JP6201017B2 - Method for producing orally disintegrating tablet excellent in hardness and disintegration, and orally disintegrating tablet produced by the production method - Google Patents

Description

  The present invention relates to a method for producing an orally disintegrating tablet excellent in hardness and disintegration, and an orally disintegrating tablet produced by the production method.

  Orally disintegrating tablets are suitable for the elderly with poor swallowing function, children who are not good at drinking tablets, and when water is not available when going out, etc. Is underway.

The technology of orally disintegrating tablets is diverse and has been actively researched and developed since 1990 in Japan and abroad.
Orally disintegrating tablets are classified based on their prescription and manufacturing method (Non-Patent Document 1). In the classification described in Non-Patent Document 1, the present invention is broadly classified as “quickly disintegrating”, medium-classified as “compressed tablet”, and further subclassified as “low-pressure tableting / humidification / drying”. Orally disintegrating tablets.

As formulation technologies belonging to the above classification, there are technologies described in Patent Documents 1 to 4.
In Patent Document 1, when a tablet material in a dry state is transferred to the next step as a tablet form, tableting is performed at a minimum pressure required to maintain the form, and this is humidified. The manufacturing method of the orally disintegrating tablet provided with the process to dry is described.
Patent Document 2 describes a method for producing an orally disintegrating tablet in which a pharmaceutical composition is tableted at a specific low pressure, humidified, and dried to adjust the tablet porosity to 20 to 40%.
Patent Document 3 describes an orally disintegrating tablet manufactured by the manufacturing method described in Patent Document 1.
Patent Document 4 describes an orally disintegrating tablet that contains a drug and a water-soluble binder but does not contain a disintegrant, wherein the water-soluble binder has a specific viscosity and an equilibrium water content. ing.

In addition, there are techniques described in Patent Documents 2, 5, and 6 as techniques focusing on the porosity of the orally disintegrating tablet.
Patent Document 2 describes an orally disintegrating tablet having a porosity of 20 to 40%.
Patent Document 5 describes an orally disintegrating tablet having a porosity of 10 to 80%.
Patent Document 6 describes an orally disintegrating tablet having a porosity of 20 to 50%.

Patent No. 2919771 specification Japanese Unexamined Patent Publication No. 2000-95674 Patent No. 4504467 Specification Japanese Patent Laid-Open No. 2001-342128 JP 2004-43472 A JP 2011-46750 A

The 6th Symposium of PLCM (Tillage) Study Group Present Status and Prospects of Orally Disintegrating Tablets, Abstracts of Lectures, 16 pages, published on January 30, 2012

A conventional method for producing an orally disintegrating tablet including a step of humidifying and drying a tablet is one of the purposes to increase tablet hardness while maintaining the disintegration property of the tablet.
In the prior art, the disintegration property of orally disintegrating tablets has been examined in relation to the porosity.
However, the orally disintegrating tablet manufactured according to the manufacturing method of the prior art and the orally disintegrating tablet in which the porosity is set according to the prior art did not satisfy the hardness and disintegration at a high level at the same time.

The present inventor conducted an optimization study on the manufacturing conditions of orally disintegrating tablets using various drugs, and when the tableted product was humidified in an environment containing a large amount of water fine particles, before and after humidification. We found a phenomenon that the disintegration time was delayed even though the porosity of the tablet was almost unchanged. As a result of further research, the present inventor found that there is not always a correlation between the porosity and disintegration property of the orally disintegrating tablet, and even if high porosity is ensured by low-pressure tableting, the humidification and drying conditions In some cases, we found that the disintegration was impaired.
Furthermore, the present inventor, when taking an orally disintegrating tablet, in order for saliva to permeate quickly from the tablet surface into the tablet and disintegrate, the pore distribution of the tablet, that is, the pore diameter and pore volume of the tablet, I found that the relationship is important.
As a result of further research, the inventor used erythritol having a specific particle size in a specific amount in the production of orally disintegrating tablets, and using specific tableting conditions and humidification conditions, the specific pores An orally disintegrating tablet having a distribution was obtained, and the orally disintegrating tablet having such a pore distribution was found to satisfy both hardness and disintegration at a high level simultaneously. The present invention has been made based on such knowledge.
That is, the present invention relates to the following.
1. A method for producing an orally disintegrating tablet comprising:
(1) Drug, mixed powder containing erythritol having an average particle size of 15 to 90 μm, binder and lubricant, or granulation containing drug, erythritol having an average particle size of 15 to 90 μm, binder and lubricant Tableting the mixture to obtain tablets,
The erythritol content of the tablet is 50 to 98% by mass with respect to the total mass of the tablet,
The tablet is applied to the orally disintegrating tablet obtained in step (3) by the following (i) and (ii):
(i) The pore volume V ₁ having a pore diameter of 0.1 to 100 μm is 0.15 to 0.40 ml / g.
(ii) a step performed at a tableting pressure to give a ratio (V ₂ / V ₁ ) of pore volume V ₂ of pore diameter 0.1 to 10 μm to V ₁ (V ₂ / V ₁ ) of 0.50 to 1.00,
(2) A step of passing the tablet obtained in step (1) through a humidifying chamber,
A process in which the dew point of water vapor generated from a humidifier connected to the humidifier is set to be 1 to 5 ° C. lower than the temperature in the humidifier; and
(3) drying the tablet obtained in step (2) to include an orally disintegrating tablet,
Pore volume V ₁ of the pore diameter 0.1~100μm of the orally disintegrating tablet is 0.15~0.40ml / g,
The ratio (V ₂ / V ₁ ) of V ₁ of the pore volume V ₂ of the pore diameter of 0.1 to 10 μm of the orally disintegrating tablet is 0.50 to 1.00,
The tablet hardness of the orally disintegrating tablet is 49-147 N, and
The manufacturing method whose disintegration time of this orally disintegrating tablet is 5 to 30 seconds.

2. The manufacturing method of said 1 which performs a process (1)-a process (3) continuously using a conveyor.

3. 3. The production method according to 1 or 2 above, wherein in the step (2), the passage time of the tablet in the humidifier is 30 seconds to 5 minutes.

