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:
BIPHASIC CONTROLLED RELEASE DOSAGE FORMS OF ZOLPIDEM OR SALT THEREOF
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra (East),
Mumbai-400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides controlled release formulations of Zolpidem or salt thereof wherein Zolpidem or salt thereof is released over a predetermined time period in monophasic profile of dissolution.
The following specification particularly describes the invention and the manner in
which it is to be performed.
4. DESCRIPTION
The present invention provides controlled release formulations of Zolpidem or salt thereof wherein Zolpidem or salt thereof is released over a predetermined time period in both monophasic and biphasic profile of dissolution.

Subunit modulation of the GABAA receptor chloride channel macromolecular complex is hypothesized to be responsible for sedative, anticonvulsant,

12 JAN 2006

anxiolytic, and myorelaxant drug properties. The major modulatory site of the GABAA receptor complex is located on its alpha (a) subunit and is referred to as the benzodiazepine (BZ) receptor.
Zolpidem is chemically is N,N,6-trimethyl-2-p-tolylimidazo[1,2-a] pyridine-3-acetamide of Formula I. It is commercially available in the form of Zolpidem tartrate in the form of Ambien® and Ambien CR® Tablet dosage forms. Zolpidem is a hypnotic agent with a chemical structure unrelated to benzodiazepines, barbiturates, pyrrolopyrazines, pyrazolopyrimidines, or other drugs with known hypnotic properties.

FORMULA I
In contrast to the benzodiazepines, which non-selectively bind to and activate all BZ receptor subtypes, Zolpidem in vitro binds the BZ1 receptor preferentially with a high affinity ratio of the alpha1/alpha5 subunits. The BZ1 receptor is found primarily on the Lamina IV of the sensorimotor cortical regions, substantia nigra (pars reticulata), cerebellummolecular layer, olfactory bulb, ventral thalamic complex, pons, inferior colliculus, and globus pallidus. This selective binding of Zolpidem on the BZ1 receptor is not absolute, but it may explain the relative
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absence of myorelaxant and anticonvulsant effects in animal studies as well as the preservation of deep sleep (stages 3 and 4) in human studies of Zolpidem at hypnotic doses.
Pharmacokinetic and pharmacodynamic data show that Zolpidem has both a rapid absorption and onset of hypnotic action. Its bioavailability is 70% following oral administration and demonstrates linear kinetics in the therapeutical dose range, which lies between 5 and 10 mg in conventional forms, peak plasma concentration is reached at between 0.5 and 3 hours, the elimination half-life is short, with a mean of 2.4 hours and a duration of action of up to 6 hours.
According to the rapidity of action of Zolpidem, immediate release dosage forms developed disintegrate and dissolve rapidly in the gastrointestinal tract and undergo systemic absorption, where Zolpidem, can exert its pharmacological effect and induce sleep of the patient.
Commercially available controlled release tablets of Ambien CR® consists of a coated two-layer tablet: one layer that releases its drug content immediately and another layer that allows a slower release of additional drug content. The controlled release dosage form of Zolpidem enable to sustain release of Zolpidem over a period compatible with the desired time of sleep and the time needed for elimination of the drug from the human body to a sufficiently low level.
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European Patent EP 173,928 discloses an oral pharmaceutical controlled release preparation which has a biphasic release profile of a pharmacologically active agent, comprising a core containing the active agent and a coating applied thereon, wherein the coating consists of a film-forming polymer which is insoluble in water and gastro-intestinal fluids and a water-soluble pore-creating material also including the active agent.
European Patent EP 361,910 discloses granules, which have a spray-dried substance carrying an adsorbed pharmaceutical and a layer comprising a pharmaceutically acceptable excipient and a pharmaceutical.
British Patent GB 2,245,492 discloses an orally administrable-programmed release pharmaceutical preparation comprising a core coated with a hydrophobic material and a surfactant.
US Patent 6,513,531 (the '531 Patent) provides controlled release dosage forms adapted to release Zolpidem or a salt thereof over a predetermined time period, according to a biphasic in vitro profile of dissolution, where the first phase is an immediate release phase having a maximum duration of 30 minutes and the second phase is a prolonged release phase, and wherein 40 to 70% of the total amount of Zolpidem is released during the immediate release phase and the time for release of 90% of the total amount of Zolpidem is between 2 and 6 hours.
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The present inventors while developing dosage forms of Zolpidem or salt thereof have now surprisingly found that by simply changing the composition the duration of immediate release phase and prolonged release phase can be significantly altered without affecting the overall dissolution profile.
In one of the aspects of present invention there is provided pharmaceutical controlled-release dosage form adapted to release Zolpidem or a salt thereof over a predetermined time period, according to a biphasic in vitro profile of dissolution when measured in a type II dissolution apparatus according to the U.S. Pharmacopoeia in 0.01 M hydrochloric acid buffer at 37°C, wherein 40% or less of the total amount of Zolpidem is released between 1 to 30 minutes as immediate phase and the time for release of 90% of the total amount of Zolpidem is between 75 to 120 minutes as prolonged phase.
In another the aspects of present invention there is provided pharmaceutical controlled-release dosage form adapted to release Zolpidem or a salt thereof over a predetermined time period, according to a biphasic in vitro profile of dissolution when measured in a type II dissolution apparatus according to the U.S. Pharmacopoeia in 0.01 M hydrochloric acid buffer at 37°C, where 40 to 70% of the total amount of Zolpidem is released between 1 to 30 minutes as immediate phase and the time for release of 90% of the total amount of Zolpidem is between 75 to 120 minutes as prolonged phase.
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In yet another aspects of present invention there is provided pharmaceutical controlled-release dosage form adapted to release Zolpidem or a salt thereof over a predetermined time period, according to a biphasic in vitro profile of dissolution when measured in a type II dissolution apparatus according to the U.S. Pharmacopoeia in 0.01 M hydrochloric acid buffer at 37°C, wherein 40% or less of the total amount of Zolpidem is released between 1 to 30 minutes as immediate phase and the time for release of 90% of the total amount of Zolpidem is between 2 to 6 hours as prolonged phase.
The first phase or immediate release phase refers to that part of the dissolution profile from 0 to 30 minutes in a suitable in vitro dissolution test and is adequately described in the '513 Patent.
The second phase or prolonged release phase is that part of the dissolution profile which is after 30 minutes, measured in a suitable in vitro dissolution test, such as described in the '513 Patent. The present invention then proposes dosage forms of the drug whose complete dissolution time for the second phase is either between 75 to 120 minutes or between 2 and 6 hours.
The rapid release in the first phase induces the immediate sleep of the patient and the second phase allows the drug blood level to be maintained at or below the peak level, but higher than the level obtained with an immediate release dosage form, at the same time after dosing, with the objective of maintaining sleep.
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The present invention then proposes dosage forms of Zolpidem or a salt thereof whose complete dissolution time, defined, as the time for release of 90% of the total amount of drug is either between 75 to 105 minutes or between 2 and 6 hours.
Either 25 to 40% or 40 to 70% of the total amount of drug can be released during the immediate release phase.
The controlled release dosage form containing Zolpidem or salt thereof adapted for biphasic dissolution profile includes solid oral dosage forms such as tablets, capsules and pellets.
The tablet can be single or multiplayer and can be coated or non-coated. Additionally as provided in the '513 Patent the tablet can contain immediate release portion of the drug mixed with prolonged release coated pellets of the drug. The tablets can contain along with Zolpidem or salt thereof, one or more pharmaceutically acceptable rate-controlling polymer along with one or more pharmaceutically acceptable excipients.
The pharmaceutically acceptable rate controlling polymers can be selected from a group comprising of one or more of carbohydrate gum, polyuronic acid salts, cellulose ethers, acrylic acid polymers and mixtures, thereof.
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Suitable carbohydrate gums include one or more of xanthan gum, tragacanth gum, gum karaya, guar gum, acacia, gellan, locust bean gum and other carbohydrate gums having similar properties.
Suitable polyuronic acid salts include one or more of alkali metal salts of alginic acid or pectic acid and mixtures thereof.
Suitable alkali metal salts of alginic acid that may be used include one or more of sodium alginate, potassium alginate, ammonium alginate and other suitable alkali metal salts of alginic acid.
Suitable cellulose ethers include one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose and other suitable cellulose ethers.
Suitable acrylic acid polymers include any suitable polyacrylic acid polymers or carboxyvinyl polymers such as those available under the brand name carbopol.
Pharmaceutically acceptable excipients can be diluent, filler, binder, lubricant, sweetener, coloring and flavoring agent, glidant and the like. The binders may be one or more of starch, sugars, gums, low molecular weight hydroxypropyl methylcellulose, polyvinyl pyrrolidone and hydroxypropyl cellulose. The lubricants may be one or more of talc, magnesium stearate, calcium stearate, polyethylene glycol, hydrogenated vegetable oils, stearic acid, sodium stearyl fumarate and sodium benzoate. The glidants may be one or both of colloidal silicon dioxide and
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talc. Suitable coloring or flavoring agents include those approved for use by the United States Food and Drug Administration (FDA) and are well known to those skilled in the art.
The tablets may be prepared by direct compression. The immediate release and the prolonged release granules can be separately prepared, blended and compressed using suitable tooling to get a single layer tablet. Alternatively the immediate release granules can be compressed along with prolonged release granules to get a bi-layered tablet.
For making immediate release granules, Zolpidem or salt thereof is mixed with suitable pharmaceutically acceptable excipients as provided herein and the blend is lubricated and compressed.
For making prolonged release granules, Zolpidem or salt thereof may be blended with one or more pharmaceutically acceptable polymers and one or more pharmaceutically acceptable excipients, which includes a mixture of lactose, tartaric acid and microcrystalline cellulose. This blend is screened and compressed after lubrication.
The tablets may also be prepared by wet granulation or dry granulation. Zolpidem or salt thereof may be blended with one or more pharmaceutically acceptable polymers and a pharmaceutically acceptable carrier, which includes a mixture of lactose, tartaric acid and microcrystalline cellulose. This blend is then
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granulated with a suitable binder solution to obtain granules. The granules are further lubricated and compressed to get desired single layer or bi-layered tablet comprising individual layers of immediate release and prolonged release.
The immediate and prolonged released granules can be filled in empty capsule shells or individual tablet of either immediate release granules and prolonged release granules or vice versa can be placed in empty capsule shells.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Examples
The composition of three batches is provided in Table 1.
Table 2 provides the dissolution data of the tablets prepared as per the Formula provided in Table 1. For determination of drug release rate, 0.01 M hydrochloric acid buffer in 900 ml of medium using USP Type 2 Apparatus (rpm 50) was used.
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Table 1:

S.No Ingredients Qty/Tablet [mg]
IR Layer Example 1 Example 2 Example 3
1 Zolpidem Tartrate 1.50 2.00 1.50
2 Lactose Monohydrate 72.40 71.90 72.40
3 Microcrystalline Cellulose 20.00 20.00 20.00
4 Plasdone S 630 2.00 2.00 2.00
5 Ac-di-sol 3.00 3.00 3.00
6 Yellow Iron Oxide 0.10 0.10 0.10
7 Magnesium Stearate 1.00 1.00 1.00
ER Layer
1 Zolpidem Tartrate 11.00 10.50 11.00
2 Lactose Monohydrate 52.00 52.50 88.00
3 Microcrystalline Cellulose 55.00 55.00 55.00
4 Hydroxypropyl cellulose [HPC-L] 60.00 60.00 24.00
5 MethocelKIOOLVCR 20.00 20.00 -
6 Methocel E 5 - - 20.00
7 Magnesium Stearate 2.00 2.00 2.00
Total Wt. 300.00 300.00 300.00
Brief Procedure:
Immediate Release Granules: Zolpidem tartrate, lactose, microcrystalline
cellulose, plasdone S630, croscarmellose sodium and yellow iron oxide were
passed through ASTM mesh #40 and mixed in suitable blender. Lubricant was
passed through ASTM mesh #40 and mixed with the earlier blend.
Prolonged Release Granules: Zolpidem tartrate, lactose, HPMC,
microcrystalline cellulose and HPC were passed through ASTM mesh #30 and
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mixed in suitable blender. Lubricant was passed through ASTM mesh #40 anc mixed with the earlier blend.
IR and ER layers were compressed as single or bi-layered tablets with suitable tooling.
Table 2: Drug Release data

Time [min] 0 fo Drug released I
Example 1 Example 2 Example 3
0 0 0 0
15 22 26 35
30 31 37 58
60 45 47 82
90 57 59 91
105 63 64 95
120 68 70 98
180 84 87 99
240 93 96 99
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WE CLAIM:
1. A pharmaceutical controlled-release dosage form adapted to release Zolpidem or a salt thereof over a predetermined time period, according to a biphasic in vitro profile of dissolution when measured in a type II dissolution apparatus according to the U.S. Pharmacopoeia in 0.01 M hydrochloric acid buffer at 37°C, wherein 40% or less of the total amount of Zolpidem is released between 1 to 30 minutes as immediate phase and the time for release of 90% of the total amount of Zolpidem is between 75 to 120 minutes as prolonged phase.
2. A pharmaceutical controlled-release dosage form adapted to release Zolpidem or a salt thereof over a predetermined time period, according to a biphasic in vitro profile of dissolution when measured in a type II dissolution apparatus according to the U.S. Pharmacopoeia in 0.01 M hydrochloric acid buffer at 37°C, where 40 to 70% of the total amount of Zolpidem is released between 1 to 30 minutes as immediate phase and the time for release of 90% of the total amount of Zolpidem is between 75 to 120 minutes as prolonged phase.
3. A pharmaceutical controlled-release dosage form adapted to release Zolpidem or a salt thereof over a predetermined time period, according to a biphasic in vitro profile of dissolution when measured in a type II dissolution apparatus according to the U.S. Pharmacopoeia in 0.01 M hydrochloric acid
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buffer at 37°C, wherein 40% or less of the total amount of Zolpidem is released between 1 to 30 minutes as immediate phase and the time for release of 90% of the total amount of Zolpidem is between 2 to 6 hours as prolonged phase.
4. A pharmaceutical controlled release dosage form of claims 1 to 3 comprising of solid oral dosage forms such as tablets, capsules and pellets.
5. A pharmaceutical controlled release dosage form of claim 4 wherein the tablet can be single layer or multi-layer.
6. A pharmaceutical controlled release dosage form of claims 1 to 5 wherein the composition further comprises of immediate release granules and prolonged release granules.
7. A pharmaceutical controlled release dosage form of claim 6 wherein the immediate release granules comprises of Zolpidem or salt thereof along with pharmaceutically acceptable excipient.
8. A pharmaceutical controlled release dosage form of claim 6 wherein the prolonged release granules comprises of Zolpidem or salt thereof along with at least one pharmaceutically acceptable rate-controlling polymer and optionally pharmaceutically acceptable excipient.
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9. A pharmaceutical controlled release dosage form of claims 7 or 8 wherein the pharmaceutically acceptable excipient is selected from diluent, filler, binder, lubricant, sweetener, coloring and flavoring agent or glidant.
10. A pharmaceutical controlled release dosage form of claim 8 wherein the pharmaceutically acceptable rate-controlling polymer is cellulose ether derivative.

Dated this 12th day of January 2006

For Wockhardt Limited

(Yatendra Kumar) Authorized Signatory
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