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Results for “Biodegradable Delivery Systems”

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PubMed2005

Novel powder formulations for controlled delivery of poorly soluble anticancer drug: application and investigation of TPGS and PEG in spray-dried particulate system.

Biodegradable poly (lactic-co-glycolic acid) (PLGA), D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) and/or polyethylene glycol (PEG) were combined as pharmaceutical excipient to fabricate microparticles containing sparingly soluble drug paclitaxel by spray-drying technique with successful achievement. The effect of formulation variety on particle morphology, surface composition, thermal property, drug entrapped capability, and drug release profile was investigated. The result indicated that the use of the appropriate mixtures of PLGA, TPGS and/or PEG produced paclitaxel-loaded microparticles characterised by acceptable pharmaceutical properties. Atomic force microcopy (AFM) and scanning electron microscopy (SEM) showed that the produced microparticles were spherical in shape with dimples or pores. The particle size ranged from 0.88 to 2.44 microm with narrow distribution. The combination of TPGS and PEG in the formulation resulted in a narrow particle size distribution in general although the influence of the formulation on the particle size was not significant. Differential scanning calorimetry (DSC) study implied that all those components in consideration were compatible well in the blend formulation systems. The paclitaxel entrapped in the particles existed in an amorphous or disordered-crystalline status in the matrices and was independent of the PLGA/TPGS/PEG ratio. X-ray photoelectron spectroscope (XPS) analysis revealed that after incorporation the particle's surface was dominated with PLGA due to its hydrophobic property. The formulation variety had an important impact on the drug release that was reduced with the presence of large fraction of TPGS resulting from a strong hydrophobic interaction between various matrix materials and the drug inside the particle. A zero order release could be yielded by optimising the ratio of PLGA/TPGS/PEG. The combination of PLGA/TPGS/PEG as safe pharmaceutical excipient to formulate particulate delivery system is beneficial in improving the pharmaceutical properties for further powder dosage application.

Antineoplastic Agents↗

PubMed1992

Microencapsulated nerve growth factor: effects on the forebrain neurons following devascularizing cortical lesions.

In this study, we report the effects of nerve growth factor (NGF) delivered into the CNS via a novel delivery system for prolonged, controlled release. The effectiveness of NGF incorporated in the biodegradable microspheres was investigated in the rat model for central cholinergic degeneration. Mature male rats were unilaterally lesioned by disruption of the pia arachnoid vessels and vehicle (alginate microspheres without NGF) and microencapsulated NGF was placed at the site of the lesion. Choline acetyltransferase (ChAT) activity was measured in the nucleus basalis magnocellularis (NBM) and cortex in the (a) non-lesioned control animals; (b) lesioned animals treated with 'empty' microspheres and (c) lesioned animals treated with microspheres containing NGF, 30 days following surgery. Similarly lesioned animals received NGF via permanently installed cannulae in order to compare the novel route of administration with the more conventional one. Immunocytochemical results showed an absence of the cholinergic cell body shrinkage in the NBM otherwise observed in lesioned animals. Furthermore, an increase in intensity of ChAT immunostaining in NGF-treated, lesioned animals was evident. The present results stress the experimental therapeutic possibilities of novel delivery systems for administration of trophic factors in the CNS.

Alginates↗

PubMed1998

Bioabsorbable polymers for implantable therapeutic systems.

