FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
MONOPHASIC 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
16] DEC 2005
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.


Subunit modulation of the GABAA receptor chloride channel macromolecular complex is hypothesized to be responsible for sedative, anticonvulsant, anxiolytic, and myorelaxant drug properties. The major modulatory site of the GABAA receptor complex is located on its alpha (α) 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.

"-CM.
M.C
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
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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 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
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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.
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
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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.
The present inventors while developing dosage forms of Zolpidem or salt thereof have now surprisingly found immediate release phase and prolonged release phase is not required for controlling the release of the drug from the dosage form. The release of Zolpidem from the dosage form can be controlled in monophasic in vitro profile of dissolution. The monophasic system developed for controlled release of Zolpidem or salt thereof offers several advantages such as cost, ease of formulation and predictable release profile over biphasic system of the '531 Patent.
In one of the aspects of present invention there is provided a pharmaceutical controlled-release dosage form adapted to release Zolpidem or a salt thereof over a predetermined time period, according to a monophasic 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 less than 40% of the total amount of Zolpidem is released between 1 to 30 minutes and the time for release of 90% of the total amount of Zolpidem is between 75 to 120 minutes.
In another the aspects of present invention there is provided a pharmaceutical controlled-release dosage form adapted to release Zolpidem or a salt thereof
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over a predetermined time period, according to a monophasic 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 and the time for release of 90% of the total amount of zolpiderm is between 75 to 120 minutes.
In yet another the aspects of present invention there is provided a pharmaceutical controlled-release dosage form adapted to release Zolpidem or a salt thereof over a predetermined time period, according to a monophasic 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 less than 40% of the total amount of Zolpidem is released between 1 to 30 minutes and the time for release of 90% of the total amount of Zolpidem is between 2 to 6 hours.
The monophasic dissolution profile obtained as part of present invention does not give rise to immediate release phase followed by prolonged release phase as the drug is continuously released from the erodible matrix at constant rate. This type of dissolution aims at achieving immediate sleep of the patient followed by maintenance of the drug blood level 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 controlled release dosage form containing Zolpidem or salt thereof adapted for monophasic dissolution profile includes solid oral dosage forms such as tablets, capsules and pellets.
The tablet can be single or multi-layer and can be coated or non-coated. Each layer of the tablet can be functional. 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. 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 methyl cellulose, 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.
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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 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. 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.
The capsule dosage form can contain a tablet mentioned above placed in empty capsule shell or granules of drug along with rate controlling polymer and excipient can be filled in the capsule. The excipients and rate controlling polymers are already provided in the present invention.
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.
Example 1
The composition of three batches is provided in Table 1. Zolpidem tartrate, tartaric acid, lactose, HPMC, microcrystalline cellulose and HPC were passed through ASTM mesh #30 and mixed in suitable blender. Lubricant was passed through ASTM mesh #40 and mixed with the earlier blend. The total blend was compressed suitable tooling.
Table 2 provides the dissolution data of the tablets prepared as per the Formula provided in Table 1. For determination of drug release rate, 0.01M hydrochloric acid buffer in 900 ml of medium using USP Type 2 Apparatus (rpm 50) was used.
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Table 1:

S.N. Ingredients Qty/Tablet [mg]Example 1 Qty/Tablet[mg] Example 2 Qty/Tablet[mg] Example 3
1 Zolpidem Tartrate 12.5 12.5 12.5
2 Tartaric acid 2.5 2.5 2.5
3 Lactose Monohydrate 73.5 43.5 96.0
4 Hydroxypropyl cellulose [HPG-L] 45.0 65.0 37.5
5 Hydroxypropyl cellulose [HPC-M] — — —
5 Methocel E-5 45.0 65.0 —
6 MethocelE-15 — — 30.0
7 Microcrystalline Cellulose 69.0 69.0 69.0
8 Magnesium Stearate 2.5 2.5 2.5
Total Wt. 250.0 250.0 250.0
Table 2: Dissolution data

Time [min] % Drug released Example 1 % Drug released Example 2 % Drug released Example 3
0 0 0 0
15 17 18 20
30 37 33 50
60 77 78 86
90 89 86 95
105 92 87 97
120 94 87 98
150 96 88 99
180 97 89 100
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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 monophasic 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 less than 40% of the total amount of Zolpidem is released between 1 to 30 minutes and the time for release of 90% of the total amount of Zolpidem is between 75 to 120 minutes.
2. A pharmaceutical controlled-release dosage form adapted to release Zolpidem or a salt thereof over a predetermined time period, according to a monophasic 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 and the time for release of 90% of the total amount of zolpiderm is between 75 to 120 minutes.
3. A pharmaceutical controlled-release dosage form adapted to release Zolpidem or a salt thereof over a predetermined time period, according to a monophasic 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 less than 40% of the total amount of
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Zolpidem is released between 1 to 30 minutes and the time for release of 90% of the total amount of Zolpidem is between 2 to 6 hours.
4. A pharmaceutical controlled release dosage form of claims 1, 2 or 3 in the form of tablet, capsule or pellet.
5. A pharmaceutical controlled release dosage form of claims 1, 2 or 3 which further comprises of at least one rate controlling polymer and at least one pharmaceutical^/ acceptable excipient.
6. A pharmaceutical controlled release dosage form of claim 5 wherein the rate controlling polymer comprises of one or more of carbohydrate gum, polyuronic acid salts, cellulose ethers, acrylic acid polymers and mixtures thereof.
7. A pharmaceutical controlled release dosage form of claims 6 wherein cellulose derivatives are HPMC and HPC.
8. A pharmaceutical composition of claim 4 wherein the tablet is monolayer or multi-layer.
9. A pharmaceutical composition of claim 8 wherein the multi-layer tablet has one or more functional layers.
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10. A pharmaceutical composition of claim 1, 2 or 3 wherein Zolpidem is present as Zolpidem tartrate.

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