FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)

1. TITLE OF THE INVENTION:
"Biphasic inlay tablet composition of Zolpidem tartrate for extended
release"
2. APPLICANT
(a) NAME: IPCA LABORATORIES LTD.
(b) NATIONALITY: Indian Company incorporated under the Indian Companies
ACT, 1956
(c) ADDRESS: 48, Kandivli Industrial Estate, Mumbai-400067,
Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and its use thereof.

Technical Field:
The present invention relates to an oral solid pharmaceutical dosage form of Zolpidem Tartrate particularly in the form of Inlay tablet comprising inner extended release core preferably, comprising hydrophilic polymeric coating effective in delaying the release profile on administration of the same and outer immediate release coat and method of preparation thereof.
Background and Prior Art:
Sleep is the state of natural rest observed in humans, regular sleep is necessary for survival. Sleep is generally characterized by a reduction in voluntary body movement, temporary blindness, decreased reaction to external stimuli, loss of consciousness, a 70% reduction in audio receptivity, an increased rate of anabolism (the synthesis of cell structures), and a decreased rate of catabolism (the breakdown of cell structures).
Infants need about 16hrs, children needs about 9-12 hrs, teenagers needs about 9 hrs and adults need about 7-8 hrs of sleep.
Usually sleepers pass through five stages: 1, 2, 3, 4 and REM (rapid eye movement) sleep. These stages progress cyclically from 1 through REM then begin again with stage 1. A complete sleep cycle takes an average of 90 to 110 minutes. The first sleep cycles each night have relatively short REM sleeps and long periods of deep sleep but later in the night, REM periods lengthen and deep sleep time decreases.
Stage 1 is light sleep where you drift in and out of sleep and can be awakened easily. In this stage, the eyes move slowly and muscle activity slows. During this stage, many people experience sudden muscle contractions preceded by a sensation of falling.
In stage 2, eye movement stops and brain waves become slower with only an occasional burst of rapid brain waves.


When a person enters stage 3, extremely slow brain waves called delta waves are interspersed with smaller, faster waves.
In stage 4, the brain produces delta waves almost exclusively.
Stages 3 and 4 are referred to as deep sleep, and it is very difficult to wake someone from them. In deep sleep, there is no eye movement or muscle activity. Breathing and heart rate slow down and your body is still. This is when some children experience bedwetting, sleepwalking or night terrors.
In the stage 5 or REM period, breathing becomes more rapid, irregular and shallow, eyes jerk rapidly and limb muscles are temporarily paralyzed. Brain waves during this stage increase to levels experienced when a person is awake. Also, heart rate increases, blood pressure rises, males develop erections and the body loses some of the ability to regulate its temperature. This is the time when most dreams occur, and, if awoken during REM sleep, a person can remember the dreams. Most people experience three to five intervals of REM sleep each night.
The mortality risk associated with different sleeping patterns was assessed by use of the 1965 Human Population Laboratory survey of a random sample of 6928 adults in Alameda County, CA and a subsequent 9-year mortality follow-up. The analysis indicates that mortality rates from ischemic heart disease, cancer, stroke, and all causes combined were lowest for individuals sleeping 7 or 8 h per night. Men sleeping 6 h or less or 9 h or more had 1.7 times the total age-adjusted death rate of men sleeping 7 or 8 h per night. The comparable relative risk for women was 1.6. (Wingard DL, Berkman LF., Mortality risk associated with sleeping patterns among adults; Sleep. 1983; 6(2): 102-7).
As per American Psychological Association survey, one of the most significant and overlooked public problems is that many adults are chronically sleep deprived, most people who are sleep deprived do not even realize it.

