Claims for Patent: 5,460,967

Summary for Patent: 5,460,967

Title:	Recycle process for the production of low-cost soluble collagen
Abstract:	The invention includes a method that produces a low cost aqueous solution of solubilized collagen by the steps of: (a) providing an aqueous ground slurry of insoluble collagen and adjusting the pH of said slurry to obtain activity for a proteolytic enzyme added in Step b; (b) adding said proteolytic enzyme to said pH adjusted slurry; (c) reacting the slurry and enzyme of Step b and/or recycled insoluble collagen and enzyme from Step e at a temperature, T, and for a time, t, effective for forming a solution increased in solubilized collagen; (d) adding additional water and insoluble collagen to said solution of Step c and mixing; (e) separating at least some of the solution of Step d containing solubilized collagen from insoluble collagen, whereby at least a portion of said insoluble collagen and proteolytic enzyme is recycled to Step c, and the separated solution containing solubilized collagen is withdrawn as product; an alternative embodiment provides for the direct production of solubilized collagen without the recycle step.
Inventor(s):	Fink; David J. (Shaker Heights, OH), Brody; Richard S. (Worthington, OH)
Assignee:	Ranpak Corp. (Concord Township, OH)
Application Number:	08/250,803
Patent Claims:	1. A method for producing a solution of soluble collagen comprising: a. providing a ground slurry of insoluble collagen; b. adjusting the water or solid content of said ground slurry whereby said insoluble collagen is at a concentration that promotes maximum soluble collagen concentration; c. adjusting the ph of said slurry from Step b to obtain activity for a proteolytic enzyme added in Step d; d. adding said proteolytic enzyme to said pH adjusted slurry and reacting at a temperature, T, and for a time, t, to produce soluble collagen from said insoluble collagen; e. controlling said reaction conditions to obtain a solution having a high concentration of soluble collagen by measuring the concentration and number average molecular weight of soluble collagen, whereby said reaction is complete when said number average molecular weight is at least about 300,000 daltons and said concentration of said soluble collagen is maximized; f. withdrawing said solution of soluble collagen as product. 2. The method of claim 1, comprising stopping said reaction by (1) adjusting said pH to that where said proteolytic enzyme is substantially inactive; and/or (2) reducing the temperature to that where said proteolytic enzyme is substantially inactive. 3. The method of claim 1, further comprising in Step b, adjusting said liquid or solids content of said ground slurry so that said solids are adjusted to a concentration of about 0.1 to about 1.0 wt %. 4. The method of claim 1, whereby said temperature, T, comprises about 5.degree. C. to about 30.degree. C. 5. The method of claim 1, whereby said temperature, T, comprises about 15.degree. C. to about 30.degree. C. 6. The method of claim 1, whereby, in Step b, said solids concentration is between about 0.3 to 0.35 wt %; and in Step e, controlling said reaction at a temperature of about 15.degree. to about 30.degree. C., and for time of 10 to 48 hours. 7. The method of claim 1, further comprising: selecting the proteolytic enzyme from the group consisting of porcine mucosal pepsin, bromelain, chymopapain, chymotrypsin, collagenase, ficin, papain, peptidase, proteinase A, proteinase K, trypsin, microbial proteases, and combinations of such enzymes. 8. The method of claim 1, further comprising: adjusting the pH to between about 1.5 to about 3.0 and the temperature to between about 15.degree. C. to about 28.degree. C., when porcine mucosal pepsin is selected. 9. The method of claim 1, further comprising: whereby at least 80 wt % of said insoluble collagen is converted to soluble collagen and the number average molecular weight is above 300,000 daltons. 10. The method of claim 1, further comprising: whereby at least 80 wt % of said insoluble collagen is converted to soluble collagen. 11. The method of claim 1, further comprising: whereby at least 90 wt % of said insoluble collagen is converted to soluble collagen. 12. The method of claim 1, comprising controlling said reaction by measuring solution viscosity at two different shear rates whereby said reaction is complete when a ratio of (viscosity at low shear)/(viscosity at high shear) is substantially maximized. 