DESC:FIELD OF THE INVENTION
The present invention relates to pharmaceutical compositions of Licofelone, or a pharmaceutically acceptable ester, salt or solvate thereof, suitable for oral administration together with one or more pharmaceutically acceptable excipients wherein the compositions apart from exhibiting good stability also have improved dissolution profile.
BACKGROUND OF THE INVENTION
Licofelone (ML-3000) is a pyrrolizine derivative orally-active dual cyclooxygenase-1 and -2 and 5-lipoxygenase inhibitor (dual acting anti-inflammatory drug), was under development as an anti-inflammatory and analgesic by the Euro Alliance consortium (Alfa Wassermann/Lacer/Merckle). Licofelone has been evaluated in clinical trials for the indication of osteoarthritis (Laufer S., Expert Opin Investig Drugs 12(7):1239-41, 2003; Reginster J. et al., Annual European Congress of Rheumatology, EULAR 2002, p.abstr. THU0189, 12 Jun. 2002), rheumatoid arthritis (Gay R. E., et al., J Rheumatol 28(9):2060-5, 2001) and pain. In animal experiments the compound showed antiphlogistic, analgesic, antipyretic, antiasthmatic and antiaggregative activity at a dosage that causes no gastrointestinal damage (Laufer S. Et al, Arzneimittelforschung 44(5):629-36), 1994). Results of a phase III trial showed that Licofelone was at least as effective as naproxen in the long-term treatment of osteoarthritis of the knee (n=704). At dosages of Licofelone 200 and 400 mg/day bid and naproxen 1000 mg/day bid, the greatest improvement in efficacy parameters was achieved with Licofelone 400 mg/day bid (Blanco F. J. Et al, Ann Rheum Dis 62(1):262, 2003).
In accordance with the prior art, Licofelone was disclosed in European patent No. 397175, US5260451 and Licofelone choline and tromethamine salt are disclosed in US patent No. 8519155 and licofelone polymorph in US patent No: 8034837. Indian patent application No. 2006DEL1652 discloses novel salts and 2004DE00004 discloses novel polymorphs.
International application No: 9641626, 2007072503 disclose combinations of a cyclooxygenase-2 inhibitor and a 5-lipoxygenase inhibitor for treatment of inflammation and inflammation-related disorders. US20050129764 discloses osmotic devices for a controlled release of licofelone to maintain therapeutically effective levels of licofelone in plasma when administered once per day.
International application No. 2005041920 discloses a solid pharmaceutical formulation containing licofelone or a physiologically acceptable salt thereof and at least one water soluble polymer. US patent application No. 20080286343 discloses a solid film enrobing a compacted fill material with at least one active material contained in a matrix that exhibits a controlled release profile for release of the active material.
In accordance with the prior art, Licofelone doses of 200 and 400 mg/day, administered as divided doses have been found effective for many patients. Following a 200 mg Licofelone dose administered twice daily, peak plasma Licofelone concentrations of about 1650-1750ng/ml were reached at 0.74-4 h post-dose. Licofelone exhibited an elimination half-life (T1/2ß) of about 8.7-11.1 hours (Albrecht W. et al., Annual European Congress of Rheumatology, EULAR 2002, p.abstr. AB0293 12 Jun. 2002). A single dose of Licofelone (800-3,200) mg (4-fold the therapeutic dose) was generally well tolerated in volunteers (Bias P. Et al., Ann Rheum Dis 62 (1): 479 2003).
