Biomedical subjects

E Mathiowitz

Publications and source records attributed to E Mathiowitz.

25 records · Page 2Linked to original sources

PubMed1989

Intracerebral drug delivery in rats with lesion-induced memory deficits.

Pharmacological treatments directed at increasing cortical acetylcholine activity in patients with Alzheimer's disease have largely been disappointing, perhaps because denervated areas of brain may not be exposed to adequate amounts of drug. A new method has been developed to enable localized intracerebral delivery of neurotransmitter substances using a polymeric drug delivery system. Microspheres of a polyanhydride sebacic acid copolymer were impregnated with bethanechol, an acetylcholinesterase-resistant cholinomimetic. Twenty rats received bilateral fimbria-fornix lesions, producing cholinergic denervation of the hippocampus and marked impairment in spatial memory. The animals were trained for 2 weeks to run after which they received bilateral intrahippocampal implants of saline (five rats), blank polymer (five rats), or bethanechol-impregnated polymer (10 rats). Following implantation, spatial memory was assessed by radial-maze performance testing for 40 days. Untreated lesioned rats showed persistently poor spatial memory, entering maze arms with near random frequency. Similarly, animals treated with saline and blank polymer did not improve after implantation. Rats treated with bethanechol-impregnated microspheres, however displayed significant improvement within 10 days after implantation; this improvement persisted for the duration of the experiment (p less than 0.05, Student's t-test). Histological analysis of regional acetylcholinesterase staining showed widespread loss of activity throughout the hippocampus bilaterally in all animals. The microsphere implants were visible within the hippocampus, with minimal reactive changes in surrounding brain. It is concluded that intracerebral polymeric drug delivery successfully reversed lesion-induced memory deficits, and has potential as a neurosurgical treatment method for Alzheimer's disease and other neurodegenerative disorders.

Anhydrides↗

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↗

PubMed1988

Enzymatically controlled drug delivery.

An approach for providing feedback control for polypeptide drugs in a polymeric controlled-release system uses a trigger molecule and a polymer-bound enzyme that, in the presence of that trigger molecule, will cause an acid or a base to form. When the pH inside the polymer system changes, the solubility of the drug shifts dramatically, which changes the diffusion or dissolution driving force, and hence the release rate changes correspondingly. This concept was tested using a controlled-release system of ethylene/vinyl acetate copolymer containing insulin and immobilized glucose oxidase. The enzymatic reaction of glucose to gluconic acid reduces the pH in the polymer microenvironment. Since insulin solubility increases with decreasing pH (at physiologic pH, this is true for an insulin with an isoelectric point of 7.4 or higher), the release of insulin increases in response to glucose concentration. The feasibility of this concept has been shown using trilysyl insulin with an isoelectric point of 7.4. Multiple exposures to buffered glucose solutions over several weeks caused insulin release to reversibly increase during each exposure. Polymer-implanted diabetic rats infused with glucose solutions showed a significant increase in insulin concentration in 30 min-an effect not observed in three different sets of control rats.

Animals↗

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↗

PubMedDate not supplied

Effect of manufacturing conditions on the formation of double-walled polymer microspheres.

This paper discusses the optimization of the solvent evaporation process to produce double-walled (DW) microspheres in a single-step. Five process variables were studied: polymer solution concentration, polymer weight ratio, polymer solution volume ratios, encapsulation temperature, and air flow rate across the top of the encapsulation vessel. The effects of these variables on the process efficiency (defined here as the percentage of microspheres with a DW configuration compared to the total number of microspheres) were examined. Total polymer concentrations of less than 20% (w/v) produced microspheres with high efficiency, with phase separation consistent across all size fractions in each batch. Changing the volume ratio of the two polymer solutions had no significant effect on the process efficiency. The weight ratio of the polymers greatly influenced the process efficiency, resulting in a low 63% efficiency for the 1:3 Poly-L-lactide (PLLA): Poly(carboxyphenoxypropane-co-sebacic)anhydride 20:80 (P(CPP:SA 20:80)) weight ratio and 0% for the 3:1 weight ratio. The 1:3 weight ratio also caused the polymers to reverse their orientation, although the efficiency for this switch was still relatively low. The temperature of the non-solvent bath affected the efficiency of certain pairs of polymers, but not all. The PLLA/Poly(lactide-co-glycolide) 50:50 (PLGA) pair was most sensitive to temperature, due to the chemical similarity of the two polymers which narrowed the range of acceptable conditions for encapsulation. Pairs of polymers which phase separated readily (e.g. polystyrene and PLLA) were the least sensitive to temperature changes. Process yield and size distribution show no clear trends with respect to air flow rate across the top of the reaction vessel. The efficiency of the process to produce DW microspheres increased and the process time decreased with increasing air flow across the surface of the encapsulation vessel.

Chemistry, Pharmaceutical↗

PubMedDate not supplied

Cytokines delivered by biodegradable microspheres promote effective suppression of human tumors by human peripheral blood lymphocytes in the SCID-Winn model.

A new technology for the local and sustained delivery of immunostimulatory molecules to the tumor environment for cancer immunotherapy was evaluated. The ability of cytokines delivered by biodegradable microspheres to promote the antitumor activity of human peripheral blood lymphocytes (PBL) was tested in a human PBL, human tumor, and SCID mouse (SCID-Winn) model. Co-engraftment of human recombinant IL-12-loaded microspheres with human PBL and tumors in SCID mice promoted complete tumor suppression in as many as 100% of the mice, whereas microspheres loaded with polyethyleneglycol-interleukin-2 suppressed but did not eliminate the growth of tumor xenografts. Control microspheres (loaded with bovine serum albumin) in the presence of human PBL or cytokine-loaded microspheres in the absence of human PBL had no tumor-suppressive effect. Coincident with the enhancement of the human PBL-mediated antitumor activity in mice treated with IL-12-loaded microspheres was the production and release of human IFN-gamma indicating that IL-12 released from the microspheres results in the activation of the engrafted human PBL. The results establish that biodegradable microspheres represent an effective tool for the local and sustained delivery of cytokines to the tumor environment for cancer immunotherapy.

Adjuvants, Immunologic↗

PubMedDate not supplied

A microtensiometer for the analysis of bioadhesive microspheres.

Bioadhesive polymer microspheres are potential vehicles for the delivery of bioactive agents to mucosal tissues. Bioadhesive delivery devices could improve drug absorption, enhance bioavailability, and increase patient compliance by minimizing dosing regimens. Identification of bioadhesive materials is the first phase in developing bioadhesive drug delivery systems. Additionally, quantification and analysis of the bioadhesive event are essential to successful development of a new generation of adhesive delivery systems. A unique, microbalance-based instrument was developed to analyze bioadhesive forces between polymer microspheres and mucosal tissue segments. A contact angle analyzer, with a custom-made physiologic tissue chamber, was linked to a computer via the serial port. Software was used to modify the microbalance operation to behave as a microtensiometer with a sensitivity of 0.1 microN. After mounting a microsphere and tissue segment in the balance and adjusting the experimental settings, the instrument performs a tensile experiment and automatically determines the following parameters: compressive deformation, peak compressive load, compressive work, yield point, deformation to yield, returned work, peak tensile load, deformation to peak tensile load, fracture strength, deformation to failure, and tensile work. Using this device the authors identified several bioadhesive materials ideally suited for orally-delivered, controlled-release systems. GI-transit studies in rats showed strong correlation between increased GI-residence time and strong bioadhesive interactions.

Adhesives↗