Title of Invention	STABLE ORAL ATORVASTATIN FORMULATION AND PROCESS OF ITS PREPARATION
Abstract	The present invention relates to a stable oral pharmaceutical formulations comprising amorphous atorvastatin calcium. The atorvastatin formulation prepared according to the present invention involves use minimum amount of pH adjusting substance preferably below 5%, more preferably below 4% by the total weight of the composition to obtain stable formulation. Further formulation provides a pH less than pKa+l of atorvastatin calcium to an aqueous solution and simultaneously improved solubility characteristics of atorvastatin calcium.

Title of Invention

STABLE ORAL ATORVASTATIN FORMULATION AND PROCESS OF ITS PREPARATION

Abstract

The present invention relates to a stable oral pharmaceutical formulations comprising amorphous atorvastatin calcium. The atorvastatin formulation prepared according to the present invention involves use minimum amount of pH adjusting substance preferably below 5%, more preferably below 4% by the total weight of the composition to obtain stable formulation. Further formulation provides a pH less than pKa+l of atorvastatin calcium to an aqueous solution and simultaneously improved solubility characteristics of atorvastatin calcium.

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 of 1970) & THE PATENTS RULES, 2003 PROVISIONAL SPECIFICATION (See section 10 and rule )3] 1. Title of the invention: "Stable oral Atorvastatin formulation and process of its 2. Macleods Pharmaceuticals Ltd., an Indian Company, having its Registered Office at 304 - Atlanta Arcade, Opp. Leela Hotel, Marol Church Road, Andheri (East), Mumbai - 400 059, Maharashta, India. 2. Macleods Pharmaceuticals Ltd., an Indian Company, having its Registered Office at 304 - Atlanta Arcade, Opp. Leeia Hotel, Marol Church Road, Andheri (East), Mumbai - 400 059, Maharashta, India. 3. The following specification describes the invention. STABLE ORAL ATORVASTATIN FORMULATION AND PROCESS OF ITS PREPARATION Field of the Invention The invention relates to stable oral pharmaceutical formulation of amorphous atorvastatin and process for preparing the same. Brief Description Atorvastatin calcium, the substance known by the chemical name (R-(R, R))-2-(4-fluorophenyl)- -dihydroxy-5-(l-methylethyl)-3-phenyl((phenylamino)carbonyl)-lH-pyrrole-I-heptanoic acid hemi calcium salt is known as HMG-CoA reductase inhibitor and is used as an antihypercholesterolemic agent. Processes for the preparation of atorvastatin and key intermediates are disclosed in the U.S. Pat. Nos. 5,003,080; 5,097,045; 5,103,024; 5,124,482; 5,149,837; 5,155,251; 5,216,174; 5,245,047; 5,248,793; 5,280,126; 5,342,952 and 5,397,792. Atorvastatin in the pharmaceutical compositions available in the market, is usually prepared as its calcium salt since it enables atorvastatin to be conveniently formulated in the pharmaceutical formulations, for examples, in tablets, capsules, powders and the like for oral administration. Amorphous form is more bioavailable than the crystalline form. But the problem of stability is more significant in case of amorphous form. WO 2002/072073 shows that too low pH impairs releasing of the active substance. The composition mentioned in this application should, after dissolution in simulated gastric juice, increase pH to pKa+1 of atorvastatin acid. 1 The instant invention provides a pharmaceutically formulation which is therapeutically equivalent to commercial product yet stable sustaining the acidic environment, while pH after dissolution in simulated gastric juice is less than pKa+1 of atorvastatin acid via selection of appropriate excipients accompanied with the use of a combination of organic bases and alkali earth metal oxides. The underlined objective involves the use of granulation technique. More particularly, the invention provides a therapeutically equivalent yet stable composition of amorphous atorvastatin calcium salts. According to one of the featured aspect of the invention, the particle size of amorphous atorvastatin calcium is not more than 50 urn. In the category of alkali earth metal oxides, calcium oxide (CaO) and magnesium oxide (MgO) may be preferred. Organic base is selected from the group consisting of meglumine, lysine, N, N'-dibenzylethylenediamine, chloroprocain, choline, di ethanol amine, ethylenediamine, procaine, and mixtures thereof. Brief Manufacturing Process Atorvastatin calcium, microcrystalline cellulose, mannitol, magnesium oxide and meglumine are sifted through #40 mesh. Sifted material is dry mixed in rapid mixer granulator (RMG).Binder solution is prepared by dissolving Polysorbate 80 in warm water and BHA in Ethanol and HPC is dissolved in water. Polysorbate 80/BHA solution is being added to HPC solution till a homogeneous binder solution is formed. Granulation is done in RMG and formed granules are being dried. Further dried granules are prelubricated with croscarmellose sodium and microcrystalline cellulose and lubricated with magnesium stearate in low shear blender. Lubricated blend is 2 compressed using suitable punches on rotary compression machine and finally compressed tablets are being coated with a coating solution. Example 1 S.No. Ingredient Weight in mg/tablet Core Composition A B 1. Atorvastatin calcium 82.72 82.72 2. Microcrystalline cellulose 428.76 188.76 3. Mannitol 360.00 600.00 4. Magnesium Oxide 18.00 18.00 6. Meglumine 24.00 24.00 7. Butylated hydroxy anisole 0.12 0.12 8. Hydroxypropyl cellulose 12.00 12.00 9. Polysorbate 80 4.80 4.80 10. Water q.s. q.s. 11. Microcrystalline cellulose 200.0 200.0 12. Croscarmellose sodium 60.00 60.00 13. Magnesium stearate 9.60 9.60 Tablet weight 1200 1200 Coating formula 10. Hypromellose q.s. to produce a non¬functional film coat 11. PEG 12. Talc 13. Titanium Dioxide Total 1224 Experimental Data S.No. Time Tablet A (pH) Tablet B (pH) I. Initial 3.0-3.1 3.0-3.1 2. After 15 min 4.6-4.7 4.7-4.8 3. After 30 min 5.2-5.3 5.3-5.4 Dated this 19th day of September, 2008 4

Full Text

FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule )3]
1. Title of the invention: "Stable oral Atorvastatin formulation and process of its

2. Macleods Pharmaceuticals Ltd., an Indian Company, having its Registered Office at 304 - Atlanta Arcade, Opp. Leela Hotel, Marol Church Road, Andheri (East), Mumbai - 400 059, Maharashta, India.
2. Macleods Pharmaceuticals Ltd., an Indian Company, having its Registered Office at 304 - Atlanta Arcade, Opp. Leeia Hotel, Marol Church Road, Andheri (East), Mumbai - 400 059, Maharashta, India.
3. The following specification describes the invention.

STABLE ORAL ATORVASTATIN FORMULATION AND PROCESS OF ITS
PREPARATION
Field of the Invention
The invention relates to stable oral pharmaceutical formulation of amorphous atorvastatin and process for preparing the same.
Brief Description
Atorvastatin calcium, the substance known by the chemical name (R-(R*, R*))-2-(4-fluorophenyl)- -dihydroxy-5-(l-methylethyl)-3-phenyl((phenylamino)carbonyl)-lH-pyrrole-I-heptanoic acid hemi calcium salt is known as HMG-CoA reductase inhibitor and is used as an antihypercholesterolemic agent. Processes for the preparation of atorvastatin and key intermediates are disclosed in the U.S. Pat. Nos. 5,003,080; 5,097,045; 5,103,024; 5,124,482; 5,149,837; 5,155,251; 5,216,174; 5,245,047; 5,248,793; 5,280,126; 5,342,952 and 5,397,792.
Atorvastatin in the pharmaceutical compositions available in the market, is usually prepared as its calcium salt since it enables atorvastatin to be conveniently formulated in the pharmaceutical formulations, for examples, in tablets, capsules, powders and the like for oral administration.
Amorphous form is more bioavailable than the crystalline form. But the problem of stability is more significant in case of amorphous form.
WO 2002/072073 shows that too low pH impairs releasing of the active substance. The composition mentioned in this application should, after dissolution in simulated gastric juice, increase pH to pKa+1 of atorvastatin acid.
1

The instant invention provides a pharmaceutically formulation which is therapeutically equivalent to commercial product yet stable sustaining the acidic environment, while pH after dissolution in simulated gastric juice is less than pKa+1 of atorvastatin acid via selection of appropriate excipients accompanied with the use of a combination of organic bases and alkali earth metal oxides. The underlined objective involves the use of granulation technique.
More particularly, the invention provides a therapeutically equivalent yet stable composition of amorphous atorvastatin calcium salts.
According to one of the featured aspect of the invention, the particle size of amorphous atorvastatin calcium is not more than 50 urn.
In the category of alkali earth metal oxides, calcium oxide (CaO) and magnesium oxide (MgO) may be preferred.
Organic base is selected from the group consisting of meglumine, lysine, N, N'-dibenzylethylenediamine, chloroprocain, choline, di ethanol amine, ethylenediamine, procaine, and mixtures thereof.
Brief Manufacturing Process
Atorvastatin calcium, microcrystalline cellulose, mannitol, magnesium oxide and meglumine are sifted through #40 mesh. Sifted material is dry mixed in rapid mixer granulator (RMG).Binder solution is prepared by dissolving Polysorbate 80 in warm water and BHA in Ethanol and HPC is dissolved in water. Polysorbate 80/BHA solution is being added to HPC solution till a homogeneous binder solution is formed. Granulation is done in RMG and formed granules are being dried.
Further dried granules are prelubricated with croscarmellose sodium and microcrystalline cellulose and lubricated with magnesium stearate in low shear blender. Lubricated blend is
2

compressed using suitable punches on rotary compression machine and finally compressed tablets are being coated with a coating solution.
Example 1

S.No. Ingredient Weight in mg/tablet
Core Composition A B
1. Atorvastatin calcium 82.72 82.72
2. Microcrystalline cellulose 428.76 188.76
3. Mannitol 360.00 600.00
4. Magnesium Oxide 18.00 18.00
6. Meglumine 24.00 24.00
7. Butylated hydroxy anisole 0.12 0.12
8. Hydroxypropyl cellulose 12.00 12.00
9. Polysorbate 80 4.80 4.80
10. Water q.s. q.s.
11. Microcrystalline cellulose 200.0 200.0
12. Croscarmellose sodium 60.00 60.00
13. Magnesium stearate 9.60 9.60
Tablet weight 1200 1200
Coating formula
10. Hypromellose q.s. to produce a non¬functional film coat
11. PEG

12. Talc

13. Titanium Dioxide

Total 1224

Experimental Data

S.No. Time Tablet A (pH) Tablet B (pH)
I. Initial 3.0-3.1 3.0-3.1
2. After 15 min 4.6-4.7 4.7-4.8
3. After 30 min 5.2-5.3 5.3-5.4
Dated this 19th day of September, 2008

4

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Patent Number

272594

Indian Patent Application Number

2019/MUM/2008

PG Journal Number

16/2016

Publication Date

15-Apr-2016

Grant Date

12-Apr-2016

Date of Filing

22-Sep-2008

Name of Patentee

MACLEODS PHARMACEUTICALS LIMITED

Applicant Address

304-ATLANTA ARCADE, OPP. LEELA HOTEL, MAROL CHURCH ROAD, ANDHERI (EAST), MUMBAI,

Inventors:

#	Inventor's Name	Inventor's Address
1	AGARWAL RAJENDRA MURLIDHAR	G-2, MAHAKALI CAVES ROAD, SHANTI NAGAR, ANDHERI (EAST), MUMBAI-400093.
2	GOGIA ASHISH	G-2, MAHAKALI CAVES ROAD, SHANTI NAGAR, ANDHERI (EAST), MUMBAI-400093.

PCT International Classification Number

A61K31/20; A61K31/401; A61K45/08

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA