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PubMed1994

Erosion of a new family of biodegradable polyanhydrides.

Studies investigating the erosion mechanism of the newly developed poly (fatty acid dimer: sebacic acid) polyanhydride (p:[FAD:SA]) are described. The overall erosion of different monomer compositions of p(FAD:SA) copolymers was examined to determine whether and to what extent copolymer properties affected polymer erosion. Increasing the hydrophobic monomer (FAD) content up to 50 wt% in the copolymer resulted in longer erosion, whereas further increases up to 70 wt% decreased the erosion period. Polymer crystallinity depended on copolymer FAD content. Copolymer degradation was studied by examining anhydride bond hydrolysis using infrared spectroscopy. Much faster hydrolysis was found in p(FAD:SA) 70:30 compared with more crystalline copolymers of higher SA content. Light microscopy indicates the presence of an erosion zone, a distinct area where mass loss occurs. This erosion zone moves from the outside toward the interior of the polymer matrix. It plays an important role in erosion because any water or monomer must diffuse through this eroded layer.

Biodegradation, Environmental↗
PubMed1986

Polyanhydrides for controlled release of bioactive agents.

This report is a review of the development of a drug delivery system based on biorodible polyanhydrides. With the water labile anhydride linkage, a wide range of matrix degradation and drug release rates can be obtained from these drug-carriers. In addition to monolithic formulations, the feasibility of an injectable system by microencapsulation is demonstrated. The possibility of enhancing the release externally by an ultrasonic source has also been explored. The polymers tested showed good tissue biocompatibility and their breakdown products showed no adverse toxicological effects. Preliminary in vivo results confirmed the efficacy of these devices.

Anhydrides↗
PubMed1995

In vivo and in vitro elimination of aliphatic polyanhydrides.

The hydrolysis and elimination processes of biopolyanhydrides has been studied using a polymer series of linear aliphatic diacids. This polymer series degrade into their monomer counterparts at about the same rate but differ in the water solubility of their degradation products. Polymers based on natural diacids of the general structure -[OOC-(CH2)x-CO]n- where x is between 4 and 12 were implanted subcutaneously in rats and the elimination of the polymers from the implantation site was observed. The in vitro hydrolysis of this polymer series was studied by monitoring the weight loss, release of monomer degradation products and the content of anhydride bonds in the polymer as a function of time. A dependence was found between the monomer solubility and the rate of polymer elimination in both in vivo and in vitro. The elimination time for polymers based on soluble monomers (x = 4-8) was 7-14 days, while the polymers based on low monomer solubility (x = 10-12) were eliminated only after 8 weeks. The in vitro degradation of polyanhydrides in the presence of several common hydrolytic enzymes found around implants did not affect polymer degradation. All polymers were biocompatible and found to be useful as carriers for drug delivery.

Anhydrides↗
PubMed1995

Prevention of venous thrombosis in microvascular surgery by transmural release of heparin from a polyanhydride polymer.

BACKGROUND: The effects of transmurally released heparin on the patency of microvenous anastomoses were studied by using a bioerodible polymer delivery system in a rat microvascular thrombosis model. METHODS: A polyanhydride carrier with heparin was wrapped around the outside of a highly thrombogenic venous inversion graft in 14 animals, and patency rates were compared with those of 17 control animals. RESULTS: Anastomotic patency was significantly greater in the groups treated with transmurally released heparin, measured both at 24 hours (86% versus 16%; p < 0.02) and at 7 days (86% versus 36%; p < 0.05) after operation. No significant complications occurred. CONCLUSIONS: Controlled release of heparin by transmural delivery is an effective and safe form of local antithrombotic therapy and may have applications both in microvascular and large vessel surgery.

Anhydrides↗
PubMed2000

A review of photocrosslinked polyanhydrides: in situ forming degradable networks.

Many orthopaedic injuries could benefit from a high-strength and degradable material with good tissue compatibility. In addition, there is a great clinical need for materials which are easily contoured or placed into complex-shaped defects by a surgeon. We have rationally designed a new class of photocrosslinkable polyanhydride monomers which in situ form high-strength and surface eroding networks of complex geometries. This paper highlights the advantages of these materials for orthopaedic applications and the technique of photopolymerization for reacting these monomers under physiological conditions. The rationale for the material design, photopolymerization kinetics, degradation behavior, and histology in subcutaneous tissue and a model bone defect are presented.

