Free Redacted Document - District Court of Delaware - Delaware

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IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF DELAWARE

SCIELE PHARMA, INC. and SCIELE PHARMA CAYMAN LTD., Plaintiffs, V. MYLAN PHARMACEUTICALS, INC. and MYLAN LABORATORIES, INC., Defendants.

C.A. No. 07-818-GMS

REDACTED

DECLARATION OF WILLIAM J. MARSDEN, JR. IN SUPPORT OF PLAINTIFFS' MEMORANDUM OF LAW IN OPPOSITION TO DEFENDANTS' MOTION TO DISMISS PLAINTIFFS' COMPLAINT FOR LACK OF STANDING AND SUBJECT MATTER JURISDICTION
I, William J. Marsden, Jr., declare as follows: 1. I am a principal at the law firm of Fish & Richardson P.C., and I am counsel for

Plaintiffs Sciele Pharma, Inc. and Sciele Pharma Cayman Ltd., in the above-captioned matter. 2. Attached hereto as Exhibit A is a true and correct copy of the New Distributorship

Agreement dated October 1, 2004 between Bayer Healthcare AG and First Horizon Pharmaceutical Corp. and First Horizon Pharmaceutical Cayman, Ltd., now known as Sciele Pharma, Inc. and Sciele Pharma Cayman Ltd. 3. Attached hereto as Exhibit B is a true and correct copy of the Second Amendment

to the Amendment and Services Agreement dated October 18, 2007 between Bayer Healthcare AG and Sciele Pharma, Inc. and Sciele Pharma Cayman Ltd. 4. Attached hereto as Exhibit C is a proposed Motion for Leave to File Amended

Complaint together with a proposed Amended Complaint.

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I declare under penalty of perjury that the foregoing is true and correct.

Dated this 28th day of January, 2008.

Al William J. Marsden, Jr. William J. Marsden, Jr.

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CERTIFICATE OF SERVICE
I hereby certify that on January 28, 2008, I electronically filed with the Clerk of Court the DECLARATION OF WILLIAM J. MARSDEN, JR. IN SUPPORT OF PLAINTIFFS' MEMORANDUM OF LAW IN OPPOSITION TO DEFENDANTS' MOTION TO DISMISS PLAINTIFFS' COMPLAINT FOR LACK OF STANDING AND SUBJECT MATTER JURISDICTION using CM/ECF which will send electronic notification of such filing(s) to the following Delaware counsel. In addition, the filing will also be sent via hand delivery:

Richard K. Herrmann Esquire Mary B. Matterer, Esquire Morris James LLP

Attorneys for Defendants Mylan Pharmaceuticals, Inc. and Mylan Laboratories, Inc.

500 Delaware Ave., Ste. 1500 P.O. Box 2306
Wilmington, DE 19899

I also certify that on January 28, 2008, I have sent by electronic mail and U.S. First Class Mail, the document(s) to the following non-registered participants:

William A. Rakoczy, Esquire Rakoczy Molino Mazzochi Siwik LLP 6 West Hubbard Street, Suite 500 Chicago, IL 60610

Attorneys for Defendants Mylan Pharmaceuticals, Inc. and Mylan Laboratories, Inc.

Is/ William J. Marsden, Jr. William J. Marsden, Jr.

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Exhibit A

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Exhibit B

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Exhibit C

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IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF DELAWARE SCIELE PHARMA, INC. and SCIELE PHARMA CAYMAN LTD., Plaintiffs, V. MYLAN PHARMACEUTICALS, INC. and MYLAN LABORATORIES, INC., Defendants.

C.A. No. 07-818-GMS

PLAINTIFFS' MOTION FOR LEAVE TO FILE AN AMENDED COMPLAINT Plaintiffs Sciele Pharma, Inc. and Sciele Pharma Cayman Ltd. ("Sciele") hereby move the Court under Federal Rule of Civil Procedure 15(a)(2) for leave to file an Amended Complaint adding Bayer Healthcare Aktiengesellschaft ("Bayer") as a co-plaintiff. Sciele believes that it has the necessary rights in U.S. Patent No. 4,892,741 to maintain its suit against Defendants Mylan Pharmaceuticals, Inc. and Mylan Laboratories, Inc. ("Mylan") in its own name. If, however, the Court determines that Sciele does not have prudential standing to sue in its own name, Sciele then respectfully requests that the Court grant this Motion for Leave to file an Amended Complaint to add Bayer as a co-plaintiff. For the reasons stated in Sciele's Memorandum of Law in Opposition to Defendants' Motion to Dismiss, Sciele respectfully requests that the Court grant leave to file an Amended Complaint. Pursuant to Rule 15.1 of the Local Rules of the United States District Court for the District of Delaware, Sciele has attached to this Motion its proposed Amended Complaint as well as a redlined version of the proposed Amended Complaint showing the alterations from the originally-filed Complaint.

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Dated: January 28, 2008

FISH & RICHARDSON P.C.

By: /s/ William J. Marsden, Jr. William J. Marsden, Jr. (#2247) Susan M. Coletti (#4690) 919 N. Market Street, Suite 1100 P.O. Box 1114 Wilmington, DE 19899-1114 Telephone: (302) 652-5070 Facsimile: (302) 652-0607 Email: [email protected]; [email protected] Jonathan E. Singer Deanna J. Reichel 3300 Dain Rauscher Plaza 60 South Sixth Street Minneapolis, MN 55402 Telephone: (612) 335-5070 Facsimile: (612) 288-9696 Nagendra Setty 1180 Peachtree Street, N.E., 21st Floor Atlanta, GA 30309 Telephone: (404) 892-5005 Facsimile: (404) 892-5002 John D. Garretson Citigroup Center - 52nd Floor 153 East 53rd Street New York, NY 10022-4611 Telephone: (212) 765-5070 Facsimile: (212) 258-2291 Attorneys for Plaintiffs SCIELE PHARMA, INC., and SCIELE PHARMA CAYMAN LTD.

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CERTIFICATE OF SERVICE I hereby certify that on January 28, 2008, I electronically filed with the Clerk of Court PLAINTIFF'S MOTION FOR LEAVE TO FILE AN AMENDED COMPLAINT using CM/ECF which will send electronic notification of such filing(s) to the following Delaware counsel. In addition, the filing will also be sent via hand delivery:

Richard K. Herrmann Esquire Mary B. Matterer, Esquire Morris James LLP 500 Delaware Ave., Suite 1500 P.O. Box 2306

Attorneys for Defendants Mylan Pharmaceuticals, Inc. and Mylan Laboratories, Inc.

Wilmington, DE 19899

I also certify that on January 28, 2008, I have sent by electronic mail and U.S. First Class Mail, the document(s) to the following non-registered participants:

William A. Rakoczy, Esquire Rakoczy Molino Mazzochi Siwik LLP 6 West Hubbard Street, Suite 500 Chicago, IL 60610

Attorneys for Defendants Mylan Pharmaceuticals, Inc. and Mylan Laboratories, Inc.

