Steven Y. Ng

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.

Controlled release of interleukin-2 for tumour immunotherapy using alginate/chitosan porous microspheres

Porous microspheres were formed by the gelation of two polysaccharides, a polyanionic sodium alginate and a polycationic chitosan, followed by lyophilization which creates the porous structure. Porous microspheres were also formed by gelation of sodium alginate with CaCl2 and gelation of sodium alginate with polylysine. FITC-BSA was incorporated into the microspheres by mixing the protein with the polysaccharide solution prior to gelation. Interleukin-2 (IL-2) was incorporated into the preformed microspheres by diffusion from an external aqueous solution of IL-2. Sustained release of the proteins from porous alginate/chitosan microspheres is of longer duration than from alginate/CaCl2, or from alginate/polylysine microspheres. Activity of the released IL-2 was investigated by determining the induction of cytotoxic T lymphocytes (CTL) when incubated with tumor cells and lymphocytes. It was found that the IL-2 remained active in the alginate/chitosan microspheres since the released IL-2 triggered induction of CTL. Further, IL-2 released in a sustained manner triggered induction of CTL more efficiently than free IL-2. Tumor-killing specific activity of CTL was the same whether induced by the sustained released IL-2 or by the addition of free IL-2.

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).

Pulsatile and delayed release of lysozyme from ointment-like poly(ortho esters)

Abstract Poly(ortho esters) have been prepared by the reaction between 1,2,6-hexanetriol and various alkyl ortho esters. Because such polymers have very flexible chains, they are viscous, ointment-like materials at room temperature. Because therapeutic agents can be incorporated into such materials by a simple mixing procedure at room temperature and without the use of solvents, they are of particular interest for the controlled release of proteins. When lysozyme, used as a model protein, was incorporated into the ointment, release occurred only after an induction period that varied from less than one day to more than 30 days. The length of the delay time was found to depend on polymer molecular weight and the nature of the alkyl substituent of the polymer. No loss of activity of the enzyme, as measured by rate of lysis of Micrococcus lysodeikticus, was noted. Thus, this system has potential usefulness for the pulsatile release of proteins.

Controlled drug release from bioerodible hydrophobic ointments

A new type of poly (ortho ester) was prepared by the condensation of a triol and an alkyl ortho ester. The condensation produces polymers that are viscous pastes at r.t. even though molecular weights in excess of 50,000 dalton can be produced. Such materials are useful as bioerodible drug delivery devices because rate of release of an incorporated therapeutic agent can be controlled by the addition of small amounts of acidic excipients to the polymer. A significant advantage of these materials is that therapeutic agents can be incorporated by simple mixing at r.t. without the use of solvents.

Use of poly(ortho esters) for the controlled release of 5-fluorouracyl and a LHRH analogue☆

Abstract The controlled release of 5-fluorouracyl (5FU) and a luteinizing hormone releasing hormone analogue (LHRH) from a crosslinked bioerodible poly (ortho ester) was studied. Unlike our previous results with levonorgestrel which was released by a predominant surface erosion process, the much more water-soluble 5FU and LHRH analogue are released predominantly by diffusion. However, rate of diffusion is strongly influenced by rate of polymer hydrolysis. Because the LHRH analogue has two reactive hydroxyl groups, some are chemically bound to the crosslinked matrix via ortho ester linkages. Analysis of a model polymer matrix indicates that 95% of the LHRH analogue is released in its original form and 5% is released as the propionate ester.

In vitro and in vivo release of levonorgestrel from poly(ortho esters)

Abstract The in vitro and in vivo release of levonorgestrel from linear poly(ortho ester) cylindrical devices containing 30 wt.% drug and 2 wt.% calcium lactate was studied. The in vitro release rate was a relatively constant 20 μg/day for about one year at which time the experiment was discontinued. The in vivo release rate in rabbits was about 33 μg/day. In both studies rate of polymer erosion is about the same and significantly leads rate of drug release. Therefore, factors other than polymer erosion determine rate of drug release. SEM studies of devices explanted from rabbits show the formation of a foamed drug layer surrounding the device. The formation of this layer is caused by polymer erosion around undissolved drug. Rate of drug delivery from the device is controlled by dissolution of levonorgestrel from the outside of the foamed drug layer. The higher in vivo release is attributed to the presence of lipophilic species that facilitate dissolution of levonorgestrel.

