PCT
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`WO 95/31979
`
`(11) International Publication Number:
`
`(51) International Patent Classification 6:
`A61K 31119, 47/14
`
`A1
`
`(43) International Publication Date:
`
`30 November 1995 (30.11.95)
`
`(21) International Application Number:
`
`PCT/US95/06183
`
`(22) International Filing Date:
`
`19 May 1995 (19.05.95)
`
`(30) Priority Data:
`08/247,028
`
`19 May 1994 (19.05.94)
`
`us
`
`(81) Designated States: AM, AT, AU, BB, BG, BR, BY, CA, CH,
`CN, CZ, DE, DK, EE, ES, Fl, GB, GE, HU, IS, JP, KE,
`KG, KP, KR, KZ, LK, LR, LT, LU, LV, MD, MG, MN,
`MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK,
`TJ, TM, TT, UA, UG, US, UZ, VN, European patent (AT,
`BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, MC, NL,
`PT, SE), OAPI patent (BF, BJ, CF, CG, CI, CM, GA, GN,
`ML, MR, NE, SN, TD, TG), ARIPO patent (KE, MW, SD,
`SZ, UG).
`
`(60) Parent Application or Grant
`(63) Related by Continuation
`us
`Filed on
`
`R.P.
`(71) Applicant (for all designated States except US):
`SCHERER INTERNATIONAL CORPORATION [US/US];
`2075 West Big Beaver Road, P.O. Box 7060, Troy, MI
`48007-7060 (US).
`
`08/247,028 (CIP) Published
`19 May 1994 (19.05.94)
`With international search report.
`Before the expiration of the time limit for amending the
`claims and to be republished in the event of the receipt of
`amendments.
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): SHELLEY, Rickey, S.
`[US/US]; 986 Wood Street, Largo, FL 31640 (US). WEI,
`Youching [US/US]; 2275 Willowbrook Drive, Clearwater,
`FL 34624 (US).
`
`(74) Agent: SARUSSI, Steven, J.; Banner & Allegretti, Ltd., Ten
`South Wacker Drive, Chicago, IL 60606 (US).
`
`(54) Title: SOLUTIONS OF ARYL OR HETEROARYL SUBSTITUTED ALKANOIC ACIDS IN LIPOPHILIC SOL VENTS AND SOFT
`GELATIN CAPSULES CONTAINING SUCH SOLUTIONS
`
`(57) Abstract
`
`Methods and compositions are disclosed for preparing liquid
`mixtures of aryl or heteroaryl alkanoic acids suitable for encapsu(cid:173)
`lation in soft gelatin capsules. The compositions comprise alkanoic
`acids of formulas (I), (Ia), (lb) or pharmaceutically acceptable salts
`thereof, wherein R, R1, Rz, R3, and R5 represent hydrogen or various
`organic substituents, and an effective solubilizing amount of at least
`one lipophilic solvent.
`
`R
`
`OH
`
`(I)
`
`(Ia)
`
`(lb)
`
`0001
`
`PSG2005
`Catalent Pharma Solutions v. Patheon Softgels
`IPR2018-00422
`
`

`

`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international
`applications under the PCT.
`
`AT
`AU
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`Cl
`CM
`CN
`cs
`cz
`DE
`DK
`ES
`FI
`FR
`GA
`
`Austria
`Australia
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`Cote d'Ivoire
`Cameroon
`China
`Czechoslovakia
`Czech Republic
`Germany
`Denmark
`Spain
`Finland
`France
`Gabon
`
`GB
`GE
`GN
`GR
`HU
`IE
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`Ll
`LK
`LU
`LV
`MC
`MD
`MG
`ML
`MN
`
`United Kingdom
`Georgia
`Guinea
`Greece
`Hungary
`Ireland
`Italy
`Japan
`Kenya
`Kyrgystan
`Democratic People's Republic
`of Korea
`Republic of Korea
`Kazakhstan
`Liechtenstein
`Sri Lanka
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`Mali
`Mongolia
`
`MR
`MW
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SI
`SK
`SN
`TD
`TG
`TJ
`TT
`UA
`us
`uz
`VN
`
`Mauritania
`Malawi
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Slovenia
`Slovakia
`Senegal
`Chad
`Togo
`Tajikistan
`Trinidad and Tobago
`Ukraine
`United States of America
`Uzbekistan
`VietNam
`
`•
`
`•
`
`0002
`
`

