TW200423972A - Tablet having improved solubility - Google Patents

Abstract

The present invention provides a tablet which comprises fused imidazopyridine derivatives and partial α-starch.

Description

200423972 (ii) Description of the invention: [Technical field to which the invention belongs] The present invention relates to a lozenge for improving dissolution. In particular, it relates to a lozenge containing an imidazopyridine derivative and a part of an alpha starch. [Prior art] Formula (I) is used in the present invention:

(In the formula, R is a aryl group which may be substituted or an aromatic heterocyclic ring which may be substituted, and the ring A may contain one or more of 0, s, SO, S02, and / or NRV. In the formula, R1 is Hydrogen, alkyl, esterified carboxyl, carbamoyl, or fluorenyl), and may have an alicyclic group of 5-9 members of a substituent, or a pharmaceutically acceptable salt or solvent thereof Chemical compounds (hereinafter all referred to as compound (I)), which are compounds described in Patent Document 1, are known to be useful as antipsychotics, anti-restoring drugs, narcotic antagonists, and brain function activating drugs. The pharmaceutical preparation of the compound is disclosed in Patent Document 2 as a hard gelatin capsule. 'This capsule is added with aminoacetic acid to prevent the gelatin of the capsule from being denatured and improve its dissolution. It does not suggest that the present invention is to partially starch. Dissolution improvement effect. Partially α-starch is generally used as a disintegrant, binder or excipient in pharmaceutical additives. Non-Patent Documents 1 to 3 are trials of Lixinping (n} fed} pine), paracetamol 200423972 (P aracetam ο 1), sulfamethoxazole (su 1 fameth 〇xa ζ ο 1 e), ibuprofen, Ciprofloxacin, diltiazem, metronidazole, and other medicinal compounds, such as the preparation of alpha starch. However, 'Non-Patent Document 2 is a lozenge that uses ciprofloxacin or ibuprofen as an active ingredient', and it has not been revealed that better disintegration and dissolution properties are obtained due to the addition of a part of α-starch. Addition of a portion of the α-starch lozenge does not necessarily show the dissolution improving effect of the pharmaceutically active ingredient.

Particularly, in the case of a tablet in which a fused imidazopyridine derivative is an active ingredient, it is unknown until now that an excellent dissolution improvement effect is exhibited due to the addition of partially α-starch. Patent Document 1: Japanese Patent Application Laid-Open No. 5-2 8 6 9 7 3 Patent Document 2: Japanese Patent Application Laid-Open No. 2000-26282 Non-Patent Literature 1: Indian Drugs, 2000, Vol. 37, No. 8, 371-374 page

Non-Patent Literature 2: International Journal of Pharmaceutical Excipients, 1999, Vol. ^, No. 3, 9 3-9 pages 5 Non-Patent Literature 3: Indian Drugs, i 9 9 '9, Vol. 3, No. 9, pages 598-600 [Summary of the invention] In order to show the medicinal effect of a solid preparation containing a fused mivacerodine derivative, the active ingredient is dissolved in the digestive organs and absorbed. It is necessary, therefore, especially fast-release lozenges are important for the rapid dissolution of active ingredients in the digestive organs, and 200423972 requires those with high dissolution. Best Mode for Carrying Out the Invention The present invention is (1) a sharpening agent characterized by containing formula (I)

R

(In the formula, R is a substituted aryl group or a substituted aromatic heterocyclic ring, and the ring A is 0, 3, 30, 3202, and / or 1 which may contain more than one (wherein, R1 is hydrogen, an alkyl group, an esterified carboxyl group, a carbamoyl group, or a fluorenyl group), and may have an alicyclic group having 5 to 9 members of one or more alkyl groups) or a pharmaceutical compound thereof Allowable salt or solvate thereof, and partially alpha starch; (2) A lozenge characterized by containing the compound represented by formula (1) described in the above (1) or a pharmaceutically acceptable salt thereof or a solvate thereof, Partially alpha starch, lactose and hydroxypropyl cellulose; (3) The lozenge according to the above (2), characterized in that it contains 3 to 80% by weight of the formula according to the above (1) with respect to the entire amount of the lozenge ( 1) The compound shown or a pharmaceutically acceptable salt or solvate thereof, 1 to 30% by weight of partially alpha starch, 20 to 95% by weight of lactose, and 0.1 to 5% by weight of hydroxypropyl cellulose (4) The lozenge according to the above (2), characterized in that it contains 5 to 40% by weight of the compound represented by the formula (1) according to the above (1) with respect to the entire amount of the lozenge or a pharmaceutical preparation thereof Allowable salt or solvate thereof, 3 to 20% by weight of partially alpha starch, 40 to 90% by weight of lactose and 0.5 to 3% by weight of hydroxypropyl cellulose; 200423972 (5) as described above ( 1) The tablet according to any one of the items (1) to (4), wherein the compound represented by the formula (1) described in the above (1) is 2-(3-isofluorenyl D-carbo) -1, 6, 7, 9- Tetrahydroimidazole [4,5-d] piperan [4,3-b] pyridine or a pharmaceutically acceptable salt thereof or a solvate thereof; (6) as described in any one of the items (1) to (5) above Sharps' which are coated;

