharmacy claims from the MarketScan database for the period from January 2010 through March 2011. The interrupted time series analysis was used to evaluate the impact of the introduction of reformulated oxycodone CR on the DACON of the 2 drugs—oxycodone CR and oxymorphone ER. The source of the databases included private-sector health data from more than 150 medium and large employers. All prescription claims containing oxycodone CR and oxymorphone ER dispensed to members from January 1, 2010, to March 31, 2011, were included in the analysis. Prescription claims containing duplicate National Drug Codes, missing member identification, invalid quantities or inaccurate days supply of either drug, and DACON values of <1 and >500 were removed. Results The database yielded 483,063 prescription claims for oxycodone CR and oxymorphone ER from January 1, 2010, to March 31, 2011. The final sample consisted of 411,404 oxycodone CR prescriptions (traditional and reformulated) dispensed to 85,150 members and 62,656 oxymorphone ER prescriptions dispensed to 11,931 members. Before the introduction of reformulated oxycodone CR, DACON values for the highest strength available for each of the 2 drugs were 0.51 tablets higher for oxycodone CR than for oxymorphone ER, with mean DACON values of 3.5 for oxycodone CR and 3.0 for oxymorphone ER (P <.001). The differences of mean DACON between the 2 drugs for all lower strengths were 0.46 tablets, with mean DACON values of 2.7 for oxycodone CR and 2.3 for oxymorphone ER (P <.001). After the introduction of the new formulation, the difference in mean DACON between the 2 drugs was slightly lower: 0.45 tablets for the highest-strength and 0.40 tablets for the lower-strength pairs. Regression analyses showed that the immediate and overall impact of the reformulation of oxycodone CR on the DACON of oxycodone CR was minimal, whereas no changes were seen in the DACON of oxymorphone ER. The estimated DACON for oxycodone CR decreased by 0.1 tablets, or 3.7% (P <.001), 6 months after the new formulation was introduced. Conclusion The mean DACON was 0.4 tablets per day higher for oxycodone CR compared with oxymorphone ER for all dosage strengths for the entire study period. After the introduction of the reformulated oxycodone CR, the DACON for this drug was slightly mitigated; however, there was a minimal impact on the mean differences between oxycodone CR and oxymorphone ER.
Puenpatom, R. Amy; Szeinbach, Sheryl L.; Ma, Larry; Ben-Joseph, Rami H.; Summers, Kent H.
Biodegradable thermosensitive poly (DL-lactide-co-glycolide-b-ethylene glycol-b-DL-lactide-co-glycolide) (PLGA-PEG-PLGA) triblock copolymers with DL-lactide/glycolide molar ratio ranging from 6/1 to 15/1 were synthesized from monomers of DL-lactide, glycolide and polyethylene glycol and were evaluated for sustained release of bee venom peptide in vitro. The resulting copolymers are soluble in water to form free flowing fluid at room temperature but become hydrogels at body temperature. The gelation temperature of the copolymer solutions can be influenced by the concentration and DL-lactide/glycolide molar ratio of the copolymers. The release of bee venom peptide from the copolymer-based hydrogel and hydrogel degradation in the phosphate buffer (pH 7.4) was studied at 37 degrees C under agitation. Bee venom peptide was released from the copolymer-based hydrogels over 40 days in vitro and the variation of DL-lactide/glycolide molar ratio in the PLGA block of the copolymer did not significantly affect the release rate of bee venom peptide (P > 0.05). The hydrogels undergo slower degradation and then faster degradation rate during the whole release stage. Accordingly, the mechanism of bee venom peptide was Fickian diffusion during initial stage and then may be a combination of diffusion and degradation. The synthesized copolymers have the advantage of gelation temperature over the ReGel system. These results indicate that the PLGA-PEG-PLGA copolymer-based hydrogel could be a promising platform for sustained delivery of bee venom peptide. PMID:16599259
Qiao, Mingxi; Chen, Dawei; Ma, Xichen; Hu, Haiyang
The purpose of this work was to study the effect of organic solvent and surfactant type on the in vitro release behavior in general and on the burst release in particular of beta-estradiol from PLA/PLGA microspheres. Also the effect of these variables on the encapsulation efficiency was investigated. The microspheres were prepared by solvent evaporation technique using dichloromethane (DCM), ethyl acetate (EtAc), tetrahydrofuran (THF), chloroform (CHCl3) or acetone (AC) as organic solvent and polyvinyl alcohol (PVA), Tween 80, sodium lauryl sulfate (SLS) or benzalkonium chloride (BKCI) as surfactant. The obtained microspheres were tested for encapsulation efficiency and in vitro drug release using 50% methanol/buffer pH 7.4 as dissolution medium. EtAC and PVA formulations showed the highest encapsulation efficiency and the lowest burst release. These microspheres were further characterized for particle size distribution, SEM and zeta potential. The results suggested that these materials could be starting materials to prepare a beta-estradiol biodegradable controlled delivery system. PMID:17020154
Zaghloul, A A
A series of novel thermo- and pH-responsive block copolymers of PHis-PLGA-PEG-PLGA-PHis composed of poly(ethylene glycol) (PEG), poly(D,L-lactide-co-glycolide) (PLGA) and poly(L-histidine) (PHis) were synthesized and used for the construction of stimuli-responsive copolymer micelles. The starting polymers of PLGA-PEG-PLGA and PHis were synthesized by ring-opening polymerization of dl-lactide and glycolide with PEG as an initiator and L-histidine N-carboxylanhydride with isopropylamine as an initiator, respectively. The final copolymer was obtained by the coupling reaction of PHis with PLGA-PEG-PLGA. The copolymer micelles were constructed to have an inner core consisting of two hydrophobic blocks (PLGA and deprotonated PHis) and an outer hydrophilic PEG shell. The temperature- and pH-induced structure changes of the micelles were characterized by an alteration in particle size, a decrease in pyrene fluorescence intensity, and a variation of (1)H NMR spectra in D2O. It was speculated that the hydrophobic-hydrophilic transitions of PEG and PHis in response to temperature and pH variations accounted for the destabilization of micelles. In vitro release profiles, cell cytotoxicity and intracellular location studies further confirmed the temperature- and pH-responsive properties of the copolymer micelles. These results demonstrate the potential of the developed copolymers to be stimuli-responsive carriers for targeted delivery of anti-cancer drugs. PMID:24365708
Hong, Wei; Chen, Dawei; Jia, Li; Gu, Jianchun; Hu, Haiyang; Zhao, Xiuli; Qiao, Mingxi
Antibodies (Abs) are prone to a variety of physical and chemical degradation pathways, which require the development of stable formulations and specific delivery strategies. In this study, injectable biodegradable and biocompatible polymeric particles were employed for controlled-release dosage forms and the encapsulation of antibodies into polylactide-co-glycolide (PLGA) based microspheres was explored. In order to avoid stability issues which are commonly described when water-in-oil (w/o) emulsion is used, a solid-in-oil-in-water (s/o/w) method was developed and optimized. The solid phase was made of IgG microparticles and the s/o/w process was evaluated as an encapsulation method using a model Ab molecule (polyclonal bovine immunoglobulin G (IgG)). The methylene chloride (MC) commonly used for an encapsulation process was replaced by ethyl acetate (EtAc), which was considered as a more suitable organic solvent in terms of both environmental and human safety. The effects of several processes and formulation factors were evaluated on IgG:PLGA microsphere properties such as: particle size distribution, drug loading, IgG stability, and encapsulation efficiency (EE%). Several formulations and processing parameters were also statistically identified as critical to get reproducible process (e.g. the PLGA concentration, the volume of the external phase, the emulsification rate, and the quantity of IgG microparticles). The optimized encapsulation method has shown a drug loading of up to 6% (w/w) and an encapsulation efficiency of up to 60% (w/w) while preserving the integrity of the encapsulated antibody. The produced microspheres were characterized by a d(0.9) lower than 110?m and showed burst effect lower than 50% (w/w). PMID:24184674
Marquette, Sarah; Peerboom, Claude; Yates, Andrew; Denis, Laurence; Goole, Jonathan; Amighi, Karim
Microspheres are produced by cobalt gamma radiation initiated polymerization of a dilute aqueous vinyl pyridine solution. Addition of cross-linking agent provides higher surface area beads. Addition of monomers such as hydroxyethylmethacrylate acrylamide or methacrylamide increases hydrophilic properties and surface area of the beads. High surface area catalytic supports are formed in the presence of controlled pore glass substrate.
Rembaum, Alan (Inventor); Gupta, Amitava (Inventor); Volksen, Willi (Inventor)
Microspheres are produced by cobalt gamma radiation initiated polymerization of a dilute aqueous vinyl pyridine solution. Addition of cross-linking agent provides higher surface area beads. Addition of monomers such as hydroxyethylmethacrylate acrylamide or methacrylamide increases hydrophilic properties and surface area of the beads. High surface area catalytic supports are formed in the presence of controlled pore glass substrate.
Rembaum, Alan (Inventor); Gupta, Amitava (Inventor); Volksen, Willi (Inventor)
A new composition and method of making same for a doped zinc oxide microsphere and articles made therefrom for use in an electrical surge arrestor which has increased solid content, uniform grain size and is in the form of a gel.
