WO2007049626A1

WO2007049626A1 - Oral solid preparation containing cabergoline

Info

Publication number: WO2007049626A1
Application number: PCT/JP2006/321202
Authority: WO
Inventors: Ken Kanada; Yasuhiro Takeda; Kazuki Mimura
Original assignee: Kissei Pharmaceutical Co., Ltd.
Priority date: 2005-10-27
Filing date: 2006-10-25
Publication date: 2007-05-03
Also published as: JPWO2007049626A1

Abstract

An oral solid preparation which is an oral solid preparation containing cabergoline having good storage stability, characterized in that it contains a) cabergoline as an active ingredient, b) a sugar and/or a sugar alcohol, and c) a hydrophobic substance, and is prepared without using a solvent or without substantially bringing cabergoline into contact with a solvent. The oral solid preparation of the invention can be produced by dry mixing or dry granulation of a) cabergoline, b) a sugar and/or a sugar alcohol, and c) a hydrophobic substance.

Description

Specification

Oral solid preparation containing strong belgorin

Technical field

[0001] The present invention relates to an oral solid preparation containing strong bergorin having good storage stability, a method for producing the same, and a method for stabilizing the same.

Background art

[0002] Strength bermolin is an ergolin derivative having an excellent dopamine D receptor stimulating action.

2

It is used to treat diseases such as Parkinson's disease, hyperprolactinemia of ovulation, hyperprolactinemia of the pituitary gland, milk leakage, and suppression of postpartum lactation.

[0003] The dose of strength bermolin is 0.25 mg to 4 mg per day for adults and is administered by oral administration. An immediate release tablet is commercially available as an oral solid preparation containing strong belgorin, and the tablet contains 0.25 mg or l.Omg strong belgorin per tablet.

[0004] Since strong belgorin is very unstable with respect to humidity, strong belgoline preparations require moisture-proof packaging, and PTP packaged products are packaged in an aluminum pack with a desiccant. ing. Also, since the PTP packaged product after opening the aluminum pack is less moisture-proof, measures are taken to store it in an aluminum bag with a desiccant. For these reasons, there is a demand for strong belgorin formulations with improved storage stability.

[0005] The following patent documents are known as pharmaceutical compositions containing force bergolin as an active ingredient.

US2002 / 0123503 discloses a strong belgorin-containing preparation prepared by wet granulation using a non-aqueous solvent, and a method for producing the same (for example, (See Patent Document 1). In this production method, a solution in which strong belgolin is dissolved in a non-aqueous solvent is used as a granulating solution. However, a preparation prepared by such wet granulation is colored during storage. If it is easy to do, it will have a flaw.

[0006] US6316027 consists of a mixture of dopamine agonist, gelatin, mannitol and water as active ingredients, and is prepared by freeze-drying water from the mixture. An internally disintegrating tablet and a method for producing the same are disclosed, and it has been suggested that force belgorin is applicable as a dopamine agonist (see, for example, Patent Document 2). However, this manufacturing method is not suitable for the formulation of drugs that are unstable in the presence of water, such as strong belgorin, because dopamine agonists and large amounts of water are in direct contact. .

Patent Document 1: US Patent Application Publication 2002Z0123503 Specification

Patent Document 2: U.S. Pat.No. 6316027

Disclosure of the invention

Problems to be solved by the invention

[0007] An object of the present invention is to provide a strong belgorin-containing oral solid preparation having good storage stability, a production method thereof, and a stabilization method thereof.

Means for solving the problem

[0008] As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that a) contains berggoline as an active ingredient, b) sugar and / or sugar alcohol, and c) a hydrophobic substance. Thus, the present invention was completed by finding that a preparation prepared without using a solvent or without substantially contacting the solvent and strong belgolin has extremely excellent storage stability.

[0009] That is, the present invention provides

[1] An oral solid preparation containing a) strong belgorin as an active ingredient, b) sugar and / or sugar alcohol, and c) a hydrophobic substance as a stabilizer;

[2] The preparation according to [1], wherein the hydrophobic substance is at least one selected from a gastric polymer, a water-insoluble polymer or a wax;

[3] The preparation according to [2], wherein the gastric soluble polymer is at least one selected from aminoalkyl methacrylate copolymer E or polybulacetal jetylaminoacetate

[4] The preparation according to [2], wherein the water-insoluble polymer is ethyl ether;

[5] Waxing power is at least one selected from higher alcohols or hydrogenated oils,

[2] The preparation described in;

[6] Hydrophobic substance is aminoalkyl methacrylate copolymer E or polyvinylaceta [1] The preparation according to [1], which is at least one selected from one rugetylaminoacetate; [7] sugar power, according to [1], which is at least one selected from lactose, sucrose, trehalose or glucose. Formulation;

[8] Sugar alcohol power D-Mannitol, sorbitol, maltitol, or at least one selected from erythritol, [1]

[9] The preparation according to [1], further comprising at least one selected from partially alpha-monified starch, corn starch, or low-substituted hydroxypropylcellulose as a disintegrant; selected from calcium stearate or L-sip Ishin The preparation according to [1], comprising at least one of

[11] The preparation according to [1], wherein the preparation is prepared without using a solvent or without substantially contacting the solvent and strong belgolin;

[12] The preparation according to [1], comprising (1) a granulated product composed of sugar and / or sugar alcohol and a hydrophobic substance, and (2) strong begoline.

[13] The ratio of sugar and / or sugar alcohol contained in the granulated product composed of sugar and / or sugar alcohol and hydrophobic substance to the total weight of sugar and / or sugar alcohol is 5 to 100% by weight. The formulation according to [12],

[14] The preparation according to [1], wherein the content of sugar and / or sugar alcohol is 10-99% by weight relative to the total weight of the preparation;

[15] The preparation according to [1], wherein the content of the hydrophobic substance is 0.:! To 50% by weight relative to the total weight of the preparation;

[16] The preparation according to [9], wherein the content of the disintegrant is 0.5 to 30% by weight based on the total weight of the preparation;

[17] The preparation according to [10], wherein the content of the lubricant is 0.:! To 5% by weight relative to the total weight of the preparation;

[18] The preparation according to [1], wherein the dosage form is a tablet;

[19] According to the 15th revised Japanese Pharmacopoeia Dissolution Test Method 2 (Paddle Method), The preparation according to [1], wherein the dissolution rate after 15 minutes is 80% or more when a dissolution test is performed using 500 mL of 0.1 mol / L hydrochloric acid as a test solution;

[20] A method for stabilizing an oral solid preparation containing strong belgorin, characterized by comprising a hydrophobic substance;

[21] Stabilizing agent comprising a hydrophobic substance for oral solid preparations containing strong belgorin;

[22] A method for producing an oral solid preparation containing force begoline, characterized by dry mixing or dry granulation of a) strong bergolin, b) sugar and / or sugar alcohol, and c) a hydrophobic substance; and

[23] Oral containing cabergoline, characterized by dry mixing or dry granulation of a) strong belgorin and b) sugar and / or sugar alcohol granulated or coated with a hydrophobic substance A method for producing a solid preparation,

About.

