Polyanhydride Copolymers Research Articles

Prolonged seizure suppression by a single implantable polymeric-TRH microdisk preparation

Thyrotropin-releasing hormone (TRH; Protirelin) is an endogenous neuropeptide known to have anticonvulsant effects in several seizure models and in intractable epileptic patients. Like most neuropeptides, its duration of action may be limited by a lack of sustained site-specific bioavailability. To attempt to provide long-term delivery, we attached TRH to a biodegradable polyanhydride copolymer as a sustained-release carrier. Utilizing the rat kindling model of temporal lobe epilepsy, a single TRH microdisk implanted stereotaxically into the seizure focus (amygdala) significantly suppressed kindling expression when assessed by the number of stimulations required to reach each behavioral stage and to become fully kindled (8.63±0.92 vs. 16.17±1.37; Mean±S.E.M.). Two indices of seizure severity, afterdischarge duration (Mean±S.E.M., sec.) (stimulated amygdala [87.40±5.47 vs. 51.80±15.65] and unstimulated amygdala [89.60±5.55 vs. 48.67±15.8] and clonus duration (71.2±5.94 vs. 29.40±8.87; Mean±S.E.M., sec.), were also significantly reduced by a single polymeric-TRH implant. Fifty days after initiation of the study a significant reduction in clonus duration (53.90±3.27 vs. 40.09±4.14) still remained in the TRH-implanted groups. This report is the first to provide evidence in support of in situ microdisk pharmacotherapy for potential neuropeptide delivery in intractable epilepsy and possibly other neurological disorders.

Morphological Characterization of a Sustained-Release Drug Implant by Scanning Electron Microscopy, Polarized Light Microscopy and Image Analysis

Abstract Septacin is a sustained-release antibiotic currently under development by the Hospital Products Division of Abbott Laboratories. The product is designed to be used as an anti-infective implant in orthopedic surgical procedures with a sustained drug release for up to six weeks in vivo. It consists of gentamicin sulfate formulated with a bioerodable polyanhydride copolymer. The polymer is biodegradable and has been approved by the FDA for human clinical trials. The final product is obtained by mixing 20% gentamicin sulfate with molten polymer and injection molding it to form cylindrical Septacin beads. The microstructure of drug particles and polymer matrix is critical to the performance of sustained release products, thus scanning electron microscopy (SEM) and polarized light microscopy (PLM) were utilized in this study. SEM has proven useful for evaluating the microstructure of drug formulations3 and was used to examine the drug-polymer matrix structure. Average drug particle size and distribution were determined, and the drug-polymer boundary was evaluated.

Degradation of porous poly(anhydride- co-imide) microspheres and implications for controlled macromolecule delivery

The degradation properties of porous microspheres made using a new family of polyanhydride copolymers, the poly(anhydride- co-imides), were studied. Poly[trimellitylimido- l-tyrosine- co-sebacic acid- co-1,3-bis(carboxyphenoxy)propane] microspheres, with and without entrapped bovine serum albumin (BSA) as a model protein, were made using the double emulsion solvent evaporation process. Water penetration and anhydride bond cleavage (polymer degradation) occurred rapidly (<5 days) compared to the time scale of overall microsphere erosion (weeks to months) with most polymer compositions. Subsequent to bond cleavage, the ultimate erosion of the microsphere and release of entrapped BSA was due mainly to the slow dissolution of the individual hydrophobic monomers (TMA-Tyr, SA and CPP) from the microsphere surface. BSA was released at approximately the same rate as the polymer eroded. Due to the fast degradation of anhydride bonds relative to microsphere erosion, initial polymer molecular weight did not have a significant effect on macromolecule release rates. Instead, monomer solubility correlated well with polymer erosion and BSA release rates. This erosion mechanism leads to predictable drug release rates which may be appropriate for the delivery of many protein therapeutics, including vaccine antigens. The anhydride–imide copolymers were well tolerated in acute toxicity studies in rats and therefore show promise as biomaterials.

The precipitation of monomers during the erosion of a class of polyanhydrides

The erosion mechanism of a class of bioerodible polyanhydride copolymers consisting of a fatty acid dimer (FAD) and sebacic acid was investigated in vitro. Special attention was given to the behaviour of the monomers that are released from the polymer matrix during the degradation process. The erosion of polymer matrix discs was followed by polarized light microscopy, differential scanning calorimetry, wide-angle X-ray spectroscopy and Fourier-transform infra-red spectroscopy. FAD, which is derived from erucic acid, was found to decrease the surface tension of the buffer significantly. Owing to its low solubility, however, as the polymer degrades, most of the FAD is deposited on the surface of the polymer matrix discs. There it forms an amorphous monomer film consisting of a mixture of FAD and FAD salts. The acid/salt ratio is pH-dependent and changes during erosion. Such films behave as diffusion barriers when these polymers are used as materials for the release of drugs from implants.

