Daravita Complaint Against Actavis - Patent Infringement

8/11/2019 Daravita Complaint Against Actavis - Patent Infringement

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IN THE UNITED STATES DISTRICT COURT

FOR THE DISTRICT OF DELAWARE

DARAVITA LIMITED,

Plaintiff,

v.

ACTAVIS LABORATORIES FL, INC.,

ANDRX CORPORATION, ACTAVIS

PHARMA, INC., and ACTAVIS, INC.,

Defendants.

)

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))

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C.A. No. ______________

COMPLAINT

Plaintiff Daravita Limited (Daravita or Plaintiff), for its Complaint against

Defendants Actavis Laboratories FL, Inc. (Actavis FL), Andrx Corporation (Andrx), Actavis

Pharma, Inc. (Actavis Pharma), and Actavis, Inc. (collectively Defendants), alleges as

follows:

PARTIES

1. Daravita is an Irish corporation having its principal place of business at

Connaught House, 1 Burlington Road, Dublin 4, Ireland.

2. On information and belief, Actavis FL is a Florida corporation having its principal

place of business at Morris Corporate Center III, 400 Interpace Parkway, Parsippany, NJ 07054.

On information and belief, Actavis FL is a wholly-owned subsidiary of Andrx.

3. On information and belief, Actavis FL is in the business of manufacturing,

marketing, importing, preparing, and selling generic pharmaceutical products that it distributes in

the State of Delaware and throughout the United States.

4. On information and belief, Andrx is a Delaware corporation having designated its

registered agent as The Corporation Trust Company, Corporation Trust Center, 1209 Orange St.,

Case 1:14-cv-01118-UNA Document 1 Filed 09/03/14 Page 1 of 8 PageID #: 1


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Wilmington DE 19801. On information and belief, Andrx is a wholly-owned subsidiary of

Actavis, Inc.

5. On information and belief, Actavis Pharma is a Delaware corporation having its

principal place of business at Morris Corporate Center III, 400 Interpace Parkway, Parsippany,

NJ 07054. On information and belief, Actavis Pharma is a wholly-owned subsidiary of Actavis,

Inc.

6. On information and belief, Actavis Pharma is in the business of, among other

things, marketing and distributing pharmaceutical products in the State of Delaware and

throughout the United States, including those that are manufactured by Actavis FL. On

information and belief, Actavis Pharma is registered with the Delaware Board of Pharmacy,

pursuant to 24 Del. C. 2540, as a licensed Pharmacy-Wholesale (License Nos. A4-0000627,

A4-0000683, and A4-0001998) and Distributor/Manufacturer CSR (License Nos. DS0503 and

DS0319).

7. On information and belief, Actavis, Inc. is a Nevada corporation having its

principal place of business at Morris Corporate Center III, 400 Interpace Parkway, Parsippany,

NJ 07054. On information and belief, Actavis, Inc. is in the business of, among other things,

marketing and distributing pharmaceutical products in the State of Delaware and throughout the

United States, including those that are manufactured by Actavis FL.

NATURE OF ACTION

8. This is an action for infringement of United States Patent Nos. 6,228,398 (the

398 patent) and 6,902,742 (the 742 patent). This action is based upon the Patent Laws of

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



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JURISDICTION AND VENUE

9. This Court has jurisdiction over the subject matter of this action pursuant to

28 U.S.C. 1331 and 1338(a).

10. This Court has personal jurisdiction over Defendants because they have

purposefully availed themselves of the privilege of selling their pharmaceutical products in the

State of Delaware and, therefore, can reasonably expect to be subject to jurisdiction in the

Delaware courts. Among other things, on information and belief, Defendants conduct marketing

and sales activities in the State of Delaware, including, but not limited to, the distribution,

marketing, and sales of pharmaceutical products to Delaware residents that are continuous and

systematic.

11. On information and belief, Defendants share common officers and directors and

are agents of each other, or work in concert with each other with respect to the development,

regulatory approval, marketing, sale, and distribution of pharmaceutical products throughout the

United States, including in the State of Delaware.

12.

In addition, Defendants have previously submitted to the jurisdiction of this Court

and have availed themselves of this Court by initiating lawsuits, consenting to this Courts

jurisdiction, and asserting counterclaims in civil actions initiated in this jurisdiction. See, e.g.,

Complaint for Patent Infringement, Sciele Pharma, Inc., Andrx Corp., et al. v. Lupin Ltd., et al. ,

No. 09-037-RBK (D. Del. Jan. 15, 2009) (D.I. 1); Defendants Answer, Defenses, and

Counterclaims, Fresenius Kabi USA, LLC v. Watson Labs., Inc. and Actavis, Inc., No. 14-161-

SLR (D. Del. Apr. 8, 2014) (D.I. 7); Watson Labs., Inc.s Answer, Affirmative Defenses, and

Counterclaims at 4,Forest Labs., Inc., et al. v. Apotex Corp. and Watson Labs., Inc. Florida, et

al., No. 14-200-LPS (D. Del. Apr. 22, 2014) (D.I. 22) (consenting to jurisdiction) and Notice of



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Name Change, No. 14-200-LPS (D. Del. June 6, 2014) (D.I. 48) (stating that Watson

Laboratories, Inc. - Florida changed its name to Actavis Laboratories FL, Inc. on April 21,

2014); Answer to First Amended Complaint and Defenses, Unimed Pharm., LLC, et al. v.

Watson Labs., Inc. and Actavis, Inc., No. 13-236-RGA (D. Del. Oct. 18, 2013) (D.I. 36), Joint

Stipulation, No. 13-236-RGA (D. Del. Apr. 1, 2014) (D.I. 77), and Joint Stipulation, No. 13-236-

RGA (D. Del. Apr. 2, 2014) (D.I. 78); Complaint for Patent Infringement, Kissei Pharm. Co.,

Ltd., Watson Labs., Inc. and Actavis, Inc. v. Hetero USA Inc., et al., No. 13-1091-LPS (D. Del.

June 17, 2013) (D.I. 1); Complaint for Patent Infringement, Kissei Pharm. Co., Ltd., Watson

Labs., Inc. and Actavis, Inc. v. Sandoz Inc., No. 13-1092-LPS (D. Del. June 17, 2013) (D.I. 1).

13. Venue is proper in this judicial district pursuant to 28 U.S.C. 1391(c) and

1400(b).

FACTUAL BACKGROUND

14. On May 8, 2001, the 398 patent, entitled Multiparticulate Modified Release

Composition, was duly and legally issued to Elan Corporation, plc (Elan) as assignee. Elans

rights were subsequently transferred to Alkermes Pharma Ireland Limited (APIL). APILs

rights were subsequently transferred to Alkermes Science One Limited, which changed its name

to Daravita Limited. A true and correct copy of the 398 patent is attached as ExhibitA.

15. On June 7, 2005, the 742 patent, entitled Multiparticulate Modified Release

Composition, was duly and legally issued to Elan as assignee. Elans rights were subsequently

transferred to APIL. APILs rights were subsequently transferred to Alkermes Science One

Limited, which changed its name to Daravita Limited. A true and correct copy of the 742 patent

is attached as Exhibit B.



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16. On October 25, 2013, the United States Food And Drug Administration (FDA)

approved new drug application No. 202880 for Zohydro ER extended-release capsules, which

contain hydrocodone bitartrate, under 505(a) of the Federal Food, Drug, and Cosmetic Act,

21 U.S.C. 355(a), for the management of pain severe enough to require daily, around-the-

clock, long-term opioid treatment and for which alternative treatment options are inadequate.

The 398 and 742 patents are listed in Approved Drug Products with Therapeut ic Equivalence

Evaluations (the Orange Book) for Zohydro ER capsules.

17. On information and belief, Defendants submitted abbreviated new drug

application (ANDA) No. 206952 to the FDA under 505(j) of the Federal Food, Drug and

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

use, and sale of hydrocodone bitartrate extended-release capsules in the 10, 15, 20, 30, 40, and

50 mg strengths, as generic versions of the Zohydro ER 10, 15, 20, 30, 40, and 50mg

capsules.

18. By letter dated August 12, 2014 (the Notice Letter), Defendants advised

Plaintiff that they had submitted ANDA No. 206952 seeking approval to manufacture, use, or

sell generic hydrocodone bitartrate extended-release capsules in the 10, 15, 20, 30, 40, and 50 mg

strengths prior to the expiration of the 398 and 742 patents.

