Karen A. Confoy Dennis A. Bennett FOX ROTHSCHILD, LLP GLOBAL PATENT GROUP, LLC Formed in the Commonwealth of Pennsylvania 1005 North Warson Road Princeton Pike Corporate Center Suite 201 997 Lenox Drive, Building 3 St. Louis, Missouri 63132 Lawrenceville, New Jersey 08648 (314) 812-8018 (609) 896-3600 Attorneys for Plaintiff Horizon Pharma AG Attorneys for Plaintiffs Horizon Pharma AG and Jagotec AG
Robert F. Green John A. Bauer Caryn C. Borg-Breen MINTZ, LEVIN, COHN, FERRIS, Jessica M. Tyrus GLOVSKY AND POPEO, P.C. Ann K. Kotze 666 Third Avenue LEYDIG, VOIT & MAYER, LTD. New York, New York 10017 Two Prudential Plaza, Suite 4900 (212) 692-6795 180 North Stetson Chicago, Illinois 60601 Attorneys for Plaintiff Jagotec AG (312) 616-5600
Attorneys for Plaintiff Horizon Pharma AG
UNITED STATES DISTRICT COURT FOR THE DISTRICT OF NEW JERSEY
HORIZON PHARMA AG and CIVIL ACTION No. JAGOTEC AG Document Filed Electronically Plaintiffs, v.
WATSON LABORATORIES, INC. – COMPLAINT FOR FLORIDA, ACTAVIS PHARMA, INC., ANDRX CORPORATION., and ACTAVIS, PATENT INFRINGEMENT INC.
Defendants.
Plaintiffs Horizon Pharma AG and Jagotec AG (collectively “Plaintiffs”) by their attorneys, for their complaint against Watson Laboratories, Inc. – Florida, Actavis
1 Pharma, Inc., Andrx Corporation, and Actavis, Inc. (collectively, “Defendants”) allege as follows:
NATURE OF THE ACTION
1. This is an action for patent infringement arising under the patent laws of the United States, Title 35, United States Code, arising from Watson’s filing of an
Abbreviated New Drug Application (“ANDA”) with the United States Food and Drug
Administration (“FDA”) seeking approval to market a generic version of Horizon’s pharmaceutical product RAYOS® prior to the expiration of United States Patent Nos.
6,488,960 (“the ’960 patent”), 6,677,326 (“the ’326 patent”), 8,309,124 (“the ’124 patent”), 8,168,218 (“the ’218 patent”), and 8,394,407 (“the ’407 patent”) which cover
RAYOS® and its use.
THE PARTIES
2. Plaintiff Horizon Pharma AG is a company organized and existing under the laws of Switzerland, with a principal place of business at Kagenstrasse 17, CH-4153
Reinach, Switzerland.
3. Plaintiff Jagotec AG is a company organized and existing under the laws of Switzerland, with a principal place of business at Eptingerstrasse 61, CH-4132
Muttenz, Switzerland.
4. On information and belief, Defendant Watson Laboratories, Inc. – Florida
(“WLF”) was formerly known as Andrx Pharmaceuticals, Inc. On information and belief, WLF is a corporation organized and existing under the laws of the State of
Florida, with a principal place of business at 4955 Orange Drive, Davie, Florida 33314.
On information and belief, WLF is in the business of, inter alia, developing,
2 manufacturing, and obtaining regulatory approval of generic copies of branded pharmaceutical products throughout the United States, including within this district.
5. On information and belief, Defendant Actavis Pharma, Inc. (“Actavis
Pharma”) was formerly known as Watson Pharma, Inc. On information and belief,
Actavis Pharma is a corporation organized and existing under the laws of the State of
Delaware, having a principal place of business at Morris Corporate Center III, 400
Interpace Parkway, Parsippany, New Jersey, 07054. On information and belief, Actavis
Pharma is in the business of, inter alia, selling and distributing generic copies of branded pharmaceutical products in New Jersey and throughout the United States, including some that are manufactured by WLF and/or for which WLF is the named applicant of the approved ANDAs.
6. On information and belief, Defendant Actavis, Inc. (“Actavis”) was formerly known as Watson Pharmaceuticals, Inc. (“WPI”) until on or around January 24,
2013. On information and belief, Actavis is a corporation organized and existing under the laws of the State of Nevada, having a principal place of business at Morris Corporate
Center III, 400 Interpace Parkway, Parsippany, New Jersey, 07054. On information and belief, Actavis is in the business of, inter alia, developing, manufacturing, obtaining regulatory approval, marketing, selling, and distributing generic copies of branded pharmaceutical products throughout the United States, including within this district, through its own actions and through the actions of its agents and subsidiaries, including at least WLF, Actavis Pharma and Andrx Corporation.
7. On information and belief, Defendant Andrx Corporation (“Andrx”) is a corporation organized and existing under the laws of the State of Delaware, having a
3 principal place of business at 4955 Orange Drive, Davie, Florida 33314. On information and belief, Andrx is in the business of, inter alia, marketing, selling, and distributing generic copies of branded pharmaceutical products throughout the United States, including within this district, through its own actions and through the actions of its agents and subsidiaries, including at least WLF.
8. On information and belief, WPI acquired Andrx Pharmaceuticals on or around November 3, 2006. On information and belief, WPI renamed Andrx
Pharmaceutials as WLF.
9. On information and belief, WLF is a wholly-owned subsidiary of Andrx, which is a wholly owned subsidiary of Actavis.
10. On information and belief, Actavis Pharma is another wholly-owned subsidiary of Actavis.
11. On information and belief, Actavis organizes its operations by divisions— including at least Generics, Brands, and Distribution—and, before the name change, WPI reported its financial results in its Securities and Exchange Commission (“SEC”) filings by reference to these divisions. On information and belief, WPI consolidated its financial results with subsidiaries in its SEC filings at least since 2007 and did not file separate reports to the SEC for each subsidiary.
12. On information and belief, Actavis’ Generics division is involved in the development, manufacture, marketing, sale, and distribution of generic pharmaceuticals.
On information and belief, each Defendant acts as an agent of the other and/or works in concert with each other as integrated parts of the Generics Division. On information and belief, the Generics Division develops and submits Abbreviated New Drug Applications
4 (“ANDAs”) to the FDA, relying on contributions from at least WLF, Actavis Pharma and
Andrx.
13. On information and belief, the head of the Generics Division is an employee of Actavis, the Generic Division’s products are developed and manufactured by at least WLF, and the Generic Division’s products are marketed, sold, and distributed throughout the United States, including in New Jersey, by at least Actavis Pharma. On information and belief, WLF, Actavis Pharma, and Andrx are parties to one or more contractual agreements regarding the distribution of generic pharmaceutical products.
14. On information and belief, each Defendant shares with the others at least some common employees, officers, and directors.
15. On information and belief, WLF, Andrx, and Actavis Pharma are within the control of Actavis for purposes of responding to discovery in this action.
16. On information and belief, Defendants collaborated in the research and development of WLF’s ANDA No. 204867 (“Watson’s ANDA”) for prednisone delayed- release tablets (“the Watson Products”), continue to collaborate in seeking approval of that application by the FDA, and intend to collaborate in the commercial manufacture, marketing, offer for sale and sale of the Watson Products throughout the United States, including in the State of New Jersey, in the event the FDA approves Watson’s ANDA.
17. On information and belief, WLF has submitted to the jurisdiction of this
Court in at least six prior New Jersey actions (Astrazeneca AB, et al. v. Watson Labs.,
Inc. – Florida, et al., Civil Action No. 13-3038; Astrazeneca AB, et al. v. Watson Labs.,
Inc. – Florida, Civil Action No. 13-1669; Depomed, Inc. v. Actavis Elizabeth LLC, et al.,
Civil Action No. 12-1358; Warner Chilcott Co., et al. v. Watson Labs., Inc. – Florida,
5 Civil Action No. 11-5989; Abbott Labs., et al. v. Watson Labs., Inc. – Florida, et al.,
Civil Action No. 10-3241; Mallinckrodt Inc. v. Watson Labs., Inc. – Florida, et al., Civil
Action No. 10-6424). On information and belief, WLF has availed itself of the rights, benefits, and privileges of this Court by asserting counterclaims in at least one prior New
Jersey action (Astrazeneca AB, et al. v. Watson Labs., Inc. – Florida, et al., Civil Action
No. 13-1669).
18. On information and belief, Actavis has submitted to the jurisdiction of this
Court in at least nine prior New Jersey actions (Astrazeneca AB, et al. v. Watson Labs.,
Inc. – Florida, et al., Civil Action No. 13-3038; Auxilium Pharms., Inc., et al. v. Watson
Labs., Inc. et al., Civil Action No. 12-3084;1 Depomed, Inc. v. Actavis Elizabeth LLC, et al., Civil Action No. 12-1358; Noven Pharms. v. Watson Labs., Inc., et al., Civil Action
No. 11-5997;2 Shire LLC, et al. v. Amneal Pharms. LLC, et al., Civil Action No. 11-3781;
King Pharms. Inc., et al. v. Actavis, Inc., et al., Civil Action No. 09-6585; Shire LLC v.
Actavis South Atlantic, LLC, et al., Civil Action No. 09-479; King Pharms. Inc., et al. v.
Actavis, Inc., et al., Civil Action No. 07-5041; Sanofi-Aventis U.S. LLC, et al. v. Actavis
Totowa LLC, et al., Civil Action No. 07-3142). On information and belief, Actavis has availed itself of the rights, benefits, and privileges of this Court by asserting counterclaims in at least one prior New Jersey action (Auxilium Pharms., Inc., et al. v.
Watson Labs., Inc. et al., Civil Action No. 12-3084).
19. On information and belief, Actavis Pharma has submitted to the jurisdiction of this Court in at least six prior New Jersey actions (Astrazeneca AB, et al. v.
1 Watson Pharmaceuticals, Inc. submitted to the jurisdiction of this Court on July 6, 2012. Watson Pharmaceuticals, Inc. thereafter changed its name to Actavis Inc. 2 Watson Pharmaceuticals, Inc. submitted to the jurisdiction of this Court on November 4, 2011. Watson Pharmaceuticals, Inc. thereafter changed its name to Actavis Inc.
6 Watson Labs., Inc. – Florida, et al., Civil Action No. 13-3038; Auxilium Pharms., Inc., et al. v. Watson Labs., Inc. et al., Civil Action No. 12-3084;3 Abbott Labs., et al. v. Watson
Labs., Inc. – Florida, et al., Civil Action No. 10-3241;4 Teva Neuroscience, Inc., et al. v.
Watson Pharma, Inc., et al., Civil Action No. 10-5078;5 Duramed Pharms. v. Watson
Pharma, Inc., Civil Action No. 07-5941;6 Hoffman La-Roche Inc., et al. v. Cobalt
Pharms. Inc., et al., Civil Action No. 07-4539).7 On information and belief, Actavis
Pharma has availed itself of the rights, benefits, and privileges of this Court by asserting counterclaims in at least one prior New Jersey action (Auxilium Pharms., Inc., et al. v.
Watson Labs., Inc. et al., Civil Action No. 12-3084). On information and belief, Actavis
Pharma is registered as a manufacturer and wholesale drug distributor in the State of New
Jersey under the registration number 5003854.
JURISDICTION AND VENUE
20. This Court has subject matter jurisdiction over this action pursuant to 28
U.S.C. §§ 1331 and 1338(a).
21. This Court has personal jurisdiction over Defendants by virtue of, inter alia, their presence in New Jersey, having conducted business in New Jersey, having availed themselves of the rights and benefits of New Jersey law such that they should reasonably anticipate being haled into court in this judicial district, previously consenting
3 Watson Pharma, Inc. submitted to the jurisdiction of this Court on July 6, 2012. Watson Pharma, Inc. thereafter changed its name to Actavis Pharma, Inc. 4 Watson Pharma, Inc. submitted to the jurisdiction of this Court on May 3, 2010. Watson Pharma, Inc. thereafter changed its name to Actavis Pharma, Inc. 5 Watson Pharma, Inc. submitted to the jurisdiction of this Court on December 23, 2010. Watson Pharma, Inc. thereafter changed its name to Actavis Pharma, Inc. 6 Watson Pharma, Inc. submitted to the jurisdiction of this Court on March 3, 2008. Watson Pharma, Inc. thereafter changed its name to Actavis Pharma, Inc. 7 Watson Pharma, Inc. submitted to the jurisdiction of this Court on September 1, 2011. Watson Pharma, Inc. thereafter changed its name to Actavis Pharma, Inc.
7 to personal jurisdiction in this Court, availing themselves of the jurisdiction of this Court, and having engaged in systematic and continuous contacts with the State of New Jersey through the marketing and sales of generic drugs throughout the United States, and in particular within this judicial district, through the receipt of revenue from the sales and marketing of generic drug products, including WLF products, within this judicial district, and through their intent to market and sell the Watson Products, if approved, to residents of this judicial district.
22. Venue is proper in this judicial district under 28 U.S.C. §§ 1391(b) and (c) and § 1400(b).
PATENTS-IN-SUIT
23. On December 3, 2002, the U.S. Patent and Trademark Office (“PTO”) duly and legally issued the ’960 patent titled “Corticosteroid Formulation.” At the time of its issue, the ’960 patent was assigned to Arakis, Ltd., Babraham Hall, Babraham,
Cambridge, United Kingdom (now known as Sosei R&D Ltd., Chesterford Research
Park, Little Chesterford, Saffron Walden, Essex, United Kingdom), which later assigned the ’960 patent to Nitec Pharma AG (now known as Horizon Pharma AG), Kagen-Strasse
17, Reinach Switzerland CH-4153. Horizon Pharma AG is the sole current assignee of the ’960 patent, which discloses and claims, inter alia, a pharmaceutical composition containing prednisone. A true and correct copy of the ’960 patent is attached hereto as
Exhibit A.
24. On January 13, 2004, the PTO duly and legally issued the ’326 patent titled “Corticosteroid Formulation Comprising Less Than 2.5 mg Prednisolone for Once
Daily Administration.” At the time of its issue, the ’326 patent was assigned to Arakis,
8 Ltd., Chesterford Research Park, Little Chesterford, Saffron Walden, Essex, United
Kingdom (now known as Sosei R&D Ltd., Chesterford Research Park, Little Chesterford,
Saffron Walden, Essex, United Kingdom), which later assigned the ’960 patent to Nitec
Pharma AG (now known as Horizon Pharma AG), Kagen-Strasse 17, Reinach
Switzerland CH-4153. Horizon Pharma AG is the sole current assignee of the ’326 patent, which discloses and claims, inter alia, a pharmaceutical composition containing prednisone. A true and correct copy of the ’326 patent is attached hereto as Exhibit B.
25. On November 13, 2012, the PTO duly and legally issued the ’124 patent titled “Delayed Release Tablet with Defined Core Geometry.” Jagotec AG is the sole current assignee of the ’124 patent, which discloses and claims, inter alia, a pharmaceutical composition containing prednisone. A true and correct copy of the ’124 patent is attached hereto as Exhibit C.
26. On May 1, 2012, the PTO duly and legally issued the ’218 patent titled
“Delayed Release Tablet with Defined Core Geometry.” Jagotec AG is the sole current assignee of the ’218 patent, which discloses and claims, inter alia, a pharmaceutical composition containing prednisone. A true and correct copy of the ’218 patent is attached hereto as Exhibit D.
27. On March 12, 2013, the PTO duly and legally issued the ’407 patent titled
“Delayed Release Tablet with Defined Core Geometry.” Jagotec AG is the owner of the
’407 patent, which discloses and claims, inter alia, a pharmaceutical composition containing prednisone. A true and correct copy of the ’407 patent is attached hereto as
Exhibit E.
9 RAYOS®
28. Horizon Pharma, Inc. is the owner of the approved New Drug Application
No. 202020 (“the RAYOS® NDA”) for prednisone delayed-release tablets in 1 mg, 2 mg, and 5 mg dosage strengths, which are sold by Horizon Pharma USA, Inc. under the trade name RAYOS®. The RAYOS® tablets are currently approved for use as an anti- inflammatory or immunosuppressive agent for certain allergic, dermatologic, gastrointestinal, hematologic, ophthalmologic, nervous system, renal respiratory, rheumatologic, specific infectious diseases or conditions and organ transplantation; for the treatment of certain endocrine conditions; and for palliation of certain neoplastic conditions.
29. Pursuant to 21 U.S.C. § 355(b)(1), and attendant FDA regulations, the
’960, ’326, ’124, ’218 and ’407 patents are listed in the FDA publication entitled
Approved Drug Products and Therapeutic Equivalence Evaluations (“the Orange Book”) for the RAYOS® NDA.
30. The ’960 and ’326 patents are listed in the Orange Book for the 1 mg and
2 mg strength RAYOS® tablets. The ’124 and ’407 patents are listed in the Orange
Book for the 1 mg, 2 mg, and 5 mg strength RAYOS® tablets. The ’218 patent is listed in the Orange Book for the 5 mg strength RAYOS® tablets.
31. The ’960, ’326, ’124, ’218 and ’407 patents cover the RAYOS® product.
WATSON’S ANDA
32. On information and belief, WLF submitted ANDA No. 204867 (“the
Watson ANDA”) to the FDA, pursuant to 21 U.S.C. § 355(j), seeking approval to market prednisone delayed-release tablets in 1 mg, 2 mg, and 5 mg dosage strengths. On
10 information and belief, the Watson ANDA is seeking approval to market the Watson
Products as an anti-inflammatory or immunosuppressive agent for certain allergic, dermatologic, gastrointestinal, hematologic, ophthalmologic, nervous system, renal respiratory, rheumatologic, specific infectious diseases or conditions and organ transplantation; for the treatment of certain endocrine conditions; and for palliation of certain neoplastic conditions.
33. The Watson ANDA refers to and relies upon the RAYOS® NDA and contains data that, according to Watson, demonstrate the bioequivalence of the Watson
Products and RAYOS®.
34. Plaintiffs have received from WLF a letter, dated July 15, 2013 (the
“Watson Notification”), stating that WLF had included a certification in the Watson
ANDA pursuant to 21 U.S.C. § 355(j)(2)(A)(vii)(IV), that the ’960, ’326, ’124, ’218 and
’407 patents are invalid or will not be infringed by the commercial manufacture, use or sale of the Watson Products (the “Paragraph IV Certification”).
COUNT I FOR INFRINGEMENT OF U.S. PATENT 6,488,960
35. Plaintiffs reallege and incorporate by reference the allegations of paragraphs 1-34 of this Complaint.
36. Defendants have infringed the ’960 patent, pursuant to 35 U.S.C.
§ 271(e)(2)(A), by submitting the Watson ANDA, by which Defendants seek approval from the FDA to engage in the commercial manufacture, use, offer to sell, sale, or importation of the Watson Products in 1 mg and 2 mg strengths prior to the expiration of the ’960 patent.
11 37. Defendants’ commercial manufacture, use, offer to sell, or sale of the
Watson Products within the United States, or importation of the Watson Products in 1 mg and 2 mg strengths into the United States during the term of the ’960 patent would further infringe the ’960 patent under 35 U.S.C. § 271(a), (b) and/or (c).
38. This action is being filed within 45 days of receipt by Plaintiffs of the
Watson Notification dated July 15, 2013, which purportedly advised Plaintiffs of
Watson’s Paragraph IV Certification with respect to the ’960 patent.
39. Upon information and belief, Defendants had actual and constructive notice of the ’960 patent prior to filing Watson’s ANDA, and Defendants’ infringement of the ’960 patent has been, and continues to be, willful.
40. Plaintiffs are entitled to the relief provided by 35 U.S.C. § 271(e)(4), including an order of this Court that the effective date of the approval of Watson’s
ANDA be a date that is not earlier than the expiration of the ’960 patent, or any later expiration of exclusivity for the ’960 patent to which they become entitled.
41. Plaintiffs will be substantially and irreparably harmed if Defendants are not enjoined from infringing or actively inducing or contributing to infringement of the
’960 patent.
42. Plaintiffs have no adequate remedy at law.
43. This case is an exceptional one, and Plaintiffs are entitled to an award of attorneys’ fees under 35 U.S.C. § 285.
COUNT II FOR INFRINGEMENT OF U.S. PATENT 6,677,326
44. Plaintiffs reallege and incorporate by reference the allegations of paragraphs 1-34 of this Complaint.
12 45. Defendants have infringed the ’326 patent, pursuant to 35 U.S.C.
§ 271(e)(2)(A), by submitting the Watson ANDA, by which Defendants seek approval from the FDA to engage in the commercial manufacture, use, offer to sell, sale, or importation of the Watson Products in 1 mg and 2 mg strengths prior to the expiration of the ’326 patent.
46. Defendants’ commercial manufacture, use, offer to sell, or sale of the
Watson Products within the United States, or importation of the Watson Products in 1 mg and 2 mg strengths into the United States during the term of the ’326 patent would further infringe the ’326 patent under 35 U.S.C. § 271(a), (b) and/or (c).
47. This action is being filed within 45 days of receipt by Plaintiffs of the
Watson Notification dated July 15, 2013, which purportedly advised Plaintiffs of
Watson’s Paragraph IV Certification with respect to the ’326 patent.
48. Upon information and belief, Defendants had actual and constructive notice of the ’326 patent prior to filing Watson’s ANDA, and Defendants’ infringement of the ’326 patent has been, and continues to be, willful.
49. Plaintiffs are entitled to the relief provided by 35 U.S.C. § 271(e)(4), including an order of this Court that the effective date of the approval of Watson’s
ANDA be a date that is not earlier than the expiration of the ’326 patent, or any later expiration of exclusivity for the ’326 patent to which they become entitled.
50. Plaintiffs will be substantially and irreparably harmed if Defendants are not enjoined from infringing or actively inducing or contributing to infringement of the
’326 patent.
51. Plaintiffs have no adequate remedy at law.
13 52. This case is an exceptional one, and Plaintiffs are entitled to an award of attorneys’ fees under 35 U.S.C. § 285.
COUNT III FOR INFRINGEMENT OF U.S. PATENT 8,309,124
53. Plaintiffs reallege and incorporate by reference the allegations of paragraphs 1-34 of this Complaint.
54. Defendants have infringed the ’124 patent, pursuant to 35 U.S.C.
§ 271(e)(2)(A), by submitting the Watson ANDA, by which Defendants seek approval from the FDA to engage in the commercial manufacture, use, offer to sell, sale, or importation of the Watson Products in 1 mg, 2 mg and 5 mg strengths prior to the expiration of the ’124 patent.
55. Defendants’ commercial manufacture, use, offer to sell, or sale of the
Watson Products within the United States, or importation of the Watson Products in 1 mg, 2 mg and 5 mg into the United States during the term of the ’124 patent would further infringe the ’124 patent under 35 U.S.C. § 271(a), (b) and/or (c).
56. This action is being filed within 45 days of receipt by Plaintiffs of the
Watson Notification dated July 15, 2013, which purportedly advised Plaintiffs of
Watson’s Paragraph IV Certification with respect to the ’124 patent.
57. Upon information and belief, Defendants had actual and constructive notice of the ’124 patent prior to filing Watson’s ANDA, and Defendants’ infringement of the ’124 patent has been, and continues to be, willful.
58. Plaintiffs are entitled to the relief provided by 35 U.S.C. § 271(e)(4), including an order of this Court that the effective date of the approval of Watson’s
14 ANDA be a date that is not earlier than the expiration of the ’124 patent, or any later expiration of exclusivity for the ’124 patent to which they become entitled.
59. Plaintiffs will be substantially and irreparably harmed if Defendants are not enjoined from infringing or actively inducing or contributing to infringement of the
’124 patent.
60. Plaintiffs have no adequate remedy at law.
61. This case is an exceptional one, and Plaintiffs are entitled to an award of attorneys’ fees under 35 U.S.C. § 285.
COUNT IV FOR INFRINGEMENT OF U.S. PATENT 8,168,218
62. Plaintiffs reallege and incorporate by reference the allegations of paragraphs 1-34 of this Complaint.
63. Defendants have infringed the ’218 patent, pursuant to 35 U.S.C.
§ 271(e)(2)(A), by submitting the Watson ANDA, by which Defendants seek approval from the FDA to engage in the commercial manufacture, use, offer to sell, sale, or importation of the Watson Products in 5 mg dosage strength prior to the expiration of the
’218 patent.
64. Defendants’ commercial manufacture, use, offer to sell, or sale of the
Watson Products within the United States, or importation of the Watson Products in 5 mg dosage strength into the United States during the term of the ’218 patent would further infringe the ’218 patent under 35 U.S.C. § 271(a), (b) and/or (c).
65. This action is being filed within 45 days of receipt by Plaintiffs of the
Watson Notification dated July 15, 2013, which purportedly advised Plaintiffs of
Watson’s Paragraph IV Certification with respect to the ’218 patent.
15 66. Upon information and belief, Defendants had actual and constructive notice of the ’218 patent prior to filing Watson’s ANDA, and Defendants’ infringement of the ’218 patent has been, and continues to be, willful.
67. Plaintiffs are entitled to the relief provided by 35 U.S.C. § 271(e)(4), including an order of this Court that the effective date of the approval of Watson’s
ANDA be a date that is not earlier than the expiration of the ’218 patent, or any later expiration of exclusivity for the ’218 patent to which they become entitled.
68. Plaintiffs will be substantially and irreparably harmed if Defendants are not enjoined from infringing or actively inducing or contributing to infringement of the
’218 patent.
69. Plaintiffs have no adequate remedy at law.
70. This case is an exceptional one, and Plaintiffs are entitled to an award of attorneys’ fees under 35 U.S.C. § 285.
COUNT V FOR INFRINGEMENT OF U.S. PATENT 8,394,407
71. Plaintiffs reallege and incorporate by reference the allegations of paragraphs 1-34 of this Complaint.
72. Defendants have infringed the ’407 patent, pursuant to 35 U.S.C.
§ 271(e)(2)(A), by submitting the Watson ANDA, by which Defendants seek approval from the FDA to engage in the commercial manufacture, use, offer to sell, sale, or importation of the Watson Products in 1 mg, 2 mg and 5 mg prior to the expiration of the
’407 patent.
73. Watson’s commercial manufacture, use, offer to sell, or sale of the Watson
Products within the United States, or importation of the Watson Products in 1 mg, 2 mg
16 and 5 mg into the United States during the term of the ’407 patent would further infringe the ’407 patent under 35 U.S.C. § 271(a), (b) and/or (c).
74. This action is being filed within 45 days of receipt by Plaintiffs of the
Watson Notification dated July 15, 2013, which purportedly advised Plaintiffs of
Watson’s Paragraph IV Certification with respect to the ’407 patent.
75. Upon information and belief, Defendants had actual and constructive notice of the ’407 patent prior to filing Watson’s ANDA, and Watson’s infringement of the ’407 patent has been, and continues to be, willful.
76. Plaintiffs are entitled to the relief provided by 35 U.S.C. § 271(e)(4), including an order of this Court that the effective date of the approval of Watson’s
ANDA be a date that is not earlier than the expiration of the ’407 patent, or any later expiration of exclusivity for the ’407 patent to which they become entitled.
77. Plaintiffs will be substantially and irreparably harmed if Defendants are not enjoined from infringing or actively inducing or contributing to infringement of the
’407 patent.
