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At least 865 records · Page 48Linked to original sources
PubMed1994

Cross-linked chitosan microspheres as carriers for prolonged delivery of macromolecular drugs.

Bovine serum albumin (BSA) and diphtheria toxoid (DT) were loaded by passive absorption from aqueous solutions into preformed glutaraldehyde cross-linked chitosan microspheres. In vitro release of BSA under sink conditions at 37 degrees C showed that even though there was a large burst effect, there was a more or less steady increase with time thereafter for several days. Coating the BSA-loaded particles with paraffin oil or with a polymer, such as polylactic acid, modulated drug release. After the initial burst from PLA coated particles, the release rate increased with time for nearly 2 months. Preliminary immunogenicity studies on Wistar rats using DT loaded chitosan spheres showed that the antibody titres were fairly constant over a 5-month period, although very low compared to DT given on alum as control. Histological studies of placebo microspheres intramuscularly injected into rats demonstrated their tissue compatibility. Biodegradation was not complete in 6 months demonstrating the potential of cross-linked chitosan spheres as a long-acting drug delivery vehicle. The study demonstrated the possibility of incorporating biological macromolecules which are very sensitive to organic solvents, pH, temperature, ultrasound, etc. by a passive absorption technique to degradable biopolymer matrices thereby preserving their biological integrity. It is also shown that drugs passively absorbed into such matrices by taking advantage of their swelling behaviour need not necessarily be released completely in the initial 'burst' and a sustained release may be possible for macromolecules thus incorporated.

Animals↗
PubMed1997

Biodegradable polymeric device for sustained intravitreal release of ganciclovir in rabbits.

PURPOSE: A scleral plug made of biodegradable polymer implanted at the pars plana was evaluated to determine its ability to control the intravitreal release of ganciclovir. METHODS: Scleral plugs containing 25% ganciclovir were prepared with poly(lactic-glycolic acid) (molecular weight, 121 kDa). The release of ganciclovir was evaluated in vitro by spectrophotometry. In vivo intravitreal ganciclovir concentrations were measured by high performance liquid chromatography following plug implantation in pigmented rabbits. The biocompatibility of the device was determined by indirect ophthalmoscopy, electroretinography, and light and electron microscopy. RESULTS: The in vitro study showed that the plug released ganciclovir throughout a 10-week period. The in vivo study demonstrated that the plugs maintained the drug concentration in the vitreous in a therapeutic range adequate to treat cytomegalovirus (CMV) retinitis for 12 weeks. No significant retinal toxicity was observed. CONCLUSIONS: This study demonstrated that this drug delivery system can potentially be useful to treat CMV retinitis.

Animals↗
PubMed2006

Biodegradability and biocompatibility of a pH- and thermo-sensitive hydrogel formed from a sulfonamide-modified poly(epsilon-caprolactone-co-lactide)-poly(ethylene glycol)-poly(epsilon-caprolactone-co-lactide) block copolymer.

A pH- and thermo-sensitive block copolymer was synthesized by adding pH-sensitive sulfamethazine oligomers (SMOs) to either end of a thermo-sensitive poly(epsilon-caprolactone-co-lactide)-poly(ethylene glycol)-poly(epsilon-caprolactone-co-lactide) (PCLA-PEG-PCLA) block copolymer. The resulting pH- and thermo-sensitive SMO-PCLA-PEG-PCLA-SMO block copolymer solution did not form a gel at high pH (pH 8.0) or at increased temperatures (ca. 70 degrees C), but did form a stable gel under physiological conditions (pH 7.4 and 37 degrees C). The degradation rate of the pH- and thermo-sensitive block copolymer decreased substantially compared with the control block copolymer of PCLA-PEG-PCLA, due to the buffering effect of the SMO-PCLA-PEG-PCLA-SMO sulfonamide groups on the acidic monomer-induced rapid degradation of PCLA-PEG-PCLA. This suitable sol-gel transition and sustained biodegradability of the pH- and thermo-sensitive SMO-PCLA-PEG-PCLA-SMO block copolymer resolves two of the major drawbacks associated with thermo-sensitive block copolymers, namely premature gelation and rapid degradation. Interestingly, SMO-PCLA-PEG-PCLA-SMO showed no evidence of cytotoxicity in vitro. However, subcutaneous injection of the pH- and thermo-sensitive block copolymer solution (20wt% in PBS at pH 8.0) into Sprague-Dawley (SD) rats resulted in rapid, stable gel formation, with the injected hydrogel being completely degraded in vivo in just 6 weeks. The injected hydrogel in vivo presented a typical acute inflammation within 2 weeks, although chronic inflammation was not observed during the first 6-week period. As such, the pH- and thermo-sensitive hydrogel of the SMO-PCLA-PEG-PCLA-SMO block copolymer is a suitable candidate for use in drug delivery systems and cell therapy.

