Liza M. Walsh 

Rukhsanah L. Lighari 

Connell Foley LLP 

85 Livingston Avenue 

Roseland, New Jersey 07068 

Tel.: (973) 535-0500 

Fax: (973) 535-9217 

Attorneys for Plaintiffs 

Nautilus Neurosciences, Inc. 

and APR Applied Pharma 

Research SA 

IN THE UNITED STATES DISTRICT COURT 

FOR THE DISTRICT OF NEW JERSEY 

NAUTILUS NEUROSCIENCES, INC. and 

APR APPLIED PHARMA RESEARCH 

SA, 

 Plaintiffs, 

 v. 

EDICT PHARMACEUTICALS PVT. 

LTD., 

 Defendant. 

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Civil Action No. _____________ 

COMPLAINT

 Plaintiffs Nautilus Neurosciences, Inc. (“Nautilus”) and APR Applied Pharma Research 

SA (“APR”) (collectively, “Plaintiffs”), by and through their attorneys, for their Complaint 

against Defendant Edict Pharmaceuticals Pvt. Ltd. (“Defendant”), hereby allege as follows: 

PARTIES

1. Nautilus is a Delaware corporation with its principal place of business at 

135 Rte 202/206, Bedminster, New Jersey 07921. 

2. APR is a corporation organized under the laws of Switzerland with its 

principal place of business at Via Corti 5, CH-6828, Balerna, Switzerland. 

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3. On information and belief, Defendant is a corporation organized and 

existing under the laws of India with its principal place of business at New No. 1/58, 

Pudupakkam Main Road, Kelambakkam, Chennai – 603 103, Tamil Nadu, India. 

4. On information and belief, Defendant has maintained a U.S. office in this 

judicial district at 9 Revere Road, Monmouth Junction, New Jersey 08852. 

5. On information and belief, Defendant authorized a U.S. agent in this 

district at 508 Elm Avenue, Moorestown, New Jersey 08057 to act on its behalf in corresponding 

with the United States Food and Drug Administration (“FDA”) regarding Defendant’s 

Abbreviated New Drug Application (“ANDA”) No. 202964. 

6. On information and belief, Defendant develops and manufactures generic 

pharmaceutical formulations for sale and use throughout the United States, including in this 

judicial district. 

NATURE OF THE ACTION

7. This is a civil action for infringement of U.S. Patent Nos. 6,974,595 (the 

“’595 patent”), 7,482,377 (the “’377 patent”), and 7,759,394 (the “’394 patent”) (collectively, 

the “patents-in-suit”), which are attached as Exhibits A, B, and C, respectively. 

8. This action is based upon the Patent Laws of the United States, 35 U.S.C. 

§ 1 et seq., and arises out of Defendant’s filing of ANDA No. 202964 seeking approval to sell 

diclofenac potassium for oral solution 50 mg prior to the expiration of the patents-in-suit, which 

are assigned to and/or exclusively licensed by Plaintiffs and listed in the publication entitled 

“Orange Book: Approved Drug Products with Therapeutic Equivalents.” 

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JURISDICTION AND VENUE

9. This action arises under the patent laws of the United States, 35 U.S.C. § 1 

et seq.

10. This Court has subject matter jurisdiction pursuant to 28 U.S.C. §§ 1331, 

1338(a), and 2201(a). 

11. Defendant is subject to personal jurisdiction in this District by virtue of,

inter alia, its manufacture of generic pharmaceutical formulations for sale and use in this 

District, its conduct of business in this District, the location of one of its offices in this District, 

the location of its U.S. agent in this District, its purposeful availment of the rights and benefits of 

New Jersey law, including its previous admissions that it is subject to personal jurisdiction in 

New Jersey, see, e.g., Orexo AB v. Edict Pharms. Pvt. Ltd., No. 3:10-cv-05548 (D.N.J. Oct. 26, 

2010), and its substantial and continuing contacts with the state of New Jersey. 

12. Venue is proper in this district pursuant to 28 U.S.C. §§ 1391(b), (c), and 

(d) and 1400(b). 

THE PATENTS-IN-SUIT

13. The ’595 patent, entitled “Pharmaceutical Compositions Based on 

Diclofenac,” was duly and legally issued by the United States Patent and Trademark Office 

(“USPTO”) on December 13, 2005. 

14. APR owns the entire right, title, and interest in the ’595 patent. Nautilus is 

the exclusive licensee of the ’595 patent for the United States. 

15. The ’377 patent, entitled “Pharmaceutical Compositions and Methods of 

Treatment Based on Diclofenac,” was duly and legally issued by the USPTO on January 27, 

2009. 

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16. APR owns the entire right, title, and interest in the ’377 patent. Nautilus is 

the exclusive licensee of the ’377 patent for the United States. 

17. The ’394 patent, entitled “Diclofenac Formulations and Methods of Use,” 

was duly and legally issued by the USPTO on July 10, 2010. 

18. APR owns the entire right, title, and interest in the ’394 patent. Nautilus is 

the exclusive licensee of the ’394 patent for the United States. 

19. Nautilus is the holder of New Drug Application (“NDA”) No. 22-165 for 

diclofenac potassium for oral solution 50 mg, sold in the United States under the trademark 

CAMBIA. The FDA approved NDA No. 22-165 on June 17, 2009. 

20. The patents-in-suit are duly listed in the Orange Book: Approved Drug 

Products with Therapeutic Equivalents for NDA No. 22-165. The claims of the patents-in-suit 

cover, inter alia, various methods of using diclofenac. 

ACTS GIVING RISE TO THIS ACTION

21. On information and belief, Defendant reviewed each of the patents-in-suit 

and certain commercial and economic information regarding CAMBIA and decided to file an 

ANDA seeking approval to market a generic version of CAMBIA. 

22. On information and belief, Defendant submitted ANDA No. 202964 to the 

FDA to seek approval to engage in the commercial manufacture, use, sale, offer for sale, and/or 

importation into the United States of generic diclofenac potassium for oral solution 50 mg. 

23. Plaintiffs received a letter dated June 8, 2011 from Defendant notifying 

them that Defendant had filed ANDA No. 202964 with the FDA under section 505(j) of the 

Federal Food, Drug, and Cosmetic Act (“FDCA”) seeking approval to market a generic version 

of CAMBIA prior to the expiry of the patents-in-suit. 

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24. The stated purpose of Defendant’s June 8, 2011 letter was to notify 

Plaintiffs that ANDA No. 202964 included a certification under 21 U.S.C. § 355(j)(2)(a)(vii)(IV) 

(“Paragraph IV Certification”) that the claims of the patents-in-suit are invalid, unenforceable, 

and/or will not be infringed by the commercial manufacture, use, sale, offer for sale, and/or 

importation into the United States of Defendant’s ANDA product. 

25. On information and belief, Defendant was necessarily aware of each of the 

patents-in-suit when Defendant filed ANDA No. 202964 with a Paragraph IV Certification. 

26. Attached to the June 8, 2011 letter was a “Detailed Statement” setting 

forth the factual and legal bases for Defendant’s opinion that the patents-in-suit are invalid 

and/or would not be infringed by the commercial manufacture, use, sale, offer for sale, and/or 

importation into the United States of Defendant’s product. 

27. Nautilus received the June 8, 2011 letter no earlier than June 13, 2011. 

APR received the June 8, 2011 letter no earlier than June 13, 2011. Plaintiffs commenced this 

action within 45 days of the date upon which they received Defendant’s June 8, 2011 letter. 

FIRST CLAIM FOR RELIEF

(Infringement of the ’595 Patent by Defendant) 

28. Paragraphs 1 through 27 are incorporated herein as set forth above. 

29. Defendant submitted ANDA No. 202964 with a Paragraph IV 

Certification to the FDA under section 505(j) of the FDCA to obtain approval to engage in the 

commercial manufacture, use, sale, offer for sale, and/or importation into the United States of 

diclofenac potassium for oral solution prior to the expiration of the ’595 patent. By submitting 

this ANDA, Defendant has committed an act of infringement under 35 U.S.C. § 271(e)(2). 

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30. Unless enjoined by this Court, Defendant, upon FDA approval of ANDA 

No. 202964, will manufacture, use, sell, offer for sale, and/or import into the United States the 

proposed generic diclofenac potassium product described in ANDA No. 202964, thereby 

actively inducing others to infringe or contributing to the infringement of the ’595 patent under 

35 U.S.C. § 271(b) and/or (c). 

31. Plaintiffs will be substantially and irreparably harmed if Defendant is not 

enjoined from infringing the ’595 patent. 

32. Plaintiffs do not have an adequate remedy at law. 

33. An actual and justiciable controversy exists between the parties with 

respect to the ’595 patent. 

34. Defendant was aware of the existence of the ’595 patent prior to the filing 

of ANDA No. 202964 but took such action knowing that it would constitute infringement of the 

’595 patent. 

35. Defendant’s actions render this an exceptional case under 35 U.S.C. § 285. 

SECOND CLAIM FOR RELIEF

(Infringement of the ’377 Patent by Defendant) 

36. Paragraphs 1 through 35 are incorporated herein as set forth above. 

37. Defendant submitted ANDA No. 202964 with a Paragraph IV 

Certification to the FDA under section 505(j) of the FDCA to obtain approval to engage in the 

commercial manufacture, use, sale, offer for sale, and/or importation into the United States of 

diclofenac potassium for oral solution prior to the expiration of the ’377 patent. By submitting 

this ANDA, Defendant has committed an act of infringement under 35 U.S.C. § 271(e)(2). 

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38. Unless enjoined by this Court, Defendant, upon FDA approval of ANDA 

No. 202964, will manufacture, use, sell, offer for sale, and/or import into the United States the 

proposed generic diclofenac potassium product described in ANDA No. 202964, thereby 

actively inducing others to infringe or contributing to the infringement of the ’377 patent under 

35 U.S.C. § 271(b) and/or (c). 

39. Plaintiffs will be substantially and irreparably harmed if Defendant is not 

enjoined from infringing the ’377 patent. 

40. Plaintiffs do not have an adequate remedy at law. 

41. An actual justiciable controversy exists between the parties with respect to 

the ’377 patent. 

42. Defendant was aware of the existence of the ’377 patent prior to the filing 

of ANDA No. 202964 but took such action knowing that it would constitute infringement of the 

’377 patent. 

43. Defendant’s actions render this an exceptional case under 35 U.S.C. § 285. 

THIRD CLAIM FOR RELIEF

(Infringement of the ’394 patent by Defendant) 

44. Paragraphs 1 through 43 are incorporated herein as set forth above. 

45. Defendant submitted ANDA No. 202964 with a Paragraph IV 

Certification to the FDA under section 505(j) of the FDCA to obtain approval to engage in the 

commercial manufacture, use, sale, offer for sale, and/or importation into the United States of 

diclofenac potassium for oral solution prior to the expiration of the ’394 patent. By submitting 

this ANDA, Defendant has committed an act of infringement under 35 U.S.C. § 271(e)(2). 

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46. Unless enjoined by this Court, Defendant, upon FDA approval of ANDA 

No. 202964, will manufacture, use, sell, offer for sale, and/or import into the United States the 

proposed generic diclofenac potassium product described in ANDA No. 202964, thereby 

actively inducing others to infringe or contributing to the infringement of the ’394 patent under 

35 U.S.C. § 271(b) and/or (c). 

47. Plaintiffs will be substantially and irreparably harmed if Defendant is not 

enjoined from infringing the ’394 patent. 

48. Plaintiffs do not have an adequate remedy at law. 

49. An actual justiciable controversy exists between the parties with respect to 

the ’394 patent. 

50. Defendant was aware of the existence of the ’394 patent prior to the filing 

of ANDA No. 202964 but took such action knowing that it would constitute infringement of the 

’394 patent. 

51. Defendant’s actions render this an exceptional case under 35 U.S.C. § 285. 

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PRAYER FOR RELIEF

WHEREFORE, Plaintiffs pray for judgment as follows: 

 A. An order decreeing that, by submitting ANDA No. 202964 to the FDA, 

Defendant has infringed the patents-in-suit under 35 U.S.C. § 271(e)(2); 

 B. A declaration that, through the commercial manufacture, use, sale, offer 

for sale, and/or importation into the United States of the proposed generic diclofenac potassium 

product described in ANDA No. 202964, Defendant will actively induce others to infringe or 

contribute to the infringement of the patents-in-suit under 35 U.S.C. § 271(b) and (c); 

 C. An order pursuant to 35 U.S.C. § 271(e)(4)(A) decreeing that the effective 

date of any approval of ANDA No. 202964 be no earlier than the expiration date of the last to 

expire of the patents-in-suit, including any applicable extensions; 

 D. A preliminary and permanent injunction restraining and enjoining 

Defendant, its officers, agents, attorneys, and employees and those acting in privity or concert 

with them, from engaging in the commercial manufacture, use, sale, and/or offer for sale within 

the United States and/or importation into the United States of the diclofenac product described in 

ANDA No. 202964 or any other product not colorably different from the product of ANDA No. 

202964 until the expiration of the last to expire of the patents-in-suit, including any applicable 

extensions; 

 E. A declaration that this case is exceptional under 35 U.S.C. § 285; 

 F. An award of attorney fees, costs, and expenses that Plaintiffs incur in 

prosecuting this action; and 

 G. Such other and further relief as the Court may deem just and proper. 

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Dated: July 20, 2011 CONNELL FOLEY LLP

 Attorneys for Plaintiffs 

Nautilus Neurosciences, Inc. and 

APR Applied Pharma Research SA 

 By: s/Liza M. Walsh 

 Liza M. Walsh 

 Rukhsanah L. Lighari 

 85 Livingston Avenue 

 Roseland, New Jersey 07068 

 Telephone: (973) 535-0500 

 Facsimile: (973) 535-9217 

Of Counsel: 

Thomas J. Meloro 

Michael W. Johnson 

Ketan Pastakia 

Laurie N. Stempler 

Willkie Farr & Gallagher LLP 

787 Seventh Avenue 

New York, NY 10019-6099 

(T) 212.728.8000 

(F) 212.728.8111 

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LOCAL CIVIL RULE 11.2 CERTIFICATION 

I certify that, to the best of my knowledge, the matter in controversy between these 

parties is not the subject of any other pending or anticipated litigation in any court or arbitration 

proceeding, nor are there any non-parties known to Plaintiffs that should be joined to this action, 

with the exception that the patents-in-suit in this matter are the subject of another action pending 

in this Court: Nautilus Neurosciences, Inc. et al. v. Wockhardt USA LLC et al., Civil Action No. 

2:11-1997 (ES) (D.N.J. April 8, 2011). 

Dated: July 20, 2011 ______s/Liza M. Walsh______ 

 Liza M. Walsh 

LOCAL CIVIL RULE 201.1 CERTIFICATION

 I hereby certify that the above-captioned matter is not subject to compulsory arbitration 

in that declaratory and injunctive relief is sought. 

Dated: July 20, 2011 ______s/Liza M. Walsh______ 

 Liza M. Walsh 

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EXHIBIT A 

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EXHIBIT B 

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EXHIBIT C 

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(12) United States Patent 

Reiner et al. 

(54) DICLOFENAC FORMULATIONS AND 

METHODS OF USE 

(75) Inventors: Giorgio Reiner, Como (IT); Alberto 

Reiner, Como (IT); Andreas Meyer, 

Neuenburg (DE) 

(73) Assignee: APR Applied Pharma Research SA, 

Balema (CH) 

( *) Notice: Subject to any disclaimer, the term of this 

patent is extended or adjusted under 35 

U.S.c. 154(b) by 0 days. 

(21) Appl. No.: 11/455,120 

(22) Filed: Jun. 16,2006 

(65) 

(60) 

(51) 

(52) 

(58) 

(56) 

Prior Publication Data 

US 2007/0015831 Al Jan. 18,2007 

Related U.S. Application Data 

Provisional application No. 60/692,024, filed on Jun. 

17, 2005, provisional application No. 60/691,757, 

filed on Jun. 17,2005. 

Int. Cl. 

A01N 37100 (2006.01) 

A61K 311185 (2006.01) 

C07C 229/00 (2006.01) 

U.S. Cl. ....................... 514/553; 514/557; 514/576; 

560/47 

Field of Classification Search ................. 514/553, 

514/557, 576; 560/47 

See application file for complete search history. 

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US007759394B2 

(10) Patent No.: US 7,759,394 B2 

(45) Date of Patent: Jul. 20, 2010 

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(Continued) 

Primary Examiner-Lawrence E Crane 

(74) Attorney, Agent, or Firm---Clark G. Sullivan; Arnall 

Golden Gregory LLP 

(57) ABSTRACT 

Methods and formulations are provided for treating migraine 

and other acute pain episodes using diclofenac, and formulations of diclofenac that provide both rapid and sustained relief 

from acute pain. Methods and formulations are also provided 

for treating symptoms that often accompany migraine and 

acute pain such as photophobia, phonophobia, nausea and 

vomiting. 

25 Claims, 1 Drawing Sheet 

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US 7,759,394 B2 

Page 2 

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Macia, M.A., et al: "Comparative bioavailability of a dispersible 

formulation of diclofenac and finding of double plasma peaks"; Int. J. 

Clin Pharmacol. Ther., 33:333-339 (1995). 

Bettini, R., et al; "Swelling force development as a result of hydrate 

formation in diclofenac sodium or nitrofurantoin tablets", S.T.P. 

Pharma Sciences 10 (4) pp. 335-339, (2000). 

Henrikson, P.A., et al; Absorption and effect of diclofenac sodium 

after surgical removal of a lower wisdom tooth; Curro Ther. Res., 

31:30-36 (1982). 

Degen, P.H., et al; "Pharmacokinetics of diclofenac and five metabolites after single doses in healthy volunteers and after repeated doses 

in patients"; Xenobiotica, 18:1449-1455 (1988). 

Maggi, C.A., et al; "Comparative bioavailability of diclofenac 

hydroxyethylpyrrolidine vs diclofenac sodium in man"; Eur. J. Clin. 

PharmacoI38:207-208 (1990). 

Mendes, G.B.B., et al; "Comparative bioavailability of two suspension formulations of potassium diclofenac in healthy male volunteers"; Int. J. Clin. Pharmacol. Thr., 32:131-135 (1994). 

Crook, P.R., et al; "The pharmacokinetics of diclofenac sodium in 

patients with active rheumatoid disease"; Eur. J. Clin. Pharmacol., 

21:331-334 (1982). 

Willis. J.y', et al; "The pharmacokinetics of diclofenac sodium following intravenous and oral administration"; Eur. J. Clin. 

Pharmacol., 16:405-410 (1979). 

Willis, J.y', et al; "The influence of food on the absorption of 

diclofenac after single and multiple oral doses"; Eur. J. Clin. 

Pharmacol., 19:33-37 (1981). 

Reiss, W., et al; "Pharmacokinetics and metabolism of the antiinflammatory agent Voltaren" Scand. J. Reumatol., Suppl. 22: 17 -29 

(1978). 

Physicians' Desk Reference; Novartis Pharmaceutical Corp., pp. 

1830-1832 (2000). 

Bakshi, R., et al; A double-blind, Placebo-controlled trial comparing 

the analgesic efficacy of two formulations of Diclofenac in postoperative dental pain; Current Therapeutic Research vol. 52, No.3, pp. 

435-442 Sep. 1992. 

Dahl Of, c., et al; Diclofenac-K (50 and 100 mg) and placebo in the 

acute treatment of migraine; Cephalalagia 13, pp. 20-26 (1993). 

McNeely, W., et al; Diclofenac-Potassium in Migraine: A Review; 

Drugs; 57; pp. 991-1003 (1999). 

Mehlisch, D.R., et al; Single-dose therapy with Diclofenac potassium, aspirin, or placebo following dental impaction surgery, Today's 

Therapeutic Trends 12; (Suppl. 1) pp. 15-31 (1995). 

The Diciofenac-KlSumatriptan Migrain Study Group; Acute treatment of migraine attacks: efficacy and safety of a nonsteroidal antiinflammatory drug, diclofenac-potassium, in comparison to oral 

sumatriptan and placebo; Cephalalgia 19, pp. 232-240 (1999). 

Ridgway, D.; Analgesics for Acute Pain, Meeting the United States 

Food and Drug Administration's Requirements for Proof of Efficacy, 

Clin J. Pain vol. 20, No.3, May/June pp. 123-132 (2004). 

Diener, H-C, et al; Efficacy and tolerability of Diclofenac potassium 

sachets in migraine: a randomized, double-blind, cross-over study in 

comparison with Diclofenac potassium tablets and placebo; 

Blackwell Publishing Ltd. Cephalalgia 26, pp. 537-547 (2005). 

Hofele, C.M., et al; Efficacy and tolerability of diclofenac potassium 

sachets in acute postoperative dental pain: a placebo-controlled, 

randomised, comparative study vS. diclofenac potassium tablets; 

2006 Blackwell Publishing Ltd. Int. J Clin Pract, Mar. 2006, 60, 3, pp. 

300-307. 

Craig, C.R.; Opioid and NonopioidAnalgesics, Modern Pharmacology 4th Edition, p. 437, (1994). 

Adkin, D. A., et al; The effect of different concentrations of Mannitol 

in solution on small intestinal transit: Implications for drug absorption; Pharmaceutical Research, vol. 12, No.3 (1995). 

Adkin, D.A., et al; The effect of Mannitol on the oral bioavailability 

of Cimetidine; Journal of Pharmaceutical Sciences vol. 84, No. 12, 

Dec. 1995. 

Kumar, A., et al.; The Mystery Ingredients: Sweeteners, Flavorings, 

Dyes and Preservatives in Analgesic/Antipyretic, AntihistaminelDecongestant, Cough and Cold, Antidiarrheal, and Liquid Theophylline 

Preparations; Pediatrics vol. 9, No.5 May 1993. 

Massiou. H., et al.; Effectiveness of oral Diclofenac in the acute 

treatment of common migraine attacks: a double-blind study versus 

placebo; Cephalalgia 11 (1991). 

Del Bene, E., et al; Intramuscular Treatment of Migraine Attacks 

Using Diclofenac Sodium: A Crossover Clinical Trial; The Journal of 

International Medical Research; 15: 44-48 (1987). 

* cited by examiner 

Case 2:11-cv-04183-ES-CLW Document 1 Filed 07/20/11 Page 54 of 70 PageID: 54
u.s. Patent Jul. 20, 2010 US 7,759,394 B2 

PROCESS STEPS IN .p ROC E S S CON T R 0 L S 

(,2) Diclofenac potassium 

Mannitol-fine qualityMannilol-coarse quality" 

(addillon In portions) 

I 

Potassium hydrogen 

carbonate 

Aspartam e 

Saccharin sodium 

Mannitol 

I "coarse quality" (pa rI) 

G 1'1 c e ril d ib e hen a te 

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+ 

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ScreenlM Ix I 

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L Screen/M II( .lI Pram Ix 2 rI 

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I ScreenlAdd/Mlx I ... I Final mixture J#- ---_ ... _ .. _._ .... 

'" '-____ F_I_I_"_n_g ____ ---'r--------------------······----···· .. 

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average fill mass 

Case 2:11-cv-04183-ES-CLW Document 1 Filed 07/20/11 Page 55 of 70 PageID: 55
US 7,759,394 B2 

1 

DICLOFENAC FORMULATIONS AND 

METHODS OF USE 

RELATED APPLICATIONS 

This application claims priority under 35 U.S.c. § 119( e) to 

U.S. Provisional Patent Application Nos. 60/692,024 (filed 

Jun. 17,2005), and 60/691,757 (filed Jun. 17,2005). 

2 

treatment for migraine. None of the studies reported to date 

suggests that a 50 mg. diclofenac product could treat all of 

these symptoms within two hours of treatment. 

In 1993, investigators studied 100 mg. and 50 mg. 

diclofenac tablets, in comparison to placebo, and determined 

that both strengths were effective against migraine pain 

within two hours of treatment, but that only the 100 mg. 

strength was effective against phonophobia and photophobia 

FIELD OF THE INVENTION 

This invention concerns methods and formulations for 

treating migraine and other acute pain episodes using 

diclofenac, and formulations of diclofenac that provide both 

rapid and sustained relief from acute pain. The invention 

further concerns methods and formulations for treating symptoms that often accompany migraine and acute pain such as 

rebound headache, photophobia, phonophobia, nausea and 

vomiting. 

10 within two hours. (Dahliif et aI., Diclofenac-K (50 and 100 

mg.) and placebo in the acute treatment of migraine. Cephalalgia 1993; 13:117-123). In 1999, a separate group ofinvestigators tested 50 mg. and 100 mg. sugar coated tablets of 

diclofenac potassium to treat migraine, and once again con15 firmed the ability of both doses to relieve migraine pain 

within two hours of treatment. (The Diclofenac-KlSumatriptan Migraine Study Group, Acute treatment of migraine 

attacks: efficacy and safety of a nonsteroidal anti-inflammatory drug, diclofenac potassium, in comparison to oral 

BACKGROUND OF THE INVENTION 

Diclofenac is a non-steroidal anti-inflammatory drug 

("NSAID") known chemically as [(2,6-dichloro-anilino)-2-

phenyl]-2-acetic acid. The drug was developed in the 1960s 

20 sumatriptan and placebo. Cephalalgia 1999; 19:232-40.) The 

investigators concluded that neither dose was effective 

against photophobia two hours after treatment, that both 

doses were effective against photophobia eight hours after 

treatment, that only the 100 mg dose was effective against 

25 phonophobia two hours after treatment, and that the 50 mg 

dose was effective against photophobia eight hours after by scientists at Ciba-Geigy and is sold around the world by 

Novartis under various trade names, including Cataflam® 

and Voltaren® in the United States. A wet granulated formulation of diclofenac potassium was recently developed to 

provide an increased rate of absorption, and its pharmacoki - 30 

netic properties tested against commercially available 

diclofenac potassium tablets. (Reiner et aI., Increased absorption rate of diclofenac from fast acting formulations containing its potassium salt. Arzniem.-Forsch.lDrug Res. 2001; 

51 :885-890.) According to the authors, the granular formula- 35 

tion showed a higher Cmax than the diclofenac potassium 

tablets, a shorter tmax (i.e. time to Cmax) and a similar AUC 

when compared to the tablet form. 

