WO1993005770A1

WO1993005770A1 - Long-acting preparation

Info

Publication number: WO1993005770A1
Application number: PCT/JP1992/001183
Authority: WO
Inventors: Yoshio Ueda; Norio Ohnishi; Mitsuru Yasumura; Kazuto Okimoto; Kouji Kitada
Original assignee: Fujisawa Pharmaceutical Co., Ltd.
Priority date: 1991-09-20
Filing date: 1992-09-17
Publication date: 1993-04-01

Abstract

A long-acting preparation having a remarkably excellent long-lasting efficacy in peroral absorption, comprising a double-layered tablet consisting of a rapidly soluble part containing a principal agent as the inner layer and a sustained-release part containing a principal agent as the outer layer.

Description

.Specification

Title of invention

Sustained preparation

Technical field

The present invention relates to a sustained-release tablet-type preparation having a multilayer structure of two or more layers. More specifically, the outer layer is provided as a sustained release to have a self-adhesive property with a time lag, and the inner layer is rapidly dissolved. The present invention relates to a long-acting preparation that can continue to provide a therapeutically or prophylactically effective high in vivo concentration even after being eluted with a time lag.

Background art

In oral administration of a drug, it is possible to control the release status of the Q drug from the oral preparation in the gastrointestinal tract. That is, if appropriate control is performed, even if the interval between doses is long, it is possible to maintain a high biological concentration that is therapeutically or prophylactically effective over a long period of time until the next dose, thus reducing the number of doses. Can be achieved. In addition, for a drug whose risk of toxicity or side effects increases when the concentration in the body rapidly rises temporarily, the concentration of the drug in the body is adjusted to a level that does not cause the above risk by performing appropriate release control. Moreover, it is strongly desired to maintain a therapeutically or prophylactically effective in vivo concentration.

Therefore, for oral drug preparations, release control as described above has been studied from the viewpoint of a new DDS (Drug Delivery System), and various sustained-release preparations have been developed. Conventional long-acting drugs include, for example, water-insoluble or poorly soluble Or a so-called matrix tablet in which a drug is dispersed in a water-insoluble or poorly soluble cross-linked matrix, etc., and these are drugs in the film or matrix. Various formulations have been designed based on the concept that release is controlled by the resistance when the drug is diffused. More specifically, the mode of drug release in these preparations is driven by the concentration gradient of the drug in the preparation caused by the permeation of water (diffusion-controlled). The elution rate is reduced due to relaxation of the diffusion and increase in the diffusion distance.

The above-mentioned other enteric-coated preparations include the above-mentioned other enteric-coated preparations, which release a substance gradually in the process of going from the stomach to the intestinal tract by utilizing the difference in solubility due to pH. However, even when focusing on certain specific parts of the body, pH is susceptible to individual differences, age differences, stomach food volume, circadian fluctuations, mental state fluctuations, etc. The disadvantage is that it must be very uncertain.

In view of the above-mentioned drawbacks of the prior art, the applicant has found that the drug release rate is close to constant (zero-order release), and is affected by fluctuations in pH conditions and changes in stirring intensity during drug disintegration tests. We have been conducting research to develop formulations that are less susceptible to inhalation. As a result, as described in Japanese Patent Disclosure No. 24516/1986 and No. 10012 in 62/1986, etc., a monocycline consisting of disintegrating granules and wax containing the active ingredient is used. Develop and disclose a soluble formulation. This preparation contains a tablet which is tableted after applying a box to the surface of a disintegrating granule containing the principal component. The wax part gradually dissolves, and the granules on the surface of the tablet come into contact with body fluids and release the drug in sequence.However, by controlling the amount of disintegrant and the amount of wax mixed into the granules This has the advantage that the degree of sustained release can be controlled. By providing such a tablet, the controlled release of the drug has been controlled with higher precision.On the other hand, even if a part of the drug is released with a delay due to the controlled release, the release of the drug is controlled. If the site is in the gastrointestinal tract with low absorption efficiency, such as the lower small intestine, the problem arises that the absorption of the drug becomes insufficient and the effect of sustained release cannot be fully enjoyed. This problem is even more pronounced when the drug is a poorly soluble drug.

The present invention has been made in view of such circumstances. The present invention controls the sustained release of a drug by giving a time difference to the release of the active ingredient, and suppresses the release of a delayed drug from the absorption in the lower small intestine. The purpose is to provide tablets that can be sufficiently absorbed at the site even if released to a part with low yield rate, and can maintain and maintain the concentration in the body at the concentration required for treatment or prevention. is there.

