JP4523265B2 - Orally disintegrating preparations for the treatment of urination disorders - Google Patents

Description

  The present invention relates to an orally disintegrating preparation containing a drug having therapeutic activity for dysuria and / or a disease related thereto suitable for taking.

  Adrenergic α1 receptor blockers and the like are known as drugs having therapeutic activity for dysuria and / or diseases related thereto. Adrenaline α1 receptor blockers are widely used as therapeutic agents for essential hypertension, renal hypertension, hypertension due to pheochromocytoma, or dysuria associated with prostatic hypertrophy. Indications requiring an adrenergic α1 receptor blocker are chronic diseases and are often taken for a long period of time, and there is an extremely high need for a dosage form preparation that is easy to drink and easy to handle according to the patient's lifestyle.

  Conventionally, tablets and capsules have been widely used as pharmaceutical forms of drugs having therapeutic activity for dysuria and / or diseases related thereto. For example, naphthopidyl, terazosin hydrochloride, bunazosin hydrochloride, and prazosin hydrochloride, each of which is an adrenergic α1 receptor blocker, are used for treatment as active ingredients. In addition, capsules containing tamsulosin hydrochloride or urapidil as active ingredients are also commercially available.

  The majority of patients who require these treatments are elderly people, and there are patients with weak swallowing power, such as difficulty in swallowing tablets or capsules and feeling uncomfortable feelings such as being used in the throat during taking. In addition, there are patients who have to refrain from taking water before going to bed due to the problem of urination at night. Furthermore, it is difficult to always carry water in daily life, and there are cases where it is difficult to obtain water depending on the situation, and conventional tablets or capsules may be inconvenient.

  In addition, other dosage forms such as powders and granules remain in the oral cavity and are difficult to swallow, and there are cases where discomfort remains in the mouth. In addition, syrup is considered to be a preferable dosage form for elderly people, but it has poor portability and is difficult to take by metering. Therefore, there is a problem that a correct amount cannot be expected.

  In International Publication No. WO 93/12769, a pharmaceutical substance, lactose and mannitol are suspended in an agar aqueous solution, filled into a molding pocket of a PTP sheet made of polypropylene, solidified in a jelly shape, dried under reduced pressure, An orally disintegrating preparation that is sealed to form a PTP package is described. The principle of these methods is based on the basic principle of making a porous tablet having a moderate porosity, including a wetting carrier such as a sugar alcohol that easily wets water during molding.

JP-A-11-189516, International Publication WO99 / 04758, and International Publication WO98 / 14179 include an effervescent preparation that promotes disintegration by blending a carbonate and an organic acid and causing foaming in a tablet. Although disclosed, in this preparation, when an acidic and easily soluble drug is applied, the drug dissolves in the mouth and bitterness is generated, and the drug may be absorbed from the oral mucosa. In order to prevent these, it is necessary to devise measures to prevent drug dissolution, but the means is not known.
International Publication WO93 / 12769 International Publication WO 98/14179 International Publication No. WO99 / 04758 JP-A-8-291051 Japanese Patent Laid-Open No. 11-189516 Japanese Patent Publication No. 60-29712 Japanese Patent Publication No. 06-2673

  An object of the present invention is to provide an orally disintegrating preparation containing a drug having therapeutic activity for dysuria and / or a disease related thereto. Furthermore, when aged or the like takes a drug having therapeutic activity for dysuria and / or a disease related thereto, it can be taken without using water, for example, an unpleasant taste or a sense of discomfort may occur. It is also an object of the present invention to provide a formulation free from the above. Furthermore, it is also an object of the present invention to provide a preparation having a strength that can be easily taken out from a PTP container (Press Through Package).

  In order to solve the above-mentioned problems, the present inventors have conducted various studies on poorly water-soluble drugs that do not dissolve in the mouth among drugs having therapeutic activity for dysuria and / or related diseases. As a result, the ratio of water-soluble substances such as sugar alcohols or saccharides as a carrier constituting the preparation is increased, and the preparation is compressed at a low pressure to increase the porosity of the tablet compared to ordinary tablets. In addition, a fast disintegrating property can be obtained by adding an additive that expands due to water absorption, and the particle size of the drug is substantially about 0.1 to 100 μm, preferably 0.4 to 105 μm. Therefore, there is no rough feeling, the swallowing is smooth, and the disintegration time in the oral cavity is within 50 seconds, preferably within 45 seconds, particularly preferably the compressed oral disintegration preparation, and a method for producing the same Found that can provide.

That is, according to the present invention, the following inventions are provided.
1. An orally disintegrating preparation containing a drug for treating dysuria and / or a disease related thereto.
2. The orally disintegrating preparation according to the above 1, wherein the tablet strength is 3 kgf or more and the disintegration time in the Japanese Pharmacopoeia disintegration test method using water as a test solution is 50 seconds or less.
3. Drug for treating dysuria and / or a disease related thereto having poor water solubility and a particle size of substantially 0.4 to 105 μm, and a water-soluble additive that is a first additive that may be added if necessary And / or without mixing with a water-insoluble additive, granulation, or granulation, and a water-soluble additive and / or a water-insoluble additive as a second additive may be mixed as necessary. Orally disintegrating preparation obtained by putting the granulated product or mixture into a mold and compression molding at a pressure of 0.1 to 100 MPa, wherein the content of the water-insoluble additive in the preparation is 10% w When it is / w or more, the orally disintegrating preparation according to 1 or 2 above, wherein the average particle size of the water-insoluble additive is 100 μm or less.
4). Drug for treating dysuria and / or a disease related thereto having poor water solubility and a particle size of substantially 0.4 to 105 μm, a water-soluble additive and / or a water-insoluble additive as a first additive And a second additive, a water-soluble additive and / or a water-insoluble additive, if necessary, and the resulting granulated product or mixture is put into a mold and added to the mold. An orally disintegrating preparation obtained by compression molding at a pressure of 1 to 100 MPa, and when the content of the water-insoluble additive in the preparation is 10% w / w or more, the water-insoluble additive 4. The orally disintegrating preparation according to any one of 1 to 3 above, wherein the average particle size of the preparation is 100 μm or less.

5). Drug for treating dysuria and / or a disease related thereto having poor water solubility and a particle size of substantially 0.4 to 105 μm, a water-soluble additive and / or a water-insoluble additive as a first additive Are mixed, granulated, and a second additive, a water-soluble additive and / or a water-insoluble additive, is mixed as necessary, and the resulting mixture or granulated product is put into a mold under wet conditions. Orally disintegrating preparation obtained by compression molding at a pressure of 0.1 to 100 MPa and drying, and the content of the water-insoluble additive in the preparation is 10% w / w or more 4. The orally disintegrating preparation according to any one of 1 to 3 above, wherein the water-insoluble additive has an average particle size of 100 μm or less.
6). Drug for treating dysuria and / or a disease related thereto having poor water solubility and a particle size of substantially 0.4 to 105 μm, a water-soluble additive and / or a water-insoluble additive as a first additive And granulating, and further mixing a second additive, a water-soluble additive and / or a water-insoluble additive (however, at least a part of the second additive is granulated), An orally disintegrating preparation obtained by putting the obtained granulated product or mixture into a mold and compression molding at a pressure of 0.1 to 100 MPa, wherein the content of the water-insoluble additive in the preparation is 10 6. The orally disintegrating preparation according to any one of 1 to 5 above, wherein the water-insoluble additive has an average particle size of 100 μm or less when it is% w / w or more.

7). The orally disintegrating preparation according to the above 6, wherein the mixing ratio of the drug-containing granulated product in the first additive to the granulated product in the second additive is 3 or less.
8). The orally disintegrating preparation according to 6 or 7 above, wherein the average particle size of the granulated product in the first additive is smaller than the average particle size of the granulated product in the second additive.
9. The average particle size of the granulated product in the first additive is smaller than the average particle size of the granulated product in the second additive, and the average particle size of the granulated product in the first additive is about 50. The orally disintegrating preparation according to any one of 6 to 8 above, wherein the preparation has a mean particle size of about 80 to 300 μm.
10. Drug for treating dysuria and / or a disease related thereto having poor water solubility and a particle size of substantially 0.4 to 105 μm, a water-soluble additive and / or a water-insoluble additive as a first additive Are mixed, granulated, and the granulated sugar or sugar alcohol, cellulose, and a disintegrant not belonging to cellulose are mixed, and if necessary, a lubricant is further added, and this granulation is performed in a dry state. An orally disintegrating preparation obtained by putting granules or a mixture into a mold and compression molding at a pressure of 0.1 to 100 MPa, wherein the content of water-insoluble additive in the preparation is 10% w / w In the above case, the orally disintegrating preparation according to any one of 1 to 4 or 6 to 9, wherein the average particle size of the water-insoluble additive is 100 μm or less.

11. (1) the first additive is a disintegrant; (2) the granulated sugar or sugar alcohol is one or more selected from erythritol, D-mannitol, sorbitol, lactose, trehalose (3) Cellulose is crystalline cellulose; and (4) A disintegrant not belonging to cellulose is crospovidone; satisfying any one or more of (1) to (4) above The orally disintegrating preparation according to 10 above.
12 In the granulated sugar or sugar alcohol, the proportion of the granulated product having a particle size of 53 μm or less is 10% or less, the proportion of the granulated product having a particle size of 500 μm or more is 15% or less, and the average particle size is 180 The orally disintegrating preparation according to the above 10 or 11, which is granulated D-mannitol having a size of ˜240 μm.
13. The orally disintegrating preparation according to 10 or 11 above, wherein the content of granulated D-mannitol is 20 to 80% of the preparation weight.
14 The above 1 thru | or containing the crystalline cellulose whose average particle diameter is 38-75 micrometers, and the average major axis minor axis ratio (L / D) of the particle | grains in the particle | grains which pass a sieve with an opening of 75 micrometers are 2.0-4.5. The orally disintegrating preparation according to any one of 13 above.

