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PubMed1995

Synthetic delivery system for tuberculosis vaccines: immunological evaluation of the M. tuberculosis 38 kDa protein entrapped in biodegradable PLG microparticles.

Tuberculosis remains a major public health burden which could be ameliorated by effective and well-defined subunit vaccines, particularly because the protective efficacy of current M. bovis BCG vaccines is both unpredictable and variable. The immunodominant 38 kDa antigen from Mycobacterium tuberculosis was entrapped in biodegradable poly (DL-lactide co-glycolide) (PLG) microparticles which served as a delivery system. Both cellular and humoral immune responses were assessed and compared with those obtained after immunization with the 38 kDa protein emulsified in incomplete Freund's adjuvant (IFA). Vaccination of mice with a single dose of antigen-loaded microparticles resulted in specific IgG titres peaking after five weeks comparable to those achieved after vaccination with protein emulsified in incomplete Freund's adjuvant (IFA). T-cell responses were found to be superior to those induced with antigen/IFA. The T- and B-cell epitope specificities ad judged with synthetic peptides were identical following immunization with antigen in microparticles or IFA. Differences in adjuvanticity were revealed by measuring antigen-specific IgG1, IgG2a and antigen-induced IFN-gamma secretion in vitro: substantially higher titres of IgG2a were observed following immunization with antigen/microparticles than with 38 kDa protein/IFA. This was paralleled by a tenfold higher secretion of IFN-gamma in mice injected with antigen/microparticles. Reduction in colony-forming units was not consistent in mice immunized with 38 kDa protein entrapped in microparticles which were subsequently infected with live tubercle bacilli. Taken together these results indicate that biodegradable PLG microparticles constitute a favorable candidate vaccine delivery system worthy of further assessment in the quest to develop better and defined agents protecting against tuberculosis.

Amino Acid Sequence↗

PubMed2004

Biodegradable self-expanding poly-L/D-lactic acid vascular stent: a pilot study in canine and porcine iliac arteries.

PURPOSE: To report results of an in vivo pilot study to evaluate the biocompatibility and delivery system of a new biodegradable vascular stent and validate the study design. METHODS: Two self-expanding intravascular stents, a biodegradable poly-D/L-lactic acid (PLA) and a medical stainless steel stent (Wallstent) were implanted in the common iliac arteries of 2 postpuberal female pigs and 3 laboratory-bred beagle dogs. Specimens were harvested after 45 days in the dogs and 32 days in the pigs for histomorphometry of the stented iliac artery segments. Preliminary measurements were made to assess the reliability of the quantitative histomorphometric measurements before final measurements. RESULTS: Histomorphometry analyses showed that mean luminal diameter and area were decreased in the PLA stent group (1.97+/-0.48 mm and 14+/-6.4 mm2, respectively) compared to the control stent group (4.28+/-0.83 mm and 61+/-19 mm2, respectively). The intimal thickness was higher in the PLA stent group (0.65+/-0.07 mm) than in the control group (0.44+/-0.21 mm). The mean injury score was 0.19+/-0.12 in the PLA stent group and 0.78+/-0.39 in the controls. In the PLA stent group, the mean inflammation score was 1.46+/-0.78 compared to 0.58+/-0.40 in the control group. There were no differences observed between the animal models. CONCLUSIONS: The PLA stent showed increased neointimal formation and reduced patency during early follow-up. Mechanical properties of the new biodegradable vascular stents are still inadequate, and the stent and the delivery device require modifications. The study methods were assessed as reliable and reproducible.

Animals↗

PubMed2005

Colon targeted delivery systems: review of polysaccharides for encapsulation and delivery.