4). 4. The production method according to any one of 1 to 3, wherein the tableting pressure in step (1) is 2942 N or less.

5). 5. The production method according to any one of 1 to 4, wherein the drug used in step (1) has an average particle size of 15 to 90 μm.

6). 6. The production method according to any one of 1 to 5, wherein a granulation mixture obtained using a wetting agent is used in step (1).

7). The orally disintegrating tablet manufactured by the manufacturing method in any one of said 1-6.

As shown in the examples described later, the orally disintegrating tablet obtained by the production method of the present invention simultaneously satisfies hardness and disintegration at a high level. The excellent disintegration property makes it possible to rapidly disintegrate in the oral cavity after taking and exert the medical effect of the drug. Excellent hardness makes it possible to stably hold the tablet shape, and leads to an improvement in handleability (for example, stability during product transportation).
Furthermore, the production method of the present invention can easily produce an orally disintegrating tablet having the above-mentioned excellent properties with a good yield.

FIG. 1 is a tablet surface SEM image of Comparative Example 5-1. FIG. 2 is a SEM image of the tablet surface of Example 5. FIG. 3 is a tablet surface SEM image of Comparative Example 5-2.

The method for producing the orally disintegrating tablet of the present invention comprises:
(1) Drug, mixed powder containing erythritol having an average particle size of 15 to 90 μm, binder and lubricant, or granulation containing drug, erythritol having an average particle size of 15 to 90 μm, binder and lubricant Tableting the mixture to obtain tablets,
The erythritol content of the tablet is 50 to 98% by mass with respect to the total mass of the tablet,
The tablet is applied to the orally disintegrating tablet obtained in step (3) by the following (i) and (ii):
(i) The pore volume V ₁ having a pore diameter of 0.1 to 100 μm is 0.15 to 0.40 ml / g.
(ii) a step performed at a tableting pressure to give a ratio (V ₂ / V ₁ ) of pore volume V ₂ of pore diameter 0.1 to 10 μm to V ₁ (V ₂ / V ₁ ) of 0.50 to 1.00,
(2) A step of passing the tablet obtained in step (1) through a humidifying chamber,
A process in which the dew point of water vapor generated from a humidifier connected to the humidifier is set to be 1 to 5 ° C. lower than the temperature in the humidifier; and
(3) drying the tablet obtained in step (2) to include an orally disintegrating tablet,
Pore volume V ₁ of the pore diameter 0.1~100μm of the orally disintegrating tablet is 0.15~0.40ml / g,
The ratio (V ₂ / V ₁ ) of V ₁ of the pore volume V ₂ of the pore diameter of 0.1 to 10 μm of the orally disintegrating tablet is 0.50 to 1.00,
The tablet hardness of the orally disintegrating tablet is 49-147 N, and
It is a manufacturing method whose disintegration time of this orally disintegrating tablet is 5 to 30 seconds.
Hereinafter, each process is explained in full detail.

Process (1)
In step (1), a drug, mixed powder containing erythritol having an average particle size of 15 to 90 μm, a binder and a lubricant, or a drug, erythritol having an average particle size of 15 to 90 μm, a binder and a lubricant are added. Tablets containing the granulated mixture are obtained.

The drug drug is not particularly limited as long as it can be administered as an orally disintegrating tablet. The drug may be in a solid or liquid state at room temperature. In addition, the drug may be systemic or local.
Specific examples of drugs include hypnotic sedatives / anti-anxiety drugs, antiepileptic drugs, antipyretic analgesic / anti-inflammatory drugs, anti-parkinsonian drugs, neuropsychiatric drugs, local anesthetics, cerebral circulation metabolism improvers, antispasmodics, antipruritic drugs, Cardiotonic, arrhythmic, diuretic, antihypertensive, vasoconstrictor, vasodilator, hyperlipidemic, respiratory stimulant, antitussive, expectorant, antitussive, a bronchodilator, gargle Drugs, antidiarrheal / intestinal drugs, anti-ulcer drugs, gastric digestive drugs, antacids, constipation drugs, antibacterial drugs, nourishing tonic health drugs, gout treatment drugs, diabetes drugs, antibiotics, antibacterial drugs, osteoporosis Examples include symptomatic drugs, skeletal muscle relaxants, anti-rheumatic drugs, hormone drugs, alkaloid narcotics, anticoagulants, antineoplastic drugs, antihistamines, and allergic drugs.
One type of drug may be used alone, or two or more types may be used in combination.

The average particle size of the drug is preferably the same average particle size as erythritol with a large amount to be described later, specifically 15 to 15 in terms of easily setting the pore distribution of the orally disintegrating tablet described later. 90 μm is preferable, and 30 to 80 μm is more preferable.
When the average particle size of the drug is 15 μm or more, an increase in the specific surface area of the drug can be suppressed, and the hardness and disintegration property of the orally disintegrating tablet can be improved. When using a drug having an average particle size of less than 15 μm, it is preferable to tablet as a granulated mixture in order to reduce the apparent specific surface area of the drug.
When the average particle size of the drug is 90 μm or less, the content uniformity of the drug in the orally disintegrating tablet can be increased. When the drug is subjected to special processing such as granulation coating for suppressing the bitterness of the drug, it may be difficult to adjust the average particle size of the drug to within 90 μm. In this case, in order to improve the content uniformity of the drug, it is preferable to tablet together with erythritol as a granulated mixture.
The average particle size of the drug was measured using the laser diffraction method described in Reference Information 30. Powder Particle Size Measurement by Laser Diffraction Method, for example, HORIBA laser particle size distribution analyzer LA-950 It can be measured by a dry method.

The content of the drug can be appropriately set according to the type of drug, etc., for example, 0.01 to 50% by mass, preferably 0.1 to 45% by mass with respect to the total mass of the tablet obtained in the step (1). is there.
When the drug content is less than 0.1% by mass with respect to the total mass of the tablet obtained in step (1), water, ethanol, or a mixture of water and ethanol is used from the viewpoint of drug content uniformity. It is preferable to dissolve or disperse the drug in (which may be a binder solution described later) and add it during granulation.

