Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Scleroproteins – e.g. – fibroin – elastin – silk – etc.
Reexamination Certificate
2000-12-12
2002-09-10
Low, Christopher S. F. (Department: 1653)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Scleroproteins, e.g., fibroin, elastin, silk, etc.
C530S342000, C530S345000, C530S402000, C514S002600, C514S021800, C514S801000, C514S912000, C514S913000
Reexamination Certificate
active
06448378
ABSTRACT:
BACKGROUND OF THE INVENTION
In general, the invention relates to rapidly dissolving collagen films, methods of preparation, and the use of these films for rapid compound delivery.
The ability to specifically deliver a compound to a particular site in the human body is a desirable goal in many areas of medicine. For example, in cancer therapy, administration of chemotherapeutic agents to a tumor site with minimal exposure to surrounding tissues would dramatically reduce undesirable side effects to the surrounding tissues, or the body as a whole, while facilitating delivery of potent doses to malignant cells.
In addition, the inhibition of wound healing is beneficial in certain circumstances, for example, following glaucoma filtration surgery (otherwise known as trabeculectomy). The initial stage in the process of wound healing is characterized by the movement of intravascular components, such as plasma and blood proteins, to the extravascular area (Peacock, In: Wound Repair, 491-492, 1984, ed. E E Peacock, WB Saunders Co, Philadelphia, Pa.). Neutrophils and macrophages then migrate to the injury site, functioning to prevent infection and promote fibroblast migration. Subsequent phases of wound healing include fibroblast secretion of collagen, collagen stabilization, angiogenesis, and wound closure (Costa et al., Opth. Surgery 24: 152-170, 1993).
During surgery for the treatment of glaucoma, a fistula is frequently created to allow for post-operative drainage of intraopthalmic fluid from the eye. Accordingly, the inhibition of fistula healing is beneficial in order to extend the drainage time and reduce intraopthalmic pressure. Several therapies have been adopted to inhibit fistula healing, including beta irradiation, 5-fluorouracil treatment, and mitomycin (also known as mitomycin-C or mitomicin) treatment (Costa et al., Opth. Surgery 24: 152-170, 1993).
SUMMARY OF THE INVENTION
The present invention provides a method of preparing a rapidly dissolving collagen film which includes a therapeutic compound. The method involves (i) preparing a purified solution of monoreactive-amine modified collagen, e.g., a glutaric anhydride derivatized collagen, (ii) heating the collagen solution to about 35-45° C. for a time sufficient to reduce collagen viscosity, (iii) adding the compound to the heated collagen solution, and iv) casting the solution into thin layers, wherein the solution dries and forms the film.
The invention also includes a collagen film prepared by the above described method and a collagen film which rapidly dissolves upon exposure to about 35° C. Preferably, the collagen film dissolves within five to ten minutes upon exposure to about 35° C. More preferably, the collagen film dissolves within two minutes upon exposure to about 35° C. Most preferably, the collagen film dissolves within one minute or 30 seconds upon exposure to about 35° C.
The therapeutic compound contained within the rapidly dissolving collagen film may be an inhibitor of cell proliferation, e.g., an anti-metabolic antibiotic, anti-metabolite, anti-fibrotic, anti-viral compound, or angiostatic compound. Preferably, the compound is an anti-metabolic antibiotic, e.g., mitomycin, daunorubicin, mithramycin, bleomycin, or doxorubicin.
Alternatively, the therapeutic compound may be an anti-metabolite. Examples of useful anti-metabolites include 5-fluorouracil, 5-fluorouridine-5′-monophosphate, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine-5′-monophosphate, and 5-fluroorotate.
