OA12666A - Intraorally disintegrating valdecoxib compositionsprepared by spray drying process. - Google Patents

Abstract

Orally disintegrating valdecoxib fast-melt tablets and processes for preparing such dosage forms are provided. The compositions are useful in treatment or prophylaxis of cycloosygenase-2 mediated conditions and disorders.

Description

4 012666 ' 1 r

INTRAORALLY DISINTEGRATING VALDECOXIB COMPOSITIONS

PREPARED BY SPRAY DRYING PROCESS

FIELD OF THE INVENTION

The présent invention relates to intraorally disintegrating pharmaceutical 5 compositions containing valdecoxib as an active ingrédient, to processes for preparingsuch compositions, and to methods of treatment of cyclooxygenase-2 mediateddisorders comprising orally administering such compositions to a subject. BACKGROUND OF THE INVENTIONThe compound 4-(5-methyl-3-phenyl-4-isoxazolyl)benzenesulfonamide, also 10 referred to herein as valdecoxib, was disclosed in U.S. Patent No. 5,633,272 to Talley,et al., herein incorporated by reference, together with processes for preparing this andrelated compounds. Valdecoxib has the structure:

The compounds reported in above-cited U.S. Patent No. 5,633,272, including 15 valdecoxib, are disclosed therein as useful anti-inflammatory, analgésie 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. Patent No. 5,633,272also contains general references to formulations for the administration of suchcompounds, including orally deliverable dosage forms such as tablets and capsules. 20 Valdecoxib has extremely low solubility in water. See for example Dionne (1999), “COX-2 inhibitors - EBC Conférence, 12-13 April 1999, Coronado, CA,U.S.A.”, IDrugs, 2(7), 664-666. U.S. Patent No. 5,576,014, incorporated herein by reference, discloses anintrabuccally dissolving compressed moîding prepared by a wet granulation process 25 wherein a low moldability saccharide is granulated with a high moldability saccharideto form a granuîate, which is then compressed into a molding. The resulting molding 012666 2 can incorporate a drug and is said to show quick désintégration and dissolution in thebuccal cavity but to maintain sufficient hardness so as not break during productionand distribution. The compressed molding of U.S. Patent No. 5,576,014 is a type ofdosage form known as a “fast-melt tablet”, exhibiting rapid désintégration, usuallyassociated with the carrier materials, typically sugars, and concomitant rapiddissolution or dispersion of the drug in the mouth, usually without need for waterother than that contained in saliva. A drug formulated in such a tablet is readilyswallowed.

Co-assigned International Patent Publication No. WO 01/41761 disclosesorally deliverable valdecoxib compositions having fast-onset properties. None of thecompositions disclosed therein is an intraorally disintegrating composition. A well-known problem with many intraorally disintegrating compositions,even those containing sugars and/or sweetening and/or flavoring agents, is anunpleasant taste resulting from the presence of an active drug therein. Generally, asthe amount of active drug présent in a particular intraorally disintegrating dosage formdecreases, and/or as the aqueous solubility of a drug decreases, the less bitter and/orsour will be the taste of the dosage form. See for example Lieberman et al. (1989),Pharmaceutical Dosage Forms: Tablets Vol. 1, pp. 381. Marcel Dekker, New York.Valdecoxib, a drug with very low water solubility and with relatively low doserequirements, would therefore be expected when formulated as an intraorallydisintegrating composition to hâve acceptable or, at worst, only moderately unpleasantorganoleptic properties. Surprisingly, however, we hâve now discovered thatvaldecoxib has an extremely unpleasant taste. Thus, there remains a need forintraorally disintegrating valdecoxib compositions having acceptable organolepticproperties.

Taste-masking technologies which act by iiéhibiting oral dissolution ofmoderately or highly water soluble drugs hâve been applied to pharmaceutical dosageforms. See for example Lieberman et al. (1989), op. cit. In such cases, improved tasteis believed to resuit from a decrease in the amount of drug which dissolves in themouth prior to entry into the gastrointestinal tract. Given the already extremely lowaqueous solubility of valdecoxib, however, it was not expected that any furtherréduction in oral dissolution of valdecoxib would lead to improved organoleptic 012666 3 properties. Further, it was expected that additional réduction in aqueous solubility ofvaldecoxib would resuit in unacceptable delay of therapeutic onset. Surprisingly,however, we hâve now discovered processes for preparing organoleptically acceptableintraorally disintegrating valdecoxib compositions, which compositions exhibit 5 improved organoleptic properties, yet which still exhibit rapid onset of therapeuticeffect. SUMMARY OF THE INVENTIONAccordingly, there is now provided a process for preparing an intraorally disintegrating valdecoxib composition {e.g. a fast-melt tablet), the process comprising 10 a step of providing valdecoxib in particulate form; a step of dissolving at least onepharmaceutically acceptable excipient which exhibits rapid oral dissolution in water ina vessel; a step of dispersing the valdecoxib in the water, and an optional step ofheating the water. The dissolving, dispersing and optional heating steps areperformed in any order or simultaneously to resuit in a sprayable liquid. The process 15 further comprises a step of spray drying the sprayable liquid to form a tableting blendand a step of compressing the tableting blend to form a tablet. In a process of theinvention, the at least one pharmaceutically acceptable excipient which exhibits rapidoral dissolution is dissolved in the water in a total amount such that upon completionof the process, the at least one excipient which exhibits rapid oral dissolution 20 comprises about 50% to about 99%, preferably about 50% to about 95% and morepreferably about 50% to about 90%, by weight, of the tablet.

The process optionally further comprises a step of adding to the vessel awetting agent or an aqueous solution of such wetting agent, prior to the spray dryingstep. 25 Compositions prepared by such a process represent an embodiment of the présent invention.

There is also now provided an intraorally disintegrating compositioncomprising (a) particulate valdecoxib in a therapeutically effective amount, and (b) atleast one pharmaceutically acceptable excipient which exhibits rapid oral dissolution 30 which is in intimate association with the valdecoxib particles. The composition is organoleptically acceptable and the at least one pharmaceutically acceptable excipientwhich exhibits rapid oral dissolution is présent in a total amount of about 50% to 012666 4 about 99%, preferably about 50% to about 95%, and more preferably about 50% toabout 90%, by weight of the composition.

An “intimate association” in the présent context includes, for example,valdecoxib admixed with the excipient which exhibits rapid oral dissolution,valdecoxib embedded or incorporated in the excipient which exhibits rapid oraldissolution, valdecoxib forming a coating on particles of the excipient which exhibitsrapid oral dissolution or vice versa, and a substantially homogeneous dispersion ofvaldecoxib throughout the excipient which exhibits rapid oral dissolution. Such anintimate association is illustratively formed by processes disclosed hereinabove;altematively or additionally, other means for forming such an intimate associationmay be employed in preparing compositions of the invention.

Valdecoxib in intimate association with an excipient which exhibits rapid oraldissolution is also referred to herein as a "valdecoxib composite". The terni“substantially homogeneous” herein with reference to a composite or pharmaceuticalcomposition that comprises multiple components means that the components aresufficiently mixed such that individual components are not présent as discrète layersand do not form concentration gradients within the composition. Without beingbound by theory, it is believed that the relatively high ratio of excipient which exhibitsrapid oral dissolution to valdecoxib in processes and compositions of the inventionand/or the intimate association of the valdecoxib with the excipient which exhibitsrapid oral dissolution results in formation of a valdecoxib composite which hasimproved organoleptic properties. A particularly useful intraorally disintegrating composition of the présentinvention is a rapidly disintegrating oral dosage form that dissolves in the mouthwithout need for drinking water or other fluid (e.g. a fast-melt). The terra “fast-melt”as used herein refers to a composition such as a tablet wherein an active agent or drugis distributed or dispersed in a matrix formed by a carrier that, upon oraladministration of the composition to a subject, disintegrates in the oral cavity, therebyreleasing the drug, typically in particulate form, for entry to the gastrointestinal tractby swallowing, and subséquent absorption. The terni “oral cavity” includes the entireinterior of the mouth, including not only the buccal cavity (that part of the oral cavityanterior to the teeth and gums) but also the sublingual and supralingual spaces. 012666 5

An "organoleptically acceptable" dosage form or a dosage form having“acceptable organoleptic properties” herein is one that, upon intraoral interaction in anamount providing a single dose of the therapeutic agent, does not hâve an excessivelyunpleasant taste, smell or mouth feel, for example a pronouncedly bitter taste, asperceived by a majority of human subjects, or as determined by analysis of a blindtaste évaluation study as is described hereinbelow.

