J. Heller

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.

Poly(ortho esters) : their development and some recent applications

Poly(ortho esters) have been under development since the early 1970s and four families of such polymers have been described. Of most interest are poly(ortho ester) III and poly(ortho ester) IV. Poly(ortho ester) III is a semisolid material that has been shown to be highly biocompatible and is currently being investigated as an adjunct to glaucoma filtering surgery and other ocular applications. However, the polymerization is difficult to control and is not readily scaled up. Poly(ortho ester) IV can be easily prepared in a highly reproducible manner, is very stable provided moisture is rigorously excluded and has also been shown to be highly biocompatible. It is currently under development for a variety of applications, such as ocular delivery, protein release, post-operative pain treatment and post-operative cancer treatment.

Concomitant and controlled release of dexamethasone and 5-fluorouracil from poly(ortho ester)

A viscous bioerodible and hydrophobic poly(ortho ester) has been developed as a biocompatible, sustained drug release system for an ophthalmic application in intraocular proliferative disorders. The combination of wound healing modulators such as 5-fluorouracil and dexamethasone is a major advantage since these drugs act at different stages of these diseases. Since 5-fluorouracil is an acidic, water-soluble compound and dexamethasone exists in three chemical forms, i.e. the water-insoluble base, the highly hydrophobic acetate ester or the basic phosphate salt, it was of interest to investigate whether the physicochemical properties of the drugs have an influence on their release rates, and whether a concomitant and sustained release of both 5-fluorouracil and dexamethasone could be achieved. It has been found that lipophilicity and acidobasicity play a major role in controlling drug release rates and polymer degradation. The combination of 5-fluorouracil and dexamethasone phosphate allows a sustained and concomitant release of both drugs, due to the basic characteristics of the corticosteroid which stabilize the polymer. This system appears to be promising for concomitant and controlled drug delivery aimed at the pharmacological treatment of intraocular proliferative disorders.

A poly(ortho ester) designed for combined ocular delivery of dexamethasone sodium phosphate and 5-fluorouracil: subconjunctival tolerance and in vitro release

A viscous hydrophobic poly(ortho ester) (POE) has been developed as a biocompatible, biodegradable sustained release system for selected cases of glaucoma filtering surgery. Dexamethasone and 5-fluorouracil (5-FU) are frequently administered together post-operatively, for their anti-fibroblastic and anti-inflammatory properties, respectively. A combined sustained release of both drugs could be advantageously used. Drug release kinetics were studied using specially designed thermostated cells. Subconjunctival tolerance was evaluated on New Zealand albino rabbits by clinical evaluation. Due to its basicity, the addition of dexamethasone sodium phosphate (DEX-P) stabilized the polymer and prolonged 5-FU in vitro release from 2 to 4 days. Both therapeutic agents were released concomitantly, according to a linear profile. The presence of 5-FU only slightly affected the overall subconjunctival tolerance of POE in rabbits, whereas the addition of DEX-P markedly improved POE tolerance by reducing the hyperemia of the conjunctiva to a minimal grade.

A viscous bioerodible poly(ortho ester) as a new biomaterial for intraocular application

The biocompatibility of a viscous, hydrophobic, bioerodible poly(ortho ester) (POE) intended for intraocular application was investigated. POE was evaluated as a blank carrier and as containing modulators of degradation. Each formulation was injected intracamerally and intravitreally in rabbit eyes, and clinical and histological examinations were performed postoperatively for 2 weeks. In the case of intracameral injections, polymer biocompatibility appeared to depend on the amount injected in the anterior chamber. When 50 microL was administered, the polymer degraded within 2 weeks, and clinical observations showed good biocompatibility of POE with no toxicity to the ocular tissues or increase in intraocular pressure. The injection of a larger volume, 100 microL, of POE, appeared inappropriate because of direct contact of polymeric material with the corneal endothelium, and triggered reversible edema and inflammation in the anterior chamber of the eye that regressed after a few days. After intravitreal administration, POE was well tolerated and no inflammatory reaction developed during the observation period. The polymer degraded slowly, appearing as a round whitish bubble in the vitreous cavity. The presence of modulators of degradation both improved POE biocompatibility and prolonged polymer lifetime in the eye. POE appears to be a promising biomaterial for clinical intraocular application.

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.

New generation of poly(ortho esters): synthesis, characterization, kinetics, sterilization and biocompatibility

Abstract After a brief historical overview of the development of three families of poly(ortho esters) (POEs), the physico-chemical characteristics, drug release properties and biocompatibility of the third generation is discussed. Its synthesis is based on a transesterification reaction between 1,2,6-hexanetriol and trimethylorthoacetate. This viscous hydrophobic polymer has been used for the sustained release of 5-fluorouracil (5-FU) or mitomycin C (MMC) in glaucoma filtering surgery. It shows a good correlation between drug release and polymer erosion and can be injected using a hydraulic syringe. Drug release can be modulated by using different molecular weights of the polymer, or by adding basic or acidic excipients. Because conventional sterilization methods using gamma or electron beam-irradiation can not be used due to changes in molecular weight and dynamic viscosity resulting from backbone cleavage, an aseptic fabrication procedure has been developed and validated. POE biocompatibility has been established after subconjunctival injections of POE, monomers and degradation products in rabbits. Better control of the microenvironmental pH during polymer degradation has been achieved by using an in situ formed buffer system.

Improved biocompatibility of a viscous bioerodible poly(ortho ester) by controlling the environmental pH during degradation

The poly(ortho ester), POE, used in this investigation, is a viscous bioerodible polymer (8 kDa), which rapidly degrades into a triol and an acidic by-product, acetic acid. In order to improve biocompatibility, we have evaluated the addition of various basic excipients, such as sodium acetate, hydroxyapatite, calcium carbonate and magnesium hydroxide, which buffered and neutralized the acidic degradation product and prolonged the polymer lifetime and drug release. This decrease of POE degradation rate results in a decreased rate of formation of the acidic by-product. Similarly, a POE of higher molecular weight (14 kDa) has been tested. Sodium acetate was too hydrophilic to affect the drug release and the biocompatibility of the polymer, whereas the presence of magnesium hydroxide markedly prolonged the drug release and improved the acceptability of the polymer. The increased molecular weight POE did not improve biocompatibility and a similar but delayed, inflammatory reaction was observed.

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.