FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION (SECTION 10 and Rule 13)
TITLE OF THE INVENTION "DEXKETOPROFEN PHARMACEUTICAL COMPOSITIONS"
Emcure Pharmaceuticals Limited,
An Indian company, registered under the Indian Company's Act 1957 and having its
registered office at
Emcure House, T-l84, M.I.D.C., Bhosari, Pune-411026, India.
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

TECHNICAL FIELD OF INVENTION
The present invention relates to pharmaceutical dosage forms comprising dexketoprofen and to the process for preparation of these dexketoprofen compositions.
BACKGROUND OF INVENTION
Dexketoprofen, chemically known as (+)-(S)-2-(3-Benzoylphenyl) propionic acid, is the S (+) enantiomer of ketoprofen which is responsible for therapeutic effect in non-steroidal antiinflammatory drugs (NSAIDs). Dexketoprofen trometamol disclosed in U.S. Patent No. 5,554,789 is an analgesic and anti-inflammatory drug characterized by advantageous pharmacokinetic and solubility properties with respect to dexketoprofen and other salts thereof. It is one of the most potent in-vitro inhibitors of prostaglandin synthesis and by blocking cyclo-oxygenase enzyme, it reduces inflammation and pain. Dexketoprofen trometamol is used for the treatment of painful musculoskeletal conditions such as osteo-arthritis and low back pain. It is also used as a treatment for post-operative pain, toothache and dysmenorrhoea.
U.S. Patent No. 5,554,789 first discloses dexketoprofen trometamol along with other dexketoprofen salts. Dexketoprofen trometamol, which is characterized by advantageous pharmacokinetic and solubility properties with respect to dexketoprofen and its other salts, is one of the most potent in-vitro inhibitors of prostaglandin synthesis. It reduces inflammation and pain by blocking cyclo-oxygenase enzyme and hence finds use in the treatment of painful musculoskeletal conditions such as osteo-arthritis and low back pain. It is also used as a treatment for post-operative pain, toothache and dysmenorrhoea.
EP 1739072 relates to the polymorph of dexketoprofen and discloses that Polymorphic form A is particularly suited for the preparation of solid oral pharmaceutical forms. The process disclosed herein for manufacture of tablets is by direct compression and it has been emphasized that the granulation techniques should be avoided in case of dexketoprofen trometamol, due to the stability issues.
International Application Publication No WO 2013/095315 relates to the effervescent composition comprising dexketoprofen that is useful as antipyretic, analgesic, anti-inflammatory

agent in treatment of mild and moderate pain such as toothache, menstrual pain, post-surgical pain, musculoskeletal pain.
International Application Publication No WO 2013/100877 discloses a pharmaceutical formulation comprising dexketoprofen characterized in that said formulation comprises talc, magnesium stearate, PEG 6000, silicon dioxide, sodium benzoate, potassium benzoate, stearic acid, sodium stearyl fumarate and/or a combination thereof as the lubricant
International Application Publication No WO 2014/007780 discloses an orally-disintegrating pharmaceutical tablet formulation, comprising dexketoprofen or a pharmaceutically acceptable salt of dexketoprofen and at least one methacrylate polymer and stearic acid.
International Application Publication No WO 2013/0182609 discloses a fast onset, stable, solid pharmaceutical composition comprising dexketoprofen trometamol. The document discloses wet granulation process to prepare the pharmaceutical compositions of dexketoprofen trometamol.
In preparation of formulations comprising dexketoprofen, it is observed that the said formulation mixtures have poor flow properties and therefore homogeneity cannot be achieved in the pharmaceutical compositions. This invariably results in weight variations and content uniform problems in the end product.
Thus, there remains a need for a solid oral dosage composition of dexketoprofen, which can be prepared by a simple process and utilizes excipients which prevent the problems arising from loss of weight and content uniformity in the formulation end product. Further there is a need for compositions which possess enhanced storage stability at ambient conditions.
SUMMARY OF INVENTION
The present invention relates to pharmaceutical formulations comprising dexketoprofen and methods for preparation of these formulations. Surprisingly, it has been found that a dexketoprofen tablet composition could be made by using a dry granulation process involving

