WO2008104880A2

WO2008104880A2 - Stable solid dosage forms of an antidepressant

Info

Publication number: WO2008104880A2
Application number: PCT/IB2008/000600
Authority: WO
Inventors: Krishna Murthy Bhavanasi; Venkata Ram Mohan Rao Visinigiri; Manoj Kanti Saha; Nagaprasad Vishnubhotla; Sivakumaran Meenakshisunderam
Original assignee: Aurobindo Pharma Limited
Priority date: 2007-03-01
Filing date: 2008-02-28
Publication date: 2008-09-04
Also published as: EP2134325A2; WO2008104880A3

Abstract

The present invention relates to a stable solid dosage form comprising an anti-depressant. More particularly, the present invention relates to stable solid dosage form of escitalopram or its salts. The present invention also relates to a process for the preparation of stable solid dosage form of escitalopram or its salts.

Description

STABLE SOLID DOSAGE FORMS OF AN ANTIDEPRESSANT

Field of the invention

The present invention relates to a stable solid dosage form comprising an anti-depressant. More particularly, the present invention relates to stable solid dosage form of escitalopram or its salts.

The present invention also relates to a process for the preparation of stable solid dosage form of escitalopram or its salts.

Background of the invention

Citalopram is a selective, centrally active serotonin reuptake inhibitor. Citalopram hydrobromide was first disclosed in US 4, 136, 193. This patent also describes the manufacture of tablets containing salts of citalopram.

Citalopram hydrobromide has been approved by USFDA in 1998. Subsequent to this, the S-enantiomer of citalopram (escitalopram) was shown to have better activity profile and has been approved by FDA in 2002.

Escitalopram is an orally administered selective serotonin reuptake inhibitor (SSRI), and is indicated for the treatment of depression. Escitalopram is marketed as oxalate salt under the trade name LEXAPRO™. Chemically, Escitalopram is (+)-l-(3-dimethylaminopropyl)- l-(4-fluorophenyl)-l,3-dihydroisobenzofuran-5-carbonitrile. Escitalopram oxalate was disclosed in US 4,943,590, reissued as US RE 34,712. This patent also describes the manufacture of tablets containing salts of Escitalopram. Escitalopram is a poorly soluble drug and hence poses serious dissolution problems, which may affect bioavailability. For drugs having low solubility, there is considerable evidence that the dissolution partially or completely controls the rate of absorption. Bioavailability can also be affected by a number of factors such as the amounts and types of adjuvants used, the manufacturing process, compression forces (in tablet manufacturing), the surface area available for dissolution etc.

The escitalopram oxalate product prepared by crystallization from acetone as outlined in US 4,943,590 has a very small particle size around 2- 20 microns resulting in poor flow properties.

It is disclosed in US 6,916,941 that the preparation of tablets with a reproducible composition can be prepared by direct compression when the active substance and all other dry ingredients have good flow properties. However, in many cases the particle size of the active substance is small, cohesive or has poor flow properties. To overcome these problems, the inventors of US '941 developed a crystallization process that produced escitalopram oxalate having the particle size of at least 40μm, which is useful for the manufacture of directly compressed tablets.

US 2005/0196453 discloses crystalline particles of escitalopram oxalate, characterized in that the ratio between the median particle size and the particle size at the 95% quantile is less than 0.42 and the tablets prepared by direct compression method.

In our PCT publication i.e. WO 2006/123243. we disclosed pharmaceutical dosage forms comprising escitalopram prepared by a granulation technique, wherein the particle size of the escitalopram oxalate is less than 20 μm.

The above prior art references disclose formulations of escitalopram and do not disclose long term stability issues of escitalopram. Further, the inventors of the present invention during their efforts to develop solid dosage forms of escitalopram found that during the long term storage of escitalopram, oxidation related impurities might be formed. To reduce the formation of oxidative impurities and to improve the long term stability of escitalopram, some stabilizers preferably antioxidants can be added to the formulation. Antioxidant added in small quantities to hydrocarbons that are susceptible to oxidation, inhibit or slow down the oxidative process, while being itself oxidized.

Objective of the invention

Accordingly, the main objective of the present invention is to provide stable solid dosage form of escitalopram or its salts, which comply with the reference product in terms of stability, in vivo parameters like C_max, t_ma^ and AUC and in vitro parameters like dissolution, disintegration.

Yet another objective of the present invention is to provide simple and efficient process for preparing stable solid dosage form of escitalopram or its salts, on a commercial scale.

