JP2014156435A - Excipient agglomerated material and tablet - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an excipient agglomerated material, and a tablet using the excipient agglomerated material which is excellent in mixing uniformly with an active ingredient, and has a good flowability and high moldability, and further, hardness and disintegratability required as a tablet product can be obtained.SOLUTION: An excipient agglomerated material is obtained by flowing a powder which contains a sugar whose volume mean particle diameter is 35 μm or less and/or a sugar alcohol in a fluidized bed granulator and atomizing a liquid including the sugar and/or sugar alcohol to the powder to granulate the powder. The agglomerated material obtained by the granulation has a volume mean particle diameter of 80 μm or less, and an angle of repose of less than 40°.

Description

  The present invention relates to an excipient granulated product and a tablet.

As a method for producing tablets, there are a direct tableting method and a granule compression method. The direct tableting method has an advantage that the manufacturing cost is reduced and the manufacturing cost can be suppressed as compared with the granule compression method.
In the direct tableting method, sugars such as lactose and D-mannitol and sugar alcohols are used as excipients for direct compression, and they are often granulated to improve their fluidity.

As the excipient for direct hitting, for example, 80% or more of lactose finer than 100 μm is suspended in a gas flow in the form of a fluidized bed, and this is sprayed with an aqueous lactose solution as a binder. Lactose granules obtained by granulation to 4 to 0.7 and an angle of repose of 45 ° or less have been proposed (see, for example, Patent Document 1).
According to the above proposal, a granule having an average particle diameter of about 220 μm, which is excellent in fluidity, compression moldability, and binding properties, is obtained.

  However, for example, when the volume average particle size of the active ingredient contained in the tablet is very small, it cannot be said that the mixing uniformity with the granulated excipient for direct compression is sufficient, and in fact, the active ingredient In many cases, a granule compression method is used in which granule is granulated together with excipients and other additives.

Therefore, in order to improve the mixing uniformity, it is conceivable to reduce the volume average particle diameter of the granulated excipient for direct hitting.
However, usually, if the granulated product is made finer, fluidity is deteriorated, tableting troubles are likely to occur, and moldability is inferior. For this reason, the volume average particle diameter of many direct injection excipients that have been distributed in the market so far is 80 μm or more. However, although these excipients have good fluidity, the problem that sufficient mixing uniformity cannot be obtained due to the difference in particle size when mixed with a minute active ingredient has not been solved.

  In recent years, the use of orally disintegrating tablets (OD tablets) that disintegrated in the oral cavity and easily swallowed has been increasing year by year, and not only the hardness of the tablet but also its disintegration is important.

  Therefore, it is excellent in mixing uniformity with the active ingredient, has good fluidity, has high moldability, and further has an excipient structure that can obtain the hardness and disintegration required for a tablet. The current situation is that rapid development of granules is required.

Japanese Patent Laid-Open No. 51-144722

  An object of the present invention is to solve the above-described problems and achieve the following objects. That is, the present invention is excellent in mixing uniformity with an active ingredient, has good fluidity, has high moldability, and can obtain the hardness and disintegration required for a tablet. An object is to provide an excipient granulated product and a tablet using the excipient granulated product.

Means for solving the problems are as follows. That is,
<1> A powder containing sugar and / or sugar alcohol having a volume average particle size of 35 μm or less is flowed in a fluidized bed granulator, and a liquid containing sugar and / or sugar alcohol is sprayed on the powder. Obtained by granulating
The granulated product obtained by the granulation is an excipient granulated product having a volume average particle size of 80 μm or less and an angle of repose of less than 40 °.
<2> The excipient granule according to <1>, wherein the content of sugar and / or sugar alcohol in the liquid containing sugar and / or sugar alcohol is 30% by mass or more.
<3> Said <1> wherein sugar and / or sugar alcohol in the powder containing sugar and / or sugar alcohol and sugar and / or sugar alcohol in the liquid containing sugar and / or sugar alcohol are the same substance To <2>.
<4> The excipient granule according to any one of <1> to <3>, wherein the sugar is lactose.
<5> The excipient granule according to any one of <1> to <4>, which is used for direct tableting.
<6> A tablet comprising the excipient granulated product according to any one of <1> to <5> and an active ingredient.
<7> The tablet according to <6>, obtained by direct tableting.

