PTO/SB/05 (04-05)
`Approved for use through 07/31/2006. OMB 0651·0032
`U.S. Patent and Trademark Office. U.S. DEPARTMENT OF COMMERCE
`Under the Paoerwork Reduction Act of 1995 no oersons are required to resoond to a collection of information unless it displays a valid OMS contro number.
`I
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`UTILITY
`PATENT APPLICATION
`TRANSMITTAL
`(Only for new nonprovisional applications under 37 CFR 1. 53(b))
`
`Attorney Doc!fet No.
`
`BAN 102
`
`First Inventor
`
`Nachiappan Chidambaram
`
`Title
`
`Solvent System for Enhancing the Solubility of Pharmaceutical Agents
`
`Express Mail Label No. EV 487330851 US
`
`..)
`
`'
`
`APPLICATION ELEMENTS
`See MPEP chapter 600 concerning utility patent application contents.
`
`ADDRESS TO:
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria VA 22313-1450
`
`2.0
`
`1.11] Fee Transmittal Form (e.g., PTO/SB/17)
`(Submit an original and a duplicate for fee processing)
`Applicant claims small entity status.
`See 37 CFR 1.27.
`(Total Pages
`20
`3.0 Specification
`Both the claims and abstract must start on a new page
`(For infonnation on the preferred arrangement, see MPEEP 608.01 (a))
`[Total Sheets
`4.0 Drawing(s) (35 U.S. C. 113)
`
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`
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`0or continuation/divisional with Box 18 completed)
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`DELETION OF INVENTOR(S)
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`name in the prior application, see 37 CFR
`1 .63(d)(2) and 1 .33(b).
`
`6.!Z] Application Data Sheet. See 37 CFR 1.76
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`11. 0
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`English .Translation Document (if applicable)
`
`("\
`1-
`~
`~
`en
`:\1
`-;
`~ ~
`-;;:;
`~
`
`~
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`T""
`
`12.
`
`lnfoEjtion Disclosure Statement (PTO/SB/08 or PT0-.1449)
`Copies of citations attached
`
`13. 0
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`14. IZJ Return Receipt Postcard (MPEP 503)
`(Should be specifically itemized)
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`Applicant must attach form PTO/SB/35 or equivalent.
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`0
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`Continuation
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`0
`
`Divisional
`
`of prior application No.: ................. ..... .........
`
`Prior application information:
`
`Examiner
`
`Art Unit:
`
`19.CORRESPONDENCEADDRESS
`
`[{]The address associated with Customer Number: I
`
`23579
`
`I OR D Correspondence address below
`
`Name
`
`Address
`
`City
`
`Country
`
`Signature
`
`Name
`!Print/Tvoe\
`
`~
`
`/
`
`I
`\I
`
`I
`
`J Date March 3. 2006
`Registration No. I
`(AttorneviAqent) 31 ·284
`This collection of information is requirEd by 37 CFR 1 .53(b). The information is re uired to obtain or retain a benefit by the public which is to file (and by the
`q
`USPTO to process) an application. Confidentiality is governed by 35 U.S.C. 122 and 37 CFR 1.11 and 1.14. This collection is estimated to take 12 minutes to
`complete, including gathering, preparing, and submitting the completed application form to the USPTO. Time will vary depending upon the individual case. Any
`comments on the amount of time you require to complete this form and/or suggestions for reducing this burden, should be sent to the Chief Information Officer.
`U.S. Patent and Trademark Office, U.S. Department of Commerce, P.O. Box 1450, Alexandria, VA 22313-1450. DO NOT SEND FEES OR COMPLETED
`FORMS TO THIS ADDRESS. SEND TO: Commissioner for Patents, P.O. Box 1450, Alexandria, VA 22313·1450.
`If you need assistance in completing the form, calf 1-800-PT0-9199 and select option 2.
`
`' (...
`
`Patrea L. I llabst
`
`I State
`1 Telephone
`
`Zip Code
`
`Email
`
`BAN 102 095161/00005
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1005, Pg. 1 of 445
`
`