Erythritol erythritol is used as an excipient. The viscosity of an aqueous solution of erythritol is low compared to the viscosity of an aqueous solution of other saccharides used as excipients. Specifically, the viscosity at 37 ° C. of a 30% by mass aqueous solution of erythritol is 1.46 cSt, and the viscosity at 37 ° C. of a 30% by mass aqueous solution of purified sucrose (Japanese Pharmacopoeia) as a comparison target is 2.19 cSt ( (Measured with Ubbelohde viscometer).
In the orally disintegrating tablet of the present invention using erythritol having a low aqueous solution viscosity, when saliva enters from the pores of the tablet after taking and proceeds into the tablet while dissolving erythritol, the low viscosity of the erythritol aqueous solution causes the tablet to enter the tablet. Infiltration occurs more quickly. Therefore, the orally disintegrating tablet of the present invention can exhibit high disintegration properties.
This erythritol compounding effect is due to the water-repellent or poorly soluble drug that tends to inhibit the infiltration of saliva into the pores of the orally disintegrating tablet, and the easily soluble drug that tends to block the pores of the orally disintegrating tablet. Can also be obtained.

The average particle size of erythritol used in the present invention is 15 to 90 μm, preferably 18 to 85 μm. When the average particle size is 15 μm or more, the volume of the pores of the orally disintegrating tablet itself is prevented from becoming too small, and it is appropriately set to the pore distribution of the orally disintegrating tablet to be described later. Can be obtained.
If the average particle size of erythritol is 90 μm or less, the volume of the pores of the orally disintegrating tablet itself is suppressed from becoming too large, and it is appropriately set to the pore distribution of the orally disintegrating tablet described later. A blending effect can be obtained.
The average particle size of erythritol was measured using the laser diffraction method described in the Japanese Pharmacopoeia No. 15 as reference information "30. Powder particle size measurement by laser diffraction method", for example, HORIBA laser particle size distribution analyzer LA-950 It can be measured by a dry method.
Erythritol having an average particle size of 15 to 90 μm is a known substance and can be easily obtained in the market or can be prepared.

The content of erythritol is 50 to 98% by mass, preferably 53 to 97% by mass, based on the total mass of the tablet obtained in step (1).
When the erythritol content is 50% by mass or more, a sufficient number of pores, which are saliva inlets, are provided in the orally disintegrating tablet, and good disintegration can be obtained.
The upper limit of the erythritol content is set in relation to the contents of other tablet components (drugs, lubricants and binders).

  The blending method of erythritol in the step (1) is preferably granulated together with the drug and a binder solution described later from the viewpoint of homogenization with the drug and the binder.

Binder A binder is formulated to bind each tablet component to increase tablet hardness.
As the binder, among substances used as binders in the pharmaceutical field, those that can be incorporated into orally disintegrating tablets can be used without particular limitation. Specific examples of the binder include povidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, methylcellulose, pullulan, agar, gelatin, sodium alginate and the like.
Among these, hydroxypropyl cellulose and povidone which are water-soluble binders that can further enhance the effect of step (2) (binding of tablet components by humidification) described later are preferable, and hydroxypropyl cellulose is more preferable.
A binder may be used individually by 1 type and may be used in combination of 2 or more types.
The binder is a known substance and can be easily obtained in the market.

The average particle size of the binder is preferably 1 to 100 μm, more preferably 10 to 60 μm in terms of enhancing the mixing uniformity with other components and easily setting the pore distribution of the orally disintegrating tablet described later. More preferably.
When the average particle size of the binder is 1 μm or more, good mixing uniformity with other components can be obtained, and the pore distribution of the orally disintegrating tablet can be easily set.
When the average particle size of the binder is 100 μm or less, the blending effect of the binder can be sufficiently obtained.
For the average particle size of the binder, use the laser diffraction method described in Reference Information 30. Measurement of powder particle size by laser diffractometry in the Japanese Pharmacopoeia, for example, HORIBA laser particle size distribution analyzer LA-950. It can be measured by a dry method.
As will be described later, when the binder is used as a solution in step (1), the average particle size is not particularly limited.

The content of the binder is preferably 0.1 to 10% by mass, more preferably 0.5 to 5% by mass, and particularly preferably 1 to 3% by mass with respect to the total mass of the tablet obtained in the step (1).
When the content of the binder is 0.1% by mass or more, an orally disintegrating tablet excellent in hardness can be obtained. When the content of the binder is 10% by mass or less, an orally disintegrating tablet that is more excellent in disintegration can be obtained.

The binder blending method in step (1) may be used as a binder solution dissolved in water, ethanol, or a mixture of water and ethanol in order to further enhance the blending effect and further increase tablet hardness.
The binder solution may be obtained by dissolving the binder in a wetting agent described below.
The solution viscosity of the binder is preferably lower from the viewpoint of tablet disintegration, and specifically, the viscosity of an aqueous solution having a binder content of 2% by mass is 1.5 to 6.0 mPas (20 ° C.). preferable.

Lubricants Lubricants are blended to prevent tablet components from sticking to a tableting machine (sticking to tableting punches and mortars) and to smoothly produce tablets.
Of the substances used as lubricants in the pharmaceutical field, a lubricant that can be blended into an orally disintegrating tablet can be used without particular limitation. Specific examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, hydrogenated vegetable oil, leucine, isoleucine, talc, silicic anhydride, sodium stearyl fumarate and the like. Among these, sodium stearyl fumarate, leucine and isoleucine are preferable because they do not deteriorate the disintegration property of the tablet from the viewpoint of hydrophilicity, and sodium stearyl fumarate is more preferable.
One type of lubricant may be used alone, or two or more types may be used in combination.
Lubricants are known substances and are readily available on the market or can be prepared.

The average particle size of the lubricant is preferably 1 to 50 μm from the viewpoint of enhancing the mixing uniformity with other components and easily setting the pore distribution of the orally disintegrating tablet described later.
When the average particle size of the lubricant is 1 μm or more, the mixing uniformity with other components can be further improved.
When the average particle size of the lubricant is 50 μm or less, a sufficient blending effect can be obtained.
The average particle size of the lubricant was measured using the laser diffraction method described in Reference Information `` 30. Powder Particle Size Measurement by Laser Diffraction Method '' in the Japanese Pharmacopoeia, Bureau 15, for example, HORIBA laser particle size distribution analyzer LA-950. It can be measured by the dry method used.