Arnold, Jr., Wesley D. (Oak Ridge, TN); Bond, Walter D. (Knoxville, TN); Lauf, Robert J. (Oak Ridge, TN)
A new composition and method of making same for a doped zinc oxide microsphere and articles made therefrom for use in an electrical surge arrestor which has increased solid content, uniform grain size and is in the form of a gel. 4 figures.
Arnold, W.D. Jr.; Bond, W.D.; Lauf, R.J.
The treatment of malignant tumors with ionizing radiation using ceramic ; microspheres that can be localized at selected sites for interstitial therapy is ; discussed. Thus, radiation damage in healthy tissues can be minimized by ; tailoring radioactivity to control dose, dose rate, and volume of tissue ; irradiated. The mean life, radiation energies, and beta-gamma dose can be ;
J. F. Perry; M. K. Loken; J. P. Ryan; L. D. MacLean
Curcumin and bovine serum albumin (BSA) were used as model drugs and loaded into micro- and nanoparticles of biodegradable poly(lactic-co-glycolic acid) (PLGA). The PLGA was incorporated into hydrophilic and biocompatible gelatin scaffolds to design a controlled drug release system. The gelatin scaffolds were cross-linked using glutaraldehyde. The controlled delivery of drugs from biologically active PLGA micro- and nanoparticles was measured
Waseem Asghar; Muhymin Islam; Aniket S. Wadajkar; Yuan Wan; Azhar Ilyas; Kytai T. Nguyen; Samir M. Iqbal
In this work, we prepared nano-emulsified paclitaxel using administration form of the self-microemulsifying drug delivery systems (SMEDDS) in order to increase efficacy of paclitaxel. As paclitaxel delivery carrier, we chose MPEG–PLGA diblock copolymers with different hydrophilic and hydrophobic balances (HLB) by changing PLGA segments under constant MPEG segment. Paclitaxel and MPEG–PLGA diblock copolymers were dissolved by solubilizer such as tetraglycol,
Soo Young Lee; Hoon Hyun; Ju Yong Youn; Byung Soo Kim; In Beum Song; Moon Suk Kim; Bong Lee; Gilson Khang; Hai Bang Lee
Magnetic nanoparticles have been proposed as interesting tools for biomedical purposes. One of their promising utilization is the MRI in which magnetic substances like maghemite are used in a nanometric size and encapsulated within locally biodegradable nanoparticles. In this work, maghemite has been obtained by a modified sol-gel method and encapsulated in polymer-based nanospheres. The nanospheres have been prepared by single emulsion evaporation method. The different parameters influencing the size, polydispersity index and zeta potential surface of nanospheres were investigated. The size of nanospheres was found to increase as the concentration of PLGA increases, but lower sizes were obtained for 3 min of sonication time and surfactant concentration of 1%. Zeta potential response of magnetic nanospheres towards pH variation was similar to that of maghemite-free nanospheres confirming the encapsulation of maghemite within PLGA nanospheres. The maghemite entrapment efficiency and maghemite content for nanospheres are 12% and 0.59% w/w respectively. PMID:23602998
Silva, Marcela Fernandes; Winkler Hechenleitner, Ana Adelina; de Oliveira, Daniela Martins Fernandes; Agüeros, Maite; Peñalva, Rebeca; Irache, Juan Manuel; Pineda, Edgardo Alfonso Gómez
Pulmonary drug delivery of controlled release formulations may provide an effective adjunct approach to orally delivered antibiotics for clearing persistent lung infections. Dry powder formulations for this indication should possess characteristics including; effective deposition to infected lung compartments, persistence at the infection site, and steady release of antibiotic. Large porous particles (?10-15 ?m) have demonstrated effective lung deposition and enhanced lung residence as a result of their large diameter and reduced clearance by macrophages in comparison to small microparticles (?1-5 ?m). In this report, Precision Particle Fabrication technology was used to create monodisperse large porous particles of poly(D,L-lactic-co-glycolic acid) (PLGA) utilizing oils as extractable porogens. After extraction, the resulting large porous PLGA particles exhibited a low density and a web-like or hollow interior depending on porogen concentration and type, respectively. Ciprofloxacin nanoparticles (nanoCipro) created by homogenization in dichloromethane, possessed a polymorph with a decreased melting temperature. Encapsulating nanoCipro in large porous PLGA particles resulted in a steady release of ciprofloxacin that was extended for larger particle diameters and for the solid particle morphology in comparison to large porous particles. The encapsulation efficiency of nanoCipro was quite low and factors impacting the entrapment of nanoparticles during particle formation were elucidated. A dry powder formulation with the potential to control particle deposition and sustain release to the lung was developed and insight to improve nanoparticle encapsulation is discussed.
Arnold, Matthew M.; Gorman, Eric M.; Schieber, Loren J.; Munson, Eric J.; Berland, Cory
A study was conducted under a common protocol in Wisconsin and Wyoming, USA, to evaluate therapeutic and persistent efficacy of two long-acting injectable formulations of moxidectin against lice populations infesting cattle. At each site, 30 beef calves were blocked into groups of three based on naturally acquired Linognathus vituli populations, then randomly assigned to treatments within blocks. Treatments, injected subcutaneously into the proximal third of the ear on Day 0, included saline, a long-acting oil-based formulation containing 10% moxidectin given at the rate of 1 mg moxidectin/kg body weight (M10/1.0), or a long-acting oil-based formulation containing 15% moxidectin given at the rate of 0.75 mg moxidectin/kg b.w. (M15/0.75). Species of sucking and chewing lice were quantified on nine predilection sites before treatment, then 28, 63, 98, 133 and 168 days after treatment. During intervals between lice counts after Day 28, study animals from the three treatment groups were commingled for 32 days with two lice-free sentinels plus four to six seeder calves with infestations of both sucking and chewing lice. Following each 32-day commingling interval, seeder and sentinel animals were removed, and principal animals were sorted into pens by treatment. Lice were quantified on sentinel animals on the day of removal, and lice were quantified on principal study animals 3 days after removal of sentinel and seeders. Moxidectin was generally not efficacious against Bovicola bovis in the injectable formulations tested, whereas Haematopinus eurysternus infestations were inadequate to judge product effectiveness. Based on geometric means, both M15/0.75 and M10/1.0 provided statistically significant therapeutic efficacy against existing infestations of L. vituli and Solenopotes capillatus (100% efficacy on Day 28), and provided persistent protection against reinfestation with L. vituli and S. capillatus (efficacy >97%) for at least 133 days following treatment. PMID:15041096
Cleale, R M; Lloyd, J E; Smith, L L; Grubbs, M A; Grubbs, S T; Kumar, R; Amodie, D M
What is known and Objective: Long-acting intramuscular penicillin G injection is an important product for the management of some severe infections. However, testing the bioequivalence of such long-acting formulations is difficult. Our aim was to undertake such a test using a generic formulation containing 1?200?000?IU of benzathine penicillin G powder and an innovator's product (Retarpen(®) 1·2 million units; Sandoz, Switzerland). Methods: In an open, double-blind, randomized, two-periods, two-group crossover study, 12 healthy male volunteers received both formulations of benzathine penicillin G on two different days with a 5-month washout period between the doses and a sampling period of over 500?h. A simple, sensitive and rapid high-performance liquid chromatography (HPLC)-UV method was developed and validated for determination of penicillin G plasma concentrations and other pharmacokinetic (PK) parameters. Results and Discussion: The analytical method used produced linear responses within a wide analyte concentration range with average within-run and between-run variations of below 15% with acceptable recovery, accuracy and sensitivity. The primary PK parameters we used were maximum plasma concentration (Cmax ), time to reach the maximal concentration (Tmax ) and the area under the plasma concentration vs. time curve from time zero to the last sampling time (AUC0?t ) using a standard non-compartmental approach. Based on these parameters, the two formulations were bioequivalent. What is new and Conclusion: We illustrate the bioequivalence testing of a very long-acting product. The data indicate that the generic test formulation and the branded reference formulation were bioequivalent in fasting healthy Iranian male volunteers. PMID:23293945
Shahbazi, M A; Azimi, K; Hamidi, M
Background Because wide variations in mental health care utilization exist throughout the world, determining long-term effectiveness\\u000a of psychotropic medications in a real-world setting would be beneficial to physicians and patients. The purpose of this analysis\\u000a was to describe the effectiveness of injectable risperidone long-acting therapy (RLAT) for schizophrenia across countries.\\u000a \\u000a \\u000a \\u000a \\u000a Methods This was a pragmatic analysis of data from two prospective observational
Tim Lambert; José M Olivares; Joseph Peuskens; Cherilyn DeSouza; Chris M Kozma; Patrick Otten; Concetta Crivera; An Jacobs; Wayne Macfadden; Lian Mao; Stephen C Rodriguez; Riad Dirani; Kasem S Akhras
Porous microspheres have drawn great attention in the last two decades for their potential applications in many fields, such as carriers for drugs, absorption and desorption of substances, pulmonary drug delivery, and tissue regeneration. The application of porous microspheres has become a feasible way to address existing problems. In this essay, we give a brief introduction of the porous microsphere, its characteristics, preparation methods, applications, and a brief summary of existing problems and research tendencies.
