Title of Invention

A PROCESS OF PREPARING A DIRECTLY COMPRESSIBLE DELAYED RELEASE MATRIX FORMULATIONS OF ACECLOFENAC AND PRODUCT THEREOF

Abstract The present invention relates to delayed release matrix formulations of aceclofenac or salts thereof and process of making such formulations. The directly compressible delayed release matrix formulation consists essentially of therapeutically effective amount of aceclofenac or salts thereof, one or more delayed release polymer and optionally pharmaceutically acceptable excipients.
Full Text THE PATENTS ACT, 1970 (39 of 1970)
COMPLETE SPECIFICATION
(See Section 10, Rule 13)
TITLE
"DIRECTLY COMPRESSIBLE DELAYED RELEASE MATRIX FORMULATIONS OF ACECLOFENAC"
APPLICANTS
Vivek Ranjan Sinha Bhinge Jayant Rajaram
T-II 59, Sector 25, Panjab University At/Post/Tal: Atpadi, Dist: Sangali
Chandigarh 160 014 Pin: 415301 (Maharashtra)
Rachana Kumria
#3332, Sector 21D
Chandigarh 160 022
The following specification describes the invention


DIRECTLY COMPRESSIBLE DELAYED RELEASE MATRIX FORMULATIONS OF ACECLOFENAC
Field of the Invention
The present invention relates to directly compressible delayed release matrix formulations of aceclofenac or salts thereof and process of making such formulations.
Background of the Invention
It is well known in the pharmaceutical art to prepare formulations, which provide delayed release of pharmacologically active substances after oral administration to humans and animals. Delayed release dosage forms find a major application for colonic drug delivery. Drug delivery to the colon has advantages for local effects, such as topical treatment of diseases such as irritable bowel syndrome, ulcerative colitis, Crohn's disease, colon carcinoma and many bacterial and helminthes infections. For colonic delivery, the main aim is to delay the release of active agent by 4-5 hours, which is the time taken by the dosage form to reach the ileocaecal region.
Aceclofenac is chemically (2-{(2, 6-dichlorophenyl) amino} phenylacetooxyacetic acid). It is newer non-steroidal anti-inflammatory agent and finds use in treating colonic carcinoma and nocturnal arthritis.
Delayed release compositions of non-steroidal anti-inflammatory drugs such as aceclofenac or salts thereof are previously known in the art.
W099/12524 discloses modified release multiple-unit compositions of non-steroidal anti-inflammatory drug substances. Multiple-units in unit dosage form comprise two nonsteroidal anti-inflammatory drugs containing fractions wherein first fraction is for quick release and other is for extended release.


WO07/092064 discloses a pH-controlled pulsatile release system comprising a core surrounded by a pH sensitive coating.
WO02/30398 teaches a delayed release composition comprising a core, which includes drug and a disruption agent, and further comprising a regulatory membrane coating on the core formed from a mixture of a water-soluble gel-forming polymer and a water-insoluble film-forming polymer.
WO03/004060 teaches a pharmaceutical preparation comprising aceclofenac, polymeric base and a surfactant. The formulation significantly increases the bioavailability of acecofenac due to the improvement of dissolution of the drug in gastrointestinal tract.
US 6,287,600 discloses a procedure to stabilize a pharmaceutical composition, which includes a nonsteroidal anti-inflammatory drug (NSAID). While manufacturing the NSAID is first granulated by blending it with acceptable ingredients in a fluid-bed granulator. The granules so obtained are coated with an enteric coat.
WO06/092064 discloses a delayed release oral dosage form comprising one or more active ingredients within a granulated composition, which further comprises one or more of waxes, oil and/or gums and polymers or copolymers exhibiting pH dependent solubility. The granulation is carried out by melt granulation technique or solvent/wet granulation.
Although these formulations are useful as delayed release compositions, there are known drawbacks to the above-described methods and compositions.
The above prior art teaches the use of regulatory membranes to achieve the desired delayed release characteristics of the incorporated medicament in the gastrointestinal tract. These regulatory membranes form the major component of the prior art formulations to delay the release of the drug and prevent it from getting released in the


