TECHNICAL FIELD OF THE INVENTION
The present invention relates to disintegrant free oral compositions of celecoxib. It also relates to the processes for preparing such compositions. Further, It relates to method of treating cyclooxygenase-2 mediated disorders using compositions of the present invention.
BACKGROUND OF THE INVENTION
Celecoxib is a non-steroidal anti-inflammatory drug belonging to the class of selective cyclooxygenase-2 inhibitors. Chemically it is 4-[5-(4-methylphenyl)-3-(trifluoromethyl) pyrazol-1-yl] benzenesulfonamide.
Celecoxib, as a compound is disclosed in US patent no. 5,466,823 assigned to G.D. Searle & Co. This patent describes a class of 1,5-diaryl pyrazoles and their salts together with processes for the preparation of such compounds.
US patent no. 5,760,068 assigned to G.D. Searle & Co. describes the use of 1,5-diaryl pyrazolyl benzenesulfonamide compounds (including celecoxib) in the treatment of pathological conditions associated with rheumatoid arthritis and osteoarthritis.
Celecoxib has unique physical and chemical properties, which present various problems in formulating effective oral compositions of celecoxib. Celecoxib has a low solubility in aqueous media. Further it is a fluffy material, with relatively low bulk and tap densities. In addition, celecoxib has certain undesirable flow characteristics, for example, is sticky and can adhere to surfaces. Celecoxib shows a pH dependent solubility. Its solubility increases in highly basic pH. These properties present a challenge in developing a formulation of celecoxib effective for oral administration.
Presently celecoxib is being marketed by Pharmacia Corporation under the trade name CELEBREX in capsule dosage form containing 100 mg or 200 mg of the drug. EP patent no. 1049467 B1 covers the marketed formulation of celecoxib. It describes the orally deliverable compositions of celecoxib comprising particulate celecoxib in intimate mixture with one or more pharmaceutically acceptable excipients, wherein said pharmaceutically acceptable excipients include a diluent, binder and a disintegrant, a surfactant and a lubricant. It has been stated in one of the examples of the present invention that the celecoxib availability from the wet granulated solid compositions can be improved by reduced particle size, increased wetting of celecoxib (by including a wetting agent like sodium lauryl sulphate in the granulating fluid) and improved dispersibility (by including disintegrant like croscarmellose sodium in the granulation).
Disintegrants constitute an important part of the formulation of tablets and capsules of a poorly soluble, fluffy and sticky drug like celecoxib. Disintegrant facilitates breakup or disintegration of a tablet into particles after administration. Disintegrants also improve the drug dissolution from encapsulated dosage forms. Encapsulation of solid material results in a plug formation, which delays the disintegration and dissolution of the drug from the capsules. Disintegrants improve the dissolution of the contents of the capsule by promoting liquid penetration into the plug and breaking the plug into smaller particles. But the addition of one more excipient i.e. disintegrant further leads to an increase in the cost of the dosage form.
The present inventors have developed a disintegrant free oral composition comprising celecoxib. It provides a reduction in dosage form weight as well as the cost without compromising the dissolution properties of the dosage form. The present formulation releases not less than 70 % of celecoxib in one-hour inspite of not including a disintegrant. The present invention provides a simple and economical method for preparing orally effective compositions of celecoxib.
SUMMARY OF THE INVENTION
The present invention relates to disintegrant free oral composition of celecoxib and processes for preparing them.
One of the aspects of the present invention relates to disintegrant free oral composition comprising celecoxib or a pharmaceutically acceptable salt thereof.
According to one of the embodiments the present invention relates to disintegrant free oral composition comprising celecoxib or a pharmaceutically acceptable salt thereof having d0.9 less than 200 urn, particularly less than 150 urn, more particularly less than 50 µm and most particularly less than 25 urn.
According to another embodiment disintegrant free oral compositions of the present invention comprise celecoxib or a pharmaceutically acceptable salt thereof in an amount of 10 mg to 1000 mg, particularly 50 mg to 800 mg, more particularly 75 mg to 400 mg, and most particularly 100 mg to 200 mg.
According to another embodiment disintegrant free oral composition of the present invention further comprises one or more pharmaceutically acceptable excipients selected from the group consisting of diluents, binders, wetting agents, lubricants and anti-adherents.
Another aspect of the present invention relates to disintegrant free oral composition comprising celecoxib or a pharmaceutically acceptable salt thereof wherein said composition is in the form of tablets, pills, capsules, lozenges, sachets or pastilles.
According to another aspect the disintegrant free oral compositions of the present invention are prepared using the process of wet granulation, compaction, dry granulation or encapsulation. Particularly the compositions of the present invention are prepared by wet granulation or dry compaction.