The content of the lubricant is preferably 0.01 to 5% by mass, more preferably 0.05 to 2% by mass, and particularly preferably 0.1 to 1.5% by mass with respect to the total mass of the tablet obtained in the step (1).
When the content of the lubricant is 0.01% by mass or more, the blending effect of the lubricant can be sufficiently obtained.
When the content of the lubricant is 5% by mass or less, an excessive increase in the water repellency of the orally disintegrating tablet can be suppressed, and the disintegration property can be maintained better.

  About the blending method of the lubricant in the step (1), it may be mixed with other tablet components as an internal lubricant, or may be sprayed as an external lubricant during tableting.

In the optional component step (1), optional components can be used as necessary in addition to the above-described essential components (drug, erythritol, binder and lubricant).
Examples of optional components include sugars (excluding erythritol), sweeteners (excluding erythritol), fragrances, flavoring agents, pigments, pH adjusters, and the like.

The average particle size of the optional component is preferably the same as the average particle size of erythritol in that the uniformity of mixing with other components can be improved and the pore distribution of the orally disintegrating tablet described later can be easily set.
For the average particle size of optional components, the laser diffraction method described in Reference Information 30. Measurement of powder particle size by laser diffractometry in the Japanese Pharmacopoeia No. 15 is used, for example, the HORIBA laser particle size distribution analyzer LA-950. It can be measured by a dry method.

The content of the optional component can be appropriately set according to the purpose of blending, but when using an optional component with high hygroscopicity, it is 1% by mass or less based on the total mass of the tablet obtained in step (1). Preferably there is.
When the content of the optional component is 1% by mass or less, a blending effect can be obtained without adversely affecting the physical properties of the orally disintegrating tablet.

  There are no particular restrictions on the method of blending the optional components in step (1). For example, when the optional component is a liquid, it may be added as it is at the time of granulation, or it may be adsorbed on a powder adsorbent such as silicic anhydride and added as a powder.

Method for Performing Step (1) The tablet components described above are subjected to a tableting operation as a mixed powder or a granulated mixture.

  The mixed powder refers to a powder in which tablet components are uniformly mixed in a raw powder state. For the production of mixed powders, among the mixing means generally used in the pharmaceutical field, those that can uniformly mix the tablet components (for example, high-speed stirring type mixing granulator, container mixer, etc.) are particularly limited. Can be used without using.

The granulation mixture refers to a product obtained by wet granulation of tablet components. Specifically, it refers to one obtained by granulating, drying and sizing all or part of the tablet components together with a wetting agent and then uniformly mixing together with the rest.
Specific examples of the wetting agent include water, ethanol, or a mixture of water and ethanol.
The wetting agent may be present independently from each tablet component, or may be a component constituting a solution of some tablet components (for example, a solvent of a binder solution).
The granulated mixture can be produced using any means generally used in the pharmaceutical field without any particular limitation. For example, a drug, erythritol, binder and wetting agent are granulated using a stirring granulator or fluid bed granulator, dried with an air dryer or fluid bed dryer, and screen granulator For example, after sizing so as to pass through a Japanese Pharmacopoeia No. 18 sieve, it can be produced by uniformly mixing with a lubricant using a mixer.
From the viewpoint of fluidity, the granulated mixture has an apparent bulk density of 0.4 to 0.6 kg / L and / or a particle size of Japanese Pharmacopoeia No. 30 sieve residue of 5% or less, and Japanese Pharmacopoeia It is preferable that the passage of No. 100 sieve is 20% or less.

The tableting in step (1) is the following (i) and (ii) in the orally disintegrating tablet obtained in step (3) described later:
(i) a pore volume V ₁ having a pore diameter of 0.1 to 100 μm is 0.15 to 0.40 ml / g, and
(ii) the ratio V ₁ of the pore volume V ₂ of the pore diameter 0.1~10μm (V ₂ / V ₁₎ is performed using a tableting pressure giving pore distribution is 0.50 to 1.00.
The pore distributions of (i) and (ii) above are the same as the pore distribution of the orally disintegrating tablet obtained in step (3). Therefore, the pore distribution will be described in detail in the column of physical properties of the orally disintegrating tablet described later.

As will be understood from the comparison between Example 5 and Comparative Example 5-1, which will be described later, the tablet obtained in the step (1) and the orally disintegrating tablet obtained in the step (3) There is little difference in distribution. Therefore, the tableting pressure used in step (1) can be easily set using the pore distribution of the orally disintegrating tablet obtained in step (3) as an index. For example, by changing only the tableting pressure, carrying out multiple manufacturing methods and clarifying the relationship between the pore distribution of the obtained orally disintegrating tablet and the tableting pressure (for example, creating a calibration curve) Thus, the tableting pressure can be easily determined. Generally, when the tableting pressure is 2942 N (300 kgf) or less, an orally disintegrating tablet satisfying the pore distributions (i) and (ii) can be obtained. Specific examples of the tableting pressure include 9 to 2942 N (1 to 300 kgf), and preferable examples include 98 to 1961 N (10 to 200 kgf).
Tableting can be performed without particular limitation using means generally used in the tablet production field (for example, a rotary tableting machine or a single-shot tableting machine).

Process (2)
Step (2) is a step of subjecting the tablet obtained in step (1) to a humidification treatment in a humidification chamber. By carrying out step (2), it is possible to bind the tablet components while maintaining the pore distribution of the tablet obtained in step (1). Subsequently, by performing the step (3) (drying step), an orally disintegrating tablet having a predetermined tablet hardness can be obtained.