roller compaction. The present inventors have found that the dexketoprofen tablet prepared by such a process posses high content uniformity and thereby has a minimum weight variation in the final product. Further the tablets produced according to present invention possess good stability.
Thus, in one embodiment, the present invention provides a pharmaceutical composition comprising dexketoprofen and pharmaceutical acceptable excipients.
In another embodiment, the present invention provides a simple and convenient process for preparation of pharmaceutical composition comprising dexketoprofen.
These and other advantages of the compositions disclosed herein, as well as additional inventive features, will be apparent from the description of the invention provided herein.
DETAIL DESCRIPTION OF INVENTION
The present invention relates to pharmaceutical formulations comprising dexketoprofen and methods for preparation of these formulations. Surprisingly, it has been found that a dexketoprofen tablet composition could be made by using a dry granulation process involving roller compaction.
As used herein, the term "dexketoprofen" includes the compound dexketoprofen, pharmaceutically acceptable salts of dexketoprofen, solvates, complexes and hydrates, anhydrous forms thereof, and any polymorphic or amorphous forms or combinations thereof. Dexketoprofen is preferably in the salt form, more preferably it is in dexketoprofen trometamol form. Dexketoprofen or pharmaceutically acceptable salt is in the range of 1-70% by weight of the composition.
Dry granulation is a well known method for preparation of tablet formulations. Dry granulation is usually described as a method of controlled crushing of precompacted powders densified by either slugging or passing the material between two counter-rotating rolls. More specifically, powdered components that may contain very fine particles are typically mixed prior to being compacted to yield hard slugs which are then ground and sieved before the addition of other

ingredients and final compression to form tablets. Because substantially no liquids are used in the dry granulation process, the issues related to wet granulation are avoided.
Dry roller compaction is the process of using mechanical pressure to compress fine powders into denser sheets. The basic concept of compaction is to force fine powders between two counter rotating rolls. As the volume decreases through the region of maximum pressure, the material is compressed into dense sticks or corrugated sheets. These sheets are then granulated through a milling system and series of screens to achieve the precise, uniform granule size specified.
The pharmaceutical formulations prepared according to the process of the present invention comprise various excipients in addition to the active agent dexketoprofen. Excipients are inert ingredients that are included to facilitate the preparation of the dosage forms or to adapt the release characteristics of the active ingredients, or for other purposes ancillary to those of the active ingredients.
The pharmaceutical formulations prepared according to the process of the present invention and comprising dexketoprofen comprise at least one excipient selected from a group comprising disintegrant, diluent, glidant, binder, colouring agent, pH regulating agent, surfactant, stabilizing agent, sweetener and/or taste regulating agent, flavouring agent in addition to the active agent dexketoprofen and the lubricant.
The disintegrant that can be used in the pharmaceutical formulations'prepared according to the process of the present invention and comprising dexketoprofen can be selected from a group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch, sodium starch glycolate and/or combination thereof.
Diluents are those substances or mixture of substances that when added to a formulation make that formulation thinner or less concentrated and may also improve manufacturability. Diluents can be used to stabilize compounds because they can provide a more stable environment. In certain embodiments, diluents increase the bulk of the composition to facilitate compression or

create sufficient bulk for a homogenous blend for capsule filling. Such compounds include e.g., lactose, starch, mannitol, sorbitol, dextrose, cellulose, microcrystalline cellulose, dibasic calcium phosphate, dicalcium phosphate dihydrate, tricalcium phosphate, calcium phosphate, lactose, anhydrous lactose, spray-dried lactose; pregelatinized starch, compressible sugar, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate, sucrose-based diluents, confectioner's sugar, monobasic calcium sulfate monohydrate, calcium sulfate dihydrate, calcium lactate trihydrate, dextrates, hydrolyzed cereal solids, amylosem, powdered cellulose, calcium carbonate, glycine, kaolin, sodium chloride; inositol, bentonite, and the like.
Lubricant means a substance that reduces friction between the composition of the present invention and the surfaces of the apparatus used to compact the composition into a compressed form. Suitable lubricants for the present invention include, for example, fatty acids, such as palmitic acid, stearic acid, oleic acid, hydrogenated vegetable oils, triglycerides of fatty acids, metal salts of fatty acids, such as for example, zinc stearate and magnesium stearate, glycols, such as polyethylene glycol, and talc, as well as mixtures thereof. Others well known lubricants are sodium benzoate, adipic acid, fumaric acid, glyceryl monostearate, glycerol distearate, gyceryl behenate, glyceryl palmitostearate, glycerol distearate. In one embodiment, the lubricant component of the composition of the present invention comprises magnesium stearate.
The glidant that can be used in the pharmaceutical formulations prepared according to the process of the present invention and comprising dexketoprofen can be selected from a group comprising tribasic calcium phosphate, colloidal silicone dioxide, magnesium silicate, magnesium trisilicate, talc and/or combination thereof.
"Binder" or "binding agent" refers to any substance or mixture that exerts a physicochemical attractive force between molecules, and hence may be used in the formulation of a dosage form. In one embodiment of the invention, the binder or the binding agent may be mixed with other components of the composition, so that it is distributed uniformly throughout the dosage form. Binders include, but are not limited to carboxymethyl cellulose sodium, ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose,