/s/ Susan M Coletti

Susan M. Coletti
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IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF DELAWARE SCIELE PHARMA, INC., SCIELE PHARMA CAYMAN LTD., BAYER HEALTHCARE AKTIENGESELLSCHAFT, Plaintiffs, V. MYLAN PHARMACEUTICALS, INC. and MYLAN LABORATORIES, INC., Defendants. FIRST AMENDED COMPLAINT FOR PATENT INFRINGEMENT Plaintiffs Sciele Pharma, Inc., Sciele Pharma Cayman Ltd. (collectively, "Sciele"), and Bayer HealthCare Aktiengesellschaft ("Bayer") (all three collectively, "Plaintiffs"), by their attorneys, Fish & Richardson P.C. for Sciele and Connolly Bove Lodge & Hutz LLP for Bayer, for their complaint against Defendants Mylan Pharmaceuticals, Inc. and Mylan Laboratories, Inc. (collectively, "Mylan" or "Defendants") allege as follows: The Nature of the Action 1. This is an action for infringement of United States Patent No. 4,892,741 ("the JURY TRIAL DEMANDED

C.A. No. 07-818-GMS

'741 patent") under 35 U.S.C. § 271(e)(2). The Parties 2. Plaintiff Sciele Pharma, Inc. is a corporation organized and existing under the

laws of the State of Delaware, with a principal place of business at 5 Concourse Parkway, Suite 1800, Atlanta, Georgia 30328. 3. Plaintiff Sciele Pharma Cayman Ltd. is a corporation organized and existing

under the laws of the Cayman Islands, with a principal place of business at Ugland House, South Church Street, Georgetown, Grand Cayman, Cayman Islands.

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4.

Plaintiff Bayer HealthCare Atkiengesellschaft is a corporation organized and

existing under the laws of the Federal Republic of Germany, with a principal place of business at 51368 Leverkusen, Federal Republic of Germany. 5. On information and belief, defendant Mylan Pharmaceuticals, Inc. ("Mylan

Pharmaceuticals") is a corporation organized and existing under the laws of the State of West Virginia, with a principal place of business at 781 Chestnut Ridge Road, Morgantown, West Virginia 26505. 6. On information and belief, Mylan Pharmaceuticals manufactures and sells

numerous generic pharmaceutical products for use throughout the United States, including this judicial district. 7. On information and belief, defendant Mylan Laboratories, Inc. ("Mylan

Laboratories") is a corporation organized and existing under the laws of the Commonwealth of Pennsylvania, with a principal place of business at 1500 Corporate Drive, Suite 400, Canonsburg, Pennsylvania 15317. 8. On information and belief, Mylan Laboratories is the parent company of Mylan

Pharmaceuticals, and Mylan Pharmaceuticals is a wholly-owned subsidiary of Mylan Laboratories. 9. On information and belief, Mylan Pharmaceuticals and Mylan Laboratories

collaborate in the manufacture, marketing, and sale of many generic pharmaceutical products, including numerous products that are marketed and sold in Delaware. 10. Mylan Laboratories states in its 2007 Annual Report that "Mylan

Pharmaceuticals, Inc., Mylan's flagship generic subsidiary, once again ranked as one of the nation's leading providers of pharmaceutical products overall, and pharmacists filled over 257 million prescriptions with products from Mylan." On information and belief, a proportionate number of those prescriptions were filled in Delaware.

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Jurisdiction and Venue 11. This action arises under the patent laws of the United States of America, United

States Code, Title 35, Section 1, et seq. This Court has subject matter jurisdiction over the action under 28 U.S.C. §§ 1331 and 1338. 12. Based on the facts and causes alleged herein, this Court has personal jurisdiction

over defendants Mylan Pharmaceuticals and Mylan Laboratories. 13. Venue is proper in this Court under 28 U.S.C. §§ 1391 and 1400(b). Background 14. The '741 patent, entitled "Press Coated DHP Tablets," issued.on January 9, 1990

to Andreas Ohm, Helmut Luchtenberg, Shinji Maegata and Wolfgang Opitz. A copy of the '741 patent is attached to this complaint as Exhibit A. 15. 16. Bayer is the assignee of the '741 patent. Sciele is the exclusive licensee of the '741 patent and possesses the exclusive

rights to make, use, and sell patented product under the '741 patent. 17. patent. 18. Sciele is the holder of approved New Drug Application ("NDA") No. 20-356 for Bayer and Sciele together hold the entire right, title, and interest in the '741

nisoldipine extended release tablets in 10mg, 20mg, 30mg, and 40mg dosages, all sold under the Sular® trademark. 19. In conjunction with NDA No. 20-356, Sciele has listed the '741 patent, which

covers various aspects of the approved formulations of Sular®, in the Orange Book. 20. On September 10, 2007, Plaintiffs received a letter ("Paragraph IV Letter"), dated

September 7, 2047, signed on behalf of Mylan. The Paragraph IV Letter represented that Mylan had filed Abbreviated New Drug Application No. 79-051 ("ANDA No. 79-051 ") with the United States Food and Drug Administration ("FDA") under section 505(j) of the Federal Food, Drug, and Cosmetic Act ("FDCA") seeking approval to engage in the commercial manufacture, use, or

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sale of a proposed generic version of Sciele's Sular® tablets 40mg, before the expiration of the '741 patent. 21. After receiving the Paragraph IV Letter, Sciele filed suit against Mylan for

infringement of the '741 patent on October 22, 2007. That case is captioned Sciele Pharma, Inc. and Sciele Pharma Cayman Ltd. v. Mylan Pharmaceuticals, Inc. and Mylan Laboratories, Inc., No. 07-664-GMS (D. Del.). 22. On January 28, 2008, Sciele filed a motion to add Bayer as a co-plaintiff in the

case captioned Sciele Pharma, Inc. and Sciele Pharma Cayman Ltd. v. Mylan Pharmaceuticals, Inc. and Mylan Laboratories, Inc., No. 07-664-GMS (D. Del.). 23. On November 7, 2007, Plaintiffs received a second letter ("Second Paragraph IV

Letter"), dated November 6, 2007, signed on behalf of Mylan. The Second Paragraph IV Letter represented that Mylan had amended ANDA No. 79-051 to seek the FDA's approval to engage in the commercial manufacture, use, or sale of proposed generic versions of Sciele's Sular® tablets 20mg and 30mg, before the expiration of the '741 patent. 24. The Second Paragraph IV Letter also stated that ANDA No. 79-051 contains a

certification pursuant to 21 U.S.C. § 355(j)(2)(A)(vii)(IV) alleging that the '741 patent is invalid, unenforceable, and/or will not be infringed by the manufacture, use, or sale of Mylan's proposed generic versions of Sciele's Sular® tablets 20mg and 30mg. 25. Mylan's Second Paragraph IV Letter claims that Mylan's proposed generic

versions of 20mg and 30mg Sular® would not infringe the '741 patent, but contains extremely limited information about those proposed generic versions. For example, although the Second Paragraph IV Letter purports to list various ingredients in the proposed generic version, it does not list the amounts of the various ingredients or provide any information about the method by which the proposed generic version is manufactured. In total, the Second Paragraph IV Letter contains fewer than 15 lines of information about Mylan's proposed generic versions of 20 mg and 30mg Sular®.

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26.

Along with the Second Paragraph IV Letter, Mylan sent to Plaintiffs a document

entitled "Offer of Confidential Access to ANDA No. 79-051" that it requested Plaintiffs sign before providing access to any portion of Mylan's ANDA No. 79-051. This document contained various restrictions on who could view the ANDA that effectively eliminated Plaintiffs' ability to meaningfully access ANDA No. 79-051 and process the information contained therein. For example, this Offer barred any access to in-house counsel, and substantially limited the fields of practice of outside counsel who might view the ANDA. 27. Under 21 U.S.C. § 355(j)(5)(C)(i)(III), an offer of confidential access "shall

contain such restrictions as to persons entitled to access, and on the use and disposition of any information accessed, as would apply had a protective order been entered for the purpose of protecting trade secrets and other confidential business information." 28. Since receiving the Second Paragraph IV Letter and the accompanying "Offer of

Confidential Access," Sciele has attempted to negotiate with Mylan to procure a copy of ANDA No. 79-051 under restrictions "as would apply had a protective order been issued." These negotiations have been unsuccessful. For example, Mylan has continued to insist on inappropriate restrictions on the fields of practice of counsel that might review the ANDA. 29. By requiring these inappropriate restrictions, Mylan has effectively refused to

provide information that would allow Plaintiffs to confirm that Mylan's proposed generic versions of Sciele's Sular® tablets 20mg and 30mg are within the lawful scope of one or more claims of the '741 patent. 30. Plaintiffs are not aware of any other means of obtaining information regarding

Mylan's proposed generic versions of Sciele's Sular® tablets 20mg and 30mg within the 45-day statutory period. In the absence of such information, Plaintiffs resort to the judicial process and the aid of discovery to obtain, under appropriate judicial safeguards, such information as is required to confirm its allegations of infringement and to present to the Court evidence that Mylan's proposed generic versions of Sciele's Sular® tablets 20mg and 30mg fall within the scope of one or more claims of the '741 patent. 5

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31.