19. The Notice Letters also advised Plaintiff that Defendants ANDA included a

certification under 21 U.S.C. 355(j)(2)(B)(ii) that, in Defendants opinion, the claims of the

398 and 742 patents are invalid or unenforceable.

COUNT I

20. Plaintiff incorporates each of the preceding paragraphs 1 to 19 as if fully set forth

herein.



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21. Defendants submission of ANDA No.206952 to the FDA for hydrocodone

bitartrate extended-release capsules in the 10, 15, 20, 30, 40, and 50 mg strengths, including the

505(j)(2)(B)(ii) allegations, constitutes infringement of the 398 patent under 35 U.S.C.

271(e)(2)(A). Defendants commercial manufacture, offer for sale, or sale of the proposed

generic for hydrocodone bitartrate extended-release capsules in the 10, 15, 20, 30, 40, and 50 mg

strengths would infringe the 398 patent.

22. On information and belief, Defendants were aware of the existence of the 398

patent and were aware that the filing of ANDA No. 206952 and certification with respect to the

398 patent constituted infringement of that patent. This is an exceptional case.

COUNT II

23. Plaintiff incorporates each of the preceding paragraphs 1 to 22 as if fully set forth

herein.

24. Defendants submission of ANDA No. 206952 to the FDA for hydrocodone

bitartrate extended-release capsules in the 10, 15, 20, 30, 40, and 50 mg strengths, including the

505(j)(2)(B)(ii) allegations, constitutes infringement of the 742 patent under 35 U.S.C.

271(e)(2)(A). Defendants commercial manufacture, offer for sale, or sale of the proposed

generic for hydrocodone bitartrate extended-release capsules in the 10, 15, 20, 30, 40, and 50 mg

strengths would infringe the 742 patent.

25. On information and belief, Defendants were aware of the existence of the 742

patent and were aware that the filing of ANDA No. 206952 and certification with respect to the

742 patent constituted infringement of that patent. This is an exceptional case.



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PRAYER FOR RELIEF

WHEREFORE, Plaintiff respectfully requests the following relief:

A. A judgment that Defendants have infringed the 398 and 742 patents;

B. An order, pursuant to 35 U.S.C. 271(e)(4)(A), that the effective date of any

approval of ANDA No. 206952 for hydrocodone bitartrate extended-release capsules in the 10,

15, 20, 30, 40, and 50 mg strengths under 505(j) of the Federal Food, Drug, and Cosmetic Act,

21 U.S.C. 355(j), shall not be earlier than the expiration dates of the 398 and 742 patents,

including any extensions;

C. A permanent injunction, pursuant to 35 U.S.C. 271(e)(4)(B), restraining and

enjoining Defendants, their officers, agents, servants, and employees, and those persons in active

concert or participation with any of them, from infringement of the 398 and 742 patents for the

full terms thereof, including any extensions;

D. A declaration that this is an exceptional case and an award of reasonable

attorneys fees pursuant to 35 U.S.C. 285;

E. Costs and expenses in this action; and

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



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MORRIS, NICHOLS, ARSHT & TUNNELL LLP

/s/ Maryellen NoreikaJack B. Blumenfeld (#1014)

Maryellen Noreika (#3208)Jeremy A. Tigan (#5239)

1201 N. Market StreetP.O. Box 1347

Wilmington, DE 19899-1347

(302) [email protected]

[email protected]

[email protected]

Attorneys for Daravita Limited

September 3, 20148473819



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EXHIBITA

Case 1:14-cv-01118-UNA Document 1-1 Filed 09/03/14 Page 1 of 31 PageID #: 9


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United S t a t e s

P a t e n t

US006228398B1

( 1 2 ) ( 1 0 )

P a t e n t

N 0 . : US 6 , 2 2 8 , 3 9 8 B 1

Devane

e t

a l . ( 4 5 ) D a t e o f P a t e n t : May , 2 0 0 1

54)

MULTIPARTICULATE MODIFIED RELE SE 5 , 8 3 7 , 2 8 4

1 1 / 1 9 9 8

Mehta e t a l . . . . . . . . . . . . . . . . . . . . . . . . . .

424/459

COMPOSITION

FOREIGN

PATENT

DOCUMENTS

7 5 )

I n v e n t o r s :

John G. Devane;

Paul

S t a r k ;

N i a l l

M . 0 2 7 4 7 3 4 A1 * 7 / 1 9 8 8 E P )

_

M

Fann i ng, a l l o f Athlone I E )

0

2 7 4 7 3 4 7 / 1 9 8 8 E P )

WO9703672 2 / 1 9 9 7

7 3 )

A s s i g n e e :

Elan C o r p o r a t i o n , PLC, D u b l i n

I E ) W 0 9 8 / 1 4 1 6 8 4 / 1 9 9 8 W0)

(

*

) N o t i c e : S u b j e c t

t o a n y d i s c l a i m e r , t h e t e r m o f

t h i s OTHER PUBLICATIONS

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

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a l . ,

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R e l . 1 9 8 9 )

9 : 1 6 9 1 7 5 .

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b y

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a l . ,

I n t . J .

Pharm

1 9 9 1 ) 7 7 : 1 7 7 1 8 1 .

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2 1 ) A p p l . N O . Z 0 9 / 5 6 6 , 6 3 6

* C i t e d

b y

e x a m i n e r

( 2 2 ) F i l e d ?

May

8 , 2 0 0 0

P r i m a r y E x a m i n e r T h u r m a n

K .

P a g e

_ _ Assistant ExaminerRachel

Bennett

R e l a t e d U - S -

A p p h c a t l o n

D a t a

7 4 ) A t t o r n e y ,

A g e n t , o r

F i r m K i l p a t r i c k

S t o c k t o n

LLP

6 3 )

C o n t i n u a t i o n

o f

a p p l i c a t i o n

N o . P C T / U S 9 9 / 2 5 6 3 2 ,

? l e d

o n 5 7 )

ABSTRACT

N o v .

1 ,

1 9 9 9 .

6 0 ) P r o v i s i o n a l a p p l i c a t i o n N O _ 6 0 / 1 0 6 , 7 2 6 ,

? l e d

o n N O V _ 2 The

i n v e n t i o n r e l a t e s t o

a

m u l t i p a r t i c u l a t e

modi?ed

r e l e a s e

1 9 9 8 . c o m p o s i t i o n t h a t i n o p e r a t i o n d e l i v e r s a n a c t i v e i n g r e d i e n t i n

5 1 ) I n t Cl 7 A61K / 1 4 a

p u l s e d

o r bimodal m a n n e r . The m u l t i p a r t i c u l a t e modi?e d

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. ~ release

Composition Comprises an immediate

release

Com_

5 2 ) US. l . . . . . . . . . . . . . . . . . . . . . . . . .

. .

4 2 4 / 4 8 4 , 4 2 4 / 4 6 4 , 4 2 4 / 4 6 5 ,

ponent

and

a

modi?ed r e l e a s e Component; t h e immediate

424/468

424/469

424/456

424/451 424/472 . . . .

_

release component comprising a ?rst

p o p ula t i o n of

active

F l e l d of Search

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . i n g r e d i e n t C o n t a i n i n g p a r t i c l e s and t h e

r e l e a s e

4 2 4 / 4 6 2 4 7 2 4 6 4 4 6 8 4 8 4 4 6 5 4 6 9 c o m p o n e n t

c o m p n s i m g

a s e c o n d p o p u l a t i o n o f a c t i v e i n g r e

4 5 6 4 5 1

d i e n t

c o n t a i n i n g

p a r t i c l e s c o a t e d W i t h a

c o n t r o l l e d

r e l e a s e

c o a t i n g ;

Wherein

t h e

combination

o f t h e immediate r e l e a s e

5 6 )

R e f e r e n c e s C l t e d a n d

m o d i ? e d r e l e a s e c o m p o n e n t s

i n o p e r a t i o n d e l i v e r t h e

us

PATENT

DOCUMENTS

a c t i v e i n g r e d i e n t

i n

a

pulsed

o r a bimodal

manner.

The

i n v e n t i o n

a l s o r e l a t e s t o a s o l i d o r a l d o s a g e f o r m

c o n t a i n i n g

4 , 7 2 8 , 5 1 2 3 / 1 9 8 8

M e ? t a e t a } . . . . . . . . . . . . . . . . . . . . . . . .

