HRP20040331A2 - Intraorally disintegrating valdecoxib compositions prepared by spray drying process - Google Patents

Description

Field of invention

This invention relates to pharmaceutical preparations that break down intraorally and which contain valdecoxib as an active substance, to methods of preparing such preparations and to methods of treating disorders mediated by cyclooxygenase-2 consisting of administering such preparations to a subject.

Background of the invention

The compound 4-(5-methyl-3-phenyl-4-isoxazole)benzenesulfonamide, also referred to herein as valdecoxib, is described in U.S. Pat. Patent no. 5,633,272, Talley et al. and is incorporated herein by reference, along with procedures for preparing this and similar compounds. Valdecoxib has the structure:

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The compounds described in the above-cited U.S. Patent no. 5, 633, 272, including valdecoxib, are described as compounds that are useful anti-inflammatory, analgesic and antipyretic drugs with a high degree of selectivity for inhibiting cyclooxygenase-2 (COX-2) over cyclooxygenase-1 (COX-1). The above-cited U.S. Patent no. 5,633,272 also contains general references to compositions for the administration of such compounds, including orally available dosage forms such as tablets and capsules.

Valdecoxib is extremely poorly soluble in water. For an example, see Dionne (1999), "COX-2 Inhibitors - IBC Conference, April 12-13, 1999, Coronado, CA, U.S.A.", Idrugs, 2 (7), 664-666.

LOUSE. Patent no. 5,576,014, herein incorporated by reference, describes an orodispersible compressed mold prepared by a wet granulation process in which a low moldability saccharide is granulated with a high moldability saccharide to form a granulate, which is then compressed into a mold. The obtained mold can be incorporated into the medicine, and it is considered that it quickly decomposes and dissolves in the oral cavity, but also maintains the appropriate hardness and does not break during preparation and distribution. The compression mold of U.S. Patent No. 5,576,014 is a dosage form known as a "fast-dissolving tablet" which is rapidly disintegrating and usually associated with carriers, usually sugars, and which at the same time rapidly dissolves or disperses in the mouth, usually without the need for water other than that contained in saliva. The medicine that is formed into such a tablet is easily swallowed.

International Patent no. WO 01/41761 describes orally available preparations of valdecoxib which have fast-acting properties. None of the preparations described here have intraoral degradation properties.

A well-known problem with many orally disintegrating formulations, even those containing sugars and/or sweeteners and/or flavor enhancers, is that they are unpalatable due to the presence of the active drug. In general, the lower the amount of active drug present in a particular orally disintegrating dosage form and/or the lower the water solubility of the drug, the less bitter and/or sour the taste of the dosage form will be. For an example, see Lieberman et al. (1989), Pharmaceutical Dosage Forms: Tablets Vol. 1, p. 381, Marcel Dekker, New York. Valdecoxib, a drug with very low water solubility and relatively low dosage requirements, when formulated as an intraorally disintegrating formulation, is expected to have acceptable or at least moderately unpleasant organoleptic properties. Valdecoxib has a surprisingly very unpleasant taste. Therefore, it is necessary to prepare a preparation of valdecoxib that breaks down intraorally, and which has acceptable organoleptic properties.

During the preparation of pharmaceutical dosage forms, procedures for improving the taste were applied, which act by inhibiting the decomposition in the oral cavity of drugs that have a moderate or high solubility in water. For an example, see Lieberman et al. (1989), op. cit. In such cases, the improved taste is a consequence of reducing the amount of medicine that dissolves in the mouth, before entering the digestive system. Considering the already existing extremely low solubility of valdecoxib in water, however, it is not expected that further reduction of the solubility of valdecoxib in the mouth would improve the organoleptic properties of valdecoxib. It is to be expected that a further decrease in the solubility of valdecoxib in water would result in an unacceptable therapeutic effect. However, a process for the preparation of organoleptically acceptable preparations of valdecoxib, which break down intraorally and have a rapid therapeutic effect, has been discovered.

The essence of invention

In accordance with this, a procedure for the preparation of valdecoxib preparation that disintegrates intraorally (e.g. fast-dissolving tablet) is provided, which consists of several steps; the step of providing valdecoxib in the appropriate form; the step of dissolving at least one pharmaceutically acceptable excipient that dissolves rapidly in water; the step of dispersing valdecoxib in water and optionally the step of heating the water. The dissolving, dispersing, and optional heating steps are performed in any order or simultaneously to produce a liquid that can be used in a sprayer. The process additionally consists of spray drying to obtain a mixture for use in tablets and compressing the mixture into tablets. In the process of the present invention, at least one pharmaceutically acceptable excipient that has fast-dissolving properties in the mouth is dissolved in water in a total amount such that at the end of the process, at least one excipient that has fast-dissolving properties in the mouth constitutes from about 50% to about 90% , preferably from about 50% to about 95%, and most preferably from about 50% to about 90% by weight of the tablet.

The process optionally includes the additional step of adding a wetting agent or an aqueous solution of such wetting agent to the mixture prior to spray drying.

Preparations prepared by such a process are the basis of this invention.

Currently, there is an intraorally disintegrating composition consisting of (a) particulate valdecoxib in a therapeutically effective amount and (b) at least one pharmaceutically acceptable excipient that rapidly dissolves in the mouth and which is tightly bound to the valdecoxib particles. Such a preparation is organoleptically acceptable and at least one excipient is present that has properties of rapid dissolution in the mouth in a total amount of about 50% to about 99%, preferably from about 50% to about 95%, and most preferably from about 50% to about 90 % mass fraction of the preparation.

"Close association" in this context means, for example, valdecoxib that is mixed with an excipient that dissolves rapidly in the mouth, valdecoxib that is incorporated or incorporated into an excipient with rapid dissolution properties in the mouth, valdecoxib coats particles of an excipient that has rapid dissolution properties in the mouth by mouth or vice versa and a significantly homogeneous dispersion of valdecoxib in an excipient that has fast dissolving properties in the mouth.

Valdecoxib in close connection with the excipient that has fast dissolving properties in the mouth is also referred to in the text as "mixed valdecoxib". The term "substantially homogeneous" in relation to a mixture or a pharmaceutical mixture containing several components, implies that the ingredients are well mixed so that they are not present in separate layers and do not form concentration gradients in the preparation. It is believed that the relatively high proportion of excipients that have fast-dissolving properties in the mouth compared to valdecoxib in the methods and preparations of the present invention and/or the close association of valdecoxib with the excipients that have fast-dissolving properties in the mouth results in a valdecoxib mixture preparation that has improved organoleptic properties.

A particularly useful orally disintegrating mixture of the present invention is a dosage form that rapidly disintegrates intraorally and dissolves in the mouth without the need for water or other liquids (ie, a fast-dissolving form). The term "fast-dissolving" used in the text refers to a preparation, such as a tablet, in which the active ingredient or drug is distributed or dispersed in a carrier, which, after oral administration of the preparation to a subject, breaks down in the oral cavity, releasing the drug, usually in particulate form as a preparation for entering the digestive system by swallowing and then absorption. The term "oral cavity" includes the entire interior of the mouth, including not only the buccal cavity (the part of the oral cavity in front of the teeth and gums) but also the sublingual and supralingual spaces.

