UNITED STATES PATENT AND TRADEMARK OFFICE
`
`200
`
`BAN 102
`
`23579
`PATREA L. PABST
`PABST PATENT GROUP LLP
`400 COLONY SQUARE
`SUITE 1200
`ATLANTA, GA 30361
`
`RECEIVED
`
`MAR 2 8 2005
`
`PATENT DEPT.
`
`Page I of2
`
`Ur-:l'l'ED STATES DEPA RTME'>I'r OF COMMEitCE
`Unitt:d S'Lutl"'-.. Pubmt nnd 'T'rDdt~murll om,:.-~
`Ad~•~COMMJSSIO:NEFI FOR PATENTEl
`P.O. Iku: 1-450
`AJr.urul:ria, V~~w lJJll+UO
`...,..,~·,w.}l!uKU"
`
`CONFIRMATION NO. 9254
`FILING RECEIPT
`llll~lll~ll~llllllllll~ll~mlll~~mn~ rn~ 1m m~m~n~ ~~~ rn~11
`'OC0000000155511 83"
`
`Date Mailed: 03/24/2005
`
`Receipt is acknowledged of this provisional Patent Application. It will not be examined for patentability and will
`become abandoned not later than twelve months after its filing date. Be sure to provide the U.S. APPLICATION
`NUMBER, FILING DATE, NAME OF APPLICANT, and TITLE OF INVENTION when inquiring about this
`application. Fees transmitted by check or draft are subject to collection. Please verify the accuracy of the data
`presented on this receipt. If an error is noted on this Filing Receipt, please write to the Office of Initial
`Patent Examination's Filing Receipt Corrections, facsimile number 703-746-9195. Please provide a copy of
`this Filing Receipt with the -changes noted thereon. If you received a "Notice to File Missing Parts" for this
`application, please submit any corrections to this Filing Receipt with your reply to the Notice. When the
`USPTO processes the reply to the Notice, the USPTO will generate another Filing Receipt incorporating
`the requested corrections (if appropriate).
`
`Applicant(s)
`
`Nachiappan Chidambaram, High Point, NC;
`Aqeel A. Fatmi, Greensboro, NC;
`
`Power of Attorney: The patent practitioners associated with Customer Number 235'[~.
`
`If Required, Foreign Filing License Granted: 03/23/2005
`
`The country code and number of your priority application, to be used for filing abroad under the Paris
`Convention, is USG0/659,679
`
`Projected Publication Date: None, application is not eligible for pre-grant publication
`
`Non-Publication Request: No
`
`Early Publication Request: No
`
`Title
`
`Solvent system for enhancing the solubility of pharmaceutical agents
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1007a, Pg. 1 of 801
`
`

`

`IP n::::: "11"' ,/ IIJ ~!;;;j; I[]IIEi, ... ···· 1[]1 :;;;jl' :;;;jl' :EI: :1:::1:
`
`Page 2 of2
`
`LICENSE FOR FOREIGN FILING UNDER
`Title 35, United States Code, Section 184
`Title 37, Code of Federal Regulations, 5.11 & 5.15
`
`GRANJJ;D
`
`The applicant has been granted a license under 35 U.S.C. 184, if the phrase "IF REQUIRED, FOREIGN FILING
`LICENSE GRANTED" followed by a date appears on this form. Such licenses are issued in all applications where
`the conditions for issuance of a license have been met, regardless of whether or not a license may be required as
`set forth in 37 CFR 5. 15. The scope and limitations of this license are set forth in 37 CFR 5.15(a) unless an earlier
`license has been issued under 37 CFR 5.15(b). The license is subject to revocation upon written notification. The
`date indicated is the effective date of the license, unless an earlier license of similar scope has been granted
`under 37 CFR 5.13 or 5.14.
`
`This license is to be retained by the licensee and may be used at any time on or after the effective date thereof
`unless it is revoked. This license is automatically transferred to any related applications(s) filed under 37 CFR
`1.53(d). This license is not retroactive.
`
`, ..
`
`The grant of a license does not in any way lessen the responsibility of a licensee for the security of the subject
`matter as imposed by any Government contract or the provisions of existing laws relating to espionage and the
`national security or the export of technical data. Licensees should apprise themselves of current regulations
`especially with respect to certain countries, of other agencies, particularly the Office of Defense Trade Controls,
`Department of State (with respect to Arms, Munitions and Implements of War (22 CFR 121-128)); the Office of
`Export Administration, Department of Commerce (15 CFR 370.10 0)); the Office of Foreign Assets Control,
`Department of Treasury (31 CFR Parts 500+) and the Department of Energy.
`
`NOT GRANTED
`
`No license under 35 U.S.C. 184 has been granted at this time, if the phrase "IF REQUIRED, FOREIGN FILING
`LICENSE GRANTED" DOES NOT appear on this form. Applicant may still petition for a license under 37 CFR
`5.12, if a license is desired before the expiration of 6 months from the filing date of the application. If 6 months
`has lapsed from the filing date of this application and the licensee has not received any indication of a secrecy
`order unqer 35 U.S.C. 181, the licensee may foreign file the application pursuant to 37 CFR 5.15(b).
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1007a, Pg. 2 of 801
`
`