Owing to its excellent analgesic properties, diclofenac is 

widely used for treating various types of pain, including both 40 

chronic and acute painful episodes. The drug is administered 

for the treatment of musculoskeletal and joint disorders such 

as rheumatoid arthritis, osteoarthritis, and ankylosing 

spondylitis; periarticular disorders such as bursitis and tendonitis; soft tissue disorders such as sprains and strains, and 45 

other painful conditions such as renal colic, acute gout, dysmenorrhoea, and following some surgical procedures. (Martindale (2000) Diclofenac. In: Reynolds, The Extra Pharmacopoeia. London: The Pharmaceutical Press; p. 31-33.) 

Diclofenac has also been studied for the treatment of head- 50 

treatment. 

The 1999 investigators also studied the effectiveness of 

100 mg and 50 mg. diclofenac-K immediate release tablets at 

preventing recurrence of headaches within 48 hours of treatment. The investigators concluded that patients treated with 

the 50 mg and the 100 mg diclofenac-K tablets actually had a 

higher incidence of headache recurrence than patients treated 

with placebo (i.e. that the diclofenac-K performed worse than 

placebo), although the statistical significance of these findings is not reported. 

This latter finding is consistent with other recent literature 

which recommends the use of a "long acting NSAID" to 

reduce the frequency of rebound headaches. For example, 

Plachetka recommends in U.S. Pat. No. 6,586,458 thattriptan 

therapy be augmented with a "long acting NSAID" to provide 

"a substantial reduction in the frequency [of] relapse of headaches." Diclofenac potassium is not considered a long acting 

NSAID because it displays an average Cmax within only about 

one hour and a terminal halflife of only about 1.9 hours when 

administered in commercially available sugar coated tablets. 

Diclofenac is generally taken orally in the form of normal 

tablets or tablets covered with coatings resistant to gastric 

juices, or rectally, or by injection, or topically. Recently, 

however, in WO 97/44023, Reiner et al. proposed to administer diclofenac in a number of less conventional dosage 

forms-including as a powder sachet for oral administration 

after dissolving in water-for quicker onset of analgesic 

ache pain from migraine attacks, using various doses and 

dosage forms, including 75 mg. intramuscular injections (Del 

Bene et aI., Intramuscular treatment of migraine attacks using 

diclofenac sodium: a cross-over trial. J. Int. Med. Res. 1987; 

1544-8), 100 mg. suppositories (Del Bene et aI., Migraine 

attack treatment with diclofenac sodium. Cephalalgia 1985; 

5:144-5), and 50 mg. enteric coated tablets. (Massiou et aI., 

Effectiveness of oral diclofenac in the acute treatment of 

common migraine attacks: a double blind study versus placebo. Cephalalgia 1991; 1:59-63.) 

55 relief. One of the primary obstacles in the manufacture of 

powder sachets is the distribution of the drug in the powder, 

and the uniformity of content in the finished product. These 

hurdles are magnified in the production of diclofenac sachets 

due to the poor aftertaste of diclofenac, and the need to 

60 incorporate additional ingredients to compensate for this poor 

Migraine taste. attacks manifest a diverse array of symptoms that 

must be resolved in order for a treatment to be deemed truly 

effective against migraine (instead of just treating the symptoms). In particular, the treatment must be effective against 

the pain, photophobia, phonophobia and nausea that are 65 

caused by migraine, and it must be effective within the first 

two hours of treatment, in order to be considered a true 

To ensure an adequately homogenous distribution of drug 

product in the bulk powder, Reiner et al. disclose a wet granulation process for manufacturing the powder sachets. In the 

first step of the process, a wet granulate is prepared from 

diclofenac potassium, potassium bicarbonate, saccharin, 

aspartame and maunitol, using 95% ethanol as the wetting 

Case 2:11-cv-04183-ES-CLW Document 1 Filed 07/20/11 Page 56 of 70 PageID: 56
US 7,759,394 B2 

3 

agent. The granulate is then mixed with over one gram of 

sugar (saccharose) and various flavoring agents to improve 

the taste of the composition. 

The method described by Reiner et a!. produces an excellent pharmaceutical dosage fonn but suffers from a number of 

disadvantages including the size of the sachet (2 g) which 

makes the sachet more difficult to dissolve, and the presence 

4 

In other embodiments the method is used to treat any 

episode of acute pain in which the pain would otherwise 

persist for at least about eight hours, and pain relief is required 

for this time period. Thus, in still another embodiment the 

invention preferably provides a method of treating acute pain 

in a human patient requiring pain relief for at least eight hours, 

comprising: (a) providing an oral fonnulation comprising 

about 50 mg. of diclofenac or a phannaceutically acceptable 

salt thereof, wherein said formulation (ii) achieves tmax in 

from about 10 to about 35,30, or 25 minutes; and (iii) optionally but preferably achieves a Cmax of from about 1400 or 

1500 to about 2500 ng/ml; and (b) orally administering said 

of sugar in the fonnulation, which should be avoided in the 

diabetic population. In addition, the process requires precise 

controls on the granulometric process to assure unifonn dis- 10 

tribution of drug in the granulate and consistent amounts of 

drug in the finished product. What is needed is an alternative 

method for producing sugar-free powder diclofenac sachets 

and other fast acting dosage fonns of diclofenac. formulation to a patient suffering from acute pain, preferably 

15 no more than 3 total times in a 24 hour period. SUMMARY OF INVENTION 

In still another embodiment the invention provides an alternative method for preparing powder diclofenac sachets that is 

based predominantly on the large proportion of mannitol in 

The inventors have unexpectedly discovered that rapidly 

bioavailable formulations of diclofenac are effective in the 

treatment of migraine and other acute pain episodes, and that 

in spite of their quick onset of action, they provide sustained 

relief against acute pain for up to twenty -four hours. Contrary 

20 the fonnulation, which preferably includes a precise control 

of particle size of diluents in the finished product. The large 

proportion of marmitol imparts surprisingly rapid bioavailability to the fonnulation, while the control of particle size to the prior art, which suggests that a long acting NSAID 

should be used to prevent rebound headache, and that a rapidly bioavailable formulation of diclofenac would be ineffec- 25 

tive against rebound headache, the inventors have discovered 

that a rapidly bioavailable fonnulation of diclofenac, as measured by tmax and Cmax' prevents recurrence of headaches for 

at least twenty four hours after treatment in a significant 

population of migraine sufferers. In addition, the consistency 30 

of bioavailability seems to improve as the bioavailability of 

the molecules becomes more rapid, which further contributes 

to the clinical efficacy observed for these formulations. 

The inventors have also surprisingly discovered that these 

rapidly bioavailable fonnulations relieve symptoms often 35 

associated with migraine and other acute pain, including photophobia and phonophobia, better than conventional immediate release tablets. These results are surprisingly seen even 

though the diclofenac in these fonnulations is more rapidly 

eliminated from the bloodstream than conventional immedi- 40 

ate release tablets of diclofenac, and even though the total 

amount of diclofenac absorbed in the blood stream (measured 

as the area under the curve (i.e. AUCOo_=)) is comparable for 

the two formulations. The formulations are thus able to meet 

all of the primary clinical endpoints for evaluating migraine 45 

treatments, and for completely treating migraine. 

assures uniform distribution of diclofenac in the material 

used to fill the sachets and consistent amounts of drug in each 

sachet without the use of sugar or large amounts of diluent as 

taught in the prior art. The method and powders produced by 

the method are characterized by, among other variables, (1) 

the ratio of the diluent to the diclofenac in the powder, (2) a 

combination of particle sizes of the diluent in the final composition, and (3) the sequence of mixing the diclofenac and 

the varying particle sizes of diluent. 

The invention further provides methods for manufacturing 

highly concentrated liquid formulations of diclofenac that 

can be drawn as drops from a bottle and administered after 

mixing the diclofenac with a suitable carrier such as water. In 

one aspect of this embodiment the invention provides a 

method of making a liquid solution of diclofenac, wherein the 

diclofenac is present in the liquid at a concentration of from 

about 10 to about 100 mg./ml., comprising (a) dissolving 

diclofenac in ethyl alcohol to fonn a solution, (b) mixing said 

solution with glycerol to form a second solution, and (c) 

mixing said second solution with water. 

Additional advantages of the invention will be set forth in 

part in the description which follows, and in part will be 

obvious from the description, or may be learned by practice of 

the invention. The advantages of the invention will be realized 

Therefore, in one embodiment the invention preferably 

provides a method of treating migraine comprising: (a) providing a liquid fonnulation comprising 50 mg. of diclofenac 

or a phannaceutically acceptable salt thereof, wherein said 

formulation: (i) is provided as a unit dose powder fonnulation 

and dissolved or suspended in water immediately before 

administration, or as a unit dose liquid fonnulation that is 

ingested with or without further mixing; (ii) achieves tmax in 

from about 10 to about 20 minutes; and (iii) optionally but 

preferably achieves a Cmax of from about 1500 to about 2500 

ng/ml; and (b) orally administering said formulation to a 

patient suffering from migraine, wherein migraine is defined 

50 and attained by means of the elements and combinations 

particularly pointed out in the appended claims. It is to be 

understood that both the foregoing general description and 

the following detailed description are exemplary and 

explanatory only and are not restrictive of the invention, as 

55 claimed. 

as a disease manifested in a population of patients by periodic 

attacks of headache pain, nausea, photophobia and phono- 60 

phobia. In one particular embodiment the method is used to 

treat migraine that is accompanied by photophobia and/or 

phonophobia. In another particular embodiment, the method 

is used to treat migraine patients who suffer from recurrent 

headache, and are diagnosed as requiring relief from recur- 65 

rent headache within twenty-four hours of the initial treatment. 

DETAILED DESCRIPTION OF THE DRAWING 

The accompanying drawing, which is incorporated in and 

constitutes a part of this specification, illustrates several 

embodiments of the invention and together with the description, serves to explain the principles of the invention. 

FIG. 1 is a flow diagram illustrating a non-granulate 

method and sequence of mixing employed in making 900 mg. 

powder sachets of the instant invention that contain 50 mg. of 

diclofenac potassium. 

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US 7,759,394 B2 

5 

DETAILED DESCRIPTION OF THE INVENTION 

The present invention may be understood more readily by 

reference to the following detailed description of preferred 

embodiments of the invention and the Examples included 

therein. 

Methods of Treating Migraine and Acute Pain 

As discussed above, the invention provides novel formulations of diclofenac---especially diclofenac potassium-that 

have proven to be remarkably effective against migraine 

headache and other forms of acute pain. The formulations 

may contain various quantities of diclofenac, in various oral 

dosage forms, ranging from about 12.S mg. to about 100 mg. 

of diclofenac or a pharmaceutically acceptable salt thereof. 

Thus, for example, the formulation can contain about 12.S, 

2S, 37.S, SO, 7S or 100mgofdiclofenac ora pharmaceutically 

acceptable salt thereof, in a tablet, a capsule, a powder for oral 

solution, an oral solution or suspension, on orally dissolving 

tablet, a mucoadhesive film, or any other orally ingestable 

dosage form. In a particularly preferred embodiment, however, the formulations of the present invention are present in 

a liquid form when ingested, and they contain about SO mg. of 

diclofenac or a pharmaceutically acceptable salt thereof. In 

another preferred embodiment, the formulations are used to 

treat migraine headache. 

Therefore, in one embodiment the invention provides a 

method of treating migraine comprising: (a) providing a liquid formulation comprising SO mg. of diclofenac or a pharmaceutically acceptable salt thereof, wherein said formulation: (i) is provided as a unit dose powder formulation and 

dissolved or suspended in water immediately before administration, or as a unit dose liquid formulation that is ingested 

with or without further mixing; (ii) achieves tmax in from 

about 10 to about 20 minutes; (iii) optionally but preferably 

achieves a Cmax of from about IS00 to about 2S00 ng/ml; and 

(b) orally administering said formulation to a patient suffering from migraine, wherein migraine is defined as a disease 

manifested in a population of patients by periodic attacks of 

headache pain, nausea, photophobia and phonophobia. 

In one particular embodiment, the methods of this invention are used to treat some of the most difficult to treat 

migraine patients-i.e. those whose headache pain is likely to 

recur within twenty-four hours of initial treatment, or those 

who also suffer from photophobia or phonophobia. Therefore, in another embodiment the invention provides a method 

6 

the patient has previously been diagnosed as requiring relief 

from photophobia, phonophobia, nausea or vomiting in conjunction with treatment for migraine pain. In another embodiment the method is performed without administering other 

medications for the relief of photophobia, phonophobia, nausea or vomiting. In still another embodiment the method is 

performed without administering other medications for the 

relief of migraine pain. 

Therefore, in still another embodiment the invention pro10 vides a method of treating migraine associated with phonophobia or photophobia in a human patient comprising: (a) 

providing a liquid formulation comprising SO mg. of 

diclofenac or a pharmaceutically acceptable salt thereof, 

wherein said formulation: (i) is provided as a powder formu15 lation and dissolved or suspended in water immediately 

before administration, or as a liquid formulation that is 

ingested with or without further mixing; (ii) achieves tmax in 

from about 10 to about 20 minutes; (iii) optionally but preferably achieves a Cmax of from about IS00 to about 2S00 

20 ng/ml; and (b) orally administering said formulation to a 

patient suffering from migraine associated with photophobia 

or phonophobia. 

