FORM 2
THE PATENTS ACT 1970 (Act 39 of 1970)
PROVISIONAL SPECIFICATION
(SECTION 10)
"PHARMACEUTICAL COMPOSITION OF ESZOPICLONE"


Glenmark Generics Limited
an Indian Company, registered under the Indian company's Act 1957
and having its registered office at
B/2, Mahalaxmi Chambers, 22 Bhulabhai Desai Road,
Mumbai - 400 026

THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION

2 JUL 2008

TECHNICAL FIELD:
The present invention provides a stable pharmaceutical composition for the treatment of insomnia. Particularly, the present invention provides a pharmaceutical composition comprising eszopiclone. More particularly, the present invention relates to the pharmaceutical composition comprising eszopiclone of median particle size not more than 40 urn.
BACKGROUND ART:
Eszopiclone is a nonbenzodiazepine hypnotic drug; previously disclosed in U.S. Pat. No. 6,444,673. Eszopiclone is available in the market under the trade name Lunesta. Lunesta is available in the form of oral tablets of lmg, 2mg, and 3mg strength. Lunesta is indicated for the treatment of insomnia.
Eszopiclone is a cyclopyrrolone that has the chemical name (+)-(5S)-6- (chloropyridin-2-yl)-7-0X0-6, 7-dihydro-5H-pyrrolo [3, 4-b] pyrazin-5-yl 4-methyl- piperazine- 1-carboxylate.
U.S. Pat. No. 6,864,257 discloses the effectiveness of eszopiclone as hypnotic, sedative and a tranquilizer.
SUMMARY OF THE INVENTION:
The present invention provides a pharmaceutical composition comprising milled eszopiclone, optionally with one or more pharmaceutically acceptable excipients. The composition of present invention is bioequivalent with marketed pharmaceutical composition of eszopiclone (Lunesta).
The present invention further provides a pharmaceutical composition of eszopiclone comprising milled eszopiclone. optionally with one or more pharmaceutically acceptable excipients, wherein the milling of eszopiclone provides median particle size not more than 40 µm
In another embodiment, the present invention provides a. pharmaceutical composition of eszopiclone comprising milled eszopiclone, optionally with one or more pharmaceutically
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acceptable excipients; wherein the milling of eszopiclone provides at least 90% particles of eszopiclone having particle size less than 110µm.
In another embodiment, the present invention provides a pharmaceutical composition of eszopiclone comprising milled eszopiclone, optionally with one or more pharmaceutically acceptable excipients, wherein the composition is in the solid dosage form.
In another embodiment of present invention, the solid dosage forms are granules, pellets, minitablets, tablets, capsules. The preferred solid dosage forms are tablets.
In another embodiment of present invention, a method for milling the eszopiclone is provided. The milling may include dry milling or wet milling or both.
It is an object of the present invention to provide eszopiclone in stable and bioavailable dosage form.
The present invention also provides a method of preparing the solid dosage form.
DETAILED DESCRIPTION OF INVENTION:
The present invention provides immediate release pharmaceutical compositions for oral administration comprising eszopiclone.
The present invention provides milled particles of eszopiclone. The particles are milled by using conventional techniques known in the art. At least 90% particles of the milled eszopiclone have particle size less than 110µrn. Preferably; at least 50% particles of the milled eszopiclone have particle size not more than 40 urn.
According to present invention, the pharmaceutical compositions comprising milled eszopiclone and one or more pharmaceutically acceptable carriers are provided. The composition includes eszopiclone having milled particles, wherein at least 90% of the particles have particle size less than 110µm and median particle size is not more than 40µm.
According to present invention, the method for milling the particles of eszopiclone are provided, which includes wet milling and or dry milling techniques.
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For the purpose of present invention, eszopicione or its mixture with one or more pharmaceutically acceptable excipient (s) is provided to the milling chamber of a mill. The non-limiting examples of mills are rotary mill, high vibration mill, ball mill, colloid mill, roller mill, mortar mill, planetary mill and the like.
In a preferred embodiment, milled eszopicione is mixed with pharmaceutically acceptable excipients, and then processed into dosage form.
The composition of present invention can be formulated into dosage forms by the conventional process of wet granulation, dry granulation or direct compression. In wet granulation, the milled mixture of eszopicione and pharmaceutically acceptable excipients may be granulated using an aqueous or organic solution of a suitable binder. The granules thus obtained may then be dried, lubricated and compressed.
According to present invention the preferred process for preparing tablets of eszopicione is dry granulation or direct compression.
The pharmaceutical composition of the present invention may also be prepared by dry granulation involving slugging the milled mixture of eszopicione and pharmaceutically acceptable excipients, lubricating the sized slugs thus obtained and compressing them to obtain the tablets. The pharmaceutical composition of the present invention may also be prepared by direct compression of the milled mixture of eszopicione and pharmaceutically acceptable excipients.
Pharmaceutical formulations include those suitable for oral administration preferable solid dosage forms, more preferable tablets.
Pharmaceutical composition comprising milled eszopicione and pharmaceutically acceptable carrier, further includes other pharmaceutical excipients for example solubilizer, buffering agents, stabilizing agents, binders, lubricants, disintegrants, complexing agents, etc.
In the present invention, carriers or diluents are selected from the group starch, saccharides (monosaccharide, disaccharides, oligosaccharide, and polysaccharides), microcrystaliine
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cellulose, other cellulose derivatives, calcium phosphate, NaCaP04, sugar alcohol and mixtures thereof.
For the purpose of this invention solubilizers can be included. The preferred solubilizers are ionic and nonionic surfactants, complexing agents.
Binders are agents used to impart cohesive properties to the pellets or granules. It includes water soluble and insoluble binder, more preferable water soluble binder. The preferred binders are cellulose derivatives, sugars, gums, gelatin, povidone, pregelatinized starch, sugar solution, and polyvinyl alcohol. Most preferred water soluble binder is hydroxypropyl methylcellulose (HPMC) of different viscosity grades.
Disintegrating agents are the substances or mixtures of substances added to a pellet to facilitate its breakup or disintegration after administration. The typical examples of disintegrants are modified or unmodified starches, cfays, cross-finked PVP, modified or unmodified celluloses.
It is also preferred, but not necessary, that the dosage form can comprise a small amount of a lubricant such as, for example, magnesium stearate.
The choice of excipients is not limited to the example disclosed herewith; it may include any suitable excipients mentioned in hand book of pharmaceutical excipients (5th ed.).
The dosage form of present invention can be prepared by tablet press, roller compactor or any other machine or machine aid used to prepare solid dosage forms, known in the art.
Finished dosage forms are packaged along with desiccant. The preferred desiccant is selected from silica gel, silica gel desiccant packets or silica gel desiccant canisters; available under trade name Sorb-IT.
The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the claims. The percent w/w formula compositions of the examples of the present invention are set forth in Example I, II and III.
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It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the claims appended hereto.
EXPERIMENTAL: Example la: Composition for 1 mg tablet of eszopiclone (median particle size 158 µm).