`

`PTO/SB/17 (01-06)
`Approved for use through 07/31/2006. OMS 0651-0032
`U.S. Patent and Trademark Office; U.S. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995 no persons are reQuired to respond to a collection of information unless it displays a valid OMS control number
`~
`Complete If Known
`~s pursuant to the Consolidated Appropriations Act, 2005 (H.R. 4818).
`
`""
`
`~FEE TRANSMITTAL Filing Date
`For FY 2006
`0 Applicant claims small entity status. See 37 CFR 1.27
`TOTAL AMOUNT OF PAYMENT I ($)
`$1750.00
`
`0
`
`March 3 2006
`First Named Inventor Nachiappan Chidambaram
`Examiner Name
`
`Art Unit
`Attorney Docket No.
`
`BAN 102
`
`Application Number
`
`METHOD OF PAYMENT (check all that apply)
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`For the above-identified deposit account, the Director is hereby authorized to: (check all that apply)
`[{] Ch~rge fee(s) indicated below
`0 Charge any additional fee(s) or underpayments of fee(s)
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`.
`under37CFR1.16and1.17
`WARNING: Information on this form may become public. Credit card information should not be included on this form. Provide credit card
`information and authorization on PT0-2038.
`
`D Charge fee(s) indicated below, except for the filing fee
`0 Credit any overpayments
`
`FEE CALCULATION (All the fees below are due upon filing or may be subject to a surcharge.)
`
`1. BASIC FILING, SEARCH, AND EXAMINATION FEES
`FILING FEES
`SEARCH FEES
`Small Entitl£
`Small Enti!l£
`.E!!J1l EiiJll
`lliJil
`150
`500
`250
`
`Agglication Tl£ee
`Utility
`Design
`
`lliJil
`300
`200
`
`EXAMINATION FEES
`Small Entill£
`lliJil
`100
`
`lliJil
`200
`
`Fees Paid !il
`~:l QQQ QQ
`
`100
`
`100
`
`150
`
`100
`300
`
`500
`
`50
`
`150
`
`250
`
`130
`160
`
`600
`
`65
`
`80
`
`300
`
`Plant
`
`Reissue
`
`200
`
`300
`
`200
`
`100
`
`0
`
`0
`
`0
`
`0
`
`Provisional
`2. EXCESS CLAIM FEES
`Fee Descrigtion
`Each claim over 20 (including Reissues)
`Each independent claim over 3 (including Reissues)
`Multiple dependent claims
`.E!!..W
`Total Claims
`Extra Claims
`:31
`$50
`- 20 or HP =
`ll
`X
`HP highest number of total claims paid for, if greater than 20.
`lndeg. Claims
`.E!!..W
`Extra Claims
`=
`$2QQ
`- 3 or HP =
`1
`~
`X
`HP = highest number of independent claims paid for, if greater than 3.
`3. APPLICATION SIZE FEE
`If the specification and drawings exceed 100 sheets of paper( excluding electronically filed sequence or computer
`listings under 37 CFR 1.52(e)), the application size fee due is $250 ($125 for small entity) for each additional 50
`sheets or fraction thereof. See 35 U.S.C. 41~)(1)(0) and 37 CFR 1.16~s).
`Total Sheets
`Extra Sheets
`Num er of each additional 50 or raction thereof
`(round up to a whole number) X
`/50=
`- 100
`4. OTHER FEE(S)
`Non-English Specification, $130 fee (no small entity discount)
`
`Fee Paid (il
`= ~55Q
`
`Fee Paid (il
`~2QQ
`
`Small Enti!l£
`lliJil
`.E!!..W
`25
`50
`100
`200
`180
`360
`Multigle Degendent Claims
`Fee Paid !il
`lliJil
`
`.E!!..W
`
`=
`
`Fee Paid (il
`
`Fees Paid !il
`
`Other (e.g., late filing ~arge):
`
`SUBMITTED BY
`Signature
`
`Name (PrinVType)
`
`'
`
`I
`I
`
`/
`(
`Patrea L Pabst
`This collection of information is require~ by 37 CFR 1.136. The information is required to obtain or retain a benefit by the public which is to file (and by the
`USPTO to process) an application. Confidentiality is governed by 35 U.S.C. 122 and 37 CFR 1.14. This collection is estimated to take 30 minutes to complete,
`including gathering, preparing, and submitting the completed application form to the USPTO. Time will vary depending upon the individual case. Any comments
`on the amount of time you require to complete this form and/or suggestions for reducing this burden, should be sent to the Chief Information Officer, U.S. Patent
`and Trademark Office. U.S. Department of Commerce, P.O. Box 1450, Alexandria, VA 22313-1450. DO NOT SEND FEES OR COMPLETED FORMS TO THIS
`ADDRESS. SEND TO: Commissioner for Patents, P.O. Box 1450, Alexandria, VA 22313-1450.
`If you need assistance in completing the form, ca/11-800-PT0-9199 and select option 2.
`
`1 Registration No. 31,284
`(Attorney/Agent)
`
`Telephone 404-879-2151
`Date March 3, 2006
`
`BAN 102 095161/00005
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1005, Pg. 2 of 445
`
`