Cai, Yunpeng; Chen, Yinghui; Hong, Xiaoyun; Liu, Zhenguo; Yuan, Weien
This paper reviews the preparation and application of radioactive microspheres for medical purposes. It first discusses the\\u000a properties of relevant radioisotopes and then explores the diagnostic uses of gamma-emitter labelled microspheres, such as\\u000a blood flow measurement and imaging of the liver and other organs. The therapeutic uses of alpha- and beta-emitting microspheres,\\u000a such as radioembolization, local tumour therapy and radiosynovectomy,
Bronchodilation with a long-acting muscarinic antagonist (LAMA) or long-acting ?(2)-agonist is central to the management of chronic obstructive pulmonary disease (COPD). Tiotropium, the first LAMA available for use in COPD, has been shown to be an effective bronchodilator and is generally safe and well tolerated. However, tiotropium has limitations that include a high incidence of dry mouth, slow onset of action and, in some studies, a part of the patient population did not achieve clinically significant bronchodilation. It also remains unclear whether tiotropium reduces progressive deterioration of lung function in patients with COPD. An ideal LAMA would provide clinically meaningful bronchodilation, deliver symptom relief, prevent disease progression, improve exercise tolerance and health status, prevent and treat complications and exacerbations and reduce mortality risk. A 24-h duration of action, rapid onset of action and a good safety and tolerability profile are also desirable. The once-daily LAMA, NVA237 (glycopyrronium bromide), may meet some of these characteristics. NVA237 has high selectivity for the muscarinic type-3 (M(3)) receptor which might potentially result in a higher therapeutic index than tiotropium, which is less selective for M(3). Phase II studies showed that NVA237 once daily provides clinically significant 24-h bronchodilation with a rapid onset of action and a favourable safety and tolerability profile. Phase III studies are ongoing that will assess the long-term safety and efficacy of NVA237. PMID:21511677
Vogelmeier, Claus; Banerji, Donald
Objective The objective of this study was to compare the effect of long acting anesthetics on postoperative pain in teeth with irreversible pulpitis. Methodology Forty patients were randomly assigned into two groups of twenty patients each. Each patient who fit the inclusion criteria was administered local anesthesia before undergoing root canal treatment. The anesthetic solution was either 2% lidocaine with 1:80,000 epinephrine or 0.5% bupivacaine with 1:200,000 epinephrine. Patients were instructed to complete a VAS pain score at 6, 12, 24 h after single visit root canal treatment. Data were analyzed by Mann–Whitney, Cochrane Q analysis and t test to compare qualitative and quantitative data between the groups. Results The results showed the levels of pain of the patients who received lidocaine as the anesthetic agent and had significantly more postoperative pain after root canal treatment (P < 0.05) but had significantly decreased pain by 24 h compared to the bupivacaine group patients who had significantly lower postoperative pain levels at 6 and 12 h. Conclusion The use of long acting local anesthetic can significantly reduce the postoperative pain in teeth with irreversible pulpitis.
Background Inhaled long-acting bronchodilators are the mainstay of pharmacotherapy for chronic obstructive pulmonary disease (COPD). Both the twice-daily long-acting ?2-adrenoceptor agonists (LABAs) salmeterol and formoterol and the once-daily LABA indacaterol are indicated for use in COPD. This review examines current evidence for the safety of LABAs in COPD, focusing on their effect on exacerbations and deaths. Methods We searched PubMed for placebo-controlled studies evaluating long-term (?24 weeks) use of formoterol, salmeterol, or indacaterol in patients with stable COPD, published between January 1990 and September 2012. We summarized data relating to exacerbations and adverse events, particularly events related to COPD. Results From 20 studies examined (8774 LABA-treated patients), there was no evidence of an association between LABA treatment and increased exacerbations, COPD-related adverse events, or deaths. Where analyzed as an efficacy outcome, LABA treatment was generally associated with significant or numerical reductions in COPD exacerbations compared with placebo. Incidences of COPD-related adverse events were similar for active and placebo treatments. The incidence of adverse events typically associated with the ?2-agonist drug class such as skeletal muscle tremors and palpitations was low (often <1% of patients), and there were no reports of increased incidence of cardiac arrhythmias. The systemic effects of ?2-adrenoceptor stimulation, such as high glucose and potassium levels, were considered minor. Conclusion Current evidence from clinical studies of the safety and tolerability profile of LABAs supports their long-term use in COPD.
Decramer, Marc L; Hanania, Nicola A; Lotvall, Jan O; Yawn, Barbara P
Thirteen patients with schizophrenia received injections of 25, 50, or 75 mg of long-acting risperidone every 2 wk. Brain D2 receptor occupancy was assessed with [11C]raclopride 2 wk after the last (fifth) injection (day 71) in seven subjects and 2 wk after the third injection (day 44) in one subject. Stable plasma concentrations were reached after the third injection and steady-state concentrations of the active moiety (risperidone + 9-hydroxyrisperidone) after the fourth injection. Steady-state plasma concentrations were maintained for 4-5 wk after the last injection and then declined rapidly. After injections of 25, 50 and 75 mg on day 44 or day 71, D2 receptor occupancy ranged from 25-48%, 59-83% and 62-72% respectively, while plasma active-moiety levels ranged from 4.4-8.8, 15.0-31.1 and 22.5-26.3 ng/ml respectively. The results indicate that brain D2 receptor occupancy at steady state after injections of long-acting risperidone was in the range found in patients effectively treated with 2-6 mg of oral risperidone. PMID:15710053
Gefvert, Ola; Eriksson, Bo; Persson, Per; Helldin, Lars; Björner, Annika; Mannaert, Erik; Remmerie, Bart; Eerdekens, Mariëlle; Nyberg, Svante
Background Salbutamol, as a short-acting ?2-agonist, was popularly used in the past for detection of reversibility in patients with airway obstruction when it was the only drug available in the treatment of airway obstruction. Today, the combination of long-acting ?2-agonists (LABA) and inhaled glucocorticoids are the first choice of therapy, with or without the presence of reversibility, in patients with airway obstruction. We aimed to compare the efficacy of salbutamol and long acting ?2-agonists plus inhaled glucocorticoids for early reversibility test in patients with airway obstruction. Methods Symptomatic patients (cough, dyspnea, and/or wheezing) with airway obstruction according to pulmonary function testing (FEV1/FVC value less than 70% of expected) who had never used bronchodilators before or had not received short- or long-acting inhaled bronchodilator therapy within the most recent 12 hours were evaluated. Reversibility measurements were made by administering the combination of long-acting ?2-agonists (LABA) and inhaled glucocorticoids after 15 minutes. Results A total of 90 patients were evaluated. The mean age of patients was 57.3±17.7 (range, 8-88) years and the male-to-female ratio was 69/21. The baseline pulmonary function test results were mean FVC; 2,747±1,181 mL and 74.7%±21.4%, mean FEV1; 1,716±825 mL and 57.5%±19.0%, mean FEV1/FVC; 61.4%±7.4%. The bronchodilator drugs given before reversibility testing were as salmeterol/fluticasone (FTC/SAL), formoterol/budesonide (BUD/FOR), beclomethasone dipropionate/formoterol (BDP/FOR) and salbutamol (SLB) in 24, 22, 24 and 20 patients, respectively. The reversibility was positive in 33 (36.7%) patients. The absolute change and percentage of change in mean FEV1 were 206±252 mL, 13.2%±16.6% for FTC/SAL group, 273±201 mL, 14%±8% for BUD/FOR group, 240±151 mL, 18.7%±15.9% for BUD/FOR groupand 171±116 mL, 13.3%±11.8% for SLB group. There was no statistically significant for reversibilty results between LABAs/inhaledsteroids and SLB group. And the patients with positivere versibility test were significantly higher in both of BUD/FOR and BDP/FOR groups than SLB group. Conclusions We think that performance of an early reversibility test using the combination of a LABA and an inhaled corticosteroid for treatment would enhance both the education of the patient in using the device and the reliability of the drug. And, we suggest that: “you should make the reversibility test with Long-Acting ?2-Agonists plus Inhaled Corticosteroids which used in treatment of obstructive lung diseases”.
