I lllll llllllll Ill lllll lllll lllll lllll lllll 111111111111111111111111111111111
`US008703196B2
`
`c12) United States Patent
`Babcock et al.
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 8,703,196 B2
`*Apr. 22, 2014
`
`(54) PHARMACEUTICAL COMPOSITIONS OF
`DISPERSIONS OF AMORPHOUS DRUGS
`MIXED WITH POLYMERS
`
`(75)
`
`Inventors: Walter C. Babcock, Bend, OR (US);
`William J. Curatolo, Niantic, CT (US);
`Dwayne T. Friesen, Bend, OR (US);
`Rodney J. Ketner, Bend, OR (US);
`Julian B. Lo, Old Lyme, CT (US);
`James A. S. Nightingale, Bend, OR
`(US); Ravi M. Shanker, Groton, CT
`(US); James B. West, Bend, OR (US)
`
`(73) Assignee: Bend Research, Inc., Bend, OR (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`This patent is subject to a terminal dis(cid:173)
`claimer.
`
`(21) Appl. No.: 13/563,536
`
`(22) Filed:
`
`Jul. 31, 2012
`
`(65)
`
`Prior Publication Data
`
`US 2012/0295988 Al
`
`Nov. 22, 2012
`
`Related U.S. Application Data
`
`( 60) Division of application No. 12/217, 700, filed on Jul. 8,
`2008, now Pat. No. 8,236,328, which is a continuation
`of application No. 10/175,640, filed on Jun. 19, 2002,
`now abandoned.
`
`(60) Provisional application No. 60/300,261, filed on Jun.
`22, 2001.
`
`(51)
`
`Int. Cl.
`A61K9/14
`A61K 47138
`(52) U.S. Cl.
`USPC ..................... 424/486; 514/772.2; 514/772.3;
`514/781
`
`(2006.01)
`(2006.01)
`
`(58) Field of Classification Search
`USPC .......... 424/400, 489, 485, 486, 487; 514/313,
`514/772.2, 781, 772.3, 772.5
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`5,368,864 A
`5,456,923 A
`5,707,655 A
`5,900,425 A
`8,236,328 B2 *
`2002/0103225 Al*
`2003/0104063 Al
`
`1111994 Lahr et al.
`10/1995 Nakamichi et al.
`111998 Kanikanti et al.
`511999 Kanikanti et al.
`8/2012 Babcock et al.
`8/2002 Curatolo et al.
`6/2003 Babcock et al.
`
`.............. 424/400
`.............. 514/313
`
`FOREIGN PATENT DOCUMENTS
`
`CA
`2245269
`298 245 Al *
`CA
`2298245 Al
`CA
`2298214
`CA
`2391078
`CA
`EP
`0901786
`EP
`1 027 886 A2 *
`EP
`1027886 A2
`0017164
`WO
`0018374
`WO
`0211710
`WO
`* cited by examiner
`
`1111999
`912000
`912000
`10/2000
`12/2002
`3/1999
`8/2000
`8/2000
`3/2000
`412000
`212002
`
`Primary Examiner - Blessing M Fubara
`(74) Attorney, Agent,
`or Firm -Chernoff Vilhauer
`McClung & Stenzel LLP
`
`(57)
`
`ABSTRACT
`
`A pharmaceutical composition comprises a dispersion com(cid:173)
`prising a low-solubility drug and a matrix combined with a
`concentration-enhancing polymer. At least a major portion of
`the drug is amorphous in the dispersion. The compositions
`improve the stability of the drug in the dispersion, and/or the
`concentration of drug in a use environment.
`
`15 Claims, No Drawings
`
`1
`
`Complex Innovations EX 1008
`IPR of U.S. Pat. No. 7,829,595
`
`

`
`US 8,703,196 B2
`
`1
`PHARMACEUTICAL COMPOSITIONS OF
`DISPERSIONS OF AMORPHOUS DRUGS
`MIXED WITH POLYMERS
`
`This application is a divisional ofU.S. application Ser. No.
`12/217,700, filed Jul. 8, 2008 now U.S. Pat. No. 8,236,328,
`which is a continuation of U.S. application Ser. No. 10/175,
`640, filed Jun. 19, 2002 now abandoned, which is a nonpro(cid:173)
`visional ofU.S. Patent Application Ser. No. 60/300,261 filed
`Jun. 22, 2001, the priority of all of which is claimed pursuant
`to 35 USC 120.