78. Plaintiffs have no adequate remedy at law.
79. This case is an exceptional one, and Plaintiffs are entitled to an award of attorneys’ fees under 35 U.S.C. § 285.
PRAYER FOR RELIEF
WHEREFORE, Horizon Pharma AG and Jagotec AG pray for a judgment in their favor against Defendants Watson Laboratories, Inc. – Florida, Actavis Pharma, Inc.,
Andrx Corporation, and Actavis, Inc., and respectfully request the following relief:
17 A. A judgment declaring that Defendants have infringed one or more claims of U.S. Patent 6,488,960;
B. A judgment declaring that Defendants have infringed one or more claims of U.S. Patent 6,677,326;
C. A judgment declaring that Defendants have infringed one or more claims of U.S. Patent 8,309,124;
D. A judgment declaring that Defendants have infringed one or more claims of U.S. Patent 8,168,218;
E. A judgment declaring that Defendants have infringed one or more claims of U.S. Patent 8,394,407;
F. A judgment pursuant to 35 U.S.C. § 271(e)(4) preliminarily and permanently enjoining Defendants, their officers, agents, servants, and employees, and those persons in active concert or participation with any of them, and their successors and assigns, from manufacturing, using, offering to sell, or selling the Watson Products in 1 mg and 2 mg dosage strengths within the United States, or importing the Watson
Products into the United States, prior to the expiration date of the ’960 patent;
G. A judgment pursuant to 35 U.S.C. § 271(e)(4) preliminarily and permanently enjoining Defendants, their officers, agents, servants, and employees, and those persons in active concert or participation with any of them, and their successors and assigns, from manufacturing, using, offering to sell, or selling the Watson Products in 1 mg and 2 mg dosage strengths within the United States, or importing the Watson
Products into the United States, prior to the expiration date of the ’326 patent;
18 H. A judgment pursuant to 35 U.S.C. § 271(e)(4) preliminarily and permanently enjoining Defendants, their officers, agents, servants, and employees, and those persons in active concert or participation with any of them, and their successors and assigns, from manufacturing, using, offering to sell, or selling the Watson Products in 1 mg, 2 mg and 5 mg dosage strengths within the United States, or importing the Watson
Products into the United States, prior to the expiration date of the ’124 patent;
I. A judgment pursuant to 35 U.S.C. § 271(e)(4) preliminarily and permanently enjoining Defendants, their officers, agents, servants, and employees, and those persons in active concert or participation with any of them, and their successors and assigns, from manufacturing, using, offering to sell, or selling the Watson Products in 5 mg dosage strength within the United States, or importing the Watson Products into the
United States, prior to the expiration date of the ’218 patent;
J. A judgment pursuant to 35 U.S.C. § 271(e)(4) preliminarily and permanently enjoining Defendants, their officers, agents, servants, and employees, and those persons in active concert or participation with any of them, and their successors and assigns, from manufacturing, using, offering to sell, or selling the Watson Products in 1 mg, 2 mg and 5 mg dosage strengths within the United States, or importing the Watson
Products into the United States, prior to the expiration date of the ’407 patent;
K. If Defendants commercially manufacture, use, offer to sell, or sell the
Watson Products within the United States, or import the Watson Products in 1 mg and 2 mg dosage strengths into the United States, prior to the expiration of the ’960 patent, including any extensions, a judgment awarding Plaintiffs monetary relief together with interest;
19 L. If Defendants commercially manufacture, use, offer to sell, or sell the
Watson Products within the United States, or import the Watson Products in 1 mg and 2 mg dosage strengths into the United States, prior to the expiration of the ’326 patent, including any extensions, a judgment awarding Plaintiffs monetary relief together with interest;
M. If Defendants commercially manufacture, use, offer to sell, or sell the
Watson Products within the United States, or import the Watson Products in 1 mg, 2 mg and 5 mg dosage strengths into the United States, prior to the expiration of the ’124 patent, including any extensions, a judgment awarding Plaintiffs monetary relief together with interest;
N. If Defendants commercially manufacture, use, offer to sell, or sell the
Watson Products within the United States, or import the Watson Products in 5 mg dosage strength into the United States, prior to the expiration of the ’218 patent, including any extensions, a judgment awarding Plaintiffs monetary relief together with interest;
O. If Defendants commercially manufacture, use, offer to sell, or sell the
Watson Products within the United States, or import the Watson Products in 1 mg, 2 mg and 5 mg dosage strengths into the United States, prior to the expiration of the ’407 patent, including any extensions, a judgment awarding Plaintiffs monetary relief together with interest;
P. Attorneys’ fees in this action as an exceptional case pursuant to 35 U.S.C.
§ 285;
Q. Costs and expenses in this action; and
20 R. Such other and further relief as the Court deems just and proper.
Date: August 26, 2013 /s/ Karen A. Confoy Karen A. Confoy FOX ROTHSCHILD, LLP 997 Lenox Drive, Building 3 Lawrenceville, New Jersey 08648 (609) 896-3600 Attorneys for Plaintiffs Horizon Pharma AG and Jagotec AG
Robert F. Green John A. Bauer Caryn C. Borg-Breen MINTZ, LEVIN, COHN, FERRIS, Jessica M. Tyrus GLOVSKY AND POPEO, P.C Ann K. Kotze 666 Third Avenue LEYDIG, VOIT & MAYER, LTD. New York, New York 10017 Two Prudential Plaza, Suite 4900 (212) 692-6795 180 North Stetson Chicago, Illinois 60601 Of Counsel for Plaintiff Jagotec AG (312) 616-5600
Attorneys for Plaintiff Horizon Pharma AG
Dennis A. Bennett GLOBAL PATENT GROUP, LLC 1005 North Warson Road, Suite 201 St. Louis, Missouri 63132 (314) 812-8018
Of Counsel for Plaintiff Horizon Pharma AG
21 EXHIBIT A |1|1111111111||||II||I|I1|||||||||||||||l|IHI11l1lIIIIIIIIIIHIIHIIIIIII US006488960B1 (12) United States Patent (10) Patent No Us 6,488,960 B1 Bardsley (45) Date of Patent Dec. 3, 2002
(54) CORTICOSTEROID FORMULATION (58) Field of Search 514/179, 180; 424/465, 489 (75) Inventor: Hazel Judith Bardsley, Cambridge
§ 371 (¢)(1), Primary Examiner ames H. Reamer (2), (4) Date: Sep. 13, 2001 (74) Attorney Ageng or Firm-Saliwanchik, Lloyd & Saliwanchik (sv) PC'l`Pub. No.: WO00/54780 7) ABSTRACT PCT Pub. Date: Sep. 21, 2000 The present invention pertains to a unit dose formulation 30) Foreign Application Priority Data comprising 0.25 to 2 mg of a corticosteroid. This small dose Mar. 15, 1999 (GB) 9905898 can be used to treat rheumatoid arthritis, especially if adapted to release at least 90% by weight of the (51) Int. C17 A61K 31/09 corticosteroid, 2 to 8 hours after administration. (52) U.s. Cl. 424/465; 424/485; 514/179 514/180 8 Claims, 1 Drawing Sheet U.S. Patent Dec. 3, 2002 Us 6,488,960 B1
Concentration (ng/ml) 50 40 30 20 L5 10 I 0 0 6 12 18 24 Time
Fig. 1 Us 6,488,960 B1 1 2 CORTICOSTEROII) FORMULATION Arvidson et al (and in U.S. Pat. No. 5792496), a much lower dosage of the glucocorticoid was also effective. Given the state of the art and the known side-eifects of conicosteroids. FIELD OF THE INVENTION this increase in their therapeutic index is surprising This invention relates to a controlled-release formulation. 5 According lo the present invention, a unit dosage com~ and in particular to a formulation of a corticosteroid, suitable prises 0.25 to 2 mg of a corticosteroid. Preferably, such a for use in the treatment of rheumatoid arthritis. dosage is in the form of a controlled-release formulation of the type generally or specifically described in U.S. Pat. No. BACKGROUND OF THE INVENTION 5,792,476. Glucocor ticoids, and in particular prednisone and 10 Thus, in accordance with the present invention, a prednisolone, are widely used for the treatment of rheuma- controlled-close formulation of the drug is adapted lo release toid arthritis. The use of glucocorticoids may be ellicacious the drug at a predetermined period of time after but has disadvantages, particularly in terms of side~elfects administration, or at a predetermined time. Advantages of such as bone loss. the invention may include enhanced ellicaey, reduced side- It appears to be generally recognised that it would be l effects, reduced Cmax and/or a reduced level of active desirable to use low doses of, say, prednisolone, in the material. treatment of rheumatoid arthritis. While it is clear that low dose oral prednisolone can be eiiieacious, there is some DESCRIPTION OF THE INVENTION controversy over what is actually meant by a low dose. The intention behind the invention is that the active 20 Kirwan, New England J. Med. 333: 142-5 (1995), indi- ingredient should be released at a predetermined time, e.g. cates that a daily dosage of 7.5 mg prednisolone is elfective. between midnight and 6 a.m., e.g. 2 a.m. and 4 a.m., or a This is supported by Boers et al, The Lancet 3502309-318 predetermined time after administration. Thus, the user can (1997). Boers et al also reports that a typical treatment of take the formulation before going to sleep, but have the full rheumatoid arthritis following initial treatment with a non- value of an effective dosage of the drug during the night, or steroidal anti-inliamrnatory dnug (NSAID) involves a high 25 during sleep, at a dosage that has minimal sideeffects. initial dose and, when the condition is under control, Accordingly, a predominant amount of the active ingredient, reduced doses, down to a "low maintenance" of 7.5 mg/day. e.g. at least 90% by weight, is released at least 2 or 3 hours Gotzsche and Johansen, B. M. J. 316811-818 (1998), after administration, and preferably no more than 6, 7 or 8 hours after administration. reviews a number of studies of low dose prednisolone in the 30 treatment of rheumatoid arthritis. Most of these studies Formulations of the invention are intended for the treat- report doses of at least 7.5 mg. There is one report, but from ment of disorders associated with the release of cytokines. ln as long ago as 1967, of a 2.5 mg dose. particular, the invention is suitable for the treatment of It is evident that, in clinical practice, rheumatologists inflammatory diseases, and most especially rheumatoid arthritis, asthma, inflammatory bowel disease and atopic taper the dose of glucocorticoid to as a low a level as they 35 can, before symptoms return. There may be patients who are dermatitis. The dwg that is used in the formulation may be stable on less than 5 mg prednisolone per day, but there is chosen accordingly. Examples are glucocortocoids and other little or no clinical data to support that such a low dose is cor ticosteroids, e.g. budesonide, methylprednisolone, actually providing any benefit. This is important, because in deflazacort, prednisone and prednisolone. lf desired, the many of these patients, prednisolone may be contributing 40 active ingredient may be formulated as a pro-dnug, so that only side-effects. There is no evidence that any dose of the active component is released in vivo. prednisolone, lower than those generally used, is effective The preferred route of administration of a formulation of when given chronically for the treatment of rheumatoid this invention is oral. However, it will be readily apparent to arthritis. those skilled in the art that other routes of administration Arvidson et al, Annals of the Rheumatic Diseases 45 may be used, e.g. having regard to the nature of the condition 56:27_31 (1997), reports that the timing of glucocorticoid being treated and the most effective means of achieving administration in rheumatoid arthritis may be important, in delayed release. controlling the acute inflammatory aspects of the disease. In The dwg may be administered in any conventional for- the reponed study, patients were woken at 2.00 a.m. and mulation that provides delayed release, via any suitable given 7.5 mg or 5 mg prednisolone. 50 route of administration. Conventional dosing parameters U.S. Pat. No. 5,792,476 claims a sustained-release for- may be adopted, i.e. those which are known to or adapted to mulation of a glucocorticoid such as prednisone or pred- the practice of those sldlled in the art. The daily dosage is nisolonhe. The formulation comprises 2.5-7 mg of the usually at least 0.25 or 0.5 mg, eg. l to 2 mg, but will be glucocorticoid and releases at least 90% of the drug during chosen according to the age, weight and health of the 40~80 minutes, starting about 1-3 hours after the entry of 55 Subject, and other factors that are routinely considered by the the drug into the small intestine. The intention is that the man skilled in the art. formulation should be taken immediately before the patient A formulation of the invention may be a unit dosage such goes to sleep, that the drug should be released during sleep, as a tablet, capsule, ampoule, vial or suspension. A and that the greatest symptoms of rheumatoid arthritis controlled-release formulation may be in matrix, coating, (which occur shortly before waking) should thus be treated 60 reservoir, osmotic, ion-exchange or density exchange form. most effectively. This is based on the same data as in It may comprise a soluble polymer coating which is dis- Arvidson et al, supra, i.e. using doses of 5 or 7.5 mg solved or eroded, after administration. Alternatively, there prednisolone given at 2 a.m. may be an insoluble coating, e.g. of a polymer, through which the active ingredient permeates, as from a reservoir, SUMMARY OF THE INVENTION 65 diifuses, e.g. through u porous matrix, or undergoes osmotic This invention is based on the discovery that, in a study exchange. A further option for a controlled-release formu- designed to test the reproducibility of the results reported by lation involves density exchange, e.g. in the case where the Us 6,488,960 B1 3 4 formulation alters on administration, e.g. from micropar- (and probably remained blind), but no placebo tablets were ticles to a gel so that the active ingredient dilfuses or used and it was possible for a patient to be un-blind. permeates out. Ion-based resins may also be used, the active Patients invited to take part in the study had the following component being released by ionic exchange, and wherein characteristics: the rate of release can be controlled by using cationic or 5 anionic forms of the drug. Another type of controlled-release Over 18 years old formulation involves pulsed dosing. Further examples are given in U.S. Pat. No. 5,792,476. Had rheumatoid arthritis by the criteria of the American An example of a controlled dose of active ingredient is College of Rheumatology; see Arnett et al, Arthritis Rheum. 31:315-324 (1988) dosing with a tablet containing 1.25 mg prednisolone. In this 10 example, a patient taking a controlled dose of 1.25 mg Had active disease as evidenced by 3 or more swollen and prednisolone takes the tablet a number of hours before it is tender joints due to be released. Time Zero on the plot (FIG. 1) denotes the Were not taking glucocorticoid medication earliest time at which active ingredient is released, probably Had not had intra-anicular glucocorticoid injections in the midnight. The plasma levels achieved by release of the 15 active agent at di5erent times (2, 4 and 6 a.m.) are shown. previous 3 weeks It can be seen that the range for Clnux obtained from the Had no medical conditions which, in the opinion of the 125 mg prednisolone dose is from approximately 20 to 50 investigator, would contraindicate low dose predniso- ng/ml (total prednisolone which includes protein bound and lone therapy unbound active) depending on how quickly a patient absorbs 20 Informed consent was obtained and the patient prescrip- the active ingredient. The time to Cmax or Tm is usually tion written by a doctor not associated with trial evaluation. between 1 and 3 hours, Where absorption is particularly fast, Medication was dispensed at 2 a.m. on each treatment day theCnmxmay be 100 ng/ml total prednisolone or higher (this is not shown on the plot). after gently waking the patient. The patient was encouraged to settle back to sleep immediately. The following Study provides the basis of the present 25 invention. On the morning before medication and on each morning Study Design on the day of medication, blood samples were taken at 8.30 The study was an assessor blind comparison of the eiects a.m. and outcome assessments recorded then, and at noon, as of two doses of prednisolone (1 mg and 5 mg) given at indicated above, 02.00. Patients stayed the night in hospital but were free to 30 Evaluation be up and about and to leave the hospital during the day. At 2 a.m. on the appropriate days patients were woken gently, Symptoms, signs and laboratory results were compared administered the prednisolone, and settled back to sleep. within and between patients, but the main assessment was Blood samples and clinical assessments were made at 08.30 visual inspection of the overall pattern of response. Means and further clinical assessments related to symptoms on the 35 and standard deviations were used to define variation rates day of drug administration at 12.00 and 08.30 the following and for calculating trial size for future studies. An overall day (except the final day when this last assessment was made assessment of practicality and the potential for more fre- before departure from the hospital). Patients were admitted quent (but smaller volume) blood taking was made by on Monday and had a "control" night that evening with no discussion arnongst the staff and patients involved. prednisolone but full assessment the following day. On each 40 of the following three nights prednisolone was administered. Results Patients went home on Friday afternoon but returned the Three patients were able to take part in the study in the following Monday to repeat the procedure. Allocation to 1 time available. One patient (3) was inadvertently given the mg or 5 mg prednisolone in the first or second week was by Hrst dose of treatment in the second week on the hrst night randomisation in sealed envelopes. The patient and assessor 45 in hospital. Patient 3 took prednisolone for the next two were not aware of which dose was given. nights and remained in hospital for a fourth night without Outcome prednisolone treatment. This patient's assessments have Clinical: Outcome was measured at 08.30 each day for: been included normally in the first week, but in the second swollen joint count (n=28); tender joint count (n=28); pain week they have been used diierently. Here, this patient's (0.100 mm, VAS). Outcome was measured at 12.00 each day 50 for. morning stihness (minutes); patient opinion of condition results have been included with those of the other patients in (0-100 mm, VAS); clinician opinion of condition (0-100 accordance with the dose of prednisolone received. This mm, VAS). Outcome was measured the following day for: patient's final assessment (no prednisolone the night before) whether the arthritis worse in the morning or afternoon on therefore appears as an extra day after the other patients in the previous day? (-1 morning, 0 equal, +1 afternoon). 55 the study. Serological: Seam samples were obtained at 08.30, kept The results for 5 mg prednisolone place the patients in this on ice for up to 1 hour, separated and stored at -70° C. to pilot study well within the range of findings published by measure: C-reactive protein (CRP); IL6 concentration; 6 Arvidson et al and reinforce the conclusions which can be soluble receptor (IL-6sR) concentration; byaluronate (HA) drawn from that paper. concentration. 60 Procedure The results from 1 mg prednisolone raise the possibility Patients acted as their own control and took each dose of that even at this dose there may be an appreciable effect on prednisolone for three consecutive nights. They were ran- symptoms. Pain, EMS, pat1ent's opinion and clin1cian's domly. allocated by cards kept in sealed envelopes to either opinion were statistically significantly reduced, even with 1 mg prednisolone on three consecutive nights followed by 65 only three patients in the study. CRP and IL-6 were reduced 5 mg on three consecutive nights, or the opposite sequence. significantly on 5 mg prednisolone and there was a tendency The assessor was not aware of the treatment order allocation for reduction on 1 mg prednisolone. Us 6,488,960 B1 5 6
TABLE 1
Mean and 95% confidence intervals for each variable
More Swollen Painful OT L Cln Dav Dose Joinis Joints Pain Less EMS Opn Opn CRP HA m e IL-6sR
Mean Results
20.3 21.0 37.7 -1.0 70.0 31.3 34.3 405 345.1 44.1 31557.8 1 18.7 20.0 26.0 -0.7 55.0 23,7 28.7 35.5 241 .9 28.1 31959.9 2 187 20.3 20.3 -0.7 51.7 26.7 29.3 31.2 320.3 31.1 31468.0 3 18.3 20.3 16.7 0.0 40.0 12.7 16.3 25.8 372.5 22.8 30898.9 10 12.3 15.3 25.0 0.3 40.0 24.3 23.3 15.0 396.3 19.3 22937.2 1 1 18.0 19.0 19.7 0.3 30.0 19.3 27.7 36.6 322.5 30.3 423%.2 12 5 17.3 0 11.7 15.7 31.1 339.5 18.5 3533 13 5 14,0 19.7 16.0 ~0.7 33.3 13.3 11.7 19.1 193.9 13.8 361727 14 0 12.0 9.0 8.0 19.5 363.5 107.1 32180.5 95% CI Resulls
0.7 5.7 24.9 0.0 19.6 20.3 213.0 18.1 8838.9 1 1 1.3 7,4 25.2 0.7 9.8 15.4 10.3 23.0 152.3 18.1 10225 3.5 7.7 20.3 0.7 8.6 5.7 10.5 27.5 321.8 32.7 102209 3.6 9.1 16.9 1.1 9.8 1 4.6 25.3 96.7 28,4 11329.4 10 0 15.2 19.2 31.8 0.8 48.0 3 29.6 22.8 718.7 23.3 27617.3 11 5 3.9 9.1 21.1 1.3 29.4 20.1 13.6 291 148.6 241 23485.3 12 5 6.5 9.6 15.4 0.7 19.6 11.6 1.7 26.0 221.4 23.6 8919.1 13 5 6.9 10.3 113.3 13,3 70695 14
What is claimed is effective amount of a controlled-release formulation com 1. A controlled-release formulation comprising from 0.25 prising from 0.25 mg to 2 mg of a corticosteroid selected 30 mg to 2 mg of a corticosteroid selected from the group from the group consisting of prednisone, consisting of prednisone, methylprednisolone, and methylprednisolone, and prednisolone, wherein said formu- prednisolone, wherein said formulation is adapted to release lation is adapted to release at least 90% by weight of the at least 90% by weight of the corticosteroid 2 hours to 8 corticosteroid 2 hours to 8 hours after administration. hours after administration. 35 6. The method according to claim 5, wherein the formu- 2. The formulation according to claim 1, which comprises lation comprises from 0.5 mg to 2 mg of the corticosteroid. from 05 mg to 2 mg of the corticosteroid. 7. The method according to claim 5, Wherein the formu- 3. The formulation according to claim 1, which comprises lation comprises from 1 mg to 1.25 mg of the corticosteroid. from l mg to 1.25 mg of the corticosteroid. 4. The formulation according to claim 1, Wherein the 8. The method according to claim 5, wherein the corti- 40 corticosteroid is prednisolone. costeroid is prednisolone. 5. A method for the treatment of rheumatoid arthritis, Wherein said method comprises administering to a patient an =t< =l< >l¢ * * EXHIBIT B ||||||||||1||||||1111||||1|||||IIIIIIIIII|11|1II111|1|I|||H||||||||I||||| US006677326B2 (12) United States Patent (10) Patent No.: US 6,677,326 B 2 Bardsley et al (45) Date of Patent: *Jan. 13, 2004
(54) CORTICOSTEROID FORMULATION (58) Field of Search 514/179, 180 COMPRISING LESS THAN 2.5 MG PREDNISOLONE FOR ONCE DAILY (56) References Cited ADMINISTRATION U.S. PATENT DOCUMENTS (75) Inventors: Hazel Judith Bardsley, Cambridge 5,792,476 A 8/1998 Hiillgren (GB); Robin Mark Bannister, Essex (GB); Julian Clive Gilbert, Essex (GB) FOREIGN PATENT DOCUMENTS WO WO 95/08323 A1 3/1 995 (73) As
Concentration (nglml)
50
r' 40 \ \l \ 3 0 4 ;\ `\ \ \ wr / x 32 iV~
U 0 + 0 6 12 18 24 Time
FIG. l Us 6,677,326 B2 1 2 C()R'1`IC()S'l`ER()ID FORMULATION the dmg into the small intestine. The intention is that the COMPRISING LESS THAN 2.5 MG formulation should be taken immediately before the patient PREDNISOLONE FOR ONCE DAILY goes to sleep, that the dwg should be released during sleep, ADMINISTRATION and that the greatest secretion of cytokines (which occur shortly before waking) should thus be treated most effec- CROSS-REFERENCE TO RELATED tively. This is based on the same data as in Arvidson et al., APPLICATIONS supra, i.e. using doses of 5 or 7.5 mg prednisolone given at 2 am. This application is a continuation of International Appli- cation PCT/GB01/04181, with an international filing date of 10 BRIEF SUMMARY OF THE INVENTION Sep. 19, 2001, published in English under PCTArticlc 21(2), and is a continuation-in-part of U.S. application Scr. No. This invention is based on the discovery that, in a study 09/936,S86, filed Sep. 13, 2001 now U.S. Pat. No. 6,488, designed to test the reproducibility of the results reported by 960. Arvidson et al. (and in U.S. Pat. No. 5,792,496), a much lower dosage of the glucocorticoid was also effective. Given 15 FIELD OF THE INVENTION the state of the art and the known side-effects of This invention relates to a controlled-release formulation, corticosteroids, this increase in their therapeutic index is and in particular to a formulation of a corticosteroid, suitable surpnsmg for use in the treatment of rheumatoid arthritis. According to the present invention, a unit dosage com- 20 prises less than 2.5 mg of prednisolone or an equivalent BACKGROUND OF THE INVENTION amount of a conicosteroid. Equivalence is in terms of Glucocorticoids, and in particular prednisone and potency. It will be understood that drugs vary in potency, and prednisolone, are widely used for the treatment of rheuma- that doses can therefore vary, in order to obtain equivalent toid arthritis. The use of glucocorticoids may be eficacious effects. but has disadvantages, particularly in terms of side-effects 25 Thus, in accordance with the present invention, a such as bone loss. controlled-dose formulation of the drug is adapted to release It appears to be generally recognized that it would be the drug at a predetermined period of time after desirable to use low doses of, say, prednisolone, in the administration, or at a predetermined time. Advantages of treatment of rheumatoid arthritis. While it is clear that low the invention may include enhanced eliicacy, reduced side- dose oral prednisolone can be elficacious, there is some 30 elfects and/or reducedCmax' Further or in addition, chrono- controversy over what is actually meant by a low dose. therapeutic administration allows the use of a reduced level of active material. Kirwan, New England J. Med. 3331142-5 (1995), indi- cates that a daily dosage of 7.5 mg prednisolone is effective. DESCRIPTION OF THE INVENTION This is supported by Boers et al., The Lancet 3501309-318 (1997). Boers et al. also reports that a typical treatment of 35 The intention behind the invention is that the active rheumatoid arthritis following initial treatment with a non- ingredient should be released at a predetermined time, e.g. steroidal anti-iniiammatory dmg (NSAID) involves a high between midnight and 6 a.m., e.g. 2 a.m. and 4 a.m., or a initial dose and, when the Condition is under control, predetermined time after administration. Thus, the user can reduced doses, down to a "low maintenance" of 7.5 mg/day. take the formulation before going to sleep, but have the full 40 Gotzsche and Johansen, B. M. J. 3162811-818 (1998), value of an eilective dosage of the dnig during the night, or reviews a number of studies of low dose prednisolone in the during sleep, at a dosage that has minimal side~elfects. treatment of rheumatoid arthritis. Most of these studies Accordingly, a predominant amount of the active ingredient, report doses of at least 7.5 mg. There is one report, but from e.g. at least 90% by weight, is released at least 2 or 3 hours as long ago as 1967, of a 2.5 mg dose. after administration, and preferably no more than 6, 7 or 8 45 It is evident that, in clinical practice, rheumatologists hours after administration. taper the dose of glucoconicoid to as a low a level as they Formulations of the invention are intended for the treat- can, before symptoms return. There may he patients who are ment of disorders associated with the release of cytokines, stable on less than 5 mg prednisolone per day, but there is e.g. TNF ot, IL-1, IL-2, IL-6 and IL-8. In particular, the invention is suitable for the treatment of inflammatory little or no clinical data to support that such a low dose is 50 actually providing any beneiit. This is important, because in diseases, including polyarthropathies, and more especially many of these patients, prednisolone may he contributing rheumatoid arthritis, asthma, inflammatory bowel disease, only side-effects. There is no evidence that any dose of chronic obstnuctive pulmonary disease, psoriasis, psoriatic prednisolone, lower than those generally used, is effective arthritis, polymyalgia rheumatica and atopic dermatitis. The drug that is used in the formulation may be chosen accord- when given chronically for the treatment of rheumatoid 55 arthritis. ingly. If desired, the active ingredient may be formulated as Arvidson et al., Annals of the Rheumatic Diseases a pro-drug, so that the active component is released in vivo. 56:27-31 (1997), reports that the timing of glucocorticoid Among active agents that can he used in the invention, administration in rheumatoid arthritis may be important, in examples are glucocorticoids and other conieosteroids, e.g. controlling thc acute inflammatory aspects of the disease. In 60 budesonide, methylprednisolone, deflazacorl, fluticasone, the reported study, patients were woken at 2.00 a.m. and prednisone and prednisolone. The appropriate dosage of given 7.5 mg or 5 mg prednisolone. each such drug depends on its potency, U.S. Pat. No. 5,792,496 claims a sustained-release for- Equivalent potency in clinical dosing is well known. mulation of a glucocorticoid such as prednisone or pred- Information relating to equivalent steroid dosing (in a non- nisolone. The formulation comprises 2.5-7 mg of the glu- 65 chronotherapeutic manner) may be found in the British cocorticoid and releases at least 90% of the drug during Nadonal Formulary (BNF), 37 March 1999, the content of 40-80 minutes, starting about 1-3 hours after the entry of which is incorporated herein by reference. Us 6,677,326 B2 3 4 The BNF guidelines are included in the table below. In An example of a controlled dose of active ingredient is addition, the proposed clinical dose equivalent to 1 Ing of dosing With a tablet containing 1,25 mg prednisolone. In this prednisolone when administered in a chronotherapeutic example, a patient taldng a controlled dose of 1.25 mg manner is included in the table. More specifically, the prednisolone takes the tablet a number of hours before it is following Table is of doses of steroids equivalent to mg of 5 due to be released. Time zero on the plot (FIG. 1) denotes the prednisolone and equivalence to 1 mg of prednisolone When earliest time at which active ingredient is released, probably administered in a chronotherapeutic manner according to midnight. The plasma levels achieved by release of the this invention and 1 mg of prednisolone. active agent at dilferent times (2, 4 and 6 a.m.) are shown, It can be seen that the range for Cmax obtained from the 10 1.25 mg prednisolone dose is from approximately 20 to 50 ng/ml (total prednisolone which includes protein bound and Euuivalent dose in chronotheraneutic administration unbound active) depending on how quickly a patient absorbs Equal to 5 mg the active ingredient. The time to Cm or Tm" is usually prednisolone Equal lo between 1 and 3 hours. Where absorption is particularly fast, Steroid Normal dosing)* 1 mg prednisolone 15 the Cmax may be 100 ng/ml total prednisolone or higher (this is not shown on the plot). bctamelhasonc 750 #S 150 /lg corlisone acetate 25 mg 5 mg The following Study provides the basis of the present dcfiazacoxt 6 me 1.2 me invention. dexamethasone 750 N8 150 #8 Study Design hydrocorlisone 20 mg 4 me methyl prednisone 4 me 0.8 mg 20 The study was an assessor blind comparison of the effects predmsone Sms 1 me of two doses of prednisolone (1 mg and 5 mg) given at triamcinolone 4m;z 0.8 me 02.00. Patients stayed the night in hospital but were free to be up and about and to leave the hospital during the day. At It is also known (BNF 37 March 1999) from clinical z a.m. on me appropriate days patients were woken gently, dosing equivalence that doses of triamcinolone, fluticasone 25 administered the prednisolone, and settled back to sleep. and budesonide are broadly similar in nasal administration Blood samples and clinical assessments were made at 08.30 (110 pg, 100 ,ug and 200 pg). Achronotherapeutic advantage and further clinical assessments related to symptoms on the may be expected upon dosing these drugs. day of drug administration at 12.00 and 08.30 the following Corticosteroids such as cortisone acetate and hydrocorti- day (except the final day when this last assessment was made sone are less preferred for use in the invention, owing to 30 before departure from the hospital). Patients were admitted their systemic side-effects on long-term use. Such on Monday and had a "control" night that evening with no compounds, having effect on glucose and mineral prednisolone but full assessment the following day. On each metabolism, will be known to those skilled in the art. of the following three nights prednisolone was administered. The preferred route of administration of a formulation of Patients went home on Friday afternoon but returned the this invention is oral. However, it will be readily apparent to 35 following Monday to repeat the procedure. Allocation to 1 those skilled in the art that other routes of administration mg or 5 mg prednisolone in the Hrst or second week was by may be used, e.g. having regard to the nature of the condition randomization in sealed envelopes. The patient and assessor being treated and the most effective means of achieving were not aware of which dose was given. delayed release. Outcome The drug may be administered in any conventional for- 40 Clinical: Outcome was measured at 08.30 each day for: mulation that provides delayed release, via any suitable swollen joint count (n=28); tender joint count (n=28); pain route of administration. Conventional dosing parameters (0.l()0 mm, VAS). Outcome was measured at 12.00 each day may be adopted, i.c. those which are known to or adapted to for: morning stiiness (minutes); patient opinion of condition the practice of those sldlled in the art. The daily dosage (0_100 mm, VAS); clinician opinion of condition (0-100 (relative to prednisolone) is usually at least 0.25 or 0,5 mg, 45 mm, VAS). Outcome was measured the following day for: e.g. 1 to 2 mg, but will be chosen according to the age, whether the arthritis was worse in the morning or afternoon weight and health of the subject, and other factors that are on the previous day (-1 morning, 0 equal, +1 afternoon). routinely considered by the man sldlled in the art. Serological: Semm samples were obtained at 08.30, kept A formulation of the invention may be a unit dosage such on ice for up to 1 hour, separated and stored at -70° C. to as a tablet, capsule, ampoule, vial or suspension. A 50 measure: C-reactive protein (CRP); IL-6 concentration; IL-6 controlled-release formulation may be in matrix, coating, soluble receptor (IL-6sR) concentration; hyaluronate (HA) reservoir, osmotic, ion-exchange or density exchange form. concentration. It may comprise a soluble polymer coating which is dis- Procedure solved or eroded, after administration. Alternatively, there Patients acted as their own control and took each dose of may be an insoluble coating, eg. of a polymer, through 55 prednisolone for three consecutive nights. They were ran- which the active ingredient permeates, as from a reservoir, domly allocated by cards kept in sealed envelopes to either dilfuses, e.g. through a porous matrix, or undergoes osmotic 1 mg prednisolone on three consecutive nights followed by exchange. A further option for a controlled-release formu- 5 mg on three consecutive nights, or the opposite sequence. lation involves density exchange, e.g. in the case where the The assessor was not aware of the treatment order allocation formulation alters on administration, e.g. from micropar- 60 (and probably remained blind), but no placebo tablets were ticles to a gel, so that the active ingredient diflitses or used and it was pomible for a patient to be un-blind. permeates out. Ion-based resins may also be used, the active Patients invited to take part in the study had the following component being released by ionic exchange, and Wherein characteristics: the rate of release can be controlled by using cationic or Over 18 years old anionic forms of the dnig. Another type of controlled-release 65 Had rheumatoid arthritis by the criteria of the American formulation involves pulsed dosing. Further examples are College of Rheumatology; see Arnett et al., Arthritis given in U.S. Pat. No. 5,792,496. Rheum. 