On information and belief, in filing ANDA No. 79-051, Mylan has requested the

FDA's approval to market generic copies of Sciele's Sular® tablets 20mg and 30mg throughout the United States, including Delaware. 32. On information and belief, if the FDA approves ANDA No. 79-05 1, Mylan will

attempt to sell the approved proposed generic versions of Sciele's Sular® tablets 20mg and 30mg throughout the United States, including Delaware, before the expiration of the '741 patent. Count I (Infringement of the '741 Patent Under 35 U.S.C. § 271(e)(2) by Mylan ' s proposed generic nisoldipine extended release tablets 20mg) 33. 34. Paragraphs 1 to 28 are incorporated herein as set forth above. On information and belief, Mylan submitted an ANDA to the FDA under section

505(j) of the FDCA to obtain approval to engage in the commercial manufacture, use, or sale of proposed generic nisoldipine extended release tablets 20mg throughout the United States. By submitting the application, Mylan has committed an act of infringement under 35 U.S.C. § 271(e)(2)(A). 35. While Mylan denied infringement of the '741 patent in its Second Paragraph IV

Letter, that Letter provides insufficient information on which Plaintiffs may evaluate that claim. Mylan has also, to date, failed to provide ANDA No. 79-051 to allow Plaintiffs to review the necessary information. In the absence of such information, Plaintiffs resort to the judicial process and the aid of discovery to obtain under appropriate judicial safeguards such information as is required to confirm its allegations of infringement and to present to the Court evidence that Mylan's proposed generic version of Sciele's Sular® tablets 20mg falls within the scope of one or more claims of the '741 patent. 36. On information and belief, Plaintiffs are entitled to a declaration whether the

commercial manufacture, use, offer for sale, sale, and/or importation of Mylan's proposed generic nisoldipine extended release tablets 20mg constitutes or will constitute an act of infringement of the '741 patent under 35 U.S.C. § 271.

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37.

Plaintiffs will be irreparably harmed by Mylan's infringing activities unless those

activities are enjoined by a Court of law. Plaintiffs do not have an adequate remedy at law. Count II (Infringement of the '741 Patent Under 35 U.S.C. § 271(e)(2) by Mylan' s proposed generic nisoldipine extended release tablets 30mg) 38. 39. Paragraphs 1 to 37 are incorporated herein as set forth above. On information and belief, Mylan submitted an ANDA to the FDA under section

505(j) of the FDCA to obtain approval to engage in the commercial manufacture, use, or sale of proposed generic nisoldipine extended release tablets 30mg throughout the United States. By submitting the application, Mylan has committed an act of infringement under 35 U.S.C. § 271(e)(2)(A)· 40. While Mylan denied infringement of the '741 patent in its Second Paragraph IV

Letter, that Letter provides insufficient information on which Plaintiffs may evaluate that claim. Mylan has also, to date, failed to provide ANDA No. 79-051 to allow Plaintiffs to review the necessary information. In the absence of such information, Plaintiffs resort to the judicial process and the aid of discovery to obtain under appropriate judicial safeguards such information as is required to confirm its allegations of infringement and to present to the Court evidence that Mylan's proposed generic version of Sciele's Sular® tablets 30mg falls within the scope of one or more claims of the '741 patent. 41. On information and belief, Plaintiffs are entitled to a declaration whether the

commercial manufacture, use, offer for sale, sale, and/or importation of Mylan's proposed generic nisoldipine extended release tablets 30mg constitutes or will constitute an act of infringement of the '741 patent under 35 U.S.C. § 271. 42. Plaintiffs will be irreparably harmed by Mylan's infringing activities unless those

activities are enjoined by a Court of law. Plaintiffs do not have an adequate remedy at law. Prayer For Relief Plaintiffs respectfully pray for the following relief7

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a.

That judgment be entered that Mylan has infringed the '741 patent under 35

U.S.C. § 271(e)(2)(A) by submitting an ANDA under section 505(j) of the Federal Food Drug, and Cosmetic Act, and that the commercial manufacture, use, offer for sale, sale and/or importation of Mylan's proposed generic nisoldipine extended release tablets 20mg will constitute an act of infringement of the '741 patent; b. That judgment be entered that Mylan has infringed the '741 patent under 35

U.S.C. § 271(e)(2)(A) by submitting an ANDA under section 505(j) of the Federal Food Drug, and Cosmetic Act, and that the commercial manufacture, use, offer for sale, sale and/or importation of Mylan's proposed generic nisoldipine extended release tablets 30mg will constitute an act of infringement of the '741 patent; c. That an order be issued under 35 U.S.C. § 271(e)(4)(A) that the effective date of

any FDA approval of Mylan's ANDA shall be a date which is not earlier than the expiration date of the '741 patent; d. That an injunction be issued under 35 U.S.C. § 271(e)(4)(B) permanently

enjoining Mylan, its officers, agents, servants, employees, licensees, representatives, and attorneys, and all other persons acting or attempting to act in active concert or participation with it or acting on its behalf, from engaging in the commercial manufacture, use, offer to sell, or sale within the United States, or importation into the United States, of any drug product covered by the '741 patent before the expiration of said patent; e. That damages or other monetary relief be awarded to Plaintiffs under 35 U.S.C. §

271(e)(4)(C) as appropriate, including an accounting for any damages not included in any judgment entered after trial; f. That this is an exceptional case under 35 U.S.C. § 285, and that Plaintiffs be

awarded reasonable attorneys' fees and costs; and g. That this Court award such other and further relief as it may deem just and proper. Demand for Jury Trial Plaintiffs demand a trial by jury on all issues appropriately tried to a jury.

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Dated: January 28, 2008

FISH & RICHARDSON P.C.

By: /s/ William J. Marsden, Jr. William J. Marsden, Jr. (#2247) Susan M. Coletti (#4690) 919 N. Market Street, Suite 1100 P.O. Box 1114 Wilmington, DE 19899-1114 Telephone: (302) 652-5070 Facsimile: (302) 652-0607 Email: [email protected]; [email protected] Jonathan E. Singer Deanna J. Reichel 3300 Dain Rauscher Plaza 60 South Sixth Street Minneapolis, MN 55402 Telephone: (612) 335-5070 Facsimile: (612) 288-9696 Nagendra Setty 1180 Peachtree Street, N.E., 21st Floor Atlanta, GA 30309 Telephone: (404) 892-5005 Facsimile: (404) 892-5002 John D. Garretson Citigroup Center - 52nd Floor 153 East 53rd Street New York, NY 10022-4611 Telephone: (212) 765-5070 Facsimile: (212) 258-2291 Attorneys for Plaintiffs SCIELE PHARMA, INC., and SCIELE PHARMA CAYMAN LTD.