A great variety of agents have the capacity to depress the function of CNS such that calming or drowsiness (sedation) is produced. A sedative drug decreases activity, moderates excitement and clams the recipients, whereas a hypnotic drug produces drowsiness and facilitates the onset and maintenance of a state of sleep that resembles natural sleep in its electroencephalographic characteristics and from which recipients can be aroused easily.
Zolpidem is a hypnotic from the therapeutical class of imidazopyridines. It is administrated orally by means of a tablet or other solid dosage form. Zolpidem acts rapidly. Pharmacokinetics and pharmacodynamic data shows that Zolpidem has both a rapid absorption and onset of hypnotic action. Its bioavilability is 70% following oral administration and demonstrates linear kinetics in the therapeutical dose range, which lies between 5 and l0mg in conventional forms, peak plasma concentration is reached at between 0.5 and 3 hours, the elimination half-life is short, with a mean 2.4 hours and duration of action of up to 6 hours.
According to the rapidity of action of Zolpidem only immediate release dosage forms were developed, which disintegrate rapidly in the gastrointestinal tract, dissolve in the fluid of the gastrointestinal tract and undergo systemic absorption, where Zolpidem can exert its pharmacological effect and induce sleep of the patient.
Zolpidem, with a half-life of about 2.5 hours, has demonstrated efficacy in sleep promotion and the capacity to increase total sleep time. Although it does increase total sleep time, it does not have an indication for sleep maintenance.
Ideally, short medication half-lives will allow a rapid decline of the sedating effects to prevent residual daytime effects.
Half-life is important consideration. For the through out sleep these longer half life hypnotic agents, sedatives and the sedating antidepressants can be considered. But it is clear these long half-life agents promote increased risk of residual sedation.


The rationale behind the development of new modified release formulation is that the immediate-release component promotes rapid sleep onset, whereas the extended-release component helps maintain sleep through the night.
Until recently, hypnotic agents were available only as immediate-release formulations. The only way to lengthen the hypnotic duration of action was to select an agent with a longer half-life or to increase the dose of the drug being used. Use of a hypnotic agent with a longer half-life will typically promote greater sedation through the night but with increased risk of next-day residual effects.
Dose escalation of hypnotic agents can increase the duration that a medication is above a minimum effective concentration threshold, promoting better sleep maintenance. However, this may increase the risk of side effects as a consequence of increases in maximal concentrations.
Modified-release formulations have been developed to provide altered pharmacokinetic profiles for hypnotic agents. In its most extreme form, such an agent would have an immediate onset, sustained effects, and stable concentrations for the desired therapeutic period, and a rapid offset of effects.
With the use of techniques to modify the release of and availability of a hypnotic agent has led to the development of extended release formulations. This compound is a combination of immediate-release and extended -release components designed to achieve initial plasma levels and peak concentrations similar to those seen with immediate-release formulations while maintaining higher plasma levels for a longer of time, extending the duration of efficacy. This technology allowed formulation to be approved for treatment of both sleep initiation and sleep maintenance complaints.
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.


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.
GB 2 245 492 discloses an orally administrable programmed release (i.e. release after a predetermined delay) pharmaceutical preparation comprising a core coated with a hydrophobic material and a surfactant.
US6514531 disclose controlled - release dosage from of Zolpidem in bilayered tablet, which release Zolpidem over predetermined time period, according to a biphasic profile of dissolution, where the first phase is an immediate release phase and second phase is a prolonged release phase.
In the prior art Zolpidem tartrate controlled release form is either bilayered tablet or conventional tablet-within-tablet. However, there are several limitations for conventional controlled release tablets such as tablet-within-tablet and the layered tablet. In the tablet-within-tablet the quantity of medicinal ingredient or ingredients forming the outer shell of the tablet is always substantially greater than almost twice the quantity of material forming the inner core of the tablet. The outer shell portion of the tablet which is first released and assimilated in the gastrointestinal tract. Which ultimately restrict the scope and utility of this tablet form. The major problem associated with the layered tablet is poor degree of control over the dissociation of the ingredients and another disadvantage of the layered tablet is that the ingredients are merged unevenly at the interface between the two layers.
Thus, there is a need to provide a pharmaceutical composition in the form of biphasic inlay tablet for extended release of the active agent with enhanced efficacy and reduced dosage frequency and hence providing patient compliance.


This is an objective of the present invention is to provide a pharmaceutical composition comprising pharmaceutical^ acceptable salt, in biphasic compositions of Inlay tablet and thereof extended release formulation and methods of preparing the same.
Further, objective of the invention is to formulate the pharmaceutical^ acceptable extended release compositions comprising reduced dosage frequency to once daily thus enhances the therapeutic effectiveness and maintenance of the sleep through out 8 hrs.
Summary Of The Invention:
In accordance of the present invention the Inlay tablet composition comprises hydrophilic polymeric coating effective in delaying the release profile on administration of the pharmaceutical composition with improved patient compliance, reduced dosage frequency to once daily and maintaining the sleep through out night.
The invention further discloses a dosage form of Zolpidem that sustained the release of Zolpidem in such a manner that an effective concentration in blood can be maintained over a longer period of time to improve maintenance of the sleep for the 8 hrs unlikely releasing also at stage 3 & 4.
Detailed Description:
The present invention provides Inlay tablet composition of Zolpidem tartrate in the form of inner extended release core preferably, comprising hydrophilic polymeric coating effective in delaying the release profile on administration of the same and outer immediate release coat and method of preparation thereof.
In an embodiment of the invention, the present pharmaceutical composition comprises Zolpidem tartrate with pharmaceutically acceptable excipients selected from diluents, binders, preservatives, pH adjuster, alkalizing agent, disintegrating agents, film formers, polymers, lubricants and/or glidants.


