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PubMed2006

Fluorescein isothiocyanate labelled bovine serum albumin (FITC-BSA) as a model protein drug: opportunities and drawbacks.

In the therapy of various diseases, parenterally administered protein drugs are of steadily rising importance. In order to reduce the application frequency, these proteins can be incorporated into drug delivery systems, e.g. biodegradable microparticles from poly(lactic-co-glycolic acid) (PLGA). To evaluate the characteristics of these vehicles, fluorescent labelled proteins like fluorescein isothiocyanate labelled bovine serum albumin (FITC-BSA) may be used as model drugs to allow the visualisation of the protein localisation within the microparticle and the detection of microparticles in cell cultures or tissues. However, the quantification of protein by fluorescence spectroscopy failed. In this study we focused on the mechanism of fluorescence dequenching in a multi-FITC-labelled protein and its impact on a reliable protein determination.

Dendritic Cells↗
PubMed2006

beta-Estradiol biodegradable microspheres: effect of formulation parameters on encapsulation efficiency and in vitro release.

The purpose of this work was to study the effect of organic solvent and surfactant type on the in vitro release behavior in general and on the burst release in particular of beta-estradiol from PLA/PLGA microspheres. Also the effect of these variables on the encapsulation efficiency was investigated. The microspheres were prepared by solvent evaporation technique using dichloromethane (DCM), ethyl acetate (EtAc), tetrahydrofuran (THF), chloroform (CHCl3) or acetone (AC) as organic solvent and polyvinyl alcohol (PVA), Tween 80, sodium lauryl sulfate (SLS) or benzalkonium chloride (BKCI) as surfactant. The obtained microspheres were tested for encapsulation efficiency and in vitro drug release using 50% methanol/buffer pH 7.4 as dissolution medium. EtAC and PVA formulations showed the highest encapsulation efficiency and the lowest burst release. These microspheres were further characterized for particle size distribution, SEM and zeta potential. The results suggested that these materials could be starting materials to prepare a beta-estradiol biodegradable controlled delivery system.

Biotransformation↗
PubMed2006

Use of fibrin sealants for the localized, controlled release of cefazolin.

BACKGROUND: Fibrin sealants are used increasingly in surgery to reduce bleeding and improve wound healing. They have great potential as biocompatible, biodegradable drug delivery systems, because the sealant may adhere to the target tissue and allow controlled release of the drug over an extended period. We investigated the encapsulation, stability and controlled release of erythromycin and cefazolin from Beriplast fibrin sealants (Aventis Behring Canada). METHODS: Drug-loaded clots were cast in glass vials and allowed to set. We observed the clots for drug precipitation and aggregation, and we assessed the effect of drug encapsulation on clot strength. Drug stability and release from the clots in phosphate buffered saline (PBS) was quantified by ultraviolet and visible violet absorbance spectroscopy and high-performance liquid chromatography. RESULTS: Erythromycin was found to release slowly from the fibrin clots over the first 2 hours but then degrade rapidly. Cefazolin was found to be very stable in clots in PBS (97% stable at 2 d and 93% stable at 5 d). The drug released in a controlled manner over 2 days, with most being released during the first day. The dose of drug released could be varied by changing the amount placed in the thrombin solution. Clot thickness had no effect on the rate of cefazolin release. CONCLUSION: Overall, the 2-day release profile and the excellent stability of the drug suggest that cefazolin-loaded fibrin sealants may offer an effective route of postoperative antibiotic delivery.

Anti-Bacterial Agents↗
PubMed1989

A comparative evaluation of the safety and contraceptive effectiveness of 65 mg and 100 mg of 90-day norethindrone (NET) injectable microspheres: a multicenter study.

The first of a second generation of slow-release injectable contraceptives is the norethindrone (NET) microspheres with a 90-day duration of action. It was evaluated at 65-mg and 100-mg doses for safety and contraceptive effectiveness in two randomized, single-blind trials among 131 women: 94 women for 12 months and 37 women for 6 months. The 6-month trial included additional evaluations of ovarian function and serum NET values. In the 6-month trial, no indication of ovulation was detected in the 100-mg dose group, while 3 of the 19 women in the 65-mg group showed signs of ovulation (progesterone greater than 3 ng/ml). No pregnancies were reported in the 100-mg group and one pregnancy in the 65-mg group resulted in a life-table pregnancy rate for that dose of 2.6 per 100 woman-years (95% confidence interval, 0 to 7.5). Days of vaginal bleeding were analyzed for 30 days before treatment and in 90-day reference periods after treatment. The mean number of vaginal bleeding and spotting days increased initially after the first injection in both dose groups, but decreased to below baseline in both dose groups after 6 months. The two doses appear comparable in clinical safety, side effects, vaginal bleeding patterns, and laboratory measures. With the preliminary estimate of efficacy, the 65-mg dose would be the minimally effective dose for the NET 90-day injectable contraceptive.