Colon-targeted delivery of bioactives has recently gained importance in addressing specific needs in the therapy of colon-based diseases. Many approaches have been attempted for the development of colon-specific delivery systems, with not much success in the past. Recent research into the utilization of the metabolic activity and the colonic microenvironment in the lower gastrointestinal tract has attained great value in the design of novel colon-targeted delivery systems based on natural biodegradable polymers. In the current article, special emphasis has been placed on polysaccharide systems, with minimal chemical modification, that have been exploitedfor colon targeting. These polysaccharide based encapsulation and targeted delivery systems are envisaged to have an immense potential for the development of food/nutraceutical formulations for colon-based diseases, including colorectal cancer.

Alginates↗

PubMed2002

Recent advances in the stabilization of proteins encapsulated in injectable PLGA delivery systems.

Injectable controlled-release systems based on biodegradable copolymers of lactic and glycolic acids (PLGAs) have become widely used for delivery of protein therapeutics and vaccine antigens. Over the last five years, great strides have been made toward overcoming the difficulty of stabilizing PLGA-encapsulated proteins. In addition to stabilizing proteins during encapsulation with anhydrous methods, two approaches have proven highly effective to stabilize proteins during 1-month release incubation under physiological conditions: protein complexation with zinc and control of PLGA microclimate pH with antacid excipients. Described here are recent advances in the stabilization of proteins encapsulated in PLGA delivery systems.

Biocompatible Materials↗

PubMed2006

Novel drug delivery systems in pain therapy.

Pain is an unpleasant sensory experience resulting from damage to bodily tissues. It is considered a significant public health problem because it affects 1/5 of the world population and causes loss of great amounts of money. Pain reflects a mixture of pathological, psychological and genetic conditions that need deep understanding to be efficiently treated. If under-treated, pain results in serious immune and metabolic problems. Pain management faces many problems that limit its control. For instance, efficiency of pain killers is limited, pain killers give rise to serious side effects and inability of drug administration methods to help in pain control. Technology can overcome some of these problems and the introduction of implantable controlled drug delivery systems (CDDS), manufactured from biodegradable materials, offers a solution. Implantable CDDS provide good level of pain control, as they continuously provide drug, reduce side effects and improve patients' compliance. Biodegradable type of implantable CDDS are polymer based devices that are fabricated to locally deliver drugs in a pre-designed manner. They are currently a focus of research in the field of pain therapy in order to explore their chance to offer an alternative to the conventional methods for drug delivery. This paper aims to highlight the dimensions of pain issue and to overview the basics of drug release from polymers used for CDDS in pain management. In addition, it discusses the recent advances in the technologically designed drug delivery systems in the field of pain medicine and their clinical applications. Future perspectives are also presented.

Analgesics↗

PubMed2005

Gelatin nanoparticles as a new and simple gene delivery system.

PURPOSE: The aim of this study was to evaluate cationized gelatin nanoparticles as biodegradable and low cell toxic alternative carrier to existing DNA delivery systems. METHODS: Native gelatin nanoparticles were produced using a two step desolvation method. In order to bind DNA by electrostatic interactions onto the surface of the particles, the quaternary amine cholamine was covalently coupled to the particles. The modified nanoparticles were loaded with different amounts of plasmid in varying buffers and compared to polyethyleneimine-DNA complexes (PEI polyplexes) as gold standard. Transfection ability of the loaded nanoparticles was tested on B16 F10 cells. Additionally, the cell toxicity of the formulations was monitored. RESULTS: Different setups resulted in efficient gene delivery displayed by exponential increase of gene expression. The gene expression itself occurred with a certain delay after transfection. In contrast to PEI polyplexes, cationized gelatin nanoparticles almost did not show any significant cytotoxic effects. CONCLUSIONS: Cationized gelatin nanoparticles have shown the potential of being a new effective carrier for nonviral gene delivery. The major benefit of gelatin nanoparticles is not only the very low cell toxicity, but also their simple production combined with low costs and multiple modification opportunities offered by the matrix molecule.

Animals↗

PubMed2004

Allergen-loaded biodegradable poly(D,L-lactic-co-glycolic) acid nanoparticles down-regulate an ongoing Th2 response in the BALB/c mouse model.