Animals↗
PubMed2006

Versatility of biodegradable poly(D,L-lactic-co-glycolic acid) microspheres for plasmid DNA delivery.

In this study, we have optimized different formulations of DNA encapsulated into PLGA microspheres by correlating the protocol of preparation and the molecular weight and composition of the polymer, with the main characteristics of these systems in order to design an efficient non-viral gene delivery vector. For that, we prepared poly(D,L-lactic-co-glycolic acid) (PLGA) microparticles with an optimized water-oil-water double emulsion process, by using several types of polymers (RG502, RG503, RG504, RG502H and RG752), and characterized in terms of size, zeta potential, encapsulation efficiency (EE%), morphology, DNA conformation, release kinetics, plasmid integrity and erosion. The size of the particles ranged between 0.7 and 5.7 microm depending on the protocol of formulation and the molecular mass of the polymer used. The microspheres prepared by using in their formulation polymers of high molecular weight (RG503 and RG504) were bigger in size than in the case of using a lower molecular weight polymer (RG502). The EE (%) of plasmid DNA increased with increasing the molecular mass of the polymer and by using the most hydrophilic polymer RG502H, which contains terminal acidic groups in its structure. The plasmid could be encapsulated without compromising its structural and functional integrity. Also a protective effect of PLGA on endonuclease digestion is observed. Plasmid DNA release from microspheres composed of low molecular weight or hydrophilic polymers, like RG502H, was faster than from particles containing high molecular weight or hydrophobic polymers. These PLGA microspheres could be an alternative to the viral vectors used in gene therapy, given that may be used to deliver genes and other bioactive molecules, either very rapidly or in a controlled manner.

Biodegradation, Environmental↗
PubMed1993

Biotolerance of a semisolid hydrophobic biodegradable poly(ortho ester) for controlled drug delivery.

We evaluated the biotolerance of a new semisolid poly(ortho ester) (POE) intended for controlled drug delivery. Two different investigations were carried out in rats: subcutaneous injections and the cage-implant system. Sodium hyaluronate (SH), 1%, in phosphate buffer was used as a noninflammatory control. When injected subcutaneously in rats, the POE induced a mild and local inflammation at 3 and 7 days followed by a minimal chronic inflammation at 14 and 21 days. When using the cage-implant system, we quantified the inflammatory components of the exudate surrounding the implanted material within the cage system at 3, 7, 14, and 21 days. The total leukocyte and macrophage concentrations were higher only at 7 days for both SH and POE compared to the control (empty cage). The other parameters were not significantly different from the control. These results show that POE is well-tolerated by rats when used subcutaneously.

Animals↗
PubMed1990

Development of enzymatically degradable protective coatings for use in triggered drug delivery systems: derivatized starch hydrogels.

Starch is a common polysaccharide which consists of glucopyranose residues in an alpha-D-(1-4) linkage that yields D-glucose upon hydrolysis. Saturated aqueous solutions of soluble starch are easily reacted in the presence of glycidyl methacrylate to produce methacrylate grafted starch. Grafted starch solutions were polymerized to produce hydrogels, with and without the addition of an unsaturated acid. The grafted starch solutions and the resulting hydrogels are both shown to be degraded by the enzyme alpha-amylase. These acidic hydrogels are potentially useful as enzymatically degradable protective coatings in self-regulated drug delivery system applications. The pH of an acidic starch hydrogel required by this self-regulated drug delivery system does indicate that an adequately acidic hydrogel can be produced.