Processes and compositions of the invention hâve been found to overcome theunacceptable organoleptic properties of valdecoxib without unacceptably sacrifîcingrapid onset characteristics or therapeutic effectiveness. Thus, in a significant advancein the art, valdecoxib is now presented in an organoleptically acceptable fast-meltformulation. Particular advantages of compositions of the invention is that they hâveimproved organoleptic properties, acceptable therapeutic onset characteristics, andsuch compositions can be effîciently prepared by processes described herein.

DETAILED DESCRIPTION OF THE INVENTION A particular embodiment of the invention is an oral fast-melt compositioncomprising (a) particulate valdecoxib in a therapeutically effective amount and (b) atleast one pharmaceutically acceptable excipient which exhibits rapid oral dissolution;wherein the composition is organoleptically acceptable. The at least onepharmaceutically acceptable excipient which exhibits rapid oral dissolution is inintimate association with the valdecoxib particles in the composition, and is présent ina total amount of about 50% to about 99%, preferably about 50% to about 95%, andmore preferably about 50% to about 90%, by weight. A related embodiment of the invention provides an intraorally disintegratingcomposition comprising (a) particulate valdecoxib in a therapeutically effectiveamount, and (b) at least one pharmaceutically acceptable excipient which exhibitsrapid oral dissolution and which is in intimate association with said valdecoxibparticles; wherein the composition is organoleptically acceptable; wherein the at leastone pharmaceutically acceptable excipient which exhibits rapid oral dissolution isprésent in a total amount of about 50% to about 99%, by weight of the composition;and wherein the composition disintegrates within about 60 seconds, preferably withinabout 30 seconds, and more preferably within about 15 seconds, after placement in theoral cavity of a human subject. 012666 6

Another related embodiment of the invention provides an intraorallydisintegrating composition comprising (a) particulate valdecoxib in a therapeuticallyeffective amount, and (b) at least one pharmaceutically acceptable excipient whichexhibits rapid oral dissolution and which is in intimate association with said 5 valdecoxib particles; wherein the composition is organoleptically acceptable; whereinthe at least one pharmaceutically acceptable excipient which exhibits rapid oraldissolution is présent in a total amount of about 50% to about 99%, by weight of thecomposition; and wherein the composition, when placed in United StatesPharmacopeia 24 in vitro disintegration Test Number 701, exhibits a disintegration 10 time of less than about 300 seconds, preferably less than about 200 seconds, and more preferably less than about 100 seconds.

Another embodiment of the invention provides an intraorally disintegratingcomposition comprising (a) particulate valdecoxib in a therapeutically effectiveamount, and (b) at least one pharmaceutically acceptable excipient which exhibits 15 rapid oral dissolution and which is in intimate association with said valdecoxib particles; wherein the composition is organoleptically acceptable; wherein the at leastone pharmaceutically acceptable excipient which exhibits rapid oral dissolution isprésent in a total amount of about 50% to about 99%, by weight of the composition;and wherein administration of the composition to a human subject results in a 20 valdecoxib threshold concentration for therapeutic effect within about 0.5 h,preferably within about 0.3 h, of oral administration.

By “a threshold concentration for therapeutic effect” is meant a minimumconcentration of valdecoxib in blood sérum consistent with therapeutic benefit for theparticular indication for which the valdecoxib is administered. Typically this 25 threshold concentration is at least about 20 ng/ml, for example about 25 ng/rnl toabout 75 ng/ml.

It will be understood that the amount of valdecoxib effective to provide athreshold concentration for therapeutic effect is dépendent, inter alia, on the bodyweight of the treated subject. Where the subject is a child or a small animal (e.g., a 30 dog), for example, an amount of valdecoxib relatively low in the therapeuticallyeffective range of about 1 mg to about 100 mg is likely to provide blood sérumconcentrations consistent with threshold concentration and Cmax criteria. Where the 012666 7 subject is an adult human or a large animal (e.g., a horse), the indicated blood sérumconcentrations of valdecoxib are likely to require a relatively greater dosage amount ofvaldecoxib. For an adult human, a suitable amount of valdecoxib per dose in acomposition of the présent invention to provide the indicated blood sérum 5 concentrations is typically about 5 mg to about 40 mg. A related embodiment of the invention provides an intraorally disintegrating composition comprising (a) particulate valdecoxib in a therapeutically effectiveamount, and (b) at least one pharmaceutically acceptable excipient which exhibitsrapid oral dissolution and which is intimate association with the valdecoxib particles; 10 wherein the composition is organoleptically acceptable; wherein the at least one pharmaceutically acceptable excipient which exhibits rapid oral dissolution is présentin a total amount of about 50% to about 99%, by weight of the composition; andwherein administration of the composition to a human subject résulte in a maximumblood sérum concentration (Cmax) not less than about 100 ng/ml. 15 Another related embodiment of the invention provides an intraorally disintegrating composition comprising (a) particulate valdecoxib in a therapeuticallyeffective amount, and (b) at least one pharmaceutically acceptable excipient whichexhibits rapid oral dissolution and which is intimate association with the valdecoxibparticles; wherein the composition is organoleptically acceptable; wherein the at least 20 one pharmaceutically acceptable excipient which exhibits rapid oral dissolution isprésent in a total amount of about 50% to about 99%, by weight of the composition;and wherein administration of the composition to a human subject results in a time toreach maximum blood sérum concentration (T™»») not greater than about 5 h,preferably not greater than about 4 h, and more preferably not greater than about 3 h. 25 Ingrédients of compositions of the invention A composition of the invention comprises valdecoxib as active ingrédient and at least one pharmaceutically acceptable excipient which exhibits rapid oraldissolution. Optionally, a composition of the invention can contain one or moreadditional pharmaceutically acceptable excipients including, but not limited to, water- 30 soluble lubricants, water-insoluble fabricants, disintegrants, glidants, sweeteners,flavoring agents, colorants, etc. Such optional additional components should bephysically and chemically compatible with the other ingrédients of the composition 012666 δ and must not be deleterious to the récipient.

Valdecoxib

Processes and compositions of the invention are particularly suitable forvaldecoxib as the active drug. Processes for preparing particulate valdecoxib areknownperse, for example as is described in above-cited U.S. Patent No. 5,474,995,incorporated herein by reference. Importantly, any solid State form of valdecoxib,illustratively that described in International Patent Publication No. 98/06708,incorporated herein by reference, can be used in processes and compositions of theinvention. A valdecoxib dosage unit of the invention comprises valdecoxib in atherapeutically effective amount of about 1 mg to about 100 mg, preferably about 5mg to about 50 mg. Compositions of the invention contain valdecoxib in particulateform. Primary valdecoxib particles, generated for example by milling or grinding, orby précipitation from solution, can agglomerate to form secondary aggregate particles.The term “particle size” as used herein refers to size, in the longest dimension, ofprimary particles, unless the context demands otherwise. Particle size is believed tobe an important parameter affecting clinical effectiveness of valdecoxib. Thus, in oneembodiment, a valdecoxib dosage form has a distribution of valdecoxib particle sizessuch that the D90 particle size is less than about 75 gm. The “D90 particle size” isdefined herein as a particle size such that 90% by weight of the particles are smaller,in their longest dimension, than that particle size.

