US009693979B2
`
`a2) United States Patent
`US 9,693,979 B2
`(10) Patent No.:
`
` Chidambaram et al. (45) Date of Patent: *Jul. 4, 2017
`
`
`(54) LIQUID DOSAGE FORMS OF SODIUM
`NAPROXEN
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`(71) Applicant! BANNER LIFE SCIENCES LLC,
`High Point, NC (US)
`&
`’
`
`5,071,643 A
`5,360,615 A *
`
`12/1991 Patel
`11/1994 YU wee A61K 9/2009
`424/455
`
`(72)
`
`Inventors: Nachiappan Chidambaram,Sandy,
`UT (US); Ageel A Fatmi, High Point,
`NC (US)
`
`1/1996 Dhabhar
`5,484,606 A
`4/1996 Shelley
`5,505,961 A
`7/1996 Bogdan
`5,541,210 A
`TA1997 Mitra
`5,648,358 A
`3/1999 McEntee
`5,885,608 A
`6/1999 Yamada
`S910 A
`9/2001 Meyer
`6,287,594 BL
`4/2002 Wilson
`6,365,180 Bl
`5/2002 Sawyer
`6,383,515 B2
`Subject to any disclaimer, the term ofthis
`5500. Cvebster
`Oeeotee BD
`patent is extended or adjusted under 35
`omez
`1
`,
`9/2006 Santos
`7,101,572 B2
`U.S.C, 154(b) by 0 days.
`
`This patent is subject to a terminal dis- 2001/0007668 Al=7/2001 Sawyer
`claimer
`2002/0187195 Al
`12/2002 Sawyer
`,
`2004/0157928 Al
`8/2004 Lee
`2005/0158377 AL*
`7/2005 Popp unc A61K 9/4866
`
`:
`:
`:
`.
`:
`(73) Assignee: Banner Life Sciences LLC, High
`Point, NC (US)
`
`(*) Notice:
`
`(22)
`
`Filed:
`
`May 20, 2016
`
`2006/0099246 AL*
`
`5/2006 Tanner ........... A61K 9/4816
`424/451
`
`(65)
`
`Prior Publication Data
`
`FOREIGN PATENT DOCUMENTS
`
`US 2016/0263063 Al
`
`Sep. 15, 2016
`
`CA
`WO
`
`2600023 C
`9531979 Al
`
`11/2011
`11/1995
`
`Related U.S. Application Data
`OTHER PUBLICATIONS
`(60) Division of application No. 14/977,808,filed on Dec.
`Wikipedia (https://en.wikipedia.org/wiki/Conjugate_acid (down-
`22, 2015, which is a continuation of application No.
`loaded on Jul. 8, 2016).*
`11/367,238, filed on Mar. 3, 2006, now abandoned.
`
`
`
`
`oe to GrantaEor EP2006737018 Intention Patent, Nov. 18,
`(60) Provisional application No. 60/659,679,filed on Mar.
`2015.
`ee ISTE EERE ENS
`NON
`8, 2005.
`EP2016163757.4 Extended European Search Report, May 19, 2016.
`Wikipedia “Self-ionization of water”, http://en.wikipedia.org/wiki/
`Selfionization_of water, Accessed Mar. 2010.
`
`(51)
`
`Int. Cl.
`AGIK 31/192
`A6IK W48
`AGIK 31/765
`AGIK 47/12
`A6IK 50
`AGIK 9/00
`(52) US. CL
`CPC veeseeeees AG61K 31/192 (2013.01); A6LK 9/0053
`(2013.01); A61K 9/4825 (2013.01); AGLK
`9/4833 (2013.01), A61K 9/4858 (2013.01):
`A61LK 9/4866 (2013.01); A6LK 9/50 (2013.01):
`AG61LK 9/5089 (2013.01); AGLK 31/765
`(2013.01), A6LK 47/12 (2013.01)
`(58) Field of Classification Search
`None
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`* cited by examiner
`
`Primary Examiner — Jake Vu
`(74) Attorney, Agent, or Firm — Brinks Gilson & Lione
`
`ABSTRACT
`(57)
`Described herein are oral pharmaceutical compositions
`comprising liquid dosage forms of sodium naproxenin soft
`gel capsules. In one embodiment, the pharmaceutical com-
`position comprises sodium naproxen, 0.2-1.0 mole equiva-
`lents of a de-ionizing agent per mole of naproxen, polyeth-
`ylene glycol, and one or more solubilizers such as propylene
`glycol, polyvinyl pyrrolidone or a combination thereof.
