JP2011079814A - Solid preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a solid preparation having suppressed expansion or swelling under high humidity or high wetting, and having a high disintegration property. <P>SOLUTION: The solid preparation is composed as an active ingredient inferior in moldability (e.g. L-carbocysteine), and a pregelatinized starch (e.g. pregelatinized potato starch). The average degree of pregelatinization of the pregelatinized starch may be about 55-95%. The pregelatinized starch may have at least one characteristic of (a) a swelling volume of about 8-20 mL/g and (b) a water-soluble component content of about 2-10%. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a solid preparation (for example, oral solid preparation) containing an active ingredient having poor moldability (for example, L-carbocysteine) and pregelatinized starch.

  There are various drugs with poor moldability among the main ingredients of cold medicines. For example, L-carbocysteine etc. are mentioned as a drug with inferior moldability. As a preparation containing L-carbocysteine, JP-A-2004-300150 (Patent Document 1) discloses an intraoral rapid disintegrating property comprising a physiologically active substance existing in a free form and a medically acceptable salt thereof. Tablets are disclosed. In this document, a mixture of a physiologically active substance (such as L-carbocysteine) existing in a free form and a pharmaceutically acceptable salt thereof (such as sodium L-carbocysteine) is compressed into tablets at the lowest possible pressure. Further, it is described that the surface layer part or the whole inside of the obtained tablet is wetted and humidified at a temperature at which sufficient tablet hardness is obtained after drying.

  However, since this tablet is compressed with the lowest pressure, it is highly disintegratable, but the tablet is likely to be cracked or cracked. Moreover, since a tablet is formed with an active ingredient having inferior moldability, formulation design is greatly restricted.

JP 2002-348251 (Patent Document 2) discloses a pharmaceutical composition containing an airway mucolytic agent (acetylcysteine, carbocysteine) and a bronchodilator (trimethquinol, methylephedrine, etc.), and ibuprofen. Contains carbocysteine, dihydrocodeine phosphate, emedastine fumarate, phenylpropanolamine hydrochloride, anhydrous caffeine, vitamin B ₁ nitrate, vitamin B ₂ , lactose, microcrystalline cellulose, magnesium stearate, hydrogenated castor oil An example tablet with an amount of 33.3% by weight is described. However, the tablet of this formulation is less disintegrating.

  JP-A-2002-363072 (Patent Document 3) discloses an antitussive composition comprising a component such as potassium guaiacol sulfonate, acetylcysteine, carbocysteine, and pseudoephedrine. Chlorpheniramine maleate, bromide Examples of tablets containing dextromethorphan hydrogenate, pseudoephedrine hydrochloride, acetylcysteine hydrochloride, lactose, lactose, low-substituted hydroxypropylcellulose, magnesium stearate, hydrogenated castor oil and containing 46.5% by weight of acetylcysteine hydrochloride are also described. ing. However, since this formulation contains a low-substituted hydroxypropylcellulose, when the tablet is stored under high humidity, it absorbs moisture and expands, causing cracks and cracks in the tablet, thereby reducing storage stability and quality.

  In JP 2007-1999 (Patent Document 4), functional starch particles having predetermined characteristics (characteristics such as a water retention amount of 400% or more) are used as a binder, and a granular material containing an active ingredient is prepared by a wet process. A method for producing a granulated granulation composition is disclosed, and it is described that the functional starch particles have both moderate binding properties and good disintegration properties. In addition, in Examples of this document, a granulated composition obtained by granulating functional starch particles, lactose and corn starch, and a tablet obtained by tableting this granulated composition are described, and the content of functional starch particles However, it is also described that the granulated composition of 15% by weight has a large particle size and a narrow particle size distribution, and the disintegration property of the tablet is lowered. JP 2007-153886 (Patent Document 5) discloses an elution control containing an active ingredient and a processed starch having a predetermined characteristic (characteristic such as a water retention amount of 400% or more) at a ratio of 5 to 99.9% by weight. A sustained-release solid preparation obtained by compression molding is disclosed, including the base, and it is described that the solid preparation can control the elution of the active ingredient to the zero-order elution and the like, and processed starch of 35 to 60 wt. An example of a tablet that is compression-compressed with a mixture containing 2% by weight, 5-30% by weight of crystalline cellulose, 0-50% by weight of polyethylene glycol and 10% by weight of acetaminophen is also described. However, the disintegration properties of the tablets described in these documents are still lowered. Furthermore, because of the strong binding with processed starch, even if these formulations are applied to formulations containing active ingredients with poor moldability (especially relatively active ingredients with poor moldability), the disintegration cannot be improved much. Or formulation design tends to be difficult.

JP 2004-300150 A (Claims 1 and 9, paragraphs [0013] [0015] [0017], Examples) JP-A-2002-348251 (Claim 1, Example) JP-A-2002-363072 (Claim 1, Example) JP 2007-1999 A (Claim 1, paragraph [0084], Example) Japanese Patent Laying-Open No. 2007-153886 (Claim 1, [Effect of the Invention], Example)

  Accordingly, an object of the present invention is to provide a solid preparation that can suppress expansion (or swelling) and retain its form even under high humidity or high humidity, and a method for producing the same. .

  Another object of the present invention is to provide a solid preparation which can suppress swelling even when it contains a large amount of an active ingredient having inferior moldability, and a method for producing the same.

  Still another object of the present invention is to provide a solid preparation that can suppress the occurrence of cracks and cracks (such as cracks) and has high storage stability, and a method for producing the same.

  Another object of the present invention is to provide a method for suppressing swelling of a solid preparation even under high humidity or high humidity.

  When the present inventors examined the relationship between expansion (or swelling) and disintegration of a solid preparation, it is quite difficult to achieve both the suppression of expansion (or suppression of swelling) and disintegration of the solid preparation. found. That is, in a solid preparation containing an active ingredient having poor moldability and a conventional disintegrant (for example, croscarmellose sodium having high disintegrability), the solid preparation expands (or swells) under high humidity or high humidity. Cracking occurs, and it is impossible to achieve both suppression of swelling and disintegration. On the other hand, in order to suppress swelling (or swelling), even if a film coating is applied to the preparation or the content of croscarmellose sodium is reduced, cracking of the solid preparation cannot be suppressed and it is more disintegratable than croscarmellose sodium. It was found that when low-substituted hydroxypropylcellulose, carmellose calcium or the like having a low viscosity is used, the swelling of the solid preparation is suppressed, but the disintegration time is delayed. In particular, it has been found that it is extremely difficult to achieve both suppression of expansion (or swelling) and disintegration in a solid preparation containing a relatively large amount of an active ingredient having poor moldability.

  Therefore, as a result of intensive studies to achieve the above-mentioned problems, the present inventors have formulated a combination of an active ingredient with poor moldability and pregelatinized starch, even if the composition is a solid preparation (especially under high humidity or high humidity). The present inventors have found that the expansion (or swelling) of a solid preparation containing a relatively large amount of an active ingredient having a poor moldability can be suppressed and that high disintegration can be exhibited.

  That is, the solid preparation of the present invention contains (A) an active ingredient having poor moldability (for example, L-carbocysteine) and (B) pregelatinized starch (for example, pregelatinized potato starch).

  (B) The pregelatinized starch may be a pregelatinized product of various starches, for example, a pregelatinized product of at least one starch selected from potato, wheat, corn, rice, tapioca, and sweet potato. Moreover, the average pregelatinization degree of (B) pregelatinized starch may be about 55-95%. Further, the pregelatinized starch may have at least one characteristic of (a) a swelling volume of about 8 to 20 mL / g and (b) a content of a water-soluble component of about 2 to 10%.

  (A) The active ingredient having inferior moldability may be an ingredient having a hardness of 25 N or less when a tablet having a mass of 330 mg and a diameter of 9 mm is formed at a tableting pressure of 10 kN. Such an active ingredient with poor moldability (A) may be at least one component selected from amino acids and vitamin Cs.

  The solid preparation of the present invention is further selected from other active ingredients such as antipyretic analgesics, anti-inflammatory drugs, antitussive expectorants, antiasthma drugs, bronchodilators, antiallergic drugs, antacids, and mucosal protective drugs May contain at least one other active ingredient. In the whole solid preparation, (A) an active ingredient having inferior formability (a total when composed of a plurality of active ingredients) and other active ingredients (a total when composed of a plurality of active ingredients) The ratio (weight ratio) may be about the former / the latter = 50/50 to 99/1. In addition, when the active ingredient (or other active ingredient) with inferior moldability is composed of a plurality of active ingredients, the ratio of the active ingredient with inferior formability (or other active ingredient) is not particularly specified. , Means the ratio based on the total amount.

  The amount of the active ingredient having poor moldability and the pregelatinized starch used is not particularly limited. For example, the proportion of the active ingredient having poor formability is about 15 to 80 parts by weight with respect to 100 parts by weight of the solid preparation. The ratio of (B) pregelatinized starch may be about 0.1 to 20 parts by weight. Moreover, about 0.5-20 weight part may be sufficient as the ratio of (B) pregelatinized starch with respect to 100 weight part of active ingredients with inferior moldability.

  The solid preparation of the present invention comprises (A) about 20 to 60 parts by weight of an active ingredient having poor formability and (B) pregelatinized starch of about 0.5 to 10 parts by weight with respect to 100 parts by weight of the solid preparation. Also included is a solid preparation containing (B) pregelatinized starch in an amount of about 2 to 16 parts by weight with respect to 100 parts by weight of the active ingredient (A) inferior in formability.

  The solid preparation of the present invention may not contain disintegrants such as carboxymethyl starches, carboxymethylcelluloses, low-substituted hydroxypropylcellulose, crospovidone and the like.

  The solid preparation of the present invention is composed of a plurality of layers, and at least one layer is a solid preparation (multi-layer solid preparation or multi-layer tablet) containing (A) an active ingredient having poor moldability and (B) pregelatinized starch. There may be. In a multi-layer solid preparation, the active ingredient having poor moldability and pregelatinized starch may be contained in different layers, but in the same layer, both the disintegration property and suppression of swelling of the solid preparation are compatible. It is preferable to contain.

  The present invention provides a method for producing a solid preparation by tableting a mixture containing (A) an active ingredient having inferior formability and (B) pregelatinized starch, and (A) an active ingredient having inferior formability. A method for suppressing swelling of the solid preparation by incorporating (B) pregelatinized starch into the solid preparation to be contained is included.

  Unless otherwise specified in the present specification, the “solid preparation” means a preparation or a preparation composition that forms a “layer (or phase) containing an active ingredient having poor moldability”. That is, the term “solid preparation” means a single-layer solid preparation having a single-layer structure such as a single-layer tablet containing an active ingredient having inferior moldability, and is composed of a plurality of layers. In the case of a multilayer solid preparation having a multilayer structure such as a multilayer tablet containing a layer containing an active ingredient having poor moldability, it means not a multilayer solid preparation but a layer containing an active ingredient having poor moldability. Moreover, the ratio of the component which comprises a solid formulation means the ratio on the basis of an uncoated solid formulation (uncoated tablet etc.) unless it mentions especially.

  Note that “pregelatinized starch” is a physically modified starch, and this modified starch is a pharmaceutical additive standard “pregelatinized starch”, USP / NF and Ph. Eur. Compatible with “pregelatinized starch”. Therefore, in the present specification, the above physically modified starch is simply referred to as “pregelatinized starch”.

  The solid preparation of the present invention exhibits high disintegration by combining an active ingredient with poor moldability and pregelatinized starch, and can suppress tablet expansion or swelling even under high humidity or high humidity. In particular, even when an active ingredient having inferior moldability is contained in a large amount, expansion of the solid preparation can be suppressed and disintegration can be improved. That is, the occurrence of cracks and cracks (cracks, etc.) in the solid preparation can be effectively suppressed, and both the retainability and disintegration of the form of the solid preparation can be achieved.

[Solid formulation]
The solid preparation of the present invention comprises (A) an active ingredient having poor moldability (hereinafter sometimes simply referred to as a first active ingredient) and (B) pregelatinized starch.

(A) First Active Ingredient The present invention is applied to a first active ingredient having a small binding force (self-binding ability) by compression molding, and the first active ingredient alone (or the first active ingredient). When only the components are compression molded (or tableted), it exhibits low hardness. For example, when the first active ingredient is compression molded at a pressure (or tableting pressure) of 10 kN to obtain a tablet having a mass of 330 mg and 9 mmφ, the hardness of the tablet is 25 N or less (for example, about 2 to 25 N), preferably It may be 20N or less (for example, about 3 to 20N), more preferably 18N or less (for example, about 5 to 18N). For example, when the first active ingredient is L-carbocysteine, the hardness of the tablet is about 10 to 18N.

  The type of the first active ingredient is not particularly limited as long as it exhibits the hardness characteristic, and can be selected from various physiologically active ingredients and / or pharmacologically active ingredients. Representative active ingredients include, for example, amino acids [eg, cysteines (eg, L-cysteine, L-methylcysteine, L-ethylcysteine, L-carbocysteine, etc.); tranexamic acid, etc.], vitamin Cs (eg, , Ascorbic acid or a pharmaceutically acceptable salt thereof (for example, alkali metal salts of ascorbic acid such as sodium ascorbate and potassium ascorbate; alkaline earth metal salts of ascorbic acid such as calcium ascorbate) and the like. . These components can be used alone or in combination of two or more. Among these components, compression molding properties are inferior, and components having a relatively large single dose or content in a solid preparation, for example, cysteines (particularly L-carbocysteine) are preferable.

  The solid preparation of the present invention may contain, in addition to the first active ingredient, other active ingredients (hereinafter sometimes simply referred to as the second active ingredient). The second active ingredient can be selected from various physiologically active ingredients and / or pharmacologically active ingredients, such as sleep sedatives, antipruritics, antipyretic analgesics or antipyretic analgesics, anti-inflammatory drugs, antiemetics, antitussives , Expectorant, antitussive expectorant, antiasthma, bronchodilator, antacid or mucosal protective, antiallergic, sympathomimetic or alpha receptor stimulant, anti-inflammatory enzyme, central nervous system, antihypertensive Anti-arteriosclerotic drugs, antiarrhythmic drugs, diabetes drugs, hyperlipidemia drugs, hyperuricemia drugs, antibiotics, herbal medicines, stomachic medicines, digestive drugs, intestinal drugs, nutrition tonics, vitamins, minerals, etc. Can be illustrated. These 2nd active ingredients can be used individually or in combination of 2 or more types. These active ingredients can be selected depending on the disease, etc. For cold medicine, antipyretic analgesics (or antipyretic analgesics and antiphlogistics), anti-inflammatory drugs, antitussives and / or expectorants (or antitussive expectorants), antiasthma Drugs, bronchodilators, antiallergic drugs, antacids or mucosal protective drugs are often used in combination, and sleep sedatives and antipruritics are also used in combination.

  Antipyretic analgesics (or antipyretic analgesics and anti-inflammatory drugs) include non-narcotic components (eg, pentazocine hydrochloride), pilin components (eg, sulpyrine), non-pyrine components (eg, acetaminophen), non-steroidal components [For example, salicylic acids (for example, aspirin, aspirin aluminum, methyl salicylate, phenyl salicylate, sodium salicylate, choline salicylate, ethenamide, sazapyrine, etc.), fenamic acids (for example, mefenamic acid, flufenamic acid, tolfenamic acid, etc.), arylacetic acids (For example, diclofenac sodium, ampenac sodium, indomethacin, acemetacin, etc.), propionic acids (for example, ibuprofen, ketoprofen, naproxen, loxoprofen sodium, aluminop Fen, etc.), oxicams (e.g., piroxicam, etc.), and others.

  Examples of anti-inflammatory drugs include salicylic acids (sodium salicylate, acetylsalicylic acid, salicylamide, etc.), fenamic acids (flufenamic acid or its aluminum salt, mefenamic acid, etc.), arylacetic acid compounds (diclofenac sodium, fenbufen, indomethacin, etodolac) Propionic acid compounds (ibuprofen, ketoprofen, naproxen, pranoprofen, loxoprofen sodium, etc.), pyrimidine compounds (bucolome, etc.), oxicams (piroxicam, ampiroxicam, etc.), basic anti-inflammatory drugs (epilysole, hydrochloric acid, etc.) Thiaramid etc.) can be exemplified.

  Antitussive expectorants (antitussives and / or expectorants) include central narcotic components (eg, codeine phosphate, dihydrocodeine phosphate, etc.), central non-narcotic components [eg, opium alkaloids (eg, noscapine, etc.) ), Antihistamine derivative components (eg, cloperastine, etc.), synthetic chemicals (eg, dextromethorphan hydrobromide, tipepidine hibenzate, etc.), etc .; bromhexine or a salt thereof (hydrochloride, etc.) ), Ambroxol hydrochloride, etc.), expectorants such as potassium guaiacol sulfonate; guaifenesin, tipepidine or its salts (hibenzate, citrate, etc.), oxymethebanol, aroclamide hydrochloride, carbetapentane phenate, tricarbate hydrochloride Examples of cough expectorants such as metquinol and methoxyphenamine hydrochloride It can be.