`

`..
`
`ASSIGNMENT
`
`We, Nachiappan Chidambaram of 4001 River Pointe Place, Apt. 3D, High Point,
`
`North Carolina 27265, and Aqeel A. Fatmi of 3809 Camden Falls Court, Greensboro,
`
`North Carolina 27410, in consideration of ten dollars and other valuable consideration paid
`
`to us by Banner Pharmacaps, Inc., a corporation of the State of Delaware, having its
`
`principal place of business at 4125 Premier Drive, High Point, North Carolina 27265
`
`(hereinafter "said Assignee"), the receipt of which is hereby acknowledged, do hereby sell,
`
`assign and transfer unto said Assignee, its successors and assigns, the entire interest for the
`
`United States of America, and its territories and all foreign countries and jurisdictions,
`
`including all rights of priority under the International Convention for the Protection of
`
`Industrial Property, in a certain invention or improvement in "SOLVENT SYSTEM FOR
`
`ENHANCING THE SOLUBILITY OF PHARMACEUTICAL AGENTS" described in U.S.
`
`Serial No. 60/659,679 filed in the United States Patent and Trademark Office on March 8,
`
`2005, by Nachiappan Chidambaram and Aqeel Fatmi, and in all Letters Patent of the
`
`United States and its territories and all foreign countries and jurisdictions which may or
`
`shall be granted on said invention, or any parts thereof, or on said application, or any
`
`provisional; divisional, continuation, continuation-in-part, reissue, or other applications
`
`based in whole or in part thereon. And we agree, for ourselves and our executors and
`
`administrators, with said Assignee and its successors and assigns, but at its or their expense
`
`or charges, hereafter to execute all applications, amended specifications, deeds or other
`
`instruments, and to do all acts necessary or proper to secure the grant of Letters Patent in
`
`the United States and its territories and in all other foreign countries and jurisdictions to
`
`said Assignee, with specifications and claims in such form as shall be approved by the
`
`counsel of said Assignee, and to vest and confirm in said Assignee, its successors and
`
`assigns, the legal title to all such patents.
`
`4SOSS206_l.DOC
`
`'t
`
`BAN 102
`095161/00005.
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1007a, Pg. 3 of 801
`
`

`

`Title: "SOLVENT SYSTEM FOR ENHANCING THE SOLUBILiTY OF PHARMACEUTICAL AGENTS"
`By: Nachiappan Chidambaram and Aqeel A. Fatmi
`Filed: March 8, 2005
`ASSIGNMENT
`
`And we do hereby authorize and request the Commissioner of Patents and
`
`Trademarks of the United States to issue such Letters Patent as shall be granted upon said
`
`application or applications based thereon to said Assignee, its successors and assigns.
`
`WITNESS my hand and seal this 23 v-lf day of_..-l_a.y_c.lv _ _ _ _ _ _ , 2005.
`
`,:in /e
`of !loe/IJ Ctzro ft;IOJ )
`County of a-u,·/ {Qrd
`)
`
`Nachia~an Chidarilbaram
`.~J c\.;~ve---:-
`
`Then personally appeared the above named Nachiappan Chidambaram and
`
`acknowledged the foregoing instrument to be his/her free act and deed, before me this
`d).'?rd day of Q)Vrch
`, 2005.
`
`My Commission expires: _,.:,6~· ~/:A .. · ~ ..... 5 .... ~'-"'=->o~;.<------
`
`Notary Public
`
`Cit
`
`•
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`45055206_1.DOC
`
`2
`
`BAN 102
`095161/00005
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1007a, Pg. 4 of 801
`
`

