1. Field of the Invention
The present invention pertains generally to degradable blends for drug delivery systems. More particularly, the invention relates to degradable compositions which include a homopolymer of ε-caprolactone, a crystallization modifier, and a biologically active drug.
2. Description of the Related Art
During the past thirty years, the use of synthetic degradable or absorbable polymers in medical devices and drug delivery systems has made a dramatic rise. Foremost in the area of absorbable medical devices has been the usage of absorbable polyesters that are usually aliphatic and linear. For example, in the area of wound closure, there has been extensive application of the homopolymer poly(glycolic acid), see for example U.S. Pat. No. 3,297,033, and copolymers of glycolic acid with a variety of other monomers which produce likewise absorbable polymers, see for example U.S. Pat. No. 3,839,297.
Dependent upon the specific application, there is a preferred time window where the synthetic polymer has been completely absorbed or degraded, that is, has lost all of its mass to the surrounding tissue. In the case of absorbable sutures in sewn tissue after surgery, that window is usually within one year, although even shorter times are more preferable (U.S. Pat. Nos. 4,027,676 and 4,201,216). For other applications such as drug delivery systems this time window could be either shorter or longer. Thus, for a given application there is a need to use absorbable polymers that degrade within the time limits of that application.
There is some leeway in the selection of synthetic absorbable polyesters for a given application since the rates of the hydrolysis of this class of polymers do vary over a wide range. Differences in the rates of hydrolysis of absorbable synthetic polyesters can be attributed to the intrinsic hydrolytic stability of their specific ester linkages and to the physical properties of their respective polymers. For instance, the hydrolytic stability of the ester linkage is strongly influenced by both electronic and steric factors. An example of an electronic effect is the increased reactivity of ester linkages which have a hydroxy substitution α to the ester linkage, as in the case of esters of glycolic acid. Physical properties which are important to the hydrolytic behavior and subsequent mass loss in synthetic absorbable polyesters include the glass transition temperature and the degree of crystallization in the polymer. In semi-crystalline polymers link poly(glycolic acid) and polycaprolactone, it has been hypothesized that hydrolysis takes place initially in the amorphous areas of the polymer, where migration or absorption of the water molecule is facile compared to the crystalline areas. Thus it appears that the water molecule prior to reaction at an ester linkage of a synthetic absorbable polyester must first have access or absorption into the polymer. Crystalline areas of the polymer have been hypothesized to impede the access or penetration of water molecules. Therefore, to the extent that this takes place, the overall hydrolytic breakdown of the absorbable polyester is retarded. In the case of polycaprolactone, the hydrolytic degradation rate and subsequent mass also is also dependent upon particle size, wherein small particles degrade and lose mass much more rapidly than a polymer cast in film form.
In the specific application of drug delivery systems, one major concern is that the use of synthetic polymer blends with biologically active proteins would inactive the proteins. Proteins may be incorporated by polymer blends by dissolving the protein and blend in an organic solvent and then casting from solution. However, proteins are known to inactivate in the presence of organic solvents. For example, proteins generally have decreased thermal stability in the presence of organic solvents, see L. Lee et al. Biochemistry, pages 7813–7819 (1987). As a further example, enzymes are known to function effectively only in aqueous solution and become unstable and catalytically inactive in the presence of organic solvents.
It is thought that, in organic solvents, enzymes change their conformation and as a consequence decrease their catalytic potential, see for example A. M. Klibanov et al. Biotechnology and Bioengineering vol XIX, pages 1351–1361 (1977).
Accordingly, an object of the invention is to provide a polymeric blend that can be mixed with a protein without inactivating the biological activity of the protein during mixing, while the protein is held within the polymeric blend or during controlled release of the protein.
A further object of the invention is to provide a controlled degradable matrix for the controlled in vivo release of biologically active proteins.