OA12686A - Fast dissolving tablets of cyclooxygenase-2 enzymeinhibitors. - Google Patents

Abstract

The present invention relates to fast dissolving tablets for oral administration comprising a therapeutically effective amount of drug(s) that acts selectively as a cyclooxygenase-2 (COX-2) enzyme inhibitor, which disintegrate quickly in mouth. The tablets are particularly suitable for patients who have difficulty in swallowing.

Description

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FAST DISSOLVING TABLETS OF CYCLOOXYGENASE-2ENZYME INHIBITORS

FIELD OF THE INVENTION 5

The présent invention relates to fast dissolving tablets for oraladministration comprising a therapeutically effective amount of drug (s) that actsselectively as a cyclooxygenase-2 (COX-2) enzyme inhibitor, which disintegratequickly in mouth. The tablets are particularly suitable for patients who hâve 10 difficulty in swallowing.

BACKGROÜND OFTHE INVENTION

Nonsteroidal anti-inflammatory drugs (NSAIDs) exert anti-inflammatory15 and analgésie effects through the inhibition of prostaglandin synthesis by blocking cyclooxygenase (COX) enzyme activity. COX enzyme has twoisoforms: COX-1 and COX-2. COX-2 enzyme is inducible by inflammation,whereas COX-1 is présent in most tissues as the house keeper enzyme. Theinhibition of COX-1 is therefore undesirable whereas on the other hand inhibition 20 of COX-2 enzyme accounts for the therapeutic benefits. ? COX-2 inhibitors are the latest addition to the growing armamentarium ofanti-inflammatory drugs. Much of the recent research has focussed uponefficacious methods for development of drug delivery of COX-2 enzyme 25 inhibitors to treat inflammation associated maladies.

The ability of COX-2 inhibitors to selectively block formation of pro-inflammatory prostaglandins while sparing those that guard the gastrointestinaltract makes them an attractive choice for long term use, such as in rheumatoid 30 arthritis or osteoarthritis.

Rheumatoid arthritis and osteoarthritis are oid âge diseases associated with joint pain, stiffness, inflammation or swelling. Many elderly persons hâve difficulty in taking conventional oral dosage forms like solutions, suspensions, 1 012686 tablets and capsules, because of hand tremors and dysphagia. Moreover,increase intake of water for swallowing conventional dosage forms results infrequent urination and nocturia. 5 Swallowing problème are also common in mentally ill, the developmentally disabled, and patients who are uncooperative, on reduced liquid-intake plans, or^are nauseated. In cases such as motion sickness, sudden épisodes of allergieattack or coughing, and an unavailability of water, swallowing the conventionaltablets becomes difficult. Consequently, there is a need to provide a fast 10 dissolving dosage form of COX-2 inhibitors for oral administration which disintegrates and dissolves rapidly in saliva without the need for drinking water.

SUMMARY OF THE INVENTION 15 lt is an object of the présent invention to provide a fast dissolving tablet which comprises a therapeutically effective amount of drug (s) that acts as acydooxygeriasé-2 enzyme (COX-2) inhibitor for oral administration whichdisintegrate quickly in the mouth. The tablets prepared by the présent inventiondisin'tegrate and dissolve in the oral cavity in less than about 30 seconds without 20 the need of water. The fast dissolving tablet of CÔX-2 of the présent inventionprocess hàs pleasant mouth feel and there is no after taste or grittiness.

The fast dissolving tablets according to the présent inventions comprisesa therapeutically effective amount of COX-2 inhibitor, a filier, and optionally other 25 pharmaceutical excipients.

Direct compression is the preferred method because of the aboveadvantages. Accordingly, the présent invention provides a process for thepréparation of fast dissolving tablets comprising a therapeutically effective 30 amount of drug(s) that acts as a cyclooxygenase-2 (COX-2) inhibitor for oraladministration. 2 012686

The fast dissolving tablets of the présent invention can either be producedby conventional methods like wet granulation, dry granulation and directcompression or by specialized techniques like tablet molding and freeze drying.