The amount of the said salt of Zolpidem is equivalent to Zolpidem tartrate, and is present in the range of 1 to 3 % in extended release core preferably 1.5 % to 2 % particularly 1.8 % and is present in the range of 1 to 2 % preferably 1 to 1.5 % particularly 1.24 % in immediate release coat.
The term Zolpidem used herein is intended to include Zolpidem salt such as tartrate.
The diluents are selected from microcrystalline cellulose, Avicel pH 101, lactose monohydrate preferably microcrystalline cellulose.
The binders are selected from the group containing polyvinylpyrrolidone preferably Polyvinylpyrrolidone K 30.
The Lubricants and glidants are selected from the group consisting of magnesium stearate and purified talc.
The said release controlling polymers are selected from the group consisting of a hydrophilic polymer, preferably hydroxy propyl methyl cellulose K 4 M.
The stabilizers are selected from the group consisting of tartaric acid and potassium bitartrate preferably potassium bitartrate.
The plasticizers are selected from the group consisting of polyethylene glycol with molecular weight 6000.
The opacifiers are selected from group consisting of titanium dioxide.
The solvents are selected from group containing isopropyl alcohol and methylene chloride.
The colors are selected from the group consisting of iron red oxide.


The tablet may be coated with hydroxy propyl methyl cellulose, talc, titanium dioxide, polyethylene glycol 6000.
Other miscellaneous auxiliaries required for processing the product and maintaining stability.
In the preferred embodiment of the invention the said inlay tablet composition comprises: i) extended release core comprising Zolpidem tartrate as an active 1.8 %, lactose monohydrate 19.42 %, microcrystalline cellulose 8.87%, hydroxypropyl methyl cellulose K 4 M 7.67 %, Potasssium bitartrate 0.6 %, Iron oxide (red) 0.18 %, Polyvinylpyrrolidone K.30 0.72 %, Isopropyl alcohol in Q. S ., colloidal silicon dioxide 200 0.36 % and magnesium stearate 0.36 %;
ii) outer immediate release coat comprising Zolpidem tartrate 1.24 %, Lactose monohydrate 7.28%, Avicel PH 101 48.51 %, Potassium bitrate 0.41 %, Pregelatinized starch 0.72 %, Purified water in Q. S., sodium starch glycolate 0.96 %, colloidal silicon dioxide 200 0.24 % and magnesium stearate 0.6 %
The said inlay tablet is coated by coating solution comprising hydroxypropyl methyl cellulose E5 4.19%, Polyethylene glycol 6000 1.67 %, titanium dioxide 0.16 %, methylene chloride in Q. S. and isopropyl alcohol in Q. S.
In another embodiment, the invention provides a process for preparation of dual release pharmaceutical composition which comprises granulating Zolpidem tartrate equivalent to Zolpidem together with selected excipients by non-aqueous granulation process, blending the said granules of Zolpidem tartrate equivalent to Zolpidem with lubricants and glidants; wherein carbomers are used both in granulation and blending stage; blending the Zolpidem tartrate with disintegrants, lubricants and glidants and compressing the said two blends into two part InLay tablet where each part repents blend comprising active ingredient with excipients.