Sr.
No. Ingredient Qty/Tab (mg) lmg Qty / batch (kg)
1. Eszopiclone 1.00 0.125
2. Lactose monohydrate 10.00 1.250
3. Anhydrous lactose 10.00 1.250
4. Dibasic calcium phosphate anhydrous 20.00 2.500
5. Microcrystalline cellulose 55.00 6.875
6 Croscarmellose sodium 2.50 0.3125
Lubrication
7. Colloidal silicon dioxide 0.50 0.0625
8. Magnesium stearate 1.00 0.125
Coating
9 Opadry blue 03G80825 3.00 0.450
10 Purified water q.s. 4.050
Process:
Lubricate the uniformly mixture of eszopiclone, lactose monohydrate, anhydrous lactose, dibasic calcium phosphate anhydrous, microcrystalline cellulose, and croscarmellose sodium by using colloidal silicon dioxide and magnessium stearate. The lubricated mixture is compressed into tablets.. The compressed tablets are coated with Opadry blue. All steps of
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manufacturing process are carried under controlled conditions of humudity (less than 40% RH) and temperature (NMT 25 °C).
Example lb: Composition for 1 mg tablet of eszopiclone (median particle size not more than 40µm). Composition and process both are same as in example la.
Example II: Composition for 2 mg tablet of eszopiclone.