(7) a dissolution improver for a tablet of the compound represented by formula (1) described in (1) above or a pharmaceutically acceptable salt or solvate thereof as an active ingredient, which is characterized by containing partially starch; And (8) A method for improving dissolution of a tablet of the compound represented by formula (1) described in the above (1) or a pharmaceutically acceptable salt or solvate thereof as an active ingredient, which is characterized by adding a part of alpha starch . In the present specification, "aryl" includes phenyl, naphthyl, anthryl, indenyl, and phenanthryl.

The "substitutable aryl group" includes one or more selected from the group consisting of alkyl, hydroxy, alkyloxy, aryloxy, fluorenyloxy, carboxyl, ester (alkoxycarbonyl, aryloxycarbonyl, etc.), cyano, Amine, mono- or di-substituted amino, hydrazine, hydroxyamino, alkoxyamine, halogen, nitro, fluorenyl, carbamoyl, thiazidine, carbamoyl, thiamine Formamyloxy, ureido, thioureido, sulfonamido, mono- or disubstituted sulfonamido, sulfonic acid, haloalkyl, hydroxyalkyl, alkoxyalkyl, oxyalkyl, nitrate Substituents consisting of alkylalkyl, aminoalkyl, fluorenylaminoalkyl, cyanoalkyl, and residue radicals. Preferred specific examples include aryl groups of substituted or unsubstituted phenyl groups. Examples of the substituent include methyl, methoxy, and chloro. 200423972

"Aromatic heterocyclyl" means a cyclic group having one or more heteroatoms selected from any of ο, s, and N in the ring, and the cyclic group is a carbon ring or other ring The ring is preferably fused. Specific examples include, for example, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, darazyl, pyrimidyl, pyrargyl, triphenyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazole 5- to 6-membered aromatic heterocycles such as sulfonyl, thiazolyl, thiadiazolyl, furyl and thienyl, or axyl, benzimidyl, D-bazolyl, indolyl, quinoline Base, isoquinolinyl, fluorenyl, phthaloyl, quinazolinyl, naphthyridinyl, quinazolinyl, pyrimidinyl, oxazolyl, benzoxazolyl, oxadiazolyl, benzo Perylene diazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuranyl, benzothienyl, carbazolyl, and fused aromatic heterocycles.

Examples of the substituent of the "aromatic heterocyclic group which may be substituted" include alkyl, hydroxyl, alkoxy, carboxy, ester (alkoxycarbonyl, aryloxycarbonyl, etc.), cyano, amino, mono or di Substituted amino, hydrazine, hydroxyamino, alkoxyamino, halogen, nitro, fluorenyl, carbamoyl, thiamethane, carbamoyl, thiamethane, carbamide Base, thioureido, sulfonamido, mono- or disubstituted sulfonamido, sulfonic acid, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxyalkyl, nitroalkyl, amine An alkyl group, a fluorenylaminoalkyl group, a cyanoalkyl group, and a carboxyalkyl group may have one or more substituents at any position. It is preferably an unsubstituted 5-membered aromatic heterocyclic ring, more preferably an unsubstituted thienyl group, an unsubstituted furyl group, an unsubstituted isoxazolyl group, or an unsubstituted pyridyl group, and most preferably an unsubstituted isoxazolyl group. "Contains more than one 0, S, so, S02 and / or NR1 (wherein R1 is hydrogen, alkyl, esterified carboxyl, carbamoyl or cyano), and may further have more than one alkyl 5- to 9-membered aliphatic cyclic groups of substituents "and adjacent pyridine rings are fused 200423972. Specific examples include carbons such as cyclopentyl ring, cyclohexyl ring, cyclobutyl ring, cyclooctyl ring, and cyclononyl ring. Cyclic groups, and pyrrolidinyl, pyrrolyl, imidazolidinyl, imidazolyl, pyrazolyl, dihydrothienyl, dihydrofuryl, thiazolyl, dihydropiperanyl, dihydrothiopiperanyl, Heteroalicyclic groups such as piperidinyl, piperidyl, morpholinyl, thiomorpholinyl, tetrahydropyridyl, and tetrahydrothiaridyl. Dihydropiperanyl, dihydrothiopiperanyl or piperidinyl is preferred, and dihydropiperanyl is particularly preferred. These groups may have an alkyl substituent (specifically, 1 to 2 methyl or ethyl, etc.).

"Alkyl" includes a straight or branched alkyl group having 1 to 10 carbon atoms, preferably a lower alkyl group having 1 to 6 carbon atoms, for example, including methyl, ethyl, η-propyl, and isopropyl , Η-butyl, isobutyl, second butyl, third butyl, η-pentyl, isopentyl, neopentyl, third pentyl, 2-methylbutyl, η-hexyl, isohexyl Base, heptyl, isoheptyl, octyl, isooctyl, nonyl and decyl, etc. "Haloalkyl", "hydroxyalkyl", "alkoxyalkyl", "fluorenylalkyl", "nitroalkyl", "aminoalkyl", "fluorenylaminoalkyl" The alkyl portions of "cyanoalkyl" and "carboxyalkyl" are the same as the above-mentioned "alkyl".

The "esterified carboxyl" may be exemplified by methoxycarbonyl, ethoxycarbonyl, tertiary butoxycarbonyl, and benzyloxycarbonyl. The "fluorenyl group" contains 1 to 10 aliphatic fluorenyl groups and aromatic fluorenyl groups. Specifically, it includes methyl fluorenyl, ethyl fluorenyl, propyl fluorenyl, butyl fluorenyl, isobutyl fluorenyl, pentamyl, trimethyl Ethyl, hexyl, propenyl, propynyl, methacryl, crotonyl, cyclohexylcarbonyl, benzamidine, 4-nitrobenzyl, 4-tert-butylbenzyl Fluorenyl, benzenesulfenyl, and tosylsulfonyl. "Alkoxy" includes a straight or branched alkoxy group having 1 to 10 carbon atoms, and is preferably a lower alkoxy group having 1 to 6 carbon atoms than -10- 200423972. For example, it includes methoxy and ethoxy groups. Group, η-propoxy, isopropoxy, η-butoxy, isobutoxy, second butoxy, third butoxy, η-pentoxy, isopentyloxy, neopentyloxy Base, tertiary pentyloxy, 2-methylbutoxy, η-hexyloxy, isohexyloxy, heptyloxy, isoheptyloxy, octyloxy, isooctyloxy, nonyloxy and decyloxy Base etc. The "alkoxycarbonyl", "alkoxyamino", "alkoxyalkyl", and "aryloxycarbonyl" have the same alkoxy moiety as the "alkoxy" described above. The aryl part of "aryloxy" and "aryloxyiron" is the same as "aryl".

The "acrylic group", "amino group" and "acid group" are the same as the "fluorenyl group" mentioned above. The substituents of "mono- or di-substituted amine group" and "mono- or di-substituted sulfonamido group" are, for example, amine groups containing 1 or 2 hydroxyl groups, halogens, alkyl groups, alkenyl groups, fluorenyl groups, aryl groups, and the like. Or sulfonamide. "Halogen" includes fluorine, chlorine, bromine and iodine.

There are three types of tautomers in the compound (I), which are not listed in the above-mentioned formula (I). Therefore, other tautomers of the compound (I) contain the following (1-2, 3 a-3 b, 4-5) a compound having a double bond (I ') and (1-3 b, 2-3, 3 a-4) a compound having a double bond (Γ').

1-200423972 When it is called "compound (i)", it includes various compounds that may be formed, and pharmaceutically acceptable salts thereof. Examples of "pharmaceutically acceptable salts" include salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, and hydrobromic acid; formic acid, acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, cis Salts of organic acids such as butenedioic acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, and toluenesulfonic acid; salts of acidic amino acids such as ornithine, aspartic acid, and glutamic acid, etc. . The compound (I) also includes its solvate, which corresponds to one molecule of the compound (I), and can have any number of solvent molecules, preferably water and compounds.