4 2 4 / 4 2 8

S u c h a r n u l t i p a r t i c u l a t e

r e l e a s e

C o m p o s i t i o n . T h e

I l l / [ S H E

: t t

: 1

6 2

p l a s m a

p r o ? l e a c h i e v e d

b y t h e m u l t i p a r t i c u l a t e

m o d i ? e d

4 9 0 4 4 7 6 2 / 1 9 9 0 M e h t a

e t

a l ' 4 2 4 /4 5 6

r e l e a s e

c o m p o s i t i o n i s a d v a n t a g e o u s i n r e d u c i n g p a t i e n t

5 : 1 5 8 : 1 7 7

1 0 / 1 9 9 2

A b r a m o w i t i 4 2 4 / 4 5 8 t o l e r a n c e

t o

t h e a c t i v e

i n g r e d i e n t

a n d

i n i n c r e a s i n g

p a t i e n t

5 , 4 4 5 , 8 2 9 * 8 / 1 9 9 5 P a r a d i s s i s e t a l . . . . . . . . . . . . . . . . . . . . 4 2 4 / 4 8 0 compllance b y reduclng dosage frequency

5 , 6 3 9 , 4 7 6 * 6/1997 Oshlack

e t

a l . .

5 , 7 2 6 , 3 1 6 *

3 / 1 9 9 8

Crooks e t a l . 37 Claims, 1 D r a w i n g Sheet

6 I I

5

4

l a s m ao n c e n t r t i o nn g l m )

C o n t r o l



11/41

U S Patent May 8 , 2 0 0 1 U S 6 , 2 2 8 , 3 9 8

B1

T l m e )

i g u r e



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US

6 , 2 2 8 , 3 9 8

B1

1

MULTIP RTICUL TE MODIFIED RELE SE

COMPOSITION

T h i s a p p l i c a t i o n i s

a

c o n t i n u a t i o n o f PCT/US99/25632,

? l e d N o v .

1 ,

1 9 9 9 , Which c l a i m s b e n e ? t o f S e r .

N o .

6 0 / 1 0 6 7 2 6 , ? l e d

N o v .

2 ,

1 9 9 8 .

FIELD OF THE INVENTION

The

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

a


modi

? e d

r e l e a s e c o m p o s i t i o n . I n p a r t i c u l a r t 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

a m u l t i p a r t i c u l a t e

modi?ed

r e l e a s e c o m p o s i t i o n

t h a t i n o p e r a t i o n d e l i v e r s a n

a c t i v e

i n g r e d i e n t i n a p u l s a t i l e

m a n n e r .

T he

p r e s e n t

i n v e n t i o n

f u r t h e r r e l a t e s t o

s o l i d o r a l

d o s a g e f o r m s c o n t a i n i n g s u c h

a m u l t i p a r t i c u l a t e

c o n t r o l l e d

r e l e a s e c o m p o s i t i o n .

DESCRIPTION

OF

THE

PRIOR

RT

T h e p l a s m a

p r o ? l e a s s o c i a t e d W i t h

t h e

a d m i n i s t r a t i o n o f

a d r u g compound may b e d e s c r i b e d

a s

a p u l s a t i l e p r o ? l e

i n

W h i c h

p u l s e s o f h i g h a c t i v e

i n g r e d i e n t c o n c e n t r a t i o n ,

i n t e r s p e r s e d W i t h

loW o n c e n t r a t i o n

t r o u g h s ,

a r e

o b s e r v e d .

p u l s a t i l e p r o ? l e c o n t a i n i n g t W o

p e a k s

may b e

d e s c r i b e d

a s

b i m o d a l . S i m i l a r l y , a c o m p o s i t i o n

o r

a d o s a g e form Which

p r o d u c e s s u c h a p r o ? l e upon

a d m i n i s t r a t i o n

may

b e

s a i d

t o

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

C o n v e n t i o n a l f r e q u e n t d o s a g e r e g i m e s i n W h i c h a n

imme

d i a t e r e l e a s e I R ) d o s a g e f o r m i s

a d m i n i s t e r e d

a t p e r i o d i c

i n t e r v a l s t y p i c a l l y

g i v e s r i s e

t o a p u l s a t i l e

p l a s m a

p r o ? l e . I n

t h i s

c a s e , a p e a k i n t h e p l a s m a d r u g

c o n c e n t r a t i o n

i s

o b s e r v e d a f t e r

a d m i n i s t r a t i o n o f e a c h

IR d o s e W i t h

t r o u g h s

r e g i o n s

o f

l o W

d r u g c o n c e n t r a t i o n ) d e v e l o p i n g

b e t W e e n

c o n s e c u t i v e


t i m e p o i n t s .

S u c h

d o s a g e

r e g i m e s

a n d

t h e i r r e s u l t a n t p u l s a t i l e

p l a s m a

p r o ? l e s )

h a v e

p a r t i c u l a r

p h a r m a c o l o g i c a l

a n d t h e r a p e u t i c

e f f e c t s

a s s o c i

a t e d

W i t h t h e m . F o r e x a m p l e ,

t h e

Wash o u t

p e r i o d

p r o v i d e d

by t h e

f a l l

o f f

o f

t h e p l a s m a c o n c e n t r 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

b e t W e e n p e a k s h a s

b e e n

t h o u g h t t o b e a c o n t r i b

u t i n g f a c t o r i n r e d u c i n g o r p r e v e n t i n g p a t i e n t

t o l e r a n c e

t o

v a r i o u s

t y p e s o f d r u g s .

Many c o n t r o l l e d

r e l e a s e

d r u g

f o r m u l a t i o n s

a r e aimed

a t

p r o d u c i n g

a

Z e r o - o r d e r r e l e a s e o f

t h e

d r u g c o m p o u n d .

I n d e e d , i t i s o f t e n

a s p e c i ? c

o b j e c t o f t h e s e f o r m u l a t i o n s t o

m i n i m i s e t h e p e a k - t o - t r o u g h

v a r i a t i o n i n d r u g p l a s m a

l e v e l s

a s s o c i a t e d W i t h

c o n v e n t i o n a l

f r e q u e n t

d o s a g e

r e g i m e s .

H o W e v e r ,

some o f

t h e t h e r a p e u t i c

a n d

p h a r m a c o l o g i c a l

e f f e c t s i n t r i n s i c i n a p u l s a t i l e system may be l o s t

o r

dimin

i s h e d

a s a r e s u l t

o f

t h e

c o n s t a n t

o r

n e a r l y

c o n s t a n t

plasma

l e v e l s a c h i e v e d

b y Z e r o - o r d e r r e l e a s e

d r u g

d e l i v e r y s y s t e m s .

T h u s , a

modi?ed r e l e a s e

c o m p o s i t i o n o r f o r m u l a t i o n

Which

s u b s t a n t i a l l y m i m i c s t h e r e l e a s e o f f r e q u e n t I R

d o s a g e

r e g i m e s ,

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6 , 2 2 8 , 3 9 8

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US. P a t . N o . 5 , 1 5 8 , 7 7 7 R . S q u i b b S o n s I n c .

d i s c l o s e s

a f o r m u l a t i o n c o m p r i s i n g c a p t o p r i l W i t h i n a n

e n t e r i c o r

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i s

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i m m e d i a t e

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a d m i n i s t r a t i o n .

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s t a b l e c o r e , c h e l a t i n g

a g e n t s

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a g e n t .

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amount

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i n

t h e

c o l o n .

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4 , 7 9 4 , 0 0 1

a n d 4 , 9 0 4 , 4 7 6

A m e r i c a n Home P r o d u c t s

C o r p . )

r e l a t e

t o

p r e p a r a t i o n s

p r o v i d i n g t h r e e d i s t i n c t

r e l e a s e s .

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t h r e e

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

a c t i v e m e d i c i n a l

s u b s t a n c e :

t h e ? r s t

g r o u p o f s p h e r o i d s

i s

u n c o a t e d

a n d

r a p i d l y

d i s i n t e g r a t e s

upon

i n g e s t i o n t o r e l e a s e a n i n i t i a l d o s e

o f m e d i c i n a l

s u b s t a n c e ;

t h e

s e c o n d

g r o u p

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i s

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c o a t

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d o s e ;

a n d

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o f

s p h e r o i d s i s

c o a t e d W i t h

a

pH

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d e s i g n e d t o p r o v i d e r e p e a t e d

r e l e a s e

o f m e d i c i n a l s u b s t a n c e s

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e x t e n s i v e l y

m e t a b o l i s e d p r e s y s t e m i c a l l y

o r h a v e

r e l a t i v e l y s h o r t

e l i m i n a t i o n h a l f - l i v e s .