`

`f' •
`
`I
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Applicants: Nachiappan Chidambaram and Aqeel Fatmi
`
`Serial No.:
`
`Filed:
`
`For:
`
`Express Mail Label No.: EV 487330851 US
`
`March 3, 2006
`
`Date of Deposit:
`
`March 3, 2006
`
`SOL VENT SYSTEM FOR ENHANCING THE SOLUBILITY OF
`PHARMACEUTICAL AGENTS
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`EXPRESS MAIL TRANSMITTAL LETTER
`FOR PATENT APPLICATION AND CERTIFICATE OF MAILING
`
`Sir:
`
`Pursuant to 35 U.S.C. § 21(a) as amended by Public Law 97-247 and 37 C.F.R. § 1.10,
`
`Applicants enclose for filing the attached patent application entitled "Solvent System for
`
`Enhancing the Solubility of Pharmaceutical Agents", which claims priority to
`
`U.S.S.N. 60/659,679 filed March 8, 2005. The application contains a total of20 pages, which
`
`include 1 page of abstract, 16 pages of specification, 3 pages of claims and a partially executed
`
`Declaration for Patent Application. A fully executed Declaration for Patent Application,
`
`Assignment of rights in the application from Nachiappan Chidambaram and Aqeel Fatmi to
`
`Banner Pharmacaps, Inc., Power of Attorney and Correspondence Address Indication Form, and
`
`a Statement Under 37 C.F.R. § 3.73(b) will be submitted shortly.
`
`The Commissioner is hereby authorized to charge Deposit Account No. 50-3129 in the
`
`amount of$1,750.00 to cover the application filing fee, search fee, and examination fee for a
`
`45064898vl
`
`. BAN 102
`095161/00005
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1005, Pg. 3 of 445
`
`

`

`r'
`
`'
`
`Title: "Solvent System for Enhancing the Solubility of Pharmaceutical Agents"
`Filed: March 3, 2006
`Express Mail Transmittal Letter for
`Patent Application and Certificate of Mailing
`Express Mail Label No.: EV 487330851 US
`Date of Deposit: March 3, 2006
`
`large entity.
`
`It is believed that this is the proper filing fee for a large entity as the application
`
`contains 4 independent claims, a total of 31 claims, and 20 total pages.
`
`This application is not entitled to claim small entity status under 3 7 C.F .R. § 1.2 7.
`
`This application is being filed on March 3, 2006 by mailing the application to
`
`Commissioner for Patents, P.O. Box 1450, Alexandria, VA 22313-1450 via the United States
`
`Postal Service "Express Mail Post Office to Addressee" service under 3 7 C.F .R. § 1.1 0.
`
`The Express Mail label number appears in the heading of this paper which is attached to the
`
`application papers pursuant to 3 7 C.F .R. § 1.1 O(b ).
`
`The Commissioner is hereby authorized to charge any additional fees that may be
`
`required, or credit any overpayment in connection with this application, to Deposit Account
`
`No. 50-3129.
`
`45064898vl
`
`2
`
`BAN 102
`095161/00005
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1005, Pg. 4 of 445
`
`

`

`Title: "Solvent System for Enhancing the Solubility of Pharmaceutical Agents"
`Filed: March 3, 2006
`Express Mail Transmittal Letter for
`Patent Application and Certificate of Mailing
`Express Mail Label No.: EV 487330851 US
`Date of Deposit: March 3, 2006
`
`All correspondence concerning this application should be mailed to:
`
`Customer No. 23579
`Patrea L. Pabst, Esq.
`PABST PATENT GROUP LLP
`400 Colony Square, Suite 1200
`1201 Peachtree Street
`Atlanta, Georgia 30361
`
`(404) 879-2151 (Telephone)
`(404) 879-2160 (Fax)
`
`Respectfully submitted,
`
`Patrea L Pabst
`Reg. No. 31,284
`
`Date: March 3, 2006.
`
`PABST PATENT GROUP LLP
`400 Colony Square, Suite 1200
`. 1201 Peachtree Street
`Atlanta, Georgia 30361
`(404) 879-2151 (Telephone)
`(404) 879-2160 (Fax)
`
`45064898vl
`
`3
`
`BAN 102
`095161/00005
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1005, Pg. 5 of 445
`
`

`

`Title: "Solvent System for Enhancing the Solubility of Pharmaceutical Agents"
`Filed: March 3, 2006
`Express Mail Transmittal Letter for
`Patent Application and Certificate of Mailing
`Express Mail Label No.: EV 487330851 US
`Date of Deposit: March 3, 2006
`
`CERTIFICATE OF MAILING UNDER 37 C.F.R. § 1.10
`
`I hereby certify that this Express Mail Transmittal Letter for Patent Application and
`
`Certificate of Mailing and any documents referred to as attached therein are being deposited with
`
`the United States Postal Service on this date, March 3, 2006, in an envelope as "Express Mail
`
`Post Office to Addressee" service under 37 C.F.R. § 1.10, Express Mail Label No. EV
`
`487330851 US, addressed to Commissioner for Patents, P.O. Box 1450, Alexandria, VA 22313-
`
`1450.
`
`Date: March 3, 2006
`
`45064898vl
`
`4
`
`BAN 102
`095161/00005
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1005, Pg. 6 of 445
`
`

`

`UNITED STATES
`
`UTILITY PATENT APPLICATION
`
`BY
`
`NACHIAPPAN CHIDAMBARAM
`
`AND
`
`AQEEL FATMI
`
`FOR
`
`SOLVENT SYSTEM FOR ENHANCING THE SOLUBILITY OF
`
`PHARMACEUTICAL AGENTS
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1005, Pg. 7 of 445
`
`

`

`SOL VENT SYSTEM FOR ENHANCING THE
`
`SOLUBILITY OF PHARMACEUTICAL AGENTS
`
`FIELD OF THE INVENTION
`
`This invention is in the field of fill materials encapsulated in soft gelatin
`
`5
`
`capsules.
`
`This application claims priority under 35 U.S.C. 119 to U.S.S.N.
`
`60/659,679 filed March 8, 2005 .
`
`. BACKGROUND OF THE INVENTION
`
`Filled one-piece soft gelatin capsules ("softgels") have been widely used
`
`10
`
`for years to encapsulate consumable materials such as vitamins and
`
`pharmaceuticals in a liquid vehicle or carrier. Because softgels have properties
`
`which are quite different from two-piece hardshell capsules, softgels are more
`
`capable of retaining a liquid fill material.
`
`Not all liquids may be enclosed in a softgel capsule. Liquids containing
`
`15
`
`more than about 20% water by weight are generally not enclosed in softgels,
`
`because the water tends to dissolve the gelatin shell. Other solvents such as
`
`propylene glycol, glycerin, low molecular weight alcohols, ketones, acids,
`
`arnines, and esters all tend to degrade or dissolve the gelatin shell to some
`
`extent.
`
`20
`
`Softgels are also somewhat sensitive to pH, and generally require a pH in
`
`the encapsulated liquid from about 2.5 to about 7.5. Highly acidic liquids may
`
`hydrolyze the gelatin, resulting in leaks, while basic liquids may tan the gelatin,
`
`resulting in decreased solubility of the gelatin shell.
`
`Pharmaceutical liquids are usually enclosed in softgels as either viscous
`
`25
`
`solutions or suspensions. Suspensions are pharmaceutically less desirable
`
`because they can settle during manufacture, which leads to a less uniform
`
`product. In contrast, solutions provide the best liquid form for obtaining optimal
`
`"content uniformity" in a batch. Further, solutions typica.lly provide a faster and
`
`more uniform absorption of an active agent than do suspensions.
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`45054234
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`Ex. 1005, Pg. 8 of 445
`
`

