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Results for “Biodegradable Delivery Systems”

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PubMed2005

In vitro uptake of gelatin nanoparticles by murine dendritic cells and their intracellular localisation.

The long term goal of this study is to develop an efficient nanoscopic vaccine delivery system, based on the biodegradable and natural polymer gelatin, to deliver therapeutic protein antigens along with adjuvants into dendritic cells (DCs). In this study, gelatin nanoparticles were tested for qualitative and quantitative uptake in murine DCs in vitro. A second aim of this study was to prove that the carrier system is able to deliver tetramethylrhodamine conjugated dextran (TMR-dextran), as a model drug into the DCs. The TMR-dextran was incorporated during the preparation of the gelatin nanoparticles. DCs were generated from murine bone marrow cells by an established ex vivo technique. Flow cytometry showed that 88% of the cells positive for the specific murine DC marker CD11c took up TMR-dextran loaded gelatin nanoparticles, whereas only 4% of the soluble form of TMR-dextran was taken up. Double color confocal laser scanning microscopy (CLSM) showed that gelatin nanoparticles were phagocytosed by DCs and the triple color CLSM showed that the TMR-dextran was localized mainly in lysosomes as expected, but partly also outside the lysosomes, presumably in the cytoplasm. An in vitro release study of TMR-dextran from gelatin nanoparticles demonstrated that there was hardly any release in phosphate buffered saline (PBS), but by trypsin-assisted degradation of gelatin nanoparticles resulted in the release of about 80% of the TMR-dextran from the particles. These results suggest that gelatin nanoparticles hold promise as a new biocompatible tool for vaccine delivery to DCs, with applications in cancer immunotherapy.

Animals↗

PubMed1998

In vitro and in vivo release of ciprofloxacin from PLGA 50:50 implants.

Poly(lactides-co-glycolides) [PLGA] are widely investigated biodegradable polymers and are extensively used in several biomaterials applications as well as drug delivery systems. These polymers degrade by bulk hydrolysis of ester bonds and break down into their constituent monomers, lactic and glycolic acids which are excreted from the body. The purpose of this investigation was to develop and characterize a biodegradable, implantable delivery system containing ciprofloxacin hydrochloride (HCl) for the localized treatment of osteomyelitis and to study the extent of drug penetration from the site of implantation into the bone. Osteomyelitis is an inflammatory bone disease caused by pyogenic bacteria and involves the medullary cavity, cortex and periosteum. The advantages of localized biodegradable therapy include high, local antibiotic concentration at the site of infection, as well as, obviation of the need for removal of the implant after treatment. PLGA 50:50 implants were compressed from microcapsules prepared by nonsolvent-induced phase-separation using two solvent-nonsolvent systems, viz., methylene chloride-hexane (non-polar) and acetone-phosphate buffer (polar). In vitro dissolution studies were performed to study the effect of manufacturing procedure, drug loading and pH on the release of ciprofloxacin HCl. The extent of penetration of the drug from the site of implantation was studied using a rabbit model. The results of in vitro studies illustrated that drug release from implants made by the nonpolar method was more rapid as compared to implants made by the polar method. The release of ciprofloxacin HCl. The extent of the penetration of the drug from the site of implantation was studied using a rabbit model. The results of in vitro studies illustrated that drug release from implants made by the nonpolar method was more rapid as compared to implants made by the polar method. The release of ciprofloxacin HCl from the implants was biphasic at < or = 20% w/w drug loading, and monophasic at drug loading levels > or = 35% w/w. In vivo studies indicated that PLGA 50:50 implants were almost completely resorbed within five to six weeks. Sustained drug levels, greater than the minimum inhibitory concentration (MIC) of ciprofloxacin, up to 70 mm from the site of implantation, were detected for a period of six weeks.

Animals↗

PubMed1999

In vitro release kinetics of gentamycin from a sodium hyaluronate gel delivery system suitable for the treatment of peripheral vestibular disease.