US.

P a t . N o .

5 , 8 3 7 , 2 8 4

M e h t a

e t

a l

d i s c l o s e s

a

meth

y l p h e n i d a t e d o s a g e f o r m

h a v i n g

i m m e d i a t e

r e l e a s e

a n d

d e l a y e d r e l e a s e p a r t i c l e s . T h e d e l a y e d r e l e a s e s p r o v i d e d

b y

t h e

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

combined

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t

i s

a n

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 t o

p r o v i c e a m u l t i p a r t i c u l a t e

m o d i ? e d

r e l e a s e

c o m p o s i t i o n

c o n t a i n i n g

a n

a c t i v e

i n g r e d i e n t W h i c h

i n o p e r a t i o n p r o d u c e s

a p l a s m a p r o ? l e s u b s t a n t i a l l y s i m i l a r t o t h e p l a s m a p r o ? l e

p r o d u c e d

by t h e a d m i n i s t r a t i o n o f tWo o r more IR d o s a g e

f o r m s g i v e n s e q u e n t i a l l y .

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t h e

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t o

p r o v i d e a m u l t i

p a r t i c u l a t e m o d i ? e d

r e l e a s e

c o m p o s i t i o n W h i c h i n

o p e r a t i o n

d e l i v e r s an

a c t i v e

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i n

a p u l s a t i l e manner.

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o b j e c t

o f t h e i n v e n t i o n i s t o p r o v i d e a m u l t i p a r

t i c u l a t e

m o d i ? e d

r e l e a s e


W h i c h

s u b s t a n t i a l l y

m i m i c s t h e p h a r m a c o l o g i c a l a n d

t h e r a p e u t i c

e f f e c t s p r o

duced by h e


o f tWo o r more IR d o s a g e

forms

g i v e n s e q u e n t i a l l y .

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t h e

p r e s e n t i n v e n t i o n

i s

t o p r o v i d e

a


m o d i ? e d

r e l e a s e


W h i c h

s u b

s t a n t i a l l y r e d u c e s

o r

e l i m i n a t e s

t h e d e v e l o p m e n t

o f p a t i e n t

t o l e r a n c e t o t h e a c t i v e i n g r e d i e n t o f t h e c o m p o s i t i o n .

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o f

t h e i n v e n t i o n

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t o

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m u l t i p a r

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a

? r s t p o r 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 i s r e l e a s e d

i m m e d i a t e l y

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a s e c o n d

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t h e a c t i v e

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i s

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manner.

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o b j e c t o f t h e i n v e n t i o n i s t o p r o v i d e

a

m u l t i p a r

t i c u l a t e m o d i ? e d

r e l e a s e


c a p a b l e o f r e l e a s i n g

t h e a c t i v e i n g r e d i e n t i n a

bimodal

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a ? r s t

p o r 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

i s

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t o

p r o v i d e

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10

1 5

20

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40

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O t h e r

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BRIEF DESCRIPTION

OF THE INVENTION

The

a b o v e

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p o p u l a t i o n o f

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i n g r e d i e n t

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

t h e s e c o n d component

a r e c o a t e d

With

a modi ? e d

r e l e a s e c o a t i n g. A l t e r n a t i v e l y

o r

a d d i t i o n a l l y , t h e s e c o n d p o p u l a t i o n o f

a c t i v e

i n g r e d i e n t

c o n t a i n i n g

p a r t i c l e s

f u r t h e r

c o m p r i s e s

a

m o d i ? e d

r e l e a s e

m a t r i X m a t e r i a l .

F o l l o W i n g

o r a l

d e l i v e r y ,

t h e

c o m p o s i t i o n i n

o p e r a t i o n

d e l i v e r s

t h e a c t i v e i n gr e d i e n t o r a c t i v e i n g r e d i e n t s

i n

a p u l s a t i l e

manner.

I n

a

p r e f e r r e d embodiment

o f a m u l t i p a r t i c u l a t e

modi?ed

r e l e a s e

c o m p o s i t i o n a c c o r d i n g

t o t h e

i n v e n t i o n t h e ? r s t

component i s a n immediate r e l e a s e c o m p o n e n t .

The modi?ed e l e a s e c o a t i n g a p p l i e d t o t h e s e c o n d popu

l a t i o n o f

a c t i v e

i n g r e d i e n t c o n t a i n i n g p a r t i c l e s c a u s e s a

l a g

t i m e

b e t W e e n

t h e r e l e a s e

o f

a c t i v e

i n g r e d i e n t

f r o m t h e ? r s t

p o p u l a t i o n o f


c o n t a i n g

p a r t i c l e s a n d t h e

r e l e a s e

o f

a c t i v e i n g r e d i e n t f r o m t h e

s e c o n d p o p u l a t i o n o f

a c t i v e

i n g r e d i e n t c o n t a i n i n g p a r t i c l e s .

S i m i l a r l y , t h e

p r e s

e n c e

o f

a modi?ed r e l e a s e m a t r i x m a t e r i a l i n t h e second

p o p u l a t i o n o f a c t i v e i n g r e d i e n t c o n t a i n i n g p a r t i c l e s

c a u s e s

a

l a g t i m e b e t W e e n

t h e r e l e a s e

o f

a c t i v e

i n g r e d i e n t f r o m

t h e

? r s t

p o p u l a t i o n o f a c t i v e

i n g r e d i e n t

c o n t a i n i n g

p a r t i c l e s

a n d

t h e

r e l e a s e o f

a c t i v e i n g r e d i e n t f r o m t h e

s e c o n d

p o p u l a t i o n

o f

a c t i v e i n g r e d i e n t c o n t a i n i n g p a r t i c l e s . T h e

d u r a t i o n o f

t h e

l a g t i m e may b e

v a r i e d b y

a l t e r i n g t h e c o m p o s i t i o n

a n d / o r

t h e

a m o u n t o f

t h e

modi?ed

r e l e a s e

c o a t i n g a n d / o r a l t e r i n g

t h e

c o m p o s i t i o n a n d / o r

amount o f

modi?ed

r e l e a s e m a t r i X

m a t e r i a l u t i l i s e d . T h u s ,

t h e

d u r a t i o n o f

t h e l a g

t i m e c a n b e

d e s i g n e d t o mimic a d e s i r e d p l a s m a p r o ? l e .

B e c a u s e t h e

p l a s m a p r o ? l e

p r o d u c e d

b y

t h e m u l t i p a r t i c u

l a t e modi?ed

r e l e a s e c o m p o s i t i o n

upon

a d m i n i s t r a t i o n i s

s u b s t a n t i a l l y s i m i l a r t o t h e p l a s m a

p r o ? l e

p r o d u c e d b y t h e


o f

tWo o r

more

IR

dosage forms

g i v e n

s e q u e n t i a l l y , t h e


c o n t r o l l e d r e l e a s e compo

s i t i o n o f t h e p r e s e n t i n v e n t i o n

i s

p a r t i c u l a r l y u s e f u l

f o r

a d m i n i s t e r i n g

a c t i v e i n g r e d i e n t s f o r

W h i c h p a t i e n t

t o l e r a n c e

may

b e p r o b l e m a t i c a l .

T h i s


modi?ed

r e l e a s e


i s t h e r e f o r e a d v a n t a g e o u s f o r r e d u c i n g

o r m i m i m i s i n g t h e

d e v e l o p m e n t

o f p a t i e nt t o l e r a n c e t o t h e

a c t i v e i n g r e d i e n t i n

t h e

c o m p o s i t i o n .

I n

a

p r e f e r r e d embodiment

o f t h e p r e s e n t

i n v e n t i o n, t h e

a c t i v e

i n g r e d i e n t

i s m e t h y l p h e n i d a t e

a n d

t h e c o m p o s i t i o n

i n

o p e r a t i o n d e l i v e r s t h e


i n a

bimodal o r

p u l s e d

m a n n e r . Such

a c o m p o s i t i o n i n o p e r a t i o n p r o d u c e s a

p l a s m a

p r o ? l e

W h i c h s u b s t a n t i a l l y m i m i c s t h a t

o b t a i n e d

b y

t h e

s e q u e n t i a l a d m i ni s t r a t i o n o f

tWo

IR d o s e s a s ,

f o r

i n s t a n c e ,

i n a

t y p i c a l


t r e a t m e n t r e g i m e .