Disclosure of the invention

The pharmaceutical preparation of the present invention, which has achieved the above object, has a two-layer structure or a multi-layer structure capable of forming a multi-layer structure as required, and the inner layer contains the active ingredient. The basic point is that the outer layer is constituted by a sustained-release part containing the same or similar main drug as the above-mentioned main drug. BRIEF DESCRIPTION OF THE FIGURES

Figure 1 shows the in vitro dissolution test results.

Figures 2 and 3 are graphs showing the results of various changes in the experimental conditions in the in vitro dissolution test.

FIG. 4 is a graph showing in vivo oral absorbability.

BEST MODE FOR CARRYING OUT THE INVENTION

The composition of the tablet of the present invention is a multi-layered type which can be composed of two layers or two or more layers as described above, but the most typical one is a two-layer type. Therefore, in the following description, the case of the two-layer type will be mainly described, that is, the case of an inner layer and an outer layer will be described. However, a coloring layer, a sugar coating layer, or a protective layer is provided further outside the outer layer, or Similarly, a fast-acting layer containing the active substance and having excellent fast solubility is provided further outside the outer layer, or an intermediate layer containing the active substance having a dissolution / release property at an intermediate level between the fast-dissolving portion and the sustained-release portion between the outer layer and the inner layer. Is not necessarily excluded. Therefore, the terms “inner layer J” and “outer layer” used in the present specification are used solely based on the positional relationship between the quick-dissolution portion and the sustained-release portion described above, and do not have an absolute meaning. The main drug contained in each layer of the tablet of the present invention includes not only a case where all the compounds are the same compound, a case where the compound is another compound having the same drug, and a case where the compound is another compound having similar drug effect. Hereinafter, the case where the compounds have the same efficacy and the same compounds will be described as representative examples.

The same compound in the above description includes the case where the compound is an acid or a base and forms a salt with various bases or acids, and the base or acid for forming the salt is different. Have been Should be considered the same compound.

Therefore, the basic composition of the pharmaceutical composition of the present invention lies in that the quick-dissolve portion containing the active substance is arranged on the center side of the tablet and the sustained-release section containing the active substance is arranged on the outer peripheral side of the tablet. After the drug is first administered, the drug-containing sustained-release part on the outer periphery first descends sequentially in the gastrointestinal tract while gradually disintegrating due to the body fluid, and after a considerable period of time, a part of the drug-containing fast-dissolving part becomes part of the body fluid. When contact begins, the collapse of the rapid melting zone starts immediately from the contact area. Here, the time lapse after taking the drug is divided into the initial, middle, and late stages of taking the drug.From the beginning to the middle of the dose, the main drug gradually released from the sustained-release part gradually disintegrates into the gastrointestinal tract. It is expected that it is gradually absorbed along the body and acts in a direction that maintains a humorous body fluid concentration.In the latter period, for example, the principal drug that is disintegrated and released from the fast-dissolving part of the tablet that has reached the middle or lower part of the small intestine, for example Is expected to be rapidly absorbed from the gastrointestinal tract and to continue to maintain the body fluid concentration at a high level.

The main drug-containing quick-dissolving portion, which is an inner layer component of the tablet of the present invention, is a portion expected to rapidly release the main drug into the body fluid when it comes into contact with the body fluid, and is a pharmaceutical preparation for rapidly dissolving the main drug. For the configuration, it is possible to use a technology that has been conventionally employed. For example, a method of mixing and kneading the active ingredient with a disintegrant, excipients, and various additives generally used in the art to form granules, and then compressing the granules into an inner layer tablet is exemplified. Is done. Here, examples of the disintegrant include various starches (eg, corn starch, corn starch, rice starch, new paper). Starch, carboxymethyl starch, etc.), rubbers (eg, gum arabic), cellulose derivatives (eg, carboxymethylcellulose calcium, carboxymethylcellulose sodium, low-substituted hydroxypropylcellulose, bridge carboxymethylcellulose sodium) And various ion-exchange resins (for example, polyamide and polymethacrylate). Examples of the excipient include lactose, sucrose, mannite and the like. The disintegrants and excipients as exemplified above are appropriately selected in consideration of the properties of the main drug and the intended cycling time, etc., and if necessary, the use of two or more in combination is also permitted.

