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PubMed2001

Elution characteristics of tobramycin from polycaprolactone in a rabbit model.

This study investigated the elution characteristics of tobramycin from polycaprolactone, a bioabsorbable polymer, in a rabbit model. Sixty rabbits were divided into two groups. Group 1 had polycaprolactone rods impregnated with 6% tobramycin surgically implanted into the proximal femoral intramedullary canal. Group 2 received polymethylmethacrylate rods of like size, shape, and antibiotic concentration. Serum and urine samples were obtained, and tobramycin levels were determined via fluorescent immunosorbent assay. Rabbits were sacrificed as long as 56 days after surgery. Local bone tobramycin concentration was determined using the agar diffusion method. Polycaprolactone delivered a significantly higher peak bone concentration of tobramycin (22.4 microg/mL) than did polymethylmethacrylate (13.59 microg/mL). Polycaprolactone also had a more gradual decrease in local tobramycin concentration than did polymethylmethacrylate. Neither polycaprolactone nor polymethylmethacrylate yielded consistently detectable (> 0.1 microg/mL) serum tobramycin levels. Urine concentrations mirrored those seen in bone, with polycaprolactone achieving significantly higher tobramycin concentrations than did polymethylmethacrylate. Polycaprolactone had superior elution characteristics compared with polymethylmethacrylate in this lapine model, suggesting that polycaprolactone might be a promising local antibiotic delivery vehicle for the treatment of osteomyelitis.

Animals↗
PubMed2001

In vitro elution of tobramycin from bioabsorbable polycaprolactone beads.

OBJECTIVES: To compare the in vitro elution characteristics of tobramycin impregnated beads made of polycaprolactone (PCL) and polymethylmethacrylate (PMMA). DESIGN: Six-millimeter PCL and PMMA beads with 6% tobramycin were formed and placed in phosphate-buffered saline or newborn calf serum and incubated at room temperature or 37 degrees C. Aliquots were taken at intervals for eight weeks. Tobramycin levels were determined by fluorescent assay and antibacterial efficacy was assessed by measuring the zones of inhibition against Staphylococcus aureus and Pseudomonas aeruginosa on agar diffusion plates. RESULTS: Tobramycin elution rates at room temperature were similar up to three weeks. At three weeks, elution rates from PCL beads were twice those from PMMA beads, and at eight weeks, elution from PCL was quadruple that from PMMA. At 37 degrees C, tobramycin elution rates from PCL were eight times greater than those from PMMA by eight weeks. Total tobramycin eluted from PCL beads was 38.9% and 20% in PMMA beads. All samples showed bacteriostatic activity against S. aureus and P. aeruginosa at eight weeks. CONCLUSIONS: These in vitro results show that PCL has superior antibiotic elution characteristics compared with PMMA, and this may translate into a more effective antibiotic delivery vehicle. In addition, PCL is a bioabsorbable polymer, which may decrease the need for a second surgical procedure to remove retained beads.

Analysis of Variance↗
PubMed1997

Synthesis, characterization, biodegradation, and drug delivery application of biodegradable lactic/glycolic acid oligomers: I. Synthesis and characterization.

A series of oligomers or low molecular weight polymers of lactic and/or glycolic acid has been synthesized with different molar ratios of lactic to glycolic acid. These oligomers have been characterized with respect to oligomer composition, molecular weight, intrinsic viscosity, crystallinity, melting temperature, and glass transition temperature. The polymerization conditions for the lactic/glycolic acid oligomer syntheses were as follows: 180-220 degrees C, 5 mm Hg, 5 h, and 0.1 wt% of catalyst (antimony oxide) concentration. The polymeric compositions correlated to the feed ratios of lactic to glycolic acid. The molecular weight of the oligomers ranged from 895.8 +/- 48.7 to 1368.0 +/- 0 D with the intrinsic viscosity ranging from 0.0513 to 0.0814 dl g-1. The lactic/glycolic acid oligomers were found to be amorphous. The glass transition temperatures of the lactic/glycolic acid oligomers were lower than physiological temperature.

Biodegradation, Environmental↗
PubMed1995

Biodegradation and tissue reaction to intravitreous biodegradable poly(D,L-lactic-co-glycolic)acid microspheres.

