Effects of 17-ß-estradiol released from shape-memory terpolymer rods on sciatic nerve regeneration after injury and repair with chitosan nerve conduit in female rats.

The aim of this study was to assess 17-ß-estradiol (E2) influence on sciatic nerve regeneration after injury followed by a repair with chitosan conduit in ovariectomized female rats. The study was performed in 2 groups (n = 16) of rats: OVChit - after excision of a fragment of the sciatic nerve, a chitosan conduit was implanted; OVChitE10 group - additionally to chitosan conduit, shape-memory terpolymer rods based on poly(L-lactide-co-glycolide- co-trimethylene carbonate) releasing 17-ß-estradiol for 20 weeks were implanted. The mean number of regenerating axons and mean fiber area were significantly greater in 17-ß-estradiol-treated animals. In this group, the infiltrate of leukocytes was diminished. The presence of 17-ß-estradiol receptors alpha and beta in motoneurons in the spinal cord were discovered. This may indicate the location where 17-ß-estradiol affects the regeneration of the injured nerve. Estradiol released from the terpolymer rods for 20 weeks could enhance, to some extent, sciatic nerve regeneration after injury, and diminish the inflammatory reaction. In the future, 17-ß-estradiol entrapped in terpolymer rods could be used in the repair of injured peripheral nerves, but there is a need for further studies.

Designing Biodegradable Wafers Based on Poly(L-lactide-co-glycolide) and Poly(glycolide-co-ε-caprolactone) for the Prolonged and Local Release of Idarubicin for the Therapy of Glioblastoma Multiforme.

PURPOSE: The blood-brain barrier limits the application of idarubicin in the therapy of glioblastoma multiforme. Biodegradable, intracranial wafers with prolonged release may increase therapy efficiency. METHODS: Blank wafers, wafers containing 5% w/w and 10% w/w of idarubicin were formulated by solution casting from poly(L-lactide-co-glycolide) and poly(glycolide-co-ε-caprolactone). The following methods were used: NMR, GPC, DSC, FTIR, AFM, UV-VIS, and a viability and proliferation assay for idarubicin action (U87MG cell line). RESULTS: Wafers showed a surface with numerous immersions and hills. A lack of interactions between idarubicin and the copolymers was observed. The substance was entrapped in the matrix and released in two phases for all wafers with the appropriate bolus and maintenance dose. The burst effect was observed for all wafers, however, the biggest bolus for poly(L-lactide-co-glycolide) wafers containing 5% w/w of idarubicin was noted. The stable and steady degradation of poly(glycolide-co-ε-caprolactone) wafers containing 5% w/w of idarubicin ensures the most optimal release profile and high inhibition of proliferation. CONCLUSIONS: Copolymer wafers with idarubicin are an interesting proposition with great potential for the local treatment of glioblastoma multiforme. The release rate and dose may be regulated by the amount and kind of wafers for various effects.

Shape-Memory Terpolymer Rods with 17-ß-estradiol for the Treatment of Neurodegenerative Diseases: an In Vitro and In Vivo Study.

PURPOSE: Estradiol (E2)-loaded poly(L-lactide-co-glycolide-trimethylenecarbonate) (P(L-LA:GA:TMC)) rods with shape-memory were developed for the treatment of neurodegenerative diseases. Usefulness of the extrusion method in the obtaining process was also considered. The influence of structural and surface properties during hydrolytic degradation was developed. The possible therapeutic aspect of rods with E2 was determined. METHODS: The extruded rods were incubated in a PBS solution (pH 7.4, 37°C, 240 rpm). The amount of released E2 in vitro conditions was estimated by UV-VIS method. The following methods in the degradation of rods were applied: NMR, DSC, FTIR, GPC, SEM, and optical microscopy. Changes in water uptake and weight loss were also determined. In vivo study was performed on rats. Measurements of E2 level were performed before and after ovariectomy of rats using ELISA method. A sample of tissue adjacent to the site of the rod implantation was analysed under an optical microscope. RESULTS: A stable and steady degradation process ensured zero-order release of E2. The in vivo study indicated a significant increase in the E2 level in serum after ovariectomy. Moreover, structural and surface features indicated that the extrusion method was appropriate for obtaining E2-loaded rods. CONCLUSIONS: Shape-memory P(L-LA:GA:TMC) rods with E2 are an adequate proposal for further research in the field of neurological disorders.

The Role of the Mechanical, Structural, and Thermal Properties of Poly(l-lactide-co-glycolide-co-trimethylene carbonate) in the Development of Rods with Aripiprazole.

In this work, we aimed to determine the role of the mechanical, structural, and thermal properties of poly(l-lactide-co-glycolide-co-trimethylene carbonate) (P(l-LA:GA:TMC)) with shape memory in the formulation of implantable and biodegradable rods with aripiprazole (ARP). Hot melt extrusion (HME) and electron beam (EB) irradiation were applied in the formulation process of blank rods and rods with ARP. Rod degradation was carried out in a PBS solution. HPLC; NMR; DSC; compression and tensile tests; molecular weight (Mn); water uptake (WU); and weight loss (WL) analyses; and SEM were used in this study. HME and EB irradiation did not influence the structure of ARP. The mechanical tests indicated that the rods may be safely implanted using a pre-filled syringe. During degradation, no unfavorable changes in terpolymer content were observed. A decrease in the glass transition temperature and the Mn, and an increase in the WU and the WL were revealed. The loading of ARP and EB irradiation induced earlier pore formation and more intense WU and WL changes. ARP was released in a tri-phasic model with the lag phase; therefore, the proposed formulation may be administered as a delayed-release system. EB irradiation was found to accelerate ARP release.

Electron beam sterilization of implantable rods with risperidone and with 17-ß-estradiol: a structural, thermal and morphology study.

PURPOSE: Poly(L-lactide-co-glycolide-co-trimethylene carbonate) rods with risperidone and 17-ß-estradiol were sterilized by electron beam irradiation. The aim of the study was to assess electron beam irradiation impact on terpolymer composition, chain microstructure, glass transition temperature, molecular weight and the morphological features of rods. METHODS: Hot melt extrusion in the formulation of rods was applied. Sterilization of the rods was performed by electron beam in an electron beam accelerator (10 MeV, 360 mA, 25 kGy). The following methods in the development of rods were applied: nuclear magnetic resonance, differential scanning calorimetry, gel permeation chromatography and scanning electron microscopy. RESULTS: Sterilization influenced only glass transition temperature in blind rods and rods with risperidone. As for the other parameters, no significant changes were observed as far as a sterilization effect is concerned. However, some changes were noted after introducing drug substances and after extrusion. CONCLUSIONS: Electron beam irradiation of rods with risperidone and rods with 17-ß-estradiol is an adequate method for sterilizing implantable drug delivery systems.

Formulation of delivery systems with risperidone based on biodegradable terpolymers.

Risperidone is applied in oral dosage formulations in the treatment of mental diseases. Current trends point toward parenteral delivery systems based on poly(lactide-co-glycolide), with wafers or rods being the more attractive option than the routinely used intramuscular suspension with microparticles. The aim of our work was to study the utility of solution casting and hot melt extrusion in the formulation of wafers and rods with risperidone based on terpolymers, namely poly(lactide-co-glycolide-co-trimethylene carbonate) and poly(lactide-co-glycolide-co-ε-caprolactone). Synthesis of the terpolymers was carried out by using a non-toxic zirconium initiator and a racemic (LL/DD) or optically active form of the lactide monomer. The delivery systems were analyzed by NMR, DSC, GPC, and SEM. The release profile was monitored by HPLC. Terpolymer chain microstructure, glass transition temperature, and morphology revealed unchanged values after formulation. Solution casting resulted in a drop in molecular weight to a smaller degree than hot melt extrusion. The presence of risperidone influenced another decrease in molecular weight. Both methods are adequate for the formulation of delivery systems based on terpolymers for prolonged release of risperidone. An adequate selection of monomer composition in terpolymers allows to control the release period. Risperidone was released in three phases, however, the burst effect was observed for poly(L-lactide-co-glycolide-co-ε-caprolactone).

Thermal properties and morphology changes in degradation process of poly(L-lactide-co-glycolide) matrices with risperidone.

Determining thermal properties and morphology seems to be useful in the analysis of release and degradation processes form polymeric materials. Risperidone is available in the formulation of a long-acting injection based on poly(D,L-lactide-co-glycolide). Currently, alternative solutions are also offered, i.e., nano- and microparticles or implants, including copolymers of lactide and glycolide. The effect of risperidone content on the properties of poly(L-lactide-co-glycolide) matrices was determined. The study also involved an assessment of the changes during degradation. Risperidone free matrices and the matrices with risperidone were obtained by solvent casting. Thermal characteristics were tested by means of differential scanning calorimetry, and the morphology was evaluated using a scanning electron microscope. Risperidone did not change significantly semi-crystalline structure of poly(L-lactide-co-glycolide) matrices. The decrease in crystallization temperature and glass transition temperature during degradation was observed. Many pores and their deformation, the widening of pore area, cracks and slits because of degradation were observed. The analysis of thermal properties and morphology allowed us to explain degradation process. Matrices exhibited stable process of degradation, which may be advantageous for development of prolonged risperidone release systems.