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Dated: January 28 , 2008

CONNOLLY BOVE LODGE & HUTZ LLP

By: /s/RudolfE. Hutz Rudolf E. Hutz (#484) Christine M. Hansen (#3098) The Nemours Building 1007 North Orange Street P.O. Box 2207 Wilmington, DE 19899 Telephone: (302) 888-6266 Facsimile: (302) 658-5614 Email: [email protected] Attorneys for Plaintiff BAYER HEALTHCARE AKTIENGESELLSCHAFT

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Exhibit A

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United States Patent [19]
Ohm et al.
[54]
[75]

[11]. Patent Number:
[45] Date of Patent:

4,892,741.
Jan. 9, 1990

PRESS COATED DHP TABLETS
Inventors: Andreas Ohm, Neuss; Helmut Luchtenberg, Niederkassel; Shinji Maegata, Oharanaka; Wolfgang Opitz, Overath, all of Fed. Rep. of Germany 4.. As'signee '. Bayer- Aktiengesellschaft, Leverkusen, Fed. Rep. of Germany

4,765 ,990 4,803,081

8/ 1988 Sigimoto et al ..................... 424/494 2/ 1989 Falk at al .........................424/480 X

FOREIGN PATENT DOCUMENTS 2331375 6/1977 France 1144915. 3/1969 United Kingdom 2123291 2/1984 United Kingdom ................ 424/480

[73]

OTHER PUBLICATIONS
104:174662y, Kimura et al., "Controlled-Release Pharmaceuticals Containing Nifedipine ... ", Chem. Ab. V. 104, May 1986, p: 391. T. Wagner, "Die Praxis der Mantel -und Mehrschichttablette", Pharmazeutische Industrie , v. 24 (9/ 1962) pp. 417-422. Primary Examiner-Thurman K. Page Attorney, Agent, or Firm Sprang Horn Kramer & Woods [57] ABSTRACT

[21] Appl. No.: 204,056
[22] [30] Filed: Jun. 8, 1988 Fed. Rep. of Germany ....... 3720751 Foreign Application Priority Data

Jun. 24, 1987 [DE] (51] [52] [58)

Int. C1.4 ................................................ A61K 9/36 U.S. Cl..................................... 424/479;424/474; 424/480;424/482 Field of Search ..:............ 424/482, 480; 479, 494, 424/474

[56]
3,184,386 3,558,768 4,654,206

References Cited
U.S. PATENT DOCUMENTS 5/1965 Stephenson ..................... 424/479 X 1/19171 Klippel ........................... 424/480 X 3/1987 Okuda et al ......................... 424/480

The invention relates to solid pharmaceutical preparations which have a long-lasting action and are for dihydropyi-idines in the form of a press coated tablet, and a : process for their preparation. 12 Claims, 1 Drawing Sheet

100r Nitrendipin (9) ^.. ,/ --Nifedipin / (7) / //

50
%// Nifedipin (1)

00

5

10

15

20

25 h

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U.S. Patent
Rio toor

Jan. 9 ,

1990

4,892,741

Nitrendipin (9) Y~Nifedipin (7)

50
j^^^ Nifedipin (1I

0

0

5

10

15

20

25 h

FIG.1

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1
PRESS COATED DHP TABLETS

4,892,741

2

Active compounds from the dihydropyridine class of substances and their use as cardiac and circulatory 5 agents have already been disclosed (compare Brit. Pat. 1,173,862, Brit. pat. 1,358,951, US-Pat. 4,25.6,749, German Offenlegungsschrift 3,311,003 and U.S. Pat. No. 4,264,611). Difficulties frequently appear in the galenical preparation of these potent active compounds, in 10 that the substances possess only a very low solubility, are frequently light-sensitive and their absorbability in biological systems frequently leads to problems. Numerous experiments have been undertaken to produce galenical preparations which improve the bioavailabil- 15 ity of these potent active compounds. Thus, for example, some active compounds have been dissolved in specific organic solvent systems and filled into gelatine capsules in order to ensure a rapid and effective commencement of action (compare Brit. Pat. 1,362,627). 20 The conversion of dihydropyridines such as nifedipine into co-precipitates or, into "solid solutions" has also been attempted using water-soluble polymers, in order to improve the bioavailability (compare Brit. Pat. 25 1,579,818). For the treatment of illnesses which must be treated over relatively long periods of time, such as, for example, hypertension, it is desirable to keep the frequency of administration of medicaments as low as possible. This

is not only more aggreeable for the patient, but also 30
increases the safety of the treatment by diminishing the disadvantages of irregular administration and leads to a uniform active compound concentration/time profile in the body. The risk of under- or overdosing is thereby 35 minimized at the same time. Both for the physician and also for the patient, there is a demand, for example for the continuous therapy or circulatory diseases, to have available the highly active dihydropyridines in a form in which a once daily application suffices for treatment of the disease. Medicament 40 preparations having delayed release of active compound (retard forms) have already been described for dihydropyridines. Thus, for example, the production of a slow-release preparation has been attempted by specific particle size distribution of the crystalline active 45 compound or by a selected specific surface area of the crystals of the active compound (compare German Offenlegungsschrift 3,033,919). Furthermore, specific tablet preparations have been proposed which, according to the principle of the osmotic pump, release the 50 active compound from the interior of a tablet which is provided with a semi-permeable coating layer through a given opening over a relatively long period of time and thus to achieve a retard effect (compare U.S. Pat. 55 No. 3,916,899). The previously known forms of preparation having retarded release ofactive compound, in particular those for. dihydropyridines, exhibit a number of disadvantages. Their retard action is, for example, only limited to' a few hours in some forms, so that the patient must, as 60 a rule, administer them two or more times daily as before. After a few hours, the rate of release of the active compound decreases markedly, so that the blood level can also drop beneath the necessary efficacy limit. . In German Offenlegungsschrift 2,651,176, pellets 65 having .controlled release of active compound are described. The formulations described there differ fundamentally from the coated tablets according to the inven-

tion, since these pellets can only be obtained in complex processes by continuous application of many layers; whereas the tablet according to the invention is prepared by simple compression. An additional substantial difference is that the spherical pellets according to this Offenlegungsschrift even when they are produced in tablet dimensions, show a terminally decreasing release rate as opposed to the stepwise terminally increasing release rate of the coated tablets according to the invention. In the embodiment examples described there, only readily soluble active compounds are employed and all the examples describe the preparation of the pellet layers using lipophilic retarding agents. The use according to the invention of hydrophilic polymers, in particular hydroxypropyl-cellulose, cannot be carried out practically by the embodiment examples of this Offenlegungsschrift. In the abovementioned osmotic system, local irritation of the tissue can occur in the stomach or gastrointestinal tract, depending on the capsule filling employed, owing to excessive concentration. Furthermore, a flattening of the release curve in the terminal region is also to be observed in. the case of this osmotic retardation principle, which should ensure a linear course of release over a relatively long period of time. Due to the nature of the osmotic system, some of the active compound remains in the medicament form and is thus not available for the desired absorption. An additional disadvantage of this system is the delayed setting in of active compound release after administration, which in some cases only begins after about 2 hours. In . addition, the production of this medicament form is very expensive, since organic solvents must be employed in the preparation process here and the coating layer of each tablet must be perforated separately with the aid of a laser beam. It has now been found that solid medicament preparations which have a long-lasting action in the form of a coated tablet and which contain a sparingly soluble dihydropyridine active compound of the general for= mula I
R1 I

H

in which RI represents a phenyl radical which is substituted by one or two identical or different substituents from the group comprising nitro, halogen and trifluoromethyl, or represents a radical from the group comprising
N