We studied the biodegradation of and the tissue reaction to microspheres of 50:50 poly(D,L-lactic-co-glycolic)acid (PLGA) (viscosity-average MW: 3000 d), injected intravitreous in rabbits. These microspheres are under investigation as injectable devices for intravitreous sustained drug delivery. The rate of intravitreous degradation of PLGA microspheres has not been well documented in the literature. Twenty two pigmented rabbits underwent gas vitrectomy in one eye: 19 eyes received 2.5 mg of PLGA microspheres in 1 ml of balanced salt solution (BSS) and 3 control eyes received 1 ml of BSS only. Slit lamp exam and indirect ophthalmoscopy were performed periodically from day 1 to 6 months after surgery. The eyes were enucleated and studied by light microscopy and immunohistochemistry at various time points. The electroretinogram (ERG) was recorded in a subgroup of rabbits before injection and after 1 and 6 months. The amount of microspheres in the vitreous cavity progressively decreased. At 6 months microspheres were found in 1/4 rabbits at indirect ophthalmoscopy and in 4/4 rabbits histopathologically. A mild localized, non progressive foreign body reaction was observed. The cell reaction was composed mostly of vimentin and glial fibrillary acidic protein positive cells which probably represent glial cells and fibroblasts. The choroid and retina were normal. The ERG showed no abnormalities. No clinical inflammatory signs were observed 4 days postoperatively and thereafter.

Animals↗
PubMed1998

Controlled drug delivery by biodegradable poly(ester) devices: different preparative approaches.

There has been extensive research on drug delivery by biodegradable polymeric devices since bioresorbable surgical sutures entered the market two decades ago. Among the different classes of biodegradable polymers, the thermoplastic aliphatic poly(esters) such as poly(lactide) (PLA), poly(glycolide) (PGA), and especially the copolymer of lactide and glycolide referred to as poly(lactide-co-glycolide) (PLGA) have generated tremendous interest because of their excellent biocompatibility, biodegradability, and mechanical strength. They are easy to formulate into various devices for carrying a variety of drug classes such as vaccines, peptides, proteins, and micromolecules. Most importantly, they have been approved by the United States Food and Drug Administration (FDA) for drug delivery. This review presents different preparation techniques of various drug-loaded PLGA devices, with special emphasis on preparing microparticles. Certain issues about other related biodegradable polyesters are discussed.

Absorption↗
PubMed1984

Biodegradable polymers in controlled drug delivery.

Erosion mechanisms are divided into three types and drug release within each type is described. Type I erosion involves hydrolysis of hydrogels and these are useful in the controlled release of macromolecules entangled within their network structure. Type II erosion involves solubilization of water-insoluble polymers by reactions involving groups pendant from the polymer backbone. Of particular interest are polymers that solubilize by ionization of carboxylic acid groups, and the utilization of those systems is described. Type III erosion involves cleavage of hydrolytically labile bonds within the polymer backbone and four distinct polymer systems within this category are under development. One system involves the diffusion of drugs from a reservoir through a bioerodible membrane, another system utilizes microcapsules, a third system utilizes monolithic devices, and the fourth system utilizes drugs chemically bound to a bioerodible polymer.

Acetals↗
PubMed2002

Remarkably high antibody levels and protection against P. falciparum malaria in Aotus monkeys after a single immunisation of SPf66 encapsulated in PLGA microspheres.

Single dose immunisation is a major goal in vaccine design. The purpose of this study was the development of a single dose delivery system for the SPf66 malaria vaccine, based on this antigen's microencapsulation in PLGA microspheres by double emulsion method. Results indicate that a single immunisation in mice and monkeys with the SPf66 malaria vaccine, encapsulated in a mixture of two formulations of PLGA microspheres, induced a remarkably high and long-lasting immune response as assessed by ELISA and Western Blott. This immune response was associated with a good protective capacity in Aotus monkeys, after experimental challenge, indicating that antigen integrity lasted following the microencapsulation process. PLGA biodegradable microspheres thus serve as an effective delivery system for the design of a single dose immunisation vaccine, such as the SPf66 synthetic malaria vaccine.

Alum Compounds↗
PubMed2001

Thiolated polymers--thiomers: development and in vitro evaluation of chitosan-thioglycolic acid conjugates.