Licofelone free Acid (LIFA) exhibits BCS –II characteristics i.e., very poor solubility; therefore, it is not surprising that the oral LIFA compositions, as observed during clinical investigations, gave rise to relatively poor bioavailability results and a large inter-individual variability.
Thus, there has been a long-felt need for a stable dosage-form comprising Licofelone which is easy to administer to the patient, sufficiently optimized and which exhibit acceptable stability and bioavailability.
SUMMARY OF THE INVENTION
In order to solve the above problems, the present inventors have carried out detailed investigations. They finally succeeded in obtaining the stable pharmaceutical compositions according to the invention.
Thus, the object of the present invention is to provide pharmaceutical compositions, suitable for oral administration, comprising Licofelone or a pharmaceutically acceptable ester, salt or solvate thereof as an active ingredient, and at least one pharmaceutically acceptable excipient, wherein the compositions apart from having a good stability also have the desired dissolution profile.
In one aspect, the present invention provides pharmaceutical compositions of Licofelone or a pharmaceutically acceptable ester, salt or solvate thereof, suitable for oral administration via a liquid- or semi-solid-filled capsule, delayed release tablets wherein the compositions exhibit acceptable stability and bioavailability and are therefore particularly suited for the delivery of therapeutically effective amount of Licofelone.
Further, in another aspect the present invention provides pharmaceutical compositions, suitable for oral administration via a liquid- or semi-solid-filled capsule, delayed release tablets comprising Licofelone, or a pharmaceutically acceptable ester, salt or solvate thereof, together with optionally, in combination with one or more pharmaceutically acceptable hydrophilic solvent, and optionally one or more pharmaceutically acceptable excipients.
In another object, the present invention provides pharmaceutical compositions comprising Licofelone, or a pharmaceutically acceptable ester, salt or solvate thereof, together with one or more pharmaceutically acceptable non-ionic surfactants, optionally, in combination with one or more pharmaceutically acceptable hydrophilic solvent, wherein the compositions exhibit acceptable stability and bioavailability and are therefore particularly suited for the delivery of therapeutically effective amount of Licofelone.
In yet another aspect, the present invention provides methods for preparation of pharmaceutical compositions of the present invention comprising of but not limited to
Step 1: Blending the excipients
Step 2: Mixing with extragranular excipients
Step 3: Seal coating to the granules obtained in step 2.
Step 4: Enteric coating or delayed release coating to the granules obtained in step 3
Step 5: Second enteric coating or delayed release coatingcoating to the granules obtained in step 4