For a long time, subcutaneous implantable drug pellets using nondegradable polymers have been used for long-term, continuous drug administration. The procedure requires surgical implantation and removal of the drug-containing devices or polymeric matrices, which has a significant negative impact on the acceptability of the product candidate. In addition, the release profile from such devices is neither constant nor readily controlled in terms of precision of rate of release and duration of action. These facts have led to the research and development of novel, controllable, nonirritating, noncarcinogenic, biocompatible, and bioabsorbable drug delivery systems for overcoming the drawbacks of nondegradable implantable pellets for prolonged continuous release. Biodegradable implantable systems release the drug over a long period of time with simultaneous or subsequent degradation in the tissue of the polymer to harmless constituents, thus avoiding removal once the therapy is complete. This approach has considerably improved patient acceptability and patient compliance. Various bioabsorbable polymers have been evaluated for controlled implantable drug delivery, including hydrogels, copolymers of polylactic and polyglycolic acids, polylactic acid, poly(orthoesters), polyanhydrides, poly(E-caprolactone), and polyurethanes. Their characteristics have been studied using a variety of drugs, like anticancer agents, hormone agonists and antagonists, nonsteroidal anti-inflammatory agents, neuroleptics, contraceptives, and others. The present paper describes the current research on implantable therapeutic systems, the bioabsorbable polymers, and the biologically active agents being used in this approach.

Absorption↗

PubMed1999

Microparticulate drug delivery systems.

Chitosan was proposed as a drug carrier for mucosal administration in ocular, buccal, nasal, gastroenteric and vaginal-uterine therapies based on its bioadhesive properties and biodegradability in vivo under the action of hydrolases. Examples are the delivery of acyclovir via ocular administration, and the delivery of 5-aminosalicylic acid to the colon. Microparticles may need to be cross-linked to retard their degradation in acidic media; yet cross-linking with glutaraldehyde introduces cytotoxic characteristics and depresses bioadhesion. Alternative cross-linking approaches are discussed along with the suitability of chitosan for the oral delivery of vaccines.

Acyclovir↗

PubMed1991

In search of missing links in otology. II. Development of an implantable middle ear drug delivery system: initial studies of sustained ampicillin release for the treatment of otitis media.

The development of a new device that consists of a biodegradable support incorporating a therapeutically releasable amount of ampicillin is presented. This device is in an insertable shape that allows placement into the middle ear via a myringotomy incision. Once in the middle ear cavity, it expands, contacts the walls, and provides extended release of ampicillin. In vitro studies (3 months) documented the consistent release of therapeutic levels of ampicillin. In vivo efficacy was demonstrated in otitis-induced chinchillas (bacterial inoculation). The device compared favorably with topical and systemic treatment and prophylaxis of otitis media. The device was also efficient in repeated bacterial challenges. Topical extended middle ear drug delivery can become a significant form of treatment for middle ear disease, and has the potential of being useful as a source for inner ear drug delivery.

Administration, Topical↗

PubMed1997

Double-stimuli-responsive degradation of hydrogels consisting of oligopeptide-terminated poly(ethylene glycol) and dextran with an interpenetrating polymer network.

Biodegradable hydrogels consisting of oligopeptide-terminated poly(ethylene glycol) (PEG) and dextran (Dex) with an interpenetrating polymer network (IPN) structure were prepared as models of novel biomaterials exhibiting a double-stimuli-response function. The IPN-structured hydrogels were synthesized by sequential cross-linking reaction of N-methacryloyl-glycylglycylglycyl-terminated PEG and Dex. In vitro degradation of the IPN-structured hydrogels was examined using papain and dextranase as model enzymes of hydrolyzing oligopeptide and Dex, respectively. Specific degradation in the presence of papain and dextranase was observed in the IPN-structured hydrogel with a particular composition of oligopeptide-PEG and Dex. This same hydrogel was not degraded by one of the two enzymes. The IPN-structured hydrogels were characterized by water content, thermal mechanical analysis, and wide-angle X-ray diffraction, and the results were compared with those of co-cross-linked hydrogels consisting of N-methacryloyl-glycylglycylglycyl-terminated PEG and methacryloyl Dex. The results suggest that the IPN-structured hydrogels contain physical chain entanglements between networks as well as chemical cross-linked networks. It is concluded that the double-stimuli-responsive degradation observed in the IPN-structured hydrogel is achieved by controlling the chain entanglements between the two biodegradable polymers. Such degradation property of the IPN-structured hydrogel can be useful as a fail-safe system for guaranteed drug delivery and/or medical micromachines.