`

`W095/31979
`
`PCTIUS95/06183
`
`SOLft:IO•a OJ' MYL OB. BBTBJlOAilYL SUB8TI:'l'U'!BD
`ALKaVOIC ACIDS I:R LIPOPHILip 80LVBBT8 ABD
`80~ GBLA~IB CA»8ULZ8 COHTAIBX»a SUCH 80LUTI:OR8
`
`s
`
`•
`
`BICIOBOUBP OF Till IBUITIOII
`
`Ziel4 of the Inyeatioa
`
`The present
`
`invention relates to solutions containing
`
`therapeutically useful substituted alkanoic acids in combination
`
`with at least one lipophilic solvent ~or encapsulation in soft
`
`10
`
`gelatin capsules (softgel capsules).
`Deaoription of tht Belated Art
`
`Hydrophilic
`
`softgels are well
`
`known
`
`for
`
`the oral
`
`administration o~ pharmaceutical agen~s. Typically, softgel
`
`capsules consist of an outer shell ~t gelatin containing a
`
`15
`
`plasticizor and an inner filling o! hydr?philic liquid containing
`
`a dissolved hydrophobic pharmaceutical! agent. The plasticizer
`
`is chosen so that the solubility in thelfill liquid is as low as
`
`possible. If the plasticizer is solub~e in the fill liquid, it
`
`can migrate out of the shell over time into the fill, leaving the
`
`20
`
`shell brittle and subject to rupture.
`
`With respect to pharmaceutical agents of relatively low
`
`solubility andfor relatively high dosage amount, softgel capsules
`
`can pose problems for the pharmaceutical formulator.
`
`For
`
`example, it a given pharmaceutical agent has a relatively low
`
`25
`
`solubility, it may need a relatively la~ge volume o~ solution in
`
`order to deliver a pharmaceutically acc$ptable unit dose. While
`
`theoretically pos•ible to encapsulate zsuch a large volume of
`
`solution in a softgel capsule, for example,
`
`the practical
`
`0003
`
`

`

`wo 95/31979
`
`-2-
`
`PCTIUS95/06183
`
`limitations on the size of capsules ~uitable for conventional
`
`oral administration to human patients could well preclude
`
`pharmaceutical use of the resulting softgel.
`
`Similarly, if a pharmaceutical ag,nt requires a relatively
`
`5
`
`high dose, a large volume of solution may again be a necessity
`
`for delivery ot the require dosage. Softgel oncapsulation of
`
`such a large solution volume may be imp~actical because th@ size
`
`of the needed sottgel would likely exceed the maximum limit tor
`
`conventional oral administration to human patients.
`
`10
`
`As one approach to handling the ~roblems of encapsulating
`
`low solubility or high dose pharmaceu~ical agents, u.s. Patent
`
`No. 5,071,643
`
`(Yu et. al.) discloses the use ot polyethylene
`
`glycol based solutions
`
`for acidic, basic and amphoteric
`
`pharmaceutical agents. These polyethyl~ne glycol based solutions
`
`15
`
`contain either an hydroxide species or a hydrogen ion species
`
`that causes the appropriate pharmaceutical agent to partially
`
`ionize, i.e., the pharmaceutical agen~ is present in both the
`
`free fora and the salt form. The pa~ial ionization described
`
`in Yu et al. results in enhanced solubi~ity for the acidic, basic
`
`20
`
`or a•pboteric pharmaceutical agent. This enhanced solubility,
`
`in
`
`turn, may permit
`
`the preparation of
`
`a
`
`solution of
`
`pharmaceutical agent that is highly c~ncentrated enouqh to be
`
`encapsulated
`
`in
`
`a
`
`capsulQ
`
`accep~ably sized
`
`for oral
`
`administration to human patients. The ~ et al. patent discloses
`
`25
`
`that enhanced solubility solutions 1can be prepared using
`
`polyethylene qlycol and contemplated e~ivalents of polyethylene
`
`0004
`
`

`

`W095/31979
`
`PCTIUS95/06183
`
`-3-
`
`glycol, such as polyethylene glycol e~ers or various alcohols
`
`and copolymers o~ polyethylene glycol.
`
`Softgel encapsulation is sometimes the preferred delivery
`
`system for many pharmaceutical aqen'bs that are adllinistered
`
`5
`
`orally to human patients. Generally, ~o be suitable for softgel
`
`encapsulation, a pharmaceutical formul~tion should be in the form
`
`I
`
`of a clear. stable solution.
`
`The present inv~ntors have
`
`discovered that the enhanced solubilitty solutions disclosed by
`I
`the Yu et al. patent are not aa effective with various
`
`10
`
`substituted alkanoic acid pharmaceutic~l agents.
`
`Therapeutically useful 2- or 3-a~yl or 2- or 3-heteroaryl
`
`substituto.d alkanoic acids function ~s anti-inflammatory and
`
`analgesic agents and may be administer~d orally. They are also
`
`essentially insoluble in water.
`
`An ~xample of such a useful
`
`15
`
`alkanoic acid suitable for use in t~e present invention is
`
`ketoprofen which is 2-(3-bGnzoylphenyl~ propionic acid.
`
`Ketoprofen is an anti-inflammator~, analgesic agent that is
`
`principally indicated for the acute an~ long-term management of
`
`rheumatoid arthritis and osteoarthriti~. Additionally it is a
`
`20
`
`nonsteroidal
`
`compound
`
`and poorly water
`
`soluble.
`
`Some
`
`gastrointestinal irritation is ordina~ily associated with oral
`
`dosage :torma of ketoprofo.n. The properties of ketoprofen render
`
`it a good candidate for formulation with the enhanced solubility
`
`I
`
`solutions disclosed in the Yu et al. patent.
`
`In a number of
`
`is
`
`experiments, the present inventors applled the Yu et al. enhanced
`
`I
`
`solubility solutions in formulations ~f ketoprofen for softgel
`
`encapsulation.
`
`0005
`
`

