WO2007102714A1

WO2007102714A1 - Safe controlled release preparation composition containing zolpidem or its salt

Info

Publication number: WO2007102714A1
Application number: PCT/KR2007/001146
Authority: WO
Inventors: Jong Lae Lim; Byoung Moo Lee
Original assignee: Chong Kun Dang Pharmaceutical Corp.
Priority date: 2006-03-08
Filing date: 2007-03-08
Publication date: 2007-09-13
Also published as: KR20070091960A

Abstract

The present invention relates to a controlled release preparation comprising Zolpidem or its salt. More particularly, it relates to a pharmaceutical composition comprising a immediately-acting part rapidly releasing a drug and delayed sustained-release pellets delaying drug release for a time of passing stomach by the enteric coating, which is characterized by timed dual release and can prevent side effects due to sudden drug release of the sustained release pellets.

Description

Safe controlled release preparation composition containing Zolpidem or its salt

Technical Field

The present invention relates to a safe controlled release preparation

comprising Zolpidem or its salt.

Background Art

Zolpidem is a sedative-hypnotic drug, which has a bioavailability of about 70%

when orally administered as a common formulation and shows linear vital dynamics in

the dose range of 5 to 10 mg, reaching the maximum blood level at 0.5 to 3 hours after

administration. However, it has very short half life of average 2.4 hours and thus, the

medical duration is less than 6 hours. Because of such a short duration effective time,

Stilnox^®, commercially available, has defects in that it cannot maintain sleep for a

sufficient period of time.

European Patent No. EP 1194132 discloses a sustained-release preparation for

releasing Zolpidem or its salt over a predetermined period of time by two-phase

dissolution profile to overcome the above-described defects. That is, the patent is

directed to a pharmaceutical composition comprising the first phase for immediate

releasing of the drug after oral administration and the second phase for sustained

releasing of the drug to induce sufficient sleep. Particularly, it discloses (i) capsules

comprising at least one intermediate drug releasing tablets and at least one delayed drug

releasing tablets, (ii) capsules comprising a mixture of delayed drug releasing pellets and immediate drag releasing pellets, (iii) tablets comprising matrix of the drag

surrounding delayed drag releasing coating pellet comprising the drag, (iv) multi-

layered tablets, or (v) multi-coated tablets. The above-described invention has been

completed by defining the drag release profile in 0.0 IM hydrochloric acid solution

according to the dissolution test of European Pharmacopeia.

The above technique is characterized in that it has pH-independent drag release

mode and the drag release profile defined under the acidic condition is also shown

under the pH 6.8 of the small intestines. That is, since the drag release is pH-

independent, though the drag release is defined under the acidic condition, it can be

applied in the conditions of the living body without particular problems. However, in

case of the pH-independent sustained-release preparation prepared by the above known

method, there may occur change in the dissolution rate due to non-uniformity in the

manufacture lot and exposure to severe environment including heat or humidity during

storage and distribution.

Particularly, as compared to the sustained-release tablet in the matrix form, the

sustained-release preparation prepared by forming a coating onto pellets comprising an

active ingredient has its drag release sensitively affected by the amount of the coating

and working conditions. Also, according to the size and the surface condition of the

used pellets as well as the amount of the coating, variation in drag release is inevitably

induced. That is, during the process for preparing sustained-release pellets by a fluid

bed coating apparatus, differences in the particle size and the surface condition between

pellets affect perfection of the coating as well as the thickness of the coating applied on

the pellets, which directly affect the drag release. With the same coating amount, as the size of the pellet is increased, the thickness of the coating is reduced and the drug

release is accelerated. In case of the pellets with rough surface, the surface area is

increased and thus, the perfection of the coating can be trouble. In spite of the

difficulties in the preparation, the sustained-release preparation in the pellet form is

preferred, as compared to the preparation in the matrix form, because the drug release

from the pellet form is seldom affected by the movement of the stomach and intestines.

In order to overcome the variation in the drug release between pellets due to the

differences in particle size and the surface condition, which inevitably occur during the

preparing process, generally, effort to accomplish homogeneous mixing has been made.