If the main ingredient is insoluble or very poorly soluble in water and is considered to be insufficiently absorbed from the digestive tract, use a natural or synthetic water-soluble polymer in combination with the above granules. Is recommended. These water-soluble polymer substances may be added together with the base drug, disintegrant, excipients, or the like, or may be added sequentially in any order and mixed and kneaded to form granules. Good, but if necessary, the active ingredient is dispersed in a water-soluble polymer in advance, dried and then led to an easily soluble dosage form such as a solid dispersion. In some cases, it may be advisable to produce granules by mixing and kneading them with an active polymer substance). As the above-mentioned water-soluble polymer substance, first, as a natural substance, for example, a cellulose derivative (for example, hydroxypizole pizoremethinoresenorelose, methinoresenolerose, hydroxypoxypyrucellulose, carboxymethylcellulose, etc.), or Polysaccharides (eg pullulan, dextran, etc.) Examples thereof include polyvinyl pyrrolidone, cross-linked polyvinyl pyrrolidone, polyethylene oxide and the like. In such a case, an appropriate selection is made according to the degree of poor solubility of the active ingredient, and two or more of them can be used in combination as needed.

The amount of disintegrant that can be used during the production of the granules is not particularly limited, but may be appropriately determined in consideration of the type of the disintegrant, the properties of the active ingredient, and the intended quick-dissolving property. It is selected from the range of 10 to 75% by weight, preferably 40 to 60% by weight. The amount of the water-soluble polymer compound used is not particularly limited, and may be appropriately determined in consideration of the degree of poor water solubility of the active ingredient, the type of the water-soluble polymer substance, and the like. It is selected from the range of 5 to 60% by weight, preferably 5 to 40% by weight.

The quick-dissolving granules thus formed are tableted with a lubricant such as magnesium stearate, calcium stearate, talc, corn starch, etc. according to a conventional method to form the fast-dissolving inner layer portion of the present invention. Is done.

Next, the main drug-containing sustained release portion, which is an outer layer component of the tablet of the present invention, is a portion expected to gradually release the main drug into the body fluid when it comes into contact with the body fluid. As for the pharmaceutical composition for release, general-purpose sustained release technology conventionally used can be used. For example, the granules prepared for the inner layer side as described above are subjected to a boxing process to prepare a box-coated outer layer side structure, which is coated on the outer periphery of the tableted quick-dissolving inner layer portion. The present invention can be obtained by press-coating. The wax used here is insoluble or difficult to dissolve in water For example, various waxes (for example, carnauba wax and the like), various hardened oils (for example, soybean hardened oil, castor hardened oil, and the like), paraffins, and the like may be used. These may be used alone, or may be used alone. The above may be used in combination.

Although there is no particular limitation on the method of box treatment, for example, the granules are added to the melt of the box described above, kneaded, dried and sized to obtain sustained-release granules. The amount of the wax used is not particularly limited, and may be determined as appropriate depending on the properties of the wax and the main drug used, the intended cycling time, and the like. From 10 to 70% by weight, preferably from 20 to 60% by weight.

In the above description, it was stated that the granules prepared as the inner layer-side structure were subjected to a boxing process to produce an outer layer-side formed body. The outer layer side structure produced by such a method has exactly the same granular structure as that of the inner layer side except for the wax treatment. Although the present invention includes such a case in the technical scope, the present invention naturally includes that the granule composition on the inner layer side and that on the outer layer side are separately formulated in accordance with the respective properties. For example, in view of the requirement that the inner layer side be rapidly soluble in disintegrants, it may be recommended to mix more disintegrant than the outer layer side granules. However, if the content of the disintegrant in the inner layer increases, the inner layer becomes larger and the whole tablet becomes larger, which may make it difficult to take the tablet. Therefore, it is necessary to reduce the size of the whole tablet to a certain size or less, which may require the inner layer granules to be compacted as much as possible. Agent, example For example, the amount of the water-soluble polymer can be reduced as necessary and possible as much as that of the granules on the outer layer side. For example, when the amount of the water-soluble polymer on the outer layer side is 100 parts by weight, It is recommended that the water-soluble polymer material on the side be 15-40% by weight, preferably 25-35% by weight. Alternatively, it is also meaningful to take measures to reduce or eliminate excipients such as emulsions, which are general additives in tablet production, from the inner layer formulation.