`

`wo 95/31979
`
`PCTIUS95/06183
`
`-·-
`
`In one formulation, polyethylene glycol 400 and potassium
`
`hydroxide were used to solubilize the ~etoprofen, with the mole
`
`ratio or potassium hydroxide to ketopr~fen being in the range of
`
`0.4
`
`to 1.
`
`It was surprisingly fqund that the resulting
`
`5
`
`formulation was not sufficiently stable !tor softgal encapsulation
`
`due to the undesirable formation or ketoprotan esters.
`
`In an attempt to completely ionize !the ketoprofen to prevent
`
`the formation of undesirable esters, t~e potassium hydroxide to
`
`ketoprofen mole ratio was adjusted to range from 1.1 to 1. With
`
`10
`
`this second formulation, concerns arose that the ketoprofen salt
`
`thus formod andtor the high pH caused by the excess potassium
`
`hydroxide used could affect the physica~ stability of the softgel
`
`capsule when the formulation was encaps~lated. Additionally, if
`
`an equilibrium amount of the ketoprotenlfree acid remained in the
`
`15
`
`solution, it could form ketoprofen est~rs that could drive the
`reaction to torm more ketoprofen !reo ~cid species, which could
`
`eventually result in a chemically unst~ble formulation.
`
`The present inventors have discdvered that non-hydroxyl
`
`containing solvents may be used t~ form pharmaceutically
`
`20
`
`acceptable solutions of 2- or 3-aryl or 3-heteroaryl substituted
`
`alkanoic acids
`
`that are stable an~ suitable for softgel
`
`encapsulation.
`
`0006
`
`

`

`wo 95/31979
`
`PCTIUS95/06183
`
`-5-
`
`IUMlQllY Ol Dl I~IOll
`
`The present
`
`invention provid's
`
`enhanced
`
`solubility
`
`pharmaceutically acceptable solutions ~f therapeutically useful
`
`substituted alkanoic acids, preferably 2- or 3-aryl or 2- or J-
`
`5
`
`heteroaryl alkanoic acids, that can b~ encapsulated in softgel
`
`capsules of a size suitable for subse~ent oral administration
`
`to human patients, having improved cheaical atability compared
`
`I
`
`with polyethylene glycol water misci~le formulations or the
`
`~lkanoic acids.
`
`10
`
`The therapeutically useful active ~gents, ~, substituted
`
`alkanoic acids, preferred for use in ~e present invention have
`
`general formulas I, Ia or Ib:
`
`OH
`
`R
`
`OH1
`
`I
`
`I a
`
`~C02H
`
`N
`
`Ib
`
`I
`or pharmaceutically acceptable salts thereof, wherein
`
`15
`
`R represents a hydrogen atom or ~n alkyl group containing
`
`I
`
`1 to 4 carbon atoms;
`R1 represents hydrogen, halogen, c1-c6 alkyl, phenylalkyl
`where the alkyl is c1-c6 alkyl, a benzoyl group of the
`formula:
`
`0007
`
`

`

`wo 95/31979
`
`PCTIUS95/06183
`
`-6-
`represents hydrog~, c1 -c6 alkyl, or an
`where R4
`alkylthio group having 1 to ~ carbon atoms; or
`
`R1 represents a group of the form*la:
`
`5
`
`10
`
`where n is o, 1 or 2;
`R2 represents hydrogen, hydroxy or
`c1-c6 alkJl
`R3 represents hydrogen,
`Rs is c1-c6 alkoxy.
`
`c1-c6 alkoxy;
`or phenyl; and
`
`The
`
`enhanced
`
`solubility pharmaceutically
`
`I
`
`acceptable
`
`solutions of
`
`15
`
`encapsulated
`
`therapeutically useful alkanoic acids can be
`I of a
`
`in softgel capsules
`
`size suitable for
`
`subsequent oral administration to huma~patients, which improves
`
`the physical stability of
`
`the so~tgel capsules used
`
`to
`
`encapsulate
`
`the
`
`pharmaceutical
`
`so~utions compared with
`
`polyethylene glycol water miscible fo~ulations of the alkanoic
`
`20
`
`acids.
`
`The present invention also provides enhanced solubility
`
`pharmaceutically acceptable solutions ot alkanoic acids that
`
`unexpectedly can be encapsulated in a ~oftgel capsule of a size
`
`smaller than what is required to encaps~late the same dose of the
`
`I
`
`25
`
`acid in polyethylene glycol water misc~ble formulations.
`
`The
`
`enhanced
`
`solubility pharmaceutically
`I
`solutions of 2- or 3-aryl or 3-heteroar~l alkanoic acids provided
`
`I
`
`acceptable
`
`0008
`
`

