Synthetic resins or natural rubbers -- part of the class 520 ser – Synthetic resins – Mixing of two or more solid polymers; mixing of solid...
Patent
1995-06-29
1997-09-30
Nutter, Nathan M.
Synthetic resins or natural rubbers -- part of the class 520 ser
Synthetic resins
Mixing of two or more solid polymers; mixing of solid...
514 2, 5147723, 5147726, 514800, 514806, 514807, 514808, 514809, 514963, 424489, 424497, 424499, 435180, 435181, 435182, A61K 916, A61K 952, A61K 3702
Patent
active
056726597
DESCRIPTION:
BRIEF SUMMARY
RELATED APPLICATION DATA
This application is a national stage application filed under 35 USC 371 of PCT/US94/00148, filed Jan. 5, 1994.
BACKGROUND OF THE INVENTION
This invention pertains to sustained release of bioactive polypeptides.
Many drug delivery systems have been developed, tested and utilized for the controlled in vivo release of pharmaceutical compositions. For example, polyesters such as poly(DL-lactic acid), poly(glycolic acid), poly(.epsilon.-caprolactone) and various other copolymers have been used to release biologically active molecules such as protesterone; these have been in the form of microcapsules, films, or rods (Pitt C. G., Marks, T. A., and Schindler, A. 1980). Upon implantation of the polymer/therapeutic agent composition, for example subcutaneously or intramuscularly, the therapeutic agent is released over a specific period of time. Such biocompatible biodegradable polymeric systems are designed to permit the entrapped therapeutic agent to diffuse from the polymer matrix. Upon release of the therapeutic agent, the poller is degraded in vivo, obviating surgical removal of the implant. Although the factors that contribute to poller degradation are not well understood, it is believed that such degradation for polyesters may be regulated by the accessibility of ester linkages to non-enzymatic autocatalytic hydrolysis of the polymeric components.
Several EPO publications and U.S. Patents have addressed issues of polymer matrix design and its role in regulating the rate and extent of release of therapeutic agents in vivo.
For example, Deluca (EPO Publication 0 467 389 A2/Univ of Kentucky) describes a physical interaction between a hydrophobic biodegradable polymer and a protein or polypeptide. The composition formed was a mixture of a therapeutic agent and a hydrophobic polymer that sustained its diffusional release from the matrix after introduction into a subject.
Hutchinson (U.S. Pat. No. 4,767,628/ICI) controlled the release of a therapeutic agent by uniform dispersion in a polymeric device. It is stated that this formulation provides for controlled continuous release by the overlap of two phases: first, a diffusion-dependent leaching of the drug from the surface of the formulation; and second, releasing by aqueous channels induced by degradation of the polymer.
SUMMARY OF THE INVENTION
In general, the invention features a sustained release pharmaceutical formulation composed of a polyester containing one or more free COOH groups ionically conjugated with a biologically active polypeptide composed of at least one effective, ionogenic amine wherein at least 50%, by weight, of the polypeptide present in the composition is ionically conjugated to the polyester.
In preferred embodiments, the polyester is modified to increase the carboxyl to hydroxyl end group ratio from more than one and approaches infinity, i.e., all of the hydroxyl groups can be substituted with carboxyls. Examples of suitable polyesters are those originating from compounds such as L-lactic acid, D-lactic acid, DL-lactic acid, .epsilon.-caprolactone, p-dioxanone, .epsilon.-caproic acid, substituted and unsubstituted trimethylene carbonate, 1,5-dioxepan-2-one, 1,4-dioxepan-2-one, glycolide, glycolic acid, L-lactide, D-lactide, DL-lactide, meso-lactide, alkylene oxalate, cycloalkylene oxalate, alkylene succinate, (.beta.-hydroxybutyrate), and optically active isomers, racemates or copolymers of any of the above. Other heterochain polymers related to traditional polyesters may also be used (e.g., polyorthoesters, polyorthocarbonates, and polyacetals).
Preferably, the polyester is made polycarboxylic by reaction with malic acid or citric acid.
In preferred embodiments the polyester is partially acid-tipped with glutaric anhydride. In yet other preferred embodiments the polyester is fully acid-tipped with glutaric anhydride. Preferably, the polyester has an average degree of polymerization between 10 and 300 and more preferably between 20 to 50.
The ionic molecular conjugates of the invention are preferably made fr
REFERENCES:
patent: 4356166 (1982-10-01), Peterson et al.
patent: 4609707 (1986-09-01), Nowinski et al.
patent: 4767628 (1988-08-01), Hutchinson
patent: 5071909 (1991-12-01), Pappin et al.
patent: 5162505 (1992-11-01), Dean et al.
patent: 5476653 (1995-12-01), Pitt et al.
Shah et al., "Poly (glycolic acid-co-DL-lactic acid): Diffusion or Degradation Controlled Drug Delivery?", Journal of Controlled Realeas, 18:261-270,1992.
Jackson Steven A.
Moreau Jacques-Pierre
Shalaby Shalaby W.
Kinerton Limited
McGowan William E.
Nutter Nathan M.
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