In performing the Peggs treatment, other components may be used in combination for the purpose of further finely controlling the sustained release property of the wax or for promoting the disintegration of the wax at a stable rate. An example of such a third component is ethyl cellulose. Since the chemical properties (eg, water solubility and viscosity) of ethyl cellulose change depending on the degree of substitution of the ethyl group, it is recommended to select the one with the optimal degree of substitution according to the purpose of addition. . In general, it is desirable to select a material having a viscosity of ffl in the range of 7 to 1 cps using viscosity as an index. The amount of the ethylcellulose is determined in consideration of the viscosity and the purpose of the mixing, or the type of the wax. Usually, the amount is 0.75 to 2.5 (weight ratio), preferably the amount of the wax used. It is selected from the range of 0.8 to 1.5 (weight ratio). In addition, when using ethyl cellulose, as shown in the Examples described later, a method in which wax treatment is performed in a state where granules containing the active substance (solid dispersion for outer layer) before wax processing and ethyl cellulose are sufficiently mixed. In addition to the above, in addition to the above, ethyl cellulose and PEX are sufficiently mixed and melted to coat the active ingredient-containing granules, or the expected amount of wax and A method in which chill cellulose is divided into two and each of the above methods is combined is freely employed. When the outer layer granules thus formed are press-coated on the outer periphery of the inner layer tablet, the lyophilic preparation of the present invention can be obtained.

Principles suitable for producing the cymbiotic preparation of the present invention are those which are considered to be suitable for oral administration, or those which are expected to be oral preparations if the cymbiotic property is achieved. All drugs are targeted. Therefore, the present invention is widely applied to cardiovascular drugs, gastrointestinal drugs, respiratory drugs, central nervous system drugs, autonomic nervous system drugs, hormonal drugs, antibiotics, and various other chemotherapeutic drugs. Among them, the development of a sustained release drug is strongly desired from the viewpoint of preventing heart attack, which is considered to be common when waking up, for example, when the cardiovascular agent is used, and the application of the present invention is particularly significant. Such a circulatory agent is not particularly limited, but a typical example thereof is a dihydropyridine compound represented by the following general formula.

[In the formula, R ¹ may be substituted by halogen, nitro and trihalo (lower) alkyl. A phenyl group, R ² is a lower alkyl group or a lower alkoxy (lower) alkyl group, and ^Ra is a shear group. R, lower alkyl, lower alkyl, or amino (lower) alkoxy (lower) alkyl, R ⁴ is lower alkyl, R ⁵ is lower alkyl, N-lower alkyl-N-al (lower) alkylamino (lower) alkyl Group or lower alkoxy (lower) alkyl group]

Preferable examples of R ¹ include 2-chlorophenyl, 2,3-dichlorophenyl, 2-difluorophenyl, 3-nitrophenyl, trifluoromethylphenyl and the like. Can be

Preferable examples of R ² include methyl, ethyl, propyl, 2-port poxicetyl and the like.

Preferred examples of R ³ include methyl, 2-aminoethoxymethyl and the like.

Preferred examples of R ⁴ include methyl and the like.

Suitable examples of R ⁵ include methyl, Echiru, isopropyl, I Sobuchiru, 2- Puropokishechiru, 2- (N- methyl-N- Benjiruami Roh) Echiru the like.

Preferable examples of the dihydropyridine compound represented by the above general formula include, for example, difendipine, dicardipine, nimodipine, disordipine, nitrendipine, amlodipine, fuerodipine, nildipine or nilvadipine, and among them, Most preferred is zirno ヽ 'dipine.

In addition to the compounds represented by the above general formula, dihydropyridin compounds such as manidipine, benidipine, dalodipine, isradipine and the like can also be exemplified as the preferred active compounds of the present invention. A prescription example and a production example of a sustained release drug containing nilvadipine as a main drug are shown.

