Aerosolized PLA and PLGA nanoparticles enhance humoral, mucosal and cytokine responses to hepatitis B vaccine

Porous poly(L-lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLGA) nanoparticles were tested for pulmonary delivery of hepatitis B vaccine. In particular, the effects of particle size and hydrophobicity on mucosal and cell-mediated immune responses were investigated. Three formulations of PLA and PLGA nanoparticles containing a fixed amount of hepatitis B surface antigen (HBsAg) were prepared by a double-emulsion-solvent-evaporation method and characterized for surface morphology, charge, size, density and in vitro release. The immune responses were studied by measuring secretory IgA levels in mucosal fluids and quantitating cytokine levels in rat spleen homogenates. Particle uptake was studied in rat alveolar macrophages. Scanning electron microscopy revealed particles with smooth surfaces. Zeta potential measurements indicated that the particles carried negative surface charges. The antigen was continuously released for 42 days in phosphate buffer. Hydrophobic particles >500 nm elicited a more robust increase in secretary IgA, interleukin-2 and interferon-γ levels compared to hydrophilic particles <500 nm. Large hydrophobic particles were more efficiently internalized by rat alveolar macrophages compared to smaller hydrophilic particles. Calu-3 cell viability studies indicate that the viability of cells is not affected by nanoparticulate formulations. This study demonstrates that inhalable nanoparticles of HBsAg produce an enhancement of immune responses.     

Intestinal lymphatic absorption of cyclosporin a following oral administration in an olive oil solution in rats

The intestinal lymphatic absorption of cyclosporin A (CyA) following oral adminstration of 6·5 0·6 and 25·2±1·4mg kg^?1 doses of the drug dissolved in an olive oil solution was studied using a thoracic duct-cannulated rat model. Cumulative lymph samples were collected for up to 114h post-dosing and assayed by liquid scintillation counting. In this study, the estimated amount of lymphatically absorbed CyA was 0·35±0·13 and 0·47±0·29 per cent of the respective doses. In terms of the overall oral bioavailability of CyA (F_po) by all absorptive mechanisms, the intestinal lymphatics accounted for the absorption of approximately 2 per cent of the total amount of absorbed drug. F_po was 21·3±2·5 per cent. The results of this study suggested that lipophilicity alone was not the only factor governing intestinal lymphatic drug absorption. An explanation for the low level of lymphatic CyA absorption is presented. In addition, some reasons for the low overall oral bioavailability of CyA are discussed.     

Absorption of interferon alpha from patches in rats

Interferon alpha (IFN-α), patch preparations composed of three layers, water-insoluble backing layer, drug containing layer with absorption enhancer and surface layer containing pH-dependent polymer were prepared. As absorption enhancer, three surfactants, Gelucire44/14 (Lauroyl macrogol-32 glycerides), Labrasol (Caprylocaproyl macrogol-8 glycerides) and HCO-60 (polyoxyethylated hydrogenerated castor oil) were used in preparing IFN-α patch preparations. The intestinal absorption of IFN-α was studied after the administration of test patch preparations into the rat jejunum, 50,000 IU/kg. The serum IFN-α levels were measured by an ELISA method and both C _max and AUC were determined as the index of absorption of IFN-α. Gelucire44/14 preparation including Pharmasol for the stable solidification showed the higher C _max, 7.66 ± 0.82 IU/ml, and AUC, 12.85 ± 1.49 IU h/ml, than Labrasol (6.51 ± 0.89 and 8.30 ± 1.34 IU h/ml) and HCO-60 (6.02 ± 1.14, 7.53 ± 1.84 IU h/ml) preparations, respectively. By comparing to the AUC obtained after s.c. injection of the same dose of IFN-α to rats, bioavailability (BA) was estimated to be 7.8% in Gelucire44/14 preparation. In vitro release study showed that the T50%s, the time when half of the formulated IFN-α is released from the patches, were 3.4 ± 0.1 min for HCO-60, 7.8 ± 0.1 min for Gelucire44/14 and 11.4 ± 0.1 min for Labrasol preparations. To study the effect of absorption site, Gelucire44/14 preparation was administered into the rat duodenum and ileum. However, there were not significant differences on AUC among the three absorption sites. By reducing the IFN-α dose from 50,000 to 25,000 IU/kg, the serum IFN-α levels vs time profile showed a tendency of dose-dependency. When the histological examination of small intestinal mucosa was carried out in this study, the small intestinal mucosa after the Gelucire44/14 patches administered and before it was administered, could not recognize impaired. From these results, the usefulness of oral patch system for the oral delivery of IFN-α has been proved in rats.     