`

`Suitable softgel solutions, however, can be difficult to achieve. One
`
`constraint is size. Many pharmaceutical agents require volumes of solvent too
`
`large to produce a softgel capsule small enough to be t*en by patients. The
`
`solvent must also have sufficient solvating power to dissolve a large amount of
`
`5
`
`the pharmaceutical agent to produce a concentrated solution and yet not
`
`dissolve, hydrolyze or tan the gelatin shell.
`
`Concentrated solutions of pharmaceutical agents for use in softgel
`
`capsules have been described. Most of these systems involve ionizing the free
`
`pharmaceutical agent in situ to the corresponding salt. For example, U.S. Patent
`
`10
`
`No. 5,360,615 to Yu et al. discloses a solvent system for enhancing the
`
`solubility of acidic, basic, or amphoteric pharmaceutical agents. The solvt:nt
`
`system comprises polyethylene glycol, an ionizing agent, and water. The
`
`ionizing agent functions by causing the partial ionization of the free
`
`pharmaceutical agent. U.S. Patent No. 6,383,515, U.S. Patent Application
`
`15
`
`Publication No. 2002/0187195, and U.S. Patent Application Publication No.
`
`2001/0007668 to Sawyer et al. discloses phamiaceutically acceptable solutions
`
`containing a medicament suitable for filling softgel capsules comprising a
`
`polymer such as polyethylene glycol and an acid salt of a compound having
`
`three or more carbon atoms, such as sodium propionate. The salt helps to ionize
`
`20
`
`the medicament without relying on the use of strong acids or bases. U.S. Patent
`
`No. 6,689,382 to Berthelet al. describes a pharmaceutical formulation suitable
`
`for filling softgel capsules comprising (a) a therapeutically effective amount of a
`
`non-steroidal anti-inflammatory drug (NSAID); and (b) a solvent system
`
`comprising 40% to 60% by weight a polyoxyethylene ether, 15% to 35% by
`
`25
`
`weight of glycerin and 15% to 35% by weight water. In cases where the NSAID
`
`has a carboxyl or an acidic functional group, the solvent system also includes
`
`hydroxide ions. U.S. Patent No. 5,505,961 to Shelley et al. describes a method
`
`for increasing the solubility of acetaminophen alone or in combination with
`
`other pharmaceutically active agents to form a clear solution for encapsulation
`
`30
`
`into a softgel capsule. The method comprises solubilizing acetaminophen in a
`
`45054234
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`
`

`

`mixture of propylene glycol, polyethylene glycol, water, polyvinylpyrrolidone
`
`and sodium or potassium acetate.
`
`The previously described methods all involve the conversion of the free
`
`pharmaceutical agent to the corresponding salt. In cases where the free
`
`5
`
`pharmaceutical agent is acidic, the resulting anion can react with the
`
`polyethylene glycol in the fill to produce polyethylene glycol esters, thus
`
`reducing the amount of available pharmaceutical agent.
`
`There is a need for a solvent system containing a meQ.icament, which can
`
`be encapsulated in a soft gel capsule, wherein the formation of PEG esters is
`
`1 0 minimized.
`
`Therefore it is an object of the invention to provide a stable solvent
`
`system for pharmaceutical agents, which is suitable for encapsulation in a
`
`softgel capsule, wherein the formation of PEG esters is minimized.
`
`BRIEF SUMMARY OF THE INVENTION
`
`15
`
`Liquid and semi-solid pharmaceutical compositions, which can be
`
`administered in liquid form or can be used for preparing capsules, are described
`
`herein. The composition comprises the salt of one or more active agents, and
`
`0.2-1.0 mole equivalents of a de-ionizing agent per mole of active agent. The
`
`pH of the composition is adjusted within the range of2.5 -7.5. The de-ionizing
`
`20
`
`agent causes partial de-ionization (neutralization) ofthe salt of the active agent
`
`resulting in enhanced bioavailability of salts of weakly acidic, basic or
`
`amphoteric active agents as well as decreased amounts of polyethylene glycol
`
`(PEG) esters.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`25
`
`I. Composition
`
`A.
`
`Fill Materials
`
`1.
`
`Drugs to be Formulated
`
`The formulation can contain any therapeutic, diagnostic, prophylactic or
`
`nutraceutical agent. Exemplary agents include, but are not limited to, analeptic
`
`30
`
`agents; analgesic agents; anesthetic agents; antiasthmatic agents; antiarthritic
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`3
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`Ex. 1005, Pg. 10 of 445
`
`

