cipher pharmaceuticals et. al. v. actavis laboratories fl et. al

8/12/2019 Cipher Pharmaceuticals et. al. v. Actavis Laboratories Fl et. al.

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NATURE O F T H E ACTION

This is an action fo r patent infringement arising under th e Food and Drug Laws

and Patent Laws of the United States, Titles 21 and 35 of the United States Code, respectively,

arising from Defendants' submission of an Abbreviated N ew Drug Application ( ANDA ) to the

Food and Drug Administration ( FDA ) seeking approval to manufacture an d sell a generic

version of Plaintiff Ranbaxy's Absorica (isotretinoin) capsules prior to the expiration of United

States Patent No. 7,435,427 ("the '427 Patent ).

T H E PARTIES

Plaintiff Ranbaxy, Inc. ( RI ) is a corporation organized and existing under the

laws of the State of Delaware, having its principle place of business at 600 College Road East,

Princeton, N ew Jersey 08540.

Plaintiff Ranbaxy Pharmaceuticals, Inc. ( RPI ) is a corporation organized under.

th e laws of Florida, having its principal place of business at 9431 Florida Mining Boulevard East,

Jacksonville, Florida 32257.

Plaintiff Cipher is a corporation organized under th e laws of Canada, having its.

principal place of business at 5650 Tomken Road, Mississauga, Ontario, Canada.

Plaintiff Galephar is a corporation organized under th e laws of Puerto Rico,

having its principal place of business at Juncos Industrial Park, Juncos, Puerto Rico 00777-3873.

On information and belief, A L F (formerly known as Watson Laboratories, Inc. -

Florida 1) is a corporation organized and existing under th e laws of the State of Florida, having a

6.

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

On information and belief, the entity's name was changed from Watson Laboratories, Inc. - Florida toALF on April 21, 2014.

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N ew Jersey 07054. On information and belief, ALF is in the business of, inter alia, developing,

manufacturing, and obtaining regulatory approval of generic copies of branded pharmaceutical

products throughout th e United States, including within this district.

On information and belief, Defendant Actavis Pharma (formerly known as

Watson Pharma, Inc.) is a corporation organized and existing under th e laws of the State of

Delaware, having a principal place of business at Morris Corporate Center III, 400 Interpace

Parkway, Parsippany, N ew Jersey 07054. O n information and belief, Actavis is in the business

o f , inter alia, selling and distributing generic copies of branded pharmaceutical products in

N ew Jersey and throughout the United States, including some that are manufactured by ALF

and/or fo r which ALF is the named applicant of the approved ANDAs.

On information and belief, Defendant Actavis (formerly known as Watson.

Pharmaceuticals, Inc. ( WPI )) is a corporation organized and existing under the laws of the

State of Nevada, having a principal place of business in Morris Corporate Center III, 400

Interpace Parkway, Parsippany, N ew Jersey 07054. On information and belief, Actavis is in

the business of , inter alia, developing, manufacturing, obtaining regulatory approval,

marketing, selling, and distributing generic copies of branded pharmaceutical products

throughout th e United States, including within this district, through its own actions and

through th e actions of its agents and subsidiaries, including at least ALF, Actavis Pharma, and

Andrx.

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

existing under the laws of the State of Delaware, having a principal place of business at 4955

Orange Drive, Davie, Florida 33314. O n information and belief, Andrx is in the business of,

inter alia, marketing, selling, and distributing generic copies of branded pharmaceutical

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products throughout th e United States, including within this district, through its own actions

and through the actions of its agents and subsidiaries, including at least ALF .

On information and belief, W P I acquired Andrx Pharmaceuticals, Inc. on or0.

around November 3, 2006. On information and belief, W P I renamed Andrx Pharmaceuticals,

Inc. as ALF.

On information and belief, ALF is a wholly-owned subsidiary of Andrx, which1.

is a wholly owned subsidiary of Actavis.

12. On information and belief, Actavis Pharma is another wholly-owned subsidiary

of Actavis.

On information and belief, ALF, Andrx, and Actavis Pharma are within the3.

control of Actavis fo r purposes of responding to discovery in this action.

On information and belief, ALF, Andrx, Actavis, an d Actavis Pharma share4.

certain common officers a nd directors and are, at the very least, agents of each other and/or work

in concert with each other and/or other direct and indirect subsidiaries of Actavis with respect to the

development, regulatory approval, marketing, sale and distribution of pharmaceutical products

throughout th e United States, including this District.

On information and belief, until January 23, 2013, Actavis w as operating under5.

th e name of W PI . W PI organized it s operations into three business segmentsGlobal

Generics, Global Brands, and ANDA Distributionrather than by subsidiary, and reported its

financial results to investors by reference to its divisions, rather than it s subsidiaries. O n

information and belief, the name change from WPI to Actavis did not impact th e organization

of its operations.

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On information and belief, until January 23, 2013, WPI's Global Generics6.

Division, which is responsible fo r developing and submitting ANDAs, as well as manufacturing

and marketing generic pharmaceuticals, relied on the concerted efforts of at least A L F, Actavis

Pharma, and Andrx. O n information and belief, th e name change from WP I to Actavis did not

impact the role of WPI's Global Generics Division.

A s reported in i ts 2012 Annual Report on behalf of itself and its7.

subsidiaries (collectively, Actavis ), Actavis operates as "a leading integrated global specialty

pharmaceutical company engaged in the development, manufacturing, marketing, sale and

distribution of ," inter alia, generic, branded generic, and brand pharmaceutical products. As

described in that Annual Report, one of Actavis' business segments is Actavis Pharma ,

formerly known as WPI 's Global Generics segment, which markets a "U.S. portfolio of

approximately 250 generic pharmaceutical product families. O n information and belief, ALF,

which is a wholly-owned subsidiary of Actavis, Inc., is part of Actavis ' Actavis Pharma

segment.

On information an d belief, Actavis directs th e activities of the other Actavis8.

entities, including ALF, and, directly or through related companies, is responsible fo r sales of

Actavis products to customers in New Jersey, from which Actavis, Inc. derives substantial

revenue.

On information and belief, Defendants collaborated in the research and9.

development of ALF's ANDA No. 205063 ("the Actavis ANDA ) fo r isotretinoin capsules ("the

Actavis ANDA Products ), continue to collaborate in seeking approval of that application by the

FDA, and intend to collaborate in the commercial manufacture, marketing, offer fo r sale, and

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sale of the Actavis ANDA Products throughout th e United States, including in the State of New

Jersey, in the event the FDA approves Actavis' ANDA.

