FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patents [Amendment] Rules, 2006
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
Oral Pharmaceutical Composition Comprising Fenofibric Acid Or Derivative Thereof
2. APPLICANT
NAME : Micro Labs Limited
NATIONALITY : IN
ADDRESS : CTS No. 73, Saki Estate, Off Chandivali Road, Chandivali, Kurla (W), Mumbai – 400 072, India
3. PREAMBLE TO THE DESCRIPTION
Complete
The following specification describes the invention and the manner in which it is to be performed:

TECHNICAL FIELD OF THE INVENTION
The present invention relates to stable oral pharmaceutical compositions comprising a coated compressed dry mix, wherein the compressed dry mix comprises active Choline Fenofibrate with one or more pharmaceutical acceptable excipients, and wherein the said composition is devoid of molecular dispersion. The present invention also provides process for the preparation of such compositions which are used for Hyperlipidemia or Mixed Dyslipidemia in humans or a disease or condition associated with these.
BACKGROUND OF THE INVENTION
Fenofibrate is a fibric acid derivative and is primary therapy for hypercholesterolaemia and hypertriglyceridaemia alone or in conjunction with statins. It acts by regulating lipid levels in body and is indicated for reducing elevated LDL-C, Total-C, Triglycerides, Apo B and to increase HDL-C in adult patients.
Fenofibrate and its salts are well known lipid-regulating agent, which are commercially available for a long time. This is usually administered orally. After its absorption which is known to take place in the duodenum and other parts of the gastrointestinal tract, fenofibrate is metabolized in the body to fenofibric acid. In fact, fenofibric acid represents the active principle of fenofibrate or, in other words, fenofibrate is a so-called prodrug which is converted in vivo to the active molecule, i.e. fenofibric acid. After oral administration of fenofibrate merely fenofibric acid is found in plasma.
US Patent number 4,058,552 claims Fenofibrate specifically. US Pat. Nos. 4,179,515 and 4,235,896 disclose the preparation of fenofibric acid and also describe acid addition salts of amine containing analogs.
Fenofibrate is known to be poorly water soluble drug, and in turn the bio availability of the drug is low. Achieving good bioavailability has always been a tedious task for poorly soluble drugs like Fenofibrate especially for oral administration. This may further impact the in vivo performance of the product. Specially micronized pharmaceutical formulations have been prepared to overcome these physicochemical demerit associated with Fenofibrate.

Several different formulations of Fenofibrate have been disclosed in U.S. Pat. Nos. 4,800,079, 4,895,726, 4,961,890, Pat. Nos. 6,074,670 and 6,042,847and WO 82/01649. The fenofibrate products currently in the market involve a formulation comprising a micronized drug substance in capsules and/or tablets.
Further, as cited above like micronization, different other process can be implemented to improve bioavailability of poorly soluble drug like Fenofibrate such as change of crystalline form of the drug to amorphous form, Semisolid lipid based system, Solid dispersion, self emulsifying system and salt form of the drug.
However, the salts of fenofibric acid are highly soluble in water and having improved bioavailability as compared to the fenofibrate.
Choline fenofibrate is marketed under the brand name Trilipix ®delayed release oral capsules containing 45mg or 135 mg of fenofibric acid by ABBOTT laboratories in US market. These Capsules are made using choline fenofibrate in strengths of 45 mg and 135 mg, expressed as fenofibric acid equivalent. Each capsule contains a multitude of small tablets of strength 11.25 mg, expressed as fenofibric acid, so that each 45 mg capsule contains 4 tablets, and each 135 mg capsule contains 12 tablets.
US 7,259,186 disclose various salts of Fenofibrate and pharmaceutical formulations, which essentially have an enteric binder and exist in a form of a molecular dispersion. US 2008/0051411 discloses various salt of Fenofibrate its pharmaceutical formulations and process for preparation, which essentially have an enteric polymer. It further discloses method of treating hyperlipidemia or coronary heart disease in a human subject by applying such composition.
US 2008/0095851 discloses nanoparticulate compositions of fenofibrate salts.
US 2008/0152714 discloses modified release formulation comprising an active agent in a hydrophilic polymer matrix.
US 2007/0026062 discloses solid dosage form comprising a solid dispersion or solid solution of fibrate.

US2011/0237675 discloses a method of treating hyperlipidemia, hypercholesterolemia, or hypertriglyceridemia comprising a step wherein the composition comprises of Fenofibric acid, hydrophilic acid and other pharmaceutical excipients. It further discloses different dissolution conditions and time points of the composition.
US20080152714 discloses a modified release formulation comprising an active agent in a hydrophilic polymer matrix wherein the active agent is a salt of fenofibric acid and wherein the solubility of the active agent is greater than 16.1 mg/ml in water.
International publication no WO2010131265 discloses a controlled release pharmaceutical composition(s) comprising choline fenofibrate wherein the core comprises choline fenofibrate and auxiliary excipient and a coating layer comprising rate controlling agent(s).
All the above listed prior art documents hereinabove disclose about various dosage forms or pharmaceutical composition which involves lengthy and expensive process. Further, this process requires specialized equipments or techniques for development. Hence, there still exists an unmet medical need for development of a simplified and comparatively less expensive composition and process for preparation thereof.
The inventors of the present invention with considerable expense of intellectual effort have done extensive research and conducted several experiments to develop a pharmaceutical composition of Choline Fenofibrate using simplified conventional and comparatively less expensive manufacturing process for preparation of the same yield with high scale up. Further, instant invention uses a composition and process for preparation comprising active Choline Fenofibrate, wherein the said active agent is not essentially present in core composition and is devoid of molecular dispersion.
The present invention also provides safe and effective compositions for the management and treatment of Hyperlipidemia or Mixed Dyslipidemia in humans or a disease or condition associated with these and therefore provides a significant advancement in the said field.

SUMMARY OF THE INVENTION
It is an objective of the present invention to provide a stable oral pharmaceutical composition comprising a coated compressed dry mix, wherein the compressed dry mix comprises active Choline Fenofibrate with one or more pharmaceutical acceptable excipients, and wherein the said composition is devoid of molecular dispersion.
It is an objective of the present invention to provide a coated dry mix comprising a dry mix portion which comprises active Choline Fenofibrate, inert filler material; one or more release controlling agent, and optionally one or more pharmaceutical acceptable excipients.
It one objective of the present invention, the compressed dry mix is coated with enteric coating.
It one objective of the present invention, the enteric coating comprises an enteric polymer or an enteric binder.
It is another objective of the present invention to provide a composition comprising hydrophilic polymer or hydrophobic polymer as a release controlling agent, or a mixture thereof.
It is further an objective of the present invention that the dry mix portion of the composition is devoid of any enteric polymer and/ or enteric binder.
It is yet another objective of the present invention to provide a stable pharmaceutical composition (s) which is administered by oral route.
It is further an objective of the present invention to provide pharmaceutical compositions can be formulated as but not limited to tablets, pellets, beads, capsules and sachets.
It is yet another objective of the present invention to provide a stable pharmaceutical composition (s) which is present in solid oral dosage form such as tablet and or capsule dosage form which can be given as Controlled release, sustained release, extended release and/or in delayed release form.
It is yet another objective of the present invention to provide a process for the preparation of such pharmaceutical compositions.

The compositions of the present invention provide effective prophylactic or therapeutic concentrations of active agent(s) for delayed release of the composition.
The present invention provides pharmaceutical formulations comprising Choline Fenofibrate which are used for the management of diseases or disorders associated with Hyperlipidemia or Mixed Dyslipidemia in humans, comprising administering a formulation containing an effective amount of the active agent.
BRIEF DESCRIPTION OF THE DRAWING:
Fig 1 Shows a comparative dissolution profile of delayed release dosage form of choline fenofibrate of example 1 (Test /Micro lab) product Vs Innovator (Reference/ Triplix) product, in pH 3.5 buffer followed by pH 6.8 phosphate buffer,50 rpm, USP Paddle.
DETAILED DESCRIPTION OF THE INVENTION:
It is believed that one skilled in the art can, based upon the description herein, utilize the present invention to its fullest extent. The following specific embodiments are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever.
The present invention provides pharmaceutical formulations comprising Fenofibrate. In embodiments, Fenofibrate is in the form of its choline salt.
In an embodiment, the present invention provides a stable oral pharmaceutical composition comprising a coated compressed dry mix, wherein the compressed dry mix comprises active Choline Fenofibrate with one or more pharmaceutical acceptable excipients, and wherein the said composition is devoid of molecular dispersion.
The term 'stable' as used herein refers to chemical stability of Choline Fenofibrate in solid dosage forms wherein there is no significant change in impurities percentages and dissolution profile when kept at accelerated temperature and humidity conditions.
The term “delayed release compositions” herein refers to any compositions or dosage form which comprises an active drug and which is formulated to provide, or being

understood to be a composition or dosage form which does not release a substantial portion of the active content for dissolution and absorption until it passes through the stomach and reaches the small intestine.
Delayed release composition include, inter alia, those compositions described elsewhere as “extended release”, “sustained release”, “prolonged released”, “timed release” and/or “rate controlled” compositions or dosage forms.
The term “delayed release composition” includes a pharmaceutical composition that encompasses one or more individual coated or uncoated units, which are present in the form of but not limited to tablets, pellets, capsules and sachets.
It would be noteworthy that innovator marketed product Trilipix uses melt extrusion as essential process for preparation of its composition containing choline fenofibrate which involves specialized equipment and techniques for development, which in turn increases the cost of development, whereas inventor of the instant invention by expense of intellectual effort have done extensive research and conducted several experiments, developed an alternative manufacturing process and/or dosage form which uses simple comparatively less time consuming conventional manufacturing process and equipment hence, cost effective.
In an embodiment the coated dry mix comprises a dry mix portion which further comprises active Choline Fenofibrate, inert filler material; one or more release controlling agent, and optionally one or more pharmaceutical acceptable excipients.
The phrase “Dry mix portion” according to the invention is defined as a part of the invention where active, inert material and other carrier materials are mixed together without involvement of any solvent and must not be considered as granules or a core composition.
In another embodiment of the present invention the carrier material present in the “Dry mix portion” comprises inert filler material optionally with one or more pharmaceutical acceptable excipient and one or more release controlling agent (s).
In one embodiment, the “dry mix portion” comprises active, inert material and release controlling material, which are mixed together without involvement of any solvent and

must not be considered as granules or a core composition.
In an embodiment of the present invention stable oral delayed release pharmaceutical composition comprises choline fenofibrate active agent which is not essentially present in core composition and optionally with one or more pharmaceutically acceptable excipient (s), wherein the said composition is devoid of molecular dispersion.
In an embodiment the active choline fenofibrate used in the invention is from about 50 to about 60 % of total weight of the composition, specifically from about 50 to about 56% of total weight of the composition.
In another embodiment of the present invention, the pharmaceutically acceptable excipient(s) of the present invention are selected from but not limited to a group comprising diluents, lubricants, binders, surfactants, colorants, glidants, complexing agents and the like known to the art used either alone or in combination thereof.
Suitable diluents include for example pharmaceutically acceptable inert fillers such as microcrystalline cellulose, lactose, starch, dibasic calcium phosphate, saccharides, and/or mixtures of the foregoing. Examples of diluents include microcrystalline celluloses such as Avicel® PH101, Avicel® PH102, Avicel® PH112, Avicel® PH200, Avicel® PH301 and Avicel® PH302; lactose such as lactose monohydrate, lactose anhydrous and Pharmatose® DCL21, including anhydrous, monohydrate and spray dried forms; dibasic calcium phosphate such as Emcompress®; starch; sucrose; glucose, and the like used either alone or in combination thereof. The amount of diluents used in the invention is from about 6 to about 12 % of total weight of the composition, specifically from 6 to 9 % of total weight of the composition.
Suitable lubricants are selected from but not limited to a group comprising talc; stearic acid, magnesium stearate, calcium stearate, colloidal silicon dioxide such as Aerosil® 200 P; sodium stearyl fumarate, hydrogenated vegetable oil and the like used either alone or in combination thereof.
Suitable binder useful in the present invention is selected from but not limited to a group comprising polyvinylpyrrolidone (e.g. PVP K-90 or PVP K-30), copovidone (e.g. Plasdone® S630), cellulosic polymers (e.g. hydroxypropyl cellulose,

hydroxypropylmethyl cellulose, or the like), gums such as xanthan, alginates such as sodium alginate, polyvinylacetate, and the like used either alone or in combination thereof. More preferably, copovidone (e.g. Plasdone® S630) is useful as a binder.
The release controlling agents are selected from but are not limited to a group comprising cellulose and cellulose derivatives like microcrystalline cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, cellulose acetate phthalate, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, cellulose acetate trimellitate, cellulose carboxymethyl ethers and their salts, polyethylene oxide(PEO), hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate; polyethylene; polyquaternium-1; polyvinyl acetate (homopolymer); polyvinyl acetate phthalate; propylene glycol alginate; polyvinylmethacrylate/maleic anhydride (PVM/MA) copolymer; polyvinylpyrrolidone (PVP)/dimethiconylacrylate/polycarbamyl/polyglycolester; PVP/dimethylaminoethyl methacrylate copolymer; PVP/dimethylaminoethyl methacrylate/polycarbamyl polyglycol ester; PVP/polycarbamyl polyglycol ester; polyvinylpyrrolidone/vinyl acetate (PVP/VA) copolymer; lanolin and lanolin derivatives; glyceryl monostearate; stearic acid; paraffins; beeswax; carnauba wax; tribehenin; polyalkylene polyols like polyethylene glycols; gelatin and gelatin derivatives; alginates; carbomers; polycarbophils; methacrylic acid copolymers; carrageenans; pectins; chitosans; cyclodextrins; lecithins; natural and synthetic gums containing galactomannans like xanthan gum, tragacanth, acacia, agar, guar gum, and the like. The release controlling agents used in the invention is from about 25 to about 35 % of total weight of the composition, specifically 25 to 30 % of total weight of the composition.
Suitable plasticizers are used in an over-coating layer to improve the mechanical properties of a film formed by a polymeric substance. These agents are selected from but not limited to a the group comprising wax, linoline-type alcohols, a gelatin, a polyethylene glycol, triacetin, tributyl citrate, tri ethyl citrate, dibutyl sebacate, medium chain length triglyceride fatty acids, resin acid, long chain fatty acids (e.g. stearic acid, palmitic acid) and the like used either alone or in combination thereof.
Suitable Glidant are selected from but not limited to a group comprising silica; colloidal silica, e.g. colloidal silica anhydrous, e.g. Aerosil® 200 P, magnesium trisilicate,

powdered cellulose, starch, talc and the like used either alone or in combination thereof. Preferably colloidal silica anhydrous or/and colloidal silicon dioxide are used.
Suitable anti-caking agents are selected from but not limited to a group comprises sodium aluminosilicate, sodium silicate, silica (silicon dioxide), calcium silicate, talc, stearic acid and the like used either alone or in combination thereof.
Solid oral dosage forms of the present invention may be prepared by any conventional techniques for example dry granulation, direct compression; wet granulation, extrusion-spheronization and (MUPS) Multiple Unit Particulate Systems. Wet granulation and/or extrusion-spheronization are the preferred techniques.
The present invention provides using pharmaceutical formulations of choline fenofibrate for the management of a disease or condition associated with Hyperlipidemia or Mixed Dyslipidemia in humans, comprising administering a formulation containing an effective amount of choline fenofibrate.
The present invention provides using pharmaceutical formulations of choline fenofibrate for the management of a disease or condition associated with Hyperlipidemia or Mixed Dyslipidemia in humans as a monotherapy as well as adjuvant therapy together with statins.
The present invention also provides processes for preparation of the compositions of choline fenofibrate. In one embodiment, the process comprises the steps of:
Procedure:
i) Desired amount of active, diluents and release controlling agent were weighed, sifted
through suitable mesh size and mixed in Rapid Mixer Granulator (RMG) for
specified time to obtain the dry mix. ii) Binder solution was prepared and added to dry mix of step i in RMG followed by
drying to obtain the desired granules. iii) Granules of the step ii were pre lubricated, lubricated and compressed to obtain mini
tablets. iv) Mini tablets of step iii were enteric coated and filled in capsule of desired size.