As discussed above, this invention also concerns methods 

for treating acute pain using diclofenac, and formulations of 

25 diclofenac that provide immediate and sustained relief from 

any type of acute pain. In addition to migraine headache pain, 

the pain may derive from a variety of sources, including 

musculoskeletal and joint disorders such as rheumatoid 

arthritis, osteoarthritis, and ankylosing spondylitis, periar30 ticular disorders such as bursitis and tendonitis, soft tissue 

disorders such as sprains and strains, and other painful conditions such as renal colic, acute gout, dysmenorrhoea, and 

following some surgical procedures. In one preferred 

embodiment the acute pain is post-operative pain, such as 

35 post-operative dental pain. 

The formulations are particularly well suited for providing 

relief from sustained acute pain, defined herein as acute pain 

that would otherwise persist for about 4, 6 or 8 hours without 

the treatment contemplated by the current invention. In one 

40 preferred embodiment the patient treated by the method has 

been previously diagnosed as requiring relief from sustained 

acute pain. A patient requiring sustained relief from acute 

pain is a patient who has either been previously diagnosed as 

requiring rescue medication within about 4, 6 or 8 hours of 

45 treatment for said acute pain, or a patient whose acute pain is 

expected to persist for 4, 6 or 8 or more hours in the absence 

of treating migraine in a human patient suffering from of treatment. 

migraine comprising: (a) providing a liquid formulation comprising about SO mg. of diclofenac or a pharmaceutically 

acceptable salt thereof, wherein said formulation: (i) is pro- 50 

vided as a powder formulation and dissolved or suspended in 

water immediately before administration, or as a liquid formulation that is ingested with or without further mixing; (ii) 

achieves tmax in from about 10 to about 20 minutes; (iii) 

optionally but preferably achieves a Cmax of from about IS00 55 

to about 2S00 ng/ml; and (b) diagnosing a patient suffering 

from migraine as requiring sustained migraine relief for at 

least 24 hours (such as a patient who is susceptible to rebound 

In another embodiment, therefore, the invention provides a 

method of treating acute pain in a human patient requiring 

pain relief for at least eight hours, comprising: (a) providing 

an oral formulation comprising about SO mg. of diclofenac or 

a pharmaceutically acceptable salt thereof, wherein said formulation: (i) achieves a Cmax of from about 1400, 14S0 or 

IS00 to about 2S00 ng/ml; and (ii) achieves tmax in from about 

10 to about 3S, 30 or 2S minutes; and (b) orally administering 

said formulation to a patient suffering from acute pain, preferably no more than 3 total times in a 24 hour period. 

The sustained relief provided by the compositions of the 

or recurrent headaches); and (c) orally administering said present invention provides numerous advantages in the treatformulation to said patient. 

Patients who are particularly well-suited for treatment by 

the methods of this invention are those patients who have 

previously been treated for migraine pain using an acute pain 

medication, but who continued to suffer from symptoms such 

60 ment of acute pain, and leads to decreased requirements for 

pain medication by many patients. Thus, in one embodiment 

the method is performed without administering other immediate pain relief or rescue medications within the first 4, 6 or 

as phonophobia, photophobia, nausea and vomiting, espe- 65 

cially those individuals who required additional medication 

for these symptoms. Thus, for example, in one embodiment 

8 hours of administering the diclofenac formulation. In one 

embodiment, the formulation is administered no more than 3 

total times in a 24 hour period. In another embodiment, the 

formulation is administered as needed for pain every 2, 4, 6 or 

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US 7,759,394 B2 

7 

8 hours (or every 4-6, 4-8, or 6-8 hours), as needed for pain, 

preferably not to exceed three times per day. In yet another 

embodiment, the formulation is administered once every 

eight hours. 

8 

As discussed above, the formulations of the present invention are preferably administered as a liquid for oral ingestion, 

and can be provided in any form suitable for such administration. In a particularly preferred embodiment, the formulation is provided in a single unit dose as a powder sachet, 

which is mixed with water before administration. In other 10 

ng/ml, for a 50 mg. diclofenac formulation. It will be understood, of course that any of these Cmax values can be normalized based on the dose administered. Thus, for example, a 

1500 ng/ml Cmax observed for a 50 mg. dose could be normalized to 30 ng/ml·g and applied to other dose amounts. In 

a particularly preferred embodiment the formulations yield 

only one peak concentration when blood concentrations are 

plotted against time. 

The median tmax (i.e. time to reach Cmax) of the formulations is preferably from about 5 or 1 ° to about 40, 35, 30, 25 

or 20 minutes. Once again, a suitable range can be derived 

from any of these upper and lower bounds, but in one particular embodiment the tmax of the formulation is most preferably 

from about 1 ° to about 35 minutes, from about 1 ° to about 30 

embodiments the formulation is already dissolved in a liquid, 

as in the drop formulation of the present invention and the unit 

dose vials discussed elsewhere herein. It will be understood, 

however, that the relief from migraine and acute pain occasioned by the methods of the present invention can be 

achieved with any oral formulation that achieves the pharmacokinetics described herein, and that the invention extends to 

any such dosage form. 

Statistically Significant Relief 

In some embodiments of the present invention, the medication is administered to a plurality of patients suffering from 

migraine, and statistically significant relief is observed based 

15 minutes, from about 10 to about 25 minutes, or from about 10 

to about 20 minutes. The inter-subject coefficient ofvariability for said Cmax preferably is less than about 70, 65, 60, 55, 

50,40 or 35%, and the inter-subject coefficient of variability 

for said tmax is preferably less than about 70, 60, 50, 40 or 

20 35%. 

on one or more primary or secondary clinical endpoints, in 

comparison to placebo or 50 mg. immediate release 25 

diclofenac potassium tablets (i.e. Cataflam), including: 

Of course, it will be understood that bioavailability can 

differ from different study sites. When a single formulation 

gives results that vary significantly among different clinical 

sites and investigators, the results can be proportionately normalized against the bioavailability of Cataflam tablets, based 

upon the results reported in the examples hereto. Thus, for 

example, if the Cmax that a laboratory observes forCatafiam is 

only 750 ng/ml, all of the Cmax results reported from the 

laboratory could be adjusted by a factor of(1037.124)/(750). 

two hour pain relief (i.e. a decrease in pain intensity from 

moderate/ severe to mild/none) 

pain free at two hours 

sustained pain relief for 6, 8 or 24 hours 

relief from phonophobia at two hours 

relief from photophobia at two hours 

relief from nausea and vomiting at two hours 

As noted above, the ability to attain statistically significant 

relief by the methods of the present invention is greatly influenced by the coefficients of variation in Cmax and tmax 

observed for this invention, which seem to decrease as the 

diclofenac in these formulations becomes more bioavailable. 

30 Methods of Formulation 

As noted previously, the invention also concerns methods 

of making a particulate f10wable diclofenac composition that 

can be defined by a number of characteristics, including the 

35 presence of a fine powdered diluent, the combination of fine 

and coarse diluent, the total amount of diluent, the size distribution of diclofenac particles, or the use of a non-hygroscopic diluent. These various features and aspects of the 

present invention are set forth in greater detail below. 

40 Diclofenac 

Of course, every patient treated by the methods of the 

present invention will not require relief from every clinical 

endpoint, or obtain relief from every clinical endpoint. In 

addition, the plurality of patients that any individual physician or physician's practice group treats may not rise to the 

level of "statistical significance," as that term is typically used 

in the pharmaceutical industry (i.e. p<0.05). In the context of 45 

this invention, the term "statistically significant" is not based 

solely upon the plurality of patients treated by the defined 

method, but takes into account well designed comparative 

clinical trials versus placebo that have previously been conducted to confirm the statistically significant relief, in addi _ 50 

tion to the clinical results obtained by practice of the present 

invention by individual patients, practitioners, or physician 

practice groups. 

The diclofenac used in the present invention can be defined 

by various parameters. In one embodiment, the raw material 

will be a powder that exhibits no more than 0.5 wt. % loss on 

drying. In another embodiment not less than 90% of the 

diclofenac particles are less than 500 micrometers in diameter, not less than 40% and not more than 70% of the particles 

are less than 200 micrometers in diameter, not less than 35% 

and not more than 65% of the particles are less than 150 

micrometers in diameter, and not less than 30% of the particles are less than 100 micrometers in diameter. (Analyses 

performed using sieves according to the Sieve Test 2.9.12 

Eur.Ph.-AlpineAir Jet Sieve.) The average particle size for 

the diclofenac powder is preferably about 150, 160, 170, 180, 

190,200,210,220,230, or 240 micrometers, and can range 

Pharmacokinetics 

In one embodiment the composition is characterized by its 

pharmacokinetics, such as Cmax (i.e. average concentration of 

active chemical in the bloodstream after oral ingestion, preferably in the fasted state), and its tmax (i.e. average time to 

reach said Cmax' in a fasted state). In a particularly preferred 

embodiment, the mean Cmax for a 50 mg. diclofenac composition ranges from about 1300, 1400, 1500, 1600 or 1700 to 

about 2600,2500,2300, 2100, 2000 or 1900 ng/m!. A suitable 

range can be derived from any of these upper and lower 

bounds, but in one embodiment the formulation preferably 

attains a Cmax of from about 1300, 1400 or 1500 to about 2500 

ng/ml; or from about 1500, 1600, or 1700 to about 2100 

55 between any two of the foregoing variables (i.e. from about 

150 to about 230 micrometers, or from about 170 to about 220 

micrometers ). 

The diclofenac can be present in acid or salt form although, 

owing to its poor solubility in water, diclofenac is normally 

60 used in salt form. The salts of diclofenac customarily used are 

those of sodium, potassium or other alkali and alkaline earth 

metals, together with salts of organic nature, such as the salts 

of basic amino acids, such as lysine, arginine and ornithine, or 

other pharmacologically acceptable organic bases which 

65 have the ability to render the resulting salt soluble in water. 

Diclofenac potassium is preferably used in this invention due 

to its fast onset of action. 

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US 7,759,394 B2 

9 

In a preferred embodiment, 50 mg. of diclofenac or its salt 

is used in the final dosage form, although other amounts could 

be used including 12.5, 25, 37.5, 50, 75 or 100 mg of 

diclofenac, or a range having as endpoints any of the foregoing amounts. The amount of diclofenac preferably does not 

vary by more than about 95-105% from dose to dose. 

Buffering Agents 

Buffering agents are not critical to the invention, but are 

preferably used to provide a rapid rate of onset for the final 

pharmaceutical product. In a preferred embodiment for powder sachets, the buffering agent controls the pH of the formulation when dissolved in water, and preferably yields a pH 

greater than about 6.8, 7.0,7.2, or 7.4, and less than about 7.8, 

7.7 or 7.6, when mixed with 50 ml or 100 or 200 m!. of water 

at 25 degrees Celsius. 

Particularly preferred buffering agents are alkali metal carbonates and bicarbonates and these agents are preferably 

employed in a weight ratio relative to the diclofenac of greater 

than about 1:5,2:5,2:1,3:1 or 5:1. Ifdesired, an upper limit 

on the buffer:diclofenac ratio can be placed at about 20: 1, 

10:1,5:1,1:1,4:5 or3:5. Ranges can be selected from any two 

of the foregoing values that are mathematically possible. In a 

preferred embodiment, the buffer:diclofenac weight ratio 

ranges from about 1:5 to about 4:5. Particularly preferred 

alkali metal bicarbonates are sodium bicarbonate and potassium bicarbonate. 

Final Powdered Sachet Product 

The powder sachets used in the methods of this invention 

can be produced by various methods including dry granulation, wet granulation and dry admixing processes. A suitable 

product produced by wet granulation is described, for 

example, by Reiner et a!. in WO 97/44023. 

In one clinical trial, a representative 50 mg. diclofenac 

formulation obtained by the method disclosed in examples 3 

and 4 was shown to exhibit the following pharmacokinetic 

properties: 

Cmax mean value 

tmax mean value 

AUC O-t mean value 

1620 nglml (CV ~ 53.8%) 

13.98 min (CV ~ 32.2%) 

1010 (CV ~ 42.4%) 

In contrast, a 50 mg. formulation prepared by the wet 

granulation process disclosed in WO 97/44023 has been 

shown to exhibit the following pharmacokinetic properties: 

Cmax mean value 

tmax mean value 

AUC O-t mean value 

2213 nglml (CV ~ 33.57%) 

13.68 min (CV ~ 16.3%) 

1332.99 (CV ~ 26.86%) 

10 

solubilize the product in a given amount of water. Therefore, 

in one embodiment a unit dose of the sachet is greater than 

75% or 85% soluble or is completely soluble in 50 m!. of 

water at 25 degrees Celsius. In another embodiment the unit 

dose is greater than 75% or 85% solubilized or is completely 

solubilized in 50 m!. of water with stirring at 25 degrees 

Celsius in less than 5 minutes. This optimized solubility 

seems to restrict absorption to a shorter part of the gastrointestinal tract, most likely contributing to the faster absorption 

10 rate and to the lower variability in the absorption compared to 

immediate release diclofenac potassium tablets. 

The water content of the final product is preferably less 

than about 1.5%. The final product is also preferably free of 

sugar (saccharose), preferably includes as sweeteners aspar15 tame and/or saccharin, and preferably includes as flavoring 

agents anise and/or mint. 

Practically any container that maintains hermetic conditions could be used for packaging the powder sachets, though 

preferably the container consists of a sachet that is hermeti20 cally sealed in four directions to maintain the product in 

hermetic conditions during storage. The sachet is preferably 

made from a three-layer coupled paper/aluminum/polyethylene foil in which the weight of the paper is from about 0.475 

to about 0.525 gil 00 cm2

, the weight of the aluminum is from 

25 about 0.203 to about 0.229 g/100 cm2

, and the weight of the 

polyethylene is from about 0.295 to about 0.365 g/100 cm2 . 