stomach. The basic difference in the prior art formulations is the mechanism of release from these membranes such as mechanical disruption, osmotic pressure, time proportional thickness, and pH dependent solubility. Further, the prior art teaches the granulated compositions (melt granulation, solvent-based granulation). The development of these membranes and granulated compositions result in additional costs, extra processing steps, energy consumption, time consumption, messy clean-up, additional excipients and the need to use special equipment such as coaters and/or granulators.
Accordingly, it is an object of the present invention to provide a delayed release matrix formulation that is prepared easily, with lesser processing steps and lower energy consumption. Surprisingly, we have found that the delayed release polymers alone without the need of any regulatory membrane or granulation step (melt granulation, solvent based granulation or slugging) can be used as a delayed release formulation component that gives a desired lag period before releasing the drug. A directly compressible matrix delayed release system is a robust dynamic system composed of polymer wetting, hydration & dissolution. Unlike prior art formulations, the formulations of the present invention are cost effective, time effective, less labor intensive, and easy to manufacture on commercial scale without requiring complex processing steps and need of sophisticated equipments.


Description of the drawings
Figure 1: Dissolution data for Examples 1-6.
Figure 2: Dissolution data for Example 7-8.
Figure 3: Dissolution data for Example 7 in presence of rat caecal content.
Figure 4: Dissolution data for Example 8 in presence of rat caecal content.
Figure 5. Particle size of Aceclofenac particles.
Summary of the Invention
The invention is related to and discloses a directly compressible delayed release matrix formulation comprising a therapeutically effective amount of aceclofenac or salt thereof, one or more delayed release polymer and optionally one or more pharmaceutically acceptable excipients.
In one aspect the invention provides a directly compressible delayed release matrix formulation comprising a therapeutically effective amount of aceclofenac or salt thereof, one or more delayed release polymer and optionally one or more pharmaceutically acceptable excipients, wherein the aceclofenac particles have a D50 ranging from 75-125 urn.
In another aspect, the amount of delayed release polymer ranges from 5-90% w/w of the total weight of the formulation. More preferably, the amount ranges from 10-75% w/w of the total weight of the formulation.
Yet another aspect provides a process for preparing the delayed release matrix formulations of aceclofenac or salts thereof.
Detailed Description of the Invention


The directly compressible delayed release matrix formulations of aceclofenac consisting essentially of therapeutically effective amount of aceclofenac or salt thereof and one or more delayed release polymer and one or more pharmaceutically acceptable excipients such that when administered orally said formulations release aceclofenac or salt thereof, in a delayed release manner. Aceclofenac particles having D50 ranging from 50-150 um. More, preferably the particle size ranges from 75 -125 um. Particle size of acecofenac particles is provided in Figure 5.
D50 represents the 50 percentile of the particle size distribution as measured by volume ie. D50 is a value on the distribution such that 50% of the particles have a volume of this value or less.
Particle size analyzer from the courtesy of 'Malvern' (Malvern Instruments Limited, Worcestershire, UK) was used to study the particle size distribution. It is highly robust, reliable and high-speed instrument. It has the flexibility to allow wet and dry measurements to be made in rapid succession as well as enabling the user to change rapidly from aqueous to solvent based dispersions.
"Aceclofenac or salts thereof as used here means any salts of aceclofenac can be used in the invention. Ex: Aceclofenac sodium.
"Delayed release polymer" as used in the disclosure means a polymer capable of preventing the substantial release of drug in the upper gastrointestinal tract (stomach and small intestine) ie. The drug is released after a lag time of 4-5 hours.
"Substantial release" used herein refers to percent releases of more than 5%, preferably 5-6%, 5-7%, 6-8%, 6-11% or more preferably 5-15% of the total drug in the formulation.
"Delayed release polymer" may be selected from one or more of microbial polysaccharides, cellulose derivatives, and acrylic acid derivatives. The microbial polysaccharides are selected from one or more of alginates, amylose, inulin,


