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PubMed2003

Histocompatibility of photocrosslinked polyanhydrides: a novel in situ forming orthopaedic biomaterial.

Cell-polymer interactions in subcutaneous and bony tissue were examined for a novel class of in situ forming and surface eroding polyanhydride networks. Specifically, photopolymerized disks of several polyanhydride compositions were implanted subcutaneously in rats, and the tissue was analyzed for an inflammatory response. The compositions elicited varied histological responses, ranging from highly active cell layers to moderate fibrous capsules, depending on the degrading polymer composition. Furthermore, one composition was photopolymerized in a model orthopaedic defect in the proximal tibia. The feasibility of photopolymerizing the methacrylated monomers in situ and the adherence of the photocrosslinked polyanhydride to the medullary canal were examined.

Anhydrides↗
PubMed1993

Polyanhydride microspheres that display near-constant release of water-soluble model drug compounds.

A new method to prepare polyanhydride microspheres capable of near-constant sustained release of low molecular weight, water-soluble molecules is presented. The polyanhydrides used were poly(fatty acid dimer) (PFAD), poly(sebacic acid) (PSA), and their copolymers [P(FAD-SA)]. Acid orange 63 (AO), acid red 8 (AR), and p-nitroaniline, were used as model release molecules. P(FAD-SA) microspheres containing the molecules with or without gelatin were prepared by a modified solvent evaporation method using a double emulsion. The microspheres were spherical with diameters of 50-125 microns and encapsulated more than 85% of the molecule, irrespective of the compound used. Near-zero-order degradation kinetics were observed for 5 days as judged by sebacic acid (SA) release. Microsphere degradation was pH sensitive, being enhanced at high pH, and became more stable in acidic conditions, irrespective of the incorporation of gelatin in the matrix. For the gelatin-free microspheres, a close correlation of SA release and AO release was observed (2% loading), suggesting a release mechanism that was controlled dominantly by degradation. However, the incorporation of gelatin into the microsphere significantly extended the periods of molecule release from P(FAD-SA) microspheres, although the degradation profile of the microspheres themselves was quite similar to that of gelatin-free microspheres. It is possible that an interaction between FAD monomers and gelatin molecules causes continued release, even after the polymer matrix completely degrades (even after complete degradation, FAD monomers remain because of their poor water solubility). Thermal analysis of polyanhydride microspheres at different degradation stages demonstrated that a crystalline structure was formed between gelatin and the FAD monomers produced with microsphere degradation.(ABSTRACT TRUNCATED AT 250 WORDS)

Calorimetry, Differential Scanning↗
PubMed1991

In vitro release of hydrophobic drugs from polyanhydride disks.

We have evaluated the feasibility of using polyanhydride disks containing hydrophobic antiproliferative agents for controlled drug release after glaucoma filtration surgery. Taxol and VP-16 were the most potent inhibitors of fibroblast proliferation tested, with ID50s of 3 ng/mL and 200 ng/mL, respectively. In vitro release of taxol occurred at concentrations exceeding its ID50 for at least 100 days; VP-16 was released for 31 days. The media into which the drugs were released were able to inhibit fibroblast proliferation in vitro, indicating that the bioactivity of the drugs withstood incorporation into, and release from, the polyanhydride. Polyanhydride disks containing taxol and VP-16 merit testing in animal models of glaucoma filtration surgery.

Alkaloids↗
PubMed2006

Amphiphilic polyanhydrides for protein stabilization and release.

The overall goal of this research is to design novel amphiphilic biodegradable systems based on polyanhydrides for the stabilization and sustained release of peptides and proteins. Accordingly, copolymers of the anhydrides, 1,6-bis(p-carboxyphenoxy)hexane (CPH) and 1,8-bis(p-carboxyphenoxy)-3,6-dioxaoctane (CPTEG), which are monomer-containing oligomeric ethylene glycol moieties, have been synthesized. Microspheres of different CPTEG:CPH compositions have been fabricated by two non-aqueous methods: solid/oil/oil double emulsion and cryogenic atomization. The ability of this amphiphilic polymeric system to stabilize model proteins (i.e., lysozyme and ovalbumin) was investigated. The structure of both the encapsulated as well as the released protein was monitored using gel electrophoresis, circular dichroism, and fluorescence spectroscopy. It was found that the CPTEG:CPH system preserves the structural hierarchy of the encapsulated proteins. Activity studies of the released protein indicate the CPTEG:CPH system retains the biological activity of the released protein. These results are promising for future in vivo studies, which involve the design of novel biodegradable polyanhydride carriers for the stabilization and sustained release of therapeutic peptides and proteins.