The aim of this study was to improve mucoadhesive properties of chitosan by the covalent attachment of thiol moieties to this cationic polymer. Mediated by a carbodiimide, thioglycolic acid (TGA) was covalently attached to chitosan. This was achieved by the formation of amide bonds between the primary amino groups of the polymer and the carboxylic acid group of TGA. Dependent on the pH-value and the weight ratio of polymer to TGA during the coupling reaction the resulting thiolated polymers, the so-called thiomers, displayed 6.58, 9.88, 27.44, and 38.23 micromole thiol groups per gram polymer. Tensile studies carried out with these chitosan-TGA conjugates on freshly excised porcine intestinal mucosa demonstrated a 6.3-, 8.6-, 8.9-, and 10.3-fold increase in the total work of adhesion (TWA) compared to the unmodified polymer, respectively. In contrast, the combination of chitosan and free unconjugated TGA showed almost no mucoadhesion. These data were in good correlation with further results obtained by another mucoadhesion test demonstrating a prolonged residence time of thiolated chitosan on porcine mucosa. The swelling behavior of all conjugates was thereby exactly in the same range as for an unmodified polymer pretreated in the same way. Furthermore, it could be shown that chitosan-TGA conjugates are still biodegradable by the glycosidase lysozyme. According to these results. chitosan-TGA conjugates represent a promising tool for the development of mucoadhesive drug delivery systems.

Adhesiveness↗
PubMedDate not supplied

Polyketal nanoparticles: a new pH-sensitive biodegradable drug delivery vehicle.

In this report, we present an acid-sensitive drug delivery vehicle, termed polyketal nanoparticles, which are designed to target therapeutics to the acidic environments of tumors, inflammatory tissues, and phagosomes. The polyketal nanoparticles are formulated from poly(1,4-phenyleneacetone dimethylene ketal) (PPADK), a new hydrophobic polymer which contains ketal linkages in its backbone. The polyketal nanoparticles undergo acid-catalyzed hydrolysis into low molecular weight hydrophilic compounds and should therefore release encapsulated therapeutics at an accelerated rate in acidic environments. Importantly, the polyketal nanoparticles do not generate acidic degradation products after hydrolysis, as with polyester-based biomaterials. Dexamethasone-loaded nanoparticles, 200-600 nm in diameter, were fabricated with PPADK via an emulsion procedure using chloroform and water. The hydrolysis half-life of PPADK was measured to be 102 h at pH 7.4 and 35 h at pH 5.0. PPADK was synthesized by a new polymerization strategy based on the acetal exchange reaction. This new delivery system should find numerous applications in the field of drug delivery because of its ease of synthesis and excellent degradation properties.

Biodegradation, Environmental↗
PubMed2002

Plasmid delivery in the rat brain.

Neurodegenerative diseases as a class do not have effective pharmacotherapies. This is due in part to a poor understanding of the pathologies of the disease processes, and the lack of effective medications. Gene delivery is an attractive possibility for treating these diseases. For the paradigm to be effective, efficient, safe and versatile vectors are required. In this study we evaluated three plasmid delivery systems for transgene expression in the rat hippocampus. Two of these systems were designed to have enhanced intracellular biodegradability. It was hypothesized that this system would be less toxic and could increase the free (non-vector) associated plasmids within the cell, leading to increased transgene activity. Polyethylenimine (PEI) and r-AAV-2 (recombinant adeno associated virus-2) were used as positive, non-viral and viral controls respectively, in the in vivo experiments. The results from the studies indicate there is a distinct difference between the various vectors in terms of total cells transfected, type of cell transfected, and toxicity. Non-viral systems were effective at transfecting both neurons and glia cells within the hippocampus, while the r-AAV-2 transfected mainly neurons. In summary, plasmid-mediated systems are effective for transgene expression within the brain and deserve further study.

Animals↗
PubMed2002

ABA-triblock copolymers from biodegradable polyester A-blocks and hydrophilic poly(ethylene oxide) B-blocks as a candidate for in situ forming hydrogel delivery systems for proteins.