`

`agents; anticancer agents; anticholinergic agents; anticonvulsant agents;
`
`antidepressant agents; antidiabetic agents; antidiarrheal agents; antiemetic
`
`agents; antihelminthic agents; antihistamines; antihyperlipidemic agents;
`
`antihypertensive agents; anti-infective agents; anti-inflammatory agents;
`
`5
`
`antimigraine agents; antineoplastic agents; anti parkinson drugs; antipruritic
`
`agents; antipsychotic agents; antipyretic agents; antispasmodic agents;
`
`antitubercular agents; antiulcer agents; antiviral agents; anxiolytic agents;
`
`appetite suppressants (anorexic agents); attention deficit disorder and attention.
`
`deficit hyperactivity disorder drugs; cardiovascular agents including calcium
`
`1 0
`
`channel blockers, anti anginal agents, central nervous system ("CNS ") agents,
`
`beta-blockers and antiarrhythmic agents; central nervous system stimulants;
`
`diuretics; genetic materials; hormonolytics; hypnotics; hypoglycemic agents;
`
`immunosuppressive agents; muscle relaxants; narcotic antagonists; nicotine;
`
`nutritional agents; parasympatholytics; peptide drugs; psychostimulants;
`
`15
`
`sedatives; sialagogues, steroids; smoking cessation agents; sympathomimetics;
`
`tranquilizers; vasodilators; beta-agonist; and tocolytic agents.
`
`A first class of drugs is selected based on inclusion in the molecule of a
`
`weakly acidic, basic or amphoteric group that can form a salt. Any drug that
`
`bears an acidic or a basic functional group, for example, an amine, imine;
`
`20
`
`imidazoyl, guanidine, piperidinyl, pyridinyl, quaternary ammonium, or other
`
`basic group, or a carboxylic, phosphoric, phenolic, sulfuric, sulfonic pr other
`
`acidic group, can react with the de-ionizing agent.
`
`Some specific drugs that bear acidic or basic functional groups and thus
`
`may be converted to the corresponding salt for use in the described formulations
`
`25
`
`include, but are not limited to, Acetaminophen, Acetylsalicylic acid, Alendronic
`
`acid, Alosetron, Amantadine, Amlopidine, Anagrelide, Argatroban,
`
`Atomoxetine, Atrovastatin, Azithromycin dehydrate, Balsalazide, Bromocriptan,
`
`Bupropion, Candesartan, Carboplatin, Ceftriaxone, Clavulonic acid,
`
`Clindamycin, Cimetadine, Dehydrocholic (acid), Dexmethylphenidate,
`
`30
`
`Diclofenac, Dicyclomine, Diflunisal, Diltiazem, Donepezil, Doxorubicin,
`
`45054234
`
`4
`
`BAN 102
`095161/5
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1005, Pg. 11 of 445
`
`

`

`Doxepin, Epirubicin, Etodolic acid, Ethacrynic acid, Fenoprofen, Fluoxetine,
`
`Flurbiprofen, Furosemide, Gemfibrozil, Hydroxyzine, Ibuprofen, Imipramine,
`
`Indomethacin, Ketoprofen, Levothyroxine, Maprolitline, Meclizine, Methadone,
`
`Methylphenidate, Minocycline, Mitoxantone, Moxifloxacin, Mycophenolic acid,
`
`5
`
`Naproxen, Niflumic acid, Ofloxacin, Ondansetron, Pantoprazole, Paroxetine,
`
`Pergolide, Pramipexole, Phenytoin, Pravastain, Probenecid, Rabeprazole,
`
`Risedronic acid, Retinoic acid, Ropinirole, Selegiline, Sulindac, Tamsulosin,
`
`Telmisertan, Terbinafine, Theophyline, Tiludronic Acid, Tinzaparin, Ticarcillin,
`
`Tometin, Valproic acid, Salicylic acid, Sevelamer, Ziprasidone, Zoledronic acid,
`
`10
`
`Acetophenazine, Albuterol, Almotriptan, Amitriptyline, Amphetamine,
`
`Atracurium, Beclomethasone, Benztropine, Biperiden, Bosentan,
`
`Bromodiphenhydramine, Brompheniramine carbinoxamine, Caffeine,
`
`Capecitabine, Carbergoline, Cetirizine, Chlocylizine, Chlorpheniramine,
`
`Chlorphenoxamine, Chlorpromazine, Citalopram, Clavunate potassium,
`
`15
`
`Ciprofloxacin, Clemastine, Clomiphene, Clonidine, Clopidogrel, Codeine,
`
`Cyclizine, Cyclobenzaprine, Cyproheptadine, Delavirdine, Diethylpropion,
`
`Divalproex, Desipramine, Dexmethylphenidate, Dexbrompheniramine,
`
`Dexchlopheniramine, Dexchlor, Dextroamphetamine, Dexedrine,
`
`Dextromethorphan, Fiflunisal, Diphemanil methylsulphate, Diphenhydramine,
`
`20
`
`Dolasetron, Doxylamine, Enoxaparin, Ergotamine, Ertepenem, Eprosartan,
`
`Escitalopram, Esomeprazole, Fenoldopam, Fentanyl, Fexofenadine, Flufenamic
`
`acid, Fluvastatin, Fluphenazine, Fluticasone, Fcisinopril, Frovatriptan,
`
`Gabapentin, Galatamine, Gatifloxacin, Gemcitabine, Haloperidol, Hyalurondate,
`
`Hydrocodone, Hydroxychloroquine, Hyoscyamine, Imatinib, Imipenem,
`
`25
`
`lpatropin, Lisinopril, Leuprolide, Levopropoxyphene, Losartan, Meclofenamic
`
`acid, Mefanamic acid, Mesalamine, Mepenzolate, Meperidine, Mephentermine,
`
`Mesalimine, Mesoridazine, Metaproteranol, Metformin, Methdialazine,
`
`Methscopolamine, Methysergide, Metoprolol, Metronidazole, Mibefradil,
`
`Montelukast, Morphine, Mometasone, Naratriptan, Nelfinavir, Nortriptylene,
`
`30
`
`Noscapine, Nylindrin, Omeprazole, Orphenadrine, Oseltamivir, Oxybutynin,
`
`45054234
`
`5
`
`BAN 102
`095161/5
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1005, Pg. 12 of 445
`
`

