Cadence Pharmaceuticals Et. Al. v. Wockhardt Et. Al

8/13/2019 Cadence Pharmaceuticals Et. Al. v. Wockhardt Et. Al.

1/39

1

LATHAM & WATKINS LLP

Gina R. Gencarelli (Bar No. GG-4858)[email protected]

885 Third Avenue

New York, NY 10022

Telephone: (212) 906-1200Facsimile: (212) 751-4864

Attorneys for PlaintiffCADENCE PHARMACEUTICALS, INC.

HOLLAND & KNIGHT LLP

Charles A. Weiss (Bar No. CW-2628)

[email protected] West 52nd Street

New York, NY 10019

Telephone: (212) 513-3200Facsimile: (212) 385-9010

Attorneys for PlaintiffSCR PHARMATOP

INTHEUNITEDSTATESDISTRICTCOURT

FORTHEDISTRICTOFNEWJERSEY

CADENCE PHARMACEUTICALS, INC. and

SCR PHARMATOP,

Plaintiffs,

v.

WOCKHARDT LIMITED; WOCKHARDT

BIO AG; and WOCKHARDT USA LLC

Defendants.

Civil Action No. ____________

COMPLAINT FOR PATENT

INFRINGEMENT


2/39

2

COMPLAINT

Plaintiffs Cadence Pharmaceuticals, Inc. and SCR Pharmatop (collectively, Plaintiffs) for

their Complaint against defendants Wockhardt Limited, Wockhardt Bio AG, and Wockhardt USA

LLC (collectively, Defendants), allege as follows:

PARTIES

1. Plaintiff Cadence Pharmaceuticals, Inc. (Cadence) is a corporation organized andexisting under the laws of the State of Delaware, having a principal place of business at 12481 High

Bluff Drive, Suite 200, San Diego, California, 92130. As set forth herein, Cadence is the exclusive

licensee of the Patents-in-Suit.

2. Plaintiff SCR Pharmatop (Pharmatop) is a business entity organized and existingunder the laws of the Republic of France, having its headquarters at 10, Square St. Florentin, 78150

Le Chesnay, France. As set forth herein, Pharmatop is the assignee of the Patents-in-Suit.

3. Upon information and belief, defendant Wockhardt Limited is an Indian corporationhaving a principle place of business at Wockhardt Towers, Bandra Kurla Complex, Bandra (East)

Mumbai 400 051, Maharashtra, India. Upon information and belief, Wockhardt Limited is in the

business of manufacturing, distributing, and selling pharmaceutical products throughout the United

States, either on its own or through its affiliates, and Wockhardt Limited regularly conducts business

in New Jersey including in this judicial district.

4. Upon information and belief, defendant Wockhardt Bio AG is a Swiss corporation,having a principal place of business at Baarerstrasse 43, 6300 ZUG, Switzerland. Upon information

and belief, Wockhardt Bio AG is a subsidiary of Wockhardt Limited. Upon information and belief,

Wockhardt Bio AG is in the business of manufacturing, distributing, and selling pharmaceutical

products throughout the United States, either on its own or through its affiliates, and Wockhardt Bio

AG regularly conducts business in New Jersey including in this judicial district.


3/39

3

5. Upon information and belief, defendant Wockhardt USA LLC is a company organizedand existing under the laws of the State of Delaware, with its principal place of business at 20

Waterview Boulevard, 3rd Floor, Parsippany, NJ 07054-1271. Upon information and belief,

Wockhardt USA LLC is a subsidiary of Wockhardt Limited. Upon information and belief,

Wockhardt USA LLC is in the business of manufacturing, distributing, and selling pharmaceutical

products throughout the United States, and Wockhardt USA LLC regularly conducts business in New

Jersey including in this judicial district.

NATURE OF THE ACTION

6. This is a civil action for infringement of United States Patent Nos. 6,028,222 and6,992,218 (collectively, the Patents-in-Suit). This action is based upon the Patent Laws of the

United States, 35 U.S.C. 100 et seq.

JURISDICTION AND VENUE

7. This Court has jurisdiction over the subject matter of this action pursuant to 28 U.S.C. 1331 and 1338(a).

8. This Court has personal jurisdiction over Defendant Wockhardt USA LLC by virtueof, inter alia, the fact that Wockhardt USA LLCs principal place of business is located in the State

of New Jersey.

9. This Court has personal jurisdiction over Defendant Wockhardt Limited because, interalia,Wockhardt Limited has purposefully availed itself of the rights and benefits of New Jersey law

by engaging in systematic and continuous contacts with New Jersey.

10. Upon information and belief, Defendant Wockhardt Limited regularly andcontinuously transacts business within the state of New Jersey, including by selling pharmaceutical

products in New Jersey, either on its own or through its affiliates, including Wockhardt USA LLC.

Upon information and belief, Wockhardt Limited derives substantial revenue from the sale of those


4/39

4

products in New Jersey and has availed itself of the privilege of conducting business within the State

of New Jersey.

11. In addition, Defendant Wockhardt Limited has previously consented to jurisdiction inthis forum for the purpose of litigating patent disputes, and has purposely availed itself of this forum

by asserting counterclaims, in at least the following actions:

Takeda Pharmaceutical Company Ltd. et al. v. Wockhardt Bio AG, WockhardtLimited, and Wockhardt USA LLC, Case No. 13-cv-06427-JAP-TJB, (D.N.J. 2013).

Intelgenx Corp. v. Wockhardt Bio AG, Wockhardt Limited, and Wockhardt USA LLC,Case No. 13-05074 (WJM) (MF), (D.N.J. 2013).

Astrazeneca et al. v. Wockhardt Limited and Wockhardt USA LLC, Case No. 3:13-CV-04854- JAP-TJB (D.N.J. 2013).

Sanofi Aventis U.S. LLC et al. v. Wockhardt LTD, Wockhardt USA LLC andWockhardt USA Inc., Case No. 10-cv-01471-GEB-TJB (D.N.J. 2010).

12. This Court has personal jurisdiction over Defendant Wockhardt Bio AG because, interalia,Wockhardt Bio AG has purposefully availed itself of the rights and benefits of New Jersey law

by engaging in systematic and continuous contacts with New Jersey.

13. Upon information and belief, Defendant Wockhardt Bio AG regularly andcontinuously transacts business within the state of New Jersey, including by selling pharmaceutical

products in New Jersey, either on its own or through its affiliates, including Wockhardt USA LLC.

Upon information and belief, Wockhardt Bio AG derives substantial revenue from the sale of those

products in New Jersey and has availed itself of the privilege of conducting business within the State

of New Jersey.

14. In addition, Defendant Wockhardt Bio AG has previously consented to jurisdiction inthis forum for the purpose of litigating patent disputes, and has purposely availed itself of this forum

by asserting counterclaims, in at least the following actions:

Takeda Pharmaceutical Company Limited et al. v. Wockhardt Bio AG, WockhardtLimited, and Wockhardt USA LLC, Case No. 13-cv-06427-JAP-TJB, (D.N.J. 2013).


5/39

5

Intelgenx Corp. v. Wockhardt Bio AG, Wockhardt Limited, and Wockhardt USA LLC,Case No. 13-05074 (WJM) (MF), (D.N.J. 2013).

15. This Court has personal jurisdiction over Defendants for additional reasons that willbe presented to the Court if such jurisdiction is challenged.

16. Venue is proper in this Court pursuant to 28 U.S.C. 1391 and 28 U.S.C. 1400(b).THE PATENTS-IN-SUIT

17. United States Patent No. 6,028,222 (the 222 Patent), titled Stable LiquidParacetamol Compositions, and Method for Preparing the Same, was duly and legally issued by the

United States Patent and Trademark Office (PTO) on February 22, 2000, to Pharmatop, the

assignee of the named inventors. Pharmatop has been, and continues to be, the sole assignee of the

222 Patent.

18. Pharmatop granted an exclusive license to the 222 Patent to Bristol-Myers SquibbCompany (BMS), with a right to sublicense. BMS in turn granted Cadence an exclusive

sublicense, exclusive even to itself, to the 222 Patent with regard to all rights pertinent hereto. A

true and correct copy of the 222 Patent is attached as Exhibit A.

19. United States Patent No. 6,992,218 (the 218 Patent), titled Method for ObtainingAqueous Formulations of Oxidation-Sensitive Active Principles, was duly and legally issued by the

PTO on January 31, 2006, to Pharmatop, the assignee of the named inventors. Pharmatop has been,

and continues to be, the sole assignee of the 218 Patent.

20. Pharmatop granted an exclusive license to the 218 Patent to BMS, with a right tosublicense. BMS in turn granted Cadence an exclusive sublicense, exclusive even to itself, to the

218 Patent with regard to all rights pertinent hereto. A true and correct copy of the 218 Patent is

attached as Exhibit B.


6/39

6

OFIRMEV

21. Cadence holds approved New Drug Application (NDA) No. 022450 forOFIRMEV, the first and only intravenous (IV) formulation of acetaminophen available in the

United States. OFIRMEV was approved by the FDA on November 2, 2010. OFIRMEV is

indicated for the treatment of mild to moderate pain, management of moderate to severe pain with

adjunctive opioid analgesics, and reduction of fever.

22. The publication Approved Drug Products with Therapeutic Equivalence Evaluations(the Orange Book) identifies drug products approved on the basis of safety and effectiveness by the

FDA under the Federal Food, Drug, and Cosmetic Act. Pursuant to 21 U.S.C. 355(b)(1) and

attendant FDA regulations, the 222 Patent and the 218 Patent were listed in the Orange Book with

respect to OFIRMEV.

DEFENDANTS INFRINGEMENT OF THE PATENTS-IN-SUIT

23. Upon information and belief, Defendant Wockhardt Bio AG submitted AbbreviatedNew Drug Application (ANDA) No. 205746 to the FDA, under the Federal Food, Drug, and

Cosmetic Act (21 U.S.C. 355(j)), seeking approval to engage in the commercial manufacture, use,

sale or offer for sale, and/or importation of acetaminophen solution 10 mg/mL (Wockhardts

Generic Product), as a generic version of the OFIRMEV product, prior to the expiration of the

Patents-in-Suit.

24. On or about December 13, 2013, outside counsel for Pharmatop received a letter datedDecember 12, 2013 on letterhead for Defendant Wockhardt USA LLC, and signed by a

representative of Defendant Wockhardt Limited and addressed to representatives of Cadence and

Pharmatop (the Wockhardt Letter). The Wockhardt Letter states that Defendant Wockhardt Bio

AG had submitted ANDA No. 205746 seeking approval to engage in the commercial manufacture,

use, sale or offer for sale, and/or importation of Wockhardts Generic Product prior to the expiration


7/39

7

of the Patents-in-Suit.

25. The Wockhardt Letter states that ANDA No. 205746 contains a Paragraph IVcertification under 21 U.S.C. 355(j)(2)(A)(vii) which alleges that claims 1-18 of the 222 Patent are

invalid, that Wockhardts Generic Product does not infringe claims 19-28 of the 222 Patent, that the

claims of the 218 Patent are invalid, and that Wockhardts Generic Product will not infringe claims

2, 5-7, 9,10 or 12-18 of the 218 Patent.

26. By filing ANDA No. 205746, Defendant Wockhardt Bio AG has necessarilyrepresented to the FDA that the components of Wockhardts Generic Product have the same active

ingredient as that of the corresponding components of OFIRMEV, have the same route of

administration, dosage form, and strengths as the corresponding components of OFIRMEV, and are

bioequivalent to the corresponding components of OFIRMEV.

27. Defendant Wockhardt Bio AGs submission of ANDA No. 205746 to the FDA,including the 355(j)(2)(A)(vii)(IV) allegations, constitutes infringement of the Patents-in-Suit under

35 U.S.C. 271(e)(2)(A). Moreover, in the event that Defendants commercially manufacture,

import, use, offer for sale, or sell Wockhardts Generic Product or induce or contribute to such

conduct, said actions would constitute infringement of the Patents-in-Suit under 35 USC 271(a), (b)

and/or (c).

28. Defendants Wockhardt Limited, Wockhardt Bio AG, and Wockhardt USA LLC arejointly and severally liable for infringement of the Patents-in Suit. Upon information and belief,

Wockhardt Limited, Wockhardt Bio AG, and Wockhardt USA LLC participated in, contributed to,

aided, abetted, and/or induced Wockhardt Bio AGs submission of ANDA No. 205746 and its section

355(j)(2)(A)(vii)(IV) allegations to the FDA.

29. Defendants were aware of the Patents-in-Suit prior to filing ANDA No. 205746, andtheir actions render this an exceptional case under 35 U.S.C. 285.


8/39

8

30. The acts of infringement by Defendants set forth above will cause Plaintiffsirreparable harm for which they have no adequate remedy at law, and will continue unless enjoined

by this Court.

COUNT I

(Infringement of the 222 Patent by Defendants)

31. Plaintiffs incorporate each of the preceding paragraphs 1 to 30 as if fullyset forth herein.

32. Defendant Wockhardt Bio AGs submission of ANDA No. 205746, including its 355(j)(2)(A)(vii)(IV) allegations, constitutes infringement of the 222 Patent pursuant to 35 U.S.C.

271(e)(2) by Defendants.