Biocompatible Materials↗

PubMed1998

The time and ease of placement of the chlorhexidine chip local delivery system.

The first local delivery system for an antimicrobial agent was a nondegradable tetracycline-impregnated fiber introduced by Goodson et al in 1979. PerioChip, a biodegradable chip containing chlorhexidine, was recently approved by the Food and Drug Administration for the treatment of adult periodontitis. During several multicenter randomized clinical trials, this product, when used as an adjunct to scaling and root planing, was found to reduce probing depth and improve attachment level significantly more than scaling and root planing alone.

Adult↗

PubMed1990

Implantable microencapsulated dopamine (DA): prolonged functional release of DA in denervated striatal tissue.

Biodegradable controlled-release microcapsule systems made with the biocompatible biodegradable polyester excipient poly [DL-lactide-co-gly-colide] constitute an exciting new technology for drug delivery to the central nervous system (CNS). The present study describes functional observations indicating that implantation of dopamine (DA) microcapsules encapsulated within two different polymer excipients into denervated striatal tissue assures a prolonged release of the transmitter in vivo. This technology has a considerable potential for basic and possibly clinical research.

Animals↗

PubMedDate not supplied

Polymeric nanofibers as novel carriers for the delivery of therapeutic molecules.

Nanotechnology and nanoscience are relatively new technological endeavors that encompass the study, control, manipulation, and assembly of multifarious nanoscale components into materials, systems and devices to serve human interest and needs. Among the various currently used nanostructures for high technology applications polymeric nanofibers have received immense interest due to the ease of fabrication, controllable size/shape, and properties. Polymeric nanofibers have been extensively investigated for diversified applications, including filtration, barrier fabrics, wipes, personal care, biomedical, and pharmaceutical applications. This review mainly focuses on the fabrication of therapeutic agent loaded polymeric nanofibers and their controlled/sustained release behavior for the delivery of these active agents for various therapeutic applications. The nonwoven biodegradable polymeric nanofiber matrices are currently being reported as topical/local therapeutic agent delivery systems and as resorbable/biodegradable gauze for wound healing applications.

Coated Materials, Biocompatible↗

PubMed1999

Microstructure and release characteristics of the minipellet, a collagen-based drug delivery system for controlled release of protein drugs.

We have developed the minipellet, a matrix-type system for the sustained delivery of protein drugs using collagen as a biodegradable drug carrier. In this study, we analyzed the microstructure and release profile of the minipellet containing human serum albumin (HSA) as a model drug.The findings suggest that the minipellet has a structure in which collagen fibers are strongly oriented in the direction of extrusion from the nozzle in the molding process of the minipellet, and that HSA exists as fine particulate clusters which are homogeneously distributed among the collagen fibers in the minipellet. During release, the HSA clusters dissolve and HSA is retained within the collagen matrix as a solution.The results of release experiments indicate that HSA release from the minipellet is mainly controlled by diffusion in the collagen matrix, and that sustained release is achieved by the dense structure of the collagen matrix which is formed in the manufacture process. In addition, more detailed study suggests that the minipellet has unique directional release behavior caused by its microstructure.

Collagen↗

PubMed1993

Sustained delivery of retinoic acid from microspheres of biodegradable polymer in PVR.