According to yet another aspect the disintegrant free oral compositions of the present invention release not less than 70 % of celecoxib in one hour. Particularly release not less than 75 % of celecoxib in one hour. More particularly release not less than 80 % of celecoxib in one hour.
Still another aspect of the present invention provides a method of treating a disorder in a subject where treatment with cyclooxygenase-2 inhibitor is indicated, using the compositions of the present invention.
DESCRIPTION OF THE INVENTION
The present invention is directed to disintegrant free oral compositions comprising celecoxib. It further relates to processes for preparing such compositions.
The phrase "pharmaceutically-acceptable salts" as used herein embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. Suitable pharmaceutically acceptable acid addition salts celecoxib may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric,
pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicyclic, p-hydroxybenzoic, phenylacetic, mandelic, embonic, methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic, b-hydroxybutyric, salicyclic, galactaric and galacturonic acid.
Suitable pharmaceutically-acceptable base addition salts of celecoxib include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Particularly compositions of the invention comprise celecoxib in its free form.
The term "do.g" as used herein with reference to the size of celecoxib particles, indicate that about 90 volume % of particles measured have a size less than the defined do.g value, and that about 10 volume % of particles measured have a size greater than the defined do.g value.
The phrase "disintegrant free oral compositions" as used herein refers to the oral compositions of celecoxib, which do not contain any disintegrant. However, when the compositions of the present invention are in the form of a tablet an extragranular disintegrant may be added.
The compositions of the present invention comprise celecoxib having do.g less than 200 µm, particularly less than 150 µm, more particularly less than 50 µm and most particularly less than 25 µm.
Celecoxib is present in an amount of 10 mg to 1000 mg, particularly 50 mg to 800 mg, more particularly 75 mg to 400 mg, and most particularly 100 mg to 200 mg in the compositions of the present invention.
The disintegrant free oral compositions of the present invention further comprise one or more pharmaceutically acceptable excipients selected from the group consisting of diluents, binders, wetting agents, lubricants and anti-adherents.
Suitable examples of diluents include, either individually or in combination, lactose USP; lactose USP, anyhydrous; lactose USP, spray dried; starch USP; directly compressible starch; mannitol USP; sorbitol; dextrose monohydrate; microcrystalline cellulose NF; dibasic calcium phosphate dihydrate NF; sucrose-based diluents; confectioner's sugar; monobasic calcium sulfate monohydrate; calcium sulfate dihydrate NF; calcium lactate trihydrate granular NF; dextrates, NF (e.g., Emdex); Celutab; dextrose (e.g., Cerelose); inositol; hydrolyzed cereal solids such as the Maltrons and Mor-Rex; amylose; Rexcel; powdered cellulose; calcium carbonate; glycine; bentonite; polyvinylpyrrolidone; and the like. Particularly lactose is used in the compositions of the present invention.
Suitable examples of binding agents include, either individually or in combination, acacia; tragacanth; sucrose; gelatin; glucose; starch; cellulose materials such as, methylcellulose and sodium carboxymethylcellulose (e.g., Tylose); alginic acid and salts of alginic acid; magnesium aluminum silicate; polyethylene glycol; guar gum; polysaccharide acids; bentonites; polyvinylpyrrolidone; polymethacrylates; hydroxypropylmethylcellulose (HPMC); hydroxypropylcellulose (Klucel); ethylcellulose (Ethocel); pregelatinized starch (such as National 1511 and Starch 1500). Polyvinylpyrrolidone is a preferred binding agent.
Examples of wetting agents include, individually or in combination, oleic acid; glyceryl monostearate; sorbitan monooleate; sorbitan monolaurate; triethanolamine oleate; polyoxyethylene sorbitan monooleate; polyoxyethylene sorbitan monolaurate; sodium oleate; and sodium lauryl sulfate. Wetting agents that are anionic surfactants are preferred. Particularly compositions of the present invention include sodium lauryl sulfate.
Suitable lubricants and/or glidants include, either individually or in combination, glyceryl behapate (Compritol 888); stearates (magnesium, calcium, and sodium); stearic acid; hydrogenated vegetable oils (e.g., Sterotex); talc; waxes: Stearowet; boric acid; sodium benzoate; sodium acetate; sodium fumarate; sodium chloride; DL-leucine; polyethylene glycols (e.g., Carbowax 4000 and Carbowax 6000); sodium oleate; sodium lauryl sulfate; and magnesium lauryl sulfate. Magnesium stearate is a preferred lubricant being used in the compositions of the present invention.