15. 15. The orally disintegrating preparation according to any one of 1 to 14 above, wherein the weight mixing ratio of the granulated D-mannitol and crystalline cellulose is 4: 1 to 1: 1.
16. Drug for treating dysuria and / or a disease related thereto having poor water solubility and a particle size of substantially 0.4 to 105 μm, a water-soluble additive and / or a water-insoluble additive as a first additive And the mixture is further granulated, and the granulated product is further mixed with a water-soluble additive and / or a water-insoluble additive as the second additive, and the dried mixture is put into a mold and put into a mold. An orally disintegrating preparation obtained by compression molding at a pressure of 1 to 100 MPa and then drying the molded article after humidification, wherein the content of the water-insoluble additive in the preparation is 10% w / w or more In some cases, the orally disintegrating preparation according to any one of 1 to 4 or 6 to 9, wherein the water-insoluble additive has an average particle size of 100 μm or less.
17. A drug for treating dysuria and / or a disease related thereto having a particle size of 0.4 to 105 μm, which is hardly water-soluble, and the first water-soluble additive and / or water-insoluble additive are mixed. Granulation, and further mixing a water-soluble additive and / or a water-insoluble additive as the second additive (however, at least a part of the second additive is granulated), An orally disintegrating preparation obtained by putting granules or a mixture into a mold in a dry state, compression molding at a pressure of 0.1 to 100 MPa, and then drying the molded article after humidification, The orally disintegrating preparation according to 16 above, wherein when the content of the water-insoluble additive is 10% w / w or more, the average particle size of the water-insoluble additive is 100 μm or less.

18. Mixing a drug for treating dysuria and / or a disease related thereto having a particle size of 0.4 to 105 μm, which is hardly soluble in water, with a water-soluble additive as a first additive, and granulating The granulated product is further mixed with a second additive, a water-soluble additive and / or a water-insoluble additive, and the dried mixture is put into a mold and compressed at a pressure of 0.1 to 100 MPa. 18. An orally disintegrating preparation obtained by molding and then drying the molded article after humidification, wherein the content of the water-insoluble additive in the preparation is 5% w / w or less. Orally disintegrating preparation.
19. The orally disintegrating preparation according to any one of 1 to 9 or 16 to 18, wherein the pressure at the time of compression molding is 0.1 to 20 MPa.
20. 20. The orally disintegrating preparation according to any one of 1 to 19, wherein roughness and / or bitterness is reduced.
21. 21. The orally disintegrating preparation according to any one of 1 to 20, wherein the drug is a drug exhibiting an unpleasant taste.
22. The orally disintegrating preparation according to any one of 1 to 21, wherein the drug is naphthopidyl, YM-905, or KMD-3213.

23. The orally disintegrating preparation according to any one of 1 to 22 above, wherein the drug is naphthopidyl and the content of naphthopidyl is 1 to 99% of the orally disintegrating preparation.
24. The orally disintegrating preparation according to any one of 1 to 23, which contains naphthopidyl and erythritol.
25. 25. The orally disintegrating preparation according to the above 24, wherein the weight ratio of naphthopidyl to erythritol is 1: 0.5 to 1:20.
26. 26. The orally disintegrating preparation according to any one of 1 to 25 above, which comprises any one of D-mannitol, xylitol, trehalose, maltitol, lactose, or sorbitol and naphthopidyl.
27. Drug for treating dysuria and / or a disease related thereto having poor water solubility and a particle size of substantially 0.4 to 105 μm, and a water-soluble additive that is a first additive that may be added if necessary And / or without mixing the water-insoluble additive, the water-soluble additive and / or the water-insoluble additive as the second additive is further mixed as necessary, and the granulated product or mixture is put into the mold. And when it is an orally disintegrating preparation obtained by compression molding at a pressure of 0.1 to 100 MPa, and the content of the water-insoluble additive in the preparation is 10% w / w or more, An orally disintegrating preparation in which the average particle size of the water-insoluble additive is 100 μm or less.
28. 28. The orally disintegrating preparation according to any one of 1 to 27, which is a compressed orally disintegrating agent.
29. 29. A method for producing an orally disintegrating preparation according to any one of 1 to 28 above.

  The preparation of the present invention is characterized in that it quickly disintegrates in the mouth and can be swallowed quickly with saliva without feeling uncomfortable or bitter, such as a rough feeling in the mouth. it can.

  The orally disintegrating preparation of the present invention is a preparation that disintegrates rapidly in the mouth and can be swallowed with saliva without using water without feeling uncomfortable or bitter, such as a rough feeling in the mouth. The preparation of the present invention is distinguished from a sublingual agent absorbed under the tongue, and the active ingredient itself is not substantially absorbed in the oral cavity.

  The preparation of the present invention rapidly disintegrates in the oral cavity such as on the tongue without taking water, but the time required for disintegration is, for example, within 50 seconds, preferably within 45 seconds. Preferably, it is within 30 seconds, particularly preferably within 20 seconds. After disintegration of the formulation, the active ingredient is swallowed with saliva without substantially dissolving in saliva. However, since human saliva has individual differences, in order to objectively evaluate the disintegration time of the preparation of the present invention, for example, a disintegration test is performed according to the Japanese Pharmacopoeia disintegration test using water as a test solution. The disintegration time is preferably within 50 seconds, more preferably within 45 seconds, and particularly preferably within 30 seconds.

The orally disintegrating preparation of the present invention is a solid preparation, and the water content is usually preferably 10% by weight or less with respect to the total weight of the preparation, more preferably 8% or less, and further preferably 6% or less.
The shape of the orally disintegrating preparation of the present invention is not particularly limited, but is preferably a radial shape such as a disc shape. A typical example is a tablet shape. The size of the preparation is not particularly limited, and for example, a size that can be easily grasped with a finger and included in the mouth can be selected. Furthermore, it is preferable that the size is slightly larger so as not to be swallowed directly. For example, the major axis (diameter in the case of a disk) is preferably 5 to 22 mm and the thickness is 1 to 8 mm, more preferably the major axis is 6 to 20 mm and the thickness is 1.5 to 6 mm, and still more preferably the major axis. Is 7 to 18 mm and the thickness is about 2 to 5 mm.

  The strength of the preparation is preferably a strength that is not broken by extrusion from a PTP container, more specifically 3 kgf or more, more preferably 3.5 kgf or more, and further preferably 4 kgf. The hardness of the preparation can be measured, for example, using a tablet hardness tester (Okada Seiko, TS-50N).

  Representative examples of drugs for treating dysuria and / or diseases related thereto include drugs having an adrenergic α1 receptor blocking activity, cholinergic drugs, and drugs having a muscarinic receptor antagonistic action. A drug having an adrenergic α1 receptor blocking activity suppresses an organ function controlled by the adrenergic α1 receptor. More specifically, it is an effective antagonist showing high affinity for the adrenergic α1 receptor of the prostate. Yes, it suppresses the contraction of the prostate and urethral smooth muscle by relieving the tension of the sympathetic nerve distributed in the urethra and prostate. Specifically, for example, naphthopidyl, tamsulosin, terazosin, bunazosin, urapidil, moxicilito, doxazosin, alfuzosin, upidocin, metazocine, fiduxosin, indazosin and salts thereof can be mentioned.

  Particularly preferred in the present invention are naphthopidyl, prazosin hydrochloride and urapidil. Furthermore, naphthopidyl is mentioned as a particularly preferable example. YM-905 (solifenacin succinate; (+)-(1S, 3′R) -quinuclidin-3′-yl-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate monosuccinate; international publication WO96 / 20144), or KMD-3213 (silodosin; (-)-(R) -1- (3-hydroxypropyl) -5- [2- [2- [2- (2,2,2-trifluoroethoxy) phenoxy] Ethylamino] propyl] indoline-7-carboxamide; U.S. Pat. No. 5,387,603) is also a preferred example.

  Naphtopidyl has the chemical name [4- (2-methoxyphenyl) piperazinyl] -3- (1-naphthyloxy) propan-2-ol and is disclosed in Japanese Patent Publication No. 60-29712. Japanese Examined Patent Publication No. 6-2673 discloses use of dysuria difficult treatment in prostatic hypertrophy using naphthopidyl and its salt. Naphtopidil is an effective antagonist with high affinity for the α1 receptor of the human prostate, and suppresses the contraction of the prostate and urethral smooth muscle by relieving sympathetic tone distributed in the urethra and prostate. In many clinical studies, naphthopidil has been shown to have an ameliorating effect on dysuria associated with benign prostatic hyperplasia, and has already been marketed as an oral tablet, ie, naphthopidyl tablet. Naftopidil tablets are administered to adults with dysuria due to benign prostatic hyperplasia as naphthopidil once a day from 25 mg. If the effect is insufficient, it is gradually increased to 50 to 75 mg at intervals of 1 to 2 weeks. Taking once a day is set based on clinical test results.

  Prazosin hydrochloride is the chemical name 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4- (2-furanylcarbonyl) piperazine hydrochloride. 2nd α Blocker Study Group Journal 121, 1984, Medical Journal, Inc. describes the effect of treatment for dysuria in benign prostatic hyperplasia. Adults with dysuria associated with benign prostatic hyperplasia (1-1.5 mg per day, 2-3 mg per day) If the effect is insufficient, it is set to be gradually increased to 1.5-6 mg at intervals of 1-2 weeks and taken 2-3 times a day.

  Urapidyl has the chemical name 6-[[3- [4- (ο-methoxyphenyl) -1-piperazonyl] propyl] amino] -1,3-dimethyluracil. Urological surgery 267, 6 (3), 1993 describes the effect of treatment for dysuria in benign prostatic hyperplasia. Starting with 30 mg / day for adults with dysuria associated with benign prostatic hyperplasia, if the effect is insufficient, 1- It is set to be gradually increased to 60-90 mg per day at intervals of 2 weeks and taken twice a day.

  Urinary disturbance associated with benign prostatic hyperplasia occurs particularly in adult males, and its occurrence has been observed since the age of 40. It has increased with age and peaked in the 70s. About 20% of elderly people over 65 years old Has been the subject of treatment.

  In the present specification, the term “poorly water-soluble” means, for example, that when powder passing through a 150 μm sieve is placed in 1000 ml of purified water and shaken vigorously at 20 ± 5 ° C. every 5 minutes for 30 seconds, This means that the amount dissolved is less than 1 g.

  A drug having an adrenergic α1 receptor blocking activity and a poorly water-soluble drug is a more preferable effect in that, when the drug has a further unpleasant taste, it can be made into a preparation that does not feel the unpleasant taste. give. As an unpleasant taste, a bitter taste is typically illustrated, for example, a naphthopidyl can be mentioned as a typical example. With regard to naphthopidyl, the content in one tablet is preferably 25 mg to 75 mg.