PURPOSE: The aims were to obtain a controlled intravitreous release of retinoic acid (RA) by injecting drug loaded microspheres of biodegradable polymers and to study the potential use of this RA delivery system in a rabbit model of proliferative vitreoretinopathy (PVR). METHODS: The release of RA in vitro from 15 mg of 50-50 poly(DL-lactide-co-glycolide) (PLGA) in 1 ml of water at room temperature was measured with a spectrophotometer. In a rabbit model of PVR, 11 eyes were injected with 5 mg of microspheres containing 22 micrograms of RA/mg of PLGA, and seven control eyes were injected with microspheres of the same polymer that did not contain RA. In a third group, six rabbits were injected with 5 mg (n = 3) and 10 mg (n = 3) of microspheres containing RA. RESULTS: The initial concentration of RA was 20.8 micrograms/mg of PLGA. The release curve showed a fairly constant daily release of 7 micrograms/d for about 30 days. At 40 days, the release rate decreased to about 6 micrograms/d. After 40 days, 82.8% of the RA was released. Four of 11 treated rabbits (36%) and 7/7 (100%) controls showed tractional retinal detachment (TRD) (P < 0.01) after 2 months. Histopathologically, a mild, localized, foreign body reaction was observed. CONCLUSIONS: The authors obtained a sustained release of RA from PLGA microspheres in vitro for 40 days. A single injection of RA-loaded microspheres in suspension in BSS was effective in reducing the incidence of TRD after 2 months in a rabbit model of PVR.

Animals↗

PubMed1999

Intracranial delivery of recombinant nerve growth factor: release kinetics and protein distribution for three delivery systems.

PURPOSE: Three different polymeric delivery systems, composed of either poly(ethylene-co-vinyl acetate) (EVAc) or poly(lactide-co-glycolide) (PLGA), were used to administer recombinant human nerve growth factor (rhNGF) intracranially in rats. METHODS: The delivery systems were characterized with respect to release kinetics, both in the brain and in well-stirred buffer solutions. RESULTS: During incubation in buffered saline, the delivery systems released rhNGF in distinct patterns: sustained (EVAc), immediate (PLGA1) and delayed (PLGA2). One 10-mg delivery system was implanted in each rat and an ELISA technique was used to determine the amount of rhNGF in 1-mm coronal brain slices produced immediately after removal of the delivery system. High levels of rhNGF (as high as 60,000 ng in a brain slice of approximately 50 microliters) were recovered from the brain tissue at 1, 2, and 4 weeks after implantation. With all three delivery systems, the amount of rhNGF in each brain slice decreased exponentially with distance from the implant site: the distance over which concentration decreased by 10-fold was 2-3 mm for all delivery systems. When rhNGF release was moderate (10 to 200 ng rhNGF/day), the total amount of rhNGF in the brain increased linearly with release rate, suggesting an overall rate of rhNGF elimination of 0.4 hr-1 or a half-life of 1.7 hr. With higher release rates (500 to 50,000 ng rhNGF/day), total amounts of rhNGF in the brain were considerably higher than anticipated based on this rate of elimination. CONCLUSIONS: Polymeric controlled release can provide high, localized doses of rhNGF in the brain. All of the experimental data were consistent with penetration of rhNGF through the brain tissue with a diffusion coefficient approximately 8 x 10(-7) cm2/s, which is approximately 50% of the diffusion coefficient in water.

Animals↗

PubMed1991

Liquid chromatographic analysis of a potential polymeric-pendant drug delivery system for peptides. Application of high-performance size-exclusion chromatography, reversed-phase high-performance liquid chromatography and ion chromatography to the evaluation of biodegradable poly[(chloromethoxytrialanine methyl ester)phosphazenes].

A novel water-soluble polymer, poly[(chloromethoxytrialanine methyl ester)phosphazene] (poly-Tame), was characterized and evaluated using high-performance size-exclusion chromatography, gradient reversed-phase high-performance liquid chromatography and ion chromatography. These novel liquid chromatographic methods were validated for application to in vitro biodegradation experiments of poly-Tame in aqueous solutions. Results from method validation experiments are presented.

Biodegradation, Environmental↗

PubMed1996

Polymeric endoluminal gel paving: therapeutic hydrogel barriers and sustained drug delivery depots for local arterial wall biomanipulation.