`
`See application file for complete search history.
`
`19 Claims, No Drawings
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1003, Pg. 1 of 7
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`Petitioner - Catalent Pharma Solutions
`Ex. 1003, Pg. 1 of 7
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`

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`US 9,693,979 B2
`
`1
`LIQUID DOSAGE FORMS OF SODIUM
`NAPROXEN
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a divisional of U.S. patent application
`Ser. No. 14/977,808,
`filed on Dec. 22, 2015, which is
`continuation of U.S. patent application Ser. No. 11/367,238,
`filed Mar. 3, 2006, which claims priority under 35 U.S.C.
`§119(e) to U.S. Provisional Patent Application No. 60/659,
`679, filed Mar. 8, 2005, each of which are incorporated
`herein in its entirety by express reference thereto.
`
`TECHNICAL FIELD
`
`This application describes liquid dosage forms of sodium
`naproxen in soft gelatin capsules.
`
`BACKGROUND
`
`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 which
`are quite different from two-piece hardshell capsules, soft-
`gels 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
`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 somewhatsensitive 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 solutions or suspensions. Suspensions are
`pharmaceutically less desirable because they can settle dur-
`ing 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 than do suspensions.
`Suitable softgel solutions, however, can be difficult to
`achieve. One constraintis size. Many pharmaceutical agents
`require volumes of solvent too large to produce a softgel
`capsule small enough to be taken by patients. The solvent
`mustalso have sufficient solvating powerto dissolve a large
`amount of the pharmaceutical agent to produce a concen-
`trated 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. Pat. No.
`5,360,615 to Yuet al. discloses a solvent system for enhanc-
`ing the solubility of acidic, basic, or amphoteric pharma-
`ceutical agents. The solvent system comprises polyethylene
`glycol, an ionizing agent, and water. The ionizing agent
`functions by causing the partial ionization of the free phar-
`maceutical agent. U.S. Pat. No. 6,383,515, U.S. Patent
`Application Publication No. 2002/0187195, and U.S. Patent
`Application Publication No. 2001/0007668 to Sawyeret al.
`
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`2
`discloses pharmaceutically acceptable solutions containing a
`medicament suitable for filling softgel capsules comprising
`a polymersuch as polyethylene glycol and an acid salt of a
`compound having three or more carbon atoms, such as
`sodium propionate. Thesalt helps to ionize the medicament
`withoutrelying on the use of strong acids or bases. U.S. Pat.
`No. 6,689,382 to Berthel et 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 carboxyl or
`an acidic functional group, the solvent system also includes
`hydroxide ions. U.S. Pat. No. 5,505,961 to Shelley et al.
`describes a method for increasing the solubility of acet-
`aminophen alone or in combination with other pharmaceu-
`tically active agents to form a clear solution for encapsula-
`tion into a
`softgel
`capsule. The method comprises
`solubilizing acetaminophen in a mixture of propylene gly-
`col, polyethylene glycol, water, polyvinylpyrrolidone and
`sodium or potassium acetate.
`The previously described methods all involve the conver-
`sion of the free pharmaceutical agent to the corresponding
`salt. In cases where the free pharmaceutical agentis acidic,
`the resulting anion can react with the polyethylene glycol in
`the fill to produce polyethylene glycol esters, thus reducing
`the amountof available pharmaceutical agent.
`There is a need for a solvent system containing a medi-
`cament, which can be encapsulated in a softgel capsule,
`wherein the formation of PEG esters is minimized.
`
`it is an object of the invention to provide a
`Therefore,
`stable solvent system for pharmaceutical agents, which is
`suitable for encapsulation in a softgel capsule, wherein the
`formation of PEG esters is minimized.
`
`SUMMARY
`
`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, such as
`naproxen, 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 of 2.5-7.5. 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 amphoteric active agents as well as
`decreased amounts of polyethylene glycol (PEG)esters.