  According to the present invention, the conventional problems can be solved, the object can be achieved, the mixing uniformity with the active ingredient is excellent, the fluidity is good, the moldability is high, Further, it is possible to provide an excipient granulated product that can obtain the hardness and disintegration required for a tablet, and a tablet using the excipient granulated product.

1A is a graph showing the relationship between tableting pressure and hardness of tablets obtained in Example 1 and Comparative Examples 1 and 2. FIG. FIG. 1B is a graph showing the relationship between the hardness and disintegration time of the tablets obtained in Example 1 and Comparative Examples 1 and 2. FIG. 2 is a diagram showing the locations where sampling was performed in Test Example 1. FIG. FIG. 3 is a graph showing the relationship between mixing time and drug content RSD in Test Example 1. FIG. 4A is a graph showing the relationship between tableting pressure and hardness of the tablets obtained in Example 2 and Comparative Examples 3 to 4. FIG. 4B is a graph showing the relationship between the hardness and disintegration time of the tablets obtained in Example 2 and Comparative Examples 3 to 4.

(Excipient granules)
The excipient granulated product of the present invention contains sugar and / or sugar alcohol.
Hereinafter, the excipient granulated product of the present invention will be described together with its preferred production method.

<Method for producing excipient granulated product>
The method for producing the excipient granulated product is not particularly limited and may be appropriately selected depending on the intended purpose. However, powder containing sugar and / or sugar alcohol is fluidized in a fluidized bed granulating apparatus. , Including a step of granulating the powder by spraying a liquid containing sugar and / or sugar alcohol (hereinafter sometimes referred to as “granulation step”), and further including other steps as necessary. The method is preferred.

<< Granulation process >>
In the granulation step, a powder containing sugar and / or sugar alcohol having a volume average particle diameter of 35 μm or less is fluidized in a fluidized bed granulator, and the powder contains sugar and / or sugar alcohol. The granulated product obtained by the granulation has a volume average particle diameter of 80 μm or less and an angle of repose of less than 40 °.

-Fluidized bed granulator-
The fluidized bed granulator sprays a liquid containing the sugar and / or sugar alcohol onto the fluidized (floating fluid) powder, and the powder contains the sugar and / or sugar alcohol. And agglomerating liquid cross-linking between the powder particles.
There is no restriction | limiting in particular as said fluidized-bed granulator, A well-known fluidized-bed granulator can be selected suitably, For example, a flow coater, Spiraflow, Granurex (all are the Freund Sangyo Co., Ltd. product) etc. Is mentioned.

−Inlet temperature, air volume−
There is no restriction | limiting in particular as inlet temperature in the case of the said flow, According to the objective, it can select suitably, For example, it can be set as 50 to 100 degreeC.
There is no restriction | limiting in particular as an air volume in the case of the said flow, According to the objective, it can select suitably.

-Powder-
The aspect of the powder is not particularly limited and may be appropriately selected depending on the purpose. Examples thereof include an aspect consisting only of a sugar, an aspect consisting only of a sugar alcohol, and an aspect consisting only of a sugar and a sugar alcohol. It is done. Among these, the aspect which consists only of saccharides is preferable.

--Sugar and / or sugar alcohol--
The volume average particle diameter of the sugar and / or sugar alcohol is not particularly limited as long as it is 35 μm or less, and can be appropriately selected according to the purpose, but is preferably 20 μm to 35 μm. When the volume average particle diameter exceeds 35 μm, it is difficult to obtain a granulated product having a volume average particle diameter of 80 μm or less and an angle of repose of less than 40 °, and even if it is obtained, the product recovery rate is low. On the other hand, it is advantageous in the said preferable range at the point which is more excellent also in the moldability of the obtained granulated material, and the disintegration property when it is set as a tablet.
The volume average particle diameter can be measured with a known apparatus, for example, with a laser diffraction / scattering type particle size distribution measuring apparatus (Microtrac HRA, manufactured by Nikkiso Co., Ltd.).