`

`wo 95/31979
`
`-7-
`
`PCT!US95/06183
`
`by
`
`the present
`
`invention may
`
`reruce or eliminate
`
`the
`
`gaatrointeatinal irritation associated\with oral dosage forms of
`
`these agents.
`
`The lipophilic solvent and the hy~oxyl containing softgel
`
`•
`
`5
`
`capsule plasticizers, such as glycerin\, are i1111isciblo, ther~y
`
`improving both the chemical stability of the acid solution and
`
`improvinq the physical stability of the softgel capsule by
`
`greatly reducing the migration of caps~le plasticizers into the
`
`encapsulated pharmaceutical formulatio~. Additionally, the use
`
`10
`
`of the lipophilic sol vent prevents the !!ormation of esters which
`
`can decrease
`
`the chemical stability of
`
`the alkanoic acid
`
`solution.
`
`suitable lipophilic solvents are polyol esters of fatty
`
`acids. The polyol esters of fatty acid" may be mono-, di-, tri-,
`
`15
`
`etc, emters of the polyols. Thus, th~e may be free hydroxyl
`
`groups present in the polyol esters qf fatty acids useful as
`
`lipophilic solvents of the invention.
`
`The lipophilic sol vent preferred for usa in the present
`
`invention is an alkylena glycol deriva~ive of formula II:
`
`20
`
`'25
`
`wherain
`A represents c1-c4 alkylene opt~onally substituted with
`alkyl or a group of the formula
`
`n
`
`0009
`
`

`

`wo 95/31979
`
`-a-
`
`; and
`
`PCTIUS95/06183
`
`the R" groups are ~e same of different and
`
`..
`
`5
`
`represent c 1-c12 alky~.
`
`Further objects and embodiments Qf the present invention
`
`I
`
`will be described in the following description ot the preferred
`
`I
`
`embodiments.
`
`0010
`
`

`

`wo 95/31979
`
`PCTIUS95/06183
`
`-9-
`
`AIICI.IHIQI 01 '1'11 IIQIIIIQ JMBODIQtrrl
`
`The
`
`pros ant
`
`invention
`
`is
`
`useful
`
`tor
`
`providinq
`
`pharmaceutically acceptable solutions of substituted alkanoic
`
`acids dissolved in at least one lipo~ilic solvent, which are
`
`5
`
`chemically stable and suitable for aof~gal encapsulation.
`
`'rhe therapeutically useful active !aqenta, ~, substituted
`
`alkanoio acida, preferred for usa in t~e preeent invention have
`
`general toraulas I, Ia or Ib:
`
`OH
`
`R
`
`0~
`
`I
`
`I a
`
`or pharmaceutically acceptable salt• thereof,
`
`1.0
`
`wherein
`
`O;;--/C02H
`
`N
`
`Ib
`
`R represents a hydrogen atom or ~ alkyl group containing
`
`1 to 4 carbon atoms;
`
`R1 reproaents hydrogen, haloqen, ~1-c6 alkyl, phenylalkyl
`where the alkyl is c1-c6 alkyl, a benzoyl group of the
`formula:
`
`0
`
`where ~ represents hydroqtn, c 1-c6 alkyl,
`alkylthio group having 1 to
`carbon atoms; or
`
`or an
`
`15
`
`20
`
`0011
`
`

`

`wo 95/31979
`
`Rl represents a group of the form~la:
`
`-10-
`
`PCTfUS95/06183
`
`5
`
`10
`
`15
`
`20
`
`where n is o, l or 2;
`R2 represents hydrogen, hydroxy or c 1-c6 alkoxy;
`R3 represents hydrogen, c1-c6 alxJl or phenyl; and
`R5 is c1-c6 alkoxy.
`
`Suitable pharmaceutically acccp~able, non-toxic salts
`
`include salts such as, for example, alk~li metal, alkaline earth
`
`metal, am.onium and amine salts. Compqunda of general formulas
`r, Ia, and Ib in which R represents anl~lkyl group can Gxist in
`optically active forms, including isomets and racemates thereof.
`
`Preferred alkanoic acids suitable f~r use
`
`in the present
`
`invention include ketoprofen (formula I\ where R is methyl, R1 is
`~ydrogen, ~. 2-(3-
`and ~ and R3
`benzoyl,
`are
`benzoylphenyl)propionic acid}; ibuprof~ (formula I where R is
`
`methyl, R1 and R2 are hydrogen, and R3 ~s isobutyl, ~. 2-(4-
`isobutylphenyl)propionic acid); naprox~n (formula Ia where R is
`methyl and Rs is methoxy, .i...a.JL_, 2- ( 6-mejthoxy naphthyl) propionic
`
`acid);
`
`and oxaprozin,
`
`(formula
`
`Ib, ~. 4,5-diphenyl-2-
`
`oxazolepropionic acid).
`
`The
`
`enhanced
`
`solubility pharmaceutically
`
`I
`
`acceptable
`
`solutions of therapeutically useful substituted alkanoic acids
`I
`can be encapsulated in softgel capsule~ of a size suitable for
`
`0012
`
`

