Biodegradable microsphere contraceptive system.
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Animals↗
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Results for “Biodegradable Delivery Systems”
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Immunostimulatory properties of CpG-oligonucleotides are enhanced by the use of protamine nanoparticles.
The aim of this paper was to investigate if the immunostimulatory effects of CpG-oligonucleotides (CpG-ODN) can be enhanced by the use of biodegradable protamine nanoparticles (proticles). We analyzed size, surface charge, and morphology of protamine nanoparticles containing CpG-ODN with photon correlation spectroscopy and transmission electron microscopy. Immunostimulatory effects of these nanoparticles on B cells, plasmacytoid dendritic cells (PDC), peripheral blood mononuclear cells, and whole blood were studied. Cytokine production, activation of the cells in terms of upregulation of surface molecules and uptake of nanoparticles were examined. We found that the use of protamine nanoparticles significantly increased (20-fold) CpG-ODN mediated interferon (IFN)-alpha production of PDC. ODN uptake in PDC was only marginally enhanced. CpG-ODN mediated IP-10 production in whole blood was strongly enhanced by the use of nanoparticles. Apart from a slight increase in CpG-ODN-induced interleukin (IL)-6 production in B cells, other parameters like the CpG-mediated activation of B cells and PDC as well as tumor necrosis factor (TNF)-alpha production of PDC remained largely unchanged. The use of control ODN indicated that the protamine nanoparticles themselves have no immunostimulatory properties. These results strongly support the use of particulate delivery systems like biodegradable protamine nanoparticles for the development of CpG-ODN-based therapeutics.
Adjuvants, Immunologic↗
Poly(ortho ester) biodegradable polymer systems.
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Anhydrides↗
Multi-center comparative evaluation of subgingivally delivered sanguinarine and doxycycline in the treatment of periodontitis. I. Study design, procedures, and management.
The design and conduct of a 9-month multi-center clinical trial to evaluate the safety and efficacy of subgingivally delivered 5% sanguinarium chloride (SC) and 10% doxycycline hyclate (DH) from a biodegradable drug delivery system in the treatment of adult periodontitis is described. The 3-group randomized study of 180 adults with moderate to severe periodontitis was a modified double-blind parallel design. One group received DH, one group received SC, and the other group received the vehicle control (VC). Patients selected had two quadrants with a minimum of four periodontal pockets > or = 5 mm in depth with two sites > or = 7 mm. All qualifying sites exhibited bleeding on gentle probing. Qualifying sites were treated at baseline and again at 4 months. Clinical response was assessed by measuring attachment level, probing depth, and bleeding on probing at monthly examinations at qualifying sites and the entire dentition. The plaque index was measured monthly to verify oral hygiene status. The parallel design afforded the opportunity to distinguish between treatment effectiveness of SC, DH, and VC independent of possible crossover effects. Also the effectiveness of oral hygiene in untreated sites of the mouth could be evaluated. Finally, treatment effects in moderate (5 to 6 mm) and deep (> or = 7 mm) pockets in both treated and untreated sites could be compared. The design was capable of simulating a periodontal practice maintenance program and assessing the response according to maintenance and treatment history. Study management procedures that emphasized center examiner and therapist training and adherence to protocol and procedures to reduce variability are described.
Administration, Topical↗
Antibiotic loaded chitosan bar. An in vitro, in vivo study of a possible treatment for osteomyelitis.
A biodegradable drug delivery system of a gentamicin loaded chitosan bar with sustained antibiotic effect is described. Chitosan has proven to be a biocompatible aminopolysaccharide and a matrix for controlled release of pharmaceuticals. Combined crosslinking, solvent evaporation, and a cylinder model cutting technique was used to prepare the chitosan bar. Sustained diffusion of gentamicin into the surrounding medium was seen using a release test in vitro. Approximately 11% gentamicin was released from the bar in the first 24 hours. The gentamicin released from the bar showed significant antibacterial activity. The bar implanted in the proximal portion of the rabbit tibia produced a low blood concentration of gentamicin, but a much higher concentration was produced in local bone and in the hematoma. In all bone tissue around the bar, the gentamicin concentration exceeded the minimum inhibitory concentration for the common causative organisms of osteomyelitis for approximately 8 weeks. The implant caused no systemic side effects. Based on these test results together with the chitosan characteristics of biodegradable, antibiotic, and immunologic activity, the gentamicin loaded chitosan bar seems to be a clinically useful method for the treatment of bone infection. This system has an advantage over other systems in that it avoids a second operation for removal of the carrier.
