JP7224624B2 - Granules and manufacturing method thereof - Google Patents

Description

TECHNICAL FIELD The present invention relates to granules that can be suitably used for producing pharmaceutical solid preparations such as capsules, sachets, orally disintegrating tablets, and a method for producing the same.

Conventionally, granules and excipients used for producing solid pharmaceutical preparations have been produced by various methods such as fluidized bed and spray drying (see, for example, Patent Document 1). Especially for tablets, granules produced using a fluidized bed have been preferred and used because tablets with high hardness can be easily obtained by using granules with irregular and porous shapes.

On the other hand, in recent years, there has been a demand for excipients that not only have high hardness but also good disintegration properties so that they can be used in orally disintegrating tablets (hereinafter sometimes referred to as “OD tablets”). In the case of OD tablets, rapid disintegration in the mouth facilitates swallowing, and therefore, there is a demand for tablets that disintegrate in a shorter period of time.

In addition, some granules used in capsules are required to disintegrate quickly so that a highly concentrated drug solution reaches the intestinal wall. This is because if the drug gradually dissolves, the blood concentration may be too low to reach the minimum effective concentration, resulting in no effect.

Therefore, at present, there is a strong demand for providing granules having disintegration properties that are even more excellent than those of conventional granules.

JP 2014-156435 A

SUMMARY OF THE INVENTION An object of the present invention is to solve the above-mentioned conventional problems and to achieve the following objects. That is, an object of the present invention is to provide granules having excellent disintegration properties and a method for producing the same.

In order to solve the above problems, the present inventors have made intensive studies, and as a result, have obtained the following findings. That is, a granule obtained by wet granulation of a saccharide consisting of sugar and/or sugar alcohol and a disintegrant, wherein the total outer peripheral length of voids per cross-sectional area in the cross section of the granule (sum of outer peripheral length of voids/cross-section It was found that when the area) is 0.040 or more, excellent disintegration properties can be obtained.

The present invention is based on the findings of the present inventors, and means for solving the above problems are as follows. Namely
<1> Granules obtained by wet granulation of sugars and/or sugar alcohols and a disintegrant,
The granule is characterized in that the sum of the outer perimeter lengths of voids per cross-sectional area in the cross section of the granule (total length of outer perimeter length of voids/cross-sectional area) is 0.040 or more.
<2> The granules according to <1> above, wherein the sum of perimeter lengths of voids per cross-sectional area is 0.050 or more.
<3> Any one of <1> to <2>, wherein the ratio of the peripheral length of the central portion in the cross section of the granule to the sum of the peripheral lengths of the voids present in the central portion is 1:2.5 or more. The granules described in
<4> The granules according to any one of <1> to <3>, further comprising an active ingredient.
<5> A wet granulated product obtained by wet granulating a saccharide consisting of a sugar and/or a sugar alcohol and a disintegrant is treated within 5 minutes so that the moisture content is 2.0 times the equilibrium moisture value of the raw material mixture. A method for producing granules, characterized in that it comprises a step of drying to reach:
<6> The method for producing granules according to <5>, wherein the drying is performed in a flash dryer.
<7> A wet granulation device and a flash drying device are connected, and the wet granules are continuously supplied from the wet granulation device to the flash drying device to continuously produce granules. A method for producing granules according to any one of <5> to <6>.
<8> The method for producing granules according to any one of <5> to <7>, wherein the wet granules further contain an active ingredient.

ADVANTAGE OF THE INVENTION According to this invention, the said various problems in the former can be solved, the said objective can be achieved, and the granule which has the outstanding disintegration property, and its manufacturing method can be provided.

FIG. 1 is a schematic diagram illustrating the central portion of a granule cross section. 2A is a diagram showing the granules of Example 1 photographed with a three-dimensional X-ray microscope in Evaluation 1. FIG. FIG. 2B is a view after processing the image of FIG. 2A. 3A is a diagram showing granules of Comparative Example 1 photographed with a three-dimensional X-ray microscope in Evaluation 1. FIG. FIG. 3B is a view after processing the image of FIG. 3A.