  In order to achieve an effect that makes it difficult to feel a rough feeling or a sense of incongruity in the mouth, for example, it is preferable that the drug particles have a particle size of substantially 105 μm or less. It is 89 micrometers or less, More preferably, it is 74 micrometers. The lower limit is not particularly problematic in terms of the effect of reducing the feeling of roughness and incongruity, but especially when the drug has an unpleasant taste, if the particle size is too small, the poorly water-soluble drug is easily dissolved and the taste is felt. There is a case. Accordingly, the particle diameter of the drug is preferably substantially 0.4 μm or more, more preferably 0.8 μm or more, and particularly preferably 1.2 μm or more. “Substantially” means that most of the particle size distribution of the pulverized product is measured, preferably 80% or more, more preferably 85% or more, and still more preferably 90% or more. Illustrated. For example, a pulverized material obtained after pulverization by appropriately selecting the conditions of the pulverizer is included. The average particle diameter of the drug particles is preferably in the range of 1 to 40 μm, more preferably 3-35 μm, and still more preferably 4 to 30 μm.

  In order to make the drug have the above-mentioned particle size, for example, a method of aligning the particle size with a sieve, a method of aligning the particle size with a membrane filter, a method of pulverizing by an appropriate method, and the like are exemplified. The method of pulverization and the pulverizer used at that time are not particularly limited. For example, use of a pin mill pulverizer, a ball mill pulverizer, or a hammer mill pulverizer is preferable. The operating conditions and the like may be determined by measuring a particle size that is appropriately created.

  The pH of saliva varies widely depending on individual differences and physical condition, and is said to be neutral-weakly alkaline (pH 6-7) (Medical Dictionary, Nanzan-do). The orally disintegrating preparation of the present invention is preferably a drug that does not dissolve at the pH of saliva when disintegrating in the oral cavity.

  The use of the orally disintegrating preparation of the present invention is not particularly limited as long as it is a drug that is expected to have a medicinal effect of an adrenergic α1 receptor blocker, and for example, essential hypertension, renal hypertension, pheochromocytoma Examples thereof include therapeutic or preventive agents for dysuria associated with hypertension and prostatic hypertrophy. When the adrenergic α1 receptor blocking agent is naphthopidil, a therapeutic and / or preventive agent for dysuria associated with prostatic hypertrophy is exemplified.

  The method for producing the orally disintegrating preparation of the present invention is not particularly limited as long as the orally disintegrating preparation of the present invention can be produced, but contains a drug having therapeutic activity for dysuria and / or related diseases. The preparation is molded by compression molding, and the disintegration time in the Japanese Pharmacopoeia disintegration test method using water as a test solution is within 50 seconds, preferably within 45 seconds, more preferably within 30 seconds, still more preferably within 20 seconds. It is preferable to select a method capable of producing an orally disintegrating preparation having a condition such that the preparation strength is 3 kgf or more.

As a preferable production method in the present invention, for example, the above-mentioned 3. The method for producing an orally disintegrating preparation according to the embodiment is exemplified.
That is, a drug for treating dysuria and / or a disease associated therewith, which is poorly water-soluble and has a particle size of about 0.4 to 105 μm, and a water-soluble additive and / or water as the first additive After mixing with an insoluble additive and preferably granulating, if necessary, a second additive, a water-soluble additive and / or a water-insoluble additive, is mixed, and this granulated product or mixture is molded. In this way, when the content of the water-insoluble additive in the preparation is 10% w / w or more, the average particle size of the water-insoluble additive is It is preferable to produce an orally disintegrating preparation that is 100 μm or less.
The above method can be carried out by an apparatus generally used in the field of pharmaceutical preparations. As a compression molding device, a tableting die used for tablet molding and upper and lower punching parts for tableting are used, and a hydraulic hand press machine, a single-shot tableting machine, or a rotary tableting machine is used. Used. These can be classified into a non-striking type and a striking type depending on the difference in compression speed during compression molding. The non-striking type is a hydraulic hand press, and the single-shot tableting machine or the rotary tableting machine is a hammering type. As the compression molding machine, either a striking type compression molding machine or a non-striking type compression molding machine can be employed, but it is preferable to employ a striking type compression molding machine when manufacturing in large quantities. Blow-type compression molding machine is a device called single-shot type tableting machine or rotary type tableting machine. Ordinary tableting machines usually used in production lines belong to this category, but compress by momentary pressure. The time during which pressure is applied is usually at most about 2 seconds or less, preferably 1 or 0.5 seconds or less. Although the number of tableting dies and the number of tableting parts of the upper and lower punches for tableting can be changed, one component is described in this specification as a single tableting machine. Further, the non-blow-type compression molding machine is one that gradually applies pressure using a hand press machine or the like, and the time during which pressure is applied is usually about 2 seconds or more and about 5 to 10 seconds. is there. For example, a hydraulic hand press is preferable.

  In general, the batting type requires a larger molding pressure to obtain the same tablet hardness than the non-blowing type. The punching force of a non-blow type compression molding machine (hydraulic hand press machine) can produce tablets having the same tablet hardness with a force of about one tenth of that of a blow type compression molding machine.

  Regarding the compression molding in the production method of the present invention, it can be molded as a tablet, and while ensuring the hardness of the tablet, it ensures the maximum void in the tablet so that it can be rapidly disintegrated as an orally disintegrating tablet. Care must be taken. The pressure used for compression molding may be selected so that the tablet itself has a tablet hardness that is easy to handle without causing damage or the like. Is preferably at a low pressure. The low pressure can be appropriately selected according to the type of compression molding machine to be used, the shape of the mortar, the manufacturing method of the tableting powder, and the tableting pressure is smaller than that of the ordinary tablet. The lower limit of the tableting pressure of the non-blow type compression molding machine (hydraulic hand press machine) is preferably 0.1 MPa or more, more preferably 0.2 MPa or more, or 0.3 MPa or more, and further 0.5 MPa. As mentioned above, More preferably, it is 1 MPa or more, More preferably, 2 MPa or more is illustrated. Further, the upper limit is usually 20 MPa or less, preferably 10 MPa or less, more preferably 8 MPa or less, and 6 MPa or less. Further, the lower limit of the tableting pressure of the blow-type compression molding machine is preferably 1 MPa or more, more preferably 2 MPa or more, particularly preferably 3 MPa or more, and the upper limit is usually 150 MPa or less, preferably 100 MPa or less, more preferably Is particularly preferably 80 MPa or less, or 70 MPa or less, and more preferably 60 MPa or less.

  As a method of drying the molded product after wetting or humidifying it, the method described in JP-A-8-291051 can be referred to. For example, the tableting pressure of the impact-type compression molding machine is preferably 20 MPa or less. Further, the upper limit is preferably 20 MPa or less, and more preferably 18 MPa or less. Moreover, as a minimum, 1 Mpa or more, Preferably 2 Mpa or more is illustrated.

  Among the additives, the method of adding the lubricant may be either a method of adding to the mixed powder to be tableted itself or a method of adhering to the inner wall of the tableting mortar. As an apparatus used for granulation, for example, in the case of wet granulation, a fluidized bed granulation dryer, a stirring granulator, a cylindrical extrusion granulator, a rolling fluidized bed granulation coating machine, or the like is used. In the case of dry granulation, a dry granulator such as a roller compactor, a slug tableting machine or the like is used. Examples of the apparatus used for drying include a shelf-type dryer and a fluidized bed granulator dryer. The shelf-type dryer does not apply physical force to the material to be dried as compared with the fluidized bed granulator dryer. Suitable for drying.

  In the above production method, whether or not the water-soluble additive and / or the water-insoluble additive, which is the first additive, is arbitrary is added to the drug, but it is usually preferable to add it. Further, the method can be classified into the case where only the water-soluble additive is used as the first additive, the case where only the water-insoluble additive is used, or the case where both the water-soluble additive and the water-insoluble additive are used. The person skilled in the art can appropriately determine which is preferable. For example, 10. In the production method of the orally disintegrating preparation according to the embodiment, it is usually preferable to use a water-soluble additive and a water-insoluble additive. In addition, 16. In the production method according to the embodiment of the orally disintegrating preparation, it is usually preferable to use only water-soluble additives as much as possible.

  In addition to mixing the drug and the first additive that may be added if necessary, it is possible to produce the orally disintegrating preparation of the present invention without granulation. As a representative example in the case of producing without granulation, the above 27. The manufacturing method which concerns on the orally disintegrating formulation according to the aspect is mentioned. In the usual case, it is preferable to granulate. The manufacturing method which concerns on the orally disintegrating formulation according to the aspect is mentioned.

  In the above production method, addition of the second additive is optional, but it is preferable to add it. Furthermore, the second additive may or may not contain a granulated product. More preferably, the second additive contains a granulated product. As a representative example when the second additive contains a granulated product, the above-mentioned 6. The manufacturing method which concerns on the orally disintegrating formulation according to the aspect is mentioned. It is also preferable to add granulated sugar or sugar alcohol as the second additive. The manufacturing method which concerns on the orally disintegrating formulation according to the aspect is mentioned. Moreover, as a representative example in the case of granulating various second additives, the above 17. The manufacturing method which concerns on the orally disintegrating formulation according to the aspect is mentioned. As the second additive, a lubricant and the like are preferably selected as necessary.

  When the granulated product or mixture prepared from the drug and the first and second additives added as necessary is put into a mold and compression-molded, it is performed under wet (or humidified) conditions and dry conditions. Can be divided into cases. As a representative example in the case of performing under wet (or humidified) conditions, the above 5. The manufacturing method which concerns on the orally disintegrating formulation according to the aspect is mentioned. Further, as a representative example in the case of carrying out under dry conditions, the above 10. And 16. The manufacturing method which concerns on each orally disintegrating formulation according to this aspect is mentioned. Furthermore, it is also preferable that the molded product after compression molding is humidified (or wet) and then dried. As a representative example, the above 16. The manufacturing method which concerns on the orally disintegrating formulation according to the aspect is mentioned.