`Described herein are oral pharmaceutical compositions
`comprising liquid dosage forms of sodium naproxenin soft
`gel capsules. In one embodiment, the pharmaceutical com-
`position comprises sodium naproxen, 0.2-1.0 mole equiva-
`lents of a de-ionizing agent per mole of naproxen, polyeth-
`ylene glycol, and one or more solubilizers such as propylene
`glycol, polyvinyl pyrrolidone or a combination thereof.
`One embodiment described herein is a pharmaceutical
`composition comprising a soft gel capsule encapsulating a
`liquid matrix comprising: (a) naproxen sodium; (b) one or
`more deionizing agents comprising fumaric acid, maleic
`acid, tartaric acid, citric acid, malic acid, acetic acid, pro-
`prionic acid, pyruvic acid, butanoic acid, or lactic acid in an
`amount of from 0.2 to 1.0 mole equivalents per mole of
`naproxen sodium;(c) one or more polyethylene glycols; and
`(d) one or more solubilizers comprising polyvinylpyrroli-
`done, propylene glycol, or a combination thereof. In one
`aspect described herein,
`the deionizing agent comprises
`Petitioner - Catalent Pharma Solutions
`Ex. 1003, Pg. 2 of 7
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`Petitioner - Catalent Pharma Solutions
`Ex. 1003, Pg. 2 of 7
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`

`

`3
`4
`The formulation can contain any therapeutic, diagnostic,
`citric acid or lactic acid. In another aspect described herein,
`prophylactic or nutraceutical agent. Exemplary agents
`the deionizing agent comprises lactic acid. In another aspect
`include, but are not limited to, analeptic agents; analgesic
`described herein, the polyethylene glycol comprises from
`agents; anesthetic agents; antiasthmatic agents; antiarthritic
`about 10% to about 80% by weight of the composition. In
`agents; anticancer agents; anticholinergic agents; anticon-
`another aspect described herein,
`the polyethylene glycol
`vulsant agents; antidepressant agents; antidiabetic agents;
`comprises one or more polyethylene glycols with a molecu-
`antidiarrheal
`agents;
`antiemetic
`agents;
`antihelminthic
`lar weight between 300 and 1500.
`In another aspect
`agents; antihistamines; antihyperlipidemic agents; antihy-
`described herein, the polyethylene glycol comprises poly-
`pertensive agents; anti-infective agents; anti-inflammatory
`ethylene glycol 600. In another aspect described herein, the
`agents; antimigraine agents; antineoplastic agents; antipar-
`solubilizer comprises from about 1% to 10% by weight of
`kinson drugs; antipruritic agents; antipsychotic agents; anti-
`the composition. In another aspect described herein,
`the
`pyretic agents; antispasmodic agents; antitubercular agents;
`solubilizer comprises about 2% polyvinylpyrrolidone and
`antiulcer agents; antiviral agents; anxiolytic agents; appetite
`about 2% propylene glycol. In another aspect described
`suppressants (anorexic agents); attention deficit disorder and
`herein,
`the composition further comprises one or more
`attention deficit hyperactivity disorder drugs; cardiovascular
`excipients comprising plasticizers, crystallization inhibitors,
`agents including calcium channel blockers, antianginal
`wetting agents, bulk filling agents, solubilizers, bioavailabil-
`agents, central nervous system (“CNS”) agents, beta-block-
`ity enhancers, solvents, dyes, preservatives, surfactants, or
`combinations thereof.
`ers and antiarrhythmic agents; central nervous system stimu-
`lants; diuretics; genetic materials; hormonolytics; hypnotics;
`Another embodiment described herein is a pharmaceuti-
`hypoglycemic agents; immunosuppressive agents; muscle
`cal composition comprising:
`(a) about 25% naproxen
`relaxants; narcotic antagonists; nicotine; nutritional agents;
`sodium by weight; (b) lactic acid in an amountof from about
`parasympatholytics; peptide drugs; psychostimulants; seda-
`0.2 to about 1.0 mole equivalents per mole of naproxen
`tives; sialagogues, steroids; smoking cessation agents; sym-
`sodium;
`(c) about 10% to about 80% of one or more
`pathomimetics; tranquilizers; vasodilators; beta-agonist; and
`polyethylene glycols by weight; and (d) about 1% to about
`tocolytic agents.