312315_324 (1988) US 6,677,326 B2 5 6 Had active disease as evidenced by 3 or more swollen and The results for 5 mg prednisolone place the patients in this tender joints pilot study Well Within the range of findings published by Were not taking glucocorticoid medication Arvidson et al. and reinforce the conclusions which can be Had not had intra-articular glucocorticoid injections in the drawn from that paper. previous 3 weeks 5 Had no medical conditions which, in the opinion of the The results from 1 mg prednisolone raise the possibility investigator, would contraindicate low dose predniso- that even at this dose there may be an appreciable elfect on lone therapy symptoms. Pain, EMS, patient's opinion and clinician's Informed consent was obtained and the patient prescrip- opinion were statistically signilicantly reduced, even with tion written by a doctor not associated with trial evaluation. 10 only three patients in the study. CRP and IL-6 were reduced Medication was dispensed at 2 a.m. on each treatment day after gently waking the patient. The patient was encouraged significantly on 5 mg prednisolone and there was a tendency to settle back to sleep immediately. for reduction on l mg prednisolone. On the morning before medication and on each morning on the day of medication, blood samples were taken at 8.30 is All patents, patent applications, provisional applications, a.m. and outcome assessments recorded then, and at noon, as and publications referred to or cited herein are incorporated indicated above. bv reference in their entirety to the extent thev are not Evaluation iriconsistcnt with the explicit ieachings of this spci:ification
TABLE 1
Mean and 95% confidence intervals for each variable
More Swollen Painful or L Cln Day Dose Joints Joints Pain Less EMS Opn Opn CRP HA IL-6 IL-6sR
Mean Results
0 20.3 21.0 37.7 1.0 70.0 31.3 34.3 40.5 345.1 44.1 315578 1 18.7 20.0 26.0 -0.7 55.0 23.7 28.7 35.5 241.9 28.1 31959.9 2 18.7 20.3 20.3 -0.7 51.7 26.7 29.3 31.2 320.3 31.1 31468.0 3 18.3 20.3 16.7 0.0 40.0 12.7 16.3 25.8 372.5 22.8 30898.9 10 12.3 15.3 25.0 -0.3 40.0 24.3 23.3 15.0 396.3 19.3 22937.2 11 18.0 19.0 19.7 -0.3 30.0 19.3 27.7 36.6 322.5 30.3 423282 12 17.3 19.7 15.7 -0.3 20.0 11.7 15.7 31.1 339.5 18.5 353316 13 14.0 19.7 16.0 -0.7 33.3 13.3 11,7 19.1 193.9 13.8 36172.7 14 12.0 9.0 0.0 0.0 0.0 0.0 8 0 19.5 363.5 1 07.1 321805 95% CI Resuhs
0 0.7 5.7 24.9 0.0 19.6 20.3 14.1 17.1 213.0 18.1 8838.9 1 1.3 7.4 25.2 0.7 9.8 15.4 10.3 23.0 15233 18.1 10225.5 2 3.5 7.7 20.3 0.7 8.6 5.7 10.5 27.5 321.8 32.7 10220.9 3 3.6 9.1 16.9 1.1 9.8 12.9 4.6 25.3 967 28.4 11329.4 10 15.2 19.2 31.8 0.8 48.0 30.2 29.6 22.8 718.7 23.3 27617.3 11 3.9 9.1 21.1 1.3 29.4 20.1 13.6 29.1 148.6 24.1 234853 12 6.5 9.6 15.4 0.7 19.6 11.6 1.7 26.0 221.4 23.6 8919.1 13 6.9 10.3 7.8 0.7 6.5 6.2 4.6 18.2 113.3 13.3 7069,5 14
Symptoms, signs and laboratory results were compared What is claimed is Within and between patients, but the main assessment was 1. Aunit dose formulation comprising less than 2.5 mg of visual inspection of the overall pattern of response. Means prednisolone or an equivalent, equipotent amount of another and standard deviations were used to define variation rates 50 corticosteroid. and for calculating trial size for future studies. An overall 2. The formulation according to claim 1, which comprises assessment of practicality and the potential for more fre- at least 0.25 mg of prednisolone or said equivalent. quent (but smaller volume) blood taking was made by 3. The formulation according to claim 2, which comprises discussion amongst the stall and patients involved. T\.,...1»._ 0.5 to 2 mg of prednisolone or said equivalent. I\ChLl1lb 55 4. The formulation according to claim 3, which comprises Three patients were able to take part in the study in the l to 1.25 mg of prednisolone or said equivalent. time available. One patient (3) was inadvertently given the 5. The formulation according to claim 1, adapted to first dose of treatment in the second week on the first night in hospital. Patient 3 took prednisolone for the next two release at least 90% by weight of prednisolone or said nights and remained in hospital for a fourth night without equivalent 2 to 8 hours after administration. prednisolone treatment. This patient's assessments have 60 6. The formulation according to claim 1, Wherein said been included normally in the first week, but in the second corticosteroid is a glucocorticoid. Week they have been used differently. Here, this patient's 7. The formulation according to claim 1, wherein said results have been included With those of the other patients in corticosteroid is selected from the group consisting of accordance with the dose of prednisolone received. This prednisone, budesonide, methylprednisolone, Iluticasone, patient's final assessment (no prednisolone the night before) 65 betamethasone, and dellazacort. therefore appears as an extra day after the other patients in 8. The formulation according to claim 7, wherein said the study. corticosteroid is prednisone. Us 6,677,326 B2 7 8 9. A method for the treatment of a patient sulfering from 13. The method according to claim 9, Wherein the for- a condition selected from the group consisting of asthma, mulation is adapted to release at least 90% by weight of the inflammatory bowel disease, psoriasis, psoriatic arthritis, prednisolone or said equivalent 2 to 8 hours after adminis- polymyalgia rheumatica, chronic obstructive pulmonary _|' .,., .__.1 _.|_ ..__ / ; : 1 -_¢L_.Z4J- -..J - 4 L .. tration > 14. The method according to claim 9, wherein said polyarthropathies, which comprises administering to the corticosteroid is a glucocorticoid. patient a unit dosage formulation comprising less than 2.5 15. The method according to claim 9, wherein said mg of prednisolone or an equivalent, equipotcnt amount of another corticosteroid. corticosteroid is selected from the group consisting of 10. The method according to claim 9, Wherein the for- 10 prednisone, budesonide, methylprednisolone, ilutacasone, mulation comprises at least 0.25 mg of prednisolone or said betamethasone, and deflazacort. equivalent. 16. The method according to claim 15, Wherein said 11. The method according to claim 10, Wherein the corticosteroid is prednisone. formulation comprises 0.5 to 2 mg of the prednisolone or 17. The method according to claim 8, wherein said said equivalent. :15 corticosteroid is administered between midnight and 6 a.m. 12. 'l`he method according to claim 11, wherein the formulation comprises 1 to 1.25 mg of the prednisolone or said equivalent. >| < >| = > l < = i < ' | = EXHIBIT C nlm|||||m1|I|IImIIIIIIIIIImuIII|ImluII|I|1|u|||1|u|Ilulnlm US008309124B2
(12> United States Patent (10) Patent No.: US 8,309,124 B2 Vergnault et al (45) Date of Patent: Nov. 13, 2012
(54) DELAYED RELEASE TABLET WITH EP 0 939 623 A1 9/1999 DEFINED CORE GEOMETRY EP 1067910 A1 1/2001 EP 1275 381 A1 1/2003 JP 200 1 -0 10950 A 1/2001 (75) Inventors: Guy Vergnault, Kcmbs (FR); Pascal WO WO-92/00064 A1 1/ 1 992 Grenier, Kappelen (FR); Christophe WO WO-92/ 1 1845 A1 7/ 1 992 Dragan, Geispitzen (FR) WO WO-93/ 19741 A1 10/ 1 993 WO WO-96/40078 A1 12/ 1996 WO WO-0 1/08421 A2 2/2001 (73) Assignee: Jagotec AG,Mut'renz (CH) WO WO-0 1/528 19 A1 7/2001 WO WO-0 1/68056 A1 9/2001 *' ) Notice: Subject to any disclaimer, the term of this WO WO-0 1/80 824 A2 11/200 1 patent is extended or adjusted under 35 WO WO-02/00204 A1 1/2002 U.S.C. 154(b) by 0 days. WO Wo.0200204 A1 1/2002 WO W0_02/072033 9/2002 WO WO~02/072034 A2 9/2002 <21> App1.No.: 13/424,069 WO W0.02072034 A2 9/2002 WO WO-03/026626 4/2003 <22> Filed Mar. 19, 2012 WO WO-03/075919 A1 9/2003 WO WO-2004/0285 10 4/2004 Prior Publication Data WO WO-2004/093 843 A1 11/2004 (65) WO WO-2004/093 850 A1 11/2004 US 201 2/0177734 A1 Jul. 12, 2012 WO WO-2004/ 103349 A2 12/2004 WO WO-200 5/027843 A2 3/2005 Related U.S. Application Data OTHER PUBLICATIONS (63) Continuation of application No. 10/554,538, Hled as Conte et al. "Press-coated Tablets for Time-programmed Release of application No. PCT/1132004/001 693 on Apr. 23, Drugs," Biomaterials. 14.l3(1993): 1017-1023. 2004, now Pat. No. 8,168,21 8 Fukui et al. "Studies on Applicability of Press-Coated Tablets Using Hydroxypropylcellulose (HPC) in the Outer Shell for Time-Release 0) Foreign Application Priority Data Preparation." J. Controlled Release. 68.2(2000):215-223. GB Search Report dated Aug. 22, 2003 corresponding to GB Apr. 24, 2003 (GB) 0309342.4 0309342.4. GB Search Report dated Oct. 23, 2003 corresponding to GB (51) Int. Cl 0309342.4. A61K 9/20 (2006.01) International Search Report mailed Oct. 21, 2004 corresponding to PCT/152004/001693. (52) U.s.C1. 424/464 Lin et al. "Compression Forces and Amount ofOuter Coating Layer (58) Field of Classification Search None Affecting the Time~Conf1ol1ed Disintegration of the Compression- See application file for complete Search histoly. Coated Tablets Prepared by Direct Compression With Micronized Ethylcellulose." .Z Pharmaceutical Sciences. 90.121 2005-2009. (56) References Cited Zlaikina, A.P., "The Modern Therapeutic Tactics of Inilaxmnalory Bowel Disease, Consilium Medicum." Gastroenterology. 6.1: 2004. U.S. PATENT DOCUMENTS >z< cited by examiner 5,279,832 A 1/1994 Greissinger et al 5,464,633 A 11/1995 Conte et al. Primary Examiner - Paul Dicldnson 5,567,696 A 10/1996 McGuire et al. 5,792,476 A »|< 8 / 1 9 9 8 Hallgren 424/465 (74) Attorney, Agent,or Hrm - Muriel Liberto, Esq.; Mintz 6,183,780 B 1 2/2001 Van Ba1ken et al Levin Cohn Ferris Glovsky and Popeo PC 6,365,185 B1 4/2002 Ritschel et al. 6,488,960 B 1 12/2002 Bardsley (57) ABSTRACT 6,599,284 B2 7/2003 Faour 6,620,439 B1 9/2003 Mehta A tablet comprising a core containing an active agent, and a 2004/0018327 A1 1/2004 Wvnn et al. coating, the core being disposed within the coating such that 2005/0008702 Al 1/2005 Fzfour et al the coating has a thickness about a longitudinal axis (X-Y) of 2006/0057200 A1 3/2006 Schaeflier about 4.85 to 4.95 nun. The position of the core within the FOREIGN PATENT DOCUMENTS coating dictating that the active agent is released rapidly after EP 0 463 877 A1 1/1992 a lag time during which time no active agent is released. EP 0 673 645 A2 9/1995 EP 0 776 660 A2 6/1997 14 Claims, 2 Drawing Sheets U.S. Patent Nov. 13, 2012 Sheet 1 of 2 US 8,309,124 B2
B I I
X Y
I I A FIG. 1 U.S. Patent Nov. 13, 2012 Sheet 2 of 2 US 8,309,124 B2
% Release - Prednisone
100.0 /
80.0 f E a> 60.0 m cv GJ '63 nc
40.0 . g
20.0 .. 1
0.0 iz '-fa d ~fz ¢ =fa Q ~rz <=z \Q Q \fa =z =Q <=: ~fa Q =Q <2 \fe <2 \-~ c\l N ¢~f> ¢n <' <1' \n u'a ¢o ¢o r~ |~ oo oo c> m 2 Test medium: Purified water lime [n] Temnerature: 37°C + 0.5°C Rotaion speed: 100 rpm FIG. 2 Us 8,309,124 B2 1 2 DELAYED RELEASE TABLET WITH peak plasma drug concentrations at a pre-detemiined time, DEFINED CORE GEOMETRY irrespective of whether a patient is in a fed or fasted state. Time controlled release formulations are known in the art RELATED APPLICATIONS that are able to deliver drug substances with a defined release 5 :ale aller a lag time during which no drug substance is This application is a continuation ofU.S. Ser. No. 10/554, released. Such a dosage form is disclosed in WO 02/072033. 538, filed on Jan. 16, 2007, which is a 35 U.S.C. 371 of This dosage form is characterized by a coating containing a PCT/IB2004/001693, filed on Apr. 23, 2004, which claims natural or synthetic gum that gels in the presence of aqueous priority to GB Application No. 0309342.4, hled on Apr. 24, media, The coating acts as a bather to the ingress of aqueous 2003, all of which are incorporated herein by reference in 10 media into an active-agent-containing core and thereby cre- their entireties. ating a lag time during which no drug substance is released. This invention is concerned with a tablet comprising a core The gellable coating acts as a medium through which drug is containing a drug substance and a coating that is applied to released in a delayed or modified manner. It is stated that the said core by means of compression-coating techniques. The lag time can be modulated by varying the coating weight. 15 tablet can contain all manner of drug substances, but is par- 'I`here are several problems with such an approach: First, ticularly suitable for administering those that are advanta- release of the drug occurs by means of diffusion through the geously released only after a predetermined lag time after gelled coating. In the case ofdrugs that have a narrow absorp- administration. The tablets are particularly suitable for tion Window, or in the case of drugs adapted to treat a rela- administering lucocorticosteroids selected from prednisone, 20 tively small affected area ofthe GI tract or colon, once the lag prednisolone or methylprednisolone. time has expired it is desirable to release the drug as rapidly as Research into the chronopharmacological field has dem- possible to ensure that all or substantially all of the drug onstrated the importance of biological rhythms in drug released at the desired site. A slow diffusion ofthe drug is not therapy. Very often, optimal clinical outcomes cannot be appropriate in such cases. Further, by attempting to control achieved if a drug is released constantly after ingestion. This 25 lag time by controlling the coating weight, the formulator's is particularly die case if symptoms of a disease display latitude is limited in this regard, because increasing coating circadian variations. ln such cases, drug release should vary weight adds additional cost to the dosage form, and it also in a manner that is sympathetic to these variations in order adds to the size of the dosage form, which may make it that dnlg plasma concentrations are at an optimal therapeutic difficult to swallow for cenain patient populations such as level only when required to treat symptoms ofa disease state. 30 minors and for the elderly or infinn. Still further, merely ln particular, if symptoms of a disease become apparent at adjusting coat weight does not ensure that a coating is of a night, or in the early hours upon Waking, the time when a desired thickness at a particular site. It remains that ifthe core patient must take its medication in order to affect the best is not correctly positioned within a die of a press coating clinical outcome requires detailed consideration. For machine, despite having selected a particular coat weight, example, most asthma attacks occur in the early hours of the 35 part of the coating may be unintentionally thinner than morning, e.g. 4 am to 6 am. This is a result of complex desired, resulting in unforeseen premature release ofthe drug. circadian rhythms such as the secretion ofhydrocortisone and The applicant has now surprisingly found that by carefully adrenaline. Ischaemic heart diseases occur most often during selecting the geometry of a core within its coating, it is pos- the night or in the early waking hours around breakfast time. sible to manipulate the coating thickness at specific points on Stiffness and pain associated with rheumatoid arthritis and 40 the tablet to ensure an appropriate coating thickness to pro- osteoarthritis occur in the early waking hours, which is duce tablets having a specifically tuned lag time. Funher- believed to be as a result of the secretion of IL-6 in the early more, because one is able to increase thickness where it is hours of the moming, e.g. around 2 am to 4 am. needed in the coating, one can reduce coating material to With conventional immediate release dosage lonns, syn- allow use of the minimum amount necessary to achieve the chronization of drug administration with a nocturnal circa- 45 desired release characteristics, thus saving on cost of materi- dian rhythm responsible for the symptoms experienced by a als and also reducing the overall tablet size. patient would require a patient having to be disturbed from Still further, the applicant has found that by selecting sleep to take a medicament during the early hours of the appropriate core and coating materials, one is able not only to morning in order to achieve the most efficacious clinical accurately control the lag time, one is also to ensure that all, outcome. Of course, this would be highly inconvenient for a 50 or substantially all, of the drug substance upon expiry of the patient. lag time is released rapidly and at the absorption site, or the Accordingly, there remains a need to provide dosage forms locally affected site. that can be taken at a convenient hour before bedtime that will Accordingly, in a first aspect of the present invention there release an effective dose of a dmg substance only after a is provided a tablet comprising a core containing an drug pre-determined lag time in order to synchronise peak plasma 55 substance, and a coating aroturd said core, the core being concentrations of dmg widr a particular circadian rhythm. disposed within said coating such that the coating thickness Funhermore, particularly in relation to dwg substances about an axis (X-Y) (see FIG. 1) is thicker than the coating that have a narrow absorption Window, or in the case of drug about an axis (A-B) (see FIG. 1) orthogonal to (X-Y), and substances that are adapted to treat a local condition in the wherein the thickness of the coating about the axis (X-Y) is colon such as Crohn's disease, ulcerative colitis, IBS and IBD 60 selected such that the coating is adapted to mpture upon there is also a need to provide a dosage fonn that rapidly immersion in an aqueous medium after a period of between releases the drug substances after reaching the end of the lag about 2 to 6 hours. time According to the present invention, the coating thickness Still further, having regard to the varied life styles of aboutthc axis (X-Y)is thicker than the coating about die axis patients, 111 order to reduce die inter- and intra-subject vari- 65 (A-B). The ratio ofthe thickness ofdie coating about the axis anee in bioavailability there is a need to provide a dosage form (X-Y) to the thickness ofthe coating about the axis (A-B) may that releases a drug with a reliable lag time, and to provide be from 2.2 to 2.611 .0 to 1.6. US 8,309,124 B2 3 4 In another aspect ofthe invention there is provided a tablet made to the thickness of the coating about an axis X-XC comprising a core containing an drug substance and a coating reference is being made the thickness about any or all ofthese around said core, the core being disposed within said coating axes. such that me coating diickness about an axis (X-Y).is thicker During the compression ofthe coating around the core, the than the coating about an axis (A-B) orthogonal to (X-Y), and 5 coating material above and below the core (the material along the thickness of the coating about the axis (X-Y) is at least and about the (A-B) axis) is relatively highly compacted and about 2.2 mm, particularly about 2.2 to 2.6 mm, more par- dense. On the other hand, the coating material disposed along ticularly about 2.35 to 2.45 nun. and about the (X-Y) axis is subjected to lower compaction forces and is relatively less dense. Accordingly, the material The thickness of the coating around or about the axis (A-B) 10 about the (X-Y) axis is relatively porous and permissive is not critical for controlling the lag time. Accordingly, the towards the ingress of aqueous media. The rate of ingress of formulator has some latitude in selecting its thickness. It the aqueous medium through the coating along the direction should not be so thick as to render the Hnal tablet to large, yet of the X-Y axis is, in part, responsible for controlling the on the other hand the coating should not be so thin that the release of the dmg substance from the core. Once the aqueous coating is render weak and liable to crack under the slightest 15 medium contacts the core, the core reacts by swelling or mechanical stress. Preferably, the thickness of the coating effervescing thereby to break open the core generally along about the axis (A-B) is about l .0 to about 1.6 mm. The coating the direction of ingress of the aqueous media (i.e. the X-Y thickness either side ofthe core on the axis (A-B) may or may axis) to fem to essentially two hemispheres of coating mate- not be equal. For example, on a Hrst side of the core (A-core) rial that may remain conjoined, which has an appearance of the coating may have a thickness ofabout l .2 to l .6 min, more 20 an opened clam shell. The reaction of the core material to the preferably 1.35 to 1.45 mm, whereas on the other side of the presence of the aqueous medium is likewise in part respon- core (B-core) the thickness may be about 1.0 to 1.4 mm, more sible for controlling the release of dmg substance from the preferably 1.15 to 1.25 mm. core. Accordingly, in a particular embodiment of the present The hardness ofthe tablet is preferably at least 60 Newtons, invention there is provided a tablet comprising a core con- 25 e.g. 60 to 80 Newtons, and more particularly 60 to 75 New- taining an drug substance, and a coating, the core being dis- tons. Hardness may be measured according to a process posed within the coating such that the coating has a thickness described in The European Pharrnacopoeia 4, 2.9.8 at page about an axis (X-Y) of at least about 2.2 mm, more particu- 201. The test employs apparatus consisting of 2 opposing larly about 2.2 to about 2.6 mm, still more particularly 2.35 to jaws, one ofwhich moves towards the other. The fiat surfaces 2.45 mm, and the thickness ofthe coating about an axis (A-B) 30 of the jaws are perpendicular to the direction of movement. The cnushing surfaces of the jaws are flat and larger than the orthogonal to (X-Y) is between 1.0 and 1.6 mm. More par- zone of contact with the tablet. The apparatus is calibrated ticularly, along the axis (A-B) on a Hrst side of the core using a system with a precision of one Newton. The tablet is (A-core) the thickness may be about 1.2 to 1.6 mm, more placed between the jaws. For each measurement, the tablet is preferably 1.35 to 1.45 mm, and on a second side of the core 35 oriented in the same way with respect to the direction of the (B-core) the thickness may be about 1.0 to 1.4 rmn, more applied force. Measurements are carried out on 10 tablets. preferably 1.15 to 1.25 mm. Results are expressed in terms of the mean, minimum and Tablets ofthe present invention are formed by compression maximum values (in Newtons) of the force needed to crush coating methods as will be described in more detail herein the tablets. below. Compression coated tablets are generally formed by 40 Tablets having a hardness within this range are mechani- placing a portion of a powdered coating material in a die and cally robust to withstand forces generated in the stomach, tamping the powder into a compact form using a punch. A panicularly in the presence offbod. Furthermore, the tablets core is then deposited onto the compacted coating material are sufliciently porous about the (X-Y) plane of the tablet to before the remainder of the coating material is introduced into permit ingress ofphysiological media to the core at an appro- the die and compression forces are applied to form the coated 45 priate rate to ensure that the dnug substance is released within tablet. To ensure that the core is placed on the tamped coating an appropriate lag time, e.g. within 2 to 6 hours. material to ensure its correct geometry relative to the coating As stated above, it is a preferred aspect of the present in the tinal tablet form, it is preferable to employ means for invention that the tablets are adapted to release a drug sub- positioning the core in relation to the coating material in a die. stance from the core after a pre-determined lag time, as well Typically such means may be provided by a pin punch. A pin 50 as being adapted to release all, or substantially all, ofthe drug punch is a pturch that has a convex surface that contacts the sub stance within a very short period oftime after the expiry of coating material to leave a small depression or hollow in the the lag time. This ensures that all, or substantially all, of the tamped coating material. Thus, when the core is placed into drug is released at the intended absorption site along the GI the die on the tamped material, it sits in the depression or tract, or onto the affected site ofthe G1 tract ifthe condition to hollow and its correct geometry is assured in the final tablet 55 be treated is a local topical condition. It is preferred that the form. tablets ofthe presentA invention release all. or substantiallv., all The thickness ofthe coating along and about the axis of the ofa drug substance within about % hour to about 1 hour after direction of movement of the ptuich (the "(A-B)" axis the selected lag time. referred to above) is determined by the amount of coating This aspect of the present invention is important for deliv- material added to the die and the compaction force applied to 60 ering drugs having a rather narrow absorption Window in the form the tablet. On the other hand, the thickness ofthe coating upper Gl tract, such as the glucocorticosteroids referred to along and about the "(X-Y)" axis is determined by the size of above. ln such cases, the drug should be released before the the core, its po sition within die die and the diameter ofthe die. tablet can pass into the bowel, where absorption of such drugs It will be apparent to the sldlled person diat there is a plurality is poor. It is made particularly important if the tablet is of axes (X-Y) orthogonal to dle axis of movement of the 65 intended to perform in the same manner independent of the punch (the "A-B" axis), which extend radially from the centre ellects ofibod. It is well known that the rate at which a tablet of the tablet to its circumlerence, and when the relerence is will pass through the GI tract will vary depending on whether US 8,309,124 B2 5 6 a patient is in a fed or fasted state. In the fasted state, a tablet ester wax and the like; or non-fatty hydrophobic substances will typically clear the stomach within about % hour and l such as calcium phosphate salts, e.g. dibasic calcium phos- hour alter ingestion, and tliereafter lake a lurther 4 to 5 hours phate. to clear the utmer GI tract dirough the ileosecal iunction. ln a Preferably the coating contains a calcium phosphate salt, fed state, a tablet may take as long as 4 hours to be cleared 5 glyceryl behenate, and polyvinyl pyrollidone, or mixtures from the stomach, and a further 4 to 5 hours to clear the upper thereof, and one or more adjuvants, diluents, lubricants or GI tract. Accordingly, if a tablet is to release of all, or sub- fillers. stantially all, of its dwg into the upper GI tract irrespective of Preferred components in the coating are as follows, with generally suitable percentage amounts expressed as percent- the fed state of a patient, it is preferable that the release the 10 age weight of the coating. drug aHer the lag time occurs within a time limit referred to in Polyvinyl pyrollidone (Povidone) is preferably present in the paragraph above. amounts of about 1 to 25% by Weight or the coating, more It should be understood that whereas it is desirable that no particularly 4 to 12%, e.g. 6 to 8%. drug substance is released during the lag time, some release Glyceryl behenate is an ester of glycerol and behenic acid may occur. However, any release ofdmg substance during the 15 (a C22 fatty acid). Glyceryl behenate may be present as its lag time should not exceed 10% of the total amount of drug mono-, di-, or tri-ester form, or a mixture thereof. Preferably substance in the core it has an HLB value of less than 5, more preferably approxi The coating employed in a tablet according to the present mately 2. It may be present in amounts of about 5 to 85% by invention is preferably formed of insoluble or poorly water weight of the coating, more panicularly from 10 to 70% by soluble hydrophobic material. ln use, the coating optimally 20 weight, and in certain preferred embodiments from 30 to acts merely as a barrier to the ingress of aqueous physiologi- 50%. cal media thereby providing a drug release lag time. For the Calcium phosphate salt may be the dibasic calcium phos- reasons set fbnh above, optimally the tablet should have the phate dihydrate and may be present in an amount of about 10 minimum thickness possible consistent Wim the desired lag to 90% by weight ofthe coating, preferably 20 to 80%, e.g. 40 time. Accordingly, employing water insoluble or poorly, 25 to 75%. soluble hydrophobic coating materials, one is able to produce The coating may contain other common tablet excipients a coating that is relative recalcitrant to the ingress ofmoisture such as lubricants, colourants, binders, diluents, glidants and and so long lag times can be achieved with relatively thin taste-masking agents or flavourants. coatings. Examples of excipients include colourants such a ferric 30 oxide, e.g. yellow ferric oxide; lubricants such as magnesium Funher, in order to achieve the rapid release of drug sub- stearate; and glidants such as silicon dioxide, e.g. colloidal stance after the lag time has expired, it is desirable that the silicon dioxide. Yellow ferric oxide may be used in amounts coating contains no, or sub stantially no, ingredients that swell of about 0.01 to 0.5% by weight based on the coating; mag- and gel agents to such an extent that the coating acts as a nesium stearate may be present in amounts of l to 20% by diffusion barrier to the release of drug substance. ln this 35 weight of the coating, more preferably 2 to 10%, e.g. 0.5 to regard, it is preferable that the coating contains no, or sub- l.0%; and colloidal silica may be used in amounts of 0.1 to stantially no, materials such as natural or synthetic gums that 20% by weight of the coating, preferably 1 to 10%, more modulate release of the drug substance through an intact preferably 0.25 to l.0%. swollen coating. Drug substance is released from the core as The core comprises in addition to a dmg substance, a a result of the physical rupturing of the coating and not as a 40 disintegrating agent or mixtures ofdisintcgrating agents used result ofthe dmg substance diffusing through a swollen coat- in immediate release fonnulations and well know to persons ing material. That the mechanism of drug release is substan- skilled in the an. The disintegrating agents useful in the tially dependent on the physical splitting of the coating, and exercise of the present invention may be materials that etter- not on a dillusion process through a swellable and gellable vesce and or swell in the presence of aqueous media thereby coating, means that a wide range of drug substances can be 45 to provide a force necessary to mechanically disrupt the coat- delivered from tablets according to the invention in a reliable ing material. and reproducible manner. Preferably a core contains, in addition to the drug sub- The tablet coating may contain one or more water insoluble stance, cross-linked polyvinyl pyrollidone and croscarmel- or poorly soluble hydrophobic excipients. Such excipients lose sodium. may be selected from any of the known hydrophobic cellulo- 50 The following is a list of preferred core materials. The sic derivatives and polymers including alkylcellulose, e.g. amounts are expressed in terms of percentage by weight ethylcellulose, hydroxypropyl cellulose, hydroxypropylm- based on the weight of the core. ethyl cellulose, carboxymethyl cellulose, and derivatives Cross-linked polyvinyl pyrollidone is described above and thereof; polymethacrylic polymers, polyvinyl acetate and is useful as a disintegrating agent, and may be employed in the cellulose acetate polymers; latty acids or their esters or salts; 55 core in the amounts disclosed in relation to the core. long chain fatty alcohols; polyoxyethylene alkyl ethers; poly- Croscamellose sodium is an internally cross-linked sodium oxyethylene stearates; sugar esters; lauroyl macrogol-32 carboxymethyl cellulose (also known as Ac-Di-Sol) useful as glyceryl, stearoyl macrogol-32 glyceryl, and the like. a disintegrating agent. Hydroxypropylmethyl cellulose materials are preferably Disintegrating agents may be used in amounts of 5 to 30% selected from those low MW and low viscosity materials such 60 by weight based on the core. However, higher amounts of as E-Type methocel, and 29-10 types as defined in the USP. certain disintegrants can swell to form matrices that may Other agents or excipients that provide hydrophobic qual- modulate the release of the dmg substance. Accordingly, ity to coatings may be selected from any waxy substance particularly when rapid release is required after the lag time it known for use as tablet excipients. Preferably they have a is preferred that the disintegrants is employed in amounts of HLB value of less than 5, and more preferably about 2. 65 up to 10% by weight, e.g. about 5 to 10% by weight. Suitable hydrophobic agents include waxy substances such as The core may additionally comprise common tablet excipi- carnauba wax, parallin, microcrystalline wax, beeswax, cetyl ents such as those describw above in relation to the coating Us 8,309,124 B2 7 8 material. Suitable excipients include lubricants, diluents and hydramine, donepezil, flecamide, lluoxetine, labetalol, Hllers, including but not limited to lactose (for example the Methadone, metoprolol, mianserin, nortripyline, mono-hydrate), ferric oxide, magnesium stearates and colloi- ondansetron, oxprenolol, oxycodone, paroxetine, perhehexy- dal silica. lene, pethidine, promethazine, risperdone, thioridazine, ticlo- Lactose monohydrate is a disaecharide consisting of one 5 pidine, timolol, trimipramine, venlafaxine, paracetamol, glucose and one galactose moiety. It may act as a filler or alprazolam, amiodarone, budesonide, buprenorphine, bus- diluent in the tablets of the present invention. It may be pirone, Calcium Channel Blockers, earbamazepine, present in a range of about l() to 90%, preferably from 20 to cisapride, clarithromycin, clonazepam, cocaine, cortisol, 80%, and certain preferred embodiments from 65 to 70%. cyclosporine, dexamethasone, erythromycin, fentanyl, keto- As stated above, it is an important aspect of the present 10 conazole, losartan, miconazole, midazolam, quinidine, ser- invention that core is correctly located within the coating to traline, statins, tacrolimus, tamoxifen, 'l`CAs, triamzolam, ensure that a tablet has the appropriate coating thickness. In zolpidem, or mixwes thereof. this way, lag times will be reliable and reproducible, and Additional examples of drug classes and drugs that can be intra-subj ect and inter-subject variance in bioavailability can employed in tablets of the present invention include: be avoided. It is advantageous to have a robust in process 15 antihistamines (e.g., azatadine maleate, brompheniramine control to ensure that tablets in a batch contain cores having maleate, carbinoxamine maleate, chlorpheniramine maleate, the appropriate geometry in relation to the coating. Controls dexchlorpheniramine maleate, diphenhydramine hydrochlo- can be laborious in that they require an operator to remove ride, doxylamine succinate, methdilazine hydrochloride, random samples from a batch and to cut them open to physi- promethazine, trimeprazine tartrate, tripelennamine citrate, cally inspect the quality of the core (i.e. whether it is intact, 20 tripelennamine hydrochloride and triprolidine hydrochlo- and whether it is correctly located). Furthermore, if a signifi- ride); cant number of tablets from the sample fail, a complete batch antibiotics (e.g., penicillin V potassium, cloxacillin sodium, oftablets may be wasted. Applicant has found that ifone adds dicloxacillin sodium, nafcillin sodium, oxacillin sodium, car- to the core a strong colourant such as iron oxide, such that the benicillin indanyl sodium, oxytetracycline hydrochloride, core visibly contrasts with the coating when as strong light is 25 tetracycline hydrochloride, clindamycin phosphate, clinda- shone on the tablet, it is possible for any faults in the position mycin hydrochloride, clindamycin palmitate HCL, lincomy- or integrity of the core to be picked up automatically by a ein HCL, novobiocin sodium, nifrofurantoin sodium, metron- camera appropriately located adj acent a tabletting machine to idazole hydrochloride); antituberculosis agents (e.g., inspect tablets as they are ej ected therefrom. ln this way, if a isoniazid); faulty tablet is identified it is possible to halt production and 30 cholinergic agents (e.g., ambenonium chloride, bethanecol correct any problems in the manufacturing process quickly, chloride, neostigmine bromide, pyridostigmine bromide); thereby potentially avoiding wastage ofbatch quantities of antimuscarinics (e.g., anisotropine methylbromide, clid- tablets. inium bromide, dicyclomine hydrochloride, glyoopyrrolate, Whereas colourants contained in the core are useful for this hexocyclium methylsulfate, homatropine methylbromide, purpose, equivalent solutions are also possible. For example, 35 hyoscyamine sulfate, methantheline bromide, hyoscine instead of a colourant, one can include a material that is hydrobromide, oxyphenonium bromide, propantheline bro- opaque to x-rays, such as barium sulphate. If an x-ray imager mide, tridihexethyl chloride); is then coupled to a tablet machine, the core will contrast with sympathomimetics (e.g., bitolterol mesylate, ephedrine, the coating material and the x-ray imager will pick up any ephedrine hydrochloride, ephedrine sulphate, orciprenaline faults in the positioning or integrity of the core in a similar 40 sulphate, phenylpropanolamine hydrochloride, pseudoephe- fashion. drine hydrochloride, ritodrine hydrochloride, salbutamol sul- The amount ofdrug substance employed in tablets of the phate, terbutaline sulphate); present invention will depend on the panicular drug sub- sympatholytic agents (e.g., phenoxybenzamine hydrochlo- stance used, the condition of the patient and the nature and ride); miscellaneous autonomic drugs (e.g., nicotine); severity of the condition to be treated. A typical drug loading 45 iron preparations (e.g., ferrous gluconate, ferrous sulphate); might be from l to 50% by weight of the core. haemostatics (e.g., aminocaproic acid); As stated above a Wide variety of drug substances may be cardiac drugs (e.g., acebutolol hydrochloride, disopyramide employed in the present invention. Drugs for treating condi- phosphate, llecamide acetate, procainamide hydrochloride, tions the symptoms of which result from nocturnal circadian propranolol hydrochloride, quinidine gluconate, timolol rhythms are particularly suitable. Accordingly, drugs for 50 maleate, tocainide hydrochloride, verapamil hydrochloride); treating incontinence, sleep disorders, apnoea, asthma, epi- antihypertensive agents (e.g., captopril, clonidine hydrochlo- lepsy, bronchitis, parkinsonism, rheumatoid arthritis, allergic ride, hydralazine hydrochloride, mecamylamine hydrochlo- rl1in.itis and ischaemic heart diseases, cluster and migraine ride, mctoprolol tartrate); vasodilators (e.g., papaverine headache, congestive head failure, and depression are par- hydrochloride); ticularly suitable for use in tablets according to the present 55 non-steroidal anti-inflammatory agents (e.g., choline salicy- invention. Further, drug substances that are metabolized by late, ibuprofen, ketoprofen, magnesium salicylate, meclofe- cytochrome P450 are also particularly suitable, they namate sodium, naproxen sodium, tolmetin sodium); includez opiate agonists (e.g., codeine hydrochloride, codeine phos- Amitriptyline, caffeine, clomipramine, clozapine, fluvoxam- phate, codeine sulphate, dextromoramide tartrate, hydroc- ine, haloperidol, imipramine, mexilitine, oestradiol, olan- 60 odone bitartrate, hydromorphone hydrochloride, pethidine zepine, paracetamol, propranolol, tacrine, theophylline, War- hydrochloride, methadone hydrochloride, morphine sul- farin, Bupropion, Cyclophosphamide, Celecoxib, phate, morphine acetate, morphine lactate, morphine mecon- Diclofenac, Flubiprofen, Ibuprofen, glimepirideindome, tha- ate, morphine nitrate, morphine monobasic phosphate, mor- cin, naproxen, phenyloin, piroxicam, tenoxicam, citalopram, phine tartrate, morphine valerate, morphine hydrobromide, diazepam, lansoprazole, omeprazole, pantoprozole, pro- 65 morphine hydrochloride, propoxyphene hydrochloride); panolol, topiramate, Aipranolol, chlorpromazine, clomi- anticonvulsants (e.g., phenobarbital sodium, phenyloin pramine, codeine, Desipramine, dextromethorphan, diphen- sodium, troxidone, ethosuximide, valproate sodium); US 8,309,124 B2 9 10 tranquilizers (e.g., acetophenazine maleate, chlorpromazine acetate, 21 -succinate sodium salt, 21 -stearoylglycolate, hydrochloride, liuphenazine hydrochloride, prochlorpera- 21-in-sulphobenzoate sodium salt, and its trimethylacetate. zine edisylate, promethazine hydrochloride, thioridazine Methylprednisolone, as used above refers to the compound hydrochloride, triiiuoroperazine hydrochloride, lidiium cit- or and its salts and derivatives thereofincluding its 21 acetate, rate, molindone hydrochloride, thiothixinc hydrochloride); 2 1 -phosphate disodium salt, 2 1 -succinate sodium salt, and its chemotherapeutic agents (e.g., doxorubicin, cisplatin, floxu- acetonatc ridine, methotrexate, combinations thereof); Typically a core may contain about 0.1 to 50% by weight, linirl lnwerino mmnteu (ao oemHl®rn7il nlnfihrme HNTG- more particularly l to 20%, still more particularly l to 10% by weight ofsteroid based on the total Weight of the core. In the CoA reductase inhibitors, such as for example, atorvastatin, 10 case ofprednisone, it may be employed in amounts to provide cerivastatin, Huvastatin, lovastatin, pravastatin, simvastatin); a total weight per unit dosage form of l or 5 mg, to offer H.sub.2-antagonists (e.g., cimetidine, famotidine, nizatidinc, convenience and flexibility ofdosing, although dosage forms ranitidine HCI); containing larger or smaller amounts of drug substance could anti-coagulant and anti-platelet agents (e.g., warfarin, cipy- be employed if desired. ridamole, ticlopidine); 15 Particularly preferred tablets according to the invention bronchodilators (e.g., albuterol, isoproterenol, metaproter- comprising in the core a glucocorticosteroid selected from the enol, terbutaline); group consisting of prednisone, prednisolone and methyl- stimulants (e.g., benzamphetamine hydrochloride, dextroarn- prednislone, and cross-linked polyvinyl pyrollidone, cross- phetamine sulphate, dextroamphetarnine phosphate, diethyl- linked sodium carboxymethyl cellulose, and one or more propion hydrochloride, fenfluramine hydrochloride, meth- 20 adjuvants diluents, lubricants or filler materials as herein- amphetamine hydrochloride, methylphenidate above described. Preferably the coating comprises a calcium hydrochloride, phendimetrazine tartrate, phenmetrazine phosphate salt, glyceryl behenate, cross-linked polyvinyl hydrochloride, caffeine citrate); pyrollidone and one or more adjuvants, diluents, lubricants or barbiturates (e.g., amylobarbital sodium, butabarmtai nuer materials as hereinabove described. sodium, secobarbital sodium); 25 The composition ofone particularly preferred embodiment sedatives (eg., hydroxyzine hydrochloride, methprylon); of the invention is: expectorants (e.g., potassium iodide); Core of 5 mg Prednisone Tablet: antiemetics (e.g., benzaquinamide hydrochloride, metoclo- Prednisone 8.33% propamide hydrochloride, trimethobenzamide hydrochlo- Lactose rnonohydrate 64.47% ride); 30 Povidone 6.67% gastro-intestinal drugs (e.g., ranitidine hydrochloride); heavy Croscannellose sodium 18.33% metal antagonists (e.g., penicillamine, penicillamine hydro- Red terric oxide 0.5% chlodde); Magnesium stearate Vegetable origin 1.0% antithyroid agents (e.g., methimazole); Colloidal silicon dioxide 0.5% genitourinary smooth muscle relaxants (e.g., flavoxate hydro- 35 Coating chloride, oxybutynin hydrochloride); Dibasic calcium phosphate dihydrate 50% Vitamins (e.g., thiamine hydrochloride, ascorbic acid); Glyceryl behenate 40% unclassified agents (e.g., amantadine hydrochloride, colchi- Povidone 8.40% cine, etidronate disodium, leucovorin calcium, methylene Yellow ferric oxide 0.1% blue, potassium chloride, pralidoxime chloride. 40 Magnesium stearate Vegetable origin 1.0% steroids, particularly glucocorticoids (e.g., prednisolone, Colloidal silicon dioxide 0.5% methylprednisolone, prednisone, eortisone, hydrocortisone, Another preferred embodiment is as follows: methylprednisolone, betamethasone, dexamethasone, triam- Core of 1 mg Prednisone Tablet: cinolone). Prednisone 1.67% Notwithstanding the general applicability of the tablets in 45 Lactose monohydrate 71 . 1 3% relation to a wide range ofdrug substances, the present inven- Povidone 6.67% tion is particularly suited to delivery of the glucocorticoster- Croscarmellose sodium 18.33% oids aforementioned, and particularly prednisone, predniso- Red fenic oxide 0.5% lone and methylprednisolone. These steroids are useful in the Magnesium stearate Vegetable origin 1.0% treatment La, of rheumatoid arthritis and joint pain. As 50 Colloidal silicon dioxide 0.5% already stated, the symptoms of these conditions appear Coating according to a circadian rhythm and with great predictability Dibasic calcium phosphate dihydrate 50% during the early hours of the morning. Accordingly, the glu- Glyceryl behenate 40% cocorticosteroids, and in particular prednisone are eminently Povidone 8.40% suited for delivery [rom tablets according to this invention not 55 Yellow ierric oxide 0.1% only because of their narrow absorption window, but also Magnesium stearate Vegetable origin 1.0% because a tablet may be administered in the evening before Colloidal silicon dioxide 0.5% bedtime anytime around 8 pm until midnight, e.g. around It is surprising tl1at the tablets containing the glucocorti- 10-12 at night, to deliver maximum plasma concentration of costeroids display such rapid release given that the rate of the drug substance before maximum secretion ofJL-6 (which 60 release relies to some extent on the wetting of the core, and occur around 2 am to 4 am), thereby effectively addressing these steroids are rather hydrophobic in nature. the underlying causes of the morning symptoms. ln this way, The tablets described above are press-coated tablets com- these symptoms are more effectively treated. prising a core and a coating covering said core. However, As used above, prednisone refers to the compound and its variants of mis basic construction are within the ambit ofthe salts or derivatives diereof, including prednisone 21 acetate. 65 present invention. Thus, the press-coating may be further As used above, prednisolone refers to the compound and its coated with an outer coating that may be functional and/or salts or derivatives including the 21 -acetate, its 21-tert-butyl aesthetic in its design. For example, functional coatings may US 8,309,124 B2 11 12 include the addition an immediate release coating containing from 10 pm to midnight, may be in a variety offed states, it is a dwg substances that may be the same or different to the drug even more advantageous that Tmax should be independent of substance contained in the core. food intake. In this manner, the tablet can affect a pulsatile release that Medicaments that can have a pre-detemiined lag time, and is of use in treating symptoms based on circadian rhythms, 5 which release drug substance after this lag time in a manner such as sleep disorders. In this regard one can employ seda- that provides a Tmax independent ofconsiderations of the fed tive hypnotics in such dosage forms, for example those drug or fasted state of a patient are of potentially great benefit, not substances mentioned described in U.S. Pat. No. 6,485,746. only in relation to the glucocorticosteroids and the treatment of arthritis, but for other active substances that are advanta- Pulsatile release dosage forms may also find general applica- 10 geously delivered in synchronicity with a circadian rhythm, bility with a wide range of active substances for the treatment or even in relation to drug substances whose emcacy depends ofa wide range of indications to provide patients with a more on their ability to be delivered accurately to a particular convenient dosage schedule. For example, pulsatile release absorption site, or a locally diseased site along the GI tract and can provide an alternative to multiple administrations of bowel. Such medicaments are provided by the present inven- immediate release fomis. 15 tion. Functional coatings also include enteric coatings covering Currently, there are no bioavailability or bioequivalence the press-coating. Enteric coated forms may be of use in regulatory guidelines available for Tmax However, the Guid- treating local conditions inthe bowel such as Crohn's disease, ance For lndustry "Food Effect Bioavailability and Fed ulcerative colitis, IBS and IBD. In this embodiment, the Bioequivalence Studies", US Department of Health (CDER) enteric coating would prevent release of any drug before the 20 December 2002 suggests that any difference inTmax should tablet enters the bowel not be clinicallv relevant. Whether such a difference will be Aesthetic coatings include taste masking coatings and clinically relevant will depend on the drug delivered and the coloured coatings as a generally well known in thean. particular indication. Applicant has found that in respect of It is well known in the art that food can change the bio- formulations ofthe present invention the effect of food on the availability of a drug, Food can alter the bioavailability of a 25 median value of TM, is a difference of only about +/-20%, drug by various means such as delaying gastric emptying, more particularly +/-10% changes in gastrointestinal pH, changes in luminal metabo- Still further, applicant has found medicaments containing lism, and physical and chemical reactions of food items with drug substances exhibiting no significant effect of food with a dosage form or drug substance. This change in bioavailabil- respect to bioavailability of the dmg substance in terms of ity as a consequence of food intake is often referred to as a 30 Cm and AUC. The "food effect" as it relates to the bioavailability ofdrug "food effect", Food effects are quite common in modified- substances is a well documented phenomenon in relation to release dosage forms, and also for drugs that have either poor dwg delivery that describes the variance in uptake of a drug solubility or poor permeability or both (BCS Class ll, Ill, and substance by patients depending upon whether the patients IV). 35 are in fed or fasted states. The presence or absence of a food The applicant has surprisingly found that a tablet that is effect may be quantified by making Area under the Curve adapted to release all, or substantially all, ofa dmg contained (AUC) andor Cmax measurements according to methods Well therein within a time (Tmg) ofbetwecn 2 and 6 hours (median known in the art. Typically AUC measurements and Cmax time) after administration. measurements are made by taking timed biological fluid Furthermore, the applicant has surprisingly developed a 40 samples and plotting the serum concentration of drug sub- tablet adapted to release a drug substance after a lag time that stance against time. The values obtained represent a number can deliver a drug to a patient, which upon absorption the ofvalues taken from subjects across a patient population and peak dmg concentration Cmax will be reached in a time Tmzut are therefore expressed as mean values expressed over the that is independent ol` a patient's food intake. entire patient population. By comparing the mean AUC and/ Tmax is a term Well known in the art that refers to the time 45 or Cmax values, one can determine whether a drug substance elapsed between drug administration and the maximum experiences a food effect. plasma concentration Cm is reached. Cmax is also an art Food effect studies may be conveniently carried out on an recognized term that relates to the peak plasma concentration adequate number of healthy volunteers, the number being of a drug. sufficient to generate sufficient data for appropriate statistical Tmax is an important parameter particularly in relation to 50 assessment to be made. Preferably the number of subjects medicaments that are intended to be taken at a time conve- should not be less than 12. nicnt for a patient, but which release drug substances after a To study the effect of food on the bioavailability of a drug lag time in ordcr to synchronise drug release with a circadian substance one may use any conventional study design known rhythm, and in particular a nocturnal circadian rhythm. By in the art, for example a randomised; balanced single-dose, way of example, the glucocorticosteroids, referred to above, 55 two-treatment, two-period, two-sequence crossover design. e.g. prednisone, are useful in the treatment of i.a. arthritic Analysis may be carried outusing any ofdre programs known conditions such as rheumatoid arthritis and osteoarthritis. in the art such as SAS PROC GLM, software from the SAS Debilitating symptoms are often experienced by a patient institute, Cary N.C. upon waking. Current therapy requires a patient to take Deco- ln quantitative terms, a drug substance may be said to rtin® upon waking. However, this is not the most efficacious 60 exhibit no food effect ifa 90% conhdence interval (Cl) for the way of treating the symptoms, as they are believed to be ratio of means (population geometric means based on log associated with the secretion oflL-6, which occurs during the transfonned data) of fed and fasted treatments fall within the early morning hours, eg. from about 2 to 4 am.A mcdicament interval of0.8 to 1.25 for AUC and/or 0.7 to 1.43 for Cmax' that can reach Cm that is coincident with or anticipates the Accordingly, the present invention provides in another of release of IL-6 is potentially of greater benefit to a patient. 65 its aspects a tablet as defined herein above displaying a ratio Furthemiore, given the varied lifestyles oi' individuals, AUC led/lasted alter single dosing of 0.8 to 1.25 or the ratio patients taking medicament between 8 pm and bedtime, e.g. Cmax lewtasted after single dosing of 0.7 to 1.43. Us 8,309,124 B2 13 14 A "fed" subject conveniently may be considered as a sub- of the coating material as a result of centrifugal force. Sub- ject that has fasted for at least 10 hours before receiving a sequent compression to form the tablet may be adjusted to standard FDA recognised high fat meal. The medicament give tablets ofrequisite hardness. Prelerably, this compres- may then be administered with water shortly after completion sion force is 400 kg, although this may be adjusted by +/-30% ofthe meal, e.g. within 5 minutes thereof. Preferably no food 5 in order to give tablets of the required hardness. should be taken for a period of eg. 4 hours after receiving The amount of coating material fed into the die can be medicarnent although small quantities of water may be per- precisely defined having regard to the density of the coating mitted alter, e.g. 2 hours after receiving the medicament. material to ensure after compression that the tablet is formed A "fastw" subject conveniently may receive rnedicament with the required coating thickness about the (A-B) axis; and with water after at least 10 hours fasting. Thereafter, no food 10 the dimensions of the die is selected to provide the diickness may be taken for a period of, e.g. 4 hours although small about die X-Y axis. Should it be necessary to change the quantities of water may be taken after, e.g. 2 hours after thickness of the coating, die of appropriate internal dimen- receiving medicament. sions may be placed in the rotating platform, and the amount A standard FDA high fat meal as referred to hereinabove ol" coating material ted into the die may be adjusted accord- may comprise any meal that would be expected to provide 15 ingly. maximal perturbation due to the presence of food in the Gl Suitable rotary tablet machines having high process speeds tract. Said high fat meal typically may comprise 50% of its are known in the art and need no further discussion here. caloric value in fat. A representative example may be 2 eggs Cores may likewise be fonned using a conventional rotary fried in butter, 2 strips of bacon, 2 slices toast with butter, 4 tablet machine. Cores are preferably compres sed under com- ounces tiied potato, and 8 ounces milk. 20 pression forces suiticient to provide cores having a hardness By application of the teachings of the present invention of about 60 Newtons at least, e.g. 50 to 70 Newtons. Cores tablets may be provided that display reduced variability in having hardness in this range give desired release character- resumption/bioavailability levels achieved both for indi- istics. lf desired, the cores can be formed at the same time as vidual patients receiving a drug as well as between individu- the press coated tablets are produced. In such case, one might als. 25 employ a Manesty Dry Cota. Such a press consists of two The tablets of the present invention may be packaged in a side-by-side and inter-connected presses where the core is variety of ways. Generally an article for distribution includes made on one press before being mechanically transferred to a container for holding the tablets. Suitable containers are the other press for compression coating. Such equipment and well known to persons skilled in the art and include materials techniques for making tablets using such equipment are such as bottles, foil packs and the like. In addition, the con- 30 l
(12> United States Patent (10) Patent No.: US 8,168,218 B2 Vergnault et al (45) Date of Patent: May 1, 2012
(54) DELAYED RELEASE TABLET WITH 5,464,633 A 1 1/1995 Conte et al. DEFINED CORE GEOMETRY 5,567,696 A 10/1996 McGuire et al. 5,792,476 A 8/1998 Hallgren (75) Inventors: Guy Vergnault, Kembs Loechle (FR) 6,183,780 B1 2/2001 Van Balken et al Pascal Grenier, Kappelen (FR); 6,365,185 B1 »!< 4/2002 Ritschel et al. .. 424/473 Christophe Dragan, Geispitzen (FR) 6,488,960 B 1 12/2002 Bardsley 6,599,284 B2 7/2003 Faour 604/892.1 (73) Assignee: Jagotec AG, Muttenz (CH) 6,620,439 B1 9/2003 Mehta 2005/0008702 A 1 1/2005 Faour et al. 424/473 ( * ) Notice: Subject to any disclaimer, the term of this (Continued) patent is extended or adjusted under 35 U.s.C. 154(b) by 1438 days. FOREIGN PATENT DOCUMENTS 10/554,538 (21) Appl. No EP 0 463 877 1/1992 (22) PCT Filed Apr. 23, 2004 (Continued)
(se) PCT No PCT/IB2004/001693 OTHER PUBLICATIONS
§ 371 (¢)(1), Zlatldna, A,P., "The Modern Therapeutic Tactics of lnflaimnatory (2), (4) Date: Jan. 16, 2007 Bowel Disease, Consilium Mcdicum," Gastroenterology 6(l):2004 (English machine translation appended). (87) PCT Pub.No.: W02004/093843 (Continued) PCT Pub. Date: Nov. 4, 2004 (65) Prior Publication Data Primary Examiner »~ Pau] Dickinson US 2007/01 10807 A1 May 17, 2007 (74) Attorney, Agent, or Firm - Mintz Levin Cohn Ferris Giovsky and Popeo, P.C.; David E. Johnson, Esq.; Muriel (30) Foreign Application Priority Data Liberto, Esq. Apr. 24, 2003 (GB) 0309342.4 (57) ABSTRACT (51) Int. C1 A press-coated tablet comprising a core containing an dwg A61K 9/20 (2006.01) substance, and a coating, the core being disposed within the (52) U.S.Cl. 424/464 coating such that the coating has a first thickness about an axis (58) Field oi Classification Search None A-B and a thickness about an onhogonal axis X-K such that See application file for complete Search history. the coating about the axis X-Y is thicker than the coating about the axis A-B, and is adapted to provide a lag time of (56) References Cited between about 2 to 6 hours during which sub stantially no drug substance is released. U.S. PATENT DOCUMENTS 5,279,832 A 1/1994 Greissinger et al 9 Claims, 2 Drawing Sheets
B I l
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I I A US 8,168,218 B2 Page 2
U.S. PATENT DOCUMENTS WO WO-02072034 A2 9/2002 WO WO 03/07591 9 9/2003 2006/0057200 Al 3/2006 Schaeffer WO WO 2004/ I 03349 A2 2/2004 FOREIGN PATENT DOCUMENTS WO WO 2004/093843 11/2004 WO WO 2004/093850 A1 11/2004 EP 0 673 645 9/1995 WO WO 2005/027843 A2 3/2005 EP 0 776 660 B1 6/1997 EP 0 939 623 2/2002 OTHER PUBLICATIONS EP 1 275 381 1/2003 EP 1 067 910 5/2004 Conte et al. (1993). Biomalerials 14: 1017-1023. JP 2001-010950 1/2001 Fukui et al. (2000)..Z Controlled Release 68: 215-223. wo WO 92/00064 1/1992 Lin et al. (2001). J Pharmaceutical Sciences 90: 2005-2009. WO WO 92/1 1 845 7/1992 GB Search Repon dated Aug. 22, 2003 corresponding to GB WO WO 93/19741 10/1993 0309342.4. WO WO 96/40078 A1 12/1996 WO WO 01/08421 2/2001 GB Search Report dated Oct. 23, 2003 corresponding to GB WO WO 01/52819 A1 7/2001 0309342.4. WO WO 01/68056 9/2001 International Search Report mailed Oct. 21, 2004 corresponding to WO WO 01/80824 11/2001 PCT/IB2004/001693. wo WO~0200204 A1 1/2002 wo WO 02/072033 9/2002 * cited by examiner U.S. Patent May 1, 2012 Sheet 1 of 2 Us 8,168,218 B2
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I I A FIG. 1 U.S. Patent May 1, 2012 Sheet 2 of 2 Us 8,168,218 B2
% Release - Prednisone
100.0 I r
80.0 ' £. a> 60.0 (D cu G) 'ii 0: 40.0
20.0