All compounds (I) are suitable for use in the preparations of the present invention, especially 2- (3-isoxazolyl) -1,6,7,9-tetrahydroimidazole [4,5-d] pyrano [ 4,3-b] Pyridyl phosphate 1 (hereinafter, also referred to as compound (I-1)) is preferred. Part of the α-starch used in the tablet of the present invention is that the starch (such as corn starch, etc.) is heated together with water, and part of the α-starch granules are dried, and the specifications of the pharmaceutical additive are 198 or 8 as the food additives. Those listed in the seventh edition of the book are appropriate.

The addition amount of some alpha starch can be appropriately changed depending on the type of the main drug and its addition amount '$ Kind of additive, its addition amount, size of lozenge, etc.', but it is 1 ~ 3 relative to the total amount of lozenge 0% by weight, preferably 3 to 20% by weight. When the amount is greater than the amount, the binding property will decrease, which may cause the coverage and the like. If the amount is less than the amount, the disintegration may decrease and the disintegration may decrease. Dissolution property, the better dissolution property cannot be obtained. In addition, "lozenges", which are "relative to the total amount of lozenges", refer to the plain lozenges before the implementation of the tincture. The present invention is characterized by a combination of a fused imidazopyridine derivative and a part of α-methylated $ -12-200423972, wherein a pharmaceutical additive commonly used in a tablet can be added in a suitable combination.

Excipients (lactose, corn starch, PEG4000, D-mannitol, calcium hydrogen phosphate, crystalline cellulose, etc.), lubricants (magnesium stearate, calcium stearate, talc, polyethylene glycol, etc.) can be appropriately selected 4000, stearic acid, etc.), disintegrating agents (partially alpha starch, sodium carboxymethyl cellulose, crystalline cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, sodium carboxymethyl starch Crospovidone (cr 〇s ρ ο ν id ο ne), low degree of substitution via propyl cellulose, etc.), binders (via propyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, Polyvinylpyridone, polyvinyl alcohol, gelatin, dextrin, etc.), preservatives (benzoic acid, sodium benzoate, sorbic acid, etc.), antioxidants (ascorbic acid, vitamin E, butylhydroxytoluene, etc.), humectants (glycerin , Propylene glycol, etc.), flavoring agents (grape, etc., sodium saccharin, sodium glutamate, etc.), colorants (carotene, titanium oxide, etc.) and spices (menthol, etc.) are commonly used additives in tablets, etc. It is added at an appropriate stage of formulation.

Preferred embodiments of the lozenges of the present invention include combinations of fused imidazopyridine derivatives, partially alpha starch, lactose, and hydroxypropyl cellulose (hereinafter referred to as HPC). Lactose and HPC can be used as described in the 14th revision of the Japan Pharmacopoeia Prescription, Pharmaceutical Additive Specification 1 998, or the Food Additives Dept. 7th Edition. Lactose includes water lactose and anhydrous lactose, especially water lactose is better. The amount of lactose can be appropriately changed according to the amount of other additives and the size of lozenges. It is 20 to 95% by weight relative to the total amount of lozenges, preferably 40 to 90% by weight, and most preferably 55 to 90% by weight. -13- 200423972 In addition, part of the corresponding lactose may be replaced by corn starch when necessary. For example, the amount of lactose may be 20-75% by weight and the corn starch may be 0-20% with respect to the whole amount of the tablet. Corn starch can be used in the fourteenth revision of the Japanese Pharmacopoeia prescription, the specifications of pharmaceutical additives 198 or the seventh edition of the Food Additives Public Draft.

HPC includes those with various viscosity such as HPC L, HPC SL, HPC SSL, and more preferably HPC L or HPC SL. This added amount may be appropriately changed depending on the type of the main drug, its added amount, the type of additives, its added amount, the size of the tablet, and the type (viscosity) of the HPC, but it is preferably relative to the total amount of the tablet.丨 ~ 5 wt%, more preferably 0.5 ~ 3 wt%, and most preferably 1 ~ 2 wt%. If it is added in an amount larger than that, it may cause adhesion and the like when it is added to the ingot; and, due to the increase of the granulation binding force, the collapse delay is caused. Conversely, when the amount is smaller than this amount, the binding property is reduced, and covering and the like are caused, and granulation cannot be performed, and good granulated material cannot be obtained. Furthermore, there may be causes of wear and tear of the circulation steps. Further, in the lozenge of the present invention, magnesium stearate may be further added if necessary.