For certain patients who experience intense vertigo arising from unilateral vestibular lesions, the primary therapy is a vestibular nerve section, an intracranial surgical procedure. One alternative to this treatment is therapeutic ablation of vestibular function on the unaffected side using an ototoxic agent. We prepared a biodegradable sustained-release gel delivery system using sodium hyaluronate that can be administered into the middle ear using only a local anesthetic. The gel contains gentamycin sulfate, the ototoxic agent of choice for treatment of unilateral vestibulopathy, and it exhibits diffusion-controlled release of the drug over a period of hours. The released gentamycin could then diffuse into the inner ear through the round membrane. This represents an important advance over previous formulations, which used only gentamycin sulfate solutions, in that it should allow more careful control of the dose, it should reduce loss of the drug from the middle ear site, and it should maintain intimate contact with the round membrane. By carefully controlling the dose, it should be possible to inhibit vestibular function while minimizing hearing loss. Herein we describe the in vitro release kinetics of gentamycin sulfate from sodium hyaluronate gels and find that the system obeys Fickian behavior.

Delayed-Action Preparations↗

PubMed2006

PLA-microparticles formulated by means a thermoreversible gel able to modify protein encapsulation and release without being co-encapsulated.

The aim of this work was to develop a novel strategy for the formulation of biodegradable PLA microspheres as delivery systems for proteins or peptides. The strategy is based on the exploitation of the gel-sol transition of the thermoreversible Pluronic F127 gel. The gel allows the formation of the particles without be co-entrapped in the matrix. The microspheres prepared using the novel technique (TG-Ms, or thermoreversible gel-method microspheres) were characterized in vitro (as concerns the size, the morphology, the protein encapsulation, the release and the protein distribution in the polymer matrix), in comparison with microspheres prepared using the classical double emulsion/solvent evaporation method (w/o/w-Ms). Two types of bovine serum albumin (BSA), with different water solubility, were used as model proteins. TG-Ms exhibited small size (7-50 m) and high protein content (8.6%, w/w) regardless of the BSA water solubility, in contrast with w/o/w-Ms, which revealed a size range of 100-130 microm and a protein content related to the BSA water solubility. TG-Ms, in spite of their smaller size respect of the w/o/w-Ms, displayed a reduced initial burst effect and a higher rate in the second release phase that resulted in a quasi-constant profile. The release behavior of the TG-Ms may be attributable to both the localization of the protein in the particle core, as shown by the confocal laser scanning microscopy analysis on labeled-BSA loaded microspheres, and the few pores in the matrix, as shown by the scanning electron microscopy. A working hypothesis about the mechanism of the particle formation was also discussed.

Drug Compounding↗

PubMed1997

The effect of intestinal bacteria adherence on drug diffusion through solid films under stationary conditions.

PURPOSE: To study the in vitro and in vivo the role of surface bacterial adhesion on the diffusion of model drugs at stationary conditions. METHODS: Salicylic acid (SA) diffusion through ethyl cellulose (EC) films was measured in vitro in side-by-side diffusion cells with and without E. coli of intestinal origin. Insulin (I) release from paper strips coated or uncoated with pectin films, with or without antibiotic treatment, was measured in vivo in conscious rats after cecal implantation by comparing blood glucose levels at Tmax of the pharmacodynamic effect. RESULTS: During five hours of diffusion studies which were performed immediately following incubation of EC films with bacteria, the diffusion rate of SA throughout the films was 2.72-fold lower in the presence of bacteria compared with the diffusion rate in the control studies conducted without bacteria. The mean blood glucose levels dropped in the rat to 40.6 +/- 21.6% of glucose basal levels within 2.4 +/- 1.4 h when uncoated I solid carriers were used. Glucose levels did not change for pectin-coated dosage forms. After antibiotic treatment which prevented the formation of bacterial biofilm on the surface of the I solid dosage forms, blood glucose levels dropped to 22.0 +/- 4.7% and 50.9 +/- 20.5% of glucose basal levels within 7.4 +/- 2.6 h and 1.8 +/- 0.9 h for pectin uncoated or coated dosage forms, respectively. Maximum bacterial adherence occurred at stationary conditions (RPM = 0), while at maximum agitation (200 RPM), almost no adherence occurred. CONCLUSIONS: (a) Bacterial adherence shows down the diffusion rate of SA through EC films; (b) Under stationary conditions bacterial adherence may also interfere with drug release from biodegradable (pectin) films; (c) Successful functioning of biodegradable colon-specific delivery systems depends on agitation and surface friction in the lumen of the colon.

Animals↗

PubMed1999

Stability of poly(L-lysine)-complexed plasmid DNA during mechanical stress and DNase I treatment.