Summary of the invention

According to the main embodiment of the present invention, there is provided a stable solid dosage form comprising escitalopram or its salts, stabilizer and one or more pharmaceutically acceptable excipients. Detailed description of the invention

The salt of escitalopram used according to present invention includes oxalate, hydrobromide and hydrochloride.

The stabilizer used according to present invention is an antioxidant selected from the group consisting of butylated hydroxy anisole (BHA), butylated hydroxytoulene (BHT), alpha tocopherol, ascorbic acid, ascorbyl palmiate, benzoic acid, cysteine hydrochloride, isoascorbic acid, propionic acid, monothioglycerol and sodium metabisulfite and the like or mixtures thereof.

The amount of stabilizer(s) used in the dosage form may range from about 0.01% to about 10% w/w, and preferably from about 0.02% to about 5% w/w.

Escitalopram may undergo oxidation during storage thereby produces oxocitalopram. The quantity of oxocitalopram may increase during long-term storage which is not acceptable. Antioxidants such as BHA and BHT react with the free radicals and decrease the rate of oxidation.

In an embodiment of the present invention, the pharmaceutically acceptable excipients include binders, diluents, disintegrants, lubricants and/or glidants and the like.

In another embodiment, the preferable stable solid dosage form according to present invention comprises about 5% to about 20% w/w of escitalopram or its salts, about 70% to about 90% w/w of diluent, about 1% to about 5% w/w of disintegrant, about 0.01% to about 5% w/w of stabilizer, about 0.1 % to about 5% w/w of glidant and about 1 % to about 5% w/w of lubricant.

The diluents used according to the present invention are selected from dibasic calcium phosphate, calcium carbonate, lactose, sucrose, cellulose microcrystalline. cellulose powdered, silicified microcrystalline cellulose, calcium silicate, starch, starch pregelatinized, polyols such as mannitol, sorbitol, xylitol, maltitol or combination thereof.

Suitable disintegrants used in accordance with the present invention are selected from croscarmellose sodium, crospovidone, carboxy methyl cellulose sodium, sodium starch glycolate, starch, pregelatinised starch and the like or combination thereof.

Suitable binders according to the present invention are selected from methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, gelatin, ethyl cellulose, polyvinyl alcohol, starch, pregelatinized starch, agar, tragacanth, sodium alginate and the like. Suitable lubricants according to the present invention are selected from sodium lauryl sulfate, talc, magnesium stearate, sodium stearyl fumarate, stearic acid, glyceryl behenate, hydrogenated vegetable oil, zinc stearate and suitable glidants include colloidal silicon dioxide and talc. In yet another embodiment, the particle size of the escitalopram oxalate used according to present invention is in the range of 2 to 100 μm, preferably less than 20 μm.

In another embodiment, the preferable stable solid dosage form of the present invention comprises about 5% to about 20% w/vv of escitalopram or its salts, about 70% to about 90% w/w of diluent selected from silicified microcrystalline cellulose, microcrystalline cellulose, lactose, mannitol or combination thereof, about 1% to about 5% w/w of disintegrant selected from croscarmellose sodium, crospovidone and sodium starch glycolate, about 0.01 % to about 5% w/vv of stabilizer selected from butylated hydroxy anisole, burylated hydroxytoulene and alpha tocopherol or combination thereof, about 0.1 % to about 5% w/w of glidant selected from colloidal silicon dioxide and talc or combination thereof and about 1 % to about 5% w/w of lubricant selected from magnesium stearate and sodium stearyl fumarate.

In another embodiment, the solid dosage form of the present invention is in the form of tablet or gelatin capsule or processed into granules for oral suspension.

In yet another embodiment the tablets of the present invention, include uncoated tablets, tablets coated with film forming polymers such as hydroxypropylmethylcellulose, ethyl cellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene oxide and the like.

In yet another embodiment, there is provided a method of treating depression comprising administering to patients in need thereof a dosage form of escitalopram or its salts of the present invention.

In another embodiment, the stable solid dosage form of escitalopram or its salts may be prepared by direct compression, wet granulation or dry granulation. In yet another embodiment, there is provided a process for the preparation of a stable solid dosage form comprising escitalopram or its salts, stabilizer and one or more pharmaceutically acceptable excipients, which comprises the steps of: i) mixing escitalopram with one or more excipients, ii) dissolving the stabilizer in the solvent and granulating the blend obtained in step (i), iii) drying the granules obtained in step (ii), iv) mixing the granules of step (iii) with one or more pharmaceutically acceptable excipients, v) lubricating the blend of step (iv) and vi) compressing the blend of step (v) into tablets.

