FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The patents rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
l.TITLE OF THE INVENTION
FAST RELEASE DOSAGE FORMS OF DICLOFENAC
2. APPLICANT
(a) Name: Umedica Laboratories PVT. LTD
(b) Nationality: Indian
(c) Address: 105/108, Rewa chambers, 1st fl, 31, New marine lines, Mumbai
400020. Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
COMPLETE
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF INVENTION
The present invention relates to novel fast release oral solid dosage forms of Diclofenac and its salts for the management of acute pain. The present invention also relates to development of formulation to achieve faster disintegration and release profile of the active ingredient.
BACKGROUND OF INVENTION
Diclofenac belongs to a class of non-steroidal anti-inflammatory drugs (NS A IDs) with antipyretic and analgesic activities. Due to its anti-rheumatic and anti-arthritic activities, it is one of the most commonly dispensed drugs. NSAIDs are usually indicated for the treatment of acute or chronic pain and inflammatory conditions. Thus, Diclofenac is generally indicated for rheumatoid arthritis, osteoarthritis, dysmenorrhea (menstrual pain), headache and migraine, postoperative pain and also for mild to moderate pain after tissue injury. Diclofenac can be administered by different routes including oral, topical as well as by parenteral route. Oral doses of Diclofenac range from 12.5-200 mg/day while parenteral doses range from 75 to 150 mg/day.
Commercially available oral pharmaceutical formulations of Diclofenac include immediate release tablets, capsules, enteric coated tablets, powder for oral solution, liquid filled capsules etc. In the conditions where strong analgesic/ anti-pyretic effect is expected, immediate release dosage forms are not satisfactory since they achieve maximum drug plasma concentration after lhr. However these Tmax levels are dependent on physical characteristics of a patient (Physicians' Desk Reference, 52 edition, 1998, pg. 1831).
Since Diclofenac is among the BCS class II drugs; its bioavailability is limited by its salvation rate. Hence attempts are made to enhance the rate of disintegration in order to increase Cmax levels in shortest period of time (Tmax).

There are several approaches to develop a fast release drug delivery system. Powder for oral solution is a commonly used dosage form when such type of release profile is intended. The main drawback of powder for oral solution is presence of acid and carbonates which provides effervescence. Moreover, hygroscopicity of excipients plays important role in manufacturing such type of dosage forms. As they are moisture sensitive, control of humidity throughout the process and final product is very essential. This entire quality check further adds to the cost of a product. Commercially, liquid filled capsules and powder for oral solution (Zipsor® and Cambia® respectively) are available in the market for fast release dosage forms for Diclofenac potassium.
There are number of prior arts covering various fast release approaches such as; WO 2003/086343 PCT application discloses a process of preparing mouth dissolving solid oral dosage form by dry granulation technique. Granules prepared with this process are either compressed in to tablets or wafers or filled in sachets. The dosage forms are designed to disintegrate in mouth within 5-90sec. •
U.S. patent No. 7687542 covers a method of treating acute pain comprising orally administering Diclofenac potassium in an intact rapidly bioavailable tablet or capsule dosage form comprising alkali metal carbonate or bicarbonate. The current formulation is designed to achieve Cmax 1700-2300ng/ml while Tmax of 5-30min.

PCT application number WO 2007/113856 discloses a directly compressible composite for oral disintegrating tablet comprising atleast one water soluble excipient. The dosage form is prepared so as to disintegrate within 60 sec in the oral cavity while lag time for mouth disintegration will be less than 10 sec.
U.S. patent application no. 20100010029 covers a process for treating pain in mammal with pharmaceutical composition comprising Diclofenac and an opioid selected from the list mentioned. The formulation is expected to release more than 85% opioid in less than 60min, while more than 85% of Diclofenac would release in less than 10min. thus the current invention is designed to achieve Tmax for Diclofenac of about 10min to 30min.
PCT application no. WO 2008/040534 discloses a non-mucoadhesive orally disintegration film which will disintegrate in the buccal cavity within 60sec. the film comprises of 10-40% of cyclodextrin or derivative.
U.S. patent no. 7662858 covers a method of treating acute post-bunionectomy pain with 13 to 30mg of Diclofenac potassium in dispersible liquid formulation. The dosage form is designed to administer evry 4 to 8 hrs over a period of atleast 24hrs. The plasma concentration of Diclofenac ranges between 670 to 1500ng/ml in less than 30min with concomitant onset of relief of acute pain while achieving Tmax of 0.47hrs.