`
`BACKGROUND OF THE INVENTION
`
`The invention relates to compositions of a dispersion com(cid:173)
`prising amorphous drug and a matrix combined with a con(cid:173)
`centration-enhancing polymer that improves the stability of
`the drug and/or enhances the concentration of the drug in a
`use environment.
`Low-solubility drugs often show poor bioavailability or
`irregular absorption, the degree of irregularity being affected
`by factors such as dose level, fed state of the patient, and form
`of the drug. Increasing the bioavailability of low-solubility
`drugs has been the subject of much research. Increasing bio(cid:173)
`availability hinges on improving the concentration of the drug
`in solution to improve absorption.
`It is well known that the amorphous form of a low-solubil-
`ity drug that is capable of existing in either the crystalline or
`amorphous form may temporarily provide a greater aqueous
`concentration of drug relative to the equilibrium concentra- 30
`tion obtained by dissolution of drug in a use environment.
`Such amorphous forms may consist of the amorphous drug
`alone, a dispersion of the drug in a matrix material, or the drug
`adsorbed onto a substrate. It is believed that such amorphous
`forms of the drug may dissolve more rapidly than the crys- 35
`talline form, often dissolving faster than the drug can precipi(cid:173)
`tate from solution. As a result, the amorphous form may
`temporarily provide a greater-than equilibrium concentration
`of drug.
`While such amorphous forms may show initially enhanced 40
`concentration of the drug in a use environment, nevertheless
`the improved concentration is often short-lived. Typically, the
`initially enhanced drug concentration is only temporary and
`quickly returns to the lower equilibrium concentration.
`One approach to increase the bioavailability of low-solu- 45
`bility drugs has involved forming amorphous dispersions of
`drugs with polymers. Examples of attempts to increase drug
`concentration by forming a dispersion of the drug with a
`polymer include Lahr et al., U.S. Pat. No. 5,368,864, Kani(cid:173)
`kanti et al., U.S. Pat. No. 5,707,655, and Nakamichi et al., 50
`U.S. Pat. No. 5,456,923.
`Curatolo et al., EP 0901786A2, disclose solid amorphous
`dispersions of poorly water soluble drugs and hydroxypropy(cid:173)
`lmethyl cellulose acetate succinate (HPMCAS). In one
`embodiment, HPMCAS is a dispersion polymer. Alterna- 55
`tively, a dispersion may be formed of a drug and conventional
`matrix material such as PVP, HPC or HPMC and then the
`dispersion is triturated with HPMCAS.
`One problem with using the amorphous form of a drug is
`that the solid drug may not be stable physically in the amor- 60
`phous form. Often the crystalline form of the drug has a lower
`free energy, and thus over time, the amorphous drug will tend
`to crystallize. The rate of crystallization may be influenced by
`storage conditions, such as temperature and humidity, as well
`as the constituents of the composition.
`Similarly, even if a dispersion of drug and polymer is
`formed, the drug in the resulting amorphous dispersion of
`
`2
`polymer and drug may in some cases be unstable. For
`example, the dispersion may be physically unstable, causing
`the amorphous drug to separate from the dispersion and/or
`crystallize. Alternatively, the drug in the amorphous disper(cid:173)
`sion may be chemically unstable. The drug may degrade over
`time at moderate temperature and humidity levels or the drug
`may convert to a lower energy and lower solubility amor(cid:173)
`phous or crystalline form.
`Alternatively, it may be difficult or, in some cases, impos-
`10 sible to form a dispersion of the drug and preferred polymer.
`In particular, the drug and preferred polymer may not both be
`amenable to a processing method that results in a dispersion
`of the drug and preferred polymer. For example, when solvent
`processing is the preferred method for forming the dispersion,
`15 the drug and preferred polymer may not both be soluble to a
`sufficient extent in an appropriate processing solvent to allow
`formation of the dispersion. In cases where melt processing is
`preferred, the drug or polymer or both may suffer unaccept(cid:173)
`able decomposition upon heating to allow the formation of
`20 the preferred composition to be practical.