Since the pharmaceutical industry is constantly making efforts to increasethe efficiency of tabletting operations and reduce costs by utilizing the smallestamount of floor space and labor as possible for a given operation, increasingattention is being given to direct compression of tablet préparation.

Direct compression is regarded as a relatively quick process where thepowdered materials are compressed directly without changing the physical andChemical properties of the drug. The advantages of direct compression include (i) few manufacturing steps, as granulation step is eliminated (ii) élimination of heat and moisture and therefore better a. physicat stability such as no change in crystallinity and,,polymorphie form of the drug, and b. Chemical stability (iii) use of conventional equipment and commonly available excipients;and (iv) low cost and less manpower.

The process comprises: a) blending a therapeutically effective amount of COX-2 inhibitors withfiller and optionally, other pharmaceutical acceptable excipients, fora time sufficient to form a homogeneous mixture. 3 012686 b) compressing the homogeneous mixture obtained in step (a) to formthe fast dissolving tabiet of COX-2 inhibitor.

DETAILED DESCRIPTION OF THE INVENTION 5

According to the présent invention, the "COX-2 inhibitor" as used hereinto embrace compounds that specifically/selectively, or preferentially inhibitscyclooxygenase-2 over cyclooxygenase-1. Illustrative examples of COX-2enzyme inhibitors that are advantageously administered by the pharmaceutical 10 compositions of this invention include “spécifie inhibitors" such as celecoxib,rofecoxib, parecoxib, valdecoxib, and the like or "preferentiel inhibitors" such asmeloxicam, nimesulide, etodolac, nabumetone, and the like. “Therapeutically effective amount" means that amount of a drug or 15 pharmaceutical agent that will elicit the biological or medical response of a‘ tissue, a System, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.

Fillers of the présent invention can be selected from any such 20 pharmaceuticallÿ acceptable excipient, which gives bulk to the COX-2 inhibitor composition and which is physically and chemically compatible with COX-2 .·) inhibitor; preferably those fillers may be selected from alkali earth métal saltssuch as directiy compressible dicalcium phosphate dihydrate, tricalciumphosphate, calcium sulfate, calcium carbonate, calcium hydroxide, aluminium 25 hydroxide, magnésium silicate, aluminium magnésium hydroxide; carbohydratessuch as directiy compressible maltose, maltitol, sorbitol, mannitol, glucose,sucrose, xylitol, lactose, lactose monohydrate, erythritol, fructose, maltodextrins;celluloses such as microcrystalline cellulose, calcium carboxy methyl cellulose;starches such as pregelatinized starch, potato starch, maize starch; clays such 30 as kaolin and polyethylene glycols (PEG) such as PEG 4000 ; or mixturesthereof.

The effective amount of the fillers found useful in the présent invention is in the range of about 10 to about 95 weight percent, preferably about 25 to 4 012686 about 85 weight percent, and most preferably about 80 weight'percent of theCOX-2 inhibitor compositions of this invention. One of the preferred fillers isdirectly compressible mannitol. 5 The direct compression excipients are chosen such that they hâve good flow and compressible characteristics and prevent ségrégation of powders in thehopper and thereby help in direct compression.

The optional pharmaceutical excipients of this invention may be selected10 from the binders, disintegrants, lubricants, glidants, colouring agents, flavouring agents and sweeteners which are chemically and physicaliy compatible withCOX-2 enzyme inhibitors.

The direct compression method for preparing tablets requires a material15 that not only is free-flowing but also sufficiently cohesive to act as a binder.

Materials such as microcrystalline cellulose, microcrystalline dextrose, mannitol,directly compressible dicalcium phosphate, amylose and polyvinylpyrrolidonehâve such properties. 20 Disintegrants preferred for the présent invention may be selected from starches or modified starches such as sodium starch glycolate, corn starch,potato starch or pregelatinized starch; clays such as bentonite, montmorilloniteor veegum; celluloses such as microcrystalline cellulose, hydroxypropyl celluloseor carboxymethyi cellulose; algins such as sodium alginate or alginic acid; cross- 25 linked cellulose such as croscarmellose sodium; gums such as guar gum orxanthan gum; cross-Iinked polymers such as crospovidone; effervescent agentsuch as sodium bicarbonate and citric acid; or mixtures thereof.