Polymeric endoluminal paving is a process in which biodegradable polymers may be locally applied percutaneously to blood vessels as endoluminal liners, resurfacing or 'paving', the underlying vascular wall. Depending upon the type of polymer selected, endoluminal polymer layers may function as wall supports, barriers, therapeutic biomaterials or depots for local sustained drug delivery. In the original description of the paving process, that is solid paving, structural polymers were utilized. In this article a second form of paving--gel paving is described. In this process, hydrogel polymers are locally applied or polymerized on vascular endoluminal surfaces. Endoluminal hydrogel layers have been demonstrated to function as physical non-pharmacological barriers limiting cell and protein deposition and effectively reducing underlying arterial wall thrombogenicity. Hydrogel paving layers also provide a means for prolonged local arterial wall drug delivery. In this report an update on gel paving is provided. The overall process of polymeric endoluminal paving is initially reviewed. Gel paving and the rationale for this approach is described. Both thermoreversible as well as photopolymerizable PEG-lactide hydrogel paving systems are outlined. Recent experimental studies with gel paving examining polymer application, haemocompatability and endoluminal surface thromboprotection, effects on post-injury neointimal thickening and local drug delivery, are then reviewed. Finally, the role of gel paving in future approaches to vascular therapy is discussed.

Angioplasty↗

PubMed2000

Bioabsorbable polymer scaffolds for tissue engineering capable of sustained growth factor delivery.

Engineering new tissues utilizing cell transplantation on biodegradable polymer matrices is an attractive approach to treat patients suffering from the loss or dysfunction of a number of tissues and organs. The matrices must maintain structural integrity during the process of tissue formation, and promote the vascularization of the developing tissue. A number of molecules (angiogenic factors) have been identified that promote the formation of new vascular beds from endothelial cells present within tissues, and the localized, controlled delivery of these factors from a matrix may allow an enhanced vascularization of engineered tissues. We have developed a gas foaming polymer processing approach that allows the fabrication of three-dimensional porous matrices from bioabsorbable materials (e.g., copolymers of lactide and glycolide [PLG]) without the use of organic solvents or high temperatures. The effects of several processing parameters (e.g., gas type, polymer composition and molecular weight) on the process were studied. Several gases (CO(2), N(2), He) were utilized in the fabrication process, but only CO(2) resulted in the formation of highly porous, structurally intact matrices. Crystalline polymers (polylactide and polyglycolide) did not form porous matrices, while amorphous copolymers (50:50, 75:25, and 85:15 ratio of lactide:glycolide) foamed to yield matrices with porosity up to 95%. The mechanical properties of matrices were also regulated by the choice of PLG composition and molecular weight. Angiogenic factors (e.g., vascular endothelial growth factor) were subsequently incorporated into matrices during the fabrication process, and released in a controlled manner. Importantly, the released growth factor retains over 90% of its bioactivity. In summary, a promising system for the incorporation and delivery of angiogenic factors from three-dimensional, biodegradable polymer matrices has been developed, and the fabrication process allows incorporation under mild conditions.

Absorption↗

PubMed2003

HPMA copolymer delivery of chemotherapy and photodynamic therapy in ovarian cancer.

Our studies document a unique and unexpected advantage of the combination of HPMA copolymer bound doxorubicin with mesochlorin e6/photodynamic therapy in the treatment of ovarian cancer. Each drug's activity is individually enhanced when compared with free (low molecular weight) drugs, furthermore, in combination these HPMA copolymer bound agents act synergistically to create an unexpected biological effect. Figure 8 depicts the known activities of each agent which may play synergistic roles. HPMA copolymer-doxorubicin has been widely evaluated in preclinical and clinical studies. It demonstrates marked advantages over free doxorubicin: control of biodistribution and accumulation via molecular weight restrictions, biodegradability, minimal immunogenicity, subcellular localization, anticancer activity, enhanced permeability and retention, increased apoptosis, lipid peroxidation, DNA damage, and reduced nonspecific toxicity. Recent clinical trials in the UK provide "proof of principle" of the "enhanced permeability and retention effect" for solid tumors and the unique advantages of this novel drug delivery system for the treatment of ovarian cancer. With regards to photodynamic therapy using the photosensitizer mesochlorin e6, the preclinical evaluations thus far document: control of biodistribution and accumulation via molecular weight restrictions, biodegradability, subcellular localization, anticancer activity, enhanced permeability and retention, and reduced nonspecific toxicity. Ongoing microarray studies document unique cellular pathways and new pharmaceutical properties which are initiated by the HPMA copolymer delivery delivery of these agents, and predict an exciting future for this novel drug delivery system.