3. above. A general combination in the method for producing an orally disintegrating preparation according to the embodiment is as follows.
Water-soluble additives can be easily understood by those skilled in the art. For example, the amount of water required to dissolve 1 g of a substance when the test method showing solubility described in the 14th revised Japanese Pharmacopoeia is followed. Can be understood as a physical property indicating a value of less than 10000 mL. For example, sugars and sugar alcohols such as glucose, fructose, lactose, sucrose, mannitol, sorbitol, xylitol, erythritol, trehalose, maltitol, polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, methylcellulose, pullulan, etc. Illustrated. Further, water-insoluble additives can be naturally understood by those skilled in the art, and are usually understood as additives other than water-soluble additives, such as ethyl cellulose, crystalline cellulose, low-substituted hydroxypropyl cellulose, etc. Organic substances, inorganic substances such as magnesium oxide, precipitated calcium carbonate, talc, light anhydrous silicic acid, synthetic aluminum silicate, or magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, hardened rapeseed oil, hardened There may be mentioned oily substances such as castor oil.

  The water-insoluble additive in the preparation is present as a residue in the oral cavity or tongue after the preparation is disintegrated in the oral cavity, and may cause a sense of incongruity such as roughness in the oral cavity. Discomfort in the oral cavity due to the agent may become prominent when the content of the water-insoluble additive in the preparation is 10% w / w or more. Therefore, when the content of the water-insoluble additive in the preparation is 10% w / w or more, the average particle size of the water-insoluble additive is preferably small. Usually, the average particle size of the water-insoluble additive is preferably 100 μm or less, more preferably the average particle size is 90 μm or less, and particularly preferably the average particle size is 80 μm or less.

  Examples of excipients include saccharides or sugar alcohols that are highly soluble in water and have a good molded state after compression molding, and more specifically, for example, glucose, fructose, lactose, sucrose, and the like. Mannitol, sorbitol, xylitol, erythritol, trehalose, maltitol and the like. Moreover, the granulated material manufactured by the spray-drying method with the favorable shaping | molding state after compression molding is suitable, and products, such as lactose, mannitol, and sorbitol, are mentioned. These granulated products have excellent fluidity, and the angle of repose is preferably 40 degrees or less, more preferably 39 degrees or less, and most preferably 38 degrees or less. These may be used alone or in combination of two or more. As the binder, for example, a water-soluble substance can be selected. In this case, for example, gelatin, agar, alginic acid, sodium alginate, chitansan gum, gum arabic powder, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone , Partially saponified polyvinyl alcohol, methyl cellulose, pullulan, partially pregelatinized starch, saccharides, sugar alcohol and the like.

  These additives may be used alone, but may be used in combination of two or more, and may be used in the granulation step after being dissolved in a solvent. Moreover, a disintegrating agent can also be used as a substance which shortens the disintegration time of a tablet by mix | blending. As the disintegrant, any of disintegrants not belonging to celluloses and disintegrants belonging to celluloses may be used. Examples of disintegrants that do not belong to celluloses include crospovidone, sodium carboxymethyl starch, partially pregelatinized starch, corn starch, lactose, calcium carbonate, precipitated calcium carbonate, calcium citrate, light anhydrous silicic acid, synthetic aluminum silicate, etc. Is mentioned. Examples of the disintegrant belonging to celluloses include crystalline cellulose, low-substituted hydroxypyrrole cellulose, croscarmellose sodium, carboxymethyl cellulose calcium, and the like. These may be used alone or in combination of two or more. Examples of solubilizers include magnesium oxide, calcium oxide, sodium citrate, magnesium chloride, sodium carbonate, and sodium bicarbonate. These may be used alone or in combination of two or more.

  As a lubricant, magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, polyethylene glycol, stearic acid, light anhydrous silicic acid, hydrogenated rapeseed oil, hydrogenated castor oil, glycerin fatty acid ester, sodium stearyl fumarate, sodium benzoate, Examples thereof include L-leucine and L-valine. These may be used alone or in combination of two or more. Examples of the sweetening agent include aspartame, sodium saccharin, dipotassium glycyrrhizin, stevia, thaumatin and the like. These may be used alone or in combination of two or more.

  Examples of the fragrances include mint, lemon and orange. Nonionics such as anionic surfactants such as sodium alkyl sulfate, sucrose fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters and polyoxyethylene castor oil derivatives for the purpose of improving the dispersibility of the suspension Surfactants such as system surfactants can be added. Furthermore, the drug contained in the orally disintegrating preparation of the present invention is preferably a drug that does not dissolve at the pH of saliva when disintegrated, but in some cases, glycine, sodium bicarbonate, calcium hydrogen phosphate, phosphorus It is also possible to use pH adjusting agents such as organic acids such as sodium oxyhydrogen, acetic acid, succinic acid, tartaric acid, fumaric acid, citric acid or salts thereof.

  Among these additives, when an additive insoluble in water is blended, in order to avoid discomfort such as a rough feeling in the oral cavity, the content in the preparation of the present invention is 10% or more, preferably 8% or more. More preferably, the water-insoluble additive having 6% or more preferably has an average particle size of usually 150 μm or less, substantially 105 μm or less, more preferably 100 μm or less. The particle size is more preferably 90 μm or less, particularly preferably 75 μm or less.

  The solvent used for wetting (or humidification) is not particularly limited as long as it can be easily removed and is a pharmaceutically acceptable solvent. For example, water, ethanol, acetone, isopropyl alcohol can be mentioned. More preferably, water or a mixed solution of water and ethanol is preferable, and water or ethanol is more preferable. It is also preferred that the drug is a poorly soluble or insoluble solvent. In the wetting (or humidifying) step, a positive step such as adding a solvent such as water or leaving it in a saturated atmosphere of the solvent can be performed, or in the previous step, a wet granulated product or When a mixture is obtained, the wet (or humidification) step can be omitted by performing the next step without drying and in a wet state (humidified state).

  Examples of the drying method include vacuum drying, ventilation drying, drying using a fluidized bed granulator, drying by microwave irradiation, and the like. Examples of other additives used include, but are not limited to, excipients, binders, disintegrants, solubilizers, lubricants, and other carriers.

  The lower limit of the content of the medicinal component in the preparation of the present invention is not particularly limited, but is preferably 1% by weight or more, more preferably 5% by weight or more, and the upper limit is preferably 90% or less, more preferably 80% by weight. % Or less, more preferably 60% by weight or less, and particularly preferably 40% by weight. The lower limit of the content of the excipient is preferably 5% by weight or more, more preferably 10% by weight or more, and particularly preferably 15% by weight or more. The upper limit is 99% by weight or less, preferably 90% by weight or less, and particularly preferably 85% by weight or less. The lower limit of the binder content is preferably 0.1% by weight or more, more preferably 0.5% by weight or more, particularly preferably 1% by weight or more, and the upper limit is 20% by weight or less, preferably 15% by weight. % Or less, more preferably 10% by weight or less. All of the above ratios are ratios relative to the total weight of the preparation (the same applies in the specification unless otherwise specified).

  In the case of adding a disintegrant, the content thereof may be a weight that keeps the function of the disintegrant and has no texture, and the lower limit is preferably 0.1% by weight or more, more preferably 0.5% by weight or more. The upper limit is preferably 30% by weight or less, more preferably 25% by weight or less, and particularly preferably 15% by weight or less. Even if there is no lubricant, it may not be added if tableting is possible, but when a lubricant is added, the lower limit of the content is preferably 0.01% by weight or more, more preferably 0.05% by weight. Above, particularly preferably 0.1% by weight or more is exemplified, and the upper limit is preferably 4% by weight or less, more preferably 3% by weight or less, particularly preferably 2% by weight or less. In the orally disintegrating preparation of the present invention, the water content is preferably 10% by weight or less, preferably 8% by weight or less, more preferably 7% by weight or less.

  As another production method, for example, an additive is mixed with a drug as an active ingredient, the mixture is wetted with a solvent in which the drug is not dissolved, and the mixture is put into a mold, preferably compression molding at a low pressure. There is a way to dry after. Specifically, it is a drug for the treatment of dysuria and related diseases, and an additive is mixed with a poorly water-soluble drug having a particle size of 0.4 to 105 μm, and the mixture is moistened to form a mold. An example is a method in which the material is injected, compression molded at a pressure of 0.1 to 100 MPa, and then dried.

  As a manufacturing method closely related to the above method, the above-mentioned 5. The manufacturing method according to the aspect of this is mentioned. In this production method, a combination of an excipient and a binder is usually preferably selected as an additive. The excipient is preferably a water-soluble additive sugar or sugar alcohol, specifically D-mannitol, sorbitol, xylitol, erythritol, trehalose, lactose, granulated lactose (usually by spray drying), granulated D- Mannitol (usually by spray drying) can be mentioned, among which D-mannitol, lactose, erythritol, granulated lactose, and granulated D-mannitol are preferable examples. It is preferable to use a water-soluble additive as the binder. Specifically, hydroxypropylcellulose, polyvinylpyrrolidone (povidone), hydroxypropylmethylcellulose, polyvinyl alcohol, gelatin, agar, alginic acid, sodium alginate, chitansan gum, gum arabic powder, Examples thereof include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, partially saponified polyvinyl alcohol, methylcellulose, pullulan, and partially pregelatinized starch. Among these, hydroxypropylcellulose and polyvinylpyrrolidone (povidone) are preferably used.

  The lower limit of the tableting pressure in the method of the present invention is not particularly limited, but is preferably 0.1 MPa or more, more preferably 0.2 MPa or more, and particularly preferably 0.5 MPa or more. The upper limit of the tableting pressure is not particularly limited, but is preferably 25 MPa or less, more preferably 22 MPa or less, and particularly preferably 20 MPa or less. Usually, the tableting pressure is preferably in the range of 0.1 to 20 MPa.

  That is, when the preferable production method of the present invention is described more specifically, an excipient (for example, mannitol and / or lactose etc.) and a binder (for example, mannitol and / or lactose) are added as an additive to a slightly water-insoluble drug having a small particle size. , Hydroxypropylcellulose, polyvinylpyrrolidone (Povidone), etc.) and mixing, then granulate the resulting mixture, if necessary lubricant (magnesium stearate, sodium stearyl fumarate, etc.), solubilizer Further, there is a method in which sweeteners, fragrances and the like are mixed as appropriate, and the resulting mixture is wetted and put into a mold, and then compression molded at an appropriate pressure and dried.

