TW200800197A - Pharmaceutical composition - Google Patents

Abstract

A preparation for oral administration comprising: a pregelatinized starch comprising N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-(2R,3R)- 2,3-tetramethylene-butyl]-(1'R,2'S,3'R,4'S)-2,3- bicyclo[2,2,1]heptanedicarboxyimide hydrochloride (lurasidone) represented by the formula (1) as an active ingredient; a water-soluble excipient; and a water-soluble polymeric binder, the preparation exhibiting an invariant level of elution behavior even when the content of its active ingredient is varied.

Description

200800197 IX. Description of the invention: [Technical field to which the invention pertains] The present invention relates to an N-[4-[4-(l,2-benzoquinoneisothiazol-3-yl)-1-hexahydropyrazinyl] -(2R,3R)-2,3_butylbutyl-butyl]-(i,R,2,S,3,R,4,S)-2,3-bicyclo[2,2,1]g The dimethyl sulphonide hydrochloride (Lurasidone) is an oral preparation having a good disintegration property as an active ingredient. Specifically, it relates to an orally administered preparation which exhibits the same dissolution state in an oral preparation containing Lurasidone as an active ingredient, particularly in the case of a change in the content of the active ingredient, in particular, a tablet. [Prior Art] Patent Document 1 discloses a compound such as Lurasidone which can be administered orally, and can be formulated by mixing a usual carrier, an excipient, a binder, a stabilizer, and the like with an active ingredient. Manufactured; however, an oral preparation which exhibits rapid solubility even when the content of the active ingredient is varied in a wide range, and which exhibits the same dissolution state, especially when the content of the active ingredient is increased, shows a low content. The oral preparations in the same dissolution state as the number of tablets of the preparation have not been disclosed. In the medical trial No. 64 (published on February 14, 2004) for the purpose of ensuring the biological equivalence of the preparations of different amounts of the same dosage, the organisms having the oral solid preparations with different contents are disclosed. The Equivalence Test Criteria", which seeks to: in different formulations, in buffers, water, corresponding to the pH values of the stomach, intestines and the mouth of ΡΗ1·2, 3·〇~5.0 and 6.8, The same dissolution state can be exhibited in each test liquid such as physiological chyme water. In the case of the pharmaceutical agent containing Lurasidone as an active ingredient, an oral preparation which exhibits rapid solubility and exhibits the same dissolution state even if the content of the active ingredient is different is disclosed, and in particular, it is revealed that it is increasing. When the active ingredient contains 1, the oral preparation which exhibits the same dissolution as that of the low-content preparation and which releases the poorly water-soluble active ingredient at a desired concentration is shown. Patent Document 2 discloses that even if the content of the active ingredient varies within a range of several mg to several tens of mg, for example, 5 mg to 2 〇 111 § or 5 mg to 4 〇 mgs, it exhibits rapid solubility, and An orally-administered formulation of the same dissolution profile is shown in the same composition ratio, and in particular, a tablet is disclosed. In oral preparations, in order to obtain a better clinical effect, a higher content of the preparation is often required; or in order to adjust the clinical effect according to the patient's symptoms, it is often necessary to display the same state in a wide range of contents, and The preparation of the active ingredient can be released at a desired concentration. In the technique disclosed in Patent Document 2, an oral preparation can be provided which, as shown in Fig. 1, is contained per ingot and exhibits an equivalent dissolution state. However, as shown in Fig. 2, it is effective in the preparation. When the content of the ingredient is increased to 2 times and the content of the active ingredient in one tablet is increased, the 80 mg ingot cannot exhibit the same dissolution state. Therefore, it is necessary to take a few tablets at a time, or to take a more difficult large tablet. Therefore, for Lurasidone which is an insoluble active ingredient, it is difficult to provide a high-content oral preparation or to dissolve in a wider range in the same state: Oral preparation. Further, in Patent Document 2, it is known that the water-soluble polymer binder can be exemplified as a version, but the powder of the gelatinized powder is not disclosed. The phlegm powder, for example, disclosed in Patent Document 3, can significantly improve the disintegratability and dissolution property of the pharmaceutical composition, as described in Non-Patent Document 1, and is usually mostly 10% or less is used. Patent Document 1: Japanese Patent No. 2800953 Patent Document 2: W02002/024166 Patent Document 3: Japanese Patent Laid-Open No. 2000-26292 Non-Patent Document 1: Handbook of Pharmaceutical Excipients, Second Edition, page 491, 1994, The Pharmaceutical Press [Problem to be Solved by the Invention] An object of the present invention is to provide an oral preparation which uses Lurasidone as an active ingredient and which exhibits rapid solubility even when the content of the active ingredient is varied within a wide range. In the case of dissolution, especially in the case of increasing the content of the active ingredient, it exhibits the same dissolution state as most of the ingots of the low-content preparation, and the active ingredient can be released at a desired concentration. It is an object of the present invention to provide a preparation for oral administration which is based on N-[4-[4-(l,2-phenylisothiathiazolyl-3-yl)-1-hexahydropyridazinyl] -(2R,3R)-2,3-butenylbutyl]-(1'11,2'8,3,4'8)-2,3_bicyclo[2,2,1]heptanthene In the oral preparation containing quinone imine hydrochloride (hereinafter, Lurasidone) as an active ingredient, even if the content of the active ingredient is changed, the same eluted state is exhibited. SUMMARY OF THE INVENTION The inventors of the present invention have made an effort to solve the above problems, and finally found that the problem can be solved by the following method. That is, the present invention is as follows. 111892.doc 200800197 (1) contains formula (1)

