111111
`
`1111111111111111111111111111111111111111111111111111111111111111111111111111
`US 20040186105Al
`
`(19) United States
`(12) Patent Application Publication
`Allenspach et al.
`
`(10) Pub. No.: US 2004/0186105 A1
`Sep. 23, 2004
`(43) Pub. Date:
`
`(54) PHARMACEUTICAL COMPOSITION
`EXHIBITING CONSISTENT DRUG RELEASE
`PROFILE
`
`(76)
`
`Inventors: Carl T. Allenspach, Chicago, IL (US);
`Sreekant R. Nadkarni, Gurnee, IL
`(US); Daryl A. Roston, Norman, OK
`(US); Brian R. Rohrs, Scotts, MI (US);
`Roxana F. Schlam, Highland Park, IL
`(US)
`
`Correspondence Address:
`PHARMACIA CORPORATION
`GLOBAL PATENT DEPARTMENT
`POST OFFICE BOX 1027
`ST. LOUIS, MO 63006 (US)
`
`(21)
`
`Appl. No.:
`
`10/647,501
`
`(22)
`
`Filed:
`
`Aug. 25, 2003
`
`Related U.S. Application Data
`
`(60) Provisional application No. 60/407,212, filed on Aug.
`30, 2002. Provisional application No. 60/479,584,
`filed on Jun. 18, 2003.
`
`Publication Classification
`
`(51)
`
`Int. CI? ....................... A61K 31/50; A61K 31!415;
`A61K 31/365; A61K 31!18
`(52) U.S. Cl. ......................... 514/247; 514/406; 514/471;
`514/602
`
`ABSTRACT
`(57)
`An orally deliverable pharmaceutical composition com(cid:173)
`prises a drug of low water solubility and a pregelatinized
`starch having low viscosity and/or exhibiting a multimodal
`particle size distribution. A process for preparing such a
`composition comprises a step of selecting a pregelatinized
`starch having low viscosity and/or exhibiting a multimodal
`particle size profile, and a step of admixing the selected
`pregelatinized starch with a drug of low water solubility.
`
`Par Pharm., Inc.
`Exhibit 1023
`Page 001
`
`

`

`Patent Application Publication Sep. 23, 2004 Sheet 1 of 3
`
`US 2004/0186105 A1
`
`3
`
`li
`
`Ill
`~ 2
`
`ll. -Ill
`... Ill ... ns
`
`Q) .c
`U)
`
`0
`
`20
`
`60
`40
`Shear rate (s"1
`
`)
`
`Fig. 1
`
`80
`
`100
`
`100
`
`0
`~
`:::::J
`.c
`
`90 -~ 0
`-r::
`'i: -II)
`
`80
`70
`60
`50
`"C
`Q) 40
`>
`~ n:s
`30
`:::::J
`E
`20
`:::::J u
`10
`0
`
`1
`
`10
`
`100
`particle size {Jlm)
`
`1000
`
`Fig. 2
`
`Par Pharm., Inc.
`Exhibit 1023
`Page 002
`
`

`

`Patent Application Publication Sep. 23, 2004 Sheet 2 of 3
`
`US 2004/0186105 A1
`
`100
`
`90 -*' 80
`-t: 70
`0
`;
`::::J .c 60
`·.:::
`.... Cl)
`50
`:e
`Q) 40
`>
`;
`~ 30
`::::J
`E 20
`::::J u
`10
`0
`
`1
`
`10
`
`100
`particle size (JJm)
`
`1000
`
`Fig. 3
`
`peak 18 peak 20
`
`I
`I
`
`5
`
`10
`
`15
`
`20
`
`35
`
`40
`
`45
`
`25
`30
`degrees 28
`
`Fig. 4
`
`Par Pharm., Inc.
`Exhibit 1023
`Page 003
`
`

`

`Patent Application Publication Sep. 23, 2004 Sheet 3 of 3
`
`US 2004/0186105 A1
`
`13
`
`12
`
`c:::
`0
`~
`E ::;,
`~ 11
`0
`u ...
`~
`Q. 10
`
`~l.o_o ______ 1 .• 02 _______ 1_,o4 _______ 1_'o6 _______ 1.'oa-------1.~1o~----1~.12
`
`peak 18/peak 20 ratio
`
`Fig. 5
`
`Par Pharm., Inc.
`Exhibit 1023
`Page 004
`
`