[0010] The content of strong belgolin contained as an active ingredient in the oral solid preparation of the present invention is usually about 0.05 to about 10.0% by weight, preferably about 0, based on the total weight of the preparation. 15 to about 3.0% by weight, more preferably about 0.25 to about 2.0% by weight.

[0011] Examples of the sugar used in the oral solid preparation of the present invention include lactose, sucrose, trehalose, glucose and the like, and lactose is preferable. These sugars may be used in combination of two or more.

[0012] Examples of the sugar alcohol used in the oral solid preparation of the present invention include D-mannitol, sorbitol, maltitol, erythritol, and the like, and D-mannitol is preferable. These sugar alcohols may be used in combination of two or more.

[0013] In addition, sugar and sugar alcoholo can also be used in appropriate combination.

[0014] The content of the sugar or sugar alcohol used in the oral solid preparation of the present invention is usually about 10 to about 99% by weight, preferably about 20 to about 95% by weight, based on the total weight of the preparation. More preferably from about 30 to about 90% by weight, still more preferably from about 50 to about 90% by weight.

[0015] When the oral solid preparation of the present invention is used in combination with sugar and sugar alcohol In general, the sugar and sugar alcohol content is generally about 10 to about 99% by weight, preferably about 20 to about 95% by weight, more preferably about 30 to about 90% by weight, based on the total weight of the preparation. Still more preferably from about 50 to about 90% by weight. In the oral solid preparation of the present invention, when sugar and sugar alcohol are used in combination, the sugar and sugar alcohol content can be used in any ratio. Preferably, sugar: sugar alcohol Used in the range of about 200: about 1 to about 1: about 9.

[0016] Examples of the hydrophobic substance used as a stabilizer in the oral solid preparation of the present invention include gastric polymers, water-insoluble polymers, waxes and the like. Examples of such a gastric polymer include aminoalkyl methacrylate copolymer E (for example, Eudragit EPO, manufactured by Laem Co., Ltd .; Eudragit E100, manufactured by Laem Co., etc.), etc., methyl methacrylate-butyl methacrylate-dimethylamino methacrylate Examples thereof include ethyl copolymers; gastric soluble polyvinyl derivatives such as polyvinyl acetate diethylaminoacetate (for example, AEA, Sankyo). Examples of the water-insoluble polymer include water-insoluble cellulose ethers such as ethyl cellulose (for example, Ethel STD10FP, manufactured by Dow Chemical Co., Ltd.). Examples of waxes include higher alcohols that may have an unsaturated bond having 10 to 22 carbon atoms such as myristyl alcohol, cetyl alcohol, stearyl alcohol; hardened oils such as hardened castor oil and hardened rapeseed oil, and the like. . Among these hydrophobic substances, since the gastric polymer has the property of dissolving quickly in the stomach, it is suitable in terms of the stabilization effect and dissolution property of the preparation, and the aminoalkyl methacrylate copolymer E ( Eudragit EP0, manufactured by Laem Co.) is most suitable. These hydrophobic substances may be used in combination of two or more as required.

[0017] In general, it is known that when a hydrophobic substance is added to a solid preparation, disintegration and dispersibility of the preparation are reduced, and dissolution of the drug from the preparation is reduced. Therefore, it is necessary to add the hydrophobic substance within a range that does not affect the dissolution of strong belgorin from the preparation while at the same time achieving the stabilizing effect of the preparation. In the oral solid preparation of the present invention, the content of the hydrophobic substance used to exhibit such stabilization of the preparation and rapid dissolution is usually about 0. 1 to about 50% by weight, preferably about 0.5 to about 30% by weight, more preferably about 1 to about 20% by weight, even more preferred. Or about 1 to about 10% by weight.

[0018] When a disintegrant is used in the oral solid preparation of the present invention, examples of the disintegrant include partial alpha-monified starch (for example, PCS, manufactured by Asahi Kasei Co., Ltd .; STARCH 1500, Nippon Colorcon, etc.), corn starch, Low-substituted hydroxypropyl cellulose (for example, LH 11, LH21, manufactured by Shin-Etsu Chemical Co., Ltd.) and the like are used. Among these disintegrants, partially alphalated starch or corn starch is preferable, and partially alpha-ized starch (particularly PCS, manufactured by Asahi Kasei Co., Ltd.) is more preferable. These disintegrants may be used in combination of two or more as appropriate. The disintegrant content is usually about 0.5 to about 30% by weight, preferably about 1 to about 20% by weight, more preferably about 1 to about 15% by weight, based on the total weight of the preparation. .

[0019] When a lubricant is used in the oral solid preparation of the present invention, stearic sodium fumarate, magnesium stearate, calcium stearate, L-leucine and the like are used as the lubricant, and among them stearyl fumarate. Sodium is preferably used. The content of the lubricant is usually about 0.1 to about 5% by weight, preferably about 0.1 to about 4% by weight, more preferably about 0.1 to about 3%, based on the total weight of the preparation. % By weight.

[0020] Further, the oral solid preparation of the present invention may contain various additives used for the preparation of the preparation as long as the effects of the invention are not hindered. Examples of such additives include excipients, binders, lubricants, sweeteners, acidulants, foaming agents, fragrances, and coloring agents. Further, disintegrants and lubricants may be blended with those other than those described above as long as the effects of the invention are not hindered.

[0021] Examples of such excipients include potato starch, crystalline cellulose, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate, and calcium lactate. Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylenosulose, polyvinylinolepyrrolidone, methinoresenolellose, polyvinylinolenoconole, sodium anoleate, polyethylene glycol and the like. Examples of the disintegrant include crospovidone, carboxymethyl starch sodium, carmellose, carmellose strength, croscarmellose sodium, and the like. Examples of the lubricant include tar, light anhydrous carboxylic acid, sucrose fatty acid ester and the like. Examples of sweeteners include Examples include aspartame (registered trademark), saccharin sodium, dipotassium glycyrrhizin, stevia, thaumatin, and acesulfame K. Examples of the acidulant include citrate, tartaric acid, malic acid, ascorbic acid and the like. Examples of the foaming agent include sodium hydrogen carbonate, sodium carbonate, calcium carbonate, and the like. Examples of the corrigent include L-aspartic acid, sodium chloride salt, magnesium chloride, sodium citrate, calcium citrate, sodium L-glutamate, and sodium bicarbonate. Examples of the fragrances include orange oil, lemon oil, menthol, and various fragrance powders. Examples of the colorant include edible pigments such as edible yellow No. 5, edible red No. 2, and edible blue No. 2, yellow ferric oxide, ferric oxide, and caramel pigment.