Though the above-described problems can be solved by homogenous mixing,

due to impacts and scratches of pellets occurring in the capsule filling process, the

sustained-release coating can be damaged. Also, the designed drug release mode can

be changed over time due to contact with heat and humidity during storage and

distribution of end product. Particularly, when water is contained in the sustained-

release pellet, due to loss of the sustained-release property as well as deformation of the

coating for controlling the drug release, sudden rapid drug release can be occurred at the

early stage. In order to solve this problem, many techniques and methods for

providing a protection coating to the sustained-release pellet have been disclosed.

Generally, such protection coating comprises mainly pH-independent polymer that does

not affect the dissolution rate and optionally a colorant to increase marketability.

The Zolpidem and its salt are psychotropic medicines and it is very important to

maintain the sustained-release of the drug in providing a sustained-release preparation,

as compared to other medicines. Thus, in the above-described preparation process, variation of drug release between pellets due to difference in particle size and surface

condition of pellets and sudden drug release caused by damage of pellets in the capsule

filling process and harsh circumstances during storage and distribution can lead severe

side effects in patients, as compared to other drugs. In order to prevent the side-effects

caused by sudden drug release in specific circumstances in the sustained-release

preparation of Zolpidem or its salt, it is preferably to delay or inhibit drug release in

specific circumstances.

Disclosure of Invention

Technical problem

It is an object of the present invention to provide a preparation

that can express rapidly Zolpidem (or its salt), a sedative-hypnotic drug, while

can maintain the stable and sustained release of Zolpidem,

that can reduce significantly the possibility of sudden release of drug, resulted

from the variation between pellets which may occur in the prior art and resulted from

the damage and the deformation of pellets which may occur in the filling process and

during storage and distribution, and

in the ultimate that can reduce remarkably the possibility of side-effects in

patients.

Technical solution

The present invention relates to a controlled release preparation composition

comprising Zolpidem or its salt and more particularly, a controlled release preparation composition comprising:

(1) a immediately-acting part comprising Zolpidem or its salt as an active

ingredient, and

(2) a delayed sustained-release pellet comprising Zolpidem or its salt as an

active ingredient and showing inhibited drug release in 0.01 Mol/L hydrochloric acid

solution.

The drug of present invention comprises Zolpidem or its pharmaceutically

acceptable salt. The most preferable salt is in the hemitartrate form, which is

commercially available under the trade name of Stilnox. hi the present invention, the

hemitartrate of Zolpidem that is readily purchased in the market is used but the present

invention is not limited thereto.

In the composition according to the present invention, the immediately-acting

part may be in the forms of granule, pellet or coating. In case of coating, for example,

the drug may be applied on the surface of the delayed sustained-release pellet. The

immediately-acting part may be prepared using spherical seeds, and it can be

exemplified as pellets having a layer containing the drug formed on the surface of the

spherical seed. The method for preparing the immediately-acting part may employ the

granulation, pellet preparation and coating method commonly used in the

pharmaceutical fields. If needed, a pH-independent polymer may be added to form a

protection coating, or a binding agent or a disintegrant may be used. As the spherical seeds, pH-independent polymers, binding agent and disintegrant, those commonly used

in the pharmaceutical fields may be used without any limit. Their composition and

amount may vary according to the method. According to the present invention, the composition and the preparation method of the immediately-acting part are not

particularly limited and preferably, the immediately-acting part is defined as having a

dissolution rate of 75% or more, as measured in 900 mL of 0.01 Mol/L hydrochloric

acid solution at 100 rpm for 30 minutes by the paddle method in the dissolution test

according to the Korea Pharmacopeia general test methods.

In the composition according to the present invention, preferably, the delayed

sustained-release pellet has a dissolution rate of 10% or less, as measured in 900 mL of

0.01 Mol/L hydrochloric acid solution at 100 rpm for 2 hours and a dissolution rate of

45% or less and 70% or more, as measured in 900 mL of pH 6.8 phosphate buffer for 2

hours and 8 hours respectively, according to the dissolution test (paddle method)

according of the Korea Pharmacopoeia.

In the composition according to the present invention, the drug content of

immediately-acting part is preferably 0.3 to 4 times of the drug content of the delayed

sustained-release pellet.

The delayed sustained-release pellet may have the following configurations.

