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PubMed2000

Biodegradable alginate antibiotic beads.

The authors investigated the poly-L-lysine-coated alginate beads as an antibiotic delivery system for the treatment of various surgical infections. The sodium alginate was mixed with vancomycin, coated with poly-L-lysine, and lyophilized to form five types of the biodegradable antibiotic beads. Type I, 2.5% alginate, nonpoly-L-lysine coated and nonlyophilized; Type II, 2.5% alginate, poly-L-lysine coated but nonlyophilized; Type III, 2.5% alginate, poly-L-lysine coated and lyophilized; Type IV, 5% alginate, poly-L-lysine coated and lyophilized; and Type V, 7.5% alginate, poly-L-lysine coated and lyophilized. Cytotoxicity of the alginate beads to fibroblasts and HeLa cells was evaluated by the MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide] colorimetric assay. A study of in vitro elution of vancomycin of the alginate antibiotic beads was performed. The results suggested that the alginate antibiotic beads present no obvious toxic risk to their use as a drug delivery system. The concentration of vancomycin in these five types of beads was well above the breakpoint sensitivity concentration (the antibiotic concentration at the transition point between bacterial killing and resistance to the antibiotic) for 9,11,12, 14, and 17 days respectively. The release was most marked during the first 3 days. The duration of antibiotic release was prolonged by using techniques of poly-L-lysine coating, lyophilization, and by increasing the content of alginate. This study offers a biodegradable delivery system of antibiotics to treat various surgical infections.

Alginates↗

PubMed2002

In vivo evaluation of novel hyaluronan/chitosan microparticulate delivery systems for the nasal delivery of gentamicin in rabbits.

Biodegradable microparticles containing gentamicin were prepared using chitosan hydroglutamate (CH), hyaluronic acid (HA) and a combination of both polymers by a solvent evaporation method. These formulations were administered nasally via an insufflator. Gentamicin was also administered nasally into rabbits as a solution and powder (a physical mixture of gentamicin and lactose), intravenously (IV) and intramuscularly (IM). The resultant serum levels of gentamicin were determined by Fluorescence Polarisation Immunoassay (FPIA). The bioavailability of gentamicin was poor when administered as a nasal solution (1.1%) and dry powder (2.1%) when compared with IV. However, the microparticulate systems composed of CH and HA/CH considerably enhanced the bioavailability of gentamicin (31.4 and 42.9%, respectively,) with HA microparticles inducing a less significant enhancement (23.3%). Previous in vitro dissolution and frog palate studies indicated that these microparticulate formulations were all mucoadhesive and demonstrated prolonged drug release. Such findings were translated into an increase in the bioavailability of gentamicin when compared with a simple nasal solution in vivo. When HA and CH were combined in the HA/CH formulation, the polymers appeared to improve the absorption of incorporated gentamicin synergistically in comparison to the individual polymers, suggesting a promising nasal delivery system.

Adjuvants, Pharmaceutic↗

PubMed1995

Biodegradable microspheres in drug delivery.

General aspects of biodegradable microspheres prepared from natural and synthesized polymers used in drug delivery systems are reviewed first from various viewpoints: characteristics of biodegradable polymers (physicochemical properties, bioerosion mechanism, biocompatibility), preparation method for the microspheres, drug release from parenteral products and briefly nonparenteral products. The relationship between release pattern and pharmacological activity of therapeutic peptides and proteins and rational controlled release design are also discussed. In the latter half, successful sustained release depot formulations of peptides, leuprorelin acetate, and thyrotropin-releasing hormone (TRH), utilizing poly(lactic acid) (PLA) and poly(lactic/glycolic acid) (PLGA) microspheres are reviewed with respect to preparation, drug release, biocompatibility, pharmacological effects, and results of clinical studies. Thereafter, studies on antitumor therapy by chemoembolization using PLGA microspheres containing an angiogenesis inhibitor (TNP-470) are described as an example of targeted drug delivery with biodegradable microspheres.

