JP7584249B2 - Method for mixing a mixture containing prasugrel and its use - Google Patents

Description

The present invention relates to a method for mixing a mixture containing prasugrel. The present invention relates to a method for producing a pharmaceutical composition containing prasugrel. The present invention relates to a method for producing a tablet and an orally disintegrating tablet containing prasugrel as an active ingredient. The present invention relates to a method for improving the dissolution property of prasugrel from a pharmaceutical formulation.

Prasugrel is a compound represented by the following formula (I), and its chemical name is 5-[(1RS)-2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate. Prasugrel is used for patients with acute coronary syndrome (unstable angina, non-ST-elevation myocardial infarction, or ST-elevation myocardial infarction), stable angina, or old myocardial infarction who are scheduled to undergo percutaneous coronary intervention (PCI). Patent Document 1 describes an example of a formulation of prasugrel hydrochloride.

In the manufacture of pharmaceutical preparations, the active ingredient and excipients are mixed and the resulting mixture is then sieved (sieving). It is known that sieving not only classifies the mixture of active ingredient and excipients, but also produces a uniform mixture. For this reason, sieving is a commonly performed operation in the manufacture of solid preparations such as tablets.

JP 2003-246735 A

The inventors produced tablets using a mixture obtained by sieving a mixture of prasugrel and excipients. When a dissolution test was performed on the obtained tablets, the dissolution of the active ingredient was not satisfactory. The present invention aims to provide a means for producing a pharmaceutical formulation containing prasugrel with improved dissolution of the active ingredient.

The present inventors mixed a mixture of prasugrel and excipients using an impact crusher, produced tablets using the resulting mixture, and performed a dissolution test. They found that the dissolution of the active ingredient was improved compared to tablets produced using a mixture obtained by sieving, and thus completed the present invention. Thus, the present invention provides a method for mixing a mixture containing prasugrel, which includes mixing a mixture of prasugrel and excipients using an impact crusher. The present invention also provides a method for producing a pharmaceutical composition, which includes mixing a mixture of prasugrel and excipients using an impact crusher to obtain a pharmaceutical composition containing prasugrel.

The present invention provides a method for producing tablets containing prasugrel as an active ingredient, which includes the steps of mixing a mixture of prasugrel and excipients using an impact mill, mixing the mixture obtained in the mixing step with tablet additives to obtain a mixture for tableting, and compressing and molding the mixture for tableting to obtain tablets.

The present invention provides a method for producing an orally disintegrating tablet containing prasugrel as an active ingredient, the method comprising the steps of: mixing a mixture of prasugrel and an excipient using an impact mill; mixing the mixture obtained in the mixing step with disintegrating particles and tablet additives to obtain a mixture for tableting; and compressing and molding the mixture for tableting to obtain an orally disintegrating tablet.

The present invention provides a method for improving the dissolution of prasugrel from a pharmaceutical preparation by mixing a mixture of prasugrel and excipients using an impact mill and producing a pharmaceutical preparation containing prasugrel as an active ingredient using the resulting mixture.

The present invention provides a means for producing a pharmaceutical formulation containing prasugrel with improved dissolution of the active ingredient.

1 is a graph showing the dissolution properties of orally disintegrating tablets of Example 1 and Comparative Example. 1 is a graph showing the dissolution properties of the orally disintegrating tablets of Examples 1 and 2. 1 is a graph showing the dissolution properties of the orally disintegrating tablets of Examples 1, 3 and 4.

[1. Mixing method for mixtures containing prasugrel]
In the method for mixing a mixture containing prasugrel of this embodiment (hereinafter also simply referred to as the "mixing method"), a mixture of prasugrel and an excipient is mixed using an impact mill.

As used herein, the term "prasugrel" includes the compound represented by the above formula (I), its enantiomers and mixtures thereof, as well as pharma- ceutically acceptable salts and solvates thereof. The enantiomers of the compound represented by the above formula (I) are derived from the asymmetric carbon at the α-position of the benzyl group in the above formula (I). A pharma-ceutically acceptable salt refers to a salt formed from an active ingredient compound and an organic or inorganic acid that is acceptable for administration to mammals, including humans. Examples of such pharma- ceutically acceptable salts include hydrohalides (hydrochlorides, hydrobromides, hydroiodides, etc.), inorganic acid salts (nitrates, sulfates, phosphates, etc.), lower alkylsulfonates (methanesulfonates, trifluoromethanesulfonates, ethanesulfonates, etc.), arylsulfonates (benzenesulfonates, p-toluenesulfonates, etc.), organic acid salts (acetates, malates, fumarates, succinates, citrates, ascorbates, tartrates, oxalates, maleates, etc.), and amino acid salts (glycine salts, lysine salts, arginine salts, ornithine salts, glutamate salts, aspartate salts, etc.). In this embodiment, prasugrel hydrochloride is preferred as the active ingredient.

A pharma- ceutically acceptable solvate is a solid molecule formed from an active compound and a solvent that is acceptable for administration to mammals, including humans. Examples of such solvents include water, acetic acid, and ethanol.

In this embodiment, the shape of prasugrel is not particularly limited as long as it is solid, and may be any shape such as powder or crystal. Among them, it is preferable to use prasugrel powder. Prasugrel powder is prasugrel in powder form, and can be obtained, for example, by crushing prasugrel in crystal form. Commercially available crushed prasugrel may be used as prasugrel powder. The particle size of the prasugrel powder is not particularly limited, and may be, for example, approximately the same as or smaller than the particle size of the crushed product obtained by the impact crusher described below. The 50% particle size (D ₅₀ ) of such prasugrel powder is, for example, 1 to 100 μm, preferably 1 to 50 μm, and more preferably 1 to 10 μm. In this specification, D ₅₀ refers to a value measured by a laser diffraction/scattering type particle size distribution measuring device. Examples of such measuring devices include "Aerotrack LDSA-SPR" by Microtrack Bell Co., Ltd. and "Mastersizer 3000" by Malvern Panalytical Co., Ltd.

The excipient to be mixed with prasugrel can be appropriately selected from pharma- ceutically acceptable excipients, and examples thereof include sugar alcohols, sugars, celluloses, and starches. Examples of sugar alcohols include D-mannitol, D-sorbitol, xylitol, and maltitol. Examples of sugars include lactose (also called lactose hydrate), sucrose, and glucose. Examples of celluloses include crystalline cellulose, carmellose, carmellose sodium, croscarmellose sodium, carboxymethylcellulose calcium, and low-substituted hydroxypropylcellulose. Examples of starches include partially pregelatinized starch and corn starch. Among these, sugar alcohols and sugars are preferred. D-mannitol and lactose are particularly preferred. One type of excipient may be used, or two or more types may be used in combination. The form of the excipient is not particularly limited as long as it is solid, and may be any form such as powder or crystal.

A mixture of prasugrel and an excipient (hereinafter also referred to as a "mixture containing prasugrel") can be obtained by mixing prasugrel and an excipient by a method known in the art. When mixing is performed manually, for example, bag mixing may be performed in which prasugrel and an excipient are placed in a suitable bag and stirred. When mixing is performed mechanically, a powder mixer known in the art may be used. The powder mixer may be either a rotary mixer or a stationary mixer. A rotary mixer is a machine that mixes powder contained in a container by rotating the container itself. A stationary mixer is a machine that mixes powder contained in a container by rotating a stirring blade, screw, etc. provided in the container. Examples of powder mixers include a V-type mixer, a double cone mixer, a ribbon mixer, and a cone screw mixer. In this specification, the powder mixer does not include an impact grinder.

In a mixture containing prasugrel, the mixing ratio of prasugrel to excipients is not particularly limited. In this embodiment, the weight ratio of prasugrel to excipients (prasugrel:excipients) in a mixture containing prasugrel is usually 1:0.1-5, preferably 1:1-5, more preferably 1:3-5, and particularly preferably 1:5.

The mixing method of this embodiment is characterized in that the mixture containing prasugrel obtained by mixing prasugrel with an excipient is further mixed by an impact mill. This feature is believed to enable the mixture containing prasugrel to be made into a pharmaceutical composition in which prasugrel is dispersed in the excipient. An impact mill is a machine having a mechanism for applying an impact to the input raw material to pulverize it into a powder having a particle size of several tens of μm to several hundreds of μm, and is itself known in the art. In this embodiment, the impact mill is preferably a mill that can pulverize the input raw material into a powder having a particle size of 10 to 100 μm, and examples of such a mill include a pin mill and a hammer mill.

A pin mill is a device that rotates one or both of two rotating plates with dozens of pins at high speed while facing each other so that the pins interlock, and pulverizes the raw material by impact and shear caused by the interlocking pins as the raw material passes between the opposing rotating plates. Examples of pin mills include the Fine Impact Mill from Hosokawa Micron Corporation and the Coroplex from Makino Sangyo Co., Ltd. A hammer mill is a device that rotates a rotating plate with multiple hammers at high speed and pulverizes the raw material by impact and stirring caused by the hammers. Examples of hammer mills include the Egg Atomizer from Fuji Paudal Co., Ltd.

In this embodiment, the type of pin mill and hammer mill is not particularly limited, but may be, for example, a pin mill and hammer mill having a rotating plate with a diameter of 10 cm or more and 16 cm or less.

The rotation speed of the rotating plate of the pin mill or hammer mill is not particularly limited, but for example, the lower limit of the rotation speed is usually 8600 rpm, preferably 9000 rpm, and the upper limit of the rotation speed is usually 18000 rpm, preferably 12000 rpm. The rotation speed of the rotating plate of the pin mill or hammer mill may be appropriately determined within the range set by the above lower and upper limits depending on the model of the pin mill or hammer mill used.

In this embodiment, the mixing and grinding time using the impact grinder is not particularly limited, but is usually from 1 g/sec to 10 g/sec, and preferably from 1.5 g/sec to 5 g/sec.

In this embodiment, it is particularly preferred to mix the mixture of prasugrel and excipients using a pin mill.

A further embodiment is a method for producing a pharmaceutical composition containing prasugrel by further mixing a mixture of prasugrel and excipients with an impact mill. The pharmaceutical composition containing prasugrel is a mixture obtained by further mixing a mixture containing prasugrel obtained by bag mixing or mixing with a known mixer with an impact mill. In this pharmaceutical composition, prasugrel is considered to be dispersed in the excipients. When a tablet containing prasugrel as an active ingredient is produced using the pharmaceutical composition obtained by this production method, a tablet with excellent dissolution properties of prasugrel is obtained. Therefore, the pharmaceutical composition containing prasugrel obtained by the production method of the pharmaceutical composition of this embodiment can be suitably used in the production method of tablets and the production method of orally disintegrating tablets described below. The details of prasugrel, excipients, and their mixture, and the mixing of the mixture with an impact mill are the same as those described in the mixing method of this embodiment.

[2. Tablet manufacturing method]
The mixture containing prasugrel mixed by the mixing method of this embodiment (same as the pharmaceutical composition containing prasugrel described above) can be used to manufacture tablets containing prasugrel as an active ingredient. As shown in Test Example 1 described later, the tablet (orally disintegrating tablet) manufactured from the mixture containing prasugrel mixed by the mixing method of this embodiment had improved dissolution of the active ingredient compared to the tablet manufactured from the mixture obtained by sieving. Thus, in a further embodiment of the present invention, a manufacturing method for tablets containing prasugrel as an active ingredient (hereinafter also referred to as "manufacturing method for tablets") is provided.

In the tablet manufacturing method of this embodiment, the details of the step of mixing the mixture of prasugrel and excipients using an impact crusher (hereinafter also referred to as the mixing step) are the same as those described for the mixing method of this embodiment. In this embodiment, the mixture obtained in the mixing step is mixed with tablet additives to obtain a mixture for tableting. The obtained mixture for tableting is then compression molded to obtain tablets containing prasugrel as an active ingredient.

Tablet additives are additives that are commonly used in the manufacture of tablets, and can be appropriately selected from pharma- ceutically acceptable excipients, disintegrants, binders, sweeteners, lubricants, colorants, and the like. Tablet additives themselves are known. Excipients include celluloses such as crystalline cellulose, carmellose, carmellose sodium, croscarmellose sodium, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, and the like, sugars such as lactose, sucrose, and glucose, sugar alcohols such as D-mannitol, D-sorbitol, xylitol, and maltitol, and starches such as corn starch and pregelatinized starch. Disintegrants include crospovidone, croscarmellose sodium, hydroxypropylcellulose, and low-substituted hydroxypropylcellulose. Binders include ethylcellulose, polyvinylpyrrolidone, and hydroxypropylcellulose. Sweeteners include acesulfame potassium, sucralose, aspartame, and erythritol. Examples of coloring agents include ferric oxide and yellow ferric oxide. Examples of lubricants include light anhydrous silicic acid, magnesium stearate, calcium stearate, and talc. Each of these additives may be used alone or in combination of two or more. The amounts of these tablet additives are not particularly limited and can be determined appropriately by those skilled in the art.

The process of obtaining a mixture for tableting and the process of obtaining tablets are specifically carried out as follows. First, the mixture containing prasugrel obtained in the above mixing process is mixed with tablet additives excluding lubricants. Next, a lubricant is added to the obtained mixture and mixed to obtain a mixture for tableting. The obtained mixture for tableting is then compressed and molded using a known tablet press to obtain tablets containing prasugrel as an active ingredient. If necessary, the obtained tablets may be made into sugar-coated tablets or film-coated tablets. Tablet coating can be carried out by known methods such as pan coating and fluidized bed coating.

In this embodiment, the weight of each tablet is, for example, 80 mg to 500 mg, and preferably 100 mg to 420 mg. Furthermore, the content of the active ingredient per tablet, when the active ingredient is a salt or solvate, is, for example, 1 mg to 30 mg, preferably 2 mg to 25 mg, and more preferably 2.5 mg to 20 mg of prasugrel (the compound represented by formula (I)).

[3. Manufacturing method of orally disintegrating tablets]
In this embodiment, the tablet may be an orally disintegrating tablet. Thus, in a further embodiment of the present invention, a method for producing an orally disintegrating tablet containing prasugrel as an active ingredient (hereinafter also referred to as a "production method for an OD tablet") is provided.

In the method for producing OD tablets of this embodiment, the details of the step of mixing a mixture of prasugrel and excipients using an impact crusher are the same as those described in the mixing method of this embodiment. In the method for producing OD tablets of this embodiment, disintegrating particles are used to impart the property of rapid disintegration in the presence of water to the tablets. The disintegrating particles themselves are known in the art and are described, for example, in WO 2017/217494 (which is incorporated herein by reference).

The disintegrating particles preferably contain a pharma- ceutically acceptable disintegrant derived from starch. Examples of disintegrants derived from starch include corn starch, partially pregelatinized starch, potato starch, and hydroxypropyl starch. Among these, corn starch and partially pregelatinized starch are particularly preferred. The disintegrants derived from starch may be used alone or in combination of two or more.

The disintegrating particles may further contain pharma- ceutically acceptable additives (such as excipients, disintegrants other than those mentioned above, binders, flow agents, and colorants). Examples of excipients include D-mannitol, lactose, and crystalline cellulose. In this embodiment, D-mannitol is particularly preferred. Examples of disintegrants other than those derived from starch include crospovidone, croscarmellose sodium, and low-substituted hydroxypropylcellulose. Examples of binders include ethyl cellulose. Examples of flow agents include light anhydrous silicic acid, synthetic aluminum silicate, and hydrated silicon dioxide. Examples of colorants include ferric oxide and yellow ferric oxide. Each of these additives may be used alone or in combination of two or more.

Disintegrating particles can be obtained, for example, as follows. First, a solution or suspension containing a starch-derived disintegrant is added to a mixture containing an excipient, a binder, and a fluidizing agent, and granules are obtained by wet granulation. For example, in the case of fluidized bed granulation, a mixture containing a binder and a fluidizing agent is fluidized and mixed with an air current, and in this state, a solution or suspension containing a starch-derived disintegrating agent is sprayed onto the mixture to obtain granules. The obtained granules are dried and sized to obtain disintegrating particles.

Each step of the method for producing OD tablets of this embodiment is carried out, for example, as follows. First, the mixture obtained in the above mixing step is mixed with disintegrating particles and tablet additives other than the lubricant. Next, the lubricant is added to the obtained mixture and mixed to obtain a mixture for tableting. Details of the tablet additives are the same as those described for the method for producing tablets of this embodiment. Then, the obtained mixture for tableting is compressed and molded using a known tablet press to obtain an orally disintegrating tablet containing prasugrel as an active ingredient.

In this embodiment, the weight of each OD tablet is, for example, 80 mg to 500 mg, and preferably 100 mg to 400 mg. Furthermore, the content of the active ingredient per orally disintegrating tablet, when the active ingredient is a salt or solvate, is, for example, 1 mg to 30 mg, preferably 2 mg to 25 mg, and more preferably 2.5 mg to 20 mg of prasugrel (the compound represented by formula (I)).

[4. Methods for improving dissolution]
The scope of the present invention also includes a method for improving the dissolution of prasugrel from a pharmaceutical preparation. In this method, a mixture of prasugrel and excipients is mixed by an impact mill, and the resulting mixture is used to produce a pharmaceutical preparation containing prasugrel as an active ingredient, thereby improving the dissolution of prasugrel from the pharmaceutical preparation. Details of mixing by the impact mill are the same as those described for the mixing method of this embodiment.

In a preferred embodiment, the pharmaceutical formulation is a solid formulation, and tablets and orally disintegrating tablets are particularly preferred. The details of the production of tablets or orally disintegrating tablets containing prasugrel as an active ingredient are the same as those described for the production method of tablets and OD tablets of this embodiment.

The dissolution property of the active ingredient of a pharmaceutical formulation can be evaluated by a person skilled in the art using a method known in the art (such as a dissolution test). Such a method is itself known, and an example of such a method is the dissolution test described in the Japanese Pharmacopoeia.

The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

[Test Example 1]
In Test Example 1, the dissolution properties of an orally disintegrating tablet (Example 1) manufactured using a pharmaceutical composition obtained by mixing a mixture of prasugrel and excipients in an impact mill, and an orally disintegrating tablet (Comparative Example) manufactured using a mixture obtained by sieving the mixture of prasugrel and excipients were compared.

1. Manufacturing of orally disintegrating tablets
(1.1) Production of disintegrating particles Table 1 shows the mixing ratio (weight ratio) of each component of the disintegrating particles. The disintegrating particles were produced as follows. D-mannitol, light anhydrous silicic acid and ethyl cellulose were charged into a fluidized bed granulator, and a dispersion of corn starch and crospovidone dispersed in purified water was sprayed. The obtained particles were dried and sized to obtain disintegrating particles.

(1.2) Preparation of the orally disintegrating tablet of Example 1 Table 2 shows the formulation (amount of ingredients per tablet) of the orally disintegrating tablet of Example 1. The orally disintegrating tablet of Example 1 was prepared as follows. Prasugrel hydrochloride powder (particle size D ₅₀ : 3.02 μm) and D-mannitol were mixed in a bag to obtain a mixture. This mixture was fed into a Fine Impact Mill (Hosokawa Micron Corporation) with a rotating plate rotation speed of 12000 rpm and passed through at a speed of 2 g/sec to obtain a pharmaceutical composition containing prasugrel hydrochloride. The obtained pharmaceutical composition, the disintegrating particles obtained in (1.1) above, and acesulfame potassium were fed into a diffusion mixer and mixed. Magnesium stearate was further added and mixed to obtain a mixture for tableting. The obtained mixture for tableting was compressed using a rotary tableting machine to obtain the orally disintegrating tablet of Example 1.

(1.3) Preparation of Comparative Orally Disintegrating Tablets As shown in Table 2, the components of the comparative orally disintegrating tablets are the same as those of Example 1. Comparative orally disintegrating tablets were prepared as follows. A mixture of prasugrel hydrochloride powder and D-mannitol was obtained in the same manner as in Example 1. This mixture was sieved through a 30 mesh sieve. The subsequent steps were the same as in Example 1, and the orally disintegrating tablets of the comparative example were obtained using the mixture containing prasugrel hydrochloride obtained by sieving.

2. Dissolution Test According to the dissolution test method (Method 2) described in the Japanese Pharmacopoeia, 14th Edition, the dissolution test of the orally disintegrating tablets of Example 1 and Comparative Example was carried out using McIlvaine buffer solution (pH 4.0, 900 mL) as the test solution at a paddle rotation speed of 50 rpm. The test solution was sampled 5, 15, 30 and 45 minutes after the start of the test, and the dissolution rate of the active ingredient, prasugrel, was measured by absorbance measurement. The test was carried out for three tablets, and the average dissolution rate was calculated. The results are shown in Figure 1.

3. Results As shown in Figure 1, the dissolution rate of the orally disintegrating tablet of Example 1 was higher than that of the Comparative Example at all times after the start of the test. This suggests that the dissolution property of prasugrel can be improved by producing a pharmaceutical preparation using a pharmaceutical composition obtained by mixing a mixture of prasugrel and excipients using an impact mill.

[Test Example 2]
In Test Example 2, the dissolution properties of the orally disintegrating tablet of Example 1 and an orally disintegrating tablet (Example 2) having a mixing ratio of prasugrel to excipients different from that of Example 1 were compared.

1. Preparation of the orally disintegrating tablet of Example 2 Table 3 shows the formulation of the orally disintegrating tablet of Example 2 (amount of ingredients per tablet). For reference, the formulation of Example 1 is also shown. As shown in Table 3, the mixing ratio of the powder of prasugrel hydrochloride to the excipient D-mannitol is 1:1 in Example 2, and 1:3 in Example 1. The orally disintegrating tablet of Example 2 was prepared as follows. A mixture of the powder of prasugrel hydrochloride and D-mannitol was obtained in the same manner as in Example 1, except that the amount of D-mannitol was changed. The obtained mixture was mixed with a pin mill in the same manner as in Example 1 to obtain a pharmaceutical composition. Then, an orally disintegrating tablet was prepared in the same manner as in Example 1, except that the amount of disintegrating particles was changed.

2. Dissolution test and results Dissolution tests of the orally disintegrating tablets of Examples 1 and 2 were conducted in the same manner as in Test Example 1. Only in the test of Example 2, test liquid was collected 5, 10, 15, 30 and 45 minutes after the start of the test, and the dissolution rate of prasugrel was measured by absorbance measurement. The results are shown in Figure 2. As shown in Figure 2, the dissolution rate of Example 1 was higher than that of Example 2 up to 15 minutes after the start of the test. After 15 minutes after the start of the test, the dissolution rate of Example 1 tended to be higher than that of Example 2, but no significant difference was observed. Therefore, it was suggested that a higher ratio of excipients in a mixture of prasugrel and excipients is preferable from the viewpoint of improving the dissolution property of prasugrel.

[Test Example 3]
In Test Example 3, the dissolution properties of the orally disintegrating tablet of Example 1 and those of orally disintegrating tablets (Examples 3 and 4) produced by changing the rotation speed of the rotating plate of the pin mill from the production conditions of Example 1 were compared.

1. Preparation of orally disintegrating tablets of Examples 3 and 4 Table 4 shows the formulations (amount of ingredients per tablet) of the orally disintegrating tablets of Examples 3 and 4. The formulations of the orally disintegrating tablets of Examples 3 and 4 are the same as those of Example 1. The orally disintegrating tablets of Example 3 were prepared in the same manner as Example 1, except that the rotation speed of the rotating plate of the pin mill during mixing of the mixture was changed to 9000 rpm. The orally disintegrating tablets of Example 4 were prepared in the same manner as Example 1, except that the rotation speed of the rotating plate of the pin mill during mixing of the mixture was changed to 15000 rpm.

2. Dissolution test and results The dissolution test of the orally disintegrating tablets of Examples 1, 3 and 4 was performed in the same manner as in Test Example 1, except that the test liquid was collected 5, 10, 15, 30 and 45 minutes after the start of the test. The results are shown in Figure 3. As shown in Figure 3, there was almost no difference in the dissolution rate between Examples 1, 3 and 4 up to 10 minutes after the start of the test. After 10 minutes after the start of the test, the dissolution rates of Examples 1 and 3 tended to be higher than those of Example 4, but there was no difference depending on the rotation speed. From these results, it was suggested that the rotation speed of the rotating plate of the pin mill during mixing and grinding of the mixture is preferably 9000 rpm or more.

Claims (11)

A method for mixing a mixture containing prasugrel , comprising mixing a mixture of prasugrel and an excipient using an impact mill, wherein the excipient comprises at least one selected from D-mannitol and lactose . A method for producing a pharmaceutical composition, comprising mixing a mixture of prasugrel and an excipient using an impact mill to obtain a pharmaceutical composition containing prasugrel, wherein the excipient contains at least one selected from D-mannitol and lactose . mixing the mixture of prasugrel and excipients by an impact mill;
A step of mixing the mixture obtained in the mixing step with tablet additives to obtain a mixture for tableting;
and compressing the mixture for tableting to obtain a tablet , wherein the excipient comprises at least one selected from D-mannitol and lactose .
A method for manufacturing tablets containing prasugrel as an active ingredient. mixing the mixture of prasugrel and excipients by an impact mill;
A step of mixing the mixture obtained in the mixing step with disintegrative particles and tablet additives to obtain a mixture for tableting;
and compressing the mixture for tableting to obtain an orally disintegrating tablet , wherein the excipient comprises at least one selected from D-mannitol and lactose .
A method for producing an orally disintegrating tablet containing prasugrel as an active ingredient. A method for improving the dissolution property of prasugrel from a pharmaceutical preparation by mixing a mixture of prasugrel and an excipient using an impact mill and producing a pharmaceutical preparation containing prasugrel as an active ingredient using the resulting mixture , comprising:
The method, wherein the excipient comprises at least one selected from D-mannitol and lactose . The method according to any one of claims 1 to 5, wherein the impact mill is a pin mill or a hammer mill. The method according to claim 6, wherein the rotational speed of the rotating plate of the pin mill or the hammer mill is at least 8600 rpm. The method according to any one of claims 1 to 7, wherein the mixture of prasugrel and excipients is obtained by mixing prasugrel and excipients using a bag mixer or a powder mixer. The method according to any one of claims 1 to 8, wherein the weight ratio of prasugrel to excipient in the mixture of prasugrel and excipient is 1:0.1-5. The method of claim 9, wherein the weight ratio is 1:1-5. The method according to any one of claims 1 to 10, wherein the 50% particle size of the prasugrel is 1 to 10 µm.