On information and belief, A L F (formerly Watson Labs., Inc. - Florida) has0.

submitted to the jurisdiction of this Court in prior N ew Jersey actions Astrazeneca A B et al. v.

Watson Labs., Inc. Florida, et al. Civil Action N o. 13-3038; Astrazeneca AB et al. v. Watson

Labs., Inc. Florida, Civil Action N o. 13-1669; Depomed, Inc. v. Actavis Elizabeth LL C et al.

Civil Action N o. 12-1358; Warner Chilcott C o. et al. v. Watson Labs., Inc. Florida, Civil

Action N o. 11-5989; Abbott Labs., et al. v. Watson Labs., Inc. Florida, et al. Civil Action No.

10-3241; Mallinckrodt Inc. v. Watson Labs., Inc. Florida, et al. Civil Action N o. 10-6424).

On information and belief, ALF has availed itself of the rights, benefits, and privileges of this

Court by asserting counterclaims in prior N ew Jersey action Astrazeneca AB et al. v. Watson

Labs., Inc. - Florida, et al. Civil Action No. 13-1669).

21. On information and belief, Actavis has submitted to the jurisdiction of this Court

in prior N ew Jersey actions Astrazeneca AB et al. v. Watson Labs., Inc. - Florida, et al. Civil

Action N o. 13-3038; Auxilium Pharms., In c. et al. v. Watson Labs., Inc. et al. Civil Action No.

12-3084; 2 Depomed, Inc. v. Actavis Elizabeth LL C et al. Civil Action N o. 12-1358; Noven

Pharms. v. Watson Labs., Inc. et al. Civil Action N o. 11-5997; 3 Shire LLC, et al . v. Amneal

Pharms. LLC et al.. Civil Action N o. 11-3781; King Pharms. Inc. et al. v. Actavis, Inc. et al.

Civil Action No. 09-6585; Shire LLC v. Actavis South Atlantic, LL C et al. Civil Action No. 09-

479; King Pharms. Inc. et al. v. Actavis, Inc. et al. Civil Action No. 07-5041; Sanofi-Aventis

U.S. LLC et al. v. Actavis Totowa LLC et al. Civil Action N o. 07-3142). On information and

2 W PI submitted to the jurisdiction of this Court on July 6, 2012. WP I thereafter changed its name toActavis Inc.3 W PI submitted to the jurisdiction of this Court on November 4, 2011. WPI thereafter changed its nameto Actavis Inc.

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belief, Actavis has availed itself of the rights, benefits, and privileges of this Court by asserting

counterclaims in prior N ew Jersey action (Auxilium Pharms., Inc . et al. v. Watson Labs., Inc. et

al. Civil Action No. 12-3084).

22. On information and belief, Actavis Pharma has submitted to the jurisdiction of

this Court in prior N ew Jersey actions Astrazeneca AB et al. v. Watson Labs., Inc. - Florida, et

al. Civil Action N o. 13-3038; Auxilium Pharms., In c. et al. v. Watson Labs., Inc. et al. Civil

Action N o. 12-3084; 4 Abbott Labs., et al. v. Watson Labs., Inc. Florida, et al. Civil Action No.

10-3241; Teva Neuroscience, Inc. et al. v. Watson Pharma, Inc . et al. Civil Action No. 10-

5078; 6 Duramed Pharms. v. Watson Pharma, Inc. Civil Action N o. 07-5941; 7 Hoffman La -

Roche Inc. et al. v. Cobalt Pharms. Inc. et al. Civil Action N o. 07-4539). 8 On information and

belief, Actavis Pharma has availed itself of the rights, benefits, and privileges of this Court by

asserting counterclaims in prior N ew Jersey action Auxilium Pharms., Inc. et al. v. Watson

Labs., Inc. et al. Civil Action No. 12-3084).

JURISDICTION AND VENUE23. This is an action f o r patent infringement arising under the patent laws of the

United States, Title 35 , United States Code. This Court has jurisdiction over th e subject matter

of this action under 28 U.S.C. 1331 and 1338(a). Venue is proper in this Court under 28

U.S.C. 1391 and 1400(b).

4 Watson Pharma, Inc. submitted to the jurisdiction of this Court on July 6, 2012. WPI thereafter changedits name to Actavis Pharma, Inc.5 Watson Pharma, Inc. submitted to the jurisdiction of this Court on May 3, 2010. WPI thereafterchanged its name to Actavis Pharma, Inc.6 Watson Pharma, Inc. submitted to the jurisdiction of this Court on December 23, 2010. WPI thereafterchanged its name to Actavis Pharma, Inc.7 Watson Pharma, Inc. submitted to the jurisdiction of this Court on March 3, 2008. W PI thereafterchanged its name to Actavis Pharma, Inc.8 Watson Pharma, Inc. submitted to the jurisdiction of this Court on September 1, 2011. W PI thereafterchanged its name to Actavis Pharma, Inc.

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24. This Court has personal jurisdiction over Defendants by virtue of , inter alia,

their presence in this State, having conducted business in this State, having availed

themselves of the rights and benefits o f New Jersey la w such that they should reasonably

anticipate being haled into court in this judicial district, previously consenting to personal

jurisdiction in this Court, availing themselves of the jurisdiction of this Court an d having

engaged in systematic and continuous contacts with th e State o f New Jersey through the

marketing a nd sales of generic drugs throughout th e United States, and in particular

within this judicial district, through the receipt of revenue from th e sales an d marketing of

generic drug products, including A L F products, within this judicial district, an d through

their intent to market and sell th e Actavis ANDA Products, if approved, to residents of

this judicial district.

TH E PATENT-IN-SUIT

On October 14, 2008, th e United States Patent and Trademark Office duly and5.

legally issued the '427 Patent, entitled Pharmaceutical Semi-Solid Composition of

Isotretinoin, to Galephar as assignee of the inventors. A true and correct copy of the '427

Patent is attached as Exhibit 1. Cipher obtained an exclusive license to use the '427 patent

rights from Galephar in or about January 2001. On or about November 12, 2012, Ranbaxy

obtained, inter alia, an exclusive license to distribute th e ABSORICA product in the United

States, its territories, possessions, and the Commonwealth of Puerto Rico.

INFRINGEMENT B Y DEFENDANTS

RI is the owner of the approved N ew Drug Application No. 021- 951 (the6.

NDA ) fo r isotretinoin capsules, fo r oral use in 10 mg, 20 mg, 30 mg, and 40 mg dosages,

which are sold under the trade name ABSORICA.

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Pursuant to 21 U.S.C. 355(b)(1), an d attendant F D A regulations, U.S. Patent No.7.

