Mechanism of drug release from poly(-lactic acid) matrix containing acidic or neutral drugs

The release profiles of acidic and neutral drugs from poly(-lactic acid) [P(L)LA] matrices were investigated to reveal their release mechanism. Cylindrical matrices (rods; 10 mm×1 mm diameter) were prepared by the heat compression method. The acidic and neutral drugs investigated were dissolved in the P(L)LA rods. It was found that the release profiles consisted of two sequential stages. At the first release stage, P(L)LA remained in an amorphous state and the drugs diffused through the hydrated matrices. At the second release stage, P(L)LA transformed to a semicrystalline state and the drugs diffused through water-filled micropores developed by polymer crystallization. In addition, the drugs were also found to precipitate out as crystals in the rods, resulting in a transformation of the rods into drug-dispersed matrices. On the basis of these findings, we derived a modified diffusion equation for the drug release at the second stage. This equation showed good fits to the release profiles of these drugs. Furthermore, the availability of the derived equation was supported by the acceleration in the fractional drug release rate noted both with decreases in the drug content in the rod and increases in the pH of the medium.     

Effect of polymer/basic drug interactions on the two-stage diffusion-controlled release from a poly(L-lactic acid) matrix.

We investigated the effect of drug physico-chemical properties on the release of basic drugs from poly(L-lactic acid) (P(L)LA) cylindrical matrices (rods; 10 mmx1 mm diameter). All the rods were revealed to exhibit two-stage diffusion-controlled release profiles resulting from the transformation of P(L)LA from an amorphous to a semicrystalline state in aqueous medium. On the assumption that interactions between polymer carboxyl residues and basic drugs control the drug release rate, we evaluated the strength of these interactions by the drug partition between the polymer and the aqueous medium. In the first release stage, the drugs diffused through the swollen polymer matrix. The polymer-drug interactions shielded the polymer terminal carboxyl residues, thereby resulting in a less hydrated matrix and consequent diminishment of drug diffusion. In the second release stage, the drugs diffused through the water-filled micropores which had developed as a result of polymer crystallization. The stronger polymer-basic drug interactions reduced the drug diffusion rate by decreasing not only the porosity of the matrix, but also the drug partition to the water-filled micropores. It was also found that the fractional drug release rate in the second stage increased with drug content of the rod at the pH where both the polymer carboxyl residues and the drugs were ionized. Since the polymer-drug interactions must be close to saturation with increasing drug content, we believe this result to be due to an increase in the ratio of the drug partition to the water-filled micropores.     

Comparative study on sustained release of human growth hormone from semi-crystalline poly(L-lactic acid) and amorphous poly(D,L-lactic-co-glycolic acid) microspheres: morphological effect on protein release.

Recombinant human growth hormone (rhGH) was encapsulated by a double emulsion solvent evaporation method within two biodegradable microspheres having different polymer compositions. Semi-crystalline poly(L-lactic acid) (PLA) and amorphous poly(D,L-lactic-co-glycolic acid) (PLGA) were used for the encapsulation of hGH. Protein release profiles from the two microspheres were comparatively evaluated with respect to their morphological difference. Both of the microspheres similarly exhibited rugged surface and porous internal structures, but their inner pore wall morphologies were quite different. The slowly degrading PLA microspheres had many nano-scale reticulated pores on the wall, while the relatively fast degrading PLGA microspheres had a non-porous and smooth wall structure. From the PLA microspheres, hGH was released out in a sustained manner with an initial approximately 20% burst, followed by constant release, and almost 100% complete release after a 1-month period. In contrast, the PLGA microspheres showed a similar burst level of approximately 20%, followed by much slower release, but incomplete release of approximately 50% after the same period. The different hGH release profiles between PLA and PLGA microspheres were attributed to different morphological characters of the pore wall structure. The inter-connected nano-porous structure of PLA microspheres was likely to be formed due to the preferable crystallization of PLA during the solvent evaporation process.     

Preparation and evaluation of poly(L-lactic acid) microspheres containing rhEGF for chronic gastric ulcer healing.

Biodegradable microspheres containing recombinant human epidermal growth factor (rhEGF) were prepared using poly(L-lactic acid) by a solvent evaporation method based on multiple w/o/w emulsion. Encapsulation efficiency and initial release were influenced by the amount of polymer, inner water phase volume and osmotic pressure difference between inner water phase and outer water phase. The effect of osmotic pressure difference between inner water phase and outer water phase in w/o/w emulsion on particle size, porosity and in vitro release of rhEGF from microspheres were also studied. Microspheres prepared with the optimized osmotic pressure, polymer amount and inner water volume produced 21% initial release on the first day with 92% encapsulation efficiency. The blood concentration of rhEGF was maintained at constant levels for 9-11 days after a single subcutaneous (s.c.) administration of rhEGF microspheres. The gastric ulcer healing effect of a single s.c. administration of rhEGF microspheres was increased 1.44-fold compared with twice a day s.c. administration of rhEGF saline solution after 11 days. The enhanced curative ratio of rhEGF loaded microspheres may be due to the optimized osmotic pressure, high encapsulation efficiency and sustained release pattern.     

Synthesis and characterisation of poly(D,L-lactic acid)-idoxuridine conjugate.

A new polymeric prodrug was prepared coupling 5-iodo-2'-deoxyuridine (IDU) to poly(d,l-lactic acid) (PLA) via a succinic acid spacer. The PLA-IDU conjugate was characterised by thermal analysis, IR and 1H and 13C NMR spectroscopy. The IDU content (0.024 mequiv.g-1 of PLA) was consistent with the carboxylic acid endgroup present in the polymer sample (0.025 mequiv.g-1 of polymer). The PLA-IDU conjugate was susceptible to degradation in biological environments containing esterase, whereas IDU was not detected by chemical hydrolysis in pH 7.4 phosphate buffer. The conjugate should be used to prepare injectable microspheres and nanospheres containing IDU chemically coupled to the polymer carrier.     

Degradation of and drug release from a novel 2,2-bis(2-oxazoline) linked poly(lactic acid) polymer.

The degradation rate of poly(lactic acid) (PLA) is typically modified by copolymerization of the glycolide with lactide. In the present study, the degradation rate of PDLLA was modified by a novel linking of PLA with 2,2'-bis(2-oxazoline). This modification resulted in formation of a more rapidly degrading poly(ester amide) (PEA) for controlled drug release. The hydrolytic degradation of PDLLA and PEA films was studied in PBS (pH 7.4, USP XXIV, 37 degrees C); the resulting decrease in molecular weight was determined by size exclusion chromatography and the weight loss of films was measured. Drug releases of guaifenesin (mw 198.2), timolol (mw 332.4), sodium salicylate (mw 160.1) and FITC-dextran (mw 4400) from PDLLA and PEA films and microspheres were examined in PBS (pH 7.4, 37 degrees C). The degradation rate of PEA was substantially greater than that of PDLLA. The release profiles of all small model drugs (mw <332.4) from PDLLA films were biphasic or triphasic, while the release profiles of small model drugs from PEA films varied extensively. Due to the faster weight loss of PEA, FITC-dextran (mw 4400) was released substantially more rapidly from PEA microspheres than from PDLLA microspheres. In conclusion, all model drugs, except guaifenesin, were released faster from PEA preparations than from PDLLA preparations.     

Controlled release of 4-nitroanisole from poly(lactic acid) nanoparticles.

The controlled release of 4-nitroanisole from polylactide nanoparticles with different morphologies is reported. Two theoretical equations have been used in an attempt to fit the experimental results. Good agreement between theory and experiment was found for short release time. The estimated values of the diffusion coefficient of 4-nitroanisole in these nanoparticles, at short times (up to 50% release), were all approximately 10(-19) m(2)s(-1). At long time some differences in release behaviour were observed for different morphologies.     

Antibacterial poly(D,L-lactic acid) coating of medical implants using a biodegradable drug delivery technology

OBJECTIVES: Biomaterial-associated bacterial infections present common and challenging complications with medical implants. The purpose of this study was to determine the antibacterial properties of a low molecular weight biodegradable poly(D,L-lactic acid) coating with integrated antibiotics gentamicin and teicoplanin. METHODS: Coating of Kirschner-wires was carried out by a solvent casting technique under aseptic conditions with and without incorporated antibiotics. Release kinetics of gentamicin and teicoplanin were studied in phosphate-buffered saline. Initial bacterial adhesion of Staphylococcus epidermidis on coated and bare implants was determined by radiolabelling and counts of detached viable organisms. RESULTS: The incorporated antibiotics showed a continuous release over a period of at least 96 h with an initial peak of release in the first 6 h. Attachment of non-viable microorganisms, detected by radiolabelled bacteria, was increased significantly by the polymer coatings (P < 0.05). In contrast, the number of viable bacteria was reduced by the pure polymer (P < 0.01) and further by the polymer-antibiotic combinations (P < 0.05). CONCLUSIONS: Poly(D,L-lactic acid) coating of implants could offer new perspectives in preventing biomaterial-associated infections. Combinations with other drugs to formulate custom-tailored implant surfaces are feasible.     

