United States Patent [19]
`Cimiluca
`
`111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US005641512A
`[11] Patent Number:
`[45] Date of Patent:
`
`5,641,512
`Jun.24, 1997
`
`[54] SOFT GELATIN CAPSULE COMPOSITIONS
`
`[75]
`
`Inventor: Paul Alfred Cimiluca, Cincinnatti,
`Ohio
`
`[73] Assignee: The Procter & Gamble Company,
`Cincinnati, Ohio
`
`[21] Appl. No.: 412,627
`
`Mar. 29, 1995
`
`[22] Filed:
`Int. CI.6
`[51]
`................................ A61K 9/48; A61K 9/66
`[52] U.S. Cl ............................ 424/455; 424/451; 424/452
`[58] Field of Search ..................................... 424/451, 452,
`424/455
`
`[56]
`
`References Cited
`
`U.S. PPJENT DOCUMENTS
`
`2,786,767
`3,389,194
`3,632,742
`3,784,684
`3,851,051
`3,865,603
`4,158,068
`4,251,195
`4,422,985
`4,426,337
`4,481,157
`4,762,719
`4,808,410
`4,888,140
`4,935,243
`5,071,643
`5,141,961
`5,173,304
`5,300,305
`5,360,615
`5,370,864
`5,376,688
`5,405,616
`
`3/1957 Novak ....................................... 99/140
`6/1968 Somerville .................................. 264/4
`1/1972 Eckert et al. . ............................ 424/37
`1/1974 Bossert et al ............................. 424/37
`1111974 Miskel et al .............................. 424/37
`2/1975 Szymanski et al ..................... 106/130
`6/1979 Lipinski et al. ........................ 426/548
`2/1981 Suzuki et al ................................ 425/6
`12/1983 Morishita et al. .. ..................... 254/4.4
`1/1984 Suzuki et al ................................ 264/4
`1111984 Morishita et al. .. ..................... 264/4.1
`8/1988 Forester .................................. 424/440
`2/1989 Sorrentino et al ...................... 424/435
`12/1989 Schlameus et al ...................... 264/4.3
`6/1990 Borkan et al ........................... 424/441
`12/1991 Yu et al. .. ............................... 514/570
`8/1992 Coapman ................................ 514/629
`12/1992 Lohner et al. .. ........................ 424/456
`4/1994 Stapler et al. .. ........................ 424/490
`1111994 Yu et al. .. ............................... 424/455
`12/1994 Peterson et al. .. ........................ 424/49
`12/1994 Morton et al ........................... 514n86
`4/1995 Wunderlich et al .................... 424/451
`
`4/1995 McLaughlin et al ..................... 424/55
`5,407,665
`7/1995 White ...................................... 424/451
`5,431,916
`5,458,879 10/1995 Singh et al. .. .......................... 424/400
`111996 Dhabhar .................................. 424/455
`5,484,606
`
`FOREIGN PPJENT DOCUMENTS
`
`121321
`0631782A1
`1060258
`W094/25008
`9504527
`W095/04527
`
`10/1984
`111995
`1/1967
`1111994
`2/1995
`2/1995
`
`European Pat. Off. .. ....... A61K 9/48
`European Pat. Off. ....... A61K 31152
`United Kingdom .
`WIPO .............................. A61K 9/48
`WIPO.
`WIPO .......................... A61K 311165
`
`OTHER PUBUCATIONS
`
`"Soft Gelatin Capsules 1: Factors Affecting Capsule Shell
`Dissolution Rate", F. S. Hom, S. A. Veresh, J. J. Miske!,
`Journal of Pharmaceutical Sciences, vol. 62, No. 6, Jun.
`1973.
`Fundamentals of Polymer Processing, pp. 484-493.
`U.S. application No. 08/054762, White, filed Apr. 29, 1993.
`U.S. application No. 08/185,576, Dhabhar, filed Jan. 24,
`1994.
`U.S. application No. 08/185,652, Dhabhar, filed Jan. 24,
`1994.
`U.S. application No. 08/204,932, Dhabhar, filed Mar. 2,
`1994.
`U.S. application No. 08/370,332, Rankell et al., filed Jan. 9,
`1995.
`
`Primary Examiner-Shep K Rose
`Attorney, Agent, or Firm-David K Dabbiere; Douglas C.
`Mohl; Mary Catherine Poland
`
`[57]
`
`ABSTRACT
`
`The present invention relates to improved pharmaceutical
`compositions containing an analgesic encapsulated within a
`soft gelatin shell wherein said shell contains a xanthine
`derivative, such as caffeine.