Magnesium stearate can be used as described in the specifications of pharmaceutical additives 198 or as a user of food additives. The blending amount of magnesium stearate can be based on the type, concentration and addition amount of the main medicine, and the type of additives. The size of the lozenges and other suitable changes are 0.1 to 5% by weight, preferably 0.5 to 3% by weight, and most preferably 1 to 2% by weight relative to the total amount of the tablets. When the amount is more than this, the hardness of the tablet will decrease, and the dissolution property and disintegrability will decrease. On the other hand, when the amount is less than the amount, the cause of sticking will be caused. The main medicine in the lozenges of the present invention may have a medicinal effect or the size of the lozenges, which may be appropriately changed in consideration of the dosage of the patient ’s disease, and may be formulated in an amount of 3 to 80% by weight relative to the total amount of the lozenges. It is preferably about 5 to 40% by weight. Adding the amount above -14-200423972 will reduce the relative amount of additives necessary for formulation, and it will be difficult to formulate. If it is the following amount, it will be difficult to ensure the uniformity of content. In addition, in order to obtain an appropriate amount of absorption in the body, it is not appropriate to increase the number of lozenges necessary for the patient's burden. The lozenges of the present invention can be prepared by methods known to those skilled in the art. For example, they can be prepared by a dry granulation method, a stirring granulation method, or a fluidized layer granulation method.

For example, when the formulation is carried out by fluidized layer granulation, the active ingredients are first sieved and mixed with lactose, and then sprayed and granulated with an HPC aqueous solution, dried, and sieved again, and then added with magnesium stearate and partially alpha starch. , Mix and beat tablets to get vegetarian lozenges. The vegetarian tablets thus obtained are used for the purposes of enteric preparation, slow release preparation, reduction of side effects, stabilization of effective ingredients, prevention of damage during transportation, improvement of feeling of taking, etc. coating. The type of the coating layer may be, for example, sugar coating, gelatin coating layer, enteric coating layer, film coating layer, etc., and a film coating layer is preferred.