The humidification process in step (2) is performed using water vapor.
The humidification process in step (2) is performed in a humidifier connected to a humidifier.
If the humidifier and humidifier can set and maintain the dew point of water vapor generated from the humidifier, equipment and equipment used in the chemical manufacturing field, the food manufacturing field, and the confectionery manufacturing field can be used. It can be used without particular limitation.
The humidification treatment in step (2) was obtained by setting the dew point of water vapor generated from the humidifier connected to the humidifier to 1 to 5 ° C lower than the temperature in the humidifier, preferably 2 to 5 ° C lower. Perform in an atmosphere.
If the dew point of the water vapor generated from the humidifier is lower by 1 ° C or more than the temperature in the humidifier, the water vapor (diameter: approx. 0.4 nm) becomes supersaturated in the humidifier and prevents the generation of water particles (diameter: approx. 10 μm or greater). be able to. When water fine particles are generated, it adheres to the pores near the surface of the tablet and the pore distribution obtained in step (1) changes, or the pores are blocked, preventing water vapor from entering the tablet. Or For this reason, binding of tablet components inside the tablet is suppressed, and an orally disintegrating tablet having a predetermined tablet hardness and disintegration time may not be obtained.
When the temperature is equal to or higher than the lower limit of the dew point temperature of the water vapor (5 ° C lower than the temperature in the humidification chamber), the water vapor does not sufficiently enter the pores of the tablet and the predetermined tablet hardness cannot be obtained. Can do.

The period during which the humidification treatment is performed in step (2), i.e., the passage time of the tablet in the humidifier, varies depending on the nature of the drug, the size of the tablet, etc., but generally 30 seconds or more, preferably 30 Second to 5 minutes, more preferably 1 to 3 minutes.
When the humidifier is provided with an inlet and an outlet for transporting tablets, the temperature may not be stable near the inlet and the outlet as compared with the inside of the humidifier. Therefore, the tablet can be sufficiently humidified by setting the passage time in the humidification chamber of the tablet to 30 seconds or longer. If the tablet passage time is 5 minutes or less, the length of the conveyor belt that transports the tablets will be shortened, making it easy to carry out continuous execution of step (1), step (2), and subsequent step (3). It can be carried out.

Process (3)
Step (3) is a step of subjecting the tablet obtained in step (2) to a drying treatment. By carrying out step (3), moisture is removed from the tablet obtained in step (2), and an orally disintegrating tablet having a predetermined tablet hardness and disintegration time can be obtained.
As long as the drying treatment in step (3) can remove moisture from the tablet obtained in step (2), an apparatus and equipment generally used in the tablet production field are used without particular limitation. be able to. Specific examples include a ventilation dryer, a far-infrared dryer, and a fluidized bed dryer.
Drying is equivalent to the moisture content of the tablet obtained in step (1) (that is, the tablet before the humidification treatment in step (2)) (for example, 0.1 to 0.5% as loss on drying at 70 ° C. for 15 minutes) ) Is preferably carried out until it is obtained.

In the production method of the present invention, the steps (1) to (3) are preferably carried out continuously (performed continuously) instead of batchwise.
If step (1) to step (3) are performed continuously, the work required for the batch method (the work of carrying in, storing, and carrying out the products of each process) becomes unnecessary, and further, it matches the tableting speed. Thus, the humidification and drying processes can be performed, so that the production efficiency can be further improved. Furthermore, the tablets obtained in step (1) have extremely low tablet hardness and require careful handling. It can also be avoided.
The continuous implementation of the steps (1) to (3) can be performed using means for continuously transporting the tablet (or its material) to the facility where each step is carried out, for example, a conveyor.

Physical properties of orally disintegrating tablet By carrying out the above steps (1) to (3), the orally disintegrating tablet of the present invention can be obtained. The orally disintegrating tablet of the present invention has the following physical properties.

Pore distribution The orally disintegrating tablet of the present invention has the following pore distributions (i) and (ii):
(i) Pore volume V ₁ having a pore diameter of 0.1 to 100 μm is 0.15 to 0.40 ml / g
(ii) the ratio V ₁ of the pore volume V ₂ of the pore diameter 0.1~10μm (V ₂ / V ₁₎ has a is 0.50 to 1.00.

In the orally disintegrating tablet of the present invention, the pore volume V ₁ having a pore diameter of 0.1 to 100 μm is 0.15 to 0.40 ml / g, preferably 0.16 to 0.39 ml / g.
When the pore volume V ₁ is located at 0.15 ml / g or more, saliva into tablets easily penetrates, it is possible to obtain a disintegration time below (5-30 seconds).
When the pore volume V ₁ is equal to or less than 0.40 ml / g, in the presence of a contact between the tablet components with a sufficient number of the tablets, it is possible to obtain a tablet hardness (49~147N) below.

In the orally disintegrating tablet of the present invention, the ratio (V ₂ / V ₁ ) of the pore volume V ₂ having a pore diameter of 0.1 to 10 μm to V ₁ (V ₂ / V ₁ ) is 0.50 to 1.00, preferably 0.52 to 0.93.
When the V ₂ / V ₁ ratio is 0.50 or more, saliva can easily enter the tablet, and a disintegration time (5 to 30 seconds) described later can be obtained. This is because the proportion of small pores (V ₂ ) in the whole pores increases, and the phenomenon that saliva penetrates into the tablets increases as the tablet pore size decreases. It is believed that there is.
The upper limit value 1.00 of the V ₂ / V ₁ ratio is a theoretical upper limit value.

The pore volumes V ₁ and V ₂ can be measured by mercury porosimetry. The measurement principle of the mercury intrusion method is published by Nikkan Kogyo Shimbun, edited by the Society of Powder Technology, Powder Engineering Series, Volume 1, Basic Physical Properties of Powder, p. 112, “5.4.2 Pore Properties, (i) Mercury Intrusion” Law ", November 30, 2005, listed in the first edition of the first edition.
Specifically, Shimadzu Micromeritics Pore Distributor Autopore 9520 was used as the measuring device, and the sample orally disintegrating tablet (one tablet) was placed in a standard 3cc large piece cell (stem volume 0.4cc). It can be measured under the following measurement conditions.

Initial pressure: 3.5 kPa
Mercury contact angle: 130 degrees (equipment default value)
Mercury surface tension: 485 dynes / cm (equipment default value)

The measurement of the pore volumes V ₁ and V ₂ can also be performed by requesting a generally available analysis organization (for example, Shimadzu Techno Research Co., Ltd.).