`10% by weight of one or more solubilizers comprising
`A first class of drugs is selected based on inclusion in the
`polyvinylpyrrolidone, propylene glycol, or a combination
`molecule of a weakly acidic, basic or amphoteric group that
`thereof. In one aspect described herein, the polyethylene
`can form a salt. Any drug that bears an acidic or a basic
`glycol comprises one or more polyethylene glycols with a
`functional group, for example, an amine, imine, imidazoyl,
`molecular weight between 300 and 1500. In another aspect
`guanidine, piperidinyl, pyridinyl, quaternary ammonium, or
`described herein, the polyethylene glycol comprises poly-
`other basic group, or a carboxylic, phosphoric, phenolic,
`ethylene glycol 600. In another aspect described herein, the
`sulfuric, sulfonic or other acidic group, can react with the
`solubilizer comprises propylene glycol and polyvinyl pyr-
`de-ionizing agent.
`rolidone. In another aspect described herein, the lactic acid
`Somespecific drugs that bear acidic or basic functional
`comprises about 0.6 mole equivalents per mole of naproxen
`groups and thus may be converted to the correspondingsalt
`sodium.
`In another aspect described herein,
`the weight
`for use in the described formulations include, but are not
`percentage of lactic acid is about 5%. In another aspect
`limited to, Acetaminophen, Acetylsalicylic acid, Alendronic
`described herein, the solubilizer comprises about 2% poly-
`acid, Alosetron, Amantadine, Amlopidine, Anagrelide, Arga-
`vinylpyrrolidone and about 2% propylene glycol. In another
`troban, Atomoxetine, Atrovastatin, Azithromycin dehydrate,
`aspect described herein, the composition further comprises
`Balsalazide, Bromocriptan, Bupropion, Candesartan, Carbo-
`one or more excipients selected from plasticizers, crystalli-
`platin, Ceftriaxone, Clavulonic acid, Clindamycin, Cimeta-
`zation inhibitors, wetting agents, bulk filling agents, bio-
`
`dine, (acid),|Dexmethylphenidate,Dehydrocholic
`
`availability enhancers, solvents, dyes, preservatives, surfac-
`Diclofenac, Dicyclomine, Diflunisal, Diltiazem, Donepezil,
`tants, or combinations thereof. In another aspect described
`Doxorubicin, Doxepin,
`Epirubicin,
`Etodolic
`acid,
`herein, the pH is from about 2.5 to about 7.5. In another
`Ethacrynic acid, Fenoprofen, Fluoxetine, Flurbiprofen,
`aspect described herein, the composition is encapsulated in
`Furosemide, Gemfibrozil, Hydroxyzine, Ibuprofen, Imip-
`a softgel capsule. In another aspect described herein, the
`ramine, Indomethacin, Ketoprofen, Levothyroxine, Mapro-
`softgel capsule comprises: (a) gelatin; (b) plasticizer; and (c)
`litline, Meclizine, Methadone, Methylphenidate, Minocy-
`purified water.
`Another embodiment described herein is a method for
`cline, Mitoxantone, Moxifloxacin, Mycophenolic acid,
`Naproxen, Niflumic acid, Ofloxacin, Ondansetron, Panto-
`making a pharmaceutical composition, the method compris-
`prazole, Paroxetine, Pergolide, Pramipexole, Phenytoin,
`ing: (a) mixing together (i) about 25% naproxen sodium by
`Pravastain, Probenecid, Rabeprazole, Risedronic acid, Ret-
`weight; (41) lactic acid in an amount of from about 0.2 to
`inoic acid, Ropinirole, Selegiline, Sulindac, Tamsulosin,
`about 1.0 mole equivalents per mole of naproxen sodium;
`Telmisertan, Terbinafine, Theophyline, Tiludronic Acid, Tin-
`(ii) about 10% to about 80% of one or more polyethylene
`zaparin, Ticarcillin, Tometin, Valproic acid, Salicylic acid,
`glycols by weight; and (iv) about 1% to about 10% by
`Sevelamer, Ziprasidone, Zoledronic acid, Acetophenazine,
`weight of one or more solubilizers comprising polyvinylpyr-
`Albuterol, Almotriptan, Amitriptyline, Amphetamine, Atra-
`rolidone, propylene glycol, or a combination thereof; and (b)
`curium, Beclomethasone, Benztropine, Biperiden, Bosen-
`encapsulating the mixture in a softgel capsule using rotary
`tan, Bromodiphenhydramine, Brompheniramine carbinox-
`die encapsulation.