Modeling monomer release from bioerodible polymers

A theoretical model was developed that describes the erosion of biodegradable polymers and the resulting release of monomers. Erosion is simulated using a Monte Carlo Model that describes the morphological changes during erosion. It allows the calculation of porosity distributions that are needed for modeling drug and monomer release using a modified diffusion equation. This equation takes into account the diffusion of monomers, the concentration dependence of diffusivities, the porosity along the diffusion pathway, as well as the presence of suspended monomers and their pH dependent dissolution. The model was used to describe the release of monomers from polyanhydride copolymers, which show a pH dependent release behavior that cannot be explained by existing models. After the determination of model parameters by fitting the model to release profiles, it was possible to predict other system properties like the amount of accumulated crystallized monomer or the total polymer matrix weight during erosion. With some modifications such models might become useful for predicting drug release from the investigated polymers.

Synthesis of 14C-labeled copolymers for drug delivery studies

14C-labeled polyanhydride copolymers [(20:80/1,3-bis)(p-carboxyphenoxy)-propane(CPP):sebacic acid (SA)] (7 and 13) were synthesized according to schemes I and II: 14C-labeled sebacic acid (2,9-14C2) (5) and 14C-labeled CPP 1,3-bis(p-carboxyphenoxy)-propane (labeled at C-1, C-3 of the propyl group) (11) were transformed to the corresponding mixed anhydrides (6 and 12) as prepolymers respectively by reaction with acetic anhydride. The labeled mixed anhydride prepolymers (6 and 12) were condensed with unlabeled counter-prepolymers (12′ and 6′) to give the labeled polyanhydride copolymers (7 and 13). The labeled copolymers (7 and 13) were identified and characterized by gel permeation chromatography (GPC).

Biodegradable polymers for controlled delivery of chemotherapy with and without radiation therapy in the monkey brain.

Sustained drug delivery by biodegradable polymer devices can increase the therapeutic efficacy of drugs by producing high local tissue concentrations over extended periods of time. It has been shown previously that implantation of controlled-release polymers impregnated with the nitrosourea carmustine (BCNU) extended the period of survival in rats bearing the 9L glioma compared with similar rats treated with systemically administered BCNU. This study evaluated the effect on the monkey brain of interstitial delivery of BCNU by the biodegradable polyanhydride copolymer poly[bis(p-carboxyphenoxy)propane]anhydride (PCPP) and sebacic acid (SA) in a 20:80 formulation (PCPP:SA). The effect of combining interstitial BCNU with radiation therapy was also evaluated. Eighteen male cynomolgus monkeys were randomly assigned to one of four groups: a control group; a group with implantation of empty polymer; a group with implantation of BCNU-loaded polymer; and a group with implantation of empty polymer in the right hemisphere and BCNU-loaded polymer in the left hemisphere, followed by irradiation. The effects were evaluated radiologically and histologically at specified times. A local reaction by the brain to the polymer was found, which was greater when the polymer contained BCNU. Local cerebral edema was observed radiographically on postoperative Day 14 and had resolved by Day 72. Histologically, a subacute cellular inflammatory response was seen on postoperative Day 16, which had changed to a chronic inflammatory response by Day 72. In the group with radiation therapy administered to the hemisphere bearing BCNU-loaded polymer, only localized pathological changes were detected. In all animals, brain distant from the polymer implantation site was normal. No neurological or general deleterious effects were seen in any of the animals. It is concluded that the interstitial delivery of BCNU by the polyanhydride polymer PCPP:SA is safe in the primate brain and that concomitant radiation therapy did not lead to any adverse effects. These experimental findings are important to an understanding of the clinical effects of PCPP:SA implants in treating brain diseases.

Bioerodible polyanhydrides for antibiotic drug delivery: In vivo osteomyelitis treatment in a rat model system

Acute and chronic osteomyelitis can be difficult to treat by conventional means. Current methods of treatment involve the use of systemic antibiotics, the local implantation of non-degradable drug carriers, and surgical débridement. Each method has specific drawbacks. We report on the use of a new controlled release system utilizing gentamicin and bioerodible, biocompatible polymers (polyanhydrides) designed for drug delivery applications for the treatment of clinical osteomyelitis. We compared this system's ability to reduce bacterial levels in infected bone with that of conventional non-degradable delivery systems based on polymethylmethacrylate (PMMA) and gentamicin. Polyanhydride copolymers of bis-carboxyphenoxypropane and sebacic acid P loaded with gentamicin sulfate and PMMA/gentamicin matrices were implanted in the long bones of Sprague-Dawley rats infected with a strain of Staphylococcus aureus. After 3 weeks of implantation, the polymeric delivery devices were removed and quantitative cultures were used to determine bacterial levels in bone. The polyanhydride/gentamicin matrices demonstrated significant degradation over the 3 week implantation period. Levels of bacteria, measured in colony forming units, were significantly lower in bone implanted with the polyanhydride/gentamicin release system than in long bones of control animals without an implant (p < 0.01), of animals with a polyanhydride polymer implant alone (p < 0.01), and of animals with a PMMA/gentamicin implant (p = 0.03). Bioerodible polyanhydrides show promise as a new treatment modality for infections in bone.

Characterization of a Polyanhydride Series by Ftir

AbstractUsing Fourier-transform infrared (FTIR) spectroscopy we have characterized a polyanhydride copolymer series composed of various ratios of the diacids 1,3-bis(p -carboxyphenoxy)propane (CPP) and sebacic acid (SA). Typical peaks corresponding to the aliphatic-aliphatic (SA-SA), aromatic-aliphatic (CPP-SA), and aromatic-aromatic (CPP-CPP) diads were found in the 1820- 1710 cm−1 wavenumber range. Further peaks corresponding to the SA-SA diads were identified in the fingerprint region at 1382, 1360, 1307, and 1286 cm−1. These peak characterizations facilitate identification of bond distribution in the CPP-SA copolymer as well as other polyanhydride copolymers, and correlate well with previously presented information obtained with nuclear magnetic resonance (NMR) spectroscopy and X-ray powder diffraction.

Dextran retention in the rat brain following release from a polymer implant.

Intracranial controlled release polymers may improve drug administration to the brain, where therapy is frequently limited due to the low permeability of brain capillaries to therapeutic agents. On the basis of drug transport and elimination rates, we proposed that high molecular weight, water-soluble molecules would be retained in the brain space following release from an intracranial implant. To test this hypothesis, solid particles of different molecular weight fractions of fluorescein isothiocyanate labeled dextran (FITC-dextran; 4 x 10(3) Da (4 kDa) < weight-averaged molecular weight (Mw) < 150 kDa) or fluorescein were uniformly dispersed in matrices of a polyanhydride copolymer synthesized from a fatty acid dimer and sebacic acid in a 50:50 ratio, P(FAD:SA). When incubated in buffered saline, FITC-dextran fractions of 70 kDa Mw were released from the polymer within 48 h; 4 kDa Mw FITC-dextran and fluorescein were released more slowly. Following implantation of P(FAD:SA) matrices containing either 70 kDa Mw FITC-dextran, 4 kDa Mw FITC-dextran, or fluorescein into the brains of normal rats, fluorescent tracers were continuously released into the brain tissue for 30 days. Tracer concentrations within the brain were significantly higher for large molecular weight tracers (70 kDa Mw FITC-dextran >> 4 kDa Mw FITC-dextran > fluorescein). The rate of elimination, kapp, of each tracer from the brain was determined by comparing experimental data with a model describing tracer diffusion/elimination in the brain extracellular space; kapp decreased with increasing molecular weight (fluorescein > 4 kDa Mw FITC-dextran > 70 kDa Mw FITC-dextran).

Controlled antibody delivery systems.

We have developed methods for controlling the release of antibodies (Ab) from biocompatible polymers. Human Ab, human Ab fragments, and mouse monoclonal antibody (mAb) directed against human chorionic gonadotropin (anti-hCG) were incorporated into matrices of poly(ethylene-co-vinyl acetate), which is stable in biological environments. Human Ab and bovine gamma-globulin were also incorporated in biodegradable matrices of a poly-anhydride copolymer composed of a stearic acid dimer and sebacic acid. Abs were slowly released from all the polymeric carriers during 30 days of continuous immersion in buffered saline. The ability of anti-hCG to bind antigen was retained following release from EVAc matrices. Only minor Ab aggregation was observed following release from either polymer. Polymeric delivery systems, similar to those described here, may become an important element in the delivery of mAbs to humans for immunoprotection against infectious diseases or the delivery of mAb-conjugates for immunotherapy against cancer.

Molecular weight changes in polymer erosion.

We report a study of the effects of polymer molecular weight on the erosion of polyanhydride copolymer matrices composed of 1,3-bis(p-carboxyphenoxy)-propane (CPP) and sebacic acid (SA) in aqueous solution. The erosion profile characteristically displays an induction period during which the erosion rate is relatively slow. The length of this period depends on the initial molecular weight of the polymer. The induction period may be characterized as a time during which a rapid decrease in polymer molecular weight occurs, the end of this period correlating with the time required for the polymer molecular weight to decrease to below a value of approximately 5000 (MW).