`

`Title: "SOLVENT SYSTEM FOR ENHANCING THE SOLUBILITY OF PHARMACEUTICAL AGENTS"
`By: Nachiappan Chidambaram and Aqeel A. Fatmi
`Filed: March 8, 2005
`ASSIGNMENT
`
`WITNESS my band and seal this 0(/.d day of_--.~./t~ltu.~U::.::./{..!:::'1/:......... ___ , 2005.
`
`--:.S;;..-1_· ~-- of Jt> fl._ C rtJ i, ~.~
`
`County of ?f1111fdo <4/v
`
`)
`
`)
`
`Aqeel A. Fatmi
`
`Then personally appeared the above named Aqeel A. Fatmi and acknowledged the
`foregoing instrument to be his/her free act and deed, before me this dJM" day of
`ihfl/t.[!_ lv
`' 2005.
`
`My Commission expires: _Q~!uf;.;;....~t..t~d..:....:..fj+'--:;..o(.._b_~-..:....~--
`l
`I
`'
`
`1 Notary Public
`
`4505S206_J.DOC
`
`J
`
`BAN 102
`095161/00005
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1007a, Pg. 5 of 801
`
`

`

`BAN 102
`
`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
`
`5
`
`gelatin 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
`
`10
`
`used 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
`
`15
`
`containing 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, amines, 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
`
`25
`
`viscous 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
`
`typically provide a faster and more uniform absorption of an active agent
`
`30
`
`than do suspensions.
`
`Suitable softgel solutions, however, can be difficult to achieve. One
`
`constraint is size. Many pharmaceutical agents require volumes of solvent
`
`1
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1007a, Pg. 6 of 801
`
`

`

`BAN 102
`P' I[~ '"II"' .... ··· II..Ji :!:::i; I!] 16, .. /· 0 :7 ::? a::1: :Ei:
`
`too large to produce a softgel capsule small enough to be taken by patients.
`
`The solvent must also have sufficient solvating power to dissolve a large
`
`amount of the pharmaceutical agent to produce a concentrated solution and
`
`yet not dissolve, hydrolyze or tan the gelatin shell.
`
`5
`
`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 No. 5,360,615 to Yu eta/. discloses a solvent system for
`
`enhancing the solubility of acidic, basic, or amphoteric pharmaceutical
`
`1 0
`
`agents. The solvent system comprises polyethylene glycol, an ionizing
`
`agent, and water. The ionizing agent functions by causing the partial
`
`ionization ofthe free pharmaceutical agent. U.S. Patent No. 6,383,515, U.S.
`
`Patent Application Publication No. 2002/0187195, and U.S. Patent
`
`Application Publication No. 2001/0007668 to Sawyer et al. discloses
`
`15
`
`pharmaceutically 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 the medicament without relying
`
`on the use of strong acids or bases. U.S. Patent No. 6,689,382 to Berthel et
`
`20
`
`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 weight of
`
`glycerin and 15% to 35% by weight water. In cases where the NSAID has a
`
`25
`
`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 into a softgel capsule. The method comprises
`
`30
`
`solubilizing acetaminophen in a mixture of propylene glycol, polyethylene
`
`glycol, water, polyvinylpyrrolidone and sodium or potassium acetate.
`
`2
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1007a, Pg. 7 of 801
`
`