`amine, Caffeine, Capecitabine, Carbergoline, Cetirizine,
`Another embodiment described herein is an oral dosage
`Chlocylizine, Chlorpheniramine, Chlorphenoxamine, Chlo-
`form produced by the method described herein.
`rpromazine, Citalopram, Clavunate potassium, Ciprofloxa-
`cin, Clemastine, Clomiphene, Clonidine, Clopidogrel,
`Codeine, Cyclizine, Cyclobenzaprine, Cyproheptadine,
`Delavirdine, Diethylpropion, Divalproex, Desipramine,
`Dexmethylphenidate, Dexbrompheniramine, Dexchlopheni-
`ramine, Dexchlor, Dextroamphetamine, Dexedrine, Dex-
`Petitioner - Catalent Pharma Solutions
`Ex. 1003, Pg. 3 of 7
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`I. Composition
`A. Fill Materials
`
`DETAILED DESCRIPTION
`
`1. Drugs to be Formulated
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`US 9,693,979 B2
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`5
`tromethorphan, Fiflunisal, Diphemanil methylsulphate,
`Diphenhydramine, Dolasetron, Doxylamine, Enoxaparin,
`Ergotamine, Ertepenem, Eprosartan, Escitalopram, Esome-
`prazole, Fenoldopam, Fentanyl, Fexofenadine, Flufenamic
`acid, Fluvastatin, Fluphenazine, Fluticasone, Fosinopril,
`Frovatriptan, Gabapentin, Galatamine, Gatifloxacin, Gem-
`citabine,
`Haloperidol,
`Hyalurondate,
`Hydrocodone,
`Hydroxychloroquine, Hyoscyamine, Imatinib,
`Imipenem,
`Ipatropin, Lisinopril, Leuprolide, Levopropoxyphene,
`Losartan, Meclofenamic acid, Mefanamic acid, Mesala-
`mine, Mepenzolate, Meperidine, Mephentermine, Mesalim-
`ine, Mesoridazine, Metaproteranol, Metformin, Methdiala-
`zine, Methscopolamine, Methysergide, Metoprolol,
`Metronidazole, Mibefradil, Montelukast, Morphine,
`Mometasone, Naratriptan, Nelfinavir, Nortriptylene,
`Noscapine, Nylindrin, Omeprazole, Orphenadrine, Oselta-
`mivir, Oxybutynin, Papaverine, Pentazocine, Phendimetra-
`zine, Phentermine, Pioglitazone, Pilocarpine, Prochlorop-
`erazine, Pyrilamine, Quetapine, Ranitidine, Rivastigmine,
`Rosiglitazone, Salmetrol, Sertaline, Sotalol, Sumatriptan,
`Tazobactam, Tacrolimus, Tamoxifen, Ticlopidine, Topira-
`mate, Tolterodine, Triptorelin, Triplennamine, Triprolidine,
`Tramadol, Trovofloxacin, Ursodiol, Promazine, Propoxy-
`phene, Propanolol, Pseudoephedrine, Pyrilamine, Quini-
`dine, Oxybate sodium, Sermorelin, Tacrolimus, Tegaseroid,
`Teriparatide, Tolterodine, Triptorelin pamoate, Scop-
`lolamine, Venlafaxine, Zamivir, Aminocaproic acid, Amin-
`osalicylic acid, Hydromorphone, Isosuprine, Levorphanol,
`Melhalan, Nalidixic acid, and Para-aminosalicylic acid.
`2. Deionizing Agent
`The deionizing agent functions by causing partial deion-
`ization (neutralization) of the salt of one or more pharma-
`ceutically active agents. When the active agentis the salt of
`a weak acid and a strong base,
`the deionizing agent is
`preferably a hydrogen ion species. When the active agentis
`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 herein,
`include, but are not limited to,
`hydrochloric acid, hydrobromic acid, hydroiodic acid, sul-
`furic 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 describedherein, 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 about 2.5 to about 7.5.
`3. 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 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 thereof.
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`In a preferred embodiment, a mixture of polyethylene
`glycol and water is used as a solventfor 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 molecular weight of polyethylene glycol is
`between 300 and 1500. Other suitable solvents include
`
`surfactants and copolymers of polyethylene glycol. Option-
`ally, glycerin, polyvinyl pyrrolidone (PVP) or propylene
`glycol (PPG) can be added to enhance the solubility of the
`drug agent.