Table 1

Medium Batch No Reference/Innovator product Trilipix Test Product/ Micro Labs Ltd

Time in minutes % Release % Release
0 0.0 0.0
p H 3.5 buffer 120 0.0 0.0
p H 6.8 buffer 135 12.1 9.6

150 23.1 25.6

165 34.5 39.3

180 45.0 50.7

210 62.8 69.0

240 75.6 83.9

270 86.6 93.2

300 93.3 97.9

360 101.7 101.6

420 102.9 103.2

480 104.8 104.0
Above Table 1 represents comparative % drug release of both the reference/ innovator drug product (Triplix) and test product (Micro Labs) in different dissolution conditions. It would be noteworthy that the % drug release of both the reference and test product appears to be of similar profile. This above percentage release of test product was generated by using the formula produced as example 1 herein below.
The term ‘q.s.’ wherever appears in the examples is an abbreviation for ‘quantity sufficient’ which is the amount of the vehicle in such quantities that is just sufficient for its use in the composition of the present invention.
Stability Study:
The formulation prepared according to Example 1 was subjected to accelerated stability testing. Stability testing was carried out by storing the capsules at a condition of 40ºC/ 75% RH. The capsules were stored in HDPE containers as well as Alu-Alu blisters. The parameters were checked at the end of one, two and three months.
Aluminum blister foil offers good protection against external factors, is compact in size and economical. HDPE containers offer good mechanical resistance and are light in

weight. The containers and their properties directly affect stability of the product. Hence, in this study, a comparison is also made between two types of packing.
Related Substances:
Table 2: Impurity Profile

Alu- Alu Blister
Strength 45 mg
Specification Initial 1 Month 2 Months 3 Months
Impurity A NMT 0.2% Not detected Not detected Not detected Not detected
Impurity G NMT 0.2% Not detected Not detected Not detected Not detected
Fenofibrate NMT 0.2% 0.01% 0.01% 0.01% 0.01%
135 mg
Specification Initial 1 Month 2 Months 3 Months
Impurity A NMT 0.2% Not detected Not detected Not detected Not detected
Impurity G NMT 0.2% Not detected Not detected Not detected Not detected
Fenofibrate NMT 0.2% 0.01% 0.01% 0.01% 0.01%
Table 3: Impurity Profile

HDPE
Strength 45 mg
Specification Initial 1 Month 2 Months 3 Months
Impurity A NMT 0.2% Not detected Not detected --- Not detected
Impurity G NMT 0.2% Not detected Not detected --- Not detected
Fenofibrate NMT 0.2% 0.01% 0.01% --- 0.01%
135 mg
Specification Initial 1 Month 2 Months 3 Months
Impurity A NMT 0.2% Not detected Not detected --- Not detected
Impurity G NMT 0.2% Not detected Not detected --- Not detected
Fenofibrate NMT 0.2% 0.01% 0.01% --- 0.01%
Table 4: ASSAY (By HPLC)

Alu- Alu
Specification Initial 1 Month 2 Months 3 Months
45mg 40.5mg- 49.5mg 90%- 110% 44.02mg 97.9% 43.97mg 97.7% 44.16mg 98.2% 44.17mg 98.2%
135mg 121.50mg-148.50mg 90%- 110% 132.96mg 98.5% 133.99mg 99.3% 135.27mg 100.2% 134.37mg 99.6%
HDPE
Specification Initial 1 Month 2 Months 3 Months
45mg 40.5mg- 49.5mg 90%- 110% 44.02mg 97.9% 44.68 99.3% --- 44.48mg 98.9%
135mg 121.50mg- 148.50mg 90%- 110% 132.96mg 98.5% 133.26mg 98.7% --- 132.84mg 98.4%
HDPE = High density Polyethylene; Alu- Alu – Aluminum Based strip packaging
As it can be observed from the table, the Related Substances (Impurities) and Assay values after accelerated stability testing fall within the values of the specification. It can therefore be concluded that the product is stable for both the strengths under specified accelerated stability conditions and shows composition is stable in both the packing materials.
It will be evident to one skilled in the art that the present invention is not limited to the above description or illustrative examples provided below, and that it can be embodied in other specific forms without departing from the essential attributes thereof. It is therefore desired that the description and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
Example –1
Table-5: Pharmaceutical composition of the invention (Choline Fenofibrate Mini tablets filed in Capsule 45MG/135MG): RMG process