In the first configuration, the delayed sustained-release pellet comprises:

(a) a core of a water-soluble or water-swellable inactive material;

(b) as a first layer, the layer containing an active ingredient, formed on the

surface of the core;

(c) as a second layer, the layer containing a polymer for controlling release of

the active ingredient, formed on the surface of the first layer; and

(d) as a third layer, the layer containing a polymer for protecting the pellet

under an acid condition, formed on the surface of the second layer. Here, it may further comprise a layer comprising a water-insoluble polymer between the core and the first

layer.

In the second configuration, the delayed sustained-release pellet includes:

(a) a core of a water-soluble or water-swellable inactive material;

(b) as a first layer, the layer containing an active ingredient, formed on the

surface of the core; and

the active ingredient and a polymer for protecting the pellet under an acid condition,

formed on the surface of the first layer. Here, it may further comprise a layer

comprising a water-insoluble polymer between the core and the first layer.

The term "water-soluble or water-swellable" in the "core of a water-soluble or

water-swellable inactive material" means that the material is substantially soluble or

swellable in water.

The term "water-insoluble" in the first layer of water-insoluble polymer formed

on the surface of the core" means that the polymer is substantially insoluble in water.

The term "polymer for controlling release of the active ingredient" means a

polymer that is effective in controlling the release of the active ingredient. The layer for

controlling the release of the active ingredient can accomplish the control of drug

release more effectively by forming a multi-layered structure with different types and

compositional ratios of the polymers.

The term "polymer for controlling the release of the active ingredient and polymer for protecting the pellet under an acidic condition" means that two or more

polymers are mixed to protect the pellet under an acidic condition while controlling the

release of the active ingredient.

The composition according to the present invention is not limited to the above-

described configurations, but any controlled release preparation including both a

immediately-acting part of Zolpidem or its salt and delayed sustained-release pellets for

preventing sudden drug release by inhibiting drug release under an acidic condition.

As to the compositional ratio of the components, preferably, the active

ingredient and the core are used in a weight ratio of 1:1 to 1:30, the active ingredient

and the polymer for controlling release are used in a weight ratio of 1 :0.1 to 1:10.0, and

the active ingredient and the polymer for protecting the pellet under an acidic condition

are used in a weight ratio to of 1 :0.1 to 1 : 10.0.

In the layer further formed between the core and the first layer, that is the layer

comprising the water-insoluble polymer, the active ingredient and the water-insoluble

polymer are used in a weight ratio of 1 :0.3 to 1 :5.0.

In practice, materials, which can be used as the core of the water-soluble or

water-swellable inactive material, include sucrose/starch spheres (Sugar Spheres NF),

sucrose crystals, or spheres prepared using typical excipient, for example,

microcrystalline cellulose and lactose by exclusion and drying. Any seeds known and

commonly used in pharmaceutical fields can be used in the present invention.

Preferably, the seeds have a particle size of 300 to 1,000 μm.

The active ingredient contained in the pellet comprises Zolpidem or its

pharmaceutically acceptable salt, and Zolpidem hemitartrate is preferable since it is readily commercially available.

The layer comprising the active ingredient may be formed of the active

ingredient alone or in combination with a polymer in order to form the layer effectively.

Here, usable examples of the polymer include polyvinylpyrrolidone (PVP);

polyalkylene glycol, for example, polyethylene glycol; gelatin; polyvinyl alcohol; starch

and a derivative thereof; cellulose derivative, for example,

hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose,

carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose,

carboxyethylcellulose and carboxymethylhydroxyethyl cellulose; acrylic acid polymer,

methacrylic acid polymer or methacrylate polymer(Eudragits),

hydroxypropylmethylcellulose phthalate and pharmaceutically acceptable polymer.

The above-described components can be used alone or as a mixture of two or more

thereof.

As the polymer for controlling release of the active ingredient in the

composition of the present invention, a water-insoluble polymer can be used alone, or in

combination with a water-soluble polymer according to the intended profile of drug

release. The usable examples of the water-insoluble polymer include ethylcellulose,

polymer of methacrylic acid and methacrylate (Eudragits), polyethylene, polyamide,

poly(ethylene-vinyl acetate), cellulose nitrate, silicone, poly(lactide-co-glycolide) and

commercially available Surelease, but are not limited thereto. Any water-insoluble

polymers that are commonly used in the pharmaceutical fields can be used in the

present invention. The above-described components can be used alone or as a mixture