`

`Papaverine, Pentazocine, Phendimetrazine, Phentermine, Pioglitazone,
`
`Pilocarpine, Prochloroperazine, Pyrilamine, Quetapine, Ranitidine,
`
`Rivastigmine, Rosiglitazone, Salmetrol, Sertaline, Sotalol, Sumatriptan,
`
`Tazobactam, Tacrolimus, Tamoxifen, Ticlopidine, Topiramate, Tolterodine,
`
`5
`
`Triptorelin, Triplennamine, Triprolidine, Tramadol, Trovofloxacin, Ursodiol,
`
`Promazine, Propoxyphene, Propanolol, Pseudoephedrine, Pyrilamine,
`
`Quinidine, Oxybate sodium, Sermorelin, Tacrolimus, Tegaseroid, Teriparatide,
`
`Tolterodine, Triptorelin pamoate, Scoplolamine, Venlafaxine, Zamivir,
`
`Aminocaproic acid, Aminosalicylic acid, Hydromorphone, Isosuprine,
`
`10
`
`Levorphanol, Melhalan, Nalidixic acid, and Para-aminosalicylic acid.
`
`2. Deionizing Agent
`
`The deionizing agent functions by causing partial deionization
`
`(neutralization) of the salt of one or more pharmaceutically active agents. When
`
`the active agent is the salt of a weak acid and a strong base, the deionizing agent
`
`15
`
`is preferably a hydrogen ion species. When the active agent is the salt of a weak
`
`base and a strong acid, the deionizing agent is preferably a hydroxide ion
`
`species. The deionizing agent is preferably present in an amount between 0.2 to
`
`1.0 mole equivalents per mole of the pharmaceutically active agent.
`
`Exemplary hydrogen ion species useful as de-ionizing agents described
`
`20
`
`herein, include, but are not limited to, hydrochloric acid, hydrobromic acid,
`
`hydroiodic acid, sulfuric acid, fumaric acid, maleic acid, tartaric acid, methane-,
`
`ethane-, and benzene sulfonates, citric acid, malic acid, acetic acid, proprionic
`
`acid, pyruvic acid, butanoic acid, and lactic acid.
`
`Exemplary hydroxide ion species useful as de-ionizing agents described
`
`25
`
`herein, include, but are not limited to, metal hydroxides such as sodium
`
`hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide,
`
`aluminum hydroxide, and magnesium hydroxide.
`
`Additional acid or base can be added to adjust the pH of the fill
`
`composition. In a preferred embodiment, the pH of the fill composition is from
`
`30
`
`about 2.5 to about 7.5.
`
`45054234
`
`6
`
`BAN 102
`095161/5
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1005, Pg. 13 of 445
`
`

`

`3. Excipients
`
`Formulations may be prepared using a pharmaceutically acceptable
`
`5
`
`carrier composed of materials that are considered safe and effective and may be
`
`administered to an individual without causing undesirable biological side effects
`
`or unwanted interactions. The carrier is all components present in the
`
`pharmaceutical formulation other than the active ingredient or ingredients. As
`
`generally used herein "carrier" includes, but is not limited to, plasticizers,
`
`10
`
`crystallization inhibitors, wetting agents, bulk filling agents, solubilizers,
`
`bioavailability enhancers, solvents, pH-adjusting agents and combinations
`
`thereof.
`
`In a preferred embodiment, a mixture of polyethylene glycol and water is
`
`used as a solvent for the salt of the active agent and the de-ionizing agent.
`
`15
`
`Polyethylene glycol is present in an amount from about 10% to about 80% by
`
`weight. Water is present in an amount from about 1% to 18% by weight. The
`
`molecular weight of polyethylene glycol is between 300 and 1500. Other
`
`suitable solvents include surfactants and copolymers of polyethylene glycol.
`
`Optionally, glycerin, polyvinylpyrrolidone (PVP) or propylene glycol (PPG)
`
`20
`
`can be added to enhance the solubility of the drug agent.
`
`B. Shell Composition
`
`1. Gelatin
`
`Gelatin is the product of the partial hydrolysis of collagen. Gelatin is
`
`classified as either Type A or Type B gelatin. Type A gelatin is derived from
`
`25
`
`the acid hydrolysis of collagen while Type B gelatin is derived from alkaline
`
`hydrolysis of collagen. Traditionally, bovine bones a:nd skins have been used as
`
`raw materials for manufacturing Type A and Type B gelatin while porcine skins
`
`have been used extensively for manufacturing Type A gelatin. In general acid(cid:173)
`
`processed gelatins form stronger gels than lime-processed gelatins of the same
`
`30
`
`average molecular weight.
`
`45054234
`
`7
`
`BAN 102
`095161/S
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1005, Pg. 14 of 445
`
`