"Organoleptically acceptable" dosage forms or dosage forms having "organoleptically acceptable properties" are those which, upon intraoral interaction in an amount providing a unit dose of the therapeutic agent, do not have an extremely unpleasant taste, for example an extremely bitter taste, as experienced by most people or as determined by blind testing as described below.

The methods and compositions of the present invention overcome the objectionable organoleptic properties of valdecoxib without unacceptable sacrifice of rapid therapeutic efficacy. Therefore, with the significant progress of the profession, valdecoxib is presented as an organoleptically acceptable preparation that dissolves quickly. Special benefits of the preparations of this invention are improved organoleptic properties, acceptable therapeutic efficacy, and such preparations can be efficiently prepared by the procedures described here.

Detailed description of the invention

A particular embodiment of the present invention is a composition that rapidly dissolves in the mouth and contains (a) particulate valdecoxib in a therapeutically effective amount and (b) at least one pharmaceutically acceptable excipient that has rapid mouth-dissolving properties; in which the preparation is organoleptically acceptable. At least one pharmaceutically acceptable excipient that has fast dissolving properties in the mouth is in close association with the valdecoxib particles present in the preparation and is present in a total amount of from about 50% to about 99%, preferably from about 50% to about 95%, and most preferably from about 50% to about 90% of the mass fraction of the preparation.

A similar embodiment of the present invention provides a composition that disintegrates intraorally and which contains (a) particulate valdecoxib in a therapeutically effective amount and (b) at least one pharmaceutically acceptable excipient that has rapid dissolution properties in the mouth and which is in close association with the particles of said valdecoxib; in which the preparation is organoleptically acceptable; and wherein at least one pharmaceutically acceptable excipient having rapid mouth-dissolving properties is present in a total amount of from about 50% to about 99% by weight of the composition; and wherein the composition is degraded within 60 seconds, preferably within 30 seconds, and most preferably within 15 seconds after oral administration.

Another similar embodiment of the present invention provides an intraorally disintegrating composition containing (a) particulate valdecoxib in a therapeutically effective amount and (b) at least one pharmaceutically acceptable excipient that has fast-dissolving properties in the mouth and is in close association with the particles of said valdecoxib; in which the preparation is organoleptically acceptable; and wherein at least one pharmaceutically acceptable excipient having rapid mouth-dissolving properties is present in a total amount of from about 50% to about 99% by weight of the composition; and wherein the composition, when subjected to the United States Pharmacopeia 24 in vitro degradation test number 701, degrades in less than 300 seconds, preferably in less than 200 seconds, and most preferably in less than 100 seconds.

Another embodiment of the present invention provides an intraorally disintegrating composition containing (a) particulate valdecoxib in a therapeutically effective amount and (b) at least one pharmaceutically acceptable excipient that has fast-dissolving properties in the mouth and is in close association with said valdecoxib particles; in which the preparation is organoleptically acceptable; and wherein at least one pharmaceutically acceptable excipient having rapid mouth-dissolving properties is present in a total amount of from about 50% to about 99% by weight of the composition; and wherein administration of the composition to humans results in a threshold concentration of valdecoxib with a therapeutic effect within 0.5 h, preferably within 0.3 h of oral administration.

"Threshold concentration with therapeutic effect" means the minimum concentration of valdecoxib in the blood serum that ensures a therapeutic effect for the specific indication for which valdecoxib is used. Typically, this threshold concentration is 20 ng/ml, for example about 25 ng/ml to about 75 ng/ml.

It is understood that the amount of valdecoxib that effectively provides a threshold concentration with a therapeutic effect depends, among other things, on the body weight of the treated subject. If the subject is a child or a small animal (eg, a dog), for example, a relatively low therapeutically effective amount of valdecoxib in the range of about 1 mg to about 100 mg will provide blood serum concentrations that are consistent with the threshold concentrations and Cmax criteria. When the subject is an adult human or a large animal (for example a horse) the indicated serum levels of valdecoxib will require a higher dosage of valdecoxib. For an adult human, the appropriate amount of valdecoxib per dosage in a composition of the present invention, to provide the indicated blood serum concentration, is usually about 5 mg to about 40 mg.

A similar embodiment of the present invention provides a composition that disintegrates intraorally and which contains (a) particulate valdecoxib in a therapeutically effective amount and (b) at least one pharmaceutically acceptable excipient that has rapid dissolution properties in the mouth and which is in close association with the particles of said valdecoxib; in which the preparation is organoleptically acceptable; and wherein at least one pharmaceutically acceptable excipient having rapid mouth-dissolving properties is present in a total amount of from about 50% to about 99% by weight of the composition; and in which administration of the composition to humans results in a maximum concentration (Cmax) in blood serum that is not below 100 ng/ml.

Another similar embodiment of the invention provides a preparation that breaks down intraorally and which contains (a) particulate valdecoxib in a therapeutically effective amount and (b) at least one pharmaceutically acceptable excipient that has properties of rapid dissolution in the mouth and which is in close association with the particles of said valdecoxib; in which the preparation is organoleptically acceptable; and wherein at least one pharmaceutically acceptable excipient having rapid mouth-dissolving properties is present in a total amount of from about 50% to about 99% by weight of the composition; and in which administration of the preparation to humans achieves a maximum concentration in a time (Tmax) of no longer than 5 h, preferably no longer than 4 h and most preferably no longer than 3 h.

Ingredients of the preparations of this invention

The composition of the present invention contains valdecoxib as an active ingredient and at least one pharmaceutically acceptable excipient that has fast dissolving properties in the mouth. Optionally, the composition of this invention may contain one or more additional pharmaceutically acceptable excipients including, but not limited to, water-soluble lubricants, water-insoluble lubricants, disintegrants, glidants, sweeteners, flavor enhancers, colorants, etc. Such optional additional ingredients should be physically and chemically compatible with the other ingredients of the preparation and should not have a harmful effect on the recipient.

Valdecoxib

The methods and compositions of the invention are particularly suitable for valdecoxib as the active drug. Processes for the preparation of particulate valdecoxib are known, so to speak, as described, for example, in the above-cited U.S. Patent No. 5, 474, 995, which is incorporated herein by reference. It is significant that any solid form of valdecoxib, for example that described in International Patent Publication no. 98/0678, which is cited in the text as a reference, can be used in the methods and preparations of this invention.

A unit dose of valdecoxib of the present invention comprises valdecoxib in a therapeutically effective amount of from about 1 mg to about 100 mg, preferably from about 5 mg to about 50 mg. The compositions of the present invention contain valdecoxib in particulate form. Valdecoxib primary particles obtained by grinding or comminution or precipitation from solution may agglomerate to form secondary aggregated particles. The term "particle size" used in the text refers to the primary particle size, unless otherwise required. Particle size is considered to be an important parameter influencing the clinical efficacy of valdecoxib. Therefore, in one embodiment of the present invention, the valdecoxib dosage form has a valdecoxib particle size distribution such that the D90 particle size is less than about 75 μm. "D90 particle size" is defined herein as a particle size such that 90% of the mass fraction of the particles is less than that particle size.

Additionally or alternatively, valdecoxib particles in the dosage form of the present invention preferably have an average particle size of from about 1 μm to about 10 μm, and most preferably from about 5 μm to about 7 μm.