[0022] Examples of the dosage form of the oral solid preparation in the present invention include various dosage forms such as powders, granules, tablets, capsules and the like, and are not particularly limited, but tablets are preferred.

[0023] Next, a method for producing the oral solid preparation of the present invention will be described.

[0024] The oral solid preparation of the present invention is prepared by a dry mixing method (direct powder compression method) or a dry granulation method by mixing a hydrophobic substance together with strong belgorin and sugar and / or sugar alcohol. .

[0025] For example, the powder is mixed with a) strong belgolin, b) sugar and / or sugar alcohol, and c) a water-phobic substance, followed by dry granulation, and further by a method such as grinding or sieving. It can be produced by adjusting the particle size within the range of.

[0026] The granule is prepared by following the same procedure as that for powders: a) strong belgorin, b) sugar and Z or sugar alcohol, and c) a hydrophobic substance, followed by dry granulation. It can be produced by adjusting the particle size within a range.

[0027] The tablet is formed by compressing the above powder or granule.

B) can be produced by direct compression molding of a mixture of sugar and Z or sugar alcohol, and c) a hydrophobic substance.

[0028] Capsule is filled with the above powder or granule in a capsule \ or directly filled into a capsule with a) a force benoregoline, b) sugar and / or sugar alcohol, and c) a hydrophobic substance Can be manufactured. [0029] As described above, in the oral solid preparation of the present invention, the storage stability of strong belgorin is improved by blending the hydrophobic substance together with strong belgorin and effectively bringing the strong begogoline into contact with the hydrophobic substance. To do. Therefore, it is desirable to use a hydrophobic substance with a large specific surface area, that is, a fine particle diameter, but increasing the amount of added calories of a hydrophobic substance with a fine particle diameter is Reduces fluidity, and further reduces the uniformity of drug content.

On the other hand, the strength berogolin contained as an active ingredient in the oral solid preparation of the present invention may contain a very low content of l.Omg or less in the unit dosage formulation. It is important to ensure sufficient content uniformity.

[0030] In order to solve the problems of storage stability and content uniformity at the same time, sugar and / or sugar alcohol that is granulated or coated with a hydrophobic substance is used. Is preferred. Even when such a production method is followed, it can be applied to various dosage forms such as powders, granules, tablets, and force capsules. Specifically, for example, tablets are preferably produced as follows.

[0031] Manufacturing method 1

A mixture containing sugar and / or sugar alcohol and a hydrophobic substance is granulated while adding a solvent. Subsequently, the granulated product is dried and sized, and a tablet can be produced by dry-mixing or dry-granulating a mixture of the obtained granulated product and strong belgorin and compression molding.

[0032] Manufacturing method 2

Granulate while adding a binding solution in which hydrophobic substances are dissolved in sugar and / or sugar alcohol. Subsequently, the granulated product is dried and sized, and a tablet can be produced by dry mixing or dry granulating the mixture of the obtained granulated product and strong belgorin and compression molding.

[0033] Manufacturing method 3

Cover the sugar and / or sugar alcohol with a binding solution in which a hydrophobic substance is dissolved. Subsequently, the coated granules are dried and sized, and a tablet can be produced by dry mixing or dry granulating the mixture of the obtained coated granules and strong belgorin and compressing the mixture. [0034] In the above production methods 1 to 3, a step of wet granulating sugar and / or sugar alcohol is incorporated, but in the manufacturing steps after the granulation step, strong belgorin is dissolved in a solvent. The process is not included. As described above, the method for producing an oral solid preparation of the present invention is characterized in that it does not include a step in which strong begogoline is dissolved in a solvent, and the strong begogoline and the solvent do not substantially contact each other.

[0035] Further, in the above production methods:! To 3, the hydrophobic substance is applied to the force contained in the granulated product composed of the hydrophobic substance and sugar and Z or sugar alcohol, or on the surface of sugar and / or sugar alcohol. Since it is coated, the fluidity of the mixed powder is not impaired by the addition of a hydrophobic substance, and the content uniformity of the preparation is good. Furthermore, since the strength belgolin and the solvent do not substantially contact, the storage stability is good. The hydrophobic substance may be further added in other steps as long as it does not hinder the fluidity of the mixed powder, in addition to being used in the granulation or coating step of sugar and / or sugar alcohol.

[0036] In the above production methods:! To 3, as long as there is no hindrance to the effect of the invention, a disintegrant, a lubricant, an excipient, a sweetener, a foaming agent, a sour agent, and a corrigent as necessary. In addition, additives such as fragrances may be appropriately blended.

[0037] In the above production methods 2 to 3, the hydrophobic substance can be produced even when suspended in the binding solution. The solvent may be water, a non-aqueous solvent (for example, ethanol, methanol, alcohol, etc.). Tolyl, acetone, etc.) or a mixture thereof.

[0038] In the above production method 3, since the surface of the sugar and / or sugar alcohol is coated with a hydrophobic substance, the sugar and Z or sugar alcohol to be used is preferably a grade having a large particle diameter and excellent fluidity. Les. Examples of such sugars and / or sugar alcohols include, for example, Tablets 80 (Magure), Tablets 70 (Magure), Flow Rack 100 (Magure), Daranulak 70 (Magure), and Sacherac. 80 (made by Megrenet), Prismaluck 40 (made by Megre), Diractouses R (made by Freund Sangyo), Diracutes S (made by Freund Sangyo), Pharmatos 50M (made by DMV), Pharmatos 80M (made by DMV) Lactose such as Pharmatose 90M (manufactured by DMV) and DCL11 (manufactured by DMV); Anhydrous lactose such as DCL21 (manufactured by DMV); Partech M200 (manufactured by Merck), Partech M300 (manufactured by Merck), -Mannitol such as Ritonore SD200 (manufactured by Rocket); trehalose such as trehalose G (manufactured by Asahi Kasei).

[0039] In the present invention, the coating includes not only the case where the entire surface or part of the sugar and / or sugar alcohol is coated, but also the case where the surface is adsorbed or absorbed on a part of the surface. As methods for granulating or coating sugar and / or sugar alcohol with a hydrophobic substance, known methods such as fluidized bed granulation / coating method, rolling granulation Z coating method, rolling fluidized bed granulation Z Examples thereof include a coating method, a high-speed stirring granulation method, and an extrusion granulation method, and a fluidized bed granulation / coating method and a rolling fluidized bed granulation / coating method are preferably used.