0 N

0 II
and

S

1 n, I ,

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3

4,892,741
4 When using crystalline dihydropyridine in the core,
the addition of readily water -soluble auxiliaries such as, for example, lactose is expedient. Likewise , the release rate can be accelerated by the use of disintegrants, such as, for example, crosslinked polyvinylpyrrolidone (PVP), or surface-active substances, such as, for example, sodium lauryl sulphate. The preparation of this rapid-release core takes place by customary methods (compare German Offenlegungsschrift 3,415,128 and German Offenlegungsschrift 3,142,853 or Brit. Pat. 1,579,818). The granules for the coat of the tablet contain 10 to 99%, preferably 20 to 90%, of the total coating weight of hydrophilic gel-forming polymers. Suitable hydrophilic gel-forming polymers are, for example, modified starch or cellulose-like substances such as, for example, methylcellulose, hydroxypropylmethyl-cellulose, hydroxypropylcellulose and sodium carboxymethyl- cellulose. Hydroxypropylcellulose (HPC) may be mentioned as being particularly preferred (compare: Hagers Handbuch der pharmazeutischen Praxis (Hager's Handbook of Pharmaceutical Practice), volume 7, part B, (1977) 130-141). Various types of HPC can be used according to the invention, in each case differing in their viscosity, for example HPC-L'(low viscosity of about 6-10 mPa.s), HPC-M (medium viscosity of about 150 mPa.s) and HPC-H (high viscosity of about 1000-4000 mPa.s). The release rate can be controlled through the different viscosity grades, the release rate increasing when lower viscosity grades are employed and slowing when using higher viscosity types. In some cases, it is expedient to apply some of the active compound as the initial dose in the form of an outer layer of the coated tablet using the known techniques and auxiliaries. Customary known galenical measures, such as, for example, the coating of the core with a gastric juiceresistant layer, the use of flavorings and aromas and lubricants and customary auxiliaries which are familiar to the galenical expert, can of course also be employed and used in the press coated tablets according to the invention. It should be expressly pointed out that the coated tablet according to the invention differs from the previously known coated tablets due to the fact that the coating contains the active compound in slow-release form and the core contains the active compound in rapid-release form. Multi-layer tablets based on casein matrices, which contain two or three layers which in each case can in turn contain active compounds (compare U.S. Pat. No. 3,184,386), have already been described in the prior art. The tablets described there contain a rapid-release preparation in the outer coating, the core primarily having the function of not allowing the surface of the outer active compound-containing layer relevant for the release to become too small. This patent specification contains no indication, however, that the core of the preparation contains a sparely soluble active compound in rapid-release form. On the contrary, both the central coat and also the core are described in the examples as slow-release-forms of highly soluble active compounds. Coated tablets which contain active compounds in slow-release form both in the core and in the coating are also described in U.S. Pat. No. 3,558,768. The release rates according to this US patent specification may be

R2 represents a nitro group or the radical COOR6, in which R6 denotes alkyl having I to 10 C atoms which is optionally substituted by alkoxy having 1 to 4 C atoms or by one or more halogens, or in which R2, together with R5, represents the lactone group -CO-O-CH2,

5

R3 represents alkyl having 1 to 10 C atoms, which
10 is optionally substituted by alkoxy having 1 to 4 C atoms or by one of more fluorine atoms and R4 and R5 are identical or different and in each case represent alkyl having 1 to 4 C atoms, which is optionally substituted by hydroxyl, 15 where the coated tablet (a) consists of a core which contains at least one of the abovementioned dihydropyridines in rapid-release form and (b) consists of a coating around the core, this coating containing at least one of the abovementioned dihy- 20 dropyridines in slow-release form, show a surprisingly long-lasting efficacy. Coated tablets may be preferably mentioned which contain 5% to 50%, preferably 10% to 40%, of the total 25 dihydropyridine active compound in the core and which contain 50% to 95%, in particular 60% to 90%, of the total dihydropyridine active compound in the coating. Particularly preferred active compounds which may 30 be mentioned are nifedipine, nitrendipine, nimodipine and nisoldipine. According to the type of active compound, the coated tablets according to the invention preferably contain 1 to 200 mg in total, in particular 10 to 150 mg, 35 of at least one active compound from the dihydropyridine class. The rapid-release core of the coated tablet preferably contains the active compound in amorphous form or in finely grounded or micronized crystalline form. When 40 using crystalline active compound, the release rate is preferably influenced by the addition of auxiliaries with good water solubility and by alteration of the particle size distribution of the active compound. Tablet cores having rapid release are preferably those 45 cores which release 75% of the dihydropyridine active compound in one hour, preferably in 30 minutes, under the following conditions: 4 liters of 0,IN hydrochloric acid and 0,1-0,5% of weight of surfactant e.g. TWEEN 80 or sodiumlaurylsulphate; 37' C.; 100 Rpm; USP-Pad- 50 dle method. If the rapid-release core contains amorphous dihydropyridine, the latter is preferably dissolved in an organic solvent together with water-soluble polymers such as polyvinylpyrrolidone, methylcellulose, hydrox- 55 ypropyl-cellulose or hydroxypropylmethylcellulose. It is expedient here to employ 2 to 10 parts by weight, in particular 3 to 8 parts by weight, of the water-soluble polymers to 1 part by weight of dihydropyridine and to prepare suitable co-precipitates from this. 60 If the rapid-release core contains dihydropyridines in crystalline form, dihydropyridine crystals having a maximum mean particle size of about 25 pm, in particular a maximum mean particle size of about 15 µm, are preferably employed. The particle size is determined by 65 the Cilas method (lit.: A. Buerkholz et al, Part. Charact. 1, 1984, 153-160, "Laser defraction spectrometers/experience in particle size analysis").

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5.

4,892,741 6 should be 20% of the total amount of the active substance.

different, but the specification refers only, to slowrelease forms..

