PTO/SB/16 (12·04)
`Approved for use through 07131/2006. OMB 0651-0032
`U.S. Patent and Trademark Office; U.S. DEPARTMENT OF COMMERCE
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`1- en
`0
`PROVISIONAL APPLICATION FOR PATENT COVER SHEET
`. to
`~~
`~
`This is a request for filing a PROVISIONAL APPLICATION FOR PATENT under 37 CFR 1.53(c).
`-...J
`(f) 0'>
`EV 487328654 US
`!Ucpress Mail Label No
`.....;
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`9-Jachiappan
`
`INVENTOR(S)
`Family Name or Surname
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`Residence
`(Citv and either State or Foreign Country)
`
`-
`
`Chidambaram
`1
`separately numbered sheets attached hereto
`Additional inventors are being named on the
`TITLE OF THE INVENTION (500 characters max\:
`
`High Point, North Carolina
`
`SOLVENT SYSTEM FOR ENHANCING THE SOLUBILITY OF PHARMACEUTICAL AGENTS
`
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`BAN 102 095161/00005 -(cid:173)
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1004, Pg. 1 of 34
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`

`

`PROVISIONAL APPLICA T/ON COVER SHEET
`Additional Page
`
`PTO/SB/16 (12-04)
`App~oved for use through 07/31/2006. OMB 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 OMB control number.
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`I First Named Inventor I Nachiappan Chidambaram
`
`I Docket Number I BAN 102
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`Given Name (first and middle [if any))
`
`Family or Surname
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`(City and either State or Foreign Country)
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`INVENTOR(S)IAPPLICANT(S)
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`Aqeel
`
`Fatmi
`
`Greensboro, North Carolina
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`2
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`included on this form. Provide credit card information and authorization on PT0-2038.
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`BAN 102 095161/00005
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`
`Petitioner - Catalent Pharma Solutions
`Ex. 1004, Pg. 2 of 34
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`

`

`Title:
`"SOLVENT SYSTEM FOR ENHANCING THE SOLUBILITY OF PHARMACEUTICAL AGENTS"
`Nachiappan Chidambaram and Aqeel Fatini
`By:
`Filed: March 8, 2005
`
`CERTIFICATE OF MAILING UNDER 37 CFR §1.10
`
`I hereby certify that this PROVISIONAL APPLICATION, and any documents referred
`
`to as attached therein, are being deposited with the United States Postal Service on this date,
`
`March 8, 2005, in an envelope as "Express Mail Post Office to Addressee" service under 37 CFR
`
`1.1 0, Mailing Label Number EV 487328654 US, addressed to Commissioner for Patents, P. 0.
`
`Box 1450, Alexandria, VA 22313-1450.
`
`Date: March 8, 2005
`
`· 45055176_1.DOC
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`BAN 102
`095161/00005
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`Petitioner - Catalent Pharma Solutions
`Ex. 1004, Pg. 3 of 34
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`

`

`UNITED STATES
`
`PROVISIONAL PATENT APPLICATION
`
`BY
`
`NACHIAPPAN CHIDAMBARAM
`
`AND
`
`AQEELFATMI
`
`FOR
`
`SOLVENT SYSTEM FOR ENHANCING THE SOLUBILITY OF
`
`PHARMACEUTICAL AGENTS
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1004, Pg. 4 of 34
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`