33. Upon FDA approval of ANDA No. 205746, Defendants will infringe the 222 Patentby making, using, offering to sell, or selling Wockhardts Generic Product in the United States and/or

importing Wockhardts Generic Product into the United States, and by actively inducing and/or

contributing to infringement by others, in violation of 35 U.S.C. 271(a), (b), and/or (c).

34. Upon information and belief, Defendants had actual and constructive knowledge ofthe 222 Patent prior to filing ANDA No. 205746 and acted without a reasonable basis for a good

faith belief that they would not be liable for infringing the 222 Patent.

COUNT II

(Declaratory Judgment of Infringement of the 222 Patent by Defendants)

35. Plaintiffs incorporate each of the preceding paragraphs 1 to 34 as if fullyset forth herein.

36. This claim arises under the Declaratory Judgment Act, 28 U.S.C. 2201 and 2202.37. Plaintiffs are further entitled to a declaration that, if Defendants, prior to patent expiry,

commercially manufacture, use, offer for sale, or sell Wockhardts Generic Product within the United

States, import Wockhardts Generic Product into the United States, or induce or contribute to such


9/39

9

conduct, Defendants would infringe the 222 Patent under 35 U.S.C. 271(a), (b), and/or (c).

38. Plaintiffs will be irreparably harmed by Defendants infringing activities unless thoseactivities are enjoined by this Court. Plaintiffs do not have an adequate remedy at law.

COUNT III

(Infringement of the 218 Patent by Defendants)

39. Plaintiffs incorporate each of the preceding paragraphs 1 to 38 as if fully set forthherein.

40. Defendant Wockhardt Bio AGs submission of ANDA No. 205746, including the 355 (j)(2)(A)(vii)(IV) allegations, constitutes infringement of the 218 Patent pursuant to 35 U.S.C.

271(e)(2) by Defendants.

41. Upon FDA approval of ANDA No. 205746, Defendants will infringe the 218 Patentby making, using, offering to sell, or selling Wockhardts Generic Product in the United States and/or

importing Wockhardts Generic Product into the United States, and by actively inducing and/or

contributing to infringement by others, in violation of 35 U.S.C. 271(a), (b), and/or (c).

42. Upon information and belief, Defendants had actual and constructive knowledge ofthe 218 Patent prior to filing ANDA No. 205746 and acted without a reasonable basis for a good

faith belief that they would not be liable for infringing the 218 Patent.

COUNT IV

(Declaratory Judgment of Infringement of the 218 Patent by Defendants)

43. Plaintiffs incorporate each of the preceding paragraphs 1 to 42 as if fully set forthherein.

44. This claim arises under the Declaratory Judgment Act, 28 U.S.C. 2201 and 2202.45. Plaintiffs are further entitled to a declaration that, if the Wockhardt Defendants, prior

to patent expiry, commercially manufacture, use, offer for sale, or sell Wockhardts Generic Product

within the United States, import Wockhardts Generic Product into the United States, or induce or


10/39


11/39

11

or any other product that infringes or induces or contributes to the infringement of the Patents-in-

Suit, within the United States before the latest expiration date of any of the Patents-in-Suit, including

any extensions and/or additional periods of exclusivity to which Plaintiffs are or become entitled;

F. A declaration that this is an exceptional case and an award of its reasonable expenses,including attorneys fees pursuant to 35 U.S.C. 285;

G. An award of costs and expenses in this action; andH. Such other and further relief as the Court may deem just and proper.

Dated: January 23, 2014 LATHAM & WATKINS LLP

By: s/ Gina R. Gencarelli____________Gina R. Gencarelli

Attorneys for Plaintiff

Cadence Pharmaceuticals, Inc.


By: s/ Charles A. Weiss____________

Charles A. Weiss


SCR Pharmatop


12/39

12

LOCAL CIVIL RULE 11.2 CERTIFICATION

Pursuant to Local Civil Rule 11.2, I hereby certify that that infringement of the patents at

issue in the above-captioned action is also the subject of Cadence Pharm., et al. v. Paddock Labs.,

Inc., et al., 11-cv-733-LPS (D. Del.); Cadence Pharm. Inc., et al. v. Fresenius Kabi USA, LLC, 13-

cv-139-LAB-MDD (S.D. Cal.); Cadence Pharm., Inc., et al. v. Fresenius Kabi USA, LLC, 13-cv-453

(N.D. Ill.); Cadence Pharm., Inc., et al. v. Sandoz Inc., 13-cv-278-JAH-BLM (S.D. Cal.); and

Cadence Pharm., Inc., et al. v. Wockhardt Limited, et al., 14-cv-94 (D. Del.). The plaintiffs are the

same in each of these actions. The defendants in the 11-cv-733-LPS Delaware action naming

Paddock Labs. as defendant were or are Paddock Laboratories, Inc., Perrigo Company, Paddock

Laboratories, LLC, Exela Pharma Sciences, Exela PharmSci, Inc., Exela Holdings, Inc. The

defendants in the Delaware action naming Wockhardt Limited as defendant are Wockhardt Limited,

Wockhardt Bio AG, and Wockhardt USA LLC. Fresenius Kabi USA, LLC is the sole defendant in

the Illinois and California actions naming Fresenius Kabi USA, LLC as defendant. Sandoz Inc. is the

sole defendant in the California action naming Sandoz Inc. as defendant. Claims 1-6 and 9-19 of

U.S. Patent No. 6,028,222 are the subject of reexamination at the United States Patent and Trademark

Office, assigned Reexamination Control No. 90/012,606. I further certify that infringement of the

patents at issue in the above-captioned action to the best of my knowledge is not the subject of any

other action pending in any court, or of any pending arbitration or administrative proceeding.

Dated: January 23, 2014 LATHAM & WATKINS LLP

By: s/ Gina R. Gencarelli____________

Gina R. Gencarelli


Cadence Pharmaceuticals, Inc.


13/39

13


By: s/ Charles A. Weiss____________

Charles A. Weiss

Attorneys for PlaintiffSCR Pharmatop


14/39

EXHIBIT A


15/39

US006028222AUlllted States Patent [ 1 9 ] [ 1 1 ] P a t e n t N u m b e r : 6 , 0 2 8 , 2 2 2D i e t l i n e t a l . [ 4 5 ] Date o f P a t e n t : F e b . 2 2 , 2000[ 5 4 ] STABLE LIQUID P R CET MOL 4 , 8 5 5 , 3 2 6 8 / 1 9 8 9 F u i s Z . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 514/777

COMPOSITIONS NDMETHODFOR 5 , 6 5 8 , 9 1 9 8 / 1 9 9 7 R a t n a r a j e t a l . . . . . . . . . . . . . . . . . . . . . . . 5 1 4 / 2 6 9PREPARING SAME

FOREIGN PATENTDOCUMENTS[ 7 5 ] I n v e n t o r s : F r a n c o i s D i e t l i n , L e P e c q ; D a n i e l eF r e d j , G i f - s u r - Y v e t t e , both o f France 9523595 9 / 1 9 9 5 WIPO

[ 7 3 ] A s s i g n e e : SCR P h a r m a t o p , F r a n c e OTHER PUBLICATIONS

[ 8 6 ] PCT N O . Z PCT/FR97/01452 XP 0 0 2 0 4 5 7 4 0 , 1 9 8 3 D a t e : J u n . 5 ,1 02 ( e ) D a t e : J u n . 5 , 1 9 9 8

[ 8 7 ] PCT P u b , N o , : WO98/05 3 1 4 P r i m a r y E x a m i n e r S h a i l e n d r a KumarA t t o r n e y , A g e n t , o r FirmBierman M u s e r l i a n a n d L u c a sPCT P u b . D a t e : F e b . 1 2 , 1 9 9 8_ _ [57] BSTR CT[ 3 0 ] F o r e i g n A p p l i c a t i o n P r i o r i t y D a t a

A u g . 5 , 1 9 9 6 [ F R ] F r a n c e . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 6 0 9 8 5 8 N o v e l S t a b l e p a r a c e t a m q l composmogs o r u s e 1 t h e r a p e l lt 1 c c h e m i s t r y a n d s p e c l ? c a l l y g a l e m c p h a r m a c y a r e d i s[ 5 1 ] I n t . C l . 7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C07C 09/90 c l o s e d . The compositions c o n t a i n a s o l u t i o n o f paracetamol[ 5 2 ] US. l . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 6 4 / 4 ; 514/617; 5 6 4 / 2 ; i n an aqueous s o l v e n t Combined With a b u f f e r having a pH

5 6 4 / 5 ; 5 6 4 / 6 ; 5 6 4 / 7 ; 5 6 4 / 2 2 3 o f 4 t o 8 , a n d a f r e e r a d i c a l c a p t u r i n g a g e n t . A a t e r[ 5 8 ] F i e l d O f Search . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 6 4 / 4 , 5 , 6 , 7 , i n s o l u b l e i n e r t g a s i s C a r e f u l l y b u b b l e d t h r o u g h t h e a 9 1 1 9 9 1 1 5

5 6 4 / 2 , 2 2 3 ; 514/617 s o l v e n t t o remove oxygen from t h e medium. S a i d c omp os i t i o n s m a y a l s o b e combined W i t h a c e n t r a l l y o r p e r i p h e r

[ 5 6 ] R e f e r e n c e s C i t e d a l l y a c t i n g a n a l g e s i c a g e n t , a n d a r e p r o v i d e d a s i n j e c t a b l ec o m p o s i t i o n s f o r r e l i e v i n g p a i n .U . S . PATENTDOCUMENTS

4 , 7 2 7 , 0 6 4 2 / 1 9 8 8 P i t h a . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 1 4 / 5 8 28 Claims N0 D r a w i n g s


16/39

6 , 0 2 8 , 2 2 21

STABLE LIQUID PARACETAMOLCOMPOSITIONS, AND METHOD FORPREPARING SAME

T h i s a p p l i c a t i o n i s 3 7 1 o f PCT/FR97/01452, ? l e d A u g .5 , 1 9 9 7 .

FIELD OF THE INVENTIONT h e p r e s e n t i n v e n t i o n r e l a t e s t o n o v e l s t a b l e , l i q u i d ,

a n a l g e s i c f o r m u l a t i o n s , c o n t a i n i n g p a r a c e t a m o l a s m a i na c t i v e i n g r e d i e n t , e i t h e r i n combination o r n o t , W i t h a na n a l g e s i c d e r i v a t i v e .

DISCUSSION OF THE PRIOR ARTI t h a s be e n knoWn f o r m a n y y e a r s and n o t a b l y from a

p a p e r o f FAIRBROTHER . E . e n t i t l e d : A c e t a m i n o p h e n ,p u b l i s h e d i n A n a l y t i c a l P r o ? l e s o f D r u g S u b s t a n c e s 1 9 7 4 ) ,volume 3 , p p . 1 1 0 9 , t h a t p a r a c e t a m o l i n t h e p r e s e n c e o fm o i s t u r e , a n d a l l t h e m o r e i n a q u e o u s s o l u t i o n , m a y b eh y d r o l y s e d t o y i e l d p - a m i n o p h e n o l , W h i c h c o m p o u n d mayi t s e l f b e b r o k e n d oW n i n t o q u i n o n e - i m i n e . The r a t e o fd e c o m p o s i t i o n o f p a r a c e t a m o l i s e n h a n c e d a s t h e t e m p e r at u r e i s i n c r e a s e d a n d u p o n e x p o s u r e t o l i g h t .

I n a d d i t i o n , t h e i n s t a b i l i t y o f p a r a c e t a m o l i n a q u e o u ss o l u t i o n a s a f u n c t i o n o f t h e s o l u t i o n s pH a s b een e x t e ns i v e l y d e s c r i b e d . T h u s , a c c o r d i n g t o a p a p e r e n t i t l e d S t ab i l i t y o f a q u e o u s s o l u t i o n o f N - a c e t y l - p - a m i n o p h e n o l (KOSHY . T . a n d LACH . I J . P h a r m . S c i , 5 0 ( 1 9 6 1 ) , p p .1 1 3 1 1 8 ) , p a r a c e t a m o l i n a q u e o u s s o l u t i o n i s u n s t a b l e , a f a c tW h i c h p r i m a r i l y c o r r e l a t e s W i t h h y d r o l y s i s b o t h i n a c i d i c a n db a s i c e n v i r o n m e n t . T h i s bre akd oWn p r o c e s s i s m i n i m a l t apH c l o s e t o 6 , t h e h a l f - l i f e o f t h e p r o d u c t t h u s d e g r a d e dn a m ely b e i n g a s h i g h a s 2 1 . 8 y e a r s a t 2 5 C .

A c c o r d i n g t o A r r h e n i u m l a W a n d k n o W i n g t h e s p e c i ? cr e a c t i o n c o n s t a n t a s d e t e r m i n e d by t h e s e a u t h o r s , t h e t i m en eeded t o o b s e r v e a 5 e c r e a s e i n p a r a c e t a m o l c o n c e n t r at i o n o f a n a q u e o u s s o l u t i o n s t o r e d a t 2 5 C . a t t h e o p t i m a l p Ha s been p r e d i c t e d t o b e 1 9 m o n t h s . B e s i d e s h y d r o l y s i s , t h ep a r a c e t a m o l m o l e c u l e s e p a r a t e l y u n d e r g o e s a n o t h e r k i n d o fd e c o m p o s i t i o n t h a t i n v o l v e s f o r m a t i o n o f a q u i n o n e - i m i n et h a t may r e a d i l y p o l y m e r i Z e W i t h g e n e r a t i o n o f n i t r o g e nc o n t a i n i n g p o l y m e r s .