There is no restriction | limiting in particular as said sugar, According to the objective, it can select suitably, For example, sucrose, lactose, fructose etc. are mentioned. These may be used individually by 1 type and may use 2 or more types together. Among these, lactose is preferable in terms of low hygroscopicity and difficulty in tableting.
Examples of the sugar include those obtained by pulverizing crystals and sieving to obtain a desired particle size, and those obtained by spray drying.

There is no restriction | limiting in particular as said sugar alcohol, According to the objective, it can select suitably, For example, a mannitol, a xylitol, an erythritol etc. are mentioned. These may be used individually by 1 type and may use 2 or more types together. Among these, mannitol is preferable in terms of low hygroscopicity and low reactivity with other components.
Examples of the sugar alcohol include those obtained by crushing crystals and sieving to obtain a desired particle size, and those obtained by spray drying.

-Liquid containing sugar and / or sugar alcohol-
The aspect of the liquid containing sugar and / or sugar alcohol (hereinafter sometimes referred to as “binding liquid”) is not particularly limited and may be appropriately selected depending on the purpose. The aspect which consists only of sugar alcohol, the aspect which consists only of saccharide | sugar and sugar alcohol, etc. are mentioned. Among these, it is preferable that it is the same substance as the saccharide | sugar and / or sugar alcohol in the said powder, and the aspect which consists only of saccharide | sugar is further more preferable.

--Sugar and / or sugar alcohol--
There is no restriction | limiting in particular as content of the said saccharide | sugar and / or sugar alcohol in the said binding liquid, Although it can select suitably according to the objective, 30 mass% or more is preferable and 40 mass%-80 mass% are more. preferable. When the content in the binding liquid is less than 30% by mass, the spraying time may be long. Moreover, when content in the said binding liquid is less than 30 mass%, when tableting using the obtained excipient granulated material, high tablet hardness may not be obtained. On the other hand, when it is in the preferred range, the spraying time can be shortened, and higher tablet hardness can be obtained when tableting.

  The ratio of the mass (A) of sugar and / or sugar alcohol in the powder to the mass (B) of sugar and / or sugar alcohol in the liquid containing the sugar and / or sugar alcohol is not particularly limited. Depending on the purpose, it can be appropriately selected, but A: B is preferably 8: 2 to 4: 6. If the amount is outside the preferred range, the amount of sugar and / or sugar alcohol in the powder is small, and it may be difficult to obtain a normal fluid state at the initial stage of granulation, or the granulation time may be prolonged.

  There is no restriction | limiting in particular as said sugar, According to the objective, it can select suitably, For example, the sugar similar to what was described with the said powder is mentioned, Lactose is mentioned suitably. The sugars may be used alone or in combination of two or more.

  There is no restriction | limiting in particular as said sugar alcohol, According to the objective, it can select suitably, For example, the sugar alcohol similar to what was described with the said powder is mentioned, A mannitol is mentioned suitably. The said sugar alcohol may be used individually by 1 type, and may use 2 or more types together.

  There is no restriction | limiting in particular as a solvent contained in the said binding liquid, Although it can select suitably according to the objective, Water is preferable. There is no restriction | limiting in particular as content of the water in the said coupling | bonding liquid, According to the objective, it can select suitably.

  The method for preparing the binding solution is not particularly limited, and can be prepared according to a known method according to the purpose. For example, the sugar and / or sugar alcohol, additional components other than the sugar and / or sugar alcohol are added. Examples of the method include mixing with water and stirring.

-Spray-
The method for spraying the binding liquid onto the powder is not particularly limited and may be appropriately selected depending on the intended purpose. For example, spray means provided in the fluidized bed granulator to be used, for example, spray The method of spraying from a gun, a spray nozzle, etc. is mentioned suitably.
At this time, the spraying conditions are not particularly limited, and publicly known conditions can be adopted. The spraying amount, the size of sprayed mist particles (mist), the spraying time, and the like are determined according to the purpose. It can be selected appropriately. When a spray gun or the like is used for spraying, the spray air pressure is preferably about 0.1 MPa to 0.5 MPa, for example.

-Excipient granules-
By the above granulation step, an excipient granulated product having a volume average particle size of 80 μm or less and an angle of repose of less than 40 ° is obtained.
In addition, you may perform the process of sieving a granulated material with a 500 micrometers sieve after a granulation process as needed.
The volume average particle diameter of the excipient granule is not particularly limited as long as it is 80 μm or less, and can be appropriately selected according to the purpose. However, in that the mixing uniformity with the active ingredient is improved. 60 μm to 70 μm are preferable.
The volume average particle diameter can be measured in the same manner as described above.