In another embodiment, the said pharmaceutically accepted solid oral extended release dosage formulation can be prepared by a process comprising wet aqueous or non-aqueous granulation method using extra-granular or/and intra-granular retarding polymers of different viscosities with one or/and two binders and then compression known in art with or without coating.
Wherein, the said tablet is optionally coated by coating solution comprising release controlling polymer, film forming polymer and other excipients. The said release controlling polymer is Hydroxypropyl methyl cellulose E 5 and film forming polymer is PEG 6000.
The said composition prepared by the said process described herein is in the form of circular, biconvex, film coated Inlay tablets wherein one side of the said tablet is pink coloured extended release (ER) part in the center surrounded by white to off-white immediate release (IR) part and other side plain, white to off-white in colour.
The process for stable extended release inlay tablet composition as described herewith, exhibits the following dissolution profile when tested in a USP type 2 apparatus at 100 rpm in 900 ml of (pi I 6.8 phosphate buffer) and at 37°C.
after 1.5 hour 35-65% of the drug is released;
after 3.5 hours 55%-85% of the drug is released;
after 5 hours not less than 70% of the drug is released.
after 8 hours not less than 80% of the drug is released
The said compositions of Zolpidem tartrate prepared by method as described thereof, are physically and chemically stable over its shelf life period.
In more preferred embodiment of the invention the said release controlling hydrophilic polymeric coating present in the said composition effectively delays the release of Zolpidem in such a manner that an effective concentration in blood can be maintained over a longer period of time thereby, maintaining the sleep for the 8 hrs unlikely releasing


also at stage 3 & 4. Further, the composition of present invention provides improved patient compliance with reduced side effects and reduced dosage frequency (once daily) and maintains the sleep through out night.
Description of Drawings:
Fig 1 illustrates front view of Inlay Tablet having conventional release phase and extended release phase.
Fig 2 illustrates dorsal view of Inlay Tablet having conventional release phase and extended release phase.
The following examples illustrate various aspects of the present invention:
Example 1
Zolpidem tartrate granules: Contains 12.5 mg Zolpidem tartrate equivalent to 12.5mg
Zolpidem along with the following excipients.

Sr. No. Ingredient Qty % w/w of total weight
1 Zolpidem tartrate 5.07%
2 Lactose Monohydrate 48.85%
3 Microcrystalline cellulose 23.53%
4 Hydroxypropyl methyl cellulose K 4 M 9.80%
5 Tartaric acid 7.84%
6 Hydroxypropyl methyl cellulose E 5 1.96%
7 Purified water q.s.
8 Magnesium stearate 0.98%
9 crosscarmellose sodium 1.96%
Preparation of Zolpidem granules:
Zolpidem tartrate, Lactose Monohydrate, microcrystalline cellulose, hydroxy propyl methyl cellulose K 4 M, tartaric acid sifted through mesh #40 and all were mixed


geometrically for 15 minuets in RMG. This blend was granulated with mixture of Hydroxypropyl methyl cellulose E 5 and purified water using aqueous wet granulation. The wet granules were milled through mesh #12. Granules are initially air-dried and then at 55°C in FBD until it reach 2-3% LOD at 105°C.
Dried granules were sifted through mesh #20 and lubricated with crosscarmellose sodium and magnesium stearate for 2 minutes. The extended release tablets were prepared using direct compression with 9 mm punch size known in art.
The coating solution to be coated on the tablets has the following composition:

Sr. No. Ingredient Qty % w/w of total weight
1 Hydroxypropyl methyl cellulose E 5 70%
2 Polyethylene glycol 6000 14%
3 Titanium dioxide 5.5%
4 Talc 5.6%
5 Iron oxide red (Lake) 4.9%
6 Methylene chloride q.s.
7 Isopropyl alcohol q.s.
There is a 2% weight gain by coating.
Take isopropyl alcohol in suitable container and disperse hydroxypropyl methyl cellulose E5 under constant stirring for approximately 10 minutes. Then add titanium dioxide, purified talc again under stirring for approximately 10 minutes. Now add methylene chloride and polyethylene glycol 6000 and iron oxide red under stirring for 10 minutes. Continue stirring for 30 minutes and pass the suspension through a bolting cloth, homogenized by passing through a homogenizer. This solution is used to coat tablet with conventional coater/auto-coater.
Tablets containing 6.25mg Zolpidem tartrate were similarly prepared.


Example 2
Zolpidem tartrate granules: Contains 12.5 mg Zolpidem tartrate equivalent to 12.5mg Zolpidem along with the following excipients.