(Granule and its manufacturing method)
The granules of the present invention are granules obtained by wet granulation of sugars and/or sugar alcohols, disintegrants, and optionally active ingredients and other additives. can be suitably produced.
Hereinafter, the granules of the present invention will be explained together with the explanation of the method for producing the granules of the present invention.

<Method for producing granules>
The method for producing granules of the present invention includes at least a drying step and, if necessary, further includes other steps.

<<Drying process>>
In the drying step, a wet granulated product obtained by wet granulating a saccharide consisting of sugar and/or a sugar alcohol and a disintegrant is dried within 5 minutes, preferably within 60 seconds. This is a step of drying to reach 2.0 times or less, preferably 1.5 times or less of the equilibrium moisture value.

- wet granulation -
The wet granules can be obtained by wet granulating a mixed powder containing sugars and/or sugar alcohols, disintegrants, and optionally active ingredients and other additives.

--Saccharides consisting of sugars and/or sugar alcohols--
The sugars are not particularly limited as long as they are sugars and/or sugar alcohols, and can be appropriately selected depending on the purpose. Examples include sucrose, lactose, fructose, maltose, trehalose, mannitol, xylitol, Erythritol, sorbitol, maltitol, isomalt, lactitol, sucrose, glycerin and the like. These may be used individually by 1 type, and may use 2 or more types together.
Among these, sugar alcohols are preferred, and mannitol is more preferred, in terms of better disintegration properties.
Commercially available products can be used as the sugars.

The content of saccharides in the mixed powder is not particularly limited and can be appropriately selected according to the purpose. 30% by mass to 99.9% by mass, more preferably 30% by mass to 99.9% by mass.

--Disintegrant--
The disintegrant is not particularly limited and can be appropriately selected depending on the intended purpose. ), crystalline cellulose, hydroxypropyl starch, starch such as cornstarch, and the like. These may be used individually by 1 type, and may use 2 or more types together.
A commercially available product can be used as the disintegrant.

The content of the disintegrant in the mixed powder is not particularly limited and can be appropriately selected according to the purpose. %, more preferably 1 mass % to 15 mass %.

--Active Ingredients--
The active ingredient is not particularly limited and can be appropriately selected depending on the intended purpose. , antiparkinson drugs, allergy medicines, oral medicines, cardiotonics, antipyretic analgesics, antiphlogistics, antihistamines, antitussives, antacids, herbal medicines, antihypertensives, antibiotics, antibacterial agents, antiarrhythmic drugs, coronary blood vessels Dilators, peripheral vasodilators, hyperlipidemia drugs, choleretic drugs, hormone drugs, antigout drugs, antirheumatic drugs, chemotherapy drugs, diabetes drugs, antiemetic drugs, antiepileptic drugs, sympathomimetic drugs, Osteoporosis drugs, antineoplastic drugs, immunosuppressive drugs, urological drugs, gastrointestinal drugs, brain metabolism improving drugs, cerebral circulation improving drugs, respiratory stimulants, vasoconstrictors, antivertigo drugs, expectorants, drugs acting on the central nervous system , ulcer therapeutic agents, gastric mucosa repair agents, analgesics, antispasmodics, etc. Specific examples include ethenzamide, acetaminophen, temocapril hydrochloride, cabergoline, amlodipine besilate, omeprazole, and lansoprazole. , famotidine, lafutidine, ecabet sodium, mosapride citrate, rebamipide, voglibose, risperidone, imidapril hydrochloride, meloxicam, milnacipran hydrochloride, levofloxacin, clarithromycin, sarpogrelate hydrochloride, tosufloxacin tosilate, 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, fujitren pivoxil, cefcapene pivoxil hydrochloride, valsartan, bicalutamide, acarbose and the like. These may be used individually by 1 type, and may use 2 or more types together.
Commercially available products can be used as the active ingredient.