Through the principle of the coated tablet according With regard to the ' long existing requirement for to the invention, the hitherto customary disadvantages medicament preparation forms having a long-lasting of normal retard tablets and also "of previously known 5 action, it is more than surprising that hitherto nobody multilayer or coated tablets or of preparation forms has described or produced the coated tablets according which depend upon the osmotic principle are avoided. to the invention having a rapid-release core which are In particular, the situation where the release rate of the simple to produce and very effective. Through the active compound becomes smaller and smaller towards present invention, the patient is placed in the position of the end of the dissolution of the tablets and the plasma 10 only having to take the medicament once daily, which levels thus sink is avoided. The decreasing release rate in continuous therapy, in particular, represents a safer of normal retard tablets due to a reduction in the voland more agreeable type of treatment. ume of the tablet is more than compensated for by the The curves in FIG. I show for several examples rapid-release action of the core of the press coated tabaccording to the invention the principle of the -coat of let according to the invention. Complete release of the 15 the tablet which is slowly released over several hours active compound is achieved at the same time, in conand the core which is released rapidly. trast to osmotic systems. . The formulation. according to the invention differs ILLUSTRATIVE EMBODIMENTS from all previously known retardation principles for Example 1 solid medicament forms through the acceleraed release 20 (A) Core rate in the terminal region. 50 g of crystalline nifedipine (mean particle size 5 Any reduced absorption of the administered medicaµm) are mixed with 388 g of lactose and 150 g of corn . ment substance in deeper intestinal sections, for example starch, and the mixture is granulated in a paste of 10 g of limited by hindrance of diffusion, may thus be better equalized. Further advantages which maybe mentioned 25 starch and 140 g of hot water and then dried. The granules are sieved and mixed with 50 g of microcrystalline . are the rapid influx of the active compound after administration with the avoidance of a retardation phase and cellulose and 2 g of magnesium stearate. This mixture is also the simple preparation technology. A further adcompressed to 65 mg weight tablets having a diameter vantage of the inventive formulations is, that they are of 6 mm. The cores are coated for resistance to gastric specially useful for those drugs, which show a higher 30 juice using an organic solution of hydroxypropylresorption in the lower parts of the gastro intestinal methylcellulose phthalate. The coated tablets weigh 72mg. tracts e.g. in the colon. This may lead to an increase of the bioavailability. of those drugs. (B) Granules for the coat Inventive composition can be manufactured by the 250 g of nifedipine are mixed with 400 g of lactose, 16 following procedure: 35 g of colloidal silica, 700 g of type M hydroxy-propylcellulose, 1747 g of type L hydroxypropylcellulose (HPC) (A) Core: and 320 g of citric acid, and the mixture is granulated in In accordance with usual techniques the active suba fluidized bed granulator with a solution of 20 g of type stance and the other ingredients are mixed and granuL hydroxypropyl-cellulose. The dried and sieved gran·lated by adding an aqueous solution of binders , e.g. in a 40 ules are mixed with 27 g of magnesium stearate. planatory mixer or in a high speed mixer or by fluidized These granules and the cores described under (A) are bed granulation. The granulate is dried, preferably in a pressed to 420 mg weight press coated tablets having a fluidized bed dryer. The dried granulate is sieved and diameter of 10 mm in a press coater. The tablets are then'. mixed with magnesiumstearate and afterwards pressed using an aqueous dispersion of hydrnxypropylto tablets. Alternatively the manufacture of the core can 45 coated coated cellulose, polyethylene glycol, titanium dioxide . be made by direct compression of the ingredients or by and iron oxide red. roller compaction .plus compression. Optionally the coure can be coated by usual methods, preferably in a Example 2 coating pan or, by.other usual means. (A) Core 50 Preparation as in Example 1. Granules for the coat: .(B) Granules for the coat: 400 g of lactose are mixed The granulate is produced preferably in a fluidized with 17 g of colloidal silica, 2196 g of type L hydroxybed granulator by spraying an aqueous suspension containing the active substance and a binder on the solid · propyl-cellulose, 250 g of type M hydroxypropylcelingredients, the obtained granules are dried, sieved and 55 lulose and 320 g of citric acid, and the mixture is granulated with an aqueous suspension of 250 g-nifedipine and mixed with a lubricant, e.g. magnesiumsiearate. 20 g of type L hydroxypropyl-cellulose in a fluidized The production of the granules can also be made by bed granulator. The dried granules are sieved and other usual techniques. mixed with 27 g of magnesium stearate. Press coating: 60 . These granules and the cores described under: (A) are . pressed to 420 mg weight press coated tablets having a. The press coating of the core is carried out on usual press coaters (e.g. machines of the company Kilian or . diameter of 10 mm in a press coater. The tablets are then, coated using an aqueous dispersion of hydroxypropyl-, Manesty). methylcellulose, polyethylene glycol, titanium dioxide Optionally the press coated tablets can be film coated with usual-laquers.. In certain cases it may be recom- 65 and iron oxide red. mendable to incorporate a small amount of the active Example 3 substance into this film coating layer,.the maximum (A) Core amount of the active substance in the film coating layer

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7

4,892,741
8

50 g of crystalline nifedipine (mean particle size 8 Example 7 µm) are mixed with 291 g of lactose and 162.5 g of corn starch, and the mixture is granulated using a paste of 7.5 (A) Core g of corn starch in 100 g of hot water. The granules are 50 g of crystalline nifedipine (mean particle size 10 dried, sieved and then mixed with 1.5 g of magnesium 5 µm) are mixed with 600 g of lactose and 228 g of corn stearate and 37.5 g of microcrystalline cellulose. This starch, and the mixture is granulated using a paste of 20 mixture is compressed to 55 mg weight cores having a g of starch and 320 g of water and then dried. The diameter of 5.5 mm. granules are sieved and mixed with 2 g of magnesium (B) Granules for the coat stearate, and the mixture is pressed to 90 mg weight 400 g of lactose are mixed with 17 g of colloidal silica, 10 tablets having a diameter of 7 mm. The cores are coated 1105 g of type L HPC, 443 g of type M HPC and 202 g using an organic solution of hydroxypropylmethylcelof citric acid, and the mixture is granulated using an lulose phthalate. The coated cores weigh 97 mg. aqueous suspension consisting of 250 g of nifedipine and (B) Granules for the coat 16 g of type L HPC. The granules are dried and sieved 250 g of nifedipine are mixed with 400 g of lactose and mixed with 17 g of magnesium stearate. 15 and 16 g of colloidal silica, and the mixture is granulated Press coated tablets having a weight of 300 mg and a using a solution of 16 g of type L hydroxypropylceldiameter of 9 mm are produced from these granules and lulose in water. The dried and sieved granules are mixed the cores. The tablets are then coated as in Example I. with 900 g of type M hydroxypropylcellulose, 2387 g of type L hydroxypropylcellulose, 400 g of citric acid and Example 4 20 61 g of magnesium stearate. (A) Core These granules and the cores described under (A) are Preparation as in Example 3. pressed to 540 mg weight tablets having a diameter of 11 mm in a press coater. The tablets are then coated The cores are coated for resistance to gastric juice using an organic solution of hydroxypropylmethyl-celusing an aqueous dispersion of hydroxypropylmethyllulose phthalate. The coated tablets weigh 60 mg. 25 cellulose, polyethylene glycol, titanium dioxide and (B) Granules for the coat iron oxide red. 250 g of nifedipine are mixed with 400 g of lactose, 17 Example 8 g of colloidal silica, 1155 g of type L HPC, 343 g of type (A) Core M HPC and 202 g of citric acid, and the mixture is 100 g of crystalline nifedipine (mean particle size 4 granulated using an aqueous solution of 16 g of type L 30 HPC. The granules are dried, sieved and mixed with 17 l.cm) are mixed with 241 g of lactose and 162.5 g of corn g of magnesium stearate. starch, and the mixture is granulated with a paste of 7.5 Press Coated tablets having a weight of 300 mg and a g of corn starch in 100 g of water. The dried granules diameter of 9 mm are prepared from these granules and are sieved and mixed with 1.5 g of magnesium stearate the cores. The tablets are then coated as in Example 1. 35 and 37.5 g of Avicel and this mixture is pressed to 55 mg weight tablets having a diameter of 5.5 mm. Example 5 (B) Granules for the coat 500 g of nifedipine are mixed with 335 g of lactose (A) Core and 16 g of colloidal silica, and the mixture is granulated 250 g of crosslinked polyvinylpyrrolidone and 197 g of microcrystalline cellulose are mixed and granulated 40 using a solution of 33 g of type L hydroxypropylcelusing a solution of 30 g of nifedipine and 150 g of polylulose in water. The dried granules are sieved and mixed vinylpyrrolidone 25 in 350 g of acetone. The granules with 443 g of type M hydroxypropylcellulose, 1105 g of type L hydroxypropylcellulose and 18 g of magnesium are dried and sieved and pressed with 3 g of magnesium stearate. stearate. This mixture is pressed to 65 mg weight tablets These granules and the cores described under (A) are having a diameter of 6 mm. The cores are coated using 45 pressed to 300 mg weight tablets having a diameter of 9 an organic solution of hydroxypiopylmethylcellulose phthalate. The coated cores weigh 72 mg. mm in a press coater. The tablets are then coated using (B) Granules for the coat an aqueous dispersion of hydroxy-propylmethylcelThe granules are prepared analogously to Example 1. lulose, polyethylene glycol, titanium dioxide and iron The additional processing is as in Example 1. 50 oxide red. Examples 9 and 10 were prepared in an analogous Example 6 manner. (A) Core Example 9 Preparation as in Example 3. 55 (B) Granules for the coat Core: 200 g of nifedipine are mixed with 350 g of lactose, 17 g of colloidal silica, 1105 g of type L HPC, 443 g of type nitrendipine mean particle size 6 Am 5.0 mg M HPC and 202 g of citric acid, and the mixture is corn starch 227.8 mg granulated using an aqueous solution of 16 g of type L microcrystalline cellulose 20.0 mg HPC. The granules are dried and sieved and mixed with 60 lactose 21.49 mg 12 g of magnesium stearate. Press Coated tablets having a weight of 290 mg are are mixed and then granulated with: pressed from these granules and the cores. 5 mg of nifedipine per tablet are coated onto these tablets from an aqueous dispersion containing hydroxy- 65 polyvinylpyrrolidone 25 5.0 mg sodium lauryl sulphate 0.5 mg propylmethylcellulose and polyethylene glycol. These FD + C blue lake No. 2 0.01 mg tablets are then covered with a light protecting coating analogously to Example 1.