Sr. No. Ingredient Qty % w/w of total weight
1 Zolpidem tartrate 5.05%
2 Lactose Monohydrate 47.68%
3 Microcrystalline cellulose 23.44%
4 Hydroxypropyl methyl cellulose K 4 M 7.81%
5 Tartaric acid 7.81%
6 Polyvinylpyrrolidone K30 4.88%
7 Isopropyl alcohol q.s.
8 Magnesium stearate 0.98%
9 crosscarmellose sodium 1.95%
Preparation of Zolpidem granules:
Zolpidem tartrate, lactose Monohydrate, microcrystalline cellulose, hydroxy propyl methyl cellulose K 4 M, tartaric acid sifted through mesh #40 and all were mixed geometrically for 15 minuets in RMG. This blend was granulated with mixture of polyvinylpyrrolidone K 30 and isopropyl alcohol using non-aqueous wet granulation. The wet granules were milled through mesh #12. Granules are initially air-dried and then at 55°C in FBD until it reach 2-3% LOD at 105°C.
Dried granules were sifted through mesh #20 and lubricated with crosscarmellose sodium and magnesium stearate for 2 minutes. The extended release tablets were prepared using direct compression with 9 mm punch size known in art.
The coating solution to be coated on the tablets remains same as example 1 and the weight
gain by coating is 2%.
Tablets containing 6.25mg Zolpidem tartrate were similarly prepared.


Example 3
Zolpidem tartrate granules: Contains 12.5 mg Zolpidem tartrate equivalent to 12.5mg
Zolpidem along with the following excipients.

Sr. No. Ingredient Qty % w/w of total weight
1 Zolpidem tartrate 1.6%
2 Lactose Monohydrate 14%
3 Avicel PH 101 6.8%
4 Pregelatinized starch 0.8%
5 Purified water q.s.
6 Sodium starch glycolate 0.8%
7 Colloidal silicon dioxide 200 5.6%
8 Magnesium stearate 0.3%
Preparation of Zolpidem granules:
Zolpidem tartrate, lactose Monohydrate and Avicel PH 101, sifted through mesh #40 and all were mixed geometrically for 15 minuets in RMG. This blend was granulated with mixture of pregelatinized starch, sodium starch glycolate and purified water using aqueous wet granulation. The wet granules were milled through mesh # 8. Granules are initially air-dried and then at 50°C in FBD until it reach 2-3% LOD at 105°C. Dried granules were sifted through mesh #30 and lubricated with colloidal silicon dioxide 200 and magnesium stearate for 2 minutes. This phase is conventional release layer.

Sr. No. Ingredient Qty % w/w of total weight
1 Zolpidem tartrate 3.57%
2 Lactose Monohydrate 31.86%
3 Microcrystalline cellulose 9.6%
4 Hydroxypropyl methyl cellulose K 4 M 22.4%
5 Polyvinylpyrrolidone K.30 1.2%
6 Isopropyl alcohol q.s.


7 Colloidal silicon dioxide 200 0.6%
8 Magnesium stearate 0.6%
9 Iron oxide (red) 0.16%
Preparation of Zolpidem granules:
Zolpidem tartrate, lactose monohydrate, macrocrystalline cellulose, hydroxy propyl methyl cellulose K 4 M and iron oxide (red) sifted through mesh #40 and all were mixed geometrically for 15 minuets in RMG. This blend was granulated with mixture of polyvinylpyrrolidone K 30 and isopropyl alcohol using non-aqueous wet granulation. The wet granules were milled through mesh # 8. Granules are initially air-dried and then at 50°C in FBD until it reach 2-3% LOD at 105°C.
Dried granules were sifted through mesh #30 and lubricated with colloidal silicon dioxide 200 and magnesium stearate for 2 minutes. This phase is extended release layer. For bilayered tablet, weighing 250mg ± 5% (containing 175mg of extended release layer and 75mg of conventional release layer) 11.9 x 6.2 mm in dimension and oval in shape was produced on tablets pressed by two stage pressing procedure as described. The granules of extended release layer are compressed first and the conventional release layer is then added and the press is operated again.
The coating solution to be coated on the tablets remains same as example 1 and the weight gain by coating is 2%.
Tablets containing 6.25mg Zolpidem tartrate were similarly prepared.
Example 4
Zolpidem tartrate granules: Contains 12.5 mg Zolpidem tartrate equivalent to 12.5mg
Zolpidem along with the following excipients.
The conventional release layer is similar as described in example 3.