8,367,102 ("the '102 Patent ) and the '427 Patent a re listed in the FDA publication,

Approved Drug Products with Therapeutic Equivalence Evaluations (commonly known as the

Orange Book ), with respect to ABSORICA in 10 mg, 20 mg, 30 mg, and 40 mg dosages.

T he claims of the '102 and '427 patents cover th e ABSORICA product.8.

29. On information and belief, Watson (now Actavis Laboratories FL, Inc.) submitted

ANDA No. 205063 to the FDA , pursuant to 21 U.S.C. 355(j), seeking approval to market

isotretinoin capsules, for oral use in 10 mg, 20 mg, 30 mg, and 40 mg dosages.

T he Actavis ANDA refers to and relies upon th e ABSORICA NDA, and0.

contains data that, according to ALF, demonstrate th e bioequivalence of the Actavis ANDA

Products and ABSORICA.

Plaintiffs received a letter from Watson (now Actavis Laboratories FL, Inc.) on or1.

about September 17, 2013, stating it had included a certification in the Actavis ANDA, pursuant

to 21 U.S.C. 355(j)(2)(A)(vii)(IV), that, inter alia, certain claims of the '102 and '427

Patents are either invalid or will not be infringed by the commercial manufacture, use, or sale

of the Actavis ANDA Products (the Paragraph IV Certification ).

CAUSE O F ACTIONInfringement of the '427 Patent)

Plaintiffs reallege an d incorporate by reference th e allegations contained in2.

paragraphs 1-31.

Defendants have infringed at least one claim of the '427 Patent, pursuant to 353.

U.S.C. 271(e)(2)(A), by submitting, or causing to be submitted the Actavis ANDA, by which

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Defendants seeks approval from the FDA to engage in the manufacture, use, offer t o sell, sale,

or importation of the Actavis ANDA Products prior to the expiration of the '427 Patent.

Defendants have declared their intent to manufacture, use , offer to sell, or sell4.

in the United States or to import into th e United States, th e Actavis ANDA Products in the event

that the FDA approves th e Actavis ANDA. Accordingly, an actual and immediate controversy

exists regarding Defendants' infringement of the '427 Patent under 35 U.S.C. 271 (a), (b)

and/or (c).

Defendants' manufacture, use, offer to sell, or sale of the Actavis ANDA Products5.

within th e United States, or importation of the Actavis ANDA Products into th e United States

during th e term of the '427 Patent would further infringe at least one claim of the '427 Patent

under 35 U.S.C. 271 (a), (b) and/or (c).

Plaintiffs will be substantially and irreparably harmed if Defendants are not6.

enjoined from infringing the '427 Patent.

P la in t i ff s have n o adequate remedy a t law.7.

This case is exceptional, an d Plaintiffs are entitled to an award of attorneys' fees8.

under 35 U.S.C. 285.

PRAYER FO R RELIEF

WHEREFORE, Plaintiffs respectfully request that th e Court enter judgment against

Defendants ALF, Andrx, Actavis, an d Actavis Pharma and for the following relief:

A judgment that Defendants have infringed at least one claim of the '427.

Patent;

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b. A judgment pursuant to 35 U.S.C. 271(e)(4)(B) and/or 35 U.S.C. 283 for a

preliminary and permanent injunction enjoining t he Defendants , their officers, agents, servants,

employees, an d those persons acting in active concert or participation with all or any of them

from: (i) manufacturing, using, offering to sell, or selling th e Actavis ANDA Products within

th e United States, or importing th e Actavis ANDA Products into the United States, prior to

th e expiration of the '427 Patent, and (ii) seeking, obtaining or maintaining approval of the

Actavis ANDA until expiration of the '427 patent, or such other later time as the Court may

determine;

A judgment ordering that pursuant to 35 U.S.C. 271(e)(4)(A), th e effective.

date of any approval of ANDA N o. 205063 under 505(j) of the Federal Food, Drug and

Cosmetic Act (21 U.S.C. 355(j)) shall not be earlier than th e latest of the expiration date of

the '427 Patent including any extensions;

d. If any of the Defendants manufactures, uses, offers to sell, or sells th e Actavis

ANDA Products within th e United States, or imports th e Actavis ANDA Products into the

United States, prior to the expiration of any of the '427 Patent, including any extensions, a

judgment awarding Plaintiffs monetary relief together with interest;

A judgment that this is an exceptional case an d that Plaintiffs be awarded their.

attorneys' fees incurred in this action pursuant to 35 U.S.C. 285;

Costs and expenses in this action; and

Such other a nd further relief as the Court deems just and appropriate..

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Respectfully Submitted,

s/ Theodora McCormickTheodora McCormick

A m y M . HandlerSILLS CUMMIS & GROSS P.C.O ne R iverfront PlazaNewark, N ew Jersey 07102(973) 643-7000

Of counsel:

Thomas F . FlemingLeora Ben-AmiJeanna Wacker

KIRKLAND & ELLIS LLP601 Lexington AvenueN ew York, N ew York 10022(212) 446-4000

Attorneys for Plaintiffs

Dated: June 6, 2014

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Exhibit A


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US007435427B2

(12) United States Patent (10) Patent N o .: U S 7 , 435 ,427 B 2(45) Date of Patent: Oct . 14,2008anderbist et al.

(58) Field of Classification Search

See application file f o r complete search history.

None54 ) PHARMACEUTICAL SEMI-SOLID

COMPOSITION O F ISOTRETINOIN

(56) References Cited(75) Inventors: Francis Vanderbist, Beersel (BE);

Cecile Servais, Malonne (BE); Philippe U.S . PATENT DOCUMENTS

Baudier, Uccle (BE) 8/1984 Bollag10/1993 Nagyetal.11/1999 Crisonetal.2/2000 Stroh et al.6/2001 Patel et al. .7/2001 Chenetal. .9/2001 Patel et al.5/2002 Chenetal.8/2005 Patel et al.

4,464,394 A5,252,604 A *5,993,858 A *6,020,003 A6,248,363 B1 *6,267,985 B1 *6,294,192 B16,383,471 B16,923,988 B2

514/559424/490(73) Assignee: Galephar M/F, Marche-en-Famenne

(BG)424/497424/451

( * ) Notice: Subject to any disclaimer, t h e term o f this

patent is extended o r adjusted under 35U.S.C. 154(b) b y 0 days.