Diluents for Powder Sachets 

Diluents or "filler excipients" are prefereably added to 

30 increase the resulting dosage units' bulk, and to improve 

blending characteristics. Freely soluble diluents are particularly preferred because they improve the solubility of the final 

product. The diluent preferably has a solubility in water at 25 

degrees Celsius of greater than about 10, 15 or 20 g/100 m!. of 

35 water. A particularly preferred diluent is maunitol, which is 

substantially non-hygroscopic, and which has a solubility in 

water of 22 gil 00 m!. Other suitable diluents include lactose, 

glucose, sucrose, xylitol, and especially lactilol monohydrate 

due to its beneficial non-hygroscopic properties. 

40 The size of the diluent, and the order of adding the diluent 

during the mixing process, have also proven important in the 

practice of the present invention. In a preferred dry mixing 

process, the diclofenac is mixed with a fine diluent powder 

before any further processing to distribute the diclofenac and 

45 to preserve its flowability. In a preferred wet granulation 

method, the diclofenac is granulated along with coarse diluent powder before any further processing. 

50 

The particles sizes for two exemplary fine diluent powders 

are reported below: 

Powder 1 (preferred) Powder 2 

In one embodiment the powdered sachet is produced by a 55 

dry mixing process and is characterized by the presence of 

diclofenac particles having one of the particle size distributions described above. In another embodiment the product is 

characterized by the total amount of powder used to fill a 

sachet, which is preferably greater than 500, 600, 700 or 800 60 

mg., and/or less than 1800, 1600, 1400, 1200, or 1000 mg., 

based on a 50 mg. diclofenac sachet. A preferred amount of 

powder is 900 mg. and the amount preferably does not vary 

outside the 855-945 mg/sachet range per package. 

Size Distribution (measured by laser) 

>250 flIIl: not more !ban 5% >500 flIIl: not more !ban 10% 

> 100 flIIl: not more !ban 25% >315 flIIl: not more !ban 25% 

>20 flIIl: not less than 55% >40 flIIl: not less !ban 60% 

Size Distribution (measured with sieves) 

> 150 flIIl not more !ban 2% >250 flIIl not more !ban 10% 

Average Particle Size (measure by laser) 

50 micrometers 160 micrometers 

In still another embodiment the invention is characterized 65 

by the solubility of the product in water, the amount of water 

required to solubilize the product, and the time required to 

The fine diluent powder can also be characterized by its 

average particle diameter, which can range from less than 

about 200, 180, 160, 140, 120, 100, or 80 micrometers, to 

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US 7,759,394 B2 

11 

greater than about 1, 5, 10,20,30 or 40 micrometers, with 

ranges defined between any two of the foregoing values. Most 

preferably, the fine diluent powder has an average particle 

size of about 50±40, 30, 20 or 10 micrometers. 

As a still further alternative, the fine diluent can be characterized by its particle size relative to the diclofenac powder. 

In such an embodiment, the fine diluent is characterized by an 

average particle size of less that 100%, 80%, 60% or 40% of 

the average particle size of the diclofenac powder, and greater 

that about 5%, 10% or 20% of the average particle size of the 10 

diclofenac powder, again with ranges defined between any 

two of the foregoing values. 

In a 50 mg. diclofenac sachet, the weight ratio of fine 

diluent to diclofenac in the final powder composition is preferably greater than about 1:5, 1:2, 1: 1 or 1.2: 1, and/or less 15 

than about 10:1, 6:1, 4:1, 3:1 or 2:1, with ranges defined 

between any two of the foregoing values. A preferred range of 

weight ratios is from about 1: 1 to about 2: 1. In a particularly 

preferred embodiment for a 50 mg. diclofenac sachet, the 

sachet comprises from about 50 to about 100 mg. of the fine 20 

diluent particles, from about 60 to about 85 mg. of fine diluent 

particles, or from about 70 to about 75 mg. of fine diluent 

particles. 

12 

A preferred range of weight ratios of the coarse diluent powder to the diclofenac in a 50 mg. diclofenac sachet is from 

about 10: 1 to about 20: 1. 

The invention can also be defined by the total amount of 

non-hygroscopic diluent (fine and coarse) relative to the 

amount of diclofenac and, in various embodiments for a 50 

mg. diclofenac sachet, the weight ratio is greater about 1.5: 1, 

2:1,4: 1,6:1,8: 1,10:1, or 12:1, and less than about 80: 1,60:1, 

40:1, 30:1, 25:1 or 20:1. In other embodiments, the total 

weight of the non-hygroscopic diluent is greater than about 

40%, 50%, 60% or 70%, and less than about 95%, 90% or 

85% of the weight of the total composition in the sachet. 

Alternative Doses and Diluent/Diclofenac Ratios 

As discussed above, the foregoing weight ratios and relative quantities of diclofenac to fine diluent, coarse diluent and 

total diluent are given for a 50 mg. dilofenac sachet, preferably in a 900 mg. formulation. It will be understood that the 

total volume of the sachet can be divided or increased by 

various factors, such as 1.5, 2 or 4 while maintaining the 

foregoing weight ratios, to lower or increase the total amount 

of the diclofenac in the formulation. Thus, for example, a 900 

mg. sachet containing 50 mg. of diclofenac potassium, 648 

mg. of coarse diluent and 73 mg. of fine diluent, could be Once the initial mixture of diclofenac and fine diluent 

powder is prepared in the preferred dry mixing process, a 

coarser diluent is preferably used to mix in the remaining 

components, preferably using a step-addition process in 

which successive amounts of the coarser diluent are added 

between each newly added ingredient. A preferred sequence 

25 divided in two to provide a 450 mg. sachet containing 25 mg. 

of diclofenac potassium, 324 mg. of coarse diluent, and 36.5 

mg. of fine diluent, or it could be divided in four to provide a 

225 mg. sachet containing 12.5 mg. ofdiclofenac, 162 mg. of 

coarse diluent and 18.25 mg. of fine diluent. 

It is also possible to simply divide the 50 mg. of diclofenac 

in the sachets described above in half, and provide 25 mg. 

diclofenac sachets while keeping the amounts of fine and 

coarse diluent substantially constant by, for example, basically doubling the ratios of fine diluent and coarse diluent to 

of mixing, for the dry blending and wet granulation pro- 30 

cesses, is set forth in the examples hereto. As with the fine 

diluent, the coarser diluent is also preferably non-hygroscopic. In a preferred embodiment, the coarser diluent is the 

same chemical entity as the fine diluent powder, which is 

preferably mannitol. In one embodiment the coarse diluent is 

characterized by an average particle size that is greater than 

the average particle size of the fine diluent, and preferably has 

35 diclofenac reported above. Thus, for example, one could prepare 25 mg. of diclofenac in a 900 mg. sachet using substantially the same amounts of fine and coarse diluent as reported 

above, simply by dividing the total diclofenac in the formulation by two. Once again, the total volume of such a sachet an average particle size greater than about 120%, 150% or 

200% of the average particle size of the fine diluent, and less 

than about 1000%,800% or 600% of the average particle size 

of the fine diluent, with ranges defined between any two of the 

foregoing values. 

40 could be divided or increased by various factors, such as 1.5, 

2 or 4 while maintaining the revised weight ratios, to lower or 

increase the total amount of the diclofenac in the formulation. 

In an alternative embodiment the coarse diluent is defined 

by its particle size relative to the particle size of the diclofenac 

powder. In this embodiment, the coarse diluent preferably has 45 

an average particle size from about 60, 80 or 100% to about 

1000,800,600,400 or 200% of the average particle size of the 

diclofenac powder, with ranges defined between any two of 

the foregoing variables. 

Lubricants for Powder Sachets 

While the use of lubricants is not strictly necessary, in a 

preferred embodiment they are added to the powder to prevent the powder from sticking to the metering machine in the 

final stage of filling the sachets. Suitable lubricants include 

magnesium stearate, stearic acid, hydrogenated castor oil, 

talc, or mixtures thereof, but a preferred lubricant is glycerol 

dibehenate. The lubricant is preferably present in an amount 

of from about 0.01 to about 2 wt. %, and preferably about 

0.2% w/w, based on the weight of the powder composition. 

In a still further alternative, the coarse diluent can be char- 50 

acterized as having an average particle diameter of greater 

than about 75, 85, or 100 micrometers, and less than about 

300, 250, 200, or 150 micrometers. In a particularly preferred 

embodiment, the coarse diluent powder has the following size 

distribution: 

In the method of manufacturing the product, the lubricant 

is preferably mixed with the diclofenac/fine diluent mixture 

55 as a separately prepared premix that also comprises diluent, 

albeit in a coarser particle size. >315 flm: not more than 10% 

>75 flm: not less than 90% 

The amount of the coarse diluent is not critical, though it is 

typically added in an amount to bring the total sachet weight 

up to about 900 mg. in a 50 mg. diclofenac formulation. The 60 

total dosage form preferably comprises from about 200 to 

about 1500 mg., from about 400 to about 1000 mg., from 

about 500 to about 800 mg., or from about 600 to about 750 

mg. of coarse diluent in a 50 mg. diclofenac sachet. In various 

embodiments, the weight ratio of coarse diluent to diclofenac 65 

in a 50 mg. diclofenac sachet is greater than about 2:1,4:1, 

6:1,8:1 or 10: 1, and less than about 40:1,30: 1,20:1 or 15:1. 

Powder Sachet Processing 

In a preferred embodiment the powder sachets used in the 

invention are made by a dry blending process in which the 

diclofenac powder and other ingredients are added sequentially to successive batches of diluent. In a particularly preferred embodiment, the diclofenac is first blended with the 

fine diluent followed by the successive addition of coarse 

particulate and further inactive ingredients. 

Therefore, in one embodiment the diclofenac composition 

is a particulate flowable diclofenac composition made by a 

Case 2:11-cv-04183-ES-CLW Document 1 Filed 07/20/11 Page 61 of 70 PageID: 61
US 7,759,394 B2 

13 

process comprising: (a) mixing powdered diclofenac with a 

fine powdered diluent to form a first mixture; and (b) mixing 

said first mixture with a coarse powdered diluent to form a 

second mixture. The second mixture is preferably obtained by 

adding the first mixture to a predefined volume of the coarse 

diluent, which has preferably been pre-loaded into a mixing 

machine. In a further embodiment the method of making the 

composition additionally comprises: 

a) mixing said second mixture with an alkali metal bicarbonate to form a third dry mixture; 

b) mixing said third mixture with coarse diluent to form a 

fourth mixture; 

c) mixing coarse diluent with a lubricant to form a fifth 

mixture; and 

d) mixing said fourth and fifth mixtures. 

10 

15 

While the preferred method of manufacturing the compositions of the present invention is dry blending, other methods 

can also be employed that do not depend on mixing of dry 

powders including wet granulation. For wet granulation, the 

binder can be added dry to the powder blend, or as a solution 20 

in the solvent. The solvent is usually ethanol, water, or a 

mixture of both . The actual granulation is performed in either 

a high-shear, or low-shear type mixer. Low-shear granulation 

requires cheaper equipment and produces a more porous 

granule. High-shear granulation is faster and affords good 25 

control over particle size. 

Fluid bed wet granulation is a variation of the process in 

which the granulation and drying is carried out in the same 

vessel (a fluid bed granulator). The powder mix is fluidized by 

dry air inside a chamber. The binder solution is sprayed onto 30 

the fluidized powder to form the agglomerates. Air fluidizing 

continues until the agglomerates are dry. The process requires 

expensive equipment, but is simpler and produces a very 

porous low-density granule, which can result in faster drug 

dissolution. Slow drug dissolution is sometimes a problem 35 

associated with wet granulation, as the active ingredient is 

locked into the granule, and initial tablet disintegration liberates the granules rather than the primary drug particles. 

14 

the wet granulate comprises from about 8 to about 15 

weight parts diclofenac (preferably 10 to 13 weight 

parts), from about 12 to about 20 weight parts coarse 

maunitol (preferably 15 to 18 weight parts); and from 

about 3 to about 7 weight parts bicarbonate (preferably 4 

to 6 weight parts). 

wet granulate including from about 8 to about 15 weight 

parts diclofenac (preferably 10 to 13 weight parts) is 

admixed with: from about 100 to about 160 weight parts 

coarse mannitol (preferably 120 to 140 weight parts); 

from about 12 to about 20 weight parts fine mannitol 

(preferably 14 to 18 weight parts); and from about 0.2 to 

about 0.7 weight parts glyceryl dibehenate (preferably 

0.4 to 0.5 weight parts), preferably in sequential order 

while stirring. 

the formulation comprises: fine mannitol and diclofenac or 

a pharmaceutically acceptable salt thereof at a weight 

ratio offrom about 1:2 to about 5:1, coarse mannitol and 

diclofenac or a pharmaceutically acceptable salt thereof 

at a weight ratio of from about 2:1 to about 40:1, 

wherein: said fine diluent has an average particle size of 

from about 10 to about 180 micrometers, said coarse 

diluent has an average particle size of from about 85 to 

about 250 micrometers, and said coarse diluent has an 

average particle size greater than the average particle 

size of said fine diluent. 

said maunitol comprises fine mannitol and coarse mannitol 

at a weight ratio offromabout 1:5 to about 1 :20; said fine 

maunitol has the following particle size distribution: 250 

f.Ull: not more than 5%; 100 f.Ull: not more than 25%; 20 

f.Ull: not less than 55%; and said coarse diluent has the 

following particle size distribution: 315 flm: not more 

than 10%; and >75 flm: not less than 90%. 