It is advisable to apply the coating according to the usual method. For example, when performing film coating, the film base and commonly used pharmaceutical additives (such as sunscreen, plasticizer, lubricant, etc.) are mixed into a coating solution and sprayed onto the above. It is advisable to use a vegetarian tablet. Examples of the preferred coating solution include 50 to 95 parts of the film base, preferably 60 to 80 parts, and 1 to 30 parts of the light-shielding agent, preferably 10 to 25 parts, and 5 to 20 parts of the plasticizer. It is preferably 5 to 15 parts. Examples of the film base include dimethyl methyl cellulose, ethyl cellulose, propyl cellulose, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, and residual methyl ethyl cellulose. Propyl methylcellulose acetate succinate, etc., shading-15-200423972 agent is titanium oxide, plasticizer is triethyl citrate, medium chain fatty acid triglyceride, polyethylene glycol (PEG), Glycerol triacetate, polypropylene glycol, etc. After the tablets have been coated, if necessary, it may be further sprayed with a small amount of lubricants such as magnesium stearate, calcium stearate, stearic acid, talc, and polyethylene glycol. The dosage of the tablets of the present invention can be set in consideration of the type and concentration of the main drug, the age of the patient, and the type or degree of the disease. For example, when administered to adults, one tablet can be used as the main drug in each tablet. It is about 1 mg to 100 mg, preferably about 5 to 40 mg. It may be suitable to administer 1 to 10 tablets once a day to several times a day. The following examples are provided to further illustrate the present invention, but they are not limited thereto. [Embodiment] Example 1 A mixture of 300 g of compound (1-1) (Ci2HiON4O2 · H3PO4 · H2O) and lactose (3840g) was subjected to HPC using a flow granulator (Dalat Corporation: WSG-5 type) (4 5 g) Dissolved as a binder solution and spray-granulated to obtain a dry product in the same device. This dried product was placed in a pulverizer equipped with a 20-mesh sieve (manufactured by Showa Chemical Machinery: P-3 P a wo er M i 1 1) to obtain granulated granules. This granule was added and mixed with 22 5 g of partially alpha starch (5.4% relative to the above granules) and 90 g of magnesium stearate (corresponding to 2.15% of the above granules) to obtain granules for tableting. The device has a 4 7. Omni pestle rotary tablet mill (manufactured by Kikusui Seisakusho: RTM-S30K-2S model) to obtain a 150 mg tablet with a thickness of 3.2 mm. This lozenge was inserted into an air-through coating machine (HC-48 manufactured by Phi · o ndo), and hydroxypropyl methyl cellulose (70 g), titanium oxide (20 g), and triethyl citrate (10 g ) After dissolving or dispersing the coating liquid to obtain a coated tablet, -16-200423972 is coated with magnesium stearate to obtain the final preparation. Examples 2 to 6 The same tablets were prepared with the following composition, Examples 2 to 6 were coated tablets, and Examples 7, Comparative Examples 1 and 2 were plain tablets. Table 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Comparative Example 1 Comparative Example 2 Compound (1-1) 20mg 100mg 10mg 20mg 40mg 40mg 40mg 40mg Lactose 118mg 38mg 108mg 98mg 75mg 83mg 83mg 83mg Corn Starch 20mg 20mg 20mg HPC 1.5mg 1.5mg 3.0 mg 3.0 mg 3.0 mg 3.0 mg 3.0 mg partially alpha starch 7.5 mg 7.5 mg 7.5 mg 7.5 mg 7.5 mg 22.5 mg Carboxymethyl cellulose Ca 22.5 mg croscarmellose Na 22.5 mg magnesium stearate 3.0 mg 3.0 mg 1.5 mg 1.5 mg 1.5 mg 1.5 mg 1.5 mg 1.5 mg coated HPMC 3.5 mg 3.5 mg 2.8 mg 2.8 mg 2.8 mg titanium oxide 1.0 mg 1.0 mg 0.8 mg 0.8 mg triethyl citrate 0.5 mg 0.5 mg 0.4 mg 0.4 mg 0.4 mg magnesium stearate 0.04 mg (trace) 0.04 mg (trace) Test Example 1 Dissolution test 1. The test method uses one tablet of Example 7 and the second liquid of the Japanese Bureau as the test liquid 900 ml. According to the dissolution test method, the test is performed at 50 revolutions per minute. Similarly, the tablets of Comparative Examples 1 and 2 Agents were tested in the same way. 5, 10, 20, 30, 60 minutes after the start of the dissolution test, use the full suction tube -17- 200423972 to accurately deliver the 5 μm 1 eluate to the final filter (Maeda Industries F2 丨 6) as the sample solution. Each was adjusted to a standard solution in the following manner. 2. Standard solution Accurately measure about 0.044g of compound (I-1), add it to the test solution to dissolve it, make it to 100m accurately, measure 10ml of this solution 'and add it to the test solution to make 100m standard solution. 3. Assay

The sample solution and 5 ml of the standard solution were subjected to a two-wavelength measurement method. The difference in absorbance between the wavelengths of 278 nm and 350 nm was used as the absorbance, and the dissolution rate (%) of the corresponding compound (Bu i) was obtained. The results are not shown in Fig. 1. As can be seen from the figure, the tablet in which the alpha powder was added as a part of the disintegrating agent showed very excellent dissolution properties compared with the lenses of Comparative Examples 1 and 2. Test example 2 Stability test 1 · Preparation of sample solution

Take one tablet of Example 6 (45 ° C, stored for 1 to 3 months, 45 ° C relative humidity 75%, stored for 1 to 3 months, 600,000 Lx * h irradiation, 3600000 Lx * h irradiation), put 1 In a conical flask of 〇m1, 30 ml of the mobile phase was precisely added, and the mixture was gently shaken by hand to irradiate with ultrasonic waves for 20 minutes to break the tablets. 2 · Determination method Take the sample solution 2 0 // 1, and then determine the content (%) and the residual ratio (%) of the corresponding compound (I-1) according to the color layer analysis conditions. -18- 200423972 3. Test conditions Detector: UV absorbance photometer (measurement wavelength: 2 7 8 nm) Column: YMC AM- 3 02 〇DS (must be 4.6 × 15〇ηπι) Mobile phase: 50mM acetic acid / Methanol mixture for HPLC (82:18) Flow rate: 1.0 mL / niin The results are shown below: Table 2 Residual conditions (%) 45 ° C · 1 month storage 100.3 451 · 2 months storage 100.1 45 ° C 10 months at 10 months 4 5 ° C 75% relative humidity 1 99.5 45 ° C one month 75% relative humidity 99.9 45 ° C two months 75% relative humidity 100.5 600000Lx * h 100.0 3600000Lx * h 100.2

It can be seen from Table 2 that the tablet of the present invention did not show a decrease in effective components after storage under various conditions, and has stability.