FOREIGN PATENT DOCUMENTS(21) Appl .No. : 10/380,619

6/19865/2000

EP A-0 184942W O 0025772O

(22) PCX Filed: Sep . 21,2001OXHER PUBLICATIONS

(86) PCX No.: PCT/BE01/00163 Koga K, Kawashima S, Murakami M. In vitro and in situ evidence forth e contribution of Labrasol an d Gelucire 44/14 on teansport ofcephalexin an d cefoperazone by rat intestine. Eur J Pharm Biopharm.371 (c)(1),

(2), (4) Date: Jul . 30,2003 Nov. 2002; 54(3): 311-8 (see abstract).*PC T International Preliminary Examination Report.= i =cited b y examiner87) PCX Pub. No.: W002/24172

Primary Examiner Michael G . HartleyAssistant Examiner Jake M. Vu(74) Attorney, Agent, or Firm William E . Beaumont

PCX Pub . Date: Mar. 28,2002

(65) Prior Publication Data

(57) ABSTRACTU S 2004/0009225 A l Jan. 15, 2004A n oral pharmaceutical composition o f isotretinoin contain-ing at least tw o lipidic excipients, one of them being hydro-philic (i.e. having a n H L B value superior o r equal to 10), theother being an oily vehicle.

(51) Int. CI.

A61K 47 00

A61K 9/24

A61K 9/14

(52) U.S. CI

(2006.01)

(2006.01)(2006.01)

424/439; 424/472; 424/484 18 Claims, 5 Drawing Sheets


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U.S. Patent Oct. 14,2008 Sheet 1 of 5 US 7,435,427 B 2

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U.S. Patent US 7,435,427 B2heet 2 of 5c t . 1 4 , 2 0 0 8

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U.S. Patent US 7,435,427 B2c t . 14, 2008 Sheet 3 of 5

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US 7,435,427 B2U.S. Patent Sheet 4 of 5ct. 14,2008

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US 7,435,427 B21 2

The U.S. Pat. No. 5,993,858 describes a self microemulsi-fying excipient formulation fo r increasing the bioavailabilityof a drug which includes an emulsion including an oil or otherlipid material, a surfactant and an hydrophilic co-surfactant.

What is not described i s a composition o f isotretinoin con-taining a t least tw o lipid materials, one of them being hydro-philic. T he said composition may be a suspension, emulsionor microemulsion.

PHARMACEUTICAL SEMI-SOLIDCOMPOSITION O F ISOTRETINOIN

Th e present invention relates to an oral pharmaceuticalcomposition of isotretinoin containing at least tw o excipients, 5one of them being hydrophilic (i.e. having an HLB valuesuperior or equal t o 10), th e other being an oily vehicle.

T H E PRIOR ART

BRIEF DESCRIPTION OF THE INVENTION0Isotretinoin (13-cis retinoic acid or 13-cis vitamine A), its

isomers an d some of its analogs ar e widely known t o have atherapeutical activity in the treatment of several severe skindisorders like cystic acne, hypertrophic lupus erythematosus,keratinization disorders. Some evidences have also been 15brought about th e activity of isotretinoin in basal cell carci-noma an d squamous cell carcinoma.

Unfortunately, isotretinoin is also a highly toxic drug.Indeed, although isotretinoin, which is a cis derivative, is

known to be less toxic than all trans vitamine A derivatives, 20side effects resulting from its use such as headache, vomiting,irritation o f mucosa and liver toxicity, occur frequently. Fur-thermore, isotretinoin is known to be highly teratogenic inboth animals an d humans.

In order to well understand the interest of this invention, it 25is important to briefly summarize th e physico-chemical phar-macokinetic properties. Isotretinoin is a reddish-orange pow-der. It is decomposed in presence of light an d atmosphericoxygen. Isotretinoin is very poorly soluble in water whatmades it s bioavailability quite low after an oral intake (25% in 30fasted conditions and 40% in fed conditions). T he maximumconcentration C max ) is reached after 2- 4 hours, while theC milx) of the active metabolite, 4-oxo-isotretinoin is reached

after 6 hours. The elimination half-life of isotretinoin is of 7 to37 hours while th e half life (tj/j ) of the active metabolite is of 3511 to 50 hours. Th e steady-state concentrations of isotretinoinar e reached after 1 week of treatment.

Very few publications and/or patents about th e pharmaceu-tical formulation of isotretinoin ar e available. The drug isavailable on most markets under th e form of a soft gelatine 40capsule containing a fatty liquid formulation o f isotretinoin.

The U.S. Pat. No. 4,464,394 describing for the first time thetherapeutical use of isotretinoin also describes briefly somepossibilities of compositions including it. It involves the useof one antioxidant agent and of one carrier like lactose, 45 y

T he advent of high throughput combinatorial chemistryan d efficient receptor based in vitro activity screen hasresulted in molecules with poor physicochemical (ex: disso-lution) properties fo r absorption across th e gastro-intestinaltract, like isotretinoin.

It is increasingly being recognized by the pharmaceuticalindustry that fo r these molecules drug delivery systems playan important role fo r improving oral bioavailability.

Although th e process o f passive diffusion is responsible forabsorption of non ionized lipophilic molecules via the trans-cellular pathway, specialized absorption mechanisms, first-pass metabolisms an d efflux systems at the gastrointestinalwall appear to play a major role for lack of absorption andpoor bioavailability fo r some molecules.

Isotretinoin is characterized by a low absolute bioavailabil-ity and a high inter a nd intra individual variability. Isotretin-oi n also presents a wide range of side effects among whichsome ar e severe (ocular, skin anemia, hepatic, . . . ). It isconsequently of a particular interest to dispose of a reliable,stable an d highly bioavailable formulation of isotretinoin.Several possibilities ar e available to the fonnulator toincrease t he bioavailability of active ingredients (Table A).

TABLE A

I. Use of salts, polymorphs. Precursors of the active molecule(=pro drugs)

II. Reduction of the particles' size of the active principle and of theexcipients used (by trituration, grinding, micronization,precipitation controlled by solvent, temperature or ultrasonics).

III. Solid dispersions:Eutectic mixesSolid solutionsVitreous solutionsRecrystallization in an aqueous solution of a surfactantModification of the microenvironment:Hydrophilizationp H (acidification)

VI . Incorporation of the active principle to lipidic systems

starches o r polyethyleneglycols.The EP patent 0184942 describes more specific composi-

tions o f isotretinoin involving the use of one antioxidant, onechelating agent, o ne pharmaceutical carrier and one suspend-in g agent. T he composition obtained i s stable during time.

The U.S. Pat. No. 4,545,977 relates to improved composi-tions o f isotretinoin wherein taurine is associated with isotre-tinoin to reduce t he side effects thereof.