Poly(ortho ester) matrices for controlled release of the antitumour agent 5-fluorouracil

Abstract Previously it has been shown that bioerodible poly (ortho ester) matrices can be synthesised to contain the anticancer drug 5-fluorouracil (5-FU) and, with adjustment of their suberic acid excipient content, designed to produce approximately zero order release of 5-FU in vitro over 15 days. This short study describes the first evaluation of such matrices against a human colorectal carcinoma model in vivo (a LS174T xenograft), colorectal cancer being the ultimate therapeutic target. First, in order to assess the potential general toxicity of the polymer, between one and four drug-free polymer matrices were implanted in the peritoneal cavity of DBA 2 mice, and the animals subsequently monitored for 60 days. Following implantation of one to three matrices (a polymer dose equivalent to 8.4 g/kg) animals showed no weight loss, and no overt signs of toxicity. However, implantation of four matrices did produce visible signs of toxicity, even though these animals displayed no significant weight loss. To evaluate their antitumour activity, 5-FU-containing matrices (one to four matrices equivalent to 5-FU doses of 280, 560, 840 and 1120 mg/kg, respectively) were implanted into the peritoneal cavity of nude mice bearing established subcutaneous LS174T xenografts, and the antitumour activity compared with that seen following bolus administration of free 5-FU at a dose of 200 or 500 mg/kg). An increased survival relative to untreated controls was observed following implantation of one, two and three matrices, the T C values being 122, 178, and 155%, respectively. The animals receiving three 5-FU-containing matrices were eventually withdrawn due to drug toxicity rather than tumour growth, and those receiving four matrices showed very early signs of drug-related toxicity ( T C . Although 5-FU did suppress tumour growth, mice treated with free drug showed either no increase in survival (200 mg/kg), or a decreased lifespan due to drug-related toxicity (500 mg/kg). Dose-dependent control of xenograft growth, and prolongation of animal survival was seen following implantation of 5-FU-containing matrices.

Recent developments in the synthesis and utilization of poly (ortho esters)

Abstract One family of poly (ortho esters) can be prepared by the reaction of diketene acetals and diols. This polymer has recently been used in the development of bioerodible implants for the release of the antineoplastic agent 5-fluorouracil (5-FU) and the narcotic antagonist naltrexone. Polymer erosion was found to depend on both the nature of the acidic excipient used to control erosion rate and on the composition of the polymer. Good control over rate of release of 5-FU was achieved by using suberic acid and a polymer based on 1,6-hexanediol. Preliminary encouraging survival times have been obtained with mice inoculated with IL1210 leukaemia. Polymers with a 50 wt% loading of naltrexone pamoate have been shown to release the drug by good zero order kinetics and in vivo studies are currently in progress. Another family of poly (ortho esters) can be prepared by a transesterification reaction between a triol and a trialkyl ortho ester. When the transesterification reaction is carried out with flexible triols such as 1,2,6-hexanetriol, ointment-like materials are obtained even though molecular weight can be in excess of 50,000. Release of therapeutic agents from such ointments can also be controlled with acidic excipients. Such materials are particularly useful for peptide release because these can be incorporated into the polymer at room temperature without the use of solvents. Preliminary indications of retention of activity have been obtained.

The effect of copolymerized 9,10-dihydroxystearic acid on erosion rates of poly(ortho esters) and its use in the delivery of levonorgestrel

Abstract Erosion, rates of poly(ortho esters) can be usefully accelerated by the copolymerization of 9,10-dihydroxystearic acid into the copolymer. This accelerating effect can be enhanced by using a hydrophilic diol such as triethylene glycol as one of the monomers. By using a combination of 9,10-dihydroxystearic acid and triethylene glycol precise control over erosion rate of the polymer can be achieved by small variations in the amount of 9,10-dihydroxystearic acid used. This technique has been used to develop levonorgestrel-containing devices.