In addition or altematively, valdecoxib particles in a dosage form of the inventionpreferably hâve a weight average particle size of about 1 gm to about 10 gm, mostpreferably about 5 gm to about 7 gm.

Excipients which exhibit rapid oral dissolution

Suitable excipients which exhibit rapid oral dissolution are thosepharmaceutically acceptable excipients which are soluble, freely soluble, or verysoluble in water, for example as described in Ansel et al. (1995) PharmaceuticalDosage Forms and Drug Deliverv Systems 6th Ed, pp. 228. Williams & Wilkins,Baltimore. Preferably, such excipients hâve a sweet taste. A presently preferred classof excipients which exhibit rapid oral dissolution for use in compositions andprocesses of the invention are carbohydrates. Particularly preferred excipients which 012666 9 exhibit rapid oral dissolution are saccharides including both low moldability and highmoldability saccharides.

Presently preferred low moldability saccharides include lactose and mannitol,particularly mannitol in its non-direct compression or powder form as described inKibbe (2000) Handbook of Pharmaceutical Excipients, 3rd Ed., Pharmaceutical Press,pp. 324-328. Presently preferred high moldability saccharides include maltose,maltitol and sorbitol. Altematively, certain oligosaccharides can be useful. Theoligosaccharide used is not particularly limited sô long as it shows rapid dissolution inthe oral cavity and consists of two or more monosaccharide residues. Where anoligosaccharide is used, one consisting of 2 to 6 monosaccharide residues ispréférable, and the type and combination of monosaccharide residues constituting theoligosaccharide are not limited. Particularly preferred high moldability saccharidesare maltose and maltitol, more particularly maltose.

Where both a high moldability saccharide and low moldability saccharide areprésent in a composition of the invention, the weight ratio of high moldabilitysaccharide to low moldability saccharide is important in maintaining a combination ofacceptable tabîet hardness and rapid intraoral désintégration. A suitable ratio is about2 to about 20 parts by weight, preferably about 5 to about 10 parts by weight, andmore preferably about 5 to about 7.5 parts by weight, of the high moldabilitysaccharide per 100 parts by weight of the low moldability saccharide.

If the ratio of high to low moldability saccharide is less than about 2:100 byweight, tablets typically do not achieve their desired hardness, resulting in increasedbreakage during storage, transportation or handling. Altematively, if the ratio of highto low moldability saccharide exceeds about 20:100 by weight, the tablets become toohard and desired rapid désintégration in the oral cavity is not achieved.

One or more excipients which exhibit rapid oral dissolution are typicallyprésent in compositions of the invention in a total amount of about 45% to about 95%,preferably about 50% to about 87%, and. more preferably about 55% to about 80%.

Wetting agents

Compositions of the présent invention optionally comprise one or morepharmaceutically acceptable wetting agents. Surfactants, hydrophilic polymers andcertain clays can be useful as wetting agents to aid in wetting of a hydrophobie drug, 012666 10 such as valdecoxib, during the spray dry granulation process.

Non-limiting examples of surfactants that can be used as wetting agents incompositions of the présent invention include quatemary ammonium compounds, forexample benzalkonium chloride, benzéthonium chloride and cetylpyridinium chloride,dioctyl sodium sulfosuccinate, polyoxyethylene alkylphenyl ethers, for examplenonoxynol 9, nonoxynol 10, and octoxynol 9, poloxamers (polyoxyethylene andpolyoxypropylene block copolymers), polyoxyethylene fatty acid glycerides and oils,for example polyoxyethylene (8) caprylic/capric mono- and diglycerides (e.g.,Labrasol™ of Gattefossé), polyoxyethylene (35) castor oil and polyoxyethylene (40)hydrogenated castor oil; polyoxyethylene alkyl ethers, for example polyoxyethylene(20) cetostearyl ether, polyoxyethylene fatty acid esters, for example polyoxyethylene(40) stéarate, polyoxyethylene sorbitan esters, for example polysorbate 20 andpolysorbate 80 (e.g., Tween™ 80 of ICI), propylene glycol fatty acid esters, forexample propylene glycol laurate (e.g., Lauroglycol™ of Gattefossé), sodium laurylsulfate, fatty acids and salts thereof, for example oleic acid, sodium oleate andtriethanolamine oleate, glyceryl fatty acid esters, for example glyceryl monostearate,sorbitan esters, for example sorbitan monolaurate, sorbitan monooleate, sorbitanmonopalmitate and sorbitan monostearate, tyloxapol, and mixtures thereof. Sodiumlauryl sulfate is a preferred wetting agent in compositions of the présent invention.

One or more wetting agents, if desired, are typically présent in compositions ofthe présent invention in a total amount of about 0.05% to about 5%, preferably about0.075% to about 2.5%, and more preferably about 0.25% to about 1%, for exampleabout 0.5%, by weight of the composition.

Water-insoluble lubricants

Compositions of the présent invention optionally comprise one or morepharmaceutically acceptable water-insoluble lubricants as a carrier material. Suitablewater-insoluble lubricants include, either individually or in combination, glycerylbehapate (e.g. Compritol™ 888), stéarates (magnésium, calcium, and sodium), stearicacid, hydrogenated vegetable oils (e.g., Sterotex™), colloïdal silica, talc, waxes andmixtures thereof. Optionally a water-insoluble lubricant can be used in mixture with awetting agent, as for example in calcium stearate/sodium lauryl sulfate mixtures (e.g.,Sterowet™). 012666 11

Magnésium stéarate, stearic acid and mixtures thereof are preferred water-insoluble lubricants.

One or more water-insoluble lubricants optionally are présent in compositionsof the présent invention in a typical total amount of about 0.05% to about 5%, 5 preferably about 0.75% to about 2.5%, and more preferably about 1 % to about 2%, forexample, about 1.5%, by weight of the composition.

Water-soluble lubricants

Compositions of the présent invention optionally comprise one or morepharmaceutically acceptable water-soluble lubricants. Water-soluble lubricants can 10 help to improve tablet dissolution characteristics. Water-soluble lubricants that can beused in compositions of the présent invention either individually or in combinationinclude, for example, boric acid, sodium benzoate, sodium acetate, sodium fumarate,

I sodium chloride, DL-leucine, polyethylene glycols (e.g., Carbowax™ 4000 andCarbowax™ 6000), and sodium oleate. 15 Disintegrants

Compositions of the présent invention optionally comprise one or morepharmaceutically acceptable disintegrants. However, the oral fast-melt tabletsprovided herein typically disintegrate rapidly in the oral cavity and hâve norequirement for added disintegrant. Suitable disintegrants, if desired, include, either 20 individually or in combination, starches, sodium starch glycolate, clays (such asVeegum™ HV), celluloses (such as purified cellulose, methylcellulose, sodiumcarboxymethylcellulose and carboxymethylcellulose), croscarmellose sodium, - alginates, pregelatinized com starches (such as National™ 1551 and National™ 1550), crospovidone, and gums (such as agar, guar, locust bean, karaya, pectin and 25 tragacanth gums). Disintegrants can be added at any suitable step during the préparation of the composition, particularly prior to granulation or during a blendingstep prior to tablet compression. Croscarmellose sodium and sodium starch glycolateare preferred disintegrants.

One or more disintegrants optionally are présent in a total amount of about 30 0.05% to about 15%, preferably about 0.5% to about 10%, and more preferably about 1% to about 3.5%, by weight of the composition. 012666 12

Glidants

Compositions of the présent invention optionally comprise one or morepharmaceutically acceptable glidants, for example to enhance flow of tabletingmaterial into tablet dies, to prevent sticking of tableting material to punches and dies,or to produce tablets having a sheen. Glidants may be added at any suitable stepduring préparation of the composition, particularly prior to granulation or during ablending step prior to tablet compression.

