JP6286690B2 - Sugar alcohol spherical granule aggregate, method for producing the same, and tablet - Google Patents

Description

  The present invention relates to a sugar alcohol spherical granule aggregate suitable as a base material for pharmaceuticals and the like, an efficient production method thereof, and a tablet using the sugar alcohol spherical granule aggregate.

  Conventionally, various spherical granulated materials used as base materials for pharmaceuticals and foods have been provided. The spherical granule is used as a preparation having a surface coated with a food material or an active ingredient (hereinafter sometimes referred to as “drug”), or a preparation having a functional coating layer formed on the surface thereof. Or, it is used as a preparation contained in a capsule.

For example, as an orally disintegrating tablet (hereinafter, sometimes referred to as “OD tablet”), the surface of the spherical granule is coated with a drug-containing layer and one or more release control layers in this order. Tablets prepared by tableting controlled particles (hereinafter sometimes referred to as “release controlled granules”) together with binders such as crystalline cellulose, disintegrants such as crospovidone, lubricants such as magnesium stearate, etc. Is used.
In the OD tablet, when the particle size of the release controlling particle is 200 μm or more, there is a problem that roughness occurs in the oral cavity.

Up to now, as a method for producing the spherical granulated product, for example, a sugar alcohol granulated particle is used as a core, and a centrifugal rolling device is used to spray a sugar alcohol aqueous solution while spraying a sugar alcohol powder. A method for producing a granulated product (see Patent Document 1), a method for producing a spherical granulated product by spraying a sugar alcohol aqueous solution with a sugar alcohol solution using a centrifugal rolling device (see Patent Document 2), a crystal A crystal grain obtained by shaving the corner of the grain, the crystal grain having a particle diameter of 50 μm to 1,000 μm as a central core particle, and using a centrifugal rolling device, sugar alcohol or the like is dissolved or dispersed in water. A method for producing a spherical granulated product by spraying a liquid (see Patent Document 3) has been proposed.
However, the present situation is that a spherical granulated product having a drug-containing layer and a release-controlling layer and having a controlled-release particle size of less than 200 μm and a manufacturing method thereof have not been developed yet. .

  In addition, when the spherical granule is used for the controlled release particles, it is desirable to make the thickness of each particle uniform in order to control the drug release time as accurately as possible. The particle size distribution of the spherical granulated product is required to be sharp.

JP-A-11-92403 JP 2001-10979 A JP 2009-155215 A

  An object of the present invention is to solve the above-described problems and achieve the following objects. That is, the present invention has a small average particle size, can reduce roughness in the oral cavity when used in an orally disintegrating tablet, has low reactivity with the drug, and further has a sharp particle size distribution. It is an object of the present invention to provide a sugar alcohol spherical granule aggregate, an efficient production method thereof, and a tablet using the sugar alcohol spherical granule aggregate.

  As a result of intensive studies to achieve the above object, the present inventors have determined that when the particle diameter of a spherical granule that is a core particle such as a release control particle is 100 μm or more, the particle diameter of the release control particle or the like is It has been found that the thickness tends to be 200 μm or more. In addition, the sugar alcohol crystal particles having an average particle diameter of more than 15 μm and less than 50 μm are rolled in a centrifugal rolling device, and granulated while spraying the sugar alcohol solution in the absence of the sugar alcohol powder, Particles such as the above-mentioned controlled release particles can be produced efficiently by using a sugar alcohol spherical granule aggregate having a small average particle size and a sharp particle size distribution, and using the sugar alcohol spherical granule aggregate as a core particle. It has been found that the diameter can be less than 200 μm.

Means for solving the problems are as follows. That is,
<1> A sugar alcohol spherical granule aggregate having an average particle diameter of less than 100 μm and a value of σ _g obtained by a particle size distribution of 1.1 to 1.5.
<2> The sugar alcohol spherical granule aggregate according to <1>, wherein the sugar alcohol is mannitol.
<3> The sugar alcohol spherical granule aggregate according to any one of <1> to <2>, which is for an orally disintegrating tablet.
<4> The sugar alcohol crystal particles having an average particle diameter of more than 15 μm and less than 50 μm are rolled in a centrifugal rolling device, and granulated while spraying the sugar alcohol solution in the absence of the sugar alcohol powder. It is a manufacturing method of the sugar alcohol spherical granule aggregate characterized by the above.
<5> The method for producing a sugar alcohol spherical granule aggregate according to <4>, wherein the sugar alcohol crystal particles are crushed.
<6> A tablet comprising the sugar alcohol spherical granule aggregate according to any one of <1> to <3> and a food material or an active ingredient.
<7> The tablet according to <6>, which is an orally disintegrating tablet.
<8> On the surface of the sugar alcohol spherical granule aggregate according to any one of <1> to <3>, a layer containing a food material or an active ingredient and a release control layer are coated in this order. This is a controlled release granule.

  According to the present invention, the conventional problems can be solved, the object can be achieved, the average particle size is small, and the roughness in the oral cavity can be reduced when used in an orally disintegrating tablet. In addition, a sugar alcohol spherical granule aggregate having low reactivity with a drug and having a sharp particle size distribution, an efficient production method thereof, and a tablet using the sugar alcohol spherical granule aggregate Can be provided.

(Aggregates of sugar alcohol spherical granules)
The sugar alcohol spherical granule aggregate of the present invention contains a sugar alcohol. The sugar alcohol spherical granule aggregate is preferably composed only of sugar alcohol.
The method for producing the sugar alcohol spherical granule aggregate is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably selected according to the method for producing a sugar alcohol spherical granule aggregate of the present invention. Can be manufactured.
Hereinafter, the sugar alcohol spherical granule aggregate of the present invention will be described together with the method for producing the sugar alcohol spherical granule aggregate of the present invention.

<Method for producing sugar alcohol spherical granule aggregate>
In the method for producing a sugar alcohol spherical granule aggregate of the present invention, sugar alcohol crystal particles having an average particle diameter of more than 15 μm and less than 50 μm are rolled in a centrifugal rolling device, and in the absence of sugar alcohol powder. And a step of granulating while spraying the sugar alcohol solution (hereinafter sometimes referred to as “granulation step”), and further including other steps as necessary.

<< Granulation process >>
In the granulation step, sugar alcohol crystal particles having an average particle diameter of more than 15 μm and less than 50 μm are rolled in a centrifugal rolling device, and granulated while spraying a sugar alcohol solution in the absence of sugar alcohol powder. It is a process to do.

-Sugar alcohol crystal particles-
The sugar alcohol crystal particles are not particularly limited as long as the average particle diameter is more than 15 μm and less than 50 μm, and can be appropriately selected according to the purpose.
Since the sugar alcohol does not have a reducing group in the molecule, it is advantageous in that the reactivity with other components contained in the tablet is relatively low.
As the sugar alcohol crystal particles, commercially available products may be used, or those prepared as appropriate may be used.

The sugar alcohol is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include mannitol (hereinafter sometimes referred to as “D-mannitol”), sorbitol, xylitol, erythritol, maltitol, isomalt. , Lactitol and the like. These may be used individually by 1 type and may use 2 or more types together, but 1 type is preferable.
Among the sugar alcohols, mannitol is preferred because of its low hygroscopicity and low reactivity with the active ingredient.

The average particle diameter of the sugar alcohol crystal particles is not particularly limited as long as it is more than 15 μm and less than 50 μm, and can be appropriately selected according to the purpose, but is preferably 18 μm to 25 μm.
When within the preferred range, the sugar alcohol spherical granule aggregate having an average particle size of less than 100 μm and a σ _g value of 1.1 to 1.5 obtained by the particle size distribution is efficiently produced. Is advantageous.
In the present invention, the average particle size refers to a particle size that is 50% cumulative of the volume-based particle size distribution. The average particle diameter can be measured and calculated by a known apparatus, for example, measured and calculated by a laser diffraction / scattering type particle size distribution measuring apparatus (Microtrac HRA, manufactured by Nikkiso Co., Ltd.). .

  The sugar alcohol crystal particles are preferably crushed. There is no restriction | limiting in particular as the method of said crushing, A well-known method can be selected suitably and can be performed, for example, the method of using a crushing type granulator, Powermill P-3 (made by Dalton Co., Ltd.), etc. Is mentioned.