Absorbable Implants↗
Chemotherapy and delivery systems--helminths.
The milbemycins are the only novel broad spectrum anthelmintic chemicals to reach the market place in the last 10 years. Many new systems for delivery and strategies for rational use have, however, been introduced. Boluses which are retained by virtue of specific gravity and by variable geometry are now available. They contain benzimidazoles, morantel, ivermectin and levamisole. Their release mechanisms involve preferential corrosion of a retaining metal core, constant diffusion from a laminated ethylene acetate sandwich, and a hydrostatic pump driven by osmotic pressure. Some are biodegradable. Experimental delivery systems have been developed incorporating ear implants and liposomes. The anthelmintic efficacy of some drugs has been potentiated by the synergistic action of metabolic inhibitors and these combinations hold promise for the future. Much new information is now available on those factors which affect anthelmintic efficacy such as concurrent administration with food and the presence of the target parasites themselves. This knowledge provides a sound basis for the rational use of anthelmintic drugs.
Alginates↗
New polymers for drug delivery systems in orthopaedics: in vivo biocompatibility evaluation.
The use of biodegradable polymers for drug delivery systems excluded the need for a second operation to remove the carrier. However, the development of an avascular fibrous capsule, reducing drug release, has raised concern about these polymers in terms of tissue-implant reaction. Five novel polymers were evaluated in vivo after implantation in the rat dorsal subcutis and compared to the reference polycaprolactone (PCL). Poly(cyclohexyl-sebacate) (PCS), poly(L-lactide-b-1,5-dioxepan-2-one-b-L-lactide) (PLLA-PDXO-PLLA), two 3-hydroxybutyrate-co-3-hydroxyvalerate copolymers (D400G and D600G), and a poly(organo)phosphazene (POS-PheOEt:Imidazole) specimens were histologically evaluated in terms of the inflammatory tissue thickness and vascular density at 4 and 12 weeks from surgery. The highest values of inflammatory tissue thickness were observed in D600G (P < 0.01), PCS (P < 0.001) and PLLA-PDXO-PLLA (P < 0.001) at 4 weeks, while POP-PheOEt:Imidazole showed the lowest value of inflammatory tissue thickness (P < 0.05) at 12 weeks. D400G, D600G, PLLA-PDXO-PPLA and POP-PheOEt:Imidazole showed higher (P < 0.001) values of vascular density near the implants in comparison to PCL at 4 weeks. Finally, D400G and D600G increased their vessel densities while POP-PheOEt:Imidazole and the synthetic polyester PLLA-PDXO-PLLA presented similar vessel density values during experimental times. These different behaviours to improve neoangiogenesis without severe inflammatory tissue-responses could be further investigated with drugs in order to obtain time-programmable drug delivery systems for musculoskeletal therapy.
Animals↗
A new long-acting injectable microcapsule system for the administration of progesterone.
A long-acting injectable microcapsule system for the controlled-release systemic administration of progesterone (P4) is described. The system consists of microcapsules made of the biodegradable polymer, d,l-polylactic acid, which contain crystalline P4. Following injection, P4 is released from the microcapsules by diffusion and biodegradation of the polymer matrix. The rate of P4 release from the prototype microcapsule system in vivo is 1.3 microgram of P4/day/mg of microcapsules, and the duration of release is 30 days. Vaginal estrous cycles in rats and cyclic ovarian function in baboons were inhibited for 1 month following a single injection of P4 microcapsules. The effects of continuous progesterone therapy on reproductive function in both rats and baboons are dose-dependent. The utility of the system as a once-a-month injectable contraceptive is established in the baboon model.