of two or more thereof. Concrete examples of the water-soluble polymer added for release control include polyethylene glycol, polyethylene oxide, gelatin, starch, dextran

sulfate, sucrose, carboxymethylcellulose, chitosan, hydroxyethylcellulose,

hydroxypropylmethylcellulose, methylcellulose, arabinogalactan, polyvinyl alcohol,

polyacrylic acid, polyvinylpyrrolidone, arabia gum and sodium alginate, but are not

limited thereto. Any water-soluble polymers which are commonly used in the

pharmaceutical fields can be used in the present invention. The above-described

components can be used alone or as a mixture of two or more thereof. For perfect

formation of the release-controlling layer, a plasticizer which is commonly used in the

pharmaceutical fields may be added. The amount of the water-insoluble polymer

forming the coating and the ratio to the water-soluble polymer adding thereto may vary

according to types and properties of the polymers to satisfy the requirements of the

controlled release preparation.

The polymer for protecting the pellet under an acidic condition includes enteric

coating materials, that is enteric polymers, known and commonly used in the

pharmaceutical fields, which can inhibit the collapse of pellets under acidic conditions

of pH 1.2 but allow the collapse over pH 5.5. Concrete examples include

hydroxypropylmethyl cellulose phthalate (HPMCP), hydroxypropylmethyl cellulose

acetate succinate (HPMCAS), cellulose acetate phthalate (CAP) and copolymer of

methacrylic acid and methyl methacrylate ester (Eudragits), but are not limited thereto.

The above described components may be used alone or as a mixture of two or more thereof. For perfect formation of the enteric coating, a pharmaceutically acceptable

plasticizer may be added.

Moreover, concrete examples of the water-insoluble polymers in the layer additionally formed between the core and the first layer, that is, the layer comprising the

water-insoluble polymer include ethylcellulose, copolymers of metachrylic acid and

methacrylate (Eudragits), polyethylene, polyamide, poly(ethylene-vinyl acetate),

cellulose nitrate, silicone, poly(lactide-co-glycolide) and commercially available

Surelease, but are not limited thereto. The above-described components may be used

alone or as a mixture of two or more thereof.

The capsule filling process is performed by mixing the immediately-acting part

and the delayed sustained-release pellet in the ratio of 0.3:1 to 4:1 based on the drug

content, and then by filling the mixture into the capsule using capsule filling apparatus

commonly used in the pharmaceutical fields. If needed, a lubricant such as talc or

magnesium stearate may be added.

In the study of sustained-release pellet comprising Zolpidem or its salt, the

present inventors have found that by filling in a capsule the immediately-acting part

which immediately releases the drug in the stomach of acidic condition, along with the

delayed sustained-release pellets showing sustained-release when reaching the intestines

without releasing the drug in the stomach, it is possible to minimize the side-effects in

patients caused by sudden drug release. Based on the finding, the present invention

has been completed. More particularly, in the first phase the drug is released

immediately after oral administration of the composition and undergoes systemic

absorption to induce rapid sleep of patients, as disclosed in European Patent No. EP

1194132, and in the second phase the sustained-release pellets having the enteric

coating slowly releases the drug when arrive in the intestines after passing time while

the sudden drug release in the stomach is inhibited by the coating, whereby the patient can sleep for a sufficient period of time. Unlike EP 1194132, in which the drag release

test of the preparation was performed under an acidic condition, the present invention is

characterized to define the drag release profile not only under the acidic condition, but

also under pH 6.8 environment, because the composition of the present invention has

pH-dependent delayed drag release mode. According to the prior art, the sudden drag

release caused by the variation of coating thickness and coating perfection among

pellets is inhibited by homogeneous mixing. However, according to the present

invention, such defects are effectively overcome by addition of the enteric coating, and

the sudden drag release caused by damage and deformation of pellets which may occur

in the filling process and during storage and distribution can be also prevented.

The composition according to the present invention is characterized by timed

dual release, which comprises both the immediately-acting part for immediately

releasing a drag and the delayed sustained-release pellets for delaying the drag release

by the enteric coating. That is, the delayed sustained-release pellet is protected by the

enteric coating, and thereby, does not release the drag for passing time until it passes the

stomach after oral administration. Therefore, it is possible to effectively prevent the

side effects caused by unexpected sudden drag release that may often occur in the

general sustained-release pellets.