T h e p r e s e n t i n v e n t i o n

a l s o

p r o v i d e s

s o l i d

o r a l

d o s a g e

f o r m s

c o m p r i s i n g

a

c o m p o s i t i o n a c c o r d i n g t o t h e i n v e n t i o n .



14/41

US

6 , 2 2 8 , 3 9 8

B1

5

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

o r a l

d o s a g e

f o r m

a c c o r d i n g

t o t h e i n v e n t i o n

t o p r o v i d e

p u l s e d

o r

b i m o d a l


o f t h e a c t i v e i n g r e d i e n t .

A d v a n t a g e s o f

t h e

p r e s e n t i n v e n t i o n i n c l u d e

r e d u c i n g

t h e

d o s i n g f r e q u e n c y r e q u i r e d

b y

c o n v e n t i o n a l m u l t i p l e

I R

d o s a g e r e g i m e s W h i l e

s t i l l

m a i n t a i n i n g

t h e

b e n e ? t s d e r i v e d

f r o m a

p u l s a t i l e

p l a s m a p r o ? l e . T h i s r e d u c e d d o s i n g f r e

q u e n c y

i s p a r t i c u l a r l y a d v a n t a g e o u s i n t h e c a s e

o f c h i l d r e n

i n

t a a t

i t

e l i m i n a t e s t h e n e e d

f o r

d o s i n g

d u r i n g

t h e

m i d d l e o f

t h e s c h o o l d a y Which c a n b e b o t h d i s r u p t i v e a n d e m b a r r a s s

i n g f o r t h e p a t i e n t . I t i s a l s o

a d v a n t a g e o u s

i n

t e r m s

o f p a t i e n t

compliance t o have

a f o r m u l a t i o n Which may

be a d m i n i s

t e r e d a t r e d u c e d f r e q u e n c y . The r e d u c t i o n

i n

d o s a g e f r e

q u e n c y

m a d e p o s s i b l e

b y

u t i l i s i n g t h e

p r e s e n t i n v e n t i o n

Would c o n t r i b u t e t o

r e d u c i n g

h e a l t h c a r e

c o s t s

by

r e d u c i n g

t h e amount o f t i m e

s p e n t

b y h e a l t h c a r e Workers on t h e


o f d r u g s . I n t h e

c a s e

o f m e t h y l p h e n i d a t e , a n d

o t h e r c o n t r o l l e d s u b s t a n c e s , t h e

u s e o f

a o n c e - d a i l y formu

l a t i o n i n p l a c e o f

m u l t i p l e

I R d o s e s )

r e d u c e s

o r

e l i m i n a t e s

t h e need

f o r

t h e

s t o r a g e o f

c o n t r o l l e d

s u b s t a n c e s

on t h e

p r e m i s e s o f s c h o o l s

o r o t h e r

i n s t i t u t i o n s .

DESCRIPTION

OF THE DRAWINGS

F I G . 1

s h o W s

m e t h y l p h e n i d a t e p l a s m a p r o ? l e s f o l l o W i n g

o r a l


t h e

f o l l o W i n g

t h r e e f o r m u l a t i o n s

t o

human

v o l u n t e e r s :

A2 m g


f o r m u l a t i o n

h a v i n g

a n i m m e d i a t e

r e l e a s e component c o m p r i s i n g

p a r

t i c l e s c o n t a i n i n g

a t o t a l

o f 1 0 mg m e t h y l p h e n i d a t e

a c c o r d i n g t o T a b l e 1 i i ) ) a n d

a

modi?ed r e l e a s e component

c o m p r i s i n g p a r t i c l e s c o n t a i n i n g a t o t a l o f

1 0

m g m e t h

y l p h e n i d a t e

a c c o r d i n g t o T a b l e 2 v i i i ) ; I R p a r t i c l e s c o a t e d

t o a

30

W e i g h t gain);B20 mg m e t h y l p h e n i d a t e

f o r m u

l a t i o n

h a v i n g a n

i m m e d i a t e r e l e a s e c o m p o n e n t

c o m p r i s i n g

p a r t i c l e s

c o n t a i n i n g

a t o t a l

1 0

m g


a c c o r d i n g t o T a b l e 1 i i ) ) a n d

a

modi?ed r e l e a s e component

c o m p r i s i n g p a r t i c l e s c o n t a i n i n g a t o t a l o f

1 0

m g

m e t h

y l p h e n i d a t e a c c o r d i n g

t o

T a b l e 2 v i i ) ; I R p a r t i c l e s c o a t e d

t o

a

30

W e i g h t g a i n ) ; a n d ControltWo

d o s e s

o f 1 0 mg

R i t a l i n H y d r o c h l o r i d e I R )

t a b l e t s

a d m i n i s t e r e d a t t i m e s

0

a n d 4

h o u r s t o t a l o f

2 0 mg


a d m i n i s t e r e d ) .

DETAILED DESCRIPTION

OF THE

INVENTION

T h e term p a r t i c u l a t e a s

used

h e r e i n r e f e r s

t o

a s t a t e ,

o f

m a t t e r

Which

i s c h a r a c t e r i s e d by

t h e

p r e s e n c e o f d i s c r e t e

p a r t i c l e s ,

p e l l e t s , b e a d s

o r

g r a n u l e s

i r r e s p e c t i v e

o f

t h e i r s i Z e ,

s h a p e o r m o r p h o l o g y . The

t e r m

m u l t i p a r t i c u l a t e a s u s e d

h e r e i n

means

a p l u r a l i t y

o f

d i s c r e t e ,

o r a g g r e g a t e d ,

p a r t i c l e s ,

p e l l e t s , b e a d s , g r a n u l e s o r

m i x t u r e t h e r e o f

i r r e s p e c t i v e

o f

t h e i r

s i Z e , s h a p e

o r m o r p h o l o g y .

T h e term mo di ?ed r e l e a s e

a s used

h e r e i n i n r e l a t i o n t o

t h e


a c c o r d i n g t o

t h e i n v e n t i o n o r a c o a t i n g o r

c o a t i n g

m a t e r i a l

o r

used

i n

any

o t h e r c o n t e x t means r e l e a s e

Which

i s n o t immediate r e l e a s e

and i s

t a k e n t o en co m pa ss

c o n t r o l l e d r e l e a s e ,

s u s t a i n e d r e l e a s e a n d

d e l a y e d r e l e a s e .

T h e

t e r m t i m e d e l a y a s used

e r e i n

r e f e r s t o t h e

d u r a t i o n

o f t i m e

b e t W e e n

a d m i n i s t r a t i o n o f t h e c o m p o s i t i o n a n d t h e

r e l e a s e o f t h e a c t i v e i n g r e d i e n t f r o m a p a r t i c u l a r

c o m p o n e n t .

T h e

t e r m

l a g t i m e a s used

h e r e i n

r e f e r s t o t h e t i m e

b e t W e e n d e l i v e r y o f a c t i v e i n g r e d i e n t f r o m o n e

component

a n d t h e s u b s e q u e n t

d e l i v e r y o f

a c t i v e

i n g r e d i e n t

f r o m

a n o t h e r

c o m p o n e n t .

The

i n v e n t i o n

W i l l b e

d e s c r i b e d

i n d e t a i l

W i t h

r e s p e c t t o

m e t h y l p h e n i d a t e a s

a s p e c i ? c

example

o f a n

a c t i v e

i n g r e d i

10

1 5

25

35

55

6

T h e


m o d i ? e d

r e l e a s e

c o m p o s i t i o n o f

t h e

i n v e n t i o n may have more

t h a n

tWo a c t i v e i n g r e d i e n t

c o n t a i n i n g

c o m p o n e n t s . I n

t h i s c a s e t h e

r e l e a s e o f

a c t i v e

i n g r e d i e n t f r o m t h e s e c o n d a n d s u b s e q u e n t

c o m p o n e n t s i s

modi?ed

s u c h

t h a t t h e r e i s a

l a g

t i m e

betWeen t h e r e l e a s e

o f

a c t i v e

i n g r e d i e n t

f r o m

t h e ? r s t

component

a n d e a c h

s u b s e

q u e n t c o m p o n e n t . T h e n u m b e r o f

p u l s e s

i n t h e p r o ? l e a r i s i n g

from

s u c h a c o m p o s i t i o n i n o p e r a t i o n W i l l d e p e n d on t h e

n u m b e r o f a c t i v e i n g r e d i e n t c o n t a i n i n g c o m p o n e n t s i n t h e

c o m p o s i t i o n . A c o m p o s i t i o n

c o n t a i n i n g

t h r e e a c t i v e

i n g r e d i e n t - c o n t a i n i n g c o m p o n e n t s

W i l l g i v e

r i s e t o

t h r e e

p u l s e s i n

t h e

p r o ? l e .

Any

c t i v e

i n g r e d i e n t

f o r

Which

t i s

u s e f u l t o

combine h e

a d v a n t a g e s o f a p u l s a t i l e p l a s m a p r o ? l e W i t h a r e d u c e d

f r e q u e n c y

d o s a g e

r e g i m e may b e u s e d

i n

p r a c t i c e o f t h e

p r e s e n t i n v e n t i o n . P a r t i c u l a r l y u s e f u l l i n t h e p r a c t i c e o f t h e

i n v e n t i o n i n c l u d e

a c t i v e i n g r e d i e n t s

W h o s e p h a r m a c o l o g i c a l

a n d / o r

t h e r a p e u t i c e f f e c t s b e n e ? t f r o m h a v i n g a

W a s h - o u t

p e r i o d b e t W e e n p l a s m a

c o n c e n t r a t i o n p e a k s , s u c h a s t h o s e

a c t i v e

i n g r e d i e n t s

s u s c e p t i b l e

t o

t h e

d e v e l o p m e n t

o f

p a t i e n t

t o l e r a n c e .

Example

a c t i v e

i n g r e d i e n t s i n c l u d e

b u t

a r e

n o t

l i m i t e d t o p e p t i d e s

o r

p r o t e i n s , h o r m o n e s , a n a l g e s i c s ,

a n t i

m i g r a i n e

a g e n t s , a n t i - c o a g u l a n t a g e n t s ,

n a r c o t i c

a n t a g o n i s t s ,

c h e l a t i n g a g e n t s , a n t i - a n g i n a l a g e n t s , c h e m o t h e r a p y a g e n t s ,

s e d a t i v e s ,

a n t i - n e o p l a s t i c s , p r o s t a g l a n d i n s a n d a n t i d i u r e t i c

a g e n t s ,

d r u g

compounds a c t i n g on t h e c e n t r a l

n e r v o u s

s y s

t e m s u c h

a s c e r e b r a l s t i m u l a nt s ,

f o r e x a m p l e m e t h y l p h e n i

d a t e ;

p a i n management c t i v e

i n g r e d i e n t s ; a l k a l o i d s

s u c h

a s

o p i a t e s ,

f o r e x a m p l e m o r p h i n e ; c a r d i o v a s c u l a r

d r u g s ,

s u c h

a s n i t r a t e s ; a n d a g e n t s f o r t r e a t i n g r h e u m a t i c c o n d i t i o n s .

I t

i s

f u r t h e r a p p r e c i a t e d

t h a t t h e p r e s e n t i n v e n t i o n

may e u s e d

t o

d e l i v e r a number

o f

d r u g s i n c l u d i n g , b u t

n o t

l i m i t e d t o ,

p e p t i d e s , p r o t e i n s o r h o r m o n e s

s u c h

a s

i n s u l i n ,

c a l c i t o n i n ,

c a l c i t o n i n

g e n e

r e g u l a t i n g

p r o t e i n ,

a t r i a l

n a t r i u r e t i c

p r o t e i n ,

c o l o n y

s t i m u l a t i n g

f a c t o r ,

b e t a s e r o n , e r y t h r o p o i e t i n E P O ) ,

i n t e r f e r o n s s u c h

a s

0 t ,

[

o r y

i n t e r f e r o n , s o m a t r o p i n ,

s o m a t o t r o p i n , s o m a s t o s t a t i n , i n s u l i n - l i k e g r o W t h f a c t o r

s o m a t o m e d i n s ) , l u t e i n i Z i n g h o i m o n e r e l e a s i n g

h o r m o n e

L H R H ) ,

t i s s u e

p l a s m i n o g e n a c t i v a t o r T P A ) , g r o W t h

h o r

mone r e l e a s i n g h o r m o n e (GHRH), o x y t o c i n , e s t r a d i o l ,

g r o W t h h o r m o n e s , l e u p r o l i d e a c e t a t e , f a c t o r V I I I , i n t e r l e u

k i n s s u c h

a s i n t e r l e u k i n - 2 , a n d

a n a l o g u e s t h e r e o f ;

a n a l g e s i c s

s u c h a s f e n t a n y l , s u f e n t a n i l , b u t o r p h a n o l ,

b u p r e n o r p h i n e ,

l e v o r p h a n o l , m o r p h i n e , h y d r o m o r p h o n e , h y d r o c o d o n e ,

o x y m o r p h o n e ,

m e t h a d o n e , l i d o c a i n e ,

b u p i v a c a i n e ,

d i c l o f e n a c ,

n a p r o x e n ,

p a v e r i n , a n d a n a l o g u e s t h e r e o f ;

a n t i

m i g r a i n e a g e n t s

s u c h a s

s u m a t r i p t a n ,

e r g o t a l k a l o i d s , a n d

a n a l o g u e s

t h e r e o f ;

a n t i - c o a g u l a n t

a g e n t s

s u c h

a s

h e p a r i n ,

h i r u d i n , a n d a n a l o g u e s t h e r e o f ; a n t i - e m e t i c a g e n t s s u c h a s

s c o p o l a m i n e , o n d a n s e t r o n , d o m p e r i d o n e , m e t o c l o p r a m i d e ,

a n d

a n a l o g u e s t h e r e o f ; c a r d i o v a s c u l a r

a g e n t s ,

a n t i

h y p e r t e n s i v e

a g e n t s

a n d

v a s o d i l a t o r s s u c h a s d i l t i a Z e m ,

c l o n i d i n e ,

n i f e d i p i n e ,

v e r a p a m i l ,

i s o s o r b i d e - S - m o n o n i t r a t e ,

o r g a n i c

n i t r a t e s ,

a g e n t s u s e d

i n

t r e a t m e n t o f h e a r t d i s o r d e r s ,

a n d a n a l o g u e s

t h e r e o f ; s e d a t i v e s

s u c h a s b e n Z o d i a Z e p i n e s ,

p h e n o t h i o Z i n e s ,

a n d

a n a l o g u e s

t h e r e o f ; c h e l a t i n g a g e n t s

s u c h a s

d e f e r o x a m i n e , a n d a n a l o g u e s t h e r e o f ; a n t i - d i u r e t i c

a g e n t s s u c h a s d e s m o p r e s s i n , v a s o p r e s s i n , a n d a n a l o g u e s

t h e r e o f ;

a n t i - a n g i n a l

a g e n t s s u c h a s n i t r o g l y c e r i n e , a n d a n a

l o g u e s

t h e r e o f

a n t i - n e o p l a s t i c s

s u c h a s ? u o r o u r a c i l ,

b l e o m y c i n ,

a n d

a n a l o g u e s

t h e r e o f ;

p r o s t a g l a n d i n s a n d a n a

l o g u e s

t h e r e o f ;

a n d

c h e m o t h e r a p y

a g e n t s

s u c h

a s v i n c r i s t i n e ,

a n d

a n a l o g u e s

t h e r e o f .

T h e

a c t i v e

i n g r e d i e n t

i n

e a c h component may e

t h e

same



15/41

US

6 , 2 2 8 , 3 9 8

B1

7

d e s i r a b l e f o r combination t h e r a p i e s . I n d e e d , tW o o r m ore

a c t i v e i n g r e d i e n t s

m a y b e

i n c o r p o r a t e d i n t o t h e

same

c o m

p o n e n t When

h e a c t i v e i n g r e d i e n t s

r e

c o m p a t i b l e

W i t h e a c h

o t h e r . r u g compound p r e s e n t i n

o n e

component

o f t h e


may b e

a c c o m p a n i e d

b y , f o r

e x a m p l e , a n

e n h a n c e r c o m p o u n d

o r

a s e n s i t i s e r

c o m p o u n d

i n

a n o t h e r

c o m p o n e n t o f

t h e

c o m p o s i t i o n ,

i n o r d e r t o m o d i f y

t h e

b i o a v a i l a b i l i t y o r

t h e r a p e u t i c e f f e c t

o f t h e

d r u g

c o m p o u n d .

