Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1997-02-24
2002-04-30
Celsa, Bennett (Department: 1627)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S017400, C530S329000, C530S330000, C435S069100, C435S173300
Reexamination Certificate
active
06380154
ABSTRACT:
FIELD OF THE INVENTION
The field of this invention is the production and use of bioresorbable polypeptide polymers. More specifically, the present invention is directed to the use of bioresorbable polypeptide polymers for the controlled release of biologically active compounds in vivo and for altering the physical dimensions of a body tissue.
BACKGROUND OF THE INVENTION
The rate at which an implanted material resorbs or biodegrades within the body can be a major factor in determining its utility as a biomaterial. So called inert materials, such as metals, ceramics and plastics have been shown to be useful for permanent implants. However, in applications in which a device serves as an aid to healing or as a temporary aid in surgical repair, a resorbable material has the advantage of not having to be removed, once healing has occurred. Resorbable sutures and staples, bone pins and screws, wound dressings, and injectable drug delivery systems or depots are examples of such devices. However, there are very few materials available today which have the physical, chemical and biological properties necessary for the fabrication of medical devices, which must degrade and resorb in the body without detrimental consequences.
Various synthetic organic polymers have found use, such as polylactides, polyglycolides, polyanhydrides and polyorthoesters, which degrade in the body by hydrolysis. Collagen, glycosaminoglycans and hyaluronic acid are examples of natural implantable materials which resorb at least partially by enzymatic degradation. However, the rates of resorption are limited to the nature of the particular material and modifications can change the rate of resorption, but at the same time may adversely affect the desired properties of the product.
Illustrative of efforts to vary resorption characteristics by compositional changes are synthetic resorbable sutures composed of copolymers of lactide and glycolide. By varying the ratio of lactic acid to glycolic acid, the rate of resorption may be varied. Unfortunately, rapidly resorbing compositions tend to be soft and weak. Slow resorbing compositions are stiff and string. However, the hydrolytic resorption of these sutures produces acid buffered by the tissue medium, where erosion occurs at the polymer surface. In addition, hydrolysis may occur internally, where the resulting acid catalyzes and accelerates the degradation of the polymer. Thus, internal pockets of degradation can lead to rapid and catastrophic failure of mechanical properties.
There is, therefore, a need for products which can be used in the production of implantable devices. Such products should have the desired mechanical properties of tensile strength, elasticity, formability, and the like, provide for controlled resorption, and be physiologically acceptable. Moreover, such products should allow for ease of administration for a variety of in vivo indications including drug delivery and tissue augmentation.
Relevant Literature
U.S. Pat. No. 5,243,038 describes the preparation of high molecular weight, protein polymers and copolymers comprising long segments of small repeating units. Bioactive Polymeric Systems, Gebelein, C. G. and Carraher, C. E., eds., Plenum Press, New York, 1985; Contemporary Biomaterials, Boretos, John W. and Eden, Murray, eds., Noyes Publications, New Jersey, 1984; and Concise Guide to Biomedical Polymers: Their Design, Fabrication and Molding, Boretos, John W., Thomas pub., Illinois, 1973, describe compositions, characteristics, and applications of biomaterials.
SUMMARY OF THE INVENTION
In one aspect, the present invention is directed to a method for delivering a biologically active substance to a localized site in vivo, wherein the method comprises:
administering a composition to the localized site, said composition comprising (i) a protein polymer of at least 15 kD which comprises alternating blocks of at least 2 units each of (a) an amino acid sequence of from about 3 to 30 amino acids which promotes protein crystallization and (b) an amino acid sequence element selected from the group consisting of an elastin-like element, a collagen-like element or a keratin-like element and (ii) a biologically active substance; wherein said composition acquires a non-liquid form under physiological conditions and wherein said biologically active substance is delivered from said non-liquid form to said localized site. In preferred embodiments of the described method, the amino acid sequence which promotes protein crystallization is GAGAGS (SEQ ID NO:1) or SGAGAG (SEQ ID NO:2) and/or the amino acid sequence element (b) above is the amino acid sequence VPGG (SEQ ID NO:3), APGVGV (SEQ ID NO:4), GXGVP (SEQ ID NO:5) or VPGXG (SEQ ID NO:6) where the amino acid X is valine, lysine, histidine, glutamic acid, arginine, aspartic acid, serine, tryptophan, tyrosine, phenylalanine, leucine, glutamine, asparagine, cysteine or methionine, more preferably valine or lysine.
The method may provide for delivery of a biologically active substance over an extended period of time. Biologically active substances which find use herein are formulated into compositions comprising the protein polymer of interest and include, for example, proteins, nucleic acids, antitumor agents, analgesics, antibiotics, anti-inflammatory compounds (both steroidal and non-steroidal), hormones, vaccines, labeled substances, and the like. The use of additional components in the compositions which, for example, affect the rate at which the polymer composition polymerizes into a non-liquid form is also provided.
In another aspect, the present invention provides compositions which are useful in the above described method.
In yet another aspect, the present invention provides a method for altering the physical dimensions of a body tissue in a mammal, wherein the method comprises:
introducing into or onto said body tissue a composition comprising a protein polymer of at least 15 kD which comprises alternating blocks of at least 2 units each of (a) an amino acid sequence of from about 3 to 30 amino acids which promotes protein crystallization and (b) an amino acid sequence element selected from the group consisting of an elastin-like element, a collagen-like element or a keratin-like element;
wherein said composition acquires a non-liquid form under physiological conditions.
In preferred embodiments of the described method, the amino acid sequence which promotes protein crystallization is GAGAGS (SEQ ID NO:1) or SGAGAG (SEQ ID NO:2) and/or the amino acid sequence element (b) above is the amino acid sequence VPGG (SEQ ID NO:3), APGVGV (SEQ ID NO:4), GXGVP (SEQ ID NO:5) or VPGXG (SEQ ID NO:6) where the amino acid X is valine, lysine, histidine, glutamic acid, arginine, aspartic acid, serine, tryptophan, tyrosine, phenylalanine, leucine, glutamine, asparagine, cysteine or methionine. more preferably valine or lysine.
Other aspects will be readily apparent to the skilled artisan upon a reading of the present specification.
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Cappello et al., “Genetic Engineering of Structural Protein Polymers,”Biotechnol. Prog., 6:198-202 (1990).
Cappello, “The Biological Production of Protein Polymers and Their Use,”TIBTECH, 8:309-311 (1990).
Cappello, “Bioresorption of Implanted Protein Polymer Films Controlled by Adjustment of Their Silk/Elastin Block Lengths,” 207th National Meeting of the American Chemical Society, San Diego, Mar. 13-17, vol. 204, No. 82 (1994) (Abstract No. XP000654884).
Cappello Joseph
Stedronsky Erwin R.
Celsa Bennett
Flehr Hohbach Test Albritton & Herbert LLP
Protein Polymer Technologies, Inc.
Trecartin Esq. Richard F.
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