Biodegradable Polymeric Drug Research Articles

Implant-associated local drug delivery systems based on biodegradable polymers: customized designs for different medical applications

Implants providing controlled, local release of active substances are of interest in different medical applications. Therefore, the focus of the present article is the development of implant-associated diffusion- or chemically controlled local drug delivery (LDD) systems based on biodegradable polymeric drug carriers. In this context, we provide new data and review our own recently published data concerning the drug release behavior of diffusion-controlled LDD systems in relation to the kind of polymer, drug content, coating mass/thickness, and layer composition. We demonstrate that polymers allow a wide range of control over the drug release characteristics. In this regard, we show that the glass transition temperature of a polymer has an impact on its drug release. Additionally, the blending of hydrophobic, semicrystalline polymers with amorphous polymers leads to an increase in the rate of drug release compared with the pure semicrystalline polymer. Moreover, the percentage loading of the embedded drug has a considerable effect on the rate and duration of drug release. Furthermore, we discuss chemically controlled LDD systems designed for the release of biomolecules, such as growth factors, as well as nanoparticle-mediated LDD systems. With our own published data on drug-eluting stents, microstents, and cochlear implants, we highlight exemplary implant-associated LDD systems designed to improve implant performance through the reduction of undesirable effects such as in-stent restenosis and fibrosis.

Poly(alkyl cyanoacrylate) nanocapsules as a delivery system in the rat for octreotide, a long-acting somatostatin analogue.

Poly(alkyl cyanoacrylate) nanocapsules have been used as biodegradable polymeric drug carriers for subcutaneous and peroral delivery of octreotide, a long-acting somatostatin analogue; their ability to reduce insulin secretion or prolactin secretion in response to oestrogens has been studied in adult male rats. The nanocapsules, prepared by interfacial emulsion polymerization of isobutyl cyanoacrylate, were 260 nm in diameter and incorporated 60% of octreotide. Administered subcutaneously, the octreotide-loaded (20 micrograms kg-1) nanocapsules suppressed the insulinaemia peak induced by intravenous glucose overload and depressed insulin secretion over 48 h, preventing the secretory rebound; however, glycaemia was unaffected. In parallel, the plasma octreotide concentration increased 2.7 times. Administered perorally to oestrogen-treated rats, octreotide-loaded nanocapsules (200 and 1000 micrograms kg-1) significantly improved the reduction of prolactin secretion (by 72 and 88%, respectively, compared with 32 and 54% with free octreotide) and slightly increased plasma octreotide level. Thus nanocapsules could be of interest as a biodegradable drug carrier for the administration of octreotide.

Effect of drug type on the degradation rate of PLGA matrices

We compare the rate of drug release through the degradation of 50:50 polylactic-co-glycolic acid polymer pellets, for six different drugs: Thiothixene, Haloperidol, Hydrochlorothiozide, Corticosterone, Ibuprofen, and Aspirin. Despite using the same polymer matrix and drug loading (20% by weight), we find that the rate of polymer degradation and the drug release profile differ significantly between the drugs. We conclude that the design of biodegradable polymeric drug carriers with high drug loadings must account for the effect of the drug on the polymer degradation and drug release rate.

Poly-(L)-glutamic acid-paclitaxel (CT-2103) [XYOTAX], a biodegradable polymeric drug conjugate: characterization, preclinical pharmacology, and preliminary clinical data.

These data describing the preclinical and early clinical development of CT-2103 demonstrate the feasibility of using polyglutamic acid homopolymers to create macromolecular cytotoxic drug conjugates. PG has the characteristics of an ideal polymeric drug carrier including biodegradability, the ability to solubilise hydrophobic agents even at high loading, stability in circulation, and apparent lack of immunogenicity. Preliminary clinical data indicate that CT-2103 is well tolerated by short infusion and has what appears to be reduced toxicity to neural tissue and hair follicles compared with paclitaxel delivered in the standard formulation. In preclinical studies, the MTD was approximately twice that of standard paclitaxel and the antitumour efficacy in was improved. Preliminary clinical data from Phase II studies indicate that the MTD will be higher than that of paclitaxel and that CT-2103 has activity, even in patients who have failed prior taxane therapy. The potentially enhanced efficacy and apparently reduced toxicity of CT-2103 can be predominantly ascribed to its improved distribution to tumour tissue through the EPR effect and the reduced exposure of normal tissues. Taken together, these data suggest that PG is an excellent polymeric backbone for the delivery of oncologic therapeutics and is likely to improve the therapeutic indices of a number of other agents. A second PG conjugate designated CT-2106, a PG camptothecin with an interposed glycine linker, will enter clinical trials shortly.

Sustained release of isoniazid from a single injectable dose of poly ( dl-lactide-co-glycolide) microparticles as a therapeutic approach towards tuberculosis

Drug delivery strategies to achieve a sustained drug release and increased bioavailability involve the use of biodegradable polymeric drug carriers. Poly ( dl-lactide-co-glycolide) (PLG) microparticles were investigated as carriers for isoniazid (INH). In vitro and in vivo release of INH from different formulations of PLG microparticles was examined. In vitro experiments showed a sustained release of INH up to 6 days from non-porous microparticles while porous microparticles released INH over 3 days. Both porous and non-porous microparticles released INH in plasma for up to 2 days. Hardened PLG microparticles sustained release of INH for up to 7 weeks both in vitro and in vivo. The concentrations of INH obtained at all times were much higher than the minimum inhibitory concentration (MIC) of INH. Controls injected with free INH showed release of INH in plasma for up to 12 h and in organs for up to 24 h. There was no hepatotoxicity induced as compared with control animals. Taken together these results suggest that PLG-based antitubercular drugs may serve as ideal therapeutic agents for the treatment of tuberculous infections.

Optimization of the preparation of loperamide-loaded poly (L-lactide) nanoparticles by high pressure emulsification-solvent evaporation

The entrapment of loperamide hydrochloride (LPM) in biodegradable polymeric drug carriers such as nanoparticles might enable its passage across the blood-brain barrier. The optimization of the preparation of the LPM-loaded PLA nanoparticles was performed employing high pressure emulsification-solvent evaporation., The resulting nanoparticles were characterized by particle sizedistributionthermal analysisand drug release profiles., The partition of LPM into the organic phase increased with an increase in pH of the aqueous phase and with addition of lipophilic surfactants such as sorbitan fatty acid estersresulting in an increase in the drug entrapment in the nanoparticles., Evaporation of the organic phase under reduced pressure and the addition of ethanol in the organic phase yielded a high drug entrapment due to the rapid polymer precipitation., The addition of the sorbitan fatty acid esters further increased the drug entrapment even at higher LPM concentrations., The results of thermal analysis suggest that LPM was homogeneously dispersed in the amorphous polymer matrix., The in vitro release of the drug from nanoparticles was biphasicwith a fast initial phasefollowed by a second slower phase., Different drug release profiles from nanoparticles can be achieved by addition of sorbitan fatty acid estersor the employment of different solvents as the organic phase.

Polymeric drug delivery of enzymatically degradable pendant agents: Peptidyl-linked procainamide model system studies

Biodegradable polymeric drug delivery systems have become increasingly important for sustained release indications when a time-limited drug implant is required. A new methacrylic copolymer consisting of enzymatically-cleavable oligopeptidyl procainamide as pendant side chains was synthesized in a series of three reactions. Using high performance liquid chromatography (HPLC) analysis, procainamide release was monitored while incubating polymer specimens in the presence of a model enzyme, α-chymotrypsin, in a physiologic buffer at 37°C. It was found that the new polymeric drug conjugate was insoluble in aqueous solutions and it was relatively stable when not in the presence of the enzyme, releasing not more than 5 mg of drug/g polymer after 30 days incubation under physiologic conditions. However, in the presence of α-chymotrypsin, the procainamide side chains were gradually enzymatically cleaved over 20 days, and the rate of hydrolysis could be controlled by varying the enzymatic incubation conditions. The enzymatic rate dependency of each formulation was dependent upon the comonomer ratio and the degree of crosslinking. These two factors influenced the accessibility of the water-insoluble polymers to enzyme. It is concluded that procainamide release from an enzymatically degradable pendant-peptide link can be achieved in an enzymatically controllable manner.

Biodegradable polymeric prodrugs of naltrexone

The development of a biodegradable polymeric drug delivery system for the narcotic antagonist naltrexone may improve patient compliance in the treatment of opiate addiction. Random copolymers consisting of the α-amino acids N 5-(3-hydroxypropyl- l-glutamine and l-leucine were synthesized with equimolar initial monomer feeds. The molecular weight of this chemical carrier was determined by viscometry and wide-angle light scattering. In order to get selective covalent coupling of drug to polymer the 3-acetate derivative and the 14-acetate derivative of naltrexone were synthesized and characterized by NMR. Hydrolytic conversion of each monoacetate to parent drug was monitored by HPLC and the rate constant was determined. Both derivatives were coupled via hydrolytically labile carbonate linkages to the polymer hydroxyl groups. The drug conjugates were prepared as particles of various size ranges between 20 and 350 μ. In vitro studies in phosphate-buffered saline (pH 7.4) demonstrated a release rate dependence on particle size. Nearly constant plasma levels of naltrexone were obtained for one month after subcutaneous injection in rats.

4863735 Biodegradable polymeric drug delivery system with adjuvant activity : Joachim B Kohn, Robert S Langer, Steven M Neimi, James G Fox assigned to Massachusetts Institute of Technology

4863735 Biodegradable polymeric drug delivery system with adjuvant activity : Joachim B Kohn, Robert S Langer, Steven M Neimi, James G Fox assigned to Massachusetts Institute of Technology

Opportunities and challenges in the design of implantable biodegradable polymeric systems for the delivery of antimicrobial agents and vaccines

An increasing number of implantable biodegradable polymeric drug systems are now in clinical use or undergoing experimental and clinical investigations for diverse therapeutic applications. This article summarizes the use of copolymers of lactic and glycolic acid as carrier materials for the controlled release of antigens for vaccination and of chemotherapeutic agents for the therapy of chronic microbial diseases. These approaches illustrate some of the important conceptual and technical issues that must be considered in the future development of implantable biodegradable polymeric systems. These systems offer considerable promise for achieving controlled release of the new classes of biological mediators produced by recombinant technology, particularly those vaccines intended for use in the Third World. The future development of these systems will almost certainly require the use of specialized approaches to particular delivery problems but, overall, the development is viewed with considerable optimism.

Biodegradable polymeric drug delivery systems

The use of biodegradable polymeric materials as drug carriers is a relatively new dimension in polymeric drug delivery systems. A number of biodegradable or bioerodible polymers, such as poly (lactic/glycolic acid) copolymer, poly(α-amino acid), polyanhydride, and poly (ortho ester) are currently being investigated for this purpose. These polymers are useful for matrix and reservoir-type delivery devices. In addition, when chemical functional groups are introduced to the biodegradable polymer backbone, such as poly (N-(2-hydroxypropy) methacrylamide), the therapeutic agent can be covalently bound directly orvia spacer to the backbone polymer. These polymer/drug conjugates represent another new dimension in biodegradable polymeric drug delivery systems. In this paper, major emphasis is placed on clinical applications of biodegradable polymeric delivery systems. In addition, examples of biodegradable polymeric durg delivery systems currently being investigated will be discussed for the purpose of demonstrating the potential importance of this new field.