Amino Acid Sequence↗
PubMed1990

Glaucoma filtration surgery in monkeys using 5-fluorouridine in polyanhydride disks.

We performed filtration surgery in glaucomatous monkeys to determine if bioerodible polyanhydride disks that contained 5-fluorouridine (5-FUR) prolonged the success of the operation. First, in vitro studies demonstrated that 5-fluorouridine was released from the disks for at least 16 days in a bioactive form that inhibited fibroblast proliferation. Next, a preliminary series of six eyes suggested that using disks that contained 5-fluorouridine extended the intraocular pressure-lowering effect of filtration surgery. This finding was confirmed in eight additional eyes of four animals in which one eye received a disk with 5-fluorouridine and the other received a disk without the drug. The duration of success of the operation was significantly longer in the eyes that received polyanhydride with 5-fluorouridine (mean +/- SD, 26.0 +/- 9.2 days) than in the controls (8.5 +/- 4.0 days). The histologic findings of the experimental eyes correlated with their prolonged clinical success.

Animals↗
PubMed1999

Crosslinked polyanhydrides for use in orthopedic applications: degradation behavior and mechanics.

High-strength, surface-eroding polymers were synthesized from methacrylated anhydride monomers of sebacic acid (MSA) and 1,6-bis(carboxyphenoxy) hexane (MCPH). These multifunctional monomers were photopolymerized using ultraviolet light to produce highly crosslinked polyanhydride networks. Through this approach, the crosslinking density of the resulting polymer network was used to control the final mechanical properties, while the degradation time scale was controlled by the chemical composition of the network. The combined hydrophobicity of the polymer backbone with the hydrolytically labile anhydride linkages led to surface-eroding networks, as confirmed by linear cumulative mass loss profiles as a function of degradation time for crosslinked polymer disks. By copolymerizing varying amounts of MSA and MCPH, the degradation rate of the final network was controlled from 2 days to 1 year. The tensile modulus of crosslinked poly(MSA) (1.4 GPa) was nearly an order of magnitude larger than that of linear poly(sebacic acid). In general, the mechanical properties of the crosslinked polyanhydrides networks were within ranges of those reported for cortical and trabecular bone. However, unlike bulk degrading polyesters such as poly(lactic acid), these surface eroding networks maintained >70% of their tensile modulus with 50% mass degradation.

Acrylic Resins↗
PubMed2000

Surface and bulk modifications to photocrosslinked polyanhydrides to control degradation behavior.

A unique class of surface-eroding polyanhydrides was developed and explored for use in medical applications requiring high-strength biomaterials (e.g., orthopedics). In particular, dimethacrylated anhydride monomers were synthesized that photopolymerize quickly to render densely crosslinked polymer networks that degrade from the surface only by hydrolysis of labile anhydride linkages. Previous research on these materials has shown that the rate of hydrolysis of the degradable linkages is dependent on the hydrophobicity of the network composition. This article demonstrates the versatility in controlling the degradation process and resulting cellular response in these materials through the incorporation of new chemistries and the formation of polymer-polymer composite structures. Specifically, the rate of mass loss was controlled by the addition of hydrophobic linear polymers [e.g., poly(methyl methacrylate)] or monovinyl monomers based on hydrophobic natural components (e.g., cholesterol, steric acid). In addition, a newly established photografting method was used to modify the network surface chemistry with cholesterol- and stearic acid-based polymer grafts to control the degradation front and cellular interactions at the polymer-tissue interface. Finally, a porogen leaching method was used to form porous polyanhydride constructs, which can be subsequently filled with osteoblasts photoencapsulated in a hydrogel, as potential synthetic allograft materials for tissue engineering bone.

Anhydrides↗
PubMed2006

Single dose vaccine based on biodegradable polyanhydride microspheres can modulate immune response mechanism.