`Accordingly, what is still desired is a composition com(cid:173)
`prising an amorphous drug that is physically and/or chemi(cid:173)
`cally stable under typical storage conditions, may be formed
`via practical processing conditions, and that may enhance the
`25 bioavailability of poorly soluble drugs. These needs and oth(cid:173)
`ers that will become apparent to one of ordinary skill are met
`by the present invention, which is summarized and described
`in detail below.
`
`BRIEF SUMMARY OF THE INVENTION
`
`The present invention, in one aspect, relates to pharmaceu-
`tical compositions comprising: (a) a solid dispersion com(cid:173)
`prising a low-solubility drug and a matrix, wherein at least a
`major portion of said drug in said dispersion is amorphous;
`and (b) a concentration-enhancing polymer, said dispersion
`being free from at least a portion of said concentration-en(cid:173)
`hancing polymer; wherein said composition provides
`improved stability of said drug relative to at least one of a first
`control composition consisting of a mixture of said low(cid:173)
`solubility drug in undispersed amorphous form and said con-
`centration-enhancing polymer, and a second control compo(cid:173)
`sition consisting of a dispersion of said low-solubility drug
`and said concentration-enhancing polymer.
`In a second aspect, the present invention relates to pharma(cid:173)
`ceutical compositions comprising: (a) a solid dispersion com(cid:173)
`prising a low-solubility drug and a matrix, wherein at least a
`major portion of said drug in said dispersion is amorphous;
`and (b) a concentration-enhancing polymer, said dispersion
`being free from at least a portion of said concentration-en(cid:173)
`hancing polymer; wherein at least 10 wt % of said matrix is
`non-polymeric.
`In a third aspect, the present invention relates to pharma(cid:173)
`ceutical compositions comprising: (a) a solid dispersion com(cid:173)
`prising a low-solubility drug and a matrix, wherein at least a
`major portion of said drug in said dispersion is amorphous;
`and (b) a concentration-enhancing polymer, said dispersion
`being free from at least a portion of said concentration-en(cid:173)
`hancing polymer; wherein said concentration-enhancing
`polymer is non-cellulosic.
`In a fourth aspect, the present invention relates to pharma(cid:173)
`ceutical compositions, comprising: (a) a solid dispersion
`comprising a low-solubility drug and a matrix, wherein at
`least a major portion of said drug in said dispersion is amor-
`65 phous; and (b) a concentration-enhancing polymer, said dis(cid:173)
`persion being free from at least a portion of said concentra(cid:173)
`tion-enhancing polymer, wherein said concentration-
`
`2
`
`

`
`US 8,703,196 B2
`
`3
`enhancing polymer is selected from the group consisting of
`non-ionizable cellulosic polymers and neutralized acidic
`polymers.
`In a fifth aspect, the present invention relates to pharma(cid:173)
`ceutical compositions, comprising: (a) a solid dispersion
`comprising a low-solubility drug and a matrix, wherein at
`least a major portion of said drug in said dispersion is amor(cid:173)
`phous; and (b) a concentration-enhancing polymer, said dis(cid:173)
`persion being free from at least a portion of said concentra(cid:173)
`tion-enhancing polymer, wherein said concentration(cid:173)
`enhancing polymer is an ionizable cellulosic polymer having
`at least one of an ester-linked carboxylic acid-functional aro(cid:173)
`matic substituent and an ether-linked carboxylic acid-func(cid:173)
`tional aromatic substituent.
`In a sixth aspect, the present invention relates to pharma(cid:173)
`ceutical compositions, comprising: (a) a solid dispersion
`comprising a low-solubility drug and a matrix, wherein at
`least a major portion of said drug in said dispersion is amor(cid:173)
`phous; (b) an amphiphilic, cellulosic concentration-enhanc(cid:173)
`ing polymer, said dispersion being free from at least a portion
`of said amphiphilic, cellulosic concentration-enhancing
`polymer; (c) said amphiphilic cellulosic concentration-en(cid:173)
`hancing polymer having at least one hydrophobic substituent
`selected from the group consisting of ether-linked alkyl sub(cid:173)
`stituents, ester-linked alkyl substituents, ether-linked aryl 25
`substituents and ester-linked aryl substituents; (d) said
`amphiphilic cellulosic concentration-enhancing polymer
`having at least one hydrophilic substituent selected from the
`group consisting of ether-linked hydroxy alkyl substituents,
`ester-linked hydroxy alkyl substituents, alkyl ether groups,
`ester-linked ionizable substituents, and ether-linked ionizable
`substituents; and (e) provided that when said concentration(cid:173)
`enhancing polymer has both the hydrophilic substituents
`hydroxypropyl and succinate, said polymer is free from both
`an ether-linked methyl substituent and an ester-linked acetate 35
`substituent.