[0040] In the above production method:! To 3, the ratio of the sugar and / or sugar alcohol granulated or coated with the hydrophobic substance to the total weight of the sugar and / or sugar alcohol may be any ratio. From the viewpoint of storage stability and fluidity of the mixed powder, about 5 to: 100% by weight is preferable, more preferably about 20 to 100% by weight, and still more preferably about 50 to: 100% by weight. Is done.

[0041] The strength belgorin-containing oral solid preparation of the present invention thus produced has excellent storage stability and good content uniformity. Furthermore, since the oral solid preparation containing strong belgorin of the present invention exhibits rapid dissolution, it can be used to prevent Parkinson's disease, hyperprolactinemia, ovulation disorders, hyperprolactinemia pituitary gland, milk leakage, and suppression of postpartum milk secretion. It is extremely useful as a remedy for diseases.

[0042] The dose of strength belgorin contained in the oral solid preparation of the present invention is about 0.

The amount of strength belgolin contained in a unit dosage form is preferably from about 0.25 mg to about l.Omg, more preferably from about 0.25 mg, about 0.50 mg and about l.Omg. Is

[0043] The packaging form of the rugbergoline-containing oral solid preparation of the present invention is preferably a PTP packaging, a strip packaging, a bottle packaging, or the like when the strength dosage form is a tablet depending on the type of dosage form. There is PTP packaging. In addition, after applying such PTP packaging, strip packaging, etc. to the oral solid preparation containing strong begogoline of the present invention, a pillow packaging may be further applied. If necessary, a desiccant, oxygen scavenger, etc. may be enclosed in the pillow package. [0044] In addition, a light-shielding packaging may be applied to the packaging of the strong belgolin-containing oral solid preparation of the present invention. As such light-shielding packaging, generally used light-shielding packaging can be used without limitation. Specifically, bags made of light-shielding materials such as plastic and aluminum, shrink wrapping or PTP wrapping using light-shielding plastic, and bottle wrapping made of light-shielding plastic glass can be used.

[0045] It is preferable that the oral solid preparation containing rovergoline of the present invention is immediate release. Specifically, in accordance with the 15th revised Japanese Pharmacopoeia Dissolution Test Method 2 (Paddle Method), a dissolution test was conducted using a rotation speed of 50 rpm and a test solution of 0.1 mL / L hydrochloric acid. Sometimes, the dissolution rate of strong belgolin after 15 minutes is preferably 80% or more, more preferably 85% or more, and still more preferably 90% or more.

The invention's effect

[0046] The strength belgorin-containing oral solid preparation of the present invention has excellent storage stability and good content uniformity, so that a product of constant quality can always be provided. Furthermore, since the oral solid preparation of the present invention can be prepared without using a complicated manufacturing method or special manufacturing equipment, it is suitable for industrial production.

BEST MODE FOR CARRYING OUT THE INVENTION

[0047] The contents of the present invention will be described in further detail with reference to the following examples, comparative examples and test examples. The contents of the present invention are not limited to these.

Example

[0048] Example 1

Strength benoregolin 0.25 mg

D_mannitol 0.73mg

Lactose 86. OOmg

Amino ano quinole methacrylate copolymer E 6. OOmg

Partially alpha-ized starch 5. OOmg

Fumanoleic acid linolenateric 2.02mg

(Total 100.00mg / l tablet) After mixing 1.5 g of strength belgolin, D-mannitol (Mannit P, manufactured by Towa Kasei Kogyo Co., Ltd.) 4. 38 g and sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) 0.12 g in a mortar, jet mill The pulverized product (a-1) was prepared by pulverization using a pulverizer (A-O JET MILL, manufactured by Seishin Enterprise Co., Ltd.).

3 minutes by adding 0.0g of lactose (tablet 80s, manufactured by Megre) and 0.6g of aminoalkyl methacrylate copolymer E (eudragit EPO, manufactured by Laem) to 0. lg of this strong belgorin (al) Mix, and then add 4.6 g of lactose and 0.5 g of partially alpha-monoized starch (PCS, manufactured by Asahi Kasei), mix for 3 minutes, and then add 0.2 g of sodium stearyl fumarate and mix for 30 seconds. . Using this tableting mixture, using a single tableting machine (N-30E, manufactured by Seida Okada), tablets were weighed under the conditions of tablet weight 100 mg, (i) 6 mm 8R round, tableting pressure 23.9 kN / cm ^2. Prepared.

Example 2

Strong belgolin 0.25 mg

D-mannitol 0. 73mg

86.OOmg

Ethi / Resenorelose 6. OOmg

Partially alpha-ized starch 5. OOmg

Sodium stearyl fumarate2.02mg

(Total 100. OOmgZl tablet) Powered belgorin pulverized product of Example 1 (a_l) 0. lg, Lactose (Tabletose 80, made from Megrenet) 4.0 g and Ethylcellulose (Ethosel STD10FP, manufactured by Dow Chemical Co.) 0 6g mixed for 3 minutes, followed by lactose 4.6g and partially alpha-monoized starch (PCS, Asahi Kasei Co., Ltd.) 0.5g, mixed for 3 minutes and then mixed with sodium stearyl fumarate (PRUV, JRS 0.2 g was added and mixed for 30 seconds. Using this tableting mixture, tablets were prepared under the conditions of tablet weight 100mg, ci) 6mm8R, tableting pressure 23.9k N / cm ² using a single tableting machine (N-30E, manufactured by Seika Okada). .

Example 3 Strong belgolin 0.25 mg

D_mannitol 0.73mg

Lactose 86. OOmg

Hardened oil (hardened castor oil) 6. OOmg

Partially alpha-ized starch 5. OOmg

Sodium stearyl fumarate2.02mg

(Total 100. OOmgZl tablets) Strong belgolin powder of Example 1 (al) O. lg, Lactose (Tabletose 80, made from Megrenet) 4.0 g and hardened castor oil (Lovely wax—101, Freund Sangyo) Mix 6g for 3 minutes, then add 4.6g of lactose and partially alpha-monoized starch (PCS, Asahi Kasei) 0.5g and mix for 3 minutes, then add sodium stearyl fumarate (PRUV, JRS Pharma 0.2 g was added and mixed for 30 seconds. Using this tableting mixture, tablets are prepared under the conditions of tablet weight 100mg, <i> 6mm8R round, tableting pressure 23.9kN / cm ² using a single tableting machine (N-30E, manufactured by Seiki Okada). did.