Thus other object of the present invention is to provide process for the preparation of the Licofelone pharmaceutical composition comprising
Step 1: Polymer is added to solvent under stirring until a clear solution is obtained.
Step 2: Antioxidant is added to the solution obtained in step 1) under stirring until a clear solution is obtained.
Step 3: Active pharmaceutical ingredient (API) is added to the solution obtained in step 2) under stirring, to obtain a uniform suspension.
Step 4: The suspension obtained in step 2) is filled in hard gelatin capsules.
Another important aspect of the present invention involves a method of treating osteoarthritis, rheumatoid arthritis, and inflammatory related disorders in a mammal by administering to the mammal a therapeutically effective amount of a pharmaceutical composition of the present invention.
BRIEF DESCRIPTION OF DRAWINGS:
Figure 1: Dissolution Graph at pH 7.5, Phosphate buffer for licofelone delayed release tablets

DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to pharmaceutical compositions, suitable for oral administration, comprising Licofelone or a pharmaceutically acceptable ester, salt or solvate thereof as an active ingredient, and at least one pharmaceutically acceptable excipient, wherein the compositions apart from having a good stability also have the desired dissolution profile.
The present invention provides for the administration of Licofelone in its free acid, racemic, optically pure, stereoisomeric and/or pharmaceutically acceptable salt forms. The invention also provides for the administration of derivatives and analogues of Licofelone.
The term “pharmaceutically acceptable ester thereof” describes any pharmaceutically acceptable ester of Licofelone, such as esters with alkyl alcohols and sugar alcohols.
The term“Pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the therapeutic compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of the Licofelone. The pharmaceutically acceptable salts include the conventional non-toxic salts, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfonic, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as amino acids, acetic, propionic, succinic, glycolic, choline, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and other known to those of ordinary skill in the pharmaceutical sciences.
The term “pharmaceutically acceptable solvate thereof” describes any pharmaceutically acceptable solvate that, administered to a patient (directly or indirectly) provides Licofelone. This term further comprises the pharmaceutically acceptable solvate of a Licofelone ester. Preferably, the solvate is a hydrate, a solvate with an alcohol such as methanol, ethanol, propanol, or isopropanol, a solvate with an ester such as ethyl acetate, a solvate with an ether such as methyl ether, ethyl ether or THF (tetrahydrofuran) or a solvate with DMF (dimethylformamide), of which a hydrate or a solvate with an alcohol such as ethanol is more preferred. A solvent for constituting the solvate is preferably a pharmaceutically acceptable solvent.
It is especially preferred that the active ingredient in the invention's compositions is Licofelone or a pharmaceutically acceptable salt thereof. It is most preferred that the active ingredient is Licofelone choline salt.
In one aspect the present invention provides pharmaceutical compositions of Licofelone or a pharmaceutically acceptable ester, salt or solvate thereof, suitable for oral administration via a liquid- or semi-solid-filled capsule, wherein the compositions exhibit acceptable stability and bioavailability and are therefore particularly suited for the delivery of therapeutically effective amount of Licofelone.
The term “semi-solid” means a material that is neither solid (elastic behaviour) nor liquid (viscous behaviour) and possesses the characteristics of both viscosity and elasticity. Examples of semi-solid materials include gels, ointments, creams, and highly viscous liquids.
The term “therapeutically effective amount” means an amount of a compound according to the invention which, when administered to a patient in need thereof, is sufficient to effect treatment of osteoarthritis, rheumatoid arthritis, and inflammatory related disorders. Such a therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their own knowledge, the prior art, and this disclosure.
In another aspect the present invention provides pharmaceutical compositions comprising Licofelone, or a pharmaceutically acceptable ester, salt or solvate thereof, together with one or more pharmaceutically acceptable non-ionic surfactants, optionally, in combination with one or more pharmaceutically acceptable hydrophilic solvent, wherein the compositions exhibit acceptable stability and bioavailability and are therefore particularly suited for the delivery of therapeutically effective amount of Licofelone.
The term “pharmaceutically acceptable” with respect to a substance as used herein means that substance which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for the intended use when the substance is used in a pharmaceutical composition.

The term "excipient" as used herein means selected from but not limited to binder, lubricant, glidant, disitengrant, surfactant or combinations thereof or a pharmacologically inactive compound such as a diluent, a disintegrant, a lubricant, a glidant, a binder, a surfactant comprised in a pharmaceutical product. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and are acceptable for human use. Reference to an excipient includes both one and more than one such excipients.

The term "binder" as used herein means a substance that helps bind the active ingredient and other excipients together in a tablet. Binder ensures that tablets and granules can be formed having desired and required mechanical strength.

The term “pharmaceutical composition” as used herein means is selected from but not limited to granules, pellets, micro-pellets, spheres, cores, coated cores, pills, tablets, beads, particles and capsules, film, liquids or semi-solid-liquids and combinations thereof and well known in the pharmaceutical field.

The term “tablet” includes solid dosage forms comprising at least one drug (active drug) and optionally at least one pharmaceutically acceptable carrier and / or additive. A tablet may include at least one active ingredient and typically a diluent (excipient), a binder, and a lubricant. The tablets include but not limited to compressed tablets, mini tablets, coated tablets, layered tablets, release control tablets, sustain release tablets, delayed release tablets, enteric coated tablets.

The term “mini-tablet” refers to a sub-form of a tablet. Mini-tablets can be tablets with typical diameters ranging from 1 mm to 4 mm and heights ranging from 1 mm to 4 mm.
The term “capsule” refers to a solid dosage form in which the drug is contained in a hard or soft soluble container or “shell”. The container or shell can be formed from gelatin, starch and / or other suitable materials.