`
`10 Claims, No Drawings
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1013, Pg. 1 of 6
`
`

`

`5,641,512
`
`1
`SOFf GELATIN CAPSULE COMPOSITIONS
`
`TECHNICAL FIELD
`
`The present invention relates to improved pharmaceutical
`compositions containing an analgesic encapsulated wi~ a
`soft gelatin shell wherein said shell contains a xanthine
`derivative, such as caffeine.
`
`BACKGROUND OF THE INVENTION
`
`5
`
`10
`
`2
`a) an outer gelatin shell comprising a xanthine derivative;
`and
`b) a concentrated liquid core composition comprising _a
`safe and effective amount of at least one analges1c
`pharmaceutical active.
`The present invention also relates to a process for pre(cid:173)
`paring soft gelatin capsules containing a solution of a
`difficultly soluble pharmaceutical active, and to the compo(cid:173)
`sitions and the filled capsules themselves.
`All percentages and ratios used herein are by weight and
`all measurements are at 25° C., unless otherwise indicated.
`
`50
`
`55
`
`SUMMARY OF THE JNVENTION
`
`The present invention relates to pharmaceutical compo(cid:173)
`sitions in the form of a soft gelatin capsule comprising:
`
`Liquid, and especially concentrated liquid ph~ceutic~
`compositions offer many advantages over solid composi(cid:173)
`tions. Liquids are easy to swallow and provide ~ exce~ent
`vehicle for the uniform delivery of phannaceutical actives.
`Liquids provide a rapid onset of phannacologic action, since 15
`the composition does not first have to disintegrate and
`dissolve in the gastrointestinal tract. Concentrated liquid
`compositions are ideally suited for encapsulation within a
`soft gelatin shell, to provide a portable and easy-to-swallow
`soft, flexible capsule. Encapsulation would also permit the 20
`accurate and uniform delivery of a unit dose of a pharma(cid:173)
`ceutical active, an advantage which becomes especially
`important when relatively small amounts of an active are t~
`be delivered. Additionally, soft gelatin capsules are aestheti(cid:173)
`cally appealing (especially when filled with a transparent 25
`liquid) and can be manufactured in a wide variety of sizes,
`shapes, and colors.
`However, despite these advantages of li9u~d
`compositions, it is not always possible to prepare a liqmd
`composition of the desired pharmaceutical active. In many 30
`instances the components to be solubilized are not compat(cid:173)
`ible with one another, or require higher solvents. Also, it
`may not be possible or desirable to incorporate water,
`water-miscible co-solvents, or surfactants into a pharmaceu(cid:173)
`tical composition. For example, certain water-miscible 35
`co-solvents may be relatively volatile, thereby resulting in
`concentration changes in the actives over time. Also, these
`co-solvents may not be compatible with the desired phar(cid:173)
`maceutical actives.
`th
`Previous investigators have attempted to circumvent ese
`incompatibility problems by modifying the gelatin in the
`capsule shell. For example, U.S. Pat. No: 3,865,603, ~o
`Szymanski et at, issued Feb. 11, _1975 di~closes ge~atin
`compositions which are extended w1th chem1cally modified
`fluidity starches; U.S. Pat. No. 2,580,683, to Kreuger, issued
`Jan. 1, 1952 discloses gelatin compositions modified by the
`addition of non-hygroscopic water soluble substances; and
`Japanese Patent No. 84044096, to Morishita, issued Jan. 26,
`1984 discloses gelatin shells modified with tannic acid, and
`sugar and/or sugar derivatives. However, it may not always
`be desirable, feasible or economical to modify the soft
`gelatin shell with such additives. The present inventor has
`found incorporating a specific component in the outer gela-
`tin shell, i.e., a xanthine derivative overcomes incompat-
`ability problems with an analgesic active.
`It is therefore an object of the present invention to provide
`a soft gelatin capsules containing an analgesic pharmace~­
`tical actives and xanthine or xanthine derivative wherem
`said xanthine or xanthine derivative is incorporated into the
`gelatin shell.
`These and other objects of this invention will become
`apparent in light of the following disclosure.
`
`DETAILED DESCRlPTION OF THE
`INVENTION
`Liquid Pharmaceutical Core Compositions
`The concentrated liquid pharmaceutical compositions of
`the present invention comprise the following essential, as
`well as optional, components.