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`SOL VENT SYSTEM FORENHANCING THE SOLUBILITY OF
`
`PHARMACEUTICAL AGENTS
`
`FIELD OF THE INVENTION
`
`This invention is in the field of fill materialsencapsulated in soft gelatin
`
`5
`
`capsules.
`
`BACKGROUND OF THE INVENTION
`
`Filled one-piece soft gelatin capsules ("softgels") have been widely used
`
`for years to encapsulate consumable materials such as vitamins and
`
`pharmaceuticals in a liquid vehicle or carrier. Because softgels have properties
`
`10
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`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
`
`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
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`15
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`propylene glycol, glycerin, low molecular weight alcohols, ketones, acids,
`
`amines, and esters all tend to degrade or dissolve the gelatin shell to some
`
`extent.
`
`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
`
`20
`
`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
`
`solutions or suspensions. Suspensions are pharmaceutically less desirable
`
`because they can settle during manufacture, which leads to a less uniform.
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`25
`
`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 than do suspensions.
`
`Suitable softgel solutions, however, can be difficult to achieve. One
`
`constraint is size. Many pharmaceutical agents require volumes of solvent too
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`30
`
`large to produce a softgel capsule small enough to be taken by patients. The
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`solvent must also have sufficient solvating power to dissolve a large amount of
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`the pharmaceutical agent to produce a concentrated solution and yet not
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`dissolve, hydrolyze or tan the gelatin shell.
`
`Concentrated solutions of pharmaceutical agents for use in softgel
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`5
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`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 et al. discloses a solvent system for enhancing the
`
`solubility of acidic, basic, or amphoteric pharmaceutical agents. The solvent
`
`system comprises polyethylene glycol, an ionizing agent, and water. The
`
`10
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`ionizing agent functions by causing the partial ionization of the 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 pharmaceutically acceptable solutions
`
`containing a medicament suitable for filling softgel capsules comprising a
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`15
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`polymer such as polyethylene glycol and an acid salt of a compound having 3 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 Berthelet al. describes a pharmaceutical formulation suitable for
`
`filling softgel capsules comprising (a) a therapeutically effective amount of a
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`20
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`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 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
`
`25
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`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 solubilizing acetaminophen in a
`
`mixture of propylene glycol, polyethylene glycol, water, polyvinylpyrrolidone
`
`and sodium or potassium acetate.
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`30
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`The previously described methods all involve the conversion of the free
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`pharmaceutical agent to the corresponding salt. In cases where the free
`
`pharmaceutical agent is acidic, the resulting anion can react with the
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`polyethylene glycol in the fill to produce polyethylene glycol esters, thus
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`5
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`reducing the amount of available pharmaceutical agent.
`
`There exists a need for a solvent system containing a medicament, which
`
`can be encapsulated in a soft gel capsule, wherein the formation of PEG esters is
`
`minimized.
`
`Therefore it is an object of the invention to provide a stable solvent
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`10
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`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 described
`
`15
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`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 weakly acidic, basic or
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`20
