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PubMed2004

Starch acetate microparticles for drug delivery into retinal pigment epithelium-in vitro study.

Starch acetates are novel biodegradable polymers which undergo slower degradation and swelling than native starch. Retinal pigment epithelium (RPE) is an important target tissue in ocular treatment. The cellular uptake of starch acetate microparticles and degradation of starch acetate by cultured human RPE-cell line (D407) was examined. Calcein-containing starch acetate microparticles were prepared by a modified water-in-oil-in-water double-emulsion technique. The cellular uptake of the starch acetate microparticles was analysed using flow cytometry and confocal microscopy. Degradation of starch acetate films by the homogenate of lysed RPE cells was determined by gel permeation chromatography. The effect of the microparticles on RPE cell viability was determined by the MTT colorimetric assay. The mean diameter (D50%) of microparticles was 11 microm. During 3-h incubation in RPE-cell culture, 8.1 +/- 0.8% of D407 cells took up starch acetate microparticles. Confocal microscopy confirmed the internalisation of microparticles. Incubation of the starch acetate film in the RPE-cell homogenate considerably decreased the molecular weight of starch acetate in the film during 24 h. The viability of cultured RPE cells was at least 82% after 24-h incubation with the microparticles. The present results show that the starch acetate microparticles are taken up by the RPE cells and the polymer can be degraded by the enzymes in these cells. Starch acetate microparticles may be suitable for drug delivery to the RPE.

Cell Line↗
PubMed1999

Modified polypeptides containing gamma-benzyl glutamic acid as drug delivery platforms.

We previously reported the development of diffusion-controlled biodegradable polypeptides for drug delivery purposes. In this paper, we describe the synthesis of three modified polypeptides that contain gamma-benzyl glutamic acid as the common structural backbone. The properties of these polymers were characterized with regard to their potential application as drug delivery platforms. Procainamide hydrochloride, a hydrophilic drug, and protamine sulfate, a low molecular weight protein, were used as model drugs for examining release rate profiles from these polymers. The homopolymer of poly(gamma-benzyl-L-glutamic acid), PBLG, showed a highly helical configuration and a moderate release rate of procainamide. Modification of structural attributes by random copolymerization of the D- and L- isomers of gamma-benzyl glutamic acid produced poly(gamma-benzyl-D,L-glutamic acid), PBDLG, which displayed a significantly slower release of procainamide when compared to PBLG. The modification of polymer bulk hydrophobicity by copolymerization of PBLG (A) with poly(ethylene glycol) (B) yielded an ABA triblock copolymer exhibiting much faster release rates for both procainamide and protamine than those demonstrated by the other two polymers. Using this triblock copolymer, protamine release rates ranging from 2 weeks to approximately 2 months were obtained by simply varying the polymer processing conditions and protein particle size. A nearly complete release of protein was obtained from the triblock copolymer blends and this occurred without reliance upon degradation of the polymer backbone. Fickian diffusion-controlled release mechanisms were implied for release of procainamide and protamine from these polypeptide formulations based on the linear relationship displayed between cumulative drug release and the square root of time.

Chemistry, Pharmaceutical↗
PubMed2001

[Preparation of cucurbitacinBE polylactic acid nano-particles for targeting cervical lymph nodes].

OBJECTIVE: Anti-cancer nano-particles for targeting cervical lymph nodes were designed and prepared on the basis of the physiologic and anatomic properties of the peri-oral cancer lymphatic capillaries. METHODS: The biodegradable polylactic acid (PLA) was selected as the carrier material, and cucurbitacinBE (CuBE) with very high anticancer activity against oral squamous cell carcinoma was used as the model drug. According to the criteria of the diameter of the nano-particles, drug loading (DL) and embedding ratio (ER), the preparing technology was optimized by uniformly designing experiment on the basis of single-factor experiment. CucurbitacinBE poly-lactic acid nano-particles (CuBE-PLA-NP) was prepared with the method of emulsion solvent evaporation, and then CuBE-PLA-NP lyophilization injection was prepared by using 10% manninositose as the supporting agent. RESULTS: The diameter distribution for optimized CuBE-PLA-NP lyophilization injection ranged from 47 nm to 120 nm, and the average diameter was 85 nm. DL and ER were 23.03% +/- 0.47% and 93.00% +/- 0.10% respectively. The release study of the thermostatics also demonstrated that Higuchi equation was adequate to fit the release curve of CuBE-PLA-NP. CONCLUSION: CuBE-PLA-NP can be used as the release agent, as CuBE-PLA-NP can enter peri-oral cancer lymphatic capillaries for targeting cervical lymph nodes by the peri-cancer submucosal injection. Therefore, it can also used for animal and clinical experiments.

Antineoplastic Agents↗
PubMed2005

Hyaluronan-based microspheres as tools for drug delivery: a comparative study.

The present paper describes the production of biodegradable microparticles using different hyaluronan polymers, such as native hyaluronan, the esterified derivative of hyaluronan Hyaff 11p50 (where 50% of the carboxy groups of hyaluronic acid are esterified with benzyl alcohol) and the autocross-linked polymer (ACP) internally esterified derivative of hyaluronan, by solvent evaporation and spray-drying methods. As model drugs cromolyn sodium salt, metronidazole and prednisolone hemisuccinate sodium salt were employed. The influence of polymer and preparation procedure has been evaluated on microparticle characteristics (i.e. morphology and encapsulation yield) and on the drug release profiles. The use of solvent evaporation method, a polymeric matrix constituted of Hyaff 11p50 3% (w/v), a dispersing phase constituted of 80 g of mineral oil (w/o ratio: 0.1), Span 85 0.1% (w/w) as stabilizer, and a stirring speed of 700 rpm resulted in the production of microspheres characterized by spherical shape, absence of aggregates, a mean diameter of 6.4 microm and a recovery of 90% (w/w). The production of drug containing microspheres led to an increase of mean diameter of microspheres and to high encapsulation yields. Moreover in vitro models have demonstrated that in all cases drugs were released from Hyaff 11p50 microspheres in a controlled fashion. Finally mathematical analysis of the drug release modalities has evidenced that drug release from Hyaff 11p50 microspheres is more consistent with kinetics of the diffusion rather than of the dissolution type.

Drug Delivery Systems↗
PubMed2000

Amphiphilic poly(ether ester amide) multiblock copolymers as biodegradable matrices for the controlled release of proteins.

Amphiphilic poly(ether ester amide) (PEEA) multiblock copolymers were synthesized by polycondensation in the melt from hydrophilic poly(ethylene glycol) (PEG), 1,4-dihydroxybutane and short bisester-bisamide blocks. These amide blocks were prepared by reaction of 1,4-diaminobutane with dimethyl adipate in the melt. A range of multiblock copolymers were prepared, with PEG contents varying from 23-66 wt %. The intrinsic viscosity of the PEEA polymers varied from 0.58-0.78. Differential scanning calorimetry showed melting transitions for the PEG blocks and for the amide-ester blocks, suggesting a phase separated structure. Both the melting temperature and the crystallinity of the hard amide-ester segments decreased with increasing PEG content of the polymers. The equilibrium swelling ratio in phosphate buffered saline (PBS) increased with increasing amount of PEG in the polymers and varied from 1.7 to 3.7, whereas the polymer that contained 66 wt % PEG was soluble in PBS. During incubation of PEEA films in PBS, weight loss and a continuous decrease in the resulting inherent polymer viscosity was observed. The rate of degradation increased with increasing PEG content. The composition of the remaining matrices did not change during degradation. A preliminary investigation of the protein release characteristics of these PEEA copolymers showed that release of the model protein lysozyme was proportional to the square root of time. The release rate was found to increase with increasing degree of swelling of the polymers.

Biocompatible Materials↗
PubMed1999

Effect of solvent on the characteristics of pentamidine loaded microcapsule.

Biodegradable microcapsules of pentamidine/poly(L-lactide-co-D,L-lactide) were prepared by solvent evaporation technique using a mixture of organic solvents. The control batch of microcapsules was prepared using dichloromethane. The effect of solvent on the characteristics of pentamidine loaded microcapsules was examined by substituting up to 30% of dichloromethane with acetone, methanol, DMSO, ethyl acetate, and ethanol, respectively. No significant change in the surface morphology was observed when dichloromethane was substituted with 20% or less amount of other solvents. These microcapsules were all porous and spherical. However, the use of 30% DMSO or ethanol, along with dichloromethane, resulted in a mixture of elongated and spherical microcapsules. The efficiency of encapsulation of these two batches was also significantly higher than the other batches of microcapsules. The average particle size of the microcapsules prepared with 30% DMSO (165 microm) was significantly higher than the other batches (< 80 microm). A substitution of 10-30% dichloromethane with other listed organic solvents also showed a significant difference in the initial drug release. The drug release within the first twenty-four hours varied from 4 to 16%. The use of a second organic solvent, except ethanol, resulted in a significantly higher drug release during the second half of the dissolution study. The drug release continued more than 60 days.

Acetates↗
PubMedDate not supplied

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.

Anti-Bacterial Agents↗
PubMed2001

Dextrins as potential carriers for drug targeting: tailored rates of dextrin degradation by introduction of pendant groups.

There is a recognised need to identify new biodegradable polymers suitable for development as targetable drug carriers. The aim of this study was to determine the rate of degradation of two dextrin fractions (Mw 15.5 and 51 KDa) by alpha-amylase and liver lysosomal enzymes (tritosomes). Also experiments were conducted to discover whether backbone modification by succinolyation (1-34 mol%) or pendant group incorporation (e.g. doxorubicin) could be used to tailor the rate of polymer degradation. Dextrin (alpha-1,4 polyglucose) is a natural polymer used clinically as a peritoneal dialysis solution and as a controlled drug delivery formulation. Size exclusion chromatography (SEC) showed that dextrin was degraded rapidly (within 20 min) by rat plasma and porcine pancreatic alpha-amylase. In contrast over 48 h no degradation was observed in the presence of tritosomes. The rate of alpha-amylase degradation of succinoylated dextrins (Mw approximately 51 KDa) was dependant on the degree of modification (dextrin >1>5>15>34 mol% succinoylation). Dextrin-doxorubicin conjugates were prepared from the 15 and 34 mol% succinoylated intermediates to have a doxorubicin loading of 8 and 12 wt.%, respectively. These doxorubicin conjugates were more stable than their parent intermediates, and SEC showed an apparently higher molecular weight. The drug conjugates did however degrade slowly over 7 days to release oligosaccharide-doxorubicin species. This fundamental study demonstrates the possibility of controlling the rate of dextrin enzymolysis by backbone modification and thus affords the potential to rationally design dextrin-drug conjugates for specific applications as targetable carriers.

Animals↗
PubMed2003

Facial nerve regeneration through progesterone-loaded chitosan prosthesis. A preliminary report.

Biodegradable nerve guides have represented new treatment alternatives for nerve repairing. They are gradually biodegradable, exert biological effects directly to the injured nerve, and act as drug- or cell-delivery devices. Furthermore, progesterone (PROG) has been demonstrated to promote injured peripheral nerve regeneration. In this study, it was hypothesized that PROG delivered from chitosan prostheses provides better facial nerve regenerative response than chitosan prostheses with no PROG. As there are no reports on the use of the former as nerve-guide material in the regeneration of injured nerves, this is the main objective of the present work. Chitosan prostheses containing PROG were used to bridge 10-mm gaps in rabbit facial nerves. The regenerated nerves were evaluated 45 days after implantation in animals with the use of light microscopy and morphometric analysis. Gas chromatography was used in order to quantify PROG content in prosthesis prior to and after implantation in subcutaneous tissue at different periods of up to 60 days. In addition, the prosthesis walls were evaluated with histological techniques in order to assess their integrity and the surrounding tissue reaction. Chitosan prostheses allowed PROG release during the time needed for nerve regeneration. At 45 days myelinated nerve fibers were observed in both the proximal and distal stumps. This parameter and the N ratio were higher in the progesterone-treated group when compared to that of the vehicle control. Findings indicate that chitosan prostheses were useful in nerve regeneration, acting as a long-lasting PROG delivery device a faster nerve regeneration.

Animals↗
PubMed2005

Preparation and characterization of methoxy poly(ethylene glycol)/poly(epsilon-caprolactone) amphiphilic block copolymeric nanospheres for tumor-specific folate-mediated targeting of anticancer drugs.

Biodegradable methoxy poly(ethylene glycol)/poly(-caprolactone) (MPEG/PCL) amphiphilic block copolymer nanospheres coupled to folic acid have been designed to target a folate-binding protein that is overexpressed on the surface of many tumoral cells. For this purpose, hydroxy groups terminated on the MPEG/PCL copolymer were converted into primary amino groups, which were used to conjugate with the carboxylic group of folic acid. Nanospheres were prepared by the formation of micelles of the copolymer with or without the anticancer agent paclitaxel. Folate-mediated MPEG/PCL nanospheres were compared with hydroxyl- and amino-terminated nanospheres in terms of their size, surface characteristics, and drug-loading efficiency. Regardless of the type of terminal group, the MPEG/PCL nanospheres showed a narrow size distribution with an average diameter <80 nm without paclitaxel, and an average diameter of 115 nm when loaded with the drug. The results from zeta potential and X-ray photoelectron spectroscopy measurements revealed that the folate molecules were partially exposed, and were expressed on the surface of the nanospheres allowing folate receptor recognition. In in vitro, cytotoxicity tests, the nanospheres loaded with paclitaxel showed a higher cell viability than in cases where paclitaxel was absent. Thus, folate-mediated nanospheres composed of MPEG and PCL are potentially new drug carriers for tumor cell-selective targeting treatments.

Animals↗
PubMed2002

Self-curing acrylic formulations containing PMMA/PCL composites: properties and antibiotic release behavior.

Partially biodegradable acrylic composites containing poly(methyl methacrylate)-poly(epsilon-caprolactone) (PMMA/PCL) systems were prepared by mixing the corresponding PMMA/PCL beads (89:11, 86:14, 83:17, and 77:23 weight ratio) used as solid phase with methyl methacrylate (MMA) (liquid phase) in a solid/liquid ratio of 1.5:1. The physical and chemical microheterogeneity of these beads influenced significantly the curing parameters, because several aspects involved in the polymerization reaction are closely related to both morphology and size distribution of the particles. In vitro behavior was studied by immersion in simulated body fluid at pH = 7.4 and 37 degrees C for more than 8 weeks and the composition was followed by 1H-nuclear magnetic resonance spectroscopy. Approximately 2% wt/wt weight loss was observed after a period of 8 weeks for the composites richest in PCL. Mechanical properties of the dry and wet specimens were evaluated by compressive and tensile tests. In all cases, the presence of PCL in the composites provided a significant decrease in both compressive strength and elastic modulus compared with plain PMMA. Tensile and compressive strength also decreased significantly after 2 weeks of immersion in simulated body fluid compared with dry specimens. The self-curing composites based on PMMA/PCL beads and loaded with 3% wt/wt vancomycin were evaluated as carriers for local release of antibiotics. The composite prepared with beads of PMMA/PCL ratio 86:14 was the most effective. It eluted 64% of the initial drug within the first 5 h, allowing progressive release of nearly the total amount of the initial drug (90%) in approximately 2 months. The results obtained suggest that the described composites can be suitable for antibiotic release in non-load bearing graft applications.

Biocompatible Materials↗
PubMed1987

Nanoparticles in drug delivery.

Alkylcyanoacrylates can be polymerized in acidified aqueous media by a process of anionic polymerization. The small particles produced tend to be monodisperse and have sizes in the range of 20 to 3000 nm depending upon the polymerization conditions and the presence of additives in the form of surfactants and other stabilizers. The polyalkylcyanoacrylate nanoparticles so produced have been studied in recent years as a possible means of targeting drugs to specific sites in the body, with particular emphasis in cancer chemotherapy. The small colloidal carriers are biodegradable and drug substances can be incorporated normally by a process of surface adsorption. The review by Davis and others considers the formulation of nanoparticles, the important physicochemical variables such as pH, monomer concentration, added stabilizers, ionic strengths, etc., as well as the characteristics of the particle so created in terms of surface charge, particle size, and molecular weight. Monodisperse particles in the range of 20 to 3000 nm can be obtained. In addition, by the use of stabilizers such as dextran and its derivatives, which can be incorporated into the nanoparticle surface by a process of polymer grafting, it is possible to make nanoparticles with interesting surface characteristics and different surface charges (sign). The stability of nanoparticles in vitro and their biodegradation in vivo are examined, and the possible formation of toxic products such as formaldehyde is highlighted. Alternative biodegradable acrylates are mentioned. Drugs can be incorporated into nanoparticles by either direct incorporation during the polymerization process or adsorption to preformed nanoparticles. The efficiency of the incorporation and the release characteristics of model compounds as well as anticancer drugs are discussed. Methods for examining these processes, including the determination of adsorption and desorption, kinetics, and isotherms, are mentioned. Selectivity in drug targeting can, in theory, be achieved by the attachment of some form of homing device, normally a monoclonal antibody or a lectin. Work in vitro and in vivo, where nanoparticles have been coated with monoclonal antibodies, is described. Finally, methods for the labeling of nanoparticles with gamma-emitting radionuclides are presented, and results obtained in animal species are given.

Antibodies, Monoclonal↗
PubMed2004

Triblock copolymers: synthesis, characterization, and delivery of a model protein.

The purpose of this study was to synthesize and characterize biodegradable and thermosensitive triblock copolymers for delivering protein at controlled rate in biologically active form for longer duration of time. A series of thermosensitive triblock copolymers with different block lengths (PLGA-PEG-PLGA) were synthesized by ring-opening polymerization of d,l-lactide and glycolide with polyethylene glycol (PEG) in the presence of stannous octoate. Compositions and molecular weight of triblock copolymers were characterized by 1H NMR spectrometry and gel permeation chromatography, respectively. A single test-tube inverting method was employed to determine the sol-gel transition temperature. Lysozyme was used as a model protein. Lysozyme solution formulation was prepared with different triblock copolymers for in vitro release. Lysozyme concentration and its biological activity in the released sample were determined using a standard MicroBCA method and bacterial cell lysis method, respectively. The effects of varying block lengths and concentrations of copolymers on the in vitro release of lysozyme were evaluated. The release profiles from formulations showed a higher initial release followed by slower release up to 4 weeks. Increasing the block lengths of copolymers decreased burst release of lysozyme from 41.2+/-5.4% to 16.1+/-3.9%. Increasing copolymer concentrations decreased the drug release. Lysozyme in the 4 weeks released samples retained most of its biological activity (>80%). It is feasible to deliver protein in biologically active form for longer duration by varying block lengths and concentrations of triblock copolymers.

Animals↗
PubMed2005

Local delivery of interleukin-2 and adriamycin is synergistic in the treatment of experimental malignant glioma.

INTRODUCTION: Local delivery of adriamycin (ADR) via biodegradable polymers has been shown to improve survival in rats challenged intracranially with 9L gliosarcoma. Likewise, local delivery of interleukin-2 (IL-2) has been shown to extend survival in experimental brain tumor models. In the current study, we hypothesized that local delivery of ADR and IL-2 might act synergistically against experimental intracranial glioma. METHODS: Polyanhydride polymers (PCPP-SA) containing 5% ADR by weight were prepared using the mix-melt method. IL-2 polymer microspheres (IL-2 MS) were produced via the complex coacervation of gelatin and chondroitin sulfate in the presence of IL-2. Sixty male Fisher 344 rats received an intracranial challenge with a lethal dose of 9L gliosarcoma cells. In addition, a group of rats were injected with either IL-2 MS or empty microspheres. Five days later they received ADR or blank polymer. There were a total of four treatment groups: (1) empty microspheres, blank polymer; (2) empty microspheres, ADR polymer; (3) IL-2 MS, blank polymer; and (4) IL-2 MS, ADR polymer. RESULTS: Compared to control animals treated with empty microspheres and blank polymer, animals receiving empty microspheres and ADR polymer (P < 0.0004), IL-2 MS and blank polymer (P < 0.0005), and IL-2 MS combined with ADR polymer (P < 0.0000002) all showed statistically significant improvement in survival. In addition, animals receiving the IL-2/ADR combination had significantly extended survival compared to either ADR or IL-2 alone (P < 0.000003 and P < 0.0004, respectively). CONCLUSIONS: Both ADR and IL-2, when delivered locally, are effective monotherapeutic agents against experimental intracranial gliosarcoma. The combination ADR and IL-2 therapy is more effective than either agent alone.

Animals↗
PubMed2000

Self-assembled hydrogel nanoparticles composed of dextran and poly(ethylene glycol) macromer.

Biodegradable hydrogel nanoparticles were prepared from glycidyl methacrylate dextran (GMD) and dimethacrylate poly(ethylene glycol) (DMP). GMD was synthesized by coupling of glycidyl methacrylate to dextran in the presence of 4-(N,N-dimethylamino)pyridine (DMAP) using dimethylsulfoxide (DMSO) as an aprotic solvent. DMP was synthesized from poly(ethylene glycol) (PEG) and methacryloyl chloride. GMD/DMP (abbreviated as DP) hydrogel was prepared by radical polymerization of GMD and DMP using ammonium peroxydisulfate (APS) as an initiator and UV curing. DP hydrogel nanoparticles were obtained by diafiltration method using DMSO solution. The GMD and DMP were characterized by fourier transform infrared spectroscopy. Fluorescence probe technique was used to investigate the self-assembly of DP in water using pyrene as a hydrophobic probe. The critical association concentration (CAC) was determined to be 5.6 x 10(-2) g/l. The shape of DP hydrogel nanoparticles was spherical when observed by transmission electron microscope (TEM). The size range of DP hydrogel nanoparticles was about 20 approximately 50 nm. The hydrodynamic size of DP hydrogel nanoparticles was measured by photon correlation spectroscopy (PCS) and gradually increased with time in PBS (0.1 M, pH 7.4). Drug release study was performed using clonazepam (CNZ) as a hydrophobic model drug. In vitro release rate of CNZ from the DP hydrogel nanoparticles was dependent on the existence of dextranase and the pH of the release medium.

Anticonvulsants↗
PubMed2000

Inhibition of neointima formation after experimental coronary artery stenting: a new biodegradable stent coating releasing hirudin and the prostacyclin analogue iloprost.

BACKGROUND: To minimize acute stent thrombosis and development of restenosis, stents coated with biodegradable and nonbiodegradable polymers have been proposed to serve as sustained-release drug carriers. METHODS AND RESULTS: In both a sheep and a pig model, we examined the vascular response to standard and high-pressure implantation of coronary Palmaz-Schatz stents coated with a 10-microm layer of polylactic acid (MW 30 kDa) releasing recombinant polyethylene glycol (r-PEG)-hirudin and the prostacyclin analogue iloprost, both drugs with antithrombotic and potentially antiproliferative effects. Study observation time was 28 days. Between the corresponding stent groups, no differences were observed with regard to preplacement and postplacement implantation parameters. The morphometric analysis demonstrated that the coating was associated with a greater lumen diameter through a reduction in the mean restenosis area by 22.9% (P<0.02) in the standard-pressure model (sheep) and by 24.8% (P<0.02) in the overstretch pig model compared with uncoated control stents without inducing a local inflammatory response. CONCLUSIONS: The results from this study demonstrate beneficial effects of a polymeric stent coating with polylactic acid releasing r-PEG-hirudin and iloprost on the development of restenosis after coronary stent placement at 4 weeks, independent of the extent of vascular injury. Future studies are proposed to investigate the integration of other substances to further enhance the potential of the stent coating on reducing neointimal formation.

Absorbable Implants↗
PubMed2002

Development of biodegradable microcapsules as carrier for oral controlled delivery of amifostine.

The primary objective of this project was to develop a biodegradable, orally active controlled-release formulation of amifostine. Development of such a formulation will mark an important advancement in the areas of chemoprotection and radioprotection. Biodegradable microcapsules of amifostine were prepared using poly(lactide/glycolide) (PLGA 50:50). The microcapsules were prepared by solvent evaporation technique. Amifostine-loaded microcapsules were evaluated for particle size, surface morphology, thermal characteristics, and drug release. Particle size and surface morphology were determined using scanning electron microscopy (SEM). Thermal characterization was conducted using differential scanning calorimetry (DSC). In vitro release study was performed at 37 degrees C using phosphate buffer (pH 7.4). Amifostine release was calculated by measuring the amount of drug remaining within the microcapsules at a specific sampling time. The amount of amifostine in the samples was determined by high-performance liquid chromatography (HPLC) using an electrochemical detector. The yield of microcapsules was 75%. Scanning electron microscopy pictures revealed that the particles were nearly spherical and smooth with an average size of 54 microm. Differential scanning calorimetry thermograms showed that microcapsules loaded with amifostine have a glass transition at 39.4 degrees C, and the melting endotherm of amifostine was absent. The absence of a melting endotherm for amifostine was an indication that amifostine was not in the crystalline state in the microcapsules, but rather in the form of a solid solution in PLGA. Approximately 50% amifostine was released during the first 6 hr of the in vitro release study. The drug, however, continued to release over the observed period of 12 hr during which 92% amifostine was released.

Administration, Oral↗
PubMed1994

[Pharmacokinetics of levonorgestrel after a single dose of biodegradable microspheres containing levonorgestrel in rats].

Pharmacokinetics of levonorgestrel (LNG) in the form of injectable microspheres made of biodegradable co-polymer of polylactic acid and polyglycolic acid(9: 1 PLGA) that contained 17.76% LNG, were tested in rats. Rats were given a single intramuscular injection (im) of LNG microspheres at doses of 20.4, 41.1 and 83.3 mg.kg-1. Six rats were treated with a single im of LNG microcrystals at dose of 35.0 mg.kg-1. Plasma samples obtained before injection and at various time after injection were analyzed for LNG by RIA method. Peak plasma LNG level of 67.66 nmol.L-1 was obtained 4.88 h after im of LNG microcrystals, T1/2 = 5.78 d, MRT = 10.16 d and T < 0.32 nmol.L-1 = 41.50 d. Plasma LNG levels among rats after im of three different doses of LNG microspheres showed similar biphasic changes. Cmax1 (the first phase) were 15.19, 33.61 and 38.55 nmol.L-1; Tp1 were 6, 4.67 and 4.33h; Ctrough were 1.21, 4.36 and 9.06 nmol.L-1; Ttrough were 55, 53.67 and 54.83 d; Cmax2 (the second phase) were 3.80, 9.48 and 19.68 nmol.L-1; Tp2 were 100.49, 102.21 and 89.27 d; AUC were 440.27, 1082.82 and 1931.47 nmol.d.L-1; MRT were 69.23, 65.12 and 63.25 d; T < 0.32 nmol.L-1 were 167.81, 169.73 and 167.23 d after im of LNG microspheres in doses of 20.4, 41.1 and 83.3 mg (LNG).kg-1, respectively. Cmax1, Ctrough, Cmax2 and AUC showed significantly positive correlation with LNG dose, while Tp1, Tp2, Ttrough, MRT and T < 0.32 nmol.L-1 did not.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