Adult↗
PubMedDate not supplied

Biodegradable polymers for ocular drug delivery.

A variety of ocular drug delivery systems, including a controlled release of the drug, drug targeting, and penetration enhancement of the drug, have been investigated. Biodegradable polymers have been widely used as the drug carrier for controlled-release systems. Biodegradable polymers release the drug as they themselves degrade and are finally absorbed within the body. Several ocular drug delivery systems using different kinds of biodegradable polymers have been studied. In this article, we describe the fundamental mechanisms of drug delivery systems, polymer erosion and drug release, and then review those systems using the most popular biodegradable polymers, poly(lactic acid) and poly(lactic-glycolic acid).

Animals↗
PubMed1984

Preparation and evaluation of biodegradable polymeric systems for the intra-articular delivery of drugs.

Colloidal suspensions of four biodegradable polymers, polylactic acid (PLA), polybutylcyanoacrylate (PBCA), gelatin (PG) and albumin (PA) were prepared within the size range 1-10 micron. In-vivo biocompatibility tests with synovial tissues were carried out to assess the irritancy of the polymers following intra-articular injection into rabbit knee joints. PLA, PBCA and PG were found to cause joint inflammation whereas PA was well tolerated by the tissues. PA microspheres may provide a means of sustaining the release and reducing the rate of clearance of drugs from the knee joint.

Albumins↗
PubMed2001

Biodegradable poly-D,L-lactic acid-polyethylene glycol block copolymers as a BMP delivery system for inducing bone.

BACKGROUND: Bone morphogenetic proteins (BMPs) are biologically active molecules capable of eliciting new bone formation. In combination with biomaterials, these proteins can be used in a clinical setting as bone-graft substitutes to promote bone repair. Collagen from animal sources has previously been the preferred carrier material in animal experiments. More recently, synthetic biodegradable polymers have been tested as a delivery vehicle for osteoinductive agents. In earlier studies performed in our laboratory, it was found that the polylactic acid homopolymers (PLA650) and poly-D,L-lactic acid-polyethylene glycol block copolymers (PLA650-PEG200) are viscous liquids that can be used as BMP delivery systems. METHODS: To obtain new PLA-PEG polymers that exhibit greater plasticity, the molecular sizes of PLA and PEG segments in the copolymer chains were increased. Plastic PLA-PEG polymers with various molecular sizes and PLA/PEG ratios were synthesized, mixed with recombinant human (rh) BMP-2, and implanted into the dorsal muscles of mice for 3 weeks to evaluate their capacity to elicit new bone formation. To compare the plastic PLA-PEG polymer with the liquid PLA650-PEG200 polymer, these two polymers were combined with rhBMP-2, implanted, and harvested after 3 weeks. Bone mineral content (BMC), bone area, and bone mineral density (BMD) of the ectopic new bone were measured by means of single energy X-ray absorptiometry (SXA). RESULTS: All of the PLA6,500-PEG3,000 implants with 10 or 20 microg of rhBMP-2 showed new bone formation. In contrast, little or no bone formation was seen in other plastic PLA-PEG implants with rhBMP-2. Control implants that lacked rhBMP-2 did not show new bone formation. Radiographic and histologic examinations showed that the PLA6,500-PEG3,000 implants with rhBMP-2 harvested 3 weeks after implantation had normal bone characteristics with hematopoietic marrow and osseous trabeculae. SXA analysis showed that the values for bone mineral content (BMC), bone area, and bone mineral density (BMD) of new bone resulting from the use of plastic PLA6,500-PEG3,000 polymers with rhBMP-2 were significantly higher than those obtained with the liquid PLA650-PEG200 polymers (p < 0.001 for each of the three values). CONCLUSIONS: These results indicate that the PLA6,500-PEG3000 block copolymer with plastic properties works effectively as a BMP delivery system. These data suggest that the total molecular size and ratio of PLA size to PEG size is an essential factor in determining the efficacy of a BMP delivery system. After implantation, it is possible that the PLA6,500-PEG3,000 pellets might have absorbed tissue fluids and become swollen, resulting in bone formation that exceeded the size of the original implants. This expansion characteristic is a potentially beneficial property, given the intended practical application of the polymer in the repair of bone defects. CLINICAL RELEVANCE: New synthetic biodegradable delivery systems will play an important role in the clinical applications of rhBMPs in which local formation of bone via an osteoinductive graft material is needed. Further pre-clinical and clinical work is necessary to establish the safety of these implants before they are adopted for widespread clinical use.

