WO1993020127A1

WO1993020127A1 - Ortho polymers having improved stability and bioerosion behavior

Info

Publication number: WO1993020127A1
Application number: PCT/US1993/002984
Authority: WO
Inventors: Estela Basso
Original assignee: Alza Corporation
Priority date: 1992-03-30
Filing date: 1993-03-30
Publication date: 1993-10-14
Also published as: AU3941193A; ZA932269B; MX9301818A

Abstract

Bioerodible poly(orthoesters) and poly(orthocarbonates) with acid catalysts bound to the molecular structure of the polymers by a bond that is susceptible to hydrolysis are treated with a solution of hydroxyl ion in a nonaqueous, non-hydrolyzing solvent, to dissociate the bound acid without harmful effect to the polymer. The resulting polymer, which may be used as a sustained-release delivery vehicle for drugs and other beneficial agents, is substantially more stable at room temperature and has a more prolonged bioerosion profile which provides greater reproducibility to the efficacy of the drug formulation.

Description

0RTH0 POLYMERS HAVING IMPROVED STABILITY AND BIOEROSION BEHAVIOR

This invention resides in the field of bioerodible polymers for use as drug delivery vehicles. In particular, this invention addresses means for providing improved stability of such polymers and for controlling the rate of biodegradation and degradation in general of the polymers.

BACKGROUND OF THE INVENTION

One of many known methods of achieving sustained delivery of a drug is by incorporating the drug in a solid polymeric matrix formed from a bioerodible polymer. Formulations of this type are primarily used for parenteral administration, the drug most often being a therapeutic agent. The matrix may assume a variety of forms, but most often are in the shape of either thin rods suitable for injection or microscopic particles suitable for application as a dry sprinkle, as an injectable or as a suspension in a suitable liquid vehicle. The term "bioerodible" refers to the quality of the polymer that causes it to be degraded or eroded in vivo. This occurs either through enzymatic, chemical or other action, and decomposes the polymer into biocompatible, non-toxic by-products which are further metabolized or excreted through the normal physiological pathways, without eliciting an immunological reaction.

Among the wide variety of polymers having this quality, some which are of particular interest in this invention are poly(orthoesters) and poly(orthocarbonates) . These are polymers formed by the polymerization of orthoester and orthocarbonate monomers, the polymer structure of which can be generically represented by the formula

where the three R-groups represent a wide array of radicals such as aliphatic, al cyclic, and aromatic hydrocarbons, as well as heteroatom-containing hydrocarbons such as carbonyl- and carbonyloxy- containing groups. The subscript "a" in this formula is either zero or 1; those structures in which "a" is zero are poly(orthoesters) and those in which "a" is 1 are poly(orthocarbonates). Bioerodible polymers of this formula and of closely related structures and similar behavior are disclosed in Schmitt, U.S. Patent No. 4,070,347, January 24, 1978; Choi, et al . , U.S. Patent No. 4,093,709, June 6, 1978; Schmitt, U.S. Patent No. 4,122,158, October 24, 1978; Choi, et al . , U.S. Patent No. 4,131,648, December 26, 1978; Choi, et al . , U.S. Patent No. 4,138,344, February 6, 1979; Schmitt, U.S. Patent No. 4,155,992, May 22, 1979; Choi, et al . , U.S. Patent No. 4,180,646, December 25, 1979; Capozza, U.S. Patent No. 4,322,323, March 30, 1982; and Schmitt, U.S. Patent No. 4,346,709, August 31, 1982. The disclosures in these patents are incorporated herein by reference.

The drug is originally dispersed in and held immobile by the polymeric matrix, and the release of the drug from the matrix occurs gradually over a period of time. This sustained release is achieved by one or a combination of mechanisms, including diffusion of the drug through molecular interstices in the polymer, diffusion of the drug through pores in the polymer (if a pore-forming excipient has been used in the formation of the polymer), and degradation of the polymer itself. The release rate may be controlled to a certain degree by varying certain system parameters, such as the size and shape of the polymeric particles, the choice of polymer used to form the matrix, the molecular weight and density of the polymer, the ratio of drug to polymer, the pore structure of the matrix, the inclusion of additional components such as erosion rate modifiers in the matrix, and the choice of carrier vehicle where one is used.