  10. above. The production method according to the embodiment is also a preferred example. In this production method, it is effective to add a water-insoluble disintegrant as a disintegrating agent in consideration of the disintegration of the granulated product when granulating by mixing the poorly soluble drug and the first additive. It is. As the water-insoluble disintegrant, crospovidone is preferable, and specific examples of preferable grades include polyplastidone XL, polyplastidone XL-10, and polyplastidone INF-10. It is preferable to use polyplastidone INF-10 having an average particle size of 10 to 30 μm. In the case of adding a disintegrant, it is preferable that the amount of the water-insoluble disintegrant is small because the swelling does not feel on the tongue. The amount of the disintegrant is not particularly limited, but is preferably 15% by weight or less, more preferably 12% by weight or less, still more preferably 10% by weight, based on the total weight of the granulated product of the drug and the first additive. It is as follows. It is also effective to add a disintegrant, particularly a water-insoluble disintegrant, as the second additive. As the water-insoluble disintegrant to be added, crospovidone is preferable, and the specific grade is as described above. For example, it is preferable to use polyplastidone XL having an average particle diameter of 80 to 100 μm. When the tablet contains water, the feeling of swelling is felt on the tongue, so it is preferable that the amount of the water-insoluble disintegrant added is small. That is, the amount of the disintegrant is preferably 10% by weight or less, more preferably 8% by weight or less, and particularly preferably 5% by weight or less based on the total weight of the preparation. It is effective to add a disintegrant as the second additive, and it is more effective to add a disintegrant to both the first and second additives. As described above, when these insoluble additives are present in an appropriate ratio or more, it is preferable to reduce the average particle diameter.

  Cellulose is generally understood as a substance having a cellulose skeleton on the chemical structure, but in the present invention, it is preferable to use water-insoluble cellulose. Specific examples include crystalline cellulose, low-substituted hydroxypropyl cellulose, carmellose, and croscarmellose sodium. Examples of crystalline cellulose include Avicel PH101, Avicel PH102, Avicel PH301, Avicel PH302, Theolas KG-801, Theolas KG-802, and the like. In particular, crystalline cellulose having an average particle diameter of 38 to 75 μm and an average major axis / minor axis ratio (L / D) of particles in particles passing through a sieve having an aperture of 75 μm is 2.0 to 4.5. It is preferable to use commercially available Theorus KG-802. The average particle size means a particle size of 50% cumulative sieving when an automatic sieving apparatus (SEISIN company, ROBOT SIFTER) is used and 10 g of powder is measured. Further, it is preferable to add granulated sugar or sugar alcohol as the second additive because the disintegration time can be shortened. Specifically, erythritol, D-mannitol, sorbitol, lactose, trehalose alone or granulated with a binder can be added. Commercially available granulated D-mannitol, sorbitol, and lactose can also be used (these are usually prepared by spray drying). Among them, the proportion of granulated material of 53 μm or less is 10% or less. A granulated D-mannitol having a ratio of granulated material of 500 μm or more of 15% or less and an average particle size of 180 to 240 μm is preferable, and it is preferable to use a commercially available Pertek M200. The content of granulated D-mannitol is preferably 15% or more, more preferably 17% or more, and particularly preferably 20% or more with respect to the total weight of the preparation. For example, the upper limit is preferably 90% or less, more preferably 85% or less, and particularly preferably 80% or less. Further, the mixing ratio of the granulated D-mannitol and the crystalline cellulose is that when the crystalline cellulose is 1 part by weight, the amount of the granulated D-mannitol is usually 4 parts by weight or less, and preferably 3 parts by weight or less. 2 parts by weight or less is more preferable, and 1 part by weight or less is particularly preferable.

  Regarding compression molding in the above production method, it is important to ensure the maximum gap in the tablet while it is molded as a tablet and ensuring the hardness of the tablet, so that it can be rapidly disintegrated as an orally disintegrating tablet. . For this reason, although the tableting pressure is smaller than that in the production of ordinary tablets, it may be preferable to use a medium pressure. The lower limit of the tableting pressure in the non-blow type compression molding machine (hydraulic hand press machine) is preferably 1 MPa or more, more preferably 2 MPa or more, particularly preferably 3 MPa or more, and the upper limit is preferably 20 MPa or less, more preferably. Is 16 MPa or less, and 12 MPa or less is particularly preferable. The lower limit of the tableting pressure of the blow-type compression molding machine is preferably 10 MPa or more, more preferably 15 MPa or more, particularly preferably 20 MPa or more, and the upper limit is preferably 150 MPa or less, more preferably 120 MPa or less, 100 MPa or less, In some cases, 80 MPa or less is particularly preferable.

  As a preferable embodiment of the above production method, a water-insoluble drug having a fine particle size, a water-soluble excipient (for example, mannitol, erythritol, etc.) as a first additive, a disintegrant (for example, crospovidone, etc.) If necessary, a water-soluble binder (for example, hydroxypropylcellulose, polyvinylpyrrolidone (povidone), etc.) and / or a solubilizing agent is added and mixed, and the resulting mixture is granulated and further granulated. Sugar or sugar alcohol (eg, granulated mannitol, granulated sorbitol, granulated erythritol, etc.), celluloses (eg, crystalline cellulose), and disintegrants that do not belong to celluloses (eg, crospovidone) Add to the above granulated material and mix, if necessary, further lubricant (magnesium stearate, sodium stearyl fumarate, etc.) Solubilizing agents, sweetening agents, appropriately mixed perfume and the like, and placed in a mold and the resulting mixture in the dry state, and a method of compression molding at a suitable pressure.

  As another manufacturing method, an additive is mixed with a drug as an active ingredient, and the resulting mixture is prepared as it is or as a granulated product, or mixed with an additive that has been separately granulated, and then poured into a mold. There is also a method of compression molding and drying the molded product by wetting or humidifying. When the compression molded product is wet (or humidified) and then dried, the additives in the molded product are cross-linked and the tablet hardness can be further increased.

  As a manufacturing method closely related to the above method, the above 16. The manufacturing method according to the aspect of this is mentioned. In this production method, a combination of an excipient, a binder and a lubricant is preferably selected as an additive. The excipient is preferably a sugar or sugar alcohol as a water-soluble additive, specifically D-mannitol, sorbitol, xylitol, erythritol, trehalose, lactose, and granulated lactose (usually prepared by spray drying) ) And granulated products such as granulated D-mannitol (usually prepared by spray drying). Moreover, erythritol is mentioned as a particularly preferable example. It is preferable to use a water-soluble additive as the binder. Specifically, hydroxypropylcellulose, polyvinylpyrrolidone (povidone), hydroxypropylmethylcellulose, polyvinyl alcohol, gelatin, agar, alginic acid, sodium alginate, chitansan gum, gum arabic powder, Examples thereof include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, partially saponified polyvinyl alcohol, methylcellulose, pullulan, and partially pregelatinized starch. Of these, hydroxypropylcellulose and polyvinylpyrrolidone (povidone) are particularly preferred.

  The lower limit of the tableting pressure by the above method is not particularly limited, but is preferably 0.1 MPa or more, more preferably 0.2 MPa or more, particularly preferably 0.5 MPa or more, and the upper limit is not particularly limited, but preferably 25 MPa. Hereinafter, more preferably 22 MPa or less, particularly preferably 20 MPa or less. The tableting pressure is usually in the range of 0.1 to 20 MPa.

  In the production method of the present invention, the above 18. As shown in the production method according to the embodiment, it is preferable to use a water-soluble additive as the first additive. The preferred production method of the present invention will be described in more detail. A water-soluble excipient (for example, erythritol, xylitol, mannitol, etc.) and a water-soluble binder as additives are added to a slightly water-soluble drug having a fine particle size. (For example, hydroxypropylcellulose, polyvinylpyrrolidone (povidone), etc.) are added and mixed, the mixture is granulated, and if necessary a lubricant (magnesium stearate, sodium stearyl fumarate, etc.), a solubilizing agent. Then, after appropriately mixing sweeteners, fragrances and the like into the above granulated product, the resulting mixture is put into a mold in a dry state and compression molded at an appropriate pressure, and the molded product is wetted or humidified and then dried. The method of doing is mentioned. Alternatively, a method may be employed in which an additive is mixed with a drug as an active ingredient, and the mixture is directly put into a mold as a mixed powder and compression molded at a low pressure. As a manufacturing method closely related to the above method, the above 27. The manufacturing method according to the aspect of this is mentioned.

  As a further option of the present invention, a granulated carrier such as lactose, mannitol, sorbitol, erythritol, lactose or the like granulated by a spray drying method or the like is added to the drug which is an active ingredient, and the resulting mixture is added. There is also a method in which the product is put into a mold as it is and compression-molded at a pressure usually selected, preferably at a low pressure. In addition, an additive is mixed with the active ingredient drug, the mixture is prepared as it is or as a granulated product, a granulated product consisting of additives prepared separately is added, and the obtained mixture is directly put into a mold. There is also a method of compression molding at a pressure usually selected, preferably at a low pressure, or in some cases at a medium pressure.

  As a preferable example in the above production method, a granulated product prepared by mixing a drug and an additive and a granulated product containing the additive is prepared, and the mixture is directly put into a mold as a mixture. Is a method of compression molding at a low pressure.

  As a manufacturing method closely related to the above method, the above 6. And more specifically, the production method according to the above-mentioned 7. Or 9. It is preferable that the production conditions according to the embodiment are satisfied. That is, the above 6. In the production method according to the embodiment, the mixing ratio represented by <drug-containing granulated product in the first additive / granulated product in the second additive> is preferably 3 or less, and is preferably 2 or less. Is more preferable and 1 or less is particularly preferable. Moreover, it is preferable that the average particle diameter of the granulated material in a 1st additive is smaller than the average particle diameter of the granulated material in a 2nd additive. Specifically, the average particle size of the granulated product in the first additive is preferably about 30 μm or more as a lower limit, more preferably about 60 μm or more, particularly preferably about 80 μm or more, and its upper limit is about 300 μm. Or less, more preferably about 200 μm or less, and particularly preferably about 150 μm or less. The average particle size of the granulated product in the second additive is preferably about 50 μm or more as a lower limit, more preferably about 60 μm or more, particularly preferably about 80 μm or more, and the upper limit is preferably about 500 μm or less. About 400 μm or less is more preferable, and about 300 μm or less is particularly preferable.