`

`US 2004/0186105 Al
`
`Sep.23,2004
`
`1
`
`PHARMACEUTICAL COMPOSITION EXHIBITING
`CONSISTENT DRUG RELEASE PROFILE
`
`RELEASE PROFILE
`
`[0001] This application claims priority of U.S. provisional
`application Serial No. 60/407,212 filed on Aug. 30,2002 and
`U.S. provisional application Serial No. 60/479,584 filed on
`Jun. 18, 2003.
`
`FIELD OF THE INVENTION
`
`[0002] The present invention relates to orally deliverable
`pharmaceutical compositions containing a drug, for example
`a selective cyclooxygenase-2 (COX-2) inhibitory drug of
`low water solubility, as an active ingredient, to processes for
`preparing such compositions, to methods of treatment of
`COX-2 mediated disorders comprising orally administering
`such compositions to a subject, and to use of such compo(cid:173)
`sitions in manufacture of medicaments.
`
`BACKGROUND OF THE INVENTION
`
`[0003] During the process of seeking approval for and
`registering a pharmaceutical product with the Food and
`Drug Administration (FDA) in the U.S. and corresponding
`regulatory authorities in other countries, a particular candi(cid:173)
`date drug product, for example a tablet, must be shown to
`meet certain pre-established in vivo bioavailability and in
`vitro dissolution rate criteria. As a quality control measure,
`once such a drug product has received FDA or similar
`regulatory approval, samples drawn from batches of manu(cid:173)
`factured product must meet the dissolution rate criteria
`established during the regulatory approval process.
`
`[0004] Typically, a drug manufacturer performs in-process
`or bulk finished product dissolution testing on a manufac(cid:173)
`tured drug product to ensure that each batch of product
`meets established dissolution criteria; any drug product not
`meeting such criteria cannot be released to market and thus
`represents potentially wasted raw materials, labor, energy
`and resources. Therefore, from regulatory, production effi(cid:173)
`ciency, financial and human resource perspectives, it is
`desirable that lot-to-lot, batch-to-batch and/or inter-tablet
`dissolution rate differences, and/or any other dissolution rate
`differences potentially present in a given manufacturing
`campaign, are negligible or small enough so as not to result
`in failure of product to meet pre-established dissolution rate
`criteria.
`
`[0005] Furthermore, it is desirable also from safety and
`efficacy standpoints that lot-to-lot, batch-to-batch and/or
`inter-tablet dissolution rate differences are minimal. Where
`substantial variability in drug dissolution exists, some tab(cid:173)
`lets can dissolve very quickly while others dissolve more
`slowly. Those tablets exhibiting increased dissolution rate
`can provide more rapid in vivo release, which in turn can
`lead to higher blood levels of the drug shortly after admin(cid:173)
`istration, with potentially increased risk for undesirable
`side-effects. Conversely, those tablets exhibiting decreased
`dissolution rate can provide less rapid in vivo release, which
`in turn can lead to lower blood levels of the drug shortly after
`administration, with potentially increased risk for reduced
`therapeutic response.
`
`[0006] The
`4-(5-methyl-3-phenyl-4-isox(cid:173)
`compound
`azolyl)benzenesulfonamide, also referred to herein as val-
`
`decoxib, was disclosed in U.S. Pat. No. 5,633,272 to Talley
`et al. together with processes for preparing this and related
`compounds. Valdecoxib has the structure:
`
`(I)
`
`0
`::::,..__/
`N
`
`[0007] The compounds reported in above-cited U.S. Pat.
`No. 5,633,272, including valdecoxib, are disclosed therein
`as useful anti-inflammatory, analgesic and antipyretic drugs
`having a high degree of selectivity for inhibition of
`cyclooxygenase-2 (COX-2) over cyclooxygenase-1 (COX-
`1). Above-cited U.S. Pat. No. 5,633,272 also contains gen(cid:173)
`eral references to formulations for the administration of such
`compounds, including orally deliverable dosage forms such
`as tablets and capsules.
`
`[0008] European Patent Application No. 0 863 134 dis(cid:173)
`closes orally deliverable compositions comprising a selec(cid:173)
`tive COX-2 inhibitory drug, specifically 2-(3,5-difiuorophe(cid:173)
`nyl)-3-( 4-methyl-sulfonyl)phenyl)-2-cyclopenten-1-one, in
`combination with excipient ingredients including microc(cid:173)
`rystalline cellulose, lactose monohydrate, hydroxypropyl(cid:173)
`cellulose, croscarmellose sodium and magnesium stearate.
`
`[0009]
`International Patent Publication No. WO 00/32189
`discloses orally deliverable compositions comprising a
`selective COX-2 inhibitory drug, specifically celecoxib, in
`combination with excipient ingredients selected from exten(cid:173)
`sive lists of suitable diluents, disintegrants, binding agents,
`wetting agents, lubricants, etc.
`
`[0010]
`International Patent Publication No. WO 01/41762
`describes orally deliverable pharmaceutical compositions
`containing, inter alia, valdecoxib and pregelatinized starch
`(e.g., National Starch 1500). Pregelatinized starch is a
`commonly used excipient in pharmaceutical dosage forms
`and is generally employed as a diluent, disintegrant, and/or
`binder.
`
`[0011] We have now discovered that pharmaceutical dos(cid:173)
`age forms (e.g., tablets) comprising a drug of low water
`solubility (e.g., valdecoxib) and pharmaceutical grade
`pregelatinized starch can exhibit the undesirable attribute of
`drug dissolution rate variability. As indicated above, drug
`dissolution rate variability is particularly undesirable as it
`can lead to side effects, lack of therapeutic response in some
`patients, and/or production inefficiencies.
`
`[0012]
`If orally deliverable pharmaceutical dosage forms
`comprising a drug of low water solubility (e.g., valdecoxib)
`and pregelatinized starch could be prepared exhibiting the
`desirable attribute of improved dissolution rate uniformity, a
`significant advance in the safety, efficacy and production
`efficiency of many pharmaceutical dosage forms would be
`realized.
`
`Par Pharm., Inc.
`Exhibit 1023
`Page 005
`
`