The content of the active ingredient in the mixed powder is not particularly limited and can be appropriately selected according to the purpose. %, more preferably 1 mass % to 80 mass %.

--Other Additives--
The other additives are not particularly limited as long as they do not impair the effects of the present invention, and excipients other than sugars, binders, and other additives known as pharmaceutical additives are appropriately selected according to the purpose. be able to. These may be used individually by 1 type, and may use 2 or more types together.
Commercially available products can be used as the other additives.
The content of other additives in the mixed powder is not particularly limited and can be appropriately selected according to the purpose.

Excipients other than the sugars are not particularly limited and can be appropriately selected depending on the intended purpose. Examples thereof include crystalline cellulose and corn starch. These may be used individually by 1 type, and may use 2 or more types together.
Commercially available products can be used as excipients other than the sugars.
The content of excipients other than sugars in the mixed powder is not particularly limited and can be appropriately selected according to the purpose. %, more preferably 0 mass % to 30 mass %.

The binder is not particularly limited and can be appropriately selected depending on the intended purpose. Examples thereof include hydroxypropylcellulose and polyvinylpyrrolidone. These may be used individually by 1 type, and may use 2 or more types together.
Commercially available products can be used as the binder.
The content of the binder in the mixed powder is not particularly limited and can be appropriately selected according to the purpose. %, more preferably 1 mass % to 10 mass %.

A method for preparing the mixed powder is not particularly limited, and a known mixing method can be appropriately selected, and examples thereof include a method of mixing using a tumbler mixer or the like.

-- wet granulation --
The wet granulation method is not particularly limited, and a known method can be appropriately selected. For example, the mixed powder is kneaded with a liquid such as water to produce a granulated product. mentioned.
The ratio of adding the liquid to the mixed powder is not particularly limited and can be appropriately selected according to the purpose. 45% by mass, more preferably 5% to 40% by mass.
The wet granulation can be performed by appropriately selecting a known wet granulation apparatus.

-Drying-
As the drying method, the wet granules are dried within 5 minutes, preferably within 60 seconds, until the moisture content is 2.0 times or less the equilibrium moisture value of the raw material mixture for the wet granulation, preferably 1. There is no particular limitation as long as it can be dried to reach 5 times or less, and it can be appropriately selected according to the purpose. is preferred.
If the water content of the granules obtained in the drying step is more than 2.0 times the equilibrium water content of the raw material mixture, the stability during storage is lowered. On the other hand, when the water content of the granules is 2.0 times or less the equilibrium water content of the raw material mixture, the stability during storage is good.
In the present invention, the equilibrium moisture value of the raw material mixture refers to the value under the temperature and relative humidity conditions of the drying step.

The airflow drying device is not particularly limited, and a known device can be appropriately selected and used.

The conditions for drying using the airflow drying device are not ^particularly limited, and can be appropriately selected according to the purpose. is mentioned.

In the conventionally used fluidized bed drying, it takes several tens of minutes until drying is completed, so the granules collide with the can body many times, and the outer peripheral side in particular is compacted. Also, during drying, it is gradually dried from the outer peripheral side, but as it dries, the water in the center moves to the outer periphery, and the sugars and the disintegrant also move to the outer periphery. Therefore, the obtained granules tend to have a hollow structure.
On the other hand, the moisture content of the wet granule reaches 2.0 times or less, preferably 1.5 times or less, the equilibrium moisture content of the raw material mixture for the wet granulation within 5 minutes, preferably within 60 seconds. Since the drying time is short, the chances of the granules colliding with the can body are reduced when the granules are dried in this way, and the granules are hardly compacted. In addition, since the water inside evaporates inside soon after it moves to the outer peripheral side, the saccharides and the disintegrant hardly move to the outer peripheral part, resulting in a generally uniform structure.
As a result, the granules of the present invention have a high porosity, a high ratio of the outer circumference length of the voids, and a substantially uniform internal structure. Therefore, in the granules of the present invention, the sum of the outer perimeter lengths of voids per cross-sectional area in the cross-section of the granules is high, as will be described later. In addition, as will be described later, in the ratio of the peripheral length of the central portion in the cross section of the granule to the sum of the peripheral lengths of the voids present in the central portion, the value of the sum of the peripheral lengths of the voids present in the central portion is growing.
In addition, since the granules of the present invention have more uniform distribution of voids than hollow granules obtained by fluidized bed drying, it is believed that the distribution of the disintegrant is also uniform. It is thought that this contributes to the improvement of the disintegrability.