In vitro and in vivo studies of cyclosporin A-loaded microspheres based on copolymers of lactide and epsilon-caprolactone: comparison with conventional PLGA microspheres

A hydrophobic peptide, cyclosporin A (CyA), was incorporated in microspheres based on poly(lactide-b-epsilon-caprolactone) (P(LA-b-CL), LA/CL (in molar ratio): 78.7/21.3 and 48.1/51.9) and poly(lactide-co-glycolide) (PLGA, LA/GA: 80/20) using oil-in-water (O/W) emulsion solvent evaporation method. The microspheres were characterized by SEM, DSC and X-ray diffraction, and CyA release rate was determined by HPLC. It was revealed that CyA can be efficiently loaded into all the microspheres (exceed 96%). Compared to PLGA microspheres, P(LA-b-CL) microspheres liberated CyA more rapidly. Within the first day, about 75, 50 and 12% of CyA released from P(LA-b-CL) (48.1/51.9), P(LA-b-CL) (78.7/21.3) and PLGA microspheres, respectively, which can be attributed to the partial crystallization occurring in P(LA-b-CL) microspheres. CyA levels in whole blood were also tested. In comparison with PLGA microspheres, P(LA-b-CL) microspheres provided a higher blood level of CyA. The maximum CyA concentration in whole blood (approximately 520, 450 and 400 ng ml(-1) for P(LA-b-CL) (48.1/51.9) P(LA-b-CL) (78.7/21.3) and PLGA microspheres, respectively) was reached at the second day post administration. And then P(LA-b-CL) microspheres showed a constant CyA level (about 100-200 ng ml(-1)) for extended periods of time (several weeks). Such CyA-loaded P(LA-b-CL) microspheres displaying higher CyA concentration during the first few days and similar constant blood CyA level thereafter showed more advantages than those prepared with PLGA and could meet clinical needs more efficiently.     

Enhanced Selective Lymphatic Delivery of Cyclosporin A by Solubilizers and Intensified Immunosuppressive Activity Against Mice Skin Allograft

The absorption and lymphatic delivery of a new immunosuppressive drug, cyclosporin A (CsA), were studied in rats by administering CsA orally after solubilization with HCO-60 (polyoxyethylated hydrogenated castor oil), sugar ester, and oils. After the administration of solubilized CsA (7 mg/kg) to rats with thoracic lymph duct cannulas, both plasma and lymph CsA levels were measured over 6 hr. The lymph CsA levels were strongly affected by the solubilizers. The rank order of the solubilizers in enhancing lymph absorption was HCO-60 (57 µg/ml) > sugar ester (46 µg/ml) > sesame oil (3.5 µg/ml) > linoleic acid (0.4 µg/ml), where the parentheses show the maximum lymph CsA levels. Plasma CsA levels were below 2 µg/ml in each group of animals and were barely altered by the solubilizers. These results support the selective lymphatic delivery of CsA with solubilizers such as HCO-60 and sugar ester. The immunosuppressive activity of CsA (1 mg/kg) solubilized with HCO-60 was nearly equivalent to the sesame oil solution with 7 to 15 mg/kg CsA in the skin-allograft mice model.     

Biodistribution of Cyclosporin Encapsulated in Liposomes Modified with Bioadhesive Polymer