The aim of this study was to investigate the formation and stability of complexes between plasmid DNA (pDNA) and poly(L-lysine) (PLL). Formation of pDNA/PLL complexes with various ratios was determined by a fluorescence spectrophotometric method using fluorescamine. The effects of sonication, vortexing, and exposure to DNase I on the stability of free pDNA and pDNA/PLL complexes are discussed. A linear correlation between PLL added and PLL bound was obtained with overall reaction efficiency of 84.2-92.6%. Sonication degraded both free and PLL-complexed pDNA within 15 sec of vortexing. However, vortexing did not alter the stability of free and complexed pDNA. Dramatic increase in the protection of pDNA in pDNA/PLL complexes was observed in the DNase I digestion experiment; 68.1-89.0% of total pDNA in the pDNA/PLL complexes was protected from DNase I digestion compared to only 19.2% of total pDNA that remained undegraded after DNase I treatment of free pDNA. An increase in the PLL/pDNA ratio led to an increase in the protection of supercoiled pDNA; 15.5-38.2% of supercoiled pDNA pin PLL/pDNA complexes was protected after DNase I treatment. The results show that complexation of pDNA with PLL can stabilize the supercoiled structure of pDNA for the development of biodegradable microspheres as a delivery system for pDNA. Stability of pDNA/PLL complex can be monitored by PicoGreen dye and fluorescence densitometric assay methods.

DNA↗

PubMed2004

[Novel dosage forms with a sustained release of aqueous cis-platinum].

The authors have been devising novel dosage forms with a sustained release of aqueous cis-platinum (CDDP), following the concept of a drug delivery system. First, we prepared biodegradable vehicles with clinically available fibrin and gelatin materials that were used with the ultraviolet (UV)-cross linking technique. Then, each carrier was loaded with CDDP to form new drugs. We basically studied degradability of the carrier, a release profile of the CDDP, and antineoplastic activities with the system. The new drugs gradually disintegrated to dissolve completely within 10-15 days, and 80-90% of the loaded CDDP was delivered in the same period. The released CDDP showed antineoplastic activities, both in vitro and in vivo, while the CDDP directly reacted with human plasma revealed little evidence of anticancer function. The scanning electron microscopic studies suggested that the release profile of the CDDP was closely related with the degradability of the carrier. We presume that UV-modification techniques play important roles in preparation of the new drug carriers. Our newly devised CDDP releasing system is promising as novel cancer chemotherapy.

Antineoplastic Agents↗

PubMed2006

The effect of poly (aspartic acid-co-lactic acid) nanospheres on the lung metastasis of B16BL6 melanoma cells by intravenous administration.

Poly (aspartic acid-co-lactic acid) (PAL) has been investigated as a new biodegradable material for Drug Delivery Systems (DDS). Similar to the poly (lactic acid-co-glycolic acid) (PLGA) nanospheres, the PAL nanospheres can control-release encapsulated drugs by hydrolysis and adhere to the mucous membranes to improve the drug absorption. In this study, the vitamin encapsulated PAL nanospheres were applied on mice to examine their effect on tumor metastasis and safety as an injectable DDS material for anti-cancer and other drugs. In the experiment, 6 C57BL/6 mice per group were intravenously administered with B16BL6 melanoma cells (1 x 10(5) per mouse) and non-encapsulated PAL nanospheres or pro-vitamin encapsulated nanospheres respectively, while the control group was administered with B16BL6 cells alone. Two weeks later, the lungs of the mice were excised and metastatic foci on the lung surface were counted. The melanoma cell metastasis to lungs was prevented by intravenous co-injection of B16BL6 melanoma cells with 1.7 microg of pro-vitamin E encapsulated PAL nanospheres. Its metastatic foci count (mean +/- SD) was 127+/-80, which was better than the control (246+/-95, p<0.02). Also, applying the pro-vitamin C and pro-vitamin A encapsulated PAL nanospheres as well as the non-encapsulated PAL nanospheres slightly decreased the number of metastasis colonies in the lungs as compared to that of the control. These results suggested that PAL nanospheres did not promote the lung metastasis of B16BL6 melanoma cells. Thus, the PAL nanospheres are safe material for injection applications.

Animals↗

PubMed1991

Subdermal progestin implant contraception.