Excipients that break down quickly in the mouth

Suitable rapidly disintegrating excipients in the mouth are those pharmaceutically acceptable excipients which are soluble, freely soluble or very soluble in water, such as those described in Ansel et al. (1995) Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th edition, p. 228, Williams & Wilkins, Baltimore. Preferably, such excipients have a sweet taste. Carbohydrates are currently the most preferred class of excipients that dissolve rapidly in the mouth for use in the compositions and methods of this invention. Particularly preferred excipients that dissolve rapidly in the mouth are saccharides, including low and high moldability saccharides.

Currently preferred low moldability saccharides include lactose and mannitol, particularly mannitol in its indirectly compressed form or in powder form, as described by Kibbe (2000) Handbook of Pharmaceutical Excipients, 3rd ed., Pharmaceutical Press, p. 324-328. Currently preferred high moldability saccharides include maltose, maltitol and sorbitol. In addition, certain oligosaccharides can be used. The oligosaccharide used is not predetermined as long as it has properties of rapid dissolution in the oral cavity and consists of two or more monosaccharide residues. When oligosaccharides are used, those having from 2 to 6 monosaccharide residues are preferred, while the type and combinations of monosaccharide residues that make up the oligosaccharide are not predetermined. Particularly preferred saccharides with high moldability are maltose and maltitol, especially maltose.

When both high and low moldable saccharides are present in the composition of this invention, the mass fraction of high moldable saccharide to low moldable saccharide is important in maintaining a favorable combination of acceptable tablet hardness and rapid intraoral disintegration. A suitable ratio is from about 2 to about 20 weight units, preferably from about 5 to about 10 weight units, and most preferably from about 5 to about 7.5 weight units of high moldability saccharide to 100 weight units of low moldability saccharide.

If the ratio of high to low moldable saccharides is less than about 2:100 by weight, the tablets typically lack adequate hardness resulting in increased breakage during storage, transportation, or handling. If the ratio of saccharides with high to saccharides with low moldability is above 20:100 by weight, the tablets are too hard and the desired rapid decomposition in the oral cavity is not achieved.

One or more excipients that rapidly dissolve in the mouth are typically present in the compositions of this invention in a total amount of from about 45% to about 95%, preferably from about 50% to about 87%, and most preferably from about 55% to about 80%.

Wetting agents

The compositions of this invention contain one or more pharmaceutically acceptable wetting agents. Surfactants, hydrophilic polymers and certain clays can be useful agents for wetting a hydrophobic drug such as valdecoxib during the spray drying granulation process.

Non-limiting examples of surfactants that can be used as wetting agents in the compositions of this invention include quaternary ammonium compounds, for example benzalkonium chloride, benzethonium chloride and cetylpyridinium chloride, dioctyl sodium sulfosuccinate, polyoxyethylene alkylphenyl ethers, for example nonoxynol 9, nonoxynol 10 and octoxynol 9, poloxamers (polyoxyethylene and polyoxypropylene block copolymers), polyoxyethylene glycerides and fatty acid oils, for example polyoxyethylene (8) caprylic/capric mono- and diglycerides (eg LabrasolTM manufactured by Gattefossé), polyoxyethylene (35) castor oil and polyoxyethylene (40) hydrogenated oil castor oil; polyoxyethylene alkyl ethers, for example polyoxyethylene (20) cetostearyl ether, polyoxyethylene fatty acid esters, for example polyoxyethylene (40) stearate, polyoxyethylene sorbitan esters, for example polysorbate 20 and polysorbate 80 (eg TweenTM 80 manufactured by ICI), propylene glycol fatty esters acids, for example propylene glycol laurate (e.g. LauroglikolTM manufactured by Gattefossé), sodium lauryl sulfate, their fatty acids and salts, for example oleic acid, sodium oleate and triethanolamine oleate, glyceryl fatty acid esters, for example glyceryl monostearate, sorbitan esters, example sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate and sorbitan monostearate, tyloxapol and their mixtures. Sodium lauryl sulfate is the preferred wetting agent in the compositions of this invention.

One or more wetting agents are optionally present in the compositions of this invention in a total amount of about 0.05% to about 5%, preferably about 0.075% to about 2.5%, and most preferably about 0.25% to about 1%. , for example 0.5% of the composition by mass.

Lubricants insoluble in water

The compositions of this invention optionally contain one or more pharmaceutically acceptable water-insoluble lubricants as carriers. Suitable water-insoluble lubricants include, either singly or in combination, glyceryl behapate (eg, CompritolTM 888), stearates (magnesium, calcium and sodium), stearic acid, hydrogenated vegetable oils (eg, SterotexTM), colloidal silica, powder, waxes and their mixtures. Optionally, a water-insoluble lubricant can be used in a mixture with a wetting agent, such as calcium stearate/sodium lauryl sulfate mixtures (eg SterowetTM).

Magnesium stearate, stearic acid and mixtures thereof are preferred water insoluble lubricants.

One or more water-insoluble lubricants are optionally present in the compositions of this invention in a typical total amount of about 0.05% to about 5%, preferably about 0.75% to about 2.5%, and most preferably about 1 % to about 2%, for example about 1.5% of the composition by mass.

Water-soluble lubricants

The compositions of this invention optionally contain one or more pharmaceutically acceptable water-soluble lubricants. Water-soluble lubricants can help improve tablet solubility. Water-soluble lubricants that can be used singly or in combination in the compositions of this invention include, for example, boric acid, sodium benzoate, sodium acetate, sodium fumarate, sodium chloride, DL-leucine, polyethylene glycols (eg, CarbowaxTM 4000 and CarbowaxTM 6000 ) and sodium oleate.

Decomposing agents

The compositions of this invention optionally contain one or more pharmaceutically acceptable disintegrants. However, the fast-dissolving tablets described in the text usually disintegrate quickly in the oral cavity, and there is no need for an additional disintegrant. Suitable disintegrants include, singly or in combination, starches, sodium starch glycolate, clays (such as VeegumTM HV), celluloses (such as purified cellulose, methylcellulose, sodium carboxymethylcellulose and carboxymethylcellulose), croscarmellose sodium, alginates, pregelatinized corn starch (such as NationalTM 1551 and NationalTM 1550), crospovidone, and resins (such as agar, guar gum, carob, caraya gum, pectin, and tragacanth gum). The disintegrants may be added at any suitable step during the preparation of the composition, particularly before granulation or during mixing prior to tablet compression. Croscarmellose sodium and sodium starch glycolate are preferred disintegrants.

Means of skating

The compositions of this invention optionally contain one or more pharmaceutically acceptable glidants, for example to improve the flow of the tablet material into the tablet inks, to prevent sticking of the tablet material to punches and inks, or to create tablet gloss. The glidants may be added at any suitable step during the preparation of the compositions, particularly prior to granulation during the mixing period preceding tablet compression.

In some cases, glidants, for example powder or silica, are thought to act to reduce the surface tension between drug particles, inhibiting and/or reducing drug agglomeration, and to act to reduce electrostatic charges on the surface of the powdered drug and act to reduce interparticle friction and surface roughness of drug particles. For an example, see York (1975) J. Pharm. Sci. 64 (7), 1216-1221.

The preferred glidant is silicon dioxide. Suitable silica products for use in the preparation of the compositions of this invention include fumed silica or colloidal silica (eg, Cab-O-Sil™ manufactured by Cabot Corp. and Aerosil™ manufactured by Degussa). Silicon dioxide is present in the compositions of the invention in a total amount of about 0.05% to about 5%, preferably about 0.1% to about 2% and most preferably about 0.25% to about 1%, for example about 0.5% mass fraction of the preparation.

Sweetening agents

The compositions of this invention optionally contain one or more pharmaceutically acceptable sweetening agents. Non-limiting examples of sweeteners that can be used in the compositions of this invention include mannitol, propylene glycol, sodium saccharin, acesulfame K, neotame, aspartame, etc.

Means for improving taste

The compositions of this invention optionally contain one or more pharmaceutically acceptable flavor enhancers. Non-limiting examples of flavor enhancers that can be used in the compositions of this invention include peppermint, spearmint, grapefruit, cherry, strawberry, lemon, etc.

Properties of tablets

Size and shape

In a preferred embodiment, the compositions of this invention are in the form of discrete solid unit doses, most preferably tablets. Tablets of the invention may be prepared in any desired size, for example 8 mm, 10 mm, 12 mm, etc.; shape, for example round, oval, oblong, etc.; weight and thickness. Optionally, the solid unit doses of the invention may have indentations or monograms on one or both sides.

Decomposition

Preferred tablet compositions of the present invention disintegrate in less than 300 seconds, preferably less than about 200 seconds and most preferably less than about 100 seconds, for example about 30 seconds after placing the tablet in a standard in vitro disintegration test (e.g., conducted according to U.S. Pharmacopeia 24 (2000), Test No. 701).

Alternatively or additionally, the preferred fast-dissolving compositions of the present invention disintegrate within 60 seconds, preferably within 30 seconds, and most preferably within 15 seconds after oral administration by a subject.

Hardness

The solid dosage forms of this invention have a hardness which, in addition to other properties, may depend on the size and shape as well as the composition of the tablet. Tablet hardness can be measured by any method known in the art, for example a tablet hardness tester (eg Schleuniger). Preferably, the compositions of this invention have a hardness of from about 1 to about 10 kp, and more preferably from about 1 to about 6 kp.

In a presently preferred embodiment of the present invention, the solid dosage forms have a suitable hardness for handling and are therefore put into practical use in the same manner as ordinary tablets. The term "adequate handling hardness" as used herein means a hardness that can at least withstand removal from a standard blister type package, or such hardness will withstand other handling methods such as packaging, shipping, handling and the like.

The tablets of the present invention preferably have a minimum hardness to avoid crushing the tablets during removal from a standard blister pack by pushing the tablet through the coating layer. A suitable hardness is about 1 kp or more for about 8 mm diameter tablets, about 1.5 kp or more for about 10 mm diameter tablets, and about 2 kp or more for about 12 mm diameter tablets.

In another currently preferred embodiment, the tablets of the present invention have a suitable hardness such that a number of these tablets can be packaged together, for example in a glass or plastic bottle, without individual packaging, without the risk of breakage and sticking or sticking of the tablets during normal transport and handling. Tablets intended for such packages preferably have a hardness of about 3 kp or more.

Packaging

The compositions of this invention may be packaged in any suitable manner known in the art. For example, a plurality of fast-dissolving tablets may be packaged together, for example in glass or plastic bottles or containers. Alternatively, the fast-dissolving tablets of the present invention may be individually wrapped, for example in plastic or foil, or packaged in known forms of blister packs. Blister packaging with improved tablet pushing properties, as described in U.S. Pat. patent no. 5,954,204 to Grabowski and incorporated herein by reference, may be particularly useful for packaging the fast-dissolving tablets of the present invention.

Administration of fast-dissolving tablets

Preparations of this invention can be taken by the subject by means of oral administration in accordance with the subject's choice or condition. For example, fast-dissolving tablets of the invention can be taken without water. After placing a tablet in the oral cavity, especially in the cheek or above the tongue, such a tablet is exposed to the action of saliva and quickly breaks down and dissolves. The rate of degradation and/or dissolution further increases with increasing pressure in the mouth, for example the pressure between the palate and the tongue or pressure from licking or sucking.

Alternatively, the tablet of this invention may be taken with water in an amount sufficient to moisten the oral cavity and aid in the dissolution of the tablet. Also, the tablet of this invention can be swallowed together with a small amount of water after complete and partial dissolution in the oral cavity. The compositions of this invention can also be swallowed directly with water.

The process of making fast-dissolving tablets

The process described below is not limiting but merely illustrates the process of preparing the fast-dissolving valdecoxib tablets of the present invention. It is important to emphasize that the skilled artisan can adjust the specific settings and parameters of this invention in order to produce tablets having particular desired properties.

In this illustrative process, maltose and mannitol are dissolved in a vessel of water that is heated to about 50°C to 80°C, for example about 70°C. After that, valdecoxib is dispersed in a container using a homogenizer. A wetting agent, for example sodium lauryl sulfate, is dissolved in another container of water. The contents of the first and second containers were mixed and the mixture was spray dried using a Niro Laboratory Mobile Minor spray dryer to obtain a dry granulate. The dry granulate is then optionally mixed with any desired excipients, for example flavoring agents, sweeteners and lubricants, to form a tablet composition. The resulting tablet mixture is then compressed on a circular tablet press to the desired tablet weight and hardness. The resulting tablets are then subjected to treatment, for example air flow treatment in a humidity controlled chamber to increase tablet hardness.

Tablet compression

Compression is the process by which an appropriate volume of the tablet granulate mixture, prepared as described above, is compressed between an upper and lower punch to compact the material into individual solid dosage forms such as a tablet. Any suitable compression process may be used in the processes for making fast-dissolving tablets of the present invention, including, for example, a single-punch tablet maker or a high-speed rotary tablet press. The pressure during the production of tablets is not predetermined, the appropriate pressure can be chosen depending on the desired hardness and the desired dissolution properties of the obtained tablets. When the tablets are subjected to heat treatment and moisture treatment as described below, the tablets are preferably compressed to an initial hardness (before heat treatment and moisture treatment) of about 0.75 to about 1.75 kp.

Heat treatment and moisture treatment

Optionally, the tablets of this invention, after the compression process, are subjected to heat treatment and moisture treatment. Such treatment can be carried out in a humid chamber, for example to increase the hardness of tablets. During this treatment, the tablets are first exposed to low temperature, air flow conditions with a high degree of humidity, for example from about 25°C to about 32°C and about 80% relative humidity, for 45 to about 120 minutes. The tablets are then exposed to conditions of high temperature and reduced humidity, for example about 35°C to about 50°C and 30% relative humidity for 45 to 120 minutes. Without being bound by theory, it is believed that treating fast-dissolving tablets in a low-temperature/high-moisture chamber and subsequently in a high-temperature/low-moisture chamber increases tablet hardness and reduces tablet friability without losing desirable properties such as rapid disintegration and rapid dissolution.

Use of the compositions of the invention

The molded compounds of the present invention, referred to herein as compositions, are useful for treating and preventing a wide variety of disorders mediated by cyclooxygenase-2 (COX-2), including, but not limited to, disorders characterized by inflammation, better and/or fever. Such compositions are particularly useful as anti-inflammatory agents, such as for the treatment of arthritis, with the added benefit of having fewer adverse side effects than conventional non-steroidal anti-inflammatory drug (NSAID) compositions that are non-selective for COX-1 and COX-2. Such preparations have a reduced potential for causing gastrointestinal toxicity or irritation including upper gastrointestinal ulcers and bleeding, a reduced potential for causing renal side effects such as decreased renal function leading to fluid retention and increased hypertension, a reduced effect on bleeding time by inhibiting platelet function, and a potentially reduced potential of causing asthma attacks in asthmatics who are sensitive to aspirin, compared to preparations of common NSAIDs. Therefore, compositions of the present invention containing a drug which is a selective inhibitor of COX-2 are particularly useful as an alternative to conventional NSAIDs where such NSAIDs are contraindicated, for example in patients with gastric ulcer, gastritis, regional enteritis, ulcerative colitis, diverticulitis or with history of repeated gastrointestinal damage; gastrointestinal bleeding; coagulation disorders including anemia such as hypoprothrombinemia, hemophilia or other bleeding problems; kidney disease; or in preoperative patients or in patients taking anticoagulants.

Such compositions are useful for treating disorders associated with arthritis, including but not limited to rheumatoid arthritis, spondyloarthropathy, gouty arthritis, osteoarthritis, systemic lupus erythematosus, and juvenile arthritis.

Such preparations are also useful for the treatment of asthma, bronchitis, menstrual pain, premature labor, tendinitis, bursitis, allergic neuritis, cytomegalovirus infection, apoptosis, including HIV-induced apoptosis, lumbago, liver diseases, including hepatitis, skin diseases such as psoriasis, eczema, acne, burns, dermatitis, and damage from ultraviolet radiation, including sunburn, and post-operative inflammation, including inflammation after eye surgery, such as cataract surgery or refractive surgery.

Such preparations are useful for treating gastrointestinal diseases such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis.

Such compositions are useful for treating inflammation in such diseases as migraine headaches, periarteris nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, scleroderma, rheumatic fever, type I diabetes, neuromuscular junction disease, including myasthenia gravis, white matter disease including multiple sclerosis, sarcoidosis, nephrotic syndrome, Benchet's syndrome, polymyositis, gingivitis, nephritis, hypersensitivity, post-injury swelling including cerebral edema, myocardial ischemia and the like.

Such preparations are useful for the treatment of eye diseases such as retinitis, scleritis, episcleritis, conjunctivitis, retinopathy, uveitis, ocular photophobia and acute injury to the eye tissue.

Such compositions are useful for treating lung inflammation such as that associated with viral infections and cystic fibrosis as well as bone resorption such as that associated with osteoporosis.

Such compositions are useful for treating certain disorders of the central nervous system such as cortical dementias including Alzheimer's disease, neurodegeneration as well as damage to the central nervous system resulting from stroke, ischemia and trauma. The term "treating" in this context means partially or completely inhibiting dementias, including Alzheimer's disease, vascular dementia, multi-infarct dementia, presenile dementia, alcoholic dementia and senile dementia.

Such preparations are useful for treating allergic rhinitis, diffuse alveolar damage, endotoxin shock syndrome and liver disease.

Such compositions are useful for treating pain, including but not limited to post-operative pain, dental pain, muscle pain and cancer pain. For example, such preparations are useful for the relief of pain, fever and inflammation in a number of conditions including rheumatic fever, influenza and other viral infections including the common cold, neck and back ailments, dysmenorrhea, headache, toothache, sprains and strains, myositis, neuralgia, synovitis , arthritis, including rheumatoid arthritis, degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns and trauma after operative and dental procedures.

Such compositions are useful for, but not limited to, the treatment and prevention of cardiovascular disorders associated with inflammation. Such compositions are useful for the treatment and prevention of vascular disease, coronary artery disease, aneurysm, vascular rejection, arteriosclerosis, atherosclerosis including post heart transplant atherosclerosis, myocardial infarction, embolism, stroke, thrombosis including venous thrombosis, angina including unstable angina, pericarditis , bacterial inflammation including inflammation caused by chlamydia, viral inflammation including inflammation associated with surgical procedures such as vascular transplants including heart bypass surgery, revascularization procedures including angioplasty, stenting, endarterectomy or other invasive procedures involving arteries, veins and capillaries.

Such compositions are useful for, but not limited to, treating disorders associated with angiogenesis, for example for inhibiting tumor angiogenesis. Such compositions are useful for treating neoplasia, including metastases; ophthalmic conditions including corneal graft rejection, ocular neovascularization, retinal neovascularization including neovascularization following injury or infection, diabetic retinopathy, macular degeneration, retrolental fibroplasia and glaucoma, including neovascular glaucoma; ulcerative diseases such as stomach ulcers; pathological but not malignant conditions such as hemangiomas, including pediatric hemangiomas, nasopharyngeal angiofibromas and avascular necrosis of bone, and disorders of the female reproductive system such as endometriosis.

Such compositions are useful for the prevention and treatment of benign and malignant tumors/neoplasias including cancer, for example colorectal cancer, brain cancer, bone cancer, epithelial cell neoplasia (epithelial carcinoma) such as basal cell carcinoma, adenocarcinoma, gastrointestinal cancer such as which is lip cancer, oral cancer, esophageal cancer, small bowel cancer, stomach cancer, colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, uterine cancer, lung cancer, breast cancer and skin cancer, such as squamous cell cancer and basal cell cancer, prostate cancer, renal cell carcinoma and other known cancers that affect the epithelial cells of the body. Neoplasias for which the compositions of this invention are particularly useful are gastrointestinal cancer, Barrett's esophagus, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate cancer, uterine cancer, lung cancer, breast cancer and skin cancer, such as squamous cell carcinoma. cell and basal cell cancer. The compositions of this invention can also be used to treat fibrosis that occurs as a result of radiation therapy. Such compositions can be used to treat subjects with adenomatous polyps, including those with familial adenomatous polyposis (FAP). In addition, such preparations can be used to prevent the development of polyps in patients at risk of developing FAP.

Such preparations inhibit prostanoid contraction of smooth muscle by preventing the synthesis of contractile prostanoids and can therefore be used to treat dysmenorrhea, premature labor, asthma, and eosinophil-related disorders. They can also be used to reduce the loss of bone mass, especially in postmenopausal women (eg treatment of osteoporosis) and to treat glaucoma.

The preferred uses of the preparations of this invention are for the treatment of rheumatoid arthritis and osteoarthritis, in general for pain relief (especially postoperative pain of dental, general and orthopedic surgery and acute inflammation of osteoarthritis), for the treatment of Alzheimer's disease and chemoprevention of colon cancer.

In addition to being useful for the treatment of humans, the compounds of this invention may also be used for the veterinary treatment of pets, exotic animals, livestock and the like, particularly mammals including rats. The compositions of this invention are particularly useful for the veterinary treatment of cyclooxygenase-2-induced disorders in horses, dogs and cats.

This invention is also intended for a therapeutic method of treating a condition or disorder requiring treatment with a drug that is a cyclooxygenase-2 inhibitor, which consists of orally administering one or more compositions of this invention to a patient in need thereof. The preferred dosage regimen for preventing, ameliorating, or ameliorating the condition or disorder is once or twice daily, but may vary according to a number of factors. These factors include the patient's type, age, weight, sex, diet and health status, as well as the nature and severity of the disorder. Therefore, the dosage regimen to be used may vary widely and deviate from the preferred dosage regimens outlined above.

Initial treatment of a patient suffering from a disease or disorder requiring treatment with a drug that is a cyclooxygenase-2 inhibitor may begin with the above dosage regimen. Treatment is usually continued as needed for several weeks to several months or years until complete control or disappearance of the disorder. Patients who undergo treatment with a composition of the invention can be routinely monitored by any of the methods well known in the art to assess the effectiveness of the therapy. The constant processing of data from such monitoring allows changing the treatment regimen during the duration of the therapy so that optimal effective amounts of the drug are given at any time and the duration of the treatment can be determined. In this way, the treatment regimen and the dosage plan can be rationally changed during the therapy so that the lowest amount of drug that shows satisfactory effectiveness is given and the administration continues as long as it is necessary to treat the disease or disorder satisfactorily.

These inventions can be used in combination therapies with opiates and other analgesics, including narcotic analgesics, Mu receptor agonists, Kappa receptor antagonists, non-narcotic analgesics (i.e., those that do not cause addiction), monamine absorption inhibitors, adenosine regulating agents, cannabis derivatives, substance P antagonists, neurokinin-1 receptor antagonists and sodium channel blockers. Preferred combination therapies include the use of the preparation of the invention with one or more compounds selected from acyclofenac, acemetacin, ε-acetamidocaproic acid, acetaminophen, acetaminosalol, acetanilide, acetylsalicylic acid (aspirin), S-adenosylmethionine, alclofenac, alfentanil, allylprodine, alminoprofen, aloxiprin, alfaprodine , aluminum bis (acetylsalicylate), amfenac, aminochlortenoxazine, 3-amino-4-hydroxybutyric acid, 2-amino-4-picoline, aminopropylone, aminopyrine, amixetrine, ammonium salicylate, ampiroxicam, amtolmetin guacil, anileridine, antipyrine, antipyrine salicylate, anthrafenin , apazone, bendazac, benorillate, benoxaprofen, benzpiperylon, benzydamine, benzylmorphine, bermoprofen, bezitramide, α-bisabolol, bromfenac, p-bromoacetanilide, 5-bromosalicylic acid acetate, bromosaligenin, bucetin, bucloxic acid, bucolom, bufexamac, bumadizone, buprenorphine, butacetin, butibufen, butophanol, calcium acetylsalicylate, carbamazepine , carbifena, carprofen, karsalam, chlorobutanol, chlortenoxazin, choline salicylate, cinchofen, cinmethacin, ciramadol, clidanac, clomethacin, clonitazen, clonixin, klopirac, clove, codeine, codeine methyl bromide, codeine phosphate, codeine sulfate, cropropamide, crotetamide, desomorphine, dexoxadrol, dextromoramide, dezocin, diampromide, diclofenac sodium, difenamizole, difenpyramide, diflunisal, dihydrocodeine, dihydrocodeinone enol acetate, dihydromorphine, dihydroxyaluminum acetylsalicylate, dimenoxadol, dimepheptanol, dimethyltiabutene, dioxaethyl butyrate, dipipanone, diprocetil, dipyrone, ditazol, droxicam, emorphazone, enfenamic acid, epirizol, eptazocin, ethersalate, ethenamide, etoheptazine, etoxazen, ethylmethylthiambutene, ethylmorphine, etodolac, etofenamate, etonitazen, eugenol, felbinac, fenbufen, fenclozic acid, fendosala, fenoprofen, fentanyl, fentiazac, fepradinol, feprazone, floctafenin, flufenamic acid, flunoxaprofen, fluoride ezone, flupirtine, fluprocazone, flurbiprofen, phosphosala, 2,5-dihydroxybenzoic acid, glafenin, glucamethacin, glycol salicylate, guaiazulene, hydrocodone, hydromorphone, hydroxypethidine, ibuprofen, ibuprofen, ibuprofen, imidazole salicylate, indomethacin, indoprofen, isofezolac, isoladol, isomethadone , isonyxin, isoxepac, isoxicam, ketobemidone, ketoprofen, ketorolac, p-lactofentide, lefetamine, levorphanol, lofentanil, lonazolac, lornoxicam, loxoprofen, lysine acetylsalicylate, magnesium acetylsalicylate, meclofenamic acid, mefenamic acid, meperidine, meptazinol, mesalamine, metazocine, methadone hydrochloride, methotrimeprazine, methiazine acid, metofolin, metopone, mofebutazone, mofezolac, morazone, morphine, morphine hydrochloride, morphine sulfate, morpholine salicylate, mirofin, nabumetone, nalbuphine, 1-naphthyl salicylate, naproxen, narcein, nefopam, nicomorphine, niphenazone, 2 -(3-(trifluoromethyl)anilino)nicotinic acid, nimesulide, 5'-nitro- 2'-propoxyacetanilide, norlevorphanol, normethadone, normorphine, norpipanone, olsalazine, opium, oxaceprol, oxamethacin, oxaprozine, oxycodone, oxymorphone, oxyphenbutazone, papaveretum, paraniline, parsalmid, pentazocine, perisoxal, phenacetin, fenadoxone, phenazocine, phenazopyridine hydrochloride, phenocol, fenoperidine, fenopyrazone, phenyl acetylsalicylate, phenylbutazone, phenyl salicylate, pheniramidol, picetoprofen, piminodine, pipebuzone, piperilone, piperofen, pyrazolac, piritramide, piroxicam, pranoprofen, proglumethacin, proheptazine, promedol, propacetamol, propiram, propoxyphene, propyphenazone, proquazone, protic acid , ramiphenazone, remifentanil, rimazolium methylsulfate, salacetamide, salicin, salicylamide, salicylamide o-acetic acid, salicylsulfate acid, salsalte, salverine, simetride, sodium salicylate, sufentanil, sulfasalazine, sulindac, superoxide dismutase, suprofen, succibuzone, talniflumate, tenidapa, tenoxicam , terofenamate, tetra ndrin, thiazolinobutazone, tiaprofenic acid, thiaramide, tilidine, tinoridine, tolfenamic acid, tolmetin, tramadol, tropezine, viminol, xenbucin, xymoprofen, zaltoprofen and zomepirac (see Merck Index, 12th edition (1996), Therapeutic Category and Biological Activity Index, lists under the headings "Analgesic", "Anti-inflammatory" and "Antipyretic").

Particularly preferred combination therapies comprise the use of the compositions of the invention, for example valdecoxib of the compositions of the present invention with an opiate compound, especially when the opiate compound is codeine, meperidine, morphine or their derivatives.

The compound to be administered in combination with valdecoxib can be prepared separately or together with valdecoxib in the composition of the invention. When valdecoxib is formulated with another drug, for example an opiate drug, the second drug may be formulated in immediate-release, rapid-release, sustained-release, or dual-release forms.

