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PubMed1983

The effect of a biodegradable contraceptive capsule (Capronor) containing levonorgestrel on gonadotropin, estrogen, and progesterone levels.

Eight ovulatory women participated in the preliminary evaluation of a new method of contraception. The technique consisted of subdermal implantation of a biodegradable capsule capable of controlled release of levonorgestrel. The study spanned five menstrual cycles: three observation cycles to confirm ovulation, a cycle with the capsule implanted, and a follow-up observation cycle after its removal. All subjects who were sexually active relied on barrier contraception during the study. Basal body temperature determinations were made throughout all five cycles, and the last three cycles included serum assays of luteinizing hormone, follicle-stimulating hormone, estradiol, progesterone, and levonorgestrel on days 5, 8 to 18, and 22. All subjects except one experienced suppression of ovulation while the capsule was in place. No serious adverse effects were encountered. These results would seem to justify a larger clinical trial to assess the actual efficacy of this contraceptive method.

Biodegradation, Environmental↗
PubMed1994

Pharmacokinetics of once-a-month injectable contraceptives.

The addition of a short- or medium-acting estrogen ester to the long-acting progestins depot-medroxyprogesterone acetate (DMPA) and norethisterone enanthate (NET-EN) to produce "combined" injectable formulations has proved a successful strategy in the development of once-a-month injectable contraceptives. Recent clinical pharmacokinetic studies undertaken on once-a-month injectable contraceptives in various WHO Collaborating Centers have guided the selection of the estrogen-progestogen combinations, ratios and dose schedules. At least three combined once-a-month injectable preparations exhibit acceptable pharmacokinetic and pharmacodynamic profiles; however, further improvement in the design of optimal estrogen/progestin injectables are expected during this decade.

Adolescent↗
PubMed1987

Norethisterone contraceptive microspheres.

Two formulations of polylactic and polyglycolic acid microcapsules containing 75 and 100 mg of NET respectively were studied for a 90-day period of anticipated contraceptive effect in two groups of five women. A 200 mg dose of NET preparation was also studied for a 180-day period of anticipated contraceptive effect in 19 women. Alteration in menstrual cycle, with tendency to short bleeding episodes, spotting days, and amenorrhea were the most important collateral effects. In the majority of cases, ovulation was inhibited. No cases of pregnancy were presented. The obtained NET circulating levels were very stable during the period of anticipated contraceptive effect.

Contraception↗
PubMed1991

Contraception with progestogens and progesterone during lactation.

The growth and development of breastfed infants whose mothers used the contraceptive implants Norplant containing levonorgestrel and the injectable containing norethisterone enanthate were studied. Each group comprised of 120 women who initiated the use during the 5th to 7th week postpartum and were compared with a similar number of IUD using mothers. The breastfeeding performance did not differ between groups. The infants of the three groups performed similarly as regards their physical growth and health as well as the time of acquisition of the various milestones of psychomental development. A vaginal ring releasing 10 mg of the "natural" progesterone per 24 h was tested in breastfeeding mothers. The continuous use of the ring produced a serum level of progesterone around 4 ng/ml. This was effective in augmenting lactational infertility even through the later phases of breastfeeding when such an effect starts to wane off. The use of the ring proved to be acceptable and had no ill-effect on breastfeeding or infant growth or health. Using the natural progesterone as a contraceptive adds a new measure of safety, since the amount of the steroid secreted in the mother's milk will not be effectively absorbed from the infant's gut. These studies suggest the possibility of using two new methods for breastfeeding mothers; Norplant and the progesterone vaginal contraceptive ring. These can be initiated early postpartum, whenever this is considered needed.

Contraceptive Devices, Female↗
PubMed2006

Effects of local continuous release of brain derived neurotrophic factor (BDNF) on peripheral nerve regeneration in a rat model.

The purpose of this study was to evaluate the effect of continuously released BDNF on peripheral nerve regeneration in a rat model. Initial in vitro evaluation of calcium alginate prolonged-release-capsules (PRC) proved a consistent release of BDNF for a minimum of 8 weeks. In vivo, a worst case scenario was created by surgical removal of a 20-mm section of the sciatic nerve of the rat. Twenty-four autologous fascia tubes were filled with calcium alginate spheres and sutured to the epineurium of both nerve ends. The animals were divided into 3 groups. In group 1, the fascial tube contained plain calcium alginate spheres. In groups 2 and 3, the fascial tube contained calcium alginate spheres with BDNF alone or BDNF stabilized with bovine serum albumin, respectively. The autocannibalization of the operated extremity was clinically assessed and documented in 12 additional rats. The regeneration was evaluated histologically at 4 weeks and 10 weeks in a blinded manner. The length of nerve fibers and the numbers of axons formed in the tube was measured. Over a 10-week period, axons have grown significantly faster in groups 2 and 3 with continuously released BDNF compared to the control. The rats treated with BDNF (groups 2 and 3) demonstrated significantly less autocannibalization than the control group (group 1). These results suggest that BDNF may not only stimulate faster peripheral nerve regeneration provided there is an ideal, biodegradable continuous delivery system but that it significantly reduces the neuropathic pain in the rat model.

Animals↗
PubMed1989

Contraceptive efficacy of norethindrone encapsulated in injectable biodegradable poly-dl-lactide-co-glycolide microspheres: phase II clinical study.

Contraceptive efficacy of injectable norethindrone (NET) microspheres of 90 day duration was evaluated for 6 months: nine women received two injections of 65 mg each and eight received two injections of 100 mg each with 90 days between each injection. Average serum NET levels were 5 to 9 ng/mL on the day after injection and subsequently remained at 1 to 3 ng/mL. With 65 and 100 mg doses, respectively, 36% and 25% of cycles had normal bleeding patterns, 36% and 48% were amenorrheic, and the remaining 28% and 27% had prolonged bleeding. Also, 56% and 40% of cycles showed increased spotting for the 65 mg and 100 mg dose, respectively. There was no incidence of pregnancy or serious side effects. The mean serum NET concentration returned to RIA nonspecific basal levels 100 days after the second injection. Women returned to ovulatory cycles between days 100 to 115 after the second injection.

Adult↗
PubMed2001

Biodegradable PLGA microspheres as a delivery system for malaria synthetic peptide SPf66.

SPf66 is the first chemically synthesised vaccine to elicit a partial protective immune response against malaria. The aluminium hydroxide (alum)-adsorbed SPf66 vaccine is weakly immunogenic and of poor to moderate efficacy in humans. To investigate the possibility of improving SPf66 vaccine immunogenicity, a delivery system based on poly-D,L-lactide-co-glycolide (PLGA) microspheres was developed and the immune response induced after its subcutaneous administration into mice was evaluated. Microspheres were prepared by a solvent extraction/double emulsion (w/o/w) method and characterised for morphology, size, peptide loading, release profile and peptide integrity. The in vitro and in vivo results obtained showed that there was no apparent effect of the encapsulation procedure on SPf66 integrity and immunogenicity. The subcutaneous administration of microspheres showed a significantly higher immune response (serum IgG levels) than that obtained with alum adsorbed SPf66 and it was comparable to that of SPf66 emulsified with Freund's adjuvant (FA). These observations illustrate the potential of PLGA microspheres as a delivery system for chemically synthesised antigens.

Amino Acid Sequence↗
PubMed2002

Co-delivery of an antisense oligonucleotide and 5-fluorouracil using sustained release poly (lactide-co-glycolide) microsphere formulations for potential combination therapy in cancer.

Antisense oligonucleotides (AODNs) can selectively inhibit oncogene expression by Watson-Crick hybridisation to target mRNA and are being increasingly considered for use in combination with conventional drugs for potential anticancer therapy. Combination therapy of AODNs and cytotoxic agents using biodegradable polymeric delivery systems potentially offers several advantages including site-specific or organ-directed targeting, protection from digesting enzymes, and improved pharmacokinetics/pharmacodynamics resulting from sustained delivery of the entrapped drugs. Using a model AODN targeting the epidermal growth factor receptor (that is over-expressed in several cancers including breast and brain cancer) and the commonly used cytotoxic agent, 5-fluorouracil (5-FU), we have examined the use of poly (lactide-co-glycolide) (P(LA-GA)) microsphere formulations for co-delivery of these agents. Both agents were either co-entrapped in a single microsphere formulation or individually entrapped in two separate microsphere formulations and release profiles determined in vitro. Using a double emulsion method for preparing the P(LA-GA) microspheres suitable entrapment and sustained release over 35 days was observed in both types of formulation. Release of AODN and 5-FU from all formulations appeared to be biphasic. However, the release rates of the two agents were significantly slower when co-entrapped as a single microsphere formulation compared to those obtained with the separate formulations. Electrophoretic mobility shift assays suggested that this might be, in part, due to an interaction of 5-FU with the oligodeoxynucleotide (ODN). Further, our data suggest that by mixing individual formulations of 5-FU and ODNs at different mass ratios allowed greater flexibility in achieving the desired release profile as well as avoiding potential drug-drug interactions. Thus, co-administration of individual P(LA-GA) microsphere formulations of AODNs and 5-FU, at appropriate mass ratios, appears worthy of further investigation for the potential co-delivery of these anti-cancer agents in vivo.

Antimetabolites, Antineoplastic↗
PubMed1983

Poly(DL-lactide-co-glycolide)/norethisterone microcapsules: an injectable biodegradable contraceptive.

Microcapsules made from a biocompatible, biodegradable polymeric excipient, poly(DL-lactide-co-glycolide) (DL-PLGA) that contained 22 weight percent (wt %) norethisterone (NET), were prepared by a solvent-evaporation microencapsulation process. The effects of changing both the lactide-to-glycolide ratio of the DL-PLGA and the size of the microcapsules on the rate of NET release and the rate of excipient biodegradation were determined in vivo. NET release rates were determined in baboons after injecting the microcapsule formulations intramuscularly. Serum samples obtained at various times following treatment were analyzed for NET, progesterone, and estrogen by radioimmunoassay (RIA). Biodegradation kinetics were determined by injecting NET microcapsules made from radiolabeled DL-PLGA intramuscularly into the hind legs of rats. Residual radioactivity at the injection site was determined at various times after treatment by combustion analysis of the muscle tissue. Changing the ratio of the comonomers to include more glycolide (DL-lactide:glycolide-96:4, 92:8, 87:13, 74:26) increased the rate of NET release and accelerated the biodegradation of the copolymer excipient. Decreasing the size of the microcapsules increased the rate of NET release. On the basis of these studies a NET microcapsule formulation has been identified for clinical testing which releases NET for 3 months and biodegrades completely within 6 months.

Animals↗
PubMed2005

Carboplatin sustained delivery system using injectable microspheres.

A controlled carboplatin delivery system using biodegradable polymer has been used in this study. The purpose was to evaluate the local and systemic effects of injectable, biodegradable microspheres containing carboplatin when injected as aqueous suspension subcutaneously in rats. Biocompatibility and toxicity of empty microspheres and microspheres loaded with carboplatin were evaluated by clinical and histological examination. The diffusion of carboplatin in tissues and time of drug release were evaluated by platinum determination in plasma and tissues over the time. The results of the study suggest that microspheres provide a sustained slow release of carboplatin and that multiple inoculations of microspheres containing drug and no evidence of local or systemic toxicity is found. This device may be useful in the treatment of solid tumours.

Absorbable Implants↗
PubMed1998

The use of locally delivered doxycycline in the treatment of periodontitis. Clinical results.