Suitable solvents used for granulation are selected from water or organic solvents such as acetone, alcohol, isopropyl alcohol dichloromethane and the like or mixture thereof.

The following examples further exemplify the invention and are not intended to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.

Example 1 (Escitalopram oxalate tablets with stabilizers)

The processing steps that are involved in making film coated tablets of escitalopram oxalate disclosed above are given below: (i) escitalopram oxalate, silicified microcrystalline cellulose, colloidal silicon dioxide, half the quantity of the croscarmellose were blended, (ii) BHA and BHT were dissolved in isopropyl alcohol and added to the blend of step (i),

(iii) granulated the blend obtained in step (ii) with water, (iii) the granules of step (iii) were blended with microcrystalline cellulose and colloidal silicondioxide,

(iv) lubricated blend of the step (iv) with talc and magnesium stearate, (v) compressed the blend of step (iv) into tablets and (vi) tablets of step (v) were then coated with a solution / suspension of opadry in water.

The compositions given in examples 2-5 were prepared using similar procedure as described in example 1. Example 2

Example 3

Example 4

Example 5 (Escitalopram oxalate tablets without stabilizer)

Stability Data: Tablets prepared according to examples 3-5 were stored at 40°C/75%RH. for two months and then tested by an HPLC method to determine the amount of oxocitalopram. The stability data is given in table 2.

Table 2

Claims

We claim:

1. A stable solid dosage form comprising escitalopram or its salts, stabilizer and one or more pharmaceutically acceptable excipients.

2. The dosage form of claim 1 , wherein stabilizer is selected from butylated hydroxy anisole (BHA), butylated hydroxytoulene (BHT), alpha tocopherol, ascorbic acid, ascorbyl palmiate, benzoic acid, cysteine hydrochloride, isoascorbic acid, propionic acid, monothioglycerol and sodium metabisulfite or mixture thereof.

3. The dosage form of claim 1 , wherein the amount of stabilizer(s) is in the range from about 0.01 % to about 10% w/w, and preferably from about

0.02% to about 5% w/w.

4. The dosage form of claim 1 , the pharmaceutically acceptable excipients include diluent, binder, disintegrant, lubricant and/or glidant.

5. The dosage form of claim 4, wherein the diluent is selected from dibasic calcium phosphate, calcium carbonate, lactose, sucrose, cellulose- microcrystalline, cellulose powdered, silicified microcrystalline cellulose, calcium silicate, starch, starch pregelatinized, polyols such as mannitol, sorbitol, xylitol, maltitol or combination thereof.

6. The dosage form of claim 4, wherein the binder is selected from methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, starch, pregelatinized starch, agar, tragacanth and sodium alginate.

7. The dosage form of claim 4, wherein the disintegrant is selected from croscarmellose sodium, crospovidone. carboxymethylcellulose sodium, sodium starch glycolate, starch, pregelatinised starch or combination thereof.

8. The dosage form of claim 4, wherein the lubricant is selected from sodium lauryl sulfate, talc, magnesium stearate, sodium stearyl fumarate, stearic acid, glyceryl behenate, hydrogenated vegetable oil and zinc stearate.

9. A stable solid dosage form comprising about 5% to about 20 % w/w of escitalopram or its salts, about 70% to about 90% w/w of diluent, about 1% to about 5 % w/w of disintegrant, about 0.01% to about 5% w/w of stabilizer, about 0.1 % to about 5 % w/w of glidant and about 1 % to about 5 % w/w of lubricant.

10. A process for the preparation of a stable solid dosage form comprising escitalopram or its salts, stabilizer and one or more pharmaceutically acceptable excipients, which comprises the steps of: i) mixing escitalopram with one or more excipients, ii) dissolving the stabilizer in the solvent and granulating the blend obtained in step (i), iii) drying the granules obtained in step (ii), iv) mixing the granules of step (iii) with one or more pharmaceutically acceptable excipients. v) lubricating the blend of step (iv) and vi) compressing the blend of step (v) into tablets.

1 1. The dosage form of claim 10, wherein the solvent used for granulation is selected from water or organic solvents such as acetone, alcohol, isopropyl alcohol dichloromethane or mixture thereof.

12. A method of treating depression comprising administering to patients in need thereof a dosage form of escitalopram or its salts of claim