Without being bound by theory, it is believed that, in some situations, glidants,for example talc or Silicon dioxide, act to reduce interfacial tension between drugparticles, having the effect of inhibiting and/or reducing drug agglomération, act todecrease electrostatic charges on the surface of drug powders, and act to reduceinterparticular friction and surface rugosity of drug particles. See, for example, York(1975) J. Pharm. Sci-, 64(7>, 1216-1221.

Silicon dioxide is a preferred glidant. Suitable Silicon dioxide products for usein preparing compositions of the invention include fumed silica or colloïdal silica(e.g., Cab-O-Sil™ of Cabot Coip. and Aerosil™ of Degussa). Silicon dioxide, whenprésent in compositions of the invention, is présent in a total amount of about 0.05%to about 5%, preferably about 0.1 % to about 2%, and more preferably about 0.25% toabout 1 %, for example, about 0.5%, by weight of the composition.

Sweetening agents

Compositions of the présent invention optionally comprise one or morepharmaceutically acceptable sweeteners. Non-limiting examples of sweeteners thatcan be used in compositions of the présent invention include mannitol, propyleneglycol, sodium saccharin, ace&ulfame K, neotame, aspartame, etc.

Flavoring agents

Compositions of the présent invention optionally comprise one or morepharmaceutically acceptable flavoring agents. Non-limiting examples of flavoringagents that can be used in compositions of the présent invention include peppermint,spearmint, grape, cherry, strawberry, lemon, etc.

Tablet characteristics 012666 13

Size and shape

In a preferred embodiment, compositions of the invention are in the form ofdiscrète solid dosage units, most preferably tablets. Tablets of the invention can bemade to any desired size, for example 8 mm, 10 mm, 12 mm, etc.', shape, for exampleround, oval, oblong, etc.', weight; and thickness. Optionally, solid dosage units of theinvention may hâve etchings or monograms on one or both sides.

Disintegration

Preferred tablet compositions of the invention disintegrate in less than 300seconds, preferably less than about 200 seconds, and more preferably less than about100 seconds, for example about 30 seconds after placement in a standard in vitrodisintegration assay (e.g., conducted according to U.S. Pharmacopeia 24 (2000), TestNo. 701).

Altematively or additionally, preferred fast-melt compositions of the inventiondisintegrate within about 60 seconds, preferably within about 30 seconds, and morepreferably within about 15 seconds after placement in the oral cavity of a subject.

Hardness

Solid dosage forms of the invention hâve a hardness that can dépend on sizeand shape as well as on composition, among other characteristics. Tablet hardnesscan be measured by any method known in the art, for example by a tablet hardnessmeter (e.g., Schleuniger). Preferably, compositions of the invention hâve a hardnessof about 1 to about 10 kp, and more preferably of about 1 to about 6 kp.

In a presently preferred embodiment, solid dosage forms of the invention hâvesufficient hardness for handling and, therefore, can be put into practical use in thesame manner as the case of ordinary tablets. The term “sufficient hardness forhandling” as used herein means a hardness which can withstand removal from at leasta standard type ofblister packaging, or such a hardness as will withstand otherhandling such as packaging, delivery, carrying and the like.

Tablets of the invention preferably hâve a minimum hardness so as to resistbreakage of the tablet during removal from standard blister packaging by pushing thetablet through a cover sheet. A suitable hardness is about 1 kp or more for a tablethaving a diameter of about 8 mm, about 1.5 kp or more for a tablet having a diameterof about 10 mm, and about 2 kp or more when the tablet has a diameter of about 012666 14 12nun.

In another presently prefeired embodiment, tablets of the invention hâvesufficient hardness such that a plurality of such tablets can be packaged together, forexample in a glass or plastic bottle, without individual packaging, yet do not exhibitsubstantial breakage or sticking and/or melding together during normal shipping andhandling. Tablets intended for such packaging preferably hâve a hardness of about3 kp or more.

Packaging

Compositions of the invention can be packaged in any suitable manner knownin the art. For example, a multiplicity of fast-melt tablets can be packaged together,for example in a glass or plastic bottle or container. Altematively, fast-melt tablets ofthe invention can be individually wrapped, for example in plastic or foil, or packagedin known forms of blister packaging. Blister packaging with improved forcedistribution properties such as is disclosed in U.S. Patent No. 5,954,204 to Grabowski,incorporated herein by reference, can be especially useful to package fast-melt tabletsof the invention.

Administration of fast-melt tablets

Compositions of the présent invention can be taken by a subject by any oraladministration means in accordance with the subject’s choice or condition. Forexample, fast-melt tablets of the invention can be taken without water. Uponplacement in the oral cavity and especially in the cheek or above the tongue, such atablet is exposed to saliva and rapidly disintegrates and dissolves therein. The rate ofdisintegration and/or dissolution increases fiirther when an intraoral pressure, forexample a pressure between the palate and tongue or a licking or sucking pressure, isapplied to the tablet.

Altematively, a tablet of the présent invention can be taken with the aid ofwater in an amount sufficient to wet the oral cavity and to assist in disintegration ofthe tablet. Also, a tablet of the invention can be swallowed together with a smallamount of water after complété or partial disintegration in the oral cavity.

Compositions of the invention can also be swallowed directly with water. 012666 15

Method to make fast-melt tablets

The process described below is a non-limiting, illustrative method to makevaldecoxib fast-melt tablets of the invention. Importantly, spécifie settings andparameters of the production process can be readily optimized by one of skill in the artin order to produce tablets with particularly desired characteristics.

In this illustrative process, maltose and mannitol are dissolved in a vessel ofwater which is heated to approximately 50 °C to about 80 °C, for example about 70°C. Valdecoxib is then dispersed in the vessel using a homogenizer. A wetting agent,for example sodium lauryl sulfate, is dissolved in a second vessel of water. Thecontents of the first and second vessels are then combined to form a mixture. Themixture is spray dried using a Niro Laboratory Mobile Minor Spray Dryer to form adry granulation. The dry granulation is then optionally blended with any desiredexcipients, for example flavorants, sweeteners and lubricants, to form a tabletingblend. The resulting tableting blend is then compressed on a rotary tablet press to atarget tablet weight and hardness. The resulting tablets are then subjected totreatment, for example air flow treatment, in a humidity-controlled chamber with the

Tablet compression

Compression is the process by which an appropriate volume of a tabletingblend of granules produced as described above is compressed between an upper andlower punch to consolidate material into a single solid dosage form such as a tablet.

In processes for manufacture of fast-melt tablets of the présent invention, any suitablemeans for compression can be used including, for example, a single punch tabletmachine or a high speed rotary tablet press. The tableting pressure is not limited, andan appropriate pressure can be selected depending on the desired hardness anddissolution properties of the resulting tablets. Where tablets are to undergotempérature and humidity treatment as described immediately below, the tablets arepreferably compressed to an initial hardness (prior to température and humiditytreatment) of about 0.75 to about 1.5 kp.

Température and humidity treatment

Optionally, tablets of the invention can undergo heat and humidity treatmentafter the tablet compression step. Such treatment can be performed in a humidity 012666 16 chamber, for example, to increase hardness of the tablets. Ulustratively, during thistreatment, tablets are first subjected to low température, high humidity air flowconditions, for example, about 25°C to about 32°C and about 80% relative humidity,for a period of about 45 to about 120 minutes. Tablets are then subjected to hightempérature, low humidity conditions, for example about 35°C to about 50°C and30% relative humidity for a period of about 45 to about 120 minutes. Without beingbound by theory, it is believed that treatment of fast-melt tablets in a lowtemperature/high humidity chamber followed by treatment in a high temperature/lowhumidity chamber increases tablet hardness and reduces tablet fnability withoutsacrificing desired fast-melt characteristics such as rapid désintégration and rapiddissolution.

Utility of compositions of the invention

Molded articles, herein also referred to as compositions, of the présent invention are useful in treatment and prévention of a very wide range of disordersmediated by cyclooxygenase-2 (COX-2), including but not restricted to disorderscharacterized by inflammation, pain and/or fever. Such compositions are especiallyuseful as anti-inflammatory agents, such as in treatment of arthritis, with theadditional benefit of having significantly less harmful side effects than compositionsof conventional nonsteroidal anti-inflammatory drugs (NSAIDs) that lack seleetivityfor COX-2 over COX-1. In particular, such compositions hâve reduced potential forgastrointestinal toxicity and gastrointestinal irritation including upper gastrointestinalulcération and bleeding, reduced potential for rénal side effects such as réduction inrénal function leading to fluid rétention and exacerbation of hypertension, reducedeffect on bleeding times including inhibition of platelet function, and possibly alessened ability to induce asthma attacks in aspirin-sensitive asthmatic subjects, bycomparison with compositions of conventional NSAIDs. Thus compositions of theinvention comprising a sélective COX-2 inhibitory drug are particularly useful as analternative to conventional NSAIDs where such NSAIDs are contraindicated, forexample in patients with peptic ulcers, gastritis, régional enteritis, ulcerative colitis,diverticulitis or with a récurrent history of gastrointestinal lésions; gastrointestinalbleeding, coagulation disorders including anémia such as hypoprothrombinemia,hemophilia or other bleeding problems; kidney disease; or in patients prior to surgery 012666 17 or patients taking anticoagulants.

Such compositions are useful to treat arthritic disorders, including but notlimited to rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis,systemic lupus erythematosus and juvénile arthritis. 5 Such compositions are also useful in treatment of asthma, bronchitis, menstrual cramps, preterm labor, tendinitis, bursitis, allergie neuritis, cytomégalovirusinfectivity, apoptosis including HTV-induced apoptosis, lumbago, liver diseaseincluding hepatitis, skin-related conditions such as psoriasis,, eczema, acné, bums,dermatitis and ultraviolet radiation damage including sunbum, and post-operative 10 inflammation including that following ophthalmic surgeiy such as cataract surgery orrefractive surgery.

Such compositions are useful to. treat gastrointestinal conditions such asinflammatory bowel disease, Crohn’s disease, gastritis, irritable bowel syndrome andulcerative colitis. 15 Such compositions are useful in treating inflammation in such diseases as migraine headaches, periarteritis nodosa, thyroiditis, aplastic anémia, Hodgkin’sdisease, sclerodoma, rheumatic fever, type I diabètes, neuromuscular junction diseaseincluding myasthenia gravis, white matter disease including multiple sclerosis,sarcoidosis, nephrotic syndrome, Behcet’s syndrome, polymyositis, gingivitis, 20 nephritis, hypersensitivity, swelling occurring after injury including brain edema,myocardial ischemia, and the like.

Such compositions are useful in treatment of ophthalmic diseases, such asretinitis, scleritis, episcleritis, conjunctivitis, rétinopathies, uveitis, ocularphotophobia, and of acute injury to eye tissue. 25 Such compositions are useful in treatment of pulmonary inflammation, such as that associated with viral infections and cystic fibrosis, and in bone résorption such asthat associated with osteoporosis.

Such compositions are useful for treatment of certain central nervous Systemdisorders, such as cortical dementias including Alzheimer’s disease, 30 neurodegeneration, and central nervous System damage resulting from stroke, ischemia and trauma. The term “treatment” in the présent context includes partial ortotal inhibition of dementias, including Alzheimer’s disease, vascular dementia, 012666 18 multi-infarct dementia, pre-senile dementia, alcoholic dementia and senile dementia.Such compositions are useful in treatment of allergie rhinitis, respiratory distress syndrome, endotoxin shock syndrome and liver disease.

Such compositions are useful in treatment of pain, including but not limited to 5 postoperative pain, dental pain, muscular pain, and pain resulting firom cancer. Forexample, such compositions are useful for relief of pain, fever and inflammation in avariety of conditions including rheumatic fever, influenza and other viral infectionsincluding common cold, low back and neck pain, dysménorrhée, headache, toothache,sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid 10 arthritis, degenerative joint diseases (osteoarthritis), goût and ankylosing spondylitis, bursitis, bums, and trauma following surgical and dental procedures.

Such compositions are useful for, but not limited to, treating and preventinginflammation-related cardiovascular disorders in a subject. Such compositions areuseful for treatment and prévention of vascular diseases, coronary artery disease, 15 aneurysm, vascular rejection, arteriosclerosis, atherosclerosis including cardiactransplant atherosclerosis, myocardial infarction, embolism, stroke, thrombosisincluding venous thrombosis, angina including unstable angina, coronary plaqueinflammation, bacterial-induced inflammation including Chlamydia-inducedinflammation, viral induced inflammation, and inflammation associated with surgical 20 procedures such as vascular grafting including coronary artery bypass surgery, revascularization procedures including angioplasty, stent placement, endarterectomy,or other invasive procedures involving arteries, veins and capillaries.

Such compositions are useful for, but not limited to, treatment ofangiogenesis-related disorders in a subject, for example to inhibit tumor angiogenesis. 25 Such compositions are useful for treatment of neoplasia, including metastasis; ophthalmological conditions such as comeal graft rejection, ocular neovascularization,retinal neovascularization including neovascularization following injury or infection,diabetic retinopathy, macular degeneration, retrolental fîbroplasia and glaucoma,including neovascular glaucoma; ulcerative diseases such as gastric ulcer; 30 pathological, but non-malignant, conditions such as hemangiomas, including infantilehemangiomas, angiofibroma of the nasopharynx and avascular necrosis of bone; anddisorders of the female reproductive System such as endometriosis. 012666 19

Such compositions are useful for prévention or treatment of benign andmalignant tumors/neoplasia including cancers, for example colorectal cancer, braincancer, bone cancer, épithélial cell-derived neoplasia (épithélial carcinoma) such asbasal cell carcinoma, adenocarcinoma, gastrointestinal cancer such as lip cancer,mouth cancer, esophageal cancer, small bowel cancer, stomach cancer, colon cancer,liver cancer, bladder cancer, pancréas cancer, ovary cancer, cervical cancer, lungcancer, breast cancer and skin cancer, such as squamous cell and basal cell cancers,prostate cancer, rénal cell carcinoma, and other known cancers that affect épithélialcells throughout the body. Neoplasias for treatment of which compositions of theinvention are contemplated to be particularly useful are gastrointestinal cancer,Barrett’s esophagus, liver cancer, bladder cancer, pancréas cancer, ovary cancer,prostate cancer, cervical cancer, lung cancer, breast cancer and skin cancer, such assquamous cell and basal cell cancers. Compositions of the invention can also be usedto treat fîbrosis that occurs with radiation therapy. Such compositions can be used totreat subjects having adenomatous polyps, including those with familial adenomatouspolyposis (FAP). Additionally, such compositions can be used to prevent polyps fromforming in patients at risk of FAP.

Such compositions inhibit prostanoid-induced smooth muscle contraction bypreventing synthesis of contractile prostanoids and hence can be of use in treatment ofdysmenorrhea, prématuré labor, asthma and eosinophil-related disorders. They alsocan be of use for decreasing bone loss particularly in postmenopausal women (i.e.,treatment of osteoporosis), and for treatment of glaucoma.

Preferred uses for compositions of the présent invention are for treatment ofrheumatoid arthritis and osteoarthritis, for pain management generally (particularlypost-oral surgery pain, post-general surgery pain, post-orthopedic surgery pain, andacute flares of osteoarthritis), for treatment of Alzheimer’s disease, and for coloncancer chemoprevention.