Sustained-release progestin contraceptives are a new approach to meeting a worldwide need for more effective and acceptable birth control. These contraceptive systems provide low, stable levels of synthetic progestins for periods of months to several years. Unlike earlier injectable and oral contraceptives, they do not cause peaks in progestin levels beyond those required for effective contraception, nor do they employ estrogens. For these reasons, sustained-release progestin systems are without some of the health risks attributed to birth control pills, and they are more effective, as well as easy to use, and completely reversible. They share common side effects, the most frequent of which is irregular menstrual bleeding caused by the erratic shedding of hypotrophic endometrium. Despite this and other minor side effects, most users find the sustained-release systems acceptable alternatives to other methods of contraception. Permanent or biodegradable subdermal implants, injections, intrauterine and intracervical devices, and vaginal rings are all employed as delivery systems for contraceptive progestins. The Norplant (Wyeth Ayerst, Radnor, PA) system, consisting of six silastic tubes filled with levonorgestrel and implanted under the skin, was recently approved by the US Food and Drug Administration and is already used by more than a half million women worldwide. The other sustained-release systems are in various stages of development, at least several years away from general use. When these new methods complete clinical trials, women will be able to choose from among implants, injections, or pellets with various durations of action, all providing convenient, highly effective contraception with low risk to health.

Biodegradation, Environmental↗

PubMedDate not supplied

Beta-tricalcium phosphate delivery system for bone morphogenetic protein.

An aggregate of biodegradable beta-tricalcium phosphate and bone morphogenetic protein (BMP/TCP) induces the differentiation of cartilage within eight days, cartilage and woven bone within 12 days, and lamellar bone, including bone marrow, within 21 days. The yield of new bone from a 1-mg dose was more than 12 times greater from the TCP/BMP than from the BMP alone. Whether TCP acts as a slow-release delivery system, potentiates the activity of BMP, or serves to distribute BMP in a favorable three-dimensional pattern requires further investigation.

Animals↗

PubMed2001

Regional drug delivery with radiation for the treatment of Ewing's sarcoma. In vitro development of a taxol release system.

Recently, several studies have suggested the radiosensitizing effect of taxol, a microtubular inhibitor. Our overall hypothesis is that a combination of radiation and taxol may demonstrate therapeutic efficacy over doses of either individually. Studies examining taxol use have mostly focused on systemic administration, which can lead to undesired effects. To circumvent these side effects, we propose a locally administered polymeric microsphere delivery system combined with radiation therapy for the treatment of Ewing's sarcoma. The present study focuses on the in vitro ability of taxol when present as a microencapsulated drug delivery system, and delivered locally at the site of the sarcoma/tumor, to block cells in the G2/M phase of the cell cycle and potentially enhance the radiation sensitivity of cells. Using the bioresorbable poly(anhydride-co-imide), poly[pyromellityl-imidoalanine-1,6-bis(carboxy-phenoxy)hexane] (PMA-CPH), and the radiosensitizing agent taxol, a microsphere based delivery system was fabricated. A solvent evaporation technique was used to encapsulate taxol at doses of 1%, 5%, and 10% in PMA-CPH microspheres. Release kinetics studies demonstrated that the total amount of taxol released and the release rate were directly dependent on loading percentage. Taxol's bioactivity and radiosensitizing ability were measured using flow cytometry. Co-culture of Ewing's sarcoma cells with and without taxol-loaded microspheres demonstrated that released taxol retained its bioactivity and effectively blocked cells in the radiosensitive G2/M phase of mitosis. The taxol-radiation delivery system studied achieved an 83% decrease in tumor cell count compared to control. Taxol effectively sensitized Ewing's sarcoma cells to radiation with radiosensitivity shown to be independent of radiation dose at levels of dosages studied. This work has demonstrated that taxol can be effectively released from a biodegradable PMA-CPH microsphere delivery system while maintaining potent combined cytotoxic and radiosensitizing abilities.

Antineoplastic Agents, Phytogenic↗

PubMed2001

Biodegradable polymeric nanoparticles as drug delivery devices.

This review presents the most outstanding contributions in the field of biodegradable polymeric nanoparticles used as drug delivery systems. Methods of preparation, drug loading and drug release are covered. The most important findings on surface modification methods as well as surface characterization are covered from 1990 through mid-2000.

Adsorption↗

PubMed1998

A poly(D,L-lactide-co-glycolide) microsphere depot system for delivery of haloperidol.

Haloperidol-loaded biodegradable poly(d,l-lactide-co-glycolide) (PLG) microspheres, with theoretical mean particle sizes of about 0. 8, 2 and 8 micrometer, have been successfully prepared by using an emulsification-solvent evaporation method. The effect of various processing parameters such as the content of polymer in dichloromethane, the content of polyvinyl alcohol in the aqueous phase, and the stirring speed of emulsification on the particle size and size distribution of microspheres has been investigated and three optimal procedures suggested. The influence of particle size on drug content and incorporation efficiency of haloperidol-loaded PLG microspheres also has been evaluated. In vitro a linear release of haloperidol from PLG microspheres over an extended period of time without a significant burst effect has been achieved; the time of 50% drug release (T50%) being around 55 days. The effect of drug content and particle size on the cumulative release of haloperidol from PLG microspheres was also studied together with the reproducibility of drug content and release profile from batch-to-batch with different particle sizes.

Antipsychotic Agents↗

PubMedDate not supplied

Design and development of multiparticulate system for targeted drug delivery to colon.

A multiparticulate system combining pH-sensitive property and specific biodegradability for colon-targeted delivery of metronidazole has been investigated. Cross-linked chitosan microspheres were prepared from an emulsion system using liquid paraffin as the external phase and solution of chitosan in acetic acid as the disperse phase. The multiparticulate system was prepared by coating cross-linked chitosan microspheres exploiting Eudragit L-100 and S-100 as pH-sensitive polymers. Morphology and surface characteristics of the formulations were determined by scanning electron microscopy. Particle size of the chitosan microspheres was determined by optical microscopy while that of coated microspheres was determined by particle size analyzer. In vitro drug-release studies were performed in conditions simulating stomach-to-colon transit in presence and absence of rat caecal contents. The size of the microspheres was small and they were efficiently microencapsulated within Eudragit microspheres, forming a multireservoir system. By coating the microspheres with Eudragit pH-dependant release profiles were obtained. No release was observed at acidic pH; however, when it reached the pH where Eudragit starts solublizing there was continuous release of drug from the formulation. Further, the release of drug was found to be higher in the presence of rat caecal contents, indicating the susceptibility of chitosan matrix to colonic enzymes released from rat caecal contents.

Animals↗

PubMed1991

Absorbable materials in orthopaedic surgery.

The most important surgical biodegradable polymers are aliphatic polyesters of -hydroxy acid derivates. Implants made of these polymers that are currently used include sutures and fiber constructions, porous composites and drug delivery system and partially or totally biodegradable devices. Development and experimental and clinical use of absorbable devices in the fixation of fractures or osteotomies are presented. The clinical experience is based on 1,300 operated patients. The results in the fixation of cancellous bone fractures or osteotomies with absorbable implants are comparable to those of metallic implants but there is no need for removal procedures as with metallic osteosyntheses. This substantially benefits the individual as well as save money.

Absorption↗

PubMed2003

Classification and characteristics of polymeric controlled-release systems.

The great importance of controlled release for the delivery of a variety of bioactive agents is evidenced by an increasing number of patents and commercial products that employ this technology. This article reviews the different controlled-release systems and their operating mechanisms.

Biocompatible Materials↗

PubMed2000

Cationic microparticles: A potent delivery system for DNA vaccines.

An approach involving the preparation of biodegradable microparticles with a cationic surface was developed to improve the delivery of adsorbed DNA into antigen-presenting cells after i.m. injection. The microparticles released intact and functional DNA over 2 weeks in vitro. In addition, the microparticles induced higher levels of marker gene expression in vivo. After i.m. immunization, the microparticles induced significantly enhanced serum antibody responses in comparison to naked DNA. Moreover, the level of antibodies induced by the microparticles was significantly enhanced by the addition of a vaccine adjuvant, aluminum phosphate. In addition, in contrast to naked DNA, the cationic microparticles induced potent cytotoxic T lymphocyte responses at a low dose.

Animals↗

PubMedDate not supplied

Fibrin based drug delivery systems.

Fibrinogen is the natural substrate for thrombin, the final proteolytic enzyme of the blood coagulation cascade. Following reaction with thrombin, fibrinogen is converted into fibrin monomers which then spontaneously polymerize into fibrin threads forming the fibrin matrix. This biochemical reaction between fibrinogen and thrombin has been used to produce natural, biodegradable, biocompatible systems for sustained drug delivery. Three potential delivery systems have been explored: 1) fibrin microparticles with drug entrapped are produced by an emulsion process, 2) reaction between fibrinogen adsorbed on suspended drug and thrombin in solution results in the formation of fibrin-coated drug particulates, and 3) fibrin sheets suitable as implants have been cast with drug entrapped. The drug release behavior of both small and large molecular weight substances from these systems was evaluated.

Delayed-Action Preparations↗