As s e d

h e r e i n , t h e

t e r m e n h a n c e r r e f e r s

t o

a c o m p o u n d

W h i c h i s

c a p a b l e o f

e n h a n c i n g t h e a b s o r p t i o n a n d / o r b i o

a v a i l a b i l i t y o f a n

a c t i v e i n g r e d i e n t by

p r o m o t i n g

n e t t r a n s

p o r t

a c r o s s t h e GIT n an a n i m a l , such a s a hum a n.

E n h a n c

e r s i n c l u d e

b u t

a r e n o t

l i m i t e d

t o m e d i u m

c h a i n

f a t t y a c i d s ;

s a l t s , e s t e r s , e t h e r s a n d

d e r i v a t i v e s

t h e r e o f ,

i n c l u d i n g

g l y c

e r i d e s a n d

t r i g l y c e r i d e s ; n o n - i o n i c

s u r f a c t a n t s

s u c h

a s t h o s e

t h a t

c a n b e

p r e p a r e d b y r e a c t i n g e t h y l e n e

o x i d e W i t h

a

f a t t y

a c i d ,

a

f a t t y a l c o h o l ,

a n a l k y l p h e n o l o r a s o r b i t a n

o r g l y c e r o l

f a t t y a c i d e s t e r ;

c y t o c h r o m e

P 4 5 0 i n h i b i t o r s , P - g l y c o p r o t e i n

i n h i b i t o r s

and t h e

l i k e ; and

m i x t u r e s o f

t Wo

o r more o f t h e s e

a g e n t s .

T h e

p r o p o r t i o n o f

a c t i v e

i n g r e d i e n t

c o n t a i n e d

i n

e a c h

c o m p o n e n t

may

e t h e s a m e o r d i f f e r e n t depending o n t h e

d e s i r e d

d o s i n g

r e g i m e .

T h e a c t i v e

i n g r e d i e n t may

e p r e s e n t ,

i n t h e

? r s t

component

i n d i v i d u a l l y o r

i n

c o m b i n a t i o n

W i t h

t h e a c t i v e i n g r e d i e n t

o r

a c t i v e i n g r e d i e n t s )

i n

t h e s e c o n d

component,

i n any

a m ou nt

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

r e s p o n s e .

T h e

a c t i v e i n g r e d i e n t o r a c t i v e i n g r e d i e n t s ) , When

a p p l i c a b l e , m ay

b e

p r e s e n t e i t h e r i n t h e form

o f

o n e s u b

s t a n t i a l l y

o p t i c a l l y

p u r e e n a n t i o m e r o r a s a m i x t u r e , r a c e m i c

o r

o t h e r W i s e ,

o f e n a n t i o m e r s . The

a c t i v e

i n g r e d i e n t

i s p r e f

e r a b l y p r e s e n t i n a c o m p o s i t i o n i n a n

amount

o f from

0 . 1 5 0 0 mg, p r e f e r a b l y i n t h e amount o f from 1100 mg.

When

h e a c t i v e i n g r e d i e n t

i s m e t h y l p h e n i d a t e , i t i s p r e f e r

a b l y p r e s e n t

i n t h e ? r s t component i n

a n

amount

o f

f r o m

0 . 5 6 0

mg; more p r e f e r a b l y


i s

p r e s e n t

i n

t h e f r r s t c o mp onent

i n

a n a m ou nt o f from 2.530

mg.

The

a c t i v e i n g r e d i e n t i s

p r e s e n t

i n t h e

s u b s e q u e n t

c o m p o n e n t s i n

a n

a m o u n t

Within a s i m i l a r range t o t h a t described f o r t h e

? r s t

c o m p o n e n t .

The

t i m e r e l e a s e

c h a r a c t e r i s t i c s f o r t h e

r e l e a s e o f

t h e


f r o m

e a c h o f t h e c o m p o n e n t s may b e

v a r i e d b y m o d i f y i n g

t h e c o m p o s i t i o n

o f e a c h

c o m p o n e n t ,

i n c l u d i n g

m o d i f y i n g a n y

o f

t h e

e x c i p i e n t s o r c o a t i n g s

W h i c h

m ay e p r e s e n t .

I n

p a r t i c u l a r t h e r e l e a s e

o f

t h e a c t i v e m ay e

c o n t r o l l e d b y

c h a n g i n g

t h e c o m p o s i t i o n a n d / o r t h e a m o u n t

o f

t h e modi?ed r e l e a s e c o a t i n g on t h e p a r t i c l e s , i f

s u c h a

c o a t i n g i s

p r e s e n t . I f

m o re t h a n one m od i?ed r e l e a s e om

p o n e n t

i s p r e s e n t , t h e modi?ed r e l e a s e

c o a t i n g

f o r e a c h o f

t h e s e

components m a y b e t h e same o r d i f f e r e n t . S i m i l a r l y ,

Whe n

modi?ed

r e l e a s e

i s

f a c i l i t a t e d

by

t h e

i n c l u s i o n o f

a

modi?ed r e l e a s e m a t r i x m a t e r i a l , r e l e a s e

o f

t h e a c t i v e i n g r e

d i e n t m ay

b e

c o n t r o l l e d by t h e c h o i c e

a n d

amount

o f


m a t r i x

m a t e r i a l u t i l i s e d . The modi?ed

r e l e a s e c o a t i n g may

b e

p r e s e n t , i n e a c h

c o m p o n e n t ,

i n

a n y

amount t h a t i s

s u f ? c i e n t t o

y i e l d t h e

d e s i r e d d e l a y t i m e

f o r

e a c h

p a r t i c u l a r c o m p o n e n t . T h e m o d i ? e d r e l e a s e c o a t i n g

m ay

b e

p r e s e t ,

i n e a c h c o m p o n e n t , i n a n y

amount t h a t

i s

s u f f i c i e n t t o y i e l d t h e

d e s i r e d

t i m e l a g b e t W e e n c o m p o n e n t s .

The l a g

t i m e o r d e l a y t i m e f o r

t h e r e l e a s e

o f

t h e a c t i v e

i n g r e d i e n t

f r o m

e a c h

c o m p o n e n t may

a l s o

b e v a r i e d

b y

m o d i f y i n g t h e

c o m p o s i t i o n o f e a c h o f

t h e c o m p o n e n t s ,

i n c l u d i n g

m o d i f y i n g a n y

e x c i p i e n t s

a n d

c o a t i n g s W h i c h may

b e

p r e s e n t . F o r

example

t h e ? r s t component m ay b e a n

i m m e d i a t e

r e l e a s e c o m p o n e n t

W h e r e i n


i s r e l e a s e d s u b s t a n t i a l l y i m m e d i a t e l y

u p o n a d m i n i s t r a t i o n .

A l t e r n a t i v e l y , t h e ? r s t

c o m p o n e n t

may b e , f o r

e x a m p l e ,

a

10

1 5

25

35

45

55

8

d e s c r i b e d o r , a l t e r n a t i v e l y , a t i m e - d e l a y e d s u s t a i n e d r e l e a s e

o r e x t e n d e d r e l e a s e component i n Which t h e a c t i v e i n g r e d i

e n t

i s r e l e a s e d i n

a

c o n t r o l l e d fashion

over

an extended

p e r i o d

o f

t i m e .

As i l l b e a p p r e c i a t e d

by

h o s e s k i l l e d i n t h e a r t ,

t h e e x a c t

n a t u r e o f

t h e plasma

c o n c e n t r a t i o n c u r v e

W i l l

be

in?uenced

by

t h e c o m b i n a t i o n o f

a l l

o f t h e s e f a c t o r s

j u s t

d e s c r i b e d . I n

p a r t i c u l a r , t h e l a g t i m e b e t W e e n t h e d e l i v e r y a n d t h u s a l s o

t h e

o n - s e t o f

a c 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 i n e a c h

c o m

p o n e n t may b e

c o n t r o l l e d

b y v a r y i n g t h e c o m p o s i t i o n a n d

c o t i n g

i f p r e s e n t )

o f e a c h o f

t h e c o m p o n e n t s . T h u s b y

v a r i a t i o n o f

t h e

c o m p o s i t i o n o f e a c h c o m p o n e n t i n c l u d i n g

t h e amount

a n d

n a t u r e

o f

t h e a c t i v e i n g r e d i e n t s ) )

a n d

by

v a r i a t i o n

o f t h e

l a g

t i m e ,

numerous

r e l e a s e

a n d

p l a s m a

p r o ? l e s

m ay b e

o b t a i n e d .