Anhydrides↗
PubMed2002

Design of an injectable system based on bioerodible polyanhydride microspheres for sustained drug delivery.

The fabrication, morphological characterization, and drug release kinetics from microspheres of three bioerodible polyanhydrides, poly[1,6-bis(p-carboxyphenoxy)hexane] (poly(CPH)), poly(sebacic anhydride) (poly(SA)), and the copolymer poly(CPH-co-SA) 50:50 (CPH:SA 50:50) is reported. The fabrication technique yields microspheres with different morphologies for each of the three polymers studied, ranging from very smooth exterior surfaces for poly(CPH) to coarse surface roughness with large pores for poly(SA). Release profiles for the model drug, p-nitroaniline are also different for each polymer. The release profile from poly(CPH) has a large initial burst and shows little additional release after 2 days. The release from poly(SA) is nearly zero-order and lasts for about 8 days. The release profile from CPH:SA 50:50 shows a relatively small burst and then exhibits zero-order release for about I month. The different release profiles are attributed to both polymer erosion rates and drug distribution characteristics of the microspheres. Tailored release profiles of a burst followed by zero-order release are obtained by appropriately combining the microspheres. This technique enables independent modulation of both the burst and the zero-order release rate by varying the number of poly(CPH) and poly(SA) microspheres respectively. Additionally, the zero-order release can be extended from about a week to a month by including CPH:SA 50:50 microspheres.

Anhydrides↗
PubMed2002

Polyanhydride implant for antibiotic delivery--from the bench to the clinic.

A polyanhydride implant (Septacin) containing gentamicin sulfate was developed for sustained local delivery of the drug to the site of infection in the treatment of osteomyelitis. Laboratory-scale injection molding equipment was utilized to fabricate the implant for in vitro characterization. Molding conditions were optimized to produce implants with a skin-core structure which was found to be critical in preventing the initial cracking of the implant during in vitro drug release test in water. A manufacturing process consisting of twin-screw extrusion, pelletizing, and injection molding was developed. Polymer-drug pellets were characterized with respect to copolymer molecular weight and drug content uniformity. The implants were terminally sterilized by gamma-radiation which was found to cause increase in copolymer molecular weight as a result of polymer chain extension. The stability of Septacin was evaluated as a function of storage temperature and time. A marked decline in copolymer molecular weight occurred in samples stored above freezing temperatures and significantly slower drug-release profiles were also exhibited by these samples. In vivo drug release from Septacin in rats showed that the gentamicin plasma levels were extremely low, indicating the low systemic exposure to gentamicin. Furthermore, Septacin samples have demonstrated efficacy in the rat skin-abscess and horse-joint infection models. Results from a human in vivo study also showed high local drug concentrations at implantation sites while systemic exposure to the drug was minimal.

Anhydrides↗
PubMed2002

Effect of gamma-radiation on a polyanhydride implant containing gentamicin sulfate.

Septacin, a polyanhydride implant containing gentamicin sulfate, was sterilized by gamma-radiation. Its copolymer molecular weight (M(w) by GPC) was increased after this radiation. No cross-linking was shown in the radiated samples as no gel content was found by the filtration method. The chemical structure as detected by 1H NMR for non-radiated and radiated samples was comparable. For samples radiated at higher dose levels (70-100 kGy), the IR spectra showed that the intensity of absorbance attributable to the C-H stretching vibration (at 2852 and 2927 cm(-1)) was attenuated, indicating free-radical formation or loss of hydrogen atoms from C-H bonds. However, the mass spectra for the gamma-radiated and the non-radiated controls after they were completely depolymerized in methylene chloride were virtually identical. Therefore, it could be concluded that the increase in copolymer molecular weight for radiated Septacin was a result of chain extension in the copolymer backbone during radiation. In addition, wide-angle X-ray diffraction and polarizing light microscopy (PLM) revealed a change in the physical structure of the radiated copolymer. There was an increase in crystallinity of the copolymer with increasing radiation doses; the greatest increase in crystallinity occurred at the dose range of 70-80 kGy, which was also shown to result in the greatest molecular-weight increase. The crystalline morphology of the samples as detected by PLM was not altered by gamma-radiation, regardless of the dose levels.