The term "pellet" and "granule" and “cores” and “spheres” and beads” and “particles” are used to describe a variety of agglomerates. Pellets in the pharmaceutical context are defined as isometric agglomerates with a smooth surface and a narrow size distribution. All these are solid agglomerates, made from powders with or without liquid binders. Pellets are isometric granules. Unless otherwise indicated, the term pellet refers to pellets as well as granules.

As used herein, the term “non-ionic surfactant” refers to an amphiphilic compound having a polar, hydrophilic group and a non-polar, lipophilic group or chain and wherein the hydrophilic and lipophilic properties of the compound are characterised by the so-called Hydrophilic-Lipophilic Balance (HLB) value. The non-ionic surfactant to be used for preparing the compositions of the present invention preferably has an HLB-value between 10 and 20 and preferably between 12 and 18. The non-ionic surfactant further has a melting point, pour point or melting range between 5° C. and body temperature (37° C.) and preferably between just below room temperature (20° C.) and body temperature. The material can be in a liquid or a semi-solid state at room temperature. The amphiphilic material is a carrier for the Licofelone active ingredient, which can be present in a dissolved form, a suspended form or partly in a dissolved and partly in a suspended form.
The present invention is based on the surprising finding that stable compositions of Licofelone having a specific and desirable dissolution profile can be obtained by incorporating into the pharmaceutical composition certain non-ionic surfactants. It has been found that if a pharmaceutically acceptable non-ionic surfactant, selected from the group consisting of a polyethoxylated castor oil or derivative thereof and a block copolymer of ethylene oxide and propylene oxide and preferably selected from the group consisting of macrogol glycerol hydroxystearate, polyoxyl-35-castor oil and ethylene oxide/propylene oxide block copolymer (Pluronic® L44 NF or Poloxamer® 124) is used as an excipient in a pharmaceutical composition comprising Licofelone or a pharmaceutically acceptable ester, a salt or a solvate thereof as an active ingredient, a particularly favourable profile of the composition with respect to stability and degradation products, dissolution, bioavailability and a reduced variability in bioavailability is achieved.
The incorporation of the above-mentioned non-ionic surfactants in Licofelone-containing compositions results in a dissolution profile of at least 60% Licofelone dissolved after 20 minutes, 70% dissolved after 40 minutes, as measured with a paddle apparatus at 75 rpm according to the European Pharmacopoeia in 500 ml of a dissolution medium (0.1N HCL (SGF)) and preferably it results in a dissolution of at least 60% Licofelone dissolved after 10 minutes, 70% after 20 minutes.
The amount of non-ionic surfactants in the composition may also vary over a wide range and the optimum amount for a particular composition will depend on the type and amount of other the other ingredients in the composition as can be determined by the skilled pharmaceutical technician. The pharmaceutically acceptable hydrophilic surfactant is preferably present in an amount of up to about 80% by weight.
The compositions of the present invention may further comprise a pharmaceutically acceptable hydrophilic solvent to: (1) enhance the solubility of the active drug substance and prevent its precipitation out of the formulation, (2) reduce the mixing time of the bulk liquid fill composition during manufacturing for encapsulation into capsules and/or (3) improve the aqueous dispersibility of the formulation. Examples of hydrophilic solvents that can be used include, for example, propylene glycol, polypropylene glycol, polyethylene glycol, glycerol, ethanol, dimethyl isosorbide, glycofurol, propylene carbonate, dimethyl acetamide, water, or mixtures thereof. Preferred hydrophilic solvents include propylene glycol, polyethylene glycol (e.g., PEG 400), ethanol, water, and mixtures thereof.

The amount of solvent in the composition may also vary over a wide range and the optimum amount for a particular composition will depend on the type and amount of other the other ingredients in the composition as can be easily determined by the skilled worker. In general, however, the solvent(s) are present in an amount of up to about 30% by weight, preferably up to 15% by weight.
Further, in another aspect the present invention provides pharmaceutical compositions, suitable for oral administration via a liquid- or semi-solid-filled capsule, comprising Licofelone, or a pharmaceutically acceptable ester, salt or solvate thereof, together with one or more pharmaceutically acceptable non-ionic surfactants, optionally, in combination with one or more pharmaceutically acceptable hydrophilic solvent, and one or more pharmaceutically acceptable excipients.
If desired, the compositions according to the present invention may further include conventional pharmaceutical additives as is necessary or desirable to obtain a suitable formulation, such as antioxidants, lubricants, disintegrants, preservatives, buffers, stabilizers, scavengers, thickening agents, coloring agents, sweetening agents, flavoring agents, fragrances, etc.