T h e s e p o l y m e r s a n d i n p a r t i c u l a r t h o s e s t e m m i n g f r o mN - a c e t y l - p - b e n Z o q u i n o n e - i m i n e h a v e b e e n f u r t h e r d e s c r i b e da s b e i n g t h e t o x i c m e t a b o l i t e o f p a r a c e t a m o l , Which i se n d o W e d n o t a b l y W i t h c y t o t o x i c a n d h e m o l y t i c e f f e c t . T h ed e c o m p o s i t i o n o f t h i s m e t a b o l i t e i n a q u e o u s m e d i u m s s t i l lm o r e c o m p l e x a n d g i v e s r i s e t o p - b e n Z o q u i n o n e a n d h y dr o q u i n o n e D . DAHLIN, J M e d . C h e m . , 2 5 ( 1 9 8 2 ) ,8 8 5 8 8 6 ) .

I n t h e c u r r e n t s t a t e o f t h e a r t and i n vieW o f t h e q u a l i t yc o n t r o l r e q u i r e m e n t s s p e c i ? c t o p h a r m a c e u t i c a l p r a c t i c er e g u l a t i o n s , t h e s t a b i l i t y o f p a r a c e t a m o l i n a q u e o u s s o l u t i o n si s t h u s i n s u f ? c i e n t and d o e s n o t a l l o W t h e f o r m u l a t i o n o fl i q u i d p h a r m a c e u t i c a l c o m p o s i t i o n s f o r i n j e c t i o n . As ar e s u l t , t h e s u c c e s s f u l p r e p a r a t i o n o f l i q u i d p h a r m a c e u t i c a lf o r m u l a t i o n s f o r p a r e n t e r a l a d m i n i s t r a t i o n , b a s e d onp a r a c e t a m o l , h a s n o t b e e n a c h i e v e d .

A n u m b e r f t r i a l s h a s be e n u n d e r t a k e n t o sloW d o W n h ed e c o m p o s i t i o n o f p a r a c e t a m o l i n a q u e o u s s o l u t i o n . T h u s , i na p a p e r e n t i t l e d : S t a b i l i z a t i o n by t h y l e n e d i a m i n e t e t r a a c e t i c

10

1 5

20

25

35

40

45

55

60

2h y d r o l y s i s o f p a r a c e t a m o l , a p p r o x i m a t i n g 1 9 , 8 o f t h ei n i t i a l c o n c e n t r a t i o n o f p a r a c e t a m o l , a s o b s e r v e d a f t e r s t o ra g e i n t h e d a r k d u r i n g 120 d a y s . A d d i t i o n o f EDTA t a r a t ed e 0.0075 b r i n g s d oW n t h e d e c o m p o s i t i o n r a t e t o 7 . Ont h e o t h e r h a n d , d i s t i l l i n g a n a l k a l i n e s o l u t i o n o f p a r a c e t a m o lr e s u l t s i n an a m m o n i a c o n c e n t r a t i o n o f 14 , i n p r e s e n c e o rn o t o f 1000 p p m o f a s c o r b i c a c i d . OWing t o i t s p r o p e r t i e s ,a s c o r b i c a c i d i s i n d e e d q u i t e a d a p t e d t o s u c h s t a b i l i Z a t i o n .H o W e v e r , upon e x p o s u r e t o b r i g h t l i g h t , a p a r a c e t a m o ls o l u t i o n c o n t a i n i n g 1000 p p m f a s c o r b i c a c i d d o e s a f t e r a l lg e n e r a t e a m m o n i a i t h a y i e l d o f 98 . I n c o n t r a s t , a d d i t i o no f EDTA (0.0075 ) t o s u c h a s o l u t i o n c u t s d o W n d e c o mp o s i t i o n r a t e , W i t h a n a m m o n i a y i e l d n o t h i g h e r t h a n 1 4 .

D e s p i t e o f s u c h e f f o r t s , i t h a s n o t b e e n p o s s i b l e t o p r e p a r ea q u e o u s l i q u i d s o l u t i o n s o f p a r a c e t a m o l . I n p a r t i c u l a r s o l ut i o n s f o r i n j e c t i o n , h a v i n g a g u a r a n t e e d s t a b i l i t y .

SUMMARY OF THE INVENTIONThe r e s e n t i n v e n t i o n i s a i m e d a t s o l v i n g t h e a b o v e s t a t e d

proble m i n a n a p p r o p r i a t e m a n n e r . I t i s d i r e c t e d t o s t a b l ep h a r m a c e u t i c a l c o m p o s i t i o n s o f p a r a c e t a m o l i n a n a q u e o u ss o l v e n t h a v i n g a d d e d t h e r e t o a f r e e r a d i c a l a n t a g o n i s t . Theaq ue ous s o l v e n t may b e Water o r e l s e aq ue ous mixturesc o n t a i n i n g W a t e r a n d a p o l y h y d r i c c o m p o u n d s u c h a sp o l y e t h y l e n e - g l y c o l ( P E G ) 3 0 0 , 4 0 0 , 1 0 0 0 , 1 5 4 0 , 4 0 0 0 o r8 0 0 0 , p r o p y l e n e g l y c o l o r t e t r a g l y c o l . A W a t e r - s o l u b l e a l c an o l s u c h a s f o r example e t h a n o l m ay a l s o b e u s e d .

DETAILED DESCRIPTION OF THEINVENTION

S t a b i l i t y o f t h e a q u e o u s s o l u t i o n s m e n t i o n e d a b o v e d o e sn o t s o l e l y depend on t h e c h o i c e o f a g i v e n c a r r i e r . I t a l s od e p e n d s o n o t h e r v a r i a b l e s , s u c h a s c a r e f u l a d j u s t m e n t o fpH, r e m o v a l o f oxygen d i s s o l v e d i n t h e c a r r i e r a n d a d d i t i o nof a f r e e r a d i c a l a n t a g o n i s t o r a f r e e r a d i c a l s c a v e n g e r .

R e m o v a l o f d i s s o l v e d o x y g e n i s r e a d i l y a c c o m p l i s h e d b yb u b bl i n g a n i n e r t g a s a n d p r e f e r a b l y b y b u b b l i n g n i t r o g e n .

The a p p r o p r i a t e f r e e r a d i c a l a n t a g o n i s t i s c h o s e n amongt h e d e r i v a t i v e s o f a s c o r b i c a c i d , t h o s e d e r i v a t i v e s b e a r i n g a tl e a s t a t h i o l f u n c t i o n a l g r o u p and s t r a i g h t c h a i n o r c y c l i cp o l y h y d r i c c o m p o u n d s .

P r e f e r r e d a s c o r b i c a c i d d e r i v a t i v e s a r e D- o r L-ascorbica c i d , a n a l k a l i m e t a l a s c o r b a t e , a n a l k a l i n e e a r t h m e t a lasc or b a t e o r e v e n t i l l a n a q u e o u s me d i u m- s o l u b l e asc or b i ca c i d e s t e r .

F r e e r a d i c a l s c a v e n g e r s , b e a r i n g a t h i o l f u n c t i o n a l g r o u pm a y be an o r g a n i c c o m p o u n d s u b s t i t u t e d by one o r m o r et h i o l f u n c t i o n a l g r o u p s , o f t h e a l i p h a t i c s e r i e s s u c h a sc y s t e i n , a c e t y l c y s t e i n , t h i o g l y c o l l i c a c i d a n d s a l t s t h e r e o f ,t h i o l a c t i c a c i d a n d s a l t s t h e r e o f , d i t h l o t h r e l t o l , r e d u c e dg l u t a t h i o n , t h i o u r e a , t h i o g l y c e r o l , m e t h i o n i n e a n d m e r c a pt o e t h a n e s u l f o n i c a c i d .

The p o l y o l u s e d a s a f r e e r a d i c a l s c a v e n g e r i s p r e f e r a b l ya s t r a i g h t c h a i n o r a c y c l i c , polyhydroxy a l c o h o l such a sm a n n i t o l , s o r b i t o l , i n o s i t o l , i s o s o r b i d e , g l y c e r o l , g l u c o s e a n dp r o p y l e n e - g l y c o l s .Among r e e r a d i c a l s c a v e n g e r s r e q u i r e d p o u r s t a b i l i Z i n g

p a r a c e t a m o l , t h e a s c o r b i c a c i d d e r i v a t i v e c u r r e n t l y p r e f e r r e di s sodi u m a s c o r b a t e . P r e f e r r e d t h i o l f u n c t i o n a l g r o u p s u bs t i t u t e d d e r i v a t i v e s a r e c y s t e i n , r e d u c e d - s l a t e g l u t a t h i o n ,N - a c e t y l c y s t e i n a n d m e r c a p t o e t h a n e s u l f o n i c a c i d .I t m a y appear a s convenient t o c o m b i n e s e v e r a l f r e e


17/39

6 , 0 2 8 , 2 2 23

I t may a p p e a r a s convenient t o add t o t h e p r e p a r a t i o n o n eo r a number o f c o m p l e x i n g a g e n t s t o i m p r o v e s t a b i l i t y o f t h em o l e c u l e s i n c e t h e a c t i v e i n g r e d i e n t i s s e n s i t i v e t o t h ep r e s e n c e o f t r a c e m e t a l s t h a t e v e n t u a l l y s p e e d u p i t s d e c a y .

C o m p l e x i n g a g e n t s a r e e x e m p l i ? e d b y n i t r i l o t r i a c e t i ca c i d , e t h y l e n e d i a m i n o t e t r a a c e t i c a c i d , e t h y l e n e d i a m i n o , N ,N - d i a c e t i c - N , N - d i p r o p i o n i c a c i d , e t h y l e n e d i a m i n o t e t r ap h o s p h o n i c a c i d , 2 , 2 - e t h y l e n e d i a m i n o ) d i b u t y r i c a c i d , o re t h y l e n e - g l y c o l b i s ( d i a m i n o e t h y l e t h e r ) N , N , N , N t e t r a a c e t i c a c i d and sodium o r c a l c i u m s a l t s t h e r e o f .

The c o m p l e x i n g a g e n t a l s o a c t s t o c o m p l e x b i v a l e n t i o n s( c o p p e r , Z i n c , c a l c i u m ) t h a t may b e p r e s e n t a n d t h a t h a v e an e g a t i v e i n ? u e n c e o f t h e a g i n g o f t h e f o r m u l a t i o n t h r o u g ho u t s t o r a g e .

T h e g a s t h a t i s bubbled i n t o t h e s o l u t i o n t o d r i v e o u toxygen, may be n i t r o g e n o r carbon d i o x i d e o r s t i l l a n i n e r tg a s . N i t r o g e n i s f a v o u r e d .

I s o t o n i c i t y o f t h e p r e p a r a t i o n may b e a c h i e v e d b y a d d i n ga n a p p r o p r i a t e q u a n t i t y o f s o d i u m c h l o r i d e , g l u c o s e , l e v ul o s e o r p o s t a s s i u m c h l o r i d e , o r c a l c i u m c h l o r i d e , o r c a l c i u mg l u c o n o g l u c o h e p t o n a t e , o r m i x t u r e s t h e r e o f . The p r e f e r r e di s o t o n i Z i n g a g e n t i s s o d i u m c h l o r i d e .

The b u f f e r u s e d i s a b u f f e r c o m p a t i b l e W i t h p a r e n t e r a la d m i n i s t r a t i o n i n h u m a n s , t h e p H o f W h i c h may b e a d j u s t e dbe tWe e n 4 and 8 . P r e f e r r e d b u f f e r s a r e based o n a l k a l i metalo u a l k a l i n e e a r t h metal a c e t a t e s o r phosphates. o r ep r e f e r r e d b u f f e r i s s o d i u m a c e t a t e / h y d r o g e n e p h o s p h a t ea d j u s t e d t o t h e r e q u i r e d p H W i t h h y d r o c h l o r i c a c i d o rsodium h y d r o x i d e . T h e c o n c e n t r a t i o n o f s u c h a b u f f e r m a yb e c o m p r i s e d b e t W e n n 0 . 1 a n d 1 0 m g / m l . T h e p r e f e r r e dc o n c e n t r a t i o n i s con?ned i n t h e r a n g e o f 0 . 2 5 t o 5 m g / m l .

On t h e o t h e r h a n d , p r e p a r a t i o n s f o r i n j e c t i o n h a v e t o b es t e r i l e and s h o u l d l e n d t h e m s e l v e s t o h e a t t r e a t m e n t s t e r i li Z a t i o n . I t i s knoW n t h a t i n c e r t a i n c o n d i t i o n s , a n t i o x i d a n t ss u c h a s g l u t a t h i o n a r e b r o k e n d o W n ]FIALAIRC A . e t a l . , J .P h a r m . B i o m e d . A n a L , v o l . 1 0 , No 6 , p p . 4 5 7 4 6 0 ( 1 9 9 2 ) ] .The breakdoWn o f r e d u c e d g l u t a t h i o n d u r i n g h e a t t r e a t m e n ts t e r i l i Z a t i o n r a n g e s from 40 t o 77 depending o n t h es e l e c t e d t e m p e r a t u r e c o n d i t i o n s . D u r i n g s u c h s t e r i l i Z a t i o np r o c e d u r e s , i t i s c o n v e n i e n t t o employ means c a p a b l e o fp r e s e r v i n g t h e i n t e g r i t y o f t h e s e a n t i o xi d a n t s . A d d i t i o n o fc o m p l e x i n g a g e n t s t o a q u e o u s s o l u t i o n s i n h i b i t s t h e r m a ld e c o m p o s i t i o n o f t h i o l d e r i v a t i v e s , s u c h a s g l u t a t h i o n .

L i q u i d p h a r m a c e u t i c a l c o m p o s i t i o n s a c c o r d i n g t o t h ei n v e n t i o n a r e p r e f e r a b l y c o m p o s i t i o n s i n t e n d e d f o r i n j e c t i o n .T h e p a r a c e t a m o l c o n t e n t o f t h e s o l u t i o n m a y r a n g e from 2mg/ml t o 50 mg/ml i n c a s e o f s o c a l l e d d i l u t e s o l u t i o n s , i et h a t c a n b e d i r e c t l y i n f u s e d by i n t r a v e n o u s r o u t e a n d from 60mg/ml t o 3 5 0 mg/ml W h e r e s o - c a l l e d c o n c e n t r a t e d s o l u t i o na r e c o n s i d e r e d , i . e . e i t h e r i n t e n d e d f o r d i r e c t i n j e c t i o n byi n t r a v e n o u s o r i n t r a m u s c u l a r r o u t e , o r intended t o be d i l u t e dp r i o r t o s l o W i n f u s i o n a d m i n i s t r a t i o n . The p r e f e r r e d c o n c e nt r a t i o n s a r e c o m p r i s e d b e t W e e n 5 a n d 20 mg/ml f o r d i l u t es o l u t i o n s a n d b e t W e e n 1 0 0 a n d 250 mg/ml f o r c o n c e n t r a t e ds o l u t i o n s .

P h a r m a c e u t i c a l c o m p o s i t i o n s a c c o r d i n g t o t h e i n v e n t i o nm a y f u r t h e r c o n t a i n a n o t h e r a c t i v e i n g r e d i e n t t h a t e n h a n c e st h e s p e c i ? c e f f e c t o f p a r a c e t a m o l .I n p a r t i c u l a r , t h e p h a r m a c e u t i c a l c o m p o s i t i o n s a c c o r d i n g

t o t h e i n v e n t i o n m a y c o n t a i n a CNS-acting a n a l g e s i c s u c h a sf o r e x a m p l e a m o r p h i n i c a n a l g e s i c .

10

1 5

20

25

30

35

40

45

50

55

60

4d r a m a d o l , c o d e i n e , d e x t r o m o r a m i d e , d e x t r o p r o p o x y p h e n e ,h y d r o c o d o n e , h y d r o m o r p h o n e , k e t o b e m i d o n e ,l e v o m e t h a d o n e , l e v o r p h a n o l , m e p t a Z i n o l , m e t h a d o n e ,m o r p h i n e , n a l b u p h i n e , n i c o m o r p h i n e , d i Z o c i n e ,d i a m o r p h i n e , d i h y d r o c o d e i n e , d i p i p a n o n e , m e t h o r p h a n e ,d e x t r o m e t h o r p h a n e .P r e f e r r e d morphinic d e r i v a t i v e s a r e c o d e i n e s u l f a t e o rm o r p h i n e h y d r o c h l o r i d e .

T h e codeine o r codeine d e r i v a t i v e c o n c e n t r a t i o n ,e x p r e s s e d i n t e r m s o f c o d e i n e b a s e , i s c o m p r i s e d b e t W e e n0.2 a n d 2 5 i n r e l a t i o n t o t h e p a r a c e t a m o l c o n t e n t . T h ep r e f e r r e d c o d e i n e d e r i v a t i v e i s c o d e i n e s u l f a t e . T h e concent r a t i o n t h e r e o f i s s e t betWeen 0 . 5 and 1 5 i n r e l a t i o n t o t h ep a r a c e t a m o l c o n t e n t .

T h e m o r p h i n e o r m o r p h i n e d e r i v a t i v e c o n c e n t r a t i o n ,e x p r e s s e d i n t e r m s o f m o r p h i n e b a s e , i s c o m p r i s e d b e t W e e n0 . 0 5 a n d 5 i n r e l a t i o n t o t h e p a r a c e t a m o l c o n t e n t . T h ep r e f e r r e d m o r p h i n e d e r i v a t i v e i s m o r p h i n e h y d r o c h l o r i d et h e c o n c e n t r a t i o n o f Which i s p r e f e r a b l y s e t betWeen 0 . 5 a n d1 5 i n r e l a t i o n t o p a r a c e t a m o l c o n t e n t .

The c o m p o s i t i o n s a c c o r d i n g t o t h e i n v e n t i o n m ay f u r t h e rhave added t h e r e t o a n a n t i - i n ? a m m a t o r y a g e n t s u c h a s o f t h eo f AINS t y p e a n d i n p a r t i c u l a r a p h e n y l a c e t i c a c i d c o mp o u n d . S u c h a g e n t s a r e e x e m p l i ? e d b y k e t o p r o f e n ,? u r b i p r o f e n , t i a p r o f e n i c a c i d , n i ? u m i c a c i d , d i c l o f e n a c o rn a p r o x e n .

C o m p o s i t i o n s a c c o r d i n g t o t h e i n v e n t i o n m ay i n a d d i t i o ni n c o r p o r a t e a n a n t i e m e t i c e i t h e r a C N S - a c t i n g n e u r o l e p t i csuch a s h a l o p e r i d o l o r chlorpromaZine o r me to p ima Zin e o ro f t h e g a s t r o k i n e t i c - m e d i a t e d t y p e s u c h a s m e t o c h l o p r a m i d eo r d o m peri d o n e o r e v e n a s e r o t o n i n e r g i c a g e n t .

C o m p o s i t i o n s i n a c c o r d a n ce W i t h t h e i n v e n t i o n may f u rt h e r i n c o r p o r a t e a n a n t i - e p i l e p t i c d r u g s u c h a s sodiumv a l p r o a t e , c l o n a Z e p a m, c a r b a ma Z e p i n e o r p h e n y t o i n .

I t m a y a l s o b e p o s s i b l e t o com b ine p a r a c e t a m o l W i t h ac o r t i c o s t e r o i d s u c h a s f o r e x a m p l e p r e d n i s o n e , p r e d n i s o l o n e ,m e t h y l p r e d n i s o n e , d e x a m e t h a s o n e , b e t a m e t a s o n e o r a ne s t e r t h e r e o f .

Paracetamol can f u r t h e r be c o mbi n ed With a t r i c y c l i ca n t i d e p r e s s a n t s u c h a s a m i t r i p t i l i n e , i m i p r a m i n e , c l o m ip r a m i n e .

A n t i - i n ? a m m a t o r y a g e n t s may b e i n c l u d e d i n c o n c e n t r at i o n s r a n g i n g from 0 . 1 0 0 g t o 0 . 5 0 0 g p e r 1000 ml o ff o r m u l a t e d p r o d u c t .

I n Case o f C o n c e n t r a t e d S o l u t i o n sThe W a t e r c o n t e n t e x p r e s s e d i n p e r c e n t a g e i s p r e f e r a b l y i n

e x c e s s o f 5 o f t h e t o t a l v o l u m e and m o r e p r e f e r a b l yc o m p r i s e d b e t W e e n 1 0 a n d 6 5 .

T h e q u a n t i t y o f p r o p y l e n e g l y c o l f o r m u l a t e d i n p e r c e n ta g e i s p r e f e r a b l y i n e x c e s s o f 5 a n d mo re p r e f e r a b l yc o m p r i s e d b e t W e e n 2 0 a n d 50 .

The PEG u s e d i s p r e f e r a b l y PEG 3 0 0 , PEG 4 0 0 , PEG1 0 0 0 , PEG 1540 o r PEG 4000. C o n c e n t r a t i o n s used a r ec o m p r i s e d b e t W e e n 1 0 a n d 6 0 i n W e i g h t . PEG 3 0 0 a n dPEG 400 a r e f u r t h e r p r e f e r r e d . P r e f e r r e d c o n c e n t r a t i o n sr a n g e fro m 20 t o 6 0 .

E t h a n o l c o n c e n t r a t i o n s r a n g e from 0 t o 3 0 o f t o t a lv o lume a n d p r e f e r a b l y r a n g e from 0 t o 2 0 .

T e t r a g l y c o l c o n c e n t r a t i o n s u s e d do n o t e x c e e d 1 5 t oa l l o W f o r maximal q u a n t i t i e s t h a t c a n d a i l y b e r e c e i v e d b y


18/39


19/39

6 , 0 2 8 , 2 2 2

S o l u b i l i t y S o l u b i l i t yT e s t Water P r o p y l e n e - PEG 400 T e t r a g l y c o l a t + 4 0 C . a t + 2 5 0 C .n ( m l ) g l y c o l ( m l ) ( m l ) E t h a n o l ( m l ) ( m g / m l ) ( m g / m l )

1 0. 3 0. 4 0. 3 110 1302 0. 4 0. 3 0. 3 110 1303 0.16 0.3 0.4 0.15 190 2304 0.5 0.5 110 1505 0.4 0.3 0.2 0 . 1 < 1 1 0 12 06 0.5 0.3 0 . 1 0 . 1 < 1 0 0 1307 0.4 0.4 0 . 1 0 . 1 < 1 0 0 1 5 08 0.5 0.3 0.2 < 1 0 0 12 09 0.6 0.3 0.2


20/39


21/39

6 , 0 2 8 , 2 2 21 1

EXAMPLE I IS t a b i l i z i n g p a r a c e t a m o l s o l u t i o n b y s e l e c t i n g t h epH t h a t a l l o w s m a x i m a l s t a b i l i t y

1 2EXAMPLE IV

S t a b i l i z a t i o n o f P a r a c e t a m o l i n S o l u t i o n b y OxygenR e m o v a l T h r o u g h N i t r o g e n B u b b l i n g5

3 . 1 C o n c e n t r a t e d s o l u t i o n 42 i l u t e d S o l u t i o nS o l u t i o n T e s t e d

I d'n g r e r e n t Q u a n t i t y 1 0P a r a c e t a m o l 0 . 1 6 0 g Q u a n t i t vP r o p y l e n e - gl y c o l 0 . 2 7 0 m lPEG 0 0 0360 m1 S o l u t i o n W i t h o u t n i t r o g e n s o l u t i o n s u b j e c t e d t oS o d i u m h y d r o x i d e 1N pH . 0 8 . 0 9 . 0 9 . 5 1 0 . 0 c o r r e s p o n d i n g I n g r e d i e n t b u b b l i n g n i t r o g e n b u b b l i n go r H y d r o c h l o r i c a c i d 1 N . s . f . t o a c t u a l p H : pH 5 . 8 6 . 7 7 . 1 7 . 5 8 . 0 8 . 5N i t r o g e n q . s . f . p u r g i n g a n d ? l l i n g 1 5 P a r a c e t a m o l 0 . 0 0 8 g 0 . 0 0 8 gWater f o r i n j e c t i o n q . s . 1000 ml Sodium c h l o r i d e 0 . 0 0 8 g 0 . 0 0 8 g

Disodium p h o s p h a t e 0 0 0 . 1 g 0 . 0 0 1 qd i h y d r a t eS o l u t i o n 20 c o n t a i n i n g p a r a c e t a m o l i n a c o n c e n t r a t i o n o f 5 0 . 7 C l m c a c l d q s f PH 0 q s f PH 3

. . , N i t r o g e n none q . s . f . pur g i n g and ?lli n g~ 1 6 0 ~ m g / I ~ n 1 W a s a d l u s t e d t o d l f f e r e n t pH t h e a p p a r e n t 2 0 W a t e r f o r i n j e c t i o n q . s . f . 1 0 0 0 m l q . s . f . 1 0 0 0 m li s g i v e n i n c o m p a r i s o n t o a c t u a l pH b e t W e e n p a r e n t h e s i s )a f t e r a 5 f o l d - d i l u t i o n : 7 , 0 ( 5 , 8 ) - 8 , 0 ( 8 , 7 ) - 8 , 5 ( 7 , 1 ) - 9 , 0( 9 7 , 5 ) - 9 , 5 ( 8 , 0 ) - 1 0 . 0 ( 8 , 5 ) u s i n g a S O d i l l I I l h Y d I O X i d f I O r T h e d i l u t e d a q u e o u s s o l u t i o n c o n t a i n i n g p a r a c e t a m o l i sn o r m a l h y d r o c h l o r i c a c i d s o l u t i o n . V i a l s t h a t h a d b e e n ? l l e d a d j u s t e d t o pH 6 , 0 by means o f a c i t r i c a c i d s o l u t i o n ,under n i t r o g e n atmosphere by d i s p e n s i n g 10 m l o f such _ _

. . . . 5s o l u t i o n s , t i g h t l y s t o p p e r e d a n d c a p p e d , W e r e s t e r i l i z e d b y d . v l a l s . t h a t l g a d i n ? ? u g d u l n c t l e r a m t r o g e t t } ? t r l I l o s F h e r e b 3a u t o c l a v i n g a t 1 2 1 C . f o r 2 0 m i n u t e s , a n d t h e n i n e v e r y c a s e l s g e n s m g d d n i h o S E 1 6 a l i e n s w e r e b l t g I ; s s c l p g e r f eexposed, e i t h e r t o a temperature of 105 C . i n t h e da rk f o r 2 1 H ; hcappe an en S O r e m sl e a n mcu a o r a o r72 h o u r s , o r t o a r a d i a t i o n o f an a c t i n i c l i g h t a t 5000 K. a n d O u r s 2 5 C . d u r i n g 264 h o u r s . 3 0 The p e r c e n t a g e o f s e c o n d a r y p e a k s i n r e l a t i o n t o t h e main

R e s u l t sA f t e r a u t o c l a v i n g , o n l y t h e s o l u t i o n a d j u s t e d t o pH 1 0

s h o W s a p i n k t i n g e . A f t e r s t o r a g e a t 1 0 5 C . f o r 7 2 h o u r s ,a b s o r b a n c e a t 500 nm a s Well a s t h e concentration ofbreakdown r o d u c t s o f p a r a c e t a m o l W e r e m i n i m a l i n t h e pHr a n g e f r o m 7 , 5 t o 9 , 5 . Upon s t o r a g e i n t h e p r e s e n c e o f l i g h t ,t h e c o l o r s t r e n g t h i s e n h a n c e d a s t h e pH s i n c r e a s e d . C o l o rd e v e l o p m e n t i s e x t r e m e l y W e a k a t pH 7 , 0 ( a c t u a l pH 5 , 8 ) .N e i t h e r t h e p a r a c e t a m o l c o n t e n t , n o r t h e breakdoWn p r o du c t s a r e a f f e c t e d by pH.

3 . 2 D i l u t e d s o l u t i o n

I n g r e d i e n t Q u a n t i t yP a r a c e t a m o l 0 . 0 0 8 gS o di u m c h l o r i d e 0.0067 gD i s o d i u m p h o s p h a t e d i h y d r a t e 0 . 0 0 1 2 g5 C i t r i c a c i d q . s . f . pH 5 . 0 6 . 0 7 . 0N i t r o g e n q . s . f . b u b b l i n g a n d ? l l i n gW a t e r f o r i n j e c t i o n q . s . f . 1 0 0 0 m l

T he aqueous s o l u t i o n d i l u t e d and b u f f e r e d h a v i n g a p a r a ce t a m o l c o n t e n t o f 8 m g/ m l W a s a d j u s t e d t o d i f f e r e n t pHv a l u e s : pH 5 , 0 7 , 0 u s i n g a c i t r i c a c i d s o l u t i o n .

V i a l s t h a t h a d b e e n p a c k e d u n d e r n i t r o g e n a t m o s p h e r e b yd i s p e n s i n g 1 0 ml o f s u c h s o l u t i o n , W e r e t i g h t l y s t o p p e r e da n d c a p p e d , s t e r i l i Z e d b y a u t o c l a v i n g a t 1 2 1 C . f o r 2 0m i n u t e s , a n d t h e n i n e v e r y c a s e e x p o s e d t o 7 0 C . i n t h e d a r kd u r i n g 2 3 1 h o u r s .

R e s u l t s

35

40

45

50

55

60

pe ak o f p a r a c e t a mo l W a s m e a s u r e d by l i q u i dc h r o m a t o g r a p h y , s o Was t h e p i n k c o l o r s t r e n g t h b y r e a d i n gt h e s o l u t i o n a b s o r b a n c e b y a b s o r b a n c e s p e c t r o p h o t o m e t r y a ta p e a k a b s o r p t i o n W a v e l e n g t h , t h a t i s 500 nm.

R e s u l t s

S e c o n d a r y p e a k s i no f p a r a c e t a m o l m a i n S o l u t i o n a b s o r b a n c e

S o l u t i o n t e s t e d peak a t 500 nmS o l u t i o n p a c k e d W i t h o u t 1 . 5 7 0 . 0 3 6n i t r o g e n a t m o s p h e r es o l u t i o n p a c k e d u n d e r 0 . 4 4 0 . 0 1 6n i t r o g e n a t m o s p h e r e

T h e p i n k c o l o r o f t h e s o l u t i o n p a c k e d u n d e r n i t r o g e na t m o s p h e r e i s c o n s i d e r a b l y t a i n t e r t h a n t h a t o b s e r v e d f o r t h es o l u t i o n o b t a i n e d a f t e r s t e r i l i Z a t i o n u n d e r n i t r o g e n o f t h es o l u t i o n p a c k e d W i t h o u t n i t r o g e n .

EXAMPLE VS t a b i l i Z i n g S o l u t i o n s o f P a r a c e t a m o l b y A d d i n g

F r e e R a d i c a l A n t a g o n i s t s5 . 1 C o n c e n t r a t e d s o l u t i o n

I n g r e d i e n t Q u a n t i t yP a r a c e t a m o l 0 . 1 6 0 gP r o p y l e n e - g l yc o l 0 . 2 7 0 m l


22/39

6 , 0 2 8 , 2 2 2R e s u l t s ( C R L = f r e e r a d i c a l s c a v e n g e r )

- c o n t i n u e dI n g r e d i e n t Q u a n t i t y

S o l u t i o nF r e e r a d i c a l s c a v e n g e r q . s . f . ( s e e q u a n t i t a t i v e r e s u l t s ) 5 a p p e a r a n c e( S 9 6 q u a n t i t a t i v e r e s u l t s ) _ _ upon e x p o s u r e S o l u t i o n a p p e a r a n c eN l t r o g e n l - S - f - P u r g l n g a n d ? n l n g C o n c e n - t o l i g h t a t 7 0 0 C .W a t e r f o r i n j e c t i o n q . s . f 1 0 0 0 m l

C . R . L u s e d t r a t i o n c o l o r s t r e n g t h c o l o r s t r e n g t h. . . . . O 'The s o l u t i o n s t h u s p r e p a r e d a r e d i v i d e d i n 1 0 ml c a p a c i t y N O . C R L p m k ( J ) p m k ( H )

_ _ _ Thiourea 0.5 rng/rnl colorless colorlessV l a l s , s t o p p e r e d W l t h a Bromobutyl S t o p p e r a n d C a p p e d W l t h D i t h i o t h r e i t o l 1 r n g / r n l c o l o r l e s s c o l o r l e s san aluminium c a p . A f t e r a u t o c l a v i n g a t 121 C . f o r 20 w r n o n o t h i o - 1 r n g / r n l c o l o r l e s s c o l o r l e s sm i n u t e s , t h e v i a l s W e r e s t o r e d f o r 4 8 h o u r s , e i t h e r i n t h e g l y c e r o l _o gluth athi on 1 rng/rnl colorless colorlessp r e s e n c e o f a c t i n i c l i g h t a t 5500 K. a t r o o m t e m p e r a t u r e o r 1 5 S o d i u m 02 m g / m l p i n k ( + ) P i n k ( J r )a t 7 0 C . i n t h e d a r k . The p r e p a r a t i o n Was eXamined f o r any a s c o r b a t e 0 . 4 m g / m l c o l o r l e s s y e l l o W ( + )C h a n g e i n C o l o r 0 . 6 r n g / r n l p i n k ( + ) y e l l o w ( + )1 . 0 r n g / r n l c o l o r l e s s y e l l o W ( + )R e s u l t s C y s t e i n 0 . 0 5 r n g / r n l c o l o r l e s s c o l o r l e s s

h y d r o c h l o r i d e 0 . 1 r n g / r n l c o l o r l e s s c o l o r l e s s2 0 0 . 2 5 r n g / r n l c o l o r l e s s c o l o r l e s s0 . 5 r n g / r n l c o l o r l e s s c o l o r l e s s

0 . 7 5 r n g / r n l c o l o r l e s s c o l o r l e s sA p p e a r a n c e A p p e a r a n c e 1 r n g / r n l c o l o r l e s s c o l o r l e s so f t h e s o l u t i o n o f s o l u t i o n 2 r n g / r n l c o l o r l e s s c o l o r l e s supon e x p o s u r e a t 7 0 0 C . 5 r n g / r n l c o l o r l e s s c o l o r l e s s

F r e e r a d i c a l t o l i g h t C o l o rs c a v e n g e r C o n c e n t r a t i o n C o l o r i n t e n s i t y i n t e n s i t y 2 5 D o s a g e s ( i n f

t h e o r e t i c a l volumeo c a v e n g e r pink ( + ) pink ( + + )odium d i s u l ? t e 0 . 2 9 5 r n g / r n l c o l o r l e s s c o l o r l e s s C o n c e n _ S o l u t i o n a p p e a r a n c e p a r - a c e .Sodium a s c o r b a t e 1 . 0 r n g / r n l y e l l o W ( + ) y e l l o W ( + )educed g l u t a t h i o n 1 mg/ml C o l o r l e s s C o l o r l e s s C . R . L u s e d t r a t i o n c o l o r s t r e n g t h C . R . L . t a r n o lR e d u c e d g l u t a t h i o n 8 r n g / r n l c o l o r l e s s c o l o r l e s s 3 0

C y s t e i n h y d r o c h l o r i d e 1 m g / m l C l o u d y C l o u d y C y s t e i n 0 . 2 r n g / r n l c o l o r l e s s 80 9 9 . 2o t - m o n o t h i o g l y c e r o l 1 r n g / r n l c o l o r l e s s c o l o r l e s s h y d r o c h l o r i d eD i t h i o t h r e i t o l 1 r n g / r n l c o l o r l e s s c o l o r l e s s I n o n o h y d r a t eM a n n i t o l 5 0 m g / m l c o l o r l e s s c o l o r l e s s C y s t e i n 05 m g / m l C o l o r l e s s 95 996h y d r o c h l o r i d e3 5 r n o n o h y d r a t e

5'2 Dilute Solution N- 0 . 2 r n g / r n l c o l o r l e s s 8 8 99.2a c e t y l c y s t e i nMannitol 20 r n g / r n l c o l o r l e s sSolunons t e s t e d M a n n i t o l 4 0 r n g / r n l c o l o r l e s sM a n n i t o l 5 0 r n g / r n l c o l o r l e s s

4 O G l u c o s e 5 0 r n g / r n l c o l o r l e s sQ u a n t i t y

I n g r e d i e n t F o r m u l a t i o n A F o r m u l a t i o n B F o r m u l a t i o n C EX MPLE IP a r a c e t a m o l 0 0 0 8 g Om 0 0 1 2 5 g S t a b i l i z a t i o n o f ' S o l u t i o n s o f P a r a c e t a m o lS o d i u m C h l o r i d e 0 0 0 8 g 0 0 0 8 g 0 0 0 4 8 6 g 4 5 Containing a M o r p h i mc C o m p o u n d b y Addition o fD i s o d i u m p h o s p h a t e 0 . 0 0 1 g 0 . 0 0 1 g 0 . 0 0 1 2 5 g a Free Radical Scavengerdihydrate or sodiuma c e t a t e 6 . 1 Concentrated s o l u t i o nH y d r o c h l o r i c a c i d q . s . pH . 0 q . s . pH 6 . 0 q . s pH . 5 S O l l l t l O I l S t e s t e dC . R . L . q . s ( s e e q u a n t i t a t i v e r e s u l t s )N i t r o g e n q . s . f . p u r g i n g a n d ? l l i n g 5 0W a t e r q . s . f . 1 0 0 0 m l

I n g r e d i e n t Q u a n t i t yT h e s o l u t i o n s t h u s p r e p a r e d Were d i v i d e d i n 10 m l , 100 ml P a r a c e t a m o l 0 - 1 6 0 g

o r 80 m l ca a c i t v i a l s s t o ered With a B r o m o b u t l C o d e i n p h o s p h a t e 0008 gp y _ PP _ _ y 55 Propylene-glycol 0.270 mls t o p p e r and capped With an aluminium c a p . T h e p r e p a r a t i o n PEG 4 0 0 0 3 6 0 m lwas examined f o r any pink c o l o r development. H y d r o c h l o r i c a c i d 1N - S - q - S - P H 6 - 0

~ ~ ~ Free r a d i c a l scavenger q . s . ( s e e q u a n t i t a t i v e r e s u l t s )A f t e r a u t o c l a v 1 n g a t 121 C . f o r 20 m i n u t e s , t h e v i a l s Were W a t e r f o r i n j e c t i o n q . s . f . 1 0 0 0 m ls t o r e d f o r 48 h o u r s , e i t h e r i n t h e p r e s e n c e o f a c t i n i c l i g h t a t 6 05500 K. a t r o o m t e m p e r a t u r e o r a t 70 C . i n t h e dark( f o r m u l a A ) .A f t e r a u t o c l a v i n g a t 1 2 4 C . f o r 7 m i n u t e s , t h e v i a l s Were

The s o l u t i o n s t h u s p r e p a r e d Were d i v i d e d i n 1 0 ml c a p a ci t y v i a l s , s t o p p e r e d W i t h a B r o m o b u t y l s t o p p e r a n d c a p p e dW i t h a removable aluminium c a p . A f t e r a u t o c l a v i n g a t 1 2 1


23/39

6 , 0 2 8 , 2 2 2R e s u l t s

S o l u t i o n a p p e r a n c eupon e x p o s u r e S o l u t i o n a p p e r a n c e