`

`BAN 102
`IP' c: "'li"' .... ··· iiJ ~:::;; i[::!ll[i, ... ···· 1[]1 ::;:w ::;;;;· ~:::1: :I::J
`
`The previously described methods all involve the conversion of the
`
`free pharmaceutical agent to the corresponding salt. In cases where the free
`
`pharmaceutical agent is acidic, the resulting anion can react with the
`
`polyethylene glycol in the fill to produce polyethylene glycol esters, thus
`
`5
`
`reducing the amount of available pharmaceutical agent.
`
`There is a need for a solvent system containing a medicament, which
`
`can be encapsulated in a softgel capsule, wherein the formation of PEG
`
`esters is minimized.
`
`Therefore it is an object of the invention to provide a stable solvent
`
`1 0
`
`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
`
`Liquid and semi-solid pharmaceutical compositions, which can be
`
`administered in liquid form or can be used for preparing capsules, are
`
`15
`
`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 agent causes partial de-ionization (neutralization) of the
`
`salt of the active agent resulting in enhanced bioavailability of salts of
`
`20
`
`weakly acidic, basic or amphoteric active agents as well as decreased
`
`amounts of polyethylene glycol (PEG) esters.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`I. Composition
`
`A.
`
`Fill Materials
`
`25
`
`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 agents; analgesic agents; anesthetic agents; antiasthmatic agents;
`
`antiarthritic agents; anticancer agents; anticholinergic agents; anticonvulsant
`
`30
`
`agents; antidepressant agents; antidiabetic agents; antidiarrheal agents;
`
`antiemetic agents; antihelminthic agents; antihistamines; antihyperlipidemic
`
`agents; antihypertensive agents; anti-infective agents; anti-inflammatory
`
`3
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1007a, Pg. 8 of 801
`
`

`

`BAN 102
`
`agents; antimigraine agents; antineoplastic agents; antiparkinson 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
`
`5
`
`attention deficit hyperactivity disorder drugs; cardiovascular agents including
`
`calcium channel blockers, antianginal 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
`
`10
`
`antagonists; nicotine; nutritional agents; parasympatholytics; peptide drugs;
`
`psychostimulants; 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
`
`15
`
`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, imidazoyl, guanidine, piperidinyl, pyridinyl, quaternary ammonium,
`
`or other basic group, or a carboxylic, phosphoric, phenolic, sulfuric, sulfonic
`
`or other acidic group, can react with the de-ionizing agent.
`
`20
`
`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 include, but are not limited to, Acetaminophen, Acetylsalicylic
`
`acid, Alendronic acid, Alosetron, Amantadine, Amlopidine, Anagrelide,
`
`Argatroban, Atomoxetine, Atrovastatin, Azithromycin dehydrate,
`
`25
`
`Balsalazide, Bromocriptan, Bupropion, Candesartan, Carboplatin,
`
`Ceftriaxone, Clavulonic acid, Clindamycin, Cimetadine, Dehydrocholic
`
`(acid), Dexmethylphenidate, Diclofenac, Dicyclomine, Diflunisal,
`
`Diltiazem, Donepezil, Doxorubicin, Doxepin, Epirubicin, Etodolic acid,
`
`Ethacrynic acid, Fenoprofen, Fluoxetine, Flurbiprofen, Furosemide,
`
`30
`
`Gemfibrozil, Hydroxyzine, Ibuprofen, Imipramine, Indomethacin,
`
`Ketoprofen, Levothyroxine, Maprolitline, Meclizine, Methadone,
`
`Methylphenidate, Minocycline, Mitoxantone, Moxifloxacin, Mycophenolic
`
`4
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1007a, Pg. 9 of 801
`
`