In one preferred embodiment, the compositions according to the present invention further contain one or more antioxidants. Preferred antioxidants include, for example, ascorbic acid, sulfatide salts, citric acid, propyl gallate, dl-alpha-tocopherol, ascorbyl palmitate, BHT or BHA. If present, the antioxidant is generally present in an amount of from about 0.01% to 1% by weight.

In another preferred embodiment, the composition of the present invention can further comprise an active carbonyl (e.g., aldehydes, ketones) scavenger (e.g., amines including TRIS and meglumine) to reduce the cross-linking of gelatin capsules which might adversely affect the release of the formulation from the dosage form.

Stabilizers that may be used can include, e.g., some alkaline agents, including amines, which raise the apparent pH of the fill formulation.
The pharmaceutical compositions according to the present invention are advantageously filled into a capsule, which can then easily be taken by the patient.
Two types of capsules are commonly used and are classified according to the nature and flexibility of the capsule shell: soft and hard capsules.
Soft capsules are single unit solid dosage forms comprising a liquid or semi-solid fill. They are formed, filled and sealed in one operation using a rotary die process. They have been used as unit dose containers for liquids for many years, whereas hard capsules have conventionally been used for the delivery of solids in the form of powders, granulates and pellets. Hard capsules are single unit dosage forms, consisting of a cap and a body, which are manufactured separately and which are supplied empty for filling.
Soft capsules are most commonly manufactured from gelatine, to which a plasticiser, usually glycerine or sorbitol, is added in addition to water. Also, for hard capsules the most commonly used polymer is gelatine.Both soft and hard capsules in addition can include colouring agents and opacifiers.
It has surprisingly been found that the compositions according to the present invention can be advantageously administered in hard gelatine capsules.
In yet another aspect, the present invention provides methods for preparation of pharmaceutical compositions of the present invention.
The composition of the present invention may be prepared in a conventional manner, for example, by a method comprising mixing together the liquid components, e.g., the pharmaceutically acceptable non-ionic surfactant(s) and hydrophilic solvent(s); optionally heating the mixture obtained, if necessary, to sufficiently melt one or more of the components of the mixture; adding active ingredient to the resulting mixture and further mixing until all or substantially all of the active ingredient is solubilized, e.g. until the solution is visually clear.

The resulting fill solution is then formulated into the desired dosage form, for example, capsules including hard shell or softgel capsules (e.g., hard or soft gelatin capsules), by known manufacturing technology.
The preferred type of capsule for the compositions according to the present invention is the hard capsule and more in particular the hard gelatine capsule. Ideally, the materials to be filled into the capsule are fluid at room temperature, which would avoid heating during the filling operation. Generally, heating could result in an easy degradation of the active component.
The present invention is also related to treating osteoarthritis, rheumatoid arthritis, and inflammatory related disorders in a mammal by administering to the mammal a therapeutically effective amount of the pharmaceutical compositions of the present invention.
The dose of the active ingredient in the pharmaceutical composition may readily be determined by the skilled artisan depending on the patient's condition, sex, body weight, body surface area, or age, especially depending on the patient's body weight and body surface area. It is preferred that the daily dosage ranges from about 50 to about 1000 mg, preferably from about 100 to about 500 mg of the active ingredient.
The daily dosage may be taken as a single dose or as multiple doses such as twice or three-times daily, most preferably as a single daily dose. The daily dose may be taken once a week or several times a week. The dosage form may contain the amount of a single daily dose or parts thereof. An appropriate therapeutically effective amount of the pharmaceutical composition to be administered can be determined routinely by one of ordinary skill in the art having regard to their own knowledge, the prior art, and this disclosure.
Combination therapy is also possible with one or more additional therapeutic or prophylactic agents. The additional agent(s) may be combined with the compounds of this invention to create a single dosage form or, alternatively, these additional agent(s) may be separately administered to a mammal as part of a multiple dosage form.
The following examples further illustrate the invention. It will be apparent to the skilled person that these examples are solely for illustrative purposes and must not be considered to limit the invention.
Example 1: Liquid filled hard capsule composition