Animals↗
PubMed2002

A biodegradable injectable implant sustains systemic and ocular delivery of an aldose reductase inhibitor and ameliorates biochemical changes in a galactose-fed rat model for diabetic complications.

PURPOSE: To fabricate and characterize in vitro and in vivo performance of a sustained release biodegradable implant for N-4-(benzoylaminophenylsulfonyl glycine) (BAPSG), a novel aldose reductase inhibitor. METHODS: The ability of BAPSG to inhibit aldose reductase activity and glucose-induced vascular endothelial growth factor (VEGF) expression was assessed in a retinal pigment epithelial cell line (ARPE-19). A poly (DL-lactic-co-glycolic acid) implant containing 50% w/w BAPSG was fabricated and characterized for drug loading, in vitro drug release, and the thermal behavior of the drug and the polymer. Implants were injected subcutaneously into a galactose-fed diabetic rat model and cataract scores, plasma and tissue drug levels, galactitol levels in the lens and the retina, glutathione levels in the plasma, lens, cornea and retina and VEGF expression in the retina were determined on or until 18 days. RESULTS: BAPSG inhibited aldose reductase activity and reduced VEGF expression in ARPE-19 cells. Implants (1 x 4 mm), with a loading efficiency of 106 +/- 7% for BAPSG, were fabricated. Upon implant fabrication, while the glass transition temperature of the polymer decreased, the melting point of the drug was not affected. In vivo drug release correlated well with in vitro release, with approximately 44% drug release occurring in vivo by the end of 18 days. The implant reduced galactitol accumulation, glutathione depletion, cataract scores, and VEGF expression in galactose-fed rats. CONCLUSIONS: An injectable biodegradable implant of BAPSG sustained drug release in vitro and in vivo, and reduced galactitol accumulation, glutathione depletion, cataract scores, and VEGF expression in galactose-fed rats.

Absorbable Implants↗
PubMedDate not supplied

Combined use of polycationic peptide and biodegradable macromolecular polymer as a novel gene delivery system: a preliminary study.

Plasmid(p) DNA was condensed by polycationic peptide polylysine (PLL) to be a core and then encapsulated in biodegradable monomethoxy (polyethyleneglycol)-poly(lactide-co-glycolide)-monomethoxy (poly-ethylene glycol) (PELGE) to form core-shell nanoparticles as a novel gene delivery system PPD (PELGE-PLL-DNA). Nanoparticles formed from PPD had several complementary properties such as improved biocompatibility, decreased cytotoxicity, enhanced pDNA integrity, and the characteristic of lysosomal escape as PLGA nanoparticles. The results demonstrated the potential of this PPD as an efficient gene delivery system.

Cell Line, Tumor↗
PubMed2004

[Studies on design, synthesis and biodegradation of carrier for colon-site specific, drug delivery system].

AIM: To design and synthesize a novel vector for colon-site specific drug delivery system and investigate the relationship between the biodegradation properties and composition of materials in the simulated colon fluid. METHODS: The azocopolymer P (HEMA-MMA-MAA) was synthesized using 2-hydroxyethylmethacrylate (HEMA), methyl methacrylate (MMA) and methacrylic acid (MAA) as comonmer, azobisisobutyronitrilel (AIBN) as initiator, cross-linked with divinylazobezene (DVAB). The chemical structure of the synthesized series of azocopolymer is examined by UV, FTIR spectroscopy and nuclear magnetic resonance data. Their swelling behavior is evaluated by the swelling equilibrium parameter Q, the biodegradation tests of the materials were carried out at physiologically relevant buffer designed to mimic the colon environment. The biodegradation properties were assessed using the differential scanning calorimeters (DSC) and gel permeation chromatography (GPC) and the morphology on the surface of materials before and after degradation was observed by scanning electron microscopy (SEM). RESULTS: The swelling equilibrium parameter Q increased with increasing the contents of HEMA and MAA in the materials. The degradation behavior was relevant to the ratio of three components in the copolymers. CONCLUSION: This materials may become a good carrier for the colon-site specific drug delivery system if the contents of commoners HEMA, MMA and MAA are adjusted reasonably.

Azo Compounds↗
PubMed2006

[Implantation of FK506 drug delivery system into the anterior chamber for inhibiting corneal rejection in high risk rabbit corneal allograft].