Best Mode

Now, the present invention is described in detail by the following examples,

however, the present invention is not limited thereto.

Example 1: Preparation of immediately-acting pellet 600 g of sugar spheres of 500 to 710 μm was placed in a fluid bed coating

apparatus and flown while spraying the solution of 45.0 g of Zolpidem hemitartrate and

5.0 g of hydroxypropylmethylcellulose dissolved in 3.0 kg of purified water to prepare

immediately-acting pellets.

Example 2: Preparation of immediately-acting pellet

600 g of sugar spheres of 500 to 710 μm was placed in a fluid bed coating

5.0 g of hydroxypropylmethylcellulose dissolved in 3.0 kg of purified water and then

the solution of 30.0 g of hydroxypropylmethylcellulose dissolved in 1.0 kg of purified

water to prepare immediately-acting pellets with a protection coating.

Example 3: Preparation of delayed sustained-release pellet

500 g of immediately-acting pellet prepared by the same procedures with

Example 1 except using 355 to 500 μm sugar spheres, was placed in a fluid bed coating

apparatus and flown while spraying the suspension of 100.0 g of Surelease (solid

content of 25.0 g) and 50.0 g of hydroxypropylmethylcellulose in 500 g of purified

water on the pellets to form a coating in a weight ratio to the immediately-acting pellet

of 6%. Then, the suspension of 100.Og of Surelease (solid content of 25.0 g) and 25.0

g of hydroxypropylmethylcellulose in 250 g of purified water was sprayed on the pellets

to form a coating in a weight ratio to the immediately-acting pellet of 6% and the suspension of 200.0 g of Surelease (solid content of 50.0 g) and 25.0 g of

hydroxypropylmethylcellulose in 250 g of purified water was sprayed on the pellets to

form a coating in a weight ratio to the immediately-acting pellet of 4%. Thus, the sustained-release pellets are formed. Next, the suspension of 450 g of Eudragit L30-

D55 in 4.0 kg of purified water was sprayed on the pellets to form a coating in a weight

ratio to the sustained-release pellet of 15% and thus, the delayed sustained-release

pellets are formed.

Example 4: Preparation of delayed sustained-release pellet

600 g of 355 to 500 jum sugar spheres were placed in a fluid bed coating

apparatus and flown while spraying the suspension of 320.0 g of Surelease (solid

content of 80.0 g) in 400 g of purified water to form a coating in a weight ratio to the

sugar spheres of 12%. Then, 600 g of the prepared pellets was used to prepare

immediately-acting pellets according to the procedures disclosed in Example 1. 500 g

of the prepared immediately-acting pellets was placed in a fluid bed coating apparatus

and flown while spraying the suspension of 100.0 g of Surelease (solid content of 25.0

g) and 50.0 g of hydroxypropylmethylcellulose in 500 g of purified water to form a

coating in a weight ratio to the immediately-acting pellet of 6%. Then, the suspension

of 100.0 g of Surelease (solid content of 25.0 g) and 25.0 g of

form a coating in a weight ratio to the immediately-acting pellet of 6% and the

suspension of 200.0 g of Surelease (solid content of 50.0 g) and 25.0 g of in 250 g of

purified water on the pellets to form a coating in a weight ratio to the immediately-

acting pellet of 4%. Thus, the sustained release pellets were prepared. Next, the

suspension of 450 g of Eudragit L30-D55 in 4.0 kg of purified water was sprayed on the

pellets to form a coating in a weight ratio to the sustained-release pellet of 15% and thus,

the delayed sustained-release pellets were prepared. Example 5: Preparation of capsule

78.6 g and 86.5 g of the pellets prepared in Example 1 and Example 3 were

mixed with 1.6 g of talc and filled into No. 2 capsule to the content of 209 mg

(Zolpidem hemitartrate of 12.5 mg) to prepare the sustained-release preparation.

Example 6: Preparation of capsule

83.3 g and 86.5 g of the pellets prepared in Example 2 and Example 4 were

mixed with 1.6 g of talc and filled into No. 2 capsule to the content of 214 mg

Example 7: Preparation of delayed sustained-release pellet

500 g of the immediately-acting pellets prepared by the same procedures with

apparatus and flown while spraying a mixture of the suspension of 300.0 g of Surelease

(solid content of 75.0 g) and 150.0 g of hydroxypropylmethylcellulose in 1.5 kg of

purified water with the suspension of 450 g of Eudragit L30-D55 in 4.0 kg of purified

water to form a coating in a weight ratio to the immediately-acting pellet of 25%.