It has been found that a semi-solid dosage form containingisotretinoin w as advantageous f o r obtaining a good bioavail-ability of the isotretinoin. A semi-solid dosage form contain-in g isotretinoin is a form in which isotretoin is mixed withsuitable melted excipients. The molten mix is then filled for

increasing bioavailability and for reducing inter an d intra 55 example into hard gelatine capsules o r other phannaceuti-cally acceptable capsules. At ambient temperature (tempera-ture fo r example of less than 20 C.), the content of thecapsule i s solid while at temperature higher than 20 C. (forexample at temperature greater or equal to 30 C., advanta-

60 geously greater o r equal to 35 C., preferably substantially a tbody temperature +/- 37 0 C .), it is liquid or semi-solid (paste).The isotretinoin may be solubilized in the mix of excipients orpartially solubilized. T he active ingredient m ay also be for-mulated as a suspension, emulsion or microemulsion. Various

50

The U.S. Pat. No. 5,716,928 describes a method for

individual variability of an orally administered hydrophobicpharmaceutical compound, which comprises orally adminis-tering t he pharmaceutical compound with an essential oil oressential oi l component in an amount sufficient to providegreater bioavailability of the active ingredient.

The U.S. Pat. No. 6,028,054 relates to a method f or increas-in g bioavailability of an orally administered hydrophobicpharmaceutical compound to human, which comprises orallyadministering th e pharmaceutical compound concurrentlywith a bioenhancer comprising an inhibitor of e-cytochrome 65 lipidic excipients ar e available to the fonnulator to obtain aP450 3 A enzyme or an inhibitor o f P-glycoprotein mediatedmembrane transport.

semi-solid formulation. Excipients compatible with hardgelatin capsule shells are: lipophilic liquid vehicles (refined


21/27

US 7,435,427 B23 4

speciality oils, medium-chain triglycerides an d relatedesters), semi-solid lipophilic vehicles, solubilizing agents,emulsifying agents a nd absorption enhancers. T he classifica-tion o f fatty excipients i s based on the hydrophilicity o r lipo-

philicity of the excipients, characterized by the hydrophilic/lipophilic balance value (HLB). Examples of lipophilicexcipients ar e vegetable oils (peanut oil, olive oil, soyabeanoil,...), fatty acids (stearic acid, palmitic acid,...), fatty

DESCRIPTION OF THE [NY ENTION A N DPREFERRED EMBODIMENTS

T he pharmaceutical composition of the invention is an oral5 semi-solid pharmaceutical composition of isotretinoin con-

taining tw o lipidic excipients, one of them being hydrophilici.e. having a FILB value of at least 10, for example equal to 10,bu t preferably greater than 10, such a s greater o r equal to 12,fo r example comprised between 12 and 14, and the other

alcohol s,... Examples o f hydrophilic excipients a re polyeth- 10 being an oily vehicle,yleneglycol (PEG) with a molecular weight superior to 3,000. T he pharmaceutical composition of the invention contains

advantageously at least o ne hydrophilic excipient with a HLBvalue of at least 10 selected from th e group consisting ofglyceroyl macrogolglycerides, polyethyleneglycol deriva-

15 tives, an d mixtures thereof. Preferably, th e pharmaceuticalcomposition contains from 20 to 80% by weight of hydro-philic excipient with a HLB value of at least 10 selected fromth e group consisting of glyceroyl macrogolglycerides, poly-ethyleneglycol derivatives, a nd mixtures thereof.

20 The oily vehicle is selected from t he group consisting ofvegetable oils, medium chain triglycerides, fatty acid esters,amphiphilic oil, glycerol oleate derivative, an d mixturesthereof. Fo r example, th e composition contains from 5 to 70%by weight of an oily vehicle selected from th e group consist-

enced th e stability of the pharmaceutical form and the bio- 25 ing of vegetable oils, medium chain triglycerides, fatty acidavailability of the isotretoin contained in it. Generally, a esters, amphiphilic oil, glycerol oleate derivative, and mix-maximum bioavailability i s achieved b y preparing a nd keep- toes thereof.

ing the drug in the amorphous/solubilized state in a soliddispersion or in a lipid-based formulation. Fo r these systems,th e barrier we are avoiding is the compound


22/27

US 7,435,427 B26

FIG. 5 gives th e comparative pharmacokinetic profile ofdifferent formulations fo r 4-oxo-isotretinoin, th e activemetabolite of isotretinoin and

FIGS. 6 and 7 describe t he mean pharmacokinetic profileof isotretinoin a nd 4-oxoisotretinoin for two formulations. 5

TABLE I-continued

Formulations n (mg)

1 3 4 5

DESCRIPTION O F EXAMPLESSoya bean oil 304 320

Th e present invention relates thus to a semi-solid formula-tion of isotretinoin containing at least 2 lipidic excipients, oneof them being an hydrophilic excipient (having a high HLBvalue namely > 10) and the other an oily excipient. The moltenmix of these tw o excipients allows to totally or partially(depending on the ratio between excipients) dissolve isotret-inoin. Different kinds of formulations (SEDDS or suspen-sions) o f isotretinoin have been formulated. Fo r suspensions,it was possible to dissolve a high fraction of isotretinoin in themix of excipients an d even th e whole quantity of the activeingredient if the manufacturing conditions (high temperaturean d long time of mixing) and the formulations were opti-mized. Excipients particluarly suitable for the dissolution o fisotretinoin were lauroyl Macrogol -3 2 glycerides (Gelu-cire 44/14, Gattefosse) an d Stearoyl Macrogol-32 glycer-ides (Gelucire 50/13, Gattefosse). When those hydrophiliccomponents a re melted together with an oily vehicle, it allowsto obtain very stable suspensions of isotretinoin in which animportant part of the active ingredient i s dissolved. A surfac-tant m ay also b e added to the formulation to still improve thephysical stability of the suspension. SEDDS formulationsof isotretinoin ar e also stable and may give an improvedbioavailability of the drug.

Ternary diagrams allow to observe different areas corre-sponding to differ ent physical states namely coarse emulsion,true emulsion, lamellar solution or micellar solution when theratio between excipients changes. The behaviour of the for-mulation in presence of water changes when th e ratiochanges. O ne example of this ternary diagram is given in FIG.1 for a formulation of isotretinoin containing Gelucire50/13 and soyabean oil.

Mygliol 32010

The use of stearoyl macroglyceride (Gelucire 50/13, Gat-tefosse) an d soyabean o il allows to obtain a formulation witha dissolution profile similar to the reference (Roaccutane 20m g, Roche).

T he formulation with labrafil o r Gelucire 50/02 are toolipophilic t o give a good dissolution in water.