Amylases↗
PubMed2005

Monitoring drug delivery processes by EPR and related techniques--principles and applications.

Electron Paramagnetic Resonance (EPR, or ESR) is a powerful non-invasive spectroscopic tool that can be used to monitor drug release processes in vitro and in vivo. Furthermore, spatial dissolution can be achieved by means of EPR-Imaging. The article introduces the basics of EPR and EPR-imaging. It discusses also the challenges of in vivo spectroscopy and imaging and presents information about new developments such as longitudinally detected EPR (LODEPR) and Proton Electron Double Resonance Imaging ((PEDRI). Examples of the usefulness of EPR in the field of drug delivery include the measurement of microviscosity and micropolarity, the direct detection of drug release mechanisms in vitro and in vivo, the monitoring of microacidity in biodegradable polymers and the characterisation of colloidal drug carriers.

Animals↗
PubMed2004

Biodegradable dextran hydrogels crosslinked by stereocomplex formation for the controlled release of pharmaceutical proteins.

Hydrogels are based on hydrophilic polymers, which are crosslinked to prevent dissolution in water. Because hydrogels can contain large amounts of water, they are interesting devices for the delivery of proteins. In this contribution a biodegradable dextran hydrogel is described which is based on physical interactions and is particularly suitable for the controlled delivery of pharmaceutically active proteins. The unique feature of our system is that the preparation of the hydrogels takes place in an all-aqueous solution, by which the use of organic solvents is avoided. Furthermore, chemical crosslinking agents are not needed to create the hydrogels, since crosslinking is established physically by stereocomplex formation between enantiomeric oligomeric lactic acid chains. The hydrogel is simply obtained after mixing aqueous solutions of dextran(l)-lactate and dextran(d)-lactate. In this contribution, the formation of the hydrogels as well as their protein release properties and degradation behavior are discussed.

Biocompatible Materials↗
PubMedDate not supplied

Delivery of anticancer drugs.

Chemotherapy is a major therapeutic approach for the treatment of both localized and metastasized cancers. Since anticancer drugs are neither specific nor targeted to the cancer cells, improved delivery of anticancer drugs to tumor tissues in humans appears to be a reasonable and achievable challenge. Scientists are working to increase the availability of drug for tumor uptake by 1) delaying the release preparations for long-lasting actions; 2) using liposome-entrapped drugs for prolonged effect or reduced toxicity; 3) administrating inert, non-toxic prodrugs for specific activation at the tumor site; 4) delivering the antibody-mediated drugs; or 5) conjugating site-specific carriers to direct the drug to the tumor target. The latter depends heavily on pharmacokinetic investigations. Some success has been achieved in enhancing the efficacy and reducing the toxicity of drugs. Pharmacokinetic and pharmacodynamic considerations are two areas which have been focused toward the quantitative pharmacological studies of anticancer drugs in this manuscript. This review covers biodistribution and elimination, furnishing information on body clearance and unveiling sites of major metabolism; administration of anticancer drugs via various routes for optimal utilization; intra-arterial infusion for localized tumors, intrathecal, intraperitoneal and intrapleural injection for regional cavity administration. Conventional delivery routes, doses, pharmacokinetics data and elimination routes of therapeutic anticancer drugs are tabled. General approaches for delivery of anticancer drugs in achieving therapeutic improvements are outlined and correlated. Mechanism of drug resistance, and specific changes affecting the delivery of available chemotherapeutic agents, as well as the drugs to restore the sensitivities to agents of resistant tumor cells, are discussed. This monograph covers the developments and progress in the delivery of anticancer drugs in two approaches: the theoretical approach, including pharmacokinetic and pharmacodynamic considerations, therapeutic implications and mechanism of drug resistance, and the practical approach, including the physical, chemical, biochemical and physiological considerations. Among these, the physical approach for the delivery of anticancer agents to target sites (via microparticulate drug carriers: nanoparticles, liposomes, microspheres and activated carbon as well as the magnetic microcapsules) has shown recognizable improvements in prolonging anticancer effects and reducing toxicities. Implantable pumps and reservoirs for regional chemotherapy provide external control of delivery rate. The implanted systems, in general, yield better results than the traditional treatments in the treatment of liver and brain cancer. Chemical approaches for the improvement of drug delivery use prodrugs, biodegradable polymers and macromolecular matrix techniques.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1981

A review of parenteral sustained-release naltrexone systems.