This study focuses on the development of single dose vaccines based on biodegradable polyanhydride microspheres that have the unique capability to modulate the immune response mechanism. The polymer system employed consists of copolymers of 1,6-bis(p-carboxyphenoxy)hexane and sebacic acid. Two copolymer formulations that have been shown to provide extended release kinetics and protein stability were investigated. Using tetanus toxoid (TT) as a model antigen, in vivo studies in C3H/HeOuJ mice demonstrated that the encapsulation procedure preserves the immunogenicity of the TT. The polymer itself exhibited an adjuvant effect, enhancing the immune response to a small dose of TT. The microspheres provided a prolonged exposure to TT sufficient to induce both a primary and a secondary immune response (i.e., high antibody titers) with high-avidity antibody production, without requiring an additional administration. Antigen-specific proliferation 28 weeks after a single immunization indicated that immunization with the polyanhydride microspheres generated long-lived memory cells and plasma cells (antibody-secreting B cells) that generally do not occur without maturation signals from T helper cells. Furthermore, by altering the vaccine formulation, the overall strength of the T helper type 2 immune response was selectively diminished, resulting in a balanced immune response, without reducing the overall titer. This result is striking, considering free TT induces a T helper type 2 immune response, and has important implications for developing vaccines to intracellular pathogens. The ability to selectively tune the immune response without the administration of additional cytokines or noxious adjuvants is a unique feature of this delivery vehicle that may make it an excellent candidate for vaccine development.

Animals↗
PubMed1988

Polyanhydride microsphere formulation by solvent extraction.

A novel process based on solvent extraction was developed to produce drug-loaded polyanhydride microspheres for controlled-release applications. The technique consists of adding a chloroform solution of polyanhydride and drug into a stirred silicone oil phase containing suspended droplets of surfactant. No chemical reaction, heating, nor contact with water was required in this process. The microspheres produced were capable of releasing various dyes for prolonged periods of time.

Anhydrides↗
PubMed1994

Injectable polyanhydride granules provide controlled release of water-soluble drugs with a reduced initial burst.

A method for preparing polyanhydride granules of an injectable size was developed. The resulting granules permitted a nearly constant release of low-molecular-weight, water-soluble drugs without an initial burst. The polyanhydrides used were poly(fatty acid dimer), poly(sebacic acid), and their copolymers. The dyes acid orange 63 and p-nitroaniline were used as model compounds for drugs. Polymer degradation and drug release for disks and variously sized granules of copolymers containing drugs, prepared by a water-in-oil (W/O) emulsion method, were compared with those for devices prepared by the usual compression method. In the W/O emulsion method, a mixture of aqueous drug solution and polymer-chloroform solution was emulsified by probe sonication to prepare a very fine W/O emulsion. The powder obtained by freeze-drying of the W/O emulsion was pressed into circular disks. In the compression method, the drug was mechanically mixed with the polymer, and the mixture was compressed into circular disks. The resulting disks were ground to prepare granules of different sizes. The granules encapsulated more than 95% of the drug, irrespective of the preparation method. Both methods were effective in preparing polymer disks capable of controlled drug release without any initial burst. However, as the granule size decreased to an injectable size (diameter, < 150 microns), a large difference in the drug release profile was observed between the two preparation methods. The injectable granules obtained by the W/O emulsion method showed nearly constant drug release without any large initial burst, in contrast to those prepared by the compression method, irrespective of the drug type.(ABSTRACT TRUNCATED AT 250 WORDS)

Delayed-Action Preparations↗
PubMed2002

Mechanistic relationships between polymer microstructure and drug release kinetics in bioerodible polyanhydrides.

This work investigates the relationship between polymer microstructure and drug release kinetics in the bioerodible polyanhydride system, poly[(1,6-bis-p-carboxyphenoxy hexane)-co-(sebacic anhydride)] (CPH-SA). Model drugs, p-nitroaniline (PNA) and disperse yellow 3 (DY), were selected based on compatibility with CPH and SA, respectively. The polymer microstructure and compatibility of the drug with the constituent monomers were determined to have significant influence over the release kinetics of the drugs studied. Polymer systems with homogeneous microstructure, poly(SA) and 50:50 CPH-SA, showed simultaneous polymer degradation and drug release, although the solubility of the drug in the polymer influenced the shape of the release profiles. For the heterogeneous copolymers, 20:80 and 80:20 CPH-SA, individual monomer release kinetics demonstrated the effects of drug partitioning within a phase-separated microstructure. The PNA molecules partition preferentially into the CPH microdomains in the 20:80 CPH-SA copolymer while the DY molecules partition preferentially into the SA microdomains in the 80:20 CPH-SA copolymer. These studies suggest that the drug release mechanism is driven by polymer microstructure, compatibility of the drug with the constituent polymer phases, and solubility of the drug within the polymer. A thorough understanding of drug-polymer interactions as well as the polymer microstructure will pave the way for more accurate predictions of drug release from bioerodible polyanhydrides.