As a method for producing the granules of the present invention, a wet granulation device and a flash drying device are connected, the wet granules are continuously supplied from the wet granulation device to the flash drying device, and continuous An embodiment in which granules are produced on a regular basis is preferred.
The apparatus used in the continuous production of granules is not particularly limited and can be appropriately selected according to the purpose. Examples thereof include Granuformer (manufactured by Freund Corporation). The granuformer is a continuous granulator with an attached granule sizing machine and a spiral dryer.

<<Other processes>>
The other steps are not particularly limited as long as they do not impair the effects of the present invention, and can be appropriately selected according to the purpose. Examples thereof include a wet granule sizing step.

The wet sizing step is a step of wet sizing the wet granulated product before subjecting it to the drying step. Coarse granules can be removed by the sizing step.
The wet granule regulating method is not particularly limited, and a known method can be appropriately selected. Examples thereof include a method using a granule regulating machine.
Conditions for the wet sizing are not particularly limited, and can be appropriately selected according to the purpose.

<Granule>
The granules of the present invention have superior disintegration properties compared to conventional granules.

<<Total Peripheral Length of Gaps/Cross-Sectional Area>>
The total perimeter length of voids per cross-sectional area in the cross section of the granule (sum of perimeter length of voids/cross-sectional area) is not particularly limited as long as it is 0.040 or more, and may be appropriately selected depending on the purpose. However, 0.050 or more is preferable from the viewpoint of better disintegration.

<<Ratio between the peripheral length of the central portion and the sum of the peripheral lengths of the voids present in the central portion>>
The central portion of the cross section of the granules in the present invention will be described with reference to the schematic diagram of FIG.
The central portion of the cross section of the granule refers to the center of the granule determined by the erosion method after binarizing the photograph of the cross section of the granule taken using image analysis software HALCON (manufactured by Lynx) (Fig. 1 Reference 1) and the part (reference 4 in FIG. 1) divided by the line connecting the middle point (reference 3 in FIG. 1) of the outer circumference of the granule (reference 2 in FIG. 1). When calculating this ratio, it is important whether or not there is a void in the central portion, so cross-sectional views of granule ends that do not pass through the central portion of the granule are excluded.

For example, when the central portion is entirely composed of voids, the ratio of the peripheral length of the central portion to the sum of the peripheral lengths of the voids present in the central portion is 1:1. In addition, as the gap existing in the central portion increases, the value on the right side of the ratio approaches 1.
On the other hand, as the number of fine voids increases in the central portion, the numerical value on the right side of the ratio increases.

The ratio between the peripheral length of the central portion in the cross section of the granule and the sum of the peripheral lengths of the voids present in the central portion is not particularly limited and can be appropriately selected depending on the purpose. 1:2.5 or more is preferable, and 1:3.0 or more is more preferable, in terms of increasing the uniformity of the distribution of the saccharide and the disintegrant in .

The cross section of the granule may be obtained by physically cutting the granule with a cutter or the like and photographing it with an electron microscope or photographing it with an X-ray microscope.
The cross section of the granule can be selected at any location, but it is preferable to select the cross section that maximizes the area of the largest voids present in the granule.