`

`US 2004/0186105 Al
`
`Sep.23,2004
`
`2
`
`SUMMARY OF THE INVENTION
`[0013] There is now provided an orally deliverable phar(cid:173)
`maceutical composition comprising a drug of low water
`solubility and a pregelatinized starch having low viscosity
`and/or exhibiting a multimodal particle size distribution.
`The composition is illustrated herein with reference to a
`selective COX-2 inhibitory drug of low water solubility, for
`example valdecoxib.
`[0014] Such a composition has been found to exhibit a
`surprising and unexpected increase in drug dissolution rate
`consistency by comparison with otherwise similar compo(cid:173)
`sitions comprising a pregelatinized starch other than that
`specified immediately above.
`[0015] There is further provided a method for improving
`drug dissolution rate consistency among pharmaceutical
`tablets prepared within a single manufacturing campaign,
`such tablets comprising a drug, illustratively a selective
`COX-2 inhibitory drug, of low water solubility and prege(cid:173)
`latinized starch. The method comprises a step of selecting a
`pre gelatinized starch having low viscosity and/or exhibiting
`a multi-modal particle size distribution.
`[0016] There is still further provided a method of treating
`and/or preventing a COX-2 mediated condition or disorder
`in a subject, the method comprising administering to the
`subject a therapeutically and/or prophylactically effective
`amount of a composition of the invention.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0017] FIG. 1 shows rheology in the form of a graph of
`shear stress versus shear rate, determined according to Test
`I described hereinbelow, for pregelatinized starch samples
`prepared in six different manufacturing lots.
`[0018] FIG. 2 shows bimodal particle size distribution
`exhibited by pregelatinized starch sampled from Lot H, as
`measured by laser diffraction according to Example 4.
`[0019] FIG. 3 shows unimodal particle size distribution
`exhibited by pregelatinized starch sampled from Lot K, as
`measured by laser diffraction according to Example 4.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`[0020] The present composition comprises a drug, illus(cid:173)
`tratively a selective COX-2 inhibitory drug, of low water
`solubility, and a pregelatinized starch having low viscosity
`and/or exhibiting a multimodal particle size distribution.
`Optionally one or more additional pharmaceutically accept(cid:173)
`able excipients are present in the composition. Preferably,
`the composition is in a form of orally deliverable tablets,
`capsules or granules.
`[0021] A "drug of low water solubility" or a "poorly water
`solubility drug" herein means a drug having solubility in
`water, measured at 37° C., not greater than about 10 mg/ml,
`and preferably not greater than about 1 mg/ml. It is con(cid:173)
`templated that compositions of the invention are especially
`advantageous for drugs having solubility in water, measured
`for example at ambient temperature (about 20° C. to about
`25° C.) and/or at body temperature (about 37° C.), not
`greater than about 0.1 mg/ml. Solubility in water for many
`drugs can be readily determined from standard pharmaceu(cid:173)
`tical reference books, for example The Merck Index, 13th
`
`ed., 2001 (published by Merck & Co., Inc., Rahway, N.J.);
`the United States Pharmacopeia, 24th ed. (USP 24), 2000;
`The Extra Pharmacopoeia, 29th ed., 1989 (published by
`Pharmaceutical Press, London); and the Physicians Desk
`Reference (PDR), 2001 ed. (published by Medical Econom(cid:173)
`ics Co., Montvale, N.J.). Unless the context demends oth(cid:173)
`erwise, "drugs" herein include prodrugs, salts and active
`metabolites of drugs.
`[0022] For example, individual drugs of low water solu(cid:173)
`bility as defined herein include those drugs categorized as
`"slightly soluble", "very slightly soluble", "practically
`insoluble" and "insoluble" in USP 24, pp. 2254-2298; and
`those drugs categorized as requiring 100 nml or more of
`water to dissolve 1 g of the drug, as listed in USP 24, pp.
`2299-2304.
`[0023]
`Illustratively, suitable drugs of low water solubility
`include, without limitation, drugs from
`the following
`classes: abortifacients, ACE inhibitors, a- and ~-adrenergic
`agonists, a- and ~-adrenergic blockers, adrenocortical sup(cid:173)
`pressants, adrenocorticotropic hormones, alcohol deterrents,
`aldose reductase inhibitors, aldosterone antagonists, ana(cid:173)
`bolics, analgesics (including narcotic and non-narcotic anal(cid:173)
`gesics), androgens, angiotensin II receptor antagonists, anor(cid:173)
`exics, antacids, anthelninthics, antiacne agents, antiallergics,
`antialopecia agents, antiamebics, antiandrogens, antianginal
`agents, antiarrhythmics, antiarteriosclerotics, antiarthritic/
`antirheumatic agents (including selective COX-2 inhibi(cid:173)
`tors), antiasthmatics, antibacterials, antibacterial adjuncts,
`anticholinergics, anticoagulants, anticonvulsants, antide(cid:173)
`pressants, antidiabetics, antidiarrheal agents, antidiuretics,
`antidotes to poison, antidyskinetics, antieczematics, anti(cid:173)
`emetics, antiestrogens, antifibrotics, antifiatulents, antifun(cid:173)
`gals, antiglaucoma agents, antigonadotropins, antigout
`agents, antihistaminics, antihyperactives, antihyperlipopro(cid:173)
`teinemics, antihyperphosphatemics, antihypertensives, anti(cid:173)
`hyperthyroid agents, antihypotensives, antihypothyroid
`agents, anti-infiammatories, antimalarials, antimanics, anti(cid:173)
`methemoglobinemics, antimigraine agents, antimuscarinics,
`antimycobacterials, antineoplastic agents and adjuncts,
`antineutropenics, antiosteoporotics, antipagetics, antiparkin(cid:173)
`sonian agents, antipheochromocytoma agents, antipneu(cid:173)
`mocystis agents, antiprostatic hypertrophy agents, antipro(cid:173)
`tozoals,
`antipruntlcs,
`antipsonatlcs,
`antipsychotics,
`antipyretics, antirickettsials, antiseborrheics, antiseptics/dis(cid:173)
`infectants, antispasmodics, antisyphylitics, antithromb(cid:173)
`ocythemics, antithrombotics, antitussives, antiulceratives,
`antiurolithics, antivenins, antiviral agents, anxiolytics, aro(cid:173)
`matase inhibitors, astringents, benzodiazepine antagonists,
`bone resorption inhibitors, bradycardic agents, bradykinin
`antagonists, bronchodilators, calcium channel blockers, cal(cid:173)
`cium regulators, carbonic anhydrase inhibitors, cardiotonics,
`CCK antagonists, chelating agents, cholelitholytic agents,
`choleretics, cholinergics, cholinesterase inhibitors, cho(cid:173)
`linesterase reactivators, CNS stimulants, contraceptives,
`debriding agents, decongestants, depigmentors, dermatitis
`herpetiformis suppressants, digestive aids, diuretics, dopam(cid:173)
`ine receptor agonists, dopamine receptor antagonists, ecto(cid:173)
`parasiticides, emetics, enkephalinase inhibitors, enzymes,
`enzyme cofactors, estrogens, expectorants, fibrinogen recep(cid:173)
`tor antagonists, fluoride supplements, gastric and pancreatic
`secretion stimulants, gastric cytoprotectants, gastric proton
`pump inhibitors, gastric secretion inhibitors, gastroprokinet(cid:173)
`ics, glucocorticoids, a-glucosidase inhibitors, gonad-stimu(cid:173)
`lating principles, growth hormone inhibitors, growth hor-
`
`Par Pharm., Inc.
`Exhibit 1023
`Page 006
`
`

`

`US 2004/0186105 Al
`
`Sep.23,2004
`
`3
`
`mane releasing factors, growth stimulants, hematinics,
`hematopoietics, hemolytics, hemostatics, heparin antago(cid:173)
`nists, hepatic enzyme inducers, hepatoprotectants, histamine
`H2 receptor antagonists, HIV protease inhibitors, HMG CoA
`reductase inhibitors, immunomodulators, immunosuppres(cid:173)
`sants, insulin sensitizers, ion exchange resins, keratolytics,
`lactation stimulating hormones, laxatives/cathartics, leukot(cid:173)
`riene antagonists, LH-RH agonists, lipotropics, 5-lipoxyge(cid:173)
`nase inhibitors, lupus erythematosus suppressants, matrix
`metalloproteinase inhibitors, mineralocorticoids, miotics,
`monoamine oxidase inhibitors, mucolytics, muscle relax(cid:173)
`ants, mydriatics, narcotic antagonists, neuroprotectives,
`nootropics, ovarian hormones, oxytocics, pepsin inhibitors,
`pigmentation agents, plasma volume expanders, potassium
`channel activators/openers, progestogens, prolactin inhibi(cid:173)
`tors, prostaglandins, protease inhibitors, radio-pharmaceuti(cid:173)
`cals, Sa-reductase inhibitors, respiratory stimulants, reverse
`transcriptase inhibitors, sedatives/hypnotics, serenics, sero(cid:173)
`tonin noradrenaline reuptake inhibitors, serotonin receptor
`agonists, serotonin receptor antagonists, serotonin uptake
`inhibitors, somatostatin analogs, thrombolytics, thrombox(cid:173)
`ane A 2 receptor antagonists, thyroid hormones, thyrotropic
`hormones, tocolytics, topoisomerase I and II inhibitors,
`uricosurics, vasomodulators including vasodilators and
`vasoconstrictors, vasoprotectants, xanthine oxidase inhibi(cid:173)
`tors, and combinations thereof.
`
`[0024] Non-limiting
`illustrative examples of suitable
`drugs of low water solubility include acetohexamide, ace(cid:173)
`tylsalicylic acid, alclofenac, allopurinol, atropine, benzthi(cid:173)
`azide, carprofen, celecoxib, chlordiazepoxide, chlorprom(cid:173)
`azine, clonidine, codeine, codeine phosphate, codeine
`sulfate, deracoxib, diacerein, diclofenac, diltiazem, estra(cid:173)
`dial, etodolac, etoposide, etoricoxib, fenbufen, fenclofenac,
`fenprofen, fentiazac, fiurbiprofen, griseofulvin, haloperidol,
`ibuprofen,
`indomethacin,
`indoprofen,
`ketoprofen,
`lorazepam, medroxyprogesterone acetate, megestrol, meth(cid:173)
`oxsalen, methylprednisone, morphine, morphine sulfate,
`naproxen, nicergoline, nifedipine, nifiumic, oxaprozin,
`oxazepam, oxyphenbutazone, paclitaxel, phenindione, phe(cid:173)
`nobarbital, piroxicam, pirprofen, prednisolone, prednisone,
`procaine, progesterone, pyrimethamine, rofecoxib, sulfadi(cid:173)
`azine, sulfamerazine, sulfisoxazole, sulindac, suprofen,
`temazepam, tiaprofenic acid, tilomisole, tolmetic, valde(cid:173)
`coxib, etc. The invention is illustrated herein with particular
`reference to valdecoxib.
`
`[0025] The amount of drug to be incorporated in a com(cid:173)
`position of the invention can be selected according to known
`principles of pharmacy. A therapeutically and/or prophylac(cid:173)
`tically effective amount of drug is specifically contemplated.
`The term "therapeutically and/or prophylactically effective
`amount" as used herein refers to an amount of drug present
`in a unit dose of the composition, for example a single tablet
`or capsule, that is sufficient to elicit a required or desired
`therapeutic and/or prophylactic response.
`
`[0026] What constitutes a therapeutically and/or prophy(cid:173)
`lactically effective amount depends greatly on the particular
`drug. In most cases, however, the drug is present in a
`composition of the invention in a concentration of at least
`about 0.01 %, preferably at least about 0.1 %, more prefer(cid:173)
`ably at least about 1%, still more preferably at least about
`2.5%, and even more preferably at least about 5%, by
`weight. Unless otherwise indicated, all concentrations given
`herein are on a weight/weight basis.
`
`[0027]
`In a preferred embodiment, the drug is a selective
`COX-2 inhibitory drug. A preferred selective COX-2 inhibi(cid:173)
`tory drug useful herein, or to which a salt or prodrug useful
`herein is converted in vivo, is a compound of formula (II):
`
`(II)
`
`[0028] wherein:
`
`[0029] A is a substituent selected from partially
`unsaturated or unsaturated heterocyclyl and partially
`unsaturated or unsaturated carbocyclic rings, prefer(cid:173)
`ably a heterocyclyl group selected from pyrazolyl,
`furanonyl, isoxazolyl, pyridinyl, cyclopentenonyl
`and pyridazinonyl groups;
`[0030] X is 0, S or CH2 ;
`[0031] n is 0 or 1;
`[0032] R 1 is at least one substituent selected from
`heterocyclyl, cycloalkyl, cycloalkenyl and aryl, and
`is optionally substituted at a substitutable position
`with one or more radicals selected from alkyl,
`haloalkyl,
`cyano,
`carboxyl,
`alkoxycarbonyl,
`hydroxyl, hydroxyalkyl, haloalkoxy, amino, alky(cid:173)
`lamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl,
`halo, alkoxy and alkylthio;
`[0033] R2 is methyl, amino or aminocarbonylalkyl;
`
`[0034] R3
`is one or more radicals selected from
`hydrido, halo, alkyl, alkenyl, alkynyl, oxo, cyano,
`carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy,
`alkylthio, alkylcarbonyl, cycloalkyl, aryl, haloalkyl,
`heterocyclyl, cycloalkenyl, aralkyl, heterocyclyla(cid:173)
`lkyl, acyl, alkylthioalkyl, hydroxyalkyl, alkoxycar(cid:173)
`bonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl,
`alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthio(cid:173)
`alkyl, aralkoxyalkyl, alkoxyaralkoxyalkyl, alkoxy(cid:173)
`carbonylalkyl, aminocarbonyl, aminocarbonylalkyl,
`alkylaminocarbonyl, N-arylaminocarbonyl, N-alkyl(cid:173)
`N-arylaminocarbonyl,
`alkylaminocarbonylalkyl,
`carboxyalkyl, alkylamino, N-arylamino, N-aralky(cid:173)
`lamino, N-alkyl-N-aralkylamino, N-alkyl-N-ary(cid:173)
`lamino, aminoalkyl, alkylaminoalkyl, N-arylami(cid:173)
`noalkyl,
`N-aralkylaminoalkyl,
`N-alkyl-N(cid:173)
`aralkylaminoalkyl,
`N-alkyl-N-arylaminoalkyl,
`aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl,
`alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl,
`N-arylaminosulfonyl, arylsulfonyl and N-alkyl-N(cid:173)
`arylaminosulfonyl, R3 being optionally substituted at
`a substitutable position with one or more radicals
`selected from alkyl, haloalkyl, cyano, carboxyl,
`alkoxycarbonyl,
`hydroxyl,
`hydroxyalkyl,
`haloalkoxy, amino, alkylamino, arylamino, nitro,
`alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alky(cid:173)
`lthio; and
`
`Par Pharm., Inc.
`Exhibit 1023
`Page 007
`
`

`

`US 2004/0186105 Al
`
`Sep.23,2004
`
`4
`
`[0035] R4 is selected from hydrido and halo.
`
`[0036] Compositions of the invention are especially useful
`for selective COX-2 inhibitory drugs of formula (III):
`
`(III)
`
`\fY'¢-........z
`I
`
`~ X'
`
`R5/ ~
`0
`
`R6
`
`[0037] where R5 is a methyl or amino group, R6 is hydro(cid:173)
`gen or a C1 _4 alkyl or alkoxy group, X' is Nor CR7 where
`R7 is hydrogen or halogen, andY and Z are independently
`carbon or nitrogen atoms defining adjacent atoms of a five(cid:173)
`to six-membered ring that is optionally substituted at one or
`more positions with oxo, halo, methyl or halomethyl groups,
`or an isomer, tautomer, pharmaceutically-acceptable salt or
`prodrug thereof. Preferred such five- to six-membered rings
`are cyclopentenone, furanone, methylpyrazole, isoxazole
`and pyridine rings substituted at no more than one position.
`
`[0038]
`Illustratively, compositions of the invention are
`suitable for celecoxib, deracoxib, valdecoxib, rofecoxib,
`etoricoxib,
`2-(3,5-difiuorophenyl)-3-[ 4-(methylsulfo(cid:173)
`nyl)phenyl]-2-cyclopenten-1-one, 2-(3,4-difiuorophenyl)-4-
`(3-hydroxy-3-methyl-1-butoxy)-5-[ 4-(methylsulfonyl)phe(cid:173)
`nyl]-3-(2H)-pyridazinone, pharmaceutically acceptable salts
`and prodrugs thereof, so long as these meet the solubility
`criteria established herein.
`
`[0039] Compositions of the invention are also useful for
`selective COX-2 inhibitory drugs of formula (IV):
`
`(IV)
`
`[0040] where X" is 0, S or N-lower alkyl; R8 is lower
`haloalkyl; R9 is hydrogen or halogen; R10 is hydrogen,
`halogen, lower alkyl, lower alkoxy or haloalkoxy, lower
`aralkylcarbonyl, lower dialkylaminosulfonyl, lower alky(cid:173)
`laminosulfonyl, lower aralkylaminosulfonyl, lower het(cid:173)
`eroaralkylaminosulfonyl, or 5- or 6-membered nitrogen(cid:173)
`containing heterocyclosulfonyl; and R 11 and R 12 are
`independently hydrogen, halogen,
`lower alkyl,
`lower
`alkoxy, or aryl; and for pharmaceutically acceptable salts
`thereof.
`
`[0041]
`In a particularly preferred embodiment, the drug of
`low water solubility is also a drug such as valdecoxib having
`a relatively low daily dose requirement, for example a
`requirement for not greater than about 100 mg/day.
`
`[0042] For many drugs including valdecoxib, particle size
`reduction can lead to improved bioavailability when the
`drug is formulated in a composition of the invention. Illus(cid:173)
`tratively in the case of valdecoxib, the D90 particle size is
`preferably less than about 75 ,urn, for example about 1 to
`about 70 ,urn, about 1 to about 40 ,urn or about 1 to about 30
`,urn. The term "D90 particle size" in relation to a drug sample
`means a diameter, in the longest dimension of the particles,
`such that 90% by weight of all particles present in the
`sample are smaller than that diameter. In addition or alter(cid:173)
`natively, valdecoxib used in a composition of the invention
`preferably has a weight average particle size of about 1 to
`about 10 ,urn, more preferably about 5 to about 7 ,urn. Any
`suitable milling, grinding or micronizing method can be
`used for particle size reduction to the desired range.
`
`[0043]
`In a preferred valdecoxib composition of the inven(cid:173)
`tion, each unit dose preferably comprises valdecoxib in an
`amount of about 1 to about 100 mg, more preferably about
`2 to about 60 mg, and more preferably about 5 to about 40
`mg, for example about 5 mg, about 10 mg, about 20 mg or
`about 40 mg.
`
`[0044]
`In addition to at least one drug as described above,
`a composition of the invention comprises a pregelatinized
`starch having low viscosity and/or exhibiting a multi-modal
`particle size distribution.
`
`[0045] Pre gelatinized starch is starch that has been physi(cid:173)
`cally and/or chemically processed to rupture some or all
`starch granules. Such processing tends to render starch
`granules fiowable and directly compressible. The term
`"pregelatinized starch" herein includes starches described
`elsewhere as partially pregelatinized starch. Illustratively,
`pregelatinized starch contains about 2% to about 10%, for
`example about 5%, free amylose, about 10% to about 20%,
`for example about 15%, free amylopectin, and about 60% to
`about 90%, for example about 80%, unmodified starch.
`Pregelatinized starch is commonly used in oral capsule and
`tablet formulations as a binder, diluent and/or disintegrant.
`Suitable pregelatinized starch can be derived from any
`botanic origin, for example corn (maize), wheat, cassaya,
`potato, etc., but preferably from corn. Non-limiting
`examples of commercially available pregelatinized corn
`starches from which a low viscosity pregelatinized starch
`useful in the invention can be selected include National
`Starch 78-1551 and Starch 1500 of Colorcon.
`
`[0046] A composition of the invention comprises not less
`than about 0.1 %, preferably not less than about 1%, more
`preferably not less than about 2.5%, and most preferably not
`less than about 5%, pregelatinized starch, by weight. Illus(cid:173)
`tratively, a composition of the invention comprises about 1%
`to about 50%, preferably about 2.5% to about 30%, and
`more preferably about 5% to about 25%, pregelatinized
`starch, by weight.
`
`[0047]
`In a first embodiment, the pregelatinized starch is
`of low viscosity. Whether a sample of pre gelatinized starch
`is one having "low viscosity" as that term is used herein can
`illustratively be determined according to Test I.
`
`[0048] Test I
`[0049] A A test sample of a pregelatinized starch is
`selected or provided.
`[0050] B. A 1 g aliquot of the test sample is placed in
`a 20 ml glass scintillation vial at room temperature.
`
`Par Pharm., Inc.
`Exhibit 1023
`Page 008
`
`