In an embodiment of this invention, especially when the condition is mediated by cyclooxygenase-2, headache or migraine, the valdecoxib preparation is given in combination therapy with a vasomodulator, preferably a xanthine derivative that has a vasomodulating effect, and more preferably with an alkylxanthine compound.

Combination therapies in which an alkylxanthine is administered in parallel with a valdecoxib preparation are encompassed by this embodiment of the invention, regardless of whether the alkylxanthine is a vasomodulator and whether the therapeutic efficacy of the combination can be attributed to a vasomodulating effect. The term "alkylxanthine" includes xanthine derivatives having one or more C1-4 alkyl, preferably methyl, substituents and pharmaceutically acceptable salts of such xanthine derivatives. Dimethylxanthines and trimethylxanthines, including caffeine, theobromine and theophylline, are particularly preferred. An even more preferred alkylxanthine compound is caffeine.

Total and relative dosage amounts of valdecoxib and vasomodulators or alkylxanthines are selected as therapeutically and/or prophylactically effective for relieving pain associated with headache or migraine. Appropriate dosage amounts will depend on the severity of the pain and the individual vasomodulator or alkylxanthine selected. For example, in combination therapy with valdecoxib and caffeine, typically valdecoxib will be administered in daily dosages of from about 1 mg to about 100 mg, preferably from about 5 mg to about 50 mg, and caffeine in daily dosages of from about 1 mg to about 500 mg, preferably from about 10 mg to about 400 mg, even more preferably from about 20 mg to about 300 mg.

The vasomodulating or alkylxanthine component of the combination therapy may be administered in suitable dosage forms by any suitable route, preferably orally. The vasomodulator or alkylxanthine can optionally be prepared in parallel with valdecoxib in the molded compound of the invention. Therefore, the molded compound of the invention optionally contains both valdecoxib and a vasomodulator or alkylxanthine such as caffeine, in total and relative amounts consistent with the above dosage amounts.

The term "in total and relative amounts effective for pain relief", with respect to valdecoxib and a vasomodulator or alkylxanthine in a composition of this embodiment, means those amounts such that (a) these ingredients together effectively relieve pain and (b) each ingredient is or could contribute to the pain-relieving effect, if the other ingredient is not present in such a large amount as to interfere with such a contribution.

Examples

The following examples illustrate aspects of the present invention, but should not be considered limiting in this respect.

Example 1

Valdecoxib fast-dissolving tablets (series A, referred to in the text as Rapid-dissolving Valdecoxib A) are prepared according to the following procedure. Maltose (28.03 g) and mannitol (367.6 g) were dissolved in water in the first vessel with heating (70°C) and stirring. Valdecoxib (46.25 g) was dispersed in a maltose/mannitol solution and homogenized for ten minutes using a Silverson homogenizer. Sodium Lauryl Sulfate (SLS) is, in another container, dissolved in water with gentle shaking to produce a wetting agent solution. A wetting agent solution was added to the first container to form a spray solution which was spray-dried to obtain a dry granulate using a Niro laboratory mobile spray-dryer under the following conditions: spray rate: 32 g/min; gas flow: 2.8 mbar; system pressure: 1.6 mbar; flow gas pressure: 20 mbar; atomization pressure: 1.6 mbar; atomization flow rate: 57; supply temperature: 160°C; outlet temperature: about 55°C; atomizing air heater temperature: 287°C.

Magnesium stearate (1 g), stearic acid (3 g), acesulfame K (1 g) and peppermint flavor (1 g) were added to a polyethylene bag and mixed vigorously until a mixture was formed. After that, the mixture was geometrically diluted with dry granulate prepared in the above-mentioned way until the addition of 200 g of dry granulate. After that, tablets were prepared by individually compressing 400 mg of the tablet mixture to form tablets of medium hardness of 1.5 kp. The obtained tablets were placed in a chamber maintained at 25°C and 80% relative humidity for 1 hour and at 40°C and 30% relative humidity for the next 1 hour. The composition (% by mass) of the fast-dissolving Valdecoxib A is shown in Table 1.

Table 1. Composition of Fast Dissolving Valdecoxib A

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Example 2

A study was conducted to determine the pharmacokinetic properties of Rapid Dissolving Valdecoxib A in beagle dogs. Fast-dissolving Valdecoxib A was administered individually to 4 dogs. Venous blood was taken before dosing and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 and 24 hours after oral dosing. Plasma was isolated from blood by centrifugation at 3000 G, and the samples were stored at -20°C until analysis. Plasma concentrations of valdecoxib were determined by HPLC analysis. The results are presented in Table 2.

Table 2. Pharmacokinetic properties of Fast Dissolving Valdecoxib A in dogs

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Example 3

Valdecoxib fast-dissolving tablets (series B, referred to in the text as Fast-dissolving Valdecoxib B) are prepared according to the following procedure. Maltose (0.158 kg) and mannitol (2.047 kg) were dissolved in water (14.167 kg) with stirring to form a solution. Sodium lauryl sulfate (0.037 kg) was added to the solution with stirring until dissolved. Valdecoxib (0.258 kg) was dispersed in solution and homogenized at approximately 5000 rpm for 15 minutes using a Silverson homogenizer to obtain a thick mixture. The thick mixture was then stirred with a conventional marine-type propeller at approximately 3000 rpm for 2 hours. The thick mixture was spray-dried to obtain a dry granulate using a Niro laboratory mobile spray-dryer under the following conditions: spray rate: 30 g/min; gas flow: 40 mm H2O; chamber pressure: -100 mm H2O; liquid atomizing spray pressure: 1.0 bar; atomization flow rate: 70; supply temperature: 175°C; outlet temperature: about 90°C. The total theoretical utilization is 2500 kg. The above process was carried out twice to obtain granulate Lot A (1414.3 g) and Lot B (1971.9 g) which were spray dried.

The spray-dried granules of Lot A and Lot B were screened and the screened granules were mixed with peppermint flavor (17.5 g) and acesulfame-K (17.5 g) in a V-mixer for 15 minutes to form a mixture. Magnesium stearate (17.5 g), micronized stearic acid (52.5 g) and colloidal silicon dioxide (8.8 g) were added to the mixture with additional mixing to form a tablet mixture. The tablets were compressed from the tablet mixture to a tablet hardness of 1.5 kp and a desired tablet weight of 391.58 mg. After compression, the tablets were transferred to an IBC moisture treatment chamber (17 liters) maintained at 25°C, 80% RH and 75 CFM air flow for 1 hour and at 40°C, 30% RH and 75 CFM air flow for the following hour. The composition of Rapid Dissolving Valdecoxib B (mg/tablet) is shown in Table 3.

Table 3. Composition of Fast Dissolving Valdecoxib B

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Example 4

In vitro dissolution profiles of Fast Dissolving Valdecoxib B from Example 3 and commercial Bextra® 40 mg tablets were determined using 1000 ml of 1% sodium lauryl sulfate solution and a USP type II apparatus. The data are shown in Table 4. Fast Dissolving Valdecoxib B showed very fast dissolving properties with all Valdecoxib dissolved within 15 minutes.