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9

4,892,741
10 -continued
Plasdone XL 7:3 mg

in aqueous suspension by means of customary granulation processes
after drying, magnesium stearate 0.2 mg

5 are granulated using an aqueous solution of.,
polyvinylpyrrolidone 25 · sodium lauryl sulphate 5 mg 0.5 mg

is admixed. The mixture is pressed to cores in a tablet press: weight: 80 mg, size- 4s6 mm 10
Granules for the coat: type L hydroxypropylcellulose type M hydroxypropylcefulose citric acid 210.0 mg 82.0 mg 146.0 mg 15

after drying,

magnesium stearate

02 mg

are mixed and granulated with an aqueous suspension of

is admixed and the mixture pressed to cores in a tablet press. Weight: 80 mg, size: 6 mm Granules for the coat:

nitrendipine (mean particle size 5 pm) hydroxypropylcellulose typie L

after drying admixing of magnesium stearate

25.0 mg 2.0 mg 5.0 mg

20

micronized nisoldipine type L hydroxypropylcellulose type M hydroxypropylcellulose lactose

12.5 mg 212 mg 82 mg 158.5 mg

Press Coated tablets are prepared with the aid of a press -Dater Total weight: 550 ma Size: AIO mm 25 g

are mixed and granulated with water admixing of
magnesium stearate 12 mg

Example 10
Core:
nitrendipine mean particle size 5 pm microcrystallme cellulose lactose corn starch mixing and granulation with poly^inylpyrrolidone 25 sodium lauryl sulphate 5.0 mg 17.5 mg 6 . 4 mg 7.5 mg 3.0 mg 0.5 mg

30 Press Coated tablets are prepared with the aid of a press coater Total weight: 557 mg Size: 10 mm Example 12
35

(A) Core
The preparation is as in Example 8, 200 g of nimodi-

in aqueous solution by means of customary granulation processes after drying, 40
magnesium stearate 0.1 mg

pine and 141 g of lactose now being employed instead of 100 g of nifedipine and 241 g of lactose. (B) Granules for the coat
Prep aration by analo g y with Examp le 8 , 600I nimodipine and 235 g of lactose now being employed instead of 500 g of nifedipine and 335 g of lactose.

The aqueous coating is likewise analogous to Example 8, but without the use of red iron oxide. is admixed and the mixture is pressed to cores in a tablet press: weight: 40 mg, size: ¢5.5 mm 45 Example 13 Granules for the coat: (A) Core The preparation is analogous to Example 8, 50 g of nifedipine, 150 g of nisoldipine and 141 g of lactose now 25.0 mg micronized nitrcndipine 221.0 mg type L hydroxypropylcellulose 50 being employed instead of 100 g of nifedipine and 241.g of lactose. (B) Granules for the coat are mixed and granulated (if desired a part of the hyThe preparation is analogous to Example 8, 200 g of droxypropylcellulose can be removed for processing in nifedipine and nisoldipine now being employed instead the granulation liquid) 55 of 500 g of nifedipine. At the same time, 518 g of HPC-M and 1030 1g of 7.0 mg admixing of magnesium stearate HPC-L are now used instead of 443 g of HPC-M and 1105 g of HPC-L. Press Coated tablets are prepared with the aid of a press Example 14 coater. Total weight: 293 mg Size: 9 mm 60 Core: Example 11
Core:
65 nitrendiplae (mean particle size 10 pm) corn starch microcrystalline cellulose lactose 2.5 23.0 20.0 21.5 mg mg mg mg

nitrendipine of mean particle size 5 pm
microcrystalline cellulose lactose Plasdone XL

8.0 mg
12.0 mg 4.0 mg 15.0 mg

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4,892,741 11
mixing and granulation with

12

using an aqueous suspension of 500 g nifedipine and 40 g HPC type L. The granules are dried and sieved and mixed with 17 g of magnesium stearate. Press coated polyvinylpyrrolidone 25 2.0 mg tablets having a weight of 300 mg and a diameter of 9 sodium lauryl sulphate 0.8 mg 5 mm are pressed from these granules and the cores. C. Coating in aqueous solution by means of customary granulation The tablets are then coated with an aqueous suspenprocesses after drying, sion of hydroxypropylmethylcellulose, polyethylene glycol, titanium dioxide and iron oxide red in order to
magnesium stearate 0.2 mg 10 give light protection.

is admixed and the mixture is pressed to cores in a tablet press: weight: 42 mg, size: 5 mm

Example 17 A. Core 150 g nifedipine (mean particle size 5 µm) are mixed 15 with 130 g lactose, 124 g corn starch. This mixture is granulated with an aqueous paste of 5 g corn starch. After drying and sieving 1 g magnesium stearate, 50 g plasdone XL and 40 g Avicel are added. The granules 20 are compressed to tablets with a size of 5 mm and a weight of 50 mg.

Granules for the coat:
micronized nitrendipine type L hydroxypropylcellulose type M hydroxypropylcellulose lactose 320 mg 77.0 mg 77.0 mg 92.5 mg

780 g hydroxypropylcellulose type L, 588 g hydroxypropylcellulose type M, 289 g lactose and 16 g of colloi25 dal silica are mixed. This mixture is granulated using an aqueous suspension of 750 g nifedipine and 60 g HPC 1.5 mg admixing of magnesium stearate type L. The granules are dried and sieved and mixed with 17 g of magnesium stearate. Press coated tablets having a weight of 300 mg and a diameter of 9 mm are Press Coated tablets are prepared with the aid of a press 30 pressed from these granules and the cores. coater. Total weight: 322.0 mg; size: 9 mm Example 15 C. Coating

are mixed and granulated (if desired a part of the hydroxypropylcellulose can be removed for processing in the granulation liquid)