F r e e r a d i c a l t o l i g h t 7 0 0 C .s c a v e n g e r C o n c e n t r a t i o n c o l o r s t r e n g t h c o l o r s t r e n g t hNo f r e e p i n k + ) p i n k + + )r a d i c a ls c a v e n g e rS o d i u m 0 . 2 9 5 m g / m l y e l l o W + ) y e l l o W + + )d i s u l ? t eS o d i u m 1 . 0 m g / m l y e l l o W + + ) y e l l o W + + + )a s c o r b a t er e d u c e d 1 m g / m l y e l l o W + ) a m b e r + + + )g l u t a t h i o n y e l l o W8 m g / m l c o l o r l e s s y e l l o W + + )

1 6 m g / m l c o l o r l e s s y e l l o W + )D i t h i o - 1 m g / m l v i o l e t + + + ) v i o l e t p i n k + + + + )t h r e i t o l p i n ks o d i u m 5 m g / m l p i n k + ) p i n k + + )h y p op h o s p h i t e

6 . 2 D i l u t e s o l u t i o n sS o l u t i o n s t e s t e d

I n g r e d i e n t Q u a n t i t yP a r a c e t a m o l 0 . 0 0 8 gC o d e i n p h o s p h a t e 0 . 0 0 0 4 gSodium c h l o r i d e 0 . 0 0 8 gD i s o d i u m p h o s p h a t e d i h y d r a t e 0 . 0 0 1 5 gH y d r o c h l o r i c a c i d q . s . f . pH 6 . 0F r e e r a d i c a l s c a v e n g e rN i t r o g e n q . s . f .W a t e r f o r i n j e c t i o n

q . s . s e e r e s u l t s )p u r g i n g a n d ? l l i n gq . s . f . 1 0 0 0 m l

The s o l u t i o n s t h u s p r e p a r e d Were d i v i d e d i n 1 0 ml c a p a ci t y v i a l s , s t o p p e r e d W i t h a B r o r n o b u t y l s t o p p e r a n d c a p p e dW i t h a n aluminium c a p . A f t e r a u t o c l a v i n g a t 1 2 1 C . f o r 20m i n u t e s , t h e v i a l s Were s t o r e d f o r 48 h o u r s , e i t h e r u n d e ra c t i n i c l i g h t a t 5500 C . a t r o o m t e m p e r a t u r e , o r a t 70 C . i nt h e d a r k . The p r e p a r a t i o n Was examined f o r a n y c h a n g e i nc o l o r .

F o r t h e s o l u t i o n n o t c o n t a i n i n g a n y f r e e r a d i c a l s c a v e n g e ra n d f o r t h e s o l u t i o n c o n t a i n i n g 0 . 5 m g / m l o f c y s t e i n h y d r oc h l o r i d e a s f r e e r a d i c a l a n t a g o n i s t , paracetamol a s W e l l a sc o d e i n a r e measured b y h i g h p e r f o r m a n c e l i q u i dc h r o m at o g r a ph y , i m m e d i a te l y a f t e r a u t o c l a v i n g , i n c o m p a r is o n W i t h i d e n t i c a l s o l u t i o n s n o t s u b j e c t e d t o a u t o c l a v i n g .

A p p e a r e n c e s c o r i n g o f t h e s o l u t i o n s


F r e e r a d i c a l t o l i g h t 7 0 0 C .s c a v e n g e r C o n c e n t r a t i o n c o l o r s t r e n g t h c o l o r s t r e n g t hNo f r e e p i n k + ) p i n k + )r a d i c a ls c a v e n g e rSodium 0 . 2 9 5 mg/ml c o l o r l e s s c o l o r l e s s

10

1 5

20

25

30

45

1 6- c o n t i n u e d


F r e e r a d i c a l t o l i g h t 7 0 0 C .s c a v e n g e r C o n c e n t r a t i o n c o l o r s t r e n g t h c o l o r s t r e n g t hM o n o t h i o - 0 . 5 mg/ml g r e y g r e yg l y c e r o lReduced 2 . 0 mg/ml c o l o r l e s s c o l o r l e s sg l u t a t h i o nN - 2 . 0 m g / m l g r e y + ) g r e y + )a c e t y l c y s t e i nC y s t e i n 0 . 0 5 m g / m l c o l o r l e s s p i n k + )h y d r o - 0 . 1 m g / m l c o l o r l e s s c o l o r l e s sc h l o r id e 0 . 2 5 mg/ml c o l o r l e s s c o l o r l e s s

0 . 5 mg/ml c o l o r l e s s c o l o r l e s s0 . 7 5 mg/ml c o l o r l e s s c o l o r l e s s1 . 0 mg/ml c o l o r l e s s c o l o r l e s s

2 . 0 mg/ml c o l o r l e s s c o l o r l e s s5 . 0 mg/ml c o l o r l e s s c o l o r l e s s

A s s a y r e s u l t s o f p a r a c e t a m o l a n d c o d e i n

I n g r e d i e n t non s t e r i l i z e dS o l u t i o n t e s t e d a s s a y e d s o l u t i o n a f t e r s t e r i l i z a t i o nS o l u t i o n s W i t h n o p a r a c e t a m o l 0 . 0 0 7 8 g / m l 0 . 0 0 7 7 g / m lf r e e r a d i c a l c o d e in 0 . 0 0 0 4 3 g / m l 0 . 0 0 0 4 2 g / m ls c a v e n g e r addedS o l u t i o n p a r a c e t a m o l 0 . 0 0 8 2 g / m l 0 . 0 0 8 1 g / m lc o n t a i n i n g 0 . 5 c o d e i n 0 . 0 0 0 4 2 g / m l 0 . 0 0 0 4 2 g / m lm g / m l o f c y s t e i nh y d r o c h l o r i d e

There s n o t e d t h e l a c k o f c o l o r development one one handa n d e x c e l l e n t p r e s e r v a t i o n o f t h e a c t i v e i n g r e d i e n t s a f t e r h e a tt r e a t m e n t s t e r i l i z a t i o n on t h e o t h e r h a n d .

EX MPLE I IB i o l o g i c a l T o l e r a n c e t o t h e P r e p a r a t i o n

7 . 1 H e m a t o l o g i c a l t o l e r a n c eT e s t e d s o l u t i o n s

I n g r e d i e n t Q u a n t i t yP a r a c e t a m o l 0 . 1 6 0 gP r o p y l e n e - g l y c o l 0 . 2 7 0 m lPEC 00 0 . 3 6 0 mlN i t r o g e n q . s . f . p u r g i n g a n d ? l l i n gW a t e r f o r i n j e c t i o n q . s . f . 1 0 0 0 m l

The s o l u t i o n pH Was n o t a d j u s t e d . The a p p a r e n t pH s 7 . 6 ,c o r r e s p o n d i n g t o a n a c t u a l p H o f 6 . 5 .

Whole human b l o o d i s i n c u b a t e d W i t h t h e s o l u t i o n u n d e rs t u d y , i n e q u a l p r o p o r t i o n s by v o l u m e . 2 ml W e r e d r a W n a t1 0 m i n u t e s i n t e r v a l s a n d c e n t r i f u g e d f o r 5 m i n u t e s a t 5000r p m . 100 p l o f t h e s u p e r n a t a n t Were d i l u t e d i n 1 ml o fd i s t i l l e d W a t e r . The absorbance o f t h i s s o l u t i o n Was d e t e rmined a g a i n s t a W a t e r b l a n k a t 540 nm peak a b s o r p t i o nW a v e l e n g t h o f h e m o g l o b i n .


24/39


25/39

6 0 2 8 2 2 21 9

6 . The f o r m u l a t i o n o f c l a i m 5 w h e r e i n t h e a s c o r b i c a c i dd e r i v a t i v e s a r s e l e c t e d from t h e group c o n s i s t i n g o fD - a s c o r b i c a c i d L - a s c o r b i c a c i d a l k a l i m e t a l a s c o r b a t e sa l k a l i n e e a r t h m e t a l a s c o r b a t e s a n d W a t e r - s o l u b l e a s c o r b i ca c i d e s t e r s .

7 . The f o r m u l a t i o n o f c l a i m 5 Wherein t h e o r g a n i c compound h a v i n g a t l e a s t o n e t h i o l i s a l i p h a t i c o r c y c l o a l i p h a t i c .8 . The f o r m u l a t i o n o f c l a i m 1 c o n t a i n i n g a f r e e r a d i c a l

s c a v e n g e r c o n t a i n i n g a t l e a s t one t h i o l i s s e l e c t e d from t h eg r o u p c o n s i s t i n g o f t h i o l y g l y c o l i c a c i d t h i o l a c e t i c a c i dd i t h i o t h r e i t o l r e d u c e d g l u t a t h i o n t h i o u r e a o t - t h i o g l y c e r o lc y s t e i n a c e t l c y s t e i n a n d m e r c a p t o e t h a n e s u l f o n i c a c i d .

9 . The f o r m u l a t i o n o f c l a i m 1 W h e r e i n t h e f r e e r a d i c a ls c a v e n g e r i s a n a l i p h a t i c p o l y h y d r o X y a l k a n o l o f 2 t o 1 0carbon a t o m s .

1 0 . The f o r m u l a t i o n o f c l a i m 9 W h e r e i n t h e p o l y h y d r o X ya l k a n o l i s a c y c l i c g l u c i t o l o r a s t r a i g h t c h a i n g l u c i t o l o f 6 t o10 carbon a t o m s .

1 1 . The f o r m u l a t i o n o f c l a i m 9 W h e r e i n t h e p o l y h y d r o X ya l k a n o l i s g l y c e r o l o r p r o p y l e n e g l y c o l .1 2 . The f o r m u l a t i o n o f c l a i m 1 0 W h e r ei n t h e c y c l i cg l u c i t o l i s s e l e c t e d f r o m t h e g r o u p c o n s i s t i n g o f m a n n i t o ls o r b i t o l i n o s i t o l g l u c o s e a n d l e v u l o s e .

1 3 . The f o r m u l a t i o n o f c l a i m 1 a l s o c o n t a i n i n g a t l e a s t onec o m p l e X i n g a g e n t .1 4 . The f o r m u l a t i o n o f c l a i m 1 W h e r e i n t h e a c e t a m i

nophen h a s a c o n c e n t r a t i o n o f 2 t o 350 m g / m l .1 5 . The f o r m u l a t i o n o f c l a i m 1 4 Wherein t h e c o n c e n t r a

t i o n i s 6 0 t o 350 m g / m l .1 6 . The f o r m u l a t i o n o f c l a i m 14 d i l u t e d t o a c o n c e n t r a t i o n

o f 2 t o 50 m g / m l .

10

1 5

20

25

30

201 7 . The f o r m u l a t i o n o f c l a i m 1 a l s o c o n t a i n i n g a n i s o t o n

i Z i n g a g e n t i n a n amount t o o b t a i n i s o t o n i c i t y .1 8 . The f o r m u l a t i o n o f c l a i m 1 s t e r i l i Z e d by h e a t t r e a t

ment.1 9 . The f o r m u l a t i o n o f c l a i m 1 f u r t h e r c o n t a i n i n g a n

e f f e c t i v e amount o f a n a n a l g e t i c a g e n t .2 0 . The f o r m u l a t i o n o f c l a i m 1 9 t h e a n a l g e t i c a g e n t i s am o r p h i n e a n a l g e t i c s e l e c t e d f r o m t h e g r o u p c o n s i s t i n g o fn a t u r a l m o r p h i n e s s e m i - s y n t h e t i c m o r p h i n e s s y n t h e t i cm o r p h i n e s p h e n y l p i p e r i d i n e s n i p e c o t i c a c i d c o m p o u n d sp h e n y l c y c l o h e X a n o l c o m p o u n d s a n d p h e n y l a Z e p i n e comp o u n d s .2 1 . The f o r m u l a t i o n o f c l a i m 20 h a v i n g a c o n c e n t r a t i o n o f

a c e t a m i n o p h e n i s 0 . 0 5 t o 5 b y W e i g h t When m o r p h i n e i sp r e s e n t .2 2 . The f o r m u l a t i o n o f c l a i m 20 h a v i n g a n a c e t a m i n o p h e n

c o n c e n t r a t i o n o f 0 . 2 t o 2.5 b y W e i g h t W he n c o d e i n e i sp r e s e n t .2 3 . The f o r m u l a t i o n o f c l a i m 1 f u r t h e r c o n t a i n i n g a n

a n t i - i n ? a m m a t o r y a g e n t o f t h e p h e n y l a c e t i c a c i d t y p e .2 4 . The f o r m u l a t i o n o f c l a i m 23 W h e r e i n t h e a n t ii n ? a m m a t o r y a g e n t s k e t o p r o f e n .2 5 . The f o r m u l a t i o n o f c l a i m 1 f u r t h e r c o n t a i n i n g a n

a n t i e m e t i c a g e n t .2 6 . The f o r m u l a t i o n o f c l a i m 1 f u r t h e r c o n t a i n i n g a na n t i p i l e p t i c a g e n t .2 7 . The f o r m u l a t i o n o f c l a i m 1 f u r t h e r c o n t a i n i n g a

c o r t i c o s t e r o i d .2 8 . The f o r m u l a t i o n o f c l a i m 1 f u r t h e r c o n t a i n i n g at r i c y c l i c a n t i d e p r e s s a n t .


26/39

UNITED STATES P TENT ND TR DEM RK OFFICECERTIFIC TE OF CORRECTION

P TENT NO. 6 , 0 2 8 , 2 2 2 P a g e 1 o f 4PPLIC TION NO. 09/051246D TED F e b r u a r y 2 2 , 2 0 0 0INVENTOR(S) F r a n c o i s D i e t l i n e t a 1 .

I t i s c e r t i f i e d t h a t e r r o r appears n t h e a b o v e - i d en t i ? e d p a t e n t and h a t s a i d L e t t e r s P a t e n t i s h e r e b y c o r r e c t e d a s shown b e l o w :

Column l i n e 2 1 , hydrolysed should be - hydrolyzedColumn l i n e 3 5 , Arrenium should be - ArrheniusColumn l i n e 6 7 , p-aminophen should be - p-aminophenolColumn , l i n e 1 1 9 , 8 should be - 19.8Column , l i n e s 26-27, a l c a - n o l should read - a l k a - n o l -Column l i n e 5 0 , c y s t e i n , a c e t y l c y s t e i n s h o u l d r e a d - - c y s t e i n e , a c e t y l c y s t e i n eColumn , l i n e 5 1 , d i t h l o t h r i t o l should read - d i t h i o t h r e i t o l -Column l i n e 6 1 , c y s t e i n , reduced s l a t e s h o u l d r e a d - - c y s t e i n e , reduced s t a t e -Column l i n e 6 2 , N - a c e t y l c y s t e i n s h o u l d r e a d - - N - a c e t y l c y s t e i n e -Column , l i n e 2 7 , cu should b e - o r -Column l i n e 28 hydrogene should be - hyd rogenColumn , l i n e 31 b et W en n should b e - b et w e e nColumn , l i n e 2 3 , IN should be - NS IDColumn , l i n e 4 4 , 1000 ml should r e ad - 1.000 mlColumn , l i n e 4 7 t a b l e ) , codein should read - codeineColumn l i n e 55 t a b l e ) , q . s . 1000 a l l t h r e e o c c u r r e n c e s , s h o u l d be - q . s . 1 . 0 0 0 ml

S i g n e d a n d S e a l e d t h i sT h i r t i e t h D ay o f N o v e m b e r , 2 0 1 0

D a v i d . KapposD i r e c t o r o f t h e U n i t e d S t a t e s P a t e n t and Trademark O ? i c e


27/39

CERTIFICATE OF ORRE TION c o n t i n u e d ) P a g e 2 o f 4US. P a t . N o . 6 , 0 2 8 , 2 2 2

Column , l i n e 1 1 , r e c r i s t a l l i z a t i o n should read - r e c r y s t a l l i z a t i o n -Column l i n e 1 2 , 6 , 2 5 ml should rea d - 6 . 2 5 mlColumn , l i n e 23 ( t a b l e , column ) , c o d e i n should r e a d - - c o d e i n e -Column , l i n e 24 ( t a b l e ) , codein s u l f a t e should read - codeine s u l f a t e -Column , l i n e 3 4 t a b l e ) , n e x t t o l a s t l i n e , q . s . f . 1 0 0 0 a l l t h r e e o c c u r r e n c e s , s h o u l d b e - - q . s . f . 1 . 0 0 0ml _

Column , l i n e 3 2 , r e c r i s t a l l i z a t i o n should read - r e c r y s t a l l i z a t i o n -Column , l i n e 3 5 , c r i s t a l s should read - c r y s t a l s -Column , l i n e 3 6 , c r i s t a l should read - c r y s t a l -

Column , l i n e 3 6 , c r i s t a l l i z a t i o n should read - c r y s t a l l i z a t i o n -olumn , l i n e 4 4 , i s should read - i n -

Column , l i n e 6 3 , Table 1 . 2 , s o r b i t a l should read - s o r b i t o l -Column , T a b l e 4 . 1 , l a s t l i n e , q . s . f . 1000 s h o u l d r e a d - - q . s . f . 1 . 0 0 0 mlColumn 1 0 , l i n e 1 2 , c r i s t a l l i z a t i o n should read - c r y s t a l l i z a t i o n -Column 1 0 , l i n e 3 1 , oxyd ati on should rea d - o x i d a t i o n -

Column 1 0 , l i n e 4 4 , oxydative should read - o x i d a t i v e -Column 1 0 , l i n e 6 2 , of y p e o f t h e t y p e s h o u l d r e a d - - o f t h e t y p eColumn 0 , l i n e 6 6 , a c e t y l c y s t e i n > p a r a c e t a m o l + c y s t e i n s h o u l d r e a d-- acetylcysteine>paracetamol cysteine

Column 1 1 , l i n e 1 6 , i n t a b l e 3 . 1 , q . s . 1000 ml s h o u l d r e a d - - q . s . 1 . 0 0 0 mlC o l u m n 1 1 , l i n e s 2 1 - 2 2 , 7 , 0 5 , 8 ) - 8 , 0 8 , 7 ) - 8 , 5 7 , 1 ) - 9 , 0 9 7 , 5 ) - 9 , 5 8 , 0 ) - 1 0 , 0 8 , 5 ) s h o u l d r e a d- - 7 . 0 ( 5 . 8 ) - 8 . 0 ( 8 . 7 ) - 8 . 5 ( 7 . 1 ) - 9 . 0 ( 7 . 5 ) - 9 . 5 am-10.0 ( 8 - 5 )

Column 1 1 , l i n e 3 6 , 7 , 5 t o 9 , 5 should rea d - 7 . 5 t o 9 . 5 -Column 1 , l i n e 3 8 , pH , 0 a c t u a l p H 5 , 8 ) s h o u l d r e a d - - pH . 0 a c t u a l pH . 8 )Column 1 1 , l i n e 5 1 , i n t a b l e 3 . 2 , q . s . f . 1000 ml s h o u l d r e a d - - q . s . f . 1 . 0 0 0 ml


28/39

CERTIFICATE OF ORRE TION c o n t i n u e d ) P a g e 3 o f 4US P a t . N o . 6 , 0 2 8 , 2 2 2

Column 1 1 , l i n e 5 6 , pH 5 , 0 - 7 , 0 s h o u l d r e a d - - pH . 0 - 7 . 0 -Column 1 1 , l i n e 6 6 , pH 6 , 0 and 5 , 0 s h o u l d r e a d - - pH . 0 and 5 . 0Column 1 2 , l i n e 2 0 , i n t a b l e 4 . 2 , q . s . f . 1000 b o t h o c c u r r e n c e s , s h o u l d r e a d - - q . s . f . 1 . 0 0 0 mlColumn 1 2 , l i n e 2 4 , pH 6 , 0 s h o u l d r e a d - - pH . 0 -Column 1 2 , l i n e 4 8 , t a i n t e r should read - f a i n t e r -Column 1 3 , l i n e 8 , i n t a b l e 5 . 1 , q . s . f . 1000 ml s h o u l d r e a d - - q . s . f . 1 . 0 0 0 mlColumn 1 3 , l i n e 3 1 , c y s t e i n should r e a d - - c y s t e i n e -Column 1 3 , l i n e s 5 0 - 5 1 , i n t a b l e 5 . 2 , q . s . f . 1000 ml s h o u l d r e a d - - q . s . f . 1 . 0 0 0 mlColumn 1 4 , l i n e 1 8 i n t h e t a b l e , c y s t e i n s h o u l d r e a d - - c y s t e i n eColumn 1 4 , l i n e 3 1 i n t h e t a b l e , c y s t e i n s h o u l d r e a d - - c y s t e i n eColumn 1 4 , l i n e 3 4 i n t h e t a b l e , c y s t e i n s h o u l d r e a d - - c y s t e i n eColumn 1 4 , l i n e 3 7 i n t h e t a b l e , a c e t y l c y s t e i n s h o u l d r e a d - - a c e t y l c y s t e i n eColumn 1 4 , l i n e 54 i n t h e t a b l e ) , c o d e i n s h o u l d r e a d - - c o d e i n eColumn 1 4 , l i n e 5 9 , i n t a b l e 6 . 1 , q . s . f . 1000 ml s h o u l d r e a d - - q . s . f . 1 . 0 0 0 mlColumn 1 5 , l i n e 3 2 , i n t h e t a b l e , codein should read - codeineColumn 1 5 , l i n e 3 7 , i n t a b l e 6 . 2 , q . s . f . 1000 ml s h o u l d r e a d - - q . s . f . 1 . 0 0 0 mlColumn 1 5 , l i n e 4 7 , c y s t e i n should r e a d - - c y s t e i n e -Column 1 5 , l i n e 4 9 , codein sh ould read - codeineColumn 1 6 , l i n e 1 2 i n t h e t a b l e , a c e t y l c y s t e i n s h o u l d r e a d - - a c e t y l c y s t e i n eColumn 1 6 , l i n e 1 3 i n t h e t a b l e , c y s t e i n s h o u l d r e a d - - c y s t e i n eColumn 1 6 , l i n e 2 1 , codein sh ould read - codeineColumn 1 6 , l i n e 27 i n t h e t a b l e ) , c o d e i n should r e a d - - c o d e i n e -Column 1 6 , l i n e 3 1 i n t h e t a b l e ) , c o d e i n should r e a d - - c o d e i n e -


29/39

CERTIFICATE OF ORRE TION c o n t i n u e d ) P a g e 4 o f 4US. P a t . N o . 6 , 0 2 8 , 2 2 2

Column 1 6 , l i n e 3 2 i n t h e t a b l e , c y s t e i n s h o u l d r e a d - - c y s t e i n eolumn 6 , l i n e 3 5 , one one hand should read - on one hand

Column 1 6 , l i n e 5 3 , i n t a b l e 7 . 1 , q . s . f . 1000 ml s h o u l d r e a d - - q . s . f . 1 . 0 0 0 mlColumn 1 7 , l i n e 2 4 , i n t a b l e 7 . 2 , q . s . f . 1000 ml s h o u l d r e a d - - q . s . f . 1 . 0 0 0 mlColumn 1 7 , l i n e 2 8 , 7 6 should read - 7 . 6 -Column 1 9 , l i n e 2 , claim 6 , a r should read - a r e -Column 9 , l i n e 1 2 , c l a i m 8 , c y s t e i n , a c e t l c y s t e i n s h o u l d r e a d - - c y s t e i n e , a c e t y l c y s t e i n e


30/39

EXHIBIT B


31/39

1 2 ) United S t a t e s PatentUS006992218B2

1 0 ) P a t e n t N 0 . : US 6 , 9 9 2 , 2 1 8 B 2D i e t l i n e t a l . 4 5 ) D a t e o f P a t e n t : J a n . 3 1 , 2 0 0 6

( 5 4 ) METHOD FOR OBT INING QUEOUS ( 5 2 ) US. C l . . . . . . . . . . . . . . . . . . . . . . 5 6 4 / 4 ; 5 6 4 / 5 ; 5 6 4 / 6 ; 5 6 4 / 7 ;FORMUL TIONS OF OXIDATION- 5 6 4 / 2 2 3 ; 5 1 4 / 6 1 7SENSITIVE CTIVE PRINCIPLES ( 5 8 ) Field of Classi?cation Search . . . . . . . . . . . . . . . . . . . . . 5 6 4 / 4 ,

7 5 ) I n v e n t o r s : F r a n c o i s D i e t l i n , L a V e s i n e t ( F R ) ;D a n i e l e F r e d j , G i f s u r Y v e t t e ( F R )

7 3 ) A s s i g n e e : P h a r m a t o p SCR F R )o t 1 c e : u ect t o a n 1sc a1mer, t e term 0 t i sN s b j yd 1 h r h

p a t e n t i s e x t e n d e d o r a d j u s t e d u n d e r 3 5U . S . C . 1 5 4 b ) b y 0 d a y s .

2 1 ) A p p l . N 0 . : 1 0 / 3 3 2 , 0 6 02 2 ) PCT i l e d : J u n . 6 , 2 0 0 1

( 8 6 ) PCT N o . : PCT/FR01/01749 3 7 1 6 X 1 ) ,2 ) , 4 ) D a t e : A u g . 4 , 2 0 0 3

( 8 7 ) P CT P u b . N o . : WO01/93830P CT P u b . D a t e : D e c . 1 3 , 2001

( 6 5 ) P r i o r P u b l i c a t i on D a t aU S 2004/0054012 A1 M a r . 1 8 , 2004

3 0 ) F o r e i g n A p p l i c a t i o n P r i o r i t y D a t aJ u n . 6 , 2000 (FR) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 07231

5 1 ) I n t . C l .C07C 2 0 9 / 9 0 ( 2 0 0 6 . 0 1 )

5 6 4 / 5 , 6 , 7 , 2 2 3 ; 5 1 4 / 6 1 7S e e a p p l i c a t i o n ? l e f o r c o m p l e t e s e a r c h h i s t o r y .5 6 ) R e f e r e n c e s C i t e d

U . S . P TENT DOCUMENTS6,028,222 * 2 / 2 0 0 0 Dietlin e t a 1 . . . . . . . . . . . . . . . . . . . 5 6 4 / 4

* c i t e d by examinerP r i m a r y E x a m i n e r S h a i l e n d r a Kumar( 7 4 ) A t t o r n e y , A g e n t , o r F i r m C h a r l e s A . M u s e r l i a n

5 7 ) ABSTRACTethod f o r o b t a i n i n g a q u e o u s f o r m u l a t i o n s W i t h e a s i l y

o x i d i Z a b l e a c t i v e p r i n c i p l e s , n o t a b l y p h e n o l s , s t a b l e o v e r ap r o l o n g e d p e r i o d , c o m p r i s i n g s u b j e c t i n g t h e m t o e x t r e m ed e o x y g e n a t i o n b y b u b b l i n g W i t h a n i n e r t g a s a n d / o r p l a c i n gW i d e r v a c c u m , p r o t e c t i n g t h e m a g a i n s t p o s s i b l e r e s o r p t i o no f o x y g e n b y k e e p i n g them u n d e r a n i n e r t g a s a t m o s p h e r e ,b y ? l l i n g , u n d e r i n e r t g a s , i n t o b o t t l e s p r e v i o u s l y c l e a r e d o fa i r b y i n s u f ? a t i o n W i t h i n e r t g a s , t h e n s u b j e c t i n g t h e m , W h i l es t o p p e r i n g , t o low p r e s s u r e a s o b t a i n e d i n t h e b o t t l e , o f6 5 , 0 0 0 Pa maximum, t o o b t a i n a q u e o u s s o l u t i o n s h a v i n g ar e s i d u a l oxygen c o n c e n t r a t i o n i n t h e s o l u t i o n beloW 2 ppm,a n d p r e f e r a b l y o f t h e o r d e r o f 1 ppm a n d e v e n 0 . 5 p pmu s e f u l a s i n j e c t a b l e p r e p a r a t i o n s h a v i n g a n oxygen concent r a t i o n i n t h e s o l u t i o n beloW 2 ppm.