OBJECTIVE: To study the effects of a biodegradable FK506 drug delivery system (DDS) on the inhibition of corneal rejection, to measure the concentration of FK506 in the aqueous humor and to study the relationship between intraocular concentration of FK506 and its immunosuppressive effects on corneal rejection. METHODS: Corneal neo-vascularization was induced by 5 - 0 silk sutures in 68 New Zealand rabbits to establish a high risk corneal transplantation model. A unilateral 7 mm diameter central penetrating corneal transplantation was performed with 7.5 mm diameter grafts from health New Zealand rabbit donors. Grafted rabbits were randomized into five groups as follows: Group A: untreated control animals; Group B: DDS anterior chamber recipients without drug; Group C: 1 mg cyclosporine DDS anterior chamber recipients; Group D: 0.1% FK506-olive oil drop recipients; Group E: 0.5 mg FK506 DDS anterior chamber recipients. Grafts were examined with a slit lamp every other day and clinical conditions were scored for up to 28 weeks. The aqueous humor and cornea of Group D and Group E were collected, and the concentration of FK506 was determined. The expression of cytokines IL-2R alpha, MCP-1, Fas and FasL mRNA was detected with in situ hybridization method. RESULTS: The median survival time was (17.9 +/- 4.7) d in Group A (untreated corneal allograft), (20.0 +/- 3.7) d in Group B, (56.3 +/- 8.8) d in Group C, (78.1 +/- 7.2) d in Group D, and over 180 d in Group E. Statistically significant difference (F = 926.37, P = 0.0000) in the survival time of allograft has been found between Group E and other groups. The concentration of FK506 in aqueous humor was (15.7 +/- 2.6) ng/ml in Group E at one week and remained stable for at least 24 weeks, much higher than that in Group D (<0.3 ng/ml). The concentration of FK506 in cornea was also higher in Group E than that in Group D. The expression of cytokines IL-2R alpha and MCP-1 mRNA was detected, but the expression of Fas and FasL mRNA was not detected in Group A. CONCLUSIONS: FK506 DDS implanted in the anterior chamber can significantly prolong corneal allograft survival in high-risk corneal graft rejection model. This intraocular DDS may be a valuable adjunct for the suppression of immune graft rejection in high-risk corneal transplants.

Animals↗
PubMed1999

Phase II results of an intraocular steroid delivery system for cataract surgery.

OBJECTIVE: To evaluate the safety and efficacy of an intraocular biodegradable polymer dexamethasone drug delivery system (DEX DDS) in treating postoperative inflammation after cataract surgery. STUDY DESIGN: Multicenter, randomized, double-masked, parallel group study comparing two dose levels of the DEX DDS to concurrent placebo and no treatment control subjects. PARTICIPANTS: Ninety patients scheduled to undergo extracapsular cataract extraction with phacoemulsification and intraocular lens implantation participated in the study. INTERVENTION: One or two DEX DDSs, each containing 60 microg of dexamethasone, were placed in the posterior chamber after cataract surgery. Patients receiving the placebo received a DDS composed of the same matrix with no active drug. In vivo rabbit studies have determined that the DEX DDS releases dexamethasone into the anterior chamber (AC) for approximately 7 to 10 days. MAIN OUTCOME MEASURES: The AC cells and the AC flare were assessed over a 60-day postoperative period using slit-lamp examination by masked observers. The number and percent of patients in each treatment group requiring additional postoperative topical anti-inflammatory medication were compared. RESULTS: Ninety patients were randomized into 4 treatment groups (30 to the 2 DEX DDS group, 30 to the 1 DEX DDS group, 15 to the placebo DDS group, and 15 to the no treatment group). The control patients required the addition of topical steroids as rescue medication more frequently and sooner than patients receiving DEX DDS (80% vs. 7% at week 2) (P < 0.001). Patients receiving DEX DDS showed a significant reduction in postoperative inflammation as assessed by the combined AC cell and flare scores when compared to the control group from day 3 (P = 0.002) through week 3. The DEX DDS was well tolerated. No clinically significant difference in any safety evaluations, including intraocular pressure, was seen between the DEX DDS-treated and control groups. CONCLUSION: The DEX DDS was safe and effective in suppressing postoperative inflammation after uncomplicated cataract surgery. Additional topical anti-inflammatory drops were not needed for most patients.

Adult↗
PubMed2006

Local antibiotic delivery with OsteoSet, DBX, and Collagraft.