Release of anti-restenosis drugs from poly(ethylene oxide)-poly(DL-lactic-co-glycolic acid) nanoparticles.

Dexamethasone- or rapamycin-loaded nanoparticles based on poly(ethylene oxide) and poly(dl-lactic-co-glycolic acid) block copolymers (PEO-PLGA) were prepared without additional stabilizer using the salting-out method. A fast release of drug in PBS (pH 7.4) at 37 degrees C resulting in 100% release within 5 h was observed for both drugs. The rate of drug release was substantially reduced by treating the particles with gelatin or albumin after drug loading, resulting in a linear drug release in time. It was shown that the rate of drug release is related to the amount of protein associated with the nanoparticles. After gelatin treatment of drug-loaded nanoparticles, sustained release of dexamethasone for 17 days and of rapamycin for 50 days could be achieved.     

Mechanism of antibiotic release from poly(methyl methacrylate) bone cement

Antibiotic loaded poly(methyl methacrylate) (PMMA) bone cement is commonly used in joint replacement surgery. The mechanism of antibiotic release was examined using a series of in-vitro experiments. An initial rapid rate of release was followed by a slower rate over 40 days. The quantity of antibiotic release was related to the surface area of the cement sample. Transfer of antibiotic across thin membranes of plain PMMA was almost negligible. The method of mixing the PMMA greatly affected the quantity of antibiotic released, the porosity and the surface features, whilst having no significant effect on the diffusion coefficient and the water equilibrium coefficient. It was established that the mechanism of antibiotic release is diffusion from the surface layers of the cement as opposed to capillary action via pores in the cement or diffusion through the entire matrix of the PMMA as previously proposed.     

载多烯紫杉醇聚乳酸-羟基乙酸微球的制备、表征及其药物稳定性

背景:目前临床使用的多烯紫杉醇注射液多采用吐温80作为增溶剂,容易导致过敏反应,且全身化疗不良反应大.采用聚乳酸-羟基乙酸包载多烯紫杉醇制备的缓释微球进行肿瘤间质化疗可提高肿瘤局部药物浓度,减轻全身不良反应.目的:制备一种用于肿瘤间质化疗的载多烯紫杉醇聚乳酸-羟基乙酸缓释微球,并考察其理化性质、体外释放及药物稳定性.方法:采用溶剂挥发法制备不同投料比载药微球,扫描电镜观察微球的表面形态、粒径,高效液相色谱法检测包封率、载药率及体外药物释放情况.将制备的微球于5,15,25 kGy 60Co 3种剂量辐照灭菌,体外细菌培养观察灭菌效果.结果与结论:制备的载药微球呈圆球形,表面光滑,分散良好,平均粒径为23.1 um.聚乳酸-羟基乙酸与多烯紫杉醇的投料比为100 mg,5 mg时可获得最佳的包封率(96 3%)和载药率(4.82%);载药微球体外4周平稳释放药物达81.6%,无明显突释效应,包裹在微球内的多烯紫杉醇结构稳定性明显提高;3种剂量60Co辐照后均未见短小芽孢杆菌生长.说明采用溶剂挥发法可制备粒径及分布适宜、释放周期较理想、药物稳定性好的载多烯紫杉醇聚乳酸-羟基乙酸缓释微球.     

Methods for improving drug release from poly(methyl)methacrylate bone cement

Poly(methylmethacrylate) (PMMA) is a widely used material with both dental and orthopaedic applications. The acrylic cement is produced by the combination of polymethylacrylate beads with methylmethacrylate monomer. After polymerisation, a heterogeneous and porous matrix is formed which can be used to deliver therapeutic agents. In this work, the release of antibiotic, growth hormone and serum albumin is demonstrated. The mechanism is similar for all agents; a rapid release followed by a slow continuous release. The quantity of drug released depends upon the formulation of both the PMMA and the drug. The polymer-to-monomer ratio can greatly affect the ratio of drug release; increased polymer-to-monomer ratio leads to increased release of antibiotic. Optimum release is achieved if a crystalline formulation of the drug is used rather than a fine powder. Experimental methods to improve the drug release performance of bone cements are presented.     

Understanding drug release from poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) gels.