Animals↗
Controlled delivery system for norethindrone based on biodegradable poly-alpha,beta-(hydroxyalkyl)-DL-aspartamide.
The article describes the preparation of poly-(hydroxyalkyl)-DL-aspartamide (PHAA) by a (ring) opening reaction by hydroxyalkylamino; norethindrone (NET), as a model drug, was coupled to the polymers via hydroxyalkylamino spacers. PHAA and NETPHAA conjugates were characterized by FTIR, DSC, x-ray,(13)C NMR, and scanning electron microscopy and their structure were confirmed. The biocompatibility of PHAA was tested. The study showed that PHAA was a hydrophilic, nontoxic in vivo, nonantigenic material and had good biocompatibility as a drug carrier. The effect on drug release from the polymer of length of side chain, initial drug loading, and particle size of the polymer drug were investigated in tris-HCl buffer solution (pH 7.4, t = 37 degrees C). In vivo release in rabbits also was performed for 120 days. The experiment indicated that the concentration of NET in rabbits can be 1-2 microg/ml serum after 1 month; 10% of NET had been released from the polymer.
Animals↗
Clinical evaluation of an improved injectable microcapsule contraceptive system.
Pharmacokinetics and pharmacodynamics of a long-acting injectable microcapsule, poly(DL-lactide-co-glycolide), delivery system were tested in 10 women. Two doses (75 or 100 mg of norethindrone) were administered by intramuscular injection. Treatment suppressed ovarian function and inhibited ovulation for 3 months in all subjects. Levels of norethindrone in subjects who received the 100 mg dose were proportionately higher than those in subjects who received the 75 mg dose. Subsequent to the injection, there was a rapid rise in the serum levels of norethindrone followed by a gradual decline until 8 to 10 weeks. Between 10 and 20 weeks after treatment, there was a secondary rise and fall in the serum levels of norethindrone. Treatment caused suppression of the endometrium for 3 months, and, except for spotting and irregular menstrual cycles, there were no adverse side effects. Treatment had no significant effect on serum lipids.
Adult↗
The use of biodegradable norethisterone implants as a 6-month contraceptive system.
The effects of a 6-month contraceptive system of biodegradable norethisterone (NET) implants on the menstrual cycle, estradiol and progesterone levels, the presence of side effects, its contraceptive effectiveness, and the NET levels achieved were studied in a group of nine women. There was practically no disruption of the menstrual cycle and no important side effects. Ovulation was inhibited in four subjects, and another four subjects remained ovulatory. In all the subjects a cyclic secretion of estradiol was maintained. No pregnancies occurred. The circulatory levels of NET were very stable throughout the 6-month period of implant use.
Adult↗
Long-acting steroidal contraception: an update.
Long-acting, injectable contraceptives first became available in the 1960s. It is currently estimated that almost 3.5 million women are now using depo-medroxyprogesterone acetate (DMPA); 800,000 are using norethindrone enanthate (NET-EN), and another few hundred thousand are using a variety of once-a-month injectables comprised of progestin plus estrogen. The advantages of injectable contraceptives are that they are highly effective, independent of coitus, easily administered, and they ensure regular contact with health services personnel. The last factor may be considered a disadvantage by some, since contact is more frequent than would be required for routine health services. The major disadvantage of the progestin-only formulations is disruption of normal menses, giving rise to unpredicted episodes of bleeding and spotting. With the once-a-month formulation, on the other hand, there are few discontinuations due to disruption of menses. For a long-acting method to be used longer than 6 months, it is desirable to choose an implant, since the method can be discontinued at will. The first implant system to be developed was Norplant, a set of six rubber capsules filled with levonorgestrel and implanted under the skin. The implant releases sufficient levels of medication to protect against pregnancy. For the first 5 years, the average failure rate was four or five per thousand users per year. The failure rate for women using standard oral contraceptives is approximately 20 to 50 per thousand. The most common side effect of the implant method is the disruption of the menstrual cycle, an effect that is particularly marked in the first month of use.(ABSTRACT TRUNCATED AT 250 WORDS)
Contraception↗
Morphological characterization of microspheres, films and implants prepared from poly(lactide-co-glycolide) and ABA triblock copolymers: is the erosion controlled by degradation, swelling or diffusion?