Sr. No. Ingredient Qty % w/w of total weight
1 Zolpidem tartrate 3.1%
2 Lactose Monohydrate 32.72%
3 Microcrystalline cellulose 10.8%
4 Hydroxypropyl methyl cellulose K 4 M 20%
5 Potassium bitartrate 1%
6 Polyvinylpyrrolidone K.30 1.2%
7 Isopropyl alcohol q.s.
8 Colloidal silicon dioxide 200 0.6%
9 Magnesium stearate 0.6%
10 Iron oxide (red) 0.1%
Preparation of Zolpidem granules:
Zolpidem tartrate, lactose monohydrate, microcrystalline cellulose, hydroxy propyl methyl cellulose K 4 M, potassium bitartrate and iron oxide (red) sifted through mesh #40 and all were mixed geometrically for 15 minuets in RMG. This blend was granulated with mixture of polyvinylpyrrolidone K 30 and isopropyl alcohol using non-aqueous wet granulation. The wet granules were milled through mesh # 8. Granules are initially air-dried and then at 50°C in FBD until it reach 2-3% LOD at 105°C.
Dried granules were sifted through mesh #30 and lubricated with colloidal silicon dioxide 200 and magnesium stearate for 2 minutes. This phase is extended release layer.
For bilayered tablet, weighing 250mg ± 5% (containing 175mg of extended release layer and 75mg of conventional release layer) 11.9 x 6.2 mm in dimension and oval in shape was produced on tablets pressed by two stage pressing procedure as described. The granules of extended release layer are compressed first and the conventional release layer is then added and the press is operated again.
The coating solution to be coated on the tablets remains same as example 1 and the weight gain by coating is 2%.


Tablets containing 6.25mg Zolpidem tartrate were similarly prepared.
Example 5
For Extended Release Tablets

Sr. No. Ingredient Qty % w/w of total weight
1 Zolpidem tartrate 1.8%
2 Lactose Monohydrate 19.42%
3 Microcrystalline cellulose 8.87 %
4 Hydroxypropyl methyl cellulose K. 4 M 7.67 %
5 Potassium bitartrate 0.6 %
Iron oxide (red) 0.18%
Blend in RMG
6 Polyvinylpyrrolidone K30 0.72 %
7 Isopropyl alcohol q.s.
Non-aqueous granulation
8 Colloidal silicon dioxide 200 0.36 %
9 Magnesium stearate 0.36 %
Dried granules of Zolpidem tartrate (prepared by following the same procedure as mentioned in Example 1) were sifted through mesh #40. Hydroxypropyl methyl cellulose K 4 M and colloidal silicon dioxide 200 sifted through mesh #40 and mixed with dried granules and lubricated with magnesium stearate for 2 minutes. The extended release tablets were prepared using compression with 8 mm punch size known in art.
For Immediate Release Part:

Sr. No. Ingredient Qty % w/w of total weight
1 Zolpidem tartrate 1.24%
2 Lactose Monohydrate 7.28 %


3 Avicel PH 101 48.51 %
4 Pregelatinized starch 0.72 %
5 Potassium bitartrate 0.41 %
6 Purified water q.s.
7 Sodium starch glycolate 0.96 %
8 Colloidal silicon dioxide 200 0.24 %
9 Magnesium stearate 0.6 %
Dried granules (prepared similarly as in Example 3) were sifted through mesh #40 and lubricated with sodium starch glycolate, colloidal silicon dioxide 200, Avicel PH 101 and magnesium stearate for 10 minutes. This phase is immediate release part.
The extended release tablets were fed in the press coater CPC 20 (tab-in-tab) machine and the extended release tablet surrounded by conventional release granules compressed into tablets. The dual release Inlay tablets were prepared using compression with 12 mm punch size.
The coating solution to be coated on the tablets has the following composition:

Sr. No. Ingredient Qty % w/w of total weight
1 Hydroxypropyl methyl cellulose E 5 35%
2 Polyethylene glycol 6000 7%
3 Titanium dioxide 0.7 %
6 Methylene chloride q.s.
7 Isopropyl alcohol q.s.
There is a 2% weight gain by coating.
Take isopropyl alcohol in suitable container and disperse hydroxypropyl methyl cellulose E5 under constant stirring for approximately 10 minutes. Then add titanium dioxide again under stirring for approximately 10 minutes. Now add methylene chloride and polyethylene glycol 6000 under stirring for 10 minutes. Continue stirring for 30 minutes


and pass the suspension through a bolting cloth, homogenized by passing through a homogenizes This solution is used to coat tablet with conventional coater/auto-coater.
Tablets containing 6.25mg Zolpidem tartrate were similarly prepared.
The dissolution profile of the extended release Inlay tablet is studied and shown as follows:
Dissolution profile: For 12.5mg