In yet other applications, the therapeutic compound contained within the rapidly dissolving collagen film is an anti-fibrotic. Examples of useful anti-fibrotics include inhibitors of prolyl hydroxylase and lysyl hydroxylase, e.g., iron chelators, &agr;,&agr;-dipyridyl, o-phenanthroline, proline analogs, lysine analogs, and free radical inhibitors and scavengers; inhibitors of collagen secretion, e.g., colchicine, vinblastin, cytochalasin B, copper, zinc, and EGTA; inhibitors of collagen secretion and maturation, e.g., BAPN, vincristine, and D-penicillamine; and stimulators of collagen degradation, e.g., EDTA and colchicine.
As noted above, the therapeutic compound may also be an anti-viral drug. Examples of anti-viral drugs that can be used in the invention include vidarabine, acyclovir, AZT, and amantadine.
Finally, angiostatic drugs, e.g., angiostatin, as well as other miscellaneous anti-cell proliferative drugs, e.g., tissue plasminogen activator (TPA), heparin, cytosine arabinoside, and gamma-interferon, may also be used in the rapidly dissolving collagen films described herein.
In addition to methods of collagen film preparation, the invention also provides a method of rapidly delivering a compound dose to a specific tissue site in a mammal. The method involves administering a collagen film containing the compound dose to the tissue site, wherein the collagen film rapidly dissolves upon exposure to the mammalian tissue site. Using this method to deliver toxic compounds, the toxic side effects are essentially restricted to the specific tissue site of compound delivery.
In a related aspect, the invention also includes a method of treating a mammal to inhibit cellular proliferation, e.g., wound healing or tumor growth, at a specific tissue site. The method involves administering a collagen film comprising an inhibitor of cell proliferation, e.g., an anti-metabolic antibiotic, anti-metabolite, anti-fibrotic, anti-viral compound, or angiostatic compound, to the tissue site, wherein the collagen film rapidly dissolves upon exposure to the tissue and delivers a dose of the compound sufficient to inhibit cell proliferation at the tissue site.
In preferred embodiments, the cell proliferation inhibitor is mitomycin, 5-fluorouracil, or an anti-fibrotic. In addition, in other preferred embodiments, the collagen film dissolves within five to ten minutes upon exposure to the mammalian tissue site, more preferably, within two minutes, and, most preferably, within one minute or 30 seconds. In addition, the mammal is preferably a human.
This method can be used, for example, in treating a mammal undergoing surgery for glaucoma. In this application, the collagen film is administered to the trabeculectomy-created fistula in the mammal, wherein the dose of cell proliferation inhibitor is sufficient to inhibit closure of the fistula. Preferably, the cell proliferation inhibitor used is mitomycin at a dose of 200-400 &mgr;g and may be administered in a 4×4 mm collagen film patch. Most preferably, the mitomycin dose is 400 &mgr;g.
Use of this treatment results in reduced post-operative intraocular pressure. Preferably, post-operative intraocular pressure as a result of this method is less than 16 mmHg, more preferably, less than 12 mmHg, and, most preferably, less than 6 mmHg.
As used herein, by “mono-reactive amine-modified” is meant reacted with a mono-reactive amine-modifying agent, also known as a monoacylating or sulfonating agent. Useful agents include, without limitation, anhydrides, acid halides, sulfonyl halides, and active esters. The modifying agent is preferably a compound or combination of compounds which contains an acidic, carboxylic, or sulfonide group, or generates an acidic, carboxylic, or sulfonic group during reaction.
By “inhibitor of cell proliferation” is meant an inhibitor of an increase in the number of cells located at a particular site. Such inhibition may occur by inhibition of cell migration or attachment, cell replication, cell survival, or angiogenesis.
By “specific tissue site” is meant the area of tissue directly in contact with the collagen film administered to the tissue.
By “rapidly dissolves” is meant dissolves, or melts, in approximately 30 minutes or less.
The present invention provides a number of advantages. For example, the present techniques and collagen film compositions facilitate an improved approach for delivering a compound in situations where both a precise dose and accurate placement are required. The dose can be adjusted to any desired amount, i.e., by modifying the concentration of compound
DeVore Dale P.
Eiferman Richard A.
Keates Edwin U.
Low Christopher S. F.
Mohamed Abdel A.
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