Component %w/w
Licofelone Choline salt 30.8
Polyoxyl 35 castor oil 67.0
Colloidal silicon dioxide 2.2

Process for preparation:
1. Colloidal silicon dioxide was added to Polyoxyl 35 castor oil under stirring until a clear solution is obtained.
2. Licofelone choline salt is added to the solution obtained in step 1) under stirring, to obtain a uniform suspension.
3. The suspension obtained in step 2) is filled in hard gelatin capsules.

Example 2: Liquid filled hard capsule composition

Component %w/w
Licofelone Choline salt 38.8
Polyoxyl 35 castor oil 45.5
Propylene Glycol 15.5
Butylated hydroxy toluene 0.2

Process for preparation:
1. Propylene glycol was added to Polyoxyl 35 castor oil under stirring until a clear solution is obtained.
2. Butylated hydroxyl toluene was added to the solution obtained in step 1) under stirring until a clear solution is obtained.
3. Licofelone choline salt is added to the solution obtained in step 2) under stirring, to obtain a uniform suspension.
4. The suspension obtained in step 2) is filled in hard gelatin capsules.
The principles, preferred embodiments, and modes of operation of the present invention have been described in the foregoing specification. The invention which is intended to be protected herein, however, is not to be construed limited to the particular forms disclosed, since these are to be regarded as illustrative rather than restrictive. Variations and changes may be made by those skilled in the art, without departing from the spirit of the invention.
Liquid filled hard capsule composition
S.No Ingredient Example 3
(% w/w) Example 4
(% w/w)
1 Licofelone choline 25.89 27.71
2 Microcrystalline cellulose 25.30 32.68
3 Di Calcium Phosphate 8.09 10.89
4 Croscarmellose sodium 2.01 2.18
5 Magnesium stearate 0.32 0.44
Extra granular
6 Croscarmellose sodium 2.18 2.18
7 Lactose anhydrous 10.25 10.25
8 Magnesium stearate 0.82 0.82
9 Microcrystalline cellulose 5.42 5.45
Core Tablet weight 78.57 92.59
Enteric coating Composition (Aqueous coating)
13 Eudragit L30D55 5.33 4.63
14 Triethyl Citrate 0.41 0.46
15 Talc (Luzenac Pharma M) 2.50 2.31
16 Water (15%) Qs Qs
Total Weight of tablet 100.00 100.00

Table 1: Dissolution profiling on stability samples of Licofelone cholineliquid filled hard capsule composition
Time Points Initial 3M
40ºC/75% RH 3M
30ºC/65% RH 3M
25ºC/60% RH
0 min 0 0 0 0
10 min 25 35 45 60
30 min 90 95 91 90
45 min 95 92 91 90
2 hrs 0 0 0 0

Table 2: Stability Data - : Licofelone choline liquid filled hard capsule composition

S. No. Test Initial 40oC/75% RH (3M) 30oC/65% RH (3M) 25oC/60% RH (3M)
2 Assay 99.9 102.4 102.8 99.9
3. Water Content 3.90 4.24 4.10 4.07