表 Ν -[4-[4·(1,2-Benzene σσ σ -3--3-yl)_ 1 -hexachloropyrene than σ-methyl]-(2R,3R)_2,3- Butyl-butyl]-(1'11,2'8,3,11,4'8)-2,3-bicyclo[2,2,1] heptadienimemine hydrochloride (Lurasidone) ), an oral preparation of a gelatinous powder, a water-soluble excipient, and a water-soluble polymer binder. (2) An oral preparation for granulating a mixed powder containing Lurasidone, a gelatinized starch, and a water-soluble dispersion agent using a solution in which a water-soluble polymer binder is dissolved. (3) An oral preparation for granulating a mixed powder containing a gelatinized starch and a water-soluble excipient by dissolving or dispersing a solution of Lurasidone and a water-soluble polymer binder. (4) The oral preparation according to any one of (1) to (3) wherein the water-soluble excipient is mannitol or lactose. (5) A method of granulating a mixed powder containing Lurasidone, a gelatinized powder, and a water-soluble excipient by using a solution in which a water-soluble polymer binder is dissolved. (6) A method of granulating a mixed powder containing a gelatinized starch and a water-soluble excipient by using a solution in which Lurasidone and a water-soluble polymer binder are dissolved or dispersed. (7) The granulation method according to item (5), wherein the water-soluble excipient is Mannan I11892.doc 200800197 sugar alcohol or lactose. (8) The oral preparation according to any one of the items (1) to (4), wherein the amount of the gelatinized starch is from 1 to 5 % by weight (wt/wt) based on the weight of the preparation. (9) The oral preparation according to any one of (1) to (4), wherein the amount of the gelatinized starch is 20 to 30% (wt/wt) based on the weight of the preparation. (10) The oral preparation according to any one of (1) to (4), wherein the Liirasidone content in the preparation is 20 to 45% (wt/wt). (11) The oral preparation according to any one of (1) to (4), wherein the preparation has a Lurasidone content of 25 to 40% (wt/wt). (12) The oral preparation according to any one of (1) to (4), wherein the content of Lurasidone in the 1 bond is 1 〇 to 160 mg 13 (13) as in the (1) to (4) The oral preparation according to any one of the items (1) to (4), wherein the Lurasidone is in an amount of from 20 to 120 mg in a tablet, wherein the Lurasidone The oral preparation of any one of the above-mentioned items (1) to (4), wherein the water-soluble excipient is mannosaccharide or lactose, and gelatinization is carried out. The amount of starch added is 10 to 50% (wt/wt), which is equivalent to the weight of the preparation. (16) The oral preparation according to any one of (1) to (4), wherein the water-soluble excipient is mannitol or lactose, and the content of Lurasidone in the preparation is 25 to 40% (wt/wt). (17) The oral preparation according to any one of (1) to (4), wherein the amount of the alpha-starch added is 10 to 50% (wt/wt) based on the weight of the preparation, in the preparation The oral preparation water according to any one of the items (1) to (4), wherein the water-soluble excipient is mannose, the sulphate is sucrose. The amount of alcohol or lactose, alpha-starch added is 10 to 50% (wt/wt), and the amount of Lurasidone in the preparation is 25 to 40% (wt/wt). (A) The oral preparation according to any one of the items (1) to (4), wherein the water-soluble excipient is mannitol or chyle, and the amount of the gelatinized starch is added relative to the weight of the preparation. The oral preparation of any one of the items (1) to (4), wherein the amount of the Lurasidone in the preparation is 2 5 to 40% (wt/wt) 〇Φ (20), the oral preparation according to any one of the items (1) to (4), Wherein, the water-soluble excipient is mannitol or lactose, and the amount of the gelatinized starch is 20 to 30% (wt/wt) relative to the weight of the preparation, and the content of Lurasidone in one tablet is 40 to 120 mg. (21) The oral preparation according to any one of (1) to (4), wherein the gelatinization rate of the alpha-starch is 50 to 95%. (22) The oral preparation according to any one of (1) to (4), wherein the average particle diameter of the Lurasidone is 0·1 to 8 μπι. The oral preparation of any one of (1) to (4), wherein the water-soluble component in the gelatinized starch is 30% or less. (24) The oral preparation according to any one of (1) to (4), wherein the water-soluble excipient is mannitol or lactose, and the amount of the gelatinized starch is 20% with respect to the weight of the preparation. 30% (wt/wt), the content of Lurasidone in the preparation is 2 5 to 40% (wt/wt), and the content of Lurasidone in 1 sharp is 20 to 120 mg 〇 [effect of the invention] 111892.doc -10- 200800197 In the technique disclosed in Patent Document 2, it was confirmed that an oral preparation which is a case in which a low-content preparation containing up to 40 mg of Lurasidone in one bond can be used to make the dissolution state uniform. However, in the preparation containing a higher content of Lurasidone, the dissolution state could not be made uniform. Therefore, for patients who have to administer Lurasidone at a high dose, the burden on the patient is increased by taking a low dose of the preparation, and the manufacturer is seeking to improve the situation. According to the preparation of the present invention characterized by containing alpha-starch starch, it is possible to provide an oral preparation containing a higher content of Lurasidone which is less burdensome to the patient. Enter

Further, according to the present invention, it is possible to provide an orally-administered preparation containing a high content of Lurasid〇ne, and an oral administration preparation which exhibits the same dissolution state even if the content of Lurasidone is changed. Moreover, its long-term storage is also excellent. [Examples] N-[4_[4_(1,2-benzoindole_3_yl)]-hexahydropyridazinyl]-(2r,3r)_ 2,3 butyl-butyl (1,11,2,853,11,4,8)_2,3_bicyclo[2,2,1]heptylimine hydrochloride (Lurasidone), with the following formula: 111892.doc

A compound that is not indicated by the pound (refer to the Japanese patent No.). LurasidGne has an antipsychotic effect and is effective as a treatment for schizophrenia. The amount of the present compound to be added may be in the range of, for example, from 1 to 50% by weight, preferably from 2 to 455% by weight, based on the total weight of the tablet, in the range of from 20 to 45% by weight, particularly preferably from 20 to 45% by weight. select. Further, it is preferable to carry out fine pulverization, for example, a particle having a volume ratio of 90% or more is 27 μm or less, and a particle diameter (50% particle diameter) as a volume ratio is, for example, in the range of 0.1 to 8 μη. Preferably, it is a range of 1 to 4 μm. The content of the Lurasidone contained in one tablet may, for example, be 10 to 160 mg, preferably 20 to 120 mg, more preferably 40 to 120 mg. The η-alphaated starch refers to a variety of starches such as corn starch, potato starch, wheat starch, starch, and tapioca starch, and as such, for example, it is compliant with the standard of pharmaceutical additives. Starch (English name: Pregelatinized Starch) or partial gelatinized powder (English name: Partly Pregelatinized Starch), etc. The degree of crystallization of alpha-starch is, for example, 50 to 100%, preferably 50 to 95%, more Preferably, it is 80 to 95%. The water-soluble component in the gelatinized starch is, for example, 40% or less, more preferably 30% or less. The gelatinized starches generally have an average particle diameter of 1 to 1000 μm, It is preferably a powder of 1 to 500 μm, more preferably 10 to 100 μm. As a commercially available gelatinized starch to be used in the present invention, for example, PCS (trade name, manufactured by Asahi Kasei Kogyo Co., Ltd.) or Starchl 00 can be cited. (Product name, Colorcon), etc., for example, PCS (trade name, manufactured by Asahi Kasei Kogyo Co., Ltd.) is preferably used. The gelatinization rate of the partially gelatinized starch is preferably 50 to 95%, more preferably Is 80 to 95%. The present invention The gelatinized starch to be used is 10% or more and 50% or less, preferably 10% or more and 40% or less, particularly preferably 20% or more and 30% or less, relative to the weight of the preparation. * As for the "water-soluble excipient" ", for example, mannitol, lactose, white sugar, sorbitol, D-sorbitol, erythritol, lignin, and the like. 111892.doc •12- 200800197 For better, mannitol and lactose are listed. Further preferably, mannitol is exemplified. Further, the water-soluble excipients may be used in combination or in combination of two or more kinds. The amount of the water-soluble excipient added may be, for example, selected from the range of 30 to 80% by weight, preferably about 10% by weight, based on the weight of the base. Further, the average particle diameter ' of mannitol' is in the range of 1 〇 to 2 〇〇 μιη. Examples of the "tolerable polymer binder" include, for example, cellulose, propylmethylcellulose, polyethylene (IV), and polyethylene glycol. As for the better ones, exemplified by propylene glycol, hydroxypropylmethylcellulose, and polyethyl alcohol. The water-soluble polymer binder, 2 = or two or more types are used at the same time. The amount of the water-soluble high-molecular viscosity σ is based on the amount of the tablet, 悤 、, and 悤 里, for example, it can be from 0.5 to 10 dong. The dry circumference is preferably selected from the range of 5 wt%. = Oral preparation of the inventive pharmaceutical composition t: Agent: capsule, granule, fine granule. In addition to the glutenous excipient, it may be made into a tablet by a conventional method, such as a water-based excipient, a binder, a disintegrator, a lubricant, etc. Further, the following may be added. (4) Small granules and fine granules for "water-insoluble excipients" Cellulose, etc. Further, it is possible to use, for example, a sapphire list, a jade powder, a crystal spear, or a combination of two or more types. Decomposing agent ", for example, corn house powder, sputum, low-substituted propyl cellulose, sulfhydryl cellulose, several methyl cellulose, methine cellulose nano, cross-cultivation, six... 4 竣 methyl cellulose nano, a few methyl methine powder sodium and ethylene __, etc.. The disintegrant can be used in W species or at the same time 111892.doc 200800197 can be used as two or more as follows: The addition amount of the disintegrant is in the range of 0 to 10% by weight. 'Based on the total weight of the tablet, for example, preferably 0.5 to 5% by weight of the lubricant, for example, hard (tetra)magnesium, talc, and polyethylene. Alcohol, cerium oxide, hardened vegetable oil, and the like. Preparation of the Oral Formulation of the Present Invention The desired dosage form can be prepared according to a usual method, depending on the dosage form desired to be obtained. (1) Preparation of an aqueous solution of a water-soluble polymer binder:

The water-soluble polymer binder is dissolved in purified water. As the water-soluble high component: the amount of the binder used is, for example, a range from 2 to 8 wt%, preferably from the range of 2 to 8 wt%, based on the amount of the purified water. U) Preparation of granules containing Lurasidone: Ugly-faced The water-soluble polymer binder prepared in the above step (1) is dispersed, and is filled with an excipient containing LUrasidone, mannitol, a part of 匕 starch and In the fluidized bed granulator of the decomposing agent, granulation was carried out on one side. As for the granulating device, for example, it can be exemplified by classification: flow granulation (Bed GranuUtion), high-speed agitation granulation (exquisite gr_iati〇n), and mobile stratified granulation (Roto Fluid Bed Granulati〇n). Device. However, it is not limited to these. (3) Drying of granules·· The granules are dried under reduced pressure or normal pressure. This drying is, for example, 3% by weight or less, preferably 1 to 2 parts by weight, based on the infrared moisture meter. /〇In the way. (4) Addition of Lubricant: 111892.doc -14- 200800197 A lubricant is added to the granules dried in the above (3) and mixed. For mixing, for example, a mixer classified as a mixer mixer [Tumble] (Diffusion mixers [Tumble]) can be used. Specific examples include a Tumble Blender, a V Blenders, a Double Cone, and a Bin Tumble. However, it is not limited to these. (5) Baking: The above mixture was tableted (pressed) to prepare a tablet. As the tableting device, for example, a tableting machine classified into a tablet press (Tablet Press) can be cited. As the tableting hardness, for example, it can be selected from the range of 30 to 200 > (6) Coating as needed: In the above-mentioned tablets, coating may be carried out as needed. As the coating device, for example, a device classified as Coating Pan can be cited. Preferably, a device classified into a perforated coating system is used. As the coating agent, for example, a base such as hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, or polyethylene glycol with, for example, polyethylene glycol, propylene glycol, or triacetin may be mentioned. A combination of plasticizers such as vinegar, citric acid triacetate, glycerin, glycerin fatty acid ester, and polyethylene glycol. Further, it may be prepared by adding an additive such as titanium oxide as needed. Further, after the coating, a palm wax or the like as a glossing agent may be added. (7) Drying: 111892.doc -15 - 200800197 The key agent obtained in the above manner is dried. (4) The drying reduction value measured by decompression or normal pressure is measured, for example, within 3% by weight, preferably within 〜2% by weight. The following examples are provided to illustrate the present invention, but are not intended to limit the invention. Example 1 A. A coated ingot containing 80 mg of Lurasidone (Example u A pellet consisting of the following composition, a bare ingot, and a ? ingot were prepared in this order. Further, the amount of the amount disclosed in the brackets in the text is used. An example of the preparation of the formulation shown in the example i can be prepared. In principle, according to the manufacturing method, other embodiments disclosed can also be prepared. The amount of the input must be changed according to the prescription. 1) Preparation of a binder (5% aqueous solution of hydroxypropylmethylcellulose): The water-soluble polymer binder hydroxypropylmethylcellulose (32 g) was dissolved in purified water (608 g) to prepare (2) Granulation: LuraSidone (320 g), mannitol (576 phantoms, partially saponified starch (320 g), cross-linked saponin cellulose (16 g) into a mobile layer In the granules (manufactured by Multiplex MP-01/P〇wrex Co., Ltd.), the conjugated liquid prepared in the above (1) was subjected to tableting and granulation under the following conditions to obtain a granulated powder. Magnesium stearate was added thereto. In the granulated powder, after mixing (4 rpm, 5 minutes), a prescription is obtained (b Granules for tableting. Further, stearin 111892.doc -16- 200800197 The amount of magnesium acid input is based on the amount of granulated powder and the amount calculated from the prescription, and is mixed in this amount. Conditional air supply temperature: 60°C Air volume: 50-65 m3/hr Pressing speed: 13 g/min Nozzle diameter: 1.2 mm Pressing pressure: 〇· 12 MPa _ Spray position: Middle section (3) Ingot: Use HT- AP12SS_II (manufactured by Nippon Iron Works Co., Ltd.), the pellet for tableting prepared in the above (2) is used as a tablet.

杵 Size: Φ10 mm 14R Thickness: 4·20~4.30 mm Tablet compression pressure: 10 KN (4) Coating: ^ Using Hicoater HCT30N (Freirnd industry), with a film volume of 5 mg, under the following conditions, The bare ingot prepared in the above (3) is coated, and then palm wax is added after the coating to obtain a coated ingot. FC condition

'Supply gas temperature: 80 ° C Air volume: 0.6 m3 / min Coated steel Rotation speed: 25 rpm Spray pressure: 0.15 MPa 111892.doc • 17- 200800197 Liquid velocity: 5 g / min According to the above method, the preparation can be The quality evaluation was carried out according to the following method, and the present invention was finally completed on the basis of the knowledge obtained therefrom. C. Quality evaluation (1) Dissolution test The dissolution test of the prototype was carried out in accordance with the second method of the Japanese Pharmacy Dissolution Test Method. The measurement conditions are disclosed below. Test solution: diluted Mcllvaine buffer (diluted Mcllvaine 10 buffer 5 pH 4.0) Paddle rotation speed: 50 rpm Test solution: 900 ml (2) The similarity of the dissolution characteristics was used as a similarity index for evaluating the dissolution characteristics to Scale-Up. Similar factor f2 as disclosed in and Past-Approval Changes for Intermediate Release Products (SUPAC-IR). F2 can be calculated according to the following formula. In the case where the f2 value calculated from the dissolution rate of each preparation according to SUPAC_IR was in the range of 50$f2$100, it was judged that each of the prepared preparations had a similar dissolution characteristic. Further, in the calculation of f 2 , the dissolution rates at 15 minutes, 30 minutes, and 45 minutes after the start of the test were used. 100

/2 = 50· LOG n 111892.doc -18- 1 + - 200800197 (Ti and Ri are the percentage of dissolution at each point. η is the number of points to be compared (3) particle size distribution by laser diffraction particle size distribution measuring device (SLAD_3000/Shimadzu Corporation) Dry spray method to measure the particle size distribution of Lurasidone. The measurement conditions are as follows: 试 Sample amount: 2 g Air pressure: 0.4 MPa or more Turntable rotation speed: 2 Parameter setting Environment setting Average monitoring times: 16 Average dark measurement Number of times: 2 Light intensity indicates the maximum value: 2000 Previous sample value: Read in the printer: Monochrome refractive index parameter Standard refractive index: 1.70-0.20 i Measurement conditions Setting measurement times: 1 Measurement interval (seconds): 1 Average number of times :64 Determination of absorbance range (maximum): 0.1 (minimum): 0.05 Trigger mode: OFF Dry threshold: 300 Optimum measurement range (maximum): 1500 (minimum): 700 (CH-1) transfer rate (bps ): 9600 sample measurement allowable maximum value: 300 sample measurement allowable turbulence range: 20 dry tolerance minimum value: 300 maximum value = 2500 evaluation target particle range (minimum value): 0.1 compensation target particle range ( Large value: 2000 sensor use start position: 1 <Test 1> In Example 1, 2 ' 3, a prototype of Lurasidone containing 20 mg, 40 mg and 80 mg was prepared in a sharp form, including water-soluble a molding agent, a partially gelatinized starch, and a key agent of a specific medical composition of a water-based gluten-like molecular binder. Further, in Comparative Examples 1 and 2, according to the prescription disclosed in Patent Document 2, a prototype was prepared in one tablet. A lozenge containing 40 mg and 80 mg of Lurasidone. -19- 111892.doc 200800197 A dissolution test was carried out on the prototype preparation under the conditions indicated in (d) and (e), and the similarity of the dissolution characteristics was evaluated. The trial production of Comparative Examples 1 and 2 was disclosed in Test 8. The results are shown in Tables 4 and 5. Further, for (d), the periodic dissolution rate is also shown in Figures 2 and 3. (a) Where the granulated powder is [Table 1] Unit: mg Ingredient Example No. Comparative Example No. 1 2 3 1 2 Lurasidone 80 40 20 40 80 Mannitol 144 72 36 188 148 Partially gelatinized starch 80 40 20 - - Cross-linked carboxylate Sodium methylcellulose 4 2 1 16 16 propylmethylcellulose 8 4 2 10 10