  Above 6. As a manufacturing method corresponding to the manufacturing method according to the above aspect, the above-mentioned 10. A preferred example is the production method according to the above-mentioned aspect or the above-mentioned 17th aspect. 10. above. In the above aspect, the granulated product containing the drug and the first additive uses the granulated sugar or sugar alcohol as the second additive. This corresponds to the granulated product found in a part of the second additive in the embodiment. In addition, the above 17. In this aspect, the granulated product containing the drug and the first additive is mixed with the granulated product separately prepared from the second additive, and if necessary, a lubricant or the like is added to produce the granulated product. Including the steps, the same as in the above 6. In the production method according to the embodiment. The above 6. In carrying out the invention according to the above aspect, the above 10. And 16. The description of the embodiment can be referred to.

  According to a preferred embodiment of the present invention, an orally disintegrating preparation containing naphthopidyl and erythritol is provided. As the oral disintegrant, as described above, a compressed oral disintegrant obtained by compression molding at an appropriate pressure is preferable. By using erythritol, naphthopidyl can be easily granulated even if water is used alone, and the resulting granulated product has moderate softness and does not feel rough in the mouth. Moreover, the granulated product does not exhibit a bitter taste, and has an unpleasant sweetness and refreshing feeling. Furthermore, the tablet does not soften even under storage conditions of 3 months at a temperature of 25 ° C./humidity of 75%. In the present invention, erythritol has an excellent effect not found in other sugars and sugar alcohols, and remarkably enhances the effect as an orally disintegrating tablet. In the present invention, the higher the content of erythritol, the easier it is to obtain the desired effect. However, considering the content of naphthopidyl in one tablet as a pharmaceutical, the weight ratio of naphthopidyl to erythritol is, for example, naphthopidyl 1 The erythritol is 0.5 parts by weight or more, preferably 0.8 parts by weight or more, particularly preferably 1 part by weight or more with respect to parts by weight. The upper limit is exemplified by 20 parts by weight or less, more preferably 15 parts by weight or less, and particularly preferably 10 parts by weight or less.

Furthermore, according to another preferred embodiment of the present invention, there is provided an orally disintegrating preparation containing any of D-mannitol, xylitol, trehalose, maltitol, lactose or sorbitol and naphthopidyl. Also in this invention, it is preferable that it is a compression orally disintegrating agent like the above. It is preferable that the weight ratio of D-mannitol, xylitol, trehalose, matitilol, lactose, or sorbitol to naphthopidyl is 1: 0.5 to 1:20, and 1: 0.8 to 1:15. It is more preferable that the ratio is 1: 1 to 1:10.
In the orally disintegrating preparation, one or more of erythritol, D-mannitol, xylitol, trehalose, maltitol, lactose, and sorbitol can be used. Moreover, in manufacture of the formulation of this invention, it can manufacture according to the above-mentioned appropriate manufacturing method.

The present invention will be described more specifically with reference to the following examples. However, the present invention is not limited to the following examples.
[Example 1]
The naphthopidyl bulk powder was sieved with a vibrating sieve separator (MS-200, ITOH) using a sieve having a mesh size of 106 μm (JIS 140 mesh) to obtain a naphthopidyl classified powder that passed through the sieve. Water was added to the end of the classification to obtain a 20% suspension, followed by filtration using a membrane filter (Isopore HT, manufactured by Millipore) having a pore size of 0.4 μm.
The residue on the membrane filter having a pore diameter of 0.4 μm was taken and dried using a vacuum dryer (VOC-400D, manufactured by EYELA) to obtain 0.4 to 105 μm naphthopidyl classified powder.

  2 g of the obtained 0.4 to 105 μm naphthopidyl classification powder, 8.7 g of D-mannitol (Merck) pulverized with a sample mill (Dalton, KIIWG-1F), and 2 g of crystalline cellulose (Asahi Kasei) for 5 minutes using a mortar. Mixed. This was dissolved in 2 g of 5% povidone aqueous solution, this solution was added to the mixed powder, kneaded for 2 minutes and granulated. The obtained wet granule is sized with a sieve having an opening of 600 μm, filled into a tableting tablet having a diameter of 10 mm, compressed at 0.2 MPa using a hydraulic hand press (Shimadzu Corporation), and passed through a draft dryer. It was dried at 50 ° C. for 30 minutes to obtain a corner flat tablet having a weight of 320 mg and a hardness of 3.2 kgf. The disintegration time obtained in the Japanese Pharmacopoeia disintegration test using water as the test solution was about 22 seconds.

[Example 2]
Naftopidil bulk powder was pulverized using a pin mill pulverizer (Alpine, 63C). This product was sieved with a vibrating sieve separator (ITOH, MS-200) using a sieve (JIS 200 mesh) having a mesh opening of 75 μm to obtain a naphthopidyl classified powder that passed through the sieve. Water was added to the end of this classification to make a 20% suspension, and the mixture was filtered using a membrane filter (Millipore, Isopore RT) having a pore size of 1.2 μm. The residue on the membrane filter having a pore diameter of 1.2 μm was taken and dried using a vacuum dryer (VOC-400D, manufactured by EYELA) to obtain 1.2-74 μm naphthopidyl classified powder. Then, a corner flat tablet having a weight of 320 mg and a hardness of 3.5 kgf was obtained by the method of Example 1. The disintegration time obtained in the Japanese Pharmacopoeia disintegration test using water as the test solution was about 26 seconds.

[Example 3]
Fluidized bed containing 50 g of 0.4 to 105 μm naphthopidyl classification powder obtained in Example 1, 223 g of D-mannitol (Merck) pulverized with a sample mill (Dalton, KIIWG-1F), and 30 g of crystalline cellulose (Asahi Kasei, Theolas KG802) It was charged in a granulator / dryer (Paurec Co., Ltd., LAB-1), sprayed with 100 g of 5% povidone aqueous solution, granulated and dried, and granulated with a sieve having an aperture of 600 μm to obtain a granulated product. Add crospovidone (ISP, polyplastidone XL) 3.0 g to 61.6 g of the granulated product, mix in a plastic bag, add 0.4 g of magnesium stearate (Taihei Chemical Industry), mix, and diameter A 10-mm tableting die was filled and compressed at 5 MPa using a hydraulic hand press (Shimadzu Corporation) to obtain a corner flat tablet having a weight of 325 mg and a hardness of 3.8 kgf. The disintegration time obtained in the Japanese Pharmacopoeia disintegration test using water as the test solution was about 25 seconds.

[Example 4]
Except changing the compression using a hydraulic hand press (Shimadzu Corporation) to 2.5 MPa or 0.50 MPa, the same procedure as in Example 3 was carried out to obtain an orally disintegrating tablet having the effects of the present invention. It was.

[Example 5]
D-mannitol used in Example 3 was replaced with trehalose (Asahi Kasei) to obtain a corner flat tablet having a weight of 325 mg and a hardness of 4.0 kgf. The disintegration time obtained in the Japanese Pharmacopoeia disintegration test using water as the test solution was about 32 seconds.

[Example 6]
D-mannitol used in Example 3 was replaced with erythritol (Nikken Chemical) to obtain a corner flat tablet having a weight of 325 mg and a hardness of 3.8 kgf. The disintegration time obtained in the Japanese Pharmacopoeia disintegration test using water as the test solution was about 30 seconds.

[Test Example 1]
0.4-105 μm naphthopidyl classification powder 50 g obtained in Example 1 and 223 g of D-mannitol (Merck) pulverized with a sample mill (Dalton, KIIWG-1F) were fluidized bed granulator / dryer (Paurec, LAB-1). ), Sprayed with 100 g of distilled water, granulated and dried, and sized with a sieve having an aperture of 600 μm to obtain a granulated product A. The granulated product had an angle of repose of 58 ° C. and an average particle size of 45 μm. The granulation was incomplete and the fluidity was insufficient, making it unsuitable as a tableting powder.

[Test Example 2]
D-mannitol used in Test Example 1 was replaced with erythritol (Nikken Chemical) pulverized with a sample mill (Dalton, KIIWG-1F) to obtain a granulated product B. The granulated product had an angle of repose of 43 ° C. and an average particle size of 150 μm, which was suitable as a tableting powder. The feeling of administration was good with no roughness and a refreshing feeling. The tableting powder was compression molded to prepare an orally disintegrating preparation. As a result, the preparation could be obtained.

[Test Example 3]
D-mannitol used in Test Example 1 was replaced with trehalose (Asahi Kasei) pulverized with a sample mill (Dalton, KIIWG-1F) to obtain a granulated product C. The granulated product had an angle of repose of 46 ° C. and an average particle size of 130 μm, which was suitable as a tableting powder. The feeling of dosing was better than granulated product B, although it was rough.

[Test Example 4]
D-mannitol used in Test Example 1 was replaced with sucrose (salt water port refined sugar) pulverized with a sample mill (Dalton, KIIWG-1F) to obtain a granulated product D. The granulated product had an angle of repose of 42 ° C. and an average particle size of 130 μm, which was suitable as a tableting powder. The feeling of taking was rough and uncomfortable. According to the above Test Examples 1 to 4, among the excipients suitable for disintegration in the oral cavity, each of erythritol and trehalose can be easily granulated when combined with naphthopidyl, and the obtained granulation The product had fluidity as a granule for tableting and could be continuously tableted, which was considered suitable for the production of orally disintegrating tablets. In addition, erythritol was particularly good, including the feeling of taking the granules after the tablets disintegrated.

[Example 7]
The tablet obtained in Example 3 was placed in a desiccator containing a saturated aqueous potassium sulfate solution (40 ° C., 96.5%) and left for 2 hours to humidify. This was dried with an air dryer at 50 ° C. for 30 minutes to obtain a corner flat tablet with a hardness of 4.0 kgf. The disintegration time obtained in the Japanese Pharmacopoeia disintegration test using water as the test solution was about 22 seconds.

[Example 8]
The tablet obtained in Example 5 was placed in a desiccator containing a saturated aqueous potassium sulfate solution (40 ° C., 96.5%) and left for 2 hours to humidify. This was dried with an air dryer at 50 ° C. for 30 minutes to obtain a corner flat tablet with a hardness of 4.8 kgf. The disintegration time obtained in the Japanese Pharmacopoeia disintegration test using water as the test solution was about 27 seconds.