`

`BAN 102
`
`acid, 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
`
`5
`
`Acid, Tinzaparin, Ticarcillin, Tometin, Valproic acid, Salicylic acid,
`
`Sevelamer, Ziprasidone, Zoledronic acid, Acetophenazine, Albuterol,
`
`Almotriptan, Amitriptyline, Amphetamine, Atracurium, Beclomethasone,
`
`Benztropine, Biperiden, Bosentan, Bromodiphenhydramine,
`
`Brompheniramine carbinoxamine, Caffeine, Capecitabine, Carbergoline,
`
`10
`
`Cetirizine, Chlocylizine, Chlorpheniramine, Chlorphenoxamine,
`
`Chlorpromazine, Citalopram, Clavunate potassium, Ciprofloxacin,
`
`Clemastine, Clomiphene, Clonidine, Clopidogrel, Codeine, Cyclizine,
`
`Cyclobenzaprine, Cyproheptadine, Delavirdine, Diethylpropion, Divalproex,
`
`Desipramine, Dexmethylphenidate, Dexbrompheniramine,
`
`15
`
`Dexchlopheniramine, Dexchlor, Dextroamphetamine, Dexedrine,
`
`Dextromethorphan, Fiflunisal, Diphemanil methylsulphate,
`
`Diphenhydramine, Dolasetron, Doxylamine, Enoxaparin, Ergotamine,
`
`Ertepenem, Eprosartan, Escitalopram, Esomeprazole, Fenoldopam, Fentanyl,
`
`Fexofenadine, Flufenamic acid, Fluvastatin, Fluphenazine, Fluticasone,
`
`20
`
`Fosinopril, Frovatriptan, Gabapentin, Galatamine, Gatifloxacin,
`
`Gemcitabine, Haloperidol, Hyalurondate, Hydrocodone,
`
`Hydroxychloroquine, Hyoscyamine, Imatinib, Imipenem, Ipatropin,
`
`Lisinopril, Leuprolide, Levopropoxyphene, Losartan, Meclofenamic acid,
`
`Mefanamic acid, Mesalamine, Mepenzolate, Meperidine, Mephentermine,
`
`25 Mesalimine, Mesoridazine, Metaproteranol, Metformin, Methdialazine,
`
`Methscopolamine, Methysergide, Metoprolol, Metronidazole, Mibefradil,
`
`Montelukast, Morphine, Mometasone, Naratriptan, Nelfinavir, Nortriptylene,
`
`Noscapine, Nylindrin, Omeprazole, Orphenadrine, Oseltamivir, Oxybutynin,
`
`Papaverine, Pentazocine, Phendimetrazine, Phentermine, Pioglitazone,
`
`30
`
`Pilocarpine, Prochloroperazine, Pyrilamine, Quetapine, Ranitidine,
`
`Rivastigmine, Rosiglitazone, Salmetrol, Sertaline, Sotalol, Sumatriptan,
`
`Tazobactam, Tacrolimus, Tamoxifen, Ticlopidine, Topiramate, Tolterodine,
`
`5
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1007a, Pg. 10 of 801
`
`

`

`BAN 102
`
`Triptorelin, Triplennamine, Triprolidine, Tramadol, Trovofloxacin, Ursodiol,
`
`Promazine, Propoxyphene, Propanolol, Pseudoephedrine, Pyrilamine,
`
`Quinidine, Oxybate sodium, Sermorelin, Tacrolimus, Tegaseroid,
`
`Teriparatide, Tolterodine, Triptorelin pamoate, Scoplolamine, Venlafaxine,
`
`5
`
`Zamivir, Aminocaproic acid, Aminosalicylic acid, Hydromorphone,
`
`Isosuprine, Levorphanol, Melhalan, Nalidixic acid, and Para-aminosalicylic
`
`acid.
`
`2. Deionizing Agent
`
`The deionizing agent functions by causing partial deionization
`
`10
`
`(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 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
`
`15
`
`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 herein, include, but are not limited to, hydrochloric acid,
`
`hydrobromic acid, hydroiodic acid, sulfuric acid, fumaric acid, maleic acid,
`
`20
`
`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 herein, include, but are not limited to, metal hydroxides such as
`
`sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium
`
`25
`
`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 about 2.5 to about 7.5.
`
`3. Excipients
`
`30
`
`Formulations may be prepared using a pharmaceutically acceptable
`
`carrier composed of materials that are considered safe and effective and may
`
`be administered to an individual without causing undesirable biological side
`
`6
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1007a, Pg. 11 of 801
`
`

`

`BAN 102
`IP' n::: '"il"' .... ··· ijJ ~~::i; n:::UI[i, , ..... lUI :;? :;;;w :1:::1: :t::l:
`
`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, crystallization inhibitors, wetting agents, bulk filling agents,
`
`5
`
`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. Polyethylene glycol is present in an amount from about 10% to about
`
`1 0
`
`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) can be added to enhance the solubility of the drug
`
`15
`
`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
`
`20
`
`from the acid hydrolysis of collagen while Type B gelatin is derived from
`
`alkaline hydrolysis of collagen. Traditionally, bovine bones and 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-processed gelatins form stronger gels than lime-
`
`25
`
`processed gelatins of the same average molecular weight.
`
`2. Other Shell Additives
`
`Other suitable shell additives include plasticizers, opacifiers,
`
`colorants, humectants, preservatives, flavorings, and buffering salts and
`
`acids.
`
`30
`
`Plasticizers are chemical agents added to gelatin to make the material
`
`softer and more flexible. Suitable plasticizers include glycerin, sorbitol
`
`7
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1007a, Pg. 12 of 801
`
`