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`amphoteric active agents as well as decreased amounts of polyethylene glycol
`
`(PEG) esters.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`I. Composition
`
`a. Fill Materials
`
`25
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`i. Drugs to be Formulated
`
`Exemplary drug agents useful for forming the composition described
`
`herein include, but are not limited to, analeptic agents; analgesic agents;
`
`anesthetic agents; antiasthmatic agents; antiarthritic agents; anticancer agents;
`
`anticholinergic agents; anticonvulsant agents; antidepressant agents; antidiabetic
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`30
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`agents; antidiarrheal agents; antiemetic agents; antihelminthic agents;
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`antihistamines; antihyperlipidemic agents; antihypertensive agents; anti(cid:173)
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`infective agents; anti-inflammatory agents; antimigraine agents; antineoplastic
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`agents; antiparkinson drugs; antipruritic agents; antipsychotic agents; antipyretic
`
`agents; antispasmodic agents; antitubercular agents; antiulcer agents; antiviral
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`5
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`agents; anxiolytic agents; appetite suppressants (anorexic agents); attention
`
`deficit disorder and attention deficit hyperactivity disorder drugs; cardiovascular
`
`agents including calcium channel blockers, antianginal agents, central nervous
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`system ("CNS ") agents, beta-blockers and antiarrhythmic agents; central
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`nervous system stimulants; diuretics; genetic materials; hormonolytics;
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`10
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`hypnotics; hypoglycemic agents; immunosuppressive agents; muscle relaxants;
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`narcotic antagonists; nicotine; nutritional agents; parasympatholytics; peptide
`
`drugs; psychostimulants; sedatives; sialagogues, steroids; smoking cessation
`
`agents; sympathomimetics; tranquilizers; vasodilators; beta-agonist; and
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`tocolytic agents.
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`15
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`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,
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`imidazoyl, guanidine, piperidinyl, pyridinyl, quaternary ammonium, or other
`
`basic group, or a carboxylic, phosphoric, phenolic, sulfuric, sulfonic or other
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`20
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`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
`
`include, but are not limited to, Acetaminophen, Acetylsalicylic acid, Alendronic
`
`acid, Alosetron, Amantadine, Amlopidine, Anagrelide, Argatroban,
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`25
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`Atomoxetine, Atrovastatin, Azithromycin dehydrate, Balsalazide, Bromocriptan,
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`Bupropion, Candesartan, Carboplatin, Ceftriaxone, Clavulonic acid,
`
`Clindamycin, Cimetadine, Dehydrocholic (acid), Dexmethylphenidate,
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`Diclofenac, Dicyclomine, Diflunisal, Diltiazem, Donepezil, Doxorubicin,
`
`Doxepin, Epirubicin, Etodolic acid, Ethacrynic acid, Fenoprofen, Fluoxetine,
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`30
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`Flurbiprofen, Furosemide, Gemfibrozil, Hydroxyzine, Ibuprofen, Imipramine,
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`Indomethacin, Ketoprofen, Levothyroxine, Maprolitline, Meclizine, Methadone,
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`Methylphenidate, Minocycline, Mitoxantone, Moxifloxacin, Mycophenolic acid,
`
`Naproxen, Niflumic acid, Ofloxacin, Ondansetron, Pantoprazole, Paroxetine,
`
`Pergolide, Pramipexole, Phenytoin, Pravastain, Probenecid, Rabeprazole,
`
`5
`
`Risedronic acid, Retinoic acid, Ropinirole, Selegiline, Sulindac, Tamsulosin,
`
`Telmisertan, Terbinafine, Theophyline, Tiludronic Acid, Tinzaparin, Ticarcillin,
`
`Tometin, Valproic acid, Salicylic acid, Sevelamer, Ziprasidone, Zoledronic acid,
`
`Acetophenazine, Albuterol, Almotriptan, Amitriptyline, Amphetamine,
`
`Atracurium, Beclomethasone, Benztropine, Biperiden, Bosentan,
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`10
`
`Bromodiphenhydramine, Brompheniramine carbinoxamine, Caffeine,
`
`Capecitabine, Carbergoline, Cetirizine, Chlocylizine, Chlorpheniramine,
`
`Chlorphenoxamine, Chlorpromazine, Citalopram, Clavunate potassium,