Animals↗

PubMed1999

Induction of cytotoxic T-cell responses following oral immunization with synthetic peptides encapsulated in PLG microparticles.

CTL responses play a critical role in clearing viral infections. We have investigated the potential of poly(lactide-co-glycolide) (PLG) microparticles as an oral delivery system for peptides representing CTL epitopes from measles virus nucleoprotein. Oral administration of CTL epitopes encapsulated in 50:50 PLG microparticles, resulted in vivo priming of splenic peptide-specific CTL responses. However, the observed CTL lysis was low and cofeeding of encapsulated peptide with cholera toxin as a mucosal adjuvant did not result in any significant enhancement of the observed CTL responses. The pronounced immunostimulatory effect of microparticles, combined with their excellent tissue compatibility and biodegradability makes them a valuable delivery system for synthetic peptide immunogens. However, further work is needed to improve their efficiency via the oral route.

Administration, Oral↗

PubMed2001

Induction of systemic and mucosal immune response in cattle by intranasal administration of pig serum albumin in alginate microparticles.

Biodegradable microparticles are an efficient mucosal delivery system that protect antigens from the harsh mucosal environment and facilitate their uptake by M cells at the epithelium of mucosal-associated lymphoid tissue. In this study, we determined the systemic and mucosal immune response in calves following intranasal and oral immunization with pig serum albumin (PSA) encapsulated in alginate microparticles. The size of the particles ranged from 1 to 50 microm in diameter, with 95% of the particles being smaller than 5 microm. High levels of anti-PSA IgG1 antibodies were found in the serum, nasal secretions, and to a less extent in saliva of calves vaccinated intranasally, but not orally, with PSA-microparticles. There was no significant increase of PSA-specific IgA. A weak lymphocyte proliferative immune response was observed in peripheral blood mononuclear cells (PBMCs), and few anti-PSA antibody-secreting cells (ASC) were detected in the blood of calves immunized intranasally. The combined systemic and mucosal response observed in intranasally immunized animals may be attributed to the wide variation in the size of the alginate microparticles, with smaller particles translocating to regional lymph nodes and inducing a systemic immune response, and larger particles being retained in the NALT and inducing a mucosal immune response. The procedure presented here may be useful as an intranasal vaccine against respiratory diseases in cattle.

Administration, Intranasal↗

PubMed1999

Biodegradable implants from poly-(alpha-hydroxy acid) polymers for isoniazid delivery.

SETTING: In vitro and in vivo study of an isoniazid (INH) drug delivery system. OBJECTIVE: To develop a system for the treatment of tuberculosis using a subcutaneous polymer implant with a large drug load released slowly over a long period. INH delivery by biodegradable poly-(alpha-hydroxy acid) polymers was evaluated using ground polymer and compression molded implants. DESIGN: Rate of drug release and structural stability of the implant in an aqueous environment were measured, as were in vivo evaluations of the duration of measurable levels of INH in serum and urine. RESULTS: Factors that influenced the suitability of an implant in an in vitro system included polymer molecular weight and crystallinity, polymer and drug particle size, drug loading dose, and press temperature and pressure. The implant characteristics that most closely approached optimal conditions include a polymer of 100% L-lactide with low intrinsic viscosity, polymer particle size <75 micron, and INH particle = 126-180 micron, INH loading dose not to exceed 46%, and press conditions of 70 degrees C and 345000 kPa. Studies of subcutaneous implants in rabbits and baboons show that INH is released from the implant for 15 to 26 weeks. CONCLUSIONS: An INH-containing polymer was developed that was structurally stable in an aqueous environment and that released INH over a period of at least 15 weeks. Studies with infected animals will be necessary to determine the dose required for prophylaxis and treatment of active disease.

Animals↗

PubMed1997

Protein delivery from biodegradable microspheres.