Example 4

0. 25mg

D_mannitol 0.73mg

Lactose 86. OOmg

Hardened oil (hardened rapeseed oil) 6. OOmg

Partially alpha-ized starch 5. OOmg

Sodium stearyl fumarate2.02mg

(Total 100. OOmgZl tablet) Powered belgorin pulverized product of Example 1 (a_l) 0. lg, lactose (Tabletose 80, made from Megrenet) 4.0 g and hydrogenated rapeseed oil (Lovely wax—103, manufactured by Freund Sangyo) Mix 6g for 3 minutes, then add 4.6g of lactose and partially alpha-monoized starch (PCS, Asahi Kasei) 0.5g and mix for 3 minutes, then add sodium stearyl fumarate (PRUV, JRS Pharma) 0.2 g was added and mixed for 30 seconds. Using this tableting mixture, tablets were prepared under the conditions of tablet weight 100mg, ci) 6mm8R, tableting pressure 23.9kN / cm ² using a single tableting machine (N-30E, manufactured by Seika Okada). .

Example 5

Strength benoregolin 0.25 mg

D_mannitol 0.73mg

Lactose 90. OOmg

Polybulassal Jetylaminoacetate 2 · OOmg

Partially alpha-ized starch 5. OOmg

(Total 100 · OOmg / 1 tablet) Polyvinylacetal Jetylaminoacetate (AEA, Sankyo) 12g was dissolved in 99.5% ethanol to prepare 120mL solution. 5 mL of this solution was granulated by stirring while gradually adding to 18.5 g of lactose (Tablet 80, made of Megrenet). This granulated product was dried at 60 ° C. for 1 hour with a shelf dryer (DN64, manufactured by Yamato Kagaku Co., Ltd.), and then sieved with a No. 30 sieve to obtain an AEA granulated product (b-1).

This AEA granulated product (bl) 4.Og and the strong belgolin ground product of Example 1 (al) O.lg were mixed for 3 minutes, followed by 3.6g of AEA granulated product (b-1), lactose (Tablet 80, made from Megrenet) 1. 6g and partially alpha-monoized starch (PCS, manufactured by Asahi Kasei) 0.5g was added and mixed for 3 minutes, then sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) 0 2g was added and mixed for 30 seconds. Using this tableting mixture, a tablet was prepared using a single tableting machine (N_30E, manufactured by Seida Okada) under the conditions of tablet weight 100 mg, ci) 6 mm8R round, tableting pressure 23.9 kN / cm ² . .

Example 6

Strength benoregolin 0.25 mg

D_mannitol 0.73mg

Lactose 91. OOmg Stearyl Alcohol 1. OOmg Partial Alpha Monoized Starch 5. OOmg

Fumanoleic acid linolenate tricum 2. 02mg

(Total 100. OOmgZl tablet) 6 g of stearyl alcohol (manufactured by Kao Corporation) was dissolved in 99.5% ethanol to prepare a 120 mL solution. 5 mL of this solution was stirred and granulated while gradually added to 18.75 g of lactose (Tabletose 80, made from Megrenet). This granulated product was dried at 60 ° C. for 1 hour with a shelf dryer (DN64, manufactured by Yamato Scientific Co., Ltd.), and then sieved with a No. 30 sieve to obtain a stearyl alcohol granulated product (c-1).

This stearyl alcohol granulation (cl) 4. Og and the strong belgorin pulverized product of Example 1 (al) 0 lg were mixed for 3 minutes, followed by stearyl alcohol granulation (cl) 3.6 g, lactose ( (Tablet 80, manufactured by Megre Co., Ltd.) 1. 6g and partially alpha starch starch (PCS, manufactured by Asahi Kasei) 0.5g was added and mixed for 3 minutes, then sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) 0.2 g was added and mixed for 30 seconds. Using this tableting mixture, use a single tableting machine (N-30E, manufactured by Seida Okada) to prepare tablets under the conditions of tablet weight 100mg, () 6mm8R round, tableting pressure 23.9kN / cm ² did.

Example 7

Force benoregolin 1. Omg

D_mannitol 3. Omg

Aminoalkyl methacrylate copolymer E 1.2 mg

Lactose 90. 5mg

Partially alpha-ized starch 3. Omg

Stemarinol sodium fumanoleate 1.3 mg

(Total 100. OmgZl Tablets) Force belgorin 3.5 g and D-mannitol (Mannit P, manufactured by Towa Kasei Kogyo Co., Ltd.) 10. 5 g were mixed in a mortar, and then mixed with a jet mill grinder (A—〇 JET MILL, Seishin) (Made by company) Was used to grind force belgolin pulverized product (a_2).

This force belgolin ground product (a-2) 2.4g, lactose (Tablet 80, made by Megre) 14.88g and aminoalkyl methacrylate copolymer E (Eudragit EPO, Lame) 0.72g mixed for 3 minutes After that, 0.18 g of sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) was added and mixed for 30 seconds. Using this mixture, a single tableting machine (N-30E, manufactured by Okada Seie Co., Ltd.) was used to produce tablets under the conditions of tablet weight 300 mg, 10 φ flat, tableting pressure 25.5 kN / cm ^2. Tablets were crushed in a mortar and further sized with a No. 30 sieve to give a dry granulated product. This granulated product (3.03 g), lactose (6.57 g) and partially alpha-monoized starch (PCS, manufactured by Asahi Kasei Co., Ltd.) (0.3 g) were mixed for 3 minutes, then 0.1 g of sodium stearyl fumarate was added, and 30 seconds Mixed. The tableting mixture, single punch tableting machine (N-30E, Okada made Seiesha) to have use a tablet weight 100mg, <i> 6mm8R circular tablets under conditions of compression pressure 23. 9 kN / cm ² Prepared.

Example 8

Strength belgolin 1. Omg

D-mannitol 3. Omg

Aminoalkyl methacrylate copolymer E 1.2 mg

Lactose 87.8mg

Partially alpha-ized starch 5. Omg

Fumanoleic acid linolenatericum 2. Omg

(Total 100. OmgZl tablet) Powered belgorin pulverized product of Example 7 (a_2) 0.4 g, lactose (Tabletose 80, made from Megrenet) 2.4 8 g and aminoalkyl methacrylate copolymer E (Eudragit EPO, manufactured by Laem) 0. 12 g is mixed for 3 minutes, followed by 6.3 g of lactose and partially alpha-monoized starch (PCS, manufactured by Asahi Kasei), 0.5 g is added and mixed for 3 minutes, and then sodium stearyl fumarate (PRUV, JR Earthen) 0.2g was added and mixed for 30 seconds. Using this tableting mixture, using a single tableting machine (N_30E, manufactured by Seida Okada), tablets were weighed under the conditions of tablet weight 100mg, (i> 6mm8R, tableting pressure 23.9kN / cm ^2). Prepared. Example 9

Force benoregolin 1. Omg

D_mannitol 3. Omg

Aminoalkyl methacrylate copolymer E 1.2 mg

Lactose 87.8mg

Partially alpha-ized starch 5. Omg

Fumanoleic acid linolenatericum 2. Omg

(Total 100 · Omg / 1 tablet) 99.5 of aminoalkyl methacrylate copolymer E (Eudragit EPO, manufactured by Laem Co.). 6 mL of ethanol solution (0 · 08 g / mL) was stirred and granulated while gradually added to 21 · 92 g of lactose (Tablet 80, manufactured by Megre). This granulated product was dried at 60 ° C for 1 hour in a shelf dryer (DN64, manufactured by Yamato Kagaku Co., Ltd.), and then sieved with No. 30 sieve to prepare an aminoalkyl methacrylate copolymer E granulated product (d- 1).