`In a preferred embodiment, the drug has improved physical
`stability in said composition relative to said first control com-
`position.
`In another preferred embodiment, at least a major portion 40
`of said drug is dissolved in said matrix.
`In another preferred embodiment, the drug has a solubility
`in said matrix that is at least 30% of a concentration of said
`drug in said matrix.
`In another preferred embodiment, the drug has a weight
`ratio to said matrix of said dispersion of less than 20.
`In yet another preferred embodiment, the dispersion has a
`glass transition temperature that is greater than a glass tran(cid:173)
`sition temperature of at least one of said low-solubility drug in
`undispersed amorphous form and said second control com(cid:173)
`position.
`In another preferred embodiment, the dispersion has a
`glass transition temperature that is greater than about 50° C.
`at 50% relative humidity.
`In another preferred embodiment, the drug in said disper(cid:173)
`sion has a crystallization rate that is less than 90% of a
`crystallization rate of said drug in undispersed amorphous
`form.
`In another preferred embodiment, the drug in said compo(cid:173)
`sition has a relative degree of improvement in chemical sta(cid:173)
`bility of at least 1.25 relative to at least one of said first control
`composition and said second control composition.
`In still another preferred embodiment, the drug is acid(cid:173)
`sensitive and said concentration-enhancing polymer is acidic.
`In another preferred embodiment, the drug in said compo(cid:173)
`sition has improved stability, preferably improved physical
`stability, relative to at least one of a first control composition
`
`4
`consisting of a mixture of said low-solubility drug in undis(cid:173)
`persed amorphous form and said concentration-enhancing
`polymer, and a second control composition comprising a
`dispersion of said drug and said concentration-enhancing
`polymer.
`In another preferred embodiment, at least 10 wt % of said
`matrix is non-polymeric. Preferred components of said
`matrix are selected from the group consisting of alcohols,
`organic acids, organic bases, amino acids, sugars, fatty acid
`10 esters, alkyl sulfates, phospholipids, waxes and salts.
`In yet another preferred embodiment, the matrix has at
`least one polymeric component. Preferred components of
`said matrix are selected from the group consisting of poly(cid:173)
`ethylene glycols, polyoxyethylene glycols, polyethylene-
`15 polypropylene glycol copolymers, polyethylene oxides,
`polyvinylpyrrolidone, polyvinyl alcohols, polyethylene-vi(cid:173)
`nyl alcohol copolymers, polyvinyl alcohol polyvinyl acetate
`copolymers, carboxylic acid-functionalized polymethacry(cid:173)
`lates, amine-functionalized polymethacrylates, proteins,
`20 xanthan gum, carrageenan, hydroxypropyl cellulose, hydrox(cid:173)
`ypropyl methyl cellulose, carboxy methyl cellulose, chitosan,
`chitin, polydextrose, dextrin and starch.
`In another preferred embodiment, the drug is substantially
`amorphous in said dispersion.
`In another preferred embodiment, the dispersion is sub(cid:173)
`stantially homogeneous.
`In another preferred embodiment, the dispersion is com(cid:173)
`pletely homogeneous.
`In another preferred embodiment, the composition is a
`30 solid mixture in which said concentration-enhancing poly(cid:173)
`mer is suspended as a separate phase within said dispersion.
`In another preferred embodiment, the composition is a
`mixture of particles of dispersion and particles of concentra(cid:173)
`tion-enhancing polymer.
`In another preferred embodiment, the mixture is formed by
`at least one of dry-granulation and wet-granulation.
`In another preferred embodiment, the dispersion and said
`concentration-enhancing polymer are each in separate
`regions.
`In another preferred embodiment, the compositions further
`comprise a blend of concentration-enhancing polymers
`selected from the group consisting of ionizable cellulosic
`polymers, non-ionizable cellulosic polymers, ioniziable non(cid:173)
`cellulosic polymers, non-ionizable non-cellulosic polymers,
`45 and neutralized acidic polymers.