Absorbable Implants↗
PubMed2001

Gamma-irradiation stability of saturated and unsaturated aliphatic polyanhydrides--ricinoleic acid based polymers.

The effect of terminal sterilization by gamma-irradiation on several ricinoleic acid based polyanhydrides was investigated. The following polymers were used: poly(ricinoleic acid maleate) [P(RAM)], poly(ricinoleic acid succinate) [P(RAS)], poly(hydroxy stearic acid succinate) [P(HSAS)], poly(hydroxy stearic acid maleate) [P(HSAM)], and their copolymers with sebacic acid. The polymers were irradiated with an absorbed dose of 2.5 or 10 Mrad by means of a 60Co source under dry ice or at room temperature. No differences were found between samples irradiated under dry ice and at room temperature. Polymers prepared from monomers containing maleate residues, which contain double bonds adjusted to the anhydride linkage along the polymer chain, decreased in molecular weight, became insoluble, and showed fast hydrolytic degradation. For example, p(RAM), p(HSAM), and their copolymers with sebacic acid decreased in Mw from about 10,000 to about 2000, and from about 30,000 to about 5000, respectively, while polymers based on RAS and HSAS remained stable. This phenomenon was explained by an anhydride interchange-self-depolymerization process of the unsaturated anhydride bonds induced by gamma-irradiation. This explanation was supported by the depolymerization of another class of polymers having an anhydride bond between two double bonds, fumaric acid anhydride polymers. The anhydride bond that lies between two double bonds was found to be more sensitive to gamma-irradiation. This anhydride bond may be cleaved to form two radicals that further react with aliphatic anhydride bonds along the polymer chain to form inter- and/or intracyclization products.

Anhydrides↗
PubMed1997

In vitro/in vivo comparison of drug release and polymer erosion from biodegradable P(FAD-SA) polyanhydrides--a noninvasive approach by the combined use of electron paramagnetic resonance spectroscopy and nuclear magnetic resonance imaging.

PURPOSE: The purpose of this study was to compare drug release and polymer erosion from biodegradable P(FAD-SA) polyanhydrides in vitro and in vivo in real time and with minimal disturbance of the investigated system. METHODS: P(FAD-SA) 20:80 and P(FAD-SA) 50:50 polymer tablets were loaded with the spin probe 3-carboxy-2,2,5,5-tetramethyl-pyrrollidine-1-oxyl (PCA) and implanted subcutaneously in the neck of rats or placed in 0.1 M phosphate buffer. 1.1 GHz EPR spectroscopy experiments and 7T MRI studies (T1 and T2 weighted) were performed. RESULTS: A front of water penetration was visible by MRI in vitro in the case of P(FAD-SA) 20:80, but not for P(FAD-SA) 50:50. For both polymers, the thickness of the tablets decreased with time and a insoluble, easy deformable residue remained. Important processes such as edema, deformation of the implant, encapsulation and bioresorption were observable by MRI in vivo. P(FAD-SA) 50:50 was almost entirely absorbed by day 44, whereas an encapsulated residue was found for P(FAD-SA) 20:80 after 65 days. The EPR studies gave direct evidence of a water penetration induced changes of the microenvironment inside the tablet. EPR signals were still detectable in P(FAD-SA) 20:80 implants after 65 days, while the nitroxide was released in vitro within 16 days. CONCLUSIONS: Important parameters and processes such as edema, deformation of the tablet, microviscosity inside the tablet and encapsulation can be monitored in real time by the combined use of the noninvasive techniques MRI and EPR leading to better understanding of the differences between the in vitro and in vivo situation.

Animals↗
PubMed2002

The effect of storage temperatures on the in vitro properties of a polyanhydride implant containing gentamicin.