Add 0.2 g of the strong belgorin product (a-2) of Example 7 to 2.8 g of this aminoalkyl methacrylate copolymer E granulated product (dl) and mix for 3 minutes, followed by lactose (Tablet 80, Meg 1. 65g and partially alpha-monoized starch (PCS, Asahi Kasei) 0.25g was added and mixed for 3 minutes, then sodium stearyl fumarate (PRUV, JRS Pharma) 0. lg was added. And mixed for 30 seconds. Using this tableting mixture, tablets were prepared under the conditions of tablet weight 100mg, ci) 6mm8R, tableting pressure 23.9kN / cm ² using a single tableting machine (N-30E, manufactured by Seika Okada). .

Example 10

Force benoregolin 1. Omg

D_mannitol 3. Omg

Aminoalkyl methacrylate copolymer E 4. 8mg

Lactose 84. 2mg

Partially alpha-ized starch 5. Omg (Total 100. OmgZl tablets) 10 mL of 99.5 o / o ethanol solution (0.32 g / mL) of aminoalkyl methacrylate copolymer E (Eudragit EPO, manufactured by Laem) and lactose (Tablet 80, manufactured by Megre) 34. The mixture was stirred and granulated while gradually adding to 14 g. This granulated product was dried at 60 ° C for 1 hour in a shelf dryer (DN64, manufactured by Yamato Scientific Co., Ltd.), and then passed through a No. 30 sieve to obtain an aminoalkyl metatalate copolymer E granulated product (e -1).

Add 0.2 g of the strong belgorin product (a-2) of Example 7 to 2.8 g of this aminoalkyl methacrylate copolymer E granulated product (e_l) and mix for 3 minutes, followed by lactose (Tablet 80, Meg 1. 65g and partially alpha-monoized starch (PCS, Asahi Kasei) 0.25g was added and mixed for 3 minutes, then sodium stearyl fumarate (PRUV, JRS Pharma) 0. lg was added. And mixed for 30 seconds. Using this tableting mixture, tablets are prepared under the conditions of tablet weight 100mg, <i> 6mm8R round, tableting pressure 23.9kN / cm ² using a single tableting machine (N-30E, manufactured by Seiki Okada). did.

Example 11

Strong belgolin 0.25 mg

D-mannitol 2. 73mg

Amino ano quinole methacrylate copolymer E 3. 60mg

Lactose 61. 80mg

Corn starch 6. OOmg

Partially alpha-ized starch 4. OOmg

Fumanoleic acid linolenate tricum 1.62mg

(Total 80. OOmgZl tablets) Lactose (Tablet 80, manufactured by Megre) 1478. 4g was charged into a fluidized bed granulator (LAB-1, Baurek), and 10% strength aminoalkyl methacrylate copolymer E After spraying 336 g of 99.5% ethanol solution (Oi Dragit EPO, manufactured by Laem Co.) with a spray nose and spraying, it was sieved with No. 18 sieve, and the coated granules (f-1) were Prepared It was.

Separately, 10 g of strength beregorin, 29.2 g of D-mannitol (Mannit P, manufactured by Towa Kasei Kogyo) and 0.8 g of sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) were mixed in a mortar, By using a mill grinder (A-O JET MILL, manufactured by Seishin Enterprise Co., Ltd.), a strong belgorin pulverized product (a-3) was prepared.

This Vegolin ground product (a-3) 9g, coated granules (f_l) 270g, corn denpun (Nippon Shokuhin Kako Co., Ltd.) 21.6g and aminoalkyl methacrylate copolymer E 21.6g -1, made by Dalton) and mixed for 30 minutes, 216 g of coated condyles (fl), 81 g of lactose, 32.4 g of corn starch and 18 g of D-mannitol were further added and mixed for 30 minutes. Subsequently, 36 g of partially alpha-monoized starch (PCS, manufactured by Asahi Kasei) was added and mixed for 10 minutes, and then 14.4 g of sodium stearyl fumarate was added and mixed for 2 minutes. Using a rotary tableting machine (Correct 12 HUK, manufactured by Kikusui Seisakusho), the tableting mixture was mixed with a tablet weight of 80mg, φ6mm flat circular shape, table rotation speed 30i "pm, tableting pressure 13.9kN / cm ² Tablets were prepared under the following conditions.

Example 12

Strong belgolin 0.25 mg

D-mannitol 2. 73mg

Amino ano quinole methacrylate copolymer E 3. 60mg

Lactose 61. 80mg

Corn starch 6. OOmg

Partially alpha-ized starch 4. OOmg

Fumanoleic acid linolenate tricum 1.62mg

(Total 80. OOmgZl tablets) Strength belgolin 2.5g, D-mannitol (Mannit P, manufactured by Towa Kasei Kogyo Co., Ltd.) 7.3g and sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) 0.2g After mixing in a mortar, the mixture was pulverized using a jet mill pulverizer (A-JET MILL, manufactured by Seishin Enterprise Co., Ltd.) to prepare a force bergoline pulverized product (a-4). 6g of this strong belgolin product (a-4), lactose (Tablet 80, manufactured by Megre) 180g, corn starch (manufactured by Nippon Shokuhin Kako Co., Ltd.) 14.4g and aminoalkyl methacrylate copolymer E (Eudragit EP〇, Laem 21. 6 g was put into a V-type mixer (DV_1, Dalton), mixed for 30 minutes, and then added with 18.8 g of lactose, 21.6 g of corn starch and 12 g of D-mannitol for 30 minutes. Mixed. Subsequently, 24 g of partially pregelatinized starch (PCS, manufactured by Asahi Kasei Corporation) was added and mixed for 10 minutes, and then 9.6 g of stearyl sodium fumarate was added and mixed for 2 minutes. Using this rotary tableting machine, using a rotary tableting machine (Correct 12HUK, manufactured by Kikusui Seisakusho), tablet weight 80 mg, φ 6 mm flat round, table rotation speed 30 rpm, tableting pressure 13.9 kN / cm ² Tablets were prepared Example 13