U.S. patent application no. 20100215736 relates to dosage form providing absorption of the drug Diclofenac in an ultrafast manner. 5 to 25mg of Diclofenac is formulated as atleast one soft gelatin capsule.
U.S. patent no. 8097651 covers a method of treating migraine associated with phonophobia or photophobia with liquid or solid formulation of Diclofenac designed to a Cmax of 1500 - 2500ng/ml in maximum time of 10 to 25min. A process of manufacture of 50mg of Diclofenac potassium dosage forms is described in the specification.
U.S. patent application no. 20120135047 discloses a novel formulation of Diclofenac where median particle size of Diclofenac on a particle volume basis is less than 300nm while 90% of Diclofenac on particle volume basis is less than 1700nm. The said composition would achieve the Tmax less than the Tmax of a conventional, non-nanop articulate form of Diclofenac administered to a human subject when the composition is administered at 20% lower dosage as the conventional, non-nanoparticulate form whereas Cmax would be atleast 10% higher.
U.S. patent application no. 20110003006 claims an orally disintegrating tablet composition comprising combinations of non-opioid and opioid analgesics. The formulation is composed of a core containing non-opioid analgesic drug with 1st coating disposed over a core comprising opioid analgesic while 2nd coating comprises water insoluble polymer.

Although, prior arts disclose the use of several technologies for faster disintegration or dissolution of Diclofenac formulations but, there is a need for simple, stable and economical dosage form to achieve faster release for acute pain.
SUMMARY OF INVENTION
In one general aspect of the invention, there is provided a fast release dosage form free of metal carbonates and any effervescent agents, comprising 10 to 100mg of Diclofenac and its salts.
In another general aspect of the invention, there is provided the use of alkali as solubility enhancers
in order to increase solubility of Diclofenac and permeability enhancers to enhance the
permeability.
Furthermore, the novel formulation comprises a unique combination of superdisintegrants,
permeability enhancer and amine salt of carbostyril derivative.
In another general aspect, there is provided a fast release dosage form of Diclofenac and its salts for the management of mild to moderate pain and migraine in which, higher Cmax achieve in shortest Tmax

DETAILED DESCRIPTION OF INVENTION
We have discovered an economical oral solid dosage form for fast release to achieve higher Cmax in shortest period of time for the management of mild to moderate pain and migraine.
Fast release tablets disintegrate or dissolve rapidly in oral cavity leading to faster absorption of a drug. There are several techniques such as chewable, mouth dissolving, liquid filled capsules, powder for oral solution; oral disintegrating tablets etc. Special manufacturing of such techniques may end up in high cost. Already there are many formulations available in market such as Zipsor and Cambia®. Commercial formulations are moisture sensitive hence should be maintained in specified storage and excipients should also be controlled throughout the manufacturing process since they are moisture sensitive.
The present invention is developed a solid oral dosage form which will achieve faster dissolution of the drug leading to have faster absorption of the drug. The prior art references disclose metal carbonates or bicarbonates are most commonly used excipients in such type of dosage forms which make the formulation more sensitive to humidity. The efforts are made to develop a novel dosage form devoid of use of carbonates or bicarbonates or any effervescent agents. It was found that unique combination of superdisintegrants, permeability enhancer and alkali gave unexpectedly fast disintegration and dissolution of the Diclofenac and its salts.

The formulation is conventional oral solid dosages form preferably a tablet comprising Diclofenac and its salts as an active ingredient mixed with excipients like diluents, disintegrant, permeability enhancer and amine derivative along with binder, glidant, lubricant which are commonly used. Diluents are used in formulations as a diluting agent or filler or thinner. Diluents are added to ease the restricted movement. In the current invention microcrystalline cellulose, dibasic calcium phosphate, lactose, sucrose, glucose, mannitol, sorbitol and calcium carbonate can be used. Disintegrants or super disintegrants are used in order to have faster absorption. For the current invention they can be selected from cross carmellose sodium, starch, sodium starch glycolate, crosspovidone, Soy polysaccharide, polyplasdone XL, polyplasdone XL 10.
Amine salt of carbostyril derivate, Meglumine was found to give unexpected faster dissolution and
disintegration which inherently would lead to faster absorption.
Permeability enhancers are also added to enhance the permeability through cells. SLS, Tween 80,
Fatty acid esters (sodium taurocholate, sodium deoxycholate)
Other excipients such as lubricants, binders, glidants and sweeteners are also used as per
requirement.
All the formulations are tested for disintegration and dissolution rate in-vitro and compared with Cambia (powder for oral solution). Dissolution test was performed in acetate buffer at pH 4.5 Following are the few working examples for fast release dosage forms of Diclofenac and its salts.

The present invention, concerning a fast releasing formulation containing Diclofenac potassium as the active drug component, was focused on:
1) Preparation of conventional formulation devoid of use of carbonates or bicarbonates or any
effervescent agents.
2) Preparation of solid dosage form composition comprising permeability enhancers and
superdisintegrants combination.
The present invention is further illustrated by the following example which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention,

EXAMPLE 1: The pharmaceutical composition of Diclofenac potassium

Sr.No. Ingredients Quantity
1 Diclofenac Potassium 50mg
2 Microcrystalline cellulose 323mg
3 Crospovidone 20mg
4 Colloidal Silicon dioxide 3mg
5 Magnesium Stearate 4mg
Procedure:
Diclofenac Potassium was sifted through #40. Microcrystalline cellulose, crospovidone were sifted through #40 and collected separately. After initial sieving procedure, Diclofenac Potassium and other excipients were co-sifted through #40 and collected separately. Colloidal silicon dioxide and magnesium Stearate were co-sifted from #40. The sifted materials were mixed well and compressed by using suitable punches.

EXAMPLE 2: The fast release composition of Diclofenac potassium

Sr.No. Ingredients Quantity
1 Diclofenac Potassium 50mg
2 Microcrystalline cellulose 301.5mg
3 Crospovidone 20mg
4 Colloidal Silicon dioxide 3mg
5 Magnesium Stearate 4mg
6 Meglumine 5mg
7 Aspartame 12.5mg
8 SLS 4mg
Procedure:
Diclofenac Potassium was sifted through #40. Microcrystalline cellulose, crospovidone, meglumine, aspartame, SLS were sifted through #40 and collected separately. After initial sieving procedure, Diclofenac Potassium and other excipients were co-sifted through #40 and collected separately. Colloidal Silicon dioxide and Magnesium Stearate were co-sifted from #40. The sifted materials were mixed well and compressed by using suitable punches.

EXAMPLE 3: The pharmaceutical composition of Diclofenac potassium

Sr.No. Ingredients Quantity
1 Diclofenac Potassium 50mg
2 Microcrystalline cellulose 302.5mg
3 Crospovidone 20mg
4 HPMC 3mg
5 Aspartame 12.5mg
6. Sodium hydroxide 3mg
7 SLS 2mg
8 Colloidal Silicon dioxide 3mg
9 Magnesium Stearate 4mg
Procedure:
Sodium hydroxide was dissolved in water and HPMC was dissolved in Ethanol. The two solutions
were mixed to obtain a clear solution. Microcrystalline Cellulose was placed in rapid mixer
granulator and granulated using the above solution.
Diclofenac, disintegrant, sweetening agent, permeation enhancer and the above granules were
uniformly mixed, co-sifted from #30. Gliadant and lubricating agent were co-sifted from #40. All
the excipients were mixed well and compressed.

In-vitro dissolution test:
Table 1 provides the dissolution data of Diclofenac Potassium FR Tablet. For determination of drug release rate, acetate buffer pH 4.5 in 400 ml of medium using USP Type II apparatus (rpm 75) was used wherein, 30- 50% of the total amount of diclofenac potassium is release within 2.5 min to 5 min.
TABLE 1: % DRUG RELEASE OF CAMBIA 50MG POWDER FOR ORAL SOLUTION AND DICLOFENAC POTASSIUM FR TABLET IN ACETATE BUFFER pH 4.5.

Time in Mitts Gambia
(powder for oral solution) Example-1 (fast release tablet) Example-!
(fast release tabtet) Example-3 (fast release tablet)
0 0 0 0 0
2.5 45.57 46.14 35.29 33.63
5 39.7 29.62 37.45 37.21

Claims
1. A fast release pharmaceutical composition comprising an effective amount of Diclofenac
potassium, as an active ingredient, amine salt of carbostyril derivative as permeability enhancer,
one or more superdisintegrant and at least one excipient, where said composition is in tablet form
and comprises from 10 to 50% by weight of said Diclofenac potassium, from 0.1 % to 10% by
weight of said permeability enhancer and 0.1% to 10% by weight of said superdisintegrant.
2. The fast release pharmaceutical composition according to claim 1, wherein said permeability enhancer is selected from the group of L-arginine, L-lysine, ethylenediamine, tris(hydroxymethyl) aminomethane, monoethanolamine, diethanolamine, diisopropanolamine, and meglumine.
3. The fast release pharmaceutical composition according to claim 2, wherein said permeability enhancer is meglumine.
4. The fast release pharmaceutical composition according to claim 1, wherein said superdisintegrants is selected from the group of Crosspovidone, Soy polysaccharide, polyplasdone XL, polyplasdone XL 10, crosscarmellose sodium.
5. The fast release pharmaceutical composition according to claim 4, wherein said superdisintegrant
is crospovidone.

6. The fast release pharmaceutical composition according to claim 1, wherein said at least one
excipient is selected from the group consisting of surfactants and lubricants.
7. The fast release pharmaceutical composition according to claim 6, wherein said surfactant is selected from the group of sodium lauryl sulphate and sodium docusate.
8. The fast release pharmaceutical composition according to any preceding claim, where, it comprises from 10% to 50% by weight of said Diclofenac potassium, from 0.1% to 10% by weight of meglumine, from 0.1% to 15% by weight of crospovidone, from 0.1% to 10% by weight of sodium lauryl sulphate.
9. The fast release pharmaceutical composition according to claim 1, wherein, said dosage form
provides an in-vitro dissolution rate is from about 30 to about 50% by weight drug release at 2.5
min to 5 min.