Sr.
No. Ingredient Qty/Tab
(mg) 2mg Qty/ batch
(kg)
1. Eszopiclone 2.00 0.250
2. Lactose monohydrate 10.00 1.250
3. Anhydrous lactose 10.00 1.250
4. Dibasic calcium phosphate anhydrous 20.00 2.500
5. Microcrystalline cellulose 54.00 6.750
6 Croscarmellose sodium 2.50 0.3125
Lubrication
7. Colloidal silicon dioxide 0.50 0.0625
8. Magnesium stearate 1.00 0.125
Coating
9 Opadry white 03G58632 3.00 0.450
10 Purified water q.s. 4.050
Process: Process is same as for 1 mg strength.
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Example III: Composition for 3 mg tablet of eszopiclone.

Sr. No. Ingredient Qty/Tab (mg) 3mg Qty / batch (kg)
1. Eszopiclone 3.00 0.375$
2. Lactose monohydrate 10.00 1.250
3. Anhydrous lactose 10.00 1.250
4. Dibasic calcium phosphate anhydrous 20.00 2.500
5. Microcrystalline cellulose 53.00 6.625#
6 Croscarmellose sodium 2.50 0.3125
Lubrication
7. Colloidal silicon dioxide 0.50 0.0625
8. Magnesium stearate 1.00 0.125
Coating
9. Opadry blue 03G80826 3.00 0.450 *
10. Purified water q.S. 4.050 *
Process: Process is same as for 1 mg strength.
Dissolution of eszopiclone tablets:
The dissolution studies were carried out in USP dissolution apparatus II, at 50 rpm by using 500 ml, 0.1N HCI as dissolution media. The release profile of composition of present invention having eszopiclone; were found to be comparable to that of Lunesta. Results of dissolution study for 3 mg tablet and Lunesta are presented in table 1.
Table 1: Results of dissolution studies.

S.No Time min Percent Release

Lunesta Invented composition
1 5 81 78
2 10 90 87
3 15 93 91
4 20 94 92
5 30 96 95
6 45 98 96
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Stability Studies:
Stability studies of above preparations (tablet) were carried out at 40 °C temperature and 75% relative humidity. The level of unknown impurity at RRT 0.48 and total impurity was monitored. The results are presented in table 2. The compositions prepared in accordance with the present invention are comparatively more stable and generates less unknown impurity. Stability results show that micronised/ milled eszopiclone is less stable than the coarse eszopiclone. Use of desiccant in packaging provides better stability to the formulations of micronised/ milled eszopiclone.
Table 2: Results of stability studies:

Batch no. Strength Stability Period Stability Condition Pack (%) DNK-1 (RRT-0.48) Total Impurities
Eszopiclone tablet with coarse API (median particle size 158 pm)
Example la I mg In ilia I - — ND 0.05

3 month 40°C/75?/oRH HDPE 0.16 0.27

3 month 40°O75%RH HDPE with Desiccant 0.04 0.16
Eszopiclone tablet with micronised/ milled API (median particle size not more than 40 \im )
Example lb 1 mg Initial _ .„ ND 0.05

3 month 40°C/75%RH HDPE with Desiccant 0.07 0.28

3 month 40°Gr75%Rr) HDPE with
Desiccant + Nylon 0.05 0.26
Limes ta
! mg Initial _ _ ND 0.41

3 month 40°G75%RH HDPE 0.41 0.85
Dated this (1th ) day of July, 2008
VIJAY NASARE (Sr. Manager-IPM)
Glenmark Generics Limited
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