The purpose of this investigation was to study the possibility of renewing the immunosuppressive activity of cyclosporin by formulating the compound in liposomes modified with bioadhesive polymers. The liposomes prepared were evaluated both pharmacokinetically and pharmacodynamically. Tissue distribution and plasma pharmacokinetics of cyclosporin and model dye, sudan black, which is as hydrophobic as cyclosporin, were studied in rats after intravenous infusion (10 mg kg^?). The immunosuppressive efficacy of liposomal cyclosporin preparations was studied in the allogenic rat-heart-transplantation model, where cyclosporin therapy (10 mg kg^?) continued for one week. The entrapment of sudan black in liposomes modified with bioadhesive polymers resulted in higher sudan black delivery to the spleen and the liver than with standard sudan-black-loaded liposomes. Among the modified liposomes, those modified with carbopol 941 showed the most remarkable enhancing effect on the delivery of sudan black to these organs and total plasma clearance of sudan black decreased to 38.6 ± 7.8 mL h^? kg^? (standard liposomes, 58.9 ± 64 mL h^? kg^?). Delivery of cyclosporin to the spleen and the liver was increased approximately twofold by modifying the liposomes with carbopol 941. In the preliminary study on the allogenic rat-heart-transplantation model, the mean survival days of the graft were 18.8 ± 2.9 days for the group receiving cyclosporin liposomes modified with carbopol 941, 14.2 ± 4.4 days for the group receiving standard cyclosporin liposomes and 7.6 ± 0.5 days for the group receiving cyclosporin solution. The encapsulation of cyclosporin in liposomes modified with bioadhesive polymer enhanced the residence time of cyclosporin in the systemic circulation, resulting in approximately twofold greater delivery of cyclosporin to the spleen and liver. However, in the allogenic rat-heart-transplantation model no significant difference was detected between the immunosuppressive efficacy of cyclosporin encapsulated in bioadhesive polymer-modified liposomes and that encapsulated in standard liposomes.     

Pharmacokinetic evaluation of the blood-to-lymph transfer of cyclosporin a in rats

The blood-to-lymph transfer kinetics of cyclosporin A (CyA) were investigated in thoracic duct cannulated rats after a 3mg kg^?1 i.v. bolus injection of tritium-labelled drug. Blood CyA concentrations declined bi-exponentially with a terminal half-life of 13·1 ± 1·8 h. The appearance rate of CyA in the lymph was also bi-phasic, initially rising and then declining in parallel with the concentrations of CyA in the blood. A pharmacokinetic model describing the blood-to-lymph transfer kinetics of CyA is presented. From the slopes of graphs relating the appearance rate of CyA in the lymph to the corresponding midpoint blood drug concentration, the estimated blood-to-lymph clearance rate of CyA (Cl_L)_b was 0·262·0·132 mlh^?1 (Cl_L)_b was positively correlated with the average lymph flow rate (Q?_L) but was significantly less than Q?_L. On the other hand, the plasma-to-lymph clearance rate of CyA (Cl_L)_P of 0·393 ± 0·198 mlh^?1 was positively correlated and similar to Q?_L. Lymph concentrations of CyA were approximately 40–60 per cent of the corresponding blood concentrations. The results of this investigation showed the existence of an intervening compartment between the blood and lymph fluids which would be consistent with the presence of lymph nodes. It was shown that the blood-to-lymph transfer of CyA was dependent on the flow rate of the lymph and that CyA appeared to be cleared from the plasma (or serum) fraction of the blood.     

pH and Osmotic Pressure Inside Biodegradable Microspheres During Erosion1

Purpose. To measure changes in pH as well as osmotic pressure in aqueous pores and cavities inside biodegradable microspheres made from polymers such as poly(D,L-lactic acid) (PLA) and poly(D,L-lactic acid -co- glycolic acid) (PLGA). Methods. The internal osmotic pressure inside eroding PLA microspheres was analyzed with differential scanning calorimetry (DSC) in a temperature range of 10 to –25°C. The osmotic pressure was calculated from the melting peaks of the aqueous phase using purity analysis. For pH determination, PLGA microspheres were loaded with a pH-sensitive spin probe which allowed the determination of pH by electron paramagnetic resonance (EPR). Results. The osmotic pressure in PLA microspheres increased to 600 mOsm within four days and decreased to 400 mOsm after two weeks. The pH in PLGA microspheres in this study was 4.7. Basic drugs such as gentamicin free base or buffering additives led to a pH increase. In no case, however, did the internal pH exceed a value of 6 within 13 hours. Conclusions. DSC and EPR are useful techniques to characterize the chemical microenvironment inside eroding microspheres. This data in combination with detailed information on peptide and protein stability could allow in the future to predict the stability of such compounds within degradable polymers.     