Dirican, Adem; Tuna, Tibel
We have earlier reported on the possible application of poly [lactide (co-glycolide)] (PLGA) nanoparticles of suitable size to serve as a (99m)Tc-labeled diagnostic tracer in sentinel lymph node detection (SLND). Additional efforts have now been made to improve both the radiolabeling yield and the biological efficacy by modifying the PLGA particles. Two approaches were taken, one based on in situ loading of mebrofenin inside PLGA nanoparticles and the second one based on functionalization of existing terminal carboxylic acid groups on the nanoparticle surface with p-aminobenzyl diethylenetriamine pentaacetic acid (p-NH2-Bz-DTPA) for enhanced availability of functional groups suitable for (99m)Tc complexation. The modified PLGA derivatives were purified and characterized. Radiolabeling of the modified PLGA nanoparticles was carried out with (99m)Tc using stannous chloride as the reducing agent. Mebrofenin encapsulated PLGA nanoparticles (mebrofenin-PLGA) did not show any significant improvement in the radiolabeling yield in comparison to the earlier reported "plain" PLGA nanoparticles, probably due to inaccessibility of the mebrofenin moiety to (99m)Tc upon encapsulation. DTPA-conjugated PLGA nanoparticles (DTPA-PLGA) showed appreciable improvement in radiolabeling yield under more moderate reaction conditions and better stability. In the biological evaluation performed in Wistar rat model, (99m)Tc-DTPA-PLGA nanoparticles showed a considerable increase in uptake in the sentinel node and the percentage popliteal extraction of the preparation was also higher. (99m)Tc-mebrofenin-PLGA did not show any improvement in SLN uptake over plain PLGA nanoparticles. The above results suggest that surface modification of PLGA by covalently coupling DTPA to PLGA nanoparticles prior to (99m)Tc labeling appears to be a superior approach to achieve a suitable (99m)Tc-labeled PLGA nanoparticle preparation for SLND. PMID:23705864
Subramanian, Suresh; Pandey, Usha; Gugulothu, Dalapathi; Patravale, Vandana; Samuel, Grace
Porous PLGA\\/PVA scaffolds as hydrophilized PLGA scaffolds for tissue engineering applications were fabricated by a novel melt-molding\\u000a particulate leaching method (non-solvent method). The prepared scaffolds exhibited highly porous and open-cellular pore structures\\u000a with almost same surface and interior porosities (pore size, 200–300 ? m; porosity, about 90%). The in vitro degradation behavior of the PLGA and PLGA\\/PVA scaffolds was compared
Se Heang Oh; Soung Gon Kang; Jin Ho Lee
AIM: To determine the effect of increasing doses of long-acting injectable vitamin B12 plus selenium (Se) given pre-mating on the vitamin B12 and Se status of ewes and their lambs from birth to weaning.METHODS: Four groups of 24 Poll Dorset ewes each were injected 4 weeks pre-mating with different doses of a long-acting vitamin B12 + Se product, containing 3
ND Grace; SO Knowles
Therearefeweffective,safemodalitiesforthemanagementof Graves' ophthalmopathy (GO), a cell-mediated immune co- morbidity of thyroid disease. Somatostatin analogs inhibit lymphocyte proliferation and activation, and accumulate in theorbitaltissueofpatientswithGO.Adouble-blind,placebo- controlled study of a long-acting somatostatin analog (16 wk of long-acting release formulation of octreotide (octreotide- LAR)) was conducted in 51 patients with mild active GO with the aim of preventing deterioration and precluding the need for
J. L. Wemeau; P. Caron; A. Beckers; V. Rohmer; J. Orgiazzi; F. Borson-Chazot; M. Nocaudie; P. Perimenis; S. Bisot-Locard; I. Bourdeix; S. Dejager
Release of BSA (model protein) from hot-melt extruded poly(lactide-co-glycolide) (PLGA)-based implants was incomplete. A residual mass of covalent BSA-PLGA adducts was still present after 6 months. The objective of this study was to increase the completeness of BSA release. BSA reduced the PLGA degradation and erosion rate as well as the extent of erosion. An increased uptake of release medium in the presence of BSA in addition to the early outflux of PLGA oligomers resulted in a reduction of the matrix acidity and thus reduction of autocatalysis effects. PLGA mass loss was incomplete at 60% and 80% for 10% and 25% BSA-containing implants. The extent of PLGA mass loss was correlated with the total releasable protein. The same release was obtained from implants prepared with pre-degraded PLGA suggesting that the induction phase did not affect the release completeness. Thus, the focus was on the erosion phase to enhance outflux of soluble oligomers. BSA release completeness increased by increasing the porosity of the implants at the onset of erosion phase. This could be obtained with a higher initial porosity, formation of porosity upon higher diffusional release and/or incorporation of pore-formers/plasticizers. Accordingly, the BSA release completeness could be improved by enhancing the outflux of soluble PLGA degradation products. PMID:23583495
Ghalanbor, Zahra; Körber, Martin; Bodmeier, Roland
Acylation of peptides occurring within controlled-release depots prepared from copolymers of lactic and glycolic acid (PLGA) is a degradation reaction that may compromise product safety and efficacy. As peptide sorption to PLGA is believed to be a common precursor to peptide acylation, a new method to inhibit acylation is presented involving disruptors of peptide sorption, namely, inorganic divalent cations. Kinetics
Andreas M. Sophocleous; Ying Zhang; Steven P. Schwendeman
This study elucidated the in vitro physicomechanical transitions of a crosslinked polylactic-co-glycolic acid (PLGA) scaffold, utilizing quantum mechanics to compute the ab initio energy requirements of a salted-out and subsequently crosslinked PLGA scaffold interacting with simulated physiological fluid, phosphate buffered saline (PBS) (pH 7.4, 37 degrees C) at a molecular level. Twenty-six salted-out PLGA scaffolds were formulated using a four factor, two centerpoint quadratic Face-Centered Central Composite Design (FCCD). PLGA molecular mass, PLGA concentration, water volume and salting-out reaction time were the dependant formulation variables. Subsequent to PLGA solubilization in dimethyl formamide (DMF), protonated water was added to induce salting-out of PLGA into a scaffolds that were immersed in PBS, oscillated at 100 rpm, and analyzed at pre-determined time intervals for their physicomechanical and ab initio quantum energy transitions. Results indicated that the matrix resilience (MR) decreased with longer incubation periods (MR=35-45%) at day 30. Scaffolds salted-out using higher PLGA concentrations exhibited minimal changes in MR and the matrix ability to absorb energy was found to closely correlate with the scaffold residence time in PBS. Spartan-based ab initio quantum energy predictions elucidated the potential scaffold stability from a molecular viewpoint and its suitability for use in rate-modulated drug delivery. PMID:17524474
Sibambo, Sibongile R; Pillay, Viness; Choonara, Yahya E; Khan, Riaz A; Sweet, Joe L
The functionality of bare polylactide-co-glycolide (PLGA) nanoparticles is limited to drug depot or drug solubilization in their hard cores. They have inherent weaknesses as a drug-delivery system. For instance, when administered intravenously, the nanoparticles undergo rapid clearance from systemic circulation before reaching the site of action. Furthermore, plain PLGA nanoparticles cannot distinguish between different cell types. Recent research shows that surface functionalization of nanoparticles and development of new nanoparticulate dosage forms help overcome these delivery challenges and improve in vivo performance. Immense research efforts have propelled the development of diverse functional PLGA-based nanoparticulate delivery systems. Representative examples include PEGylated micelles/nanoparticles (PEG, polyethylene glycol), polyplexes, polymersomes, core-shell–type lipid-PLGA hybrids, cell-PLGA hybrids, receptor-specific ligand-PLGA conjugates, and theranostics. Each PLGA-based nanoparticulate dosage form has specific features that distinguish it from other nanoparticulate systems. This review focuses on fundamental concepts and practices that are used in the development of various functional nanoparticulate dosage forms. We describe how the attributes of these functional nanoparticulate forms might contribute to achievement of desired therapeutic effects that are not attainable using conventional therapies. Functional PLGA-based nanoparticulate systems are expected to deliver chemotherapeutic, diagnostic, and imaging agents in a highly selective and effective manner.