Thus, delayed sustained-release pellets were prepared.

Example 8: Preparation of capsule

78.6 g and 81.3 g of pellets prepared in Example 1 and Example 7 were mixed

with 1.6 g of talc and filled into No. 2 capsule to the content of 199 mg (Zolpidem

hemitartrate of 12.5 mg) to prepare the sustained-release preparation.

Dissolution test 1: Dissolution test of immediately-acting pellet The pellets corresponding to 12.5 mg of Zolpidem hemitartrate were precisely

weighted and subjected to dissolution test at 100 rpm in 900 mL of 0.01 Mol/L

hydrochloric acid solution according to a dissolution test (paddle method) of Korea

Pharmacopeia. After 30 minutes, the dissolution sample was taken.

Dissolution test 2: Acid resistant test of delayed sustained-release pellet

The pellets corresponding to 12.5 mg of Zolpidem hemitartrate were precisely

weighted and subjected to dissolution test at 100 rpm in 900 mL of 0.01 Mol/L

Pharmacopeia 100 rpm. After 2 hours, the dissolution sample was taken.

Dissolution test 3: Dissolution test of delayed sustained-release pellet

The pellets corresponding to 12.5 mg of Zolpidem hemitartrate were precisely

weighted and subjected to dissolution test at 100 rpm in 900 mL of pH 6.8 phosphate

buffer according to a dissolution test (paddle method) of Korea Pharmacopeia. After 2

hours and 8 hours, the dissolution sample was taken, respectively.

Dissolution test 4: dissolution test of capsules

6 capsules were taken from each group of capsules prepared in Examples 5, 6

and 8 and subjected to a dissolution test (paddle method) of Korea Pharmacopeia at 100

rpm in 900 mL of 0.01 Mol/L hydrochloric acid solution. After 30 minutes, the

dissolution sample was taken from the solution of 900 mL and after 2 hours and 8 hours, the dissolution sample was taken from 900 mL of the solution of pH 6.8 phosphate

buffer.

Analysis of Zolpidem and calculation of dissolution rate 20 mg of standard Zolpidem hemitartrate was placed in 200 mL flask and

purified water was added thereto for dissolution. 10 mL of the solution was decanted,

and placed in 100 mL flask. Purified water added thereto to prepare a standard

solution. Each of the sampled solutions for dissolution test was filtered through 0.45

μm membrane filter paper and the filtrate was measured for UV absorbance at 254 nm

to calculate the dissolution rate.

Dissolution rate = [At/As] x [9/10] x [reference weight (mg)/20] x reference

purity (%)

At: absorbance of the tested sample

As: absorbance of the standard solution

[Table 1]

Dissolution test

Industrial Applicability

The present invention relates to a safe controlled release preparation comprising

Zolpidem or its salt. By the preparation according to the present invention, it is

possible to accomplish both the immediately-acting release in the early stage and

sustained release after several hours later and significantly reduce possibility of side

effects in patients caused by sudden drug release which may result from damage and

deformation in pellet occurring during the filling process or storage and distribution

process resulting. Therefore, while effectively inhibiting side effects due to the

unexpected sudden release of the delayed sustained-release pellet contained in general

sustained-release pellets, it is possible to rapidly induce sleep, stably control drug

release and maintain continuous sleep by single administration. Also, by using the

preparation composition according to the present invention, it is possible to prevent

misuse of the drug.

Claims

1. A controlled release preparation composition comprising:

(1) a immediately-acting part comprising Zolpidem or its salt as an active

ingredient, and

(2) a delayed sustained-release pellet comprising Zolpidem or its salt as an

solution.

2. The composition according to claim 1, wherein the immediately-acting part

has a dissolution rate of 75% or more, as measured at 100 rpm for 30 minutes in 900

mL of 0.01 Mol/L hydrochloric acid solution by the dissolution test according to paddle

method of Korea Pharmacopoeia.