Enzymatic triggered release of an HIV-1 entry inhibitor from prostate specific antigen degradable microparticles

To achieve sustained release of 3-ethyl-4-(4-methylisoxazol-5-yl)-5-(methylthio) thiophene-2-carboxamide (BFB0261), a new potent osteogenic compound for treating bone disorders, we prepared film formulations containing BFB0261 and the following newly synthesized biodegradable polymers by a solvent casting technique: poly(D,L-lactic acid) (PLA), poly(D,L-lactic acid-co-glycolic acid) (PLGA), poly(D,L-lactic acid)-block-poly(ethylene glycol) (PLA-PEG), and poly(D,L-lactic acid-co-trimethylene carbonate) (PLA-TMC) polymers or copolymers. Powder X-ray diffractometry (PXRD), differential thermal analysis (DTA), scanning electron microscopy (SEM), and tensile testing were performed to examine the physicochemical properties of these films. Almost all the films exhibited a smooth and homogeneous surface, as observed by SEM. In addition, PXRD and DTA revealed that BFB0261 existed in an amorphous state in the films. The in vitro release of BFB0261 from PLA100 (M(w): 251 kDa), PLAPEG9604H (PLA/PEG ratio: 96:4; M(w): 181 kDa), PLAPEG8515H (PLA/PEG ratio: 85:15; M(w): 51.5 kDa), or PLAPEG8020 (PLA/PEG ratio: 80:20; M(w): 33.7 kDa) films followed zero-order kinetics with slow release up to 12 weeks following incubation. Although release of BFB0261 from PLA-TMC films followed first-order kinetics, sustained release of BFB0261 for 12 weeks was still observed for PLATMC8416 (PLA/TMC ratio: 84:16; M(w): 170 kDa) films. Furthermore, when the BFB0261-loaded films constructed from various polymers were implanted subcutaneously on rat backs, the PLAPEG8515H and PLATMC8416 films were capable of achieving sustained release of BFB0261 at the administrated site for 12 weeks. Therefore, the present data indicate that films constructed from PLAPEG8515H or PLATMC8416 may be applicable to bone or tissue engineering.     

Improved bioavailability of orally delivered insulin using Eudragit-L30D coated PLGA microparticles

Large porous microparticles of PLGA entrapping insulin were prepared by solvent evaporation method and evaluated in diabetes induced rat for its efficacy in maintaining blood sugar level from a single oral dose. Incorporation of Eudragit L30D (0.03% w/v) in the external aqueous phase resulted in formation of pH responsive enteric coated polymer particles which release most of the entrapped insulin in alkaline pH. At acidic pH, release of insulin from uncoated PLGA microparticles and Eudragit L30D coated PLGA microparticles was 31.62?±?1.8% and 17.5?±?1.29%, respectively, for initial 30 min. However, in 24 h, in vitro released insulin from uncoated PLGA and Eudragit coated particles was 96.29?±?1.01% and 88.30?±?1%, respectively. Released insulin from composite polymer particles were mostly in monomer form without aggregation and was stable for a month at 37°C. Oral administration of insulin loaded PLGA (50 : 50) and Eudragit L30D coated PLGA (50 : 50) microparticles (equivalent to 25 IU insulin/kg of animal weight) in alloxan induced diabetic rats resulted in 37.3?±?11% and 62.7?±?3.8% reduction in blood glucose level, respectively, in 2 h. This effect continued up to 24 h in the case of Eudragit L30D coated PLGA microparticles. Results demonstrate that use of stabilizers during PLGA particle formulation, large porous particle for quick release of insulin and coating with Eudragit L30D resulted in a novel oral formulation for once a day delivery of insulin.     

Physicochemical characterization of poly(L-lactic acid) and poly(D,L-lactide-co-glycolide) nanoparticles with polyethylenimine as gene delivery carrier

Polymer nanoparticles have been used as non-viral gene delivery systems and drug delivery systems. In this study, biodegradable poly(L-lactic acid) (PLA)/polyethylenimine (PEI) and poly(D,L-lactide-co-glycolide) (PLGA)/PEI nanoparticles were prepared and characterized as gene delivery systems. The PLA/PEI and PLGA/PEI nanoparticles, which were prepared by a diafiltration method, had spherical shapes and smooth surface characteristics. The size of nanoparticles was controlled by the amount of PEI, which acted as a hydrophilic moiety, which effectively reduced the interfacial energy between the particle surface and the aqueous media. The nanoparticles showed an excellent dispersive stability under storage in a phosphate-buffered saline solution for 12 days. The positive zeta-potentials for the nanoparticles decreased and changed to negative values with increasing plasmid DNA (pDNA) content. Agarose gel electrophoresis showed that the complex formation between the nanoparticles and the pDNA coincided with the zeta-potential results. The results of in vitro transfection and cell viability on HEK 293 cells indicated that the nanoparticles could be used as gene delivery carriers.     