-Sugar alcohol solution-
The sugar alcohol solution is a liquid containing sugar alcohol (hereinafter sometimes referred to as “binding liquid”).
The sugar alcohol in the sugar alcohol solution is not particularly limited and may be appropriately selected depending on the purpose. Examples thereof include the same sugar alcohol as the crystal particles, but the same as the sugar alcohol of the crystal particles. It is preferable to use one.

There is no restriction | limiting in particular as content of the sugar alcohol in the said sugar alcohol solution, Although it can select suitably according to the objective, 5 mass%-40 mass% are preferable, and 10 mass%-
30 mass% is more preferable, and 15 mass%-25 mass% is especially preferable. When the content of the sugar alcohol in the sugar alcohol solution is within the particularly preferable range, the sugar alcohol solution has a binding force capable of efficiently producing a sugar alcohol spherical granule aggregate.

  There is no restriction | limiting in particular as a solvent of the said sugar alcohol solution, 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 sugar alcohol solution, According to the objective, it can select suitably.

  There is no restriction | limiting in particular as a preparation method of the said sugar alcohol solution, A well-known method can be selected suitably, For example, the method of mixing the said sugar alcohol and water, stirring, etc. are mentioned.

-Granulation-
As the centrifugal rolling device used in the granulation step (hereinafter sometimes referred to as “centrifugal rolling granulator”), sugar alcohol crystal particles are rolled in the centrifugal rolling device, If granulation can be performed while spraying a sugar alcohol solution in the absence, there is no particular limitation and a known apparatus can be appropriately selected.
As an example of the centrifugal rolling device, a rotating shaft that rotates a smooth rotating disc that rotates substantially horizontally on the bottom of the processing vessel, an inner wall portion of the processing vessel, and an edge located at a circumferential portion of the rotating disc A slit that is an annular gap formed between the slit, a slit air supply device for supplying slit air into the processing container from the slit, and the sugar alcohol solution to the sugar alcohol crystal particles in the processing container And a spray nozzle for spraying a liquid. Specific examples of the apparatus include a CF granulator (manufactured by Freund Sangyo Co., Ltd.), a centrifugal rolling granulation coating device, and a granurex (Freund Sangyo Co., Ltd.). Manufactured).
In addition, the centrifugal rolling device may be a device having a configuration other than the above-described configuration. For example, a rolling fluidized bed granulation coating device, Spiraflow (manufactured by Freund Sangyo Co., Ltd.), or the like can be used. .
The operation condition of the centrifugal rolling device is not particularly limited and can be appropriately selected according to the purpose. The rotational speed of the rotating disk is 150 rpm to about 360 mm if its diameter is about 360 mm. About 250 rpm is preferable.

In the granulation step, granulation is performed while spraying the sugar alcohol solution in the absence of the sugar alcohol powder.
The method for spraying the sugar alcohol solution onto the crystal particles of the sugar alcohol is not particularly limited and may be appropriately selected depending on the intended purpose. For example, spray means provided in the centrifugal rolling device to be used, for example, A method of spraying from a spray gun, a spray nozzle or the like is preferable.
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 is used for spraying, the spray air pressure is preferably about 0.1 MPa to 0.5 MPa, for example.

  The spray amount of the sugar alcohol solution is not particularly limited and may be appropriately selected depending on the intended purpose. The mass of the solid content of the sugar alcohol with respect to the mass of the crystal particles is 1% by mass to 10% by mass. Is preferable, 2% by mass to 9% by mass is more preferable, and 5% by mass to 8% by mass is particularly preferable. When the spray amount of the sugar alcohol solution is within the particularly preferable range, it is advantageous in that a sugar alcohol granule aggregate having an average particle diameter of less than 100 μm can be efficiently produced.

  In the production method of the present invention, granulation is performed while spraying a sugar alcohol solution in the absence of a sugar alcohol powder, and therefore a sugar alcohol granule aggregate having an average particle diameter of less than 100 μm can be efficiently produced. This is advantageous.