Power belgolin 1. OOmg

D-mannitol 2. 92mg

Aminoalkyl methacrylate copolymer E 3. 60mg

Lactose 60. 80mg

Corn starch 6. OOmg

Partially alpha-ized starch 4. OOmg

Fumanoleic acid linolenate tricum 1.68mg

(Total 80. OOmgZl tablet) 24 g of force belgolin pulverized product of Example 11 (a_3), 24 g of coated granule of Example 11 (f_l), 180 _g of corn starch (manufactured by Nippon Shokuhin Kako), 14.4 g and aminoalkyl methacrylate 1 g copolymer E 14.4g was put into a V-type mixer (DV-1, Dalton), mixed for 30 minutes, and then 144g coated granules (f_l), 48g lactose and 21.6g corn starch were added, Mix for 30 minutes. Subsequently, 24 g of partially alpha-monified starch (PCS, manufactured by Asahi Kasei) was added and mixed for 10 minutes, and then 9.6 g of sodium stearyl fumarate was added and mixed for 2 minutes. Using this tableting mixture, rotary tableting machine (Correct 12H UK, manufactured by Kikusui Seisakusho), tablet weight 80mg, φ6mm flat round, table rotation Number 30 rpm, to prepare a tablet under conditions of compression force 13. 9kNZcm ^2.

Comparative Example 1

Strength benoregolin 0.25 mg

D_mannitol 0.73mg

Lactose 92. OOmg

Partially alpha-ized starch 5. OOmg

Fumanoleic acid linolenateric 2.02mg

(Total 100 · OOmg / 1 tablet) Strong belgolin powder of Example 1 (al) O.lg and lactose (Tabletose 80, made from Megrenet) 4. Og mixed for 3 minutes, followed by lactose 5.2g and portions Alpha-ized starch (PCS, manufactured by Asahi Kasei Co., Ltd.) 0.5 g was added and mixed for 3 minutes, and then 0.2 g of sodium stearyl fumarate was added and mixed for 30 seconds. Using this tableting mixture, a tableting machine (N-30E, manufactured by Seida Okada) was used to produce tablets under the conditions of tablet weight 100mg, 6φ8R round, tableting pressure 23.9kN / cm ^2. Prepared.

Comparative Example 2

Strength belgolin 1. Omg

Aminoalkyl methacrylate copolymer E 1.2 mg

Lactose 93.8 mg

Partially alpha-ized starch 3. Omg

Fumanoleic acid linolenate tricum 1. Omg

(Total 100. OmgZl tablet) 0.67 g of strength belgorin and aminoalkyl methacrylate copolymer E (Eudragit EP0, manufactured by Laem) 0.85 g of 99.5% ethanol was added to prepare a 5 mL solution. 4.5 mL of this solution was granulated by stirring while gradually adding to 16.68 g of lactose (Tablet 80, manufactured by Megre). This granulated product was dried at 60 ° C for 1 hour in a shelf dryer (DN64, manufactured by Yamato Kagaku Co., Ltd.), and then sieved with No. 30 sieve to give an aminoalkyl methacrylate copolymer E granulated product (g- 1).

To 3 g of this granulated product (g_l), 6.6 g of lactose and 0.3 g of partially pregelatinized starch (PCS, manufactured by Asahi Kasei) were added and mixed for 3 minutes, and then sodium stearyl fumarate (manufactured by PRUV JRS Pharma) 0 Add lg and mix for 30 seconds. Tablets were prepared from this tableting mixture under the conditions of a tablet weight of 100 mg 6φ8R and a tableting pressure of 23.9 kNZcm ² using a single tableting machine (N_30E, manufactured by Seika Okada).

Comparative Example 3

Strength belgolin 1. Omg

D-mannitol 3. Omg

Aminoalkyl methacrylate copolymer E 1.2 mg

Lactose 90. 8mg

O. Omg

(Total 100 · Omg / 1 tablet) Strong belgolin powdered rice cake of Example 7 (a-2) 2. 4g and lactose (Tablet 80, made of Megrenet) 14. 88g were mixed in a mortar and aminoalkyl methacrylate copolymer E ( A 99.5% ethanol solution (0.16 g / mL) of Eudragit EP O, manufactured by Laem Co., Ltd. was granulated by stirring while gradually adding 4.5 mL. The granulated product was dried at 60 ° C. for 1 hour using a shelf dryer (DN64, manufactured by Yamato Kagaku Co., Ltd.) and then passed through a No. 30 sieve to obtain an aminoalkyl methacrylate copolymer E granulated product (h_l).

After adding 6.6 g of lactose and 0.3 g of partially pregelatinized starch (PCS, manufactured by Asahi Kasei Co., Ltd.) to 3 g of this granulated product (hl) and mixing for 3 minutes, sodium stearyl fumarate (manufactured by PRUV JRS Pharma) 0 Add lg and mix for 30 seconds. Tablets were prepared from this tableting mixture under the conditions of a tablet weight of 100 mg 6φ8R and a tableting pressure of 23.9 kNZcm ² using a single tableting machine (N_30E, manufactured by Seika Okada).

Test example 1

Stability test 1) Storage stability test

Examples:! ~ 5 and 7 ~: 13 and comparative examples:! ~ 3 tablets stored at a temperature of 40 ° C and a relative humidity of 75% after 3 and 7 days Was measured according to the following method.

[0065] When the content of force belgolin is 0.25 mg, take 2 tablets, add 0.1. OlmolZL hydrochloric acid test solution, shake to disintegrate the tablet, make 5 mL, and filter to make it insoluble. The thing was removed. Also, if the content of strong belgolin is 1. Omg, take 2 tablets, add 0. OlmolZL hydrochloric acid test solution, shake to disintegrate the tablet, make 20 mL, and filter to insoluble matter. Was removed. The obtained filtrate was used as each sample solution, and the test was performed by liquid chromatography. Except for the solvent peak of the sample solution and the peak derived from the excipient, the peak areas of strong belgorin and related substances were measured by the automatic integration method, and the total amount (%) of the related substances was determined by the area percentage method. The results are shown in Table 1.

[0066] 2) Appearance test

The appearance of the tablets in the storage stability test was visually observed. The results are shown in Table 1.