The angle of repose of the excipient granule is not particularly limited as long as it is less than 40 °, and can be appropriately selected according to the purpose. However, handling in the process and mixing with other components are considered. Thus, 35 ° to 38 ° is preferable.
The angle of repose can be measured by the Nogami-Sugihara method described in JP-A-6-205959.

The bulk density of the excipient granule is not particularly limited and may be appropriately selected depending on the intended purpose. However, in consideration of fluidity and miscibility with other components, 0.40 g / mL to 0.55 g / mL is preferred.
The bulk density can be obtained by the following formula 1 after weighing the weight Wb obtained by scraping and weighing the excipient granule in a 100 mL stainless steel measurement container (weight W).
Bulk density (weight / mL) = (W−Wb) / 100 Formula 1

The excipient granulated product of the present invention is granulated under normal granulation conditions when the angle of repose is less than 40 °, although the volume average particle size is 80 μm or less. Excellent fluidity compared to. Therefore, there is an advantage that the mixing uniformity with a minute active ingredient is excellent. In addition, since a fine raw material powder having a volume average particle diameter of 35 μm or less is used as the powder containing sugar and / or sugar alcohol, compared with the case where a powder having a volume average particle diameter of 35 μm or more is used as the raw material. Further, the specific surface area of the granulated product is increased, and high moldability and disintegration can be obtained.
Therefore, the excipient granulated product of the present invention can be used particularly suitably for direct tableting.

(tablet)
The tablet of this invention contains an excipient | filler granulated material and an active ingredient, and also contains another component as needed.

<Excipient granules>
The excipient granulated product is the above-described excipient granulated product of the present invention.
There is no restriction | limiting in particular as content of the said excipient granulated material in the said tablet, According to the objective, it can select suitably, For example, 20 mass%-99.9 mass% are mentioned.

<Active ingredient>
The active ingredient is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include hypertensive drugs, angina drugs, bronchodilators, psychotropic drugs, anxiolytic drugs, antidepressant drugs, and hypnotic sedative drugs. , Antiparkinson, allergy, dental, oral, cardiotonic, antipyretic analgesic, antihistamine, antitussive, antacid, herbal medicine, antihypertensive, antibiotic, antibacterial, arrhythmia, coronary Dilators, peripheral vasodilators, hyperlipidemic drugs, antibacterial drugs, hormonal drugs, gout drugs, antirheumatic drugs, chemotherapy drugs, antidiabetic drugs, antiemetics, antiepileptic drugs, sympathomimetic drugs, Osteoporosis drugs, antineoplastic drugs, immunosuppressive drugs, urological drugs, gastrointestinal drugs, cerebral metabolism improving drugs, cerebral circulation improving drugs, respiratory stimulants, vasoconstrictors, antipruritic drugs, expectorants, drugs for central nervous system action , Active ingredients used in ulcer treatment, gastric mucosal repair, analgesic and antispasmodics, etc. Specifically, acetaminophen, temocapryl hydrochloride, cabergoline, amlodipine besylate, omeprazole, lansoprazole, famotidine, lafutidine, ecabet sodium, mosapride citrate, rebamipide, voglibose, risperidone, imidapril hydrochloride, meloxicam, Milnacipran hydrochloride, levofloxacin, clarithromycin, sarpogrelate hydrochloride, tosufloxacin tosylate, tamsulosin hydrochloride, mizoribine, tacrolimus hydrate, fluvoxamine maleate, glimepiride, ramosetron hydrochloride, nicorandil, donepezil hydrochloride, tartaric acid Zolpidem, pioglitazone hydrochloride, alendronate sodium hydrate, risedronate sodium hydrate, atorvastatin calcium hydrate Fluvastatin sodium, loratadine, losartan potassium, paroxetine hydrochloride hydrate, rabeprazole sodium, ribavirin, sumatriptan succinate, perospirone hydrochloride hydrate, quetiapine fumarate, olopatadine hydrochloride, fexofenadine hydrochloride, ebastine, cefditoren Pivoxil, cefcapene hydrochloride pivoxil, valsartan, bicalutamide, acarbose and the like.
There is no restriction | limiting in particular as a volume average particle diameter of the said active ingredient, Although it can select suitably according to the objective, 60 micrometers or less are preferable.