0.0 =Q Ca =fe Q ~Q Q ~Q Q =Q Q uq q mq q mq q uq © \" \"° (\| (\| C"') ¢") |' V' ¢o co |~ 1\ oo oo cn o> 1* Test medium Purified water Time lm Temperature: 37°C + 0.5°C Rotation speed; 100 rpm FIG. 2 US 8,168,218 B2 1 2 DELAYED RELEASE TABLET WITH media. The coating acts as a barrier to the ingress of aqueous DEFINED CORE GEOMETRY media into an active-agcnt~containing corc and thereby cre- ating a lag time during which no drug substance is released. This invention is concerned with a tablet comprising a core The gellable coating acts as a medium through which drug is containing a drug substance and a coating that is applied to 5 released in a delayed or modified manner. It is stated that the said core by means of compression-coating techniques. The lag time can be modulated by varying the coating weight. tablet can contain al] manner of drug substances, but is par- There are several problems with such an approach: First, ticularly suitable for administering those that are advanta- release of the drug occurs by means of dilTusion through the geously released only alter a predetermined lag time after gelled coating. ln the case ofdrugs that have a narrow absorp- io administration. The tablets are particularly suitable lor tion window, or in the case of drugs adapted to treat a rela- administering lucocorticosteroids selected from prednisone, tively small affected area ofthe GI tract or colon, once the lag prednisolone or methylprednisolone. time has expired it is desirable to release the drug as rapidly as Research into the chronopharmacological Held has dem- possible to ensure that all or substantially all of the drug onstrated the importance of biological rhythms in drug released at the desired site. A slow diffusion ofthe drug is not therapy. Very often, optimal clinical outcomes cannot be 15 achieved if a drug is released constantly alter ingestion. This appropriate in such cases. Further, by attempting to control is particularly the case if symptoms of a disease display lag time by controlling the coating weight, the formulator's circadian variations. ln such cases, drug release should vary latitude is limited in this regard, because increasing coating in a manner that is sympathetic to these variations in order weight adds additional cost to the dosage fonn, and it also that dwg plasma concentrations are at an optimal therapeutic 20 adds to the size of the dosage form, which may make it level only when required to treat symptoms ofa disease state. difficult to swallow for certain patient populations such as In particular, if symptoms of a disease become apparent at minors and for the elderly or inlirm. Still further, merely night, or in the early hours upon walking, the time when a adjusting coat weight does not ensure diat a coating is of a patient must take its medication in order to attect the best desired thickness at a particular site. It remains that if the core clinical outcome requires detailed consideration For 25 is not correctly positioned within a die of a press coating example, most asthma attacks occur in the early hours of the machine, despite having selected a particular coat weight, moming, e.g. 4 am to 6 am. This is a result of complex part of the coating may be unintentionally thinner than circadian rhythms such as the secretion ofhydrocortisone and desired, resulting in unforeseen premature release ofthe drug. adrenaline. lschaemic heart diseases occur most often during The applicant has now surprisingly found that by carefully the night or in the early waking hours around breakfast time. 30 selecting the geometry of a core Within its coating, it is pos- Stiffness and pain associated with rheumatoid arthritis and sible to manipulate the coating thickness at specific points on osteoanhritis occur in the early Walking hours, which is the tablet to ensure an appropriate coating thickness to pro- believed to be as a result of the secretion of IL-6 in the early duce tablets having a specifically ttuied lag time. Further- hours of the morning, eg. around 2 am to 4 am. more, because one is able to increase thickness where it is With conventional immediate release dosage forms, syn- 35 needed in the coating, one can reduce coating material to chronization of drug administration with a nocturnal circa- allow use of the minimum amount necessary to achieve the dian rhythm responsible for the symptoms experienced by a desired release characteristics, thus saving on cost ofmateri- patient would require a patient having to be disturbed from als and also reducing the overall tablet size. sleep to take a medicament during the early hours of the Still iilrther, the applicant has tbund that by selecting morning in order to achieve the most eflicacious clinical 40 appropriate core and coating materials, one is able not only to outcome. Of course, this would be highly inconvenient for a accurately control the lag time, one is also to ensure that all, patient. or substantially all, of the drug substance upon expiry of the Accordingly, there remains a need to provide dosage forms lag time is released rapidly and at the absorption site, or the that can be taken at a convenient hour before bedtime that will locally affected site. release an effective dose of a drug substance only after a 45 Accordingly, in a first aspect of the present invention there pre-determined lag time in order to synchronise peak plasma is provided a tablet comprising a core containing an drug concentrations of drug with a particular circadian rhythm. substance, and a coating around said core, the core being Furthermore, particularly in relation to drug substances disposed within said coating such that the coating thickness that have a narrow absorption window, or in the case of dmg about an axis (X-Y) (see FIG. 1) is thicker than the coating substances that are adapted to treat a local condition in the 50 about an axis (A-B) (see FIG. 1) orthogonal to (X-Y), and colon, such as Crohn's disease, ulcerative colitis, irritable wherein the thickness of the coating about the axis (X-Y) is bowel syndrome (IBS) and intlammatory bowel disease selected such that the coating is adapted to rupture upon (IBD), there is also a need to provide a dosage form that immersion in an aqueous medium after a period ofbeween rapidly releases the drug substances after reaching the end of about 2 to 6 hours. the lag time. 55 According to the present invention, the coating thickness Still further, having regard to the varied life styles of about the axis (X-Y) is thicker than the coating about the axis patients, in order to reduce die inter- and intra-subject vari- (A-B). The ratio ofthe thickness ofthe coating about the axis ance inbioavailability there is a need to provide a dosage form (X-Y) to the thickness ofthe coating about the axis (A-B) may that releases a drug with a reliable lag time, and to provide be from 2.2 to 2.6:1.0 to 1.6. peak plasma drug concentrations at a pre-determined time, 60 ln another aspect ofthe invention there is provided a tablet irrespective ofwhether a patient is in a led or lasted state. comprising a core containing an drug substance and a coating Time controlled release formulations are known in the art around said core, the core being disposed within said coating that are able to deliver drug substances with a defined release such that the coating thickness about an axis (X-Y) is thicker rate after a lag time during which no dnlg substance is than the coating about an axis (A-B) orthogonal to (X-Y), and released. Such a dosage form is disclosed in WO 02/072033. 65 the thickness of the coating about the axis (X-Y) is at least This dosage form is characterized by a coating containing a about 2.2 mm, particularly about 2.2 to 2.6 mm, more par- natural or synthetic gum that gels in the presence of aqueous ticularly about 2.35 to 2.45 mm. Us 8,168,218 B2 3 4 The thickness ofthe coating around or about thc axis (A-B) towards the ingress of aqueous media. The rate of ingress of is not critical for controlling the lag time. Accordingly, the the aqueous medium through the coating along the direction formulator has some latitude in selecting its thickness. It of the X-Y axis is, in part, responsible for controlling the should not be so thick as to render the final tablet to large, yet release of the dwg substance from the. core. Once the aque- on the other hand the coating should not be so thin that the 5 ous medimn contacts the core, the core reacts by swelling or coating is render weak and liable to crack under the slightest effervescing thereby to break open the core generally along mechanical stress. Preferably, the thickness of the coating the direction of ingress of the aqueous media (i.e. the X-Y about the axis (A-B) is about 1.0 to about 1.6 mm. The coating axis) to form to essentially two hemispheres ofcoating mate- thickness either side ofthe core on the axis (A-B) may or may rial that may remain conjoined, which has an appearance of not be equal. For example, on a lirst side of the core (A-core) 10 an opened clam shell. The reaction of the core material to the the coating may have a thickness ofabout 1 .2 to 1 .6 mm, more presence of die aqueous medium is likewise in part respon- preferably 1.35 to 1.45 mm, whereas on the other side of the sible for controlling the release of drug substance from the core (B-core) the thickness may be about 1.0 to 1.4 mm, more core. preferably 1.15 to 1.25 mm. The hardness ofthe tablet is preferably at least 60 Newtons, Accordingly, in a particular embodiment of the present 15 invention there is provided a tablet comprising a core con- e.g. 60 to 80 Newtons, and more panicularly 60 to 75 New- taining an drug substance, and a coating, the core being dis- tons. Hardness may be measured according to a process posed within the coating such that the coating has a thickness described in 'lhe European Pharmacopoeia 4, 2.9.8 at page about an axis (X-Y) of at least about 2.2 mm, more particu- 201. The test employs apparatus consisting of 2 opposing larly about 2.2 to about 2.6 mm, still more particularly 2.35 to 20 jaws, one ofwhich moves towards die other. The Hat surfaces 2.45 mm, and the thickness ofthe coating about an axis (A-B) of die jaws are perpendicular to the direction of movement. orthogonal to (X-Y) is between 1.0 and 1.6 mm. More par- The cmshing surfaces of die jaws are fiat and larger than the ticularly, along the axis (A-B) on a first side of the core zone of contact with the tablet. The apparatus is calibrated (A-core) the thickness may be about 1.2 to 1.6 mm, more using a system with a precision of one Newton. The tablet is preferably 1.35 to 1.45 nun, and on a second side of the core 25 placed between thejaws. For each measurement, the tablet is (B-core) the thickness may be about 1.0 to 1.4 mm, more oriented in the same way with respect to the direction of the preferably 1.15 to 1.25 mm. applied force. Measurements are carried out on 10 tablets. Tablets of the present invention are fonned by compression Results are expressed in terms of the mean, minimum and coating methods as will be described in more detail herein maximum values (in Newtons) of the force needed to crush below. Compression coated tablets are generally formed by 30 the tablets. placing a portion of a powdered coating material in a die and Tablets having a hardness within this range are mechani- tamping the powder into a compact term using a punch. A cally robust to withstand forces generated in the stomach, core is then deposited onto the compacted coating material particularly in the presence of food. Furthermore, the tablets before the remainder ofthe coating material is introduced into are sufiiciently porous about the (X-Y) plane of the tablet to the die and compression forces are applied to form the coated 35 tablet. To ensure that the core is placed on the tamped coating permit ingress ofphysiological media to the core at an appro- material to ensure its correct geometry relative to the coating priate rate to ensure that the drug substance is released within in the final tablet form, it is preferable to employ means for an appropriate lag time, e.g. within 2 to 6 hours. positioning the core in relation to the coating material in a die. As stated above, it is a preferred aspect of the present Typically such means may be provided by a pin punch. A pin 40 invention that the tablets are adapted to release a drug sub- punch is a punch that has a convex surface that contacts the stance from the core after a pre-determined lag time, as well coating material to leave a small depression or hollow in the as being adapted to release all, or substantially all, ofthe drug tamped coating material. Thus, when the core is placed into substancewithin a very short period oftime after the expiry of the die on the tamped material, it sits in the depression or the lag time. This ensures that all, or substantially all, of the hollow and its correct geometry is assured in the final tablet 45 drug is released at me intended absorption site along me GI form. tract, or onto the affected site ofthe Gl tract ifthe condition to The thickness ofthe coating along and about the axis ofthe be treated is a local topical condition. lt is preferred that the direction of movement of the punch (the "(A-B)" axis tablets ofthe present invention release all, or substantially all referred to above) is determined by the amount of coating ofa drug substance within about % hour to about 1 hour after material added to the die and the compaction force applied to 50 the selected lag time. form the tablet. On the other hand, the thickness of the coating This aspect of the present invention is important for deliv- along and about the "(X-Y)" axis is determined by the size of cring drugs having a rather narrow absorption window in the the core, its po sition within the die and the diameter ofthe die. upper G1 tract, such as the glucocorticosteroids referred to lt will be apparent to the skilled person that there is a plurality above. ln such Cases, the drug should be released before the of axes (X-Y) orthogonal to the axis of movement of the 55 tablet can pass into the bowel, where absorption of such dnlgs punch (the "A-B" axis), which extend radially from the centre is poor. lt is made particularly important if the tablet is of the tablet to its circumference, and when the reference is intended to perform in the same manner independent of the made to the thickness of the coating about an axis X-Y effects of food.It is well known that the rate at which a tablet reference is being made the thickness about any or all of these will pass through me GI tract will vary depending on whether axes. 60 a patient is in a fed or fasted state. In die fasted state, a tablet During the compression of the coating around the core, the will typically clear the stomach within about 16 hom and l coating material above and below the core (the material along hour after ingestion, and thereafter take a mrther 4 to 5 hours and about the (A-B) axis) is relatively highly compacted and to clear the upper GI tract through the ileosecal junction. In a dense. On the other hand, the coating material disposed along fed state, a tablet may take as long as 4 hours to be cleared and about the (X-Y) axis is subjected to lower compaction 65 from the stomach, and a iiurther 4 to 5 hours to clear the upper forces and is relatively less dense. Accordingly, the material GI tract. Accordingly, if a tablet is to release of all, or sub- about the (X-Y) axis is relatively porous and permissive stantially all, of its drug into die upper GI tract irrespective of US 8,168,218 B2 5 6 the fed state of a patient, it is preferable that die release the Polyvinyl pyrollidone (Povidonc) is preferably present in drug alter the lag time occurs Within a time limit referred to in amounts of about 1 to 25% by Weight or the coating, more the paragraph above. particularly 4 to 12%, e.g. 6 to 8%. It should be understood that whereas it is desirable that 110 Glyceryl behenate is an ester of glycerol and behenic acid drug substance is released during the lag time, some release 5 (a C22 fatty acid). Glyceryl behenate may be present as its may occur. However, any release of drug substance during the mono-, di-, or tri-ester form, or a mixture thereof. Preferably lag time should not exceed 10% of the total amount of drug it has an HLB value of less than 5, more preferably approxi- substance in the core. mately 2. lt may be present in amounts of about 5 to 85% by The coating employed in a tablet according to the present weight of the coating, more particularly from 10 to 70% by invention is prelerably formed of insoluble or poorly water 10 weight, and in certain preferred embodiments from 30 to soluble hydrophobic material. In use, the coating optimally 50%. acts merely as a barrier to the ingress of aqueous physiologi- Calcium phosphate salt may be the dibasic calcium phos- cal media thereby providing a drug release lag time. For the phate dihydrate and may be present in an amount ofabout 10 reasons set forth above, optimally the tablet should have the to 90% by Weight ofthe coating, preferably 20 to 80%, e.g. 40 minimum thickness possible consistent with the desired lag 15 time. Accordingly, employing water insoluble or poorly to 75%. soluble hydrophobic coating materials, one is able to produce The coating may contain other common tablet excipients a coating that is relative recalcitrant to the ingress ofmoisture such as lubricants, colourants, binders, diluents, glidants and and so long lag times can be achieved with relatively thin taste-masking agents or ilavourants. coatings, 20 Examples of excipients include colourants such a ferric Further, in order to achieve the rapid release of drug sub- oxide, e.g. yellow ferric oxide; lubricants such as magnesium stance after the lag time has expired, it is desirable that the stearate; and glidants such as silicon dioxide, e.g. colloidal coating contains no, or substantially no, ingredients that swell silicon dioxide. Yellow ferric o>dde may be used in amounts and gel agents to such an extent that the coating acts as a of about 0.01 to 0.5% by weight based on the coating; mag- diffusion barrier to the release ol" drug substance. In this 25 nesium stearate may be present in amounts of l to 20% by regard, it is preferable that the coating contains no, or sub- weight of the coating, more preferably 2 to 10%, e.g. 0.5 to stantially no, materials such as natural or synthetic gums that l.0%; and colloidal silica may be used in amounts of 0.1 to modulate release of the drug substance through an intact 20% by Weight of the coating, preferably l to 10%, more swollen coating. Drug substance is released from the core as preferably 0.25 to l.0%. a result of the physical rupturing of the coating and not as a 30 The core comprises in addition to a drug substance, a result of the drug substance diffusing through a swollen coat- disintegrating agent or mixtures ofdisintegrating agents used ing material. That the mechanism ofdrug release is substan- in immediate release formulations and Well know to persons tially dependent on the physical splitting of the coating, and skilled in the art. The disintegrating agents useful in the not on a diffusion process through a swellable and gellable exercise of the present invention may be materials that effer- coating, means that a wide range of drug substances can be 35 vesce and or swell in the presence of aqueous media thereby delivered from tablets according to the invention in a reliable to provide a force necessary to mechanically disrupt the coat- and reproducible manner. ing material. The tablet coating may contain one or more waterinsoluble Preferably a core contains, in addition to the drug sub- or poorly soluble hydrophobic excipients. Such excipients stance, cross-linked polyvinyl pyrollidone and croscarmel- may be selected from any of the known hydrophobic cellulo- 40 lose sodium. sic derivatives and polymers including alkylcellulose, e.g. The following is a list of preferred core materials. The ethylcellulose, hydroxypropyl cellulose, hydroxypropylm- amounts are expressed in terms of percentage by weight ethyl cellulose, carboxymethyl cellulose, and derivatives based on the weight of the core. thereof; polymethacrylic polymers, polyvinyl acetate and Cross-linked polyvinyl pyrollidone is described above and cellulose acetate polymers; fatty acids or their esters or salts; 45 is useful as a disintegrating agent, and may be employed in the long chain fatty alcohols; polyoxyethylene alkyl others; poly- core in the amounts disclosed in relation to the core. oxyethylene stearates; sugar esters; lauroyl macrogol-32 Croscarmellose sodium is an internally cross-linked glyceryl, stearoyl macrogol-32 glyceryl, and the like. sodium carboxymethyl cellulose (also known as Ac-Di-Sol) Hydroxypropylmethyl cellulose materials are preferably useful as a disintegrating agent. selected from those low MW and low viscosity materials such 50 Disintegrating agents may be used in amounts of 5 to 30% as E-Type methocel, and 29-10 types as defined in the USP. by weighbasea 01 the core. However, higher amounts of Other agents or excipicnts duat provide hydrophobic qual- certain disintegrants can swell to form matrices that may ity to coatings may be selected from any waxy substance modulate the release of the dmg substance. Accordingly, known for use as tablet excipients. Preferably they have a particularly when rapid release is required after the lag time it HLB value of less than 5, and more preferably about 2. 55 is preferred that the disintegrants is employed in amounts of Suitable hydrophobic agents include waxy substances such as up to 10% by weight, e.g. about 5 to 10% by weight. carnauba wax, paraffin, microcrystalline wax, beeswax, cetyl The core may additionally comprise common tablet excipi- ester wax and the like; or non-fatty hydrophobic substances ents such as those described above in relation to the coating such as calcium phosphate salts, e.g. dibasic calcium phos~ material. Suitable excipients include lubricants, diluents and phate. 60 fillers, including but not limited to lactose (for example the Prelerably the coating contains a calcium phosphate salt, mono-hydrate), ferric oxide, magnesium stearates and colloi- glyceryl behenate, and polyvinyl pyrollidone, or mixtures dal silica. thereof, and one or more adjuvants, diluents, lubricants or Lactose monohydrate is a disaccharide consisting of one fillers. glucose and one galactose moiety. It may act as a filler or Preferred components in the coating are as follows, with 65 diluent in the tablets of the present invention. lt may be generally suitable percentage amounts expressed as percent- present in a range of about 10 to 90%, preferably from 20 to age weight of the coating. 80%, and in certain preferred embodiments from 65 to 70%. Us 8,168,218 B2 7 8 As slated above, it is an important aspect of die present traline, statins, tacrolimus, tamoxifen, TCAS, triamzolam, invention that core is correctly located within the coating to zolpidem, or mixtures thereof. ensure that a tablet has the appropriate coating thickness. In Additional examples of drug classes and drugs that can be this way, lag times will be reliable and reproducible, and employed in tablets of the present invention include: intra-subj ect and inter-subject variance in bioavailability can antihistamines (e.g., azatadine maleate, brornpheniramine be avoided. It is advantageous to have a robust in process maleate, carbinoxamine maleate, chlorpheniramine maleate, control to ensure that tablets in a batch contain cores having dexchlorpheniramine maleate, diphenhydramine hydrochlo- me appropnatc geometry ln relation ro me coating. LOHIYOIS ride, doxylamine succinate, methdilazine hydrochloride, can be laborious in that they require an operator to remove promethazine, trimeprazine tartrate, tripelennamine citrate, random samples from a batch and lo cut them open to physi- 10 tripelcnnaminc hydrochloride and triprolidine hydrochlo- cally inspect the quality of the core (i.e. whether it is intact, ride); and whether it is correctly located). Furthermore, if a signifi- antibiotics (e.g., penicillin V potassium, cloxacillin cant number of tablets from the sample fail, a complete batch sodium, dicloxacillin soditun, nafcillin sodium, oxacillin oftablets may be wasted. Applicant has found that ifone adds sodium, carbenicillin indanyl sodium, oxytetracycline hydro- to the core a strong colourant such as iron oxide, such that the 15 core visibly contrasts with the coating when as strong light is chloride, tetracycline hydrochloride, clindamycin phosphate, shone on the tablet, it is possible lor any faults in the position clindamycin hydrochloride, clindamycin palmitate HCL, lin- or integrity of the core to be picked up automatically by a comycin HCL, novobiocin sodium, nitrofurantoin sodium, camera appropriately located adjacent a tabletting machine to metronidazole hydrochloride); antituberculosis agents (e.g., inspect tablets as they are ej ected therefrom. In this Way, if a 20 isoniazid); faulty tablet is identified it is possible to halt production and cholinergic agents (e.g., ambcnonium chloride, bethanecol correct any problems in the manufacturing process quicldy, chloride, neostigmine bromide, pyridostigmine bromide); thereby potentially avoiding wastage of batch quantities of antimuscarinics (e.g., anisotropine methylbromide, clid- tablets. inium bromide, dicyclomine hydrochloride, glycopyrrolate, Whereas colourants contained in the core are uselul ior this 25 hexocyclium methylsulfate, homatropine methylbromide, purpose, equivalent solutions are also possible. For example, hyoscyamine sulfate, rnethantheline bromide, hyoscine instead of a colourant, one can include a material that is hydrobromide, oxyphenonium bromide, propantheline bro- opaque to x-rays, such as baritun sulphate. If an x-ray imager mide, tridihexethyl chloride); is then coupled to a tablet machine, the core will contrast with sympathomimetics (e.g., bitolterol mesylate, ephedrine, the coating material and die x-ray imager will pick up any 30 ephedrine hydrochloride, ephedrine sulphate, orciprenaline faults in the positioning or integrity of the core in a similar sulphate, phenylpropanolamine hydrochloride, pseudoephe- fashion. drine hydrochloride, ritodrine hydrochloride, salbutamol sul- The amount of drug substance employed in tablets of the phate, terbutaline sulphate); present invention will depend on the particular drug sub- sympatholytic agents (e.g., phenoxybenzamine hydro- stance used, the condition of the patient and the nature and 35 chloride); miscellaneous autonomic drugs (e.g., nicotine); severity of the condition to be treated. A typical drug loading might be from l to 50% by weight of the core. iron preparations (e.g., ferrous gluconate, ferrous sul- As stated above a wide variety of drug substances may be phate); employed in the present invention. Drugs for treating condi- haemostatics (e.g., aminocaproic acid); tions the symptoms ofwhich result from nocturnal circadian 40 cardiac drugs (e.g., acebutolol hydrochloride, disopyra- rhythms are particularly suitable. Accordingly, drugs for mide phosphate, flecainide acetate, procainamide hydrochlo- treating incontinence, sleep disorders, apnoea, asthma, epi- ride, propranolol hydrochloride, quinidine gluconate, timolol lepsy, bronchitis, parkinsonism, rheumatoid arthritis, allergic maleate, tocainide hydrochloride, verapamil hydrochloride); rhinitis and ischaemic heart diseases, cluster and migraine antihypertensive agents (e.g., captopril, clonidine hydro- headache, congestive heart failure, and depression are par- 45 chloride, hydralazine hydrochloride, mecamylamine hydro- ticularly suitable for use in tablets according to the present chloride, metoprolol tartrate ); vasodilators (e.g., papaverine invention. Further, drug substances that are metabolized by hydrochloride); cytochrome P450 are also particularly suitable, they non-steroidal anti-inflammatory agents (e.g., choline sali- include:-Amitriptyline, caffeine, clomipramine, clozapine, cylate, ibuprofen, ketoprofen, magnesium salicylate, Huvoxamine, haloperidol, imipramine, mexilitine, oestradiol, 50 meclofenamate sodium, naproxen sodium, tolmetin sodium); olanzepine, paraeetamol, propranolol, tacrine, theophylline, opiate agonists (e.g., codeine hydrochloride, codeine phos- warfarin, Bupropion, Cyclophosphamide, Celecoxib, phate, codeine sulphate, dextromorarnide tartiate, hydroc- Diclofenac, Flubiprofen, Ibuprofen, glimepirideindome, tha- odone bitartrate, hydromorphone hydrochloride, pethidine Cin, naproxen, phenytoin, piroxicam, tenoxicam, citalopram, hydrochloride, methadone hydrochloride, morphine sul- diazepam, lansoprazole, omeprazole, pantoprozole, pro- 55 phate, morphine acetate, morphine lactate, morphine meeon- panolol, topiramate, Alpranolol, chlorpromazine, clomi- ate, morphine nitrate, morphine monobasic phosphate, mor- pramine, codeine, Desipramine, dextromethorphan, diphen- phine tartrate, morphine valerate, morphine hydrobromide, hydramine, donepezil, flecainide, Huoxetine, labetalol, morphine hydrochloride, propoxyphene hydrochloride); Methadone, metoprolol, mianserin, nortripyline, anticonvulsants (e.g., phenobarbital sodium, phenytoin ondansetron, oxprenolol, oxycodone, paroxetine, perhehex- 60 sodium, troxidone, ethosuximide, valproate sodium); ilene, pethidine, promethazine, risperdone, thioridazine, tranquilizers (e.g., acetophenazine maleate, chlorprom- ticlopidine, timolol, trimipramine, venlafaxine, paracetamol, azine hydrochloride, fluphenazine hydrochloride, prochlor- alprazolam, amiodarone, budesonide, buprenorphine, bus- perazine edisylate, promethazine hydrochloride, thioridazine pirone, Calcium Channel Blockers, carbamazepine, hydrochloride, triliuoroperazine hydrochloride, lithium cit- cisapride, clarithromycin, clonazepam, cocaine, cortisol, 65 rate, molindone hydrochloride, thiothixine hydrochloride); cyclosporine, dexamethasone, erythromycin, fentanyl, keto- chemotherapeutic agents (e.g., doxombicin, cisplatin, conazole, losartan, miconazole, midazolam, quinidine, ser- iooxuridine, methotrexate, combinations thereof); US 8,168,218 B2 9 10 lipid lowering agents (e.g., gemfibrozil, clohbrate, HMG- weight of steroid based on the total weight of the core. ln the COA reductase inhibitors, such as for example, atorvastatin, case ofprednisone, it may be employed in amounts to provide cerivastatin, lluvastatin, lovastatin, pravastatin, simvastatin); a total weight per unit dosage form of l or 5 mg, to offer H.sub.2-antagonists (e.g., cirnetidine, famotidine, nizati- convenience and flexibility of dosing, although dosage forms dine, ranitidine HCI); 5 containing larger or smaller amounts of drug substance could anti-coagulant and anti-platelet agents (e.g., warfarin, be employed if desired, cipyridamole, ticlopidine); Particularly preferred tablets according to the invention bronchodilators (e.g,, albuterol, isoproterenol, mctaproter- comprising in the core a glucocortico steroid selected from the enol, terbutaline); group consisting of prwnisone, prednisolone and methyl- stimulants (e.g., benzamphetamine hydrochloride, dextro- 10 prednislone, and cross-inked polyvinyl pyrollidone, cross- amphetamine sulphate, dextroamphetarnine phosphate, linked sodium carboxymetbyl cellulose, and one or more diethylpropion hydrochloride, feniiuramine hydrochloride, adjuvants diluents, lubricants or Hller materials as herein- methamphetamine hydrochloride, methylphenidate hydro- above described. Preferably the coating comprises a calcium chloride, phendimetrazine tartrate, phenmetrazine hydro- phosphate salt, glyceryl behenate, cross-linked polyvinyl chloride, caffeine citrate); 15 pyrollidone and one or more adjuvants, diluents, lubricants or barbiturates (e.g., amylobarbital sodium, butabarbital filler materials as hereinabove described. sodium, secobarbital sodium); The composition ofone particularly preferred embodiment sedatives (e.g., hydroxyzine hydrochloride, methprylon); of the invention is: expectorants (e.g., potassium iodide); Core of 5 mg Prednisone Tablet: antiemetics (e.g., benzaquinamide hydrochloride, meto- 20 Prednisone 8.33% cloproparnide hydrochloride, trimethobenzamide hydrochlo- Lactose monohydrate 64.47% ride); Povidone 6.67% gastrointestinal drugs (e.g., ranitidine hydrochloride); Croscarmellose sodium 18.33% heavy metal antagonists (e.g., penicillamine, penicillamine Red ferric oxide 0.5% hydrochloride); 25 Magnesium stearate Vegetable origin 1.0% antithyroid agents (e.g., methimazole); Colloidal silicon dioxide 0.5% genitourinary smooth muscle relaxants (e.g., tiavoxate Coating hydrochloride, oxybutynin hydrochloride); Dibasic calcium phosphate dihydrate 50% vitamins (e,g., thiarnine hydrochloride, ascorbic acid); Glyceryl behenate 40% unclassihed agents (e.g., amantadine hydrochloride, 30 Povidone 8.40% colchicine, etidronate disodium, leucovorin calcium, methyl- Yellow ferric oxide 0.1% ene blue, potassium chloride, pralidoxime chloride. Magnesium stearate Vegetable origin 1.0% steroids, particularly glucocorticoids (e.g., prednisolone, Colloidal silicon dioxide 0.5% methylprednisolone, prednisone, cortisone, hydrocortisone, Another preferred embodiment is as follows: methylprednisolone, betamethasone, dexamethasone, triam- 35 Core of 1 mg Prednisone Tablet: cinolone). Prednisone 1.67% Notwithstanding the general applicability of the tablets in Lactose monohydrate 71.13% relation to a wide range ofdrug substances, the present inven- Povidone 6.67% tion is particularly suited to delivery of the glucocorticoster- Croscarmellose sodium 18.33% oids aforementioned and particularly prednisone, predniso- 40 Red ferric oxide 0.5% lone and methylprednisolone. These steroids are useful in the Magnesium stearate Vegetable origin 1.0% treatment i.a, of rheumatoid arthritis and joint pain. As Colloidal silicon dioxide 0.5% already stated, the symptoms of these conditions appear Coating according to a circadian rhythm and with great predictability Dibasic calcium phosphate dihydrate 50% during the early hours of the morning. Accordingly, die glu- 45 Glyceryl behenate 40% cocorticosteroids, and in particular prednisone are eminently Povidone 8.40% suited for delivery from tablets according to this invention not Yellow ferric oxide 0.1% only because of their narrow absorption window, but also Magnesium stearate Vegetable origin 1.0% because a tablet may be administered in the evening before Colloidal silicon dioxide 0.5% bedtime anytime around 8 pm until midnight, e.g. around 50 It is surprising that the tablets containing the glucocorti- 10-12 at night, to deliver maximum plasma concentration of costeroids display such rapid release given that the rate of the drug substance before maximum secretion ofIL-6 (which release relics to some extent on the wetting of die core, and occur around 2 am to 4 am), thereby effectively addressing these steroids are rather hydrophobic in nature. the underlying causes of the morning symptoms. In this way, The tablets described above are press-coated tablets com- these symptoms are more effectively treated. 55 prising a core and a coating covering said core. However, As used above, prednisone refers to the compound and its variants of this basic construction are within the ambit ofthe salts or derivatives thereof, including prednisone 21 acetate. present invention. Thus, the press-coating may be further As used above, prednisolone refers to the compound and its coated with an outer coating that may be functional and/or salts or derivatives including the 21 -acetate, its 21-tert-butyl aesthetic in its design. For example, functional coatings may acetate, 21-succinate sodium salt, 21-stearoylglycolate, 60 include the addition an immediate release coating containing 21 -rn-sulphobenzoate sodium salt, and its trimethylacetate. a drug substances that may be the same or different to the drug Methylprednisolone, as used above refers to the compound substance contained in the core. or and its salts and derivatives thereofincluding its 21 acetate, In this manner, the tablet can affect a pulsatile release that 2 1 -phosphate disodium salt, 2 l -succinate sodium salt, and its is of use in treating symptoms based on circadian rhythms, acetonate. 65 such as sleep disorders. In this regard one can employ seda- Typically a core may contain about 0.1 to 50% by weight, tive hypnotics in such dosage forms, for example those dntg more particularly l to 20%, still more particularly l to 10% by substances mentioned described in U.S. Pat. No. 6,485,746 Us 8,168,218 B2 11 12 Pulsatile release dosage forms may also find general applica- or even in relation to dnig substances whose efficacy depends bility with a Wide range ofactive substances for the treatment on their ability to be delivered accurately to a particular ofa wide range ofindications to provide patients with a more absorption site, or a locally diseased site along the GI tract and convenient dosage schedule. For example, pulsatile release bowel. Such medicaments are provided by the present inven- can provide an alternative to multiple administrations of 5 tion. immediate release forms. Currently, there are no bioavailability or bioequivalence Functional coatings also include enteric coatings covering regulatory guidelines available forTmax' However, the Guid- the press-coating. Enteric coated forms may be of use in ance For lndustry "Food Effect Bioavailability and Fed treating local conditions in the bowel such as Crohn's disease, Bioequivalence Studies", US Depanment of Health (CDER) ulcerative colitis, IBS and IBD. In this embodiment, the 10 December 2002 suggests that any diflerence in Tm" should enteric coating would prevent release of any drug before the not be clinically relevant. Whether such a difference will be tablet enters the bowel. clinically relevant will depend on the drug delivered and the Aesthetic coatings include taste masking coatings and particular indication. Applicant has found that in respect of coloured coatings as a generally Well known in the art. formulations ofthe present invention the effect of food on the It is well known in the art that food can change the bio- 15 median value of Tm is a difference of only about +/-20%, availability of a drug. Food can alter the bioavailability of a more particularly +/-10% drug by various means such as delaying gastric emptying, Still further, applicant has found medicaments containing changes in gastrointestinal pH, changes in luminal metabo- dwg substances exhibiting no significant effect of food with lism, and physical and chemical reactions of food items with respect to bioavailability of the dmg substance in terms of a dosage form or drug substance. This change in bioavailabil- 20 Cn," and AUC. ity as a consequence of food intake is often referred to as a The "food effect" as it relates to the bioavailability of drug "food effect". Food effects are quite common in modified- substances is a well documented phenomenon in relation to release dosage forms, and also for drugs that have either poor drug delivery mat describes the variance in uptake of a dwg solubility or poor penneability or both (BCS Class ll, Ill, and substance by patients depending upon whether the patients IV). 25 are in fed or fasted states. The presence or absence of` a lbod The applicant has surprisingly found that a tablet that is effect may be quantified by making Area under the Cuwe adapted to release all, or substantially all, of a drug contained (AUC) and/or Cmax measurements according to methods well therein within a time ( ag) ofbetween 2 and 6 hours (median known in the art, Typically AUC measurements and Cmax time) after administration. measurements are made by taking timed biological fluid Furthermore, the applicant has surprisingly developed a 30 samples and plotting the serum concentration of drug sub- tablet adapted to release a dnug substance after a lag time that stance against time. The values obtained represent a number can deliver a drug to a patient, which upon absorption the ofvalues taken from subjects across a patient population and peak drug concentration Cmax will be reached in a time Tniax are therefore expressed as mean values expressed over the that is independent of a patient's food intake. entire patient population. By comparing the mean AUC and/ Tmax is a term well known in the art that refers to the time 35 or Cmax values, one can determine whether a drug substance elapsed between drug administration and the maximum experiences a food effect. plasma concentration Cm is reached. Cm" is also an art Food effect studies may be conveniently carried out on an recognized term that relates to the peak plasma concentration adequate number of healthy volunteers, the number being of a drug. suflicient to generate sufficient data for appropriate statistical 'rmax is an important parameter particularly in relation to 40 assessment to be made. Preferably the number of subjects medicaments that are intended to be taken at a time conve- should not be less than 12. nient for a patient, but which release drug substances after a To study the effect of food on the bioavailability of a drug lag time in order to synchronise drug release with a circadian substance one may use any conventional study design known rhythm, and in particular a nocturnal circadian rhythm. By i11 the art, for example a randomised, balanced single-dose, way of example, the glucoconicosteroids, referred to above, 45 two-treatment, two-period, two-sequence crossover design. e.g. prednisone, are useful in the treatment of i.a. arthritic Analysis may be canied out using any ofthe programs known conditions such as rheumatoid arthritis and osteoarthritis. in the art such as SAS PROC GLM, software from the SAS Debilitating symptoms are often experienced by a patient institute, Cary N.C. upon waking. Current therapy requires a patient to take Deco- ln quantitative terms, a drug substance may be said to ninR upon waking. However, this is not the most efficacious 50 exhibit no food effect ifa 90% confidence intewal (Cl) for the way of treating the symptoms, as they are believed to be ratio of means (population geometric means based on log associated with the secretion oflL-6, which occurs during the transformed data) offcd and fasted treatments fall within the early moming hours, e.g. from about 2 to 4 am. A rnedicament intewal of0.8 to 1.25 for AUC andor 0.7 to 1.43 for Cmar that can reach Cm" that is coincident with or anticipates the Accordingly, the present invention provides in another of release of lL-6 is potentially of greater benent to a patient. 55 its aspects a tablet as defined herein above displaying a ratio Furthennore, given the varied lifestyles of individuals, AUC fed/fasted aher single dosing of 0.8 to 1.25 or the ratio patients taking rnedicament between 8 pm and bedtime, e.g. Cm fed/fasted after single dosing of 0.7 to 1.43. from 10 pm to midnight, may be in a variety offed states, it is A "fed" subject conveniently may be considered as a sub- even more advantageous that TW. should bc independent of ject that has fasted for at least 10 hours before receiving a food intake. 60 standard FDA recognised high fat meal. The medicament Medicaments that can have a pre-determined lag time, and may then be administered with water shortly alter completion which release dwg substance after this lag time in a manner ofthe meal, e.g. within 5 minutes thereof. Preferably no food that provides a Tmax independent of considerations of the fed should be taken for a period oi e.g. 4 hours alter receiving or fasted state ofa patient are ofpotentially great benefit, not medicament although small quantities of Water may be per- only in relation to die glucocorticosteroids and the treatment 65 mitted after, e.g, 2 hours after receiving the medicament. of a1tMtis, but for other active substances that are advanta- A "fasted" subject conveniently may receive medicament geously delivered in Synchronicity with a circadian rhythm, with water after at least 10 hours fasting. Thereafter, no food Us 8,168,218 B2 13 14 may be taken for a period oi e.g. 4 hours although small about the X-Y axis. Should it be necessary to change the quantities of water may be taken after, e.g. 2 hours alter thickness of the coating, die of appropriate internal dimen- receiving medicament. sions may be placed in the rotating platform, and the amount A standard FDA high fat meal as referred to hereinabove of coating material fed into the die may be adjusted accord- may comprise any meal that would be expected to provide 5 ingly. maximal perturbation due to the presence of food in the Gl Suitable rotary tablet machines having high process speeds tract. Said high fat meal typically may comprise 50% of its are known in the art and need no further discussion here. caloric value in fat. A representative example may be 2 eggs Cores may likewise be formed using a conventional rotary fried in butter, 2 strips ofbacon, 2 slices toast with butter, 4 tablet machine. Cores are preferably compressed under com- ounces ined potato, and 8 ounces milk. 10 pression forces suiiicient to provide cores having a hardness By application of the teachings of the present invention of about 60 Newtons at least, e.g. 50 to 70 Newtons. Cores tablets may be provided that display reduced variability in having hardness in dns range give desired release character- resumption/bioavailability levels achieved both for indi- istics. lf desired, the cores can be formed at the same time as vidual patients receiving a dmg as Well as between individu- the press coated tablets are produced. In such case, one might als. 15 employ a Manesty Dry Cota. Such a press consists of two The tablets of the present invention may be packaged in a side-by-side and inter-connected presses where the core is variety ofways. Generally an article for distribution includes made on one press before being mechanically transferred to a container for holding the tablets. Suitable containers are the other press for compression coating. Such equipment and well known to persons skilled in the art and include materials techniques for making tablets using such equipment arc such as bottles, foil packs and the like. In addition, the con- 20 known in the art and no more needs to be said about this here. tainer will have a label and an insert that describes the con- (fnres are ["""""'Jnreferahlv ilirmed aecorflino'"""'"-C: tn wet srranulatinnD"""""'"""" tents ofthe container and any appropriate warnings or instruc- techniques generally known in the art. In a typical procedure, tions for use. It is an advantage of die present invention that core materials are sieved and blended. Granulating fluid, typi- the insert and/or label may contain instmctions that the tablet cally water is then added to the blend and the mixture is may be taken with or without food, or may be absent a 25 homogenized to form a granulate, which is then sprayed dried warning or instruction that the tablet should be taken only or dried on a fiuid bed drier to obtain a granulate with requisite with food or only without food. residual moisture. Preferably the residual moisture content is The invention provides in another aspect, a method of from about 0.4 to 2.0% by weight. The granulate is then sized forming tablets as herein above described. The tablets may be by passing it through screens of desired aperture. At this formw on conventional press coating equipment. Typically 30 stage, a11y adjuvants are sized and added to the granulate to such equipment is composed ofa series ofdie are arranged on form the core composition suitable for compression. The a rotating platfbm. The die are removably mounted in the sldlled person will appreciate that a coating composition can platform such that differently sized die may be employed as be formed in an analogous manner. The skilled person will appropriate. Each die is hollow to receive a lower punch. The also appreciate that granulates may be obtained having a punch is positioned within the die such that the upper surface 35 range of particle sizes. It is preferred that the coating granu- of the punch and the inner surface of the die define a volume late has a fine fraction that is less than 30%. By "fine fraction" for receiving a precise amount coating material. Once loaded, is meant granulate having particle size of up to about 63 the platform is rotated until the die is positioned under an microns. upper punch. The upper punch is then urged down onto the Preferred features for the second and subsequent aspects of coating material under a defined compression force and the 40 the invention may be as for the first aspect mutatis mutandis. coating material is pre-compressed or tamped between the FIG. 1: is a representation of a tablet in cross section upper and lower punch. A pre-formed core is then fed into die showing the coating and core and the axes (A-B) and (X-Y). to rest on the tamped coating. Conventional press coating FIG. 2: Shows an in-vitro dissolution profile of the dosage apparatus may be equipped with centering devices that enable form of Example 2. cores to be positioned both vertically and radially. This might 45 There now follows a series of examples that sewe to illus- be achieved by a tamping process, whereby an initial amount trate the invention. of coating material is placed in a die and is tamped with a shaped punch, such as a pin punch, that leaves an indentation EXAMPLE 1 in the coating material in which to receive a core. Thereafter, in a second filling operation, a precise amount of coating 50 Preparation of a Prednisone-Containing Tablet material is fed into the die to cover the core, and an upper punch compresses the coating material with a defined com- The active core was prepared for the press coated system as paction force to form tablets according to the present inven- follows. The composition of the core is detailed in Table 1. tion. Lactose monohydrate (Lactose Pulvis~H2O®, Danone, 'Ihe compression force applied during the tamping process 55 France and Lactose Fast Flo® NF 3 l 6, Foremost Ing. Group, is relatively light and is just sufhcient to provide a bed of USA) is a filling agent with interesting technical and func- coating material to receive the core and to prevent movement tional properties. Lactose Pulvis°II2O is used in a blend pre- of the coating material as a result of centrifugal force. Sub- pared by wet granulation and Lactose Fast Flo is used in a sequent compression to form the tablet may be adjusted to blend prepared for direct compression. Microcrystalline cel- give tablets of requisite hardness. Preferably, this compres- 60 lulose (Avicel® pH 101, FMC International, Ireland) is used sion force is 400 kg, although this may be adjusted by +/-30% as an insoluble diluent for direct compression. Polyvinyl pyr- in order to give tablets of the required hardness. rolidone (Plasdone® K29-32, ISP Technology, USA) is a The amount of coating material fed into the die can be trranulatingV agent.v 1 soluble in water., which has the abilitv.f of precisely defined having regard to the density of the coating binding the powder particles. Croscarmellose sodium (Ac- matenal to ensure after compression that the tablet is formed 65 Di-Sol®, FMC Corporation, USA) is used in the fonnulation with the required coating thickness about the (A-B) axis; and as a super disintegrant. As the external phase, magnesium die dimensions of the die is selected to provide the thickness stearate (Merck, Switzerland) was added as a lubricant and US 8,168,218 B2 15 16 silicon dioxide (Aerosil® 200> Degussa AG, Germany) in 0.710 mm apertures. They were placed in a Niro-Fielder order to improve How properties of the granular powder. PMA 65-liter mixing granulator. Then, the components were homogeneously mixed for 6 min, at impeller speed 200 rpm, TABLE 1 without chopper. Subsequently, the granulating solution (pu- 5 rified water, 8. 1 2% ofthe weight of the dry blend) was added Ingredients Content (mg/mb let) - within 2 min at impeller speed 200 rpm and chopper speed Prednisone 5.00 1500 rpm using a nozzle 4,9 (spraying rate of 520 g/min). Lactose (Lactose Pulvis H20 NF 316) 39.10 Mixing was continued for homogenisation and massing for l Polyvinyl pyrrolidone (Plasdonc ® K29-32) 4.00 min at impeller speed 400 rpm and chopper speed 3000 rpm. Sodium cafooxymethyl cellulose (Ac~Di»Sol ®) 11.00 10 The mixed wet granulate was then dried in a Niro-Fielder Magnesium steamte 0.60 Silicon dioxide (Aerosil ® 200) 0.30 TSG 2 fluidised air bed dryer. The inlet temperature was maintained at 45° C. during drying. The drying lasted 33 min Total 60.00 to have residual moisture less than 2.5%. The yielded dry granulate was calibrated in a Prewitt MGI 205 granulator The coating of the prednisone press coated tablet is of a 15 using a screen having 0.8 mm apenures for 4 min at speed 244 hydrophobic, water insoluble nature. This barrier is mainly osc/min (graduation 7). Appropriate amounts of Aerosil® composed of dibasic calcium phosphate (Emcompress®, 200 and magnesium stearate were manually sieved using a Mendell, USA) and glyceryl behenate (Co1npritol® 888ATO, screen with 1.0 mm apertures. Gattefossé, France). Polyvinylpyrrolidone (P1asdone® K29- Half of the dry granulate was put in a Niro-Fielder PMA 32) is a granulating agent, soluble in water, which has the 20 65-liter, followed by Aerosil® 200 and then by the other half ability ol' binding the powder particles. Yellow ierric oxide of the dry granulate. The ingredients were mixed for 2 min at (Sicovit® Yellow 10, BASF, Germany) was added as a dye. A impeller speed 200 rpm, without chopper. Finally, magne- detailed composition of this barrier blend is given in table 2. sium stearate was addw and mixing was continued for 2 more minutes at impeller speed 200 rpm, without chopper. TABLE 2 25 440 mg of coating blend was press coated on a core to provide press coated tablets (9 mm diameter). 305 mg of Combosition of the coatiniz coating blend was press coated on a core to provide press coated tablets (8 mm diameter). These different press coat- Ingredients Content (%) ings were done utilising a Kilian RUD tabletting machine. Dibasic calcium phosphate (Emcomprcss ®) 50.00 First and second loadinglioppers are Hlled up with the coating 30 Glyceryl Behenate (Compritol ® 888 ATO) 40.00 granulate. Between the two loading hoppers, the machine is Polyvinylpyrrolidone (Plasdone ® K29-32) 840 equipped with a transfer system adapted to feed the cores. For Yellow Ferris Oxide (Sicovit ® yellow 10 E 172) Q10 Silicon dioxide (Aerosil ® 200) 0.50 each tablet, the first loading hopper supplies with about half Magnesium stearate 1.00 of the quantity to be applied to the core. Then, the feeding system provides and positions a core centred in the die. Sub~ lbtai 100.00 35 sequently, the second loading hopper supplies with the other halfofthe quantity to be applied to the core. The compression The required amounts ofprednisone, Ac-Di-Sol®, Lactose step Lneu L)CCUI`S Pulvis H2O®, Plasdone® K29-32 were weighed and manu- ally sieved with a screen having 0.710 mm apenures. The TABLE 3 components were homogeneously mixed in a Niro-Fielder 40 luinmcnt imnlemenfed for the manllfachlrinsz nroccss PMA 25-liter mixing granulator for 6 min at impeller speed Ec 250 rpm without chopper. A prednisone assay was perfomied Equ ipment Brzuld nzune/Type Manufactumr/Supplier on this premix. Subsequently, the granulating solution (puri- fled water, 25.47% ofthe weight of the dry blend) was added Mixing Niro~Fielder PMA Aéromatic-Fielder AG, within 4 min at impeller speed 250 rpm and chopper speed 45 granulator 25/65 litres Bubendorfl Switzerland Fluidised air Glatt WSG5 Maschinen und appamtebau 1500 rpm, using a nozzle Hl/4VV-95015 (spraying rate of bed dryer AG, Pratteln, Switzerland 250 g/min). Mixing was continued for homogenisation and Fluidised air Niro-Fielder TSG 2 Aémmalic-Fielder AG, massing of the wet mass for 3 min at impeller speed 500 rpm bed dryer Bube11dor£ Switzerland and chopper speed 3000 rpm. Granulator Frewitt MGI 205 Frewitt SA, Granges-Pacot, The mixed wet granulate was then dried in a Glatt WSG5 Switzerland 50 Infrared Mettler PE 360 Mettler Toledo AG fluidised air bed drier. The inlet temperature was maintained moisture Moistuurc Analyzer Grcifensee, Switzerland at 45° C. during drying. The drying lasted 20 min to get a analyser granulate with a residual moisture less than 2 .5%. The yielded Multilayer Hata HT-AP55LS-U/3L Elisabeth-Carbide, Antwerp, dry granulate was calibrated in a Frewitt MGI 205 granulator tablet press Belgium using a screen with 0.8 mm apertures for 3 min at speed 244 Dry coating Kilian RUD Kilian & Co GmbH, Cologne, 55 tablet press Genuany osc/min (graduation 7). Appropriate amounts of Aerosil® 200 and magnesium stearate were manually sieved using a screen. with 1.0 mm apertures. Halfof the dry granulate was put in a Niro-Fielder PMA 25-liter mixing granulator, fol- EXAMPLE 2 lowed by Acrosil® 200 and then by the other half of the dry granulate. The ingredients were mixed for 2 min at impeller 60 ln Vitro Dissolution Profile speed 250 rpm. Finally, magnesium stearate was added and mixing was continued for 2 min at impeller speed 250 rpm. The in vitro dissolution profile ofa tablet containing a 5 mg The coating blend was prepared according to the process loading of prednisone prepared according to the method of described below. Batch size for the barrier blend was 13 kg. Example 1 was detennined using USP dissolution apparatus Weighed amounts of Emcompress®, Compritol® 888 ATO, 65 No, 2 (paddles) and stationary baskets and applying a stirring Lactose pulvis-H2O®, Plasdone® K29-32 and Sicovit® Yel- rate of 100 rpm. The dissolution medium was purified water, low 10 E 172 were manually sieved with a screen having with a volume of 500 ml. Us 8,168,218 B2 17 18 After 4 hours no drug substance release is observed. How- Wherein coating material about the (X-Y) axis is relatively ever, within 4.5 hours there is approximately 80% release and less dense than the coating material disposed about the by 5 hours 100% release of the drug substance (see FIG. 2). (A-B) axis and the coating material about the (X-Y) axis is more permissive towards ingress of aqueous media EXAMPLE 3 c than the coating material disposed about the axis (A-B), and wherein the axis (A-B) is the axis of the direction of A study was carried out to determine the effect of food on movement of the punch used in the press-coating of the the bioavailability of a 5 mg prednisone tablet described tablet: above. said tablet comprising the following ingredients The study did not compare the tablet in the fed and fasted 10 Core of 5 mg prednisone tablet: state. Rather, the study was adjusted to take into account the Prednisone 8.33% as a percentage by weight in said core; Chrono-pharmacokinetics ofprednisone and the fact that it is Lactose monohydratc 64.47% as a percentage by weight in to be administered in the evening, eg. about 8 pm, which is said core; required in order that the blood plasma levels will peak before Povidone 6.67% as a percentage by Weight in said core; Croscarmellose sodium 18.33% as a percentage by weight secretion of IL-6 to improve the ellicacy of the treatment. 15 in said Core; Thus the study was designed to compare the tablet during real Red ferric oxide 0.5% as a percentage by weight in said time administration and with likely food intake scenarios at core this time. It was considered unreasonable that at 8 pm a Magnaium stearate Vegetable origin 1.0% as a percentage subject would be approximately 8 hours fasted. Accordingly, by Weight in said core; the following food intake scenarios were tested: 20 Colloidal silicon dioxide 0.5% as a percentage by weight in a) To simulate a lasted state at 8 pm in the evening, a light said core; meal was given 21/2 hours before administration that con- Coating: tained a limited number of calories (i.e. 22% of total daily Dibasic calcium phosphate dihydrate 50% as a percentage calories and with a limited fat content of 15.5 g) and being by weight in said coadng; devoid ofany slowly digestible nutrients. This is called the 25 Glyceryl behenate 40% as a percentage by weight in said "semi-fasted" state. The composition of this meal con- coating; sisted of brown bread, margarine, cheese spread, an apple Povidone 8.40% as a percentage by weight in said coating; (sldn removed) and fruit cocktail in syrup. Yellow ferric oxide 0. l % as a percentage by weight in said b) Fed state is simulated by giving a higher fat meal % hour coating; before dosing containing 35% of the daily intake of calo- 30 Magnesium stearate Vegetable origin 1.0% as a percentage ries and 26 g offat. by weight in said coating; Anassumption made was that in the case ofthe semi-fasted Colloidal silicon dioxide 0.5% as a percentage by weight in said coating. state, after 2% hours the stomach was already emptied, or 4 cm.- |.1_1-A...-..-...1:..,_ ..|..:... 1 ._.I..._,.:.. .\.I....I..I.~ substantially emptied of food, L. inc: Laurel aucurcung tu cialul 1 wuciern, upuu 21LlUlllLlb' tration to a patient, the lag time before drug release is 2 to 6 The composition of the high fat meal was pasta with spa- 35 hours. ghetti sauce, soup and vegetables, Applejuice, Ice cream and 3. The tablet according to claim 1, said tablet having an in whipped cream. vitro dissolution profile using USP dissolution apparatus No. The methodology consisted ofan open, randomized, 3-pe~ 2, at a stirring rate of 100 rpm and in a dissolution medimn of riod crossover single oral dose study with 7 days washout 500 mL purified water, wherein said dissolution profile com- periods. The patient population consisted of 27 healthy male 40 prises a median lag time of about 4 hours with at least 80% of volunteers. a dwg substance being released after 4.5 hours and about The pharmacokinetics of the formulation was compared 100% of the drug substance being released alter 5 hours. lor each of the led and semi-lasted states with a standard 4. The tablet according to claim 1 wherein intra»subject or immediate release form (DecortinR) administered at 2 am. inter-subject variability in Tmax differs by less than +/-20% ln the semi-fasted state the formulation exhibited a median 45 whetherornot a patient is in a fed ora fasted (fed/fastw) state. lag time of 3.5 hours. Relative to Decortink dosed at 2 am, the 5. The tablet according to claim 1 wherein upon adminis- formulation was fully bioequivalent with a Cmax of 97% and tration to a patient the ratio of Cmfzx fed/fasted upon single relative bioavailability of 101% (AUC0_in/i,,i,y). dosing is 0.7 to 1.43. ln the fed state, the median lag time was 4 hours. Cmax was 6. The tablet according claim 1 wherein upon administra- 105% compared to DecortinR, and relative bioavailability 50 tion to a patient the ratio of AUC fed/fasted upon single (AUC0.i,v,,/i¢) was 113%. dosing is 0.8 to 1.25. Compared to the formulation in the semi-fasted state, the 7. A pharmaceutical package containing a tablet according formulation in the fed state was 108% on Cnzax and 112% on to claim 1 together with labelling or instmetions that the tablet can be taken with or without food. AUCC-f»y'inizy 8. A method of treating arthritic pain, allergies, asthma, These results demonstrate that formulations of the present 55 Crohn's disease, ulcerative colitis, irritable bowel syndrome invention display excellent bioavailability with no significant (IBS) and inflammatory bowel disease (IBD) by providing to effect of food. a patient in need of treatment a tablet according to claim 1. The invention claimed is: 9. A method of preparing a tablet according to claim 1 1. A press-coated tablet comprising a core containing 5 mg comprising the steps of: ofprednisone and a coating around thecore, said core being 60 (a) forming a first granulate-containing coating material; disposed within said coating such that the coating thickness (b) forming a core comprising a second granulate-contain- about an axis (X-Y) is thicker than the coating about an axis ing core material; and (A-B) orthogonal to (X-Y), (C) press coating the first granulate-containing coating Wherein the thickness ofthe coating about the axis (X-Y) is material around the core. selected such that the coating ruptures upon immersion 65 in an aqueous medium after a period ofbetween about 2 to about 6 hours to release the drug, >! < >| < > I< > |= >| < EXHIBIT E |1111\|||||||||1||||||||||||||1IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIq US008394407B2
<12> United States Patent (10) Patent No.: US 8,394,407 B2 Vergnault et al (45) Date of Patent: *Man 12, 2013
(54) DELAYED RELEASE TABLET WITH 5,567,696 A 10/1996 McGuire et al. DEFINED CORE GEOMETRY 5,792,476 A 8/1998 Hallgrcn 6,183,780 B 1 2/2001 Van Balkcn et al 6.365.185 B1 4/2002 Ritschel et al. (75) Inventors: GuyVergnault,Kembs (FR);Pascal 6,488,960 B1 12/2002 Bardsley Grenier, Kappelen (FR); Christophe 6,599,284 B2 7/2003 Faour Dragan, Geispitzen (FR) 6,620,439 B 1 9/2003 Mehta 6,733,784 B1 5/2004 Ayres (73) Assignee: Jagotec AG, Muftenz (CH) 8,168,218 B2 *K 5/20 12 Vergnault et al 424/464 2004/0018327 A1 1/2004 Wynn et al. 2005/0008702 A1 1/2005 Faour et al. ( *' ) Notice: Subject to any disclaimer, the term ofthis 2006/0057200 A1 3/2006 Schaeflier patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. FOREIGN PATENT DOCUMENTS EP 0 463 877 A1 1/ 1 992 Thls patent 1s subject to a termmal d1s- EP 0 673 645 A2 9/ 1 995 claimer. FD 0 776 660 A2 6/ 1 997 EP 0 939 623 A1 2/2002 (21) Appl. No.: 13/428,548 EP 1 275 381 A1 1/2003 EP I 067 910 A1 5/2004 <22> Filed Mar. 23, 2012 JP 2001_010950 A 1/2001 (Continued) (65) Prior Publication Data US 2012/0177739 A1 Jul. 12, 2012 OTHER PUBLICATIONS
Related U.S. Application Data Conte et al. (1993) Biomaterials 14: 1017-1023 (63) Continuation of application No. 10/554,538, filed as (Continued) application No. PCT/1B2004/001693 on Apr. 23, 2004, now Pat. No. 8,168,218 Primary Examiner - Paul Dickinson 30 Foreign Application Priority Data (74) Attorney, Agent, or Firm - Muriel Libeno, Esq.; Mintz Levin Cohn Ferris Glovsky and Popeo, P.C. Apr. 24, 2003 (GB) 0309342.4
(51> Int. cl (57) ABSTRACT A6IK 9/48 (2006.01) (52) U.S.Cl. 424/463 A tablet comprising a core containing an active agent, and a (58) Field of Classification Search None coating, the core being disposed within the coating such that See application Hle for complete search history the coating has a thickness about a longitudinal axis (X-Y) of about 4.85 to 4.95 mm. The position of the core within the 5 References Cited coating dictating that the active agent is released rapidly after a lag time during which time no active agent is released. U.S. PATENT DOCUMENTS 51279,832 A 1/1994 Greissinger et al 5,464,633 A 11/1995 Conte et al. 19 Claims, 2 Drawing Sheets