Experimental and mathematical studies were performed to understand the release mechanism of small molecular weight compounds from poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) polymer gels (trademarked Pluronic by BASF Corp.) of various concentrations. Studies of the diffusion coefficient of solutes in the polymer gels were performed using a novel technique to predict movement of drugs within the gel as release occurs. Studies were also performed to determine the diffusion coefficient of water in the polymer gel, as it is this parameter that controls the dissolution rate of the polymer, and in turn, the drug release rate. A model was formulated and solved numerically to determine the controlling release mechanism. By parameter modification, this algorithm for determining the overall mass of drug released from a drug loaded gel can be used for a number of drugs and for a wide range of initial polymer concentrations. Drug release data were obtained with a novel experimental setup and were used to verify the accuracy of the overall solution of the model. The results of the model indicate that although the rate of polymer dissolution ultimately controls the drug release, about 5% of the release is due to diffusion at the gel/liquid interface, giving rise to a slightly non-linear release. It was also found that agitation speed greatly affects the dissolution rates of these polymer gels.     

聚磷酸钙/左旋聚乳酸软骨组织工程支架复合材料的分析

背景用左旋聚乳酸(PLLA),聚羟基乙酸(PGA)等可降解吸收性高分子材料加工而成的纤维状支架材料和海绵状支架材料在软骨组织工程中已获得广泛应用.但这类支架材料存在着弹性模量低,受力时易变形,容易导致种子细胞损伤和降解吸收时间过长等缺陷.目的研制出可任意调控降解速率且具有良好力学性能、生物相溶性能和毒理学性能的聚磷酸钙(Calcium Polyphosphate,CPP)纤维,并用该纤维为增强材料研制软骨组织工程复合材料.设计以不同质量比例分组对照的实验研究.地点和对象实验在兰州交通大学材料工程研究所完成,基体材料选用PLLA(中科院化学所高分子合成室提供),增强材料选用自制CPP纤维.干预以高强度、高模量可设计降解速率的CPP纤维为增强材料,PLLA为基体材料,应用溶媒投放、颗粒滤取技术制备出CPP/PLLA软骨组织工程支架复合材料,测试了该支架复合材料的物理力学性能和体外37℃下Hank's人工降解液中的生物降解特性.主要观察指标物理力学性能,降解性能.结果CPP/PLLA支架复合材料具有三维连通、微孔、网状微观结构,微孔分布均匀,微孔尺寸为130～350μm,孔隙率90%;压缩模量随CPP纤维体积分数的增加而增加;降解速率随CPP纤维体积分数的增大而增大.结论CPP/PLLA支架复合材料的物理力学性能和体外降解性能在体外构建的组织化软骨的早期生物学性能基本满足软骨组织工程的要求,故可用作软骨组织工程支架材料.     

HPMA-hydrogels containing cytostatic drugs. Kinetics of the drug release and in vivo efficacy.

This study proposes a strategy to generate new anticancer therapy using hydrogel-based drug delivery systems to improve drug bioavailability and increase the therapeutic efficacy. We have synthesized biodegradable hydrogels based on N-(2-hydroxypropyl)methacrylamide (HPMA) with prolonged drug release. Pharmacokinetic data from in vitro studies showed that the in vitro release of hydrophilic drugs (doxorubicin, vinblastine) from HPMA-hydrogels is affected mainly by drug diffusion and only partially by hydrogel degradation. The release of hydrophobic drugs (cyclosporine A, CsA) actually copies the process of degradation and therefore it is slower. Hydrogels with degradation time of 50 h released the doxorubicin over a period of at least 96 h after s.c. implantation. Drug concentration at pharmacologically active levels was maintained in the bloodstream over a period of at least 4 days, ranging between 0.1 and 1 microg/ml. The therapeutic potential of HPMA-hydrogels in vivo was studied in Bcl1 leukemia. HPMA-hydrogels containing DOX were significantly more effective in inhibition of Bcl1 leukemia in comparison with free DOX or non-targeted polymeric drug (PK1). The efficacy of therapeutic combination using unspecific, hydrogel-based therapy with specific, antibody-targeted therapy at late stages of Bcl1 leukemia was also tested. In contrast to application of DOX alone, a cocktail of DOX with CsA as a blocker of P-glycoprotein (Pgp) incorporated into HPMA-hydrogel blocked the proliferation of Pgp-overexpressing multidrug resistant cell lines in vitro by induction of apoptosis.     

Effect of enzymatic degradation on the release kinetics of model drug from Pluronic F127/poly(lactic acid) nano-particles.