When the cross section of the granule is photographed with an X-ray microscope, for example, a three-dimensional X-ray microscope (nano3DX manufactured by Rigaku) is used, and the photograph is taken under the conditions of a tube voltage of 40 kv, a tube current of 30 mA, and a spatial resolution of 0.52 μm/voxcel. be able to.
The cross-sectional area of the granules, the sum of the perimeter lengths of the voids, the perimeter length of the central portion of the cross section, and the sum of the perimeter lengths of the voids present in the center portion) were obtained from the photographed image analysis software HALCON (manufactured by Lynx). can be calculated from the binarized image.

The granules of the present invention can be used as excipients and the like for the production of pharmaceutical solid preparations, etc., and can be suitably used for capsules and sachets, particularly for orally disintegrating tablets.

EXAMPLES The present invention will be described below with reference to Examples and Comparative Examples, but the present invention is not limited to these Examples.

(Example 1)
30% by mass of ethenzamide (ethenzamide A (powder type) manufactured by Yamamoto Chemical Industry Co., Ltd.) as an active ingredient; Asahi Kasei Co., Ltd.) 10% by mass, 5% by mass of low-substituted hydroxypropylcellulose (LH-21, manufactured by Shin-Etsu Chemical Co., Ltd.) as a disintegrant, and 3% by mass of hydroxypropylcellulose (HPC-L, manufactured by Nippon Soda Co., Ltd.) as a binder. were mixed in a tumbler mixer for 5 minutes. This mixed powder was wet granulated using a continuous granulator (Granuformer Gf-2050, manufactured by Freund Corporation) so that the proportion of water added to the mixed powder was 16% by mass. Subsequently, after wet granulation with a grain regulating machine (screen diameter φ3.0 mm) attached to the granuformer, the air flow type granulating machine attached to the granuformer operates at an air volume of 8.5 m ³ /min and an air supply temperature of 120 ° C. In a dryer (spiral dryer), while continuously supplying the granulated wet granules, the moisture content becomes 2.0 times or less the equilibrium moisture value of the raw material mixture of the wet granules within 60 seconds. The dried granules were collected with a cyclone collector.

(Example 2)
Granulation, sizing and drying were carried out in the same manner as in Example 1 except that D-mannitol in the mixed powder of Example 1 was replaced with lactose (Pharmatose 200M DPE Pharma) to obtain dry granules.

(Example 3)
Granulation, sizing, and drying were performed in the same manner as in Example 1, except that ethenzamide in the mixed powder of Example 1 was omitted, to obtain dry granules.

(Comparative example 1)
The sieved wet granules obtained in the same manner as in Example 1 were charged into a fluidized bed granulator dryer (Flow coater FLO-5M, manufactured by Freund Corporation) at an air volume of 3 m ³ /min and an air supply temperature of 80. C. for 40 minutes until the exhaust temperature reaches 40.degree.

(Comparative example 2)
The mixed powder of Example 1 from which hydroxypropyl cellulose was removed was charged into a fluidized bed granulator dryer (Flow coater FLO-5M, manufactured by Freund Corporation) under the conditions of an air flow rate of 3 m ³ /min and an air supply temperature of 80°C. Then, wet granulation was performed by spraying a 5% by weight aqueous solution of hydroxypropyl cellulose (HPC-L, manufactured by Nippon Soda Co., Ltd.) as a binder, and drying was performed in the same manner as in Comparative Example 1 to obtain dry granules. The proportion of hydroxypropylcellulose in the granules was adjusted to the same proportion as in Example 1.