Antibiotics, Antineoplastic↗

PubMed1997

Treatment of osteomyelitis with a biodegradable antibiotic implant.

A biodegradable antibiotic implant was developed and evaluated in a localized osteomyelitic rabbit model. The biodegradable antibiotic implant was made of polylactic acid and poly(DL-lactide):co-glycolide combined with vancomycin. Localized rabbit tibial osteomyelitis was developed with Staphylococcus aureus. Infected rabbits were divided into eight groups, depending on treatment with or without debridement, systemic antibiotics, or biodegradable beads. After 4 weeks of therapy, the radiographs were obtained of the involved bones, which also were cultured for concentrations of Staphylococcus aureus per gram of bone. Treatment with antibiotic containing polylactic acid and poly(DL-lactide):co-glycolide beads, with and without systemic vancomycin, resulted in bone colony forming unit levels of 10(2.93) and 10(2.84) colony forming units per gram bone, respectively. These bacterial concentrations were approximately 100 times lower than those observed for all other treatment groups. A biodegradable antibiotic bead may provide extended bactericidal concentrations of antibiotics for the time needed to completely treat the particular orthopaedic infection and does not require the surgery needed to remove the polymethylmethacrylate beads.

Animals↗

PubMed1994

Successful antidote of multiple lethal infections using sustained delivery of difluoromethylornithine by means of ceramic drug delivery devices.

The objectives of this study were (1) to cure multiple infections of trypanosomiasis in rats by the sustained release of DFMO from biodegradable tricalcium phosphate (TCP) and aluminum-calcium-phosphorous oxide (ALCAP) delivery systems, and (2) to determine if the side effects associated with oral administration of DFMO can be avoided by using TCP and ALCAP capsules. Sixty-eight SD male albino rats (235-270 g) were divided randomly into five groups. Each rat in group I (n = 16) was implanted subcutaneously (s.c.) with four TCP capsules (two large TCP (L-TCP), one PLA-impregnated large TCP (IL-TCP) and one thin TCP capsule (TN-TCP)). Rats in group II (n = 16) were implanted s.c. with four ALCAP ceramics (two large ALCAP (L-ALCAP), one PLA-impregnated large ALCAP (IL-ALCAP) and one thin ALCAP capsule (TN-ALCAP)). Rats in groups III (n = 16), IV (n = 4) and V (n = 16) were left without implants. Rats in group III (n = 16) were given 4% (w/v) DFMO (pH 7) in drinking water at the day of inoculation and continued up to 7 days postinoculation. Rats in group IV (n = 4) served as a nontreated group. Rats in group V (n = 16) served as normal controls. The results showed that all rats implanted with with TCP or ALCAP implants had no intoxications symptoms or side effects such as diarrhea during the treatment period. In contrast, rats given DFMO in drinking water exhibited foul-smelling diarrhea during the treatment period. Microscopic evaluation of blood smears collected from rats receiving DFMO chemotherapy showed an occasional or limited number of stumpy shape (SS) trypanosomes. This study suggests that (1) ceramic drug delivery systems are capable of delivering DFMO in a sustained manner for two months, and were able to cure repeated infections of trypanosomiasis; (2) the use of ceramic implants avoided widely fluctuating, irregular levels of DFMO in the body by keeping sustained levels above minimal effective concentrations; (3) ceramic drug delivery systems provide a pharmacological potentiality for drugs such as DFMO which have been withheld from the market because of severe side effects when administered using conventional methods of drug administration; and (4) DFMO-filled ceramic devices can be implanted subcutaneously in animals that face a threat of lethal protozoal infections in highly infested areas of the world.

Administration, Oral↗