`Analgesic Pharmaceutical Actives
`Useful analgesic pharmaceutical actives in the composi(cid:173)
`tions of the present invention include aspirin and acetami(cid:173)
`nophen as well as the non-steroidal_anti-infl~tory ~~s
`(NSAIDS) selected from the followmg categones: propwmc
`acid derivatives; acetic acid derivatives; fenarnic acid
`derivatives; biphenylcarboxylic acid derivatives; and oxi(cid:173)
`carns. All of these NSAIDS are fully described in the U.S.
`Pat. No. 4,985,459 to Sunshine et al., issued Jan. 15, 1991,
`incorporated by reference herein. Particularly preferred are
`the dextrorotatory or S(+) isomers of these agents.
`Examples of preferred analgesic pharmaceutical actives
`useful in the present invention include, but are not limited to,
`acetaminophen, acetylsalicylic acid, ibuprofen,
`fenbuprofen, fenoprofen, flurbiprofen, indomethacin,
`ketoprofen, naproxen, their pharmaceutically-acceptable
`salts,_ enantiomers thereof, and mixtures thereof.
`Acetaminophen, ibuprofen and naproxen are especially ~re­
`ferred for use in the compositions of the present invention.
`The term "pharmaceutically acceptable salts" refers to
`salts prepared from pharmaceutically accept:able non-toxic
`bases including inorganic bases and orgamc bases. Salts
`derived from nonorganic bases include sodium, potassium,
`lithium, ammonia, calcium, magnesium, ferrous, zinc,
`manganous, aluminum, ferric, manganic salts and ~e like.
`Salts derived from pharmaceutically acceptable orgamc non(cid:173)
`toxic bases include salts of primary, secondary, tertiary and
`quaternary arnines, substituted ~es i!lcluding na~~y
`occurring substituted arnines, cyclic armnes and bas1c 10n
`exchange resins, such as triethylamine, tripropylamine,
`2-dimethylarninoethanol, 2-diethylarninoethanol, lysine,
`arginine, histidine, caffeine, procaine, N-ethylpi~ri~e,
`hydrabamine, oholine, betaine, ethylened1anl:me,
`glucosarnine, methylglycamine, th_eobromine, . punnes,
`piperazine, piperidine, polyamine resms and the like.
`Additional Phannaceutical Actives
`The liquid phannaceutical core compositions ~~ the
`instant invention can also contain one or more additional
`pharmaceutical actives. Useful cl~sses of a~ditio~al
`phannaceutically-active compounds mclude a?tipyre~cs,
`60 calcium channel blockers, beta-blockers, antibacterials,
`antidepressants, antidiabetics, anti-emetics, antihistamines,
`cerebral stimulants sedatives, anti-parasitics, expectorants,
`diruetics, decongestants, antitussives, muscle relaxants, anti(cid:173)
`Parkinsonian agents, bronchodilators, cardiotonics,
`65 antibiotics, antivitals, nutritional supplements (such as
`vitamins, ininerals, fatty acids, amino acids, and the like),
`and mixtures thereof.
`
`40
`
`45
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1013, Pg. 2 of 6
`
`

`

`3
`Examples of additional pharmaceutical actives useful in
`the present invention include, but are not limited to, pseu(cid:173)
`doephedrine and its salts such as pseudoephedrine hydro(cid:173)
`chloride; dextromethorphan and its salts such as dex(cid:173)
`tromethorphan hydrobromide; doxylamine and its salts such 5
`as doxylamine succinate; phenindarnine and its salts such as
`phenindarnine hydrogen tartrate; pheniramine and its salts
`such as pheniramine maleate; chlorpheniramine and its salts
`such as chlmpheniramine maleate; ephedrine and its salts
`such as ephedrine sulfate; triprolidine and its salts such as 10
`triprolidine hydrochloride; diphenhydramine and it salts
`such as diphenhydramine hydrochloride, diphenhydramine
`titrate, and diphenhydramine 8-chlorotheophyllinate;
`phenyltoxyl- amine and its salts; guaifenesin; phenylpro(cid:173)
`panolamine hydrochloride; and mixtures thereof. Preferred 15
`additional pharmaceutical actives are dextromethorphan
`hydrobromide, doxylamine succinate, pseudoephedrine
`hydrochloride, chlorpheniramine maleate, guaifenesin,
`triprolidine hydrochloride, diphenydramine hydrochloride
`and mixtures thereof.
`The concentrated liquid core compositions of the instant
`invention optionally comprises adding from about 0.5% to
`about 20% of such a second pharmaceutical active, or
`mixtures thereof.