<Other ingredients>
The other components are not particularly limited and may be appropriately selected depending on the purpose. Lubricants, fluidizers, sweeteners, hygroscopic agents, dehumidifiers, coating agents, pigments, flavoring agents, dissolution An adjuvant etc. are mentioned. These may be used alone or in combination of two or more.

  The lubricant is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include magnesium stearate, stearic acid, calcium stearate, talc, and hardened oil.

  The fluidizing agent is not particularly limited and may be appropriately selected depending on the intended purpose. For example, hydrophilic silica, hydrophobic silica, calcium silicate, alkyl phosphate (PAP), water-soluble polymer compound, Anhydrous calcium hydrogen phosphate, magnesium silicate, calcium silicate, light anhydrous silicic acid, hydrous silicon dioxide, magnesium oxide and the like can be mentioned.

  The sweetener is not particularly limited and may be appropriately selected depending on the intended purpose.For example, aspartame, glucose, galactose, mannose, ribose, arabinose, maltose, lactose, isomaltose, cellobiose, gentiobiose, palatinose Can be mentioned.

<Tablet production method>
There is no restriction | limiting in particular as a manufacturing method of the said tablet, Although it can select suitably according to the objective, The direct tableting method is mentioned suitably. At this time, generally used mixers and tableting machines can be used.

Examples of the present invention will be described below, but the present invention is not limited to these examples.

Example 1
<Excipient granulated product 1>
4,000 g of lactose powder (lactose monohydrate, volume average particle size: 29.8 μm) was charged into a fluidized bed granulator (trade name: Flow Coater, manufactured by Freund Sangyo Co., Ltd.). 500g was sprayed and granulated. The obtained granulated product is sieved with a 500 μm sieve to obtain a lactose granulated product (excipient granulated product 1) having a volume average particle size of 66 μm, an angle of repose of 38 °, and a bulk density of 0.52 g / mL. It was. In addition, the volume average particle diameter, the angle of repose, and the bulk density of the excipient granulated product 1 were measured as follows.

-Measurement of volume average particle size-
The volume average particle size was measured by a laser diffraction / scattering particle size distribution measuring device, Microtrac HRA (manufactured by Nikkiso Co., Ltd.).

-Angle of repose-
The angle of repose was measured by the Nogami-Sugihara method described in JP-A-6-205959.

-Measurement of bulk density-
The bulk density was determined by the following formula 1 after weighing the excipient granulated product 1 in a 100 mL stainless steel measuring container (weight W) and then weighing the ground weight Wb.
Bulk density (weight / mL) = (W−Wb) / 100 Formula 1

<Tablets>
1.0 mass% of magnesium stearate was added to the excipient granulated product 1 and mixed for 3 minutes with a V-type mixer (micro-type S-3 see-through mixer, manufactured by Tsutsui Rika Kikai Co., Ltd.). The obtained mixed powder was tableted with a rotary tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.) with a diameter of 8 mm, 10 R, 200 mg / tablet under the conditions of tableting pressure of 8 kN, 10 kN, 12 kN. Tableting was possible without causing any tableting problems.
The hardness of the tablets obtained at each tableting pressure was measured with a tablet hardness tester (Freund Sangyo Co., Ltd.). The results are shown in FIG. 1A.
Moreover, the disintegration time of each tablet was measured by the method described in the Japanese Pharmacopoeia. The results are shown in FIG. 1B.

(Comparative Example 1)
<Excipient granulated product 2>
4,000 g of lactose powder (lactose monohydrate, volume average particle size: 37.1 μm) was charged into a fluidized bed granulator (trade name: Flow coater, manufactured by Freund Sangyo Co., Ltd.), and lactose 50 mass% aqueous solution 2, 000 g was sprayed and granulated. The obtained granulated product is sieved with a 500 μm sieve to obtain a lactose granulated product (excipient granulated product 2) having a volume average particle size of 73 μm, an angle of repose of 40 °, and a bulk density of 0.53 g / mL. It was. The volume average particle diameter, the angle of repose, and the bulk density were measured in the same manner as in Example 1.