Erosion of biodegradable parenteral delivery systems (PDS) based on ABA copolymers consisting of poly(L-lactide-co-glycolide) (PLGA) A-blocks attached to polyethylene oxide (PEO) B-blocks, or PLGA is important for the release of macromolecular drugs. The degradation behavior of four types of PDS, namely extruded rods, tablets, films and microspheres, was studied with respect to molecular weight, mass, polymer composition and shape and microstructure of the PDS. For each device the onset time of bulk erosion (t(on)) and the apparent rate of mass loss (k(app)) were calculated. In the case of PLGA, the t(on) was 16.2 days for microspheres, 19.2 days for films and 30.1 days for cylindrical implants and tablets. The k(app) was 0.04 days(-1) for microspheres, 0.09 days(-1) for films, 0.11 days(-1) for implants and 0.10 days(-1) for tablets. The degradation rates were in the same range irrespective of the geometry and the micrographs of eroding PDS demonstrated pore formation; therefore, a complex pore diffusion mechanism seems to control the erosion of PLGA devices. In contrast, PDS based on ABA copolymers showed swelling, followed by a parallel process of molecular weight degradation and polymer erosion, independent of the geometry. The contact angles of ABA films increased either with decreasing PEO content or with increasing chain length of the PEO B-blocks. In summary, the insertion of a hydrophilic B-block leads to an erosion controlled by degradation of ABA copolymers, whereas for PLGA a complex pore diffusion of degradation products controls the rate of bulk erosion.
Biodegradation, Environmental↗
An in vivo study of the chlorhexidine release profile of the PerioChip in the gingival crevicular fluid, plasma and urine.
The release profile of chlorhexidine from the PerioChip (Chip), a biodegradable local delivery system that contains 2.5 mg of chlorhexidine gluconate (CHX) in a cross-linked hydrolyzed gelatin matrix, into the gingival crevice, was evaluated in an in vivo, open label, single-center, 10-day pharmacokinetic study conducted on 19 volunteers with chronic adult periodontitis. Each volunteer had a single chip inserted into each of 4 selected pockets, with probing pocket depths of between 5-8 mm, at time 0. Gingival crevicular fluid (GCF) samples were collected using filter paper strips prior to Chip placement and at 2 h, 4 h, 24 h and 2, 3, 4, 5, 6, 8, and 9 days post-Chip placement. The GCF volume was measured using a calibrated Periotron 6000. Blood samples were collected at times 0, 1, 4, 8, 12 h and 5 days post-dosing. Urine was collected as a total 24-h specimen immediately post-dosing and 2 single samples at time 0, prior to dosing, and 5 days. The CHX was eluted from the paper strips and the CHX levels in GCF, blood and urine quantified using HPLC. The results indicate an initial peak concentration of CHX in the GCF at 2 h post-Chip insertion (2007 microg/ml) with slightly lower concentrations of between 1300-1900 microg/ml being maintained over the next 96 h. The CHX concentration then progressively decreased until study conclusion with significant CHX concentrations (mean=57 microg/ml) still being detectable at study termination. CHX was not detectable in any of the plasma or urine samples at any time point during the study. These results indicate that the PerioChip can maintain clinically effective levels of CHX in the GCF of periodontal pockets for over 1 week with no detectable systemic absorption.
Adult↗
Clinical evaluation of injectable biodegradable contraceptive system.