A weight ratio of mannitol to diclofenac of greater about 

1.5:1,2:1,4: 1,6:1,8: 1,10: 1, or12:1, and less than about 

80:1,60:1,40:1,30:1,25:1 or 20:1. 

Total mannitol percentage greater than about 40%, 50%, 

60% or 70%, and less than about 95%, 90% or 85%, of 

the weight of the total composition in the sachet. 

Liquid Formulations 

The invention further provides methods for using 

diclofenac compositions that are provided as liquids having 

the diclofenac already dissolved therein. Practically any sort 

In dry granulation, particle size enlargement is achieved by 

aggregating the powder particles under high pressure (i.e., by 40 

compaction) then milling the compressed material to the 

desired size. Fines generated by milling are recycled back 

through the compactor. The compression step is typically 

carried out in a roller compactor in which the powder is 

compressed between two rollers. 

Therefore, in another embodiment the invention provides a 

method of making a wet granulated powder formulation of 

diclofenac comprising: (a) wet granulating an admixture of 

diclofenac (or a pharmaceutically acceptable salt thereof), a 

first portion of coarse mannitol, and a suitable bicarbonate to 50 

form a wet granulate; and (b) admixing said wet granulate 

with a second portion of coarse mannitol and fine mannito!' In 

another embodiment the invention provides a method of making a wet granulated powder formulation of diclofenac comprising: (a) wet granulating an admixture of diclofenac (or a 55 

pharmaceutically acceptable salt thereof), a first portion of 

mannitol and optionally a bicarbonate to form a wet granulate; and (b) admixing said wet granulate with a second portion of mannitol, wherein the weight ratio of maunitol and 

diclofenac in said final formulation is greater than about 60 

1.5: 1. 

45 of single use "vial" can be used for containing a liquid dosage 

form. For purposes of this application, "vial" means a small 

glass container sealed with a suitable stopper and seal, or any 

other suitable container such as breakable and non-breakable 

Further sub embodiments of the foregoing principal 

embodiments can be defined by one or more of the following 

additional parameters: 

the wet granulation is performed in ethanol; 

the method further comprises admixing said wet granulate 

with glyceryl dibehenate. 

glass and plastic vials, miniature screw-top jars, and any other 

type of container of a size capable of holding a small amount 

of diclofenac liquid. Thus, for example, when the diclofenac 

is formulated in liquid solutions that contain approximately 

50 mg. diclofenac potassium in every m!. of liquid, the formulation can be packaged in a dropper bottle that contains 

any suitable quantity of liquid, typically from about 15 to 

about 100 m!. of solution. The concentration of diclofenac in 

these formulations typically will be about 50 mg/ml, but 

could range from about 10 to about 100 mg/ml, including 10, 

25, 50, 75 and 100 mg./m!. Alternatively, the vial can be a 

single use vial, which would contain a suitable quantity of 

liquid such as about 15 m!. for a 50 mg. dose of diclofenac 

potassium. 

As with the other formulations of this invention, buffering 

agents can be used in the drop formulations where a rapid rate 

65 of onset is desired for the final pharmaceutical product. In a 

preferred embodiment for the drop formulation, the buffering 

agent most preferably imparts a pH ranging from about 7 to 

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US 7,759,394 B2 

15 

about 10.5, from about 8 to about 10, from about 8.5 to about 

9.5, and most preferably about 9. 

Drop formulations are preferably prepared in a three step 

process comprising (a) dissolving diclofenac in ethyl alcohol 

to form a solution, (b) mixing said solution with glycerol to 

form a second solution, and (c) mixing said second solution 

with water to form a third solution. In a further embodiment, 

a fourth solution is made by dissolving any desired buffers in 

water, which is then mixed with the third solution to provide 10 

a final solution. The final solution preferably comprises from 

about 35 to about 45 wt. % water, from about 25 to about 35 

wt. % ethyl alcohol, and from about 15 to about 25 wt. % 

16 

invention is as follows: not less than 85, 90 or 95% after 15 

minutes in simulated intestinal fluid (i.e. water) at pH=6.8. 

EXAMPLES 

The following examples are put forth so as to provide those 

of ordinary skill in the art with a complete disclosure and 

description of how the compounds claimed herein are made 

and evaluated, and are intended to be purely exemplary of the 

invention and are not intended to limit the scope of what the 

inventors regard as their invention. Efforts have been made to 

ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.) but some errors and deviations should be 

accounted for. Unless indicated otherwise, parts are parts by glycerol. 

In another embodiment the liquid solution is characterized 15 weight, temperature is in 0 C. or is at room temperature, and 

pressure is at or near atmospheric. 

by its pharmacokinetics, such as Cmax (i.e. average concentration of active chemical in the bloodstream after oral ingestion), and its tmax (i.e. average time to reach said Cmax). A 

representative 50 mg. drop diclofenac formulation obtained 20 

by the method disclosed in examples 6 and 7 herein exhibits 

the following pharmacokinetic properties: 

Example 1 

Comparative Study of Diclofenac-K Sachet, 

Diclofenac-K Tablets, and Placebo in Treatment of 

Migraine 

A randomized, double-blind, double-dummy multi-center, 

Cmax mean value 

T max mean value 

AUCO_tmean value 

1679 nglml (CV ~ 39.85%) 

15.0 min (CV ~ 56%) 

1383 (CV ~ 30.59%) 

25 single dose, placebo- and active-controlled crossover study, 

with an eight hour evaluation was undertaken in adult 

migraine patients. 328 patients were randomized among 

treatments and a comparison made among treatments with a 

50 mg. diclofenac potassium sachet formulation, the 50 mg. 

Capsule and Tablet Formulations 

Examplary solid oral formulations contemplated by the 

present invention are set forth in Example 12. Preferred Cmax 

and tmax ranges for tablet and capsule dosage forms of the 

invention are set forth below: 

30 diclofenac potassium sugar coated tablet marketed commercially as Cataflam®, and placebo. Results are reported in 

Table 1. 

35 

Mean Cm= (ng/ml) Mean tm= (min) 

40 50 mg. 1300-2300; 1400-2200; 5-35; 10-30; 12-25; 

diclofenac tablet 1500-2100; 1750-2000; 15-20 

or capsule 1600-1900 

25 mg. 700-1150; 750-950; 800-900; 5-35; 10-30; 15-30; 

diclofenac tablet 850-1050; 900-1000 15-25 

or capsule 

12.5 mg. 350-650; 400-600; 450-550 5-35; 10-30; 15-25 45 

diclofenac tablet 

or capsule 

Disintegration times for the tablet and capsule dosage 50 

forms of the present invention, when tested according to USP 

28 <701>, are preferably less than about 20 minutes, 15 

minutes, 10 minutes, 5 minutes, or even 4 minutes, and 

greater than about 1, 2 or 3 minutes, most preferably from 

about 3 to about 5 minutes. In one particular embodiment, the 55 

dosage form is a tablet, and the tablet has a disintegration time 

that increases as the hardness of the tablet decreases. In 

another embodiment, the tablet has a disintegration time that 

increases as the moisture absorption by the tablet increases. 60 

TABLE 1 

Pain on Verbal Scale 

Diclofenac-K Diclofenac-K 

Sachet Tablet Placebo 

Parameter % of patients % of patients % of patients 

Pain free at 2 hours 

ITT pop 24.7% 18.5% 11.7% 

PP pop 23.6% 17.8% 12.9% 

Mod-sev 24.2% 17.0% 12.5% 

baseline pain 

Headache response 2 46.0% 41.6% 24.1% 

hours 

Sustained response 36.8% 30.9% 18.4% 

Sustained pain free 22.3% 15.1% 9.4% 

Example 2 

Comparative Study of Diclofenac-K Sachet, 

Diclofenac-K Tablets, and Placebo in Treatment of 

Acute Dental Pain 

A double-blind, randomized, parallel-group trial compared the analgesic efficacy of single 50 mg doses of 

diclofenac potassium sachets and tablets with placebo in 184 

patients with moderate/severe pain after extraction of 

impacted third molar(s). The primary efficacy variable was 

the average pain reduction from baseline during the first 2 

hours after intake of study medication, assessed using a visual 

analog scale (VAS). During the first 2 hours post-dose sachets 

Dissolution times for the tablet and capsule dosage forms 

of the present invention, when tested according to USP 28 

<711>, based on the time it takes to dissolve 90 or 95 wt. % of 

the drug substance, are preferably less than about 20 minutes, 

15 minutes, 10 minutes, 5 minutes, or even 3 minutes, and 

greater than about 1 or 2 minutes. In a preferred embodiment 

the dissolution profile of the dosage forms of the present 

65 and tablets demonstrated significantly less pain (P<0.05) versus placebo and sachets were more effective than tablets 

(P<0.05). Onset of analgesic effect (VAS) was maintained for 

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US 7,759,394 B2 

17 

8 hours for sachets and tablets (P<0.05). Fewer patients 

remedicated versus placebo and the results for pain relief and 

intensity assessed on a verbal scale confirmed the findings for 

VAS pain intensity. No safety issues were identified. Results 

are reported in Table 2. 

TABLE 2 

Average VAS Pain Reduction from Baseline during the First 2 Hours 

(ITT Population) 

Treatment effect and contrast 

Diclofenac Sachet 

Diclofenac Tablet 

Placebo 

Diclofenac Sachet - Placebo 

Diclofenac SachetDiclofenac Tablet 

Diclofenac Tablet - Placebo 

LS = least squares, 

SE - standard error of the mean, 

CI-confidence interval. 

Average VAS pain 

reduction in mm 

N LS mean (SE) 95% CI P valuea 

73 36.3 (2.4) 31.7-41.0 <.0001 

71 29.1 (2.4) 24.4-33.9 <.0001 

39 11.7 (3.1) 5.5-17.8 .0002 

24.7 (3.8) 17.3-32.1 <.0001 

(1) 

7.2 (3.1) 1.0-13.4 <.0001 

(2) 

17.5 (3.8) 10.0-24.9 <.0001 

(1) 

Name of the 

component 

Diclofenac 

potassiwn1 

Glycerol dibehenate 

Saccharin sodium 

10 Anise flavor 

Potassium hydrogen 

Carbonate 

Mint flavor 

Aspartame 

15 Mannitol2 

Total weight 

18 

TABLE 3 

Unit 

(mg.) Function 

50.0 Active substance 

2.0 Lubricant 

5.0 Sweetening agent, 

Flavoring enhancer 

15.0 Flavoring agent 

22.0 Buffering agent 

35.0 Flavoring agent 

50.0 Sweetening agent, 

Flavoring enhancer 

721.0 Diluent 

900.0 

Ipartic1e size distribution: 

20 Not less than 90% ~500 ~ 

Not less than 40% and not more than 70% ~200 ~ 

Not less than 35% and not more than 65% ~150 ~ 

Not less than 30% ~100 ~ 

Reference standard 

Ph. Eur. 

Ph. Eur. 

Ph. Eur. 

In-house specifications 

Ph. Eur. 

In-house specifications 

Ph. Eur. 

Ph. Eur. + 

additional specification 

2As Marmitol "coarse quality" (648.0 rug) and Mannitol "fine quality" (73.0 rug). 

25 Example 4 

Manufacturing Process for 900 mg. Powder Sachets 

Containing 50 mg. of Diclofenac Potassium 

All statistics for treatment effects and treatment contrasts are based on !be analysis of 30 covariance model: Average pain reduction = treatment + country + baseline VAS pain 

intensity. 

A representative process for manufacturing 900 mg. powder sachets containing 50 mg. of diclofenac potassium is set 

forth below, using the equipment set forth in Table 1. The 

manufacture is performed under controlled temperature and 

relative humidity according to the following process. 

ap values are two-sided for treatment effects (difference to 0), (1) one-sided P value for 

verum # placebo, (2) one-sided P value for dic10fenac potassium sachet < dic10fenac 

potassium tablet - 10 (non-inferiority test) 

Example 3 

Step 

Sieve using a vibrating sieving machine (typically 850 flIIl) 47.45 Kg of 

Mannitol "fine quality" and 33.15 kg of Diclofenac Potassium. Load in a 

high shear mixer and mix for approx. 6 minutes. Repeat this step once. 

(pre-mixture 1) 

2 Sieve using a vibrating sieving machine (typically 850 flIIl), and load in a 

convection mixer (in the following order) 120.0 kg of mannitol "coarse 

quality," the pre-mixture 1, 100.0 kg of mannitol "coarse quality," 28.6 kg 

of potassium hydrogen carbonate, 100.0 kg of mannitol "coarse quality," 

65.0 kg of aspartame, 100.0 kg of mannitol "coarse quality," 6.5 kg of 

saccharin sodium and 100.0 kg of mannitol "coarse quality." Mix for 

approx. 5 minutes (pre-mixture 2). 