<Tablets>
A tablet was obtained by mixing and tableting in the same manner as in Example 1 except that the excipient granulated product 1 in Example 1 was replaced by the excipient granulated product 2. It was.
In the tableting, although no tableting troubles such as sticking and capping were observed, the fluidity tended to be somewhat inferior.
The results of measuring the hardness and disintegration time of the tablets in the same manner as in Example 1 are shown in FIGS. 1A and 1B.

(Comparative Example 2)
<Excipient granulated product 3>
4,000 g of lactose powder (lactose monohydrate, volume average particle size: 37.1 μm) was charged into a fluidized bed granulator (trade name: Flow coater, manufactured by Freund Sangyo Co., Ltd.), and lactose 20 mass% aqueous solution 5, 000 g was sprayed and granulated. The obtained granulated product is sieved with a 500 μm sieve to obtain a lactose granulated product (excipient granulated product 3) having a volume average particle size of 95 μm, an angle of repose of 37 °, and a bulk density of 0.53 g / mL. It was. The volume average particle diameter, the angle of repose, and the bulk density were measured in the same manner as in Example 1.

<Tablets>
A tablet was obtained by mixing and tableting in the same manner as in Example 1 except that the excipient granulated product 1 in Example 1 was replaced with the excipient granulated product 3. It was.
In the tableting, tableting was possible without causing tableting troubles such as sticking and capping.
The results of measuring the hardness and disintegration time of the tablets in the same manner as in Example 1 are shown in FIGS. 1A and 1B.

Table 1 shows the raw materials, granulation conditions, and powder physical properties in Example 1 and Comparative Examples 1 and 2. In addition, FIG. 1A and FIG. 1B show tablet physical properties.
From these results, the excipient granulated product 1 obtained in Example 1 showed a tendency to have better fluidity than Comparative Example 1. Moreover, the moldability and disintegration of the tablet produced using the excipient granulated product 1 obtained in Example 1 were superior to any of the comparative examples.

(Test Example 1: Mixing uniformity)
4,995.0 g of the excipient granulated product 1 obtained in Example 1 and 5.0 g of acetaminophen (volume average particle diameter: 48 μm) as an active ingredient were mixed with a V-type mixer (V-10). , Manufactured by Tokuju Kogakusho Co., Ltd. for 30 minutes, and sampled from the locations (A to E) shown in FIG. 2 at a predetermined time (1 minute, 5 minutes, 10 minutes, 20 minutes, 30 minutes). The content of acetaminophen in the powder sampled at each time was measured to evaluate the mixing uniformity. The drug content RSD (relative standard deviation) 30 minutes after the start of mixing showed a value of 3.0% or less, and good mixing uniformity was obtained. In FIG. 2, the gray part represents powder.
On the other hand, when the same test as described above was performed using the excipient granulated product 3 obtained in Comparative Example 2, the drug content RSD was 6.2% after 30 minutes from the start of mixing. The variation in drug content tended to be higher than that in the case of 1 excipient granulated product 1.
The results of the above test are shown in FIG.

(Example 2)
<Excipient granulated product 4>
3,000 g of D-mannitol powder (volume average particle size: 20.3 μm) was charged into a fluidized bed granulator (trade name: Flow coater, manufactured by Freund Sangyo Co., Ltd.), and 6,000 g of 50% by weight aqueous solution of D-mannitol was added. Sprayed and granulated. The obtained granulated product is sieved with a 500 μm sieve and a D-mannitol granulated product having a volume average particle size of 68 μm, an angle of repose of 35 ° and a bulk density of 0.57 g / mL (excipient granulated product 4). Got. The volume average particle diameter, the angle of repose, and the bulk density were measured in the same manner as in Example 1.

<Tablets>
1.0 mass% of magnesium stearate was added to the excipient granulated product 4 and mixed for 3 minutes with a V-type mixer (micro-type S-3 see-through mixer, manufactured by Tsutsui Rika Kikai Co., Ltd.). When the obtained mixed powder was tableted with a rotary tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.) at a tableting pressure of 8 kN, 10 R, 200 mg / tablet under the conditions of tableting pressure of 8 kN, 10 kN, 12 kN, 14 kN, Tableting was possible without causing tableting problems such as capping.
The results of measuring the hardness and disintegration time of the tablets in the same manner as in Example 1 are shown in FIGS. 4A and 4B.