[Example 9]
The tablet obtained in Example 6 was placed in a desiccator containing a saturated aqueous potassium sulfate solution (40 ° C., 96.5%) and left for 2 hours to humidify. This was dried with an air dryer at 50 ° C. for 30 minutes to obtain a corner flat tablet with a hardness of 4.5 kgf. The disintegration time obtained in the Japanese Pharmacopoeia disintegration test using water as the test solution was about 23 seconds.

[Example 10]
A fluidized bed granulator / dryer of 105.0 g of 0.4 to 105 μm naphthopidyl classification powder obtained in Example 1, 124.6 g of pulverized D-mannitol (Merck), and 34.3 g of crystalline cellulose (Asahi Kasei, Theolas KG802) ( It was charged in Paulek, LAB-1), sprayed with 280 g of 5% povidone aqueous solution, granulated and dried, and sized with a sieve having an aperture of 600 μm to obtain a granulated product. To 39.7 g of the granulated product, 3 g of crospovidone (ISP Co., polyplastidone XL) and 17 g of lactose (DMV, DCL-11) were added and mixed in a plastic bag to obtain a mixed powder. Furthermore, 0.3 g of magnesium stearate (Taihei Chemical Industry) was added and mixed, and then filled into a tableting tablet having a diameter of 10 mm, compressed at 6 MPa using a hydraulic hand press machine (Shimadzu Corporation), weight 300 mg, A corner flat tablet with a hardness of 3.8 kgf was obtained. The disintegration time obtained in the Japanese Pharmacopoeia disintegration test using water as the test solution was about 28 seconds.

[Example 11]
A small amount of magnesium stearate (Taihei Chemical Industry) previously attached to the brush was applied to the inner surface of the tableting die having a diameter of 10 mm and the contact surface of the punch, and then the mixed powder obtained in Example 10 was 298. The tablet was filled in a 5 mg diameter 10 mm tablet and compressed using a hydraulic hand press (Shimadzu Corporation) at 6 MPa to obtain a corner flat tablet with a hardness of 4.2 kgf. The disintegration time obtained in the Japanese Pharmacopoeia disintegration test using water as the test solution was about 18 seconds.

[Example 12]
Crospovidone (ISP, polyplastidone XL) 15 g and granulated lactose (DMV, DCL-11) 100 g were added to 198.5 g of the granulated product obtained in Example 10, and mixed in a plastic bag to obtain a mixed powder. Obtained. Furthermore, 1.5 g of magnesium stearate (Taihei Chemical Industry) was added and mixed to obtain a tableting powder. This was compressed with a single tableting machine (Okada Seiko Co., Ltd., N-30E) at a pressure of 60 MPa using a tableting punch having a diameter of 10 mm to obtain a corner flat tablet having a weight of 300 mg and a hardness of 4.4 kgf. The disintegration time obtained in the Japanese Pharmacopoeia disintegration test using water as the test solution was about 38 seconds.

[Example 13]
Crospovidone (ISP Co., polyplastidone XL) 15 g and granulated lactose (DMV, DCL-11) 85 g were added to 198.5 g of the granulated product obtained in Example 10, and mixed in a plastic bag to obtain a mixed powder. Obtained. Furthermore, 1.5 g of magnesium stearate (Taihei Chemical Industry) was added and mixed to obtain a tableting powder. This was compressed with a single tableting machine (Okada Seiko, N-30E) using a tableting punch having a diameter of 10 mm at 60 MPa to obtain a corner flat tablet having a weight of 300 mg and a hardness of 4.2 kgf. The disintegration time obtained in the Japanese Pharmacopoeia disintegration test using water as the test solution was about 35 seconds.

[Example 14]
The tableting powder obtained in Example 10 was compressed with a single tableting machine (Okada Seiko Co., Ltd., N-30E) using a tableting punch having a diameter of 10 mm at 100 MPa, a corner having a weight of 300 mg and a hardness of 6.3 kgf. Square flat tablets were obtained. The disintegration time obtained in the Japanese Pharmacopoeia disintegration test using water as the test solution was about 45 seconds.

[Example 15]
0.4-105 μm naphthopidyl classification powder obtained in Example 1, 60 g, D-mannitol (Merck) 15.6 g pulverized in a sample mill (Dalton, KIIWG-1F), crospovidone (ISP, polyplastidone INF- 10) 8.4 g was weighed and mixed. The mixed powder was dropped into a stirring granulator (Mechanom Mill, Okada Seiko Co., Ltd.), mixed for 5 minutes at 600 rpm, distilled water was added, and granulated for 5 minutes to obtain a granulated powder. After drying with a shelf-type dryer (50 ° C, 1 hour), the size is adjusted with a sieve having an opening of 850 µm, and dried again with a shelf-type dryer (50 ° C, 3 hours), with an opening of 600 µm. After sizing with a sieve, sieved using a sieve having an opening of 300 μm (JIS 50 mesh) and a sieve having an opening of 75 μm (JIS 200 mesh), a sized powder A having a particle size of 75-300 μm was obtained. 70 g of the obtained sized powder A, 79 g of granulated D-mannitol (Merck, Pertec M200) with an average particle size of 180-240 μm, 40 g of crystalline cellulose (Asahi Kasei, Theolas KG802), 10 g of crospovidone (ISP, Polyplastidone XL) After mixing 0.2 g of mint flavor with a V-type mixer, an amount of magnesium stearate equivalent to 0.5% (Taihei Chemical Industry) was added and mixed with a mixer to obtain a tableting powder. The obtained tableting powder was tableted with a tableting machine (Kikusui Seisakusho, CP-6 type) using a mortar with a diameter of 8.5 mm and a flat tablet punch at a pressure of 50 MPa, and the tablet weight was 200 mg. A corner flat tablet with a hardness of 5.3 kgf was obtained. The disintegration time obtained in the Japanese Pharmacopoeia disintegration test using water as the test solution was about 20 seconds.

[Example 16]
The granulated D-mannitol (Merck, Pertec M200) 59.3 g having an average particle diameter of 180 to 240 μm, crystalline cellulose (Asahi Kasei, Theolas KG802) 30 g, crospovidone (ISP, Polyplus) After mixing 7.5g of Don XL) and 0.15g of mint flavor with a V-type mixer, add an amount of magnesium stearate equivalent to 0.5% (Taihei Chemical Industry) and mix with a mixer to form a tableting powder. Obtained. The obtained tableting powder was tableted with a tableting machine (Kikusui Seisakusho, CP-6 type) using a mortar with a diameter of 8.5 mm and a flat tablet punch at a pressure of 50 MPa, and a tablet weight of 167 A 7 mm corner flat tablet with a hardness of 4.8 kgf was obtained. The disintegration time obtained in the Japanese Pharmacopoeia disintegration test using water as the test solution was about 23 seconds.

[Example 17]
An angle flat tablet with a hardness of 3.0 kgf was obtained by replacing magnesium stearate in an amount corresponding to 0.5% in Example 15 with sodium stearyl fumarate (Wako Pure Chemical Industries, Ltd.) corresponding to 1.0%. The disintegration time obtained in the Japanese Pharmacopoeia disintegration test using water as the test solution was about 23 seconds.

[Example 18]
A corner flat tablet with a hardness of 3.0 kgf was obtained by replacing the sized powder A (70 g) of Example 15 with 100 g and the granulated D-mannitol (Merck, Pertec M200) 79 g with 49 g. The disintegration time obtained in the Japanese Pharmacopoeia disintegration test using water as the test solution was about 39 seconds.

[Example 19]
An angular flat tablet with a hardness of 3.0 kgf was obtained by replacing the sized powder A (70 g) of Example 15 with 112 g and the granulated D-mannitol (Merck, Pertec M200) 79 g with 37 g. The disintegration time obtained in the Japanese Pharmacopoeia disintegration test using water as the test solution was about 48 seconds.

[Example 20]
An angular flat tablet with a hardness of 3.0 kgf was obtained by changing the sized powder A (70 g) of Example 15 to 30 g and the granulated D-mannitol (Merck, Pertec M200) 79 g to 119 g. The disintegration time obtained in the Japanese Pharmacopoeia disintegration test using water as the test solution was about 16 seconds.

[Example 21]
The sized powder A of Example 15 was sieved using a sieve having an opening of 300 μm (JIS 50 mesh) and a sieve having an opening of 180 μm (JIS 83 mesh) to obtain a sized powder having a particle size of 180 to 300 μm. Then, a corner flat tablet having a hardness of 3.0 kgf was obtained by the method of Example 15. The disintegration time obtained in the Japanese Pharmacopoeia disintegration test using water as the test solution was about 33 seconds.

[Example 22]
The sized powder A of Example 15 was sieved using a sieve having an opening of 150 μm (JIS 100 mesh) and a sieve having an opening of 75 μm (JIS 200 mesh) to obtain a sized powder having a particle size of 75-150 μm. Then, a corner flat tablet having a hardness of 3.0 kgf was obtained by the method of Example 15. The disintegration time obtained in the Japanese Pharmacopoeia disintegration test using water as the test solution was about 14 seconds.

[Example 23]
50 g of 0.4 to 105 μm naphthopidyl classification powder obtained in Example 1 and 242 g of erythritol (Nikken Chemical) pulverized with a sample mill (Dalton, KIIWG-1F) were fluidized bed granulator / dryer (Paurec, LAB-1). ) Was sprayed with 100% of 5% povidone aqueous solution, granulated and dried, and then granulated with a sieve having an aperture of 600 μm to obtain a granulated product. An amount of magnesium stearate corresponding to 0.5% was added and mixed with a mixer to obtain a tableting powder. The obtained tableting powder was tableted using a tableting machine (Kikusui Seisakusho, CP-6 type), using a 9.5 mm caliber mortar and a flat tablet punch, with a pressure of 18 MPa, and the tablet weight A 300 mg flat tablet was obtained. The obtained tablet was placed in a desiccator containing a saturated aqueous potassium sulfate solution (40 ° C., 96.5%) and left for 2 hours. This was dried with an air dryer at 50 ° C. for 30 minutes to obtain a corner flat tablet with a hardness of 4.5 kgf. The disintegration time obtained in the Japanese Pharmacopoeia disintegration test using water as the test solution was about 28 seconds. The preparation of this example was unwrapped and stored for 3 months under storage conditions of a temperature of 25 ° C./humidity of 75%, but the preparation did not soften.