A new long-acting injectable contraceptive system was tested in 24 women. The system consists of microspheres made of biodegradable d,l-polylactic acid in which micronized crystals of norethisterone (NET) are homogeneously dispersed. In previous animal studies we showed that NET is slowly released from the microspheres for 6 months, and after the drug is released, the microspheres biodegrade into lactic acid by the process of hydrolysis. The serum levels of NET, estrogen, and progesterone were monitored by radioimmunoassay, and the effects of treatment on ovarian function and menstrual bleeding were evaluated. The doses ranged from 29 to 370 mg of microspheres containing 7.25 to 94.5 mg of NET or 0.134 to 2.30 mg of NET/kg of body weight. The duration of the NET release was 6 months, and the serum NET profiles in women were similar to those previously described in subhuman primates. Following a small burst, there was a gradual decline in the serum levels of NET over 6 months after treatment. The serum levels of NET varied in proportion to the dose. Doses less than 0.267 mg of NET/kg had no discernible effect on either ovarian function or menstrual bleeding. Doses ranging from 0.419 to 2.30 mg had variable effects on ovarian function and menstrual bleeding. Higher doses caused suppression of ovarian function for longer periods of time, increased the interval between episodes of menstrual bleeding, and decreased the quantity of blood loss during each episode. The treatment was well tolerated by all subjects, and, with the exception of spotting and irregular menstrual cycles, there were no adverse side effects. Based on this initial study, it was determined that doses ranging from 1.33 to 3.45 mg of NET/kg are necessary to suppress ovulation for 6 months. Additional studies with the use of higher doses are currently under way.
Adult↗
Uptake of poly(D,L-lactic-co-glycolic acid) microspheres by antigen-presenting cells in vivo.
Dendritic cells are the most potent antigen-presenting cells (APC) and the most effective stimulators of primary T cell responses. Based on the strong influence of the APC on the immune response, we investigated cellular uptake of a biodegradable antigen delivery system, poly(D,L-lactic-co-glycolic acid) (PLGA) microspheres, at two sites of injection: intraperitoneal and intradermal. We hypothesized that a fluorescent probe, tetramethylrhodamine labeled dextran, loaded in PLGA microspheres would be taken up by APCs and thereby provide a means for studying cellular uptake of PLGA microspheres in vivo. Phagocytic load and cell phenotype were determined using flow cytometry and confocal laser scanning microscopy. The results revealed cellular uptake of tetramethylrhodamine dextran loaded PLGA microspheres at both injection sites. After intraperitoneal immunization, the predominant cell phagocytosing PLGA microspheres in the peritoneal cavity was the macrophage whereas the intradermal immunization resulted in uptake of PLGA microspheres by dendritic cells. Hence, these results suggest that the profile for cellular uptake varies with the site of injection. More importantly, this study provides direct and conclusive evidence of uptake of PLGA microspheres by the most potent APC, the dendritic cell.
Animals↗
The effects of ultrasound irradiation on a biodegradable 50-50% copolymer of polylactic and polyglycolic acids.
The aim of this study was to investigate the effects of ultrasound irradiation on a biodegradable drug delivery system. Microporous, disk-shaped specimens of a 50-50% copolymer of polylactic and polyglycolic acids were gel cast from an acetone solution. A protein was incorporated in these specimens, which were then immersed in phosphate buffered saline and subjected to ultrasound irradiation every second day. The investigation was performed in two phases: in the first, a study was performed for 58 days to determine if ultrasonic irradiation affected the kinetics of protein release from the specimens. In the second phase, effects of frequency and duration of the ultrasound signal on the degradation of the implant were studied for 40 days. The results indicate that ultrasound irradiation resulted in almost a threefold increase in protein elution from the specimens. Both the ultrasound frequency and signal duration affected the molecular weight loss and mass loss, and changed the overall degradation kinetics of the polymer.
Biocompatible Materials↗
Neurosurgical advances in the treatment of brain tumors.
Surgery remains an important part of the treatment of primary malignant brain tumors. When surgery is utilized, care must be taken to maximize the safety of the procedures. This article emphasizes advances in lesion localization within the brain and technology used to identify the function of normal tissue around the tumor. Many of the new treatment paradigms involve a surgical procedure. For example, surgery is necessary for biodegradable treatment delivery systems, and for some focal radiation therapy. Neurosurgeons are familiar with implantable catheter systems for other types of disease such as hydrocephalus; however, there is now an opportunity to take advantage of such technology to assist in the delivery of treatment agents locally within a tumor. Although no specific surgical advance has offered cure of malignant tumors, surgery remains necessary for utilization of the treatment advances now becoming available.
Brachytherapy↗