`B. Shell Compositions
`1. Gelatin
`Gelatin is the productof the partial hydrolysis of collagen.
`Gelatin is classified as either Type A or Type B gelatin. Type
`A gelatin is derived 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-processed gelatins of
`the same average molecular weight.
`2. Other Shell Additives
`
`Other suitable shell additives include plasticizers, opaci-
`fiers, colorants, 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.
`Opacifiers are used to opacify the capsule shell when the
`encapsulated active agents are light sensitive. Suitable
`opacifiers include titantum 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 combinationsthereof.
`Humectants can be used to suppress the water activity of
`the softgel. Suitable humectants include glycerin and sorbi-
`tol, which are often components of the plasticizer compo-
`sition. 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
`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 syn-
`thetic 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 alde-
`hydes in order to inhibit cross-linking of the gelatin.
`II. Methods of Making
`A. Fill Material
`Thefill material is prepared by mixing the agent (such as
`a salt of the drug), the deionizing agent, water, and poly-
`ethylene 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 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 poly-
`Petitioner - Catalent Pharma Solutions
`Ex. 1003, Pg. 4 of 7
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1003, Pg. 4 of 7
`
`

`

`US 9,693,979 B2
`
`7
`ethylene 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 10%.
`B. Gel Mass
`
`The main ingredients of the softgel capsule shell are
`gelatin, plasticizer, and purified water. Typical gel formula-
`tions 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 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 plas-
`ticizer 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.). The mixture
`is cooked (57-95° C.) under vacuum for 15-30 minutes to a
`homogeneous, deaerated gel mass. Additional shell addi-
`tives can be addedto 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.
`2. Hot Melt Process
`
`The hot melt process involves adding, under mild agita-
`tion,
`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 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. The metering devices control
`the flow of gel into cooled (10-18° 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 the ribbons to reduce
`their tackiness and facilitate their transfer. Suitable lubri-
`cants include mineral oil, medium chain triglycerides, and
`soybean oil. Fill formulations are fed into the encapsulation
`machine by gravity. In the preferred embodiment, the soft-
`gels contain printing on the surface, optionally identifying
`the encapsulated agent and/or dosage.
`II. Methods of Use
`
`The softgels may be used to encapsulate a wide range of
`pharmaceutically active agents, nutritional agents and per-
`sonal care products. Softgel capsules may be administered
`orally to a patient to deliver a pharmaceutically active agent.
`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 ofthe present invention which will be limited only by
`the appendedclaims.
`technical and scientific
`Unless defined otherwise, all
`terms used herein have the same meanings as commonly
`understood by one ofskill 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 testing of the present
`invention,
`the
`
`15
`
`25
`
`40
`
`45
`
`50
`
`8
`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.
`
`EXAMPLES
`
`In the following examples, the fill material can be pre-
`pared 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
`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
`PEG 400
`Water
`
`TOTAL
`
`% (by weight)
`
`25.50
`3.00
`1.85
`62.30
`740
`
`100%
`
`Example 2. Naproxen Sodium with Citric Acid as the Deionizing Agent
`Fill Material
`
`Ingredients
`
`Naproxen Sodium
`Citric Acid
`PVP
`PEG 400
`Water
`
`TOTAL
`
`% (by weight)
`
`25.50
`4.75
`1.85
`60.50
`7.40
`
`100%
`
`Example 3 Naproxen Sodium with Hydrochloric
`Acid as the Deionizing Agent
`Fill Material
`
`Ingredients
`
`Naproxen Sodium
`Hydrochloric Acid
`PVP
`PEG 400
`Water
`TOTAL
`
`% (by weight)
`
`25.50
`4.72
`1.85
`63.52
`7.40
`100%
`
`Example 4. Naproxen Sodium with Acetic Acid as the Deionizing Agent
`Fill Material
`
`Ingredients
`
`Naproxen Sodium
`Acetic Acid
`PVP
`PEG 400
`Water
`PEG 600
`
`% (by weight)
`
`25.50
`3.00
`1.85
`31.15
`740
`31.15
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1003, Pg. 5 of 7
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1003, Pg. 5 of 7
`
`

`

`9
`-continued
`
`US 9,693,979 B2
`
`10
`
`Example 4. Naproxen Sodium with Acetic Acid as the Deionizing Agent
`Fill Material
`
`:
`Ingredient:
`greens
`TOTAL
`
`:
`t
`% (b
`® (by weight)
`100%
`
`Example 9. Naproxen Sodium with Lactic Acid as the Deionizing Agent
`Fill Material
`
`5
`
`10
`
`
`Ingredients
`% (by weight)
`Naproxen Sodium
`25.00
`Lactic Acid
`5.00
`Propylene Glycol
`2.00
`PEG 600
`61.20
`PEG 1000
`6.80
`TOTAL
`100%
`
`
`Example 5. Naproxen Sodium with Citric Acid as the Deionizing Agent
`Fill Material
`
`15
`
`Example 10. Naproxen Sodium with Lactic Acid as the Deionizing Agent
`Fill Material
`
`Ingredients
`
`.