SN. Ingredients Quantity/tab
Dry mix
1. Choline Fenofibrate 14.89
2. Microcrystalline cellulose (Avicel pH 101) 2.24
3. Hydroxy propyl methyl cellulose (Methocel K15 M Premium) 4.35
Binder solution
4. Povidone (Kollidon - 30) 0.61
5. Purified Water q.s
Prelubrication
6. Hydroxy Propyl Cellulose (Klucel LF) 0.20
7. Colloidal Silicon Dioxide (Aerosil 200) 0.15
Lubrication
8. Sodium Stearyl Fumarate 0.56
Enteric Coating
9. Eudragit L 30 D-55 (equivalent to Eudragit L 100-55) 3.58
10. Talc
11. Tri Ethyl Citrate
12. Purified Water

Capsule Filling
13. Reddish Brown Opaque Cap, Yellow Opaque body, Size “3” hard gelatin plain capsule Size “3”
14. Blue Opaque Cap, Yellow Opaque body, Size “0” hard gelatin plain capsule Size “0”
Note: During Capsule filling, 4 mini tablets to be filled in size “3” capsule for Choline Fenofibrate Delayed Release Capsules 45 mg & 12 mini tablets to be filled in size “0” capsule for Choline Fenofibrate Delayed Release Capsules 135 mg
Procedure:
i) Choline Fenofibrate, Microcrystalline cellulose (Avicel pH 101) and Hydroxy propyl methyl cellulose (Methocel K15 M Premium) were weighed and passed through #30 sieve.

ii) Sifted materials of step i were mixed in RMG for specified time at slow speed. iii) Binder solution was prepared by adding Povidone (Kollidon - 30) to purified
water under constant stirring. iv) Binder solution of step iii was added to step ii in RMG followed by drying in
FBD v) Granules of step iv were sifted through # 30 sieve and further milled through
1.0mm, if left after sifting. vi) Hydroxy Propyl Cellulose (Klucel LF) and Colloidal Silicon Dioxide (Aerosil
200) were sifted through #40 sieve and blended with the granules of step 5 for
10 minutes at slow speed. vii) Sift Sodium Stearyl Fumarate was sifted and passed through #60 sieve and
mixed with prelubricated blend of step vi followed by compression to obtained
the desired minitablets. viii) Enteric coating solution was prepared by mixing Eudragit L 30 D-55, Talc and
Tri Ethyl Citrate in purified water followed by filtration of the solution
through #30 sieve. ix) Mini tablets of step vii were coated with solution of step viii. x) Coated mini tablets of step ix were filled in capsule of desired size.
Example –2
Table-6: Pharmaceutical composition of the invention (Choline Fenofibrate Granules filled in Capsule 45MG/135MG): Extrusion and Marumarization Process

SN. Ingredients Quantity/tab (mg)

45mg 135mg
Dry mix
1. Choline Fenofibrate 59.56 178.68
2. Microcrystalline cellulose (Avicel pH 101) 8.96 26.88
3. Hydroxy propyl methyl cellulose (Methocel K15 M Premium) 17.40 52.20
Binder solution
4. Povidone (Kollidon - 30) 2.44 7.32
5. Purified Water q.s q.s

Ente ric Coating
9. Eudragit L 30 D-55 (equivalent to Eudragit L 100-55) 14.32 42.96
10. Talc 2.04 6.12
11. Tri Ethyl Citrate 2.04 6.12
12. Purified Water q.s q.s
Lubrication
6. Sodium Stearyl Fumarate 2.24 6.72
7. Colloidal Silicon Dioxide (Aerosil 200) 0.60 1.80
Capsule Filling
13. Reddish Brown Opaque Cap, Yellow Opaque body, Size “3” hard gelatin plain capsule Size “3”
14. Blue Opaque Cap, Yellow Opaque body, Size “0” hard gelatin plain capsule Size “0”
Procedure:
i) Choline Fenofibrate, Microcrystalline cellulose (Avicel pH 101) and Hydroxy
propyl methyl cellulose (Methocel K15 M Premium) were weighed and passed
through #30 sieve. ii) Sifted materials of step i were mixed in RMG for specified time at low speed. iii) Binder solution was prepared by adding Povidone (Kollidon - 30) to purified
water under constant stirring. iv) Binder solution of step iii was added to step ii in RMG followed by extrusion
and marumarization. v) Pellets of step iv were dried in FBD for specified time. vi) Enteric coating solution was prepared by mixing Eudragit L 30 D-55, Talc and
Tri Ethyl Citrate in purified water followed by filtration of the solution
through #80 sieve. vii) Dried pellets of step v were coated with solution of step 6 followed by sifting
through vibratory sifter.

viii) Sift Sodium Stearyl Fumarate and Colloidal Silicon Dioxide (Aerosil 200 P) was sifted and passed through #60 and #40 sieve and mixed with blend of step vii for lubrication.
ix) Pellets of step viii were filled in capsule shell of desired size.
Example –3
Table-7: Pharmaceutical composition of the invention (Choline Fenofibrate Mini tablets filed in Capsule 45MG/135MG): RMG process

SN. Ingredients Quantity/tab
Dry mix
1. Choline Fenofibrate 14.89 2.24 4.35
2. Microcrystalline cellulose (Avicel pH 101)

3. Poly ethylene Oxide

Binder solution
4. Povidone (Kollidon - 30) 0.61 q.s
5. Purified Water

Prelubrication
6. Hydroxy Propyl Cellulose (Klucel LF) 0.20 0.15
7. Colloidal Silicon Dioxide (Aerosil 200)

Lubrication
8. Sodium Stearyl Fumarate 0.56
Enteric Coating
9. Eudragit L 30 D-55 (equivalent to Eudragit L 100-55) 3.58 0.51 0.51 q.s
10. Talc

11. Tri Ethyl Citrate

12. Purified Water

Capsule Filling
13. Reddish Brown Opaque Cap, Yellow Opaque body, Size “3” hard gelatin plain capsule Size “3”
14. Blue Opaque Cap, Yellow Opaque body, Size Size

“0” hard gelatin plain capsule “0”
Note: During Capsule filling, 4 mini tablets to be filled in size “3” capsule for Choline Fenofibrate Delayed Release Capsules 45 mg & 12 mini tablets to be filled in size “0” capsule for Choline Fenofibrate Delayed Release Capsules 135 mg
Procedure:
i) Choline Fenofibrate, Microcrystalline cellulose (Avicel pH 101) and Poly
ethylene Oxide were weighed and passed through #30 sieve. ii) Sifted materials of step i were mixed in RMG for specified time at slow speed. iii) Binder solution was prepared by adding Povidone (Kollidon - 30) to purified
water under constant stirring. iv) Binder solution of step iii was added to step ii in RMG followed by drying in
FBD v) Granules of step iv were sifted through # 30 sieve and further milled through
1.0mm, if left after sifting. vi) Hydroxy Propyl Cellulose (Klucel LF) and Colloidal Silicon Dioxide (Aerosil
200) were sifted through #40 sieve and blended with the granules of step v for
10 minutes at slow speed. vii) Sift Sodium Stearyl Fumarate was sifted and passed through #60 sieve and
mixed with prelubricated blend of step vi followed by compression to obtained
the desired minitablets. viii) Enteric coating solution was prepared by mixing Eudragit L 30 D-55, Talc and
Tri Ethyl Citrate in purified water followed by filtration of the solution
through #30 sieve. ix) Mini tablets of step vii were coated with solution of step viii. x) Coated mini tablets of step ix were filled in capsule of desired size.

WE CLAIM:
1. A stable oral pharmaceutical composition comprising a coated compressed dry mix, wherein the compressed dry mix comprises active Choline Fenofibrate with one or more pharmaceutical acceptable excipients, and wherein the said composition is devoid of molecular dispersion.
2. The composition according to claim 1, wherein the dry mix comprises active Choline Fenofibrate, inert filler material, one or more release controlling agent, and optionally one or more pharmaceutical acceptable excipients.
3. The composition according to claim 2, wherein the release controlling agent is a hydrophilic polymer, hydrophobic polymer, or a mixture thereof.
4. The composition according to claim 3, wherein the release controlling agent is selected from the group comprising Hydroxypropyl methylcellulose, hydroxypropyl cellulose, cellulose acetate, natural and synthetic gums containing galactomannans like xanthan gum, tragacanth, acacia, agar, guar gum, carrageenans, chitosans, polyalkylene polyols like polyethylene glycols; gelatin and gelatin derivatives; alginates; carbomers; polycarbophils; pectins, polyvinylpyrrolidone (PVP), polyethylene oxide(PEO), polyvinylpyrrolidone/vinyl acetate (PVP/VA), cellulose acetate butyrate, cellulose acetate propionate, cellulose acetate trimellitate, polyvinylmethacrylate/maleic anhydride (PVM/MA) copolymer, polyquaternium-1,cellulose carboxymethyl ethers and their salts, polyvinyl acetate (homopolymer); propylene glycol alginate, ethyl cellulose, methyl cellulose, cellulose acetate phthalate, lanolin and lanolin derivatives; glyceryl monostearate; stearic acid; paraffins; beeswax; carnauba wax; methacrylic acid copolymers; hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate;tribehenin, PVP/dimethylaminoethyl methacrylate copolymer; PVP/dimethylaminoethyl methacrylate/polycarbamyl polyglycol ester; polyethylene, polyvinyl acetate phthalate, dimethiconylacrylate/polycarbamyl/polyglycolester; PVP/polycarbamyl polyglycol ester or a combination thereof.
5. The composition according to any of the preceding claims, wherein the coating is an enteric coating.
6. The composition according to claim 5, wherein the enteric coating comprises an enteric polymer or an enteric binder.

7. The composition according to claim 6, wherein the enteric polymer and/ or enteric binder is selected from the group hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, carboxymethylethyl cellulose, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl methyl cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methyl cellulose acetate trimellitate, polyvinyl acetate phthalate, vinyl acetate-maleic anhydride copolymer, polyacrylates, methyl acrylate-methacrylic acid copolymers, ethyl acrylate-methacrylic acid copolymers, styrene-maleic acid copolymers, shellac, and mixtures thereof.
8. The composition according to any of the preceding claims, wherein the amount of active Choline Fenofibrate is from about 50 to about 60 % by weight, amount of release controlling agent is from about 25 to about 35% by weight and the amount of inert filler is from about 6 to about 12% by wt of the composition.
9. The composition according to any of the preceding claims, wherein the composition is prepared in the form of tablets, pellets, capsules or beads.
10. A process for preparing a stable oral pharmaceutical composition comprising a coated compressed dry mix, wherein the compressed dry mix comprises active Choline Fenofibrate, inert filler, release controlling agent and optionally one or more pharmaceutical acceptable excipients, and wherein the said composition is devoid of molecular dispersion, the process comprising the steps of:

(a) weighing desired amount of active, inert filler and release controlling agent, and passing through suitable mesh size and mixing to obtain a dry mix,
(b) preparing a binder solution and adding the binder solution to the dry mix of step (a), followed by drying to obtain granules of dry mix,
(c) lubricating the granules of the step (b), and compressing to obtain compressed dry mix, and
(d) coating the compressed dry mix of step (c) to obtain the composition.

11. The process according to claim 10, wherein the coating is an enteric coating comprising an enteric polymer or an enteric binder.
12. The process according to claim 10, further comprising filling the prepared coated compressed dry mix into capsules.
Dated this 25th day of January, 2013