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FOREIGN PATENT DOCUMENTS WO WO-2004/093850 A1 11/2004 WO WO-2004/l03349 A2 12/2004 WO WO-92/00064 A1 1/1992 WO WO-2005/027843 A2 3/2005 WO WO-92/1 1845 A 1 7/1992 OTHER PUBLICATIONS WO WO-93/19741 A1 10/1993 WO WO-96/40078 A1 12/1996 Fukui et al, (2000) J Controlled Release 68: 215-223. WO WO-0 1/08421 A2 2/2001 Lin et al. (2001) .L Pharmaceutical Sciences 90: 2005-2009. WO WO-01/52819 A1 7/2001 Zlatldna, A.P., "The Modem Therapeutic Tactics of Inflammatory WO WO-0 1/68056 9/2001 Bowel Disease, Consilium Medicum", Gastroenterology 6 (1): 2004 WO WO-0 1/68056 A1 9/2001 (English machine translation appended), WO WO-01/80824 A2 11/2001 GB Search Report dated Aug. 22, 2003 corresponding to GB WO WO-02/00204 A1 1/2002 0309342.4. WO WO-02/072033 9/2002 GB Search Report dated Oct. 23, 2003 corresponding to GB WO WO-02/072034 A2 9/2002 0309342.4. WO WO-03/075919 A1 9/2003 International Search Report mailed Oct. 21, 2001 corresponding to WO WO-03026626 A3 10/2003 PCT/1B2004/001693. WO WO-2004028510 A1 4/2004 WO WO-2004/093843 A1 11/2004 * cited bv examiner U.S. Patent Mar. 12, 2013 Sheet 1 of 2 Us 8,394,407 B2
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1 2 DELAYED RELEASE TABLET WITH media into an active-agent-contailling core and thereby cre- DEFINED CORE GEOMETRY ating a lag time during which no drug substance is released. The gellable coating acts as a medium through which drug is This invention is concerned with a tablet comprising a core released in a delayed or modified manner. lt is stated that the containing a drug substance and a coating that is applied to 5 lag time can be modulated by varying the coating Weight. said core by means of compression-coating techniques. The There are several problems with such an approach: First, tablet can contain all manner of drug substances, but is par- release of the drug occurs by means of diffusion through the ticularly suitable tbr administering those that are advanta- gelled coating. In the case ofdrugs that have a narrow absorp- geously released only after a predetermined lag time after tion window, or in the case of drugs adapted to treat a rela» administration. The tablets are particularly suitable for 10 tively small affected area ofthe Gl tract or colon, once the lag administering lucocorticosteroids selected from prednisone, time has expiredit is desirable to release the drug as rapidly as predni solone or methylpredni solone. possible to ensure that all or substantially all of the drug Research into the chronopharmacological field has dem- released at the desired site. A slow diifusion ofthe drug is not onstrated the importance of biological rhythms in drug appropriate in such cases. Further, by attempting to control therapy. Very often, optimal clinical outcomes cannot be 15 lag time by controlling the coating weight, the formulator's achieved if a drug is released constantly after ingestion. This latitude is limited in this regard, because increasing coating is particularly the case if symptoms of a disease display weight adds additional cost to the dosage form, and it also circadian variations. ln such cases, drug release should vary adds to the size of the dosage form, which may make it in a manner that is sympathetic to these variations in order difficult to swallow for certain patient populations such as that drug plasma concentrations are at an optimal therapeutic 20 minors and tbr the elderly or infimi. Still further, merely level only when required to treat symptoms ofa disease state. adjusting coat weight does not ensure that a coating is of a ln particular, if symptoms of a disease become apparent at desired thickness at a particular site. It remains that ifthe core night, or in the early hours upon waking, the time when a is not correctly positioned within a die of a press coating patient must take its medication in order to affect the best machine, despite having selected a particular coat weight, clinical outcome requires detailed consideration. For 25 part of the coating may be unintentionally thinner than example, most asthma attacks occur in the early hours of the desired, resulting in unforeseen premature release ofthe drug. moming, e.g. 4 am to 6 am. This is a result of complex The applicant has now surprisingly found that by carefully circadian rhythms such as the secretion ofhydrocortisone and selecting the geometry of a core Within its coating, it is pos- adrenaline. lschaemie heart diseases occur most often during sible to manipulate the coating thickness at specihc points on the night or in the early waking hours around breakfast time. 30 the tablet to ensure an appropriate coating thickness to pro- Stillness and pain associated with rheumatoid arthritis and duce tablets having a specifically tuned lag time. Further- osteoanhritis occur in the early waking hours, which is more, because one is able to increase thickness where it is believed to be as a result of the secretion of lL-6 in the early needed in the coating, one can reduce coating material to hours of the morning, e.g. around 2 am to 4 am. allow use of the minimum amount necessary to achieve the With conventional immediate release dosage fonns, syn- 35 desired release characteristics, thus saving on cost of materi- chronization of drug administration with a nocturnal circa- als and also reducing the overall tablet size. dian rhythm responsible for the symptoms experienced by a Still further, the applicant has found that by selecting patient would require a patient having to be disturbed from appropriate core and coating materials, one is able not only to sleep to take a medicament during the early hours of the accurately control the lag time, one is also to ensure that all, moming in order to achieve the most efficacious clinical 40 or substantially all, of the drug substance upon expiry of the outcome. Of course, this would be highly inconvenient for a lag time is released rapidly and at the absorption site, or the patient. locally aliected site. Accordingly, there remains a need to provide dosage forms Accordingly, in a first aspect ofthe present invention there that can be taken at a convenient hour belbre bedtime that will is provided a tablet comprising a core containing an drug release an effective dose of a drug substance only after a 45 substance, and a coating aromid said core, the core being pre-determined lag time in order to synchronise peak plasma disposed within said coating such that the coating thickness concentrations of drug with a particular circadian rhythm. about an axis (X-Y) (see FIG. 1) is thicker than the coating Furthermore, particularly in relation to drug substances about an axis (A-B) (see FIG. 1) orthogonal to (X-Y), and that have a narrow absorption window, or in the case of drug wherein the thickness of die coating about the axis (X-Y) is substances that are adapted to treat a local condition in the 50 selected such that the coating is adapted to rupture upon colon such as Crohn's disease, ulcerative colitis, IBS and IBD immersion in a11 aqueous medituu after a period of between there is also a need to provide a dosage fonn that rapidly about 2 to 6 hours. releases die drug substances after reaching the end of the lag According to the present invention, the coating thickness time about the axis (X-Y) is thicker than the coating about the axis Still further, having regard to the varied lite styles of 55 (A-B). The ratio of the thickness of the coating about the axis patients, in order to reduce the inter- and intra-subject vari- (X~Y) to the thickness ofthe coating about the axis (A-B) may ance in bioavailability there is a need to provide a dosage form be from 2.2 to 2.6:l.0 to 1.6. that releases a dwg with a reliable lag time, and to provide ln another aspect of the invention there is provided a tablet peak plasma dwg concentrations at a pre-determined time, comprising a core containing an drug substance and a coating irrespective of Whether a patient is in a fed or fasted state. 60 around said core, the core being disposed within said coating Time controlled release formulations are known in the art such that the coating thickness about an axis (X-Y) is thicker that are able to deliver drug substances with a delined release than the coating about an axis (A-B) orthogonal to (X-Y), and rate after a lag time during which no drug substance is die thickness of the coating about the axis (X~Y) is at least released. Such a dosage form is disclosed in WO 02/072033. about 2.2 nun, particularly about 2.2 to 2.6 mm, more par- This dosage form is characterized by a coating containing a 65 ticularly about 2.35 to 2.45 mm. natural or synthetic gum that gels in the presence of aqueous The thickness of the coating around or about the axis (A-B) media. The coating acts as a barrier to the ingress of aqueous is not critical lor controlling the lag time. Accordingly, the Us 8,394,407 B2 3 4 formulator has some latitude in selecting its thickness. It of the X-Y axis is, in part, responsible for controlling the should not be so thick as to render the final tablet to large, yet release of the druLg substance from the core. Once the aqueous on the other hand the coating should not be so thin that the medium contacts the core, the core reacts by swelling or coating is render weak and liable to crack under the slightest effervescing thelreby to break open the core generally along mechanical stress. Preferably, me thickness of the coating the direction of ingress of the aqueous media (i.c. the X-Y about thc axis (A-B) is about 1 .0 to about 1.6 mm. The coating axis) to fonn to e:ssentially two hemispheres of coating mate- thickness either side ofthe core on the axis (A-B) may or may . 1 ~ r \ 1 ,~ . - 1 1-.1 /A \ rial that may renmain conjoined, which has an appearance of not ne equal. FOI' example, on a nrst side OI me core tA-core) an opened clam shell. The reaction of the core material to the the coating may have a thickness ofabout 1 .2 to 1.6 mm, more presence of the aqueous medium is likewise in part respon- preferably 1.35 to 1.45 mm, whereas on the other side of the 10 sible for controlling the release of drug substance from the core (B-core) the thickness may be about 1 .0 to 1.4 mm, more core. preferably 1.15 to 1.25 mm. The hardness ofthe tablet is preferably at least 60 Newtons, Accordingly, in a particular embodiment of the present e.g. 60 to 80 Newtons, and more particularly 60 to 75 New- invention there is provided a tablet comprising a core con- tons. Hardness may be measured according to a process taining an dwg substance, and a coating, the core being dis- 15 posed within die coating such that the coating has a thickness described in 'lhc European Pharmacopoeia 4, 2.9.8 at page about an axis O(-Y) of at least about 2.2 mm, more particu- 201. The test employs apparatus consisting of 2 opposing larly about 2.2 to about 2.6 mm, still more particularly 2.35 to jaws, one ofwhich moves towards the other. The flat surfaces 2.45 mm, and the thickness ofthe coating about an axis (A-B) of the jaws are perpendicular to the direction of movement. orthogonal to (X-Y) is between 1.0 and 1.6 mm. More par- 20 The crushing surfaces of the jaws are flat and larger than the ticularly, along the axis (A-B) on a first side of the core Zone of contact with the tablet. The apparatus is calibrated (A-core) the thickness may be about 1.2 to 1.6 mm, more using a system with a precision of one Newton. The tablet is preferably 1.35 to 1.45 mm, and on a second side of the core placed between thejaws. For each measurement, the tablet is (B-core) the thickness may be about 1.0 to 1.4 mm, more oriented in the same way with respect to the direction of the preferably 1.15 to 1.25 mm. 25 applied force. Measurements are carried out on 10 tablets. Tablets ofthe present invention are fonned by compression Results are expressed in tenns of the mean, minimum and coating methods as will be described in more detail herein maximum values (in Newtons) of the force needed to crush below. Compression coated tablets are generally fonned by the tablets. placing a ponion of a powdered coating material in a die and Tablets having a hardness within this range are mechani- tamping the powder into a compact form using a punch. A 30 cally robust to withstand forces generated in the stomach, core is then deposited onto the compacted coating material particularly in the presence of food. Furthermore, the tablets before the remainder ofthe coating material is introduced into are sufficiently porous about the (X-Y) plane of the tablet to the die and compression forces are applied to form the coated permit ingress ofphysiological media to the core at an appro- tablet. To ensure that the core is placed on the tamped coating priate rate to ensure that the drug substance is released within material to ensure its correct geometry relative to the coating 35 an appropriate lag time, e.g. within 2 to 6 hours. in the Hnal tablet form, it is preferable to employ means for As stated above, it is a preferred aspect of the present positioning the core in relation to the coating material ina die. invention that the tablets are adapted to release a drug sub- Typically such means may be provided by a pin punch. A pin stance from the core after a pre-determined lag time, as well punch is a ptmch that has a convex surface that contacts the as being adapted to release all, or substantially all, ofthe dwg coating material to leave a small depression or hollow in the 40 substance within a very short period oftime after the expiry of tamped coating material. Thus, when the core is placed into the lag time. This ensures that all, or substantially all, of the the die on the tamped material, it sits in the depression or drug is released at the lntended absorption site along the Gl hollow and its correct geometry is assured in the final tablet tract, or onto the affected site ofthe GI tract ifthe condition to form. be treated is a local topicalcondition. lt is preferred that the The thickness ofthe coating along and about the axis ofthe 45 tablets ofthe present invention release all, or substantially all direction of movement of the punch (the "(A-B)" axis ofa drug substance within about % hour to about l hour after referred to above) is determined by the amount of coating the selected lag time. material added to the die and the compaction force applied to This aspect of the present invention is important for deliv- form die tablet. On the other hand, the thickness ofthe coating ering drugs having a rather narrow absorption window in the along and about the "(X-Y)" axis is determined by the size of 50 upper GI tract, such as the glucocorticosteroids referred to the core, its position within the die and the diameter ofthe die. above. In such cases, the dwg should be released before the lt will be apparent to the skilled person that there is a plurality tablet can pass into the bowel, where absorption ofsuch drugs of axes (X-Y) orthogonal to die axis of movement of the is poor. lt is made particularly important if the tablet is punch (the "A-B" axis), which extend radially from the centre intended to perform in the same manner independent of the of the tablet to its circumference, and when the reference is 55 ellects of food, lt is well known that the rate at which a tablet made to the diickness of the coating about an axis X- will pass through the GI tract willvary depending on whether reference is being made the thickness about any or all ofthese a patient is in a fed or fasted state. In the fasted state, a tablet axes. will typically clear the stomach within about 'é hour and 1 During the compression ofthe coating around the core, the hour after ingestion, and thereafter take a further 4 to 5 hours coating material above and below the core (the material along 60 to clear the upper GI tract dirough the ileosecal junction. In a and about the (A~B) axis) is relatively highly compacted and fed state, a tablet may take as long as 4 hours to be cleared dense. On the other hand, the coating material disposed along from the stomach, and a further 4 to 5 hours to clear the upper and about the (X-Y) axis is subjected to lower compaction GI tract. Accordingly, if a tablet is to release of all, or sub- forces and is relatively less dense. Accordingly, tl1c material stantially all, of its drug into the upper Gl tract irrespective of about the (X-Y) axis is relatively porous and pennissive 65 the fed state of a patient, it is preferable that the release me towards the ingress of aqueous media The rate of in ress of drug after the lag time occurs within a time limit referred to in the aqueous medium through the coating along the direction the paragraph above. Us 8,394,407 B2 5 6 It should be understood that whereas it is desirable that no Glyceryl behenate is an ester of glycerol and behenic acid drug substance is released during the lag time, some release (a C22 fatty acid). Glyceryl behenate may be present as its may occur. However, any release ofdrug substance during the mono-, di-, or tri-ester form, or a mixture thereof. Preferably lag time should not exceed 10% of the total amount of drug it has an HLB value of less than 5, more preferably approxi- substance in the core. 5 mately 2. It may be present in amounts of about 5 to 85% by The coating employed in a tablet according to the present weight of the coating, more particularly from 10 to 70% by invention is preferably formed of insoluble or poorly water weight, and in certain preferred embodiments from 30 to soluble hydrophobic material. ln use, the coating optimally 50%. acts merely as a barrier to the ingress of aqueous physiologi- Calcium phosphate salt may be the dibasic calcium phos- cal media thereby providing a drug release lag time. For the 10 phate dihydrate and may be present in an amount ofabout 10 reasons set forth above, optimally the tablet should have the to 90% by Weight ofthe coating, preferably 20 to 80%, e.g. 40 minimum thickness possible consistent Wim the desired lag to 75%. time. Accordingly, employing water insoluble or poorly, The coating may contain other common tablet excipients soluble hydrophobic coating materials, one is able to produce such as lubricants, colourants, binders, diluents, glidants and a coating that is relative recalcitrant to the ingress ofmoistuure 15 taste-masking agents or flavourants. and so long lag times can be achieved with relatively thin Examples of excipients include colourants such a ferric coatings. oxide, e.g. yellow ferric oxide; lubricants such as magnesium Further, in order to achieve dw rapid release of drug sub- stearate; and glidants such as silicon dioxide, e.g. colloidal stance alter the lag time has expired, it is desirable that the silicon dioxide. Yellow ferric oxide may be used in amounts coating contains no, or substantially no, ingredients that swell 20 of about ().()l to 0.5% by weight based on the coating; mag- and gel agents to such an extent that the coating acts as a nesium stearate may be present in amounts of 1 to 20% by diflilsion barrier to the release of drug substance. In this weight of the coating, more preferably 2 to 10%, e.g. 0.5 to regard, it is preferable that the coating contains no, or sub- l.0%; and colloidal silica may be used in amounts of 0.1 to stantially no, materials such as natural or synthetic gums that 20% by weight of the coating, preferably l to 10%, more modulate release of the drug substance through an intact 25 preferably 0.25 to l.0%. swollen coating. Drug substance is released from the core as The core comprises in addition to a dmg substance, a a result of the physical mpturing of the coating and not as a disintegrating agent or mixmres of disintegrating agents used result of thc drug substance difliising through a swollen coat- in immediate release fonnulations and well know to persons ing material. That the mechanism of drug release is substan- sldllcd in the art. The disintegrating agents useful in the tially dependent on the physical splitting of the coating, and 30 exercise ofthe present invention may be materials that effer- not on a diilusion process through a swellable and gellable vesce and or swell in the presence of aqueous media thereby coating, means that a wide range of drug substances can be to provide a force necessary to mechanically disnupt the coat- delivered from tablets according to the invention in a reliable ing material. and reproducible manner. Preferably a core contains, in addition to the drug sub- The tablet coating may contain one or more water insoluble 35 stance, cross-linked polyvinyl pyrollidone and croscarmel- or poorly soluble hydrophobic exciplents. Such excipients lose sodium. may be selected from any of the known hydrophobic cellulo- The following is a list of preferred core materials. The sic derivatives and polymers including alkylcellulose, e.g. amounts are expressed in terms of percentage by weight ethylcellulose, hydroxypropyl cellulose, hydroxypropylm- based on the Weight of the core. ethyl cellulose, carboxymethyl cellulose, and derivatives 40 Cross-linked polyvinyl pyrollidone is described above and thereof; polymethacrylic polymers, polyvinyl acetate and is useful as a disintegrating agent, and may be employed in the cellulose acetate polymers; fatty acids or their esters or salts; core in the amotmts disclosed in relation to the core. long chain fatty alcohols; polyoxyethylene alkyl ethers; poly- Croscarmellose sodium is an intemally cross-linked oxyethylene stearates; sugar esters; lauroyl macrogol-32 sodium carboxymethyl cellulose (also known as Ac-Di-Sol) glyceryl, stearoyl macrogol-32 glyceryl, and the like. 45 useful as a disintegrating agent. Hydroxypropylmethyl cellulose materials are preferably Disintegrating agents may be used in amounts of 5 to 30% selected from those low MW and low viscosiw materials such bv weight based on the core. However, higher amounts of as E-Type methocel, and 29-10 types as defined in the USP. certain disintegrants can swell to form matrices that may Other agents or excipients that provide hydrophobic qual- modulate the release of the drug substance. Accordingly, ity to coatings may be selected from any waxy substance 50 particularly when rapid release is required after the lag time it known for use as tablet excipients. Preferably they have a is preferred that the disintegrants is employed in amounts of HLB value of less than 5, and more preferably about 2. up to 10% by weight, e.g. about 5 to 10% by weight. Suitable hydrophobic agents include waxy substances such as The core may additionally comprise common tablet excipi- carnauba wax, paraffin, rnicroerystalline wax, beeswax, cetyl ents such as those described above in relation to the coating ester wax and the like; or non-latty hydrophobic substances 55 material. Suitable excipients include lubricants, diluents and such as calcium phosphate salts, eg. dibasic calcium phos- fillers, including but not limited to lactose (for example the phate. mono-hydrate), ferric oxide, magnesium stearates and colloi- Preferably the coating contains a calcium phosphate salt, dal silica. glyceryl behenate, and polyvinyl pyrollidone, or mixtures Lactose monohydrate is a disaccharide consisting of one thereot and one or more adjuvants, diluents, lubricants or 60 glucose and one galactose moiety. lt may act as a tiller or fillers. diluent in the tablets of the present invention. lt may be Preferred components in the coating are as follows, with present in a range of about 10 to 90%, preferably from 20 to generally suitable percentage amounts expressed as percent- 80%, and certain preferred embodiments from 65 to 70%. age weight of the coating. As stated above, it is an important aspect of the present Polyvinyl pyrollidone (Povidone) is preferably present in 65 invention that core is correctly located within the coating to amounts of about 1 to 25% by weight or the coating, more ensure that a tablet has the appropriate coating thickness. In particularly 4 to 12%, e.g. 6 to 8%. this way, lag times will be reliable and reproducible, and US 8,394,407 B2 7 8 intra-subj ect and inter-subject variance in bioavailability can antihistamines (e.g., azatadine maleate, brompheniramine be avoided. It is advantageous to have a robust in process maleate, carbinoxamine maleate, chlorpheniramine maleate, control to ensure that tablets in a batch contain cores having dexchlorpheniramine maleate, diphenhydramine hydrochlo- the appropriate geometry in relation to the coating. Controls ride, doxylamine succinate, methdilazine hydrochloride, can be laborious in that they require an operator to remove 5 promethazine, trirneprazine tartrate, tripelemiamine citrate, random samples from a batch and to cut them open to physi- tripelennamine hydrochloride and triprolidine hydrochlo- cally inspect the quality of the core (i.e. whether it is intact, ride); and whether it is correctly located). Furthermore, if a signifi- antibiotics (e.g., penicillin V potassium, cloxacillin cant ntunber of tablets from the sample fail, a complete batch sodium, dicloxacillin sodium, nafcillin sodium, oxacillin oftablets may be wasted. Applicant has found that ifone adds 10 sodium, carbenicillin indanyl sodium, oxytetracycline hydro- to the core a strong colourant such as iron oxide, such that the chloride, tetracycline hydrochloride, elindamycin phosphate, core visibly contrasts with the coating when as strong light is clindamycin hydrochloride, clindamycin palmitate HCL, lin- shone on the tablet, it is possible for any faults in the position comycin HCL, novobiocin sodium, nitrofurantoin sodium, or integrity of the core to be picked up automatically by a metronidazole hydrochloride); antituberculosis agents (e.g., camera appropriately located adjacent a tabletting machine to 15 inspect tablets as they are ej ected therefrom. In this way, if a isoniazid); faulty tablet is identified it is possible to halt production and cholinergic agents (e.g., ambenonium chloride, bethanecol correct any problems in the manufacturing process quicldy, chloride, neostigmine bromide, pyridostigmine bromide); thereby potentially avoiding wastage of batch quantities of antimuscarinics (e.g., anisotropine methylbromide, clid- tablets. 20 inium bromide, dicyclomine hydrochloride, glycopyrrolate, Whereas colourants contained in the core are useful for this hexocyclium methylsulfate, homatropine methylbromide, purpose, equivalent solutions are also possible. For example, hyoscyamine sulfate, methantheline bromide, hyoscine instead of a colourant, one can include a material that is hydrobromide, oxyphenoniuin bromide, propantheline bro- opaque to x-rays, such as barium sulphate. lf an x-ray imager mide, tridihexethyl chloride); is then coupled to a tablet machine, the core will contrast with 25 sympathomimetics (e.g., bitolterol mesylate, ephedrine, the coating material and the x-ray imager will pick up any ephedrine hydrochloride, ephedrine sulphate, orciprenaline faults in the positioning or integrity of the core in a similar sulphate, phenylpropanolamine hydrochloride, pseudoephe- fashion. drinc hydrochloride, ritodrine hydrochloride, salbutamol sul- The amount of dwg substance employed in tablets of the phate, terbutaline sulphate); present invention will depend on the particular drug sub- 30 sympatholytic agents (e.g., phenoxybenzamine hydro- stance used, the condition of the patient and the nature and chloride); miscellaneous autonomic drugs (e.g., nicotine); severity ofthe condition to be treated. A typical drug loading iron preparations (e.g., ferrous gluconate, ferrous sul- might be from l to 50% by weight of the core. phate); As stated above a wide variety of drug substances may be haemostatics (e.g., aminocaproic acid); employed in the present invention. Drugs for treating condi- 35 cardiac dmgs (e.g., acebutolol hydrochloride, disopym- tions the symptoms of which result from noctumal circadian mide phosphate, flecamide acetate, procainamide hydrochlo- rhythms are particularly suitable. Accordingly, drugs for ride, propranolol hydrochloride, quinidine gluconate, timolol treating incontinence, sleep disorders, apnoea, asthma, epi- maleate, tocamide hydrochloride, verapamil hydrochloride); lepsy, bronchitis, parldnsonism, rheumatoid arthritis, allergic antihypertensive agents (e.g., captopril, clonidine hydro- rhinitis and ischaemic heart diseases, cluster and migraine 40 chloride, hydralazine hydrochloride, mccamylarnine hydro- headache, congestive hean failure, and depression are par- chloride, metoprolol tanrate); vasodilators (e.g., papaverine ticularly suitable for use in tablets according to the present hydrochloride); invention. Further, drug substances that are metabolized by non-steroidal anti-inflarmnatory agents (e.g., choline sali- cytochrome P450 are also panicularly suitable, they include: cylate, ibuproien, ketoprofen, magnesium salicylate, Amitriptyline, caffeine, clomipramine, clozapine, fluvox- 45 meclofenamate sodium, naproxen sodium, tolmetin sodium); amine, haloperidol, imipramine, mexilitine, oestradiol, olan- opiate agonists (e.g., codeine hydrochloride, codeine phos- zepine, paracetamol, propranolol, tacrine, theophylline, War- phate, codeine sulphate; dextromoramide tartrate, hydroc- farin, Bupropion, Cyclophosphamide, Celecoxib, odone bitanrate, hydromorphone hydrochloride, pethidine Diclofenac, Flubiprofen, Ibuprofen, glimepirideindome, tha- hydrochloride, methadone hydrochloride, morphine sul- cin, naproxen, phenyloin, piroxicam, tenoxicam, citalopram, 50 phate, morphine acetate, morphine lactate, morphine mecon- diazepam, lansoprazole, omeprazole, pantoprozole, pro- ate, morphine nitrate, morphine monobasic phosphate, mor- panolol, topiramate, Alpranolol, chlorpromazine, clomi- phine tartrate, morphine valcrate, morphine hydrobromide, pramine, codeine, Desipramine, dextromethorphan, diphen- morphine hydrochloride, propoxyphene hydrochloride); hydramine, donepezil, flecamide, fluoxetine, labetalol, anticonvulsants (e.g., phenobarbital sodium, phenyloin Methadone, metoprolol, mianserin, nortripyline, 55 sodium; troxidone, ethosuximide, valproate sodium); ondansetron, oxprenolol, oxycodone, paroxetine, perhehexy- tranquilizers (e.g., acetophenazine maleate, chlorprom- lene, pethidine, promethazine, risperdone, thioridazine, ticlo- azine hydrochloride, fluphenazine hydrochloride, prochlor- pidine, timolol, trimipramine, venlafaxine, paracetamol, perazine edisylate, promethazine hydrochloride, thioridazine alprazolam, amiodarone, budesonide, buprenorphine, bus- hydrochloride, trifluoroperazine hydrochloride, lithium cit- pirone, Calcium Channel Blockers, carbamazepine, 60 rate, moliudone hydrochloride, thiothixine hydrochloride); cisapride, clarithromycin, clonazepam, cocaine, cortisol, chemotherapeutic agents (e.g., doxorubicin, cisplatin, cyclosporine, dexamethasone, erythromycin, fentanyl, keto- floxuridine, methotrexate, combinations thereoD; conazole, losartan, miconazolc, midazolam, quinidine, ser- lipid lowering agents (e.g., gemfibrozil, clonbratc, HMG- traline, statins, tacrolimus, tamoxifen, TCAS, triamzolam, CoA reductase inhibitors, such as for example, atorvastatin, zolpidem, or mixtures thereof. 