Hrs. Results
0.5 46.31-50.33%
1.5 62.75-66.02%
3.5 77.81-82.22%
5 88.12-91.89%
8 91.96-94.64%
The pharmaceutical composition of is physically and chemically stable over its shelf life period. The stability data for 12.5mg is as follows:

Test Specification Hrs. Initial After 02 months
Appearance Circular, biconvex, film coated Inlay tablets consist of one side pink coloured ER part in the center surrounded by white to off-white IR part and other side plain, white to off-white in colour. Complies Complies
Dissolution 40±2°C & 75±5%Rh 0.5 46.31-50.33% 47.24-51.03%
1.5 62.75-66.02% 64.83-68.92%
3.5 77.81-82.22% 82.73-88.72%
5 88.12-91.89% 92.47-96.43%
8 91.96-94.64% 96.95-100.42%
Dissolution profile: For 6.25mg
Hrs. Results


0.5 46.39-50.61%
1.5 63.25-70.43%
3.5 83.76-90.75%
5 88.20-95.72%
8 90.84-99.05%
The stability data for 6.25mg is as follows:

Test Specification Hrs. Initial After 02months
Appearance Circular, biconvex, film coated Inlay tablets consist of one side pink coloured ER part in the center surrounded by white to offwhite IR part and other side plain, white to offwhite in colour. Complies Complies
Dissolution 40±2°C & 75±5%Rh 0.5 46.39-50.61% 41.64-49.92%
1.5 63.25-70.43% 59.94-70.42%
3.5 83.76-90.75% 82.03-92.29%
5 88.20-95.72% 88.87-99.54%
8 90.84-99.05% 92.58-102.30%


We Claim
1. A once-a-day, stable pharmaceutical composition for oral administration in the form
of inlay tablet comprises:
i) an extended release core comprising Zolpidem tartrate as an active 1.8 % w/w of
the tablet wt., microcrystalline cellulose 8.87 % w/w of the tablet wt,
hydroxypropyl methyl cellulose K 4 M 7.67 % w/w of the tablet wt. and other
excipients
ii) an outer immediate release coat comprising Zolpidem tartrate 1.24 % w/w of the
tablet wt., Avicel PH 101 in an amount of 48.51 % w/w of the tablet wt. and other
excipients;
iii) and an outer coating.
2. The composition as claimed in claim 1, wherein the said other excipients are selected from diluents, binders, lubricants, glidants, stabilizers, opacities, colours and plasticizers.
3. The composition as claimed in claim 1 and 2 wherein the said diluent is lactose monohydrate and is present in an amount of 19.42 % of w/w of the tablet wt.
4. The composition as claimed in claim 1 and 2, wherein the said binder is polyvinylpyrrolidone.
5. The composition as claimed in claim 1 and 7, wherein the K value of said polyvinylpyrrolidone is 30.
6. The composition as claimed in claim 1 and 2, wherein the said preferred lubricants and glidants are magnesium stearate and purified talc.
7. The composition as claimed in claim 10, wherein magnesium stearate, used in the range of 0.25 %to 5.0% of w/w tablet, and purified talc is used in the range of 0.1% to 2% of w/w tablet.
8. The composition as claimed in claim 1 and 2. wherein the preferred stabilizers are tartaric acid and potassium bitartrate.


9. The composition as claimed as claimed in claim 12, wherein tartaric acid and potassium bitartrate is used in the range of 0.2% to 0.8% of w/w tablet.
10. The composition as claimed in claims 1 and 2, wherein the preferred opacifier is titanium dioxide.
11. The composition as claimed in claim 1 and 14, wherein titanium dioxide is used in the range of 0.1% to 2.7% of w/w tablet.
12. The composition as claimed in claim 1 and 2, wherein the preferred colour for extended release phase is iron red oxide.
13. The composition as claimed in claim 1 and 16, wherein iron red oxide is used in the range of 0.1% to 5% of w/w tablet.
14. The composition as claimed in claims 1 and 2, wherein plasticizers are selected from the family of glycols such as polyethylene glycol 6000 and the like, in the range of 5%- 15% wt. of the tablet.
15. The composition as claimed in any of preceding claims 1 - 14 as substantially described herein with reference to the examples 1 to 5.




Abstract:
A once-a-day, stable pharmaceutical composition of Zolpidem tartrate for improving maintenance of sleep though out 8 hrs in the form of Inlay tablet comprising an inner extended release core and an outer immediate release coat, wherein said hydrophilic polymeric coating is effective in delaying the release profile on administration of the same; and method of preparation thereof.