`

`BAN 102
`IP' 11::::: "'If" ....... til :!::;;; [II IE:u .... ··· [II :;;;w :;?' :1:::1: :~:;;~
`
`solutions which are mixtures of sorbitol and sorbitan, and other polyhydric
`
`alcohols such as propylene glycol and maltitol or combinations thereof.
`
`Opacifiers are used to opacify the capsule shell when the
`
`encapsulated active agents are light sensitive. Suitable opacifiers include
`
`5
`
`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 natural dyes and combinations thereof.
`
`Humectants can be used to suppress the water activity of the soft gel.
`
`10
`
`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 yeasts. For this reason, preservatives can be incorporated
`
`into the capsule shell. Suitable preservatives include alkyl esters of p-
`
`15
`
`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
`
`formulations. Suitable flavorings include synthetic and natural flavorings.
`
`The use of flavorings can be problematic due to the presence of aldehydes
`
`20
`
`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-linking of the gelatin.
`
`II. Method of Making
`A. Fill Material
`
`25
`
`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
`
`30
`
`about 0.2 to 1.0 mole per mole of the 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.
`
`8
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1007a, Pg. 13 of 801
`
`

`

`BAN 102
`lf::J• u::: il"' ... ···· iiJ ~::~;; [il !l~:i, ....... U] :;;;w ::;;jl' :1:::1: :1::3:
`
`Optionally, propylene glycol and/or polyvinylpyrrolidone are present in an
`
`amount from about 1% to about 10%.
`
`B. Gel Mass
`
`The main ingredients of the softgel capsule shell are gelatin,
`
`5
`
`plasticizer, and purified water. Typical gel formulations contain (w/w) 40-
`
`50% gelatin, 20-30% plasticizer, and 30-40% purified water. Most ofthe
`
`water is subsequently lost during capsule drying. The ingredients are
`
`combined to form a molten gelatin mass using either a cold melt or a hot
`
`melt process. The prepared gel masses are transferred to preheated,
`
`10
`
`temperature-controlled, jacketed holding tanks where the gel mass is aged at
`
`5lJ-60°C until used for encapsulation.
`
`1. Cold Melt Process
`
`The cold melt process involves mixing gelatin with plasticizer and
`
`chilled water and then transferring the mixture to a jacket-heated tank.
`
`15
`
`Typically, gelatin is added to the plasticizer at ambient temperature ( 18-
`
`220C). The mixture is cooked (57-95°C) under vacuum for 15-30 minutes to
`
`a homogeneous, deaerated gel mass. Additional shell additives can be added
`
`to the gel mass at any point during the gel manufacturing process or they
`
`may be incorporated into the finished gel mass using a high torque mixer.
`
`20
`
`2. Hot Melt Process
`
`The hot melt process involves adding, under mild agitation, the
`
`gelatin to a preheated (60-80°C) mixture of plasticizer and water and stirring
`
`the blend until complete melting is achieved. While the hot melt process is
`
`faster than the cold melt process, it is less accurately controlled and more
`
`25
`
`susceptible to foaming and dusting.
`
`C. Softgel Capsule
`
`Softgel capsules are typically produced using a rotary die
`
`encapsulation process. The gel mass is fed either by gravity or through
`
`positive displacement pumping to two heated ( 48-65°C) metering devices.
`
`30
`
`The metering devices control the flow of gel into cooled (10-l8°C), rotating
`
`casting drums. Ribbons are formed as the cast gel masses set on contact with
`
`the surface of the drums.
`
`9
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1007a, Pg. 14 of 801
`
`