Aniline Compounds↗
PubMed2000

Investigation of the in vitro release of gentamicin from a polyanhydride matrix.

Septacin¿trade mark omitted¿ is a sustained release formulation consisting of gentamicin sulfate dispersed in a biodegradable polyanhydride matrix. The polyanhydride matrix is a copolymer of erucic acid dimer (EAD) and sebacic acid in a 1:1 weight ratio. In vitro drug release was performed in both water and pH 7.4 phosphate buffer. The drug release in water was faster than that in the buffer, which was the opposite of what would be expected based upon a faster polymer hydrolysis rate in the buffer. Theoretical treatment of the data using the Peppas model revealed that release in water was anomalous, while the release in pH 7.4 phosphate buffer was diffusion-controlled. Profound bead morphology differences were observed between beads in these two in vitro release media. Cracking was observed in beads in water and swelling with no apparent cracking was seen in beads in buffer. Concurrent monitoring of drug and sebacic acid release indicated that drug release is not via surface erosion. Osmotic effects were found to play little role in the in vitro drug release. There was no spectroscopic evidence of amide formation between the drug and copolymer. Sulfate release was monitored along with drug release and the results indicate that there is ion-exchange occurring during the pH 7.4 in vitro release. It was subsequently demonstrated that gentamicin can form an insoluble salt with EAD. This salt formation explains the slower drug release in pH 7.4 phosphate buffer.

Decanoic Acids↗
PubMed2003

Synthesis, characterization and in vitro release of 5-aminosalicylic acid and 5-acetyl aminosalicylic acid of polyanhydride--P(CBFAS).

A novel polyanhydride, poly[(5-carboxybutyl formamide)-2-acetyl salicylic anhydride] (P(CBFAS)), with 5-aminosalicylic acid (5-ASA) incorporated into the polymer backbone was synthesized and characterized by infrared, (1)H-nuclear magnetic resonance, differential scanning calorimetry, vapor pressure osmometry, etc. The polyanhydride was subjected to degradation and simultaneously released 5-ASA and its derivative 5-acetyl aminosalicylic acid (5-acetyl ASA) in vitro under various conditions. The factors influencing the release profiles of 5-ASA and 5-acetyl ASA, including polymer molecular weights, pH value, enzyme and rat gastrointestinal contents, were examined. The results showed that the release rate of 5-ASA and 5-acetyl ASA increases with increasing pH value and with decreasing molecular weights. In PBS (pH 8.0, 37 degrees C) total ASA released was 8.0% for P(CBFAS)(1) (Mn 10770) in 13 h, but only 1.1 and 2.6% at pH 2.0 and 6.5, respectively. Enzymes including pepsin and trypsin, as well as rat gastric and jejunum contents had little effect on the release rate of 5-ASA and 5-acetyl ASA at pH 2.0 and 6.5 (less than 4% in 13 h). However, the release rate of 5-ASA and 5-acetyl ASA was much fast in PBS(pH 8.0) containing 5% of cecal contents, the total ASA released was 13.6% for the polymer in 13 h. Considering the high drug loading of the polymer (50.2% of 5-ASA moieties in the backbones) and the degradation characters, it is possible to reach high local concentration of 5-ASA in the colon site via oral administration. Therefore, P(CBFAS) may be potentially useful in the colon specific delivery of 5-ASA.

Aminosalicylic Acids↗
PubMed1990

Morphology of polyanhydride microsphere delivery systems.