`

`W095/31979
`
`-11-
`
`PCT!US95/06183
`
`sUbsequent oral administration to humaq patients, which improvas
`
`the physical stability of
`
`the so*tqel capsules used
`
`to
`
`encapsulate
`
`the
`
`pharmaceutical
`
`s91utions
`
`coapared with
`
`polyethylene glycol water miscible fo~ulations ot the alkanoic
`
`s
`
`acids.
`
`The present invention also provldaa enhanced soluhili ty
`I
`pharmaceutically accaptable solutions pr kotoproten that can be
`
`encapsulated in a aottgel capsule or a ~ize smaller than wbat is
`
`required
`
`to encapsulate
`
`the
`
`same dose of
`
`the acids
`
`in
`
`10
`
`polyethylene glycol water miscible fo~ulations.
`
`The present invention provides ph.rmaceutically acceptable
`
`solutions containing from about 0.1 to ~000 mg, preferably about
`
`5 to 200 mq, and most prererably abdut 10 to 100 mg, ot an
`
`I
`
`alltanoic acid dissolved in at lea•t . one lipophilic solvent,
`
`15
`
`resulting in a clear solution suitable tPr sottgel encapsulation.
`
`Tba lipophilic solvent and the hyc1J.ioxyl containing softqel
`
`capsule plasticizers, such as glycerin~ are immiscible, thereby
`improving both the chemical stabili tbr of the alkanoic acid
`solution and aproving the physical stability of the softgal
`
`I
`
`20
`
`capsule by greatly reducing the miqratidn of capsule plasticizers
`
`I
`
`into the encapsulated pharmaceutical ropmulation. Additionally,
`
`the use of the lipophilic sol vent pz1eventa the formation of
`
`esters which can dacreaaa the chemical ~tability of the alkanoic
`
`acid solution.
`
`Suitable lipophilic solvents are polyol esters of fatty
`
`acids. The polyol esters of fatty aci~ may be mono-, di-, tri-,
`
`etc, eaters of the polyols. Thus, th~re may be free hydroxyl
`
`0013
`
`

`

`wo 95/31979
`
`-12-
`
`PCTIUS95/06183
`
`groups praaent in the polyol esters d! fatty acids useful as
`
`lipophilic solvents of the invention.
`
`The lipophilic sol vent prererred for uae in the present
`
`5
`
`invention is an alkylene glycol derivative of formula II:
`
`I
`
`wherein
`A represents c1-c4 alkylene optiJonally substituted with
`alkyl or
`
`n
`
`; and
`
`the R" groups are th~ same or dit!erent and
`represent c1-c12 alkylr
`Suitable lipophilic solvents inclUde those of formula III:
`
`m
`
`where the R" groups are the same or di~ferent and represent c 1-
`c12 alkyl and R''' is hydrogen or
`0
`
`"oJlR.
`
`10
`
`1.5
`
`20
`
`25
`
`0014
`
`

`

`W095/31979
`
`PCTIUS95/06183
`
`suitable lipophilic solventc also include those ot formula
`
`-13-
`
`IV:
`
`IV
`
`whera the R" groups are the same or ditferent and represent c1-
`c12 alkyl and R' is c1-c6 alkyl.
`Other suitable lipophilic solvants are those of formula III
`where the R" groups are the same and ~epresent c1-c4 alkyl and
`R''' ia
`
`5
`
`10
`
`15
`
`still other suitable lipophilic solvents are those of
`
`!ormula IV whera the R" qroups ara t~e same or difterent and
`represent c1-c4 alkyl and R' ia methyl.
`Most preferrad lipophilic solvents' of formula III ara those
`
`~0
`
`where R" is aethyl. Most preferred lipophilic sol vents of
`
`formula IV are those whare the R" dp-oups are the same or
`
`difterent and represent CH3 (CH2 ) 6 or CH~(CH2 ) 8 •
`Particularly preferrod solvents ar~ selected from the group
`
`!5
`
`consistinq ot propylene glycol dicaptylate/dicaprate, 1,2, 3-
`
`propanetriol triacetate and mixtures t~ereot. Most preferably
`
`the solvents suitable for use in the p~esent invention include
`
`0015
`
`

`

`wo 95/31979
`
`-14-
`
`PCTIUS95/06183
`
`propylene glycol
`
`dicaprylate/dicap~ate, 1,2,3-propanetriol
`
`triacetata
`
`and
`
`llixtures
`
`thereo~~
`
`Propylene
`
`glycol
`
`dicaprylatafdicaprate is available un4er the trade name Captex
`
`200 fro• .Karlahum Lipid Specialtie• and 1,2,3-prop~tnetriol
`
`I
`
`5
`
`triacetate is available undar the trade name Triac•tin from
`
`I
`
`Eastaan Chemicals.
`
`The
`
`inventive solutions may ~lao contain optional,
`
`additional
`
`inqradients
`
`to
`
`improve
`
`the dispersivity
`
`and
`
`dissolution of
`
`the substituted al~anoic acid.
`
`Suitable
`
`10
`
`additional components include surtactants such as, for example,
`
`I
`
`polyglycaryl esters of fatty acids, polyglycolyzed glycerides,
`I
`propylene glycol eatars, mono- and di-g~ycerides, sorbitan fatty
`
`acid esters, polyoxyethylene sorbi~n fatty acid esters,
`
`polyoxyethylene
`
`sorbitol
`
`estara,
`
`polyoxyethylene
`
`acids,
`
`l.S
`
`polyoxyethylene alcohols, and mixture~ thereof. A preferred
`
`class of surfactanta for uao in combin~tion with the lipophilic
`
`solvents is the polyoxyethylene sorbitan fatty acid esters.
`I
`suitable sorbitan esters are sold under the trade name TWeen.
`
`I
`
`A particularly useful TWeen is polyo~ethylene (20) sorbitan
`
`20
`
`mono-oleate (Tween 80).
`
`The active substituted alkanoic apid pharmaceutical agent
`
`may be present in the solution in amoun~s ranging up to about JOt
`I
`Preferrefi concentrations of the
`
`by weight of the solution.
`
`active agent ara from about 5-20%, more preferably about 10-lSt,
`
`25
`
`by weight of the final solution. Co'llbinations of lipophi lie
`
`I
`
`solvents may be used to obtain a desir~d final concentration.
`
`0016
`
`