Prescription A

'Inner layer 锭 (solid dispersion formulation)

Nilvadipine 4mg HPMC 2910 12rag

(Hydroxylpropyl methylcellulose)

L-HP C 33.8mg

(Low-substituted hydroxypropylcellulose)

Magnesium stearate 0.2mg

(Subtotal) 50mg outer layer

Nilvadipine 8mg

HPMC 2910 40mg L-HPC 45mg Lactose 57mg Soybean hardened oil 150mg Magnesium stearate 0.6mg

(Subtotal) 300.6mg (Total) 350.6mg Prescription B

Inner tablets (solid dispersion formulation)

Nilnogu dipin

HPMC 2910 12mg L-HP C 33.8mg Magnesium stearate 0.2mg

(Subtotal) 50mg outer layer

Nilvadipine 8mg H PMC 2910 40mg L-HPC 45mg Lactose 57mg Soybean hardened oil 78mg Ethyl Senorelose 82mg Magnesium stearate 0.6mg

(Subtotal) 310.6nig (Total) 360.6mg Prescription C

Inner tablets (solid dispersion formulation)

Ninoreno * dipine 4 mg HPMC 2910 12 mg L-HPC 19 mg magnesium stearate 0.14 mg

(Subtotal) 35.14mg outer layer

Nilvadipine 8mg H PMC 2910 40mg L-HPC 25mg. Lactose 20mg Soybean hydrogenated oil 57.9mg Ethyl cellulose 60.8mg Magnesium stearate 0.41mg

(Subtotal) 212. Umg (Total) 247.25mg Production Example 1 (Production of inner layer of Formulations A and B)

Dissolve nilvadipine (24g) in ethanol (660ml) in a 60 ^ warm bath and cool to 40. On the other hand, HPMC 2910 (72 g) and L-HPC C202.8 g) were sufficiently mixed, and the 40 ^ 2 Nilvadipine solution obtained above was added to the mixture, and the mixture was mixed for 10 minutes and dried in vacuum. The obtained dried product was pulverized and sized, magnesium stearate (L2g) was added and mixed, and the mixture was tableted with a tableting machine to produce an inner layer tablet.

Production Example 2 (Production of solid dispersion particles for outer layer of formulas A and B)

Dissolve nilvadipine (48 g) in ethanol (1320 ml) in a 60 ^ hot bath and cool to 40 40. On the other hand, a mixture of HPMC 2910 (240 g), L-HPC (270 g) and lactose (342 g) was prepared, and the previously obtained 4 (TC solution of nilvadipine was added. The obtained dried product was pulverized and sized to prepare a solid dispersion for the outer layer.

Black ink (manufacture of prescription C inner layer)

Dissolve ilvadipine (24 g) in ethanol (660 ml) in a 60 * Ό warm bath, cool to 4 (TC), and mix well HPMC 2910 (72) and L-HPC (114 g). To the mixture was added the previously obtained diluvadipine solution of 40, kneaded for 10 minutes, and dried under vacuum. After adding and mixing gnesium (0.84 g), the mixture was pressed with a tableting machine to produce an inner layer.

Production Example 4 (Production of solid dispersion particles for outer layer of Formula C)

Dissolve nilvadipine (48g) in ethanol (1320ml) in a 60 ° C warm bath and cool to 40 ^. On the other hand, a mixture of HPMC 2910 (240 g), L-HPC (150 g) and lactose (120 g) was prepared, and the previously obtained 4 (TC solution of diluvadipine was added thereto, and kneaded for 10 minutes. The resulting dried product was pulverized and sized to produce a solid dispersion for the outer layer.

Production Example 5. (Production of granules for outer layer using outer solid dispersion of formula A)

Melt soybean hardened oil (900g) at 80 ° C, add the outer layer solid dispersion of formula A (900g) to this, and granulate while melting at 80 ^. This was allowed to cool to room temperature and then sized.

Production Example 6 (Production of granules for outer layer using outer layer solid dispersion of formula B)

80 Soy Hardened Oil (468g). C. Melt the mixture, add a mixture of ethyl cellulose (viscosity 45 cps, 492 g) and the solid dispersion of the outer layer of formulation B (900 g), and granulate while melting at 80. This was allowed to cool to room temperature and then sized.

-Production Example 7 (Production of granules for outer layer using outer layer solid dispersion of formula C)

Melt soybean hardened oil (900 g) with 80 ^, add the outer layer solid dispersion of formula C (1446 g) to this, and granulate while melting at 80 ° C. This was allowed to cool to room temperature and then sized. Example 8 (Manufacture of two-layer tablets)

The outer layer granules obtained in Production Examples 5 to 7 were press-coated on the outer periphery of the inner layer tablets produced in Production Examples 1 to 3, and the bilayer 锭 A, B, C ( The prescription was as shown in C above).

Example of Hiraki Kaizo 1 (Manufacture of ordinary rice containing Nilvadipine)

According to the following formulation, a common tablet containing nilvadipine was produced.