Tablet hardness The hardness of the orally disintegrating tablet of the present invention is 49 to 147N, preferably 50 to 100N.
When the tablet hardness is 49 N or more, the shape of the tablet can be stably maintained, and excellent handleability (for example, stability during product transportation) can be obtained.
When the tablet hardness is 147N or higher, it is above the required level, so it is better to increase the productivity by shortening the humidification time.
Tablet hardness can be measured using a measuring apparatus (for example, Tablet Tester 8M (manufactured by DR. SCHLEUNIGER)) generally used in the pharmaceutical field.

Disintegration time The disintegration time of the orally disintegrating tablet of the present invention is 5 to 30 seconds, preferably 10 to 30 seconds.
When the disintegration time is 5 to 30 seconds, excellent disintegration property as an orally disintegrating tablet (disintegrating rapidly in the oral cavity at the time of taking) can be obtained.
In addition, the disintegration time of 5 to 30 seconds also satisfies “within 30 seconds” recommended by the USP US Pharmacopoeia as the disintegration time of Orally Disintegrating Tablets.
The disintegration time can be measured using a disintegration tester (for example, a disintegration tester NT-200 manufactured by Toyama Sangyo Co., Ltd.) according to the disintegration test method defined in the Japanese Pharmacopoeia.

Examples of the present invention will be described below, but the present invention should not be limited to these examples, and many variations are possible by those skilled in the art within the technical idea of the present invention.
In the following examples, details of the orally disintegrating tablet of the present invention and detailed specific examples of the production method thereof are described, and these disintegrating tablets satisfy the constituent requirements of the present invention, unlike the comparative examples. To verify that the desired effect is achieved.

Preparation of orally disintegrating tablets Orally disintegrating tablets of the following Examples and Comparative Examples were prepared according to the following procedure.

Process (1)
A granulation mixture was prepared by a wet granulation method according to the procedure shown below.
The drug and erythritol are mixed and granulated uniformly using a high-speed agitating granulator VG-25 (manufactured by POWREC) together with a binder solution in which wetting agent (50% by mass ethanol aqueous solution) is dissolved. Obtained.
The granulated product was dried at 60 ° C. for 2 hours using a ventilating dryer, and the loss on drying (15 minutes at 70 ° C.) was adjusted to 0.5% or less. The dried granulated product was sized so as to pass through a Japanese Pharmacopoeia No. 18 sieve with a screen-type granulator Comil (manufactured by POWREC).
A lubricant was added to the sized granulated product, and the mixture was uniformly mixed with a cross rotary mixer to obtain a granulated mixture. Regarding the granulated mixture, the Japanese Pharmacopoeia No. 30 sieve residue was 5% or less, and the Japanese Pharmacopoeia No. 100 sieve passage was 20% or less.
The granulated mixture was tableted with a rotary tableting machine clean press 12 (Kikusui Seisakusho).

Process (2)
The compressed tablet was passed through the humidifier by a conveyor. The humidifier was connected with a humidifier capable of controlling the dew point of the generated water vapor.

Process (3)
The tablet passed through the humidifier was dried by passing through a dryer equipped with a ventilating dryer to obtain an orally disintegrating tablet.

The physical properties and production conditions of the tablet components not described above were those described in each example and comparative example.

The physical properties of the starting material and the orally disintegrating tablet were measured by the following methods.

Average particle size of drug
Dry method using HORIBA laser particle size distribution analyzer LA-950.

Average particle size of erythritol
Dry method using HORIBA laser particle size distribution analyzer LA-950.

Average particle size of lubricant
Dry method using HORIBA laser particle size distribution analyzer LA-950.

Oral disintegrating tablet pore volume V ₁ and V ₂
Mercury intrusion method. Specifically, using an autopore 9520 type micromeritics pore distribution meter manufactured by Shimadzu Corporation, the sample orally disintegrating tablet (1 tablet) was taken in a standard 3cc large piece cell (stem volume 0.4cc), and the following Measurement was performed under measurement conditions.
Initial pressure: 3.5 kPa
Mercury contact angle: 130 degrees (equipment default value)
Mercury surface tension: 485 dynes / cm (equipment default value)

Tablet hardness of orally disintegrating tablets
It measured using Tablet Tester 8M (made by DR.SCHLEUNIGER). Ten tablets were measured for each Example and Comparative Example.

Using an orally disintegrating tablet, a disintegration time disintegration tester (Toyama Sangyo Disintegration Tester NT-200) was measured according to the Japanese Pharmacopoeia Disintegration Test Method. Six tablets were measured for each Example and Comparative Example.

The porosity of the orally disintegrating tablet was calculated according to the following formula.
Porosity (%) = (V ₃ -W / M) / V ₃ × 100
M: True density of the granulation mixture (g / cm ³ )
V ₃ : Orally disintegrating tablet volume (cm ³ )
W: Mass of orally disintegrating tablet (g)

Example 1 and Comparative Example 1
In Example 1 and Comparative Example 1, the effect of setting the dew point of water vapor generated from the humidifier was examined.
Manufacturing conditions common to Example 1 and Comparative Example 1 (except for setting of the dew point of water vapor generated from the humidifier) were as follows.
Process (1)
Tableting pressure of granulation mixture: 686N (70kgf)

Process (2)
Humidifier temperature: 50 ℃
Dew point setting of water vapor generated from the humidifier: -6 to 0 ° C with respect to the temperature of the humidifier (50 ° C) Passing time in the humidifier: 3 minutes

Process (3)
Drying temperature: 60 ℃
Drying time: 10 minutes

Other manufacturing conditions are shown in Table 1.
The tablet mass of the obtained orally disintegrating tablet was 400 mg, and the tablet diameter was 11 mm.
The results are shown in Table 1.

Table 1

In Comparative Example 1-1 in which the dew point of water vapor generated from the humidifier was 6 ° C. lower than the temperature of the humidifier, the tablet hardness did not satisfy the criteria (49 to 147 N) of the present invention. This is presumably because the amount of water vapor for humidification was insufficient and the cross-linked structure formed between the powders in the tablet was not sufficient.
In addition, Comparative Example 1-2, in which the dew point of water vapor generated from the humidifier is the same as the temperature of the humidifier, V ₂ / V ₁ is less than 0.50, and the disintegration standard of the present invention (5 to 30 seconds). Did not meet.
On the other hand, in Example 1-1 in which the dew point of water vapor generated from the humidifier is −5 ° C. with respect to the humidifier temperature, and in Example 1-2 in which the dew point is −1 ° C., both V ₁ is 0.15 to 0.40 It was in the range of ml / g and V ₂ / V ₁ was in the range of 0.50 to 1.00, and both tablet hardness and disintegration met the criteria of the present invention.
This test result shows that even if there is no difference in the porosity of the tablet, the state of the pores, that is, V ₂ / V ₁ changes greatly depending on the setting of the dew point of the humidifier, which affects the physical properties of the tablet.