In general, the use of an oily excipient can improve theabsorption of lipophilic drug by increasing th e solubility ofth e drug in the lipidic phase, but the release of the activeingredient from th e formulation can be slowed down due toth e high affinity of the drug for the oily phase.

The use of dispersed systems (emulsions or suspensions)instead of only lipophilic or hydrophilic vehicles, improvesth e absorption of the drug as well as increasing a largercontact surface.

Concerning th e Gelucire, th e process of drug releasevaries according to the FILB of the excipient. Gelucire withhigh H L B values were found to be the most favorable for arapid release of the drug (b y diffusion a nd erosion).

T he drug release profiles of the formulations 1 to 5 wereevaluated in phosphate buffer pH 7.5 with laurylsulfate andpancreatin. T he percent of isotretinoin released after 4 hoursis given in the following table 11.

15

20

25

30

35

TABLE If40

percent of isoti'etinoiii released after 4 hoursEXAMPLES

Formulations n 0T- I t

Example I2 4

45Effect of Different lipophilic Compounds % released 20.1 69.1 46.0 60.3 78.1

Th e percent of isotretinoin released from th e reference (Roaccutane 20

m g) after 4 hours is 55.37%Th e effect of different lipophilic excipients w as evaluated

in the form o f semi-solid capsules. The semi-solid capsuleswere made by addition of the active substance at the pre- 50melted lipophilic compounds followed by the filling of theliquid into hard gelatin capsule.

Th e active substance w as incorporated into formulations,listed in table 1, consisting of glyceroyl macrogolglycerideassociated with soyabean oil or derivative, medium chain 55triglyceride.

Example 2

Influence of the Ratio Oily Vehicle/Surfactive Agenton the Dissolution a nd Absorption of the

Formulation

T he study of the ratio oily vehicle/surfactive agent with theconstruction of a ternary diagram gives information on the

60 dissolution profile of the formulation in water.

Stearoyl macrogolglyceride (Gelucire 50/13) known as a

drug solubilizer a nd emulsifying agent of different drugs (inSMEDDS or SEDDS) w as tested in association with

6 5 soyabean oil.

This component has the ability to solubilize a great part o fisotretinoin in the formulation.

TABLE I

Formulations n" (mg)

1 3 4

IsotretinoinLabrafil M1944 CSGelucire 50/02Gelucire 44/14Gelucire 50/13

20 20 20 20 20132198 93

21776 60 60


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US 7,435,427 B28

This is listed i n table III ResultsIt was first proven that neither th e active ingredient nor the

excipient used in the formulations were toxic for the cells. I tw as also proven that th e integrity of the membranes of the

5 cells w as maintained during t he whole experience.

TABLE III

Formulations n (mg)

1 3 4 6 Methodology:T he formulations tested are put in solution in 250 ml of

B M E . Taurocholate (10 mM) was added to the solutions to10 better mimate the in physiological conditions. The different

solutions so prepared are put in contact with Caco-2 cells atth e apical o r basolateral side. The cells culture inserts) areincubated for 3 hours at 37 C. and samples of 100 |il are takenevery hours

T he formulations tested were t he following:

IsotretinoinSoyabean oilGelucire 50/13Filling weightRatio oil/Gelucire

20 10 10

270 135 40 15284 42 200 228

374 187 260 4003.2 3.2 0.2 0.67

20 20 20

57 133323 247400 400

0.17 0.5450/13

In the presence of water, th e behaviour of these formulations a re differentformulations 1 and 2: formation of coarse emulsion with large droplet sizesformulations 3 and 5: formation of micellar phase or microemulsionformulations 4 and 6: formation of emulsion with homogeneous droplet sizeT he percentage of isotretinoin released increases generally with th e percent-age of Gelucire in the formulation (increased solubility of the active inthis vehicle). For the formulation 1 (ratio oil/Gelucire 50/13 = 3.2) 54.9%released after 4 hours and for the formulation 3 (ratio oil/Gelucire 50/13:

0.2) , 91.2% released after 4 hours.

15

Formulation SEDDS (batch number 26F97/1):Isotretinoin: lOmgGelucire 50/13: 134 mgPhospholipon 90: 11 mgTween 80: 71 mgIPP: 24 mg

20

Dissolution TestFo r poorly soluble molecules, th e prediction power of the

in vitro dissolution test is weak since the in vitro/in vivocorrelation is known to be poor. Nevertheless, an optimized 25 Isotretinoin: 20 mgdissolution test (using enzymes an d surfactant) is of somehelp to assess t he rate of release of the drug from th e lipidiccomposition. It must be noted that th e conditions of the dis-solution (dissolution medium, speed of the paddles, tempera-ture,...) test influence dramatically th e results of the test and 30should consequently be standardized to allow comparisonbetween various formulations.

Pr o capsula unaFormulation suspension (batch number 25F97/1)

Gelucire 50/13: 83.7 mgSoyabean oil: 270 mgProcapsula una

ResultsPassage of formulations from apical side^bas olater al side

Th e conditions of the solution test used fo r assessing the

dissolution o f isotretinoin were t he following:paddle apparatus

Time SEDDS Suspension SEDDS + Suspension +minutes (26F97/1) (25F97/1)5 controlC TC

150 rpm

37 C.60 0.7721

12 0 2.409618 0 2.6226

0.67080.87491.1311

0.70191.43473.2419

0.64690.95131.5073

0.07180.18360.6156buffer pH 7.5 with laurylsulfate 2.5% and pancreatin 1 g/L

FIG. 2 shows th e dissolution rate of a refe rence product 40(Roaccutane20 m g active agent), of a suspension con-taining 20 mg Isotretoin and of an emulsion SEDDS con-taining 10 mg Isotretoin (formulation given hereinbelow).

As the information brought by the dissolution test is poor interm o f correlation with in vivo bioavailability, it is of interest 45to dispose of other means to predict the in vivo bioavailability.

H ie caco-2 cell culture system can be used f or determining

permeability of compounds (especially for poorly solublecompounds). Th e caco-2 cell model allows to measure thetransport o f drug from the apical to the serosal side as well a s -0

from th e serosal to the apical side. This allows to determine ifan eff lux system is operational.

Th e caco-2 cells model is interesting because:

Th e cells used ar e from human origin (contrary to themodels using segments of animal's guts). They are com-in g from an adenocarcinoma of the human colon butspontaneously differentiate into small intestine's epithe-lail cells. When put in culture, they form a monolayer o fpolarized cells expressing several enzymatic systems.