Nilvadipine 2mg

H P M C. LOmg

L-HPC 30 mg Lactose 137.5 mg Magnesium stearate 0.5 mg

(Total) 180mg Experimental Example 1

The two-layer tablet A consisting of Formulation A of the present invention and the comparative plain tablet were in vitro in vitro at 200 rpm and 900 ml (first wave: pH 1.2) according to the Japanese Pharmacopoeia 12th Edition, Method II (paddle method). Was subjected to a dissolution test. The results are as shown in Fig. 1, where the measured values (each plot) for each of the comparison ordinary cells (the seals) exceeded 100% at all times, and were released immediately in a short time. However, the two-layer tablet A (marked with 〇) of Honkiaki showed an elution rate that was almost proportional to the time elapsed until the 7th hour, indicating excellent sustained release.

Experimental example 2

An in vitro dissolution test was performed on the bilayer tablets A and B of the present invention by changing either one of the rotation speed conditions and the eluate conditions used in Experimental Example 1. (A- l) and (A- 2) in Fig. 2 (B-1) and (Β-2) in Fig. 2 show the results of double-layer tablet Β, respectively. In (Α-1) and (Β-1), the number of revolutions was changed using the first solution, and in (Α-2) and (Β-2), the number of revolutions was fixed at 200 rpm to change the eluate. As can be seen from the figure, the two-layer tablets A and B of the present invention both exhibited excellent sustained-release properties, but the sustained-release property of the two-layer tablet B using ethyl cellulose in the outer layer was extremely stable. You can say things.

Experiment 3

The same dissolution test as in Experimental Example 2 was performed on the bilayer tablet C. The results are as shown in Fig. 3, and all of the first solution (parable mark), pH 6.5 buffer solution (〇 mark) and distilled water (△ mark) show stable sustained release. I understand.

Experimental Example 4 (Evaluation of oral absorption in vivo using dogs)

Approximate body weight: 6 male beagle dogs weighing 1 Okg, fasting the normal tablet from the day before the test, orally administering 2 mg x 3 tablets, and oral administration immediately after that, forcibly administering 30 ml water per mouth did. The two-layer tablet A was fasted from the day before the experiment, and fed 100 g of dog chow 30 minutes before administration of the two-layer tablet A, and orally administered one tablet. After each administration, approximately 3 ml of blood was collected from the forearm vein at each passage of time, and parin (5000 units) was added to the local administration. When the concentration of nilvadipine in poultry plasma was measured by gas chromatography, the results shown in Fig. 4 were obtained. It can be seen that the bilayer tablet A of the present invention exhibits excellent sustained release properties and also maintains a high blood concentration for a considerably long time.

Industrial applicability The integrative fissure of the present invention has the following structure and structure, and the soil in the layer is gradually evacuated and exhibits excellent long-term gunning properties, while the main drug in the inner layer is At the time of release, the active drug in the inner layer is released rapidly, so that a high level of blood concentration is continuously maintained, and the effective blood concentration in the treatment and prevention is reduced. It was extremely prolonged.

Claims

The scope of the claims

1. A sustained-release preparation characterized in that an inner layer is constituted by a quick-dissolving portion containing a main drug and an outer layer is constituted by a sustained-release portion containing a main drug having the same or similar efficacy to the main drug.

2. The sustained-release preparation according to claim 1, wherein each of the active substances contained in the quick-dissolution part of the inner layer and the sustained-release part of the outer layer is a substance that dilates coronary blood vessels and / or peripheral blood vessels.

3. The sustained release preparation according to claim 2, wherein the main drug is a dihydropidine compound.

4. The sustained-release preparation according to claim 3, wherein the main drug is nilvadipine.

5. The fast-dissolving part is composed of an easily soluble solid containing the active substance and hydroxypropylmethylcellulose, and the sustained-release part is composed of a disintegrating granule and a base containing the active substance. The sustained-release preparation according to any one of claims 1 to 4, wherein the preparation is composed of a body.

6. The content of hydroxypropylmethylcellulose in the fast-dissolving part is 3 to 7 times (by weight) the active substance in the quick-dissolving part, and the content of the disintegrant in the sustained-release part is 10 to The sustained-release preparation according to claim 5, wherein the sustained-release preparation is 60% by weight, and the content of the wax in the sustained-release part is 20 to 65% by weight based on all components of the sustained-release part.