Controlled release of vancomycin from biodegradable microcapsules

Poly D,L-lactic acid (PLA) and its copolymers with glycolide PLGA 90:10 and 70:30 were polymerized under various conditions to yield polymers in the molecular weight range 12000-40000 daltons, as determined by gel permeation chromatography. Vancomycin hydrochloride was the hydrophilic drug of choice for the treatment of methicillin resistant Staphyloccoccal infections. It was microencapsulated in the synthesized polymers using water-oil-water (w/o/w) double emulsion and solvent evaporation. The influence of microcapsule preparation medium on product properties was investigated. An increase in polymer-to-drug ratio from 1:1 to 3:1 caused an increase in the encapsulation efficiency (i.e. from 44-97% with PLGA). An increase in the emulsifier (PVA) molecular weight from 14-72 kD caused an increase in encapsulation efficiency and microcapsule size. The in vitro release of vancomycin from microcapsules in phosphate buffer saline (pH 7.4) was found to be dependent on molecular weight and copolymer type. The kinetic behaviour was controlled by both diffusion and degradation. Sterilization with ⁶⁰Co (2.5 Mrad) also affected the degradation rate and release profiles. Degradation of microcapsules could be seen by scanning electron microscopy, by the increase in the release rate from PLA and by the decrease in the T_g values of microcapsules. In vitro bactericidal effects of the microcapsule formulations on S.aureus were determined with a special diffusion cell after the preparations had been sterilized, and were found to have bactericidal effects lasting for 4 days.     

5-Fluorouracil-loaded microspheres prepared by spray-drying poly(D,L-lactide) and poly(lactide-co-glycolide) polymers: Characterization and drug release

5-Fluorouracil (5-FU), a hydrosoluble anti-neoplastic drug, was encapsulated in microspheres of poly(D,L-lactide) (PLA) and poly(lactide-co-glycolide) (PLGA) polymers using the spray-drying technique, in order to obtain small size microspheres with a significant drug entrapment efficiency. Drug-loaded microspheres included between 47?±?11 and 67?±?12?µg 5-FU?mg^?1 microspheres and the percentage of entrapment efficiency was between 52?±?12 and 74?±?13. Microspheres were of small size (average diameter: 0.9?±?0.4–1.4?±?0.8?µm microspheres without drug; 1.1?±?0.5–1.7?±?0.9?µm 5-FU-loaded microspheres) and their surface was smooth and slightly porous, some hollows or deformations were observed in microspheres prepared from polymers with larger T_g. A fractionation process of the raw polymer during the formation of microspheres was observed as an increase of the average molecular weight and also of T_g of the polymer of the microspheres. The presence of 5-FU did not modify the T_g values of the microspheres. Significant interactions between the drug and each one of the polymers did not take place and total release of the included drug was observed in all cases. The time needed for the total drug release (28–129?h) was in the order PLA?>?PLGA 75/25?>?PLGA 50/50. A burst effect (17–20%) was observed during the first hour and then a period of constant release rate (3.52?±?0.82–1.46?±?0.26?µg 5-FU?h^?1 per milligram of microspheres) up to 8 or 13?h, depending on the polymer, was obtained.     

Ketotifen-loaded microspheres prepared by spray-drying poly(D,L-lactide) and poly(D,L-lactide-co-glycolide) polymers: characterization and in vivo evaluation

Ketotifen (KT) was encapsulated into poly(D,L-lactide) (PLA) and poly(D,L-lactide-co-glycolide) (PLGA 50/50) by spray-drying to investigate the use of biodegradable drug-loaded microspheres as delivery systems in the intraperitoneal cavity. Ketotifen stability was evaluated by HPLC, and degradation was not observed. Drug entrapment efficiency was 74 +/- 7% (82 +/- 8 microg KT/mg for PLA) and 81 +/- 6% (90 +/- 7 microg KT/mg for PLGA 50/50). PLA microspheres released ketotifen (57% of encapsulated KT) in 350 h at two release rates (221 microg/h, 15 min to 2 h; 1.13 microg/h, 5-350 h). A quicker release of ketotifen took place from PLGA 50/50 microspheres (67.4% of encapsulated KT) in 50 h (322 microg/h, 15 min to 2 h; 16.18 microg/h, 5-50 h). After intraperitoneal administration (10 mg KT/kg b.w.), microsphere aggregations were detected in adipose tissue. Ketotifen concentration was determined in plasma by HPLC. The drug released from PLA and PLGA 50/50 microspheres was detected at 384 and 336 h, respectively. Noncompartmental analysis was performed to determine pharmacokinetic parameters. The inclusion of ketotifen in PLGA and PLA microspheres resulted in significant changes in the plasma disposition of the drug. Overall, these ketotifen-loaded microspheres yielded an intraperitoneal drug release that may be suitable for use as delivery systems in the treatment of inflammatory response in portal hypertension.     

