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:
MONOLITHIC CONTROLLED RELEASE FORMULATIONS 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 pharmaceutical monolithic matrix based controlled release formulations of Zolpidem or salt thereof wherein Zolpidem or salt thereof is released over a predetermined time period.
The following specification particularly describes the invention and the manner in
which it is to be performed.
4. Description
The present invention provides pharmaceutical monolithic matrix based controlled release formulations of Zolpidem or salt thereof wherein Zolpidem or salt thereof is released over a predetermined time period.
16 DEC 2005
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.

FORMULA I
In contrast to the benzodiazepines, which non-selectively bind to and activate all BZ receptor subtypes, Zolpidem in vitro binds the BZi receptor preferentially with a high affinity ratio of the alphai/alphassubunits. The BZi 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 BZi 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,
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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.
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.
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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.
The present inventors while developing dosage forms of Zolpidem or salt thereof have now surprisingly found that release of Zolpidem from the dosage form can be controlled from a monolithic matrix in a manner exactly similar to that provided in the '531 Patent. The term monolithic matrix in the present invention refers to a composition, which does not have immediate and prolonged release phases for controlling the delivery, and the release of the drug from polymer matrix is on continuous basis.
In one of the aspect of the present invention there is provided a pharmaceutical controlled-release dosage form adapted to release Zolpidem or a salt thereof over a predetermined time period, wherein the dosage form comprises of Zolpidem or salt thereof, hydroxypropylmethyl cellulose and hydroxypropyl cellulose along with one or more other pharmaceutical^ acceptable excipients.
In yet another aspect of the present invention there is provided a pharmaceutical controlled-release monolithic polymeric matrix tablet adapted to release Zolpidem or a salt thereof over a predetermined time period, according to an 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 to 70% of the total amount of Zolpidem is released within 30 minutes and the time for release of 90% of the total amount of Zolpidem is between 2 and 6 hours.
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The controlled release dosage form containing Zolpidem or salt thereof embedded in a monolithic polymer matrix includes solid oral dosage forms such as tablets, capsules and pellets.
The tablet can be coated or non-coated. 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 pharmaceutical^ 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 (HPMC), hydroxypropyl cellulose (HPC) 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. The combination of HPMC and HPC provides unique characteristic in terms of controlling the release in required manner.
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 glidant may be one or both of colloidal silicon dioxide and
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talc or magnesium stearate. 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 granulated with a suitable binder solution to obtain granules. The granules are further lubricated and compressed.
The capsule may be prepared by filling in the empty capsule shells granules containing Zolpidem or salt thereof along with at least one rate controlling polymer and at least one pharmaceutically acceptable excipient. A controlled release tablet of Zolpidem or salt thereof can also be placed in empty capsule shell.
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.
The composition of three batches is provided in Table 1. Varying percentages of HPMC and HPC were used as rate controlling polymers.
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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, 0.01 M hydrochloric acid buffer in 900 ml of medium using USP Type 2 Apparatus (rpm 50) was used.
Table 1:

S.N. Ingredients Qty/Tablet [mg]Example 1 Qty/Tablet [mg]Example 2 Qty/Tablet [mg]Example 3 Qty/Tablet [mg]Example 4
1 Zolpidem Tartrate 12.5 12.5 12.5 12.5
2 Tartaric acid 2.5 — 2.5 2.5
3 Lactose Monohydrate 103.5 93.5 88.5 63.5
4 Hydroxypropyl cellulose [HPC-L] 30.0 37.5 — 50.0
5 Hydroxypropyl cellulose [HPC-M] — 5.0 37.5 —
5 Methocel E-5 — 30.0 37.5 50.0
6 Methocel E-15 30.0 —
7 Microcrystalline Cellulose 69.0 69.0 69.0 69.0
8 Magnesium Stearate 2.5 2.5 2.5 2.5
Total Wt. 250.0 250.0 250.0 250.0
Table 2: Dissolution data

Time [min] % Drug released Example 1 % Drug released Example 2 % Drug released Example 3 % Drug released Example 4
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0 0 0 0 0
15 41 21 22 15
30 67 36 49 37
60 82 84 85 68
90 86 99 91 73
105 87 101 91 76
120 88 102 92 82
150 89 102 94 89
180 90 103 96 92
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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, wherein the dosage form comprises of Zolpidem or salt thereof, hydroxypropylmethyl cellulose and hydroxypropyl cellulose along with one or more other pharmaceutically acceptable excipients.
2. A pharmaceutical controlled-release monolithic polymeric matrix dosage form comprising Zolpidem or salt thereof along with at least one rate controlling polymer and at least one pharmaceutical acceptable excipient, adapted to release Zolpidem or a salt thereof over a predetermined time period, according to an 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 to 70% of the total amount of Zolpidem is released within 30 minutes and the time for release of 90% of the total amount of Zolpidem is between 2 and 6 hours.
3. A pharmaceutical controlled release dosage form of claims 1 or 2 in the form of tablet, capsule or pellet.
4. A pharmaceutical controlled release dosage form of claims 1 or 2 wherein pharmaceutically acceptable excipients comprises of diluent, filler, binder, lubricant, sweetener, coloring and flavoring agent and glidant.
5. A pharmaceutical controlled release dosage form of claim 2 wherein the rate-controlling polymer is selected from group comprising of one or more of carbohydrate gum, polyuronic acid salts, cellulose ethers, acrylic acid polymers and mixtures thereof.
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6. A pharmaceutical controlled release dosage form of claim 5 wherein the rate-controlling polymers are cellulose derivatives.
7. A pharmaceutical controlled release dosage form of claims 6 wherein cellulose derivatives are HPMC and HPC.
8. A pharmaceutical controlled-release dosage form of claim 1 adapted to release Zolpidem or a salt thereof over a predetermined time period, according to an 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 to 70% of the total amount of Zolpidem is released within 30 minutes and the time for release of 90% of the total amount of Zolpidem is between 2 and 6 hours.
9. A pharmaceutical controlled-release dosage form of claim 1 adapted to release Zolpidem or a salt thereof over a predetermined time period, according to an 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 within 30 minutes and the time for release of 90% of the total amount of Zolpidem is between 2 and 6 hours.
10. A pharmaceutical controlled-release dosage form of claim 1 adapted to release Zolpidem or a salt thereof over a predetermined time period, according to an 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 to 70% of the total amount of Zolpidem is released within 30 minutes and the time for release of 90% of the total amount of Zolpidem is between 75 and 120 minutes.
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11 .A pharmaceutical controlled-release dosage form of claim 1 adapted to release Zolpidem or a salt thereof over a predetermined time period, according to an 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 within 30 minutes and the time for release of 90% of the total amount of Zolpidem is between 75 and 120 minutes.

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