arabinogalactan, arabinoxylan, chitosan, chondroitin sulphate, guar gum, xanthan gum, karaya gum, dextran, locust bean gum, tragacanth gum, pectin, xylan, boswellia gum, almond gum. The cellulose derivatives are selected from one or more of cellulose acetate pthalate, hydroxypropyl methylcellulose acetate phthalate. The acrylic acid derivatives are selected from one or more of acrylates, methacrylic acid copolymers, and carbomers. The preferred delayed release polymers are inulin, guar gum and carbomers. More preferably, the carbomer is carbopol 71G.
In a preferred embodiment the amount of delayed release polymer ranges from 5-90% w/w of the total weight of the formulation. More preferably, the amount ranges from 10-75% w/w of the total weight of the formulation.
The delayed release formulation may also contain "pharmaceutically acceptable excipients" selected from one or more of diluents, binders, lubricants, glidants and mixtures thereof.
The diluents are selected from one or more of microcrystalline cellulose, lactose, dicalcium phosphate and starch.
The "binders" are selected from one or more of starch, polyvinylpyrrolidone, natural or synthetic gum and cellulosic polymers.
The lubricants and glidants are selected from one or more of talc, colloidal silicon dioxide and magnesium stearate.
The delayed release formulation of aceclofenac may be obtained in the form of various dosage forms like tablets, beads, pellets or capsules. The tablet may be a coated tablet or minitablets. The preferred tablets are matrix tablets with or without a non-functional coating.
The tablet is prepared by direct compression process without any step of granulation.


The following non-limiting examples further illustrate the delayed release formulations of aceclofenac or salt thereof, and process of making such formulations.
Example 1: Process of manufacturing Aceclofenac formulation
1. All ingredients were accurately weighed.
2. Aceclofenac, Inulin, Guar gum, Carbomer (Carbopol 71G), and Lactose monohydrate, were sifted through a #22 mesh sieve and blended.
3. Magnesium stearate and talc were sifted through a #60 mesh sieve and blended.
4. Blend of Step 2 was mixed with blend of step 3.
5. The final blend was compressed into tablets using suitable punches.
Table 1 provides the combination of excipients in different concentrations used in the formulation numbered as Examples 1 to 8.
Table 1: Various Aceclofenac formulations tested with other pharmaceutical ingredients

Ingredient Quantity in percentage
Example no: 1 2 3 4 5 6 7 8
Aceclofenac 33.33 33.33 33.33 33.33 33.33 33.33 33.33 33.33
Inulin 40 30 20 10 5 - - -
Guar gum - - - - - - 20 10
Carbomer (Carbopol 71G) 10 20 30 40 45 50 30 40
Lactose 13.67 13.67 13.67 13.67 13.67 13.67 13.67 13.67
Magnesium stearate 1 1 1 1 1 1 1 1
Talc 2 2 2 2 2 2 2 2
Total 100 100 100 100 100 100 100 100
Example 2: Measurement of Release Profile
The in vitro release profile of aceclofenac was carried out according to USP 27 method for delayed release tablets (Method A). Dissolution study was carried out using USP apparatus type-II i.e. paddle type at 50 rpm and temperature of 37±0.5°C. Initial studies were carried out for 2h in 750 ml of 0.1N HC1 (pH 1.2) after which 250 ml of a 0.2M trisodium orthophosphate, solution was added into the dissolution media and pH was adjusted to 6.8. To maintain the sink conditions sodium lauryl sulphate (1% w/v, SLS)


was added to dissolution medium. The dissolution profiles of the formulations are provided in Table 2 and Figures 1 and 2.
Table 2: Dissolution Profile of aceclofenac formulations