Degradation of the polymer is potentially the greatest contributing factor to the release of the drug, since degradation reduces and ultimately eliminates the diffusion barriers which retard the passage of the drug through the matrix. Erosion rate modifiers may be incorporated in the matrix as a means of controlling the release profile, but such modifiers are not always a satisfactory solution, since as an added ingredient they must also be non-toxic and biodegradable. Furthermore, as the polymer slowly erodes, the modifiers themselves are released and their effectiveness is reduced or lost.

Also, the polymer stabilizer or erosion rate modifier needs to be compatible with the drug to be delivered. As an example, the use of a base to stabilize poly(orthoester) bonds might compromise the stability of base-sensitive drugs in the delivery system. Examples of this type of drug can be found among the peptides and proteins. Combination of these drugs with bioerodible delivery systems may be a highly desirable method of controlled, prolonged administration, but the presence of a stabilizing base in a poly(orthoester) would make additional formulation efforts necessary in order to avoid base-induced damage to the protein drug. In general, a method that would avoid the use of additional stabilizers, such as bases, would be considered highly advantageous. In fact, one of the inventors of certain of the poly(orthoesters) has called the necessity to use a base as a stabilizer an inherent disadvantage of certain types of poly(orthoesters) (J. Heller, Biomaterials, 1990, Ji:659). The present invention addresses these and other disadvantages and shortcomings of sustained drug release systems.

SUMMARY OF THE INVENTION It has now been found by the inventor that for poly(orthoesters) and poly(orthocarbonates), degradation is attributable in part to the presence of acid catalyst in the polymer matrix. The acid most commonly used is a proton-donating, or Brønsted, acid, which is used at low concentrations as a catalyst for the polymerization reaction. In the past, when the final polymer was assayed for residual acid catalyst, none was found. However, it has now been discovered that, contrary to the knowledge in the art, acid catalyst is in fact retained in the poly(orthoester) or poly(orthocarbonate) polymer structure after the reaction is complete. It has further been discovered that retained acid catalyst is not loosely retained but is instead bound covalently in such a manner that its release in a biological environment is attributable to hydrolysis. This arises from the discovery that when the polymer is dissolved in certain organic solvents, the resulting solution does not contain the acid, whereas when the polymer is placed in water, residual acid is detected. In a biological environment, water acts as a hydrolyzing agent, and the hydrolytic release of the acid generates hydrogen ion which further accelerates the hydrolysis. Once recognizing that the acid is bound by a bond susceptible to hydrolysis, the problem of removing the acid without damage to the polymer remains.

In light of these problems, it has been discovered that the bound acid catalyst can be removed without inducing further hydrolysis of the polymer by treatment with hydroxyl ion in an inert solvent, followed by an extraction procedure, to give a polymer substantially free of bound proton-donating acid. By "substantially free of bound proton-donating acid", as used herein, is meant that at least 80%, and preferably at least 90%, more preferably at least 95%, of the initially bound proton-donating acid has been removed from the polymer. Among various inert solvents suitable for use in this invention are weakly basic solvents. Prominent among these are ethers, and further discussion and description of preferred solvents is included in the succeeding section of this specification.

The cleavage and elimination of the acid catalyst from the polymer offers certain advantages to the polymer. One advantage is the avoidance of a need for incorporating and retaining a base in the polymer, and thus the sustained release formulation as a whole, because the stability of the treated or purified polymer is significantly increased under the normal conditions of use. Also, the polymer can now be further stabilized, if such is necessary for a particular use, by addition of neutral buffer components, instead of bases. These neutral buffers do not have the detrimental effects on many drugs that basic stabilizers produce.

Another advantage is greater reproducibility in the degradation behavior of the polymer in a biological environment by eliminating such factors as the diffusion behavior of the base through the polymer matrix and any inhomogeneities in the distribution of the base through the matrix.

A further, and surprising, advantage is that the improved stability of the treated polymer facilitates the handling of the material, making shipping and fabrication processes, for example, much easier. It also allows the production of certain types of systems, such as microparticles and powders, which were not possible with the unpurified material. Further features and advantages of the invention will become apparent from the description which follows.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS Hydroxyl ion for use in the practice of the present invention may be supplied as any otherwise inert species which releases hydroxyl ion in solution. The species is preferably an inorganic base, and most preferably a base such as an alkali or alkaline earth metal hydroxide. Sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, and magnesium hydroxide are examples. Among these, sodium hydroxide and potassium hydroxide are presently preferred, and sodium hydroxide is particularly preferred.