(Evaluation 1)
The granules obtained in Examples 1 to 3 and Comparative Examples 1 and 2 were examined with a three-dimensional X-ray microscope (nano3DX manufactured by Rigaku) under the conditions of tube voltage of 40 kv, tube current of 30 mA, and spatial resolution of 0.52 μm/voxcel. Taken with
Using the image analysis software HALCON (manufactured by Lynx), from the binarized image of the photograph taken, the sum of the cross-sectional area of the granule and the outer circumference of the voids in the cross section (hereinafter referred to as "peripheral length of voids") There is.) was calculated. Furthermore, by the erosion method, the cross section of the granule is divided into a central portion and a peripheral portion, and the peripheral length of the central portion (hereinafter sometimes referred to as “the peripheral length of the central portion”) and the The sum total of the outer circumference of the voids (hereinafter sometimes referred to as the "central void outer length") was calculated. Table 1 shows the pore perimeter (A), the granule cross-sectional area (B), A/B, and the ratio between the central part perimeter and the central part pore perimeter.
Examples of photographs taken are shown in FIG. 2A (Example 1) and FIG. 3A (Comparative Example 1). Symbol Z in FIGS. 2A and 3A represents the granules for which the measurements were made. 2B and 3B show the images after processing the images of FIGS. 2A and 3A, respectively.

Next, 1% by mass of magnesium stearate was added to each of the granules of Examples 1 and 2 and Comparative Examples 1 and 2, and mixed. Under tableting conditions, an appropriate tableting pressure was selected so that the tablet hardness was about 50N, and tableting was performed. The granules of Example 3 were mixed with 30% by mass of ethenzamide, then mixed with magnesium stearate in the same manner as the other granules, and tableted. Then, the disintegration time of the tablet was measured using an intraoral (rapidly) disintegrating tablet measuring device (Tricorp Tester manufactured by Okada Seiko Co., Ltd.). Table 1 shows the results.

(Evaluation 2)
In a beaker containing 900 mL of purified water at normal temperature, rotate the stirrer at 800 rpm, add 100 mg or 200 mg of the granules obtained in Example 1 or Comparative Example 1, respectively, and stir until the granulated granules can no longer be visually confirmed. time was measured. Table 2 shows the results.

From the above results, it was confirmed that the granules of the present invention have extremely excellent disintegration properties.

Since the granules of the present invention have excellent disintegration properties, they can be suitably used as granules for producing pharmaceutical solid preparations such as capsules, sachets and orally disintegrating tablets.
When the granules of the present invention are used in an orally disintegrating tablet, they quickly disintegrate in the mouth and are smooth to swallow. In addition, when the granules of the present invention are used in capsules or sachets, the granules inside disintegrate quickly when the capsule is dissolved, and a high-concentration drug solution flows out into the intestinal tract and is absorbed, so the designed efficacy can be expected.

1 ... Center 2 ... Periphery of granule 3 ... Periphery of central part (line connecting midpoints from center of gravity of granule cross section to outer periphery of granule)
4 ・・・ central part Z ・・・ granules

Claims (7)

Granules obtained by wet granulation of sugars and/or sugar alcohols and a disintegrant,
The sum of the outer peripheral lengths of the pores per cross-sectional area in the cross section of the granule (sum of the outer peripheral length of the pores/cross-sectional area) is 0.040 or more,
A granule, wherein the ratio of the peripheral length of the central portion of the cross section of the granule to the sum of the peripheral lengths of voids present in the central portion is 1:2.5 or more. 2. The granules according to claim 1, wherein the sum of the outer perimeter lengths of the voids per cross-sectional area is 0.050 or more. 3. Granules according to any of claims 1-2, further comprising an active ingredient. A method for producing the granules according to any one of claims 1 to 3,
The moisture content of a wet granulated product obtained by wet granulating a saccharide consisting of sugar and/or sugar alcohol and a disintegrant reaches 2.0 times or less the equilibrium moisture value of the raw material mixture within 5 minutes. A method for producing granules, characterized by including a step of drying as follows. 5. The method for producing granules according to claim 4, wherein the drying is performed with a flash dryer. A wet granulation device and a flash drying device are connected, and the wet granules are continuously supplied from the wet granulation device to the flash drying device to continuously produce granules. 6. A method for producing the granules according to any one of 5. The method for producing granules according to any one of claims 4 to 6, wherein said wet granules further contain an active ingredient.

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