BACKGROUND AND OBJECTIVE: Biocompatible and biodegradable microparticles have gained interest as antigen delivery systems during the recent years. We investigated whether biodegradable poly(d,l-lactic-co-glycolic) acid (PLGA) nanospheres could be used as allergen vehicles for few-shot therapy of type I allergy. METHODS: The major birch pollen allergen Bet v 1 was encapsulated in PLGA nanospheres (PLGA-Bet v 1). We examined the antigenicity and the immune response to PLGA-Bet v 1 in a BALB/c mouse model. RESULTS: The antigenicity of Bet v 1 was largely unaffected by PLGA entrapment. When BALB/c mice were immunized subcutaneously with PLGA-Bet v 1, they formed allergen-specific IgG antibodies, but did not develop hypersensitivity to Bet v 1, as shown by type I skin tests. To evaluate their therapeutic potential, PLGA-Bet v 1 with or without Al(OH)3 or non-entrapped Bet v 1 with Al(OH)3 were used for single-shot treatment of sensitized mice. Both groups treated with PLGA-Bet v 1 developed high levels of Bet v 1-specific IgG2a antibodies (P<0.01), whereas IgG1 levels decreased significantly (P<0.01). Moreover, T cells from mice treated with PLGA-Bet v 1 showed IFN-gamma and IL-10 production. The synthesis of these cytokines was enhanced in the groups where Al(OH)3 had been added to the vaccine formulation. CONCLUSION: Allergen-loaded PLGA nanoparticles modulate an ongoing Th2 response in the BALB/c mouse model, as demonstrated by down-regulation of IgG1 and production of IFN-gamma and IL-10. Our data strongly suggest that PLGA nanospheres can advantageously be used for formulations of allergen extracts or allergen derivatives for the few-shot treatment of type I allergy.

Allergens↗

PubMed1993

Bone induction and bone repair by composites of bone morphogenetic protein and biodegradable synthetic polymers.

We developed adequate delivery systems for bone morphogenetic protein (BMP) to express its bone-inducing activity by combining it with biodegradable synthetic polymers, these causing no unfavorable tissue reaction or anti-BMP effect. Their efficacy was tested for ectopic bone formation in mice and reconstruction of large segmental bone defects of the tibiae in rabbits. Composites of semipurified BMP and polylactic acid--polyethylene glycol block copolymer (PLA-PEG), and composites of BMP, PLA-PEG and lactic acid--glycolic acid copolymer (PLGA) were implanted under the fasciae of the dorsal muscles of mice. Three weeks after implantation, both the BMP/PLA-PEG and BMP/PLA-PEG/PLGA composites were completely absorbed and replaced by newly induced bone with hematopoietic marrow. Because the BMP/PLA-PEG composite is a viscous semiliquid and the BMP/PLA-PEG/PLGA composite is a plastic and moldable, the former can be used as an injectable bone-inducing material and the latter as a plastic mold. The BMP/PLA-PEG/PLGA composites were implanted in large segmental bone defects in the tibiae in rabbits. Twelve weeks after implantation, the bone defect was completely restored by a newly formed bone mass of the original thickness and structure.

Animals↗

PubMed2004

Celecoxib incorporated chitosan microspheres: in vitro and in vivo evaluation.

Recently, considerable interest has been focussed on the use of biodegradable polymers for specialized applications such as controlled release of drug formulations; meanwhile, microsphere drug delivery systems using various kinds of biodegradable polymers have been studied extensively during the past two decades. In the present investigation, it was aimed to prepare microsphere formulations of celecoxib using a natural polymer, chitosan as a carrier for intra-articular administration to extend the retention of the drug in the knee joint. Microsphere formulations were evaluated in vitro for particle size, entrapment efficiency, surface morphology and in vitro drug release. For in vivo studies, (99m)Technetium- labeled glutathione was used as a radiopharmaceutical to demonstrate arthritic lesions by gamma scintigraphy. Evaluation of arthritic lesions post therapy in rats showed a significant difference (P < 0.005) in the group treated with celecoxib solution compared to the group treated with celecoxib loaded chitosan microspheres.