It offers a better prediction of the human intestine absorp-tion than t he animals models

Passage of formulations from basolateral sid e^a pica l side

Time SEDDS Suspension SEDDS + Suspension +minute (26F97/1) (25F97/1) TC TC control

60 2.049612 0 3.0844

18 0 4.3653

0.39480.9068

1.0763

8.12918.3496

9.7110

0.87131.8460

2.0779

0.06500.1131

0.1481

T he results demonstrate that t he passage of isotretinoin i ssuperior for the SEDDS formulation than for the suspen-sion formulation. In order to confirm these results, a com-parative pharmacokinetics study h as been performed.

PK Studies

T he bioavailability o f SEDDS (26F97/1) a nd suspension(25F97/1) isotretinoin formulations ha s been assessed andcompared to the bioavailability of the reference (Roaccu-

60 tane 20 mg, Hoffman LaRoche) on six healthy volunteers ina single dose, three way, cross-over pharmacokinetic study).The drug w as taken with food (standardized breakfast). The

plasma concentration o f isotretinoin and its active metabolite4-oxo-isotretinoin were quantified using a fully validated

Th e reproducibility of the test is relatively highIt allows t o take samples from both apical an d basolateral

sides Caco-2 cells experiments have been performed 65 LC/MS/MS method,with o ne SEDDS and one suspension isotretinoin for-mulations.

The FIG. 3 described th e mean pharmacokinetic profileobtained fo r each formulation.


24/27

US 7,435,427 B29 10

Th e foll owing table gives the value of the main pharmaco- been assessed an d compared to the bioavailability of thekinetics parameters obtained f o r each formulation of isotret- reference (ROACCUTANE 20 mg capsule, Roche) on 24inoin. healthy subjects.

This study (SMB-ISO-SDOll) was a single dose, two5treatment, tw o period, tw o sequence, randomised, crossover

an d with a t least 18 days wash-out between the two periods.UC 721l C m T m

Formulations (ng. li/ml) (ng/ml) (h)T he subjects were healthy caucasian volunteers of both

10 sexes (non-pregnant, non-breast-feeding), aged 18 to 50

years, no n smokers o r smoking less than 1 0 cigarettes per day.

T he drugs w as taken with food (a standardized breakfast).

Roaccutane 20 mg 1747.89 116.63 1.83(96C15315AA)

Suspension 20 mg 4308.72 230.96 5.67(25F97/1)

SEDDS 10 mg(26F97/1)

1494.64 98.36 3.00

Blood samples were collected according to the following

15 sampling schedule: pre-dose and 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7

h, 8 h, 10 h, 12 h, 14 h, 24 h, 36 h, 48 h, 72 h, 96 h, 120 h, 168It appears that both th e SEDDS and the suspension for-

mulation ar e able to significantly increase t he bioavailabilityof isotretinoin in comparison to the marketed reference.Indeed th e ratio between AUC 72A of the supension 20 mg and

Roaccutane 20 mg is of 2.47. The SEDDS 10 mg present 20 metabolite 4-oxo-isotretinoin were quantified using a lully

h and 216 hours post-dose.

T he plasma concentration of isotretinoin and its active

an AUC 72A similar to this o f Roaccutane 20 mg what meansan approximately 2-fold increase of bioavailability (ratio

validated LC/MS/MS method. Th e continuous variables were

evaluated according to an univariate ANOVA, based on log-

transformed data. T he Wilcoxon non-parametric ANOVA

25 were used where appropriate. Bioequivalence w as evaluated

using th e Shuirman tw o one-sided t-test (90% CI) and the

westlake single sided confidence interval (95% CL)

T he FIGS. 6 an d 7 describe th e mean pharmacokinetic

30 profile o f isotretinoin an d 4-oxoisotretinoin for the two for-

mulations (n=24 subj ects) while th e tables herebelow give the

comparative main pharmacokinetic parameters.

Formulation o f isotretinoin 16 mg (mg/capsule)

AU C SEDDS 10mg/AUC 72A Roaccutane20mg=0.86).Furthermore, th e suspension an d SEDDS formulationsboth presented a lower intraindividual variability of the bio-availability as demonstrated by the values o f relative standarddeviations (rsd) which are of 36.0%, 22.72% a nd 28.18% forRoaccutane 20 mg, suspension 20 mg and SEDDS 10 mgrespectively.

Nevertheless, th e results obtained in vivo are not correlatedwith t he results obtained on caco-2 cells since on this modelth e permeability of the SEDDS formulation w as much

higher than th e permeability of the suspension formulationwhile in vivo th e suspension formulation gives th e bestresults.

35

isotretinoin

stearoyl macrogol glycerides (Gelurire 50/13 CD)

soya bean oil refined

sorbitane oleate (Span 80 )

16A second pharmacokinetic study was performed on com-pletely different formulations ( 6 subjects, 2-way, fed, cross-over study). Those were formulations of isotretinoin under 40th e form of a suspension in which th e ratio between Gelu-cire 50/13 and soyabean oil was very different that theprevious formulation o f suspension

The two formulations tested were t he following:

F l : suspension without surfactant (batch number H23K99 /l)

Isotretinoin: 20 mg

192

104

16

A s seen, t he dose of 16 mg of the formulation correspond-

ing to the present invention gives a bioavailability similar to

20 mg of the marketed formulation, what is the evidence of

th e supra-bioavailability of the formulation corresponding to

th e present invention.T he tables hereinbelow gives th e value of the main phar-

macokinetics results a nd statistical analysis obtained fo r each

formulation o f isotretinoin an d 4-oxoisotretinoin.

Gelucire 50/13: 247 mgSoyabean oil: 133 mg

F2: suspension with surfactant (batch number H07L99/1)

Isotretinoin: 20 mg

50

Gelucire 50/13: 240 mgThis study demonstrated that ROACCUTANE 20 mg and

Soyabean oil: 130 mg5 5 isotretinoin 16 mgxare bioequivalent after a single oral dose

administration o f each product in fed conditions, indeed, the

primary parameters AUC (AUC^ and AUC 216A ) were within

th e predetermined confidence interval.

Span 80: 20 mg

The FfG. 4 gives the comparative pharmacokinetic profileof each formulation f or isotretinoin

The FIG. 5 gives the comparative pharmacokinetic profileof each formulation fo r 4-oxo-isotretinoin, th e active metabo- 60lite o f isotretinoin.

In order to confirm t he first bioavailability data obtainedwith the present invention, a larger pharmacokinetic study ha s ROACCUTANE 20 mg.been performed.