`In still another preferred embodiment, the concentration(cid:173)
`enhancing polymer has a hydrophobic portion and a hydro(cid:173)
`philic portion.
`In another preferred embodiment, the concentration-en-
`50 hancing polymer is an ionizable cellulosic polymer such as
`polymers selected from the group consisting ofhydroxypro(cid:173)
`pyl methyl cellulose succinate, cellulose acetate succinate,
`methyl cellulose acetate succinate, ethyl cellulose acetate
`succinate, hydroxypropyl cellulose acetate
`succinate,
`55 hydroxypropyl methyl cellulose acetate succinate, hydrox(cid:173)
`ypropyl cellulose acetate phthalate succinate, cellulose pro(cid:173)
`pionate succinate, hydroxypropyl cellulose butyrate succi(cid:173)
`nate, hydroxypropyl methyl cellulose phthalate, cellulose
`acetate phthalate, methyl cellulose acetate phthalate, ethyl
`60 cellulose acetate phthalate, hydroxypropyl cellulose acetate
`phthalate, hydroxypropyl methyl cellulose acetate phthalate,
`cellulose propionate phthalate, hydroxypropyl cellulose
`butyrate phthalate, cellulose acetate trimellitate, methyl cel(cid:173)
`lulose acetate trimellitate, ethyl cellulose acetate trimellitate,
`65 hydroxypropyl cellulose acetate trimellitate, hydroxypropyl
`methyl cellulose acetate trimellitate, hydroxypropyl cellulose
`acetate trimellitate succinate, cellulose propionate trimelli-
`
`3
`
`

`
`US 8,703,196 B2
`
`5
`tate, cellulose butyrate trimellitate, cellulose acetate tereph(cid:173)
`thalate, cellulose acetate isophthalate, cellulose acetate
`pyridinedicarboxylate, salicylic acid cellulose acetate,
`hydroxypropyl salicylic acid cellulose acetate, ethylbenzoic
`acid cellulose acetate, hydroxypropyl ethylbenzoic acid cel(cid:173)
`lulose acetate, ethyl phthalic acid cellulose acetate, ethyl
`nicotinic acid cellulose acetate, ethyl picolinic acid cellulose
`acetate, carboxy methyl cellulose, carboxy ethyl cellulose,
`ethyl carboxy methyl cellulose, and blends thereof. More
`preferably, the concentration-enhancing polymer is selected
`from the group consisting ofhydroxypropyl methyl cellulose
`acetate succinate, hydroxypropyl methyl cellulose phthalate,
`cellulose acetate phthalate, and cellulose acetate trimellitate,
`and blends thereof.
`In another preferred embodiment, the concentration-en(cid:173)
`hancing polymer is a non-ionizable cellulosic polymer, such
`as polymers selected from the group consisting of hydrox(cid:173)
`ypropyl methyl cellulose acetate, hydroxypropyl methyl cel(cid:173)
`lulose, hydroxypropyl cellulose, methyl cellulose, hydroxy(cid:173)
`ethyl methyl cellulose, hydroxyethyl cellulose acetate, and
`hydroxyethyl ethyl cellulose, and blends thereof.
`In another preferred embodiment, the concentration-en(cid:173)
`hancing polymer is an ionizable, non-cellulosic polymer,
`such as polymers selected from the group consisting of car(cid:173)
`boxylic acid functionalized polymethacrylates, carboxylic
`acid functionalized polyacrylates, amine-functionalized
`polyacrylates, amine-functionalized polymethacrylates, pro(cid:173)
`teins, and carboxylic acid functionalized starches, and blends
`thereof.
`In another preferred embodiment, the concentration-en(cid:173)
`hancing polymer is a non-ionizable, non-cellulosic polymer
`such as polymers selected from the group consisting of vinyl
`polymers and copolymers having at least one substituent
`selected from the group consisting of hydroxyl, alkylacyloxy,
`and cyclicamido; vinyl copolymers of at least one hydro(cid:173)
`philic, hydroxyl-containing repeat unit and at least one hydro(cid:173)
`phobic, alkyl- or aryl-containing repeat unit; polyvinyl alco(cid:173)
`hols that have at least a portion of their repeat units in the
`unhydrolyzed form, polyvinyl alcohol polyvinyl acetate
`copolymers, polyethylene glycol polypropylene glycol 40
`copolymers, polyvinyl pyrrolidone, and polyethylene poly(cid:173)
`vinyl alcohol copolymers, and blends thereof.
`In yet another preferred embodiment, the concentration(cid:173)
`enhancing polymer is selected from the group consisting of
`hydroxypropyl cellulose acetate phthalate succinate, hydrox(cid:173)
`ypropyl methyl cellulose phthalate, cellulose acetate phtha(cid:173)
`late, methyl cellulose acetate phthalate, ethyl cellulose
`acetate phthalate, hydroxypropyl cellulose acetate phthalate,
`hydroxypropyl methyl cellulose acetate phthalate, cellulose
`propionate phthalate, hydroxypropyl cellulose butyrate 50
`phthalate, cellulose acetate trimellitate, methyl cellulose
`acetate trimellitate, ethyl cellulose acetate trimellitate,
`hydroxypropyl cellulose acetate trimellitate, hydroxypropyl
`methyl cellulose acetate trimellitate, hydroxypropyl cellulose
`acetate trimellitate succinate, cellulose propionate trimelli(cid:173)
`tate, cellulose butyrate trimellitate, cellulose acetate tereph(cid:173)
`thalate, cellulose acetate isophthalate, cellulose acetate
`pyridinedicarboxylate, salicylic acid cellulose acetate,
`hydroxypropyl salicylic acid cellulose acetate, ethylbenzoic
`acid cellulose acetate, hydroxypropyl ethylbenzoic acid eel- 60
`lulose acetate, ethyl phthalic acid cellulose acetate, ethyl
`nicotinic acid cellulose acetate, ethyl picolinic acid cellulose
`acetate, carboxy methyl cellulose, carboxy ethyl cellulose,
`ethyl carboxy methyl cellulose, and blends thereof.
`In another preferred embodiment, the amphiphilic, cellu(cid:173)
`losic concentration-enhancing polymer is selected from the
`group consisting of hydroxypropyl cellulose acetate succi-
`
`6
`nate, hydroxypropyl methyl cellulose, hydroxypropyl methyl
`cellulose acetate, hydroxypropyl methyl cellulose succinate,
`hydroxypropyl methyl cellulose phthalate, hydroxypropyl
`methyl cellulose acetate phthalate, hydroxyethyl methyl cel(cid:173)
`lulose, hydroxyethyl methyl cellulose succinate, hydroxy(cid:173)
`ethyl cellulose acetate succinate, hydroxyethyl methyl cellu(cid:173)
`lose acetate succinate, hydroxyethyl methyl cellulose acetate
`phthalate, hydroxyethyl cellulose acetate, hydroxyethyl ethyl
`cellulose, carboxymethyl ethyl cellulose, cellulose acetate
`10 phthalate, hydroxypropyl cellulose acetate phthalate, methyl
`cellulose acetate phthalate, ethyl cellulose acetate phthalate,
`hydroxypropyl cellulose acetate phthalate succinate, cellu(cid:173)
`lose propionate phthalate, hydroxypropyl cellulose butyrate
`15 phthalate, cellulose acetate trimellitate, methyl cellulose
`acetate trimellitate, ethyl cellulose acetate trimellitate,
`hydroxypropyl cellulose acetate trimellitate, hydroxypropyl
`methyl cellulose acetate trimellitate, hydroxypropyl cellulose
`acetate trimellitate succinate, cellulose propionate trimelli-
`20 tate, cellulose butyrate trimellitate, cellulose acetate tereph(cid:173)
`thalate, cellulose acetate isophthalate, cellulose acetate
`pyridinedicarboxylate, salicylic acid cellulose acetate,
`hydroxypropyl salicylic acid cellulose acetate, ethylbenzoic
`acid cellulose acetate, hydroxypropyl ethylbenzoic acid cel-
`25 lulose acetate, ethyl phthalic acid cellulose acetate, ethyl
`nicotinic acid cellulose acetate, and ethyl picolinic acid cel(cid:173)
`lulose acetate, and blends thereof.
`In still another preferred embodiment, at least a portion of
`said concentration-enhancing polymer is neutralized. In other
`30 preferred embodiments, concentration-enhancing polymer is
`a neutralized acidic polymer.