Tablet hardness of orally disintegrating tablets Each orally disintegrating tablet of Example 1 and Comparative Example 1 was blister-packed (blister: polyvinylidene chloride (Sumitomo Bakelite VSL-4601), aluminum foil: thickness 20 μm). A nail was put up in the center of the tablet and the tablet was taken out of the blister, and the presence or absence of cracking of the tablet was confirmed. For each of Example 1 and Comparative Example 1, 100 tablet blisters were evaluated. The results are shown in Table 2.

Table 2
Table 2 shows that in Comparative Example 1-1, which does not satisfy the tablet hardness standard (49 to 147N) of the present invention, tablet cracking occurred.

Oral disintegration tablet disintegration The sensory test was conducted by 10 persons on the disintegration property of each orally disintegrating tablet of Example 1 and Comparative Example 1. The results are shown in Table 3.

Table 3

  Table 3 shows that in Comparative Example 1-2, which did not satisfy the tablet disintegration time standard (5 to 30 seconds) of the present invention, a person who felt that the disintegration of the tablet was slow appeared.

Example 2 and Comparative Example 2
In Example 2 and Comparative Example 2, the influence of the average particle size of erythritol was examined.
The production conditions common to Example 2 and Comparative Example 2 were as follows.
Process (1)
Tableting pressure of granulation mixture: 294N (30kgf)

Process (2)
Humidifier temperature: 45 ℃
Dew point setting of water vapor generated from the humidifier: 43 ° C (-2 ° C with respect to the temperature of the humidifier)
Passing time in humidifier: 2 minutes

Process (3)
Drying temperature: 60 ℃
Drying time: 5 minutes

Other manufacturing conditions are shown in Table 4.
The tablet mass of the obtained orally disintegrating tablet was 250 mg, and the tablet diameter was 9.0 mm.
The results are shown in Table 4.

Table 4

In Example 2-1, Example 2-2, and Example 2-3 in which the average particle diameter of erythritol satisfies the standard of the present invention (15 to 90 μm), V ₂ / V ₁ is the standard of the present invention (0.50 -1.00), and further satisfied the criteria of tablet hardness (49-147N) and disintegration (5-30 seconds).
On the other hand, in Comparative Example 2-1, in which the average particle size of erythritol was less than 15 μm, V ₂ / V ₁ was outside the range of the standard of the present invention, and the standard of tablet hardness of the present invention was not satisfied.
Further, in Comparative Example 2-2 in which the average particle size of erythritol exceeds 90 μm, V ₂ / V ₁ is outside the range of the standard of the present invention, and does not satisfy the standard of tablet hardness and disintegration property of the present invention.

Example 3 and Comparative Example 3
In Example 3 and Comparative Example 3, the influence of the blending amount (content) of erythritol was examined.
Manufacturing conditions common to Example 3 and Comparative Example 3 were as follows.
Process (1)
Tableting pressure of granulation mixture: 490N (50kgf)

Process (2)
Humidifier temperature: 50 ℃
Dew point of water vapor generated from the humidifier: 47 ° C (-3 ° C with respect to the temperature of the humidifier)
Passing time in humidifier: 3 minutes

Process (3)
Drying temperature: 65 ° C
Drying time: 10 minutes

Other manufacturing conditions are shown in Table 5-1.
The tablet mass of the obtained orally disintegrating tablet was 300 mg, and the tablet diameter was 11 mm.
The results are shown in Table 5-1.

Table 5-1

Examples 3-1 and 3-2 are examples in which acetaminophen was used as a drug with a large amount.
Therefore, Example 3-3 was evaluated as an example using scopolamine hydrobromide hydrate as a drug with a small amount.
The production conditions of Example 3-3 were as follows.
Process (1)
Tableting pressure of granulation mixture: 392N (40kgf)

Process (2)
Humidifier temperature: 45 ℃
Dew point setting of water vapor generated from the humidifier: 43 ° C (-2 ° C with respect to the temperature of the humidifier)
Passing time in humidifier: 2 minutes

Process (3)
Drying temperature: 60 ℃
Drying time: 5 minutes

Other manufacturing conditions are shown in Table 5-2.
The tablet mass of the obtained orally disintegrating tablet was 250 mg, and the tablet diameter was 9.0 mm.
The results are shown in Table 5-2.

Table 5-2

About Table 5-1, Example 3-1 and Example 3-2 whose erythritol content has satisfy | filled the criteria (50-98 mass% with respect to the total mass of the tablet obtained at the process (1)) of this invention. V ₂ / V ₁ was within the range of the standard of the present invention (0.50 to 1.00), and also satisfied the standards of tablet hardness (49 to 147 N) and disintegration (5 to 30 seconds).
On the other hand, Comparative Example 3-1 and Comparative Example 3-2 having an erythritol content of less than 50% by mass did not satisfy the criteria of the present invention in both hardness and disintegration.
Table 5-2 shows that even when the amount of the drug is small, by setting the erythritol content within the criteria of the present invention, the criteria of tablet hardness and disintegration can be satisfied.

Example 4 and Comparative Example 4
In Example 4 and Comparative Example 4, the influence of the tableting pressure in the step (1) causing the fluctuation of V ₁ was examined.
The production conditions common to Example 4 and Comparative Example 4 were as follows.

Process (2)
Humidifier temperature: 55 ° C
Dew point setting of water vapor generated from the humidifier: 53 ° C (-2 ° C with respect to the temperature of the humidifier)
Passing time in humidifier: 3 minutes

Process (3)
Drying temperature: 60 ℃
Drying time: 20 minutes

Other manufacturing conditions are shown in Table 6.
The tablet mass of the obtained orally disintegrating tablet was 300 mg, and the tablet diameter was 10 mm.
The results are shown in Table 6.