In the granulation step, the granulated sugar alcohol spheres are granulated using a fluidized bed apparatus (hereinafter sometimes referred to as “fluidized bed granulated apparatus”) after granulation using the centrifugal rolling device. It is preferred to coat the grains.
There is no restriction | limiting in particular as said fluidized bed apparatus, A well-known apparatus can be selected suitably.
As an example of the fluidized bed device, a fluidized air supply device for supplying fluidized air to fluidize the granulated product and a spray nozzle for spraying a sugar alcohol solution onto the granulated product in a container are provided. Specific examples of the apparatus include a flow coater (manufactured by Freund Sangyo Co., Ltd.).
Further, the fluidized bed apparatus may be an apparatus having a configuration other than the above configuration, for example, a rolling fluidized bed granulation coating apparatus, Spiraflow (manufactured by Freund Sangyo Co., Ltd.), centrifugal rolling type granulation A coating apparatus, Granurex (manufactured by Freund Sangyo Co., Ltd.) or the like can also be used.
The operating conditions of the fluidized bed apparatus are not particularly limited and may be appropriately selected depending on the intended purpose. The temperature during the coating is preferably about 20 ° C. to 40 ° C. as the exhaust temperature.

The sugar alcohol solution used for coating using the fluidized bed apparatus is not particularly limited and can be appropriately selected according to the purpose. For example, the sugar alcohol solution is the same as the sugar alcohol solution used for granulation by the centrifugal rolling device. Things can be used.
The spray amount of the sugar alcohol solution is not particularly limited and may be appropriately selected depending on the purpose. For example, the mass of the sugar alcohol solution is 10 mass as a solid content of the sugar alcohol spherical particles. %.

Through the above steps, a sugar alcohol spherical granule aggregate having an average particle size of less than 100 μm and a σ _g value of 1.1 to 1.5 obtained by the particle size distribution can be obtained.
In addition, you may sieve the spherical granule aggregate obtained at the said granulation process after the said granulation process as needed. As a sieve used for the sieving, for example, 53 μm and 106 μm sieves can be used.

<Aggregate of sugar alcohol spherical granules>
-Average particle size-
The average particle size of the sugar alcohol spherical granule aggregate of the present invention is not particularly limited as long as it is less than 100 μm, and can be appropriately selected according to the purpose, but is preferably 45 μm to 95 μm, preferably 50 μm to 90 μm. Is more preferable, and 60 μm to 80 μm is particularly preferable.
When the average particle size of the sugar alcohol spherical granule aggregate is within the particularly preferable range, when used in an orally disintegrating tablet described later, the roughness in the oral cavity can be further reduced. Is advantageous.

-Value of σ _g obtained by particle size distribution-
The value of σ _g obtained by the particle size distribution of the sugar alcohol spherical granule aggregate of the present invention is not particularly limited as long as it is 1.1 to 1.5, and can be appropriately selected according to the purpose. However, 1.1-1.4 are preferable and 1.1-1.3 are more preferable.
When the value of σ _g obtained by the particle size distribution of the sugar alcohol spherical granule aggregate is within the more preferable range, the release time of the active ingredient and the like is more accurately controlled when used in a tablet to be described later. This is advantageous.
In the present invention, the value of σ _g obtained from the particle size distribution refers to a standard deviation obtained by the following equation (1).
σ _g = D _84.13 / D ₅₀ ... Formula (1)
In the above formula (1), “D _84.13 ” represents the particle diameter (μm) at the point where the cumulative curve is 84.13% when the cumulative curve of the volume-based particle size distribution of the powder is obtained. “D ₅₀ ” represents the particle diameter (μm) at which the cumulative curve is 50% when the cumulative curve of the volume-based particle size distribution of the powder is obtained.
The value of σ _g obtained by the particle size distribution can be measured and calculated with a known device, for example, measured with a laser diffraction / scattering particle size distribution measuring device (Microtrac HRA, manufactured by Nikkiso Co., Ltd.). Can be calculated.

-Sphericality-
The sphericity of the sugar alcohol spherical granule aggregate of the present invention is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 0.70 or more, and more preferably 0.80 or more.
When the sphericity value of the sugar alcohol spherical granule aggregate is within the more preferable range, it is advantageous in that the release time of the active ingredient and the like can be more accurately controlled when used in a tablet to be described later. It is.
In the present invention, the sphericity is expressed by the ratio of the minor axis / major axis of the sugar alcohol spherical granule. The minor axis / major axis ratio is the ratio between the minor axis and the major axis of the sugar alcohol spherical granulated product, and is a measure of sphericity. The ratio between the short axis and the long axis is determined by randomly placing sugar alcohol spherical granules on the sample stage, taking a photograph, and measuring the length of the long axis (major axis) and the long axis of 50 sugar alcohol spherical granules. The length (minor axis) of the minor axis orthogonal to the midpoint of each is measured, the ratio of the minor axis to the major axis is determined for each, and the average value of 50 is shown.