`In still another preferred embodiment, the composition
`when administered to a use environment provides a dissolu(cid:173)
`tion area under the concentration versus time curve for a time
`35 period of at least 90 minutes during the 270 minutes imme(cid:173)
`diately following introduction to said use environment that is
`at least 1.25-fold the corresponding area under the curve
`provided by a control composition comprising an equivalent
`amount ofundispersed amorphous drug alone.
`In another preferred embodiment, the composition when
`administered to a use environment provides a maximum con(cid:173)
`centration of said drug in said use environment that is at least
`1.25-fold a maximum concentration of said drug provided by
`a control composition comprising an equivalent amount of
`45 undispersed amorphous drug alone.
`In another preferred embodiment, the composition when
`administered to an animal provides a relative bioavailability
`of at least 1.25 relative to a control composition comprising
`an equivalent amount ofundispersed amorphous drug alone.
`In another preferred embodiment, the composition when
`administered to a use environment provides a dissolution area
`under the concentration versus time curve for a time period of
`at least 90 minutes during the 270 minutes immediately fol(cid:173)
`lowing introduction to said use environment that is at least
`55 1.25-fold the corresponding area under the curve provided by
`a control composition comprising an equivalent amount of
`said dispersion but with no concentration-enhancing poly(cid:173)
`mer.
`In another preferred embodiment, the composition when
`administered to a use environment provides a maximum con(cid:173)
`centration of said drug in said use environment that is at least
`1.25-fold a maximum concentration of said drug provided by
`a control composition comprising an equivalent amount of
`said dispersion but with no concentration-enhancing poly-
`65 mer.
`In another preferred embodiment, the composition when
`administered to an animal provides a relative bioavailability
`
`4
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`
`US 8,703,196 B2
`
`7
`of at least 1.25 relative to a control composition comprising
`an equivalent amount of said dispersion but with no concen(cid:173)
`tration-enhancing polymer.
`In another preferred embodiment, the drug is selected from
`the group consisting of antihypertensives, antianxiety agents,
`anticlotting agents, anticonvulsants, blood glucose-lowering
`agents, decongestants, antihistamines, antitussives, antine(cid:173)
`oplastics, beta blockers, anti-inflammatories, antipsychotic
`agents, cognitive enhancers, cholesterol-reducing agents,
`antiobesity agents, autoimmune disorder agents, anti-impo- 10
`tence agents, antibacterial and antifungal agents, hypnotic
`agents, anti-Parkinsonism agents, anti-Alzheimer's disease
`agents, antibiotics, anti-depressants, antiviral agents, anti(cid:173)
`atherosclerotic agents, glycogen phosphorylase inhibitors,
`and cholesterol ester transfer protein inhibitors.
`In another preferred embodiment, the drug is a glycogen
`phosphorylase inhibitor selected from the group consisting of
`[R-(R *S *)]-5-chloro-N-[2-hydroxy-3-{ methoxymethy(cid:173)
`lamino }-3-oxo-l-(phenylmethyl)propyl-1 H-indole-2-car(cid:173)
`boxamide and 5-chloro-lH-indole-2-carboxylic acid [(IS)- 20
`benzyl-(2R)-hydroxy-3-((3R,4S)-dihydroxy-pyrrolidin-1-
`yl-)-3-oxypropyl]amide.
`In another preferred embodiment, the drug is a cholesterol
`ester transfer protein inhibitor selected from the group con(cid:173)
`sisting of [2R,4S]-4-[acetyl-(3,5-bis-trifluoromethyl-ben- 25
`zyl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H(cid:173)
`quinoline-l-carboxylic acid isopropyl ester, [2R,4S]-4-[(3,5-
`bis-trifluoromethyl-benzyl )-methoxycarbony I-amino ]-2-
`ethyl-6-trifluoromethyl-3 ,4-dihydro-2H-quinoline-l -
`carboxylic acid ethyl ester, and [2R,4S] 4-[(3,5-bis- 30
`trifluoromethy 1-benzyl )-methoxycarbony I-amino ]-2-ethyl-
`6-trifluoromethyl-3 ,4-dihydro-2H-quinoline-l -carboxy lic
`acid isopropyl ester.