(b) Particles for bonding keys/naked bonds [Table 2] Unit: mg Ingredient Example No. Comparative Example No. 1 1 1 1 2 Particles of the above (a) 316 158 79 254 254 Lactose - - 62 62 Magnesium stearate 4 2 1 4 4 (c) Where the FC bond is located 111892.doc -20- 200800197 [Table 3] Unit: mg Component Example No. Comparison Example No. 1 2 3 1 2 Bare ingot of the above (b) 320 160 80 320 320 Hydroxypropyl methylcellulose 3.25 1.95 1.3 2.6 2.6 Titanium oxide 1 0.6 0.4 0.8 0.8 Polyethylene glycol 6000 0.75 0.45 0.3 0.6 0.6 Palm powder wax 0.01 0.006 0.004 0.01 0.01 (d) Lurasidone per container is 80 mg System dissolution test

For each of the coated tablets containing 80 mg, 40 mg, and 20 mg of Lurasidone in a system containing 80 mg of Lurasidone per container, a dissolution test was performed, and the similarity of the respective dissolution characteristics was evaluated by f2. As shown in Table 4, the f2 values of Examples 2 and 3 showed similarities to those of Example 1, and the f2 values of Comparative Example 2 did not show similarities with Comparative Example 1. That is, as shown in Table 4 and Fig. 3, in Examples 1 to 3, the f2 value showing the similarity of the dissolution characteristics was in the range of 50$f2$100, and even in the preparations having different contents, the f2 value was obtained without dependence. A formulation having a content of a tablet (force) and exhibiting similarity in dissolution characteristics. On the other hand, as shown in Table 4 and Fig. 2, the details are disclosed in Test 8, and Patent Document 2 discloses Comparative Example 2 of the prescription, and the dissolution of the preparation 2 ingot from the side of Comparative Example 1 is significantly later, and The similarity of the dissolution profile is not shown. [Table 4] Similar Factor Example No. Comparative Example No. 1 2 3 1 2 £2 - 88 97 - 37 (e) Dissolution test of a system of 40 mg of Lurasidone per 1 container 111892.doc -21 - 200800197 Per 1 In the system of 40 mg of Lurasidone in the container, the coating test of 40 mg and 20 mg of Lurasidone was carried out, and the dissolution test was carried out, and the f2 value was also used to evaluate the similarity of the respective dissolution characteristics. As shown in Table 5, the f2 values of Example 3 and Comparative Example 1 showed similarities to those of Example 2. That is, in the system of 40 mg of Lurasidoiie per container, the f2 value is in the range of 50 Sf 2 $ 100, and the similarity of the dissolution characteristics can be exhibited without depending on the tablet content (force price). [Table 5] Similar Factor Example No. Comparative Example No. 2 3 1 η - 88 97 <Test 2> In Examples 1 and 4, preparation of a water-soluble excipient and a water-soluble polymer binder and a part of α were prepared. A preparation of a pharmaceutical composition composed of starch. Further, in Comparative Examples 3, 4 and 5, a preparation containing a water-soluble excipient and a pharmaceutical composition comprising corn starch which is a water-soluble polymer binder and an ungelatinized starch was prepared. The dissolution test of each preparation was carried out, and the similarity of the dissolution characteristics was evaluated based on the f2 value. The results are shown in Table 9. (a) Where the granulated powder is located 111892.doc 22- 200800197 [Table 6]

Unit: mg Ingredient Example No. Comparative Example No. 1 4 3 4 5 Lurasidone 80 80 80 80 80 Mannitol 144 176 108 108 - Lactose - - - - 108 Partially gelatinized starch 80 40 - - Cornstarch - - 40 40 40 Cross-linked carboxymethylcellulose sodium 4 8 16 16 16 Hydroxypropyl methylcellulose 8 12 10 10 10 (b) Particles/naked bonds for bonding [Table 7] Unit: mg Ingredient Example No. Comparative Example No. 1 4 3 4 5 Particles of the above (a) 316 316 254 254 254 Mannitol - - 62 - - Magnesium stearate 4 4 4 4 4 (c) Where the FC bond is [Table 8] Unit: mg Component Example number Comparative Example No. 1 4 3 4 5 The above-mentioned Ct〇 bare ingot 320 320 320 258 258 Hydroxypropyl fluorenyl cellulose 3.25 - 2.6 2.6 2.6 Titanium oxide 1 - 0.8 0.8 0.8 Polyethylene glycol 6000 0.75 - 0.6 0.6 0.6 (d Dissolution test 111892.doc -23- 200800197 As shown in Table 9, Example 4 shows similarity to Example 1, but the f 2 values of Comparative Examples 3, 4, and 5 did not show the same as Example 1. Similarity. Namely, the corn starch-containing preparations of Comparative Examples 3, 4 and 5 had different elution characteristics than the preparations containing the partially gelatinized starch of Examples 1 and 4, and were slow-dissolving preparations. [Table 9] Ingredient Example No. Comparative Example No. 1 4 3 4 5 £2 - 67 44 29 26 <Test 3> In Examples 4, 5, 6, and 7, the amount of partial alpha-starch added to the dissolution property The impact is evaluated. The results are shown in Table 13. (a) where the granulated powder is located [Table 10]

Unit: mg Ingredient Example No. 1 4 5 6 7 Lurasidone 80 80 80 80 80 Mannitol 144 176 116 136 156 Section (X-starch 80 40 100 80 60 croscarmellose sodium 4 8 8 8 8 Propylmethylcellulose 8 12 12 12 12 (b) Particles for bonding/naked bonds 111892.doc -24- 200800197 [Table 11] Unit: mg Ingredient Example No. 1 4 5 6 7 (a) Granule 316 316 316 316 316 Magnesium stearate 4 4 4 4 4 (c) Where the FC ingot is [Table 12] Unit: mg Ingredient Example No. 1 4 5 6 7 Particles of the above (b) 320 320 320 320 320 Hydroxyl Propyl fluorenyl cellulose 3.25 - - Titanium oxide 1 - - - - Polyethylene glycol 6000 0.75 - - - - Palm wax 0.01 - - - (d) Dissolution test:

As shown in Table 13, the f2 values of Examples 4, 5, 6, and 7 showed similarities to those of Example 1. Namely, a preparation comprising a pharmaceutical composition containing a part of a gelatinized starch having a composition of 10% by weight or more or more showed rapid solubility and exhibited similar dissolution characteristics. [Table 13] Ingredients 施 • Example No. 1 4 5 6 7 £2 - 67 60 62 81 &lt;Test 4 &gt; In Comparative Example 6, an attempt was made to prepare a water-soluble excipient and a partially gelatinized starch, but A tablet containing no water-soluble polymer binder, in the tableting step, 111892.doc -25-200800197 is covered and adhered and cannot be tableted, so that the tablet can not be obtained, and a similar dissolution profile is not obtained. In Examples 8, 9, 10 and 11, a preparation of a pharmaceutical composition containing a water-soluble excipient and a partially gelatinized starch and a water-soluble polymer binder different in added amount was prepared. The results are shown in Table 17. (a) Where the granulated powder is [Table 14] Unit: mg Ingredient Example No. Comparative Example No. 1 8 9 10 11 6 Lurasidone 80 80 80 80 80 80 Mannitol 14 13 138 140 142 148 4 6 Partially colored hall Powder 80 80 80 80 80 80 croscarmellose sodium 4 8 8 8 8 8 decyl cellulose 8 12 10 8 6

(b) Ingot tablet/bare ingot [Table 15] Unit: mg Ingredient Example No. Comparative Example No. 1 8 9 10 11 6 Particles of the above (a) 316 31 316 316 31 316 6 6 Magnesium stearate 4 4 4 4 4 4 (c) Where the FC key is 26-111892.doc 200800197 [Table 16]

Unit: mg Ingredient Example No. Comparative Example No. 1 8 9 10 11 6 Particles of the above (b) 320 32 32 32 32 320 0 0 0 0 Propylmethylcellulose 3.25 - - - - - Titanium oxide 1 - - - polyethylene glycol 6000 0.75 - - - - - palm wax 0.01 - - - - - (d) dissolution test table as shown in Table 17, the f2 values of Examples 8, 9, 10, 11 are shown and examples 1 similarity. Namely, a formulation composed of a pharmaceutical composition containing a water-soluble polymer binder in a range of 1.8% wt/wt to 3.8% wt/wt showed rapid solubility and exhibited similar dissolution characteristics. [Table 17] Similarity factor ^ Example number 1 8 9 10 11 £2 - 77 81 73 73 &lt;Test 5&gt;

In Example 12, lactose was used as a water-soluble excipient to prepare a preparation containing a pharmaceutical composition comprising a water-soluble polymer binder and a partially gelatinized starch. The results are shown in Table 21. (a) granulated powder side 111892.doc -27- 200800197 [Table 18] Unit: mg Ingredient Example No. 1 6 12 Lurasidone 80 80 80 Mannitol 144 136 Lactose - - 136 Partially gelatinized starch 80 80 80 Sodium carboxymethylcellulose 4 8 8 Hydroxypropyl methylcellulose 8 12 12 (b) Particles for bonding/naked: Where? [Table 19] Unit: mg Ingredient Example No. 1 6 12 (a) above Granules 316 316 316 Magnesium stearate 4 4 4 (c) FC Record: Where square [Table 20] Unit: mg Ingredient. Example No. 1 6 12 The above-mentioned (b) bare ingot 320 320 320 by propyl methyl Cellulose 3.25 - - Titanium oxide 1 - Polyethylene glycol 6000 0.75 - - Palm wax 0.01 - _ (d) Dissolution test: 111892.doc -28- 200800197 As shown in Table 21, the f2 values of Examples 6 and 12, The similarity to Example 1 is shown. Namely, using mannitol and lactose as water-soluble excipients showed rapid solubility and exhibited similar dissolution characteristics. [Table 21] Ingredient Example No. 1 6 12 η - 62 66 <Test 6 &gt; In Examples 4, 13, 14, and 15, a raw powder of Lurasidone having a different particle size distribution was used to prepare a content containing a water-soluble excipient. And a preparation of a specific pharmaceutical composition of a water-soluble polymer binder and a partially gelatinized starch. The results are shown in Table 25. (a) Particle size distribution of the original powder of Lurasidone, so-called D50% (50% particle diameter), which means a particle diameter at a point where the cumulative distribution can be calculated according to the volume standard, so-called D90% (90% particle diameter), The volume basis calculates the particle diameter at a point where the cumulative distribution is 90% (under the sieve). [Table 22] Unit: mg Particle size distribution Example No. 4 13 14 15 Particle diameter D10% 0.5 , 0.9 1.0 1.5 D50% 1.6 5.9 7.6 13.9 D90% 4.7 17.5 26.9 58.3 (b) Particles for ingots/naked ingots 111892 .doc •29- 200800197 [Table 23] Unit: mg Ingredient Example No. 4 13 14 15 Lurasidone 80 80 80 80 Mannitol 176 144 144 144 Partially gelatinized starch 40 80 80 80 Croscarmellose sodium 8 4 4 4 Hydroxypropyl base cellulose 12 8 8 8 Magnesium stearate 4 4 4 4 (c) Where the FC bond is [Table 24] Unit: mg Ingredient Example No. 4 13 14 15 Naked (b) above Ingot 320 320 320 320 Hydroxypropyl methylcellulose - 3.25 3.25 3.25 Titanium oxide - 1 1 1 Polyethylene glycol 6000 - 0.75 0.75 0.75 Palm wax - 0.01 0.01 0.01 (d) Dissolution test As shown in Table 25, examples The f2 values of 13, 14, and 15 show similarities to those of the fourth embodiment. That is, it was found that a similar dissolution profile can be obtained when a preparation prepared by using a raw material of Lurasidone having a particle size distribution of 50% particle diameter in the range of 1 to 8 μηη and 90% particle diameter of 27 μπη or less 30. 111892.doc 200800197 [Table 25] Similar Factor Example No. 4 13 14 15 {2 - 56 56 46 &lt;Experiment 7&gt; Using the technique disclosed in Patent Document 2, a preparation of a formulation having a Lurasidone content of 10 mg and 40 mg in one tablet; In Document 2, it was confirmed whether or not an oral preparation exhibiting the same dissolution state can be provided in the range of 10 mg to 40 mg of Lurasidone in one tablet. The results are shown in Figure 1. The following oral preparations can be provided: as shown in Fig. 1, the dissolution characteristics of the preparations containing different contents of Lurasidone obtained by the technique disclosed in Patent Document 2 are indicated by the value of f2, and the drum containing 10 mg of Lurasidone in one tablet The agent and the preparation containing 40 mg can show the dissolution state (a) of the particle equivalent to Patent Document 2 [Table 26]

Unit: mg Ingredient 10 mg Key 40 mg Key Lurasidone 10 40 Mannitol 47 188 Cross-linked carboxymethylcellulose sodium 4 16 Hydroxypropyl fluorenylcellulose 2.5 10 (b) Bare ingots 111892.doc -31 - 200800197 [Table 27] Unit: mg Ingredient 10 mg Suspected 40 mg Ingot (a) Granules 63.5 254 Lactose 15.5 62 Magnesium stearate 1 4 (c) Where the FC bond is [Table 28] Unit: mg Ingredient 10 mg Ingot 40 Mg bond of the above (b) particles 80 320 hydroxypropyl methylcellulose 1.3 2.6 titanium oxide 0.4 0.8 polyethylene glycol 6000 0.3 0.6 palm butterfly 0.006 0.01 &lt;Test 8 &gt; It is confirmed that the technique disclosed in Patent Document 2 It is possible to provide an oral preparation in which the preparation of Lurasidone containing up to 40 mg in one tablet shows the same dissolution state. Here, using the technique disclosed in Patent Document 2, a preparation containing no Lurasidone content of 80 mg in a single bond of a part of α-starch was prepared. Since the enlargement of the tablet increases the burden on the patient, it can be made by increasing the content of the effective ingredient by a factor of two to achieve the same weight of the bond as the 40 mg tablet. The results of Comparative Examples 1 and 2 are shown in Table 4 and Figure 2. As shown in Table 4 and Figure 2, the technique disclosed in Patent Document 2 indicates by the value of f2 that the content of Lurasidone is increased by a factor of 2, and the 80 mg bond of the gelatinized starch is not displayed, and it cannot be displayed with the 40 mg ingot. The same dissolution properties of the ingot. 111892.doc -32- 200800197 (a) Where the granules are [Table 29] Unit: mg Ingredient 40 mg Spiral 80 mg Spiral Lurasidone 40 80 Mannitol 188 148 Cross-linked carboxymethylcellulose sodium 16 16 propylmethyl Cellulose 10 10 (b) where the bare key is