  Anti-asthma drugs include ephedrines [for example, ephedrine or a salt thereof (such as hydrochloride), dl-methylephedrine or a salt thereof (such as hydrochloride), pseudoephedrine or a salt thereof (hydrochloride), etc.), an anticholinergic agent (Belladonna) Total alkaloids, belladonna extract, atropine, homatropine, scopolamine, funnel extract, duck extract, isopropamide iodide, methylbenactidium bromide and propantheline bromide or salts thereof), xanthines [eg, xanthine, caffeine (eg, Anhydrous caffeine, sodium benzoate caffeine, etc.), theophylline, diprofylline, theobromine, aminophylline, proxyphylline, pentoxyphylline, or a pharmaceutically acceptable salt thereof.

  Examples of bronchodilators include α-adrenergic receptor stimulators (phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, phenylephrine, norepinephrine, methoxamine, naphazoline, xylometazoline, clonidine, etc.), β-adrenergic receptor stimulators (ephedrine hydrochloride, hydrochloric acid, etc.) Methylephedrine, trimethquinol hydrochloride, isoproterenol hydrochloride, isoprenaline sulfate, methoxyphenamine hydrochloride, chlorprenalin hydrochloride, salbutamol sulfate, terbutaline sulfate, formoterol fumarate, procaterol hydrochloride, clenbuterol hydrochloride, etc.), anticholinergic agents (belladonna alkaloids) , Sympathetic nerve blockers such as belladonna total alkaloids, belladonna extract, funnel extract, isopropamide iodide; ipratropium bromide , Flutropium bromide, oxitropium bromide, etc.).

  Examples of antiallergic agents include antihistamines [for example, ethanolamine components (such as diphenhydramine hydrochloride), propylamine components (such as chlorpheniramine d-maleate, chlorpheniramine maleate), phenothiazine components (Eg, alimemazine tartrate, promethazine hydrochloride, etc.), piperazine components (eg, hydroxyzine, etc.), piperidine components (eg, cyproheptadine hydrochloride, etc.), ketotifen fumarate, azelastine hydrochloride, oxatomide, mequitazine, fexofenadine hydrochloride , Emedastine fumarate, epinastine hydrochloride, ebastine, cetirizine hydrochloride, bepotastine besylate, olopatadine hydrochloride, loratadine, etc.)], mediator release inhibitors (amlexanox, cromogli) Sodium acid, tranilast, amlexanox, repirinast, ibudilast, Tazanorasuto, other such pemirolast potassium, etc. These salts), and others.

  Examples of antacids or mucosal protective agents include magnesium hydroxide, magnesium oxide, magnesium carbonate, magnesium silicate, aluminum sulfate, synthetic aluminum silicate, synthetic hydrotalcite, dihydroaluminum aminoacetate, aluminum hydroxide gel Examples thereof include magnesium aluminate metasilicate, aluminum hydroxide / sodium bicarbonate coprecipitate, sucralfate, and the like.

  Sleep sedatives include benzodiazepines (triazolam, zolpidem tartrate, zopiclone, midazolam, brotizolam, rilmazafone hydrochloride, lormetazepam, flunitrazepam, nimetazepam, estazolam, nitrazepam, flurazepam hydrochloride, haloxazolam derivative, quazebarbital, Calcium, amobarbital, barbital, etc.).

  Examples of antipruritic agents include dimenhydrinate, isoprenaline hydrochloride, diphenidol hydrochloride, betahistine mesylate, tofisopam, ifenprodil tartrate, nicergoline, dihydroergotoxin mesylate, and the like.

  These components can be used alone or in combination of two or more. Some of these components may exhibit multiple activities, such as antipyretic analgesics (or antipyretic analgesics and antiphlogistics), anti-inflammatory drugs, antitussives and / or expectorants (or antitussive expectorants), Ingredients exemplified as asthma drugs, bronchodilators and antiallergic drugs are combined with two or more of antipyretic analgesic, anti-inflammatory, antitussive expectorant, antiasthmatic, bronchodilator and antiallergic It may be shown in

  In the solid preparation, the ratio (weight ratio) between the first active ingredient and the second active ingredient is the former / the latter = 40/60 to 100/0 (for example, 50/50 to 99/1), preferably It may be about 70/30 to 95/5, more preferably about 75/25 to 90/10. Further, in the entire multilayer solid preparation, the ratio (weight ratio) between the first active ingredient and the second active ingredient can be selected from the range of the former / the latter = 1/99 to 99/1. / 80 to 80/20, preferably 30/70 to 70/30, more preferably about 40/60 to 60/40, and usually 40/60 to 99/1 (for example, 50/50 to 90). / 10) grade.

  The average particle diameter of the first active ingredient and the second active ingredient is not particularly limited as long as it does not adversely affect the moldability. For example, 0.01 to 500 μm, preferably 0.1 to 250 μm, more preferably 1 It may be about 150 μm (for example, 3 to 100 μm), particularly about 5 to 50 μm (for example, 5 to 25 μm). The average particle size may be classified by a sieve and calculated from the particle size distribution as a particle size corresponding to 50% by weight of the total amount of all particles, and a conventional device such as a laser diffraction / scattering particle size distribution measuring device. You may measure using.

  The ratio of the first active ingredient is 15 to 80 parts by weight (for example, 20 to 70 parts by weight), preferably 25 to 65 parts by weight (for example, 30 to 60 parts by weight), based on 100 parts by weight of the solid preparation. More preferably, it may be about 35 to 55 parts by weight (for example, 40 to 50 parts by weight), and is usually about 20 to 60 parts by weight. The ratio of the 1st active ingredient with respect to the whole multilayer solid formulation is not restrict | limited, It can select from the wide range about 0.1 to 80 weight% (for example, 0.5 to 70 weight%).