`Solvents
`A sufficient quantity of solvent is utilized to aid in the
`solubilization of the analgesic active. By "sufficient" is
`meant a quantity of solvent that will ensure solubility of the
`components of the composition and yet not dilute the
`composition to the point where it occupies an unreasonably
`large volume. The solubilizing agent for the analgesic active
`can be any of a number of materials. After mixing and
`solubilization of the components of the instant invention,
`any solvents with sufficiently low boiling points such as an
`alcohol can be removed using standard evaporation tech(cid:173)
`niques until the composition is substantially free from such
`solvents. Preferably the compositions comprise no more
`than from about 0.1% to about 6% of such solvents after the
`evaporation step.
`Particularly preferred solvents include polyethylene
`glycols, polyvinylpyrrolidone and propylene glycol. These
`solvents are fully described in U.S. Pat No. 5,141,961 to
`Coapman, issued Aug. 25, 1992 which is incorporated by
`reference herein. Also useful are other glycols such as 45
`butylene glycol and hexylene glycol.
`Polyethylene glycols generally are dear, viscous liquids or
`white solids which are soluble in water and many organic
`solvents. These polymers correspond to the general formula:
`
`40
`
`50
`
`H(OCH2CH2)nOH
`
`where n is greater than or equal to 4. The polyethylene
`glycols useful herein are those which are liquids at room
`temperature or have a melting point slightly thereabove. 55
`Preferred are the polyethylene glycols having a molecular
`weight range from about 300 to about 1000 and correspond(cid:173)
`ing n values from about 6 to about 20. More preferred are the
`polyethylene glycols having a molecular weight range from
`about 400 to about 1000 and corresponding n values from 60
`about 8 to about 20. Moreover, mixtures of two or more
`polyethylene glycols of different average molecular weight
`range or n value can also be employed in the present
`invention. Liquid and low-melting polyethylene glycols are
`commercially available from Union Carbide (Danbury, 65
`Conn.) under the Carbowax® trademark. See "Carbowax®
`Polyethylene Glycols", Union Carbide Technical Bulletin
`
`5,641,512
`
`4
`f-4772M-ICD 11/86-20M, this reference being incorporated
`herein by reference in its entirety.
`Polyvinylpyrrolidone has different solubility characteris(cid:173)
`tics based on its polymeric structure. Long-chain
`polyvinylpyrrolidone, which is also known as povidone, has
`good solubility in water and a number of organic solvents.
`Crosslinked polyvinylpyrrolidone, which is also known as
`crospovidone. is insoluble in virtually all common solvents.
`Both the soluble and insoluble forms of polyvinylpyrroli(cid:173)
`done are commercially available from GAF Chemicals
`Company (Wayne, N.J.) under the Plasdone® and Polyplas-
`done® trademarks, respectively, and from BASF Aktieng(cid:173)
`esellschaft (Ludwigshafen, Germany) under the Kollidon®
`trademark. Soluble forms of polyvinylpyrrolidone include
`Plasdone® K-25, Plasdone® K-26/28. Plasdone® K-29/32.
`Plasdone® C-15, Plasdone® C-30, Plasdone® C-90, Kolli-
`don®12 PF, Kollidon®17 PF. Kollidon®25, Kollidon®30,
`and Kollidon® 90. Insoluble forms of polyvinylpyrrolidone
`include Polyplasdone XL®, Polyplasdone XL®10, Kolli-
`20 don® CL, and Kollidon® CL-M. See ''Tableting With
`Plasdone®", GAF Technical Bulletin 2302-llORl (1986);
`"Polyplasdone XL®, Polyplasdone XL®lO", GAF Techni(cid:173)
`cal Bulletin 2302-099 R2 (1984); and "Kollidon® Grades,
`Polyvinylpyrrolidone for the Pharmaceutical Industry",
`25 BASF Technical Bulletin MEF 129e, Register 2, May 1986
`(Bn); these references being incorporated herein by refer(cid:173)
`ence in their entirety.
`The soluble forms of polyvinylpyrrolidone are preferred
`for use in the present invention. Preferred are soluble
`30 polyvinylpyrrolidones having an average molecular weight
`in the range from about 2900 to about 1,100,000; more
`preferred are those having an average molecular weight in
`the range from about 9000 to about 45,000; and most
`preferred are those having an average molecular weight of
`35 about 29,000. Moreover, mixtures of two or more soluble
`polyvinylpyrrolidones of different average molecular weight
`can be employed.