Depending on t h e

d u r a t i o n o f

t h e

l a g t i m e b e t W e e n

t h e r e l e a s e o f a c t i v e i n g r e d i e n t f r o m

e a c h

component a n d t h e n a t u r e

o f

t h e r e l e a s e from

e a c h

c o m p o

n e n t i . e . i m m e d i a t e r e l e a s e ,

s u s t a i n e d r e l e a s e e t c . ) ,

t h e

p u l s e s i n t h e p l a s m a

p r o ? l e

may b e

W e l l s e p a r a t e d

a n d

c l e a r l y

d e ? n e d p e a k s eg when h e l a g

t i m e

i s l o n g )

o r

t h e

p u l s e s

may

e s u p e r i m p o s e d

t o a

d e g r e e

eg

n

When

h e

l a g

t i m e i s s h o r t ) .

I n a p r e f e r r e d e m b o d i m e n t , t h e m u l t i p a r t i c u l a t e modi?ed

r e l e a s e c o m p o s i t i o n a c c o r d i n g

t o t h e

p r e s e n t

i n v e n t i o n

h a s

an

immed iate

r e l e a s e c o m p o n e n t

and

a t l e a s t

one

m o d i ? e d

r e l e a s e component,

t h e


component

c o m

p r i s i n g a

? r s t

p o p u l a t i o n

o f a c t i v e i n g r e d i e n t c o n t a i n i n g

p a r t i c l e s

a n d

t h e m o d i ? e d r e l e a s e

c o m p o n e n t s

c o m p r i s i n g

s e c o n d a n d s u b s e q u e n t

p o p u l a t i o n s o f

a c t i v e

i n g r e d i e n t

c o n t a i n i n g p a r t i c l e s . T h e s e c o n d a n d s u b s e q u e n t m o d i ? e d

r e l e a s e components

m a y c o m p r i s e a

c o n t r o l l e d

r e l e a s e

c o a t

i n g .

A d d i t i o n a l l y

o r

a l t e r n a t i v e l y ,

t h e

s e c o n d

a n d s u b s e q u e n t

modi?ed

r e l e a s e components m ay

c o m p r i s e a modi?ed

r e l e a s e m a t r i x m a t e r i a l .

I n o p e r a t i o n ,

a d m i n i s t r a t i o n o f s u c h

a


m o d i ? e d

r e l e a s e


h a v i n g ,

f o r

e x a m p l e , a s i n g l e modi?ed r e l e a s e

component

r e s u l t s i n

c h a r a c t e r i s t i c p u l s a t i l e p l a s m a


l e v e l s o f t h e

a c t i v e i n g r e d i e n t i n W h i c h t h e

i m m e d i a t e

r e l e a s e component

o f t h e c o m p o s i t i o n g i v e s r i s e t o a ? r s t p e a k i n t h e p l a s m a

p r o ? l e a n d t h e modi?ed r e l e a s e component

g i v e s

r i s e t o

a

s e c o n d p e a k i n t h e p l a s m a p r o ? l e . E m b o d i m e n t s

o f

t h e

i n v e n t i o n comprising m o re t h a n

one

m o d i ? e d r e l e a s e

com

p o n e n t

g i v e

r i s e t o f u r t h e r

p e a k s i n t h e

p l a s m a

p r o ? l e .

S u c h

a

p l a s m a

p r o ? l e

p r o d u c e d f r o m

t h e a d m i n i s t r a t i o n o f

a s i n g l e d o s a g e

u n i t

i s a d v a n t a g e o u s

When

t

i s d e s i r a b l e t o

d e l i v e r

t W o o r

m o r e )

p u l s e s o f a c t i v e i n g r e d i e n t W i t h o u t t h e

n e e d f o r


t W o o r

m o r e )

d o s a g e u n i t s .

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

u s e f u l

t o h a v e s u c h a b i m o d a l p l a s m a

p r o ? l e .

F o r e x a m p l e ,

a

t y p i c a l


t r e a t m e n t

r e g i m e

c o n s i s t s

o f


o f

tWo

d o s e s o f a n


dosage

f o r m u l a t i o n

g i v e n

f o u r

h o u r s

a p a r t .

T h i s

t y p e o f r e g i m e

h a s

b e e n

f o u n d t o b e t h e r a p e u t i c a l l y

e f f e c t i v e a n d

i s

W i d e l y

u s e d . T h e

p l a s m a

p r o ? l e p r o d u c e d

b y

s u c h a n a d m i n i s t r a t i o n

r e g i m e i s i l l u s t r a t e d by t h e

C o n t r o l c u r v e

i n F I G . 1 . As

p r e v i o u s l y m e n t i o n e d ,

t h e d e v e l o p m e n t o f p a t i e n t

t o l e r a n c e

i s a n a d v e r s e e f f e c t

sometimes a s s o c i a t e d

W i t h m e t h y l p h e n i

d a t e t r e a t m e n t s . I t i s b e l i e v e d t h a t t h e t r o u g h

i n

t h e

p l a s m a

p r o ? l e b e t W e e n t h e t W o p e a k p l a s m a

c o n c e n t r a t i o n s

i s

a d v a n t a g e o u s

i n

r e d u c i n g

t h e d e v e l o p m e n t

o f

p a t i e n t t o l e r

a n c e

by

p r o v i d i n g a

p e r i o d

o f Wash

o u t

o f t h e a c t i v e

i n g r e d i e n t .

D r u g d e l i v e r y

s y s t e m s W h i c h

p r o v i d e Z e r o o r d e r

o r pseudo

Z e r o o r d e r

d e l i v e r y o f

t h e a c t i v e

i n g r e d i e n t

d o n o t

f a c i l i t a t e t h i s

Wash o u t

p r o c e s s .

Any c o a t i n g

m a t e r i a l W h i c h

m o d i ? e s

t h e r e l e a s e

o f t h e

a c t i v e i n g r e d i e n t i n t h e d e s i r e d manner m a y b e u s e d . I n



16/41

US

6 , 2 2 8 , 3 9 8

B1

9

p h t h a l a t e , p o l y v i n y l a c e t a t e p h t h a l a t e , a m m o n i o

m e t h a c r y

l a t e copolymers s u c h a s t h o s e s o l d u n d e r t h e T r a d e Mark

E u d r a g i t RS

a n d

R L , p o l y

a c r y l i c

a c i d

a n d

p o l y

a c r y l a t e

a n d

m e t h a c r y l a t e c o p o l y m e r s s u c h

a s

t h o s e s o l d

u n d e r t h e

T r a d e

Mark E u d r a g i t S a n d

L ,

p o l y v i n y l a c e t a l d i e t h y

l a m i n o

a c e t a t e ,


m e t h y l c e l l u l o s e

a c e t a t e

s u c c i n a t e ,

s h e l l a c ;

h y d r o g e l s

a n d

g e l - f o r m i n g

m a t e r i a l s ,

s u c h

a s c a r b o x y v i n y l

p o l y m e r s ,

s o d i u m a l g i n a t e , s o d i u m

c a r m e l l o s e , c a l c i u m c a r m e l l o s e ,

s o d i u m c a r b o x y m e t h y l

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

c e l l u l o s e , g e l a t i n ,

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m i c r o c r y s t a l l i n e

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AquaKeep c r y l a t e p o l y m e r s , d i e s t e r s

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10

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a r e

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t h e

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b u t

a r e n o t l i m i t e d t o m i c r o c r y t a l l i n e c e l l u l o s e ,

s o d i u m

c a r b o x y m e t h y l c e l l u l o s e , h y d o x y a l k y l c e l l u l o s e s

s u c h a s h y d r o x y p r o p y l m e t h y l c e l l u l o s e and

h y d r o x y p r o p y l c e l l u l o s e , p o l y e t h y l e n e o x i d e , a l k y l c e l l u l o s e s

s u c h

a s

m e t h y l c e l l u l o s e a n d

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a c e t at e b u t y r a t e , c e l l u l o s e a c t e a t e p h t h a l a t e , c e l l u l o s e

a c t e

a t e t r i m e l l i t a t e , p o l y v i n y l a c e t a t e p h t h a l a t e ,

p o l y a l k y l m e t h a c r y l a t e s ,

p o l y v

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