Animals↗

PubMed1995

Aspects of the design and delivery of microparticles for vaccine applications.

Mortality and morbidity data continue to indicate there is a compelling need for the derivation of a new generation of vaccine delivery systems that can be usefully applied via injection and also mucosally. One technology that has potential for design as an effective vaccine delivery system is the formulation of biodegradable microparticles from the polymers and poly lactide co-glycolide (PLGA) in particular. The potential advantages of the delivery of vaccines within such microparticles is discussed. The potential for eliciting and optimising immunity after the mucosal delivery of biodegradable microparticles is also discussed.

Administration, Inhalation↗

PubMed1997

Microencapsulation of antigens using biodegradable polyesters: facts and phantasies.

New vaccination approaches and new delivery systems have been subject of intensive research activities recently. Controlled release vaccine delivery systems depend on the microencapsulation of antigens into biodegradable polymers, yielding small spherical polymeric particles, in the size range of 1-100 microns. By manipulating the micromorphology of the microparticles and degradation properties of the polymer either continuous or pulsatile release patterns can be adjusted. As biodegradable polymers mainly copolymers of lactic- and glycolic acid have been utilized, since these materials are known to be biocompatible and non-toxic. Apart from modulation of antigen release, an improvement of the adjuvant effect and an increase of in vitro (shelf-life) and in vivo stability of the antigen are issues of general interest with respect to parenteral vaccine delivery systems. Using different microparticles that release antigens in a pulsatile pattern at predetermined timepoints one hopes to induce protective immunity by a single administration of the vaccine delivery system. Using tetanus toxoid (TT) as a model antigen we have examined the stability during preparation, in vitro release and storage of TT microparticles. TT is a complex protein mixture sensitive to changes in pH conditions (pH < 5) and to thermal stress. TT microparticles can be prepared by a W/O/W double emulsion technique with satisfactory encapsulation efficiencies in good yields. In accordance with other investigators we observe an adjuvant effect of TT microspheres in mice upon sc administration leading to a long-lasting antibody response. In challenge experiments we could demonstrate a protective effect. The issue of an ideal release pattern remains open, since a boosting of the antibody titers during the bioerosion of the TT microspheres was not observed, possibly due to desactivation of TT in the degrading microspheres.

Animals↗

PubMed2000

Diclofenac sodium incorporated PLGA (50:50) microspheres: formulation considerations and in vitro/in vivo evaluation.

Recently, considerable interest has been focused on the use of biodegradable polymers for specialized applications such as controlled release of drug formulations; meanwhile, microsphere drug-delivery systems using various kinds of biodegradable polymers have been studied extensively during the past two decades. Poly (lactide-co-glycolide) (PLGA) polymers have been proven to be excellent drug carriers for microparticulate systems due to their advantages, e.g. biocompatibility and regulatory approval. The administration of nonsteroidal anti-inflammatory drugs (NSAIDs) into the intra-articular cavity in patients with chronic inflammatory disease is complicated due to the short duration of effect. In the present study, controlled-release parenteral formulations of diclofenac sodium (DS), a commonly used NSAID, were prepared for intra-articular administration, and evaluated in vitro for particle size, yield, drug loading, surface morphology and release characteristics. For in vivo studies, Technetium-99m labelled polyclonal human immunogammaglobulin (99m Tc-HIG) was used as the radiopharmaceutical to demonstrate arthritic lesions by gamma scintigraphy. Evaluation of arthritic lesions post-therapy in rabbits showed no significant difference in the group treated with PLGA (50:50) (mw 34000) DS microspheres compared to control groups.

Animals↗

PubMed2001

Biodegradable scleral plugs for vitreoretinal drug delivery.