  Since the sugar alcohol spherical granule aggregate of the present invention has a small average particle size, a sharp particle size distribution, and low reactivity with the drug, it is used as a core particle of the controlled release granule in the orally disintegrating tablet described later. It can be used suitably.

(tablet)
The tablet of the present invention contains the sugar alcohol spherical granule aggregate of the present invention and a food material or an active ingredient, and further contains other ingredients as necessary.
There is no restriction | limiting in particular as a kind of said tablet, Although it can select suitably according to the objective, It can use suitably as an orally disintegrating tablet.

-Sugar alcohol spherical granule aggregate-
The sugar alcohol spherical granule aggregate is the sugar alcohol spherical granule aggregate of the present invention described above.
There is no restriction | limiting in particular as content of the said sugar alcohol spherical granule aggregate in the said tablet, According to the objective, it can select suitably, For example, it can be 20 mass%-70 mass%.

-Food ingredients or active ingredients-
−−Food ingredients−−
The food material is not particularly limited as long as it can be used for food, and can be appropriately selected according to the purpose. For example, glucosamine, amino acids, vitamins, chondroitin, minerals, collagen, turmeric, ginkgo leaves, blueberries , Soy isoflavones, royal jelly, chlorella and the like. These may be used individually by 1 type and may use 2 or more types together.
There is no restriction | limiting in particular as content of the said foodstuff material in the said tablet, According to the objective, it can select suitably.

-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 treatments, gastric mucosal repair drugs, analgesic antispasmodics, etc. Specifically, acetaminophen, temocapril 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, Zolpidem tartrate, 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, cefdi Examples include trenpivoxil, cefcapene pivoxil hydrochloride, valsartan, bicalutamide, and acarbose. These may be used individually by 1 type and may use 2 or more types together.
There is no restriction | limiting in particular as content of the said active ingredient in the said tablet, According to the objective, it can select suitably.

-Other ingredients-
The other components are not particularly limited and may be appropriately selected depending on the purpose. For example, excipients, disintegrants, lubricants, binders, fluidizers, sweeteners, coating agents, moisture absorption Agents, dehumidifiers, pigments, flavoring agents, solubilizing agents and the like. These may be used alone or in combination of two or more.
There is no restriction | limiting in particular as content of the said other component in the said tablet, According to the objective, it can select suitably.

  There is no restriction | limiting in particular as said excipient | filler, According to the objective, it can select suitably, For example, lactose, crystalline cellulose, D-mannitol, etc. are mentioned. These may be used alone or in combination of two or more.

  There is no restriction | limiting in particular as said disintegrating agent, According to the objective, it can select suitably, For example, crospovidone, low substituted hydroxypropyl cellulose (L-HPC), carboxymethylcellulose (carboxymethylcellulose Na, carboxymethylcellulose Ca etc.) ) And the like, crystalline cellulose, starch such as hydroxypropyl starch and the like. 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. These may be used alone or in combination of two or more.

  There is no restriction | limiting in particular as said binder, According to the objective, it can select suitably, For example, crystalline cellulose etc. are mentioned. These may be used alone or in combination of two or more.

  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. These may be used alone or in combination of two or more.

  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. These may be used alone or in combination of two or more.

  The coating agent is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include ethyl acrylate / methyl methacrylate copolymer, ethyl cellulose and shellac. These may be used alone or in combination of two or more.

-Aspect-
The tablet comprises a sugar alcohol spherical granule aggregate as a core particle, a layer containing a food material or an active ingredient on the surface thereof (hereinafter sometimes referred to as a “drug-containing layer”), a functional coating An embodiment in which the layers include coated granules coated in this order is preferable.
There is no restriction | limiting in particular as said functional coating layer, According to the objective, it can select suitably, For example, a release control layer, a masking layer, etc. are mentioned.
Among the coated granules, controlled release granules in which the surface of the core particle is coated with the drug-containing layer and the release control layer in this order are preferable.

The method for producing the coated granules is not particularly limited and may be appropriately selected depending on the intended purpose. For example, stirring granulation, centrifugal rolling granulation, fluidized bed granulation, normal type or aeration type coating pan And the like.
The apparatus used for the production of the coated granule is not particularly limited and can be produced by appropriately selecting and using a known apparatus. For example, a composite fluidized bed granulation coating apparatus, Spiraflow (Freund Industrial Co., Ltd.) Company-made). The operating conditions of the composite fluidized bed granulation coating apparatus are not particularly limited and can be appropriately selected according to the purpose.

The coating amount of the drug-containing layer is not particularly limited and may be appropriately selected depending on the purpose. For example, the amount of the food material or active ingredient is 10% by mass with respect to the mass of the core particles. Is mentioned.
Further, the coating amount of the functional coating layer is not particularly limited and can be appropriately selected according to the purpose. For example, the core particles (hereinafter referred to as “drug granules”) in which the drug-containing layer is formed. The amount of the coating agent relative to the mass of

  Since the coated granules use the sugar alcohol spherical granule aggregate of the present invention as the core particles, the particle diameter can be made 200 μm or less. Therefore, for example, when the release control granule is used in an orally disintegrating tablet, roughness in the oral cavity can be reduced, so that it can be suitably used for an orally disintegrating tablet.

  The method for producing the tablet is not particularly limited, and a known method can be appropriately selected depending on the purpose. For example, the coated granule, the excipient, the binder, and the disintegrant And a method of tableting after mixing with the lubricant. 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: Production of sugar alcohol spherical granule aggregate)
<Preparation of crystal particles>
As crystal particles, D-mannitol (average particle diameter 20 μm) was crushed. In addition, the said crushing was performed as follows.
-Disintegration-
The D-mannitol crystal particles were put into a power mill P-3 (manufactured by Dalton Co., Ltd.), a crushing granulator equipped with a screen having 3 mm diameter pores (punching).

<Granulation>
The D-mannitol crystal particles were put into a granulation vessel of a centrifugal rolling granulator, CF granulator CF-360 (manufactured by Freund Sangyo Co., Ltd.). While supplying slit air, the rotating disk was rotated at 230 rpm, and a 20% by mass aqueous solution of D-mannitol was used as a sugar alcohol solution, and the solid content of D-mannitol was 7.6% by mass relative to the mass of the crystal particles. Spray granulation was performed at a flow rate of 12 mL / min until it became a wet D-mannitol spherical particle.

  Next, the D-mannitol spherical particles in the wet state are put in a granulation container of a fluidized bed granulator, Flow Coater FL-5 (manufactured by Freund Sangyo Co., Ltd.) and dried at an exhaust temperature of 30 ° C. 944 mL of a 20% by weight aqueous solution was spray coated at a rate of 20 mL / min.

After the spray coating, sieved with 53 μm and 106 μm sieves, a sugar alcohol spherical granule aggregate having a sphericity of 0.84, an average particle diameter of 69 μm, and a σ _g value of 1.22 obtained from the particle size distribution Was obtained in a yield of 76%.
The average particle size and the value of σ _g obtained from the particle size distribution were measured and calculated using a laser diffraction / scattering particle size distribution measuring device, Microtrac HRA (manufactured by Nikkiso Co., Ltd.).
The sphericity is expressed as a minor axis / major axis ratio of the sugar alcohol spherical granule. The minor axis / major axis ratio is the ratio between the minor axis and the major axis of the sugar alcohol spherical granulated product, and is a measure of sphericity. The ratio between the short axis and the long axis is determined by randomly placing sugar alcohol spherical granules on the sample stage, taking a photograph, and measuring the length of the long axis (major axis) and the long axis of 50 sugar alcohol spherical granules. The length (minor axis) of the minor axis orthogonal to the midpoint of each is measured, the ratio of the minor axis to the major axis is determined for each, and the average value of 50 is shown.

(Comparative Example 1: Production of sugar alcohol spherical granule aggregate)
<Preparation of crystal particles>
In the same manner as in Example 1, D-mannitol crystal particles were prepared.

