John Barr

Poly(ortho esters): synthesis, characterization, properties and uses

Over the last 30 years, poly(ortho esters) have evolved through four families, designated as POE I, POE II, POE III and POE IV. Of these, only POE IV has been shown to have all the necessary attributes to allow commercialization, and such efforts are currently underway. Dominant among these attributes is synthesis versatility that allows the facile and reproducible production of polymers having the desired mechanical and thermal properties as well as desired erosion rates and drug release rates that can be varied from a few days to many months. Further, the polymer is stable at room temperature when stored under anhydrous conditions and undergoes an erosion process confined predominantly to the surface layers. Important consequences of surface erosion are controlled and concomitant drug release as well as the maintenance of an essentially neutral pH in the interior of the matrix because acidic hydrolysis products diffuse away from the device. Two physical forms of such polymers are under development. One form, solid materials, can be fabricated into shapes such as wafers, strands, or microspheres. The other form are injectable semi-solid materials that allow drug incorporation by a simple mixing at room temperature and without the use of solvents. GMP toxicology studies on one family of POE IV polymers has been concluded, an IND filed and Phase I clinical trials are in progress. Important applications under development are treatment of post-surgical pain, osteoarthritis and ophthalmic diseases as well as the delivery of proteins, including DNA. Block copolymers of poly(ortho ester) and poly(ethylene glycol) have been prepared and their use as a matrix for drug delivery and as micelles, primarily for tumor targeting, are being explored.

Release of BSA from poly(ortho ester) extruded thin strands

A solventless procedure was used where powdered polymer and micronized protein were intimately mixed and then extruded into 1 mm strands that were cut to the desired length. The polymers used were poly(ortho esters) specifically designed to allow extrusion in the neighborhood of 70 degrees C. At these temperatures many proteins maintain activity in the dry state. In vitro erosion and BSA release results indicate that after a fairly long lag-time, BSA release and polymer erosion occur concomitantly indicating an erosion-controlled process. The lag-time could be eliminated by the addition to the mixture prior to extrusion between 1 and 5 wt% poly(ethylene glycol) or its methoxy derivatives. The lag-time could also be eliminated by using an AB-block copolymer where A is poly(ortho ester) and B is poly(ethylene glycol).

Control of Molecular Weight for Auto-Catalyzed Poly(ortho ester) Obtained by Polycondensation Reaction

Polycondensation of auto-catalyzed poly(ortho ester)s (POE x LA y ) containing lactic acid units in the polymer backbone is described. The use of n-decanol during the polymerization as a chain stopper allows good control of polymer molecular weight. POE 70 LA 30 based on 3,9-diet-hylidene-2,4,8,10-tetraoxaspiro[5.5]undecane (DETOSU), 1,10-decanediol-lactate and 1,10-decanediol and synthesized by using 5, 10 and 15 mol % of n-decanol were characterized by 13 C NMR, 1 H NMR and FT-IR. The thermal and viscoelastic properties of such polymers as well as their molecular weight distribution are also reported.

Development of poly(ortho esters) and their application for bovine serum albumin and bupivacaine delivery

The preparation of drug delivery devices using solventless fabrication procedures is of significant interest and two such procedures are described. In one such procedure, powdered polymer and micronized protein are intimately mixed and then extruded into 1 mm strands that are cut to the desired length. The polymers used were specifically designed to allow extrusion at temperatures where proteins maintain activity in the dry state. In vitro erosion and BSA release show that BSA release and polymer erosion occur concomitantly indicating an erosion-controlled process. There is a lag-time, but that can be eliminated by the addition to the mixture prior to extrusion small amounts of poly(ethylene glycol) or its methoxy derivatives. The lag-time could also be eliminated by using an AB-block copolymer where A is poly(ortho ester) and B is poly(ethylene glycol). Another means of using solventless fabrication methods is to use a semi-solid material into which drugs can be mixed at room temperature and the semi-solid injected. Data on BSA and bupivacaine release are presented.

Optimization of a novel bioerodible device based on auto-catalyzed poly(ortho esters) for controlled delivery of tetracycline to periodontal pocket

Local delivery of antimicrobial agents in inflamed periodontal pocket has been shown to be effective in reducing periodontopathic microorganisms. This research focuses on developing and characterizing bioerodible formulations based on auto-catalyzed poly(ortho esters) (POExLAy) for modulated release of tetracycline over 2 weeks. POExLAy are a new versatile family of POE-containing lactoyl lactyl dimers in the polymer backbone. By modifying the proportion of lactic acid in the polymer, viscous or solid materials having different degradation rate can be produced. The formulations can be either injected or placed as a solid device directly into the periodontal pocket. Tetracycline-free base incorporated into these materials was released within 10-14 days depending on polymer structure. Increase in lactic acid content in the polymer tended to increase the drug release rate and to reduce the initial lag time. Tetracycline release from such bioerodible delivery system occurs predominantly by surface erosion of the polymeric matrix, leading to kinetics which can be zero order. This periodontal drug delivery system is designed to be used as an adjunct in the treatment of periodontal diseases. Clinical studies are currently in progress.

Development and applications of injectable poly(ortho esters) for pain control and periodontal treatment.

Poly(ortho esters) with a low glass transition temperature are semi-solid materials so that therapeutic agents can be incorporated at room temperature, without the use of solvents, by a simple mixing procedure. When molecular weights are limited to < 5 kDa, such materials are directly injectable using a needle size no larger than 22 gauge. Somewhat hydrophilic polymers can be produced by using the diketene acetal 3,9-diethylidene-2,4,8,10-tetraoxaspiro[5.5]undecane and triethylene glycol (TEG), while hydrophobic materials can be produced by using the diketene acetal and 1,10-decanediol. Molecular weight can be reproducibly controlled by using an excess of the diol, or by use of an alcohol that acts as a chain-stopper. Erosion rates can be controlled by varying the amount of latent acid incorporated into the polymer backbone. Toxicology studies using the TEG polymer have been completed and have shown that the polymer is non-toxic. Toxicology studies using the decanediol polymer are underway. Development studies using the TEG polymer aimed at providing a sustained delivery of an analgesic agent to control post-surgical pain are under development and human clinical trials using the decanediol polymer for the treatment of periodontitis are also underway.

Post surgical pain management with poly(ortho esters)

Poly(ortho esters), POE, are synthetic bioerodible polymers that can be prepared as solid materials, or as viscous, injectable polymers. These materials have evolved through a number of families, and the latest member of this family, POE IV, is particularly well suited to drug delivery since latent acid is integrated into the polymer backbone, thereby, modulating surface erosion. POE IV predominantly undergoes surface erosion and is able to moderate drug release over periods from days to many months. One indication in which the POE IV polymer is currently being investigated is in sustained post-surgical pain management. The local anesthetic agent, mepivacaine, has been incorporated into a viscous, injectable POE IV and its potential to provide longer-acting anesthesia has been explored in non-clinical models.

Protein release from poly(ortho ester) extruded rods

Poly(ortho ester) rods containing 15 wt% FITC-BSA were prepared by extruding an intimate mixture of finely powdered polymer and protein at a temperature where protein activity is retained. After an induction period, linear in vitro release kinetics were obtained with concomitant polymer weight loss.