Example 5: Licofelone delayed release tablets 200 mg

S.No Ingredient % w/w
Intragranular
1 Licofelone choline 27.71
2 Microcrystalline cellulose 32.68
3 Di Calcium Phosphate 10.89
4 Croscarmellose sodium 2.18
5 Magnesium stearate 0.44
Extra granular
6 Microcrystalline cellulose 2.18
7 Croscarmellose sodium 10.25
8 Lactose anhydrous 0.82
9 Magnesium stearate 5.45
Core Tablet weight 92.59
Seal coating
10 HPMC E5 2.63
11 DMC (70%) Qs
12 IPA (30%) Qs
EC-I Coating Solids
13 Methacrylic acid co-polymer, Type-A 2.33
14 Triethyl Citrate 0.41
15 Talc (Luzenac Pharma M) 0.17
16 IPA (70%) NA
17 Acetone (30%) NA
EC-II Coating Solids
18 Methacrylic acid 2.40
19 Triethyl Citrate 0.40
20 Talc (Luzenac Pharma M) 1.20
21 Water (15%) Qs
Total Weight of tablet 100.00

Table 3: Stability Data - : Licofelone choline delayed release Tablets 200 mg
S. No. Test Initial 40oC/75% RH (3M) 30oC/65% RH (3M) 25oC/60% RH (3M)
2 Assay 99.9 102.4 102.8 99.9
3. Water Content 3.90 4.24 4.10 4.07

Table 4: Dissolution profiling on stability samples of Licofelone choline delayed release Tablets 200 mg.
Time Points Initial 3M
40ºC/75% RH 3M
30ºC/65% RH 3M
25ºC/60% RH
0 min 0 0 0 0
10 min 20 23 37 46
30 min 92 89 92 90
45 min 92 90 93 91
2 hrs 0 0 0 0

Example 6: Process of preparing the delayed release tablets 200 mg
Step 1: Blending the excipients
Step 2: Mixing with extragranular excipients
Step 3: seal coating to the granules obtained in step 2.
Step 4: enteric coating or delayed release coating to the granules obtained in step 3
Step 5: second enteric coating or delayed release coating coating to the granules obtained in step 4
,CLAIMS:Claims:
1. An oral pharmaceutical composition comprising licofelone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.
2. The oral pharmaceutical composition as claimed in claim 1 wherein the oral pharmaceutical composition is selected from but not limited to granules, pellets, micro-pellets, spheres, cores, pills, tablets, mini tablets, beads, particles and capsules,film, liquids or semi-solid-liquids.
3. The oral pharmaceutical composition as claimed in claim 1 wherein the said at least pharmaceutically acceptable excipient is selected from but not limited to binder, lubricant, glidant, disitengrant, surfactant or combinations thereof.
4. The oral pharmaceutical composition as claimed in claim 1comprises a delayed release tablet.
5. The oral pharmaceutical composition as claimed in claim 1 comprises a liquid or semisolid liquid
6. The oral pharmaceutical composition as claimed in claim 5 comprises a liquid or semi-solid liquid filled into capsule.
7. The oral pharmaceutical composition as claimed in claim 1 is used to treat but not limited osteoarthritis, rheumatoid arthritis, inflammatory related disorders and pain.
8. The process of preparing the oral pharmaceutical composition as claimed in claim 1 comprises:
1. Polymer is added to oil solution under stirring until a clear solution is obtained.
2. Antioxidant is added to the solution obtained in step 1) under stirring until a clear solution is obtained.
3. Active pharmaceutical ingredient is added to the solution obtained in step 2) under stirring, to obtain a uniform suspension.
4. The suspension obtained in step 2) is filled in hard gelatin capsules.
9. The process of preparing the oral pharmaceutical composition as claimed in claim 1 comprises:
1. Blending the excipients
2. Mixing with extragranular excipients
3. Seal coating to the granules obtained in step 2.
4. Enteric coating or delayed release coating to the granules obtained in step 3
5. Second enteric coating or delayed release coating coating to the granules obtained in step 4
10. The pharmaceutical composition prepared by the process as claimed in claim 8 or claim 9 is used but not limited to treat osteoarthritis, rheumatoid arthritis, inflammatory related disorders and pain.