The ideal naltrexone sustained-release delivery system should be easy to inject or implant, not cause adverse tissue reaction, release the drug at a relatively constant rate for at least 30 days, and biodegrade within a short time afterwards. Mechanisms which can be used for sustaining drug release include reducing solubility and surface area, coating, encapsulation and microencapsulation, complexation, binding and hydrophilic gelation. Drug release from such systems is controlled by diffusion through a barrier/film, diffusion from a monolithic device, erosion of the surface, hydrolysis, ion exchange, biodegradation, or a combination of these. Injectable systems would seem to be ultimately preferred because of the ease of administration and handling, while the implantable devices may find first use in man since they are easily removable, should that be necessary. Maintaining particulate-free products and sterilization methods are two problems with all parenteral dosage forms. Production must be particularly well controlled and validated.

Biodegradation, Environmental↗
PubMed1990

Drug delivery systems: 3A. Role of polymers in drug delivery.

At present, polymers represent a class of ubiquitous materials. They are being used for a multitude of purposes and the almost inexhaustible varieties of molecular architecture that macromolecular materials can possess provides the possibility for a myriad of applications. Because of the increased interest being shown in the macromolecules by the pharmaceutical industry for the fabrication of drug delivery systems, numerous polymers have been synthesized and successfully used in drug delivery devices. The necessary conditions for developing the concept of pharmaceutically applicable polymers depend upon delineating a detailed knowledge of the relationship between the structure and properties of polymer networks. A number of polymers have been studied systematically from this point of view and there is every indication that the systems described have the potential to become clinically valuable and therefore marketable drug delivery systems. The potential of these promising polymers is still far from being exhausted and there is a strong possibility that many important developments will be forthcoming in this field in the future. In the current review article, polymers for controlled release have been divided into four major categories: diffusion-controlled systems; chemically controlled systems; solvent-activated systems; and magnetically controlled systems. Polymers as drug carriers also have been divided into various subgroups: soluble, biodegradable, mucoadhesive and other polymeric systems. The latter group includes polymers containing pendant bioactive substituents, matrix systems, heparin-releasing polymers, ionic polymers, oligomers and miscellaneous. At an introductory and fundamental level, an overview of these polymers and the materials science for the design of drug delivery systems will be discussed.

Animals↗
PubMed1991

Direct intraarterial wall injection of microparticles via a catheter: a potential drug delivery strategy following angioplasty.

Local delivery into the arterial wall of medications at high concentrations may evolve as a method to reduce postangioplasty restenosis. However, since the atherosclerotic artery has increased vasa vasorum, medications injected in a fluid state may diffuse out of the arterial wall too quickly to have a therapeutic effect. Thus we evaluated whether microparticles as a model for a particulate microcarrier drug delivery system, injected via a porous balloon catheter, could be retained within the atherosclerotic rabbit femoral arterial wall. Arteries were injected with a 5 microns microparticle suspension for 45 seconds at either 3 or 5 atm of infusion pressure immediately following balloon angioplasty. Arteries were obtained immediately following the procedure or at 1, 3, 7, or 14 days after infusion to evaluate for the presence of retained microparticles. Of 34 arteries, 30 contained retained microparticles, with 21 exhibiting microparticles in the neointimia, 12 in the media, and 25 in the adventitia. Microparticles were retained for as long as 14 days, and there was no difference between the distribution or quantity of microparticles at 3 or 5 atm of infusion pressure. The mode of microparticle distribution probably involved deposition within dissection planes, although evidence for vasa vasorum transport was observed. We hypothesize that biodegradable microparticles could serve as a vehicle for intramural drug delivery in the treatment of restenosis.