`

`wo 95/31979
`
`-15-
`
`PCTIUS95/06183
`
`For example, ketoprofen may be pr.sent in the solution in
`
`amounts ranging up to about st by wei9ht of the solution when
`
`dissolved only
`
`in propylene glycol dicaprylate/dicaprate.
`
`Ketoprofen aay be present in the solutipn in aaounts ranging up
`
`• 5
`
`to about 14\ by weight of the solution when dissolved only in
`
`1,2,3-propanetriol triacetate. When dtssolved in a mixture of
`
`propylene glycol dicaprylate/dic:aprate,
`
`1,2,3-propanetriol
`
`triacetate and Tween, the ketoprofen ph~rmaceutical agent may be
`
`present in solution in amounts ranging ~p to about 22t by weight
`
`10
`
`ot solution.
`
`In addition to the ketoprofen pharmaceutical agent and the
`
`lipophilic solvents, other adjuncta mat optionally be present.
`
`Polyoxyethylene
`
`(20) sorbitan mono-ol.ate
`
`(Tween 80) may be
`
`included in the solution up to aboutj !SOt by weight of th@
`
`L5
`
`solution.
`
`Once the appropriate pharmaceuti~lly acceptable solution
`
`of the aubsti tuted alkanoic acid is formulated, it can be
`
`encapsulated
`
`into conventional softg~l capsules using any
`
`suitable encapsulation method, such as for example, the rotary
`
`:o
`
`die process.
`
`All documents, ~' patents and ~ournal articles, cited
`
`above or below are hereby incorporated by reference in their
`
`entirety.
`
`One skilled in the art will recoqni:Ja that modifications 11ay
`
`5
`
`be made in the present invention wit~out deviating from the
`
`spirit or scope ot the invention. The tnvention is illustrated
`
`further by the following examples which.are not to be construed
`
`0017
`
`

`

`wo 95/31979
`
`-16-
`
`PCTIUS95/06183
`
`as limiting the invention or scope ofj the specific procedures
`
`described herein.
`
`5
`
`Pharmaceutically acceptable solutipns containing ketoprofen
`
`are prepared in the following manner. Firat, mix the following
`
`'EXample 1
`
`•
`
`until hom()9eneous:
`
`(1)
`
`(2)
`
`about 92 mg of propylene glyc~l dicaprylata/dicaprate;
`
`about 92mg of 1,2,3-propanatriol acetate; and
`
`10
`
`(3)
`
`about 10 mg of polyoxyethyl~e (20) sorbitan mono-
`
`oleate.
`
`Second, add about 25 mg of ketoproten tQ the homogeneous mixture
`
`ot propylene glycol dicaprylate, 1,2,J~propanetriol acetate and
`
`polyoxyathylene (20) sorbitan mono-olea~e, and aix again. While
`
`15
`
`mixing in the ketoprofen, heat the mlf.xture and maintain the
`
`temperature between 110-125°F until thelketoprofen is dissolved.
`
`Once the ketoprofen is fully dissolve~, the solution is then
`
`cooled and deaerated. After being c®led and deaerated, the
`
`katoproten solution can be encapsulatted in suitable sottgel
`
`20
`
`capsules, such as 4 oval softgel. The tilled sottgel capsules
`
`are thereafter dry finished to the app~opriate hardness.
`
`Example 2
`
`Pharmaceutically acceptable soluti~ns containingketoprofen
`
`~5
`
`are prepared in the following manner.
`
`,irst, mix the following
`
`until ho•ogeneous:
`
`0018
`
`

`

`W095/31979
`
`-17-
`
`PCTIUS95/06183
`
`(1) about
`
`112
`
`mq
`
`ot
`
`propylene
`
`glycol
`
`dicaprylate/dicaprate;
`
`(2) about 72 mg or 1,2,3-propan~riol acetate; and
`
`(3) about 14 ag of polyoxyethy~ene (20) sorbitan mono-
`
`5
`
`oleate.
`
`Second, add about 25 mg or ketoprofen ~ the homogeneous mixture
`
`ot propylene glycol dicaprylate, 1,2,3rpropanetriol acetate and
`
`polyoxyethylene (20) sorbitan mono-ole~te, and. mix aqain. While
`
`mixinq in the ketoprofan, heat the lllixture and maintain the
`
`10
`
`temperature between 110-125oy until th~ ketoprofen is dissolved.
`
`Once the ketoprofen is fully disaolv~d, the solution is then
`
`cooled and daaerat•d. After being c~oled and deaerated, the
`
`ketoprofen solution can be encapeula~ed in suitable softgel
`
`capsules, such as 4 oval softqel. Th~ filled aoftgel capsules
`
`15
`
`are thereafter dry tinished to the apptopriate hardnesa.
`
`Example 3
`
`Pharmaceutically acceptable solutifms containing up to about
`
`22t ketoprofan by weight of solution are prepared in the
`I
`'elf-emulsifying system.
`
`following manner, which provides a
`
`20
`
`First, mix the following until homoqen.ous:
`
`25
`
`(1) propylene glycol dicaprylat~/dicaprate in an amount
`
`ran9ing trom about 40\ to about 9$t by weight;
`
`(2) 1,2,3-propanetriol acetate i~ an amount ranging from
`
`about lt to about 55% by weight; and
`I
`(3) polyoxyethylene (20) sorbita~mono-oleata in an amount
`ranqinq from about lt to about so% by weight.
`
`0019
`
`