`In a seventh aspect, the present invention relates to methods
`of administering a drug comprising co-administering to a 35
`patient in need of said drug: (a) a solid dispersion comprising
`a low-solubility drug and a matrix, wherein at least a major
`portion of said drug in said dispersion is amorphous; and (b)
`a concentration-enhancing polymer, said dispersion being
`free from at least a portion of said concentration-enhancing 40
`polymer; wherein said dispersion provides improved stability
`of said drug relative to at least one of a first control compo(cid:173)
`sition consisting of a mixture of said low-solubility drug in
`undispersed amorphous form and said concentration-enhanc(cid:173)
`ing polymer, and a second control composition consisting of 45
`a dispersion of said low-solubility drug and said concentra(cid:173)
`tion-enhancing polymer.
`In a preferred embodiment, the dispersion is administered
`separately from said concentration-enhancing polymer.
`In another preferred embodiment, the dispersion and said 50
`concentration-enhancing polymer are administered at
`approximately the same time.
`In another preferred embodiment, the dispersion and said
`concentration-enhancing polymer are present in a single dos(cid:173)
`age form.
`The present invention also relates to, in an eighth aspect,
`methods of administering a drug comprising co-administer(cid:173)
`ing to a patient in need of said drug: (a) a solid dispersion
`comprising a low-solubility drug and a matrix, wherein at
`least a major portion of said drug in said dispersion is amor- 60
`phous; and (b) a concentration-enhancing polymer, said dis(cid:173)
`persion being free from at least a portion of said concentra(cid:173)
`tion-enhancing polymer;
`wherein at least 10 wt% of said matrix is non-polymeric.
`In a ninth aspect, the present invention relates to methods 65
`of administering a drug comprising co-administering to a
`patient in need of said drug: (a) a solid dispersion comprising
`
`8
`a low-solubility drug and a matrix, wherein at least a major
`portion of said drug in said dispersion is amorphous; and (b)
`a concentration-enhancing polymer, said dispersion being
`free from at least a portion of said concentration-enhancing
`polymer; wherein said concentration-enhancing polymer is
`non-cellulosic.
`In a tenth aspect, the present invention relates to methods of
`administering a drug comprising co-administering to a
`patient in need of said drug: (a) a solid dispersion comprising
`a low-solubility drug and a matrix, wherein at least a major
`portion of said drug in said dispersion is amorphous; and (b)
`a concentration-enhancing polymer, said dispersion being
`free from at least a portion of said concentration-enhancing
`polymer, wherein said concentration-enhancing polymer is
`15 selected from the group consisting of non-ionizable cellulosic
`polymers and neutralized acidic polymers.
`In an eleventh aspect, the present invention relates to meth-
`ods of administering a drug comprising co-administering to a
`patient in need of said drug: (a) a solid dispersion comprising
`a low-solubility drug and a matrix, wherein at least a major
`portion of said drug in said dispersion is amorphous; and (b)
`a concentration-enhancing polymer, said dispersion being
`free from at least a portion of said concentration-enhancing
`polymer, wherein said concentration-enhancing polymer is
`an ionizable cellulosic polymer having at least one of an
`ester-linked carboxylic acid-functional aromatic substituent
`and an ether-linked carboxylic acid-functional aromatic sub(cid:173)
`stituent.
`In a twelfth aspect, the present invention relates to methods
`of administering a drug comprising co-administering to a
`patient in need of said drug: (a) a solid dispersion comprising
`a low-solubility drug and a matrix, wherein at least a major
`portion of said drug in said dispersion is amorphous; (b) an
`amphiphilic, cellulosic concentration-enhancing polymer,
`said dispersion being free from at least a portion of said
`amphiphilic, cellulosic concentration-enhancing polymer;
`( c) said amphiphilic cellulosic concentration-enhancing
`polymer having at least one hydrophobic substituent selected
`from the group consisting of ether-linked alkyl substituents,
`ester-linked alkyl substituents, ether-linked aryl substituents
`and ester-linked aryl substituents; ( d) said amphiphilic cellu-
`losic concentration-enhancing polymer having at least one
`hydrophilic substituent selected from the group consisting of
`ether-linked hydroxy alkyl substituents, ester-linked hydroxy
`alkyl substituents, alkyl ether substituents, ester-linked ion(cid:173)
`izable substituents, and ether-linked ionizable substituents;
`and (e) provided t