Poly(lactic acid) (PLA) was successfully grafted to both ends of Pluronic F127 block copolymer (PEO-PPO-PEO) to obtain amphiphilic PLA-F127-PLA block copolymers. The effect of enzymatic degradation on the release behaviors of hydrophobic model drug 9-(methylaminomethyl)anthracene (MAMA) from PLA-F127-PLA nano-particles with vesicular structure was studied by UV-Vis spectroscopy. It was observed that the release rate of MAMA from PLA-F127-PLA nano-particles with the enzymatic degradation varied with temperature due to the activity of the enzyme with temperature. However, the enzyme concentration has negligible effect on the release rates of MAMA.     

Receptor-mediated delivery of all trans-retinoic acid to hepatocyte using poly(L-lactic acid) nanoparticles coated with galactose-carrying polystyrene.

All trans-retinoic acid (RA)-loaded poly(L-lactic acid) (PLA) nanoparticles coated with galactose-carrying polymer, as hepatocyte-specific targeting material using galactose ligands as recognition signals to asialoglycoprotein receptors were prepared by the diafiltration method. Effects of released RA from its loaded nanoparticles on morphology and DNA synthesis of hepatocytes were studied. Receptor-mediated endocytosis of the nanoparticles was checked by fluorescence and confocal laser microscopy. It was found that the shapes of most hepatocytes attached onto polystyrene dish precoated with collagen solution were flat and spreading at low concentration of RA for the RA-loaded nanoparticles, whereas their shapes were round at even low concentration of RA when RA was mixed with the nanoparticles. From the fluorescence and confocal laser microscopic studies, it was suggested that the nanoparticles coated with galactose-carrying polymers were internalized by the hepatocytes through the receptor-mediated mechanism. The RA-loaded nanoparticles were more potent stimulators of hepatocyte DNA synthesis than the free RA system in the presence of epidermal growth factor (EGF) owing to the controlled release of RA from the RA-loaded nanoparticles.     

Controlled release from erod1ble poly(ortho ester) drug delivery systems

Variable rate zero order release from surface erosion controlled ercdible polyfortho ester) devices was reproducibly attained with the use of latentiated acid catalysts. Various chemical and physical characteristics of the drug release system affected its erosion/drug release performance. The greatest effect was achieved with the choice of anhydride catalyst. A range in release rates of over two orders of magnitude was obtained with acid catalysts having a first pK_a from 1.8 (maleic) to 4.3 (glutaric). The control over the erosion rate was extended by altering the amount of catalyst present in the device. Increasing the anhydride content increased the zero order release up to a point, thereafter having no effect. The physical properties of the polymer, such as thermal and mechanical properties, were a function of the molecular weight and composition of the copolymer. Both had an effect on release rate: increasing either molecular weight or glass transition temperature or both decreased the rate. Increasing release rates were observed at higher drug loadings, possibly due to plasticization of the matrix by the drug and/or leaching of the drug by diffusive mechanisms. Release rates were proportional to the surface area and durations were proportional to thickness of the test slabs, agreeing with the proposed surface erosion mechanism. All of these parameters were capable of being adjusted to give zero order release devices covering a wide range of useful release rates.     

The effect of poly(ethylene glycol)-poly(D,L-lactic acid) diblock copolymers on peptide acylation.

The combination of poly(ethylene glycol) (PEG) with a biodegradable poly(ester), such as poly(D,L-lactic acid) (PLA), is an approach that has been successfully used for the stabilization of proteins and peptides in several biodegradable delivery devices. The acylation of peptides inside degrading PLA microspheres has been described only recently as another instability mechanism related to the accumulation of polymer degradation products inside eroding PLA. We investigated whether the block copolymerization of PLA with PEG reduces peptide acylation inside degrading microspheres. Diblock copolymers consisting of poly(D,L-lactic acid) covalently bound to poly(ethylene glycol)-monomethyl ether (Me.PEG-PLA) were used for these investigations. Human atrial natriuretic peptide (ANP) was incorporated into microspheres manufactured from Me.PEG5-PLA45, a diblock copolymer with an overall PEG content of 10%. Peptide integrity inside the microspheres was monitored by HPLC-MS analysis during 4 weeks of microsphere degradation in isotonic phosphate buffer (pH 7.4) at 37 degrees C. Inside the degrading Me.PEG5-PLA45 microspheres, acylation products as well as an oxidation product of ANP were formed. The results demonstrate that the combination of PEG with PLA does not necessarily display a favorable effect concerning peptide acylation inside degrading polymer microspheres. However, they also suggested that the acylation reaction is mainly driven by the formation and accumulation of polymer degradation products inside the degrading microspheres.