United States Patent:  5,968,543

Assignee:  Advanced Polymer Systems, Inc. (Redwood City, CA)

Filed:  December 5, 1997

Polymers useful as orthopedic implants or vehicles for the sustained delivery of pharmaceutical, cosmetic and agricultural agents are prepared in such a manner that the rate and degree to which they are hydrolyzed can be controlled without addition of exogenous acid. This control results from the incorporation of esters of short-chain .alpha.-hydroxy acids such as esters of glycolic acid, lactic acid or glycolic-co-lactic acid copolymer into the polymer chain and variation of the amount of these esters relative to the polymer as a whole.

SUMMARY OF THE INVENTION

It has now been discovered that polymers useful as orthopedic implants or vehicles for the sequestration and sustained delivery of drugs, cosmetic agents and other beneficial agents can be prepared in such a manner that the rate and degree to which they are hydrolyzed by contact with bodily fluids at normal body temperature and pH can be controlled without addition of exogenous acid. This discovery resides in the incorporation of esters of short-chain .alpha.-hydroxy acids such as esters of glycolic acid, lactic acid or glycolic-co-lactic acid copolymer into the polymer chain and variation of the amount of these esters relative to the polymer as a whole.

In the presence of water, these esters, when incorporated into the polymer chain, are readily hydrolyzed at a body temperature of 37^oC. and a physiological pH, in particular at a pH of 7.4, to produce the corresponding .alpha.-hydroxy acids. The .alpha.-hydroxy acids then act as an acidic excipient to control the hydrolysis rate of the polymer. When the polymer is used as a vehicle or matrix entrapping an active agent, the hydrolysis of the polymer causes release of the active agent.

In addition, the mechano-physical state of the polymer may also be controlled. This is achieved by the inclusion of the residues of certain diols in selected proportions relative to the polymer as a whole. For example, a high content of the residue of trans-cyclohexanedimethanol relative to a "soft" diol (definition of which is given below) produces a relatively rigid polymer chain and a more solid substance, and by decreasing the trans-cyclohexanedimethanol content relative to the "soft" diol, the polymer will change progressively through the stages of a rigid thermoplastic, a soft thermoplastic, a low melting solid to an ointment-like (viscous liquid) material, and any stage in between.

The polymers of the present invention are prepared by condensation reactions between diketene acetals and polyols, preferably diols, and the variation in mechano-physical state and rate of hydrolysis (bioerodibility) is achieved by the selection and use of combinations of different types of diols.

Claim 1 of 30 Claims

1. A polymer of Formula I 

where R* is a C₁ -C₄ alkyl; each A is selected from the group consisting of --O--R¹ --, --O--R² --, or (--O--R³)_q --, where q is 1 to 20;

n is at least 5; and

R¹ is

in which p is 1-10;

R⁴ is hydrogen or a C₁ -C₆ alkyl; and

R⁵ is 

where: s is 1 to 100;

t is 1 to 12;

R² is 

when q is 1, R³ is 

in which: x is 1 to 100;

y is 1 to 12;

R⁶ and R⁷ are independently a C₁ -C₁₂ alkylene;

R⁸ is hydrogen or a C₁ -C₆ alkyl; and

R⁹ is a C₁ -C₆ alkyl; or

R⁸ and R⁹ taken together are a C₃ -C₁₀ alkylene; and

when q is 2 to 20, each R³ may be the same or different and is 

where x, y, R⁶, R⁷, R⁸ and R⁹ are as defined above, R¹⁰ is

hydrogen or a C₁ -C₄ alkyl, and R¹¹ is a C₁ -C₄ alkyl; provided that the polymer comprises at least 0.1 mole percent of units in which A is --O--R¹ --.

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