Table 6

V ₁ and V ₂ / V _{1 of} the orally disintegrating tablet obtained in step (3) are the criteria of the present invention (V ₁ is 0.15 to 0.40 ml / g and V ₂ / V ₁ ) is 0.50 to 1.00) Examples 4-1 and 4-2 produced using a tableting pressure satisfying the above conditions satisfied the criteria of tablet hardness (49 to 147 N) and disintegration (5 to 30 seconds) of the present invention.
Meanwhile, V ₁ is Comparative Example 4-1 prepared by using a tableting pressure exceeds the upper limit of the present invention did not meet the criteria of the tablet hardness of the present invention. This is presumably because the number of contacts between powders, which are tablet components, is small, and crosslinking between powders is insufficient.
Further, V ₁ is Comparative Example 4-2 prepared by using a tableting pressure becomes lower than the lower limit of the present invention did not satisfy the tablet hardness and disintegration of the reference of the present invention. This is presumably because, since V ₁ is small, water vapor hardly penetrates into the tablet during humidification, and the cross-linking by water vapor between the powders which are tablet components is insufficient.

Example 5 and Comparative Example 5
In Example 5 and Comparative Example 5, the influence of the conditions of steps (2) and (3) was examined.
Manufacturing conditions common to Example 5 and Comparative Example 5 were as follows.
In Comparative Example 5-1, Steps (2) and (3) were not carried out, and the tablet obtained in Step (1) was used as an orally disintegrating tablet.

Process (1)
Tableting pressure of granulation mixture: 785N (80kgf)

Process (2) (not implemented in Comparative Example 5-1)
Temperature of the condition humidifier used in Example 5: 45 ° C
Dew point setting of water vapor generated from the humidifier: 43 ° C (-2 ° C with respect to the temperature of the humidifier)
Passing time in humidifier: 2 minutes

Temperature of the condition humidifier used in Comparative Example 5-2: 45 ° C
Dew point of water vapor generated from the humidifier: 46 ° C (+ 1 ° C with respect to the temperature of the humidifier)
Passing time in humidifier: 2 minutes

Process (3) (not implemented in Comparative Example 5-1)
Drying temperature: 60 ℃
Drying time: 10 minutes

Other manufacturing conditions are shown in Table 7.
The tablet mass of the obtained orally disintegrating tablet was 250 mg, and the tablet diameter was 9 mm.
The results are shown in Table 7.

Table 7

Comparison with Comparative Example 5-1 to Example 5 of the V ₁ and V ₂ / V _1, the step (2) and the presence or absence of implementation of the step (3) is a significant change in V ₁ and V ₂ / V ₁ It does not bring about. This is because the V ₁ and V ₂ / V _{1 of} the tablet set by the step (1) (tablet) are retained after the execution of the step (2) (humidification) and the step (3) (drying). It shows that.

This can be understood from the tablet surface SEM image of Comparative Example 5-1 (FIG. 1) and the tablet surface SEM image of Example 5 (FIG. 2).
FIG. 1 shows that the tablet surface of Comparative Example 5-1 (without steps (2) and (3)) is porous.
FIG. 2 shows that the tablet surface of Example 5 (with steps (2) and (3)) is porous as in Comparative Example 5-1.
While there was no difference in the state of the tablet surface, the orally disintegrating tablet of Comparative Example 5-1 did not satisfy the criteria of the present invention (49 to 147N) for tablet hardness, and was brittle.
Here, FIG. 3 is a tablet surface SEM image of Comparative Example 5-2. In Comparative Example 5-2, the setting of the dew point of water vapor generated from the humidifier in step (2) does not satisfy the conditions of the present invention.
FIG. 3 shows that the tablet surface of Comparative Example 5-2 is smoother than that of Example 5, and the pores on the tablet surface are reduced. This is presumably because the water vapor became supersaturated in the humidification chamber to form water fine particles, which dissolved the drug, erythritol, etc. on the tablet surface. Table 7 also shows that V ₂ of Comparative Example 5-2 is lower than that of Example 5 and that the decay time of Comparative Example 5-2 is also inferior to that of Example 5. This is because water vapor is supersaturated in the humidification chamber to form water fine particles, and the water fine particles penetrate into the pores near the surface of the tablet, and the pores obtained in step (1) (particularly, the pore diameter of 0.1 to This is thought to be because the pores (V ₂ ) of 10 μm were blocked.
These results show that the V ₁ and V ₂ / V _{1 of} the tablet set by the step (1) are retained after the execution of the step (2) and the step (3), and the step (2) And step (3) results in tablet hardness and disintegration time as defined in the present invention.

  The present invention can be used in the pharmaceutical field.

Claims (5)

An orally disintegrating tablet comprising a drug, erythritol, a binder and a lubricant,
The erythritol content of the orally disintegrating tablet is 50 to 98% by mass with respect to the total mass of the orally disintegrating tablet,
Pore volume V ₁ of the pore diameter 0.1~100μm of the orally disintegrating tablet is 0.15~0.40ml / g,
The ratio (V ₂ / V ₁ ) of V ₁ of the pore volume V ₂ of the pore diameter of 0.1 to 10 μm of the orally disintegrating tablet is 0.50 to 1.00,
The tablet hardness of the orally disintegrating tablet is 49-147 N, and
An orally disintegrating tablet, wherein the disintegration time of the orally disintegrating tablet is 5 to 30 seconds. Pore volume V ₁ of the pore diameter 0.1~100μm of the orally disintegrating tablet is 0.16~0.39ml / g, orally disintegrating tablet according to claim 1. The orally disintegrating tablet according to claim 1 or 2, wherein a ratio (V ₂ / V ₁ ) of V ₁ of pore volume V ₂ having a pore diameter of 0.1 to 10 µm of the orally disintegrating tablet is 0.52 to 0.93.   The orally disintegrating tablet according to any one of claims 1 to 3, wherein the tablet hardness of the orally disintegrating tablet is 50 to 100N.   The orally disintegrating tablet according to any one of claims 1 to 4, wherein the disintegration time of the orally disintegrating tablet is 10 to 30 seconds.