Treatment of the polymer in the practice of the invention is achieved by contacting the polymer with a solution of the hydroxyl ion in the solvent. Preferred solvents are those which dissolve the polymer as well as the hydroxyl ion, or dissolve the ion and swell the polymer. Accordingly, both the choice of compound supplying the hydroxyl ion and the choice of solvent will be governed by the solubility considerations. The solvent, in addition, will be a solvent which is inert, or at least substantially inert, relative to the polymer, and particularly one which does not itself induce hydrolysis of the polymer. Weakly basic nonaqueous solvents are preferred, and among these, ethers are presently more preferred. Examples of ether solvents for use in this invention include ethers with aromatic groups, ethers with aliphatic groups, and ethers with both. Examples also include single and multiple ethers, i . e. , ethers with two or more ether linkages. Examples of aromatic groups are phenyl, benzyl and naphthyl, with phenyl and benzyl preferred. Aliphatic groups include alkyl, alkenyl and alkynyl, with alkyl and alkenyl preferred, and alkyl the most preferred. Prominent examples of alkyl groups are methyl, ethyl, n-propyl , isopropyl, n-butyl , isobutyl and -butyl . Prominent examples of alkenyl groups are ethenyl (vinyl) and 2-propenyl (ally!). Examples of ethers containing the above groups are diethyl ether, methyl vinyl ether, diisopropyl ether, di-n-propyl ether, methyl n-butyl ether, di-n-butyl ether, divinyl ether, diallyl ether, methyl phenyl ether and diphenyl ether. Examples of multiple ethers are ethers of ethylene glycol and diethylene glycol, with fully etherified compounds preferred. Examples are ethylene glycol dimethyl ether, diethylene glycol dimethyl ether (diglyme), and trimethylene glycol dimethyl ether (triglyme). Cyclic ethers are also included. Examples are ethylene oxide, propylene oxide, tetrahydrofuran and 1,4-dioxane. Preferred ethers are diethyl ether, diisopropyl ether, tetrahydrofuran and 1,4-dioxane. Tetrahydrofuran is presently preferred. In still further preferred embodiments, the solvent and hence the solution are anhydrous.

The concentration of hydroxyl ion in the solution is not critical and may vary widely. In most applications, concentrations ranging from about 0.01M to about 10M OH^", preferably from about O.IM to about 1M OH^", will provide the best results. The polymer itself may be any of a wide variety of the type depicted in Formula I above. Preferred among such structures are those in which:

The substituent R¹ is a divalent aliphatic, alicyclic or aromatic radical. The substituents R² and R³ either: (a) are both monovalent radicals, not connected other than through the linkage shown in the formula, and are the same or different, or (b) together form a single divalent radical, thereby forming a heterocyclic ring with the two lower 0 atoms and the C atom shown in the formula. Whether monovalent or divalent, i . e. , whether taken individually or combined, the two groups are either aliphatic, alicyclic or aromatic radicals, or radicals which are combinations of these types, or radicals of these types which further contain carbonyl or carbonyloxy groups.

As indicated above, the index "a" is zero or 1. When "a" is zero, the polymer is a poly(orthoester), and when "a" is 1, the polymer is a poly(orthocarbonate) . Finally, the index "n" is a positive integer in excess of

3, and usually in excess of 10, indicating the length of the polymer chain. Various subclasses within the scope of Formula I are preferred. For example, preferred groups for R² and R³, whether monovalent or divalent, are aliphatic, alicyclic or aromatic radicals, or radicals which are combinations of two or all three of these types. In a further preferred subclass, R² and R³, whether monovalent or divalent, are aliphatic or alicyclic. In a still further preferred subclass, R² and R³ when monovalent are aliphatic or alicyclic and when divalent form an aliphatic group, preferably saturated, and most preferably linear. As for R¹, preferred groups are divalent aliphatic and alicyclic groups, the aliphatic groups being preferably alkyl groups.