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`Ciprofloxacin, Clemastine, Clomiphene, Clonidine, Clopidogrel, Codeine,
`
`Cyclizine, Cyclobenzaprine, Cyproheptadine, Delavirdine, Diethylpropion,
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`15
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`Divalproex, Desipramine, Dexmethylphenidate, Dexbrompheniramine,
`
`Dexchlopheniramine, Dexchlor, Dextroamphetamine, Dexedrine,
`
`Dextromethorphan, Fiflunisal, Diphemanil methylsulphate, Diphenhydramine,
`
`Dolasetron, Doxylamine, Enoxaparin, Ergotamine, Ertepenem, Eprosartan,
`
`Escitalopram, Esomeprazole, Fenoldopam, Fentanyl, Fexofenadine, Flufenamic
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`20
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`acid, Fluvastatin, Fluphenazine, Fluticasone, Fosinopril, Frovatriptan,
`
`Gabapentin, Galatamine, Gatifloxacin, Gemcitabine, Haloperidol, flyalurondate,
`
`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,
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`30
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`Pilocarpine, Prochloroperazine, Pyrilamine, Quetapine, Ranitidine,
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`Rivastigmine, Rosiglitazone, Salmetrol, Sertaline, Sotalol, Sumatriptan,
`
`Tazobactam, Tacrolimus, Tamoxifen, Ticlopidine, Topiramate, Tolterodine,
`
`Triptorelin, Triplennamine, Triprolidine, Tramadol, Trovofloxacin, Ursodiol,
`
`Promazine, Propoxyphene, Propanolol, Pseudoephedrine, Pyrilamine,
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`5
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`Quinidine, Oxybate sodium, Sermorelin, Tacrolimus, Tegaseroid, Teriparatide,
`
`Tolterodine, Triptorelin pamoate, Scoplolamine, Venlafaxine, Zamivir,
`
`Aminocaproic acid, Aminosalicylic acid, Hydromorphone, Isosuprine,
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`Levorphanol, Melhalan, Nalidixic acid, and Para-aminosalicylic acid.
`
`ii. Deionizing Agent
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`10
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`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
`
`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
`
`15
`
`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
`
`herein, include, but are not limited to, hydrochloric acid, hydrobromic acid,
`
`hydroiodic acid, sulfuric acid, fumaric acid, maleic acid, tartaric acid, methane-,
`
`20
`
`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 hydroxide,
`
`25
`
`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.
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`iii. Excipients
`
`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 effects
`
`5
`
`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, solubilizers,
`
`bioavailability enhancers, solvents, pH-adjusting agents and combinations
`
`10
`
`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 80% by
`
`weight. Water is present in an amount from about 1% to 18% by weight. The
`
`15
`
`molecular weight of polyethylene glycol is between 300 and 1500. Other
`
`suitable solvents include surfactants and copolymers of polyethylene glycol.
`
`Optionally, glycerin, polyvinyl pyrrolidone (PVP) or propylene glycol (PPG)
`
`can be added to enhance the solubility of the drug agent.
`
`b. Shell Composition
`
`20
`
`i. Gelatin
`
`Gelatin is the product of the partial hydrolysis of collagen. Gelatin is
`
`classified as either Type A or Type 8 gelatin. Type A gelatin is derived from
`
`the acid hydrolysis of collagen while Type 8 gelatin is derived from alkaline
`
`hydrolysis of collagen. Traditionally, bovine bones and skins have been used as
`
`25
`
`raw materials for manufacturing Type A and Type 8 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
`
`average molecular weight.
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`ii. Other Shell Additives
`
`Other suitable shel~ additives include plasticizers, opacifiers, colorants,
`
`humectants, preservatives, flavorings, and buffering salts and acids.
`
`Plasticizers are chemical agents added to gelatin to make the material
`
`5
`
`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.
`
`Opacifiers are used to opacify the capsule shell when the encapsulated
`
`active agents are light sensitive. Suitable opacifiers include titanium dioxide,
`
`1 0
`
`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.
`
`15
`
`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-hydroxy benzoic acid such as
`
`20
`
`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 which can
`
`25
`
`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.
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`30
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`45054234
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`BAN 102
`095161/5
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`Petitioner - Catalent Pharma Solutions
`Ex. 1004, Pg. 12 of 34
`
`

`

`II. Method of Making
`
`a. Fill Material
`
`The fill material is prepared by mixing the drug agent (salt), the
`
`deionizing agent, water, and polyethylene glycol at a temperature of 50°C to
`
`5
`
`70°C. The resulting solution is used for encapsulation using the appropriate gel
`
`mass. The pharmaceutical agent is present in an amount from about 10% to
`
`about 50% by weight. The deionizing agent is present in an amount from 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
`
`10
`
`present in amount from about 10% to about 80% by weight. 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, plasticizer,
`
`15
`
`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
`
`gelatin mass using either a cold melt or a hot melt process. The prepared gel
`
`·masses are transferred to preheated, temperature-controlled, jacketed holding
`
`20
`
`tanks where the gel mass is aged at 50-60°C until used for encapsulation.
`
`i. 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.
`
`Typically, gelatin is added to the plasticizer at ambient temperature (18-22°C).
`
`25
`
`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.
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`30
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`45054234
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`9
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`BAN 102
`095161/5
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1004, Pg. 13 of 34
`
`

`

`ii. 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
`
`5
`
`cold melt process, it is less accurately controlled and more 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
`
`10
`
`pumping to two heated ( 48-65°C) metering devices. The metering devices
`
`control the flow of gel into cooled (1 O-l8°C), rotating casting drums. Ribbons
`
`are formed as the cast gel masses set on contact with the surface of the drums.
`
`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
`
`15
`
`the ribbons to reduce their tackiness and facilitate their transfer. Suitable
`
`lubricants include mineral oil, medium chain triglycerides, and 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.
`
`20
`
`III. Method of Use
`
`The softgels may be used to encapsulate a wide range of
`
`pharmaceutically active agents, nutritional agents and personal care products.
`
`Softgel capsules may be administered orally to a patient to deliver a
`
`25
`
`pharmaceutically active agent.
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`30
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`45054234
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`BAN 102
`095161/5
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1004, Pg. 14 of 34
`
`

`

`Examples
`
`In the following examples, the fill material can be prepared by 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
`
`5
`
`solution can be encapsulated in a softgel capsule using the appropriate gel mass.
`
`Example 1. Naproxen Sodium with Acetic Acid as the Deionizing
`
`Agent
`
`Fill Material:
`
`Ingredients
`
`Naproxen Sodium
`
`Acetic Acid
`
`PVP
`
`PEG400
`
`Water
`
`% {b:y weight}
`
`25.50
`
`3.00
`
`1.85
`
`62.30
`
`7.40
`
`Example 2. Naproxen Sodium with Citric Acid as the Deionizing
`
`Agent
`
`Fill Material:
`
`Ingredients
`
`Naproxen Sodium
`
`Citric Acid
`
`PVP
`
`PEG 400
`
`Water
`
`% {b:y weight}
`
`25.50
`
`4.75
`
`1.85
`
`60.50
`
`7.40
`
`10
`
`15
`
`45054234
`
`11
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`BAN 102
`095161/5
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1004, Pg. 15 of 34
`
`

`

`Example 3. Naproxen Sodium with Hydrochloric Acid as the
`
`Deionizing Agent
`
`Fill Material:
`
`Ingredients
`
`Naproxen Sodium
`
`Hydrochloric Acid
`
`PVP
`
`PEG400
`
`Water
`
`% (by weight)
`
`25.50
`
`4.72
`
`1.85
`
`63.52
`
`7.40
`
`5
`
`Example 4. Naproxen Sodium with Acetic Acid as the Deionizing
`
`Agent
`
`Fill Material:
`
`Ingredients
`
`Naproxen Sodium
`
`Acetic Acid
`
`PVP
`
`PEG400
`
`Water
`
`PEG 600
`
`% (by weight)
`
`25.50
`
`3.00
`
`1.85
`
`31.15
`
`7.40
`
`31.15
`
`10
`
`15
`
`45054234
`
`12
`
`BAN 102
`095161/5
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1004, Pg. 16 of 34
`
`

`

`· Example 5. Naproxen Sodium with Citric Acid as the Deionizing
`
`Agent
`
`Fill Material:
`
`Ingredients
`
`Naproxen Sodium
`
`Citric Acid
`
`PVP
`
`PEG400
`
`Water
`
`PEG600
`
`0/o {b:y 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
`
`PEG600
`
`% {b:y weight}
`
`25.50
`
`4072
`
`1.85
`
`30.25
`
`7.40
`
`30.25
`
`10
`
`15
`
`45054234
`
`13
`
`BAN 102
`095161/5
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1004, Pg. 17 of 34
`
`

`

`Example 7. Naproxen Sodium with Lactic Acid as the Deionizing
`
`Agent
`
`Fill Material:
`
`Ingredients
`
`Naproxen Sodium
`
`Lactic Acid
`
`Propylene Glycol
`
`PEG400
`
`Water
`
`% {by weight}
`
`27.50
`
`5.27
`
`2.00
`
`64.64
`
`0.60
`
`5
`
`Example 8. Naproxen Sodium with Lactic Acid as the Deionizing
`
`Agent
`
`Fill Material:
`
`Ingredients
`
`Naproxen Sodium
`
`Lactic Acid
`
`Propylene glycol
`
`PEG 600.
`
`% {by weight}
`
`25.00
`
`0.24-0.35 M
`
`2.00
`
`q.s.
`
`Example 9. Naproxen Sodium with Lactic Acid as the Deionizing
`
`10
`
`Agent
`
`Fill Material:
`
`Ingredients
`
`Naproxen Sodium
`
`Lactic Acid
`
`Propylene glycol
`
`PEG 600
`
`PEG 1000
`
`% {by weight}
`
`25.00
`
`5.00
`
`2.00
`
`61.2
`
`6.80
`
`45054234
`
`14
`
`BAN 102
`095161/5
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1004, Pg. 18 of 34
`
`