Time(h) Percent of Aceclofenac dissolved
Example l Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8
0 0 0 0 0 0 0 0 0
1 11.69 5.85 4.21 3.69 3.59 3.08 4.62 3.80
2 30.12 7.94 6.70 6.49 6.39 5.67 4.24 5.67
3 97.70 8.88 8.44 8.33 7.49 4.76 4.97 8.33
4 101.82 11.34 8.69 8.37 7.01 6.36 6.38 9.33
5 13.60 9.89 9.872 8.61 8.49 7.87 11.488
6 11.13 11.72 9.93 9.70 7.69 9.049 11.30
8 17.89 16.50 15.22 12.58 7.94 10.35 12.82
10 78.04 25.49 17.60 14.11 10.49 11.14 14.14
12 86.50 54.23 21.98 19.74 11.90 12.24 15.05
24 97.10 96.11 96.83 95.72 36.49 28.65 26.34

Example 3: Drug Release Studies
Drug release studies in the presence of caecal content were also carried out using USP dissolution test apparatus. Initial drug release studies were conducted in 375 ml of 0.1 N HC1 for 2 h. Then, 125 ml of 0.2 M trisodium phosphate was added to the dissolution media and the pH adjusted to 6.8. The study at a pH of 6.8 was continued for 3 h, after which caecal content equivalent to 10 g was added to 500 ml of buffer (pH 6.8) to give a final caecal dilution of 2% w/v. Dissolution in the caecal content media was carried out until completion at 24 h Dissolution percentage of sample 7 is provided in Table 3. The experiments in caecal content media were carried out in the presence of a continuous supply of carbon dioxide. At different time intervals a 5-mL sample was withdrawn from the dissolution medium and replaced with fresh buffer containing caecal content. Samples were filtered thought a 0.45-um membrane filter and were analyzed by validated RP-HPLC method.


Table 3: Dissolution percentage over 24 hours for Example 7

Time (h) Percent of Aceclofenac dissolved
Example 7 without rat ceacal content Example 7 with rat ceacal content Example 8 without rat ceacal content Example 8 with rat ceacal content
0 0 0 0 0
1 0.36 0.13 0.12 0.09
2 0.38 0.25 0.16 0.19
3 4.12 1.32 1.69 0.83
4 4.86 4.86 2.46 2.45
5 5.78 5.00 3.13 3.12
6 7.45 5.51 4.82 6.36
8 10.18 12.20 8.06 12.41
10 13.94 32.45 11.27 39.14
12 16.99 60.96 14.98 65.14
24 32.98 100.12 36.35 100.63


We claim:
1. A directly compressible delayed release matrix formulation comprising a
therapeutically effective amount of aceclofenac or salt thereof and one or more delayed
release polymer.
2. The delayed release matrix formulation according to claim 1, wherein the delayed release polymer is selected from the group consisting of microbial polysaccharides, cellulose derivatives, acrylic acid derivatives and combinations thereof.
3. The delayed release matrix formulation according to claim 2, wherein the microbial polysaccharides are selected from the group consisting of alginates, amylose, inulin, arabinogalactan, arabinoxylan, chitosan, chondroitin sulphate, guar gum, xanthan gum, karaya gum, dextran, locust bean gum, tragacanth gum, pectin, xylan, boswellia gum, almond gum and mixture thereof.
4. The delayed release formulation according to claim 2, wherein the cellulose derivative is selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose acetate pthalate and mixtures thereof.
5. The delayed release formulation according to claim 2, wherein the acrylic acid
derivative is selected from the group consisting of acrylate, methacrylic acid copolymer,
carbomer and mixtures thereof.
6. The delayed release matrix formulation of claim 1, wherein the particle size of aceclofenac ranges from 50 -150 urn.
7. The delayed release matrix formulation according to claim 1, wherein the amount of delayed release polymer ranges from 10-75% w/w of the total weight of the formulation.