Angioplasty, Balloon↗
PubMed2001

Poly(lactide-co-glycolide)/hydroxyapatite delivery of BMP-2-producing cells: a regional gene therapy approach to bone regeneration.

Currently, functional treatment of fracture non-unions and bone loss remains a significant challenge in the field of orthopaedic surgery. Tissue engineering of bone has emerged as a new treatment alternative in bone repair and regeneration. Our approach is to combine a polymeric matrix with a cellular vehicle for delivery of bone morphogenetic protein-2 (BMP-2), constructed through retroviral gene transfer. The objective of this study is to develop an osteoinductive, tissue-engineered bone replacement system by culturing BMP-2-producing cells on an osteoconductive, biodegradable, polymeric-ceramic matrix. The hypothesis is that retroviral gene transfer can be used effectively in combination with a biodegradable matrix to promote bone formation. First, we examined the in vitro attachment and growth of transfected BMP-producing cells on a PLAGA-HA scaffold. Second, the bioactivity of the produced BMP in vitro was evaluated using a mouse model. It was found that the polymer-ceramic scaffold supported BMP-2 production, allowing the attachment and growth of retroviral transfected, BMP-2-producing cells. In vivo, the scaffold successfully functioned as a delivery vehicle for bioactive BMP-2, as it induced heterotopic bone formation in a SCID mouse model.

Animals↗
PubMed2006

Local intracerebral administration of Paclitaxel with the paclimer delivery system: toxicity study in a canine model.

INTRODUCTION: Paclitaxel, a microtubule binding agent with potent anti-glioma activity in vitro, exhibits poor penetrance to the CNS when delivered systemically. To minimize toxicity and reach therapeutic concentrations in the CNS, paclitaxel was previously incorporated into biodegradable microspheres (Paclimer), and the efficacy of Paclimer was determined in a rat model of malignant glioma. In this study we report the safety of intracranial Paclimer in a canine dose escalation toxicity study to prepare its translation into clinical scenarios. METHODS: Twelve normal beagle dogs underwent a right parieto-occipital craniectomy and were randomized to receive either Paclimer at 2-mg/kg (n=5), empty microspheres at 2-mg/kg (n=1), Paclimer at 20-mg/kg (n=5), or empty microspheres at 20-mg/kg (n=1). Post-operatively, dogs were observed daily for signs of neurotoxicity. Complete blood counts and plasma levels of paclitaxel were obtained weekly. CSF levels and MRI scans were obtained on days 14-120. Paclitaxel concentrations were quantified by LC-MS. RESULTS: Animals treated with 20-mg/kg Paclimer had minimal paclitaxel levels in plasma (range 0-7.84 ng/ml) and CSF (range 0-1.16 ng/ml). Animals treated with 2 mg/kg Paclimer had undetectable levels of paclitaxel in plasma, CSF was not obtained to minimize animal suffering. All animals exhibited normal behavior and weight gain, and were alive post-operatively through the last day of the study (day 60-120) without signs of neurological toxicity. There was no evidence of systemic toxicity or myelosuppression. MR imaging was comparable between Paclimer animals and controls. Adverse effects included wound infections and a brain abscess, all of which responded to antibiotic therapy, and one ventriculomegaly due to communicating hydrocephalus. CONCLUSIONS: Paclimer-based delivery of paclitaxel is safe for intraparenchymal delivery at the tested doses in normal dogs.

Animals↗
PubMed1994

Prevention of experimental proliferative vitreoretinopathy with a biodegradable intravitreal implant for the sustained release of fluorouracil.

OBJECTIVE: To test the efficacy of a biodegradable device for the intravitreal sustained release of fluorouracil in the treatment of tractional retinal detachment due to proliferative vitreoretinopathy. METHODS: A 6 x 0.9-mm (20-gauge) cylindrical solid implant molded from copolymers of lactide and glycolide admixed with 1 mg of fluorouracil was placed in the vitreous cavity of rabbits in which retinal detachment with proliferative vitreoretinopathy had been initiated. Comparisons of the control (drug-free polymer) and experimental (fluorouracil polymer) groups were made with weekly indirect ophthalmoscopic examinations. In another experiment, the intravitreal concentration of fluorouracil was tested at each time point. RESULTS: Retinas of eight (89%) of nine rabbits that received the polymer with fluorouracil remained attached compared with only one animal (11%) that received the control polymer without the drug. The therapeutic effect of the drug-containing implant was associated with sustained intravitreal concentrations of fluorouracil between 1 and 13 mg/L for at least 14 days, and fluorouracil concentrations remained above 0.3 microgram/mL for almost 21 days. No evidence of the toxic effects of the drug or polymer implant was observed with electroretinographic and histopathologic study. CONCLUSION: Intravitreal implantation of biodegradable polymers containing fluorouracil can prevent proliferation of epiretinal membranes resulting in complicated retinal detachment in an animal model of proliferative vitreoretinopathy and indicate their possible usefulness for intravitreal delivery of therapeutic agents.

Animals↗
PubMed2005

Poly(lactide) stereocomplexes: formation, structure, properties, degradation, and applications.

Poly(lactide)s [i.e. poly(lactic acid) (PLA)] and lactide copolymers are biodegradable, compostable, producible from renewable resources, and nontoxic to the human body and the environment. They have been used as biomedical materials for tissue regeneration, matrices for drug delivery systems, and alternatives for commercial polymeric materials to reduce the impact on the environment. Since stereocomplexation or stereocomplex formation between enantiomeric PLA, poly(L-lactide) [i.e. poly(L-lactic acid) (PLLA)] and poly(D-lactide) [i.e. poly(D-lactic acid) (PDLA)] was reported in 1987, numerous studies have been carried out with respect to the formation, structure, properties, degradation, and applications of the PLA stereocomplexes. Stereocomplexation enhances the mechanical properties, the thermal-resistance, and the hydrolysis-resistance of PLA-based materials. These improvements arise from a peculiarly strong interaction between L-lactyl unit sequences and D-lactyl unit sequences, and stereocomplexation opens a new way for the preparation of biomaterials such as hydrogels and particles for drug delivery systems. It was revealed that the crucial parameters affecting stereocomplexation are the mixing ratio and the molecular weight of L-lactyl and D-lactyl unit sequences. On the other hand, PDLA was found to form a stereocomplex with L-configured polypeptides in 2001. This kind of stereocomplexation is called "hetero-stereocomplexation" and differentiated from "homo-stereocomplexation" between L-lactyl and D-lactyl unit sequences. This paper reviews the methods for tracing PLA stereocomplexation, the methods for inducing PLA stereocompelxation, the parameters affecting PLA stereocomplexation, and the structure, properties, degradation, and applications of a variety of stereocomplexed PLA materials.

Absorbable Implants↗
PubMed2005

Effect of poly(ethylene oxide) on the release behaviors of poly(epsilon-caprolactone) microcapsules containing erythromycin.

The biodegradable poly(epsilon-caprolactone) (PCL)/poly(ethylene oxide) (PEO) microcapsules and the analyzing of form and features for the manufacturing conditions were investigated in a prospective drug delivery systems (DDS) through drug release. The effects of emulsifier, emulsifier concentration, and stirring rate on the diameter and form of the microcapsules were examined using image analyzer (IA) and scanning electron microscope (SEM). The role of interfacial adhesion between PCL/PEO and drug was determined by contact angle measurements, and the drug release rate of the microcapsules was characterized by UV-vis spectroscopy. As a result, the microcapsules were made in spherical forms with a mean particle size of 170 nm approximately 68 microm. And the work of adhesion between water and PCL/PEO was increased with increasing the PEO content, which is due to higher hydrophilicity of PEO. The drug release rate of the microcapsules was significantly increased as the PEO content increased, which could be attributed to the increasing of the hydrophilic groups or the degree of adhesion at the interfaces.

Adhesiveness↗