3. The composition according to claim 1, wherein the delayed sustained-release

pellet has a dissolution rate of 10% or less, as measured at 100 rpm for 2 hours in 900

mL of 0.01 Mol/L hydrochloric acid solution by a dissolution test according to paddle

method of Korea Pharmacopoeia, and a dissolution rate of 45% or less and 70% or more,

as measured in 900 mL of pH 6.8 phosphate buffer for 2 hours and 8 hours, respectively.

4. The composition according to claim 1, wherein the immediately-acting part

and the delayed sustained-release pellet are in the ratio of 0.3:1 to 4:1 based on the drug

content.

5. The composition according to claim 1, wherein the salt of Zolpidem is

Zolpidem hemitartrate.

6. The composition according to claim 1, wherein the delayed sustained-release

pellet comprises:

(a) a core of a water-soluble or water-swellable inactive material;

(b) as a first layer, the layer containing an active ingredient formed on the

surface of the core;

the active ingredient, formed on the surface of the first layer; and

(d) as a third layer, the layer containing a polymer for protecting the pellet

under an acid condition, formed on the surface of the second layer.

7. The composition according to claim 6, wherein the delayed sustained-release

pellet further comprises a layer comprising a water-insoluble polymer between the core

and the first layer.

8. The composition according to claim 1, wherein the delayed sustained-release

pellet comprises:

(a) a core of a water-soluble or water-swellable inactive material;

(b) as a first layer, the layer containing an active ingredient, formed on the

surface of the core; and

(c) as a second layer, the layer containing a polymer for controlling release of the active ingredient and a polymer for protecting the pellet under an acid condition,

formed on the surface of the first layer.

9. The composition according to claim 8, wherein the delayed sustained-release

and the first layer.

10. The composition according to claim 6 or 8, wherein the active ingredient

and the core are in a weight ratio of 1 :1 to 1:30, the active ingredient and the polymer

for controlling release are in a weight ratio of 1:0.1 to 1:10.0, and the active ingredient

and the polymer for protecting the pellet under an acidic condition are in a weight ratio

to of 1:0.1 to 1:10.0.

11. The composition according to claim 7 or 9, wherein the active ingredient

and the water-insoluble polymer are in a weight ratio of 1 :0.3 to 1:5.0.

12. The composition according to claim 6 or 8, wherein the polymer for

controlling release of the active ingredient is a water-insoluble polymer alone or a

combination of a water-insoluble polymer and a water-soluble polymer.

13. The composition according to claim 12, wherein the water-insoluble

polymer is at least one selected from the group consisting of ethylcellulose, polymer of

methacrylic acid and methacrylate (Eudragits), polyethylene, polyamide, poly(ethylene- vinyl acetate), cellulose nitrate, silicone, poly^actide-co-glycolide) and Surelease, and

the water-soluble polymer is at least one selected from the group consisting of

polyethylene glycol, polyethylene oxide, gelatin, starch, dextran sulfate, sucrose,

carboxymethylcellulose, chitosan, hydroxyethylcellulose,

polyacrylic acid, polyvinylpyrrolidone, arabia gum and sodium alginate.

14. The composition according to claim 6 or 8, wherein the polymer for

protecting the pellet under an acidic condition is an enteric polymer.

15. The composition according to claim 14, wherein the enteric polymer is at

least one selected from the group consisting of hydroxypropylmethyl cellulose phthalate

(HPMCP), hydroxypropylmethyl cellulose acetate succinate (HPMCAS), cellulose

acetate phthalate (CAP) and copolymer of methacrylic acid and methyl methacrylate

ester.

16. The composition according to claim 7 or 9, wherein the water-insoluble

methacrylic acid and methacrylate(Eudragits), polyethylene, polyamide, poly(ethylene-

vinylacetate), cellulose nitrate, silicone, poly(lactide-co-glycolide) and Surelease.

17. The composition according to claim 6 or 8, wherein the layer containing

the active ingredient further comprises a polymer.

18. The composition according to claim 17, wherein the polymer is at least one

selected from the group consisting of polyvinylpyrrolidone (PVP); polyalkylene glycol;

gelatin; polyvinyl alcohol; starch and a derivative thereof; cellulose derivative; acrylate

polymer; and Hydroxypropylmethylcellulose phthalate.

19. The composition according to claim 1, wherein the immediately-acting part

is in the form of granules, pellets or a coating applied on the delayed sustained-release

pellets.