The effective amount of a disintegrant found useful for the COX-2 inhibitor 30 compositions of this invention is in the range of about 1.0 to about 10.0 weightpercent, preferably about 1.5 to about 2.5 weight percent and most preferablyabout 2.0 weight percent of the COX-2 inhibitor compositions by this invention.The preferred disintegrant is croscarmellose sodium. 5 012686

The lubricants of the présent invention may be selected from talc,magnésium stéarate, calcium stéarate, stearic acid, magnésium lauryi sulphateand hydrogenated vegetable oil. Soluble lubricants include sodium benzoate, amixture of sodium benzoate and sodium acetate, sodium chloride, leucine, 5 sodium stearyl fumarate and PEG 4000.

The effective amount of lubricant found useful in the présent invention isin the range of about 0.25 to about 4 weight percent, preferably about 0.5 toabout 2 weight percent, and most preferably 1.0 weight percent of the COX-2 10 inhibitor compositions of this invention. The preferred lubricant is magnésiumstéarate.

The glidants of the présent invention may be selected from colloïdalSilicon dioxide and talc. 15

The coloring agent of the présent invention may be selected from anycolorant used in pharmaceuticals which is approved and certified by the FDA.

The flavouring agent of the présent invention include both naturel and20 artificial flavours such as ârtificial vanilla, cinnamon, various fruit flavours, both individual and mixed; mints such as peppermint, menthol; essentiel oils such asthymol, eculyptol and methyl salicylate and the like. The flavours are generallyutilized in amounts that will vary depending upon the individual flavour, and mayrange in amounts of about 0.5% to about 3% by weight of the final composition 25 weight.

The sweeteners for the présent invention include both natural and artif icialsweetners. The sweetners may include, among Others, water-solublesweetening agents such as monosaccharides, disaccharides and 30 polysaccharides such as xylose, ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, maltose, partiafly hydrolyzed starch, or corn syrup solids and sugar alcohols such as sorbitol, xylitol, mannitol and mixtures thereof; water- soluble artificial sweeteners such as the soluble saccharin salts, cyclamate salts, acesulfam-K and the like, and free acid form of saccharin and dipeptide based 6 012686 sweeteners. The amount of sweetener will vary with the desired sweetenersselected for a particular tablet composition.

The process of the présent invention comprises sieving of the COX-25 inhibitors, fillers, disintegrants, binders, giidants, colouring agents, flavouring agents and sweeteners, through a suitabie sieve and admixing them to make auniform blend. The lubricant is also passed through the suitabie sieve andmixed with the blend. The blend is directly compressed using the suitabietooling. 10

The tablets made by the présent inventive process disintegrate ! dissolvein less than about 30 seconds preferably in about 25 seconds. The process ofthis invention for preparing rapidly dissolving tablet may be used for anystrength of COX-2 inhibitor tablets without deviating from this invention. 15

The présent invention is illustrated by, but by no means limited to, thefollowing examples: EXAMPLE 1 20

Rofecoxib mouth dissolving tablets - 25 mg.

Ingrédient Quantity (mg) Rofecoxib 25.28 Aspartame 0.35 Mannitol 166.67 Croscarmellose sodium 4.00 Colloïdal Silicon dioxide 1.00 . Mixed fruit flavour 0.70 Magnésium stéarate 2.00 Total 200.00 7 012686 1. Rofecoxib, aspartame, mannitol, croscarmellose sodium, colloïdal Silicondioxide and mixed fruit flavour are sifted through the sieve #44 BSS andadmixed for about 15 minutes to make a uniform blend. 5 2. Magnésium stéarate ispassed through sieve #100 BSS and mixed with the blend of step 1 for sufficient time. ί 3. Uniform blend of step 2 is directly compressed using 9 mm, roundbiconcave tooling to make the tablets of about 3.8±0.1 mm thickness. 10