Biodegradable local antibiotic delivery systems have gained interest for prophylaxis and treatment of musculoskeletal infections. We studied the biodegradable materials Osteo- Set, DBX and Collagraft for local delivery of vancomycin and gentamicin in vitro. We determined the antimicrobial activity of vancomycin and gentamicin after mixing with each biodegradable material and determined the release of each antimicrobial from each material in an intermittent flow chamber. Antimicrobial activity was expressed as percent of antimicrobial loaded into each sample that was detected; antimicrobial release was expressed as concentration (microg/mL) after timed intervals of chamber flow, peak concentration, area under the curve and percent antimicrobial recovered. Activity of vancomycin after mixing with Osteo- Set, DBX and Collagraft was > 73%. Activity of gentamicin after mixing with DBX was 100%; after mixing with OsteoSet and Collagraft it was reduced to < 61%. AUC0-48hrs of vancomycin was 469, 426 and 432 microg x hr/mL, and the AUC0-48hrs of gentamicin was 368, 306 and 301 microg x hr/mL after release from OsteoSet, DBX, and Collagraft, respectively. Recovered percentages of vancomycin were 39%, 11% and 25%, and recovered percentages of gentamicin were 39%, 9% and 23% after release from OsteoSet, DBX, and Collagraft, respectively. OsteoSet, DBX and Collagraft may be suitable for local delivery of vancomycin and gentamicin.

Absorbable Implants↗
PubMed1996

Biodegradable injectable implant systems for long term drug delivery using poly (lactic-co-glycolic) acid copolymers.

Poly (lactide-co-glycolide) (PLG), is one of the most widely employed biodegradable synthetic polymers for sustained-release preparations. In the present work, PLG (50:50) copolymer has been used to deliver diclofenac sodium in the form of microspheres and in situ gel-forming systems, both of which can be injected subcutaneously. The pharmacodynamic and pharmacokinetic studies in the adjuvant-induced arthritic rats showed that the microspheres offered steady therapeutic levels of the drug in the plasma for about 16 days following a single subcutaneous injection. However, the in situ gel-forming system provided a significantly higher maximum plasma concentration and increased inhibition of inflammation, maintained for about 10 days. Injectable microspheres and in situ gel-forming implant systems of PLG (50:50) copolymer may therefore be considered as prospective implantable controlled-release dosage forms to deliver drugs in long-term therapy of chronic ailments.

Animals↗
PubMed2000

Biodegradable poly (lactic acid) microspheres for drug delivery systems.

In connection with aim of maximizing the bio-availability of conventional drugs with minimum side-effects, new drug delivery systems (DDS) continue to attracted much attention. The controlled or sustained release of drugs represents one such approach, and in this regard report upon a study of DDS using biodegradable polymers which include poly (lactic acid) (PLA), poly (glycolic acid), and their copolymers (PLGA). Much attention is being paid to the controlled release of bio-active agents from microcapsules and microspheres made of biodegradable polymers, such as lactic acid homopolymers, as well as copolymers of glycolic acid. (11-21) Microcapsules or microspheres are injectable and able to provide pre-programmed durations of action, offering several advantages over the conventional dosage forms. This article reviews the results of a work program conducted in collaboration with a medical doctor upon DDS using biodegradable microspheres, such as PLA and PLGA.

Animals↗
PubMed1991

Biodegradable microparticles as controlled release antigen delivery systems.

A model but poor immunogen, ovalbumin (OVA), was entrapped in a novel antigen delivery system comprising poly (D,L-lactide-co-glycolide) (PLGA) microparticles. Both the primary and the secondary IgG antibody responses obtained with OVA in microparticles were compared to those obtained with OVA emulsified in Freunds' adjuvants by two routes of immunization, intraperitoneal (i.p.) and subcutaneous (s.c.) injection. Following single i.p. or s.c. injections, the IgG serum antibody responses to OVA in microparticles were significantly greater than the responses to OVA in Freunds' complete adjuvant (FCA) for up to 10 weeks. After s.c. booster doses of OVA, the secondary IgG antibody responses to OVA in microparticles remained greater than the secondary responses to OVA in Freunds', but not significantly so. Furthermore, the primary IgG responses to OVA in microparticles obtained 8-12 weeks after a single i.p. injection were greater than the secondary responses to OVA in Freunds' obtained by repeat s.c. injections at Weeks 0 and 6. These results demonstrate that microparticles can function as potent antigen delivery systems for an entrapped antigen. Due to their ability to degrade slowly in vivo and to release entrapped antigens, microparticles have considerable potential as controlled release antigen delivery systems for the induction of long-term immune responses.

Animals↗