This invention is in the area of biodegradable polymer blends for use as carriers of pharmaceutically active agents.
Many drugs useful for the treatment of disease that are administered in an unmodified form fail to reach the target organ in an effective concentration, or are not effective over a length of time due to facile metabolism. This lack of effectiveness of the drug can result from a number of factors, including acid hydrolysis in the stomach, inability of the drug to cross membranes such as the blood brain barrier, enzymolysis of the compound, including deactivation of the drug in the liver prior to reaching the target organ, and even simple degradation or undesirable reaction of the drug in the cell or blood. In order to avoid these problems and achieve effective concentrations of drugs at the target organs, the drug is usually combined with a carrier that is biocompatible and biodegradable
Suitable carriers for drug incorporation range in size from small molecules to macromolecules, including high molecular weight polymers. Polymeric devices can be used to release drug at a specific location at a controlled rate over a period of time. The most desirable polymeric matrix for drug delivery is one that is hydrophobic, stable, strong, flexible, soluble in organic solutions, has a low melting point, and degrades linearly over time in an aqueous environment. Polyanhydrides are useful for controlled drug delivery because they degrade uniformly into non-toxic molecules that are non-mutagenic, non-cytotoxic, and non-inflammatory. Further, the release rates of polyanhydride fabricated devices can be altered over a thousand-fold by simple changes in the polymer backbone. Each class of polymers has a different degradation profile, as well as other properties. It is difficult to predict if different classes of polymers can be combined to form a uniform, stable blend, and whether it will have desirable properties, including both mechanical properties and release properties.
Macroscopically uniform, single-phase, polymer--polymer blends, also referred to as polyblends, have been prepared from miscible or compatible polymer solutions for use in a variety of nonmedical applications, including in the coatings industry. However, attempts to improve the properties of varnishes and paints by blending various polymer constituents have often been frustrated by the incompatibility of the polymers. This incompatibility is manifested by the formation of films that are not homogeneous but are turbid or opaque and possess mechanical properties that are inferior to films of the separate polymer constituents.
The problems encountered by the coatings industry in their attempts to develop effective polymer blends illustrates a characteristic property of macromolecules. In general, if a polymer mixture possesses properties analogous to those expected for a single-phase material, the mixture is considered as a blend. In most instances, the critical property will be the transition temperature; a polymer blend with a single melting temperature will be classified as miscible or compatible. If the polymer mixture does not exhibit a single transition temperature, then the two polymers when mixed will often show properties of incompatibility, including nonuniformity of mixture, opacity, and separation under certain conditions.
Probably the most widely used method of determining polymer--polymer miscibility is the mutual-solvent approach, wherein an equal mixture of two polymers is dissolved at low to medium concentration in a mutual solvent. The mixture is then allowed to stand, usually for one to two days. Miscibility is considered to prevail if phase separation does not occur during this time; if phase separation does occur, the two polymers are considered immiscible.
The mutual solvent approach was first used in the field of paints and lacquers. Dobry and Boyer-Kawenoki, J. Polym. Sci. 2, 90 (1947), reported a study involving 78 mixtures of polymers made from 14 different polymers dissolved in 13 solvents. They concluded that most polymers show separation indicative of the immiscibility or incompatibility. Further, it was determined that when two polymers are incompatible in one solvent, they are generally incompatible in other solvents. The researchers also found that although molecular weight of the polymers is of great importance to the issue of miscibility there is no obvious relationship between the compatibility of two polymers and the chemical nature of their monomers. Additionally, the similarity of the principal chain of the polymer is not sufficient to insure miscibility of two polymers. Based on these conclusions, it is clear that miscibility of two polymers is unlikely and very hard to predict.
It is therefore an object of the present invention to provide compatible blends of biodegradable polymers for use as matrix materials in delivery devices, as well as methods for their preparation.
It is a further object of the present invention to provide compatible polymer blends that provide uniform release of incorporated substance over an extended period of time.