<Granulation>
The D-mannitol crystal particles were put into a granulation vessel of a centrifugal rolling granulator, CF granulator CF-360 (manufactured by Freund Sangyo Co., Ltd.). While supplying slit air, the rotating disk was rotated at 190 rpm, and a 20% by mass aqueous solution of D-mannitol was used as a sugar alcohol solution, and the solid content of D-mannitol was 2.5% by mass relative to the mass of the crystal particles. Spray granulation was performed at a flow rate of 12 mL / min until it became a wet D-mannitol spherical particle. Subsequently, a D-mannitol powder having an average particle diameter of 9 μm was sprayed at a rate of 34 g / min until the mass of the crystal particles became 120% by mass, while a 20% by mass aqueous solution of D-mannitol was flowed at a flow rate of 8 mL / min. Was spray granulated to obtain wet D-mannitol spherical particles.

  Next, in the same manner as in Example 1, the wet D-mannitol spherical particles were spray coated.

  As a result of sieving with 53 μm and 106 μm sieves after the spray coating, almost no sugar alcohol spherical particles having a particle diameter of less than 100 μm were obtained.

(Example 2: Production of sugar alcohol spherical granule aggregate)
In the granulation of Example 1, a 20 mass% aqueous solution of D-mannitol was spray granulated at a flow rate of 12 mL / min until the mass of the solid content of D-mannitol was 7.6 mass% with respect to the mass of the crystal particles. Except that the 20 mass% aqueous solution of D-mannitol was spray granulated at a flow rate of 18 mL / min until the solid mass of D-mannitol was 3.7 mass% with respect to the mass of the crystal particles. In the same manner as in Example 1, a sugar alcohol spherical granule aggregate was produced, and the sugar alcohol having a sphericity of 0.84, an average particle diameter of 75 μm, and a σ _g value of 1.19 obtained from the particle size distribution was A spherical granule aggregate was obtained with a yield of 37%.

From the above results, sugar alcohol crystal particles having an average particle diameter of more than 15 μm and less than 50 μm are rolled in a centrifugal rolling device, and granulated while spraying a sugar alcohol solution in the absence of sugar alcohol powder. Thus, it was shown that a sugar alcohol spherical granule aggregate having an average particle diameter of less than 100 μm and a σ _g value of 1.1 to 1.5 obtained by the particle size distribution can be efficiently produced.
Since the sugar alcohol spherical granule aggregate has an average particle diameter of less than 100 μm, by using the sugar alcohol spherical granule aggregate, the particle diameter of the controlled release particles can be less than 200 μm. Conventionally, roughness in the oral cavity that has occurred when used as controlled release particles for orally disintegrating tablets can be reduced.

Claims (8)

A sugar alcohol spherical granule aggregate used as a core particle of controlled release particles,
A sugar alcohol spherical granule aggregate having an average particle diameter of less than 100 μm and a value of σg obtained from a particle size distribution of 1.1 to 1.5.   The sugar alcohol spherical granule aggregate according to claim 1, wherein the sugar alcohol is mannitol.   The sugar alcohol spherical granule aggregate according to any one of claims 1 to 2, which is used for orally disintegrating tablets. The sugar alcohol spherical granule aggregate according to any one of claims 1 to 3, wherein the sugar alcohol spherical granule is coated with a sugar alcohol. A method for producing a sugar alcohol spherical granule aggregate used as a core particle of controlled release particles,
A step of rolling sugar alcohol crystal particles having an average particle diameter of more than 15 μm and less than 50 μm in a centrifugal rolling device, and granulating while spraying a sugar alcohol solution in the absence of sugar alcohol powder;
And a step of spraying a sugar alcohol solution onto the granulated product obtained in the above step to coat the granulated product, and a method for producing a sugar alcohol spherical granule aggregate. 6. The method for producing a sugar alcohol spherical granule aggregate according to claim 5, wherein the sugar alcohol crystal particles are crushed. A tablet comprising a sugar alcohol spherical granule aggregate used as a core particle of a controlled release particle according to any one of claims 1 to 4, and a food material or an active ingredient. The tablet according to claim 7, which is an orally disintegrating tablet.