Besides being useful for human treatment, compositions of the invention arealso useful for veterinary treatment of companion animais, exotic animais, fannanimais, and the like, particularly mammals including rodents. More particularly,compositions of the invention are useful for veterinary treatment of cyclooxygenase-2mediated disorders in horses, dogs and cats. 012666 20

The présent invention also is directed to a therapeutic method of treating acondition or disorder where treatment with a cyclooxygenase-2 inhibitoiy drug isindicated, the method comprising oral administration of one or more compositions ofthe présent invention to a patient in need thereof. The dosage regimen to prevent, giverelief ffom, or ameliorate the condition or disorder preferably corresponds to once-a-day or twice-a-day treatment, but can be modified in accordance with a variety offactors. These include the type, âge, weight, sex, diet and medical condition of thepatient and the nature and severity of the disorder. Thus, the dosage regimen actuallyemployed can vary widely and can therefore deviate ffom the preferred dosageregimens set forth above.

Initial treatment of a patient suffering from a condition or disorder wheretreatment with a cyclooxygenase-2 inhibitory drug is indicated can begin with a doseregimen as indicated above. Treatment is generally continued as necessary over aperiod of several weeks to several months or years until the condition or disorder hasbeen controlled or eliminated. Patients undergoing treatment with a composition ofthe invention can be routinely monitored by any of the methods well known in the artto détermine the effectiveness of therapy. Continuous analysis of data from suchmonitoring permits modification of the treatment regimen during therapy so thatoptimally effective amounts of the drug are administered at any point in time, and sothat the duration of treatment can be determined. In this way, the treatment regimenand dosing schedule can be rationally modified over the course of therapy so that thelowest amount of the drug exhibiting satisfactory effectiveness is administered, and sothat administration is continued only for so long as is necessary to successfully treatthe condition or disorder.

The présent compositions can be used in combination thérapies with opioidsand other analgésies, including narcotic analgésies, Mu receptor antagoniste, Kappareceptor antagonists, non-narcotic (i.e. non-addictive) analgésies, monamine uptakeinhibitors, adenosine regulating agents, cannabinoid dérivatives, Substance Pantagonists, neurokinin-1 receptor antagonists and sodium channel blockers, amongothers. Preferred combination thérapies comprise use of a composition of theinvention with one or more compounds selected from aceclofenac, acemetacin,e-acetamidocaproic acid, acetaminophen, acetaminosalol, acetanilide, acetylsalicylic 012666 21 acid (aspirin), 5-adenosylmethionine, alclofenac, alfentanil, allylprodine,alminoprofen, aloxiprin, alphaprodine, aluminum bis(acetylsalicylate), amfenac,aminochlorthenoxazin, 3-amino-4-hydroxybutyric acid, 2-amino-4-picoline,aminopropylon, aminopyrine, amixetrine, ammonium salicylate, ampiroxicam,amtolmetin guacil, anileridine, antipyrine, antipyrine salicylate, antrafenine, apazone,bendazac, benorylate, benoxaprofen, benzpiperylon, benzydamine, benzylmorphine,bermoprofen, bezitramide, α-bisabolol, bromfenac.p-bromoacetanilide, 5-bromosalicylic acid acetate, bromosaligenin, bucetin, bucloxic acid, bucolome,bufexamac, bumadizon, buprenoiphine, butacetin, butibufen, butophanol, calciumacetylsalicylate, carbamazepine, carbiphene, caiprofen, carsalam, chlorobutanol,chlorthenoxazin, choline salicylate, cinchophen, cinmetacin, ciramadol, clidanac,clometacin, clonitazene, clonixin, clopirac, clove, codeine, codeine methyl bromide,codeine phosphate, codeine sulfate, cropropamide, crotethamide, desomoiphine,dexoxadrol, dextromoramide, dezocine, diampromide, diclofenac sodium,difenamizole, difenpiramide, diflunisàl, dihydrocodéine, dihydrocodeinone enolacetate, dihydromorphine, dihydroxyaluminum acetylsalicylate, dimenoxadol,dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, diprocetyl,dipyrone, ditazol, droxicam, emorfazone, enfenamic acid, epirizole, eptazocine,etersalate, ethenzamide, ethoheptazine, ethoxazene, ethylmethylthiambutene,ethylmorphine, etodolac, etofenamate, etonitazene, eugenol, felbinac, fenbufen,fenclozic acid, fendosal, fenoprofen, fentanyl, fentiazac, fepradinol, feprazone,floctafenine, flufenamic acid, flunoxaprofen, fluoresone, flupirtine, fluproquazone,flurbiprofen, fosfosal, gentisic acid, glafenine, glucametacin, glycol salicylate, _guaiazulene, hydrocodone, hydromorphone, hydroxypethidine, ibufenac, ibuprofen,ibuproxam, imidazole salicylate, indomethacin, indoprofen, isofezolac, isoladol,isomethadone, isonixin, isoxepac, isoxicam, ketobemidone, ketoprofen, ketorolac,p-lactophenetide, lefetamine, levorphanol, lofentanil, lonazolac, lomoxicam,loxoprofen, lysine acetylsalicylate, magnésium acetylsalicylate, meclofenamic acid,mefenamic acid, meperidine, meptazinol, mesalamine, metazocine, methadonehydrochloride, methotrimeprazine, metiazinic acid, metofoline, metopon,mofebut^zone, mofezolac, morazone, morphine, morphine hydrochloride, morphinesulfate, morpholine salicylate, myrophine, nabumetone, nalbuphine, 1-naphthyl 012666 22 salicylate, naproxen, narceine, nefopam, nicomorphine, nifenazone, niflumic acid,nimesulide, 5'-nitro-2'-propoxyacetanilide, norlevoiphanol, normethadone,normorphine, norpipanone, olsalazine, opium, oxaceprol, oxametacine, oxaprozin,oxycodone, oxymorphone, oxyphenbutazone, papaveretum, paranyline, parsalmide, 5 pentazocine, perisoxal, phenacetin, phenadoxone, phenazocine, phenazopyridinehydrochloride, phenocoll, phenoperidine, phenopyrazone, phenyl acetyl salicylate,phenylbutazone, phenyl salicylate, phenyramidol, piketoprofen, piminodine,pipebuzone, piperylone, piprofen, pirazolac, piritramide, piroxicam, pranoprofen,proglumetacin, proheptazine, promedol, propacetamol, propiram, propoxyphene, 10 propyphenazone, proquazone, protizinic acid, ramifenazone, remifentanil, rimazoliummetilsulfate, salacetamide, salicin, salicylamide, salicylamide o-acetic acid,salicylsulfuric acid, salsalte, salverine, simetride, sodium salicylate, sufentanil,sulfasalazine, sulindac, superoxide dismutase, suprofen, suxibuzone, talniflumate,tenidap, tenoxicam, terofenamate, tetrandrine, thiazolinobutazone, tiaprofenic acid, 15 tiaramide, tilidine, tinoridine, tolfenamic acid, tolmetin, tramadol, tropesin, viminol,xenbucin, ximoprofen, zaltoprofen and zomepirac (see The Merck Index, 12th Edition(1996), Therapeutic Categoiy and BioIogical.Activity Index, lists therein headed“Analgésie”, “Anti-inflammatory” and “Antipyretic”).

Particularly preferred combination thérapies comprise use of a composition of 20 the invention, for example valdecoxib composition of the invention, with an opioidcompound, more particularly where the opioid compound is codeine, meperidine,morphine or a dérivative thereof.

The compound to be administered in combination with valdecoxib can beformulated separately from the valdecoxib or co-formulated with the valdecoxib in a 25 composition of the invention. Where valdecoxib is co-formulated with a second drug,for example an opioid drug, the second drug can be formulated in immediate-release,rapid-onset, sustained-release or dual-release form.

In an embodiment of the invention, particularly where the cyclooxygenase-2mediated condition is headache or migraine, the valdecoxib composition is 30 administered in combination therapy with a vasomodulator, preferably a xanthine dérivative having vasomodulatory effect, more preferably an alkylxanthine compound.