In further ways of characterizing the preferred subclasses, R¹ is preferably 2 to 12 carbon atoms, and most preferably 4 to 10 carbon atoms. Likewise, monovalent options for R² and R³ are preferably 2 to 12 carbon atoms each, whereas divalent options are preferably 2 to 12 carbon atoms, more preferably 2 to 6 carbon atoms, and most preferably 3 to 4 carbon atoms. The index "n" may be characterized by its value as it is above, or it may be characterized in terms of the molecular weight of the resulting polymer. In terms of molecular weight, "n" is preferably of a value which would provide the polymer with a molecular weight of at least about 1,000, and most preferably within a range of from about 1,000 to about 100,000.

Formula II below represents one preferred subclass of poly(orthoesters) :

In this subclass, R⁴ is either divalent cyclohexyl or divalent C^C_jg alkyl, and R⁵ is either -(CH₂)₂-, -(CH₂)₃-, -(CH₂)₄- or -(CH₂)₅-. The index " " is the counterpart to the index "n" in Formula I above, and has the same meaning and preferred ranges.

A still further subclass of poly(orthoesters) is that shown in Formula III:

In this subclass, R is either divalent cyclohexyl or divalent C₃-C₇ alkyl. Here again, the index "m" has the same meaning and range as "n" described earlier.

Two particularly preferred poly(orthoesters) are those of Formulas IV and V:

In both Formulas IV and V, the index "m" is a positive integer of appropriate range such that the polymer has a molecular weight of from about 1,000 to about 100,000.

Acid catalysts addressed by this invention are proton- donating acids, of which a wide variety are known in the art, and are known for their utility in the polymerization of orthoesters and orthocarbonates. Examples of types of proton-donating acids which may be used are mineral acids, sulfonic and sulfinic acids, phosphoric, phosphonic and phosphinic acids, polyphosphoric acids and silicic acids. Examples of specific acids within these types are p-toluene sulfonic acid, polystyrene sulfonic acid, polyphosphoric acids, and acidic silica gel (silicic acid). An acid of particular interest is p-toluene sulfonic acid.

The amount of acid catalyst present in the prior art, untreated, unpurified "classical" polymer is not critical to the effectiveness of the present invention, and the invention is effective over a wide range of catalyst levels. In preparations of the classical polymer, the catalyst level generally ranges from about 0.001% to about 2.0% on a weight basis, relative to the molar amounts of the starting monomer. In more common preparations, the catalyst level is most likely to range from about 0.01% to about 0.5%.

Treatment of the unpurified polymer with the treatment s solution in accordance with this invention may be done in any conventional manner. For treatment solutions which do not dissolve the polymer, the polymer may be dispersed in the solution to form a slurry, dispersion or gel, which will be held in suspension by agitation or other conventional means for a sufficient period of time o for the acid to become dissociated and dissolve in the solution. For treatment solutions which do dissolve the polymer, a homogeneous solution may be formed and let stand, again for a sufficient period of time to permit dissociation of the acid. The polymer may then be extracted from the solution by .conventional means. For example, s polymers of this type are generally insoluble in water, and may thus be precipitated by contacting the non-aqueous polymer solution with water in such a manner as to induce precipitation of the polymer. When the nonaqueous solvent is miscible with water, for example, the polymer may be precipitated by diluting the non-aqueous polymer 0 solution with water, thereby causing the polymer to precipitate. The amount of treatment solution relative to the amount of polymer is not critical and may vary widely, subject only to considerations of efficiency in terms both of the amount and cost of the materials used and the time required to achieve the dissociation of the acid and the 5 recovery of the polymer in a usable form. Appropriate or optimal amounts for any single case will be readily apparent to those skilled in the art or readily determinable by routine experimentation.

While biodegradable poly(orthoesters) and poly(orthocarbonates) treated in accordance with this invention are o useful for a wide variety of purposes and applications, one use of particular interest is as a sustained-release vehicle for active agent delivery systems. The devices can be a single matrix, a container with a reservoir therein, or a number of layers, for example. When used in this manner, the polymers can be formed into 5 various shapes such as flat, square, round, tubular, disc, ring, spherical, spheroid, and the like geometrical configurations which incorporate the active agent. Presently preferred embodiments are films, rods, pellets and particles. Devices utilizing the polymers of the present invention can be sized, shaped and adapted for implantation, insertion, placement, depositing or spreading on the body, in the body, or in cavities and passageways of the body of an animal.

The active agent may be incorporated into the polymer in a variety of forms. As one example, the active agent may be present as small globules randomly dispersed throughout a continuous matrix of the polymer. As another, individual molecules of the active agent may be uniformly mixed in with the polymer chains. As a third example, the polymer may be formed as a porous body with an interconnected porous network and with the agent occupying the pores. In the first and second examples, the active agent is released by a combination of diffusion of the agent into and through the polymer matrix and the breakdown of the polymer matrix by bioerosion. In the third example, these mechanisms are present as well, in addition to the diffusion of the agent through the pore network.

The incorporation of the active agent into the polymer network may be achieved in various ways, the optimal method in any single case depending on which of the various ways described above is used for retaining the active agent by the polymer. The polymer may thus be formed into a solid article of its ultimate size and shape before the incorporation of the agent, or the agent may be incorporated during the formation of the polymer. Depending on the active agent, the treatment of the polymer to remove the acid catalyst may be done either before the agent is incorporated into the polymer or after. In most cases, the preferred method is to treat the polymer to remove the acid catalyst prior to incorporation of the active agent. Incorporation of the agent may then be achieved in any of the various ways described in the prior art. A prominent example is to combine the active agent with the polymer in a liquid form to achieve the appropriate weight ratio and consistency, and then to solidify the combined polymer and agent while forming the combination into the desired size and shape. The term "active agent" refers to any agent which provides an active, beneficial or therapeutic effect, such as a drug, and which is to be delivered or dispersed from the polymer matrix into an environment of use. Exemplary active agents that can be delivered according to this invention are those that are compatible with the polymeric matrix and include, among others, biocides, sterilization agents, food supplements, nutrients, vitamins, sex sterilants, fertility inhibitors, and fertility promoters. They can include drugs that act on the peripheral nerves, adrenergic receptors, cholinergic receptors, nervous system, skeletal muscles, cardiovascular system, smooth muscles, blood circulatory system, synoptic sites, neuroeffector junctional sites, endocrine and hormone systems, immunological system, reproductive system, skeletal system, autocoid systems, alimentary and excretory systems, histamine system, and central nervous system. Suitable agents may be selected from, for example, polysaccharides, steroids, analgesics, local anesthetics, antibiotic agents, anti-inflammatory corticosteroids, opiates, ocular drugs, and synthetic analogs of these molecules. The term "drug" is used in this specification in a broad, generic sense, to include any physiologically or pharmacologically active substances that produce a localized or systemic effect or effects in animals. Additional examples of drugs will be readily apparent to those skilled in the art. Therapeutic agents or drugs with which the polymers of the present invention are particularly useful are those agents which are sensitive to bases, such as, for example, proteins and peptides.

The active agent is typically present in the polymer in a beneficial or therapeutically effective amount, by which is meant an amount that is beneficial to the environment of use or necessary to effect a therapeutic result. In practice, the particular amount will vary widely, depending on many factors, such as the agent to be delivered, the therapeutic effect desired, the chosen environment of use, the rate of delivery, the length of treatment, and the like. In the practice of the present invention, devices incorporating the polymers of the invention are placed in or on an environment of use. The environments in which the devices may be used include physiological environments within the body of a human or animal or aqueous environments such as pools, tanks, reservoirs, and the like serving recreational, industrial or residential purposes. The devices may also be utilized in the biotechnology area, such as to deliver nutrients or growth regulating compounds or other agents to cell cultures, for example. In the presently preferred embodiments, the environment of use is the body of an animal. Included in the term "animal" are humans, primates, mammals, domesticated or semi-domesticated animals (such as household, pet, and farm animals), laboratory animals (such as mice, rats and guinea pigs), birds, reptiles, fish, zoo animals, and the like. The devices may be placed on or in wounds, spread as a thin film, or injected as microparticles or placed subcutaneously or interperitoneally as an implant into the body, for example. As a result of the removal of the bound acid catalyst according to this invention, the purified poly(orthoester) and poly(orthocarbonate) polymers exhibit significantly increased stability. This improved stability greatly improves the handling of the material, making shipping and fabrication processes, for example, much easier. The previous, unpurified ("classical") poly(orthoesters), for example, were very unstable under ambient conditions, tending to be "sticky" and subject to aggregation. As a result, preparation of delivery systems or devices with the classical polymers was performed in special dryboxes. Larger-scale manufacturing would be required to take place in specially equipped rooms with ultra-low environmental humidity, followed by extensive drying procedures of the devices. In contrast, the purified polymers of this invention are so stable that not only can systems be prepared under normal ambient conditions, but it is also possible to perform an aqueous extraction procedure on the polymer without unacceptable loss of stability. The much less stringent environmental conditions required to process the new polymers is an enormous advantage in commercial scale production. Also as a result of their increased stability, transporting of the polymers becomes much easier. It was necessary to ship the classical polymers in bulk form in heatable containers that had to be warmed to temperatures above 100°C, after which the polymer was pressure-transferred out of the shipping containers. The new polymers, in contrast, can be transported in the normal manner under ambient conditions and as powders or pellets, for example.