`Propylene Glycol
`Propylene glycol, which is represented by the formula:
`
`CH3CHOHCH20H
`is well known in the art for its solvent and/or humectant
`properties and is described in Hawley's Condensed Chemi(cid:173)
`cal Dictionary, pp. 970-971, (Revised by Richard J. Lewis,
`Sr.) (12th eel. 1993), herein incorporated by reference.
`Propylene glycol suitable for use in the present invention is
`obtainable from any number of suppliers, Dow Chemical
`being one.
`The liquid core compositions of the instant invention
`comprises adding from about 1% to about 50% of solvent,
`more preferably from about 5% to about 40%, and most
`preferably from about 10% to about 30%. Suitable solvents
`which include polyethylene glycol, propylene glycol poly(cid:173)
`vinylpyrrolidone are preferred as the solvent for use in the
`processes of the instant invention and are discussed briefly
`below.
`Optional Components for Liquid Core
`Other components which can be incorporated into the
`liquid pharmaceutical core compositions of the instant
`invention include colorings, flavorings, preservatives,
`lubricants, flow-enhancers, filling aids, anti- oxidants,
`essences, and other aesthetically pleasing components.
`Process for Solubilizing Pharmaceutical Actives
`The concentrated liquid cores containing pharmaceutical
`actives are prepared using art-recognized principles and
`methodologies in mixing the ingredients together and in
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1013, Pg. 3 of 6
`
`

`

`5,641,512
`
`6
`plasticizer, and most preferably from about 10% to about
`20% plasticizer. A preferred plasticizer useful in the present
`invention is glycerin.
`Water
`The soft gelatin shells of the instant invention also com-
`prise water. Without being limited by theory, the water is
`believed to aid in the rapid dissolution or rupture of the soft
`gelatin shell upon contact with the gastrointestinal fluids
`encountered in the body.
`The shell of the present invention, as initially prepared,
`generally comprises from about 15% to about 50% water,
`more preferably from about 25% to about 40% water, and
`most preferably from about 30% to about 40% water.
`Xanthine Derivatives
`A xanthine derivative is incorporated into the soft gelatin
`shell of the present invention.
`The term "xanthine derivative" as used herein are defined
`as xanthine or a compound comprising the xanthine nucleus
`substituted with the substitutents defined hereinafter as well
`20 as any pharmaceutical acceptable salts or esters thereof (e.g.,
`acid addition salts such as acetate, benzoate, salicylate, and
`alkaline salts thereof) complexes, double salts and mixtures.
`The xanthine derivatives of the invention comprise com(cid:173)
`pounds of the general formula:
`
`5
`choosing the type of mixing equipment to be used. In a
`preferred mauner of execution, the analgesic pharmaceutical
`active, polyethylene glycol, polyvinylpyrrolidone, and sol(cid:173)
`vent are combined and mixed until dissolved to form a
`homogeneous solution. Any optional components can either 5
`be added initially or after the essential components are
`combined.
`Next, any volatile solvent is removed from the resulting
`homogeneous solution until the residual amount of solvent
`is present at no more than from about 0.1 percent to about 10
`6 percent by weight of the composition. Such solvents can
`be removed using any art-recognized evaporation tech(cid:173)
`niques including, but not limited to, rotary evaporation,
`spray-drying, flash evaporation, film evaporation, freeze(cid:173)
`drying, thin film evaporation, forced circulation evaporation, 15
`wiped film evaporation, falling film evaporation, and the
`like. This resulting solution is suitable for encapsulation in
`a soft gelatin capsule using standard encapsulation tech-
`Diques.
`Soft Gelatin Capsules
`Preselected amounts of the liquid core pharmaceutical
`compositions of the present invention are encapsulated in a
`soft gelatin shell containing a xanthine derivative described
`below. Optionally, the soft gelatin shell is essentially trans(cid:173)
`parent so as to enhance the aesthetic qualities of the capsule. 25
`The soft gelatin shells comprise the following essential, as
`well as optional, components.