[Comparative Example 1]
Japanese Pharmacopoeia Disintegration Test using a formulation containing 25 mg of naphthopidyl in 1 tablet (Asahi Kasei, Frivus Tablets 25 mg, Lot. FVA14FY, Formulation Weight 160 mg, Hardness 6.3 Kgf, Corner Plate with a diameter of 8.0 mm) using water as the test solution The disintegration time obtained was about 2 minutes 30 seconds. (The oral disintegration time was about 3 minutes.)

[Comparative Example]
[Comparative Example 1]
Naftopidil bulk powder was added with water to make a 20% suspension, and pulverized for 60 minutes using a bead mill (DYNO-MILL PILOT, manufactured by Willy A. Bachofen). This suspension was filtered using a membrane filter (Isopore HT, manufactured by Millipore) having a pore size of 0.4 μm. This filtrate was filtered using a membrane filter (Isopore VC, manufactured by Millipore) having a pore size of 0.1 μm. The residue on the membrane filter membrane filter having a pore diameter of 0.1 μm was taken and dried using a vacuum dryer (VOC-400D, manufactured by EYELA) to obtain a 0.1 to 0.3 μm naphthopidyl classified powder. A formulation was obtained by the method of Example 1 below.

[Comparative Example 2]
Naftopidyl bulk powder is sieved using a sieve with a mesh opening of 150 μm (JIS 100 mesh) and a sieve with a mesh opening of 106 μm (JIS 140 mesh) with a vibrating sieve separator (MS-200, ITOH) to obtain a 106-149 μm naphthopidyl classification powder. It was. A formulation was obtained by the method of Example 1 below.

In order to explain the effects of the present invention in more detail, the preparations obtained in Examples 1, 2, 7, 8, 9, 15, 18, 19, 20, 21, 22, 23 and Comparative Examples 1 and 2 The following tablet characteristics were measured.
Disintegration time by the Japanese Pharmacopoeia disintegration test: Measured according to the disintegration test method described in Japanese Pharmacopoeia 14th revision. Six preparations were taken, and the disintegration time of the preparation was measured using water as a test solution. (Do not use auxiliary panels)

Disintegration time in the oral cavity: 10 healthy adult males were selected as panelists, and the time (seconds) required for the preparation to disintegrate while gently touching with the tongue without being swallowed in the oral cavity. Evaluation of taste: 10 healthy adult males Was selected as a panelist, and after taking the preparation, the bitterness was evaluated in a state where it was lightly touched with the tongue without being irritated in the oral cavity.
Bitter: 2 points, slightly bitter: 1 point, no bitterness: 0 points Roughness evaluation: 10 healthy adult males were selected as panelists, and they were rough when touched lightly with the tongue, without tingling in the oral cavity The feeling was evaluated.
Roughness: 2 points, 1 rough surface, no roughness: 0 points The results obtained are averaged and shown in Table 1.

  As a result of the above, when producing an orally disintegrating tablet containing a drug according to a comparison between Examples 15 and 18 to 22, it is more divided into a tablet hardness and a drug-containing granulated product and a drug-free granulated product. It was confirmed that the balance of shortening the collapse time was excellent. That is, according to the comparison of Examples 20, 15, 18, and 19, the effect is better as the amount of the granulated product containing the drug decreases, and the ratio of the granulated product containing the drug to the non-containing granulated product is shown. It has been confirmed that it is preferable that is at least 3 or less. Further, according to the comparison between Example 22 and Example 21, it is preferable to use a sized powder having a particle size of 180 to 300 μm as a drug-containing granulated product, rather than using a sized powder having a particle size of 180 to 300 μm, It was more effective that the granule particle size of the granule containing the drug was smaller than the granule particle size of the non-containing granule. When tested with granules of various particle size distributions, it is particularly preferred that the drug-containing granulate is smaller than the non-containing granule and the drug-containing granule has an average particle size of about 50-150 μm, The average particle size of the granulated product in the second additive was preferably about 80-300 μm.

  Generally, there is a phenomenon that the tablet disintegration time is delayed as the tablet hardness increases. While it is not easy to shorten the disintegration time while maintaining the same tablet hardness as ordinary tablets as orally disintegrating tablets, especially when poorly water-soluble substances are present in the granules, While it is more difficult to shorten the disintegration time while maintaining, an orally disintegrating preparation having a preferable effect according to the present invention can be obtained as described above.

Claims (27)

Naphtopidil having a particle size of 0.4 to 105 μm is mixed with the water-soluble additive and / or water-insoluble additive as the first additive, granulated, and further the water-soluble additive as the second additive. Orally disintegrating containing naphthopidil obtained by mixing a product and / or a water-insoluble additive as necessary, putting the obtained granulated product or mixture into a mold and compression molding at a pressure of 0.1 to 100 MPa An orally disintegrating preparation, wherein the average particle size of the water-insoluble additive is 100 μm or less when the content of the water-insoluble additive in the preparation is 10% w / w or more. The orally disintegrating preparation according to claim 1, wherein the obtained mixture or granulated product is put into a mold under wet conditions, compression molded, and then dried. The oral disintegration according to claim 1 or 2, wherein a water-soluble additive and / or a water-insoluble additive (however, at least a part of the second additive is granulated) is mixed as a second additive. Formulation. The orally disintegrating preparation according to claim 3, wherein the ratio of the granulated product before mixing of the second additive to the mixture containing the second additive is 3 or less. The orally disintegrating preparation according to claim 3 or 4, wherein the average particle size of the granulated product in the first additive is smaller than the average particle size of the granulated product in the second additive. 6. The average particle size of the granulated product in the first additive is 50 to 150 [mu] m, and the average particle size of the granulated product in the second additive is 80 to 300 [mu] m. The orally disintegrating preparation according to Item. As a second additive, granulated sugar or sugar alcohol, cellulose, and a disintegrant not belonging to cellulose are mixed, and if necessary, a lubricant is further added, and the resulting mixture is molded in a dry state. The orally disintegrating preparation according to claim 1 or any one of claims 3 to 6, which is introduced into the oral cavity. (1) the first additive is a disintegrant; (2) the granulated sugar or sugar alcohol is one or more selected from erythritol, D-mannitol, sorbitol, lactose, trehalose (3) Cellulose is crystalline cellulose; and (4) A disintegrant not belonging to cellulose is crospovidone; satisfying any one or more of (1) to (4) above The orally disintegrating preparation according to claim 7. The granulated sugar or sugar alcohol is granulated D-mannitol, the proportion of the granulated product having a particle size of 53 μm or less is 10% or less, and the proportion of the granulated product having a particle size of 500 μm or more is 15% or less. The oral disintegrating preparation according to claim 8, further comprising an average particle size of 180 to 240 µm. The orally disintegrating preparation according to claim 9, wherein the content of the granulated D-mannitol is 20 to 80% of the preparation weight. 2. A crystalline cellulose having an average particle diameter of 38 to 75 μm and an average major axis / minor axis ratio (L / D) of particles in a particle passing through a sieve having an aperture of 75 μm is 2.0 to 4.5. Orally disintegrating preparation of any one of thru | or 10. The orally disintegrating preparation according to any one of claims 1 to 11, wherein a weight mixing ratio of the granulated D-mannitol and crystalline cellulose is 4: 1 to 1: 1. It is obtained by mixing a water-soluble additive and / or a water-insoluble additive as the second additive, putting the obtained mixture into a mold in a dry state, compression molding, and drying the molded product after humidification. The orally disintegrating preparation according to claim 1 or any one of claims 3 to 6. A water-soluble additive and / or a water-insoluble additive which is the second additive is mixed (however, at least a part of the second additive is granulated), and the resulting mixture is put into a mold in a dry state. The orally disintegrating preparation according to claim 13, which is obtained by adding and compressing and molding and then drying the molded product after humidification. The orally disintegrating preparation according to claim 13 or 14, wherein the content of the water-insoluble additive in the preparation is 5% w / w or less. The orally disintegrating preparation according to any one of claims 1 to 15, wherein the pressure at the time of compression molding is 0.1 to 20 MPa. The orally disintegrating preparation according to any one of claims 1 to 16, wherein roughness and / or bitterness are reduced. The orally disintegrating preparation according to any one of claims 1 to 17, wherein the content of naphthopidyl is 1 to 99% of the orally disintegrating preparation. The orally disintegrating preparation according to any one of claims 1 to 18, comprising erythritol. The orally disintegrating preparation according to claim 19, wherein the weight ratio of naphthopidyl to erythritol is 1: 0.5 to 1:20. The orally disintegrating preparation according to any one of claims 1 to 20, comprising any one of D-mannitol, xylitol, trehalose, maltitol, lactose, or sorbitol. A method for producing an orally disintegrating preparation containing naphthopidil, wherein naphthopidyl having a particle size of 0.4 to 105 μm is mixed with a water-soluble additive and / or a water-insoluble additive as a first additive, Granulated and further mixed with a water-soluble additive and / or a water-insoluble additive as the second additive as necessary (however, the content of the water-insoluble additive in the preparation is 10% w / w or more). In this case, the average particle size of the water-insoluble additive is 100 μm or less), and the obtained granulated product or mixture is put into a mold and compression molded at a pressure of 0.1 to 100 MPa. Production method. The manufacturing method according to claim 22, wherein the obtained mixture or granulated product is put into a mold under a wet condition and compression molded, and then the molded product is dried. Claims in which a water-soluble additive and / or a water-insoluble additive as a second additive are mixed (at least a part of the second additive is granulated), and the resulting mixture is put into a mold. Item 24. The method according to Item 22 or 23. As a second additive, granulated sugar or sugar alcohol, cellulose, and a disintegrant not belonging to cellulose are mixed, and if necessary, a lubricant is further added, and the resulting mixture is molded in a dry state. The manufacturing method of Claim 22 or 24 thrown into. A water-soluble additive and / or a water-insoluble additive as a second additive is mixed, the resulting mixture is put into a mold in a dry state and compression molded, and then the molded product is dried after humidification. The production method according to 22 or 24. The method for producing an orally disintegrating preparation according to claim 24, wherein the obtained mixture is put into a mold in a dry state and subjected to compression molding, and then the molded product is dried after humidification.