The key components to the successful development of a biodegradable microsphere formulation for the delivery of proteins are polymer chemistry, engineering, and protein stability. These areas are intricately related and require a thorough investigation prior to embarking on the encapsulation of proteins. While each of these components is important for the development of a biodegradable microsphere formulation for protein delivery, other critical issues should also be considered. In particular, preclinical studies in the appropriate animal model are usually necessary to assess the potential feasibility of a continuous-release dosage form. These studies should be performed at the earliest possible stage of development to validate the feasibility of a controlled release formulation. After the utility of a controlled release formulation has been demonstrated, the polymer matrix should be chosen and bench-scale production of microspheres initiated. The only polymers presently approved for human use for controlled delivery are the polylactides [poly(lactic acid), poly(glycolic acid), and poly(lactic-coglycolic) acid]. These polymers require multiphase processes involving several steps to produce microspheres containing the desired protein. A thorough review of previous work on encapsulation with these polymers should provide some insight into conditions to be assessed in developing a process. Once a process is chosen, it must be optimized to provide the highest possible yield of microspheres with the desired characteristics (e.g., loading, release, size, etc.). Finally, the final aseptic process should be validated and methods generated to assess the final product. The clinical studies should then start upon approval of the IND application. In the future, the biotechnology industry, and the pharmaceutical industry in general, will be seeking new methods to improve the delivery of therapeutic agents such as proteins and peptides. Formulations like biodegradable microspheres significantly reduce health-care costs since fewer administrations are needed, and they provide a competitive advantage in markets with several competing products (e.g., LHRH agonist market). Further, many new indications such as neurological diseases may require a long-term delivery system. The future success of biodegradable microsphere formulations will primarily depend on the commitment of the pharmaceutical and biotechnology industries to the development of this technology.

AIDS Vaccines↗

PubMedDate not supplied

Iodo-2'-deoxyuridine (IUdR) and 125IUdR loaded biodegradable microspheres for controlled delivery to the brain.

The aim of this work was to develop sustained local release systems for radioiodinated iodo-2'-deoxyuridine (125IUdR) from biodegradable polymeric microspheres to facilitate the controlled delivery of 125IUdR to brain tumours. The selective uptake of IUdR into the cell nucleus results in cell disruption over the short range of the low energy Auger electrons. The biodegradable microspheres can be precisely implanted in the brain by stereotactic techniques and the IUdR within the microspheres is protected from degradation and thus a sustained source of radiolabelled IUdR is available in the vicinity of the residual tumour cells. Poly(lactic-co-glycolic acid), PLGA (85:15), microspheres containing cold IUdR and the Auger-electron emitter 125I, as 125IUdR were prepared using the O/W, O/O and W/O/W emulsion-solvent evaporation methods. The W/O/W emulsion method was most effective in achieving good drug loading with the use of bovine plasma in the internal water phase. Also effective in improving the drug loading was the use of 20% acetone in the dichloromethane and the presence of Span 40 in the organic phase. Electrolytes (NaCl and IUdR) in the external aqueous phase also improved drug loading. After an initial rapid release from the microspheres, a sustained release was observed over 15 days for the 'cold' IUdR. The sustained release portions of the release curves showed Higuchi (t1/2), diffusion controlled release kinetics. The radiolabelled IUdR microspheres showed a burst release effect of 30-40% followed by a sustained release over 35 days.

Antimetabolites↗

PubMed1981

Development of drug delivery systems for use in treatment of narcotic addiction.

The long term goal of the NIDA narcotic antagonist program of developing an implantable, biodegradable, naltrexone/PLGA matrix system which will sustain the delivery of naltrexone to biological systems for one month has been achieved. The dosage forms which provide the desired delivery characteristics are 1.5 mm diameter beads composed of 70% by weight naltrexone base in 40,000 molecular weight, 90L/10G poly (L(+)-lactic-co-glycolic acid). Other dosage forms, including 1.5 mm diameter rods which provide 6 months' naltrexone release, finely divided injectable powders which provide up to 30 days' naltrexone release, and 1.5 mm diameter rods which provide 2 weeks' sustained delivery of morphine, have also been investigated. In vitro and in vivo release rates have been determined by measuring chemical concentrations in pH 7 buffer solution and urine, respectively. In vivo efficacy of naltrexone sustained delivery devices has been measured by direct challenge with morphine (Dewey-Harris mouse tail-flick test) and inhibition of morphine self-administration in monkeys. Good Manufacturing Practices documentation has been developed and used to produce a large batch of the 1.5 mm diameter naltrexone bead dosage forms at an FDA-registered pharmaceutical manufacturer. These beads, produced at the University of North Carolina School of Pharmacy, are awaiting use in human clinical trials.

Animals↗

PubMed2005

Potentiation of the activity of bone morphogenetic protein-2 in bone regeneration by a PLA-PEG/hydroxyapatite composite.

Bone morphogenetic proteins (BMPs) are biologically active molecules capable of inducing new bone formation, and show potential for clinical use in bone defect repair. However, an ideal system for delivering BMPs that can potentiate their bone-inducing ability and provide initial mechanical strength and scaffold for bone ingrowth has not yet been developed. In this study, to construct a carrier/scaffold system for BMPs, we combined two biomaterials: interconnected-porous calcium hydroxyapatite ceramics (IP-CHA), and the synthetic biodegradable polymer poly D,L,-lactic acid-polyethyleneglycol block co-polymer (PLA-PEG). We used a rabbit radii model to evaluate the bone-regenerating efficacy of rhBMP-2/PLA-PEG/IP-CHA composite. At 8 weeks after implantation, all bone defects in groups treated with 5 or 20 microg of BMP were completely repaired with sufficient strength. Furthermore, using this carrier scaffold system, we reduced the amount of BMP necessary for such results to about a tenth of the amount needed in previous studies, probably due to the superior osteoconduction ability of IP-CHA and the optimal drug delivery system provided by PLA-PEG, inducing new bone formation in the interconnected pores. The present findings indicate that the synthetic biodegradable polymer/IP-CHA composite is an excellent combination carrier/scaffold delivery system for rhBMP-2, and that it strongly promotes the clinical effects of rhBMP-2 in bone tissue regeneration.

Animals↗

PubMedDate not supplied

Chitosan-based particles as controlled drug delivery systems.

Chitosan, a natural-based polymer obtained by alkaline deacetylation of chitin, is nontoxic, biocompatible, and biodegradable. These properties make chitosan a good candidate for conventional and novel drug delivery systems. This article reviews the approaches aimed to associate bioactive molecules to chitosan in the form of colloidal structures and analyzes the evidence of their efficacy in improving the transport of the associated molecule through mucosae and epithelia. Chitosan forms colloidal particles and entraps bioactive molecules through a number of mechanisms, including chemical crosslinking, ionic crosslinking, and ionic complexation. A possible alternative of chitosan by the chemical modification also has been useful for the association of bioactive molecules to polymer and controlling the drug release profile. Because of the high affinity of chitosan for cell membranes, it has been used as a coating agent for liposome formulations. This review also examines the advances in the application of chitosan and its derivatives to nonviral gene delivery and gives an overview of transfection studies that use chitosan as a transfection agent. From the studies reviewed, we concluded that chitosan and its derivatives are promising materials for controlled drug and nonviral gene delivery.

Chitosan↗

PubMed1987

Prevention of peritoneal adhesions in the rat with sustained intraperitoneal dexamethasone delivered by a novel therapeutic system.

The rat caecal crush model for the production of intraperitoneal adhesions was optimized with respect to an objective adhesion grading system based on the determination of the incidence of adhesions and the caecal adherent surface area. Intraperitoneal saline solution given before closure of the peritoneum significantly reduced the severity but not the incidence of adhesions. The addition of dexamethasone crystal suspension led to somewhat lower incidence of adhesions but the mean adherent surface area values were not different from the saline regimen. However, sustained release of dexamethasone by use of intraperitoneal biodegradable poly(lactide-co-glycolide) microparticles as a novel therapeutic system further reduced both the incidence and the severity of adhesions. Despite of the differences in therapeutic effects glucocorticoid-associated local and systemic adverse effects were similar in both regimens. As effective adhesion prophylaxis with glucocorticoids appears to be a balance between benefit and adverse reactions, optimal drug delivery is mandatory. The novel biodegradable therapeutic system is superior to the intraperitoneal crystal suspension regimen in the rat and should be tested further in clinical trials.

Animals↗

PubMed2006

A biodegradable poly(ester amine) based on polycaprolactone and polyethylenimine as a gene carrier.

The aim of research was to develop and optimize delivery systems for plasmid DNA (pDNA) based on biodegradable polymers, in particular, poly(ester amine)s (PEAs), suitable for non-viral gene therapy. Poly(ester amine)s were successfully synthesized by Michael addition reaction between polycaprolactone (PCL) diacrylate and low molecular weight polyethylenimine (PEI). PEA/DNA complexes showed effective and stable DNA condensation with the particle sizes below 200nm, implicating its potential for intracellular delivery. PEAs showed controlled degradation and were essentially non-toxic in all three cells (293T: Human kidney carcinoma, HepG2: Human hepatoblastoma and HeLa: Human cervix epithelial carcinoma cell lines) at higher doses in contrast to PEI 25K. PEAs also revealed much higher transfection efficiencies in three cell lines as compared to PEI 25K. The highest reporter gene expression was observed for PCL/PEI-1.2 (MW 1200) complex having transfection efficiency 15-25 folds higher than PEI 25K in vitro. Also PEA/DNA complexes successfully transfected cells in vivo after aerosol administration than PEI 25K. These PEAs can be used as most efficient polymeric vectors which provide a versatile platform for further investigation of structure property relationship along with the controlled degradation, significant low cytotoxicity and high transfection efficiency.

Biocompatible Materials↗

PubMed2004

Characterization of poly(D,L-lactic-co-glycolic acid) based nanoparticulate system for enhanced delivery of antigens to dendritic cells.

Biodegradable nanoparticles made of poly(D,L-lactic acid-co-glycolic acid) (PLGA) copolymer were characterized for enhanced delivery of antigens to murine bone marrow derived dendritic cells (DCs) in vitro. PLGA nanoparticles were efficiently phagocytosed by the DCs (CD11c+, MHC class II+, CD86+) in culture, resulting in their intracellular localization. The efficiency of the uptake was influenced by the incubation time and nanoparticle concentration. DCs pulsed with PLGA nanoparticles containing an immunomodulator, monophosphoryl lipid A (MPLA), showed upregulation of surface expression of MHC class II and CD86 molecules. Delivery of a cancer-associated antigen (MUC1 mucin peptide: BLP25) and MPLA in PLGA nanoparticles was shown to be superior to their delivery in the soluble form for activation of naïve T cells of normal and MUC1-transgenic mice. These results strongly suggest that PLGA nanoparticles provide an efficient vaccine delivery system for targeting DCs and the development of DC based cellular vaccines.

Animals↗

PubMed2006

Preparation and characterization of liposomes-in-alginate (LIA) for protein delivery system.

This paper describes the preparation and characterization of a novel drug delivery system for protein, liposomes-in-alginate (LIA) of biodegradable polymers, which is conceived from a combination of the polymer and the lipid-based delivery systems. LIA were prepared by first entrapping bovine serum albumin (BSA), a model protein within multivesicular liposomes (MVLs) by double emulsification process, which are then encapsulated within alginate hydrogel microcapsule, with untrapped BSA which are added during preparation of MVLs. Factors impacting encapsulation efficiency of MVLs are investigated and release of protein from the microcapsules in vitro is studied. At the same time, characterization of MVLs, microcapsules encapsulated protein formulation and integrality analyse of BSA in microcapsules are also studied, with the aim of improving the entrapment efficiency and prolonging release time. It is found that encapsulation efficiency and size of MVLs are affected by the composition and fabrication parameters of LIA. The data also show LIA have high encapsulation efficiency (up to 95%), little chemical change in drug caused by the formulation process, narrow particle size distribution and spherical particle morphology. Drug release assays conducted in vitro indicates that these formulations provide sustained release of encapsulated drug over a period, about 2 weeks.