`Gelatin
`Gelatin is an essential component of the soft gelatin shells
`of the instant invention. The starting gelatin material used in 30
`the manufacture of soft capsules is obtained by the partial
`hydrolysis of collagenous material, such as the skin, white
`connective tissues, or bones of animals. Gelatin material can
`or a pharmaceutically acceptable non-toxic salt thereof
`be classified as Type A gelatin, which is obtained from the
`acid-processing of porcine skins and exhibits an isoelectric 35 wherein RcR3 , inclusive independently represent hydrogen
`CcC6 alkyl (straight or branched), CcC6 alkoxy, CcC6
`point between pH 7 and pH 9; and Type B gelatin, which is
`obtained from the alkaline-processing of bone and animal
`haloalkyl, C3-C6 cycloalkyl, hydroxy (CcC6) alkyl,
`(bovine) skins and exhibits an isoelectric point between pH
`halogen, hydroxy (Cc.C4 ) alkylamino (CcC4 ) alkyl, CcC4
`4.7 and pH 5.2. Blends of Type A and Type B gelatins can
`(dialkyl)amino(CcC4 )alkyl, CcC4 alkylcarbonyl(CcC4 )
`be used to obtain a gelatin with the requisite viscosity and 40 alkyl, CcC6alkylamino, CcC6( dialkyl)amino, indoloyn,
`bloom strength characteristics for capsule manufacture.
`phenyl or allyl.
`R4 is hydrogen, CcC6alkyl, halo(CcC 6) alkyl,
`Gelatin suitable for capsule manufacture is commercially
`CcC6alkylamino, Cr-C6alkylthio, nitro, carboxy, CcC6
`available from the Sigma Chemical Company, St Louis,
`Mo. For a general description of gelatin and gelatin-based
`(dialkyl)amino, C3-C6 cycloalkyl, phenyl, naphthyl,
`capsules, see Remington's Phannaceutical Sciences, 16th 45 ar(CcC4 )alkyl, or a group of the formula:
`ed., Mack Publishing Company, Easton, Pa. (1980), page
`1245 and pages 1576-1582; and U.S. Pat. No. 4,935,243, to
`Borkan et at., issued Jun. 19, 1990; these two references
`being incorporated herein by reference in their entirety.
`The soft gelatin shell of the capsules of the instant 50
`invention, as initially prepared, comprises from about 20%
`to about 60% gelatin, more preferably from about 25% to
`about 50% gelatin, and most preferably from about 40% to
`about 50% gelatin. The gelatin can be of Type & Type B, or
`a mixture thereof with bloom numbers ranging from about 55
`60 to about 300.
`Plasticizer
`A plasticizer is another component of the soft gelatin
`shells of the instant invention. One or more plasticizers is
`incorporated to produce a soft gelatin shell. The soft gelatin
`thus obtained has the required flexibility characteristics for
`use as an encapsulation agent. Useful plasticizers of the
`present invention include glycerin, sorbitan, sorbitol, or
`similar low molecular weight polyols, and mixtures thereof.
`The shell of the present invention, as initially prepared,
`generally comprises from about 10% to about 35%
`plasticizer, preferably from about 10% to about 25%
`
`where R5 is halo, CcC6 alkyl, Cc-C6alkyl, Cc-C6alkoxy,
`CcC6alkylthio, nitro or CcC6alkylamino and n is 1, 2 or 3.
`Exemplary preferred compounds within the scope of the
`above xanthine derivatives formula include caffeine,
`pentoxifylline, theophylline, theobromine, barnifylline,
`diprophylline, 1-methylxanthine, 1-methyl-8-
`methylxanthane, 8-phenyl-1-methylxanthine, 1,7-
`dimeth ylxan thine,
`1,3- dimethylxan thine,
`60 8-methyltheophylline, 8-ethyltheophylline,
`8-nitrotheophylline, 8-methylaminotheophylline,
`8-dimethylaminotheophylline, 8-methyltheophylline,
`8-ethyltheophylline, 8-( ethy !propionate )theophylline,
`8-cyclopropyltheophylline, 8-cydopentyltheophylline,
`65 8-cyclohexyltheophylline, 8-phenyltheophylline, 8-(para(cid:173)
`chlorophenyl)theophylline, 8-bromophenyl)theophylline,
`8-(para-methoxyphenyl)theophylline, 8-(para-nitrophenyl)
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1013, Pg. 4 of 6
`
`

`

`5,641,512
`
`8
`Ingredients are identified by chemical or CTFA name.
`
`EXAMPLE!
`A soft gelatin capsule containing a concentrated liquid
`5 core composition is prepared from the following ingredients.
`Liquid Core Composition
`
`Ingredient
`
`Ibuprofen
`Polyethylene Glycol 600
`Polyvinylpyrrolidone1
`Propylene Glycol
`Water
`
`Weight%
`
`23.00
`50.00
`2.00
`13.00
`QSlOO
`
`1 Available as Plasdone ® K-29/32 from GAF Chemicals Co.
