JP6245786B2 - Pharmaceutical binding agent and preparation using the binding agent - Google Patents

Description

  The present invention relates to a pharmaceutical binder and a preparation using the binder.

  As the final form of solid pharmaceuticals, tablets, capsules and sachets are widely used. As a typical method for producing the tablet, 1) wet granulate the drug powder, binder and excipient, dry and size the mixture, mix an appropriate amount of lubricant and use a tableting machine. Tableting method (wet granulation method), 2) Pressurized dry granulation of drug powder, binder and excipient using a roller compactor, etc., sizing and mixing with lubricant There are three methods: a method of locking (dry granulation method), and 3) a method of mixing a drug powder, a binder and an excipient, mixing a lubricant and making a tablet (direct tableting method). is there.

  In recent years, various studies have been conducted on orally disintegrating tablets (OD tablets) as dosage forms that are easy to take in consideration of convenience for elderly patients whose swallowing function has decreased with aging. For example, as a manufacturing method of OD tablets, there are reports of a method of injecting a wet powder or solution into a mold and drying to give a porous structure of the tablet, or a method of increasing hardness by drying a low-pressure compressed wet tablet. (Non-Patent Document 1). Recently, a successful example of an OD tablet not using a special manufacturing method has been reported (Non-patent Document 2). In addition, since OD tablets generally have low tablet hardness, it is a problem to handle tablets at production sites and prevent tablet breakage at medical sites afterwards. As a solution to this problem, reports on fast-dissolving film coating have been made. (Non-patent Document 3).

  As excipients used in OD tablets, sugar alcohols such as mannitol, erythritol and xylitol are frequently used from the viewpoint of oral roughness, sweetness and solubility, and binders include polyvinylpyrrolidone and hydroxypropylcellulose. (Non-Patent Documents 1 and 2). Polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer (POVACOAT®) has been used as a functional water-soluble film coating base due to its barrier properties against oxygen and odor and high moisture-proof properties as a pharmaceutical additive. (Non-Patent Document 4). On the other hand, it has been reported that by using POVACOAT® as a binder, good disintegration can be obtained with high tablet hardness (moldability) (Non-patent Documents 5 to 7).

  Patent Document 1 describes a solid dispersion base comprising a polyvinyl alcohol copolymer for the purpose of improving the solubility of a poorly soluble component such as a poorly soluble drug. However, Patent Document 1 uses a polyvinyl alcohol copolymer as a solid dispersion base, and does not consider it as a binder. In Patent Document 2, at least one selected from polyvinyl alcohol and its derivatives and polymerizable vinyl are used for the purpose of suppressing the growth of bacteria, making the preparation of the coating solution simple, and further improving the dispersion stability of the additive. An aqueous solution containing a polyvinyl alcohol copolymer obtained by polymerizing a monomer is described. However, in patent document 2, although it uses as a binder, the examination which uses a polyvinyl alcohol-type copolymer as a powder is not performed. In addition, in the solid dispersion base and the aqueous liquid preparation described in Patent Documents 1 and 2, the component comprising a polyvinyl alcohol copolymer is used as a binder used as a powder, and the direct tableting method is applied. Nothing has been studied about the application and the functions required of orally disintegrating tablets.

  Therefore, as binders used for tablets, 1) optimal binders for orally disintegrating tablets (OD tablets) (tablets showing disintegration of 30 seconds or less without water), 2) optimal binders for direct tableting It is required to become.

Yuki Tsushima, Abstracts of 5th Pharmaceutical Additives Seminar, P43-54 (2006) Hiroki Kikuoka, Pharm Tech Japan, Vol.27 No.1, P83-86 (2011) Takagi Taku et al., 131st Annual Meeting of the Japanese Pharmaceutical Society, 29P-0468 (2011) Toraharu Uramatsu, Toshinobu Uemura et al., Abstracts of 27th Symposium on Formulation and Particle Design, P108-109 (2010) Toraharu Uramatsu, Toshinobu Uemura and others, Abstracts of the 1st Standard Prescription Research Forum, P6-7 (2008) Toraharu Uramatsu, Toshinobu Uemura et al., Abstracts of the 26th Formulation and Particle Design Symposium, P140-141 (2009) Toraharu Uramatsu, Toshio Shimamoto, etc., Journal of Pharmaceutical Technology Research Group, Vol.19 No.2, P60-66 (2010)

International Publication WO2008 / 133102 Japanese Patent Publication No. 2009-269874

  The present invention relates to a binder used for a tablet, 1) an optimal binder for an orally disintegrating tablet (OD tablet) (a tablet showing disintegration of 30 seconds or less without water), and 2) an optimal tablet for direct compression. The main problem is to provide a binder.

  As a result of intensive studies in view of the above-mentioned problems of the prior art, the present inventors have found that a pharmaceutical binder comprising a polyvinyl alcohol (co) polymer is 1) an orally disintegrating tablet (OD tablet) (without water). It was found to be an optimal binder for tablets exhibiting disintegration of 30 seconds or less, and 2) an optimal binder for direct tableting.

This invention provides the pharmaceutical binder, tablet, and pharmaceutical composition which are shown to the following items 1-15.
Item 1. A pharmaceutical binder comprising a polyvinyl alcohol (co) polymer.
Item 2. Item 2. The pharmaceutical binder according to Item 1, wherein the polyvinyl alcohol (co) polymer has an average particle size of 130 µm or less.
Item 3. Item 3. The pharmaceutical binder according to Item 1 or 2, which is used for orally disintegrating tablets.
Item 4. Item 4. The pharmaceutical binder according to any one of Items 1 to 3, which is used for direct tableting.
Item 5. Any one of Items 1 to 4, wherein the polyvinyl alcohol-based (co) polymer is obtained by polymerizing at least one selected from polyvinyl alcohol and derivatives thereof and at least one polymerizable vinyl monomer. A pharmaceutical binder according to 1.
Item 6. Item 6. The pharmaceutical binder according to Item 5, wherein the polymerizable vinyl monomer contains at least one selected from the group consisting of acrylic acid and methyl methacrylate.
Item 7. Item 7. The pharmaceutical according to Item 6, wherein in the polyvinyl alcohol-based (co) polymer, the amount of acrylic acid used is 0.5 to 20% by mass, and the amount of methyl methacrylate used is 5 to 40% by mass. Binding agent.
Item 8. The above item, wherein the polyvinyl alcohol-based (co) polymer is a copolymer obtained by graft polymerization of at least one selected from the group consisting of acrylic acid and methyl methacrylate on at least one selected from polyvinyl alcohol and derivatives thereof. The pharmaceutical binder according to 7.
Item 9. Item 9. The pharmaceutical binder according to any one of Items 1 to 8, wherein the polyvinyl alcohol-based (co) polymer has a weight average molecular weight of 10,000 to 500,000.
Item 10. 10. A tablet containing a medicinal component and the pharmaceutical binder according to any one of Items 1 to 9.
Item 11. Item 11. The tablet according to Item 10, wherein the tablet is produced by wet granulation of a mixture of the medicinal ingredient and the pharmaceutical binder.
Item 12. Item 11. The tablet according to Item 10, which is produced by directly tableting the mixture of the medicinal ingredient and the pharmaceutical binder.
Item 13. Furthermore, the tablet in any one of said claim | item 10-12 containing sugar alcohol.
Item 14. Item 14. The tablet according to any one of Items 10 to 13, which is an orally disintegrating tablet.
Item 15. 10. A pharmaceutical composition comprising the pharmaceutical binder according to any one of items 1 to 9.