Sah, Hongkee; Thoma, Laura A; Desu, Hari R; Sah, Edel; Wood, George C
Osteomyelitis is an infection of the bone, and successful treatment involves local administration for about 6 weeks. Gentamicin is a very hydrophilic drug and tends to come out into the water phase when microspheres are fabricated using solvent evaporation method. Hence, spray drying is an option, and it was observed that the release rate tends to be fast when the particle size is small and large particles cannot be prepared by spray drying. In an effort to get better encapsulation efficiency and release rate, we have worked on the possibility of compressing the microspheres into discs and modifying the porosity of the discs by using biocompatible materials like polyethylene glycol (PEG) and calcium phosphates and also on the fabrication of double-walled and composite microspheres. In the case of microspheres, two methods of fabrication both based on solvent evaporation method were employed. The two polymers used are poly-L-lactide (PLLA) and copolymers of poly-DL-lactic-co-glycolic acid (PLGA). One method is based on the spreading coefficient theory for the formation of double-walled microspheres by using single solvent, while the other is based on the property of PLLA not being soluble in ethyl acetate (EA). Characterization to check if the microspheres formed are double-walled was performed. The fabrication method where two solvents, dichloromethane (DCM) and ethyl acetate, were used gave double-walled microspheres, while the other where only dichloromethane was used gave composites. The double-walled microspheres were smaller in size compared to the composites, which were in the range of 100-600 microm. This can be attributed to the difference in the fabrication procedure. We were able to achieve better encapsulation efficiencies of more than 50% and slower release rates, which lasted for about 15 days. It was observed that size played a major role in the encapsulation efficiency and release rates. The possibility of achieving better results by studying the effect of concentration of polymer in solvent and the effect of using different polymers was investigated. PMID:15653156
Naraharisetti, Pavan Kumar; Lew, Magdeleine Duan Ning; Fu, Yin-Chih; Lee, Duu-Jong; Wang, Chi-Hwa
A new method for fabrication of optical microspheres with the use of a CW CO2 laser is reported. Conventional method for fabrication of microspheres includes grinding and polishing processes which is not only time consuming, but also difficult of getting optical spheres with diameter less than 500 mum. It will be demonstrated that the laser method is very simple and
Q. K. Kieu; Vadim P. Veiko
Rifampicin polylactic acid microspheres for lung targeting were prepared by a modified emulsion-solvent diffusion method. The microspheres were free flowing, spherical with regular surface. Drug content, particle size distribution and in vitro release properties of the prepared microspheres were evaluated. In vivo experiments on rabbits showed remarkable accumulation of microspheres in the lung. PMID:11063425
Zhang, W; Jiang, X; Hu, J; Fu, C
Background Long-acting beta-agonists and inhaled corticosteroids have both been recommended in guidelines for the treatment of chronic obstructive pulmonary disease. Their co-administration in a combined inhaler is intended to facilitate adherence to medication regimens, and to improve efficacy. Two preparations are currently available, fluticasone/salmeterol (FPS) and budesonide/formoterol (BDF). Objectives To assess the efficacy of combined inhaled corticosteroid and long-acting beta-agonist preparations, compared to inhaled corticosteroids, in the treatment of adults with chronic obstructive pulmonary disease. Search methods We searched the Cochrane Airways Group Specialised Register of trials. The date of the most recent search is April 2007. Selection criteria Studies were included if they were randomised and double-blind. Studies compared combined inhaled corticosteroids and long-acting beta-agonist preparations with the inhaled corticosteroid component. Data collection and analysis Two reviewers independently assessed trial quality and extracted data. The primary outcome were exacerbations, mortality and pneumonia. Health-related quality of life (measured by validated scales), lung function and side-effects were secondary outcomes. Dichotomous data were analysed as fixed effect odds ratios or rate ratios with 95% confidence intervals, and continuous data as mean differences and 95% confidence intervals. Main results Seven studies of good methodological quality met the inclusion criteria randomising 5708 participants with predominantly poorly reversible, severe COPD. Exacerbation rates were significantly reduced with combination therapies (Rate ratio 0.91; 95% confidence interval 0.85 to 0.97, P = 0.0008). Data from two FPS studies indicated that exacerbations requiring oral steroids were reduced with combination therapy. Data from one large study suggest that there is no significant difference in the rate of hospitalisations. Mortality was also lower with combined treatment (odds ratio 0.77; 95% confidence interval 0.63 to 0.94). Quality of life, lung function and withdrawals due to lack of efficacy favoured combination treatment. Adverse event profiles were similar between the two treatments. No significant differences were found between FPS and BDP in the primary outcomes, but the confidence intervals for the BDP results were wide as smaller numbers of patients have been studied. Authors’ conclusions Combination ICS and LABA significantly reduces morbidity and mortality in COPD when compared with monocomponent steroid. Adverse events were not significantly different between treatments, although evidence from other sources indicates that inhaled corticosteroids are associated with increased risk of pneumonia. Assessment of BDF in larger, long-term trials is required. Dose response data would provide valuable evidence on whether efficacy and safety outcomes are affected by different steroid loads.
Nannini, Luis Javier; Cates, Christopher J; Lasserson, Toby J; Poole, Phillippa
Polymeric functional microspheres containing metal or metal compounds are formed by addition polymerization of a covalently bondable olefinic monomer such as hydroxyethylmethacrylate in the presence of finely divided metal or metal oxide particles, such as iron, gold, platinum or magnetite, which are embedded in the resulting microspheres. The microspheres can be covalently bonded to chemotherapeutic agents, antibodies, or other proteins providing a means for labeling or separating labeled cells. Labeled cells or microspheres can be concentrated at a specific body location such as in the vicinity of a malignant tumor by applying a magnetic field to the location and then introducing the magnetically attractable microspheres or cells into the circulatory system of the subject. Labeled cells can be separated from a cell mixture by applying a predetermined magnetic field to a tube in which the mixture is flowing. After collection of the labeled cells, the magnetic field is discontinued and the labeled sub-cell population recovered.
Yen, Shiao-Ping S. (Inventor); Rembaum, Alan (Inventor); Molday, Robert S. (Inventor)
Microsphere-based immunoassays were devised for compounds of agricultural and biomedical interest (e.g., digoxin, theophylline, and zearalenone). Commercially available microspheres with surface functional groups for chemical derivatization were used as solid carriers. After immobilizing the target substances, the surface of the haptenized microspheres was blocked by a protein to reduce aspecific binding. Competitive immunoassays were performed using the functionalized microspheres and antibodies labeled with horseradish peroxidase. Immunofluorescence signal amplification was achieved by enzyme-catalyzed reporter deposition (CARD). An epifluorescence microscope, a CCD camera interfaced with a computer, and microscopy image analysis software were employed for quantitative detection of fluorescent light emitted from individual microspheres. Integration of several such immunoassays and application of an optical encoding method enabled multianalyte determination. These immunoassays can also be utilized in an immunosensor array format. This immunoarray format could facilitate miniaturization and automation of multianalyte immunoassays.
Szurdoki, Ferenc; Michael, Karri L.; Agrawal, Divya; Taylor, Laura C.; Schultz, Sandra L.; Walt, David R.
Polylactide-co-glycolide (PLGA) and PLGA\\/Bioglass® foams of tubular shape have been prepared with a 1 wt.% 45S5 Bioglass® content. Porous membranes with varying thickness and porosity were fabricated via a thermally induced phase separation process, from which tubes of controlled diameter and wall thickness in the range 1.5–3 mm were produced. Scanning electron microscopy (SEM) revealed that the structure of the
A. R. Boccaccini; J. J. Blaker; V. Maquet; R. M. Day; R. Jérôme
Calcium-based minerals have consistently been shown to stimulate osteoblastic behavior in vitro and in vivo. Thus, use of such minerals in biomaterial applications has become an effective method to enhance bone tissue engineered constructs. In the present study, for the first time, human bone marrow stromal cells (hBMSC) were osteogenically differentiated on scaffolds consisting only of hydroxyapatite (HAp)-loaded poly(D,L-lactic acid-co-glycolic acid) (PLGA) microspheres of high monodispersity. Scaffold formulations included 0, 5, 10, and 20 wt% Hap, and the hBMSC were cultured for 6 weeks. Results demonstrated suppression of some osteogenic genes during differentiation in the HAp group, but higher end-point glycosaminoglycan and collagen content in 10% and 20% HAp samples, as evidenced by biochemical tests, histology, and immunohistochemistry. After 6 weeks of culture, constructs with 0% and 5% HAp had average compressive moduli of 0.7 ± 0.2 and 1.5 ± 0.9 kPa, respectively, whereas constructs with 10% and 20% HAp had higher average moduli of 17.6 ± 4.6 and 18.9 ± 8.1 kPa, respectively. The results of this study indicate that HAp inclusion in microsphere-based scaffolds could be implemented as a physical gradient in combination with bioactive signal gradients seen in previous iterations of these microsphere-based scaffolds to enhance osteoconduction and mechanical integrity of a healing site. PMID:21992088
Dormer, Nathan H; Qiu, Yue; Lydick, Anna M; Allen, Nicholas D; Mohan, Neethu; Berkland, Cory J; Detamore, Michael S
The objective of this study was to develop an in vitro release method for relatively unstable drugs in long-term modified release (MR) formulations, such as microspheres. Drug stability in the release medium can complicate in vitro release testing of such delivery systems. To overcome this problem, a method has been developed where the model drug, cefazolin, and its degradation products are monitored simultaneously, using UV fiber optic probes, to account for cumulative drug release from poly(lactic-co-glycolic) acid (PLGA) microspheres. United States Pharmacopeia (USP) Apparatus 2 and 4 were used to evaluate cefazolin release throughout the 30-day study period. Cefazolin exhibits an isosbestic point (wavelength where the drug and the degradation products have the same absorbance). Cumulative drug release was compared at the isosbestic (288 nm) point and at the UV max (270 nm). Monitoring at the isosbestic point allowed determination of total drug release with approximately 100% release by day 25. Whereas, at the UV max approximately 61% release was detected by day 25 as a result of drug degradation. Problems were encountered using USP Apparatus 2 with the in situ UV fiber optic probes as a result of microsphere accumulation at and interference with the probe detection window. PMID:18329196
Voisine, Jennifer M; Zolnik, Banu S; Burgess, Diane J
New compounds nobilamides A-H and related known compounds A-3302-A and A-3302-B were isolated based upon their suppression of capsaicin-induced calcium uptake in a mouse dorsal root ganglion primary cell culture assay. Two of these compounds, nobilamide B and A-3302-A, were shown to be long-acting antagonists of mouse and human TRPV1 channels, abolishing activity for >1 h after removal of drug presumably via a covalent attachment. Other derivatives also inhibited the TRPV1 channel, albeit with low potency, affording a structure-activity profile to support the proposed mechanism of action. While the activities were modest, we propose a new mechanism of action and a new site of binding for these inhibitors that may spur development of related analogues for treatment of pain. PMID:21524089
Lin, Zhenjian; Reilly, Christopher A; Antemano, Rowena; Hughen, Ronald W; Marett, Lenny; Concepcion, Gisela P; Haygood, Margo G; Olivera, Baldomero M; Light, Alan; Schmidt, Eric W
New compounds nobilamides A-H and related known compounds A-3302-A and A-3302-B were isolated based upon their suppression of capsaicin-induced calcium uptake in a mouse dorsal root ganglion primary cell culture assay. Two of these compounds, nobilamide B and A-3302-A, were shown to be long-acting antagonists of mouse and human TRPV1 channels, abolishing activity for >1 h after removal of drug presumably via a covalent attachment. Other derivatives also inhibited the TRPV1 channel, albeit with low potency, affording a structure-activity profile to support the proposed mechanism of action. While the activities were modest, we propose a new mechanism of action and a new site of binding for these inhibitors that may spur development of related analogs for treatment of pain.