`
`15
`
`The ibuprofen, polyethylene glycol 600,
`polyvinylpyrrolidone, propylene glycol and water are com(cid:173)
`bined in a suitable vessel and warmed to 70° C. until a
`homogeneous solution is obtained.
`Gelatin Capsule
`
`25
`
`Ingredient
`
`Gelatin
`Glycerin
`Caffeine
`Water
`
`Weight%
`
`47.00
`15.00
`5.00
`QSlOO
`
`The above ingredients are combined in a suitable vessel and
`heated with mixing at about 65° C. to form a uniform
`solution. Using standard encapsulation methodology, the
`resulting solution is used to prepare soft gelatin capsules
`containing the liquid core composition formed above. The
`resulting soft gelatin ibuprofen capsules are suitable for oral
`administration.
`
`EXAMPLE IT
`A soft gelatin capsule containing a concentrated liquid
`core composition is prepared from the following ingredients
`as described in Example 1
`Liquid Core Composition
`
`Ingredient
`
`Naproxen
`Polyethylene Glycol 600
`Polyviny lpyrrolidone1
`Propylene Glycol
`Water
`
`Weight%
`
`28.00
`43.00
`2.50
`5.00
`QS100
`
`50 1 Available as Plasdone ® K-29/32 from GAF Chemicals Co.
`
`Gelatin Capsule
`A soft gelatin mixture is prepared from the following
`ingredients.
`
`7
`theophylline, 8-( dime thy lamin ophenyl )theophylline,
`8-(methylphenyl)theophylline, 8-(3,4-dichlorophenyl)
`theophylline, 8-(meta-nitrophenyl) theophylline, 8-(ortho(cid:173)
`nitrophenyl)theophylline, 8-( 1-napththyl)theophylline, 8-(2,
`6-dimethyl-4-hydroxyphenyl)theophylline, 7 -(2-
`chloroethyl)theophylline, 1-methyl-3 ,7 -diethylxanthine,
`1 -methyl-3-isobutylxanthine, 1 -ethyl-3,7-
`dirnethylxanthine, 1,3-diethylxanthine, 1 -ethyl-3 -propyl-
`7-butyl-8-methylxanthine, 1,3 -dipropylxanthine, 1,3-
`diethylxanthine and 1-butyl-3,7-dimethylxanthine. Most 10
`preferred for use herein are caffeine and pentoxifylline.
`Other optional components which can be incorporated
`into the soft gelatin shells include colorings, flavorings,
`preservatives, anti-oxidants, essences, and other aestheti(cid:173)
`cally pleasing components.
`Soft Gelatin Shell Preparation and Encapsulation
`The solubilized pharmaceutical compositions of the
`present invention can be encapsulated within any conven(cid:173)
`tional soft gelatin shell that is capable of substantially
`containing the composition for a reasonable period of time. 20
`The soft gelatin shells of the instant invention can be
`prepared by combining appropriate amounts of gelatin,
`water, plasticizer, xanthine derivative and any optional com(cid:173)
`ponents in a suitable vessel and agitating and/or stirring
`while heating to about 65° C. until a uniform solution is
`obtained. This soft gelatin shell preparation can then be used
`for encapsulating the desired quantity of the solubilized fill
`composition employing standard encapsulation methodol(cid:173)
`ogy to produce one-piece, hermetically-sealed, soft gelatin
`capsules. The gelatin capsules are formed into the desired 30
`shape and size so that they can be readily swallowed. The
`soft gelatin capsules of the instant invention are of a suitable
`size for easy swallowing and typically contain from about
`100 mg to about 2000 rng of the solubilized pharmaceutical
`active composition. Soft gelatin capsules and encapsulation 35
`methods are described in P. K. Wilkinson et at., "Softgels:
`Manufacturing Considerations", Drugs and the Pharmaceu(cid:173)
`tical Sciences, 41 (Specialized Drug Delivery Systems), P.
`Tyle, Ed. (Marcel Dekker, Inc., New York, 1990)
`pp.409-449; F. S. Horn et at., "Capsules, Soft", Encyclope- 40
`dia of Pharmaceutical Technology, vol. 2, J. Swarbrick and
`J. C. Boylan, eds. (Marcel Dekker, Inc., New York, 1990)
`pp. 269-284; M. S. Patel et at., "Advances in Softgel
`Formulation Technology", Manufacturing Chemist, vol. 60,
`no. 7, pp. 26-28 (July 1989); M. S. Patel et al., "Softgel 45
`Technology", Manufacturing Chemist, vol. 60, no. 8, pp.