[0067] [Table 1]

Related substances (%) Appearance 3 days after start 7 days after start 3 days after 7 days after start Example 1 ND 0.71 1.56 White White White Example 2 ND 0.38 0.51 White White White Example 3 ND 1.02 1.55 White White White Example 4 ND 0.98 1.51 White White White Example 5 ND 0.77 1.14 White White White Example 7 ND 0.44 0.96 White White White Example 8 ND 0.43 0.91 White White White Example 9 ND 0.40 0.92 White White White Example 10 ND 0.38 0.85 White White White Example Example 11 ND 0.58 1.22 White White White Example 12 0.18 0.81 1.73 White White White Example 13 ND 0.35 0.64 White White White Comparative Example 1 ND 1.43 3.79 White White White Comparative Example 2 ND 0.62 1.63 White Slight Yellow Slight Yellow Comparative Example 3 ND 0.57 1.65 White Slight yellow Slight yellow

N.D .: not detected

[0068] As a result of these tests, it was shown that the production amount of the related substance was suppressed in the preparation supplemented with the hydrophobic substance, compared with the preparation without addition (Comparative Example 1). It was. In addition, even in preparations with hydrophobic substances added, changes in appearance were observed in the production method (Comparative Examples 2 and 3) in which strong belgorin was in contact with or dissolved in a non-aqueous organic solvent. On the other hand, no change in appearance was observed when the solvent was not used at all, or when the production method was such that strong belgolin and the solvent were not in direct contact.

[0069] Test Example 2

Content uniformity test

The content uniformity of the tablets produced in Examples 11 and 12 was measured according to the following method.

[0070] Ten tablets were taken, each containing 0. Olmol / L hydrochloric acid test solution, shaken to disintegrate the tablets, and then filtered to remove insolubles. Using the obtained filtrate as a sample solution, the amount of drug contained was quantified by the liquid chromatographic method, and the average content (%), standard deviation (%) and coefficient of variation (CV value,%) of the drug amount were determined. The results are shown in Table 2. [0071] [Table 2]

[0072] As a result of these tests, a preparation (Example 11) containing condyles in which sugar and / or sugar alcohol is coated with a hydrophobic substance is combined with a preparation (Example 12) in which the entire amount of the hydrophobic substance is dry-mixed. In comparison, it was shown that better content uniformity can be obtained.

[0073] Test Example 3

Dissolution test

The tablets prepared in Examples 11 and 13 were prepared according to the 15th revised Japanese Pharmacopoeia · Dissolution Test Method 2 (Paddle Method), paddle rotation speed 50 rpm, and O. lmol / L hydrochloric acid 500 mL as the test solution. The dissolution test was conducted. The eluate 15 minutes after the start was filtered to obtain a sample solution, and the amount of drug contained was quantified by liquid chromatography to determine the elution rate (%). The results are shown in Table 3.

[0074] [Table 3]

[0075] As a result of these tests, it was shown that the oral solid preparation of the present invention has a dissolution rate of 80% or more after 15 minutes and has a rapid dissolution property.

Industrial applicability

[0076] The oral solid preparation of the present invention has excellent storage stability and good content uniformity.

Furthermore, since the oral solid preparation containing strong belgorin of the present invention exhibits rapid dissolution, Parkinson's disease, hyperprolactinemia of ovulation, hyperprolactinemia of pituitary gland, milk leakage, suppression of postpartum milk secretion, etc. It is useful as a therapeutic drug.

Claims

The scope of the claims

[I] An oral solid preparation comprising a) strength belgolin as an active ingredient, b) sugar and / or sugar alcohol, and c) a hydrophobic substance as a stabilizer.

[2] The preparation according to claim 1, wherein the hydrophobic substance is at least one selected from gastric polymers, water-insoluble polymers or waxes.

[3] The preparation according to claim 2, wherein the gastric soluble polymer is at least one selected from aminoalkyl methacrylate copolymer E or polyvinylacetylethylaminoacetate.

[4] The preparation according to claim 2, wherein the water-insoluble polymer is ethyl cellulose.

[5] The formulation according to claim 2, which is at least one selected from a higher alcohol or hydrogenated oil.

[6] The preparation according to claim 1, wherein the hydrophobic substance is at least one selected from aminoalkyl methacrylate copolymer E or polybulucetal jetylaminoacetate.

[7] Sugar power The preparation according to claim 1, which is at least one selected from lactose, sucrose, trehalose or glucose.

[8] Sugar alcohol power D-mannitol, sonorebitol, maltitol or erythritol power The preparation according to claim 1, which is at least one selected.

[9] The preparation according to claim 1, further comprising at least one selected from partially alpha-monified starch, corn starch or low-substituted hydroxypropylcellulose as a disintegrant.

[10] The preparation according to claim 1, further comprising at least one selected from the group consisting of sodium stearyl fumarate, magnesium stearate, calcium stearate or L-sip Icin as a lubricant.

[I I] The preparation according to claim 1, characterized in that it is prepared without using a solvent or without substantially contacting the solvent with strong belgorin.

[12] The preparation according to claim 1, comprising (1) a granulated product composed of sugar and / or sugar alcohol and a hydrophobic substance, and (2) cabergoline.

[13] sugar and / or sugar alcohol relative to the total weight of sugar and / or sugar alcohol 13. The preparation according to claim 12, wherein the ratio of the sugar and / or sugar alcohol contained in the granulated product composed of and a hydrophobic substance is from 5 to 100% by weight.

[14] The preparation according to claim 1, wherein the content of sugar and Z or sugar alcohol is 10 to 99% by weight based on the total weight of the preparation.

[15] The preparation according to claim 1, wherein the content of the hydrophobic substance is 0.:! To 50% by weight based on the total weight of the preparation.

[16] The preparation according to claim 9, wherein the content of the disintegrant is 0.5 to 30% by weight based on the total weight of the preparation.

[17] The preparation according to claim 10, wherein the content of the lubricant is 0.:! To 5% by weight based on the total weight of the preparation.

[18] The preparation according to claim 1, wherein the dosage form is a tablet.

[19] According to the 15th revised Japanese Pharmacopoeia Dissolution Test Method 2 (Paddle Method), 15 minutes later when the dissolution test was performed using a rotation speed of 50 rpm and 0.1 mol / L hydrochloric acid 500 mL as the test solution. 2. The preparation according to claim 1, wherein the dissolution rate is ¾0% or more.

[20] A method for stabilizing an oral solid preparation containing strong bergolin, which comprises adding a hydrophobic substance.

[21] A stabilizer composed of a hydrophobic substance, for use in an oral solid preparation containing forcevergoline.

[22] A method for producing an oral solid formulation containing strong belgorin, characterized by dry mixing or dry granulation of a) strong bergolin, b) sugar and Z or sugar alcohol, and c) a hydrophobic substance .

[23] containing strength belgolin, characterized by dry mixing or dry granulation of a) strength belgolin, b) sugar granulated or coated with a hydrophobic substance and Z or sugar alcohol. A method for producing an oral solid preparation.