Test Example 3 The dissolution test uses the tablet of Example 6 and performs "before storage" and "4 5 ° C · 1 month storage", "4 5 ° C · 3 months storage", "4 5 ° C · Relative humidity 7 5% · 1 month storage "," 4 5 ° C · 75% RH · 3 months storage "tablet dissolution test. Using the first Japanese liquid (pH 1.2) and the second Japanese liquid (p Η 6 · 8) as the test liquid, the dissolution rate was determined in the same manner as in Test Example -19- 200423972 (%). The results of the first round of the game are shown in Figure 2 and the results of the second round of the Japanese game are shown in Figure 3. It can be seen from the figure that the dissolution of this tablet after storage is the same as that before storage. Industrial Applicability It is clear from the above test examples that the lozenges of the present invention exhibit excellent dissolution properties and can be expected to exhibit rapid medicinal effects. Therefore, the lozenges of the present invention are orally administered with the compound (I) as an active ingredient. It is very useful on preparations.

[Schematic description] Figure 1 shows the dissolution profile of lozenges using partially starch, carboxymethylcellulose calcium (CMCCa) or croscarmellose Na as disintegrating agents. Fig. 2 is a graph showing the dissolution property of the α-M powder added with a sharpening agent in part 3 of Example 3 when the first liquid of the Japanese Bureau was used as the test liquid. Fig. 3 is a graph showing the dissolution property of the α-starch added lozenges in part 3 of Example 3 when the second liquid of the Japanese Bureau was used as the test liquid.

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Claims (1)

200423972 Scope of patent application: 1. A lozenge, characterized in that it contains a compound represented by formula (I): R (I) (wherein R is a substituted aryl group or a substituted aromatic heterocyclic ring, Ring A may contain one or more of 0, S, SO, s02, and / or NR1 (wherein R1 is hydrogen, alkyl, esterified carboxyl, carbamoyl, or fluorenyl), and 'may A cycloaliphatic group of 5-9 members having 1 or more alkyl groups, or a pharmaceutically acceptable salt or a solvate thereof, and a partially alpha starch. 2 · —A lozenge, which is characterized by containing the formula as shown in item 1 of the scope of patent application (I) A compound or a pharmaceutically acceptable salt or solvate thereof, a partially hydrolyzed starch, lactose, and hydroxypropyl cellulose. 3. The tablet according to item 2 of the patent application, which contains 3 to 80% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof as shown in item 1 of the patent application, relative to the entire amount of the tablet. A solvate, 1 to 30% by weight of partially alpha starch, 20 to 95% by weight of lactose, and 0.1 to 5% by weight of hydroxypropyl cellulose. 4. The tablet according to item 2 of the patent application, which contains 5 to 40% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof as shown in item 1 of the patent application, relative to the entire amount of the tablet. Its solvate, 3 ~ 20% by weight of 21-21200423972 alpha starch, 40 ~ 90% by weight of lactose and 0.5 ~ 3% by weight of hydroxypropyl cellulose. 5. The lozenge according to any one of the claims 1 to 4 of the scope of the patent application, wherein the compound of formula (I) shown in the scope of the first scope of the patent application is 2-(3-isoxazolyl) -1,6,7 , 9-tetrahydroimidazole [4,5-d] piperan [4,3-b] pyridine or a pharmaceutically acceptable salt or solvate thereof. 6. The tablet according to any one of claims 1 to 5, which is coated. 7. A dissolution improving agent for lozenges, characterized in that it contains a part of α-starch, and uses the compound of formula (I) or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient as shown in item 1 of the patent application scope. 8. A method for improving the dissolution of lozenges, which is characterized by adding a part of α-starch, and using the compound of formula (I) or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient as shown in item 1 of the scope of patent application. -twenty two-