Septacin is a biodegradable sustained-release implant containing 20% (w/w) gentamicin sulfate. The matrix of the implant is a polyanhydride copolymer composed of erucic acid dimer (EAD) and sebacic acid (SA) in a one-to-one weight ratio. The effect of storage temperatures (-15 degrees C and 25 degrees C) on the stability of Septacin was evaluated with respect to gentamicin potency, copolymer molecular weight, and in vitro drug release. The drug in polymer matrix was stable for at least 12 months when stored at 25 degrees C, but the molecular weight of the copolymer declined rapidly at this temperature. At -15 degrees C, there was no change in the molecular weight of the copolymer. However, the placebo (copolymer without gentamicin) exhibited a significant drop in copolymer molecular weight at both temperatures. The drug release profiles showed no change for samples stored at -15 degrees C for the duration of this study, while the release of drug slowed down significantly for samples stored at 25 degrees C for longer than one month. A pronounced difference in the morphology of the -15 degrees C samples and the 25 degrees C samples was observed during the in vitro dissolution test; cracking of the -15 degrees C samples was evident, but the 25 degrees C samples remained intact.

Anhydrides↗
PubMed2004

Effect of postmolding heat treatment on in vitro properties of a polyanhydride implant containing gentamicin sulfate.

A polyanhydride implant containing gentamicin sulfate was fabricated using a laboratory-scale injection-molding machine. After injection molding, the implants were subject to heat treatment at 60 degrees C for various time periods with or without nitrogen protection. The impact of this heat treatment on the in vitro properties of the implants including copolymer molecular weights, mechanical properties, and in vitro drug-release profiles was investigated. This heat treatment caused a drastic drop in the molecular weight of the copolymer. Heating without nitrogen protection resulted in the hardening of the implant, but heating in the presence of nitrogen rendered the implant less rigid. It was also found that a faster in vitro drug release profile was shown by implants heated without nitrogen protection and a pronounced slowing down in drug release was exhibited by implants heated with nitrogen protection.

Anti-Bacterial Agents↗
PubMed1994

Controlled release of macromolecules from a degradable polyanhydride matrix.

Polymeric matrices that slowly release macromolecules may be useful for the controlled delivery of proteins or polymer-drug conjugates for targeted drug delivery. Solid particles of fluorescein and fluorescently-labeled, size-fractionated dextran (4000-150,000 number average molecular weight) were dispersed in degradable polyanhydride matrices composed of a 1:1 copolymer of fatty acid dimers and sebacic acid. The release of macromolecules from the polymer matrix into buffered saline was measured; changes in the polymer during immersion were monitored by infrared spectroscopy, differential scanning calorimetry, and scanning electron microscopy. Although significant hydrolysis of the polymer occurred within the first day, the matrices remained intact and water-soluble tracers were slowly released for several days. During polymer hydrolysis and erosion, micron-sized pores developed throughout the 2 mm thick polymer matrix, permitting water penetration into the matrix and tracer diffusion out of the matrix. The rate of tracer release from the matrix depended on tracer particle size; rates of fluorescein isothiocyanate dextran release were controlled by adjusting the size of particles dispersed in the matrix.

Biodegradation, Environmental↗
PubMedDate not supplied

The development of an injection-molding process for a polyanhydride implant containing gentamicin sulfate.

A production-scale manufacturing process has been developed for polyanhydride/gentamicin sulfate implants for the treatment of osteomyelitis. Gentamicin sulfate was first dried to an acceptable moisture level by using a tumble vacuum dryer. Dried gentamicin sulfate powder and polyanhydride granules were separately fed into the twin-screw extruder at a pre-determined metering rate using a gravimetric feeding device. The extruded molten mixture was solidified to form strands which were subsequently cut into pellets by using a pelletizer. The pellets were characterized with respect to copolymer molecular weight and drug content uniformity. The pellets were later fed into production-scale injection-molding equipment for implant fabrication. The injection-molding cycle was developed and evaluated in terms of cycle reproducibility. Implants were tested and shown to yield an oriented skin-core structure exhibiting a desirable in-vitro drug release profile.

Anhydrides↗
PubMedDate not supplied

Salicylic acid and PEG-contained polyanhydrides: synthesis, characterization, and in vitro salicylic acid release.