The mouth dissolving tablets prepared by the above composition andprocess had hardness in the range of 2.2 to about 4.0 Kp. The disintegrationtime in water was less than 15 seconds, whereas the mouth dissolving time wasless than 25 seconds. The friability was about 0.4 % w/w. The mouth dissolving 15 rofecoxib tablets are tested in 1% sodium lauryl sulphate (SLS) according to theprocedure described in the United States Pharmacopoeia XXIII, Apparatus 1 @ ' 100 rpm and found to hâve the foliowing release profile:

Time (Minutes) % Rofecoxib dissolved 15 74 30 83 45 88 EXAMPLE 2 20

Rofecoxib mouth dissolving tablets - 50 mg.

Ingrédient Quantity (mg) Rofecoxib 50.56 Aspartame 0.70 Mannitol 333.34 Croscarmellose sodium 8.0 Colloïdal Silicon dioxide 2.0 8 012636

Mixed fruit flavour 1.4 Magnésium stéarate 4.0 Total 400.0

The procedure of Example 1 was followed to préparé the tablets of abovecomposition. 5 The rofecoxib mouth dissolving tablet of 50 mg strength had an average weight of 400±20 mg, thickness of 4.9±0.2 mm, hardness of 4.5-5.0 Kp,disintegration time of less than 20 seconds, mouth dissolving time of about 25seconds, friability of about O.44% w/w and dissolution upto 86% in 45 minutes. 10 EXAMPLE 3

Nimesulide mouth dissolving tablet -100 mg. ' - Ingrédient Quantity (mg) ’ Nimesulide 100.00 Aspartame 4.5 Mannitol 318.75 ·* Croscarmellose sodium 10.5 Colloïdal Silicon dioxide 2.25 Orange flavour 4.5 Monosodium citrate 5.0 Magnésium stéarate 4.5 Total 450.0

The procedure of Example 1 was followed to préparé the above tablets.

The nimesulide mouth dissolving tablet of 100 mg strength had an average weight of 450+22.5 mg, thickness of 5.7±0.2 mm, hardness of 2-5 Kp, disintegration time of less than 20 seconds, mouth dissolving time of about 25 seconds and friability of about 0.9% w/w. 9 012686

While the présent invention has been described in terms of its spécifieembodiments, certain modifications and équivalents will be apparent to thoseskilled in the art and are intended to be included within the scope of the présentinvention. 10

Claims (21)

1. CLAIMS WE CLAIM: 5 1. A fast dissolving tablet which comprises a therapeutically effective amount of drug(s) that acts as a cyciooxygenase-2 (COX-2) inhibitor for oraladministration.
2. 2. The tablet according to claim 1 wherein the tablet comprises a 10 therapeutically effective amount of COX-2 inhibitor, a Aller and optionally, other pharmaceutical excipients.
3. 5. The tablet according to claim 1 wherein the fast dissolving tablet dissolvesinthemouth. 15