`

`2. Other Shell Additives
`
`Other suitable shell additives include plasticizers, opacifiers, colorants,
`
`5
`
`humectants, preservatives, flavorings, and buffering salts and acids.
`
`Plasticizers are chemical agents added to gelatin to make the material
`
`softer and more flexible. Suitable plasticizers include glycerin, sorbitol
`
`solutions which are mixtures of sorbitol and sorbitan, and other polyhydric
`
`alcohols such as propylene glycol and maltitol or combinations thereof.
`
`10
`
`Opacifiers are used to opacify the capsule shell when the encapsulated
`
`active agents are light sensitive. Suitable opacifiers include titanium dioxide,
`
`zinc oxide, calcium carbonate and combinations thereof.
`
`Colorants can be used to for marketing and product
`
`identification/differentiation purposes. Suitable colorants include synthetic and
`
`15
`
`natural dyes and combinations thereof.
`
`Humectants can be used to suppress the water activity of the softgel.
`
`Suitable humectants include glycerin and sorbitol, which are often components
`
`of the plasticizer composition. Due to the low water activity of dried, properly
`
`stored softgels, the greatest risk from microorganisms comes from molds and
`
`20
`
`yeasts. For this reason, preservatives can be incorporated into the capsule shell.
`
`Suitable preservatives include alkyl esters of p-hydroxy benzoic acid such as
`
`methyl, ethyl, propyl, butyl and heptyl (collectively known as "parabens") or
`
`combinations thereof.
`
`Flavorings can be used to mask unpleasant odors and tastes of fill
`
`25
`
`formulations. Suitable flavorings include synthetic and natural flavorings. The
`
`use of flavorings can be problematic due to the presence of aldehydes which can
`
`cross-link gelatin. As a result, buffering salts and acids can be used in
`
`conjunction with flavorings that contain aldehydes in order to inhibit cross(cid:173)
`
`linking of the gelatin.
`
`30
`
`45054234
`
`8
`
`BAN 102
`095161/5
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1005, Pg. 15 of 445
`
`

`

`II. Method of Making
`
`A. Fill Material
`
`5
`
`The fill material is prepared by mixing the agent (such as a salt of the
`
`drug), the deionizing agent, water, and polyethylene glycol at a temperature of
`
`50°C to 70°C. The resulting solution is encapsulated using the appropriate gel
`
`mass. The pharmaceutical agent is present in an amount from about 1 0% to
`
`about 50% by weight. The deionizing agent is present in an amount from about
`
`10
`
`0.2 to 1.0 mole per mole ofthe pharmaceutical agent. Water is present in an
`
`amount from about 1% to about 20% by weight' and polyethylene glycol is
`
`present in amount from about 10% to about 80% by weight. Optionally,
`
`propylene glycol and/or polyvinyl pyrrolidone are present in an amount from
`
`about 1% to about 1 0%.
`
`15
`
`B. Gel Mass
`
`The main ingredients of the softgel capsule shell are gelatin, plasticizer,
`
`and purified water. Typical gel formulations contain (w/w) 40-50% gelatin, 20-
`
`30% plasticizer, and 30-40% purified water. Most of the water is subsequently
`
`lost during capsule drying. The ingredients are combined to form a molten
`
`20
`
`gelatin mass using eit~er a cold melt or a hot melt process. The prepared gel
`
`masses are transferred to preheated, temperature-controlled, jacketed holding
`
`tanks where the gel mass is aged at 50-60°C until used for encapsulation.
`
`1. Cold Melt Process
`
`The cold melt process involves mixing gelatin with plasticizer and
`
`25
`
`chilled water and then transferring the mixture to a jacket-heated tank.
`
`Typically, gelatin is added to the plasticizer at ambient t