Lin, Zhenjian; Reilly, Christopher A.; Antemano, Rowena; Hughen, Ronald W.; Marett, Lenny; Concepcion, Gisela P.; Haygood, Margo G.; Olivera, Baldomero M.; Light, Alan; Schmidt, Eric W.
The antihypertensive action of OPC-13340, a new dihydropyridine, was studied in rats and compared with the action of nicardipine and other dihydropyridines. OPC-13340 showed more potent and longer hypotensive action than nicardipine when administered either intravenously (i.v.) or orally in normotensive and hypertensive rats. Among 6 compounds tested, (OPC-13340, nifedipine, nitrendipine, nisoldipine, nicardipine and diltiazem), OPC-13340 was the most potent and long-acting when administered orally to spontaneously hypertensive rats (SHR). Tachycardia after administration of OPC-13340 was less or diminished earlier than that of nicardipine. Oral administration of OPC-13340 (3 mg/kg) once daily for 13 days did not cause any rebound phenomena in SHR. The compound inhibited Ca- or K-induced contractions in isolated rat aorta and shortened action potential duration in guinea pig papillary muscle, suggesting Ca channel blocking action. OPC-13340 might be useful as a drug for once-daily therapy of essential hypertension. PMID:1692946
Nakayama, N; Ikezono, K; Mori, T; Yamashita, S; Nakayama, S; Tanaka, Y; Hosokawa, T; Minami, Y; Masutani, K; Yamamura, Y
A multivalent approach focused on amine-based secondary binding groups was applied to the discovery of long-acting inhaled ?2-agonists. Addition of amine moieties to the neutral secondary binding group of an existing ?2-agonist series was found to provide improved in vivo efficacy, but also led to the formation of biologically active aldehyde metabolites which were viewed as a risk for the development of these compounds. Structural simplification of the scaffold and blocking the site of metabolism to prevent aldehyde formation afforded a potent series of dibasic ?2-agonists with improved duration of action relative to their monobasic analogs. Additional optimization led to the discovery of 29 (TD-4306), a potent and selective ?2-agonist with potential for once-daily dosing. PMID:24835980
McKinnell, R Murray; Klein, Uwe; Linsell, Martin S; Moran, Edmund J; Nodwell, Matthew B; Pfeiffer, Juergen W; Thomas, G Roger; Yu, Cecile; Jacobsen, John R
The advent of recombinant technology has made the production of modified proteins with desired properties possible. Corifollitropin alfa is a successful example of the first available long-acting, follicle stimulating hormone. Corifollitropin alfa has prolonged half-life and a slower absorption rate, but has the same receptor-binding and biological activity as recombinant FSH (rFSH). Its application is associated with the arrival of a novel simplified approach for controlled ovarian stimulation in IVF patients. Different studies have proven the efficiency of a single corifollitropin alfa dose to initiate and sustain multiple follicular development in a gonadotropin-releasing hormone antagonist protocol. Finally, corifollitropin alfa is well tolerated and is not correlated with serious adverse events, except for the slightly higher incidence of ovarian hyperstimulation syndrome compared with traditional management with recombinant FSH. PMID:20887164
Loutradis, D; Vlismas, A; Drakakis, P
In this research poly (d,l-lactide-coglycolide acid) (PLGA) as polymeric nanospheres, poly(vinyl alcohol) (PVA) with 87-89% hydrolysis degree as surfactant and distilled water as suspending medium were used. The encapsulated drug was Bethametasone. The nanospheres were prepared by an emulsion-solvent evaporation method. The nanospheres characterized by photon correlation spectroscopy (PCS) and scanning electron microscopy (SEM). The amount of drug release was determined by HPLC. In emulsion-solvent evaporation technique, time of ultrasound exposure, surfactant content in the formulation and evaporation rate of organic solvents were considered as formulation variables.
Khosroshahi, Mohammad E.; Enayati, Marjan; Shafiei, Sara; Tavakoli, Javad
Whether the long acting somatostatin analogue SMS 201-995 (octreotide, Sandostatin) could inhibit the basal and meal stimulated hypergastrinaemia and hyperpepsinogenaemia induced by omeprazole was investigated. Eight healthy subjects were randomised to receive five day courses of SMS 201-995 (25 micrograms subcutaneously three times daily), omeprazole (40 mg once a day), a combination of both drugs, or placebo. Basal and meal stimulated serum gastrin and basal serum pepsinogen A and C values were measured the day before treatment, on day five of treatment, and the day after each course of treatment. Omeprazole caused significant increases in basal and meal stimulated peak and integrated serum gastrin values and pepsinogen A and C levels, which were still significantly raised the day after stopping omeprazole treatment. Giving SMS 201-995 with omeprazole significantly reduced any omeprazole induced increases in basal and meal stimulated peak and integrated serum gastrin levels; serum pepsinogen A and C values were significantly inhibited too. Serum gastrin values during combined therapy were not significantly different from those during placebo treatment, whereas pepsinogen A and C levels were still significantly raised. On the day after stopping combined therapy, basal and meal stimulated peak and integrated serum gastrin and serum pepsinogen C (but not pepsinogen A) levels were not significantly different from values obtained on the day after stopping omeprazole alone. SMS 201-995 without omeprazole significantly inhibited basal and meal stimulated peak and integrated serum gastrin levels. Pepsinogen A was also significantly inhibited by SMS 210-995, but the reduction in pepsinogen C failed to reach statistical significance. In conclusion, SMS 201-995 prevents basal and meal stimulated increases in serum gastrin during omeprazole therapy. This finding may have clinical importance in the few patients who have pronounced hypergastrinaemia because of profound long acting acid inhibition.
Meijer, J L; Jansen, J B; Crobach, L F; Biemond, I; Lamers, C B
The objectives of this study were first to show adrenocortical response to a long-acting adrenocorticotropic hormone preparation (tetracosactide acetate zinc suspension) (ACTH-Z) and its effect on adrenocortical function in beef cows (Experiment 1) and second to apply the ACTH-Z challenge in dairy cows based on cortisol concentrations in milk collected at routine milking (Experiment 2). In Experiment 1, four beef cows in luteal phase were challenged with ACTH-Z, and plasma cortisol concentrations were determined for 48 h after the injection at 30-min to 2-h intervals. A rapid ACTH test was conducted 3 days before and 2 h after the completion of ACTH-Z injection for 48 h to investigate the effect on adrenocortical function. Plasma cortisol concentrations increased significantly 30 min after ACTH-Z injection (p < 0.001), and the high cortisol levels were maintained for approximately 10 h after the injection. In Experiment 2, eight dairy cows were subjected to ACTH-Z challenge 1-2 weeks and 4-5 weeks post-partum. Blood and milk samples were taken at morning and afternoon milking. All the cows showed a significant increase in cortisol concentrations in plasma as well as in skim milk 8 h after ACTH-Z injection 1-2 weeks and 4-5 weeks post-partum (p < 0.001). There was a significant correlation between plasma and skim milk cortisol concentrations 8 h after ACTH-Z challenge (r = 0.74, p < 0.001). The results obtained in this study suggest that elevated levels of plasma cortisol are maintained for approximately 10 h after ACTH-Z treatment without adverse effect on adrenocortical function and a long-acting ACTH-Z challenge based on cortisol concentrations in milk, which were collected at the morning and the afternoon milking, can be a useful tool to monitor adrenocortical function in cows. PMID:20626680
Thinh, N C; Yoshida, C; Long, S T; Yusuf, M; Nakao, T
Objectives Long-acting nanoformulated antiretroviral therapy (nanoART) with improved pharmacokinetics, biodistribution and limited systemic toxicities will likely improve drug compliance and access to viral reservoirs. Design Atazanvir and ritonavir crystalline nanoART were formulated in a poloxamer-188 excipient by high-pressure homogenization. These formulations were evaluated for antiretroviral and neuroprotective activities in humanized NOD/scid-IL-2Rgcnull (NSG) mice. Methods NanoART-treated NSG mice were evaluated for drug biodistribution, pharmacodynamics and nanotoxicology. CD34+ human hematopoietic stem cells were transplantation at birth in NSG mice. The mice were infected with HIV-1ADA at 5 months of age and 8 weeks later, infected animals were treated with weekly subcutaneous injections of nanoformulated ATV and RTV. Peripheral viral load, CD4+ T cell count, lymphoid tissue and brain pathology were evaluated. Results NanoART treatments by 6 once a week injections reduced viral loads >1000 fold and protected CD4+ T cell populations. This paralleled high ART levels in liver, spleen and blood that were in or around the human minimal effective dose concentration without notable toxicities. Importantly, examination of infected brain subregions showed that nanoART elicited neuroprotective responses with detectable increases in microtubule-associated protein-2, synaptophysin and neurofilament expression when compared to untreated virus-infected animals. Therapeutic interruptions produced profound viral rebounds. Conclusions Long-acting nanoART has translational potential with sustained and targeted efficacy and with limited systemic toxicities. Such success in drug delivery and distribution could improve drug adherence and reduce viral resistance in infected people.