magnesium aluminium silicate, maltodextrin, methyl cellulose, povidone, starch and/or combination thereof.
In dry granulation, the powder blend is compacted by applying a force onto the powder, which in general causes a considerable size enlargement. The compacts thus obtained are called briquettes, flakes or ribbons. In order to obtain the desired granules, the compaction process is followed by a milling step. Principally there are two methods to obtain the compacts when using dry granulation, viz. slugging and roller compaction. In an embodiment, the present inventors have found that roller compaction is most suited for the preparation of dexketoprofen tablet formulation according to present invention. A typical process for preparation of tablet is as follows:
1. Sift dexketoprofen trometamol and other excipients through suitable size mesh
2. Mix dexketoprofen trometamol with suitable excipients;
3. Compress the mixture of step 2 with roller compaction;
4. Sift the compressed granules of step 3;
5. Add lubricants to the granules of step 4; and
6. Compress the lubricated granules of step 5 to get the tablet.
The following examples further illustrate the invention but should not be construed as in any way limiting its scope. In particular, the processing conditions are merely exemplary and can be readily varied by one of ordinary skill in the art.
Examples:
Preparation of dexketoprofen trometamol by dry granulation using roller compression
approach
Dexketoprofen trometamol, Perlitol SD 200, Sodium Starch Glycolate, Maize Starch & LHPC LH-11 was sifted through 40 # and mixed in blender for 10 min at 12±1 rpm. Magnesium stearate was sifted through 60 # sieve and mixed with above for 2 min at 12=1=1 rpm. Blend is compacted with roller compaction with compaction parameters as summarized in Table -1. Compressed granules were sifted through 18 # sieve and mix the compacted granules in blender for 5 min atl2±l rpm. Prelubrication was done by sifting, Sodium Starch Glycolate, Perlitol SD 200, & LHPC LH-11 from 40# sieve & mixing this with sized granules in blender for 10 minutes and above mixer was lubricated for 3 min with magnesium stearate which was already passed

through 60# sieve. The lubricated granules were then compressed in to tablets. In present invention stability of the formulation manufactured by such process is improved with respect to related substances test Table 1: Process parameters of roller compression for previous & final formulations

Compaction parameters
Screw feeder speed (rpm) 40-45
Roller unit speed (rpm) 08
Hydraulic pressure (bar) 200 to 250
Fine granulator speed (rpm) 40-60
Roller gap (mm) 1.0
Pre granulator screen size (mm) 3.15
Fine granulator screen size (mm) 2.00
Vacuum ON
Roller gap control OFF Mode

Table 2: Formulations of dexketoprofen trometamol tablets

Ingredients Batch qty (mg)

Fl F2 F3 F4 F5 F6 F7 F8
Dry mix:
Dexketoprofen trometamol 37.099 37.009 37.099 37.009 37.009 37.009 37.099 36.910
Low-Substituted Hydroxypropyl Cellulose (LH-11) NA — — — — 10.000
Mannitol (Perlitol SD200) — — — — — — 149.9011 130.090
Pregelatinized starch 1500 40.000 40.000 33.000 33.000 33.000 33.000 —
Microcrystalline Cellulose (AvicelPH102) 127.901 — —
Sodium Starch Glycolate (Primojel) — 10.000 10.000 10.000 10.000 10.000 10.000 10.000
Microcrystalline Cellulose (AvicelPHlOl ) — 157.991 100.401 95.401 105.416 105.491 —
Maize Starch — — — 24.00 24.000 24.000 40.000 40.000
Magnesium Stearate — — — — — — 1.500 1.500
Binder:
Purified water Q.S Q.S Q.S Q.S Q.S Q.S —
Maize Starch 24.00 — — —
Povidone (PVPK-30) —- — 7.000 7.000 7.000 7.000
Citric Acid 10.00 — —
Tris-Buffer — — 5.000 — —
Sodium hydroxide - — 0.075 —
Prelubrication:
Mannitol (Perlitol SD200) .„ —- — — — — 40.000 30.000
Microcrystalline Cellulose (Avicel PH 102) 76.000 40.00 34.00 34.00 34.000. 34.000 —
Sodium Starch Glycolate (Primojel 13.000 10.00 10.00 10.00 10.000 10.000 5.000 5.000
Low-Substituted Hydroxypropyl Cellulose (LH-11) NA — — — — 10.000
Colloidal Silicon Dioxide — — 4.500 4.500 4.500 4.500
Lubrication:
Magnesium Stearate NA 5.000 5.000. 5.000 5.000 5.000. 2.500 2.500
Coating Material:
Opadry White 06G28430 6.000 6.000 5.400 5.400 5.400 5.400 —
Opadry White 03B28796 NA — — — — — — 5.520
IPA NA — — — — — —
MDC NA — — — — — —
Purified Water Q.S Q.S Q.S Q.S Q.S Q.S Q.S