`

`US 2004/0186105 Al
`
`Sep.23,2004
`
`5
`
`[0051] C. Water at room temperature, in an amount of
`10 ml, is added to the scintillation vial to form a
`mixture with the starch.
`
`[0052] D. The mixture is vortexed for 1 minute and
`then stirred for 2 hours at 500 rpm on an orbital
`stirrer.
`
`[0053] E. A 2 g sample of the mixture is then drawn
`and placed in a viscometer sensor (illustratively a
`Haake CV 100 rotational viscometer with a PK30-40
`sensor).
`
`[0054] F. Shear stress, increasing from 0 to 100 s- 1
`over a period of 3 minutes, is applied to the sample
`in the viscometer and dynamic viscosity is measured.
`
`[0055] G. If the sample exhibits, at a shear rate of 20
`s- 1
`, a shear stress of not more than about 1 Pa,
`preferably not more than about 0.75 Pa, the prege(cid:173)
`latinized starch is deemed have "low viscosity" as
`required in the present embodiment.
`
`[0056]
`It will be understood that small variations can be
`made in the conditions under which Test I is run without
`significantly affecting the outcome.
`
`[0057]
`It is preferred according to the present embodiment
`that the pregelatinized starch additionally exhibit, in Test I,
`a shear stress of not more than about 2 Pa, more preferably
`not more than about 1.5 Pa, at a shear rate at 60 s- 1
`.
`
`[0058] For example, a low viscosity pregelatinized starch
`can be selected that exhibits, in Test I, a shear stress of not
`more than about 1 Pa at 20 s- 1
`, not more than about 2 Pa at
`, and not more than about 3 Pa at 100 s- 1
`60 s-1
`.
`
`[0059] Alternatively, a low viscosity pregelatinized starch
`can be selected that exhibits, in Test I, a shear stress of not
`more than about 0.75 Pa at 20 s- 1
`, not more than about 1.5
`Pa at 60 s-1, and not more than about 2.5 Pa at 100 s- 1
`.
`
`[0060] Alternatively, a low viscosity pregelatinized starch
`can be selected that exhibits, in Test I, a shear stress of not
`more than about 0.5 Pa at 20 s- 1
`, not more than about 1 Pa
`at 60 s-1, and not more than about 1.5 Pa at 100 s- 1
`.
`
`[0061]
`In a second embodiment, the pregelatinized starch
`is one exhibiting a multimodal particle size distribution. The
`term "multimodal" herein embraces any particle size distri(cid:173)
`bution having more than one maximum, i.e., including
`bimodal and trimodal but not unimodal distributions.
`
`[0062] Whether a sample of pre gelatinized starch exhibits
`a multimodal particle size distribution can be determined
`using any suitable analytical particle size technique. Illus(cid:173)
`tratively, particle size distribution of dry pregelatinized
`starch can be determined by laser diffraction, for example
`using a Sympatec HELOS in Fraunhofer optical mode and
`using a 500 mm lens.
`
`[0063] Compositions of the invention are orally deliver(cid:173)
`able and can be in a form, for example, of tablets, caplets,
`hard or soft capsules, lozenges, cachets, dispensable powder
`blends, granules, etc. Once a pregelatinized starch having
`low viscosity and/or multimodal particle size distribution
`has been selected, such a composition can be prepared by
`any suitable method of pharmacy that includes a step of
`bringing into association the drug, the pregelatinized starch
`and any other desired excipient(s). In general, a composition
`
`is prepared by uniformly and intimately admixing the drug,
`the pregelatinized starch and the optional additional excipi(cid:173)
`ents with a liquid or finely divided solid diluent, and then, if
`capsules or tablets are required, encapsulating or tableting
`the resulting blend. For example, a tablet can be prepared by
`compressing or molding a powder or granules of such a
`blend, optionally together with one or more additional
`excipients. Compressed tablets can illustratively be prepared
`by compressing, in a suitable machine, a free-flowing com(cid:173)
`position, such as a powder or granules, comprising the
`admixture of the drug and the pregelatinized starch option(cid:173)
`ally mixed with one or more diluents, disintegrants, binding
`agents and/or lubricants. Molded tablets can illustratively be
`prepared by molding, in a suitable machine, a powder
`comprising the admixture of the drug and the pre gelatinized
`starch optionally mixed with one or more excipients, moist(cid:173)
`ened with a liquid diluent.
`
`[0064] A composition of the invention can be in standard(cid:173)
`release, immediate-release, rapid-onset, sustained-release or
`dual-release form. Where the composition comprises valde(cid:173)
`coxib, it is preferably an immediate-release composition that
`releases at least about 75%, more preferably at least about
`80%, of the valdecoxib within