Poly [bi(o-carboxyphenyl)adipate-polyethylene glycol] anhydrides--P(BOCA-PEG)--polymeric drugs were synthesized and characterized by Fourier transformed infrared spectroscopy, NMR, DSC, gel permeation chromatography, etc. Salicylic acid loading efficiency of these polymers ranged from 43.5% to 71.3%, which was much higher than that of other polymeric drugs with salicylic acid. The in vitro release of salicylic acid from the polymers was carried out in buffer conditions with different pH values and and rat gastrointestinal contents. The results showed the release rate of salicylic acid increased with the increase of PEG content in the polymers and the increase of pH value of degradation buffer solution. The rat cecal contents also greatly promoted the release of salicylic acid. In 0.1M phosphate buffer solution at pH8.0, 37 degrees C containing 5% rat cecal contents, P(BOCA-PEG200)(80:20) had 15% salicylic acid released in 21 hr, indicating its potential use in colon-specific salicylic acid delivery.

Animals↗
PubMed1997

Treatment of experimental osteomyelitis by surgical debridement and the implantation of bioerodable, polyanhydride-gentamicin beads.

Osteomyelitis was induced in the radius in 77 rabbits and confirmed by histological examination and culture. At 4 weeks, the wounds were debrided and the animals were treated with (a) fatty acid dimer-sebacic acid beads (a bioerodable composite) impregnated with 20% or (b) 10% gentamicin sulfate, (c) placebo beads and intramuscular gentamicin sulfate, (d) placebo beads alone, or (e) debridement only. After 4 weeks, eradication of infection was determined by histological examination and culture. Osteomyelitis was eradicated in 93% of the animals treated with the beads and 20% gentamicin, in 67% of those treated with the beads and 10% gentamicin, in 25% of those treated with placebo beads and intramuscular gentamicin, in 7% of those treated with placebo beads alone, and in 12.5% of those treated with debridement only (p values from < 0.001 to 0.02). Fatty acid dimer-sebacic acid beads with gentamicin were then implanted in noninfected rabbits, and gentamicin sulfate concentrations in bone, serum, urine, and wound exudate were measured. Gentamicin sulfate was detectable in bone for as long as 8 weeks after implantation. Levels as high as 4,746 micrograms/ml were present in the wound exudate for the first 7 days. Levels in the serum peaked at 1.03 micrograms/ml. Urine levels peaked at 135 micrograms/ml.

Anhydrides↗
PubMed2004

Microsphere size, precipitation kinetics and drug distribution control drug release from biodegradable polyanhydride microspheres.

A thorough understanding of the factors affecting drug release mechanisms from surface-erodible polymer devices is critical to the design of optimal delivery systems. Poly(sebacic anhydride) (PSA) microspheres were loaded with three model drug compounds (rhodamine B, p-nitroaniline and piroxicam) with a range of polarities (water solubilities). The drug release profiles from monodisperse particles of three different sizes were compared to release from polydisperse microspheres. Each of the model drugs exhibited different release mechanisms. Drug distribution within the polymer was investigated by laser scanning confocal microscopy and scanning electron microscopy. Rhodamine, the most hydrophilic compound investigated, was localized strongly toward the microsphere surface, while the much more hydrophobic compound, piroxicam, distributed more evenly. Furthermore, all three compounds were most uniformly distributed in the smallest microspheres, most likely due to the competing effects of drug diffusion out of the nascent polymer droplets and the precipitation of polymer upon solvent extraction, which effectively "traps" the drug in the polymer matrix. The differing drug distributions were manifested in the drug release profiles. Rhodamine was released very quickly independent of microsphere size. Thus, extended release profiles may not be obtainable if the drug strongly redistributes in the microspheres. The release of p-nitroaniline was more prolonged, but still showed little dependence on microsphere size. Hence, when water-soluble drugs are encapsulated with hydrophobic polymers, it may be difficult to tailor release profiles by controlling microsphere size. The piroxicam-loaded microspheres exhibit the most interesting release profiles, showing that release duration can be increased by decreasing microsphere size, resulting in a more uniform drug distribution.

Anhydrides↗