A significant advantage of the new purified polymers is that it is now possible to fabricate certain types of delivery platforms or systems that were not possible with the unpurified, classical material. The sticky nature of the classical material caused pellets or particles of the material to aggregate at room temperature, making impossible the production of these types of systems, as well as powders and stable microparticles of injectable size. The new, purified polymers do not possess the sticky character of the unpurified material. Powders of purified poly(orthoester) of Formula IV above, for example, have been prepared and are stable at room temperature and do not exhibit signs of aggregation. Thus, the purified polymers of the present invention can take a variety of shapes and sizes, such as sheets, films, rods, fibers, onofilaments, pellets, spheres and spheroids, particles and microparticles, powders, tubes, discs, rings, and the like, depending on the use to which they will be applied. The devices can be sized, shaped and adapted for implantation, insertion, placement, depositing or spreading on the body, in the body, or in cavities and passageways of the body of an animal. The devices can be manufactured by standard techniques known to the art and are stable under ambient conditions.

The following example is offered for purposes of illustration, and is intended neither to limit nor to define the invention in any manner.

EXAMPLE 1 A sample of prior art classical poly(orthoester) of

Formula IV above, unpurified according to the present invention, with a molecular weight of approximately 30,000, was formed by polymerization of the appropriate monomer with p-toluene sulfonic acid (PTSA) as catalyst, at 1 part by weight of catalyst to 500 parts by weight of monomer. Polymerization was performed in accordance with known methods of the prior art, and the catalyst was retained in the polymer following completion of the polymerization reaction.

To establish that the catalyst was not retained in free ^• form by the polymer, the polymer with retained catalyst was dissolved in anhydrous tetrahydrofuran (THF), and the resulting solution analyzed by HPLC for the presence of free acid. No free acid was detected. In a separate experiment, the polymer was placed in water and permitted to erode for several days. During the first day, the pH of the water dropped from approximately neutral to approximately 5.0, and during the next six days to a level below 4.0. This indicated the release of free acid upon water-induced hydrolysis of the polymer. In a third experiment, the polymer was first dissolved in acetonitrile and then hydrolyzed by addition of water, after which the resulting solution was analyzed. PTSA was readily detectable in the solution.

EXAMPLE 2

To test the process of the present invention, the polymer of Example 1 (1.46g) was combined with dry THF (lOmL) plus three pellets of sodium hydroxide (0.3g). The mixture was placed in a closed Erlen eyer flask at 40°C .for 24 hours with a magnetic stirrer. The result was a moderately turbid solution.

The solution was then sprayed over water, whereby a film of solid polymer formed on the water surface. The film was withdrawn from the water surface and washed repeatedly with water until the pH of the wash water no longer became basic. The polymer was then removed from the water a final time, and dried in a vacuum oven at room temperature for 48 hours.

The dried polymer was then melt-pressed at 90°C into a 1 inch x 1 inch x 0.25mm sheet (25.4 x 25.4 x 0.25mm) and weighed. The yield was 0.5g. The sheet contained cloudy zones (indicating incompletely melted polymer) in an otherwise clear (completely melted) polymer; two pieces from the clear region were cut and used in an erosion experiment as follows. In this experiment, the two pieces were tested side-by-side with two pieces of a sheet prepared in the identical manner but without treatment with the NaOH/THF solution.

The two pieces of treated polymer were placed in 5cc of water at 37°C, and the two pieces of untreated polymer were placed in a separate 5cc of water, also at 37°C. The pieces were then withdrawn at intervals and weighed. The results are shown in Table I below. TABLE I Erosion Test Results on Non-Irradiated Polymer

As a test for its susceptibility to acid hydrolysis, the treated polymer (12.7mg) was contacted with hydrochloric acid (0.1N, l.OOmL) at 37°C. The polymer was completely hydrolyzed within two hours of contact with the acid in this manner. The erosion test was repeated, with the added step of irradiating the polymer sheets at 2.5 Mrads before placing them in water. All other conditions were the same. The results are shown in Table II below.