Combination thérapies wherein an alkylxanthine compound is co-administered 012666 23 with a valdecoxib composition as provided herein are embraced by the présentembodiment of the invention whether or not the alkylxanthine is a vasomodulator andwhether or not the therapeutic effectiveness of the combination is to any degreeattributable to a vasomodulatory effect. The term “alkylxanthine” herein embracesxanthine dérivatives having one or more C1.4 alkyl, preferably methyl, substituents,and pharmaceutically acceptable salts of such xanthine dérivatives.

Dimethylxanthines and trimethylxanthines, including caffeine, theobromine andtheophylline, are especially preferred. Most preferably, the alkylxanthine compoundis caffeine.

The total and relative dosage amounts of valdecoxib and of the vasomodulatoror alkylxanthine are selected to be therapeutically and/or prophylactically effective forrelief of pain associated with the headache or migraine. Suitable dosage amounts willdépend on the severity of pain and the particular vasomodulator or alkylxanthineselected. For example, in a combination therapy with valdecoxib and caffeine,typically the valdecoxib will be administered in a daily dosage amount of about 1 mgto about 100 mg, preferably about 5 mg to about 50 mg, and the caffeine in a dailydosage amount of about 1 mg to about 500 mg, preferably about 10 mg to about 400mg, more preferably about 20 mg to about 300 mg.

The vasomodulator or alkylxanthine component of the combination therapycan be administered in any suitable dosage form by any suitable route, preferablyorally. The vasomodulator or alkylxanthine can optionally be coformulated with thevaldecoxib in the molded article of the invention. Thus a molded article of theinvention optionally comprises both valdecoxib and a vasomodulator or alkylxanthinesuch as caffeine, in total and relative amounts consistent with the dosage amounts setout hereinabove.

The phrase “in total and relative amounts effective to relieve pain”, withrespect to amounts of valdecoxib and a vasomodulator or alkylxanthine in acomposition of the présent embodiment, means that these amounts are such that (a)together these components are effective to relieve pain, and (b) each component is orwould be capable of contribution to a pain-relieving effect if the other component is orwere not présent in so great an amount as to obviate such contribution. 012666

J 24

EXAMPLES

The following examples illustrate aspects of the présent invention but shouldnot be construed as limitations. Ëxample 1

Valdecoxib Fast-Melt Tablets (Batch A, hereinafter also referred to as Fast-Melt A) were prepared according to the following procedure. Maltose (28.03 g) andmannitol (367.6 g) were dissolved in water in a fîrst vessel with heat (70 °C) andstining. Valdecoxib (46.25 g) was dispersed in the maltose/mannitol solution andhomogenized for ten minutes using a Silverson homogenizer. Sodium lauryl sulfate(SLS) was dissolved in water in a second vessel with gentle agitation to form awetting agent solution. The wetting agent solution was added to the first vessel toform a sprayable solution. The sprayable solution was spray dried to form a drygranulation using a Niro Laboratoiy Mobile Minor Spray Dryer under the followingconditions: spray rate: 32 g/min; inletprocess gas flow: 2.8 mbar; System pressure: 1.6mbar; inlet process gas pressure 20 mbar, atomization pressure 1.6 bar; percentatomization flow: 57; inlet température: 160 °C; outlet température: about 55 °C;atomization air heater température: 287 °C.

Magnésium stéarate (1 g), stearic acid (3 g), acesulfame K (1 g) andpeppermint flavor (1 g) were added to a polyethylene bag and vigorously shaken toform a mixture. The mixture was then geometrically diluted with the dry granulationprepared above until 200 g of dry granulation had been added. Tablets were thenprepared by individually compressing 400 mg of the tableting blend to form tabletshaving an intermediate hardness of 1.5 kp. Resulting tablets were placed in a chambermaintained at 25 °C and 80% relative humidity for 1 hour, and at 40 °C and 30%relative humidity for a second hour. Composition (% weight) of Fast-Melt A is shownin Table 1. 012666 25

Table 1. Composition of Fast-Melt A

Component Aniount Valdecoxib 10 Maltose 6.06 Mannitol 79.48 SLS 1.45 Magnésium stéarate 0.5 Stearic acid 1.5 Acesulfame K 0.5 Peppermint 0.5

Example 2 A study was performed in order to détermine pharmacokinetic properties ofthe Valdecoxib Fast-Melt A in beagle dogs. Valdecoxib Fast-Melt A was individually 5 administered to each of 4 dogs. Venous blood was collected pre-dose, and at 0.5,1,1.5,2,2.5,3,4,6, 8,12 and 24 hours after oral dose administration. Plasma wasseparated from blood by centrifugation at 3000 G and samples were stored at -20°Cuntil analysis. Concentrations of valdecoxib in plasma were determined using anHPLC assay. Results are shown in Table 2. 10 Table 2 Pharmacokinetic properties of Valdecoxib Fast-Melt A in Dogs

Parameter Fast-Melt A Cmax (ng/ml) 8800 AUC (h*ng/ml) 2710 Tjjiax (h) 1.4

Example 3

Valdecoxib Fast-Melt Tablets (Batch B, hereinafter also referred to as Fast-Melt B) were prepared according to the following procedure. Maltose (0.158 kg) and 15 mannitol (2.047 kg) were dissolved in water (14.167 kg) with mixing to form a solution. Sodium lauryl sulfate (0.037 kg) was added to the solution with mixing untildissolved. Valdecoxib (0.258 kg) was dispersed in the solution and homogenized atapproximately 5000 RPM for 15 minutes using a Silverson homogenizer to form aslurry. The slurry was then mixed with a conventional marine-type impeller at 20 approximately 300 RPM for approximately 2 hours. The slurry was spray dried toform a dry granulation using a Niro Laboratory Mobile Minor Spray Dryer under the 012666 26 following conditions: spray rate: 30 g/min; inlet process gas flow: 40 mm HfeO;chamber pressure: -100 mm HfeO; fluid spray atomization pressure 1.0 bar; percentatomization flow: 70; inlet air température: 175 °C; outlet air température: about 90°C. The total theoretical yield was 2.500 Kg. The above procedure was performed in 5 duplicate to resuit in spray dried granulation Lot A (1414.3 g) and Lot B (1971.9 g).Spray dried granulation Lot A and Lot B were and sieved and the sieved granulations were dry blended with peppermint flavor (17.5 g) and acesulfame K(17.5 g) in a V-blender for 15 minutes to form a mixture. Magnésium stéarate (17.5 g), micronized stearic acid (52.5 g) and colloïdal Silicon dioxide (8.8 g) were added to 10 the mixture with additional mixing to form a tableting blend. Tablets were compressed from the tableting blend to a target hardness of 1.5 Kp and a target tabletweight of 391.58 mg. After compression, tablets were transferred to an IBC humiditytreatment chamber (17 liter) maintained at 25 °C, 80% relative humidity and 75 CFMair flow for 1 hour, and at 40 °C, 30% relative humidity and 75 CFM air flow for a 15 second hour. Composition of Fast-Melt B (mg/tablet) is shown in Table 3.

Table 3. Composition of Fast-Melt B.

Component Amount (mg) Granulation Lot A 158.22 Granulation Lot B 220.61 Magnésium stéarate NF 1.96 Stearic acid NF (micronized) 5.87 Colloïdal Silicon dioxide 1.00 Acesulfame K 1.96 Peppermint 1.96 Total 391.58

Example 4

In vitro dissolution profiles of Fast-Melt B of Example 3 and a commercial 4020 mg Bextra® tablet were determined using 1000 ml of 1% sodium lauryl sulfate solution and USP Type Π Apparatus. Data are shown in Table 4. Fast-melt Bexhibited very rapid dissolution with ail of the valdecoxib being dissolved by 15minutes in the assay.

Table 4. Amount (% weight) of valdecoxib dissolved

Time (min)

Fast-Melt B

Bextra® Tablet 012666 27 15 101 62 30 101 79 45 100 88 60 101 93 Ëxample 5

Fast-Melt B of Example 3 was individually administered to 25 humansubjects. Oral bioavailability parameters were determined and compared with those of 5 a 40 mg commercial Bextra® tablet. Data are shown in Table 5.

Table 5. Oral bioavailability of Fast-Melt B and a 40 mg

Bextra® tablet in human subjects

Parameter Fast-MeltB Bextra® tablet Tmax(hr) 3.22 3.3 Cmax (ng/ml) 580 468 AUC (ng/ml)/hr 6833 6126

These data indicate that Fast-Melt B exhibits very good bioavailability propertiesupon administration to human subjects. 10 Example 6

Fast-Melt B of Example 3 was evaluated in a taste study according to thefollowing procedure. Four to five professional sensory panelists were selected andeach panelist was given a Fast-Melt tablet to place on his/her tongue. The panelistgently rolled the tablet against the roof of his/her mouth without chewing, and 15 simultaneously recorded sensory information and time to complété désintégration.Sensory information included organoleptic attributes associated with each tablet suchas flavor quality, bittemess, fullness, texture, mouth feel and aftertaste. Each of theseattributes were defined along a categorical unit scale of 1 - 5 to express perceptualdifférences from other commercially marketed melt products, by comparison with 20 comparator valdecoxib fast-melt tablets which comprised one of cherry, strawberry,orange, peppermint, or spearmint flavor, and by comparison with fast-melt tabletscomprising different active ingrédients.

After total désintégration of a tablet, the panelist recorded sensory aftertasteover a period of 30 minutes. Each tablet was evaluated in triplicate and ail samples 25 were coded for présentation to panelists. Fast-Melt B exhibited an average 012666 28 disintegration time of 23.6 seconds. Overall, valdecoxib Fast-Melt B exhibitedacceptable flavor quality (data not shown) and disintegration time.

Claims (30)

1. 29 012666 WHATIS CLAIMED IS:

   1. An oral fast-melt composition comprising: (a) particulate valdecoxib in a therapeuticaHy effective amount, and (b) at least one pharmaceutically acceptable excipient which exhibits rapid 5 oral dissolution and which is in intimate association with the valdecoxib particles; wherein the at least one excipient which exhibits rapid oral dissolution is présentin a total amount of about 50% to about 99%, by weight.
2. 2. The composition of Claim 1 wherein the at least one pharmaceutically acceptable 10 excipient which exhibits rapid oral dissolution is a carbohydrate.
3. 3. The composition of Claim 1 wherein the at least one pharmaceuticallyacceptable excipient which exhibits rapid oral dissolution is a saccharide.
4. 4. The composition of Claim 1 wherein the at least one pharmaceuticallyacceptable excipient which exhibits rapid oral dissolution is selected firom the 15 group consisting of maltose, maltitol, sorbitol, lactose and mannitol.
5. 5. The composition of Claim 1 wherein the at least one excipient which exhibitsrapid oral dissolution is présent in a total amount of about 50% to about 90%, byweight.
6. 6. The composition of Claim 1 wherein the at least one pharmaceutically 20 acceptable excipient which exhibits rapid oral dissolution comprises a saccharide of high moldability and a saccharide of low moldability.
7. 7. The composition of Claim 6 wherein the weight ratio of saccharide of highmoldability to saccharide of low moldability is about 2 to about 20 parts ofsaccharide of high moldability per 100 parts of saccharide of low moldability.
8. 8. The composition of Claim 6 wherein the weight ratio of saccharide of high moldability to saccharide of low moldability is about 5 to about 7.5 parts ofsaccharide of high moldability per 100 parts of saccharide of low moldability.
9. 9. The composition of Claim 1 having a hardness of about 1 to about 10 kp.
10. 10. The composition of Claim 1 wherein the valdecoxib is présent in an amount of 30 about 5 to about 50 mg.
11. 11. The composition of Claim 1 which, when placed in United States Pharmacopeia24 in vitro disintegration Test Number 701, exhibits a disintegration time of less * 012666 30 than about 300 seconds.
12. 12. The composition of Claim 1 which, when placed in United States Pharmacopeia24 in vitro disintegration Test Number 701, exhibits a disintegration time of lessthan about 100 seconds.
13. 13. The composition of Claim 1 which disintegrates within about 60 seconds afterplacement in the oral cavity of a human subject.
14. 14. The composition of Claim 1 which disintegrates within about 30 seconds afterplacement in the oral cavity of a human subject.
15. 15. The composition of Claim 1 which is organoleptically acceptable.
16. 16. A process for preparing an intraorally disintegrating valdecoxib tabletcomposition, the process comprising: a step of providing valdecoxib in particulate form; a step of dissolving at least one pharmaceutically acceptable excipient whichexhibits rapid oral dissolution in water in a vessel, said at least oneexcipient being dissolved in a total amount such that upon completion ofthe process the excipient comprises about 50% to about 99% of the totaltablet weight; a step of dispersing the valdecoxib in the water;wherein said dissolving and dispersing steps are performed in any order orsimultaneously to resuit in a sprayable liquid; a step of spray drying the sprayable liquid to form a tableting blend; anda step of compressing the tableting blend to form a tablet.
17. 17. The process of Claim 16 further comprising a step of heating the vessel of waterprior to, simultaneously with or after said dissolving and/or dispersing steps, butprior to said spray drying step.
18. 18. The process of Claim 16 further comprising a step of dissolving a wetting agentin the water prior to, simultaneously with, or after said dispersing and/ordissolving steps, but prior to said spray drying step.
19. 19. The process of Claim 16 further comprising a step of dissolving an aqueoussolution of a wetting agent in the water prior to, simultaneously with, or aftersaid dispersing and/or dissolving steps, but prior to said spray drying step.
20. 20. The process of Claim 16 wherein the at least one pharmaceutically acceptable si 012666 excipient which exhibits rapid oral dissolution is a carbohydrate.
21. 21. The process of Claim 16 wherein the at least one phannaceutically acceptableexcipient which exhibits rapid oral dissolution is a saccharide.
22. 22. The process of Claim 16 wherein the at least one phannaceutically acceptableexcipient which exhibits rapid oral dissolution is selected from the groupconsisting of maltose, maltitol, sorbitol, lactose and mannitol.
23. 23. The process of Claim 16 wherein the at least one excipient which exhibits rapidoral dissolution is dissolved in a total amount such that upon completion of theprocess the excipient comprises about 50% to about 95% of the total tabletweight.
24. 24. The process of Claim 16 wherein the at least one excipient which exhibits rapidoral dissolution is dissolved in a total amount such that upon completion of theprocess the excipient comprises about 50% to about 90% of the total tabletweight.
25. 25. The process of Claim 16 wherein the at least one phannaceutically acceptableexcipient which exhibits rapid oral dissolution comprises a saccharide of highmoldability and a saccharide of low moldability.
26. 26. The process of Claim 25 wherein the weight ratio of saccharide of highmoldability to saccharide of low moldability is about 2 to about 20 parts ofsaccharide of high moldability per 100 parts of saccharide of low moldability.
27. 27. The process of Claim 25 wherein the weight ratio of saccharide of highmoldability to saccharide of low moldability is about 5 to about 7.5 parts ofsaccharide of high moldability per 100 parts of saccharide of low moldability.
28. 28. An intraorally disintegrating valdecoxib tablet composition prepared by theprocess Claim 16.
29. 29. Use of a composition of Claim 1 in the manufacture of a médicament for treatingor preventing a medical condition or disorder in a subject where treatment with acyclooxygenase-2 inhibitoiy drug is indicated.
30. 30. Use of a composition of Claim 28 in the manufacture of a médicament for treatingor preventing a medical condition or disorder in a subject where treatment with acyclooxygenase-2 inhibitory drug is indicated.