(Comparative Example 3)
<Excipient granulated product 5>
3,000 g of D-mannitol powder (volume average particle size: 56.3 μm) was charged into a fluidized bed granulator (trade name: Flow Coater, manufactured by Freund Sangyo Co., Ltd.), and 6,000 g of 50% by weight aqueous solution of D-mannitol was added. Sprayed and granulated. The obtained granulated product is sieved with a 500 μm sieve and a D-mannitol granulated product having a volume average particle size of 95 μm, an angle of repose of 36 ° and a bulk density of 0.60 g / mL (excipient granulated product 5). Got. The volume average particle diameter, the angle of repose, and the bulk density were measured in the same manner as in Example 1.

<Tablets>
Example 2 except that the excipient granulated product 4 in Example 2 was replaced with the excipient granulated product 5 and no tableting was performed under the conditions of a tableting pressure of 8 kN. In the same manner, mixing and tableting were performed to obtain tablets.
In the tableting, capping occurred in some tablets at a tableting pressure of 14 kN.
The results of measuring the hardness and disintegration time of the tablets in the same manner as in Example 1 are shown in FIGS. 4A and 4B.

(Comparative Example 4)
<Excipient granulated product 6>
3,000 g of D-mannitol powder (volume average particle size: 56.3 μm) was charged into a fluidized bed granulator (trade name: Flow Coater, manufactured by Freund Sangyo Co., Ltd.), and 9,000 g of a 20% by mass aqueous solution of D-mannitol was added. Sprayed and granulated. The obtained granulated product is sieved with a 500 μm sieve, and a D-mannitol granulated product (excipient granulated product 6) having a volume average particle size of 90 μm, an angle of repose of 38 °, and a bulk density of 0.58 g / mL. Got. The volume average particle diameter, the angle of repose, and the bulk density were measured in the same manner as in Example 1.

<Tablets>
Example 2 except that the excipient granulated product 4 in Example 2 was used instead of the excipient granulated product 6 and tableting was not performed under the condition of a tableting pressure of 14 kN. In the same manner, mixing and tableting were performed to obtain tablets.
In the tableting, capping occurred in some tablets at a tableting pressure of 12 kN.
The results of measuring the hardness and disintegration time of the tablets in the same manner as in Example 1 are shown in FIGS. 4A and 4B.

Table 2 shows the raw materials, granulation conditions, and powder physical properties in Example 2 and Comparative Examples 3 to 4. 4A and 4B show the tablet physical properties.
From these results, the excipient granulated product 4 obtained in Example 2 is more formable and disintegratable than Comparative Examples 3 and 4 granulated using a raw material having a volume average particle size of 56.3 μm. It was excellent.

  The excipient granulated product of the present invention is excellent in mixing uniformity with the active ingredient, has good fluidity, has high moldability, and further has hardness and disintegration required for a tablet. Can be used for the production of tablets, and in particular, it can be suitably used for direct tableting of tablets containing a minute active ingredient having a volume average particle size of 60 μm or less.

Claims (5)

A powder containing sugar and / or sugar alcohol having a volume average particle diameter of 35 μm or less is fluidized in a fluidized bed granulating apparatus, and a liquid containing sugar and / or sugar alcohol is sprayed on the powder and granulated. Is obtained by
The granulated product obtained by the granulation has a volume average particle size of 80 μm or less and an angle of repose of less than 40 °.   The excipient granulated product according to claim 1, wherein the content of sugar and / or sugar alcohol in the liquid containing sugar and / or sugar alcohol is 30% by mass or more.   The sugar and / or sugar alcohol in the powder containing sugar and / or sugar alcohol and the sugar and / or sugar alcohol in the liquid containing sugar and / or sugar alcohol are the same substance. An excipient granulated product according to claim 1.   The excipient granulated product according to any one of claims 1 to 3, wherein the sugar is lactose.   A tablet comprising the excipient granulated product according to any one of claims 1 to 4 and an active ingredient.