8. The delayed release matrix formulation according to claim 1, optionally comprising
one or more pharmaceutically acceptable excipients.
9. The delayed release matrix formulation according to claim 9, wherein the pharmaceutically acceptable excipients is selected from one or more of diluents, disintegrants, binders, lubricants or glidants.
10. The delayed release matrix formulation of claim 1, wherein the formulation is in the form of tablets, beads, pellets or capsules.
11. A process of preparing a tablet consisting the formulation of claim 1 consisting the steps of:
(a) Accurately weighing aceclofenac, inulin, guar gum, carbomer and Lactose
monohydrate;
(b) Sifting the ingredients of (a) through a #22 mesh sieve and blending;
(c) Sifting magnesium stearate and talc through a #60 mesh sieve and blending;
(d) Mixing blend of (b) with blend of (c);
(e) Compressing the final blend into tablets using suitable punches.

Abstract
The present invention relates to delayed release matrix formulations of aceclofenac or salts thereof and process of making such formulations. The directly compressible delayed release matrix formulation consists essentially of therapeutically effective amount of aceclofenac or salts thereof, one or more delayed release polymer and optionally pharmaceutically acceptable excipients.


Documents:

1736-mum-2007-abstract(3-2-2009).pdf

1736-mum-2007-abstract(granted)-(25-1-2010).pdf

1736-mum-2007-abstract.doc

1736-mum-2007-abstract.pdf

1736-mum-2007-abstractgranted)-(25-1-2010).pdf

1736-mum-2007-cancelled pages(17-7-2009).pdf

1736-mum-2007-cancelled pages(8-9-2009).pdf

1736-mum-2007-claims(amended)-(3-2-2009).pdf

1736-MUM-2007-CLAIMS(AMENDED)-(8-9-2009).pdf

1736-mum-2007-claims(granted)-(25-1-2010).pdf

1736-MUM-2007-CLAIMS(MARKED COPY)-(8-9-2009).pdf

1736-mum-2007-claims.doc

1736-mum-2007-claims.pdf

1736-mum-2007-correspondence(17-7-2009).pdf

1736-mum-2007-correspondence(ipo)-(27-1-2010).pdf

1736-mum-2007-correspondence-received.pdf

1736-mum-2007-description (complete).pdf

1736-mum-2007-description(granted)-(25-1-2010).pdf

1736-mum-2007-drawing(granted)-(25-1-2010).pdf

1736-mum-2007-drawings.pdf

1736-mum-2007-form 18(25-10-2007).pdf

1736-mum-2007-form 2(granted)-(25-1-2010).pdf

1736-mum-2007-form 2(title page)-(complete)-(11-9-2007).pdf

1736-mum-2007-form 2(title page)-(granted)-(25-1-2010).pdf

1736-mum-2007-form 26(3-2-2009).pdf

1736-mum-2007-form 9(25-10-2007).pdf

1736-mum-2007-form-1.pdf

1736-mum-2007-form-2.doc

1736-mum-2007-form-2.pdf

1736-mum-2007-form-26.pdf

1736-mum-2007-form-3.pdf

1736-mum-2007-form-5.pdf

1736-mum-2007-marked copy(17-7-2009).pdf

1736-mum-2007-marked copy(3-2-2009).pdf

1736-MUM-2007-REPLY TO EXAMINATION REPORT(8-9-2009).pdf

1736-mum-2007-specification(amanded)-(3-2-2009).pdf

abstract1.jpg


Patent Number 238193
Indian Patent Application Number 1736/MUM/2007
PG Journal Number 5/2010
Publication Date 29-Jan-2010
Grant Date 25-Jan-2010
Date of Filing 11-Sep-2007
Name of Patentee VIVEK RANJAN SINHA
Applicant Address T-II 59, SECTOR 25, PANJAB UNIVERSITY,
Inventors:
# Inventor's Name Inventor's Address
1 VIVEK RANJAN SINHA T-II 59, SECTOR 25, PANJAB UNIVERSITY,
2 BHINGE JAYANT RAJARAM AT/POST/TAL:ATPADI, DIST:SANGALI-415301
3 RACHANA KUMRIA #3332,SECTOR 21D
PCT International Classification Number A61K9/22,A61K31/216
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA