Title of Invention	A NOVEL SYNERGISTIC PHARMACEUTICAL COMPOSITION
Abstract	A synergistic pharmaceutical composition comprising two anti hypercholesterolemic drugs such as micronized Fenofibrate of 13-22 microns and an inhibitor of cholesterol absorption such as Ezetimibe; along with various pharmaceutical auxiliaries formulated as tablet or capsule dosage form used for the treatment of Diabetic dyslipidemia.

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FORM 2 THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule!3) 1. TITLE OF THE INVENTION: "A novel synergistic pharmaceutical composition" 2. APPLICANT (a) NAME: M/S. INDOCO REMEDIES LIMITED. (b) NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956 (c) ADDRESS: Indoco House, 166 C. S. T. Road, Santacruz (East), Mumbai 400 098. Maharashtra, India 3.PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention and the manner in which it is to be performed Field of Invention: This invention relates to a novel synergistic pharmaceutical composition for the treatment of diabetic dyslipidemia. More particularly this invention relates to pharmaceutical compositions comprising two antihypercholesterolemic drugs Fenofibrate and ezetimibe using pharmaceutically acceptable auxiliaries. Background of Invention: Patients with type-2 diabetes mellitus have a peculiar lipid profile. The triglyceride levels in blood are usually raised and the levels of HDL cholesterol (HDLc) are low. The total Cholesterol and LDL cholesterol (LDLc) levels are usually near normal as per the conventional standards for the normal population. However the LDL particles are smaller and more dense.. Diabetic dyslipidemia contributes significantly to the etiopathogenesis of atherosclerosis leading to a high incidence of CVD morbidity and mortality. Correction of diabetic dyslipidemia involves a correction of all the three abnormalities with the treatment goal being triglyceride levels less than 150 mg/dl, HDLc levels greater than 40 mg/dl in men and more than 50 mg/dl in women and LDLc levels less than 100 mg/dl. Drugs commonly used to treat Diabetic Dyslipidemia includes Statins and Fibric acid Derivatives. Various Statins have been shown to be highly effective in reducing the total and LDL cholesterol. They also increase LDL particle size and reduce their density, making the LDL particles less atherogenic. They are one of the most effective drugs in achieving the LDL goal of less than 100 mg/dl. Statins at conventional doses however, have only modest effect in triglyceride reduction and a very minimal effect on increasing the HDLc. Tackling the elevated Triglyceride and low HDLc, especially the later, is also essential in reducing the risk of atherosclerosis. The fibric Acid derivatives are more effective in reducing the elevated Triglycerides and increasing the levels of HDLc. The newer derivatives like Fenofibrate.also effective in reducing the total and LDL cholesterol to some extent. Some fibrates like 2 Fenofibrate also help in converting the small dense highly atherogenic LDL to medium density LDL which are less atherogenic. However, the effect of Fibric Acid derivatives on reducing the LDL cholesterol is much inferior to that of Statins. Hence, if used alone, they are not capable of achieving the LDL cholesterol goal of less than 100 mg/dl in most patients. It is thus evident that Statins are effective in achieving the LDLc goal of less than 100 mg/dl, but they fail to reduce the Triglycerides and elevate the HDLc sufficiently. On the other hand, the Fibric Acid derivatives are more effective in reducing the Triglycerides and elevating the HDLc but they fail to achieve the LDLc goal. As it is essential to tackle all these abnormalities to achieve good results, a combination therapy is often suggested for the treatment of diabetic dyslipidemias. The first logical choice for combination therapy would seem to be Statins with fibric Acid derivatives. Such a combination has undoubtedly been shown to be more effective in achieving the treatment goals of LDLc,HDLc & triglycerides than monotherapy. However , such a combination can be potentially risky. Individually, statins and Fibric Acid derivatives cause Myopathy. When used together, the risk of this adverse effect increases still further. It can also lead to a higher incidence of Rhabdomyolysis which can be fatal. Thus, the combination of Statins and Fibric Acid derivatives can cause serious complications and it is recommended that such a combination should be avoided when possible. Niacin is another lipid lowering agent that reduces the Triglycerides and elevates HDLc. Hence one may consider of combining Niacin with statins. However, combining statins with Niacin have also been reported to increase the risk of myopathy and therefore requires careful monitoring. A combination of Fenofibrate with ezetimibe is more promising than any of the therapies mentioned above. This combination helps to achieve the desired lipid goals in a patient with diabetic dyslipidemia, without increasing incidence of side effects. Ezetimibe is the first of a new class of drugs that specifically reduces the intestinal absorption of cholesterol. The drug is absorbed into intestinal epithelial cells and 3 remains associated in great part with the apical cell membrane where it is believed to interfere with the putative sterol transporter system. This apparently prevents both free cholesterol and plant sterols (phytosterols) from being transported into the cell from intestinal lumen. The chemical name of Ezetimibe is l-(4-fluorophenyl)-3(R)[3-(4-fluorophenyl)-3(S)-hydroxypropyl ]-4(S)-(4-hydroxyphenyl)-2-azetidinone. Fenofibrate is used to reduce the amount of cholesterol and triglycerides in the blood. The chemical name of Fenofibrate is 2-[4-(4-chlorobenzoyl)phenoxy ]-2methyl propionic acid 1-methyl ester. US2004116358 discloses a method of treatment of a cholesterol associated benign and malignant tumors comprising administering therapeutically effective amount of an azetidinone-based cholesterol absorption inhibitor to a patient. US2004110842 describes self-emulsifying formulations of Fenofibrate and/or Fenofibrate derivatives with improved oral bioavailability and reduced food effect. Pharmaceutical compositions containing combination of Fenofibrate and co-enzyme Q10 for the treatment of endothelial dysfunction are described in HU0302566. Pharmaceutical compositions comprising a combination of metformin and fibrate, and its use for the preparation of medicines intended to reduce hyperglycaemia are reported in US6372790. Objective of the Invention: An objective of the present invention is to provide a synergistic pharmaceutical composition comprising Fenofibrate and Ezetimibe to achieve desired lipid profiles in a patient with diabetic dyslipidemia. Further objective of the present invention is to provide better patient compliance. Summary of the Invention : A novel synergistic pharmaceutical composition for the treatment of Diabetic dyslipidemia comprising two antihypercholesterolemic drugs viz-Fenofibrate and 4 Ezetimibe, formulated as tablet or capsule dosage form using various pharmaceutical auxiliaries. Detailed Description: Ezetimibe inhibits the absorption of biliary as well as dietary cholesterol from the intestine. It thus helps to reduce the LDLc by 15-20%.It also causes a small rise in the HDLc by 2.5-5.0%. Ezetimibe's side effect profile resembles that of a placebo and due to its minimal systemic absorption, no significant drug interactions occur. A synergistic composition of Fenofibrate and Ezetimibe, would be ideal in achieving the goals in Diabetic Dyslipidemia. Fenofibrate causes a reduction in the LDLc by about 15-20 mg/dl. Ezetimibe too causes a similar reduction in LDLc. As both these drugs act at different sites, viz Fenofibrate on PPARα and Ezetimibe on intestinal mucosal cells, giving together their effects on LDLc would be additive. Thus the said combination of Fenofibrate and Ezetimibe would cause a reduction in LDLc by about 30-40 mg/dl. This reduction would enable the diabetic patient to achieve the LDLc goal of less than 100 mg/dl. Fenofibrate also tends to reduce the density of LDL particles, changing their profile from small dense particles to medium dense particles, thus making them less atherogenic. Moreover, Fenofibrate is highly effective in increasing HDLc. An increase in HDLc by about 11-16% has been reported with Fenofibrate. Ezetimibe would also make a small contribution to the rise in HDLc. The combination would thus significantly elevate the HDLc to achieve the desired goal. Lastly, Fenofibrate by itself is highly effective in reducing the raised Triglycerides. Thus, all the abnormalities of Diabetic Dyslipidemia, viz raised triglycerides, Low HDLc and elevated small, dense LDLc, can be corrected using the said combination of Fenofibrate and Ezetimibe. Other important facts to be noted are that the combination of Fenofibrate with Ezetimibe will not lead to an increase in the incidence of side effects. This is unlike the increased potential risk of Myopathy which is noted when Statins are combined 5 with Fibrates or Niacin. Also as both Fenofibrate and ezetimibe have to be taken just once daily, the combination too needs to be taken just once daily. This ensures good patient compliance. The present invention also describes various formulations consisting of combination of the two antihypercholesterolemic drugs- Fenofibrate and Ezetimibe. Fenofibrate in combination with Ezetimibe may be presented as a tablet or capsule dosage form. The present invention describes the tablet which may be uncoated, film coated or bilayerd. The present invention describes that the uncoated or film coated tablets may be prepared by wet granulation process wherein both Fenofibrate and Ezetimibe are added to the dry mix and granulated by using appropriate binding agent and compressed to give tablets or may be granulated separately and compressed as bilayered tablets. The pharmaceutical auxiliaries are selected from the group comprising of diluents, binding agents, disintegrating agents, surfactants, glidants, lubricants and any such substance known in the art. Diluents used are selected from the group comprising of Dicalcium Phosphate, lactose, mannitol, microcrystalline cellulose, Maize starch either used alone or used in combination to give desired product parameters. Binding agents are selected from the group comprising of starch in the form of paste, polyvinyl pyrrolidone, Pregelatinised starch, Hydroxypropylmethylcellulose. Surfactants are selected from the group comprising of tween 80, sodium lauryl sulphate. Disintegrating agents are selected from the group comprising of crosscarmellose sodium, sodium starch glycollate, crosslinked polyvinylpyrolline, maize starch. 6 Lubricants and glidants are selected from the group comprising of Magnesium stearate, Colloidal silicon dioxide, calcium Stearate, Talc, Sodium Stearyl Fumarate. Fenofibrate is used in the micronised form for better bioavailability as reported in the prior art. The present invention is further illustrated in detail by the way of following examples. Example 1: In the present example, Fenofibrate and ezetimibe have been granulated together with PVP K-30 as a binding agent at 3% concentration of the tablet weight in Purified water. Lactose monohydrate has been used as a diluent, at 50.5%) concentration of tablet weight and Sodium lauryl Sulphate as a surfactant at 1% concentration of tablet weight. Crospovidone has been used as a disintegrant at 2% concentration of tablet weight, Aerosil 200 as a glidant and Sodium Stearyl Fumarate as a lubricant both at 0.5% concentration of tablet weight. The pharmaceutical composition has been given in table 1. Example 2 : In the present example, only Fenofibrate has been granulated with PVP K-30 as a binding agent at 3%o concentration of the tablet weight in Purified water. Ezetimibe has been added in the lubrication stage. Lactose monohydrate has been used as a diluent.at 50.5% concentration of tablet weight and Sodium lauryl Sulphate as a surfactant at 1% concentration of tablet weight. Crospovidone has been used as a disintegrant at 2% concentration of tablet weight, Aerosil 200 as a glidant and Sodium Stearyl Fumarate as a lubricant both at 0.5% concentration of tablet weight. The pharmaceutical composition has been given in table 1. Example 3 : In the present example, Fenofibrate and ezetimibe have been granulated together with PVP K-30 as a binding agent at 3% concentration of the tablet weight in Isopropyl Alcohol. Lactose monohydrate has been used as a diluent.at 50.5% concentration of tablet weight and Sodium lauryl Sulphate as a surfactant at 1% concentration of tablet weight. Crospovidone has been used as a disintegrant at 2% concentration of tablet 7 weight, Aerosil 200 as a glidant and Sodium Stearyl Fumarate as a lubricant both at 0.5% concentration of tablet weight. The pharmaceutical composition has been given in table 1. Example 4 : In the present example, only Fenofibrate has been granulated with PVP K-30 as a binding agent at 3% concentration of the tablet weight in Isopropyl Alcohol. Ezetimibe has been added in the lubrication stage. Lactose monohydrate has been used as a diluent at 50.5% concentration of tablet weight and Sodium lauryISulphate_ as a surfactant at 1% concentration of tablet weight. Crospovidone_has been used as a disintegrant at 2% concentration of tablet weight, Aerosil 200 as a glidant and Sodium Stearyl Fumarate as a lubricant both at 0.5% concentration of tablet weight. The pharmaceutical composition has been given in table 1. Table 1 : Ingredients Composition (mg/tablet) Dry Mixing : Example 1 Example 2 Example 3 Example 4 Fenofibrate 160.0 160.0 160.0 160.0 Ezetimibe 10.0 - 10.0 - Lactose monohydrate 202.0 202.0 202.0 202.0 Sodium Lauryl Sulphate 4.0 4.0 Granulation : Sodium Lauryl Sulphate 4.0 4.0 PVP K-30 12.0 12.0 12.0 12.0 Purified water - - Isopropyl Alcohol Lubrication : Crospovidone 8.0 8.0 8.0 8.0 Aerosil 200 2.0 2.0 2.0 2.0 *..' '*.'." Sodium Stearyl Fumarate 2.0 2.0 2.0 2.0 Ezetimibe - 10.0 - 10.0 Total 400.0 400.0 400.0 400.0 The stability data of all above 4 examples has been given in Table 2. Table 2 : Example 1 Example 2 Example 3 Example 4 Tests Initial 40°C/75 % RH/6M Initial 40°C/75 % RH/6M Initial 40°C/75 % RH/6M Initial 40°C/75 % RH/6M Hardness (Kg/cm2) 3-5 3-4 3-4 3-4 3-4 3-4 DT(min) 4'29" 8'00" 8'20" 8'10" 3'50" 3'00" Assay (%): Fenofibrate 100.5 100.43 104.9 101.25 99.3 95.27 103.5 96.36 Ezetimibe 103.4 101.34 99.4 100.03 103.6 101.62 102.0 98.90 Dissolution(%): Fenofibrate 79.9-82.9 75.88-80.97 76.54-79.6 81.33-86.56 76.12-86.61 57.98-67.19 74.69-81.88 74.17-85.28 Ezetimibe 73.9-77.4 93.16-97.74 75.74-86.4 97.78-105.58 80.87-87.03 82.97-92.65 74.28-78.99 93.56-99.67 From the above table it can be concluded that both Fenofibrate and Ezetimibe can be granulated together with either PVP in water or Isopropyl Alcohol. To improve the DT of tablets: 9 Example 5 : In the present example, Fenofibrate and Ezetimibe have been granulated together with PVP K-30 as a binding agent at 3% concentration of the tablet weight in Purified water. Lactose monohydrate and starch have been used as a diluent at 38.75%) and 9.75% concentration of tablet weight. Sodium lauryl Sulphate has been used as a surfactant at 1% concentration of tablet weight. Ac-Di-sol has been used as a disintegrant at 4% concentration of tablet weight, both intra and extragranularly. Aerosil 200 has been used as a glidant and Sodium Stearyl Fumarate as a lubricant both at 0.5% concentration of tablet weight. The pharmaceutical composition has been given in table 3. Example 6 : In the present example, Fenofibrate and Ezetimibe have been granulated together with PVP K-30 as a binding agent at 4% concentration of the tablet weight in Isopropyl Alcohol. Lactose monohydrate and starch have been used as a diluent at 38.75% and 9.75% concentration of tablet weight. Sodium lauryl Sulphate has been used as a surfactant at 1% concentration of tablet weight. Ac-Di-sol has been used as a disintegrant at 4% concentration of tablet weight, both intra and extragranularly. Aerosil 200 has been used as a glidant and Sodium Stearyl Fumarate as a lubricant both at 0.5% concentration of tablet weight. The pharmaceutical composition has been given in table 3. Table 3 : Ingredients Composition (mg/tablet) Dry mixing : Example 5 Example 6 Fenofibrate 160.0 160.0 Ezetimibe 10.0 10.0 Lactose Monohydrate 155.0 155.0 Starch 39.0 39.0 Sodium Lauryl Sulphate - 4.0 Ac-Di-Sol 8.0 8.0 Granulation : 10 Sodium Lauryl Sulphate 4.0 - PVP K-30 12.0 16.0 Purified Water - Isopropyl Alcohol - Lubrication : Ac-Di-Sol 8.0 8.0 Aerosil 200 2.0 2.0 Sodium Stearyl Fumarate 2.0 2.0 Total 400.0 404.0 The stability data of above examples 5&6 have been given in table 4. Table 4 : Example 5 Example 6 Tests Initial 40°C/75% RH/6M Blister pack 40°C/75% RH/6M Alu. Pouch Initial 40°C/75% RH/6M Blister pack 40°C/75% RH/6M Alu. Pouch Hardness (Kg/cm2) 5-6 6-8 6-7 4-6 8-8.5 5-7 DT(min) 4'00" 1'40" 6'50" 3'20" 4'49" 1'09" Assay (%): Fenofibrate 101.0 102.43 104.19 100.7 101.92 102.75 Ezetimibe 103.0 106.47 106.65 103.9 102.9 108.37 Dissolution(%) Fenofibrate 101.9-103.10 91.51-93.77 96.75-99.58 97.3-100.2 89.35-94.37 94.12-98.3 Ezetimibe 97.9-103.7 97.88-101.0 100.85-102.13 100.2-101.1 94.29-103.01 100.63-102.27 From the above table, it can be concluded that both physically and chemically both the above examples seem to be stable in both the packs viz- blister pack and Aluminium pouch pack. Also, there is an improvement in the dissolution of Fenofibrate and ezetimibe. Example 7: In the present example, Fenofibrate and Ezetimibe have been granulated together with PVP k-30 as a binding agent at 4% concentration of the fill weight of capsule in Purified water. Lactose monohydrate and starch have been used as a diluent at 38.75% and 9.75% concentration of the fill weight of capsule. Sodium lauryl Sulphate has been used as a surfactant at 1% concentration of the fill weight of capsule. Ac-Di-sol has been used as a disintegrant at 5% concentration of fill weight of capsule, both intra and extragranularly. Aerosil 200 has been used as a glidant and Sodium Stearyl Fumarate as a lubricant both at 0.5% concentration of fill weight of capsule. The initial analysis results are as follows: Assay % Dissolution % Fenofibrate 103.41 82.76-92.99 Ezetimibe 103.07 85.42-95.40 12 We claim, 1. A synergistic pharmaceutical composition comprising two anti hypercholesterolemic drugs such as micronized Fenofibrate of 13-22 microns and an inhibitor of cholesterol absorption such as Ezetimibe; along with various pharmaceutical auxiliaries formulated as tablet or capsule dosage form used for the treatment of Diabetic dyslipidemia. 2. The pharmaceutical composition as claimed in claim 1, wherein the dose of said Fenofibrate is 160 mg per tablet. 3. The pharmaceutical composition as claimed in claim 1, wherein the dose of said Ezetimibe is 10 mg per tablet. 4. The pharmaceutical composition as claimed in claim 1, wherein the micron size of said Fenofibrate is preferably 13 microns. 5. The pharmaceutical composition as claimed in claim 1, wherein said pharmaceutical auxiliaries are selected from the group comprising of diluents, binding agents, disintegrating agents, surfactants, glidants and lubricants. 6. The pharmaceutical composition as claimed in claim 5, wherein said diluents are selected from the group comprising of dicalcium phosphate, lactose monohydrate, mannitol, microcrystalline cellulose, maize starch either used alone or in combination. 7. The pharmaceutical composition as claimed in claim 6, wherein the said diluent is lactose monohydrate in the concentration of 38.75-50.5% of the tablet weight. 8. The pharmaceutical composition as claimed in claim 5, wherein said binding agents are selected from the group comprising of starch in the form of paste, polyvinyl pyrrolidone, Pregelatinised starch or hydroxypropylmethylcellulose. 9. The pharmaceutical composition as claimed in claim 8, wherein said binding agent is polyvinyl pyrrolidone in the concentration of 3-4% of the tablet weight. 10. The pharmaceutical composition as claimed in claim 5, wherein said surfactants are selected from the group comprising of Tween 80 and Sodium lauryl sulphate. 11. The pharmaceutical composition as claimed in claim 10, wherein said surfactant is sodium lauryl sulphate in the concentration of 1% of the tablet weight. 12. The pharmaceutical composition as claimed in claim 5, wherein said disintegrating agents are selected from the group comprising of croscarmellose sodium, sodium starch glycolate, crosslinked polyvinylpyrrolidone or starch. 13. The pharmaceutical composition as claimed in claim 12, wherein said disintegrating agent is croscarmellose sodium in the concentration of 2% of the tablet weight. 14. The pharmaceutical composition as claimed in claim 5, wherein said glidant and lubricants are selected from the group comprising of magnesium stearate, colloidal silicon dioxide, calcium stearate, talc or sodium stearyl fumarate. 15. The pharmaceutical composition as claimed in claim 14, wherein the said glidant is colloidal silicon dioxide and said lubricant is sodium stearyl fumarate in the concentration of 0.5% of the tablet weight. 16. The composition as claimed in claim 1, wherein both Fenofibrate and Ezetimibe are granulated together. 17. The composition as claimed in claim 1, wherein Fenofibrate and Ezetimibe are granulated separately. Dated this 28th day of July 2005 v Dr. Gopakumar G. Nair Agent for the Applicant

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804-MUM-2004-ABSTRACT(2-8-2005).pdf

804-mum-2004-cancelled pages(2-8-2005).pdf

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804-mum-2004-correspondence(ipo)-(5-11-2008).pdf

804-MUM-2004-DESCRIPTION(COMPLETE)-(2-8-2005).pdf

804-mum-2004-description(granted)-(5-11-2008).pdf

804-MUM-2004-DESCRIPTION(PROVISIONAL)-(29-7-2004).pdf

804-MUM-2004-FORM 1(18-8-2004).pdf

804-MUM-2004-FORM 1(25-7-2004).pdf

804-mum-2004-form 1(28-7-2004).pdf

804-mum-2004-form 1(29-7-2004).pdf

804-MUM-2004-FORM 13(15-7-2011).pdf

804-mum-2004-form 18(2-4-2007).pdf

804-mum-2004-form 2(2-8-2005).pdf

804-MUM-2004-FORM 2(COMPLETE)-(2-8-2005).pdf

804-mum-2004-form 2(granted)-(02-08-2005).doc

804-mum-2004-form 2(granted)-(2-8-2005).pdf

804-mum-2004-form 2(granted)-(5-11-2008).pdf

804-MUM-2004-FORM 2(PROVISIONAL)-(29-7-2004).pdf

804-MUM-2004-FORM 2(TITLE PAGE)-(COMPLETE)-(2-8-2005).pdf

804-mum-2004-form 2(title page)-(granted)-(5-11-2008).pdf

804-MUM-2004-FORM 2(TITLE PAGE)-(PROVISIONAL)-(29-7-2004).pdf

804-MUM-2004-FORM 26(10-9-2008).pdf

804-MUM-2004-FORM 26(29-7-2004).pdf

804-mum-2004-form 26(29-8-2003).pdf

804-mum-2004-form 26(6-4-2007).pdf

804-MUM-2004-FORM 3(10-9-2008).pdf

804-MUM-2004-FORM 3(29-7-2004).pdf

804-MUM-2004-FORM 5(2-8-2005).pdf

804-MUM-2004-REPLY TO EXAMINATION REPORT(10-9-2008).pdf