JP2017075139A - Orally disintegrating tablet containing low-dose drug - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide pharmaceutical compositions, particularly orally disintegrating tablets, having inhibited content segregation, an improved feel of ingestion and excellent drug dissolution properties, regarding a physiologically active component (drug) which has a low content (microdose) and has a problem of feel of ingestion.SOLUTION: An orally disintegrating tablet contains a physiologically active component exerting physiological activity in microdose, wherein a) orally disintegrating time is within 30 seconds; b) in a dissolution test performed according to the dissolution test method described in the Japanese Pharmacopoeia 16th edition, General Test Method (test solution: water 900 mL, 37°C), the dissolution rate in 15 minutes of the physiologically active component is 80 mass% or more; and c) in a dissolution test performed according to the dissolution test method described in the Japanese Pharmacopoeia 16th edition, General Test Method (test solution: water 900 mL, 37°C), the dissolution rate in the time needed for oral disintegration of the physiologically active component of the test liquid is 5 mass% or less.SELECTED DRAWING: None

Description

  The present invention relates to an orally disintegrating tablet containing a physiologically active ingredient exhibiting physiological activity in a trace amount, such as a hormone-like substance, and a method for producing the same.

  Several proposals have been made so far as attempts to use orally disintegrating tablets as drugs that are problematic in taking. For example, Patent Document 1 discloses a film layer (A) containing an unpleasant-tasting drug and a water-swelling polymer on the surface of the core particles (P) not containing an unpleasant-tasting drug and a water-swelling polymer. And a drug-containing film-coated particle formed with a plurality of film layers including a film layer (B) containing a water-insoluble polymer, a water-soluble substance and an inorganic compound, and the film layer of the plurality of film layers (A) is the innermost membrane layer, the ratio of the mass of the core particles (P), the content of the drug, the content of the water-swelling polymer, the water-insoluble high content in the total amount of the drug-containing film-coated particles of 100% by mass. The content of the molecule, the ratio of the content of the water-soluble substance contained in the membrane layer (B) / the content of the water-insoluble polymer, and the content of the inorganic compound in 100% by mass of the membrane layer (B) , Each of which contains a drug-containing film-coated particle defined in a specific range. According to the coated particles, there is a unpleasant taste is available for rapidly disintegrating tablet having fast disintegration are shielded, even a small amount of water or without water in the oral cavity.

  Patent Document 2 is not an orally disintegrating tablet technique, but as a technique for controlling the dissolution of a drug, a spherical granulated product made of crystalline cellulose and lactose (however, the crystalline cellulose content is less than 50% by weight) There is disclosed a nucleated powder which is coated with at least one physiologically active substance together with propylcellulose and / or hydroxypropylmethylcellulose and has a particle diameter of substantially 500 μm or less. According to this, even if the particle size is small, it is possible to provide a powder capable of accurately controlling the drug dissolution, a granule containing the powder, a tablet and a capsule. Patent Document 3 discloses fine particles containing a drug having an unpleasant taste as follows: (1) a pH-independent water-insoluble polymer having a ratio of 60% or more and less than 80% in the film; The drug elution rate from the drug-containing microparticles coated with a coating consisting of a pH-independent water-soluble substance having a ratio of greater than 20% and not more than 40% is 0% -10% in 1 minute, and 30 minutes The drug-containing coated fine particles for orally disintegrating tablets are disclosed, characterized in that the average particle size is not more than 80-100% and the average particle size is 350 μm or less. According to this particle, the drug-containing coated fine particles for orally disintegrating tablets that sufficiently suppress instantaneous discomfort in the oral cavity of various drugs having an unpleasant taste and further elute the drug immediately after entering the gastrointestinal tract It can be provided. However, in Examples, the amount of drug with respect to the core particle is large (the amount of drug when the core particle is 100 parts by mass is 50 to 200 parts by mass), and the drug fine particles formed using the core particle, drug and binder are used. The structure is different from the structure forming a thin drug layer coating on the outside of the core particle. In addition, there is no mention of drug content uniformity, which tends to be a problem when the drug content is low.

WO2012 / 036078 Japanese Patent No. 2820829 WO2005 / 039542

In the case of producing an orally disintegrating tablet containing a physiologically active ingredient showing physiological activity in a trace amount such as a hormone-like substance, for example, an orally disintegrating tablet in which the content of the physiologically active ingredient in one tablet is 3 mg or less, a plain tablet When the amount of powder for use is large, the physiologically active ingredient is classified in the powder for uncoated tablets, or the physiologically active ingredient is classified when transported to a tableting machine. It is difficult to stably produce an orally disintegrating tablet in which the content of components varies and the variation in content is small. For this reason, measures such as reducing the amount of powder for uncoated tablets per batch and preventing classification when transported to a tableting machine have been taken, but no fundamental solution has been reached.
The present invention relates to a pharmaceutical composition having a low content (a trace amount) and a physiologically active ingredient (drug) having a problem of ingestion, the content segregation being suppressed, the ingestion feeling being improved, and good drug dissolution properties, In particular, it aims to provide an orally disintegrating tablet.
Another object of the present invention is to provide an efficient method for producing such an orally disintegrating tablet.

This invention has the following aspects which achieve the said objective.
(1-1) contains a physiologically active component that exhibits physiological activity in a trace amount,
a) The oral disintegration time is within 30 seconds,
b) When the dissolution test was performed according to the dissolution test method described in JP 16th edition, general test method (test solution: water 900 mL, 37 ° C.), the dissolution rate of the physiologically active component in 15 minutes was 80% by mass or more. Yes, and c) When the dissolution test was carried out according to the dissolution test method described in JP 16th edition, general test method (test solution: water 900 mL, 37 ° C.) An orally disintegrating tablet, wherein the dissolution rate of a physiologically active ingredient is 5% by mass or less.
(1-2) The orally disintegrating tablet according to (1-1), comprising an excipient, a water-insoluble cellulose polymer, and a water-soluble cellulose polymer.
(1-3) The orally disintegrating tablet according to (1-1) or (1-2), wherein the excipients are sugar alcohol and crystalline cellulose.
(1-4) The orally disintegrating tablet according to any one of (1-1) to (1-3), wherein the physiologically active ingredient is a hormone-like substance.

(1-5) The orally disintegrating tablet according to (1-4), wherein the hormone-like substance is dienogest.
(1-6) The orally disintegrating tablet according to any one of (1-1) to (1-5), wherein the content of the physiologically active ingredient in one tablet is 0.1 μg or more and 3 mg or less.
(1-7) having a first coating layer containing a physiologically active ingredient and a water-soluble cellulose polymer on a core particle containing at least one selected from the group consisting of crystalline cellulose, crospovidone and sugar alcohol; And further comprising coated particles having a second coating layer containing a water-insoluble cellulosic polymer and a water-soluble cellulosic polymer on the outside of the oral cavity according to any one of (1-1) to (1-6) Inner disintegrating tablet.
(1-8) The orally disintegrating tablet according to any one of (1-1) to (1-7), comprising coated particles according to (1-7) and an excipient.
(1-9) The orally disintegrating tablet according to any one of (1-1) to (1-8), which contains at least one selected from the group consisting of a disintegrant and a lubricant.
(1-10) The orally disintegrating tablet according to any one of (1-1) to (1-9), wherein the coated particle is contained in an amount of 2 to 60 parts by mass with respect to 100 parts by mass of the tablet.

(1-11) The amount of the physiologically active ingredient is 1 part by mass to 20 parts by mass with respect to 100 parts by mass of the core particles as dry mass
The amount of the first coating layer is 3 parts by mass to 20 parts by mass with respect to 100 parts by mass of the core particles as a dry mass, and the total amount of the core particles and the first coating layer as the dry mass. The oral cavity according to any one of (1-1) to (1-10), comprising coated particles in which the amount of the second coating layer is 1 part by mass to 5 parts by mass with respect to 100 parts by mass Inner disintegrating tablet.
(1-12) The orally disintegrating tablet according to any one of (1-1) to (1-11), wherein an average particle size of the physiologically active ingredient is 0.1 μm or more and 30 μm or less.
(1-13) The orally disintegrating tablet according to any one of (1-1) to (1-12), wherein the average particle size of the core particles is 50 μm to 200 μm.

(1-14) The orally disintegrating tablet according to any one of (1-1) to (1-13), wherein the coated particles have an average particle size of 55 μm to 250 μm.
(1-15) The ratio of the water-insoluble cellulose polymer to the water-soluble cellulose polymer in the second coating layer in the dry mass is from 1: 1 to 9: 1. Orally disintegrating tablet according to any one of 1-14).
(1-16) The orally disintegrating tablet according to any one of (1-1) to (1-15), wherein the water-insoluble cellulose polymer is ethyl cellulose.
(1-17) The orally disintegrating tablet according to (1-16), which contains 0.1 to 5 parts by mass of ethylcellulose with respect to 100 parts by mass of the dry tablet.
(1-18) The orally disintegrating tablet according to any one of (1-1) to (1-17), further having a third coating layer on the outside of the tablet.
(1-19) The orally disintegrating tablet according to any one of (1-1) to (1-18), wherein the second coating layer contains titanium oxide.

(2-1) On the core particles having an average particle diameter of 50 μm to 200 μm containing at least one selected from the group consisting of crystalline cellulose, crospovidone and sugar alcohol,
Applying a first coating layer containing a physiologically active ingredient and a water-soluble cellulose polymer exhibiting physiological activity in a trace amount of 0.1 μm or more and 30 μm or less, and then
Further, on the outer side of the coated particles, characterized in that a second coating layer containing a water-insoluble cellulose polymer and a water-soluble cellulose polymer is applied, from an excipient, a disintegrant and a lubricant. The method for producing an orally disintegrating tablet according to any one of (1-1) to (1-19), wherein tableting is performed by adding at least one selected from the group consisting of:
(2-2) A hydrophilic solvent capable of dissolving a water-soluble cellulose polymer, water or a mixture thereof is used as a solvent, and the first coating layer and the second coating layer are applied by a fluidized bed granulation method (2- 1) Production method.
(2-3) The coated particles of (1-7) are mixed with at least one selected from sugar alcohol and crystalline cellulose, then tableted, and then a third coating layer is formed on the outside of the obtained tablet. The method for producing an orally disintegrating tablet according to (2-1) or (2-2).

  According to the present invention, for a physiologically active ingredient (drug) having a low content (a trace amount) and a feeling of ingestion, the segregation is suppressed, the feeling of ingestion is improved, and the drug composition has a good drug elution property. Products, particularly orally disintegrating tablets, can be provided.

Examples of the physiologically active component showing physiological activity in a trace amount used in the present invention include, for example, norethisterone, medroxyprogesterone acetate, methyltestosterone, didrogesterone, estradiol, ethinylestradiol, levonorgestrel, pregnanediol, salivary gland hormone, dienogest, drospirenone, es Hormone-like substances such as triol, conjugated estrogens, mestranol, norgestrel, dexamethasone, betamethasone, prednisolone, prostaglandins such as dinoprostone, limaprost alphadex, beraprost sodium, synthetic vitamin D such as alfacalcidol, calcitriol, methotrexate, Metabolism of tumor drugs such as anastrozole and tamibarotene, and minodronic acid hydrate Such as chemicals and the like. Of these, hormone-like substances are preferred, and dienogest is particularly preferred.
Dienogest (17-Hydroxy-3-oxo-19-nor-17α-pregna-4,9-diene-21-nitrile), which is one of the preferred physiologically active ingredients of the present invention, is the product name “Dinagest Tablets 1 mg”. And “Dinagest OD Tablets 1 mg”. The indication is endometriosis.

The orally disintegrating tablet of the present invention contains at least one physiologically active ingredient, and may contain two or more physiologically active ingredients.
Since the physiologically active ingredient used in the present invention exhibits physiological activity in a minute amount, for example, the physiologically active ingredient content per unit dosage form (for example, one tablet) is 0.1 μg or more and 3 mg or less. Is done. Another embodiment is exemplified in which the content of the physiologically active ingredient per unit dosage form is 0.3 μg or more and 2 mg or less, and in another aspect, the content of the physiologically active ingredient per unit dosage form is 0. Examples are those of 5 μg or more and 1 mg or less. In addition, when two or more physiologically active ingredients are contained per unit dosage form, it means that the content per ingredient of the physiologically active ingredients is included in the above range.
When the physiologically active ingredient used in the present invention is dienogest, the content of dienogest per unit dosage form is preferably 0.1 mg or more and 3 mg or less, more preferably 0.25 mg or more and 2 mg or less. It is.

The physiologically active ingredient used in the present invention preferably has an average particle size of 0.1 μm or more and 30 μm or less, more preferably 0.3 μm or more and 20 μm or less, particularly preferably 0.5 μm or more, 10 μm or less.
When the physiologically active ingredient used in the present invention is dienogest, it is preferable to use finely divided (micronized) dienogest. By making fine particles, there is an advantage that it is easy to obtain uniform content of the preparation. In the present invention, the method and apparatus used in the step of micronizing the physiologically active ingredient are not particularly limited, and for example, an atomizer, a pin mill, a jet mill, a ball mill, or the like can be used.
The preferable average particle diameter of dienogest used in the present invention is 0.5 μm to 20 μm, more preferably 1 μm to 15 μm, and further preferably 1 μm to 10 μm.
In addition, in this specification, the numerical range shown using "to" shows the range which includes the numerical value described before and behind "to" as a minimum value and a maximum value, respectively.
The dienogest used in the present invention preferably contains 95% by mass or more of particles of 25 μm or less, more preferably 99% by mass or more of particles of 25 μm or less.

  In the present invention, the particle diameter measurement method is not particularly limited, and for example, a laser diffraction method, an image imaging method, or the like can be used. As a measuring device, for example, a laser diffraction / scattering type particle size / particle size distribution measuring device (for example, Microtrack MT3100II (Nikkiso Co., Ltd.), a laser diffraction type particle size distribution measuring device (dry / wet) (for example, Mastersizer 3000 (Malvern )), Wet flow type particle size / shape analyzer (eg FPIA-3000 (Malvern)), static automatic image analyzer (eg Morphologi G3 (Malvern)), etc., preferably dry type Measurement using a laser diffraction particle size distribution measuring device is preferable, and generally, conditions for measuring the particle size of an object to be measured accurately and reproducibly are selected, and those skilled in the art can set appropriate conditions. For example, a laser diffraction particle size distribution analyzer (HELOS & LODOS) (manufactured by Sympatec) is used in the present invention. When measuring the particle size of dienogest, which is one of the preferable physiologically active components, the measurement range is preferably 0.5 μm to 175 μm.

The orally disintegrating tablet of the present invention is a tablet that satisfies all of the following evaluation criteria a) to c), and satisfying these can solve the problems of the present invention. That is, the orally disintegrating tablet targeted in the present invention is
a) The oral disintegration time is within 30 seconds,
b) When the dissolution test was performed according to the dissolution test method described in JP 16th edition, general test method (test solution: water 900 mL, 37 ° C.), the dissolution rate of the physiologically active component in 15 minutes was 80% by mass or more. Yes, and c) When the dissolution test was carried out according to the dissolution test method described in JP 16th edition, general test method (test solution: water 900 mL, 37 ° C.) The elution rate of the physiologically active ingredient is 5% by mass or less.
The orally disintegrating tablet used in the present invention has a) an oral disintegration time of 30 seconds or less, preferably 25 seconds or less, and more preferably 20 seconds or less. Here, the disintegration time in the oral cavity is a disintegration time measured for the target tablet using a texture analyzer (model number: TA-XT Plus: Eihiro Seiki) under the following conditions.

<Measurement method>
The tablet was immersed in 0.5 mL of purified water, and the stress was measured with a texture analyzer. The time from when the tablet was immersed in water until the probe touched the tablet was taken as the measurement time, and the shortest measurement time when no peak was found in the middle of the stress curve was taken as the oral disintegration time (the peak was found in the middle of the stress curve). If it is, it indicates that water has not reached the inside of the tablet and is a so-called “state in which the core remains”.
<Measurement conditions>
Pre-Test speed: 2.0mm / sec
Test speed: 2.0mm / sec
Trigger type: Auto (Force)
Trigger force: 5.0g
Measurement time: 10, 15, 30, 45, 60, 90, 120 seconds

Furthermore, the orally disintegrating tablet targeted by the present invention was subjected to a dissolution test according to the dissolution test method described in b) JP 16th edition, general test method (test solution: water 900 mL, 37 ° C.), 15 minutes. The elution rate of the physiologically active ingredient in is 80% by mass or more, preferably 85% by mass or more.
In addition to these, the orally disintegrating tablets targeted by the present invention were subjected to a dissolution test according to the dissolution test method described in c) JP 16th edition, general test method (test solution: water 900 mL, 37 ° C.) The dissolution rate of the physiologically active component in the test solution is 5% by mass or less at the time of the time required for the oral disintegration (oral disintegration time) measured by the method a) for the target tablet, Is 3% by mass or less. Since the orally disintegrating tablet of the present invention has a low elution rate of the physiologically active component when disintegrated in the oral cavity, an unpleasant feeling of taking (eg, bitterness) caused by the physiologically active component is improved.

  One of several preferable embodiments of the orally disintegrating tablet of the present invention is an orally disintegrating tablet containing a physiologically active ingredient, an excipient, a water-insoluble cellulose polymer, and a water-soluble cellulose polymer. The excipient is preferably at least one selected from the group consisting of sugar alcohols and crystalline cellulose, more preferably at least one selected from the group consisting of D-mannitol and crystalline cellulose, more preferably , D-mannitol and crystalline cellulose. Moreover, in the said aspect, it is preferable to contain further at least 1 sort (s) chosen from the group which consists of a disintegrating agent and a lubricant. By using such an additive, an orally disintegrating tablet that solves the problem can be produced.

One of several preferable embodiments of the orally disintegrating tablet of the present invention is that a physiologically active ingredient and a water-soluble cellulose system are formed on core particles containing at least one selected from the group consisting of crystalline cellulose, crospovidone and sugar alcohol. A tablet comprising coated particles having a first coating layer containing a polymer and further having a second coating layer containing a water-insoluble cellulose polymer and a water-soluble cellulose polymer on the outside thereof. By using such coated particles, it is possible to produce an orally disintegrating tablet that solves the problem.
In this case, the coated particles are preferably orally disintegrating tablets produced by tableting by adding an excipient and at least one selected from the group consisting of a disintegrant and a lubricant. .
Another preferred embodiment of the orally disintegrating tablet of the present invention includes a thin first coating layer containing an excipient as a core particle and a trace amount of a physiologically active ingredient on the outside thereof, and Forming coated particles having a thin second coating layer containing a water-insoluble cellulosic polymer and a water-soluble cellulosic polymer on the outside, and mixing with an excipient having a particle size comparable to the coated particles Produced by tableting, the segregation of the content of the drug is suppressed, and even if the amount of the second coating is small, the elution of the physiologically active ingredient in the oral cavity can be effectively suppressed. Orally disintegrating tablets that have good drug-dissolving properties because the feeling of dosing is improved and the physiologically active ingredient is rapidly released after swallowing.

An excipient | filler and / or a disintegrating agent can be used for the core particle used for the orally disintegrating tablet of this invention. The core particles preferably contain at least one selected from the group consisting of crystalline cellulose, crospovidone and sugar alcohol, more preferably at least one selected from the group consisting of sugar alcohol and crystalline cellulose. It is more preferable to contain at least one selected from the group consisting of D-mannitol and crystalline cellulose, and it is particularly preferable to contain D-mannitol and crystalline cellulose.
The average particle size of crystalline cellulose, crospovidone and sugar alcohol used as the core particles is preferably 30 μm to 200 μm, more preferably 40 μm to 180 μm.

The crystalline cellulose used in the present invention can be easily obtained from the market. Examples include Theolas KG-802, Theolas PH-101, Theolas KG-1000 (Asahi Kasei Chemicals Corporation).
Crospovidone is a crosslinked polymer of 1-vinyl-2-pyrrolidone. Insoluble in water. Used as a disintegrant as a pharmaceutical additive.
Crospovidone used in the present invention can be easily obtained from the market. For example, Kollidon CL (BASF Japan), Polyplusdon XL (ISP Japan) and the like can be mentioned.
Preferred examples of the sugar alcohol used in the present invention include one kind of D-mannitol (for example, Pertec M100: Merck), erythritol, maltitol, xylitol, sorbitol, or a mixture of two or more thereof. Of these, erythritol, D-mannitol or a mixture thereof is preferred, and D-mannitol is most preferred.

As the water-soluble cellulose polymer used in the first coating layer and the second coating layer of the orally disintegrating tablet of the present invention, hypromellose, hydroxypropylcellulose (for example, HPC-L: Nippon Soda), methylcellulose, hydroxyethylcellulose One type or a mixture of two or more types thereof may be mentioned as a preferable one, and hydroxypropyl cellulose is more preferable.
Examples of the water-insoluble cellulose polymer used in the second coating layer of the orally disintegrating tablet of the present invention include ethyl cellulose (for example, ETHOCEL STANDARD 7 PREMIUM: DAW CHEMICAL), hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate 1 A seed or a mixture of two or more of these may be mentioned as preferred, and ethyl cellulose is more preferred.

Another preferred embodiment of the orally disintegrating tablet of the present invention includes:
In terms of dry mass, the amount of the physiologically active component is 1 to 20 parts by mass with respect to 100 parts by mass of the core particles.
The amount of the first coating layer is 3 parts by mass to 20 parts by mass with respect to 100 parts by mass of the core particles as a dry mass, and the total amount of the core particles and the first coating layer as the dry mass. It is an orally disintegrating tablet containing coated particles in which the amount of the second coating layer is 1 part by mass to 5 parts by mass with respect to 100 parts by mass.
The amount of the physiologically active ingredient is more preferably 1 to 15 parts by mass with respect to 100 parts by mass of the core particles, and more preferably the amount of the physiologically active ingredient is 1 to 10 parts by mass with respect to 100 parts by mass of the core particles. is there.
In another preferred embodiment, the amount of the first coating layer is more preferably 3 to 15 parts by mass with respect to 100 parts by mass of the core particles, and still more preferably the first coating layer is 100 parts by mass with respect to 100 parts by mass of the core particles. The amount of one coating layer is 3 to 12 parts by mass.

Another preferred embodiment of the orally disintegrating tablet of the present invention is an orally disintegrating tablet containing coated particles having an average particle diameter of core particles of 50 μm to 200 μm. More preferably, it is an orally disintegrating tablet containing coated particles having an average particle size of the core particles of 60 μm to 180 μm.
Another preferred embodiment of the orally disintegrating tablet of the present invention is an orally disintegrating tablet containing coated particles having an average particle diameter of 55 μm to 250 μm. More preferably, it is an orally disintegrating tablet containing coated particles in which the average particle diameter of the coated particles is 70 μm to 200 μm.
The coated particles used in the orally disintegrating tablet of the present invention are extremely thin in both the first coating layer and the second coating layer. The physiologically active ingredient is contained in the first coating layer, and the outside thereof is covered with the second coating layer, so that even if the coating amount of the second coating layer is very small, the oral cavity is effectively effective. Oral disintegration that can suppress elution of physiologically active ingredients in the mouth, and as a result, the feeling of taking is improved, and the physiologically active ingredients are rapidly released after swallowing, so that it has good drug dissolution properties It becomes a tablet.

In another preferred embodiment of the orally disintegrating tablet of the present invention, the ratio of the water-insoluble cellulose polymer to the water-soluble cellulose polymer in the second coating layer is 1 in terms of dry mass. : Orally disintegrating tablets containing coated particles of 1 to 9: 1. More preferably, the oral disintegration contains coated particles having a dry mass and the ratio of the water-insoluble cellulose polymer to the water-soluble cellulose polymer in the second coating layer being 1: 1 to 6: 1. It is a tablet.
Another preferred embodiment of the orally disintegrating tablet of the present invention is an orally disintegrating tablet containing ethyl cellulose as a water-insoluble cellulose polymer. Orally disintegrating tablets containing 0.1 to 5 parts by weight of ethyl cellulose with respect to 100 parts by weight of the tablet in terms of dry mass are preferred. More preferably, an orally disintegrating tablet containing 0.1 to 3 parts by weight of ethylcellulose is used with respect to 100 parts by weight of the tablet, more preferably 100 parts by weight of the tablet. An orally disintegrating tablet containing 0.1 to 2 parts by mass of ethyl cellulose with respect to parts is mentioned.
Another preferred embodiment of the orally disintegrating tablet of the present invention includes an orally disintegrating tablet that further contains coated particles containing titanium oxide in the coating layer. In the case where the physiologically active component is an unstable component to light, by including titanium oxide in the coating layer, a light shielding effect can be expected, and an effect of suppressing degradation product production by light is expected.

Another preferred embodiment of the orally disintegrating tablet of the present invention includes at least one selected from the group consisting of coated particles, excipients, and disintegrants and lubricants prepared as described above. It is an orally disintegrating tablet.
Another preferred embodiment of the orally disintegrating tablet of the present invention is an orally disintegrating tablet produced by mixing coated particles with an excipient and compressing the tablet. In the present specification, additives such as excipients, disintegrants, lubricants and the like mixed with the coated particles are collectively referred to as “external addition”.
Another preferred embodiment of the orally disintegrating tablet of the present invention is an orally disintegrating tablet containing 2 to 60 parts by weight of coated particles with respect to 100 parts by weight of the tablet as dry weight. is there. Orally disintegrating tablets containing 10 to 50 parts by weight of coated particles with respect to 100 parts by weight of the tablet in terms of dry mass are more preferable, and 15 particles with respect to 100 parts by weight of the tablet in terms of dry weight. Orally disintegrating tablets containing from 40 parts by weight to 40 parts by weight are more preferred.

Examples of excipients used for external addition of the orally disintegrating tablet of the present invention include sugar alcohol, crystalline cellulose, precipitated calcium carbonate, calcium monohydrogen phosphate, calcium hydrogen phosphate, sodium hydrogen phosphate, diphosphate phosphate. Potassium, potassium dihydrogen phosphate, calcium dihydrogen phosphate, sodium dihydrogen phosphate, calcium sulfate, calcium lactate, synthetic aluminum silicate, synthetic hydrosite, dry aluminum hydroxide, magnesium carbonate, magnesium oxide, carmellose, carmellose Examples thereof include calcium, sodium carmellose, carboxymethylethyl cellulose, sodium carboxy starch, various starches, sugar alcohols and crystalline cellulose are preferred, and sugar alcohols and crystalline cellulose are most preferably used in combination.
Preferred examples of the sugar alcohol include one kind of D-mannitol (for example, Pertec M100: Merck), erythritol, maltitol, xylitol, sorbitol, or a mixture of two or more thereof. Of these, erythritol, D-mannitol or a mixture thereof is preferred.
Crystalline cellulose can be easily obtained from the market. Examples include Theolas KG-802, Theolas PH-101, Theolas KG-1000 (Asahi Kasei Chemicals Corporation).

Another preferred embodiment of the orally disintegrating tablet of the present invention is an orally disintegrating tablet in which the excipient used for external addition has an average particle size of 40 μm to 250 μm. More preferably, it is an orally disintegrating tablet in which the excipient used for external addition has an average particle size of 50 μm to 200 μm.
Another preferred embodiment of the orally disintegrating tablet of the present invention is that the average particle size of the excipient during external addition is 50% to 320% of the average particle size of the coated particles. It is a tablet. The difference between the average particle size of the excipient and the average particle size of the coated particles is preferably smaller. By preparing in this way, segregation of the physiologically active ingredient is suppressed when the coated particles containing the physiologically active ingredient and the external additive are mixed.
Another preferred embodiment of the orally disintegrating tablet of the present invention is an orally disintegrating tablet in which the ratio of the excipient in the external addition is 30% by mass to 99% by mass. More preferably, it is an orally disintegrating tablet in which the ratio of the excipient in the external addition is 40% by mass to 98% by mass.

Examples of the disintegrant include crospovidone, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethyl starch sodium, croscarmellose sodium, low-substituted hydroxypropylcellulose, hydroxypropyl starch and the like, and crospovidone is preferred.
Crospovidone is readily available from the market. For example, Kollidon CL (BASF Japan), Polyplusdon XL (ISP Japan) and the like can be mentioned.
Examples of the lubricant include talc, magnesium stearate, glyceryl monostearate, glyceryl palmitostearate, sodium stearyl fumarate, sucrose fatty acid ester, carnauba wax, L-leucine, macrogol, and the like. Magnesium stearate is preferred, and talc and magnesium stearate are most preferably used in combination.
The orally disintegrating tablet of the present invention may contain other additives in addition to the additives specified so far as long as the effects of the invention are not impaired.

The orally disintegrating tablet of the present invention has an average particle size of 50 μm to 200 μm containing at least one selected from the group consisting of crystalline cellulose, crospovidone and sugar alcohol,
Applying a first coating layer containing a physiologically active ingredient and a water-soluble cellulose polymer exhibiting physiological activity in a trace amount of 0.1 μm or more and 30 μm or less, and then
Further, on the outer side of the coated particles, characterized in that a second coating layer containing a water-insoluble cellulose polymer and a water-soluble cellulose polymer is applied, from an excipient, a disintegrant and a lubricant. It is preferable to produce by a method including a step of tableting by adding at least one selected from the group consisting of
As one of several preferred embodiments of the method for producing an orally disintegrating tablet of the present invention, preferred embodiments of the core particles, the first coating layer, the second coating layer, and the additive in the external addition are as described above. It is.

Here, it is preferable to apply the first coating layer and the second coating layer by a fluidized bed granulation method using a hydrophilic solvent capable of dissolving the water-soluble cellulose polymer, water or a mixture thereof as a solvent. In addition, about fluidized bed granulation, it can implement by a conventional method using a fluidized bed granulation dryer (for example, MP-01, GPCG-5: all are Paulek). An apparatus, a method, etc. are not specifically limited. Here, the hydrophilic solvent means a solvent having good miscibility with water. Examples include, but are not limited to, lower alcohols such as methanol and ethanol, acetone and the like. The hydrophilic solvent used in the method for producing an orally disintegrating tablet of the present invention is preferably ethanol.
For mixing each component before tableting, for example, using a V-type mixer (V-600: Deoksugaku Kosakusho), Boule container mixer (PM200: Hitachi, Ltd.), etc., after mixing each component uniformly. Although it is preferable to tablet, it is not limited to these methods.
The tableting process is preferably carried out at room temperature using a tableting machine such as a single-shot tableting machine or a rotary tableting machine. When a single-shot tableting machine, a rotary tableting machine or the like is used, it is usually preferable to employ a tableting pressure of 1 to 30 kN, preferably 3 to 20 kN. At this time, it is preferable that the hardness of the obtained tablet is about 20N to 150N. In addition, the hardness of a tablet can be easily measured by a conventional method using, for example, a tablet hardness meter (8M: Dr. Schleuniger Pharmatron AG).

  In another preferred embodiment of the orally disintegrating tablet of the present invention, a third coating layer can be further applied to the outside of the tablet. Here, as the third coating layer, for example, a coating layer as described in WO2012 / 147873 and WO2013 / 161103 is preferable, for example, trehalose and / or erythritol, and an average particle diameter of 0.1 μm to 50 μm. 100 μm or less containing at least one water-insoluble inorganic compound and / or water-insoluble fatty acid, salt or ester thereof selected from the group consisting of water-insoluble inorganic salts, silicate compounds, aluminum hydroxide, magnesium oxide and zinc oxide A thick film can be used. Alternatively, for example, (a) containing at least one selected from titanium oxide, (b) crystalline cellulose, crospovidone and albumin and (c) a saccharide or sugar alcohol, and with respect to 100 parts by weight of component (a), A coating layer having a thickness of 100 μm or less can be mentioned as a coating layer of a rapidly disintegrating tablet, wherein the proportion of component (b) is 50 parts by mass or more.

In another preferred embodiment of the orally disintegrating tablet of the present invention, the content of the physiologically active ingredient in the orally disintegrating tablet obtained as described above is 90% to 110% of the prescribed amount. Orally disintegrating tablet. More preferably, it is an orally disintegrating tablet in which the content of the physiologically active ingredient in the orally disintegrating tablet is 95% to 105% of the prescribed amount.
The usage / dosage of the orally disintegrating tablet of the present invention is appropriately determined depending on the physiologically active ingredient contained therein and its efficacy / effect, and is not particularly limited. For example, when the bioactive component is dienogest, the endometriosis can be administered orally from the 2nd to 5th day of the menstrual cycle, usually 2 mg per day as dienogest. .

Next, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples.
Reference Examples 1 to 3 (Evaluation of content segregation during mixed powder flow)
D-mannitol (Partec M100: Merck: average particle size 70 μm) and / or crystalline cellulose (Theoras PH-101: Asahi Kasei Chemicals: average particle size 50 μm) in the amounts shown in Table 1 were fluidized bed granulator / dryer (MP- 01: Paulek) and preheated. Next, a solution in which dienogest (99% or more of particles of 25 μm or less) is dispersed in a 5% aqueous solution of hydroxypropyl cellulose (HPC-L: Nippon Soda) at a concentration of about 11% by mass is prepared. The previous mixture was sprayed using a grain dryer and dried. Next, a 5% ethanol solution of hydroxypropyl cellulose (HPC-L: Nippon Soda) and a 5% ethanol solution of ethyl cellulose (ETHOCEL STANDARD 7 PREMIUM: DAW CHEMICAL) were mixed so as to have the ratio shown in Table 1, and flowed. Using a layer granulation dryer, the previous granulated product was sprayed and dried to obtain coated particles shown in Table 1.

Subsequently, the obtained coated particles were mixed with the respective components (D-mannitol, crystalline cellulose, crospovidone, talc and magnesium stearate) for the undisintegrated tablets for orally disintegrating tablets listed in Table 1, and orally disintegrating. A mixed powder for uncoated tablets was prepared. In Reference Examples 1 to 3, the ratio (wt%) of the coated particles in the mixed powder was prepared as 60.0 mass%, 40.0 mass%, and 22.2 mass%, respectively.
The obtained mixed powder for uncoated tablets was subjected to a segregation test in accordance with the method described in Powder Technology, 36, 39-53 (1983), and dienogest, which is a physiologically active component at the time of mixed powder flow. Content segregation was evaluated. That is, a plurality of sampling points were set, samples corresponding to 2 to 3 tablets were collected, and the amount of dienogest contained in the sample was measured. Table 1 shows the average and range of dienogest content (%) in each example. From these results, it was found that all of Reference Examples 1 to 3 had a fluctuation in the range of 90% to 110%, and the content segregation was small and good results were obtained.

Table 1

Example 1
<Manufacture of coated particles>
300 g of D-mannitol (Partec M100: Merck: average particle size 70 μm) and 300 g of crystalline cellulose (Theorus PH-101: Asahi Kasei Chemicals: average particle size 50 μm) were placed in a fluidized bed granulator / dryer (MP-01, Powrec). Preheated and mixed. Next, a solution in which 30 g of dienogest (99% or more of particles of 25 μm or less) is dispersed in 240 g of a 5% aqueous solution of hydroxypropylcellulose (HPC-L: Nippon Soda) is prepared, and a fluidized bed granulation dryer is used. The previous mixture was sprayed and dried. Then, 168 g of a 5% ethanol solution of hydroxypropyl cellulose (HPC-L: Nippon Soda) and 168 g of a 5% ethanol solution of ethyl cellulose (ETHOCEL STANDARD 7 PREMIUM: DAW CHEMICAL) are mixed, and the above is used using a fluidized bed granulation dryer. The granulated product was sprayed and dried to obtain 658.8 g of coated particles.

<Manufacture of orally disintegrating tablets>
658.8 g of the coated particles obtained above, 1582.2 g of D-mannitol (Partec M100: Merck), 525 g of crystalline cellulose (Theolas PH-101: Asahi Kasei Chemicals), crospovidone (Collidon CL-F: BASF: average particle) 150 g of diameter (20 μm to 40 μm) and 60 g of talc (HiFiller # 017: Matsumura Sangyo) were added and mixed manually. Next, magnesium stearate (magnesium stearate plant: Taihei Chemical Industry) was added, mixed manually, and then compressed with a tableting machine (HT-X10SS-UW, Hata Iron Works) at a pressure of 2.7 kN. Thus, an orally disintegrating tablet was produced (100 mg / tablet, φ6.5 mm, 8R).

Examples 2 to 6, Reference Example 4 and Comparative Examples 1 to 4
According to Example 1, the orally disintegrating tablets described in the Examples, Reference Examples and Comparative Examples in Tables 2 to 3 were produced. In addition, when manufacturing the tablet of the Example as described in a table | surface, the following each component was used suitably.
Crystalline cellulose (Theorus KG-1000: Asahi Kasei Chemicals: average particle size 50 μm)
Fragrance (Dry coat: Takada fragrance)

The characteristics of each tablet obtained in Examples 1 to 6, Reference Example 4 and Comparative Examples 1 to 3 were evaluated by the following methods.
Test Example 1 <Hardness>
About the obtained tablet, it measured by the conventional method using the tablet hardness meter (8M: Dr. Schleuniger Pharmatron AG). The average value of the measured values of 5 tablets was defined as hardness (Newton: N).
Test Example 2 <Oral disintegration time>
The disintegration time in the oral cavity was measured by the following method using a texture analyzer (model number: TA-XT Plus: Eihiro Seiki). The tablet was immersed in 0.5 mL of purified water, and the stress was measured with a texture analyzer. The time from when the tablet was immersed in water until the probe touched the tablet was taken as the measurement time, and the shortest measurement time when no peak was found in the middle of the stress curve was taken as the oral disintegration time (the peak was found in the middle of the stress curve). If it is, it indicates that water has not reached the inside of the tablet and is a so-called “state in which the core remains”.
<Measurement conditions>
Pre-Test speed: 2.0mm / sec
Test speed: 2.0mm / sec
Trigger type: Auto (Force)
Trigger force: 5.0g
Measurement time: 10, 15, 30, 45, 60, 90, 120 seconds

Test Example 3 <Dissolution>
Using the dissolution tester (model number: NTR-8400AC: Toyama Sangyo Co., Ltd.), the dissolution test was carried out on the obtained tablets (dienogest 1 mg tablet) according to the dissolution test method described in JP 16 revision, general test method (test) Liquid: water 900 mL, 37 ° C.). The elution rate of the physiologically active component at 15 minutes is shown in the table.
Test Example 4 <Elution in the oral cavity>
Using the dissolution tester (model number: NTR-8400AC: Toyama Sangyo Co., Ltd.), the dissolution test was carried out on the obtained tablets (dienogest 1 mg tablet) according to the dissolution test method described in JP 16 revision, general test method (test) Liquid: water 900 mL, 37 ° C.). The elution rate of the physiologically active ingredient at the time corresponding to the “oral disintegration time” in each example and test example 2 of the test example is shown in the table.
The results are summarized in Table 2 and Table 3. In addition, the numerical value about the component in a table | surface is a mass part.

Table 2

  As shown in Table 2, the orally disintegrating tablets described in Examples 1 to 6 obtained results satisfying the criteria for all of the oral disintegration time, dissolution rate, and oral dissolution property. From the comparison between Examples 1 and 2, it was observed that the dissolution property in the oral cavity was lowered by increasing the ratio of ethyl cellulose in the second coating layer. From the comparison between Examples 3 and 4, it was observed that the dissolution property in the oral cavity was lowered by increasing the ratio of the second coating layer. Moreover, from the result of Reference Example 4, it was confirmed that the core particles satisfy the criteria for the disintegration time in the oral cavity even when only crystalline cellulose is used.

Table 3

As described in Comparative Examples 1 and 2 in Table 3, those that did not contain D-mannitol and crystalline cellulose as “external addition” did not satisfy the criteria for oral disintegration time.
Example 7
About the formulation examples 1-4 which show a composition in following Table 4, the orally disintegrating tablet was prepared according to Example 1, and characteristics, such as hardness, were investigated by the method similar to Example 1. FIG. As a result, the orally disintegrating tablets of these formulations all showed the same values as the orally disintegrating tablets of Examples 1-6. In addition, the numerical value about the component in a table | surface is a mass part.

Table 4

Claims (1)

Contains physiologically active ingredients that show physiological activity in trace amounts,
a) The oral disintegration time is within 30 seconds,
b) When the dissolution test was performed according to the dissolution test method described in JP 16th edition, general test method (test solution: water 900 mL, 37 ° C.), the dissolution rate of the physiologically active component in 15 minutes was 80% by mass or more. Yes, and c) When the dissolution test was carried out according to the dissolution test method described in JP 16th edition, general test method (test solution: water 900 mL, 37 ° C.) An orally disintegrating tablet, wherein the dissolution rate of a physiologically active ingredient is 5% by mass or less.