13. The method of claim 12, whereby said viscosity ratio is at least about 75% of the maximum attained. 14. A method for producing a solution of soluble collagen comprising: a. providing a ground slurry of insoluble collagen; b. adding a proteolytic enzyme to said ground slurry; c. reacting said ground slurry with said proteolytic enzyme to produce a solution of soluble collagen; d. withdrawing said solution of soluble collagen as product. 15. The method of claim 14, comprising stopping said reaction by: (1) adjusting the pH of said ground slurry and proteolytic enzyme of Step c to that where said proteolytic enzyme is substantially inactive; and/or (2) reducing the temperature of said ground slurry and proteolytic enzyme of Step c to that where said proteolytic enzyme is substantially inactive. 16. The method of claim 14, further comprising controlling said reaction by measuring solution viscosity at two different shear rates whereby said reaction is complete when a ratio of, (viscosity at low shear)/(viscosity at high shear) is substantially maximized. 17. The method of claim 16, whereby said viscosity ratio is at least about 75% of the maximum attained. 18. The method of claim 14, further comprising controlling said reaction by measuring the concentration and the number average molecular weight of said soluble collagen, whereby said reaction is complete when said concentration and said number average molecular weight are maximized. 19. The method of claim 14, further comprising in Step a, adjusting the liquid or solids content of said ground slurry whereby said insoluble collagen is at a concentration that promotes maximum concentration and number average molecular weight of said soluble collagen of Step d. 20. The method of claim 19, further comprising in Step a, adjusting said liquid or solids content of said ground slurry so that said solids are at a concentration of about 0.1 to about 1.0 wt %. 21. The method of claim 19, further comprising in Step a, adjusting said liquid or solids content of said ground slurry so that said solids concentration is between about 0.3 to 0.35 wt %. 22. The method of claim 14, further comprising in Step a, adjusting the pH of said ground slurry to obtain activity for said proteolytic enzyme added in Step b. 23. The method of claim 14, further comprising in Step c, reacting said ground slurry with said proteolytic enzyme at a temperature, T, and for a time, t, to produce a solution of soluble collagen. 24. The method of claim 23, whereby said temperature, T, comprises about 5.degree. C. to about 35.degree. C. 25. The method of claim 23, whereby said temperature, T, comprises about 15.degree. C. to about 30.degree. C. 26. The method of claim 23, whereby said temperature, T, comprises about 20.degree. to about 30.degree. C., and said time, t, comprises about 24 to 48 hours. 27. The method of claim 14, further comprising: selecting the proteolytic enzyme from the group consisting of porcine mucosal pepsin, bromelain, chymopapain, chymotrypsin, collagenase, ficin, papain, peptidase, proteinase A, proteinase K, trypsin, and combinations of such enzymes. 28. The method of claim 27, further comprising: adjusting the pH of said ground slurry of Step a to between about 1.5 to about 3.0 and the temperature, T, of Step c to between about 26.degree. to about 28.degree. C., when porcine mucosal pepsin is selected. 29. The method of claim 14, further comprising: whereby at least 80 wt % of said insoluble collagen is converted to soluble collagen and the number average molecular weight of said soluble collagen is at least about 300,000 daltons. 30. The method of claim 26, further comprising: whereby at least 80 wt % of said insoluble collagen is converted to soluble collagen and the number average molecular weight of said soluble collagen is above 600,000 daltons. 31. The method of claim 14, further comprising: whereby at least 90 wt % of said insoluble collagen is converted to soluble collagen and the number average molecular weight of said soluble collagen is above 1,000,000 daltons.

Details for Patent 5,460,967

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Discure Medical, Llc	CHYMODIACTIN	chymopapain	For Injection	018663	11/10/1982		2013-06-16
Discure Medical, Llc	CHYMODIACTIN	chymopapain	For Injection	018663	08/21/1984		2013-06-16
Smith & Nephew, Inc.	SANTYL	collagenase	Ointment	101995	06/04/1965		2013-06-16