The clinical safety and effectiveness of a subgingivally delivered biodegradable drug delivery system containing doxycycline hyclate (DH) has been evaluated in 3 large 9-month multicenter randomized parallel-design controlled clinical trials. A total of 1002 patients having at least 2 quadrants with a minimum of 4 qualifying pockets > or = 5 mm that bled on probing were enrolled. Each subject had > or = 7 mm probing depths in 2 of the qualifying pockets. Study 1 (n=180) compared DH to sanguinarine chloride (SC) and vehicle control (VC). Study 2 (n=411) and study 3 (n=411) compared DH to VC, scaling and root planing (SRP), and oral hygiene (OH). Clinical measurements included probing depth reduction (PDR), attachment level gain (ALG), bleeding on probing reduction (BOP) and plaque index (PI). Analysis of efficacy data from these 3 trials show all treatments gave significant positive clinical changes from baseline at most time points. Study 1 results indicate that DH was superior to SC and VC in PDR at all time points. Similar results were obtained for ALG when DH was compared to SC and VC. For BOP reductions, DH was superior to VC at all time points and to SC at months 5 through 9. For DH, mean ALG in deep (> or = 7 mm) pockets was 1.4 mm; mean PDR for DH was 2.6 mm. For moderate (5 to 6 mm) pockets, ALG was 0.8 mm and PDR 1.5 mm. Studies 2 and 3 reported mean month 9 ALG for SRP as 0.7 mm and 0.8 mm, respectively. For DH, ALG was 0.8 mm in both studies 2 and 3. At month 9 in studies 2 and 3, 29% and 31% of DH sites and 27% and 34% of SRP sites showed ALG > or = 2 mm. Probing depth reductions followed the same pattern, with 32% of DH sites and 32% of SRP sites showing > or = 2 mm PD reductions in study 2, and 41% of DH and 43% of SRP sites showing PDR of > or = 2 mm in study 3. Comparisons between DH, VC, and OH treatment groups in studies 2 and 3 showed DH treatment was statistically superior to VC and OH at most time points. Results of these 3 large clinical trials demonstrate that treatment of periodontitis with 10% doxycyline hyclate in a bioabsorbable delivery system is equally as effective as SRP and superior in effect to VC and OH in reducing the clinical signs of adult periodontitis.

Administration, Topical↗
PubMed1977

Some mechanical property considerations of reconstituted collagen for drug release supports.

Reconstituted collagen, having been shown previously to be biodegradable and to have low immunologic activity, has been further evaluated here as a vehicle for drug delivery. Mechanical stress-strain (Young's Modulus), mechanical abrasion resistance, and steroid (medroxyprogesterone) diffusion rates have been determined for collagen films subjected to nine different chemical preparative treatments. The treatments fall into three categories: formaldehyde crosslinking, chrome tanning, and a combination of formaldehyde and chrome. Based on our conditions, the formaldehyde films have been found to have higher Young's Moduli and lower diffusion release rates of medroxyprogesterone acetate (MPA) than the untreated films. The largest chrome complexes apparently open up the collagen matrix to yield higher diffusion release rates than the untreated film. The Young's Modulus is 2--3 times higher for the chrome films that the untreated film but the abrasion resistance is generally substantially less. Combination chrome/formaldehyde treatments yield film properties between those of the two separate treatments.

Chromium↗
PubMed2004

[Mechanisms of age-related hearing loss and strategies for protection and restoration of hearing].

Hearing impairment is the most frequent disability in elderly individuals; however, we have limited options for treatment of age-associated hearing loss. To establish novel strategies for the treatment of age-associated hearing loss, it is crucial to elucidate the mechanisms of age-associated hearing loss. Studies on animal models and human temporal bones have indicated a close relationship between degeneration of the spiral ganglion neurons and stria vascularis and age-associated hearing loss. We have developed a drug delivery system using biodegradable gel for the inner ear to protect inner ears against aging. In addition, recent studies on cell therapy for the inner ear have suggested the efficacy of cell transplantation for restoration of hearing.

Absorbable Implants↗
PubMed1983

Controlled release of contraceptive steroids from biodegradable poly (ortho esters).

The synthesis of poly (ortho esters) by the condensation of diols and diketene acetals and the in vitro drug release from devices containing norethindrone or levonorgestrel and either Na2C03 or Na2S04 is described. Drug release kinetics are rationalized in terms of an osmotically driven water imbibition and release of the steroid from the swollen polymer. No polymer erosion occurs when Na2C03 is used. When Na2S04 is used, polymer erosion does take place but lags drug release. As expected from the known acid lability of ortho ester linkages, drug release is strongly dependent on the pH of the external environment and a dramatic increase occurs between pH 5.5 and 5.0. The glass transition temperature of the poly (ortho esters) can be continuously and predictably varied between 115 and 20 degrees Celsius by using an appropriate ratio of 1,6-hexanediol, and trans-cyclohexanedimethanol in the condensation reaction with the diketene acetal. Polymer hydrophilicity can be varied by the incorporation of varying amounts of the hydrophilic diol diethylene glycol into the polymer. Molecular weight control can be readily achieved by skewing the stoichiometry, and polymers with weight average molecular weights between 20,000 and in excess of 100,000 have been produced. Hydrolytic degradation of the poly (ortho esters) produces the expected products.

Clinical Laboratory Techniques↗