Other carrier materials (such as anti-adherent agents, colorants, flavors, sweeteners and preservatives) are known in the pharmaceutical art and can be included in compositions of the present invention.
According to one of the embodiments disintegrant free oral compositions of the present invention are in the form of tablets, pills, capsules, lozenges, sachets or pastilles.
The composition of the present invention may be prepared in accordance with methods well known to the person skilled in the field of pharmacy. For example, wet granulation, dry granulation, compaction or encapsulation method can be employed to prepare the compositions of the present invention. Particularly the compositions of the present invention are prepared by wet granulation or dry compaction.
According to another embodiment disintegrant free oral compositions of the present invention show a similar release profile at four different pH values i.e highly basic pH 12, very slightly acidic pH 6.8, slightly acidic pH 4.5 and highly acidic pH 1.2.
The present invention also relates to a method of treatment of disorder where treatment with cyclooxygenase-2 inhibitor is indicated (for example osteoarthritis, rheumatoid arthritis and ankylosing spondylitis) by administering an effective amount of a composition of the present invention to a patient in need of such treatment.
The following examples represent various embodiments of the present invention. The examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention, as many variations thereof are possible without departing from the spirit and scope of the invention.
EXAMPLE
Oral capsule containing celecoxib

(Table Removed)
Process
1. Celecoxib, polyvinylpyrrolidone and lactose were sifted through a sieve.
2. Material of step 1 was then mixed in a high shear mixer.
3. Sodium lauryl sulphate was dissolved in purified water to prepare a solution.
4. Material of step 2 was granulated using the solution of step 3.
5. Wet mass of step 4 was then dried in a Fluid bed dryer.
6. The dried granules were then sifted and milled.
7. Magnesium stearate was sifted through a sieve and blended with the granules of step 6.
8. Finally the above blend was filled in hard gelatin capsules of suitable size.
Comparative dissolution data of the disintegrant free compositions of the present invention with the marketed formulation of celecoxib i.e. CELEBREX are given in Tables 1, 2, 3 & 4. Capsules were tested for drug release in four different media.
Table 1
Drug release was determined in 1000 ml of disodium phosphate buffer (containing 1% sodium lauryl sulphate; pH 12) at 37 °C using USP apparatus II with paddle speed at 50 rpm.
(Table Removed)
Table 2
Drug release was determined in 1000 ml of acetate buffer (containing 1% sodium lauryl sulphate; pH 4.5) at 37 °C using USP apparatus II with paddle speed at 50 rpm.
Table 3
(Table Removed)
Drug release was determined in 1000 ml of 0.1 N HCI (containing 1% sodium lauryl sulphate; pH 1.2) at 37 °C using USP apparatus II with paddle speed at 50 rpm.

Table 4
(Table Removed)
Drug release was determined in 1000 ml of sodium phosphate buffer (containing 1% sodium lauryl sulphate; pH 6.8) at 37 °C using USP apparatus II with paddle speed at 50 rpm.
(Table Removed)
While several particular forms of the invention have been illustrated and described, it will be apparent that various modifications and combinations of the invention detailed in the text can be made without departing from the spirit and scope of the invention. Accordingly, it is not intended that the invention be limited, except as by the appended claims.

WE CLAIM:
1. A disintegrant free oral composition comprising celecoxib or a pharmaceutically acceptable salt thereof.
2. The disintegrant free oral composition of claim 1 wherein the d0.9 of celecoxib particles is less than 200 µm.
3. The disintegrant free oral composition of claim 1 wherein celecoxib is present in an amount of about 10 mg to about 1000mg.
4. The disintegrant free oral composition of claim 1 further comprising one or more pharmaceutically acceptable excipients selected from one or more of diluents, binders, wetting agents, lubricants, anti-adherents or mixtures thereof.
5. The disintegrant free oral composition of claim 1 wherein said composition is in the form of tablets, pills, capsules, lozenges, sachets or pastilles.
6. The disintegrant free oral composition of claim 5 wherein said composition is prepared by directly encapsulating or directly comprising celecoxib with one or more excipients.
7. The disintegrant free oral composition of claim 5 wherein said composition is prepared by wet granulating celecoxib with one or more excipients prior to encapsulation or compression.
8. The disintegrant free oral composition of claim 5 wherein said composition is prepared by dry granulating celecoxib with one or more excipients prior to encapsulation or compression.
9. The disintegrant free oral composition wherein said composition is used for the treatment or prophylaxis of a cyclooxgenase-2 mediated condition or disorder.
10. A disintegrant free oral composition comprising celecoxib or a pharmaceutically acceptable salt thereof substantially as described and illustrated herein.