Cross-linked high amylose starch for use in controlled-release pharmaceutical formulations and processes for its manufacture

• US 6,607,748 B1
• Filed: 06/29/2000
• Issued: 08/19/2003
• Est. Priority Date: 06/29/2000
• Status: Expired due to Term

• Current Assignee: Paladin Labs Europe Ltd. (Endo International PLC)
• Original Assignee: Cerestar Holding BV (Cargill, Inc. (Agricultural Services Division)), Labopharm Incorporated (Endo International PLC)
• Inventors: Lenaerts, Vincent, Beck, Roland Herwig Friedrich, Chouinard, Francois, Van Bogaert, Elsie, Höpcke, Reiner, Désévaux, Cyril
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): FUBARA, BLESSING M
• Application Number:
  US09/606,399
• Time in Patent Office: 1,146 Days
• Field of Search: 424/464, 424/468, 424/489, 424/488, 424/422
• US Class Current: 424/464
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/2059 Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: C08B 33/00 Preparation of derivatives of amylose

Abstract

The present invention relates to a novel form of cross-linked high amylose starch and processes for its manufacture. Such cross-linked high amylose starch is useful as an excipient in a controlled-release pharmaceutical formulation when compressed with pharmaceutical agent(s) in a tablet. Such cross-linked high amylose starch is prepared by (a) cross-linking and chemical modification of high amylose starch, (b) gelatinization, and (c) drying to obtain a powder of said controlled release excipient. In a preferred embodiment, such cross-linked high amylose starch is prepared in the following steps: (1) granular cross-linking and additional chemical modification (e.g., hydroxypropylation) of high-amylose starch; (2) thermal gelatinization of the starch from step (1); and (3) drying the starch from step (2) to yield a powder capable of being used as a controlled release excipient.

Claims

1. A process for manufacturing, in an aqueous medium, a controlled release excipient consisting primarily of cross-linked high amylose starch, for use in preparation of tablets, said process comprising

(a) cross-linking high amylose starch thereby forming a reaction medium containing a reaction product consisting of a cross-linked high amylose starch slurry;

(b) subjecting said cross-linked high amylose starch slurry from step (a) to chemical modification at a temperature of about 10 to about 90°

C. for about 1 to about 72 hours;

(c) neutralizing said reaction medium obtained in step (b) with an acid, washing the slurry formed and optionally dewatering or to form a starch cake or a dry powder;

(d) diluting said slurry or re-slurrifying said starch cake or said dry powder from step (c) with water to form a slurry at a concentration of about 2% to about 40% w/w, adjusting pH to a desired value between about 3 and about 12, and gelatinizing said slurry at a temperature of about 80 to 180°

C. for about 1 second to about 120 minutes; and

(e) drying the thermally treated product obtained in step (d) to obtain said controlled release excipient consisting mainly of chemically modified and cross-linked high amylose starch in form of a powder.

2. The process according to claim 1, wherein steps (a) and (b) are performed at the same time.

3. The process according to claim 1 comprising,

(a) cross-linking high amylose starch containing at least 70% w/w of amylose with about 0.005 g to about 0.3 g cross-linking reagent per 100 g of dry-based high amylose starch in an aqueous medium at a temperature of about 10 to about 90° C. thereby forming a reaction medium containing a reaction product consisting of a cross-linked high amylose starch slurry;

(b) subjecting said cross-linked high amylose starch slurry from step (a) to hydroxypropylation with propylene oxide at a temperature of about 10 to about 90°

C. for about 1 to about 72 hours to yield a reaction medium containing a hydroxypropylated cross-linked high amylose starch slurry;

(c) neutralizing said reaction medium obtained in step (b) with a dilute aqueous acid, washing slurry formed and optionally dewatering to obtain a starch cake or a dry powder;

(d) diluting said slurry, or re-slurrifying starch cake or dry powder from step (c) with water to form a slurry at a concentration of about 2% to about 40% w/w, adjusting pH to about 4.0 to about 9.0, and gelatinizing said slurry formed in current step at a temperature of about 80 to about 180°

C. for about 1 second to about 120 minutes; and

(e) drying said thermally treated product obtained in step (d) to obtain said controlled release excipient consisting mainly of hydroxypropylated and cross-linked high amylose starch in form of a powder.

4. The process of claim 3, wherein, in step (a), said cross-linking reagent is phosphorous oxychloride in an amount of between about 0.01 and about 0.2 g per 100 g starch dry basis or sodium trimetaphosphate in an amount of between about 0.05 and about 0.3 g per 100 g starch dry basis.

5. The process of claim 3 wherein step (a) is performed in an aqueous alkaline medium.

6. The process of claim 4, wherein, in step (a), said cross-linking is carried out at a pH of about 10 to about 14 and at a temperature of about 15 to about 90°

C. for about 0.2 to about 40 hours.

7. The process of claim 3, wherein, in step (b), said hydroxypropylation is carried out with up to 10% propylene oxide at a temperature of about 40 to about 80°

C. for about 10 to about 72 hours.

8. The process of claim 3, wherein, in step (c), said neutralization of said reaction medium is carried out with dilute sulfuric acid or hydrochloric acid.

9. The process of claim 3, wherein, in step (d), said gelatinization is carried out by direct steam injection into an aqueous suspension of said cross-linked high amylose starch.

10. The process of claim 3, wherein, in step (d), said pH is adjusted to about 6.0 and said temperature is kept at about 80 to about 180°

C. for about 2 to about 10 minutes.

11. The process of claim 3, wherein, in step (e), said drying is carried out by spray-drying.

12. The process of claim 11, wherein, in step (e), inlet temperature is from about 60 to about 350°

C., and outlet temperature is set from about 40 to about 210°

C.

13. A process for manufacturing, in an aqueous medium, a controlled release excipient consisting primarily of cross-linked high amylose starch, for use in preparation of tablets, said process comprising

(a) subjecting high amylose starch to chemical modification at a temperature of about 10 to about 90°

C. for about 1 to about 72 hours thereby forming a reaction medium containing a chemically modified high amylose slurry;

(b) cross-linking said chemically modified high amylose starch in said slurry obtained in step (a);

(c) neutralizing said slurry obtained in step (b) with an acid, washing the slurry formed and optionally dewatering to form a starch cake or drying to form dry powder;

(d) diluting said slurry, or re-slurrifying said starch cake or said dry powder from step (c) with water to form a slurry at a concentration of about 2% to about 40% w/w, adjusting pH to a desired value between about 3 and about 12, and gelatinizing said slurry at a temperature of about 80 to 180°

C. for about 1 second to about 120 minutes; and

(e) drying the thermally treated product obtained in step (d) to obtain said controlled release excipient consisting mainly of chemically modified and cross-linked high amylose starch in form of a powder.

14. The process according to claim 13, wherein steps (a) and (b) are performed at the same time.

15. The process according to claim 13 comprising

(a) subjecting high amylose starch containing at least 70% w/w of amylose to hydroxypropylation With propylene oxide at a temperature of about 10 to about 90° C. for about 1 to about 72 hours to yield a reaction medium containing a reaction product of consisting primarily of a hydroxypropylated high amylose starch slurry;

(b) cross-linking said hydroxypropylated high amylose starch slurry with about 0.005g to about 0.3 g cross-linking reagent per 100 g of dry-based high amylose starch in an aqueous medium at a temperature of about 10 to about 90°

C. to yield a reaction medium containing a cross-linked hydroxypropylated high amylose starch slurry;

(c) neutralizing said reaction medium obtained in step (b) with a dilute aqueous acid, washing slurry formed and optionally dewatering to obtain a starch cake or a dry powder;

(d) diluting said slurry, or re-slurrifying said starch cake or said dry powder from step (c) with water to form a slurry at a concentration of about 2% to about 40% w/w, adjusting pH to about 4.0 to about 9.0, and gelatinizing said slurry formed in current step at a temperature of about 80 to about 180°

C. for about 1 second to about 120 minutes; and

(e) drying said thermally treated product obtained in step (d) to obtain said controlled release excipient consisting mainly of hydroxypropylated and cross-linked high amylose starch in form of a powder.

16. All The process of claim 15, wherein, in step (a), said cross-linking reagent is phosphorous oxychloride in an amount of between about 0.01 and about 0.2 g per 100 g starch dry basis or sodium trimetaphosphate in an amount of between about 0.05 and about 0.3 g per 100 g starch dry basis.

17. The process of claim 15 wherein step (b) is performed in an aqueous alkaline medium.

18. The process of claim 16, wherein, in step (b), said cross-linking is carried out at a pH of about 10 to about 14 and at a temperature of about 15 to about 90°

C. for about 0.2 to about 40 hours.

19. The process of claim 15, wherein, in step (a), said hydroxypropylation is carried out with up to 10% propylene oxide at a temperature of about 40 to about 80°

C. for about 10 to about 72 hours.

20. The process of claim 15, wherein, in step (c), said neutralization of said reaction medium is carried put with dilute sulfuric acid or hydrochloric acid.

21. The process of claim 15, where, in step (d), said gelatinization is carried out by direct steam injection into an aqueous suspension of said cross-linked high amylose starch.

22. The process of claim 15, wherein, in step (d), said pH is adjusted to about 6.0 and said temperature is kept at about 80 to about 180°

C. for about 2 to about 10 minutes.

23. The process of claim 15, wherein, in step (e), said drying is carried out by spray-drying.

24. The process of claim 23, wherein, in step (e), inlet temperature is from about 60 to about 350°

C., and outlet temperature is set from about 40 to about 210°

C.

25. A controlled release tablet comprising a compressed blend of at least two dry powders, including a powder of at least one pharmaceutical agent and a powder of a controlled release excipient;

wherein said controlled release excipient comprises a chemically-modified, cross-linked high amylose starch prepared by a method comprising;

(a) cross-linking high amylose starch, followed by

(b) chemically modifying the cross-linked high amylose starch, followed by

(c) gelatinization, and

(d) drying to obtain a powder of said controlled release excipient;

wherein said cross-linked high amylose starch is characterized in that upon solubilization in 90% DMSO at 80°

C. for about three days and gel permeation chromatography, the height of the peak corresponding to amylose in said cross-linked high amylose starch is at least 90% of that of the peak corresponding to amylose in said high amylose starch prior to (a).

29. The tablet of claim 25, wherein said tablet is for oral administration.

30. The tablet of claim 25, wherein said tablet is an implant.

31. The tablet of claim 25, wherein said controlled release excipient comprises cross-linked high amylose starch prepared by cross-linking said high amylose starch and by a chemical modification selected from the group consisting of esterification and etherification.

32. The tablet of claim 31, wherein said chemical modification is hydroxypropylation.

33. The tablet of claim 32, wherein said cross-linked high amylose starch is hydroxypropylated with propylene oxide.

34. The tablet of claim 25, wherein said high amylose starch is cross-linked with a reagent selected from the group consisting of epichlorohydrin, adipic acid anhydride, sodium trimetaphosphate and phosphorous oxychloride.

35. The tablet of claim 25, wherein said cross-linked high amylose starch is gelatinized at a temperature of about 80°

C. to about 180°

C.

36. The tablet of claim 25, wherein said blend of dry powders comprises a lubricant and a filler.

37. The tablet of claim 36, wherein said lubricant is magnesium stearate.

38. The tablet of claim 37, where said filler is lactose.

39. The tablet of claim 25, wherein said pharmaceutical agent is pseudoephedrine hydrochloride, acetaminophen, diclofenac sodium, verapamil, glipizide, nifedipine, felodipine, betahistine, albuterol, acrivastine, omeprazole, misoprostol, tramadol, ciprofloxacin, oxybutynin, trimebutine, ketoconazole, acetylsalicylic acid, ibuprofen, ketoprofen, indomethacin, diflunisol, naproxen, ketorolac, diclofenac, tolmetin, sulindac, phenacetin, piroxicam, mefamanic acid, dextromethorphan, salicylates, pharmaceutically acceptable salts thereof or mixtures thereof.

26. A controlled release tablet comprising a compressed blend of at least two dry powders, including a powder of at least one pharmaceutical agent and a powder of a controlled release excipient;

wherein said controlled release excipient comprises a chemically-modified, cross-linked high amylose starch prepared by a method comprising;

(a) cross-linking high amylose starch, followed by

(b) chemically modifying the cross-linked high amylose starch, followed by

(c) gelatinization, and

(d) drying to obtain a powder of said controlled release excipient;

wherein said cross-linked high amylose starch is characterized in that less than about 20% of the amylose present in said high amylose starch prior to (a) is chemically cross-linked to amylopectin.

27. A controlled release tablet comprising a compressed blend of at least two dry powders, including a powder of at least one pharmaceutical agent and a powder of a controlled release excipient;

wherein said controlled release excipient comprises a chemically-modified, cross-linked high amylose starch prepared by a method comprising;

(a) cross-linking high amylose starch, followed by

(b) chemically modifying the cross-linked high amylose starch, followed by

(c) gelatinization, and

(d) drying to obtain a powder of said controlled release excipient;

wherein said cross-linked high amylose starch is characterized in that upon solubilization in 90% DMSO at 80°

C. for about three days and gel permeation chromatography, less than about 20% of the amylose present prior to (a) is chemically cross-linked to and eluted with amylopectin.

28. A controlled release tablet comprising a compressed blend of at least two dry powders, including a powder of at least one pharmaceutical agent and a powder of a controlled release excipient;

wherein said controlled release excipient comprises a chemically-modified, cross-linked high amylose starch prepared by a method comprising;

(a) cross-linking high amylose starch, followed by

(b) chemically modifying the cross-linked high amylose starch, followed by

(c) gelatinization, and

(d) drying to obtain a powder of said controlled release excipient;

wherein said cross-linked high amylose starch is characterized in that upon solubilization in 90% DMSO at 80°

C. for about three days and gel permeation chromatography, the height of the peak corresponding to amylose is higher than that of the peak corresponding to amylopectin-containing entities.

40. A chemically-modified, cross-linked high amylose starch prepared by a method comprising:

(a) cross-linking high amylose starch, followed by

(b) chemically modifying the cross-linked high amylose starch, followed by

(c) gelatinization, and

(d) drying to obtain a powder of said controlled release excipient;

wherein said cross-linked high amylose starch is characterized in that upon solubilization in 90% DMSO at 80°

C. for about three days and gel permeation chromatography, the height of the peak corresponding to amylose in said cross-linked high amylose starch is at least 90% of that of the peak corresponding to amylose in said high amylose starch prior to (a).

41. A chemically-modified, cross-linked high amylose starch prepared by a method comprising:

(a) cross-linking high amylose starch, followed by

(b) chemically modifying the cross-linked high amylose starch, followed by

(c) gelatinization, and

(d) drying to obtain a powder of said controlled release excipient;

wherein said cross-linked high amylose starch is characterized in that less than about 20% of the amylose present in said high amylose starch prior to (a) is chemically cross-linked to amylopectin.

42. A chemically-modified, cross-linked high amylose starch prepared by a method comprising:

(a) cross-linking high amylose starch, followed by

(b) chemically modifying the cross-linked high amylose starch, followed by

(c) gelatinization, and

(d) drying to obtain a powder of said controlled release excipient;

wherein said cross-linked high amylose starch is characterized in that upon solubilization in 90% DMSO at 80°

C. for about three days and gel permeation chromatography, less than about 20% of the amylose present prior to (a) is chemically cross-linked to and eluted with amylopectin.

43. A chemically-modified, cross-linked high amylose starch prepared by a method comprising:

(a) cross-linking high amylose starch, followed by

(b) chemically modifying the cross-linked high amylose starch, followed by

(c) gelatinization, and

(d) drying to obtain a powder of said controlled release excipient;

wherein said cross-linked high amylose starch is characterized in that upon solubilization in 90% DMSO at 80°

C. for about three days and gel permeation chromatography, the height of the peak corresponding to amylose is higher than that of the peak corresponding to amylopectin-containing entities.