Controlled release of vancomycin from biodegradable microcapsules

Poly D,L-lactic acid (PLA) and its copolymers with glycolide PLGA 90:10 and 70:30 were polymerized under various conditions to yield polymers in the molecular weight range 12000-40000 daltons, as determined by gel permeation chromatography. Vancomycin hydrochloride was the hydrophilic drug of choice for the treatment of methicillin resistant Staphyloccoccal infections. It was microencapsulated in the synthesized polymers using water-oil-water (w/o/w) double emulsion and solvent evaporation. The influence of microcapsule preparation medium on product properties was investigated. An increase in polymer-to-drug ratio from 1:1 to 3:1 caused an increase in the encapsulation efficiency (i.e. from 44-97% with PLGA). An increase in the emulsifier (PVA) molecular weight from 14-72 kD caused an increase in encapsulation efficiency and microcapsule size. The in vitro release of vancomycin from microcapsules in phosphate buffer saline (pH 7.4) was found to be dependent on molecular weight and copolymer type. The kinetic behaviour was controlled by both diffusion and degradation. Sterilization with 60Co (2.5 Mrad) also affected the degradation rate and release profiles. Degradation of microcapsules could be seen by scanning electron microscopy, by the increase in the release rate from PLA and by the decrease in the Tg values of microcapsules. In vitro bactericidal effects of the microcapsule formulations on S. aureus were determined with a special diffusion cell after the preparations had been sterilized, and were found to have bactericidal effects lasting for 4 days.     

In vitro degradation and dissolution behaviours of microspheres prepared by three low molecular weight polyesters

Three low-molecular weight polyesters, poly(L-lactic acid) (PLA), copoly(lactic acid/glycolic acid) (PLGA) and poly(delta-valerolactone) (PV), were used to prepare water-soluble sodium diclofenac-loaded microspheres by using the oil-in-oil (o/o) emulsification-solvent evaporation method. Their micromeritic and physicochemical properties, and degradation and dissolution behaviours were determined in vitro. The results indicate that high encapsulation efficiency and better monodispersity might be achieved by the o/o emulsification-solvent evaporation method, depending on the amount of drug loading used. The slower evaporation of organic solvent from the system during microencapsulation seemed to modify the crystallinity of drug and polyester in the microspheres, determined by powder x-ray diffractometry and differential scanning calorimetry. The in vitro degradation rate of all the microspheres in pH7.4 phosphate buffer solution showed first-order kinetics and ranked in the order of PLGA > PLA > PV microspheres. Furthermore, the first-order release rate was also found in all the microspheres after an initial drug burst and ranked in the order of PLGA> PLA > PV microspheres, too. The relationship between degradation and dissolution behaviours of these microspheres is discussed.     

Vancomycin release from poly(D,L-lactide) and poly(lactide-co-glycolide) disks

A biodegradable and biocompatible polymeric system was developed for the controlled release of vancomycin for the treatment of brain abscesses. Poly(D,L-lactic acid) (PLA) and its copolymers poly(lactide-co-glycolide) PLGA 90:10 and PLGA 70:30, were prepared. Polymer disks containing vancomycin (VN) were prepared by solvent casting from methylene chloride solutions. Degradation of the polymer disk was studied by scanning electron microscopy, NMR and GPC. SEM revealed an increasing degree of degradation with time with both PLGAs, the effect being more distinct in the PLGA with the higher glycolide content (PLGA 70:30), which was confirmed with GPC, which showed both a decrease in the molecular weights of PLGA and a decrease in the heterogeneity index (chain length distribution) upon incubation in isotonic phosphate buffer at 37#176;C for up to 5 weeks. NMR showed a decrease in the CH 2 contents of the copolymers, implying that the glycolide component of the copolymers is being preferentially degraded. In situ, vancomycin release behaviour of the disks in pH 7.4 phosphate buffer saline (PBS) was followed for ~2 months in a static system. It was observed that release was according to Higuchi kinetics (Q vs. t 1/2) , and introduction of low molecular weight PLA or hydrophilic compounds like PEG increased the release rate.     