`

`BAN 102
`,... 1111 c: il'"lt!C"'
`.•· !l"'ll ..... ,,"'"I' ,
`...
`... ,,,
`
`1 ,.,fl •.,.,!f !f.,,if {,:;u ,/ . ,.J .i .i ! :~ft I~; I
`••'
`1
`1
`
`1,
`
`n:::1• ii'"'' "'IJ"'
`f!
`iJ
`!!,,I'
`
`The ribbons are fed through a series of guide rolls and between
`
`injection wedges and the capsule-forming dies. A food-grade lubricant oil is
`
`applied onto the ribbons to reduce their tackiness and facilitate their transfer.
`
`Suitable lubricants include mineral oil, medium chain triglycerides, and
`
`5
`
`soybean oil. Fill formulations are fed into the encapsulation machine by
`
`gravity. In the preferred embodiment, the softgels contain printing on the
`
`surface, optionally identifying the encapsulated agent and/or dosage.
`
`III. Method of Use
`
`The softgels may be used to encapsulate a wide range of
`
`10
`
`pharmaceutically active agents, nutritional agents and personal care products.
`
`Softgel capsules may be administered orally to a patient to deliver a
`
`pharmaceutically active agent.
`
`Examples
`
`In the following examples, the fill material can be prepared by
`
`15
`
`mixing the salt of one or more pharmaceutically active agents, the deionizing
`
`agent, water and polyethylene glycol at a temperature of 50°C to 70°C. The
`
`resulting solution can be encapsulated in a softgel capsule using the
`
`appropriate gel mass.
`
`20
`
`Example 1. Naproxen Sodium with Acetic Acid as the Deionizing
`
`Agent
`
`Fill Material:
`
`Ingredients
`
`Naproxen Sodium
`
`Acetic Acid
`
`PVP
`
`PEG400
`
`Water
`
`% {by weight}
`
`25.50
`
`3.00
`
`1.85
`
`62.30
`
`7.40
`
`10
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1007a, Pg. 15 of 801
`
`

`

`BAN 102
`IP· 11::::: '"!I"' .... ··· 11...11 ~!:::ii [!I lEi~ .... ··· II] ::?· :;;;il' :1:::1: :1:::1:
`
`Example 2. Naproxen Sodium with Citric Acid as the Deionizing
`
`Agent
`
`Fill Material:
`
`Ingredients
`
`Naproxen Sodium
`
`Citric Acid
`
`PVP
`
`PEG400
`
`Water
`
`% {b.Y weight}
`
`25.50
`
`4.75
`
`1.85
`
`60.50
`
`7.40
`
`5
`
`Example 3. Naproxen Sodium with Hydrochloric Acid as the
`
`Deionizing Agent
`
`Fill Material:
`
`Ingredients
`
`Naproxen Sodium
`
`Hydrochloric Acid
`
`PVP
`
`PEG400
`
`Water
`
`% {b.Y weight}
`
`25.50
`
`4.72
`
`1.85
`
`63.52
`
`7.40
`
`Example 4. Naproxen Sodium with Acetic Acid as the Deionizing
`
`10
`
`Agent
`
`Fill Material:
`
`Ingredients
`
`Naproxen Sodium
`
`Acetic Acid
`
`PVP
`
`PEG400
`
`Water
`
`PEG 600
`
`% {b.Y weight}
`
`25.50
`
`3.00
`
`1.85
`
`31.15
`
`7.40
`
`31.15
`
`11
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1007a, Pg. 16 of 801
`
`

`

`BAN 102
`F~ u:::: "'f .... ··· 11 . ..11 ~::ii f]IIEit ....... U:::ll ~?' :;;;w :l:::i: :1:::1:
`
`Example 5. Naproxen Sodium with Citric Acid as the Deionizing
`
`Agent
`
`Fill Material:
`
`Ingredients
`
`Naproxen Sodium
`
`Citric Acid
`
`PVP
`
`PEG400
`
`Water
`
`PEG 600
`
`% {by weight}
`
`25.50
`
`4075
`
`1.85
`
`30.25
`
`7.40
`
`30.25
`
`5
`
`Example 6. Naproxen Sodium with Hydrochloric Acid as the
`
`Deionizing Agent
`
`Fill Material:
`
`Ingredients
`
`Naproxen Sodium
`
`Hydrochloric Acid
`
`PVP
`
`PEG400
`
`Water
`
`PEG 600
`
`% {by weight}
`
`25.50
`
`