65 cerivastatin, liuvastatin, lovastatin, pravastatin, aimvastatin); Additional examples ofdrug classes and drugs that can be H.sub.2-antagonists (e.g., cimetidine, lamotidine, nizati- employed in tablets of the present invention include: dine, ranitidine HCl); Us 8,394,407 B2 9 10 anti-coagulant and anti-platelet agents (e.g., warfarin, convenience and flexibility of dosing, although dosage fonns cipyridamole, ticlopidine); containing larger or smaller amounts ofdrug substance could bronchodilators (e.g., albuterol, isoproterenol, metaproter- be employed if desired. enol, terbutaline); Particularly preferred tablets according to the invention stimulants (e.g., benzamphctaminc hydrochloride, dextro- 5 comprising in the core a glucocorticosteroid selected from the amphetamine sulphate, dextroamphetamine phosphate, group consisting of prednisone, prednisolone and methyl- diethylpropion hydrochloride, fenfluramine hydrochloride, prednislone, and cross-linked polyvinyl pyrollidone, cross- methamphetamine hydrochloride, niethylphenidate hydro- linked sodium carboxymethyl cellulose, and one or more adjuvants diluents, lubricants or filler materials as herein- chloride, phendimetrazine tartrate, phenmetrazine hydro- 10 above described. Preferably the coating comprises a calcium chloride, caffeine citrate); phosphate salt, glyceryl behenate, cross-linked polyvinyl barbituratcs (e.g., amylobarbital sodium, butabarbital pyrollidone and one or more adjuvants, diluents, lubricants or sodium, secobarbital sodimn); tiller materials as hereinabove described. sedatives (e.g., hydroxyzine hydrochloride, rnediprylon); The composition ofone particularly preferred embodiment expectorants (e.g., potassium iodide); 15 of the invention is: antiemetics (e.g., benzaquinarnide hydrochloride, rneto- Core of 5 mg Prednisone Tablet: clopropamide hydrochloride, trirnethobenzamide hydrochlo- Prednisone 8.33% ride); Lactose monohvdratc 64.47% gastro-intestinal drugs (e.g., ranitidine hydrochloride); Povidone 6.67% heavy metal antagonists (e.g., penicillamine, penicillamine 20 Croscarmellose sodium 18.33% hydrochloride); Red ferric oxide 0.5% antithyroid agents (e.g., methimazole); Magnesium stearate Vegetable origin 1.0% genitourinary smooth muscle relaxants (e.g., iiavoxate Colloidal silicon dioxide 0.5% hydrochloride, oxybutynin hydrochloride); Coating vitamins (e.g., thiamine hydrochloride, ascorbic acid); 25 Dibasic calcium phosphate dihydrate 50% unclassihed agents (e.g., amantadine hydrochloride, Glyceryl behenate 40% colchicine, etidronate disodium, leucovorin calcium, methyl- Povidoue 8.40% ene blue, potassium chloride, pralidoxime chloride. Yellow ferric oxide 0.1% steroids, panicularly glucocorticoids (e.g., prednisolone, Magnesium stearate Vegetable origin 1.0% Colloidal silicon dioxide 0.5% methylprednisolone, prednisone, cortisone, hydrocortisone, 30 Another preferred embodiment is as follows methylprednisolone, betamethasonc, dexamethasone, triam- Core of 1 mg Prednisone Tablet: cinolone). Drnrlnicnnn 1 $704. Notwithstanding the general applicability of the tablets in Lactose monohydrate 71.13% relation to a wide range ofdrug substances, the present inven- 35 Povidone 6.67% tion is particularly suited to delivery of the glucocorticoster- Croscarmellose sodium 18.33% oids aforementioned and particularly prednisone, predniso- Red ferric oxide 0.5% lone and methylprcdnisolone. These steroids are useful in the Magnesium stearate Vegetable origin 1.0% treatment i.a, of rheumatoid arthritis and joint pain. As Colloidal silicon dioxide 0.5% already stated, the symptoms of these conditions appear 40 Coating according to a circadian rhythm and with great predictability Dibasic calcium phosphate dihydrate 50% during the early hours of the morning. Accordingly, the glu- Glyceryl behenate 40% coconicosteroids, and in panicular prednisone are eminently Povidone 8.40% suited for delivery irom tablets according to this invention not Yellow ferric oxide 0.1% only because of their narrow absorption window, but also 45 Magnesium stearate Vegetable origin 1.0% because a tablet may be administered in the evening before Colloidal silicon dioxide 0.5% bedtime anytime around 8 pm tuitil midnight, e.g. around It is surprising that the tablets containing the glucocorti- 10-12 at night, to deliver maximum plasma concentration of costeroids display such rapid release given that the rate of the dmg substance before maximum secretion ofIL-6 (which release relies to some extent on the wetting of the core, and occur around 2 am to 4 am), thereby effectively addressing 50 these steroids are rather hydrophobic in nature. the underlying causes of the morning symptoms. In this way, The tablets described above are press-coated tablets com- these symptoms are more effectively treated. prising a core and a coating covering said core. However, As used above, prednisone refers to the compound and its variants of this basic construction are within the ambit ofthe salts or derivatives thereof, including prednisone 21 acetate. present invention. Thus, the press-coating may be thrther As used above, prednisolone refers to the compound and its 55 coated with an outer coating that may be ihnctional and/or salts or derivatives including die 21 -acetate, its 21-tert-butyl aesthetic in its design. For example, functional coatings may acetate, 21-succinate sodium salt, 21-stearoylglycolate, include the addition an immediate release coating containing 21-m-sulphobenzoate sodium salt, and its trimethylacetate. a drug substances that may be the same or different to the drug Methylprednisolone, as used above refers to the compound substance contained in the core. or and its salts and derivatives thereofincluding its 21 acetate, 60 In this manner, the tablet can affect a pulsatile release that 21-phosphate disodium salt, 21-succinate sodium salt, and its is of use in treating symptoms based on circadian rhythms, acetonate such as sleep disorders. In this regard one can employ seda Typically a core may contain about 0.1 to 50% by weight, tive hypnotics in such dosage forms, for example those drug more particularly 1 to 20%, still more particularly l to 10% by substances mentioned described in U.S. Pat. No. 6,485,746 weight of steroid based on dle total weight of the core. In me 65 Pulsatile release dosage forms may also find general applica- case ofprednisone, it may be employed in amounts to provide bility with a wide range ofactive substances for the treatment a total Weight per unit dosage lorm of 1 or 5 mg, to otler ofa wide range ofindications to provide patients with a more US 8,394,407 B2 12 convenient dosage schedule. For example, pulsatile release absorption site, or a locally diseased site along the GI tract and can provide an alternative to multiple administrations of bowel. Such medicaments are provided by the present inven- immediate release lorms. tion Functional coatings also include enteric coatings covering Currently, there are no bioavailability or bioequivalence the press-coating. Enteric coated forms may be of use in regulatory guidelines available forTmax' However, the Guid- treating local conditions in the bowel such as Crohn's disease, ance For Industry "Food Effect Bioavailability and Fed ulcerative colitis, IBS and IBD. In this embodiment, the Bioequivalence Studies", US Department of Health (CDER) enteric coating would prevent release of any drug before the December 2002 suggests that any difference in Tmax should tablet enters the bowel. not be clinically relevant. Whether such a difference will be 10 Aesthetic coatings include taste, masking coatings and clinically relevant will depend on die drug delivered and the coloured coatings as a generally well known in the art. particular indication. Applicant has found that in respect of lt is well known in the art that food can change the bio- formulations ofthe present invention the effect of food on the availability of a drug. Food can alter the bioavailability of a median value of Tm is a difference of only about +/-20%, more particularly +/-l0% dwg by various means such as delaying gastric emptying, 15 changes in gastrointestinal pH, changes in luminal metabo- Still further, applicant has found medicaments containing lism, and physical and chemical reactions of food items with drug substances exhibiting no significant effect of food with a dosage form or drug substance. This change in bioavailabil- respect to bioavailability of the drug substance in terms of ity as a consequence of food intake is often referred to as a Cmax and AUC. "food effect". Food effects are quite common in modified- 20 The"food effect" as it relates to the bioavailability of drug release dosage forms, and also for drugs that have either poor substances is a well doctunented phenomenon in relation to solubility or poor permeability or both (BCS Class ll, lll, and drug delivery that describes the variance in uptake of a drug IV). substance by patients depending upon whether the patients The applicant has surprisingly found that a tablet that is are in fed or fasted sfates. The presence or absence of a food adapted to release all, or substantially all, of a drug contained 25 effect may be quantified by making Area under the Cuwe therein within a time (Tlag) ofbetween 2 and 6 hours (median (AUC) and/or Cmax measurements according to methods well time) after administration. known in the art. Typically AUC measurements and Cmax Funhermore, the applicant has surprisingly developed a measurements are made by taking timed biological fiuid tablet adapted to release a drug substance after a lag time that samples and plotting the serum concentration of drug sub- can deliver a drug to a patient, which upon absorption the 30 stance against time. The values obtained represent a number peak drug concentration Cmax will be reached in a time Tmax ofvalues taken from subjects across a patient population and that is independent of a patient's food intake. are therefore expressed as mean values expressed over the 'l`,,,ax is a term well known in the art that refers to the time entire patient population. By comparing the mean AUC and/ elapsed between drug administration and the maximum or Cmax values, one can determine whether a drug substance plasma concentration CM is reached. Cnzax is also an art 35 experiences a food effect. recognized term that relates to the peak plasma concentration of a drug. Food effect studies may be conveniently carried out on an Tmax is an important parameter particularly in relation to adequate number of healthy volunteers, the number being medicaments that are intended to be taken at a time conve- sufficient to generate sufficient data for appropriate statistical nient for a patient, but which release dmg substances after a 40 assessment to be made. Preferably the number of subjects lag time in order to synchronise drug release widi a circadian should not be less than 12. rhythm, and in particular a nocturnal circadian rhythm. By To study the effect of food on the bioavailability of a drug way of example, the glucocorticosteroids, referred to above, substance one may use any conventional study design known e.g. prednisone, are useful in the treatment of i.a. arthritic in the art, for example a randomised; balanced single-dose, conditions such as rheumatoid arduitis and osteoarthritis. 45 two-treatment, two-period, two-sequence crossover design. Debilitating symptoms are often experienced by a patient Analysis may be carried outusing any of the programs known upon waking. Current therapy requires a patient to take Deco- in the art such as SAS PROC GLM, software from the SAS rtinR upon waking. However, this is not the most efficacious institute, Cary N.C. Way of treating the symptoms, as they are believed to be ln quantitative terms, a drug substance may be said to associated with the secretion oflL-6, which occurs during the 50 exhibit no food effect ifa 90% conndence interval (Cl) for the early mominghours, e.g. from about 2 to 4 am.A medicament ratio of means (population geometric means based on log that can reachC/:mx that is coincident Wim or anticipates the transformed data) offw and fasted treatments fall within the release of IL-6 is potentially of greater benefit to a patient. interval of 0.8 to 1.25 for AUC and/or 0.7 to 1.43 for C,.,.,, Funhennore, given the varied lifestyles of individuals, Accordingly, the present invention provides in another of patients taking medicament between S pm and bedtime, e.g. 55 its aspects a tablet as defined herein above displaying a ratio from 10 pm to midnight, may be in a variety of fed states, it is AUC fed/fasted after single dosing of 0.8 to 1 .25 or the ratio even more advantageous thatTmax should be independent of Cm" fed/fasted after single dosing of 0.7 to 1.43. food intake. A "fed" subject conveniently may be considered as a sub- Medicaments that can have a pre-determined lag time, and ject that has fasted for at least 10 hours before receiving a which release drug substance after this lag time in a manner 60 standard FDA recognised high fat meal. The medicament that provides a Tmax independent of considerations of the fed may then be administered with water shortly after completion or fasted state of a patient are ofpotentially great benefit, not ofthe meal, e.g. within 5 minutes thereof. Preferably no food only in relation to die glucocorticosteroids and the treatment should be taken for a period of, e.g. 4 hours after receiving of ardiritis, but for other active substances that are advanta- medicarnent although small quantities of water may be per- geously delivered in synchronieity Wim a circadian rhythm, 65 mitted after, e.g. 2 hours after receiving the medicament. or even in relation to drug substances whose eflicacy depends A "fasted" subject conveniently may receive medicament on their ability to be delivered accurately to a particular with water alter at least 10 hours fasting. Thereafter, no food Us 8,394,407 B2 13 14 may be taken for a period of, e.g. 4 hours although small thickness of the coating, die of appropriate internal dimen- quantities of Water may be taken after, e.g. Z hours after sions may be placed in the rotating platfonn, and the amount receiving medicament. of coating material fed into the die may be adjusted accord- A standard FDA high fat meal as referred to hereinabove ingly. may comprise any meal that would be expected to provide 5 Suitable rotary tablet machines having high process speeds maximal perturbation due to the presence of food in the GI are known in the art and need no further discussion here. tract. Said high fat meal typically may comprise 50% of its Cores may likewise be formed using a conventional rotary caloric value in fat. A representative example may be 2 eggs tablet machine. Cores are preferably compressed under com- fried in butler, 2 strips of bacon, 2 slices toast with butter, 4 pression forces suiiicient to provide cores having a hardness ounces fried potato, and 8 ounces milk. 10 of about 60 Newtons at least, e.g. 50 to 70 Newtons. Cores By application of the teachings of the present invention having hardness in this range give desired release character- tablets may be provided that display reduced variability in istics. If desired, the cores can be formed at the same time as resumption/bioavailability levels achieved both for indi- the press coated tablets are produced. In such case, one might vidual patients receiving a drug as well as between individu- employ a Manesty Dry Cota. Such a press consists of two als. 15 The tablets of the present invention may be packaged in a side-by-side and inter-connected presses where the core is variety of ways. Generally an article for distribution includes made on one press before being mechanically transferred to a container for holding the tablets. Suitable containers are the other press for compression coating. Such equipment and Well known to persons skilled in the art and include materials techniques for making tablets using such equipment are such as bottles, foil packs and the like. In addition, the con- 20 known in the art and no more needs to be said about this here. tainer will have a label and an insert that describes the con- Cores are preferably formed according to wet granulation tents ofthe container and any appropriate warnings or instruc- techniques generally known in the art. ln a typical procedure, tions for use. It is an advantage of the present invention that core materials are sieved and blended. Granulating fluid, typi- the insert and/or label may contain instructions that the tablet cally water is then added to me blend and the mixture is may be taken with or without food, or may be absent a 25 homogenized to form a granulate, which is then sprayed dried warning or instruction that the tablet should be taken only or dried on a lluid bed drier to obtain a granulate with requisite with food or only without food. residual moisture. Preferably the residual moisture content is The invention provides in another aspect, a method of from about 0.4 to 2.0% by weight. The granulate is then sized forming tablets as herein above described. The tablets may be by passing it through screens of desired aperture. At this formed on conventional press coating equipment. Typically 30 stage, any adjuvants are sized and added to the granulate to such equipment is composed ofa series ofdie are arranged on form the core composition suitable for compression. The a rotating plattonn. The die are removably mounted in the sldlled person will appreciate that a coating composition can platform such that differently sized die may be employed as be formed in an analogous manner. The skilled person will appropriate. Each die is hollow to receive a lower punch. The also appreciate that granulates may be obtained having a punch is positioned within the die such that the upper surface 35 range of panicle sizes. lt is preferred that the coating granu- of the punch and the inner surface of the die define a volume late has a fine fraction that is less than 30%. By "fine fraction" for receiving a precise amount coating material. Once loaded, is meant granulate having particle size of up to about 63 the platform is rotated until the is positioned under an upper microns. punch. The upper punch is then urged down onto the coating Preferred feamres forthe second and subsequent aspects of material under a defined compression force and the coating 40 the invention may be as for the first aspect muratis mutandis. material is pre~compressed or tamped between me upper and FIG. 1: is a representation of a tablet in cross section lower punch. A pre-tonned core is then led into die to rest on showing the coating and core and the axes (A-B) and (X-Y). the tamped coating. Conventional press coating apparatus FIG. 2: Shows an in-vitro dissolution profile of the dosage may be equipped with centering devices that enable cores to form of Example 2. be positioned both vertically and radially. This might be 45 There now follows a series of examples that serve to illus- achieved by a tamping process, whereby an initial amount of trate the invention. coating material is placed in a die and is tamped with a shaped punch, such as a pin punch, that leaves an indentation in the EXAMPLE l coating material in which to receive a core. Thereafter, in a second filling operation, a precise amount of coating material 50 Preparation of a Prednisone-Containing Tablet is fed into the die to cover the core, and an upper punch compresses die coating material widi a defined compaction The active core was prepared for the press coated system as force to form tablets according to the present invention. follows. The composition of the core is detailed in Table l. The compression force applied during the tamping process Lactose rnonohydrate (Lactose Pulvis°H2O®, Danone, is relatively light and is just sufficient to provide a bed of 55 France and Lactose Fast Flo® NF 316, Foremost lag. Group, coating material to receive the core and to prevent movement USA) is a filling agent with interesting technical and fmrc- of the coating material as a result of centrifugal force. Sub- tional properties. Lactose Pulvis'H2O is used in a blend pre- sequent compression to form the tablet may be adjusted to pared, by wet granulation and Lactose Fast Flo is used in a give tablets of requisite hardness. Preferably, this compres- blend prepared for direct compression. Microcrystalline cel- sion force is 400 kg, although this may be adjusted by +/-30% 60 lulose (Avicel® pH 101, FMC International, Ireland) is used in order to give tablets of the required hardness. as an insoluble diluent for direct compression. Polyvinyl pyr- The amount of coating material fed into the die can be rolidone (Plasdone® K29-32, ISP Technology, USA) is a precisely defined having regard to the density of the coating granulating agent, soluble in water, which has the ability of material to ensure after compression that the tablet is formed binding the powder particles. Croscarmellose sodium (Ac- with the required coating thickness about the (A-B) axis; and 65 Di-Sol®, FMC Corporation, USA) is used in the fonnulation the dimensions of the die is selected to provide the thickness as a super disintegrant. As the external phase, magnesium about the X-Y axis. Should it be necessary to change the stearate (Merck, Switzerland) was added as a lubricant and US 8,394,407 B2 15 16 silicon dioxide (Aerosi1® 200, Degussa AG, Germany) in The coating blend was prepared according to the process order to improve How properties of the granular powder. described below. Batch size for the barrier blend was 13 kg. Weighw amounts of Emcompress®, Comprilol® 888 ATO, TABLE 1 Lactose pulvis'H20®, Plasdone® K29-32 and Sicovit® Yel- 5 low 10 E 172 Wcrc manually sieved with a screen having Ingredients Content (mg/tablet) 0.710 mm apenures. They were placed in a Niro-Fielder Prednisone 5.00 PMA 65-litre mixing granulator. Then, the components were Lactose (Lactose Pulvis H20 NF316) 39.10 homogeneously mixed for 6 min, at impeller speed 200 rpm, Polyvinyl pyrrolirlone 4.00 (Plasdonc ® K29~32) without chopper. 10 Sodium carhoxymcthyl 11.00 Subsequently, the granulating solution (purified water, cellulose (Ac-Di-Sol ®) Magnesium stearate 0. 60 8.12% of the weight ofthe dry blend) was added within 2 min Silicon dioxide (Aerosil ® 200) 0.30 at impeller speed 200 rpm and chopper speed 1500 rpm using a nozzle 4.9 (spraying rate of 520 g/min). Mixing was con- Total 60.00 15 tinued for homogenisation and massing for 1 min at impeller speed 400 rpm and chopper speed 3000 rpm. The coating of the prednisone press coated tablet is of a The mixed wet granulate was then dried in a Niro-Fielder hydrophobic, water insoluble nature. This barrier is mainly TSG 2 Fluidised air bed dryer. The inlet temperature was composed of dibasic calcium phosphate (Emcompress®, maintained at 45° C. during drying. The drying lasted 33 min 20 Mendell, USA) and glyceryl behenate (Compritol® 888ATO, to have residual moisture less than 25%. The yielded dry Gattefossé, France). Polyvinylpyrrolidone (Plasdone® K29- granulate was calibrated in a Frewitt MGI 205 granulator 32) is a granulating agent, soluble in water, which has the using a screenhaving 0.8 mm apertures for 4 min at speed 244 ability of binding the powder particles. Yellow ferric oxide osc/min (graduation 7). Appropriate amounts of Aerosil® (Sicovit® Yellow 10, BASF, Germany) was added as a dye. A 200 and magnesium stearate were manually sieved using a 25 detailed composition of this barrier blend is given in table 2. screen with 1.0 mm apertures. TABLE 2 Half of the dry granulate was pul in a Niro-Fielder PMA 65-liter, followed by Aerosil® 200 and then by the other half Comnosition of the coating of the dry granulate. The ingredients were mixed for 2 min at 30 impeller speed 200 rpm, without chopper. Finally, magne- Ingredienrs Content (%) sium stearate was added and mixing was continued for 2 more Dibasic calcium phosphate (Emcompress ®) 50.00 minutes at iinpeller speed 200 rpm, without chopper. Glyceiyl Behenate (Compritol ® 888 ATO) 40.00 Polyvinylpyrrolidone (Plasdone ® K29-32) 8.40 440 mg of coating blend was press coated on a core to Yellow Ferric Oxide (Sicovit ® yellow 10 172) 0.10 provide press coated tablets (9 mm diameter). 305 mg of Silicon dioxide (Aerosil ® 200) 0.50 35 Magnesium stearate 00 coating blend was press coated on a core to provide press coated tablets (8 mm diameter). These different press coat- Total 100.00 ings were done utilising a Kilian RUD tabletting machine. First and second loading hoppers are filledup with the coating The required amounts ofprednisone, Ac-Di-Sol®, Lactose 40 granulatc. Between the two loading hoppers, the machine is Pulvis H2O®, Plasdone® K29-32 were weighed and manu- equipped with a transfer system adapted to feed the cores. For ally sieved with a screen having 0.710 mm apertures. The each tablet, the first loading hopper supplies with about half components were homogeneously mixed in a Niro-Fielder of the quantity to be applied to the core. Then, the feeding PMA 25-litre mixing granulator for 6 min at impeller speed system provides and positions a core centred in the die. Sub- 250 rpm without chopper. A prednisone assay was performed 45 sequently, the second loading hopper supplies with the other on this premix. Subsequently, the granulating solution (puri- halfofthe quantity to be applied to the core. The compression tied water, 25.47% ofthe Weight of the dry blend) was added step then occurs. Within 4 min at impeller speed 2.50 rpm and chopper speed 1500 rpm, using a nozzle H1/4VV-95015 (spraying rate of TABLE 3 50 250 g/min). Mixing was continued for homogenisation and Eciuioment implemented for the manufacturing process rnassing of the wet mass for 3 min at impeller speed 500 rpm and chopper speed 3000 rpm. Equipment Brand name/Type M anufacturer /Supplier The mixed wet granulate was then dried in a Glatt WSG5 Mixing granulator Niro-Fielder PMA Aéromatic-Fielder AG, fluidised air bed drier. The inlet temperature was maintained 55 25/65 litres Bubendorf, Switzerland at 45° C. during drying. The drying lasted 20 min to get a Fluidised nir Glntt WSG5 Maschinen und apparatebau bed dryer AG, Pratteln, Switzerland granulate with a residual moisture less than 2 .5%. The yielded Fluidised air Niro-Fielder TSG 2 Aéromatic-Fielder AG, dry granulate was calibrated in a Frewitt MGI 205 granulator bed dryer Bubendor£ Switzerland using a screen with 0.8 mm apertures for 3 min at speed 244 Granulator Frewitt MGI 205 Frewitt SA, Granges The in vitro dissolution profile ofa tablet containing a 5 mg 5 What is claimed is: loading of prednisone prepared according to the method of 1 . A press-coated tablet comprising a defined core contain- Example 1 was detennined using USP dissolution apparatus ing a pharmaceutically active agent, and a compression coat- No. 2 (paddles) and stationary baskets and applying a stirring ing around said core, the core being disposed Within said rate of 100 rpm, The dissolution mwium was purified water, compression coating such that the coating thickness about an i0 with a volume of 500 ml. axis (X-Y) is thicker and less dense than the coating about an After 4 hours no drug substance release is observed. How- axis (A-B) orthogonal to (X-Y), wherein said compression ever, within 4.5 hours there is approximately 80% release and coating is formed of an insoluble or poorly water soluble by 5 hours 100% release of the drug substance (see FIG. 2). hydrophobic material and said coating is sufficiently porous is aiJoutthe (X-Y) plane of the tablet to permit the ingress of EXAMPLE 3 aqueous media to the core at a rate to ensure release of the active agent after a period of time between 2 to 6 hours A study was carried out to detennine the effect of food on wherein said period of time is followed by rupture of the the bioavailability of a 5 mg prednisone tablet described coating along the X-Y axis, wherein the compression coating above. 20 lacks ingredients that swell and gel to such an extent that the The study did not compare the tablet in the fed and fasted coating acts as a diffusion barrier to the release of the active state. Radier, the study was adjusted to take into account the agent. chrono-pharmacoldnetics of prednisone and the fact that it is 2. The tablet of claim 1, wherein the coating thickness to be administered in the evening, e.g. about 8 pm, which is about the axis (X-Y) is about 2.2 mm to about 2.6 mm and the required in order that the blood plasma levels will peak before 25 thickness about the orthogonal axis (A-B) is about 1.0 to secretion of IL-6 to improve the efticacy of the treatment, about 1.6 mm. Thus the study was designed to compare the tablet during real 3. The tablet of claim 1, wherein said water insoluble or time administration and with likely food intake scenarios at poorly soluble hydrophobic material is selected from the this time. It was considered unreasonable that at 8 pm a group consisting of hydrophobic cellulosic derivatives and subject would be approximately S hours fasted. Accordingly, 30 polymers including alkylcellulose, hydroxypropyl cellulose, the following food intake scenarios were tested: hydroxypropylmethyl cellulose, carboxymethyl cellulose, a) To simulate a fasted state at 8 pm in the evening, a light and derivatives thereof; polymethacrylic polymers, polyvinyl acetate and cellulose acetate polymers, fatty acids, fatty acid meal was given 2% hours before administration that con- esters, fatty acid salts, long chain fatty alcohols, polyoxyeth- tained a limited number of calories (i.e. 22% of total daily 35 ylene alkyl ethers, polyoxyethylene stearates, sugar esters, calories and widi a limited Bit content of 15.5 g) and being lauroyl macrogol-32 glyceryl, and stearoyl macrogol-32 devoid of any slowly digestible nutrients. This is called the glyceryl, and combinations thereof. "semi-fasted" state. 4. The tablet of claim 1, wherein the coating comprises The composition of this meal consisted of brown bread, calcium phosphate salt, glyceryl behenate, and polyvinyl margarine, cheese spread, an apple (skin removed) and fruit 40 pyrollidone, or mixtures thereof. cocktail in symp. 5. The tablet of claim 1, wherein the core comprises a b) Fed state is simulated by giving a higher fat meal 'A hour disintegrating agent. before dosing containing 35% of the daily intake of calories 6. The tablet of claim 1, further comprising cross-linked and 26 g of fat. polyvinyl pyrollidone and croscarmellose sodium. An assumption made was that in the case ofthe semi-fasted 45 7. The tablet of claim 1, wherein the active agent is a state, after 2% hours the stomach was already emptied, or glucocorticosteroid selected from prednisone, prednisolone substantially emptied of food, . or methylprednisolone. The composition of the high fat meal was pasta with spa- 8. The tablet of claim 7, wherein the active agent is pred- ghetti sauce, soup and vegetables, Applejuice, Ice cream and nisone and the prednisone is present in an amount of l mg or whipped cream. 50 5 mg. The methodology consisted ofan open, randomized, 3-pe- 9. The tablet of claim 8, wherein the prednisone is present riod crossover single oral dose study with 7 days washout in an amount of 5 mg and the tablet comprises the following periods. The patient population consisted of 27 healthy male ingredients in each of the core and coating in a weight per- volunteers. centage by weight ofeach of the core and coating: The phamiacoldnetics of the iormulation was compared 55 Core: for each of the fed and semi-fasted states with a standard Prednisone 8.33% immediate release form (DecortinR) administered at 2 am. Lactose monohydrate 64.47% In the semi-fasted state the fonnulation exhibited a median Povidone 6.67% lag time of3.5 hours. Relative to Decortinl dosed at 2 am, the Croscarmellose sodium 18.33% formulation was fully bioequivalent with a Cmax of 97% and 60 Coating relative bioavailability of 101% (AUC0.,.a..y>. Dibasic calcium phosphate dihydrate 50% ln the fed state, the median lag time was 4 hours.Cmax was Glyceryl behenate 40% 105% compared to DecortinR, and relative bioavailability Povidone 8.40%. (AUC0_i,v,/i¢y) was 113%. 10. The tablet of claim 1, wherein me active agent is a Compared to the formulation in the semi~fasted state, the 65 sympadiomimetic agent, lormulation in the led stale was 108% on Cmar and1 12% on 11. The tablet of claim 10, wherein the active agent is AUCO-iry'ir1 ity terbutaline sulphate. US 8,394,407 B2 1 9 20 12. The tablet of claim 10, wherein the active agent is 16. The tablet ofclaim 1, wherein at least 80% of the active present in amounts of 1 to 50% based on the weight of the agent is released after 4.5 hours. core 17. The tablet of claim 1. wherein about 100% ofthe active 13. The tablet ofclaini 1, wherein the tablet has an in vitro agent is released after 5 hours. dissolution prolile using USP dissolution apparatus No. 2 at a 5 18. A method ofadministering a glucocorticosteroid active stirring rate of 100 rpm and in a dissolution medium of 500 ml substance selected from prednisone, prednisolone or methyl- ofpurihed water such that there is a median lag time of about prednisolone to a patient in need thereoi the method com- 4 hours and at least 80% of active agent is released after 4.5 prising administering the tablet of claim 7 to the subject. hours and about 100% of the active agent is releasw after 5 19. A method of making the tablet of claim 1, the method hours. 10 comprising the steps of forming a first granulate containing 14. The tablet of claim 13, wherein the active agent is coating material; providing a second granulate containing selected from prednisone, prednisolone or methylpredniso- core material; forming the second granulate into a core; and lone. press coating the first granulate around the core. 15. The tablet of claim 1, wherein the ratio of coating thickness about the X:Y to A:B axes is 1.3-2.6 to 1. >F >l< =i< * >i= UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO 8,394,407 B2 Page 1 ofl APPLICATION NO 13/428548 DATED March 12, 2013 INVENToR(s) Guy Vergnault et al It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below In the specification At column 1, line number 11, the Word "lucocorticosteroids" Should be deleted and replaced with the word "g1ucocorticoids' At column 2, line number 59, the Word "an" should be deleted and replaced with the word ccaaa At column 4, line number 4, the Word "core" should be deleted and replaced with the Word "coat At column 4, line number 60, the word "ileosecal" should be deleted and replaced with the word "ileocecal" At column 11, line numbers 47-48, the Word "Deco-1'tin®" should be hyphenated as "Decor tin® Signed and Sealed this Twenty-first Day of May, 2013 . f . . feresa Stanek Rea Acting Director ofthe United States Patent and Trademark Ojice