B. granules for the coat

The tablets are then coated with an aqueous suspen50 g Nifedipine (mean particle size 5 µm) are mixed sion of hydroxypropylmethylcellulose, polyethylene with 170 g lactose and 173,5 g corn starch. This mixture 35 glycol, titanium dioxide and iron oxide red in order to is granulated with an aqueous paste of 5 g corn starch. give light protection. After drying and sieving 1,5 g magnesium stearate, 50 g Example 18 plasdone XL and 50 g Avicel are added. The granules are compressed to tablets with a size of 5 mm and a A. Core 40 weight of 50 mg. 8 g nitrendipine (mean particle size 5 µm) are mixed B. granules for the coat with 4 g lactose, 15 g crosslinked PVPP and 12,3 g 1101 g hydroxypropylcellulose type L, 755 g hydroxmicrocrystalline cellulose. This mixture is granulated ypropylcellulose type M, 341 g lactose and 16 g of with an aqueous solution of 1,8 g PVP and 0,8 g sodium colloidal silica are mixed. This mixture is granulated laurylsulfate. After drying and sieving 0,1 g magnesium using an aqueous suspension of 250 g nifedipine and 20 45 stearate are added. The granules are compressed to g HPC type L. The granules are dried and sieved and tablets with a size of 5 mm and a weight of 42 mg. mixed with 17 g of magnesium stearate. Press coated B. granules for the coat tablets having a weight of 300 mg and a diameter of 9 104,5 g hydroxypropylcellulose type L, 40 g hydroxmm are pressed from these granules and the cores. ypropylcellulose type M and 88,5 g lactose are mixed. 50 C. Coating This mixture is granulated using an aqueous suspension The tablets are then coated with an aqueous suspenof 32 g nitrendipine and 1,5 g HPC type L. The granules sion of hydroxypropylmethylcellulose, polyethylene are dried and sieved and mixed with 1,5 g of magnesium glycol, titanium dioxide and iron oxide red in order to stearate. Press coated tablets having a weight of 310 mg give light protection. 55 and a diameter of 9 mm are pressed from these granules Example 16 and the cores. C. Coating A. Core The tablets are then coated with an aqueous suspen100 g nifedipine (mean particle size 5 µm) are mixed sion of hydroxypropylmethylcellulose, polyethylene with 160 g lactose, 148,8 corn starch. This mixture is granulated with an aqueous paste of 5 g corn starch, 60 glycol and titanium dioxide. After drying and sieving 1,3 g magnesium stearate, 50 g Example 19 plasdone XL and 34,9 g Avicel are added. The granules A. Core are compressed to tablets with a size of 5 mm and a 20 g nitrendipine (mean particle size 5 µm) are mixed weight of 50 mg. 65 with 15 g crosslinked PVP and 7,2 g microcrystalline B. granules for the coat cellulose. This mixture is granulated with an aqueous 1010 g hydroxypropylcellulose type L, 628 g hydroxsolution of 1,8 g PVP and 0,9 g sodium,lauryl sulfate. ypropylcellulose type M, 289 g lactose and 16 g of After drying and sieving 0,1 g magnesium stearate are colloidal silica are mixed, This mixture is granulated

A. Core:

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4,892,741
13 added. The granules are compressed to tablets with a size of 5 mm and a. weight of 45 mg.
B. granule for the coat 144.5 g hydroxypropylcellulose type L and 97,5 g lactose are mixed. This mixture is granulated using an 5 aqueous suspension of 20 g nitrendipine and 1,5 g HPC type L. The granules are dried and sieved and mixed with 1,5 g of magnesium stearate. Press coated tablets having a weight of 310 mg and a-diameter of 9 mm are pressed from. these granules and the cores. to C. Coating The tablets are then coated with an aqueous suspension of hydroxypropylmethylcellulose, polyethylene glycol and titanium dioxide. 15 Example 20

14
aqueous solution of 1,8 g PVP .and 0,8 g sodium laurylsulfate. After drying and sieving 0,1 g magnesium stearate are added . The granules are compressed to tablets with a size of 5 mm and a weight of 42 mg. B. granule for the coat 175 g hydroxypropylccllulose type M and 74,5 g lactose are mixed. This mixture is granulated using an aqueous suspension of 16 g nisoldipine and 1,5 g HPC type L. The granules are dried and sieved and mixed with 1'g of magnesium stearate. Press coated tablets having a weight of 310 mg and a diameter of 9 mm are pressed from these granules and the cores. C. Coating The tablets are then coated with an aqueous suspension of hydroxypropylmethylcellulose, polyethylene, glycol, titanium dioxide and iron oxide red in order to give light protection. It will be understood that the specification and examples are illustrative but not . limitative of the present invention and that other embodiments within the spirit and scope of the invention will suggest themselves to those skilled in the art. We claim. 1. A solid medicament preparation having a long -last-. ing action in the form of a press coated tablet which contains a sparingly soluble dhydropyridine , the press coated tablet comprising (a) a core which contains a dihydropyridine in rapidrelease form, and

A. Core

4 g nisoldipine (mean particle size 5 µm) are mixed with 8 g lactose, 15 g crosslinked PVPP and 12,3 g microcrystalline cellulose. This mixture is granulated 20 with an aqueous solution of 1,8 g PVP and 0,8 g sodium laurylsulfate. After drying and sieving 0,1 g magnesium stearate are added. The granules are compressed to tablets with a size of 5 mm and a weight of 42 mg. 25 B. granule for the coat 46,5 g hydroxypropylcellulose type L, 100 g hydroxypropylcellulose type M and 103 g lactose are mixed. This mixture is granulated using an aqueous suspension of 16 g nisoldipine and 1,5 g HPC type L. The granules are dried and sieved and mixed with 1 g of magnesium 30 (b) a coat around the core, the coat containing a' stearate. Press coated tablets having a weight of 310 mg dihydropyridine in slow-release form. and a diameter of 9 mm are pressed from these granules 2. A press coated tablet according to claim 1, wherein and the cores. the dihydropyridine is of the formula C. Coating The tablets are then coated with an aqueous suspen- 35 I sion of hydroxypropylmethylcellulose, polyethylene R1 R' R3000 glycol, titanium dioxide and iron oxide red in order to give light protection. Example 21
40 R4 I N H R5

A. Core 4 g nisoldipine (mean part icle size 5 µm) are mixed in which with 8 g lactose, 15 g crosslinked PVPP and 12,3 g RI represents a phenyl r adical which is substituted by microcrystalline cellulose. This mixture is ,granulated one or two identical o r different substituents from with an aqueous solution of 1,8 g PVP and 0,8 g sodium 45 the group comprising nitro, halogen and trifluorolaurylsulfate. After drying and sieving 0,1 g magnesium methyl, or represent s a radical from the group stearate are added. The granules are compressed to comprising tablets with a size of 5 nun and a weight of 42 mg.

B. granule for the coat
92,5 g hydroxypropylcellulose type L, 54 g hydroxy- 50 · propylcellulose type M and 103 g lactose are mixed. This mixture is granulated using an aqueous suspension of 16 g nisoldipine and 1,5 g HPC type L. The granules are dried and sieved and mixed with 1 g of magnesium stearate. Press coated tablets having a weight of 310 mg 55 and a diameter of 9 mm are pressed from these granules and the cores. C. Coating The tablets are then coated with an aqueous suspension of hydroxypropylcellulose, polyethylene glycol, 60 titanium dioxide and iron oxide red in order to give light protection, Example 22
N

0 N

0 II
and

R2 represents a nitro group or the radical COOR6, in which R6 denotes alkyl having I to 10 C atoms which is 65 A. Core optionally substituted by alkoxy having 1 to 4 C 4 g nisoldipine (mean particle size 5 µm). are mixed atoms or by one or more halogens, with 8 g lactose, 15 g crosslinked PVP and 12,3 g microor in which . crystalline cellulose. This mixture is granulated with an

Case 1:07-cv-00818-GMS-LPS

Document 20-4

Filed 02/04/2008

Page 25 of 36

4,892,741
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16

selected from the group consisting of nifedipine, nitrenR2, together with R5, represents the lactone group dipine, nimodipine and nisoldipine. -CO-O-CH2, R3 represents alkyl having 1 to 10. A press coated tablet according to claim 1, 10 C atoms, which is optionally substituted by wherein the core contains the dihydropyridine in crys.alkoxy having 1 to 4 C atoms or by one or more fluorine atoms and R4 and R5 are identical or differ- 5 talline form and further contains at least one of a readily water-soluble auxiliary, disintegrant and wetting agent. ent and in each case represent alkyl having 1 to 4 C 11. A press coated tablet according to claim 1, atoms, which is optionally substituted by hydroxyl. wherein the coating is itself coated with a layer of dihy3. A press coated tablet according to claim 1 , containdropyridine in rapid-release form. ing about 5 to 50 % of the total dihydropyridine in the 10 12. A process for manufacturing solid medicament core and about 95 to 50 % of the total dihydropyridine preparations having a long lasting action containing a in the coat. sparingly soluble dihydropyridine in form of a press 4. A press coated tablet according to claim 1, containcoated tablet comprising: ing about 10 to 40% of the total dihydropyridine in the (a) a core which contains a dihydropyridine in rapid core and about 90 to 60% of the total dihydropyr