Intraocular controlled drug release is one way to facilitate drug efficacy and decrease side effects that occur with systemic administration. Vitreoretinal drug delivery with the biodegradable scleral plug has been investigated. The scleral plug, which is made of biodegradable polymers and drugs, can be implanted at the pars plana using a simple procedure, and it gradually releases effective doses of drugs with polymer biodegradation for several months. The release profiles of the drugs were dependent on the kind of polymers used, their molecular weights, and the amount of drug in the plug. The plugs are effective for treating vitreoretinal diseases such as proliferative vitreoretinopathy. The implantation site was replaced with connective tissue. Electroretinography and histologic studies revealed little retinal toxicity. This implantable scleral plug was supposed to be advantageous for diseases such as cytomegalovirus retinitis that respond to repeated intravitreal injections and for vitreoretinal disorders that require vitrectomy.

Animals↗

PubMed2000

The degradation, swelling and erosion properties of biodegradable implants prepared by extrusion or compression moulding of poly(lactide-co-glycolide) and ABA triblock copolymers.

In the design of parenteral delivery systems the modulation of the biodegradation of a polymer matrix represents a promising strategy to control drug release. We have investigated the degradation of ABA triblock copolymers, consisting of poly(lactide-co-glycolide) A-blocks and poly(oxyethylene) B-blocks, and PLG, poly(lactide-co-glycolide), with respect to swelling behaviour, molecular weight loss and polymer erosion. Implants were prepared by either compression moulding or extrusion using a laboratory ram extruder. Insertion of an elastoplastic B-block did not lower the processing temperature, but the entanglement of the polymer chains was significantly reduced as can be seen from the diameters of the extruded rods. The swelling of the rods showed a volume extension of 130% for an ABA containing 50% PEO and 20% for an ABA containing 20% PEO. Using 1H-NMR it was found that protons in the B-blocks of the swollen ABA copolymers were mobile, while the A-blocks remained rigid during incubation. The analysis of the pH inside ABA rods using electron paramagnetic resonance, EPR, gave a pH of 5.2 after incubation with a subsequent increase to pH 6.0 during the first day, approaching the pH of the medium after nearly 33 d. Acidic degradation products did not accumulate inside the ABA rods. Degradation and erosion started immediately upon incubation. By contrast, PLG rods showed the typical profile of degradation and erosion. In this case, the influence of the geometry of the device was insignificant. Consequently, ABA triblock copolymers may widen the spectrum of parenteral drug delivery with regard to release of pH-sensitive drugs as well as erosion-controlled release kinetics.

Biodegradation, Environmental↗

PubMed2004

Development and characterization of biodegradable chitosan films for local delivery of Paclitaxel.

Intratumoral and local drug delivery strategies have gained momentum recently as a promising modality in cancer therapy. In order to deliver paclitaxel at the tumor site in therapeutically relevant concentrations, chitosan films were fabricated. Paclitaxel could be loaded at 31% wt/wt in films, which were translucent and flexible. Physicochemical characterization of paclitaxel via thermal, spectroscopic, x-ray diffraction, and electron microscopy techniques revealed information on solid-state properties of paclitaxel as well as chitosan in films. While chitosan was in amorphous form, paclitaxel seemed to be present in both amorphous and crystalline forms in film. The polymeric dispersion of paclitaxel in poloxamer formed fibrous structures generating discontinuities in the film matrix, thereby leading to the introduction of perturbations in the packing arrangement of polymer chains. These films released only 10% to 15% of loaded paclitaxel by a burst effect under in vitro testing conditions, with lysozyme having no effect on the release. However, films softened after implantation in mice and lost integrity over time. The implantable delivery system is not only biodegradable but also well tolerated in vivo and hence, biocompatible as revealed by histological studies. The lack of formulation-induced local inflammatory responses of paclitaxel chitosan films suggests a new paradigm for localized chemotherapy based on implantable systems.

Animals↗

PubMed2003

Local bone formation by injection of recombinant human bone morphogenetic protein-2 contained in polymer carriers.