Dash, Prasanta K.; Gendelman, Howard E.; Roy, Upal; Balkundi, Shantanu; Alnouti, Yazen; Mosley, R. Lee; Gelbard, Harris A.; McMillan, JoEllyn; Gorantla, Santhi; Poluektova, Larisa Y.
Long acting ?(2)-adrenoceptor agonists as exemplified by salmeterol and formoterol, exhibit reassertion behaviour in isolated airway preparations. This phenomenon is the inhibition of relaxation by a ?(2)-antagonist (e.g. sotalol), followed by the re-establishment of the relaxation when all drugs have been washed out and in the absence of any further agonist addition to the bathing solution. In this study we have compared the reassertion behaviour of salmeterol and formoterol with the new long acting ?(2)-adrenoceptor agonists indacaterol, carmoterol and three Pfizer agonists (PF610,355, PF613,322, UK503590) in the guinea pig isolated trachea and in a novel assay developed in CHO cells expressing the recombinant human ?(2)-adrenoceptor. The results obtained can be divided into two groups: salmeterol-like (persistent duration of action following agonist removal--coupled with reassertion behaviour), as exemplified by indacaterol, PF610,355, PF613,322 and UK503,590 and, formoterol-like (short duration of agonist action and little reassertion behaviour unless supramaximal concentrations are used), as exemplified by carmoterol. Results are discussed in the context of the two theories proposed to explain the long duration of action of salmeterol (binding to a specific 'exosite' of the ?(2)-adrenoceptor) and formoterol (membrane deposition: micro-kinetic theory). Our data suggest that the micro-kinetic theory is an adequate explanation to explain the long duration of action of the ?(2)-adrenoceptor agonists studied in these two assays, although with the current data set we cannot definitively exclude the 'exosite' theory. PMID:21134482
Patel, S; Summerhill, S; Stanley, M; Perros-Huguet, C; Trevethick, M A
As second-generation antipsychotic long-acting injections (SGA-LAIs) are rapidly replacing depot first-generation antipsychotics as first-line agents in treating schizophrenia spectrum disorders, a systematic assessment of their adverse effects is timely. English-language, peer-reviewed articles reporting original data on the safety and tolerability of SGA-LAIs were identified electronically by searching the MEDLINE, EMBASE, PsycINFO, and DARE databases and the Cochrane Library (January 2001-April 2013). In addition to second-generation (atypical) antipsychotics and long-acting injection (depot) antipsychotics, a separate search was performed for each available drug: aripiprazole LAI, olanzapine pamoate, paliperidone palmitate, and risperidone LAI. Articles were excluded if they were review articles, post hoc analyses, analyses of subsets of patients enrolled in previous trials, single case reports, case series studies, small naturalistic studies (involving less than 50 patients), studies providing no safety data, and studies lasting less than 8 weeks. Of 181 articles identified from the search, 140 were excluded; thus, 41 articles met the inclusion criteria. Predictably, the reviewed information revealed that SGA-LAIs have safety profiles consistent with their oral parent formulations. However, they seem to also show unforeseen and worrisome safety signals. Indeed, the routine use of olanzapine-LAI in clinical practice could be limited not only by the well-known risk of postinjection syndrome, whose clinical management remains a matter of concern, but also by the risk of worsening of psychosis. The reviewed information seems to suggest that worsening of psychotic symptoms and depression could also be associated with both risperidone-LAI and paliperidone palmitate. The leading cause of death among patients enrolled in risperidone-LAI studies was suicide. Given the exponential growth in the clinical use of SGA-LAIs, further studies must be urgently performed in order to confirm or exclude the potential safety signals associated with such drugs. PMID:23776129
Acrylamide (AAm)-methacrylic acid (MAc)-methylenebisacrylamide (MBAAm) terpolymer microspheres and AAmMAc-MBAAm-nitrophenyl acrylate (NPA) quaterpolymer microspheres with high monodispersity were prepared by precipitation polymerization in alcohol. The former were modified into composite microspheres containing hydrophobic domains or magnetite nanospheres. The active ester in the quaterpolymer microspheres was allowed to undergo hydrolysis or aminolysis to prepare novel microspheres such as highly negative, amphoteric, hydrophobic
Haruma Kawaguchi; Keiji Fujimoto; Yoshiyuki Nakazawa; Mami Sakagawa; Yasushi Ariyoshi; Miwako Shidara; Hitoshi Okazaki; Yukio Ebisawa
The purpose of this study was to develop a parenteral delivery system of Risperidone that would provide initial and extended drug release and thereby avoid the need for co-administration of oral tablets. Key formulation parameters utilized to achieve desired therapeutic levels in vivo were particle size and drug loading. Three poly (D,L-lactide-co-glycolide) (PLGA) microsphere formulations (Formulations A, B, and C) that encapsulated Risperidone were prepared by varying particle size (19-49 ?m) and drug loading parameters (31-37%) but with a uniform bulk density (0.66-0.69)g/cc and internal porosity, utilizing the solvent extraction/evaporation method. The microspheres were characterized for drug content by HPLC, particle size by laser diffractometry, surface morphology by scanning electron microscopy (SEM), and in vivo drug release. In vivo studies were performed in male Sprague-Dawley rats, and levels of the active moiety (Risperidone and its metabolite, 9-hydroxyrisperidone) were assessed. In vivo release profiles from the three microsphere formulations were dependent on particle size and drug loading. The smaller sized microspheres (Formulation A) exhibited a large initial burst and a shorter duration of action, while the larger particles exhibited a smaller initial burst (Formulations B and C) but released drug for a much longer period in vivo. Extended duration of drug release was ascribed to higher drug content in the microspheres. A biweekly simulation of multiple dosing revealed that Formulation C, the selected formulation, with a high load and large particle size would provide adequate initial and maintenance levels of the active moiety (Risperidone and its metabolite, 9-hydroxyrisperidone). A comparison of biweekly dosing in vivo of Formulation C with the marketed product showed that at steady state, though average concentrations for both preparations were similar, the time taken to achieve steady state was much faster for Formulation C. The delay in attaining steady state with Risperdal Consta® was attributed to the 3 week latency in drug release from the microspheres and was in accordance with previous studies indicating a good corroboration with clinical findings. Calculated cumulative AUC (area under the curve) levels for Formulation C were similar to the Risperdal Consta®, though there were marked differences in AUC levels at the early time points. Comparison of Risperidal Consta® and Formulation C by multiple dosing in vivo experiments revealed that the marketed preparation demonstrated a substantial delay in providing an initial loading dose, continuous circulating levels, and attainment of steady state; all of which were observed rapidly with Formulation C. Findings from the current study strongly suggest that a microsphere dosage form of Risperidone can be formulated with an optimum particle size and drug loading to provide an initial bolus followed by maintenance levels, thereby eliminating combination therapy and improving patient compliance. PMID:23892159
D'Souza, Susan; Faraj, Jabar; DeLuca, Patrick
The purpose of this study was to develop a stable single-dose vaccine based on recombinant hepatitis B surface antigen (HBsAg) in poly(D,L-lactic-co-glycolic acid) (PLGA) microspheres, in which HBsAg was stabilized by a protein stabilizer (trehalose) and an antacid (Mg(OH)2). The microspheres were prepared by the double emulsion method and characterized by scanning electron microscopy. To neutralize the acids liberated by the biodegradable lactic/glycolic acid based polymer, we coincorporated into the polymer an antacid, Mg(OH)2, which neutralized the acidity during degradation of the polymer and also prevented HBsAg structural losses and aggregation. The antigen integrity after encapsulation was examined by sodium dodecyl sulfate polyacrylamide gel electrophoresis followed by silver staining, isoelectric focusing and Western blotting techniques, which confirmed that antigen remained intact after encapsulation. In-vitro release experiments were performed in phosphate-buffered saline (pH 7.4) and the release of antigen was found to be improved by the protein stabilizer (trehalose). In stability studies, performed at 37 degrees C, the microspheres were found to be stable for 16 days. The immunogenicity of stable microsphere formulations bearing HBsAg was compared with the conventional alum-absorbed HBsAg vaccine in a guinea-pig model. The antibody titre indicated that a single injection of stabilized HBsAg-PLGA microspheres produced a better immune response than two injections of alum-formulated HBsAg vaccine. The findings suggest that recombinant HBsAg can be stabilized by use of a protein stabilizer and antacid during entrapment, and this stabilized preparation can be useful for antigen delivery. PMID:15482638
Jaganathan, K S; Singh, Paramjit; Prabakaran, D; Mishra, Vivek; Vyas, Suresh P