1 9 C l a i m s , No D r a w i n g s


32/39

US 6 , 9 9 2 , 2 1 8 B21

METHOD FOR OBTAINING QUEOUSFORMUL TIONS OF OXID TIONSENSITIVE CTIVE PRINCIPLES

T h i s a p p l i c a t i o n i s a 371 o f PCT/FR01/01749 ? l e d J u n .6 , 2 0 0 1 .

The o b j e c t o f t h e p r e s e n t i n v e n t i o n i s a neW method f o rp r o d u c i n g i n j e c t a b l e a q u e o u s s o l u t i o n s W i t h a c t i v ep r i n c i p l e s , i n p a r t i c u l a r a c t i v e p r i n c i p l e s W h i c h a r e u s e f u l i nt h e r a p e u t i c s a n d s u s c e p t i b l e t o o x y g e n , a n d a l s o a p r o c e d u r ef o r p r e p a r a t i o n o f t h e s e m e t h o d s o f p a c k a g i n g , a n d t h e i ru t i l i Z a t i o n .

I t s o b j e c t i s , more p r e c i s e l y , a neW method f o r aqueousf o r m u l a t i o n s W i t h a c t i v e p r i n c i p l e s s u s c e p t i b l e t o o x i d a t i o nW h i c h c a n n o t a b l y b e u t i l i Z e d i n i n j e c t a b l e p r e p a r a t i o n sb e i n g s t a b l e o v e r a l o n g p e r i o d , a n d c o n t a i n i n g , f o r e x a m p l e ,p h e n o l i c o r p o l y p h e n o l i c s u b s t a n c e s , amino a l c o h o l s o rs u l p h u r - c o n t a i n i n g s u b s t a n c e s .A q u e o u s s o l u t i o n s W i t h a c t i v e p r i n c i p l e s t r a d i t i o n a l l yh a v e d i f f e r e n t a p p l i c a t i o n s , n o t a b l y i n t h e r a p e u t i c s , i n p a rt i c u l a r i n t h e f o r m o f i n j e c t a b l e s o l u t i o n s i n t e n d e d f o rhumans o r a n i m a l s . HoWever t happens t h a t some o f t h e s ea c t i v e p r i n c i p l e s p r e s e n t p r o b l e m s o f s t a b i l i t y i n s o l u t i o n .T h e s e p r o b l e m s may b e c o n n e c t e d W i t h t h e f a c t t h a t t h ea c t i v e p r i n c i p l e s a r e s u s c e p t i b l e t o o x i d a t i o n a n d f o r mu n d e s i r e d d e g r a d a t i o n p r o d u c t s b y r e a c t i o n W i t h t h e o x y g e ni n t h e a i r , o r a b o v e a l l W i t h t h e oxygen d i s s o l v e d i n t h eaqueous s o l u t i o n . O t h e r a c t i v e p r i n c i p l e s a r e i n d i r e c t l y s u sc e p t i b l e t o o x y g e n , i . e . W h i l s t b e i n g k e p t t h e y a r e l i k e l y t of o r m , b y c h e m i c a l r e a c t i o n s , o x i d i Z a b l e d e r i v a t i v e s . T h e s ed e r i v a t i v e s , b y r e a c t i n g W i t h o x y g e n , t h e n l e a d t o t h ef o r m a t i o n o f u n d e s i r e d s e c o n d a r y p r o d u c t s . T h i s i s t h e c a s e ,i n p a r t i c u l a r , W i t h p a r a c e t a m o l . T h e A p p l i c a n t s h a v e , i n f a c t ,d e m o n s t r a t e d t h e f a c t t h a t p a r a c e t a m o l , i n a q u e o u s s o l u t i o n ,undergoes h y d r o l y s i s on t h e one h a n d , and on t h e o t h e rh a n d , d e g r a d e s t o f o r m a q u i n o n e - i m i n e s u s c e p t i b l e t op o l y m e r i Z a t i o n i n t o n i t r o g e n o u s p o l y m e r s . T h e d e r i v a t i v e sr e s u l t i n g from t h e s e r e a c t i o n s a r e t h e m s e l v e s a l s o s u s c e pt i b l e t o o x i d a t i o n a n d f o r m u n d e s i r e d s e c o n d a r y p r o d u c t s .T h e s e c o n d a r y p r o d u c t s f o r m e d b y r e a c t i o n o f t h e o x ygen W i t h t h e s e a c t i v e p r i n c i p l e s , o r t h e i r d e r i v a t i v e s , l e a d s t onumerous d i s a d v a n t a g e s s u c h a s , f o r e x a m p l e , a l o s s o fa c t i v i t y o r t h e p r o d u c t i o n o f a l l e r g e n i c p r o d u c t s .

I n f a c t , a s a r e s u l t o f d e g r a d a t i o n by o x i d a t i o n , t h e t i t r eo f a c t i v e p r i n c i p l e i n t h e a q u e o u s s o l u t i o n i s c o n s i d e r a b l yr e d u c e d , i n a n u n c o n t r o l l a b l e manner and p o s e s a majorp r o b l e m , e s p e c i a l l y When t h e s e s o l u t i o n s a r e u s e d i nt h e r a p e u t i c s , more p a r t i c u l a r l y i n t h e f o r m o f i n j e c t a b l es o l u t i o n s , When i t i s i m p o r t a n t t h a t t h e d o s e o f a c t i v ep r i n c i p l e i s p r e c i s e l y d e t e r m i n e d .

M o r e o v e r , t h e o x i d a t i o n p r o d u c t s l e a d t o t h e f o r m a t i o n o fc o l o u r e d c o m p o u n d s , t h u s m a k i n g t h e a q u e o u s s o l u t i o nu n s u i t a b l e f o r t h e r a p e u t i c a p p l i c a t i o n s .I n a d d i t i o n , t h e f o r m a t i o n o f s e c o n d a r y p r o d u c t s mayf u r t h e r i n c r e a s e a s a r e s u l t o f a r i s e i n t e m p e r a t u r e , Whichc o n s e q u e n t l y , m a y c a u s e h e a t - s t e r i l i Z a t i o n o f t h e aqueouss o l u t i o n s W i t h t h e s e a c t i v e p r i n c i p l e s , i m p o s s i b l e , o r a t l e a s td i f ? c u l t .

H e r e a n d i n t h e f o l l o W i n g t e x t , t h e t e r m p h e n o l i c a c t i v ep r i n c i p l e s u s c e p t i b l e t o o x i d a t i o n means a n y s u b s t a n c e ,Which m ay o r m ay n o t b e m e d i c i n a l , c o m p r i s i n g a p h e n o l i cs t r u c t u r e a n d / o r f u n c t i o n s s u p p o r t e d b y t h e p h e n o l i c s t r u ct u r e Which r e a c t e a s i l y W i t h o x y g e n , a n d Which d e g r a d e sf o r m i n g o x i d a t i o n p r o d u c t s , c o l o u r e d o r c o l o u r l e s s , o rh y d r o l y s i s p r o d u c t s o r p o l y m e r i Z a t i o n p r o d u c t s .

The a c t i v e p r i n c i p l e s s u s c e p t i b l e t o oxygen a r e e s s e nt i a l l y o r g a n i c s u b s t a n c e s b e a r i n g o x i d i Z a b l e f u n c t i o n s ,

10

1 5

25

35

40

45

55

6 5

2a m o n g s t W h i c h t h e f o l l o W i n g may i n p a r t i c u l a r b e c i t e d :p h e n o l s , p o l y p h e n o l s , a m i n o p h e n o l s , p h e n o l i c a l c o h o l s a n dp h e n o l i c k e t o n e s , a s W e l l a s a r o m a t i c amines o r p a r t i a l l yh y d r o g e n a t e d c y c l i c a l s t r u c t u r e s s u c h a s d e r i v a t i v e s o fa n t h r a q u i n o n e . The f o l l o W i n g o n e s may a l s o b e c i t e d : c o mpo und s With an e n o l i c s t r u c t u r e o r With an aldehydef u n c t i o n , o r a ketone function o r an alcohol f u n c t i o n .

Aminosides Which a r e a l s o s u s c e p t i b l e t o t h e p r e s e n c e o foxygen may a l s o b e c i t e d .Amongst h e e a s i l y o x i d i Z a b l e a c t i v e p r i n c i p l e s t h a t W i l lb e i n c o r p o r a t e d i n t o t h e a q u e o u s s o l u t i o n s o f t h e i n v e n t i o n ,t h e f o l l o W i n g m ay b e c i t e d more p a r t i c u l a r l y : p h e n o l s o ra m i n o p h e n o l s , s u c h a s p a r a c e t a m o l , e p i n e p h r i n e ,n o r e p i n e p h r i n e , a d r e n a l o n e , i s o p r e n a l i n e , o r c i p r e n a l i n e ,i s o x u p r i n e , p h e n y l e p h r i n e o r d o b u t a m i n e ; t h e f o l l o W i n g W i l lb e c i t e d a s a r o m a t i c a m i n e s : p r o c a in e , b u p i v a c a i n e ,t e t r a c a i n e , b u t o f o r m , L - d o p a o r C a r b i d o p a ; t h e f o l l o W i n gone W i l l be c i t e d a s aminoketones:Propaphenone; t h e f o lloWing ones W i l l be c i t e d a s aminoglucosides: t h eg e n t a m y c i n e s , a m i k a c i n e , d i b e k a c i n e , n e t i l m y c i n ,s i s o m y c i n , t o b r a m y c i n , m i c r o n o m y c i n e ; a s p h e n o t h i a Z i n e s ,p r o m e t h a Z i n e ; a s h y d r o a r o m a t i c m o l e c u l e s , r i b o ? a v i n ,9 - a m i n o d i h y d r o a c r i d i n e ; f u r t h e r c o r t i s o n i c d e r i v a t i v e s mayb e c i t e d , s u c h a s dexamethasone betamethasonet r i a m c i n o l o n e , ? u o c i n o n i d e , ? u n i s o l i d e , ? u o c i n o l o n ea c e t o n i d e , ? u o c o r t o l o n e , C l o b e t a s o n e a n d t h e i r d e r i v a t i v e s ,b e c l o m e t a s o n e a n d i t s e s t e r s ; T e t r a c y c l i n e d e r i v a t i v e s , s u c ha s Doxycycline o r M i n o c y c l i n e .

F o r t h e p u r p o s e o f i m p r o v i n g t h e s t a b i l i t y o f s u c hm e d i c i n a l a c t i v e p r i n c i p l e s Which a r e s u s c e p t i b l e t oo x i d a t i o n , a n d t h u s t o overcome h e d i s a d v a n t a g e s d e s c r i b e da b o v e , a p r o p o s a l h a s a l r e a d y b e e n made t o p r e v e n t t h ea c t i o n o f t h e o x y g e n , e i t h e r b y e l i m i n a t i n g t h e o x y g e n , o r b yn e u t r a l i Z i n g i t o r a g a i n b y c o m b i n i n g b o t h t h e s e t y p e s o fo p e r a t i o n .

S e v e r a l methods h a v e been u s e d f o r t h i s p u r p o s e :a e l i m i n a t i o n o f t h e o x y g e n b y r a i s i n g t h e t e m p e r a t u r e o f

t h e a q u e o u s s o l u t i o n , b y p u t t i n g t h e a q u e o u s s o l u t i o nunder v a c u u m o r b y bubbling an i n e r t gas such a sn i t r o g e n , c a r b o n d i o x i d e o r a r g o n t h r o u g h t h e s o l u t i o n .HoWever t h e s e m e t h o d s h a v e t h e d i s a d v a n t a g e o f a l l o W

i n g o n l y a p a r t i a l a n d i n s u f f i c i e n t e l i m i n a t i o n o f t h e o x y g e n ,o r r e q u i r

Documents

Cadence Pharmaceuticals Et. Al. v. Wockhardt Et. Al