TABLE II

Erosion Test Results on Irradiated Polymer

Untreated samples #1 and #2 were completely hydrolyzed in 1-2 hours. Irradiation is often used to sterilize drug delivery systems that will be implanted into humans. In the past, such irradiation has caused the untreated, classical poly(orthoesters) of the prior art to rapidly erode, as illustrated in the above Table II. Table II also illustrates that the purified poly(orthoesters) of the present invention (treated samples) are very stable for several days following irradiation, in contrast to the prior art polymers. EXAMPLE 3 Bupivacaine base (8 wt%) was mixed with 92 wt% of the treated polymer of Example 2 over a hot plate at 120°C for 10 min. The resulting mix was cooled to room temperature and ground into particles 0.25-0.5 mm in diameter. A suspension of 300 mg of such particles was stirred with 3 mL of citrate buffer (pH 7, containing 18.7 mg/mL of tribasic sodium citrate dihydrate and 0.2 mg/mL of citric acid) and 3 mL of distilled water.

The pH of the above solution was determined each day and samples were taken to determine polymer erosion. Results showed that the pH of the solution remained at 7 for the duration of the experiment (nine days), while the polymer particles remained stable. No diol was released for the first four days, after which there was a slow release of diol (up to 20% of the total theoretical amount).

These test results clearly indicate that treatment of the polymer in accordance with the invention removes the acid catalyst without harm to the polymer, and results in a polymer which erodes at a much slower rate.

The foregoing is offered primarily for purposes of illustration. It will be readily apparent to those skilled in the art that the operating conditions, materials, procedural steps and other parameters of the methods and compositions described herein may be further modified or substituted in various ways without departing from the spirit and scope of the invention.

Claims

We cl aim:

1. A method for treating an ortho polymer to improve the stability thereof, said ortho polymer having been prepared by the polymerization of a member selected from the group consisting of orthoester and orthocarbonate monomers with a proton-donating acid having served as a catalyst for said polymerization and bound in said ortho polymer with a bond susceptible to hydrolysis, said method comprising contacting said ortho polymer with a solution of hydroxyl ion in an inert nonaqueous solvent to extract said proton-donating acid from said ortho polymer to give an ortho polymer with improved stability.

2. A method for purifying an ortho polymer, said ortho polymer having been prepared by the polymerization of a member selected from the group consisting of orthoester and orthocarbonate monomers with a proton-donating acid having served as a catalyst for said polymerization and bound in said ortho polymer with a bond susceptible to hydrolysis, said method comprising contacting said ortho polymer with a solution of hydroxyl ion in an inert nonaqueous solvent to extract said proton-donating acid from said ortho polymer to give a purified ortho polymer.

3. A method in accordance with claim 1 or 2 in which said inert nonaqueous solvent is an ether.

4. A method in accordance with claim 1 or 2 in which said inert nonaqueous solvent is a member selected from the group consisting of diethyl ether, diisopropyl ether, tetrahydrofuran and 1,4-dioxane.

5. A method in accordance with claim 1 or 2 in which said ortho polymer is a polymer having the formula

i n whi ch :

R¹ is a member selected from the group consisting of divalent aliphatic, alicyclic and aromatic radicals; either R² is a member selected from the group consisting of monovalent aliphatic, alicyclic and aromatic radicals and carbonyl-containing and carbonyloxy- containing aliphatic radicals, and R³ is a member selected from the group consisting of monovalent aliphatic, alicyclic and aromatic radicals and . carbonyl-containing and carbonyloxy-containing aliphatic radicals, or R² and R³ together form a single divalent radical which is a member selected from the group consisting of divalent aliphatic, alicyclic and aromatic radicals and carbonyl- containing and carbonyloxy-containing aliphatic radicals; a is zero or 1; and n is a positive integer high enough such that said ortho polymer has a molecular weight of at least about 1,000.

6. A method in accordance with claim 1 or 2 in which said ortho polymer is a polymer having the formula

in which m is a positive integer high enough such that said ortho polymer has a molecular weight of from about 1,000 to about 100,000.