Table 4. Amount (% mass fraction) of dissolved valdecoxib

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Example 5

The fast-dissolving Valdecoxib B of Example 3 was administered individually to 25 human subjects. Oral bioavailability parameters were determined and compared with those of the commercial Bextra® 40 mg tablet. The data are presented in Table 5.

Table 5. Oral bioavailability of Rapid-dissolving Valdecoxib B and Bextra® 40 mg tablets in humans

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Example 6

The fast-dissolving Valdecoxib B of Example 3 was evaluated in a taste test according to the following procedure. Four to five expert tasters were chosen and each was given a fast-dissolving tablet on their tongue. The taster gently passed the tablet over the palate with his tongue, simultaneously recording sensory data and the time of complete decomposition. Sensory data include organoleptic properties associated with each tablet such as taste quality, bitterness, fullness, texture, mouthfeel and aftertaste. Each of these properties is defined according to a scale of categories from 1 to 5, in order to express the difference with other commercially available fast-dissolving products, compared to valdecoxib fast-dissolving tablets with cherry, strawberry, orange, peppermint or spearmint flavor and compared to fast-dissolving tablets that contain different active ingredients.

After the tablet has completely dissolved, the taster records the time during which the taste of the tablet is felt in the mouth for 30 minutes. Each tablet was tested three times and all samples were coded for presentation to the tasters. Fast-dissolving Valdecoxib B has an average dissolution time of 23.6 seconds. Overall, Rapid Dissolving Valdecoxib B has an acceptable taste (data not shown) and degradation time.

Claims (30)

1. A tablet that quickly dissolves in the mouth, characterized by the fact that it consists of: (a) particulate valdecoxib in a therapeutically effective amount and (b) at least one pharmaceutically acceptable excipient with rapid oral disintegration properties, which is in close association with the valdecoxib particles, and where at least one excipient with properties of fast decomposition in the mouth is present in a total amount of about 50% to about 99% of the mass fraction of the preparation. 2. The preparation of claim 1, characterized in that at least one pharmaceutically acceptable excipient with fast-dissolving properties in the mouth is a carbohydrate. 3. The preparation of claim 1, characterized in that at least one pharmaceutically acceptable excipient with properties of fast decomposition in the mouth is a saccharide. 4. The preparation of claim 1, characterized in that at least one pharmaceutically acceptable excipient with properties of fast decomposition in the mouth is selected from the group consisting of maltose, maltitol, sorbitol, lactose and mannitol. 5. The preparation of claim 1, characterized in that at least one pharmaceutically acceptable excipient with properties of fast decomposition in the mouth is present in a total amount of about 50% to about 90% of the mass fraction of the preparation. 6. The preparation of claim 1, characterized in that at least one pharmaceutically acceptable excipient with properties of fast decomposition in the mouth contains a high moldability saccharide and a low moldability saccharide. 7. The composition of claim 6, characterized in that the weight ratio of high moldability saccharide to low moldability saccharide is about 2 to about 20 parts of high moldability saccharide to 100 parts of low moldability saccharide. 8. The composition of claim 6, characterized in that the weight ratio of high moldability saccharide to low moldability saccharide is about 5 to about 7.5 parts of high moldability saccharide to 100 parts of low moldability saccharide. 9. The preparation of claim 1, characterized in that it has a hardness of about 1 to about 10 kp. 10. The composition of claim 1, wherein valdecoxib is present in an amount of about 5 to about 50 mg. 11. The formulation of claim 1, which, when subjected to the United States Pharmacopeia 24 in vitro degradation test number 701, has a degradation time of less than about 30 seconds. 12. The formulation of claim 1, wherein when subjected to the United States Pharmacopeia 24 in vitro degradation test number 701, it has a degradation time of less than about 100 seconds. 13. The preparation of claim 1, characterized in that it decomposes within 60 seconds after taking it into the oral cavity. 14. The preparation of claim 1, characterized in that it decomposes within 30 seconds after taking it into the oral cavity. 15. The preparation of claim 1, characterized in that it is organoleptically acceptable. 16. The procedure for preparing valdecoxib tablets that disintegrate intraorally, characterized by the fact that it consists of the following steps: - the step of providing valdecoxib in particulate form; - the step of dissolving at least one pharmaceutically acceptable excipient that has properties of rapid decomposition in the mouth in a container with water, and that at least one excipient is dissolved in a total amount such that at the end of the procedure, the excipient makes up about 50% to about 99% of the total weight of the tablet; valdecoxib dispersion step in water, wherein said dissolving and dispersing steps are performed in any order or simultaneously to produce a dispersible liquid; - a spray drying step of the spray liquid to obtain a tablet mixture; and - the step of compressing the tablet mixture to obtain a tablet. 17. The method of claim 16, characterized in that it further consists of the step of heating the container with water, before, simultaneously or after the steps of dissolution and/or dispersion, but before the step of spray drying. 18. The method of claim 16, characterized in that it further consists of the step of dissolving the wetting agent in water, before, simultaneously or after the mentioned steps of dissolving and/or dispersion, but before the mentioned step of spray drying. 19. The method of claim 16, characterized in that it further consists of the step of dissolving the aqueous solution of the wetting agent in water, before, at the same time or after the said steps of dissolution and/or dispersion, but before the said step of spray drying. 20. The method of claim 16, characterized in that at least one pharmaceutically acceptable excipient with properties of fast decomposition in the mouth is a carbohydrate. 21. The method of claim 16, characterized in that at least one pharmaceutically acceptable excipient with properties of fast decomposition in the mouth is a saccharide. 22. The method of claim 16, characterized in that at least one pharmaceutically acceptable excipient with properties of fast decomposition in the mouth is selected from the group consisting of maltose, maltitol, sorbitol, lactose and mannitol. 23. The process of claim 16, characterized in that at least one excipient with fast disintegration properties in the mouth is dissolved in a total amount such that at the end of the process, the excipient constitutes about 50% to about 95% of the total weight of the tablet. 24. The method of claim 16, characterized in that at least one excipient with properties of fast decomposition in the mouth is dissolved in a total amount such that at the end of the process, the excipient constitutes about 50% to about 90% of the total weight of the tablet. 25. The method of claim 16, characterized in that at least one pharmaceutically acceptable excipient with properties of fast decomposition in the mouth contains a high moldability saccharide and a low moldability saccharide. 26. The method of claim 25, characterized in that the weight ratio of high moldability saccharide to low moldability saccharide is about 2 to about 20 parts of high moldability saccharide to 100 parts of low moldability saccharide. 27. The method of claim 25, characterized in that the weight ratio of high moldability saccharide to low moldability saccharide is about 5 to about 7.5 parts of high moldability saccharide to 100 parts of low moldability saccharide. 28. An intraorally disintegrating valdecoxib tablet, characterized in that it is prepared by the process of claim 16. 29. A method of treating or preventing a disease or disorder when treatment with a cyclooxygenase-2 inhibitor drug is indicated, characterized in that it consists of orally administering to the subject the tablet of claim 1. 30. A method of treating or preventing a disease or disorder when treatment with a cyclooxygenase-2 inhibitor drug is indicated, characterized in that it consists of oral administration to the subject of the preparation of claim 28.