`

`wo 95/31979
`
`-18-
`
`PCT!US95/06183
`
`second, add ketoproten to the homogenepus mixture of propylene
`
`9lycol
`
`dicaprylate,
`
`1, 2, 3-propanett.r'iol
`
`triacetate
`
`and
`
`polyoxyethylane (20) sorbitan mono-olea(te, and •ix again. While
`
`mixing in the ketoprofen, heat the m~xtura and maintain the
`
`5
`
`temperature between 110-l25°F until the ketoprofan is dissolved.
`
`once the ketoprofen is rully dissolve~, the solution is then
`
`cooled and deaerated. Attar being cqoled and deaerated, the
`
`ketoproten solution can be encapsulated in suitable softgel
`
`capsules.
`
`The filled sottgel capsulles are thereafter dry
`I
`
`10
`
`finished to the appropriate hardness.
`
`Example 4
`
`Pharmaceutically acceptable solutiqns containing up to about
`
`14% ketoprofen by weight of solution are prepared
`I
`following manner. First, mix the tollo¥ing until homogeneous:
`
`in the
`
`L5
`
`(l) propylene glycol dicaprylate~dicaprate in an amount
`ranqing from about 1\ to about sot! by weight; and
`
`(2) 1,2,3-propanetriol acetate in an amount ranging from
`about sot to about 99\ by weight.
`
`:o
`
`second, add ketoprofen to the homogeneous aixture of propylene
`
`glycol dicaprylate and 1,2,3-propanetridl acetate and aix again.
`
`I
`
`While mixinq in the ltetoprofen, heat the jmixture and maintain the
`
`temperatura between ll0-125°F until the ~etoprofen is dissolved.
`
`Once the katoprofen is fully dissolve9, the solution is then
`
`5
`
`cooled and deaerated. After bainq coaled and deaerated, the
`
`I
`
`ketoprofen solution can be encapsulated in suitable softgal
`
`0020
`
`

`

`wo 95/31979
`
`PCT!US95/06183
`
`-19-
`
`capsules.
`
`The filled softgel caps~les are thereafter dry
`
`finished to the appropriate hardness.
`
`EXample 5
`
`5
`
`Pharmacautically acceptable soluti~ns containing up to about
`
`5' ketoprofen by weight of solution ar~ prepared by mixing the
`
`ketoprofen with propyleno glycol dicfprylate/dicaprate while
`
`heating the mixture. The temperature pf the mixture should be
`
`maintained between l10-125°F until the lketoprofen is dissolved.
`
`10
`
`Once the ketoprofen is fully dissolvefi, tha solution is then
`
`cooled and deaerated. After being cqoled and deaeratad, the
`
`ketoprofen solution can be encapsula*ad in suitable softqel
`
`capsules.
`
`The filled softgel capsujles are thereafter dry
`
`finished to the appropriate hardness.
`
`15
`
`Example 6
`
`Pharmaceutically acceptable soluticlms containing up to about
`
`14% ketoprofen by weight of solution a~e prepared by mixing the
`
`ketoprofen with 1, 2, 3-propanetriol ac~tate while beating the
`
`20
`
`mixture. The temperature of the mixt~e should be maintained
`
`between 110-125°F until the ketoprofen is dissolved. once the
`
`ketoprofen ia fully dissolved, the sol~tion is than cooled and
`-
`deaarated. After being cooled and deaerated, the ketoprofen
`
`solution can be encapsulated in suitab~ softgel capsules. The
`
`25
`
`filled softgel capsules are thereaft.r dry finished to the
`
`appropriate hardness.
`
`0021
`
`

`

`wo 95/31979
`
`PCT!US95/06183
`
`-20-
`ExamPle z
`The following formulations are pfepared according to the
`invention uainq the procedure set fo~ above in Example 1.
`
`Ingredient
`
`A l(Dl9)
`
`B (mq)
`
`c (mq)
`
`5
`
`Propylene glycol
`dicaprylate/dicaprate
`
`1,2,3-Propanetriol triacetate
`
`Polyoxyethylene (20) sorbitan
`mono-oleate
`
`192
`
`~~
`
`~0
`
`184
`
`276
`
`184
`
`20
`
`276
`
`30
`
`10
`
`Ketoproten
`
`Final softqel size
`
`50
`
`~5
`4 ~val 7.5 oval 12 oval
`
`75
`
`Example 8
`
`The
`
`following
`
`comparative
`
`formulations are preparod
`
`15
`
`essentially as in the procedure set for~h above in Example 1 but
`
`do not include the lipophilic sol vent aqcordinq to the invention.
`
`Ingredient
`
`Water
`
`D
`
`liCJ)
`
`E (mq)
`
`F (mq)
`
`5 46
`
`10.92
`
`].6.38
`
`Potassium hydroxide
`
`6~06
`
`12.12
`
`18.18
`
`20
`
`Polyoxyathylene glycol 400
`
`438.4a
`
`I
`
`876.96 1315.44
`
`Propylene glycol
`
`Ketoprofan
`
`Final sortgel size
`
`*5
`
`25
`
`50
`
`so
`
`75
`
`75
`
`12 ~val 20 oval 30 oval
`
`25
`
`certain specific embodiments of tde present invention have
`
`I
`
`been discussed and disclosed in detail. Many other embodiments
`
`0022
`
`