7. A method in accordance with claim 6 in which said proton-donating acid is p-toluene sulfonic acid, and said inert nonaqueous solvent is tetrahydrofuran.

8. An improved ortho polymer, said ortho polymer having been prepared by the polymerization of a member selected from the group consisting of orthoester and orthocarbonate monomers with a proton-donating acid having served as a catalyst for said polymerization, wherein the improvement comprises said ortho polymer being substantially free of proton-donating acid.

9. An ortho polymer substantially free of proton- donating acid, said ortho polymer having been prepared by the polymerization of a member selected from the group consisting of orthoester and orthocarbonate monomers with a proton-donating acid having served as a catalyst for said polymerization and bound in said ortho polymer with a bond susceptible to hydrolysis, said ortho polymer having been contacted with a solution of hydroxyl ion in an inert nonaqueous solvent to extract said proton-donating acid from said ortho polymer.

10. An ortho polymer substantially free of proton- donating acid in accordance with claim 8 or 9, wherein said polymer is stable at room temperature.

11. An ortho polymer substantially free of proton- donating acid in accordance with claim 8 or 9, wherein said polymer exhibits improved bioerosion behavior.

12. An ortho polymer substantially free of proton- donating acid in accordance with claim 8 or 9 wherein said polymer has the formula

in which:

R¹ is a member selected from the group consisting of divalent aliphatic, alicyclic and aromatic radicals; either R² is a member selected from the group consisting of monovalent aliphatic, alicyclic and aromatic radicals and carbonyl-containing and carbonyloxy- containing aliphatic radicals, and R³ is a member selected from the group consisting of monovalent aliphatic, alicyclic and aromatic radicals and carbonyl-containing and carbonyloxy-containing aliphatic radicals, or R² and R³ together form a single divalent radical which is a member selected from the group consisting of divalent aliphatic, alicyclic and aromatic radicals and carbonyl- containing and carbonyloxy-containing aliphatic radicals; a is zero or 1; and n is a positive integer high enough such that said ortho polymer has a molecular weight of at least about 1,000.

13. An ortho polymer substantially free of proton- donating acid in accordance with claim 8 or 9 in which said polymer has the formula

14. An ortho polymer substantially free of proton- donating acid in accordance with claim 9 in which said inert nonaqueous solvent is an ether selected from the group consisting of diethyl ether, diisopropyl ether, tetrahydrofuran and 1,4-dioxane.

15. A delivery device for the controlled administration of an active agent to an environment of use, wherein the device comprises: (a) a shaped matrix sized and adapted for administering an active agent to an environment of use and formed of an improved ortho polymer, said ortho polymer having been prepared by the polymerization of a member selected from the group consisting of orthoester and orthocarbonate monomers with a proton-donating acid having served as a catalyst for said polymerization, wherein the improvement of said ortho ester comprises said ortho polymer being substantially free of proton- donating acid; and

(b) the active agent to be delivered within said matrix.

16. A delivery device in accordance with claim 15, wherein said improved ortho polymer is stable at room temperature.

17. A delivery device in accordance with claim 15, wherein said improved ortho polymer exhibits improved bioerosion behavior.

18. A delivery device in accordance with claim 15 wherein the shape of said matrix is selected from rods, sheets, films, pellets, powders, particles and microparticles.

19. A delivery device in accordance with claim 15 in which said polymer has the formula

in which:

R is a member selected from the group consisting of divalent aliphatic, alicyclic and aromatic radicals; either R² is a member selected from the group consisting of monovalent aliphatic, alicyclic and aromatic radicals and carbonyl-containing and carbonyloxy- containing aliphatic radicals, and R³ is a member selected from the group consisting of monovalent aliphatic, alicyclic and aromatic radicals and carbonyl -containing and carbonyloxy-containing aliphatic radicals, or R² and R³ together form a single divalent radical which is a member selected from the group consisting of divalent aliphatic, alicyclic and aromatic radicals and carbonyl - containing and carbonyloxy-containing aliphatic radicals; a is zero or 1; and n is a positive integer high enough such that said ortho polymer has a molecular weight of at least about 1,000.

20. A delivery device in accordance with claim 15 in which said polymer has the formula

21. A delivery device in accordance with claim 15 wherein said improved ortho polymer is prepared by the method of claim 1 or 2.