Table: 3 Comparison of Related Substance of formulation according to present invention With Marketed formulation

Product Name Condition Assay
(%) Related substance % Drug Release

45 minutes

Dexketoprofen Tromatamide Any
Unspecified
Impurity Total Impurity Avg Min Max
KERAL (Innovator) Initial 100.71 0.63 0.15 0.98 98.2 95.6 100.6

55C1M NA 2.04 0.23 2.64 NA NA NA

lM40°C/75 % 97.45 1.09 0.15 1.49 99.8 98.3 102.4

2M40C/75 % 98.2 1.09 0.15 1.53 97.9 96.3 98.9

3M40C/75 % 95.32 1.95 0.34 2.94 100.4 98.9 102.3

6M 40C/75 % 96.13 3.09 1.42 6.3 96 94.9 96.6
Dexketoprofen Tablets 25 mg Initial 99.34 0.01 0.020 0.060 97.70 96.20 101.14

55C1M 99.73 0.24 0.15 0.6

1M 40C/75% 99.3 0.07 0.11 0.31 101.6 100.4 103.1

3M 30C/75 % 100.19 ND ND ND 104.2 103.7 104.6
3M 30C/65 % 99.94 ND ND ND 102.1 100.7 104.3
3M 40C/75 % 99.72 0.1 0.1 0.3 102.3 100.6 103.5
6M
30C/75 % 100.1 0.03 0.04 0.13 NA NA NA
6M
40C/75 % 100.5 0.16 0.04 0.29 102 100.1 103.1

WE CLAIM:
1. Pharmaceutical compositions comprising dexketoprofen and pharmaceutically acceptable excipients.
2. The dexketoprofen compositions as claimed in claims 1, prepared by using a dry granulation process involving roller compaction.
3. The pharmaceutical composition as claimed in claims 1, wherein the composition is in solid dosage form preferably tablet dosage form
4. The pharmaceutical compositions as claimed in claim 1, wherein dexketoprofen is preferably in the salt form, more preferably it is trometamol salt, which is present in the range of 1 -70% by weight of the composition.
5. The pharmaceutical compositions as claimed in claim 1, wherein, the pharmaceutically acceptable excipients are selected from the group comprising of disintegrant, diluent, lubricant, binder, colouring agent, pH regulating agent, surfactant, stabilizing agent, sweetener and/or taste regulating agent and flavouring agent.
6. The pharmaceutical compositions as claimed in claim 5, wherein the disintegrants are selected from a group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch, sodium starch glycolate and/or combinations thereof.
7. The pharmaceutical composition as claimed in claim 5, wherein the diluents are selected from group consisting of lactose, starch, mannitol, sorbitol, dextrose, cellulose, microcrystalline cellulose, dibasic calcium phosphate, dicalcium phosphate dihydrate, tricalcium phosphate, calcium phosphate, lactose, anhydrous lactose, spray-dried lactose; pregelatinized starch, compressible sugar, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate, sucrose-based diluents, confectioner's sugar,

monobasic calcium sulfate monohydrate, calcium sulfate dihydrate, calcium lactate trihydrate, dextrates, hydrolyzed cereal solids, amylosem, powdered cellulose, calcium carbonate, glycine, kaolin, sodium chloride; inositol, bentonite, and/or combinations thereof.
8. The pharmaceutical compositions as claimed in claim 5, wherein the lubricants are selected from group consisting of sodium benzoate, adipic acid, fumaric acid, glyceryl monostearate, glycerol distearate, gyceryl behenate, glyceryl palmitostearate, glycerol distearate and/or combinations thereof.
9. The pharmaceutical composition as claimed in claim 5, wherein the binders are selected from carboxymethyl cellulose sodium, ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminium silicate, maltodextrin, methyl cellulose, povidone, starch and/or combination thereof.
10. The process for preparation of pharmaceutical compositions as claimed in claim 5, wherein the processing steps are as follows:
a. sifting dexketoprofen and other excipients through suitable size mesh,
b. mixing dexketoprofen with suitable excipients,
c. compressing the mixture of step b with roller compaction,
d. sifting the compressed granules of step c,
e. adding lubricants to the granules of step d, and
f. compressing the lubricated granules of step e to get the tablet.