(B) Pregelatinized starch The pregelatinized starch has a function of suppressing expansion (or swelling) of the solid preparation and a function of disintegrating the solid preparation. The pregelatinized starch may be a modified starch (or modified starch), for example, a chemically and / or physically modified starch. The chemical modification method may be, for example, a chemical modification method by reaction with reaction components. On the other hand, the physical modification method may be, for example, a method of drying starch by heating (for example, heating in the presence of water). Suitable pregelatinized starch has been modified by physical modification methods.

  The starch constituting the pregelatinized starch (or the raw material component of the pregelatinized starch) is rice, glutinous rice, corn, waxy corn, amylo corn, sorghum, wheat, barley, taro, mung bean, potato, lily, corn chestnut, tulip And natural starches such as canna, pea, perilla, chestnut, kudzu, yam, sweet potato, broad bean, kidney bean, sago, tapioca (cassava), bracken, lotus, and horsetail, aging starch, and cross-linked starch. These starches can be used alone or in combination of two or more. Of these starches, it is often at least one starch selected from potato, wheat, corn, rice, tapioca, and sweet potato. In particular, natural starch such as potato starch is preferred as the starch. Potato starch has high swellability of starch particles, and it is easy to control the amount of water retained.

The form of the alphalated starch particles may be spherical, ellipsoidal, polygonal or polygonal, irregular, etc., and is usually a sphere or ellipsoid, and may have a structure having at least one recess. . The pregelatinized starch may have an outer shell structure inherent to the raw material starch. The presence or absence of the outer shell structure is discriminated by, for example, dispersing 1 g of pregelatinized starch in 100 cm ³ of pure water and leaving it for 16 hours, and observing the upper and lower lower layer portions with an optical microscope (magnification 10 times). it can.

  The pregelatinized starch may be amorphous, but is preferably crystalline (having a crystal structure close to that of native starch). Whether it is crystalline or not can be discriminated by, for example, a polarization image of an optical microscope (magnification of about 10 times), and if it is crystalline, a bright polarization image (for example, what is called a polarization cross for raw starch) Can be determined using as an index.

  The pregelatinized starch may be fully or partially pregelatinized starch. For example, the average degree of pregelatinization may be 55 to 95%, preferably 60 to 90%, more preferably about 65 to 85%. The average degree of pregelatinization can be calculated by a conventional method such as a glucoamylase method.

  The pregelatinized starch may have at least one of the following properties (i) to (iv) (that is, any or all of the properties). Pregelatinized starch with these characteristics has low hygroscopicity, excellent stability with active ingredients, and some have a disintegrating power comparable to that of a super disintegrant.

  (I) The average particle diameter is 10 to 100 μm (for example, 20 to 90 μm), preferably 30 to 80 μm (for example, 35 to 75 μm), more preferably 40 to 70 μm (for example, 45 to 65 μm, particularly 45 to 60 μm). ) Degree. In addition, an average particle diameter can be measured using the laser diffraction type particle size measuring apparatus HELOS & RODOS (dry method).

  (Ii) The bulk density is 0.05 to 1.0 g / mL, preferably 0.1 to 0.7 g / mL, and more preferably 0.2 to 0.6 g / mL (for example, 0.3 to 0.00). About 5 g / mL). The bulk density can be measured as the sample weight (g) when the graduated cylinder is filled with the sample and the sample filling amount is 100 mL.

  (Iii) The swelling volume can be selected from the range of about 5 to 25 mL / g, 6 to 20 mL / g (for example, 7 to 19 mL / g), preferably 8 to 18 mL / g (for example, 9 to 17 mL / g). More preferably, it may be about 10 to 16 mL / g (for example, 11 to 15 mL / g). The swelling volume is room temperature (20 to 25 ° C.), 1 g of the sample is dispersed in water, transferred to a 50 mL settling tube, the total amount is 50 mL, and the volume (mL) of the lower layer after standing for 16 hours is the sample volume. It can be measured as a value divided by 1 g dry weight [weight (g) after drying at 105 ° C. for 6 hours].

  (Iv) The content of the water-soluble component can be selected from a range of about 0.1 to 20% (for example, 0.5 to 15%), and 1 to 11% (for example, 1.5 to 10.5%). Preferably, it may be about 2 to 10% (for example, 2.5 to 9.5%), and more preferably about 3 to 9% (for example, 3.5 to 8.5%). The ratio of the water-soluble component can be calculated by the formula [(W1 × 50 ÷ 5) ÷ W0 × 100] (where W1 (g) is room temperature (20 to 25 ° C.) and 49.5 g of water. Add 0.5 g of sample and disperse by stirring for 1 hour. Transfer 20 mL of the resulting dispersion to a 30 mL sedimentation tube, centrifuge at 10000 rpm (9400 G) for 10 minutes, and put 5 mL of this supernatant into a weighing bottle. The weight after drying at 105 ° C. until a constant weight is obtained (for example, 6 hours), and W0 (g) is the weight after drying 1 g of the sample at 105 ° C. for 6 hours).

  Of these properties, pregelatinized starch useful in the present invention often has at least one property (particularly both properties) of (iii) swelling volume and (iv) content of water-soluble components. .

  The proportion of the pregelatinized starch can be selected from a range of about 0.1 to 100 parts by weight (for example, 0.5 to 20 parts by weight) with respect to 100 parts by weight of the first active ingredient. For example, 1.5 to 17 parts by weight), preferably 2 to 16 parts by weight (for example, 2.5 to 15 parts by weight), more preferably about 3 to 14 parts by weight (for example, 3.5 to 13 parts by weight). It may be.

  Moreover, the ratio of pregelatinized starch can be selected from the range of about 0.01 to 50 parts by weight (for example, 0.1 to 20 parts by weight) with respect to 100 parts by weight of the solid preparation, and 0.5 to 10 parts by weight. (E.g. 1-8 parts by weight), preferably 1.2-7 parts by weight (e.g. 1.3-6.5 parts by weight), more preferably 1.4-6 parts by weight (e.g. 1.5- 5.5 parts by weight). The ratio of pregelatinized starch to the entire multilayer solid preparation is not particularly limited, and can be selected from a wide range of about 0.01 to 50% by weight (for example, 0.05 to 40% by weight). % By weight, preferably about 1 to 10% by weight.

  The solid preparation of the present invention may contain a conventional carrier component or additive as long as the low expansibility is not impaired. Carrier components or additives include excipients, binders, disintegrants, lubricants, antioxidants, preservatives (such as paraoxybenzoates), colorants (turmeric extract, riboflavin, carotene, tar Pigments, caramel, titanium oxide, bengara, etc.), flavoring agents (sweeteners such as aspartame, ascorbic acid, stevia, menthol, licorice crude extract, simple syrup, etc.), surfactants (polyoxyethylene hydrogenated castor oil, monostearic acid) Glycerin, sorbitan fatty acid esters (such as sorbitan monostearate, sorbitan monolaurate), polyoxyethylene polyoxypropylene, polysorbates, sodium lauryl sulfate, macrogol, sucrose fatty acid esters, etc.], fluidizing agents (light anhydrous silicic acid) , Talc, hydrous silicon dioxide, etc.) Agents (triethyl citrate, polyethylene glycol, triacetin, cetanol, etc.), sweeteners (natural or synthetic sweeteners such as sucrose, mannitol, D-sorbitol, xylitol, aspartame), flavoring agents (menthol, etc.), adsorbents, Examples thereof include preservatives and wetting agents. These carrier components or additives can be used alone or in combination of two or more. Of these carrier components or additives, usually at least one selected from excipients, binders, disintegrants and lubricants is often used.

  Examples of excipients include sugar alcohols such as D-mannitol, D-sorbitol, erythritol, xylitol, and powdered reduced maltose starch syrup, lactose, glucose, fructose, sucrose, and other sugars, crystalline cellulose, powdered cellulose, starches (potato) Starch, corn starch, etc.), dextrin, β-cyclodextrin, carmellose sodium, light anhydrous silicic acid, hydrous silicon dioxide, silicon dioxide, precipitated calcium carbonate, anhydrous calcium hydrogen phosphate, magnesium oxide, titanium oxide, calcium lactate, Examples thereof include magnesium aluminate metasilicate, synthetic hydrotalcite, talc, and kaolin. These excipients can be used alone or in combination of two or more. Among these excipients, it is preferable to use at least a saccharide such as powdered reduced maltose starch syrup from the viewpoint of hygroscopicity and moldability of the solid preparation.

  Examples of the binder include cellulose derivatives such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, crystalline cellulose, polyvinyl alcohol, polyvinylpyrrolidone (povidone), vinylpyrrolidone copolymer (copolyvidone), Examples include acrylic acid polymers, gelatin, gum arabic, pullulan, agar, tragacanth, sodium alginate, propylene glycol ester alginate, sucrose, and the like. These binders can be used alone or in combination of two or more. Of these binders, cellulose derivatives such as hydroxypropylcellulose and hydroxypropylmethylcellulose are widely used.

  Examples of the disintegrant include carboxymethyl starches (such as carboxymethyl starch sodium), carboxymethyl celluloses (carmellose, carboxymethyl cellulose calcium (carmellose calcium), carboxymethyl cellulose such as croscarmellose sodium, cross-linked products thereof or alkalis thereof. Metal or alkaline earth metal salt), low-substituted hydroxypropylcellulose (L-HPC), crospovidone, starches (such as corn starch), hydroxypropyl starch, alginic acid, bentonite and the like.

  Examples of the lubricant include stearic acid, magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, glycerin fatty acid ester, hydrogenated oil, polyethylene glycol, dimethylpolysiloxane, beeswax, and white beeswax. These lubricants can be used alone or in combination of two or more. Of these lubricants, stearates such as magnesium stearate are widely used.

  In addition, in this invention, from the point which balances the expansibility and disintegrating property of a solid formulation, the disintegrating agent (including the disintegrating agent called a super disintegrating agent) which provides high disintegrating property, for example, the said carboxymethyl starch ( Carboxymethyl starch sodium, etc.), carboxymethylcelluloses (carmellose, carmellose calcium, carboxymethylcellulose such as croscarmellose sodium, cross-linked products thereof or alkali metal or alkaline earth metal salts thereof), low-substituted hydroxypropylcellulose and cloth There may be no at least one disintegrant selected from povidone. In particular, the layer containing the first active ingredient may not contain these disintegrants.

  The dosage form of the solid preparation of the present invention is not particularly limited, and may be, for example, powder, fine granules or granules, pills, tablets, capsules, chewable tablets and the like, and is usually a tablet. The tablet may be any of a monolayer tablet, a multilayer tablet (two-layer tablet, three-layer tablet, etc.) having a layer containing at least the first active ingredient, and a coated tablet (sugar-coated tablet, gelatin-encapsulated tablet, film-coated tablet, etc.) Form may be sufficient. In the present invention, even if the dosage form has a relatively large surface area and a large contact area with air, the expansion of the solid preparation can be effectively suppressed.

  The solid preparation of the present invention has a low expansion rate (swelling rate) even when stored under high humidity. For example, the expansion rate (%) of the tablet after 3 days under the conditions of 25 ° C. and 75% RH [100 × (swelling) Subsequent tablet thickness / initial tablet thickness)] is 120% or less (about 105 to 120%), preferably 118% or less (about 105 to 118%), more preferably 115% or less (about 105 to 115%). The expansion rate of the tablet after 10 days may be 125% or less (about 105 to 125%), preferably 122% or less (about 105 to 122%), more preferably 120% or less (105 to 120%). Degree). Further, the expansion rate of the tablet after 3 days under conditions of 25 ° C. and 83% RH is 130% or less (about 105 to 130%), preferably 125% or less (about 105 to 125%), more preferably 120%. The following (about 105-120%) may be sufficient.

  The disintegration time (measured by the disintegration test method described in the 14th revision of the Japanese Pharmacopoeia) varies depending on the prescription of pregelatinized starch and other ingredients. For example, for uncoated tablets, it is about 5 to 25 minutes. In the case of a film-coated tablet, it may be about 5 to 30 minutes.

  The solid preparation of the present invention may be administered once or a plurality of times (for example, 2 to 6 times) per day. The dose per dose (single dose) can be selected according to gender, age, degree of illness, etc. For example, for tablets, one tablet or multiple tablets (for example, 2 to 6 tablets) ) May be administered.

[Method for producing solid preparation]
The solid preparation of the present invention can be produced by a conventional method. That is, it can be produced by mixing the first active ingredient, the pregelatinized starch, and the carrier component, and if necessary, granulating, sizing, compression molding (tableting) or filling the capsule. In particular, in the present invention, a powder mixture is prepared by mixing (a) the first active ingredient, the carrier ingredient, and, if necessary, the second active ingredient, from the viewpoint of achieving both form retention and disintegration of the solid preparation. (B) granulating the powder mixture to prepare a granulated product, and adjusting the granulated product as necessary to prepare granules (fine granules or granules); (c) the granulating A plain tablet (plain tablet) may be prepared by tableting a mixture of a granule or granule, pregelatinized starch, and, if necessary, a carrier component (excipient etc.).

  Granulation can be performed by a conventional method, for example, stirring granulation method, fluidized bed granulation method, extrusion granulation method, dry granulation method and the like. For example, the first active ingredient, the carrier ingredient and optionally the second active ingredient may be granulated using a solution containing a binder (eg, hydroxypropylcellulose, hydroxypropylmethylcellulose, etc.), for example, You may manufacture a granulated material by spraying the solution containing a binder to the fluidized bed containing a 1st active ingredient, a carrier component, and a 2nd active ingredient as needed. The ratio of the binder in the solid preparation may be about 1 to 6% by weight (for example, 3 to 4% by weight).

  Tableting can be performed using a conventional tableting machine, a single-shot tableting machine, a rotary tableting machine or the like. The solid preparation of the present invention contains an active ingredient having inferior moldability. However, since pregelatinized starch is blended, it is possible to achieve both form retention and disintegration of the solid preparation.

  In the solid preparation of the present invention, the swelling of the solid preparation can be suppressed and the generation of cracks and cracks can be prevented without coating, but the coating may be applied if necessary. The coating method may be, for example, a method of spraying a coating agent containing a coating base onto an uncoated solid preparation (elementary granule, uncoated tablet, etc.) using a film coating machine. Coating bases include hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, povidone, copolyvidone, polyvinyl alcohol, polyvinyl alcohol copolymers, water soluble bases such as macrogol, water insoluble bases such as ethyl cellulose, hydroxypropyl methylcellulose phthalate , Hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, methacrylic acid copolymer, acrylic acid copolymer, enteric base such as carboxyvinyl polymer, polyvinyl acetal diethylaminoacetate, aminoalkylmeta Acrylate copolymer, polyvinyl acetate Gastric base such as diethylamino acetate, gum arabic, pullulan, carnauba wax, shellac, macrogols, glycerol fatty acid ester, magnesium stearate, titanium oxide, talc, and others. These coating bases can be used alone or in combination of two or more. The coating layer may be formed in one layer or a plurality of layers.

  Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples.

Example 1
According to the formulation shown in Table 1, an aqueous solution of hydroxypropylcellulose (HPC-L) as a binder is sprayed using a fluidized bed granulator (Paurec Co., Ltd., FD-3SN), and granulation and sizing are carried out by a conventional method. To obtain sized powder A. 16.3 g of sized powder A 0.36 g of pregelatinized starch (Asahi Kasei Chemicals Co., Ltd., swellstar PD-1), 1.232 g of crystalline cellulose (Asahi Kasei Chemicals Co., Ltd., Theola KG802) as an excipient, 0.108 g of magnesium stearate as an agent was added and mixed, and 200 mg / tablet, 9 mmφ uncoated tablet was produced at a tableting pressure of 10 kN using an autograph.

Comparative Example 1
0.36 g of croscarmellose sodium (manufactured by Meidai Kako Co., Ltd.), a general disintegrant, instead of pregelatinized starch (swellstar PD-1) in 16.3 g of the sized powder A of Example 1 and excipient 1.232 g of crystalline cellulose (Asahi Kasei Chemicals Co., Ltd., Theolas KG802) and 0.108 g of magnesium stearate as a lubricant were added, mixed, and autographed at a tableting pressure of 10 kN at 200 mg / tablet, A 9 mmφ uncoated tablet was produced.

Example 2
According to the formulation shown in Table 2, an aqueous solution of hydroxypropylcellulose (HPC-L) as a binder is sprayed using a fluidized bed granulator (Paurec Co., Ltd., FD-3SN), and granulation and sizing are performed by a conventional method. To obtain sized powder B. 15.76 g of the sized powder B, 0.9 g of pregelatinized starch (Asahi Kasei Chemicals Co., Ltd., swellstar PD-1), 1.232 g of crystalline cellulose (Asahi Kasei Chemicals Co., Ltd., Theola KG802) as an excipient, 0.108 g of magnesium stearate as an agent was added and mixed, and 200 mg / tablet, 9 mmφ uncoated tablet was produced at a tableting pressure of 10 kN using an autograph.

Example 3
In the same manner as in Example 2, a sized powder B was obtained. This sized powder B 1576 mg, pregelatinized starch (Asahi Kasei Chemicals Co., Ltd., swellstar PD-1) 90 mg, crystalline cellulose (Asahi Kasei Chemicals Co., Ltd., Theola KG802) as an excipient 123.2 mg, as a lubricant 10.8 mg of magnesium stearate was added and mixed to obtain mixed powder B.

  According to the formulation shown in Table 3, an aqueous solution of hydroxypropylcellulose (HPC-L) as a binder is sprayed using a fluidized bed granulator (Paurec Co., Ltd., FD-3SN), and granulation and sizing are carried out by a conventional method. To obtain sized powder C.

  30 mg of croscarmellose sodium (manufactured by Meidai Chemical Co., Ltd.) as a disintegrant, 37.5 mg of crystalline cellulose (Asahi Kasei Chemicals Co., Ltd., Theola KG802) as an excipient, 35.1 mg of acid and 3.4 mg of magnesium stearate as a lubricant were added and mixed to obtain mixed powder C.

  After 200 mg tableting of the above mixed powder B with a tableting pressure of about 0.7 kN, 130 mg of the above mixed powder C with a tableting pressure of about 12.0 kN was further tableted on the tablet, and 330 mg / tablet, 9 mmφ double layer An uncoated tablet was obtained. A coating base was coated on the two-layer uncoated tablet according to the formulation shown in Table 4 using a coating machine (DRC-500 type, POWREC Co., Ltd.) by a conventional method to obtain a film-coated tablet.

Experimental example (expansion rate)
The uncoated tablets of Example 1 and Comparative Example 1 were placed in a weighing bottle and stored under conditions of 25 ° C., 75% or 83% RH for 3 days or 10 days. The tablet thickness before and after storage was measured, and the degree of swelling was compared. The results are shown in Table 5.

The expansion rate (%) is calculated by the expansion rate = 100 × (tablet thickness after expansion [mm] / initial tablet thickness [mm]).
(Collapse time)
The disintegration time was measured by the disintegration test method described in Japanese Pharmacopoeia 14th revision. The disintegration time of the uncoated tablet of Comparative Example 1 containing croscarmellose sodium was 7.5 to 9.9 minutes, whereas the disintegration time of the uncoated tablet of Example 1 containing pregelatinized starch was 10 2 to 11.4 minutes. That is, no great difference was found in the disintegration properties of the uncoated tablets of Examples and Comparative Examples. In addition, the disintegration time of the uncoated tablet containing no disintegrant was 13.0 to 15.2 minutes.
(appearance)
The uncoated tablet of Example 1 formulated with an alpha starch had a low degree of swelling (swelling) even when stored under high moisture, and there was no noticeable change in the surface or shape of the uncoated tablet. However, the uncoated tablet of Comparative Example 1 using croscarmellose sodium was greatly expanded, and the uncoated tablet itself was fragile.

  The solid preparation of the present invention has high disintegration property, and can maintain the form by suppressing the expansion of the solid preparation even under high humidity, and has storage stability. Furthermore, the solid preparation of the present invention is suitable for oral administration in that there is no decrease in hardness, and is useful as an oral solid preparation.

Claims (13)

  (A) A solid preparation containing an active ingredient having poor moldability and (B) pregelatinized starch.   (B) The solid preparation according to claim 1, wherein the pregelatinized starch is an alphalyzed product of at least one starch selected from potato, wheat, corn, rice, tapioca, and sweet potato.   The solid preparation according to claim 1 or 2, wherein (B) the pregelatinized starch has an average degree of pregelatinization of 55 to 95%.   The (B) pregelatinized starch has at least one characteristic of (a) a swelling volume of 8 to 20 mL / g and (b) a content of 2 to 10% of a water-soluble component. Solid formulation.   (A) The solid component according to any one of claims 1 to 4, wherein the active ingredient having inferior moldability is a component having a hardness of 25 N or less when a tablet having a mass of 330 mg and a diameter of 9 mm is formed at a tableting pressure of 10 kN. Formulation.   (A) The solid preparation according to any one of claims 1 to 5, wherein the active ingredient having inferior moldability is at least one component selected from amino acids and vitamin C.   (A) The active ingredient with inferior moldability is L-carbocysteine, The solid preparation according to any one of claims 1 to 6.   (B) The solid preparation according to any one of claims 1 to 7, wherein the pregelatinized starch is pregelatinized potato starch.   The composition according to any one of claims 1 to 8, comprising (A) 15 to 80 parts by weight of an active ingredient having poor moldability and (B) 1 to 20 parts by weight of pregelatinized starch with respect to 100 parts by weight of the solid preparation. The solid preparation described.   (A) The solid formulation in any one of Claims 1-9 which contains 0.5-20 weight part of (B) pregelatinized starch with respect to 100 weight part of active ingredients with inferior moldability.   (A) 20 to 60 parts by weight of an active ingredient having inferior moldability, (B) 0.5 to 10 parts by weight of pregelatinized starch, and (A) moldable The solid preparation according to any one of claims 1 to 10, wherein the proportion of (B) pregelatinized starch is 2 to 16 parts by weight with respect to 100 parts by weight of the inferior active ingredient.   (A) A method for producing a solid preparation by tableting a mixture comprising an active ingredient having poor moldability and (B) pregelatinized starch.   (A) A method for suppressing swelling of a solid preparation by blending (B) pregelatinized starch with a solid preparation containing an active ingredient having poor moldability.