Hydrogels are very attractive delivery systems for hydrophilic macromolecules such as proteins and DNA because they provide a protective environment and allow control of diffusion by adjusting cross-link densities. Physically cross-linked hydrogels generated by rapid swelling upon exposure to an aqueous environment can be obtained from ABA triblock copolymers containing hydrophobic polyester A-blocks and hydrophilic polyether B-blocks. They provide an attractive alternative to chemically cross-linked systems since they allow incorporation of macromolecular drug substances under mild process conditions. Moreover, they show controlled degradation behavior and excellent biocompatibility. In this review the synthesis and characterization of ABA triblock copolymers from polyester hard segments and poly(ethylene oxide) [PEO] soft segments as well as their biological and degradation properties will be discussed. Their use as biodegradable drug delivery devices in the form of implants, micro- and nanospheres has attracted considerable interest especially for proteins and may provide an alternative to poly(lactide-co-glycolide).

Animals↗
PubMed1998

A novel peptide-grafted liposomal delivery system targeted to macrophages.

The interaction of chemotactic peptide (e.g., fMet-Leu-Phe)-grafted liposomes with macrophages is noted to be rapid and specific. At a grafted peptide concentration of 100 nmol, internalization of the peptide-grafted liposomes by the macrophages is found to reach equilibrium in 30 min. The peptide alone and the peptide-grafted empty liposomes are found to show moderate antileishmanial activity in vitro. Primaquine, which is known to generate O2- in phagocytic cells, showed leishmanicidal properties when it was tested in vitro against parasite-infected macrophages over a certain range of concentrations. It showed much better efficacy against experimental leishmaniasis when it was used in the fMet-Leu-Phe-grafted liposomal form in comparison with its efficacy when it was either in the free form or encapsulated in ungrafted liposomes. The conventional toxicity parameters (e.g., blood pathology and tissue histology-specific enzyme levels related to normal liver function) are found to be very close to normal when fMet-Leu-Phe-grafted liposomal primaquine is used. The biodegradabilities of both the drug and the delivery systems are also found to be very satisfactory. Thus, this delivery system may have possible applications for the treatment of leishmaniasis as well as other macrophage-associated disorders.

Animals↗
PubMed2006

Molecular design of biodegradable polymeric micelles for temperature-responsive drug release.

We designed thermo-responsive and biodegradable polymeric micelles for an ideal drug delivery system whose target sites are where external stimuli selectively release drugs from the polymeric micelles. The thermo-responsive micelles formed from block copolymers that were composed both of a hydrophobic block and a thermo-responsive block. Poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) showing a lower critical solution temperature (LCST) around 40 degrees C was synthesized for the thermo-responsive block, while biodegradable poly(D,L-lactide), poly(epsilon-caprolactone), or poly(D,L-lactide-co-epsilon-caprolactone) was used for the hydrophobic block. By changing both the block lengths of the poly(D,L-lactide)-containing block copolymers, physical parameters such as micelle diameter and critical micelle concentration were varied. On the other hand, the choice of the hydrophobic block was revealed to be critical in relation to both on the thermo-responsive release of the incorporated anti-cancer drug, doxorubicin, and the temperature-dependent change of the hydrophobicity of the micelles' inner core. One polymeric micelle composition successfully exhibited rapid and thermo-responsive drug release while possessing a biodegradable character.

Antibiotics, Antineoplastic↗
PubMed2003

Surface modification of poly(glycolic acid) (PGA) for biomedical applications.

The immobilization of biological ligands (such as biotin and peptides) onto biodegradable polymer surfaces, including poly(glycolic acid) (PGA) sutures, is complicated by the absence of functional groups on the polymer backbone. We demonstrate a method for overcoming this problem, by attaching (+)-biotinyl-3,6,9-trioxaundecanediamine to the surface of PGA sutures, which immobilizes the ligand through an amide bond between amine (ligands) and carboxylic acid groups (surface-hydrolyzed PGA sutures). Fluorescence microscopy was used to verify the attachment of the biotin ligand to the surface of the PGA suture after a complexation with fluorescein-conjugated streptavidin. The strategy can be generalized to surface modifications of other biodegradable aliphatic polyesters, which would improve the properties of the polymers in biomedical applications such as active targeting of drugs based on ligand-attached, polymeric drug delivery systems.