`Naproxen Sodium
`Citric Acid
`PVP
`PEG 400
`Water
`
`PEG 600
`TOTAL
`
`% (by weight)
`
`25.50
`40.75
`1.85
`30.25
`7.40
`
`30.25
`100%
`
`:
`:
`:
`Example 6. Naproxen Sodium with Hydrochloric
`Acid as the Deionizing Agent
`Fill Material
`
`Inoredients
`-
`Naproxen Sodium
`Hydrochloric Acid
`PVP
`PEG 400
`Water
`PEG 600
`TOTAL
`
`% (by weight
`® (oy
`weight)
`25.50
`40.72
`1.85
`30.25
`7.40
`30.25
`100%
`
`30
`
`25
`
`30
`
`35
`
`40
`
`Example 7. Naproxen Sodium with Lactic Acid as the Deionizing Agent
`Fill Material
`
`45
`
`Ingredients
`=
`Naproxen Sodium
`Lactic Acid
`
`Propylene Glycol
`PEG 400
`Water
`
`TOTAL
`
`% (by weight
`2 by
`weight)
`27.50
`5.27
`
`2.00
`64.64
`0.60
`0,
`100%
`
`Example 8. Naproxen ieracic Acid as the Deionizing Agent
`ill
`Materia.
`
`Ingredients
`% (by weight)
`"
`Naproxen Sodium
`25.00
`Lactic Acid
`0.24-0.35M
`Propylene Glycol
`2.00
`PEG 600
`g:S-
`TOTAL
`100%
`
`50
`
`ss
`
`69
`
`65
`
`Ingredients
`
`Naproxen Sodium
`Lactic Acid
`Propylene Glycol
`PEG 600
`PEG 1000
`
`TOTAL
`
`% (by weight)
`
`25.00
`5.00
`2.00
`51.00
`17.00
`
`100%
`
`Example 11. Naproxen Sodium with Lactic Acid as the Deionizing Agent
`Fill Material
`
`:
`Ingredients
`
`:
`6
`% (by weight)
`
`;
`25.00
`Naproxen Sodium
`5.00
`Lactic Acid
`2.00
`Propylene Glycol
`34.00
`PEG 600
`34.00
`PEG 1000
`TOTAL
`100%
`
`
`Example 12. Naproxen Sodium with Lactic Acid as the Deionizing Agent
`Fill Material
`
`Ingredients
`
`"
`Naproxen Sodium
`Lactic Acid
`Propylene Glycol
`PEG 600
`PEG 1000
`
`TOTAL
`
`% (by weight)
`
`25.00
`5.00
`2.00
`17.00
`51.00
`
`100%
`
`.
`.
`.
`.
`The invention claimedis:
`1. A pharmaceutical composition comprising a soft gelatin
`capsule encapsulating a liquid matrix comprising:
`(a) naproxen sodium;
`(b) about 5% lactic acid by weight of the matrix;
`(c) one or more polyethylene glycols; and
`(d) one or more solubilizers comprising polyvinylpyrroli-
`done, propylene glycol, or a combination thereof.
`oe
`:
`:
`2. The composition of claim 1, wherein the polyethylene
`glycol comprises from about 10% to about 80% by weight
`of the matrix.
`3. The composition of claim 1, wherein the polyethylene
`glycol comprises o