   4. The tablet according to claim 1 or 2 wherein the drug(s) that acts as aί Ί ' cyclooxygenase-2 (COX-2) inhibitor is spécifie or preferential COX-2 inhibitor. 20 5. ' The tablet according to claim 4 wherein the COX-2 inhibitor is selected frôm the group consisting of meloxicam, rofecoxib, celecoxib, valdecoxib,parecoxib, nabumetone, nimesulide and etodolac.
4. 6. The tablet according to claim 2 wherein the filler may be selected from the 25 group consisting of alkali earth métal salts, carbohydrates, celluloses, starches, clays and polyethylene glycols, and mixtures thereof.
5. 7. The tablet according to claim 9 wherein the filler may be selected from thegroup consisting of directly compressible dicalcium phosphate dihydrate, 30 tricalcium phosphate, calcium sulfate, calcium carbonate, calcium hydroxide, aluminium hydroxide, magnésium silicate, aluminium magnésium hydroxide, maltose, maltitol, sorbitol, mannitol, glucose, sucrose, xylitol, lactose, lactose monohydrate, erythritol, fructose, maltodextrins, microcrystalline cellulose, calcium carboxy methyl 012686 cellulose, pregelatinized starch, potato starch, maize starch, kaolin,polyethylene glycol 4000, and mixtures thereof.
6. 8. The tablet according to claim 2 wherein the pharmaceutical excipientscomprises binders, disintegrants, lubricants, glidants, colouring agents,fiavouring agents and sweeteners.
7. 9. The tablet according to claim 8 wherein the binders may be selected fromthe group consisting of microcrystalline cellulose, mannitol,microcrystalline dextrose, directly compressible dicalcium phosphate,amylose and polyvinylpyrrolidone.
8. 10. The tablet according to claim 8 wherein the disintegrant is selected fromthe group consisting of starches or modified starches, clays, celluloses,algins, cross-linked celluloses, gums, cross-linked polymers, effervescentagents, and mixtures thereof. 1T The tablet according to claim 10 wherein the disintegrant is selected fromthe group consisting of sodium starch glycolate, corn starch, potatostarch, pregelatinized starch, bentonite, montmorillonite, veegum,microcrystalline cellulose, hydroxypropyl cellulose, carboxymethylcellulose, sodium alginate, alginic acid, croscarmellose sodium, guar gum,xanthan gum, crospovidone; sodium bicarbonate and citric acid, andmixtures thereof.
9. 12. The tablet according to claim 8 wherein the lubricants may be selectedfrom the group consisting of talc, magnésium stéarate, calcium stéarate,stearic acid, magnésium lauryl sulphate and hydrogenated vegetable oil,sodium benzoate, sodium acetate, sodium chloride, leucine, sodiumstearyl fumarate, PEG 4000, and mixtures thereof.
10. 13. The tablet according to claim 8 wherein the glidants may be selected fromthe group consisting of colloïdal Silicon dioxide and talc. 12 «· , 012686
11. 14. The tablet according to claim 8 wherein the colourîng agents may beselected from any colorant used in pharmaceuticals which is approvedand certified by the FDA.
12. 15. The tablet according to claim 8 wherein the flavouring agent may be selected from the group consisting of natural and artificial flavours, mintsand essential oils or the mixtures thereof.
13. 16. The tablet according to claim 15 wherein the flavouring agent may be 10 selected from the group consisting of peppermint, menthol, artificial vanilla, cinnamon, various fruit flavours, both individual and mixed,thymol, eculyptol and methyl salicylate and the like.
14. 17. The tablet according to the claim 8 wherein the sweetener may be 15 selected from the group consisting of natural and artificial sweeteners.
15. 18. Thé tablet according to the claim 17 wherein the sweetener may be - sélectéd from the group consisting of monosaccharides, disaccharides,polysaccharides, partially hydrolyzed starch, corn syrup solids, sugar 20 alcohols, water-soluble artificial sweeteners, and mixtures thereof.
16. 19. The tablet according to the claim 18 wherein the sweetener may beselected from the group consisting of xylose, ribose, glucose, mannose,galactose, fructose, dextrose, sucrose, maltose, sorbitol, xylitol, mannitol, 25 solublé saccharin salts, cyclamate salts, acesulfam-K and free acid form of saccharin and dipeptide based sweeteners, and mixtures thereof.
17. 20. A mouth dissoiving tablet of COX-2 inhibitor consisting of a COX-2inhibitor, croscarmellose sodium, mannitol, aspartame, colloïdal Silicon 30 dioxide, magnésium stéarate and flavouring agent.
18. 21. A process for preparing a fast dissoiving tablet according to claim 2comprising the steps of: 13 012686 (a) blending a therapeutically effective amount of COX-2 inhibitor, afiller, and optionally, other pharmaceutical excipients; (b) compréssing the homogeneous mixture obtained in step (a).
19. 22. The process açcording to claim 21 wherein the blend is granulated before compression.
20. 23. The process according to claim 22 wherein the granulation is done by wetor dry granulation methods. 0
21. 24. The process according to claim 23 wherein the dry granulation is done byslugging or roller compaction.

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