Sieve using an oscillating sieving machine (typically 850 flIIl), and load in 

(final mixture) the convection mixer, in the following order, 72.4 kg of mannitol "coarse 

quality," 52.6 kg of the glidant pre-mixture consisting of2.6 kg of 

Glyceryl dibehenate and 50.0 kg of mannitol "coarse quality," 45.5 kg of 

mint flavour, 100.0 kg of mannitol "coarse quality," 19.5 kg of anise 

flavour and 100.0 kg of mannitol "coarse quality." 

Mix for approx. 7 minutes in order to obtain the final homogenous 

mixture to fill into sachets. 

4 Fill the final mixture into sachets at the target weight. 

(filling) 

60 TABLE 4 

Representative 900 mg. Powder Sachet Formulation 

Manufacturing eguipment 

Table 3 describes the composition of a representative 900 

mg. powder sachet formulation containing 50 g. of diclofenac 

potassium that is suitable for practicing the present invention. 

Unit operation 

65 Sieving 

Premixing (pre-mixture 1) 

Type of equipment 

Screening mill, oscillating bar 

High shear mixer 

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US 7,759,394 B2 

19 

TABLE 4-continued 

Manufacturing eguipment 

Unit operation Type of equipment 

Mixing (pre-mixture 2 and 

final mixture) 

Convection mixer, planetary blenders 

Filling into sachet Powder filler, Volumetric filling station 

Example 5 

Wet Granulated Powder Sachet Manufacturing 

Process 

The manufacture of 50 mg, diclofenac potassium sachets 

having the formulation prescribed in Example 3, via wet 

granulation, is set forth in Tables 5 and 6, 

TABLE 5 

Batch formula 

Name of the components 

Diclofenac potassium 

Glycerol dibehenate 

Saccharin sodium 

Anise flavour 

Potassium hydrogen carbonate 

Mint flavour 

Aspartame 

Mannitol "fine quality" 

Mannitol "coarse quality" 

Ethyl Alcohol 

Total 

Amount (kg) 

11.25 1 

0.450 

1.125 

3.375 

4.95 

7.875 

11.25 

16.425 

145.845 

3.88* 

202.5 

*Eliminated during the drying process of the wet granulate. 

Step 

2 

TABLE 6 

Manufacturing process 

Load in a wet granulator 16.2 kg ofmarmitol "coarse 

quality," 11.25 kg of diclofenac potassium, 4.95 kg 

of potassium bicarbonate, 1.125 kg of saccharin sodium 

and 11.125 kg of aspartame; mix for approx. 5 minutes; 

add 3.88 kg of ethyl alcohol and mix for 5 minutes; load 

the wet granulate in oven at 50 C C. until the humidity 

of granulate is below 1 %. 

Sieve using an oscillating sieving machine (typically 

850 flIIl) the following excipients: marmitol "coarse 

quality," marmitol "fine quality," glyceryl 

dibehenate, mint flavour and anice flavour; load the 

granulate obtained in step 1 in a convection mixer 

and add, in the following order, 129.475 kg of mannitol 

"coarse quality," 16.425 kg of mannitol "fine 

quality," 0.45 kg of glyceryl dibehenate, 7.875 kg 

of mint flavour and 3.375 kg of anise flavour; mix for 

approx. 30 minutes 

Fill the final mixture into sachets at the target weight. 

Example 6 

Representative Drop Formulation (50 mg. 

Diclofenac Potassium/m!. of Solution) 

Table 7 describes a representative formulation for a drop 

formulation of diclofenac in which one milliliter solution 

10 

15 

20 

20 

contains 50 mg. of diclofenac potassium. The formulation is 

administered by adding the drops to water and orally ingesting the mixture. 

TABLE 7 

DroJ2 Solution ComJ2osition 

Reference 

Names of ingredients Unit (g) FlUlction standards 

Active ingredients 

Diclofenac potassiwn 5.0a Anti-inflanunatory Eur. Ph. 

agent 

Solution excipients 

Ethyl alcohol 30.0 Solubilizing and Eur. Ph. 

preservative agent 

Glycerol 20.0 Solubilizing agent Eur. Ph. 

Potassium hydrogen 2.5 Buffering agent Eur. Ph. 

carbonate 

Saccharin sodium 1.5 Sweetening agent Eur. Ph. 

Caramel E 150a 0.25 Colouring agent Int. standardb 

Purified water 42.9 Diluent agent Eur. Ph. 

Total weightb 102.15 

GThis amount refers to active substance material with 100.0% assay. 

25 hweight of 100.0 ml of solution (relative density = 1.0215 g/ml). 

The formulation is preferably contained in a brown colored 

glass container, equipped with dropper and screw-cap closure, holding 20 or 100 ml of Diclofenac potassium solution. 

30 The glass container (type III) is suitable for liquid preparations that are for parenteral use. The dropper is made from 

polyethylene low density (PE-LD) material, according to 

food and pharmaceutical regulations. The screw cap is made 

from polypropylene, suitable as child proof closure. 35 

40 

45 

50 

55 

60 

65 

Example 7 

Manufacturing Process for Drop Formulation 

The raw materials necessary for the production of a pilot 

standard batch of250 liters of solution (volume required to fill 

12,500 or 2,500 bottles with a capacity of 20 ml or 100 ml, 

respectively) are listed in Table 8. 

TABLE 8 

Manufacturing formula for a pilot standard batch of 250 liters 

of solution 

Names ofIngredients Unit (kg) 

Active ingredients 

Diclofenac potassiumG 12.500 

Solution excipients 

Ethyl alcohol 96% 75.000 

Glycerol 50.000 

Potassiwn hydrogen carbonate 6.250 

Saccharin sodium 3.750 

Caramel E 150a 0.625 

Purified water 107.250 

Total weightb 255.375 

GAnalytical specifications ofDiclofenac potassium are the same used for the sachets 

hweight of 250 liters of solution (relative density 1.0215 glml). 

12.5 kg of Diclofenac potassium, 6.25 kg of potassium 

hydrogen carbonate, 75 kg of ethyl alcohol 96%, 50 kg of 

glycerol, 3.75 kg of saccharin sodium, 0.625 kg of Caramel E 

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US 7,759,394 B2 

21 

150a and two different amounts (76 kg and 31.25 kg) of 

purified water are first weighed. 

A first mixture is then prepared by adding the ethyl alcohol 

96% into a mixing vessel and then, under stirring, adding the 

active ingredient diclofenac potassium. After stirring for 

10-15 minutes, the glycerol is added and the mixture stirred 

for another 10-15 minutes. While stirring, 76 kg of purified 

water is added to the mixture and stirred until a complete clear 

solution is obtained. 

A second mixture is prepared by adding 31.25 kg of purified water into a separate mixing vessel and, under stirring, 

adding the remaining excipients (potassium hydrogen carbonate, saccharin sodium and Caramel E 150a). The mixture 

is stirred for 15-30 minutes. 

While stirring, the first mixture is added to the second 

mixture and the resultant mixture stirred until a complete 

clear brown solution is obtained. Under mixing, water is 

added to the solution until a weightof255.375 kg (250 liter of 

solution) is obtained. The solution is particle-free filtrated. 

Example 8 

Additional Drop Formulations (25 mg. Diclofenac 

Potassium/ml) 

Tables 9 and 10 describe representative formulations of 

drops containing 25 mg. of diclofenac potassium per m!. of 

solution. 

Names of ingredients 

Active ingredients 

Diclofenac potassiwn 

Solution excipients 

TABLE 9 

Unit (g) Function 

2.50 Antiinflannnatory 

agent 

Reference 

standard 

Eur. Ph. 

Names of ingredients 

Saccharin sodium 

Acesulfame 

Caramel E 150a 

MintflavolIT 

Anise flavour 

10 Purified water 

Total volume 

15 

Names of ingredients 

Active ingredients 

20 Diclofenac potassiwn 

Solution excipients 

25 Ethyl alcohol 96% 

Glycerol 

Potassium hydrogen 

carbonate 

Saccharin sodium 

Acesulfame 30 Caramel E 150a 

Cola flavour 

Purified water 

Total volume 

35 

22 

TABLE 9-continued 

Unit (g) FlUlction 

1.50 Sweetening agent 

3.00 Sweetening agent 

0.25 Colouring agent 

1.40 Flavouring agent 

0.60 Flavouring agent 

Qb to 100 ml Diluent agent 

100.00 

TABLE 10 

Unit (g) FlUlction 

2.50 Antiinflammatory 

agent 

30.00 Solubilizing and 

preservative agent 

20.00 Solubilizing agent 

1.25 Buffering agent 

Reference 

standard 

Eur. Ph. 

Eur. Ph. 

Int. standard 

Int. standard 

Int. standard 

Eur. Ph. 

Reference 

standard 

Eur. Ph. 

Eur. Ph. 

Eur. Ph. 

Eur. Ph. 

1.50 Sweetening agent Eur. Ph. 

3.00 Sweetening agent Eur. Ph. 

0.25 Colouring agent Int. standard 

2.00 Flavouring agent Int. standard 

q b a 100 ml Diluent agent Eur. Ph. 

100.00 

Example 9 

Ethyl alcohol 96% 30.00 Solubilizing and 

preservative agent 

Eur. Ph. 40 

900 mg. Powder Sachet Formulation Containing 25 

mg of Diclofenac Sodium 

Glycerol 

Potassium hydrogen 

carbonate 

20.00 

1.25 

Solubilizing agent 

Buffering agent 

Eur. Ph. 

Eur. Ph. The ingredients of the product diclofenac sodium 25 mg 

powder for oral solution (sachets, weighing 900.0 mg) are 

listed in Table 11 below. 

Names of ingredients 

Active ingredients 

Diclofenac sodiwn 

Excipients 

Potassiwn hydrogen carbonate 

Mannitolb 

MannitolC 

Acesulfarne Potassiwn 

Glycerol Dibehenate 

(compritol 888 ATO) 

Mint flavour 

Anise flavour 

Total weight 

TABLE 11 

Reference 

Unit (mg.) FlUlction standard 

25a mg Anti -inflannnatory Eur. Ph. 

agent 

11.0 mg Buffering agent Eur. Ph. 

698.0 mg Diluent agent Eur. Ph. 

74.00 g Diluent agent Eur. Ph. 

40.0 mg Sweetening agent Eur. Ph. 

2.0 mg Lubricant agent Eur. Ph. 

15.0 mg Flavouring agent Manufacturer 

35.0 mg Flavouring agent Manufacturer 

900.0 mg 

GThis amount refers to active substance material with 100.0% assay. The diclofenac sodium has the following 

particle size distribution: not less than 95% of the particles are less than 500 micrometers in diameter, not more 

than 90% are less than 250 micrometers in diameter, not more than 60% are less than 180 micrometers in 

diameter, and not more than 30% are less than 125 micrometers. 

bpearlitol SD 200, conform to Em. Ph. 

"Marmito135, conform to Eur. Ph .. 

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US 7,759,394 B2 

23 

Example 10 

Method of Preparing 900 mg. Powder Sachets 

Containing 25 mg. of Diclofenac Sodium 

A representative process for manufacturing 900 mg. powder sachets containing 25 mg. of diclofenac sodium is set 

forth below, using the equipment set forth in Table 1. The 10 

manufacture is performed under controlled temperature and 

relative humidity according to the following process. 

Preparation of the Pre-mixture 

Sieve all the ingredients necessary for the production of the 15 

powder, then weigh 1.375 kg of diclofenac sodium, 0.605 kg 

of potassium hydrogen carbonate, 38.390 kg of mannitol 

(pearlitol SD 200), 4.070 kg of mannitol 35, 2.200 kg of 

acesulfame K, 0.825 kg of mint flavour, 1.930 kg of anise 

Statistic 

N 

Geometric 

mean 

Mean 

SD 

CV% 

Median 

Minimum 

Maximum 

Statistic 

N 

Geometric 

mean 

Mean 

SD 

CV% 

Median 

Minimum 

Maximum 

24 

flavour and 0.11 kg of glyceryl dibehenate. Load in the mixer: 

diclofenac sodium, potassium hydrogen carbonate, mannitol 

35, acesulfame K, mint flavour and anise flavour. Mix for 25 

minutes. 

Preparation of the Mixture 

Transfer the premix into mixer; add mannitol SD 200 and 

glyceryl dibehenate, mix for 30 minutes. 