The regenerating potential of human bone is limited. The repair of large bone defects often associated with bone tumor resections is not observed, and nonunion or delayed union of bone is a serious problem for fracture treatment. In these cases, autogeneic or allogeneic bone grafting has been routinely indicated, but these approaches require invasive surgical procedures. An alternative approach described in this paper involves the injection of bone morphogenetic proteins (BMPs) in a polymeric delivery system. We demonstrate that synthetic biodegradable polymers, poly-D,L-lactic acid-polyethylene glycol (PLA-PEG) block copolymers, which exhibit an exquisite temperature-dependent liquid-semisolid transition, work well as an injectable delivery system for recombinant human (rh) BMP-2. The thermosensitive property of the PLA-PEG/rhBMP-2 composite is permissive to percutaneous injection when heated. The fluidity of this composite decreases as it cools down to body temperature and the resultant semisolid form provides a scaffold for bone formation through the gradual local release of the rhBMP-2. This new type of injectable osteoinductive material will enable a less invasive approach to surgeries involving the restoration or repair of bone tissues.

Animals↗

PubMed1989

In vivo characteristics of low molecular weight copoly (D,L-lactic acid) formulations with controlled release of LH-RH agonist.

Amorphous and crystalline copolymers with a relatively low molecular weight of 1800 were synthesized by direct copolycondensation of D-lactic acid and L-lactic acid in the absence of a catalyst, to evaluate their in vivo capabilities as biodegradable carriers for drug delivery systems. A luteinizing hormone-releasing hormone agonist, des-Gly10-(D-Leu6)-LH-RH ethylamide, was incorporated in a fine cylindrical copolymer formulation, under melt-pressing technique, a mild heat-pressure condition. This formulation was implanted subcutaneously in the back of male rats. The rate of in vivo degradation of amorphous copolymer was much faster than that of crystalline copolymer. Contrary to this tendency, the in vivo release of the drug from this amorphous formulation was held constant over a longer period, compared with the crystalline formulation. This can be closely related to the difference in dispersion of the drug in the formulation.

Animals↗

PubMed2002

Radioprotection, pharmacokinetic and behavioural studies in mouse implanted with biodegradable drug (amifostine) pellets.

PURPOSE: We evaluated the use of a subcutaneously (s.c.) implantable, biodegradable pellet as a drug delivery system for the radioprotector amifostine. MATERIALS AND METHODS: Mice were implanted s.c. with either the custom-made biodegradable amifostine drug pellet or the placebo pellet without amifostine, exposed to cobalt-60 gamma-radiation (bilateral, 1 Gy min(-1), 7-16 Gy), and the 30-day survival rate was monitored. The non-irradiated mouse was used for pharmacokinetic and behavioural tests. RESULTS: Significant radioprotection (85-95% survival) at 10 Gy was observed in the three-amifostine pellet implanted group 3-5 h after implantation. LD50/30 was 7.97, 8.74 and 16.64 Gy for the control, three-placebo pellet (dose reduction factor, DRF=1.10, p<0.01), and three-amifostine pellet (DRF=1.79, p<0.01) groups respectively in mouse exposed to radiation 2h after implantation. Radioprotection at 12 Gy was observed up to 4h after s.c. amifostine administration and up to 3h after implantation. Pharmacokinetic data revealed that the three-amifostine pellet group had sustained blood WR-1065 levels at 2 h after implantation, in contrast to the reported sharp peak at 30 min for s.c. administration. Although locomotor activity was significantly reduced (p<0.01) in the amifostine pellet group, the onset of the locomotor decrement was delayed as compared with groups that received 400 and 750 mg kg(-1) s.c. amifostine. CONCLUSIONS: Amifostine in biodegradable implant was effective. The radioprotection observed was comparable between conventional s.c. administration of the drug and implantation. Pharmacokinetic data and locomotor activity suggest that the implantation was beneficial though radioprotection data warrants formulation improvements in implants.

Amifostine↗