Scanning electron microscopy (SEM) was used to elucidate the mechanism of polymer degradation and drug release in polyanhydride microspheres. Three different fabrication methods--solvent removal, solvent evaporation, and hot melt microencapsulation--were used to prepare polyanhydride microspheres containing a variety of drugs. The morphology of these microspheres releasing drug in vitro and in vivo was studied by SEM and compared with degradation and release data measured by conventional methods. Microspheres prepared by the three techniques were shown to have distinctive morphological characteristics induced by the nature of the fabrication method. In addition, SEM analysis could be used to explain the drug release profiles and polymer degradation behavior seen in vitro as well as the in vivo effects of insulin-loaded microspheres on diabetic rats. This study has shown SEM to be an important and powerful tool for analyzing the effects of microsphere fabrication method on drug release.

Anhydrides↗
PubMed1993

Glaucoma filtration surgery in nonhuman primates using taxol and etoposide in polyanhydride carriers.

PURPOSE: To determine the effect of taxol and etoposide, hydrophobic drugs with antifibrosis activity, on the outcome of filtration surgery in glaucomatous monkeys. METHODS: Elevated intraocular pressure was produced bilaterally in eight cynomolgus monkeys by laser treatment of the trabecular meshwork. Four animals subconjunctivally received a polyanhydride disk containing 1 mg etoposide at the time of posterior lip sclerectomy in one eye; the other eye received an identical disk without drug. Similarly, four animals received a disk containing 50 micrograms of taxol in one eye and a blank disk in the other. RESULTS: Eyes treated with taxol had lower intraocular pressures than control eyes from 20 days after surgery until death. Eyes with satisfactory filtration bleb appearance and patent fistulae on histologic examination had lower intraocular pressures. The intraocular pressure was lower and the duration of success longer in the etoposide-treated eyes (mean, 16 days) compared to that of the fellow eyes (mean, 10 days), but the difference was not statistically significant. CONCLUSIONS: Use of polyanhydride disks containing taxol, but not etoposide, had a marked beneficial effect on intraocular pressure and bleb appearance after experimental filtration surgery in monkeys. The difference between the two agents may result from the greater antiproliferative potency of taxol and its greater duration of release from the polymer.

Animals↗
PubMed2004

Encapsulation, stabilization, and release of BSA-FITC from polyanhydride microspheres.

In order to determine the efficacy of using polyanhydrides as a carrier for therapeutic proteins, the model protein bovine serum albumin labeled with fluorescein isothiocyanate (BSA-FITC) was encapsulated in microspheres of poly sebacic anhydride (poly(SA)), and random copolymers of poly(SA) and poly(1,6-bis-p-carboxyphenoxy)hexane (poly(CPH)). The microspheres were fabricated via the double emulsion (water/oil/water) technique and were characterized using scanning electron microscopy, gel permeation chromatography, confocal microscopy, and a Coulter counter. The effect of protein loading, protein distribution, and change in polymer composition was examined in an in vitro release study. The secondary structure of the encapsulated BSA-FITC was determined with Fourier transform infrared spectroscopy. The primary structure of the released protein was analyzed using sodium dodecyl sulfate polyacrylamide gel electrophoresis. Poly(SA) and 20:80 (CPH:SA) microspheres were found to conserve the primary structure of the released protein and the secondary structure of the encapsulated protein, and showed a sustained delivery for approximately 15 and 30 days, respectively. As the CPH content in the copolymer increased, the secondary structure of FITC-BSA was not conserved, as indicated by the steep decrease in the alpha-helix content.

Electrophoresis, Polyacrylamide Gel↗
PubMed2005

Synthesis and characterization of polyanhydride for local BCNU delivery carriers.

p-Carboxyphenoxy propane (CPP) prepolymer consisting of 4 units and sebacic acid (SA) prepolymer consisting of about 10 units were synthesized by reacting CPP and SA in the presence of excess acetic anhydride, respectively. Polyanhydride, poly(CPP-SA) copolymers were copolymerized by a melt polycondensation process with a mixture of CPP and SA prepolymer. Copolymers of average molecular weight up to 110,000 g/mol were achieved. The crystallinity of poly(CPP-SA) copolymers was decreased by the addition of the CPP homopolymer segment to SA homopolymer. Poly(CPP-SA) copolymers gradually degraded for period of 10 days. No large difference of weight loss observed according to molecular weight variation of poly(CPP-SA) copolymers. BCNU release from wafers fabricated by poly(CPP-SA) showed a sustained release pattern with no initial burst and delay of drug release.

Anhydrides↗