Example 11 

Diclofenac K Sachet Bioavailability Comparison 

Test Formulations: Diclofenac potassium 50 mg powder for 

oral solution (Example 4) 

Reference Formulation: Diclofenac potassium, 50 mg filmcoated tablets, Cataflam by Novartis Pharma 

TABLE 12 

Test Formulation fasting 

AUCCO-inf) AUCCO-t) Tmax TIl, 

(ng * hr/mL) (ng * hr/mL) Cmax (ng/mL) (hr) Kel (lIhr) (hr) 

32 33 33 33 32 32 

1201.001 1185.573 1505.296 0.264 0.54616 1.269 

1232.925 1216.609 1586.502 0.277 0.56938 1.322 

283.9458 277.7587 513.3048 0.1035 0.167653 0.3803 

23.03 22.83 32.35 37.32 29.45 28.76 

1177.67 1164.38 1528.20 0.25 0.5389 1.29 

686.48 668.10 800.58 0.17 0.3442 0.74 

1912.34 1896.02 2800.55 0.67 0.9352 2.01 

TABLE 13 

Cataflam fasting 

AUCCO-inf) AUCCO-t) Tmax Kel TIl, 

(ng * hr/mL) (ng * hr/mL) Cmax (ng/mL) (hr) (lIhr) (hr) 

32 33 33 33 32 32 

1064.370 1045.187 1037.124 0.618 0.56098 1.236 

1097.185 1077.596 1146.649 0.788 0.58669 1.290 

275.9971 272.7532 450.9879 0.7524 0.182630 0.3808 

25.16 25.31 39.33 95.53 31.13 29.51 

1078.28 1059.80 1125.91 0.50 0.5843 1.19 

537.38 524.43 197.17 0.25 0.3378 0.63 

1975.32 1959.12 1972.74 4.00 1.1013 2.05 

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US 7,759,394 B2 

25 

Example 12 

50 mg. Diclofenac K Tablet Comparison 

Test Formulations: Tl: Diclofenac potassium 50 mg filmcoated tablets, alcohol granulation T2: Diclofenac potassium 50 mg film-coated tablets, dry granulation 

Reference Formulation: Diclofenac potassium, 50 mg filmcoated tablets, Voltarene® Rapid by Novartis Pharma 

26 

Study design: Single dose, 3-way, crossover randomised on 6 10 

healthy volunteers 

Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application 

in order to more fully describe the state of the art to which this 

invention pertains. It will be apparent to those skilled in the art 

that various modifications and variations can be made in the 

present invention without departing from the scope or spirit of 

the invention. Other embodiments of the invention will be 

apparent to those skilled in the art from consideration of the 

specification and practice of the invention disclosed herein. It 

is intended that the specification and examples be considered 

as exemplary only, with a true scope and spirit of the invention 

being indicated by the following claims. 

Blood samples drawn: 0 (pre-dose), 5,10,15,20,30,45,60, 

90 min, 2, 3, 4, 5, 6, 8, 10, 12 h 

Assay: LC-MS-MS//LOQ 5 ng/ml 

Description 

Active 

ingredient 

Excipients 

Total 

weight 

Cm= 

AUC 

tm= 

Mean 

SD 

CV% 

Min 

Max 

Mean 

SD 

CV% 

Min 

Max 

Mean 

SD 

CV% 

Min 

Max 

TABLE 14 

Formulation of Comparison Tablets 

T2, K salt, 50 mg, 

T1, K salt, 50 mg, tablets tablets 

Diclofenac potassiwn Diclofenac potassiwn 

50 mg film-coated tablets 50 mg film-coated 

(by alcoholic granulation) tablets 

(by direct compression) 

Diclofenac potassiwn mg Diclofenac potassiwn 

50 mg50 

Potassium bicarbonate mg Potassiwn bicarbonate 

22 mg22 

Marmitol mg 50 Marmitol400 mg 119.9 

Maize starch mg 25 Sodium laurylsulfate mg 

Hydroxypropylmethylcellulose 0.1 

mgO.2 Polyvinylpyrrolidone 

Sodium laurylsulfate mg 0.1 mg6 

Polyvinylpyrrolidone mg 1 Magnesium stearate mg 2 

Sodium starch glycollate Film Coating Opadry 

mg2.5 Clear (HPMC 2910, 

Magnesium stearate mg 4.5 polyethyleneglycol400) 

Silicium aerosil FK 160 mg 1 mg4 

Coating Opadry Clear 

(HPMC 2910 and 

polyethyleneglycol 400) mg 4 

160.3 mg 204mg 

TABLE 15 

Pharmacokinetics of Comparison Tablets 

PKresults 

Test 1 Test 2 Reference 

(K, tablets 50 mg) (K, tablets 50 mg) (K, tablets 50 mg) 

1873.30 1744.8 1307.0 

553.80 572.3 558.4 

29.5 32.8 42.7 

1228.9 1057.4 581.8 

2516.5 2468.9 1935.5 

1219 1237 1168 

246 276 282 

20.2 22.3 24.1 

874 848 913 

1615 1668 1642 

0.31 h (18.6 min) 0.28 h (16.8 min) 0.68 h (40.8 min) 

0.04 0.07 0.65 

12.9 25.0 95.6 

0.25 h (15 min) 0.17 h (10.2 min) 0.25 h (15 min) 

0.33 h (19.8 min) 0.33 h (19.8 min) 2.00 h (120 min) 

Reference, K salt, 50 mg, 

Voltaren ® Rapid tablets 

Diclofenac potassium 

50 mg film-coated tablets 

Diclofenac potassium mg 

50 

Calcium phosphate 

Saccharose 

Maize starch 

Talc 

Sodium 

carboxymethylcellulose 

Colloidal anbydrous 

siliciwn 

Polyvinylpyrrolidone 

Microcrystalline cellulose 

Magnesium stearate 

Polyethylenglycole 

Titanidioxide (EI71) 

Iron oxide red (EI72) 

What is claimed is: 

45 1. A method of treating migraine associated with phonophobia and photophobia in a human patient within two hours 

of administration comprising: 

a) providing a liquid formulation comprising about 50 mg. 

of diclofenac or a pharmaceutically acceptable salt 

50 thereof in combination with an alkali metal carbonate or 

bicarbonate, wherein said formulation: 

i) is provided as a powder formulation and dissolved or 

suspended in water immediately before administration, or as a liquid formulation that is ingested with or 55 without further mixing; 

ii) optionally has been found to achieve a maximum 

plasma concentration (Cmax) (arithmetic mean) of 

from about 1500 to about 2500 ng/ml; and 

60 iii) has been found to achieve a time to maximum plasma 

concentration (tmax) (arithmetic mean) in from about 

10 to about 25 minutes; 

b) orally administering said formulation to a patient suffering from migraine associated with photophobia and 

65 phonophobia, and 

c) thereby relieving said photophobia and said phonophobia in said patient within two hours of administration. 

Case 2:11-cv-04183-ES-CLW Document 1 Filed 07/20/11 Page 68 of 70 PageID: 68
US 7,759,394 B2 

27 

2. The method of claim 1 wherein said patient is suffering 

from migraine that requires sustained migraine relief for at 

least 24 hours. 

3. The method of claim 1 wherein said liquid formulation 

comprises about 50 mg. of diclofenac potassium. 

4. The method of claim 1 wherein said formulation has 

been found to achieve tmax in from about 10 to about 20 

minutes. 

5. The method of claim 1 wherein said formulation is 

provided as a powder formulation, further comprising dis- 10 

solving or suspending said powder in water immediately 

before administration. 

28 

b) orally administering said formulation to a patient suffering from migraine, including headache pain, nausea, 

photophobia and phonophobia; and 

c) thereby treating said migraine, headache pain, nausea, 

photophobia and phonophobia in said patient within two 

hours of administration, wherein said migraine is 

defined as a disease manifested in a population of 

patients by periodic attacks of headache pain, nausea, 

photophobia and phonophobia. 

14. The method of claim 13 wherein said patient suffers 

from headache pain and either photophobia or phonophobia 

or both. 

6. A method of treating recurrent migraine requiring 24 

hour treatment in a human patient suffering from migraine 

comprising: 

15. The method of claim 13 wherein said Cmax has been 

found to have an inter-subject variability of less than about 

15 70%. 

16. The method of claim 13 wherein said tmax has been 

found to have an inter-subject variability of less than about 

70%. 

a) providing a liquid formulation comprising about 50 mg. 

of diclofenac or a pharmaceutically acceptable salt 

thereof in combination with an alkali metal carbonate or 

bicarbonate, wherein said formulation: 

i) is provided as a powder formulation and dissolved or 

suspended in water immediately before administration, or as a liquid formulation that is ingested with or 

without further mixing; 

17. The method of claim 13 wherein said liquid formula20 tion comprises about 50 mg. of diclofenac potassium. 

ii) optionally has been found to achieve a maximum 

plasma concentration (Cmax) (arithmetic mean)of 25 

from about 1500 to about 2500 ng/ml; and 

iii) has been found to achieve time to maximum plasma 

concentration (tmax) (arithmetic mean) in from about 

10 to about 25 minutes; 

b) orally administering said formulation to said patient; 30 

and 

c) thereby providing sustained migraine relief to said 

patient for at least 24 hours. 

7. The method of claim 6 wherein said patient suffers from 35 

headache pain and either photophobia or phonophobia or 

both. 

8. The method of claim 6 wherein said liquid formulation 

comprises about 50 mg. of diclofenac potassium. 

9. The method of claim 6 wherein said Cmax has been found 40 

to have an inter-subject variability ofless than about 70%. 

10. The method of claim 6 wherein said tmax has been found 

to have an inter-subject variability ofless than about 70%. 

11. The method of claim 6 wherein said formulation has 

been found to achieve tmax in from about 10 to about 20 45 

minutes. 

18. The method of claim 13 wherein said formulation has 

been found to achieve tmax in from about 10 to about 20 

minutes. 

19. The method of claim 16 wherein said formulation is 

provided as a powder formulation, further comprising dissolving or suspending said powder in water immediately 

before administration. 

20. A method of treating headache pain, nausea, phonophobia and photophobia in a human patient within two hours 

of administration comprising: 

a) providing a pharmaceutical formulation comprising 

about 50 mg. of diclofenac or a pharmaceutically acceptable salt thereof in combination with an alkali metal 

carbonate or bicarbonate, wherein said formulation: 

i) has been found to achieve an average maximum 

plasma concentration (Cmax) (arithmetic mean) of 

from about 1400 to about 2500 ng/ml; and 

ii) has been found to achieve an average time to maximum plasma concentration tmax (arithmetic mean) in 

from about 10 to about 35 minutes; and 

b) orally administering said formulation to a patient suffering from photophobia and Phonophobia; 

thereby treating said headache pain, nausea, photophobia and 

phonophobia within two hours of administration. 

21. The method of claim 20 wherein said formulation has 

been found to reach a Cmax of greater than 1500 ng/ml, and a 

tmax ofless than 30 minutes, and further wherein saidCmaxhas 

been found to reach an average Cmax when tested in a fasted 

state, and said tmax has been found to reach an average tmax 

12. The method of claim 6 wherein said formulation is 

provided as a powder formulation, further comprising dissolving or suspending said powder in water immediately 

before administration. 50 when tested in a fasted state. 

13. A method of treating migraine in a human patient, 

including headache pain, nausea, photophobia and phonophobia, within two hours after administration, comprising: 

a) providing a liquid formulation comprising about 50 mg. 

of diclofenac or a pharmaceutically acceptable salt 55 

thereof in combination with an alkali metal carbonate or 

bicarbonate, wherein said formulation: 

i) is provided as a powder formulation and dissolved or 

suspended in water immediately before administration, or as a liquid formulation that is ingested with or 60 

without further mixing; 

ii) optionally has been found to achieve a maximum 

plasma concentration (Cmax) (arithmetic mean) of 

from about 1500 to about 2500 ng/ml; and 

iii) has been found to achieve time to maximum plasma 65 

concentration (tmax) (arithmetic mean) in from about 

10 to about 20 minutes; 

22. A method of treating recurrent migraine requiring 24 

hour treatment in a human patient suffering from migraine, 

and providing relief from said migraine for at least 24 hours 

without rebound, comprising: 

a) providing a pharmaceutical formulation comprising 

about 50 mg. of diclofenac or a pharmaceutically acceptable salt thereof in combination with an alkali metal 

carbonate or bicarbonate, wherein said formulation: 

i) has been found to achieve an average maximum 

plasma concentration (Cmax) (arithmetic mean) of 

from about 1400 to about 2500 ng/ml; and 

ii) has been found to achieve an average time to maximum plasma concentration tmax (arithmetic mean) in 

from about 10 to about 35 minutes; and 

b) orally administering said formulation to said patient; 

thereby treating said recurrent migraine and providing relief 

from said migraine for at least 24 hours without rebound. 

Case 2:11-cv-04183-ES-CLW Document 1 Filed 07/20/11 Page 69 of 70 PageID: 69
US 7,759,394 B2 

29 

23. The method of claim 22 wherein said formulation has 

been found to reach a Cmax of greater than 1500 ng/ml, and a 

tmax ofless than 30 minutes, and further wherein said Cmaxhas 

been found to reach an average Cmax when tested in a fasted 

state, and said tmax has been found to reach an average tmax 

when tested in a fasted state. 

24. A method of treating headache pain, nausea, phonophobia and photophobia in a human patient within two hours 

of administration comprising: 

a) providing a pharmaceutical formulation comprising 10 

about 50 mg. of diclofenac or a pharmaceutically acceptable salt thereof in combination with an alkali metal 

carbonate or bicarbonate, wherein greater than 90% of 

said diclofenac dissolves completely in 50 m!. of water 

at 25° C. under continuous stirring for fifteen minutes at 15 

pH 6.8; and 

b) orally administering said formulation to a patient suffering from photophobia and phonophobia, and thereby 

relieving said photophobia and phonophobia within two 

hours of administration. 

30 

25. A method of treating recurrent migraine requiring 24 

hour treatment in a human patient suffering from migraine 

comprising: 

a) providing a pharmaceutical formulation compnsmg 

about 50 mg. of diclofenac or a pharmaceutically acceptable salt thereof in combination with an alkali metal 

carbonate or bicarbonate, wherein greater than 90% of 

said diclofenac dissolves completely in 50 m!. of water 

at 25° C. under continuous stirring for fifteen minutes at 

pH 6.8; 

b) orally administering said formulation to said patient; 

thereby treating said recurrent migraine for at least twenty 

four hours after administration. 

* * * * * 

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