`

`W095/31979
`
`-21-
`
`PCT!US95/06183
`
`tbat have not bean diaclosed or described are nevertheless the
`
`equivalent of and fall within the sco~ of the present invention
`
`and/or the following claims •
`
`•
`
`0023
`
`

`

`wo 95/31979
`
`Wll CLaDII
`
`PCT!US95/06183
`
`-22-
`
`1.
`
`A pharmaceutical composition comprising alkanoic acids
`
`sal ectad from the· group consisting or alkanoic acids of the
`I
`
`.)
`
`formulas:
`
`R
`
`OH
`
`R
`
`0~
`
`O~C02H
`
`N
`
`or pharmaceutically acceptable salts ~ereof,
`
`wherein
`
`R represents a hydrogen atom or ~n alkyl group containing
`
`l to 4 carbon atoms;
`R1 represents hydrogen, halogen, c1-c6 alkyl, phenylalkyl
`where the alkyl is c1-c6 alkyl, a benzoyl group of the
`formula:
`
`0
`
`represents hydroq4m, c1-c6 alkyl, or an
`where R4
`alkylthio group having l to 1 carbon atoms; or
`R1 represents a group of the for.m~la:
`
`5
`
`10
`
`15
`
`20
`
`0024
`
`

`

`wo 95/31979
`
`-23-
`
`PCT!US95/06183
`
`where n is o, l or 2;
`R2 represents hydrogen, hydroxy of c1-c6 alkoxy;
`R3 repreaents hydrogen, c1-c6 alk*l or phenyl; and
`Rs is c1-c6 alkoxy.
`the 2-phenyl or naphthyl alkanoic acid being solubilized in a
`
`I
`
`lipophilic solvent.
`
`2.
`
`A pharmaceutical composition accorc:Unq to Claim 1
`I
`wherein tha lipophilic solvent has thai formula:
`
`wherein
`A represents c1-c4 alkylene opt~onally substituted with
`alkyl or
`
`and
`
`the RM groups are the same of diff~ent and represent c1-c12
`alkyl.
`
`10
`
`15
`
`zo
`
`0025
`
`

`

`wo 95/31979
`
`-24-
`
`PCTIUS95/06183
`
`3.
`
`A pharmaceutical. compoaitiQn accordinq to Claim 1
`
`wherein the lipophilic solvent has th~ formula:
`
`•
`
`where the R" qroups ara the same or dir~arent and represent c1 -
`c12 alkyl and R''' is hydrogen or
`
`4.
`
`A pharmaceutical compositior accorclinq to Claim 1
`
`wherein the lipophilic solvent has thejformula:
`
`0
`O~R"
`II
`R"~O~ n
`R'
`0
`
`where the R" groups are the same or di~ferent and represent c1-
`c12 alkyl and R' ia c 1-c6 alkyl.
`
`5.
`A pharmaceutical compositio~ accordinq to Claim· 3,
`where the aw groups are the same and ~apresent c 1-c4 alkyl and
`R''' is
`
`5
`
`10
`
`15
`
`20
`
`25
`
`0026
`
`

`

`W095/31979
`
`-25-
`
`PCT!US95/06183
`
`6. A pharmaceutical composi tioljl accoridinq to Claim 4 ,
`where the R" groups are the same or dit*erent and ropreaent c1-c4
`alkyl and R' is methyl.
`
`7.
`
`A pharmaceutical compositio1 accoridinq to claim 1,
`
`wherein the lipophilic solvent comprises a aixture ot a alkylene
`
`glycol derivative ot the formulaz
`
`where the R" groups are the same or di.ferent and represent c1-
`c12 alkyl and R''' is hydrogen or
`
`a alkylene qlycol derivative of tije formula:
`
`f
`
`•
`
`5
`
`10
`
`20
`
`where tha R" groups are the same or di~ferent and·repreaent c1 -
`
`a. A pharmacoutical composition! ot Claim 1 whorein at
`
`~25
`
`least one lipophilic solvent has no fr~e hydroxyl qroups.
`
`0027
`
`

`

`wo 95/31979
`
`-26-
`
`PCTIUS95/06183
`
`9.
`
`A pharmaceutical compos! tioh comprisinq ketoprofen,
`
`naproxen, oxaprozin or ibuprofen solub~lized up to 14' by weight
`
`in 1,2,3-propanetriol triacatate.
`
`5
`
`10. A pharmaceutical compositio!t comprising ketopro