Th e bioavailability o f a capsule o f isotretinoin 16 mg (seeth e formulation herebelow) from th e present invention has

This study demonstrated also that Isotretinoin 16 mg has a

safety profile comparable with that described in the literature

fo r other isotretinoin preparations an d similar to this of

6 5 Pharmacokinetic results an d statistical analysis of com-

parative study in 24 volunteers fo r isotretinoin (log-trans-

formed data)


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US 7,435,427 B211 12

Bioequivalence tests

Results Sliuiiman

90% CIRange

Westlake95% CL

ROACCUTANE Parameter 20 mg Isotretinoin 16 mg

5657.09 (ng.h/ml) 2682.98 "47.42

5601.36 (ng.h/ml) 2670.85 47.68386.68 (ng/ml) 218.21 "56.434.92 (li) 2.22

45.24

5696.92 (ng.lr'ml) 1938.89

AUC 92423 19.07SD RSD 34.03

5664.39 (ng.li'ml) 1953.52

92-124 19.51SD RSD 34.48

441.79 (ng/ml) 197.4344.684.50 (li) 0 .66

103-140 28.81SD RSDT ma X

SD RSD 14.65

20

Pharmacokinetic results an d statistical analysis of com-parative study in 24 volunteers fo r 4-oxoisotretinoin (log-transformed data)

consisting of sorbitan fatty acid esters, polysorbate com-pounds, polyoxyethylene sorbitan fatty acid esters, sodiumlaurylsulfate, lecithin, propylene glycol esters, fatty acid

Bioequivalence tests

Results Sliuirman

Westlake95% CL

90% CIRange

ROACCUTANE Parameter 20 mg Isotretinoin 16 mg

AI T , 5750.36 (ng.li'ml) 2717.38 47.26

Al .( ,. l61l 5638.32 (ng.h/ml) 2704.73 47.80111.52 (ng/ml) 69.62

5769.04 (ng.li/ml) 2161.97 37.485712.21 (ng.li'ml) 2126.61

92-124 19.65SD RSD

92-125 20.46SD RSD 37.23

115.15 (ng/ml)66.25

94-125 20.18SD RSD 62.43 57.53

16.33 (li) 10.11

17.83 (h) 10.60

T m > *

SD RSD 59.43 61.88

Th e invention claimed is:

1. A n oral pharmaceutical composition o f isotretinoin con-tained in a pharmaceutically acceptable capsule which com-

prises a semi-solid suspension containing a t least two lipidicexcipients, at least in an amount of about 20 to 80% of onebeing hydrophilic having a HLB value equal to or greater than10 selected from th e group consisting of glyceroyl mac-rogolglycerides, polyethylene glycol esters, an d mixturesthereof; th e other in an amount of about 5 to 70% and being anoily vehicle selected from th e group consisting of vegetable 55oils, medium chain triglycerides, fatty acid esters, glycerololeate an d mixtures thereof; and an amount o f about 1 to 10%of at least on e additional surfactant.

2. T he pharmaceutical composition of claim 1, wherein theleast o ne hydrophilic lipidic excipient has an HLB value of atleast 12.

3. T he pharmaceutical composition of claim 1, wherein theleast o ne hydrophilic lipidic excipient has an HLB value of atleast 13.

4. T he pharmaceutical composition of claim 1, wherein theat least on e additional surfactant i s selected from the group

45 esters o f propylene glycol, fatt y acid esters o f glycerol, poly-ethylene glycol an d mixtures thereof.

5. The pharmaceutical composition o f claim 1, which fur-

ther comprises at least one disintegrant.6. The pharmaceutical composition o f claim 5 , wherein at

least on e disintegrant is selected from t he group consistingpovidone, sodium croscarmellose an d mixtures thereof.

7. The capsule o f claim 1, in which t he pharmaceutically-acceptable capsule is selected from t he group consisting ofhard gelatin capsules, soft gelatin capsules, hypromellosecapsules, an d starch capsules.

8. The pharmaceutical composition of claim 1 , wherein thecomposition comprises about 10-20 mg of isotretinoin.

9. The pharmaceutical composition of claim 8, wherein the6 0 composition comprises about 16-20 mg of isotretinoin.

10. A method o f administering th e pharmaceutical compo-sition o f claim 1, which comprises administering t o a human

about 10-20 mg of the composition for a total daily dose.11. T he method o f claim 1 0, wherein th e total daily dose is

65 about 16-20 mg.

12 . The pharmaceutical composition of claim 1, whereinth e composition contains about 20-80% b y weight of glycer-

50


26/27

US 7,435,427 B213 14

oy l macrogolglycerides, about 5 -70% by weight of an oilyvehicle an d about 1-10% of an additional surfactant.

15. The pharmaceutical composition of claim 1, whereinth e hydrophilic lipidic excipients further comprise a n excipi-en t having an HLB value of at least 12, and the oily vehicle issoybean oil.

16 . The pharmaceutical composition of claim 1, whereinth e isotretinoin i s contained within an emulsion.

13. The oral pharmaceutical composition of claim 1,wherein th e pharmaceutically-acceptable capsule i s filled bya process comprising filling into a capsule a composition 5prepared by mixing isotretinoin and one or more of the pre-melted lipidic excipients.

14. The oral pharmaceutical composition of claim 1, 17. The pharmaceutical composition of claim 1, whereinwherein th e pharmaceutically-acceptable capsule i s filled by the at least on e hydrophilic lipidic excipient having an HLBa process comprising filling into a capsule a composition 10 value equal to or greater than 10 is glycerol macrogolglycer-prepared b y mixing:

(a ) isotretinoin, . .(b) one or more of said hydrophilic lipidic excipients, 1 8 - T h e Phanmceutical composition of claim 1, wherein(c ) said oily vehicle and vshici 6 i s a medium chain triglycerides or a mixture(d) one or more additional ingredients selected from the 15 ofm edi um chain triglycerides.

group consisting of disintegrants, surfactants and com-binations thereof. * * * * *

ides.


27/27

UNITED STATES PATENT A N D TRADEMARK OFFICE

CERTIFICATE O F CORRECTION

PATENT NO.APPLICATION NO.DATEDINVENTOR(S)

7,435,427 B210/380619October 14,2008Vanderbist et al.

Page 1 of 1

It is certified that error appears in the above-identified patent a n d that said Letters Patent ishereby corrected as shown below:

On the Title Page, item (86),Please delete "PCX No.: PCT/BE01/00163andreplace with- PCT/IB00/00163 -

On the Title Page, item (86),Please insert - PCT/BE00/00111 -

Signed and Sealed this

Sixth Day of January, 2009

, < rv \

JON W. DUDASDirector of the United States Patent and Trademark Office

cipher pharmaceuticals et. al. v. actavis laboratories fl et. al

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