[Table 30] Unit: mg Ingredient 40 mg ingot 80 mg bond (a) Particle 254 254 Lactose 62 62 Magnesium stearate 4 4 (c) Where FC bond is present [Table 31] Unit: mg Ingredient 40 mg Spiral 80 mg The particles of the above (b) 320 320 hydroxypropyl methylcellulose 2.6 2.6 titanium oxide 0.8 0.8 polyethylene glycol 6000 0.6 0.6 brown wax 0.01 0.01 <Test 9> The trials of Examples 1 to 3 of Test 1 The three formulations having different contents were evaluated for dissolution. The results are shown in Figure 3. 111892.doc -33- 200800197 As shown in Fig. 3, in the preparation of Lurasidone containing 20 mg to 80 mg in one tablet according to the present invention, it is also confirmed that the content of the spinning agent (the price) is the same. Dissolution. (a) where the granulated powder is [Table 32] Unit 2 mg Ingredient 80 mg ingot 40 mg bond 20 mg Suspected Lurasidone 80 40 20 Mannitol 144 72 36 Partially gelatinized starch 80 40 20 Cross-linked carboxymethylcellulose sodium 4 2 1 Hydroxypropyl methylcellulose 8 4 2 (b) Particles for tableting / bare ingots [Table 33] Unit: mg Ingredient 80 mg Ingot 40 mg Bond 20 mg Ship 316 158 of (a) above 79 Lactose - - Magnesium stearate 4 2 1 (c) Where is the FC bond?

[Table 34] Unit: mg Ingredient 80 mg Spin 40 mg Bond 20 mg Bond Particles of the above (b) 320 160 80 Hydroxypropylmethylcellulose sodium 3.25 1.95 1.3 Titanium oxide 1 0.6 0.4 Polyethylene glycol 6000 0.75 0.45 0.3 Palman can be used in the following manner: The dissolution state of the preparation. (a) Experimental method According to the present invention, the production method and the production method 2 of Patent Document 2 (disclosed below) were reduced to 12 〇 mg of Lurasid〇ne ingot preparation (Table 35). The test preparations were subjected to a dissolution test after partially changing the conditions described in the c. quality evaluation and price dissolution test of the examples of the present application. The dissolution test was carried out by changing the pH of the diluted solution as the test solution from pH 4·〇 to ρΗ 3·8. (b) The method of the present invention comprises 8000 g of Lurasidone, 14200 g of D-mannitol, 8000 g of partially alpha-killing powder, and 400 g of croscarmellose sodium into a fluidized bed granulator ( In the FLOW COATER FLF-30/Freund industry, a pre-prepared 5% hydroxypropyl methylcellulose solution was dispersed on one side with an inhalation temperature of 8 ° C and an inspiratory volume of 7 m 3 /min. Granulation was carried out at a spray rate of 200 mL/min and a spray air flow rate of 200 L/min. The obtained granules were placed in a granulator, and dried at a drying temperature of 80 ° C and a drying time of 10 minutes, and the drying loss was confirmed to be within 2 ° / Torr by a halogen moisture meter. The obtained granules were granulated using a granulator (FIORE F-0 type). Next, using a mixer (Container size 110L), the obtained 18,000 g of the granules was mixed with 228 g of magnesium stearate at a rotation speed of 20 rpm and a mixing time of 5 minutes. Finally, using a tableting machine (HT-111892.doc -35-200800197 AP12SS-II/畑铁工所), the resulting mixture was tableted at a bark pressure of 12.5 kN to make a 120 mg Lurasidone bond bare ingot. . (c) Production method 2 of Patent Document 2 160 g of Lurasidone, 296 g of D-mannitol, and 32 g of crosslinked fluorenyl cellulose sodium were placed in a fluidized bed granulator (Multiplex MP_ 01/Powrex). The previously prepared 5% hydroxypropylmethylcellulose solution was dispersed, and granulation was carried out under the conditions of a supply air temperature of 60 ° C and a granulation time of 45 minutes. The obtained granules were placed in a granulator, and dried at a drying temperature of 80 ° C and a drying time of 5 minutes, and the dry reduction value was confirmed to be within 1% by a halogen water content. Next, 254 g of the obtained granules were mixed with 62 g of lactose using a mixer (tube chemistry apparatus) at a rotation speed of 40 μ: pm and a mixing time of 30 minutes. Thereafter, a mixture of 316 g and 4 g of magnesium stearate were mixed using a mixer (tube chemistry apparatus) at a rotation speed of 40 rpm and a mixing time of 5 minutes. Using a tableting machine (^^-八?1288-11/畑铁工所), the resulting mixture was tableted with a press of 12.5 1^^ to make a 120 mg Lurasidone bare ingot. (d) Experimental results The composition of the prototype prepared and the results of the dissolution test are disclosed below. 111892.doc 36· 200800197 [Table 35] Formulation of tablet composition 034-15-120-1000 RP-03323-1204000 (Technology of the present application) (Disclosure technique of Patent Document 2) Lurasidone 120 120 Mannitol 213 222 Partially modified starch 120 24 Crosslinked methylcellulose sodium 6 TablettoseTO 93 Hydroxypropyl decyl cellulose magnesium stearate 15 6 15 6 Total 480 480 Dissolution status time (minutes) Dissolution rate (%) 10 83 54 15 91 66 30 95 80 45 96 84 £2 value - 37 Based on the results, it was confirmed that the Lurasidone 120 mg bond was experimentally produced according to the technique disclosed in the present application as compared with the Lurasidone 120 mg ingot prepared according to the technique disclosed in Patent Document 2. Shows fast solubility. &lt;Test 11&gt; The applicable range of the drug substance content of the present invention was evaluated in accordance with the dissolution state of the preparation. (a) Experimental method According to the production method of the present invention, 80 mg of Lurasidone ingot (Table 36) was experimentally produced. The dissolution test was carried out on the prototypes prepared in the C. Quality Evaluation (1) dissolution test of the examples of the present specification. 111892.doc -37- 200800197 (b) Manufacturing method Lurasidone, D-mannitol, partially gelatinized starch, and croscarmellose sodium are introduced into a fluidized layer granulator (Multiplex ΜΡ-01/Ρowrex). The previously prepared 5% hydroxypropyl fluorenylcellulose solution was dispersed, and granulation was carried out under the conditions of a supply air temperature of 60 ° C and a granulation time of 45 minutes or 60 minutes. The obtained granules were placed in a granulator, and dried at a drying temperature of 80 ° C and a drying time of 5 minutes, and the drying loss was confirmed to be within 2% by halogen water. Next, the obtained granules and magnesium stearate were mixed using a mixer (tube well chemistry apparatus) at a rotation speed of 40 rpm and a mixing time of 5 minutes. Finally, the obtained mixture was subjected to tableting using a tableting machine (HT-AP12SS-II/畑铁工所) at a tableting pressure of 10 kN to prepare an 80 mg Lurasidone screw. c) Experimental results The composition of the prototype prepared and the results of the dissolution test are disclosed below.

111892.doc 38- 200800197 [Table 36] Prescription 034-15-80- RP- RP- RP- 1000 03320 03321 03322 Lurasidone 80 80 80 80 Mannitol 142 104 67 30 Partial Alpha Powder 80 80 80 80 Crosslinking Carboxymethyl cellulose sodium 4 4 4 4 Hydroxypropyl decyl cellulose 10 8 6 4 Magnesium stearate 4 4 3 2 Total 320 280 240 200 Dissolution time (minutes) Dissolution rate (%) 10 85 73 71 68 15 89 80 80 81 30 93 88 88 89 45 94 90 91 91 Ω value - 60 60 63 Based on the results, it is confirmed that the content in the Lurasidone preparation is

In the range of 25 to 40%, it is a formulation which exhibits similar dissolution characteristics &lt;Test 12&gt; Evaluation of the dissolution state of the preparation of the water-soluble polymer binder of the present invention (a) Experimental method Manufacturing according to the present invention Method, trial production of Lurasidone 80 mg suspect (Table 37). C. Quality evaluation (1) The conditions recorded in the dissolution test in the examples of the present specification, and the dissolution test was carried out on the prototypes prepared. (b) Method of manufacture 160 g of Lurasidone, 284 g of D-mannitol, 160 g of partially alpha-dose powder, and 8 g of cross-linked Weimethylcellulose into a fluidized layer granulator 111892.doc -39- In 200800197 (Multiplex MP-01/Powrex), a 5% water-soluble polymer binder solution prepared in advance was dispersed, and granulation was carried out under the conditions of a supply air temperature of 60 ° C and a granulation time of 45 minutes. The obtained granules were placed in a granulator, and dried at a drying temperature of 80 ° C and a drying time of 5 minutes, and the dry reduction amount was confirmed to be within 2% by halogen water. Next, the obtained granules were mixed with magnesium stearate using a mixer (Tujing Chemical Instruments Co., Ltd.) under the conditions of a rotation speed of 40 rpm and a mixing time of 5 minutes. Finally, using a tableting machine (HT-AP12SS-II/畑铁工所), the resulting mixture was tableted with a 10 kN tableting pressure to make an 80 mg Lurasidone bond to the bare 0 (c) experiment. Results The composition of the prototype and the results of the dissolution test are disclosed below. [Table 37]

Formulation of lozenge 034-15-80- 1000 RP-03326 RP-03327 RP-03328 Lurasidone 80 80 80 80 Mannitol 142 142 142 142 Partially gelatinized starch 80 80 80 80 Crosslinked carboxymethylcellulose 4 4 4 4 Nano 10 - - - Hydroxypropyl methylcellulose 10 - - Polyvinyl alcohol - - 10 - Polyvinyl pyrrolidone _ - - 10 Hydroxypropyl cellulose 4 4 4 4 Magnesium stearate total 320 320 320 320 Dissolution status time (minutes) Dissolution rate (%) 10 83 59 78 80 15 91 76 82 87 30 95 94 88 91 45 96 96 90 92 £2 value - 53 56 69 111892.doc -40- 200800197 Based on the result It is confirmed that 'the use of polyvinyl alcohol, polyethylene TJ piroxicam _, hydroxypropyl cellulose as a water-soluble polymer binder preparation, can be satisfied to meet the sixth page of this manual &quot; C · quality evaluation (2) dissolution A standard of similarity &quot; a similar formulation (similar to the dissolution profile). &lt;Experiment 13&gt; The dissolution state of the FC ingot of the manufactured Lurasidone 20, 40, 80, and 120 mg bonds was evaluated by the technique of the present invention. (a) Experimental method According to the production method of the present invention, FC ingots of Lurasidone 20, 40, 80, and 120 mg ingots were produced (Table 38). (b) Method of manufacture 8000 g of Lurasidone, 14200 g of D-mannitol, 8000 g of partially gelatinized starch, and 400 g of croscarmellose sodium into a flow layer granulator (FLOW COATER FLF_30/ In the Freimd industry, a pre-prepared aqueous solution of 5% hydroxypropylmethylcellulose was dispersed on the one hand at an inhalation temperature of 80 ° C, an inspiratory flow of 7 m 3 /min, and a spray rate of 200 mL/min. Granulation was carried out at a spray air flow rate of 200 L/min. After the completion of the liquid discharge, the drying was carried out under the conditions of a drying temperature of 80 ° C and a drying time of 10 minutes, and the dry reduction amount was confirmed to be within 2% by a halogen moisture meter. The obtained granulated powder was granulated using a granulator (FIORE F-0 type / Deshou Work). Next, using a mixer (Container size 110L/Furukawa Altech), 18,000 g of the obtained granulated powder was mixed with 228 g of magnesium stearate at a rotation speed of 20 rpm and a mixing time of 5 minutes. Use a tablet machine (for Lurasidone 20, 40, 80 spinning bare ingots, use 111892.doc -41 - 200800197 CLEANPRESS Correct 12HUK / Kikusui Manufacturing Co.; for the bare key of the Lurasidone 120 mg ingot, use HT-AP12SS-Π /畑铁In the factory, the obtained mixed powder is ingot at a tableting pressure of about 10 kN to produce a bare bond of the Lurasidone 20, 40, 80, and 120 mg bonds. Secondly, the bare ingot was coated at a supply air temperature of 80 ° C, an air volume of 0.6 m 3 /min, a coating pan rotation speed of 25 rpm, a spray hydraulic pressure of 0.55 MPa, and a liquid velocity of 5 g/min to obtain a Lurasidone 20, FC ingots of 40, 80, 120 mg ingots. (c) Dissolution test # The dissolution test of the test preparation was carried out in accordance with the second method of the Japanese Pharmacy Dissolution Test Method. The measurement conditions are disclosed below. Test solution: diluted Mcllvaine buffer (diluted Mcllvaine buffer, pH 3·8 and 4·0) Paddle rotation speed: 50 rpm Test solution: 900 ml (d) Experimental results The composition of the prototype preparation and the results of the dissolution test are disclosed below.

-42- 111892.doc 200800197 [Table 38]

Composition of tablets

Lurasidone Lurasidone Lurasidone Lurasidone Product Name 20 mg Ingot 40 mg Ingot 80 mg Ingot 120 mg FC Ingot FC Ingot FC Ingot FC Ingot Lot No. 034-15-20 034-15-40 034-15-80 034-15- 120 Lurasidone Mannitol 20 mg 40 mg 80 mg 120 mg Partially gelatinized starch 35.5 mg 71 mg 142 mg 216 mg croscarmellose 20 mg 1 mg 40 mg 2 mg 80 mg 4 mg 120 mg 6 mg 2.5 mg 5 mg 10 mg 15 Mg hydroxypropyl methylcellulose 1 mg 2 mg 4 mg 6 mg magnesium stearate subtotal 80 mg 160 mg 320 mg 480 mg hydroxypropyl methylcellulose 1.001 mg 1.690 mg 2.730 mg 1.100 mg titanium oxide 0.308 mg 0.520 mg 0.840 mg 0.825 mg Macrogol 6000 0.231 mg 0.390 mg 0.630 mg 5.500 mg Palm wax 0.01 mg 0.01 mg 0.01 mg 0.01 mg Total 81.55 mg 162.61 mg 324.21 mg 485.51 mg Dissolution status time (minutes) Dissolution rate (%) 10 80 77 77 77 15 91 90 88 92 30 100 98 93 96 45 101 100 94 , 97 pH of the test solution 4.0 ^ 4.0 4.0 3.8 Based on the results, it was confirmed that the test was carried out according to the technique disclosed in the present application.

Lurasidone FC ingots of 20, 40, 80, and 120 mg bonds showed fast solubility. &lt;Test 13&gt; FC ingot for 1 ingot 40 mg ingot FC ingot/ingot in 20 mg ingot, FC ingot in 1 ingot 80 mg ingot, ingot in FC ingot in 40 mg ingot , FC bond of 1 ingot 120 mg/3 recording: The similarity of the dissolution state of the FC ingot of 40 mg ingot/FC ingot of 6 suspected 20 mg ingot was evaluated. (a) Experimental method 111892.doc -43 - 200800197 The manufacturing method and test method are the same as the dissolution state of the test 12, and the omission thereof (b) The experimental results show the dissolution state of the preparation prepared as follows and the like (Table 39) 40 20-key agent mg mg ingot record: number of tablets 1 ingot 2 tablets dissolved β U rate (%) 1 hour 0 between 1 77 79 ( 5 90 90 \ 3 98 98 knife 0 100 100 ) 4 5 Ω value - 100 δϋ mg —1 spindle 40 mg one spindle 20 120 tons rotary mg ingot 40 mg ingot 20 mg ingot 2 ingot L, 4 ingots 1 ingot 3 ingots 6 ingot dissolution rate (%) Dissolution rate (%) 77 88 93 94 78 86 91 93 75 77 84 go 90 96 92 97 90 94 97 98 83 90 94 95 85 74 _ Ί 88 Page 83 “0:•Quality evaluation (2) Dissolution characteristics similarity”. [Industrial Applicability] According to the present invention, a ruthenium _[4_[4_(ι,2_benzoquinone-3-yl)-1-hexahydropyridazinyl]-(2R,3R) can be provided. -2,3-Butyl butyl butyl ketone (1 R'2 S,3'R,4'S)-2,3-bicyclo[2,2,1]heptanimide hydrochloride (Lurasidone) is an orally administered preparation which exhibits the same eluted state even if the content of the active ingredient is changed in the oral preparation which is excellent in disintegration of the active ingredient. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a graph showing the comparison of dissolution characteristics of formulations having different Lurasidone contents. In the one-piece trial produced by the technique disclosed in Patent Document 2, 111892.doc -44- 200800197

Formulations with a dose of 10 mg (4 spindles) and 40 mg (1 bond) of Lurasidone were measured for their dissolution characteristics. Figure 2 is a graph showing the dissolution characteristics of formulations having different Lurasidone contents. For the preparation of the product having a content of Lurasidone of 40 mg (2 recordings:) and 80 mg (1 tablet) in one tablet which was experimentally produced by the technique disclosed in Patent Document 2, the dissolution characteristics were measured. Figure 3 is a graph showing the dissolution characteristics of formulations having different Lurasidone contents. For the preparation of the ingots having a Lurasidone content of 20 mg (4 bonds), 40 mg (2 bonds) and 80 mg (1 bond:) in one tablet which was experimentally produced by the technique of the present invention, the dissolution characteristics were measured.

111892.doc 45-

Claims (1)

200800197 X. Patent application scope: 1. An oral preparation containing: N-[4-[4-(1,2-Benzoisothiazol-3-yl)-1-hexahydropyridazinyl]-(2R,3R)-2,3-butylene-butyl Base)_(l,R,2'S,3'R,4'S)-2,3-bicyclo[2,2,1]heptyl-imidemine hydrochloride (Lurasidone), alpha-dose powder, Water-soluble excipients, water-soluble polymer binders. 2. An oral preparation for granulating a mixed powder comprising Lurasid〇ne, a gelatinized starch and a water-soluble excipient using a solution in which a water-soluble polymer binder is dissolved. 3. A t-block preparation which is obtained by granulating a mixed powder containing a gelatinized starch and a water-soluble excipient by dissolving or dispersing a solution of a Lurasidone and a water-binding surface molecular binder. 4. An oral preparation according to any one of the above 1 2 rK, wherein the water-soluble excipient is mannitol or lactose. 5. A method of granulating, which is carried out by using a solution in which a water-soluble polymer binder is dissolved, and a mixed powder of Lurasidone, a starch, and a water-soluble excipient. The method of granules. 6.: Species: granule method </ RTI> A method of granulating a mixed powder comprising a gelatinized starch and a water-soluble form d using a solution in which a water-soluble south molecular bond is dissolved or dispersed. A granulation method according to the item 5, wherein the water-soluble excipient is mannitol 111892.doc 200800197 or lactose. The oral preparation according to any one of claims 1 to 4, wherein the amount of the gelatinized starch is 10 to 5 % by weight (wt/wt) based on the weight of the preparation. The oral preparation according to any one of claims 1 to 4, wherein the added mash of the gelatinized starch is 20 to 30% by weight (wt/wt) of the weight of the preparation. The oral preparation according to any one of claims 1 to 4, wherein the Lurasidone content in the preparation is 20 to 45% (wt/wt) ° II. The method according to any one of claims 1 to 4 Oral preparation wherein the Lurasidone content in the preparation is 25 to 40% (wt/wt). 12. The oral preparation according to any one of items 1 to 4, wherein the amount of Lurasidone in one tablet is 10 to 160 mg. The oral preparation according to any one of claims 1 to 4, wherein the amount of Lurasidone in one tablet is 20 to 120 mg. The oral preparation according to any one of claims 1 to 4, wherein the amount of Lurasidone in one tablet is 40 to 120 mg. The oral preparation according to any one of items 1 to 4, wherein the water-soluble excipient is mannitol or lactose, and the amount of the gelatinized starch is 10 to 50% based on the weight of the preparation. (wt/wt). The oral preparation according to any one of claims 1 to 4, wherein the water-soluble excipient is mannitol or lactose, and the Lurasidone content in the preparation is 25 to 40% (wt/wt) 〇17·if requested The oral preparation according to any one of items 1 to 4, wherein the starch is added in an amount of 10 to 5 % by weight based on the weight of the preparation, and the Lurasidone content in the preparation is 25 to 40% (wt/ Wt). The oral preparation according to any one of claims 1 to 4, wherein the water-soluble excipient is mannitol or chyle, and the amount of the gelatinized starch is 10% relative to the weight of the preparation. The oral preparation of any one of claims 1 to 4, wherein the water-soluble excipient is mannose, 50% (wt/wt), the amount of the Lurasidone in the preparation is 25 to 40% (wt/wt). Alcohol or chyle, alpha-starch is added in an amount of 20 to 30% (wt/wt) relative to the weight of the preparation, and the amount of Lurasidone in the preparation is 25 to 40% (wt/wt) 〇20. The oral preparation according to any one of 4, wherein the water-soluble excipient is mannitol or chyle, and the amount of the gelatinized starch is 20 to 30% (wt/wt) based on the weight of the preparation, and Lurasidone is 1 The content of the ingot is 40 to 120 mg. The oral preparation according to any one of claims 1 to 4, wherein the gelatinization rate of the alpha-starch is 50 to 95%. The oral preparation according to any one of claims 1 to 4, wherein the average particle diameter of the Lurasidone is 〇·1 to 8 μηι. The oral preparation according to any one of claims 1 to 4, wherein the water-soluble component in the gelatinized starch is 30% or less. The oral preparation according to any one of claims 1 to 4, wherein the excipient is mannitol or lactose, and the amount of the gelatinized starch is 20 to 30% (wt/wt) based on the weight of the preparation. The Lurasidone content in the preparation is 25 to 40% (wt/wt), and the content of Lurasidone in one tablet is 20 to 120 mg. 111,892.doc