  The pharmaceutical binder of the present invention is optimal for 1) orally disintegrating tablets (OD tablets) (tablets showing disintegration of 30 seconds or less without water) as binders used for tablets, and 2) directly compressing tablets. It is an optimal binder for the above.

The density calculation method of a tablet is shown. The moldability of the tablets of Example 1, Reference Example 1, and Comparative Examples 1 and 2 are shown. The moldability and disintegration properties of the tablets of Examples 2 and 3 and Reference Example 2 are shown. The moldability by the direct compression method of Example 4 and Reference Example 3 is shown. The moldability by the direct tableting method of Example 5 is shown. The moldability with respect to the quantity of the lubricant of Examples 6-8 and disintegration are shown. The moldability with respect to the excipient | filler of Examples 9-11 and disintegration are shown. The state of disintegration when water is added to the tablet of Example 12 is shown. The disintegration mechanism of a tablet is shown.

  The pharmaceutical binder of the present invention comprises a polyvinyl alcohol (co) polymer (hereinafter sometimes referred to as a PVA (co) polymer).

  The pharmaceutical binder of the present invention comprises a PVA-based (co) polymer, and 1) an optimal binder for orally disintegrating tablets (OD tablets) (tablets exhibiting disintegration of 30 seconds or less without water) Become. For OD tablets, a binder that can exhibit low pressure tableting and appropriate hardness (not broken in the manufacturing process, not broken in the blister, which is the final packaging, and not broken during packaging in hospitals and pharmacies) is required. That is, a property that expresses an appropriate tablet hardness at a low pressure and rapidly disintegrates (a property that hardly disturbs disintegration) is desired. In addition, sugar alcohols, which are said to be low-molding excipients, are frequently used as excipients for OD tablets. However, conventional binders do not provide sufficient practical tablet hardness, and are not manufactured. After locking, a method of increasing the hardness of the tablet by applying heat and humidity treatment has been adopted. The pharmaceutical binder of the present invention uses a PVA-based (co) polymer (preferably fine particles), so that it has sufficient tablet hardness with normal tableting (low pressure tableting) and exhibits rapid disintegration. It becomes.

  Further, the pharmaceutical binder of the present invention comprises a PVA (co) polymer, so that 2) it is an optimal binder for direct tableting. In the case of commercially available PVA-based (co) polymers (for example, POVACOAT Type F: manufactured by Daido Kasei Kogyo Co., Ltd.), when mixed with medicinal ingredients and excipients, the particle size is large. Considering the weight variation between tablets due to segregation caused by different fluidity, there was room for improvement. By using the PVA-based (co) polymer (preferably fine particles) of the present invention, the above points are improved and a better tablet hardness is exhibited.

  In particular, the average particle diameter of the PVA (co) polymer obtained by emulsifying and polymerizing acrylic acid and a methyl methacrylate monomer in a polyvinyl alcohol aqueous solution (PVA aqueous solution) is reduced by drying or pulverizing to 130 μm or less. Even when sugar alcohol, which is a moldable excipient, is used, granules for tableting obtained by granulating these (powder addition method) can achieve both excellent moldability and rapid disintegration by tableting. it can. In order to make the average particle size of the PVA-based (co) polymer 130 μm or less, the PVA-based (co) polymer is pulverized by a method using a pulse combustion type dryer or other drying methods. It is preferable. Furthermore, a tablet having excellent moldability can be prepared by using a PVA (co) polymer having an average particle size of 130 μm or less as a dry binder.

(1) Polyvinyl alcohol (co) polymer (PVA (co) polymer)
The PVA (co) polymer is at least one PVA polymer selected from polyvinyl alcohol (hereinafter sometimes referred to as PVA) and derivatives thereof, and at least one selected from PVA and derivatives thereof. And a PVA copolymer obtained by polymerizing at least one polymerizable vinyl monomer. In the present specification, they are collectively referred to as a PVA-based (co) polymer.

(2) Polyvinyl alcohol and its derivative Polyvinyl alcohol (PVA) and its derivative should just use a well-known thing, and should just be a commercial item easily available.

  The degree of polymerization of PVA and its derivatives may be optimally selected at a concentration and viscosity according to the intended use, and is not particularly limited, but is, for example, about 200 to 2000, preferably about 300 to 1000. is there. PVA and its derivatives preferably use partially saponified PVA having a saponification degree of preferably about 60 to 100 mol%, more preferably about 78 to 96 mol%, and still more preferably about 85 to 90 mol%. Such a saponified PVA can be produced by radical polymerization of vinyl acetate and appropriately saponifying the resulting vinyl acetate. In order to produce the desired PVA, it is achieved by appropriately controlling the degree of polymerization and the degree of saponification by a method known per se.

  As derivatives of PVA, for example, various modified PVAs such as amine-modified PVA, ethylene-modified PVA, and terminal thiol-modified PVA can be used in addition to completely saponified products, intermediate saponified products, and partially saponified products of PVA. Examples of commercially available PVA derivatives include JP-05 (partially saponified PVA, degree of polymerization 500, degree of saponification 88%) manufactured by Nippon Vinegar Poval.

  In this invention, PVA and its derivative (s) may be used individually by 1 type, and 2 or more types may be mixed and used for them.

(3) Polymerizable vinyl monomer In the present invention, as the polymerizable vinyl monomer, for example,
(1) Acrylic acid, methacrylic acid, fumaric acid, maleic acid, itaconic acid and the like;
(2) sodium salt, potassium salt, ammonium salt and alkylamine salt of (1) above; and
(3) methyl methacrylate, methyl acrylate, ethyl methacrylate, ethyl acrylate, butyl methacrylate, butyl acrylate, isobutyl methacrylate, isobutyl acrylate, cyclohexyl methacrylate, cyclohexyl acrylate, 2-ethylhexyl methacrylate, 2-ethylhexyl acrylate, lauryl methacrylate, lauryl acrylate, stearyl Methacrylate, stearyl acrylate, acrylonitrile, acrylamide, dimethylacrylamide, styrene, vinyl acetate, hydroxyethyl methacrylate, hydroxyethyl acrylate, ester of polyethylene glycol and methacrylic acid, ester of polyethylene glycol and acrylic acid, polypropylene glycol Esters of methacrylic acid, esters of polypropylene glycol and acrylic acid, N- vinyl pyrrolidone, acryloyl morpholine, N, N- dimethylaminoethyl methacrylate and methacryloyloxyethyl trimethyl ammonium chloride.

Preferred polymerizable vinyl monomers include the following general formula (A)
^{_{H 2 C = C (R 1}} ) -COOR 2 (A)
[Wherein, R ¹ represents a hydrogen atom or a methyl group, and R ² represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. ]
The compound represented by these is mentioned.

A polymeric vinyl monomer may be used individually by 1 type, and 2 or more types may be mixed and used for it. When two or more kinds of polymerizable vinyl monomers are mixed and used, the polymerizable vinyl monomer is a compound represented by the general formula (A), in which R ² is a hydrogen atom and R ² has 1 to 4 carbon atoms. And a compound containing an alkyl group.

In the general formula (A), the proportion of the compound in which R ² is a hydrogen atom and the compound in which R ² is an alkyl group having 1 to 4 carbon atoms is selected from PVA (co) polymers, that is, PVA and its derivatives. The total amount of at least one kind and the polymerizable vinyl monomer is 100% by mass, preferably about 0.5 to 20% by mass of a compound in which R ² is a hydrogen atom, and R ² is an alkyl group having 1 to 4 carbon atoms. About 5 to 40% by mass of the compound, more preferably about 1.0 to 10% by mass of the compound in which R ² is a hydrogen atom, and 10 to 30% of the compound in which R ² is an alkyl group having 1 to 4 carbon atoms. %.

  Further, the polymerizable vinyl monomer preferably includes at least one selected from the group consisting of acrylic acid and methyl methacrylate, and particularly preferably uses only acrylic acid and methyl methacrylate.

  The proportion of acrylic acid and methyl methacrylate used in the PVA-based (co) polymer, that is, the total amount of at least one selected from PVA and its derivatives and the polymerizable vinyl monomer is 100% by mass, preferably acrylic. About 0.5 to 20% by mass of acid and about 5 to 40% by mass of methyl methacrylate, more preferably about 1.0 to 10% by mass of at least one selected from the group consisting of acrylic acid and methacrylic acid and methyl methacrylate 10 About 30% by mass.

(4) Production of PVA-based (co) polymer Examples of a method for producing a PVA-based (co) polymer include the method described in Patent Document 1 (International Publication 02/17848). As the method for producing the copolymer, for example, water and at least one selected from PVA and derivatives thereof are mixed, and the obtained mixed solution is heated to at least one selected from PVA and derivatives thereof. Examples include a method in which a seed is dissolved in water, and then a polymerizable vinyl monomer and a polymerization initiator are added to perform polymerization or copolymerization reaction. Moreover, a commercial item can also be obtained as a PVA-type (co) polymer.

  In the method for producing a PVA-based (co) polymer, at least one usage ratio selected from water and PVA and a derivative thereof is at least one selected from PVA and a derivative thereof per 100 parts by mass of water. Preferably it is about 5-70 mass parts, More preferably, it is about 15-40 mass parts.

  In the method for producing a PVA-based (co) polymer, the temperature at which at least one mixed solution selected from water and PVA and derivatives thereof is heated and dissolved is at least 1 selected from PVA and derivatives thereof used. What is necessary is just to set to the temperature which a seed melt | dissolves in water suitably, for example, what is necessary is just to be about 80-100 degreeC.

  In the method for producing a PVA (co) polymer, the above-described polymerizable vinyl monomer may be used. What is necessary is just to select suitably the usage-amount of a polymerizable vinyl monomer according to the composition etc. of the target PVA type | system | group (co) polymer, Preferably with respect to 100 mass parts of at least 1 sort (s) selected from PVA and its derivative (s). Is about 5 to 100 parts by mass, more preferably about 11 to 66 parts by mass.

  Further, when the polymerizable vinyl monomer contains at least one selected from the group consisting of acrylic acid and methyl methacrylate, the amount of acrylic acid and methyl methacrylate used in the PVA-based (co) polymer, that is, PVA and The total amount of at least one selected from the derivatives and the polymerizable vinyl monomer is 100% by mass, preferably about 0.5 to 20% by mass of acrylic acid, about 5 to 40% by mass of methyl methacrylate, more preferably acrylic. The acid is about 1.0 to 10% by mass and methyl methacrylate is about 10 to 30% by mass.

In the method for producing a PVA (co) polymer, known polymerization initiators can be used, for example, 2,2′-azobis (2-amidinopropane) dihydrochloride, AIBN (azoisobutyronitrile). ) And other azo compounds; potassium persulfate, sodium persulfate,
Persulfates such as ammonium persulfate; organic peroxides such as t-butyl hydroperoxide; redox initiators such as hydrogen peroxide-tartaric acid and hydrogen peroxide-sodium tartrate can be used.

  The amount of the polymerization initiator used is preferably about 0.1 to 5.0 parts by mass, more preferably about 0.5 to 3.0 parts by mass with respect to 100 parts by mass of the total amount of polymerizable vinyl monomers. .

  The reaction temperature of the PVA-based (co) polymerization reaction may be appropriately selected according to at least one molecular weight selected from PVA and its derivatives, the type of polymerizable vinyl monomer, etc., preferably about 30 to 80 ° C. More preferably, it is about 40-60 degreeC.

  Examples of the PVA (co) polymer include those obtained by graft polymerization of a polymerizable vinyl monomer to PVA (chain), and preferably at least one selected from PVA and derivatives thereof is acrylic acid and methacrylic acid. At least one selected from the group consisting of methyl is a graft-polymerized PVA (co) polymer.

  The weight average molecular weight of the PVA-based (co) polymer is preferably about 10,000 to 500,000, more preferably about 35,000 to 300,000.

  The average particle size of the PVA (co) polymer is preferably about 130 μm or less, more preferably about 125 μm or less, further preferably about 100 μm or less, particularly preferably about 100 to 1 μm, most preferably. It is about 50-1 micrometer.

  By setting the average particle diameter of the PVA-based (co) polymer within the above range, it is particularly suitable for 1) an orally disintegrating tablet (OD tablet) (a tablet showing disintegration of 30 seconds or less without water). be able to. Especially for OD tablets, it should be a binder that can exhibit proper hardness (not broken in the manufacturing process, not broken in the blister, which is the final package, and not broken during packaging in hospitals and pharmacies) with low-pressure tableting. In other words, it can have the property of expressing an appropriate tablet hardness at a low pressure and rapidly disintegrating (a property that does not easily disturb disintegration). Even when a sugar alcohol type, which is said to be a low moldability excipient, is used as an excipient for an OD tablet, a fine PVA (co) polymer can be used to produce a normal product. A tablet (low pressure tablet) can have a sufficient tablet hardness and a pharmaceutical binder exhibiting rapid disintegration. In addition, by setting the average particle diameter of the PVA-based (co) polymer within the above range, 2) an optimum binder for direct tableting can be obtained.

  In particular, when the average particle size is within the above range, when mixed with medicinal ingredients and excipients, it can be mixed more uniformly, fluidity can be matched with other ingredients, segregation is unlikely to occur, and tablet weight variation is also suppressed. It is possible. Furthermore, it shows a good tablet hardness. The average particle size of the PVA (co) polymer obtained by emulsifying and polymerizing acrylic acid and methyl methacrylate monomers in a PVA aqueous solution is adjusted to 130 μm or less, and dried or pulverized. Even when sugar alcohol, which is an excipient, is used, granules for tableting obtained by granulating these can achieve both excellent moldability and rapid disintegration by tableting. Furthermore, a tablet having excellent moldability can be prepared by using a PVA (co) polymer having an average particle size of 130 μm or less as a dry binder.

  In order to adjust the average particle size of the PVA-based (co) polymer to 130 μm or less, a method using a pulse combustion dryer, a method using a spray dryer, a method of pulverizing after freeze-drying It is preferable to pulverize a dried product obtained by a method of cooling and pulverizing a PVA-based (co) polymer using liquid nitrogen or dry ice (freeze pulverization method) or other drying methods.

  A commercial item can also be used for a PVA-type (co) polymer. When using a commercially available product, for example, POVACOAT (Povacoat: registered trademark: manufactured by Daido Kasei Kogyo Co., Ltd.) can be used. POVACOAT (polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer) is a synthetic polymer obtained by copolymerizing partially saponified polyvinyl alcohol with acrylic acid and methyl methacrylate. The general formula of the PVA (co) polymer is represented by the following structural formula.

  In the structural formula, when the sum of k, l, m, and n is 100%, k is about 60 to 85%, l is about 5 to 20%, m is about 0.5 to 15%, and n is 0.00. About 3 to 25% is preferably included. The average molecular weight (Mw) is preferably about 25,000 to 200,000. The average degree of polymerization is preferably about 300 to 1500. The indicated viscosity is preferably about 5.5 to 20 mPa · S. For example, TypeF having an average molecular weight (Mw) of about 40,000 or TypeR having an average molecular weight (Mw) of about 200,000 can be used.

  It is also possible to adjust the average particle diameter to 130 μm or less using the commercially available PVA (co) polymer.

(5) Pharmaceutical binder The pharmaceutical binder of the present invention comprises a PVA (co) polymer. The PVA (co) polymer obtained by the PVA (co) polymerization reaction may be used for the pharmaceutical binder of the present invention after drying and pulverization as necessary.

(6) Tablet / Pharmaceutical Composition The pharmaceutical binder of the present invention itself can be preferably used as a pharmaceutical composition for oral administration. Add additives as necessary, and use in dosage forms such as fine granules, fine granules, granules, tablets, capsules, suppositories, ointments, plasters, poultices and aerosols by conventional methods. You can also. Preferred dosage forms are tablets, fine granules, fine granules, granules, and capsules.

  Since the dosage form containing the pharmaceutical binder of the present invention expresses appropriate tablet hardness at low pressure and has a property of rapidly disintegrating, the tablet is a more preferable dosage form, and is an orally disintegrating tablet. preferable.

  The tablet of the present invention contains a medicinal ingredient and the pharmaceutical binder. The present invention may also be a pharmaceutical composition containing the pharmaceutical binder.

  Examples of medicinal ingredients include the following.

(1) Antipyretic, analgesic, anti-inflammatory drug salicylic acid, sulpyrine, flufenamic acid, diclofenac, indomethacin, atropine, scopolamine, morphine, pethidine, levorfinol, ketoprofen, naproxen, ibuprofen, oxymorphone, aspirin, aminopyrine, phenacetin, acetamino Phenone, phenylbutazone, ketophenylbutazone, mefenamic acid, bucolome, benzidamine, mepyrizole, thiaramide, tinolidine, xylocaine, pentazocine, dexamethasone, hydrocortisone, prednisolone, azulene, isopropylantipyrine, sazapyrine, clofesone, etdrug, ethenamide (2 -Ethoxybenzamide) or a salt thereof.

(2) Tranquilizers Diazepam, lorazepam, oxazepam, oxazolam, clothiazepam, medazepam, temazepam, fludiazepam, meprobamate, nitrazepam, chlordiazeboxide and the like.

(3) Antipsychotic drugs Chlorpromazine, prochlorperazine, trifluoroperazine, sulpiride, clocapramine hydrochloride, zotepine, haloperidol and the like.

(4) Antibacterial drugs Griseofulvin, Lancacidins [J. Antibiotics, 38, 877-885 (1985)], azole compounds [2-[(1R, 2R) -2- (2,4-difluorophenyl) -2- Hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl-3- (2H , 4H) -1,2,4-triazolone, fluconazole, itraconazole, etc.], nalidixic acid, pyromido acid, pipemidic acid trihydrate, enoxacin, sinoxacin, ofloxacin, norfloxacin, cyproxacin hydrochloride, sulfamethoxazole, trimethoprim, etc. .

(5) Antibiotics Gentamicin, Dipecacin, Canendomycin, Ribidomycin, Topramycin, Amikacin, Dibekacin, Fradiomycin, Sisomycin, Tetracycline, Oxytetracycline, Loritetracycline, Doxycycline, Ampicillin, Piperacillin, Ticarcillin, Cephaloridine, Cephaloridine , Cefotiam hexetyl, cefsulosin, cefmenoxime, cefmethazole, cefazoline, cefotaxime, cefoperazone, ceftizoxime, moxalactam, thienamycin, sulfazecin, azthreonam, amoxiline, cephalexin, erythromycin, bacampicin, ramocyclin, ramucine,

(6) Antitumor drug 6-O- (N-chloroacetylcarbamoyl) fumagillol, bleomycin, methotrexate, actinomycin D, mitomycin C, daunorubicin, adriamycin, neocartinostatin, cytosine arazinoside, fluorouracil, tetrahydrofuryl-5 -Fluorouracil, picibanil, lentinan, levamisole, bestatin, azimexone, glycyrrhizin, HER2 inhibitor (heterocyclic compounds described in WO01 / 77107, etc.), taxol, doxorubicin hydrochloride, etoposide, mitoxantrone, mesna, dimesna, aminoglutethimi Tamoxifen, acroline, cisplatin, carboplatin, cyclophosphamide, lomustine (CCNU), carmustine (BCNU) and the like.

(7) Antihyperlipidemic drug clofibrate, ethyl 2-chloro-3- [4- (2-methyl-2-phenylpropoxy) phenyl] propionate [Chem. Pharm. Bull., 38, 2792-2796 ( 1990)], clinofibrate, cholestyramine, soysterol, tocopherol nicotinate, nicomol, niceritrol, probucol, elastase and the like.

(8) Antitussive and expectorant ephedrine, methylephedrine, noscapine, codeine, dihydrocodeine, aloclamide, chlorfedianol, picoperidamine, cloperastine, protochelol, isoproterenol, saltamol, tereptaline, bromhexine, carbocystine, ethylcystine, methylcystine Or its salt.

(9) Muscle relaxants Pridinol, tubocurarine, pancuronium, chlorphenesine carbamate, tolperisone hydrochloride, eperisone hydrochloride, tizanidine hydrochloride, mefenesin, chlorzoxazone, fenprobamate, metcarbamol, chlormezanone, pridinol mesylate, afloqualone, baclofen, dantrolene Sodium etc.

(10) Antiepileptic drugs Phenytoin, ethosuximide, acetazolamide, chlordiazepoxide, phenobarbital, carbamazepine, primidone and the like.

(11) Anti-ulcer drugs Lansoprazole, metoclopramide, famotidine, omeprazole, sulpiride, trepibutone, cetraxate hydrochloride, gefernate, irsogladine maleate, cimetidine, ranitidine hydrochloride, nizatidine, roxatidine acetate hydrochloride and the like.

(12) antidepressants imipramine, clomipramine, noxiptylline, phenelzine and the like.

(13) Antiallergic drugs Diphenhydramine, chlorpheniramine, tripelenamine, methodiramine, clemizole, diphenylpyralin, methoxyphenamine, clemastine fumarate, cyproheptadine hydrochloride, mequitazine, alimemazine tartrate, and the like.

(14) Cardiotonic drugs Transbioxocamphor, telephilol, aminophylline, ethylephrine and the like.

(15) Arrhythmia drug Propranolol, alprenolol, pfetolol, oxprenolol, procainamide hydrochloride, disopyramide, adimarin, quinidine sulfate, aprindine hydrochloride, propafenone hydrochloride, mexiletine hydrochloride and the like.

(16) Vasodilators Oxyfedrine, diltiazem, trazoline, hexobenzine, bamethane, nifedipine, nilvadipine, isosorbite dinitrate, diltiazem hydrochloride, trapidyl, dipyridamole, dilazep hydrochloride, verapamil, nicardipine hydrochloride, ifenprodil tartrate, cinepaside maleate, cyclamate Randelate, cinnarizine, pentoxifylline, etc.

(17) Antihypertensive diuretics Hexamethonium bromide, pentolinium, mecamylamine, ecarazine, clonidine, diltiazem, nifedipine, furosemide, trichlormethiazide, metichlothiazide, hydrochlorothiazide, hydroflumethiazide, ethiazide, cyclopenthiazide, fluorothiazide, ethacrynic acid, etc. .

(18) Antidiabetic drugs Grimidine, glipzide, phenformin, pformin, metformin, glibenclamide, tolbutamide and the like.

(19) Antituberculosis drugs isoniazid, ethambutol, paraaminosalicylic acid and the like.

(20) narcotic antagonists levalorphan, nalolphine, naloxone or a salt thereof.

(21) Hormone drugs Steroid hormones such as dexamethasone, hexestrol, methimazole, petamethasone, triamcinolone, triamcinolone acetonide, fluocinolone acetonide, prednisolone, hydrocortisone, estriol and the like.

(22) bone and cartilage disease preventive and therapeutic agent prostaglandin A1 derivative, vitamin D derivative, vitamin K ₂ derivative, eicosapentaenoic acid derivative, benzylphosphonic acid, bisphosphonic acid derivative, sex hormone derivative, phenol sulfonium phthalein derivative, Non-peptide osteogenesis promoting substances such as benzothiopyran or benzothiepine derivatives, thienoindazole derivatives, menatetrenone derivatives, helioxanthin derivatives, and peptide osteogenesis promoting substances.

(23) Joint disease therapeutic agents p38 MAP kinase inhibitors (thiazole compounds described in WO00 / 64894 etc.), matrix metalloproteinase inhibitors (MMPI), prednisolone, hydrocortisone, methylprednisolone, dexamethamethasone, betamethasone, and other anti-inflammatory steroids Agents, non-steroidal anti-inflammatory analgesics such as indomethacin, diclofenac, loxoprofen, ibuprofen, piroxicam, sulindac.

(24) Frequent urine treatment agent: Flavoxate hydrochloride, oxybutynin hydrochloride, terridine hydrochloride, etc.

  (25) Antiandrogens such as oxendron, allylestrenol, chlormadinone acetate, guestnolone caproate, osapron acetate, flutamide, bicalutamide and the like.

(26) Fat-soluble vitamin drugs Vitamin K: Vitamin K ₁ , K ₂ , K ₃ and K ₄ , folic acid (vitamin M) and the like.

(27) Vitamin derivatives Various vitamin derivatives, for example, vitamin D ₃ derivatives such as 5,6-trans-cholecalciferol, 2,5-hydroxycholecalciferol, 1-α-hydroxycholecalciferol, 5,6- trans - vitamin D ₂ derivatives such as ergocalciferol and the like.

(28) Others such as hydroxycam, diacerine, megestrolacetic acid, falselogolin, prostaglandins, ischemic diseases, immune diseases, Alzheimer's disease, osteoporosis, angiogenesis, retinopathy Therapeutic agent, Retinal vein obstruction treatment agent, Senile discoid macular degeneration treatment, Cerebral vasospasm treatment agent, Cerebral thrombosis treatment agent, Cerebral infarction treatment agent, Cerebral obstruction treatment agent, Intracerebral hemorrhage treatment agent, Subarachnoid Hemorrhagic treatment, hypertensive encephalopathy treatment, transient cerebral ischemic attack treatment, multiple infarct dementia treatment, arteriosclerosis treatment, Huntington's disease treatment, brain tissue disorder treatment, optic neuropathy treatment, Glaucoma drug, ocular hypertension drug, retinal detachment drug arthritis drug, antirheumatic drug, antiseptic drug, antiseptic shock drug, antiasthma drug, atopic dermatitis drug, allergic nose Flame remedies.

  The tablet and pharmaceutical composition of the present invention include various pharmaceutically acceptable carriers and excipients commonly used as pharmaceutical materials within the scope of the effects of the present invention, in addition to the pharmaceutical binder and the medicinal component. Additives such as agents, lubricants, binders, disintegrants, surfactants, preservatives, antioxidants, colorants and sweeteners can be added singly or in combination of two or more. Tablets and pharmaceutical compositions can be produced by appropriately applying known formulation methods. An additive may be added to the pharmaceutical binder to prepare a tablet and a pharmaceutical composition.

  The following can be illustrated as an additive.

  Sugar alcohols (such as maltitol, xylitol, sorbitol and erythritol), lactose, sucrose, sucrose, sodium chloride, glucose, starch, sucrose, mannitol, reduced paratinome, carbonates (calcium carbonate, etc.), kaolin, crystalline cellulose, Silicic acid, methylcellulose, sodium alginate, gum arabic, talc, phosphates (potassium hydrogen phosphate, calcium hydrogen phosphate, sodium hydrogen phosphate, dipotassium phosphate, disodium phosphate, potassium dihydrogen phosphate, phosphoric acid Excipients such as calcium dihydrogen and sodium dihydrogen phosphate), calcium sulfate, calcium lactate and oligosaccharides (such as lactulose, raffinose, lactosucrose).

  Polyhydric alcohols such as glycerin, ethylene glycol, and propylene glycol; various waxes such as monostearin, PEG4000, PEG6000, and PEG20000; plasticizers such as organic fatty acids such as stearic acid and magnesium stearate.

  Surfactants such as triethyl citrate, Tween 80, HCO 60 and triacetin.

  Viscosity modifiers such as simple syrup, glucose solution, starch solution and gelatin solution.

  Hydroxypropylcellulose, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxyvinyl polymer, crystalline cellulose, powdered cellulose, crystalline cellulose / carmellose sodium, shellac, methylcellulose, ethylcellulose, potassium phosphate, gum arabic powder , Pullulan, pectin, dextrin, corn starch, pregelatinized starch, hydroxypropyl starch, gelatin, xanthan gum, carrageenan, tragacanth, tragacanth powder and polyethylene glycol.

  Starch, dried starch, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethyl starch, methylcellulose, carmellose calcium, low-substituted hydroxypropylcellulose, sodium starch glycolate, partially pregelatinized starch, sodium alginate, agar Disintegrants such as powder, sodium bicarbonate and calcium carbonate.

  Absorption promoters such as quaternary ammonium salts and sodium lauryl sulfate.

  Adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid.

  Lubricants such as magnesium stearate, calcium stearate, talc, magnesium oxide, colloidal silica, boric acid powder and polyethylene glycol.

  Dispersants such as sucrose fatty acid ester, sorbitan fatty acid ester and saponin.

  Antioxidants such as ascorbic acid and tocopherol.

  Acidulants such as lactic acid, citric acid, gluconic acid and glutamic acid.

  Fluidizing agent such as silicon dioxide.

  Sweeteners such as sucralose, acesulfame potassium, aspartame, glycyrrhizin. Perfumes such as peppermint oil, eucalyptus oil, cinnamon oil, fennel oil, clove oil, orange oil, lemon oil, rose oil, fruit flavor, mint flavor, peppermint powder, dl-menthol and l-menthol.

  The content of the pharmaceutical binder is preferably 0.1 to 20% by mass, more preferably 0.2 to 10% by mass in the tablet (and pharmaceutical composition) from the viewpoint of the disintegration time of the tablet. More preferably, it is 0.5-5 mass%.

  The content of the lubricant (for example, magnesium stearate) is preferably 0.01 to 2% by mass in the tablet (and pharmaceutical composition) from the viewpoint of sticking and tablet disintegration, and more preferably It is 0.05-1 mass%, More preferably, it is 0.1-0.5 mass%.

  The content of the medicinal component in the tablet (and the pharmaceutical composition) can be appropriately selected according to bioavailability.

  The dosage of the tablet (and pharmaceutical composition) containing the pharmaceutical binder of the present invention can be appropriately selected according to the content of the medicinal ingredients and bioavailability.

(7) Production of tablet / pharmaceutical composition The tablet (and pharmaceutical composition) of the present invention can be produced , for example, by wet granulating the mixture of the medicinal ingredients and the pharmaceutical binder (wet granulation). Law). Wet granulation is a method in which medicinal ingredients, binders and excipients are wet granulated, dried and sized, and then mixed with an appropriate amount of lubricant and tableted by a tableting machine. . Specifically, the medicinal components, excipients and binder are granulated in a conventional manner using purified water using a high-speed agitation granulator or fluidized bed granulator. The wet granulation method is preferable when a medicinal component having poor content uniformity and compression moldability is used.

  The tablet (and pharmaceutical composition) of the present invention can also be produced, for example, by directly tableting the mixture of the medicinal ingredients and the pharmaceutical binder (direct tableting method). The direct tableting method is a method in which a medicinal ingredient, a binder and an excipient are mixed, and a lubricant is mixed to produce a tablet. The direct tableting method is preferable when a medicinal component having good or improved fluidity is used or when a medicinal component unstable to water is used.

  The tablet (and pharmaceutical composition) of the present invention is prepared by, for example, subjecting a medicinal ingredient, a binder and an excipient to pressure dry granulation using a roller compactor, etc., sizing and mixing a lubricant. Then, it may be granulated by a dry granulation method for tableting.

  Hereinafter, although an example is given and the present invention is explained still in detail, the present invention is not limited to these.

  In the following examples and comparative examples, the following materials and test methods were used.

(1) Material Polyvinyl alcohol-based (co) polymer is referred to as PVA-based (co) polymer.
POVACOAT Type SFP (SFP): PVA-based (co) polymer of Daido Kasei Kogyo Co., Ltd., average particle size 20 μm
POVACOAT Type 55 (55): PVA-based (co) polymer of Daido Kasei Kogyo Co., Ltd., average particle size 55 μm
POVACOAT Type MP (MP): Daido Kasei Kogyo PVA-based (co) polymer, average particle size 125 μm
・ Hydroxypropylcellulose (HPC); manufactured by Nippon Soda (grade; HPC-L)
-Polyvinylpyrrolidone (PVP): reagent grade (grade; K-30)
Etenzamid (ETZ): model drug, average particle size 192 μm
Acetaminophen (APAP): model drug, particle size 75-106 μm
Erythritol: excipient, average particle size 61 μm
Crospopidone (C-PVP): disintegrant, average particle size 96 μm
Magnesium stearate (St-Mg): Lubricant

(2) Evaluation of moldability The thickness and weight of the tablet obtained by changing the tableting pressure are measured, the density of the tablet is calculated according to FIG. 1 (tablet density calculation method), and the hardness of the tablet is made by Schleuniger It was measured with a tablet hardness meter.

(3) Evaluation of disintegration Tablet density was calculated by the same operation as evaluation of moldability, and the disintegration time of the tablet was tested according to the Japanese Pharmacopoeia disintegration test method. (Test conditions: purified water, 900 mL, no disk)

(4) Example 1, Reference Example 1, Comparative Examples 1 and 2: Evaluation of moldability 38 g of erythritol charged in a stirring granulator (Mixer Torque Rheometer, Caleva biaxial rotary granulator), as a binder To a mixed powder of POVACOAT Type SFP (Example 1), POVACOAT Type MP (Reference Example 1), HPC (Comparative Example 1) or PVP (Comparative Example 2) 2 g, a predetermined purified water was added, and the stirring speed was 50 rpm. Agitation granulation was performed with a granulation time of 5 minutes (wet granulation method, powder-added granulation method). The obtained granulated product was dried at 60 ° C. and then sieved with a 1 mm sieve to prepare tableting granules. The optimal amount of purified water was determined according to the method reported previously (Toshinobu Uemura, Toshiharu Uramatsu et al., Abstracts of the 26th Formulation and Particle Design Symposium, pp.100-101 (2009)). The amount of liquid (PL value) was measured and taken as the amount corresponding to the 0.6 × PL value.

  The obtained granules for tableting were tableted with a rotary tableting machine (manufactured by Kikusui Seisakusho), and 8 mmφ, 12R, 200 mg tablets were tableted. The hardness of the obtained tablets was measured with a Schleuniger hardness tester.

  The evaluation results of formability are shown in FIG.

  When HPC or PVP was used, a hardness of 5 kp or more, which is said to be the target hardness of the orally disintegrating tablet (OD tablet), was not obtained (Comparative Examples 1 and 2).

  On the other hand, when MP and SFP were used, sufficient tablet hardness was obtained, and in particular, SFP showed good moldability (Example 1 and Reference Example 1).

(5) Examples 2 and 3 and Reference Example 2: Preparation of orally disintegrating tablets ETZ12g, crospopidone 2g, erythritol 24.8g, POVACOAT Type as binder, charged in a stirring granulator (Mixer Torque Rheometer, manufactured by Caleva) Predetermined purified water is added to 1.2 g of mixed powder of SFP (Example 2), Type 55 (Example 3) or Type MP (Reference Example 2), and stirred at a stirring speed of 50 rpm and a granulation time of 5 minutes. Granulation was performed (wet granulation method). The obtained granulated product was dried at 60 ° C. and then sieved with a 1 mm sieve to prepare tableting granules.

  The obtained granules for tableting were tableted with a rotary tableting machine (manufactured by Kikusui Seisakusho), and 8 mmφ, 12R, 200 mg tablets were tableted (orally disintegrating tablets). The hardness of the obtained tablets was measured with a Schleuniger hardness tester, and the disintegration time (DT) was measured using purified water according to the JP disintegration test method.

  The evaluation results of moldability and disintegration are shown in FIG.

  Three types of SFP (20 μm), 55 (55 μm) and MP (125 μm) have a density region (namely, tableting pressure) showing a target hardness of 5 kp or more, and even when erythritol is used as an excipient, disintegrating tablets The hardness of 5 kp or more, which is said to be the target tablet hardness, was obtained. Moreover, as the particle diameter of the PVA-based (co) polymer (POVACOAT), which is a powder additive binder, becomes smaller, the moldability improved. In all cases, the friability was about 0.3% in the tablet hardness 5 kp region. On the other hand, the disintegration property is very characteristic, and in either case, the disintegration property shows a two-phase property of a region where the disintegration time is fast and a region where the disintegration time is delayed. From the two-phase results of moldability and disintegration, the smaller the particle diameter of the PVA-based (co) polymer (POVACOAT), the wider the density region that has a hardness of 5 kp or more and exhibits rapid disintegration. Recognize. In particular, when using SFP (20 μm) and 55 (55 μm), since there are more density regions showing a hardness of 5 kp or more and a disintegration time of 30 seconds or less, it is possible to prepare a tablet preferable for the design of OD tablets. (Examples 2 and 3). In particular, SFP (20 μm) was good. As a result, it was found that by using a PVA-based (co) polymer (POVACOAT) as a powder-added binder, it can be used as an erythritol OD tablet by an ordinary production method.

(6) Example 4 and Reference Example 3: Formability 1 by direct compression method
ETZ85g, crospovidone 5g, St-Mg 0.1g, and POVACOAT Type SFP (Example 4) or Type MP (Reference Example 3) 10g as a binder were mixed and punched with a rotary tableting machine (manufactured by Kikusui Seisakusho). Tableting was performed to produce 8 mmφ, 12R, 200 mg tablets (direct compression method).

  The evaluation results of formability are shown in FIG.

  When MP (125 μm) was used, sufficient tablet hardness was obtained by increasing the density (Reference Example 3). When SFP (20 μm) was used, good tablet hardness was obtained even in the case of low-pressure tableting (low density) (Example 4).

(7) Example 5: Formability 2 by direct compression method
85 g of acetaminophen (APAP), 5 g of crospovidone, 0.1 g of St-Mg, and 10 g of POVACOAT Type SFP (Example 5) as a binder were mixed, and tableting was performed with a rotary tableting machine (manufactured by Kikusui Seisakusho). 8mmφ, 12R, 200mg tablets were made (direct tableting method).

  The evaluation results of formability are shown in FIG.

  Even in the case of a high content containing 85% of APAP, which is said to be a low formability model drug, good moldability is exhibited when using SFP (20 μm). Further, even when tableting was continued for 1 hour, no tableting troubles such as sticking (powder adhesion to the punch) and capping were observed.

(8) Examples 6 to 8: Tablet hardness and disintegration with respect to the amount of lubricant (St-Mg) Generally, lubricants are commonly used for tableting to avoid tableting troubles. There have been many reports that the mixing time and the amount of addition cause a decrease in tablet hardness and an increase in disintegration time (Abstracts of the 2nd Standard Formulation Research Forum Lecture, Standard Formulation Study Group Report P18-47 (2009)) . For this reason, the addition amount of St-Mg (lubricant, magnesium stearate), which is thought to affect tablet hardness and disintegration time, was examined.

  FIG. 6 shows the result.

  In the granule for tableting obtained by ETZ / erythritol / crospopidone / POVACOAT Type SFP = 30/62/5/3, 0% (Example 6) and 0.1% by mass (Example 7) of St-Mg. Then, 0.5% by mass (Example 8) was added to examine moldability and disintegration. The tablet density obtained by changing the tableting pressure on the horizontal axis (obtained from the tablet volume calculated from the weight of each individual tablet and the tablet thickness) is plotted, and the tablet hardness and disintegration time are plotted on the vertical axis. doing. This has linearity between the tablet density and the tablet hardness arranged by this method, and is very effective for quantitative grasping of moldability. The tableting pressure is about 10 kN in the highest tablet density region.

  From FIG. 6, when St-Mg is 0.1% by mass, the moldability and disintegration showed the same moldability and disintegration pattern as those without St-Mg, whereas St-Mg was 0.5. In the case of mass%, a decrease in hardness and a delay in the disintegration rate were observed. On the other hand, the tabletability was greatly different when St-Mg was not present and 0.1% by mass. When St-Mg was 0.1% by mass, adhesion of the tablet granules to the turntable and variation in tablet weight did not occur, tableting could be performed without problems, and sticking was not observed. For this reason, 0.1 mass% of St-Mg is preferable.

(9) Examples 9 to 11: Moldability to various excipients and disintegration For the purpose of obtaining basic knowledge on the moldability and disintegration of OD tablets using POVACOAT, three types each (a: lactose (Examples) 9), b: Mannitol (average particle size: 68 μm, Example 10), c: Erythritol (average particle size: 61 μm, Example 11)) excipient (1% formulation): Type Using SFP (20 μm), disintegrant: C-PVP (crospopidone) (5%), the influence of the disintegrant on moldability and disintegration was examined.

  The results are shown in FIG.

  By mix | blending a disintegrating agent (C-PVP), the moldability at the time of using a mannitol and an erythritol as an excipient | filler improved. This tendency is particularly remarkable in mannitol. Regarding the disintegration property, the disintegration agent (C-PVP) was blended to show very fast disintegration. Moreover, it turns out that the decay | disintegration pattern has shown biphasic like the previous result. From this result, it was found that the disintegration biphasic obtained in FIG. 3 is not specific to the drug formulation or the specific excipient (erythritol).

(10) Example 12: Disintegration characteristics FIG. 8 shows the state of disintegration when a 12Mesh sieve is placed on a plastic tray, and the tablet is allowed to stand on the sieve, and purified water is poured in such an amount that about half of the tablet is immersed. It is the result image | photographed every 3 seconds with the microscope (x25). As the tablet used in the test, a tablet having a tablet hardness of 5 kp obtained with a formulation of ETZ / erythritol / crospopidone / POVACOAT SFP = 30/64/5/1 was used (Example 12).

As a result, it was observed that the tablets rapidly disintegrated from the surface layer, and the disintegrated particles quickly disappeared from the mesh, and a state in which the tablet central portion remained (after 6 seconds) was observed. From these results and various past examination results, tablets obtained using POVACOAT as a binder often show the characteristics of disintegration shown schematically in FIG. The disintegration behavior when a general-purpose binder has been used so far shows a disintegration pattern known as so-called dissolution disintegration.

  This is considered to be due to the property of swelling and dissolving in water at room temperature without forming “mako” despite the fact that POVACOAT is a water-soluble polymer. That is, it is considered that a region in which the tablet density does not greatly affect the disintegration time is generated as a result of the expansion of the disintegrant preferentially while the local viscosity inside the tablet immediately after water penetration is low. On the other hand, in the region where the tablet hardness is high, the tablet surface hardness is high, so that the disintegration time is delayed because the penetration of water into the disintegrant is hindered. As a result, it is thought that the two-phase disintegration appears. Such a biphasic disintegration is also obtained when mannitol is used as an excipient. In designing OD tablets, it is considered useful that sufficient tablet hardness is obtained at low pressure and that the disintegration is biphasic.

  The two-phase disintegration obtained from the above results is considered as follows.

  While the local viscosity inside the tablet immediately after water permeation is low (it does not form a residue), swelling and expansion of the disintegrant preferentially acts, resulting in a region where the tablet density does not significantly affect the disintegration time. It is considered a thing. On the other hand, in the region where the tablet hardness is high, the disintegration time is delayed due to the fact that the tablet density is high and the penetration of water into the disintegrant is hindered. As a result, it is thought that the two-phase disintegration appears.

Claims (9)

A method for producing a tablet by a direct compression method , wherein a pharmaceutical binder comprising a polyvinyl alcohol copolymer is used ,
The polyvinyl alcohol copolymer is obtained by polymerizing at least one selected from polyvinyl alcohol and derivatives thereof and at least one polymerizable vinyl monomer, and the polymerizable vinyl monomer is acrylic acid or methacrylic acid. Including at least one selected from the group consisting of methyl acid,
The average particle size of the polyvinyl alcohol copolymer is 55 μm or less,
The manufacturing method whose said tablet is an orally disintegrating tablet . The production method according to claim 1, wherein the polyvinyl alcohol copolymer has an average particle size of 55 to 1 μm. 3. The production according to claim 1, wherein in the polyvinyl alcohol copolymer, the amount of the acrylic acid used is 0.5 to 20% by mass, and the amount of the methyl methacrylate used is 5 to 40% by mass. Way . The polyvinyl alcohol copolymer is a copolymer obtained by graft polymerization of at least one selected from the group consisting of acrylic acid and methyl methacrylate on at least one selected from polyvinyl alcohol and derivatives thereof. The manufacturing method in any one of -3 . The polymerizable vinyl monomer, The process according to any one of claims 1-4 is made of only acrylic acid and methyl methacrylate. The weight average molecular weight of the polyvinyl alcohol-based copolymer, the production method according to any one of claims 1 to 5, which is from 10,000 to 500,000. The process according to any one of claims 1 to 6 for mixing the drug active ingredient and the pharmaceutical binders. Furthermore, sugar alcohol is added , The manufacturing method in any one of Claims 1-7 . The process according to any one of claims 1 to 8 wherein the pharmaceutical binder Ru pharmaceutical powder addition binder der.

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