`

`Example 10. Naproxen Sodium with Lactic Acid as the Deionizing
`
`Agent
`
`Fill Material:
`
`Ingredients
`
`Naproxen Sodium
`
`Lactic acid
`
`Propylene glycol
`
`PEG600
`
`PEG 1000
`
`% {by weight}
`
`25.00
`
`5.00
`
`2.00
`
`51.00
`
`17.00
`
`5
`
`Example 11. Naproxen Sodium with Lactic Acid as the Deionizing·
`
`Agent
`
`Fill Material:
`
`Ingredients
`
`Naproxen Sodium
`
`Lactic Acid
`
`Propylene glycol
`
`PEG 600
`
`PEG 1000
`
`% {by weight}
`
`25.00
`
`5.00
`
`2.00
`
`34.00
`
`34.00
`
`Example 12. Naproxen Sodium with Lactic Acid as the Deionizing
`
`10
`
`Agent
`
`Fill Material:
`
`Ingredients
`
`Naproxen Sodium
`
`Lactic acid
`
`Propylene glycol
`
`PEG 600
`
`PEG 1000
`
`% {by weight}
`
`25.00
`
`5.00
`
`2.00
`
`17.00
`
`51.00
`
`45054234
`
`15
`
`BAN 102
`095161/5
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1004, Pg. 19 of 34
`
`

`

`It is understood that the disclosed invention is not limited to the
`
`particular methodology, protocols, and reagents described as these may vary. It
`
`is also to be understood that the terminology used herein is for the purpose of
`
`describing particular embodiments only, and is not intended to limit the scope of
`
`5
`
`the present invention which will be limited only by the appended claims.
`
`Unless defined otherwise, all technical and scientific terms used herein
`
`have the same meanings as commonly understood by one of skill in the art to
`
`which the disclosed invention belongs. Although any methods and materials
`
`similar or equivalent to those described herein can be used in the practice or
`
`1 0
`
`testing of the present invention, the preferred methods, devices, and materials
`
`are as described. Publications cited herein and the materials for which they are
`
`cited are specifically incorporated by reference. Nothing herein is to be
`
`construed as an admission that the invention is not entitled to antedate such
`
`disclosure by virtue of prior invention.
`
`15
`
`Those skilled in the art will recognize, or be able to ascertain using no
`
`more than routine experimentation, many equivalents to the specific
`
`embodiments of the invention described herein. Such equivalents are intended
`
`to be encompassed by the following claims.
`
`45054234
`
`16
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`BAN 102
`095161/5
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1004, Pg. 20 of 34
`
`

`

`We claim:
`
`1. A pharmaceutical composition comprising
`
`(a) a salt of one or more pharmaceutically active agents; and
`
`(b) a deionizing agent.
`
`2. The composition of claim 1 wherein the pharmaceutically active agent is
`
`selected from the group consisting of bioactive agents, diagnostic agents, and
`
`prophylactic agents.
`
`3. The composition of claim 1 wherein the deionizing agent is present in an
`
`amount from about 0.2 to 1.0 mole equivalents per mole of the pharmaceutically
`
`active agent(s).
`
`4. The composition of claim 1 wherein the deionizing agent is selected from
`
`the group consisting of hydrogen ion and hydroxide ion ..
`
`5. The composition of claim 1 further comprising polyethylene glycol.
`
`6. The composition of claim 5 wherein polyethylene glycol is present in an
`
`amount from about 10%