The biodistribution of nanoparticles is significantly influenced by their interaction with plasma proteins. In order to optimize and possibly monitor the delivery of drugs bound to nanoparticles across the blood-brain barrier (BBB), the protein adsorption pattern of uncoated poly(lactic-co-glycolic acid) (PLGA) nanoparticles after their incubation in human plasma was studied by mass spectrometry. After washing of the particles with water, the proteins were directly digested on the nanoparticle surface using trypsin and then analyzed by nLC MALDI-TOF/TOF. Up to now, the standard method for investigation into the plasma protein adsorption to the particles was 2D gel electrophoresis (2D-PAGE), in certain cases followed by mass spectrometry. The non-gel-based method proposed in the present study provides novel insights into the protein corona surrounding the nanoparticles. The proteins adsorbed on the PLGA nanoparticles after incubation that gave the best signal in terms of quality (high MASCOT score) in human plasma were apolipoprotein E, vitronectin, histidine-rich glycoprotein and kininogen-1. These proteins also are constituents of HDL. PMID:23395970
Sempf, Karim; Arrey, Tabiwang; Gelperina, Svetlana; Schorge, Tobias; Meyer, Björn; Karas, Michael; Kreuter, Jörg
Probiotic bacteria have gained popularity as a defence against disorders of the bowel. However, the acid sensitivity of these cells results in a loss of viability during gastric passage and, consequently, a loss of efficacy. Probiotic treatment can be supplemented using 'prebiotics', which are carbohydrates fermented specifically by probiotic cells in the body. This combination of probiotic and prebiotic is termed a 'synbiotic'. Within this article a multiparticulate dosage form has been developed, consisting of poly(d,l-lactic-co-glycolic acid) (PLGA) microcapsules containing prebiotic Bimuno™ incorporated into an alginate-chitosan matrix containing probiotic Bifidobacterium breve. The aim of this multiparticulate was that, in vivo, the probiotic would be protected against gastric acid and the release of the prebiotic would occur in the distal colon. After microscopic investigation, this synbiotic multiparticulate was shown to control the release of the prebiotic during in vitro gastrointestinal transit, with the release of galacto-oligosaccharides (GOS) initially occurred over 6h, but with a triphasic release pattern giving further release over 288h. Encapsulation of B. breve in multiparticulates resulted in a survival of 8.0±0.3logCFU/mL cells in acid, an improvement over alginate-chitosan microencapsulation of 1.4logCFU/mL. This was attributed to increased hydrophobicity by the incorporation of PLGA particles. PMID:24657143
Cook, Michael T; Tzortzis, George; Charalampopoulos, Dimitris; Khutoryanskiy, Vitaliy V
Goal of the present study was to develop and to characterize in situ-hardening, porous PLGA-based systems for their future application as bone grafting materials. Therefore, we investigated the precipitation behavior of formulations containing PLGA and a water-miscible solvent, DMSO, PEG 400, and NMP. To increase porosity, a pore forming agent (NaCMC) was added and to enhance mechanical properties of the system, an inorganic filler (?-TCP) was incorporated. The behavior upon contact with water and the influence of the prior addition of aqueous media on the morphology of the corresponding hardened implants were investigated. We proved cell-compatibility by live/dead assays for the hardened porous polymer/ceramic-composite scaffolds. The IsHS formulations can therefore be used to manufacture hardened scaffolds ex vivo by using molds with the desired shape and size. Cells were further successfully incorporated into the IsHS by precultivating the cells on the ?-TCP-powder prior to their admixing to the formulation. However, cell viability could not be maintained due to toxicity of the tested solvents. But, the results demonstrate that in vivo cells should well penetrate, adhere, and proliferate in the hardened scaffolds. Consequently, we consider the in situ hardening system being an excellent candidate as a filling material for non-weight-bearing orthopedic indications, as the resulting properties of the hardened implant fulfill indication-specific needs like mechanical stability, elasticity, and porosity. PMID:22947486
Schloegl, W; Marschall, V; Witting, M Y; Volkmer, E; Drosse, I; Leicht, U; Schieker, M; Wiggenhorn, M; Schaubhut, F; Zahler, S; Friess, W
Objectives: To examine factors associated with the uptake of i) long-acting reversible, ii) permanent and iii) traditional contraceptive methods among Australian women. Methods: Participants in the Australian Longitudinal Study on Women's Health born in 1973-78 reported on their contraceptive use at three surveys: 2003, 2006 and 2009. The participants were 5,849 women aged 25-30 in 2003 randomly sampled from Medicare. The main outcome measure was current contraceptive method at age 28-33 years categorised as long-acting reversible methods (implant, IUD, injection), permanent (tubal ligation, vasectomy), and traditional methods (oral contraceptive pills, condoms, withdrawal, safe period). Results: Compared to women living in major cities, women in inner regional areas were more likely to use long-acting (OR=1.26, 95%CI 1.03-1.55) or permanent methods (OR=1.43, 95%CI 1.17-1.76). Women living in outer regional/remote areas were more likely than women living in cities to use long-acting (OR=1.65, 95%CI 1.31-2.08) or permanent methods (OR=1.69, 95%CI 1.43-2.14). Conclusions: Location of residence is an important factor in women's choices about long-acting and permanent contraception in addition to the number and age of their children. Implications: Further research is needed to understand the role of geographical location in women's access to contraceptive options in Australia. PMID:24690048
Lucke, Jayne C; Herbert, Danielle L
Immune responses against the Leishmania antigens are not sufficient to protect against a leishmania challenge. Therefore these antigens need to be potentiated by various adjuvants and delivery systems. In this study, Poly (d,l-lactide-co-glycolide (PLGA) nanospheres as antigen delivery system and Quillaja saponins (QS) as immunoadjuvant have been used to enhance the immune response against autoclaved Leishmania major (ALM). PLGA nanospheres were prepared by a double-emulsion (W/O/W) technique. Particulate characteristics were studied by scanning electron microscopy and particle size analysis. Mean diameter for nanospheres loaded with ALM+QS was 294 ± 106 nm. BALB/c mice were immunized three times in 3-weeks intervals using ALM plus QS loaded nanospheres [(ALM+QS)PLGA], ALM encapsulated with PLGA nanospheres [(ALM)PLGA], (ALM)PLGA + QS, ALM + QS, ALM alone or PBS. The intensity of infection induced by L. major challenge was assessed by measuring size of footpad swelling. The strongest protection, showed by significantly (P < 0.05) smaller footpad, were observed in mice immunized with (ALM)PLGA. The (ALM+QS)PLGA group showed the least protection and highest swelling, while the (ALM)PLGA+QS, ALM+QS and ALM showed an intermediate protection with no significant difference. The mice immunized with ALM and ALM+QS showed the highest IgG2a/IgG1 ratio (P < 0.01), followed by (ALM)PLGA+QS. The highest IFN-? and lowest IL-4 production was seen in (ALM)PLGA+QS, ALM+QS groups. The highest parasite burden was observed in (ALM)PLGA+QS and (ALM+QS)PLGA groups. It is concluded that PLGA nanospheres as a vaccine delivery system could increase the protective immune responses, but QS adjuvant has a reverse effect on protective immune responses and the least protective responses were seen in the presence of this adjuvant. PMID:21399606
Tafaghodi, M; Eskandari, M; Kharazizadeh, M; Khamesipour, A; Jaafari, M R
Background The aim of this study was to investigate the effects of poly-lactic-co-glycolic acid (PLGA) nanotopographies with alginate or chitosan protein preadsorption on the functioning of healthy and cancerous lung and breast cells, including adhesion, proliferation, apoptosis, and release of vascular endothelial growth factor (VEGF), which promotes tumor angiogenesis and secretion. Methods We used a well established cast-mold technique to create nanoscale surface features on PLGA. Some of the nanomodified PLGA films were then exposed to alginate and chitosan. Surface roughness and the presence of protein was confirmed by atomic force microscopy. Surface energy was quantified by contact angle measurement. Results Nanostructured PLGA surfaces with 23 nm features decreased synthesis of VEGF in both lung and breast cancer cells compared with conventional PLGA. Preadsorbing alginate further decreased cancer cell function, with nanostructured PLGA preadsorbed with alginate achieving the greatest decrease in synthesis of VEGF in both lung and breast cancer cells. In contrast, compared with nonmodified smooth PLGA, healthy cell functions were either not altered (ie, breast) or were enhanced (ie, lung) by use of nanostructured features and alginate or chitosan protein preadsorption. Conclusion Using this technique, we developed surface nanometric roughness and modification of surface chemistry that could selectively decrease breast and lung cancer cell functioning without the need for chemotherapeutics. This technique requires further study in a wide range of anticancer and regenerative medicine applications.
Zhang, Lijuan; Webster, Thomas J