Alginates↗

PubMed1999

Local and sustained delivery of 5-fluorouracil from biodegradable microspheres for the radiosensitization of glioblastoma: a pilot study.

BACKGROUND: The authors have developed a new method of drug delivery into the brain using implantable biodegradable microspheres. In this study, this method was used to provide localized and sustained delivery of 5-fluorouracil (5-FU) after the surgical resection of glioblastoma. This antimetabolite and radiosensitizing drug was selected in an attempt to decrease the rate of local recurrence of the tumor. METHODS: Eight patients with newly diagnosed glioblastoma were included in the study and 2 increasing amounts of 5-FU were studied (70 mg and 132 mg). After surgical resection of the tumor, poly(D-L lactide-co-glycolide) 5-FU-loaded microspheres with an average dimension of 45 microm were implanted in the wall of the surgical bed. External beam radiation (59.4 grays) was initiated before the seventh postsurgical day. Patients were followed by clinical examination, magnetic resonance imaging, and 5-FU assays in the blood and cerebrospinal fluid (CSF). RESULTS: 5-FU assays confirmed sustained concentrations in the CSF for at least 1 month. Concentrations of 5-FU in the blood were lower and transitory. Systemic tolerance to the treatment was good; one case of recurrent brain swelling was observed at the higher dose studied. At the time of last follow-up the overall median survival time was 98 weeks from the time of implantation and 2 patients had achieved disease remission at 139 and 153 weeks, respectively. CONCLUSIONS: This study demonstrates that biodegradable microspheres are efficient systems for drug delivery into the brain and may have future application in the treatment of brain tumors. Further studies are needed to confirm the potential of 5-FU-loaded microspheres for the radiosensitization of glioblastoma. [Please see editorial on pages 197-9, this issue].

Adolescent↗

PubMed1994

Immunopotentiation and delivery systems for antigens for single-step immunization: recent trends and progress.

The use of adjuvants for immunopotentiation has been investigated since the 1920s and a number of comprehensive reviews and monographs have been published on this subject. A recent trend in immunopotentiation has been the use of delivery systems which allow for sustained or controlled release of antigens and which induce prolonged immunity following a single dose. This concept has been termed either single-step or single-shot immunization. The delivery system has been modulated to potentiate the immune response either by delivering the antigen (and perhaps an adjuvant or adjuvants) either over a prolonged period of time or in a predetermined sequence or by incorporating substances with immunoadjuvant properties (e.g., lecithin and certain biodegradable polymers) as carriers within the delivery system. This Review focuses on the progress made in the design of delivery systems for immunopotentiation. Particular emphasis is given to delivery systems designed to achieve single-step immunization.

Adjuvants, Immunologic↗

PubMed2004

Efficacy of nonhormonal vaginal contraceptives from a hydrogel delivery system.

This investigation describes the synthesis of a biodegradable hydrogel composed of a core surrounded by four concentric sheaths containing dextran, copolymers of polylactide and epsilon-caprolactone. The hydrogel was impregnated with iron (II) d-gluconate dihydrate, which causes complete spermiostasis due to lipid peroxidation, ascorbic acid to increase the viscosity of the cervical mucus and mixtures of polyamino and polycarboxylic acids to sustain vaginal pH close to 4.5. The combined effects of the agents in the daily eluates of the hydrogel were efficacious up to 16 days, within 30 s, as shown by sperm penetration tests. For in vivo studies, rabbits were chosen as the experimental model because they are easy to handle and the female is always in estrus. The anterior vagina of estrous female rabbits was instilled with the hydrogel, and then inseminated with the semen from a fertile male. Postinsemination flush from the female rabbits showed that all of the sperm were dead. These observations demonstrate the potential for the development of a biocompatible, nonhormonal, intravaginal contraceptive device.

Administration, Intravaginal↗