`47-49 (August 1989); R. F. Jimerson, "Softgel (Soft Gelatin
`Capsule) Update", Drug Development and Industrial Phar(cid:173)
`macy (Interphex '86 Conference), vol. 12, no. 8 & 9, pp.
`1133-1144 (1986); and W. R. Ebert, "Soft Elastic Gelatin
`Capsules: A Unique Dosage Form", Pharmaceutical
`Technology, vol. 1, no. 5, pp. 44-50 (1977); these references
`are incorporated by reference herein in their entirety. The
`resulting soft gelatin capsule is soluble in water and in
`gatrointestinal fluids. Upon swallowing the capsule, the 55
`gelatin shell rapidly dissolves or ruptures in the gastrointes- - - - - - - - - - - - - - - - - - - - - - -
`tinal tract thereby introducing the xanthine derivatives from
`Ingredient
`Weight%
`the shell and the pharmaceutical actives from the liquid core
`into the physiological system.
`
`60
`
`EXAMPLES
`The following examples further describe and demonstrate
`embodiments within the scope of the present invention. The
`examples are given solely for the purpose of illustration and
`are not to be construed as limitations of the present 65
`invention, as many variations thereof are possible without
`departing from the spirit and scope of the invention.
`
`Gelatin
`Glycerin
`Pentoxifylline
`Water
`
`47.00
`15.00
`5.00
`QSlOO
`
`EXAMPLEffi
`A soft gelatin capsule containing a concentrated liquid
`core composition is prepared from the following ingredients
`as described in Example 1
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1013, Pg. 5 of 6
`
`

`

`9
`Liquid Core Composition
`
`Ingredient
`
`Ketorolac Tromethamine
`Polyethylene Glycol 600
`Polyvinylpyrrolidone'
`Ethanol 95% USP
`
`Weight%
`
`30.00
`40.00
`3.00
`QS100
`
`1 Available as Plasdone ® K-29/32 from GAF Chemicals Co.
`
`Gelatin Capsule
`A soft gelatin capsule containing a concentrated liquid
`core composition is prepared from the following ingredients.
`
`5,641,512
`
`5
`
`10
`temperature until a homogeneous solution is formed. Next,
`the ethanol is removed by rotary evaporation. The resulting
`liquid core composition is encapsulated in the gelatin cap-
`sule described in Example L
`What is claimed is:
`1. A pharmaceutical composition in the form of a soft
`gelatin capsule of a size suitable for easy swallowing and
`typically containing from about 100 mg to about 2000 mg of
`10 a solubilized pharmaceutical active composition, compris(cid:173)
`ing:
`
`Ingredient
`
`Gelatin
`Glycerin
`Pentoxifylline
`Water
`
`Weight%
`
`47.00
`15.00
`5.00
`QS100
`
`15
`
`20
`
`EXAMPLE IV
`
`A soft gelatin capsule containing a concentrated liquid
`core composition is prepared from the following ingredients.
`Liquid Core Composition
`
`25
`
`Ingredient
`
`Weight%
`
`30
`
`Acetaminophen
`26.00
`52.00
`Polyethylene Glycol 600
`3.00
`Polyvinylpyrrolidone'
`QS100
`Ethanol 95% USP
`- - - - - - - - - - - - - - - - - - - - -
`'Available as Plasdone ® K-29/32 from GAF Chemicals Co.
`
`The acetaminophen, polyethylene glycol 600, polyvinyl(cid:173)
`pyrrolidone, and ethanol are combined in a suitable vessel
`and mixed at room temperature until a homogeneous solu(cid:173)
`tion is obtained. Next, the ethanol is removed by rotary 40
`evaporation at room temperature. The resulting liquid core
`composition is encapsulated in the gelatin capsule described
`in Example L
`
`EXAMPLEV
`
`A soft gelatin capsule containing a concentrated liquid
`core composition is prepared from the following ingredients.
`Liquid Core Composition
`
`a) an outer gelatin shell containing a xanthine derivative
`incorporated into the soft gelatin of the outer shell; and
`b) a concentrated liquid core composition, which is
`encapsulated by said outer gelatin shell, comprising a
`solvent solution of a safe and effective mount of at least
`one solubilized analgesic pharmaceutical active; said
`soft gelatin capsule upon swallowing dissolves or rup(cid:173)
`tures in the gastroi