Biodegradation, Environmental↗
PubMed1997

Poly(alkyl cyanoacrylate) nanocapsules as a delivery system in the rat for octreotide, a long-acting somatostatin analogue.

Poly(alkyl cyanoacrylate) nanocapsules have been used as biodegradable polymeric drug carriers for subcutaneous and peroral delivery of octreotide, a long-acting somatostatin analogue; their ability to reduce insulin secretion or prolactin secretion in response to oestrogens has been studied in adult male rats. The nanocapsules, prepared by interfacial emulsion polymerization of isobutyl cyanoacrylate, were 260 nm in diameter and incorporated 60% of octreotide. Administered subcutaneously, the octreotide-loaded (20 micrograms kg-1) nanocapsules suppressed the insulinaemia peak induced by intravenous glucose overload and depressed insulin secretion over 48 h, preventing the secretory rebound; however, glycaemia was unaffected. In parallel, the plasma octreotide concentration increased 2.7 times. Administered perorally to oestrogen-treated rats, octreotide-loaded nanocapsules (200 and 1000 micrograms kg-1) significantly improved the reduction of prolactin secretion (by 72 and 88%, respectively, compared with 32 and 54% with free octreotide) and slightly increased plasma octreotide level. Thus nanocapsules could be of interest as a biodegradable drug carrier for the administration of octreotide.

Animals↗
PubMed1993

Oral immunization with influenza virus in biodegradable microspheres.

Polymeric microspheres were evaluated as an oral antigen delivery system for immunization with influenza virus. The immune responses obtained were compared after either oral or systemic immunization of BALB/c mice using purified, formalin-inactivated influenza virus type A/H3N2, either encapsulated in biodegradable and biocompatible microspheres or free in solution. The immunogenicity of formalin-treated influenza vaccine was preserved during the microencapsulation process, and the microencapsulated antigen induced protective immune responses after systemic immunization that were equal to or higher than those induced by conventional vaccine. When administered orally to primed animals, microencapsulated antigen induced levels of anti-influenza antibodies in saliva that were higher than and in serum that were comparable to those obtained by systemic immunization. Furthermore, oral booster immunization provided virtually complete protection of animals challenged with live virus.

Administration, Oral↗
PubMed2001

Indomethacin-loaded methoxy poly(ethylene glycol)/ poly(epsilon-caprolactone) diblock copolymeric nanosphere: pharmacokinetic characteristics of indomethacin in the normal Sprague-Dawley rats.

We prepared the drug-loaded polymeric nanospheres composed of the methoxy poly(ethylene glycol) (MePEG) and poly(epsilon-caprolactone) (PCL) that showed a narrow size distribution and average diameter of less than 200 nm. We could obtain the nanosphere having a relatively high drug-loading efficiency of about 42% when the feed weight ratio of indomethacin (IMC) to polymer was 1:1. To investigate the IMC pharmacokinetics in the IMC-loaded MePEG/PCL nanosphere (DMEP70) using the rats as animal model, we analyzed the IMC concentration in plasma with HPLC after i.v. bolus administered at a dose of 10 mg/kg in free IMC (control) and IMC-loaded MePEG/PCL nanosphere (DMEP70) groups via tail vein. Pharmacokinetics parameters (mean +/- s.d.) such as the mean residence time (MRT, h), the steady-state volume of distribution (Vdss, l), the terminal half-time (t 1/2, h) and the plasma clearance (CL, l/h) of IMC in each groups (control vs. DMEP70) were determined; MRT (16.97 +/- 4.83 vs. 28.69 +/- 11.28, p < 0.01); Vdss (14.26 +/- 4.86 vs. 20.37 +/- 12.04, p < 0.05); t 1/2 (15.12 +/- 4.77 vs. 23.1 +/- 8.24, p < 0.01); CL (0.84 +/- 0.27 vs. 0.71 +/- 0.41). From these results, we could concluded that MEP70 has a significant potential for sustained release and the enhancement of circulation time of loaded drug by prolonging terminal half-life, increasing MRT and Vdss of IMC. Therefore, The MePEG/PCL block copolymeric nanosphere system is being considered as promising biodegradable and biocompatible drug carrier vehicles for parentral use and may be useful as sustained release injectable delivery systems for hydrophobic drugs.

Animals↗