Enhanced Oral Cyclosporine Absorption With Water-Soluble Vitamin E Early After Liver Transplantation

We evaluated the effect of Liqui-E, a water-soluble vitamin E preparation, on cyclosporin A (CyA) whole blood concentration in liver transplant recipients, and its impact on the cost of CyA. Patients were 26 liver transplant recipients (19 adults, 7 children) who were unable to achieve and maintain therapeutic CyA whole blood concentrations with the standard recommended oral daily dose in the early post-transplant period. Liqui-E 6.25 IU/kg orally was administered with CyA every 12 hours (median time of starting Liqui-E day 14.5). With Liqui-E, the daily oral CyA requirements (mean ± SD) were decreased in adults from 22.6 ± 8.9 to 16.2 ± 7.3 mg/kg/day (p<0.001) and in children from 78.6 ± 34.1 to 53.7 ± 35.0 mg/kg/day (pl0.02); intravenous administration of CyA was unnecessary. The CyA trough concentrations (mean ± SD) before and after Liqui-E were 670 ± 186 and 1012 ± 216 ng/ml, respectively, in adults (pl0.001) and 732 ± 187 and 1052 ± 166 ng/ml, respectively, in children (pl0.01). When given with Liqui-E, the daily cost of CyA decreased by 26% in both adults and children. No clinical or biochemical evidence of Liqui-E toxicity was observed. Thus its administration in the early post-transplantation period can enhance CyA absorption in adults and children who are unable to achieve adequate whole blood concentrations with the usual recommended oral dosages. In addition, a significant cost saving can be realized by coadministration.     

The effective therapy of cyclosporine A with drug delivery system in experimental colitis

Cyclosporine A (CyA) is a useful immunosuppressive agent for steroid-dependent or steroid-refractory ulcerative colitis. However, side effects have been reported in clinical trials of ulcerative colitis treated with CyA. Biodegradable microspheres (MS) have been investigated as drug delivery system. We evaluated the effect of a drug delivery system with poly(d,l-lactic acid)-MS containing CyA. Colitis was induced in C57BL/6 mice by 3% dextran sulfate sodium (DSS). Mice with DSS-induced colitis were treated with oral administration of CyA or CyA-MS: CyA (0.2?mg/kg/day)-MS; CyA (2?mg/kg/kg)-MS). Serum levels of CyA were significantly less elevated after oral administration of CyA (2?mg/kg/day)-MS compared with CyA (2?mg/kg/day) (CyA (2?mg/kg/day), 44.7 ± 0.8?ng/ml; CyA (2?mg/kg/day)-MS, 7.7 ± 1.3?ng/ml). The body weight at day 10 was significantly recovered in the mice treated with CyA (0.2?mg/kg/day)-MS and CyA (2?mg/kg/day)-MS compared with CyA (0). The histological score and myeloperoxidase activity in the mice treated with CyA-MS was significantly lower than CyA (0). Gene expressions of interleukin-1β (IL-1β), IL-6, and CXCL1 in the mice treated with CyA (0.2?mg/kg/day)-MS and CyA (2?mg/kg/day)-MS were downregulated compared with CyA (0)-MS. CyA-MS might be possible to treat ulcerative colitis effectively by decreasing the total dosage without the elevation of the serum level or the side effects of CyA.     

Controlled delivery of a hydrophilic drug from a biodegradable microsphere system by supercritical anti-solvent precipitation technique

The purpose of this study was to prepare microspheres loaded with hydrophilic drug, bupivacaine HCl using poly(D,L-lactic-co-glycolic acid) (PLGA) and poly(L-lactic acid) (PLLA). Microspheres were prepared with varying the PLGA/PLLA ratio with two different levels of bupivacaine HCl (5 and 10%) using a supercritical anti-solvent (SAS) technique. Microspheres ranging from 4-10 microm in geometric mean diameter could be prepared, with high loading efficiency. Powder X-ray diffraction (PXRD) revealed that bupivacaine HCl retained its crystalline state within the polymer and was present as a dispersion within the polymer phase after SAS processing. The release of bupivacaine HCl from biodegradable polymer microspheres was rapid up to 4 h, thereafter bupivacaine HCl was continuously and slowly released for at least 7 days according to the PLGA/PLLA ratio and the molecular weight of PLLA.