JP2008127320A - Solid preparation quickly disintegrating in oral cavity - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a solid preparation quickly disintegrating in the oral cavity, which comprises D-mannitol as a base, is produced by a general formulation technology and has strength not to be disintegrated during a production process and a distribution process. <P>SOLUTION: The solid preparation quickly disintegrating in the oral cavity is obtained by mixing (a) a medicine active ingredient with (b) D-mannitol and (c) one or more kinds of disintegrators selected from a starch, a hydroxypropyl cellulose having a low substitution degree, cellulose glycolate and a hydroxypropyl starch, uses ≤2 wt.% based on the total of a solid agent composition of a binder having a viscosity (hereinafter a named display viscosity) of 2% aqueous solution of ≤25 mPa s and is obtained by wet granulation, drying and compression molding. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a rapidly disintegrating solid preparation in the oral cavity, particularly to a rapidly disintegrating tablet based on D-mannitol.

  Intraoral rapidly disintegrating tablets have been devised in various ways depending on the purpose, such as rapid disintegration in the oral cavity, smooth mouthfeel, and taste. Since this tablet dissolves rapidly in the oral cavity and can be easily taken without water, it is attracting attention as a dosage form suitable for patients having problems with swallowing function such as the elderly and children.

  Tablets and capsules require water at the time of taking, and there are problems such as difficulty in swallowing and use in the pharynx and esophagus when large preparations or large quantities are taken. This problem is particularly serious in elderly people, children, and patients who have difficulty swallowing, and sometimes the throat is clogged or attached to the esophagus and inflamed due to the effects of drugs.

  In recent years, for severely ill patients who have difficulty swallowing, tablets and granules are crushed or powdered as they are, suspended in water, inserted into the catheter orally or nasally with a syringe, and the drug is injected However, there is a problem that the operation is complicated, and sometimes the inner diameter of the catheter is thin, so that it is likely to be clogged.

  As these backgrounds, dosage forms suitable for elderly people, children or patients who have difficulty swallowing are known which rapidly disintegrate or dissolve when contained in the mouth or when placed in water.

  For example, in foreign countries, R.I. P. “Zysis” using lyophilization by Scherer (UK) is commercialized, but the preparation produced by the lyophilization method has rapid disintegration, but is weak and cannot measure hardness. There is a drawback of being fragile. In addition, since freeze-drying production equipment is required and production takes a long time, industrial productivity is also inferior.

  International Publication No. WO93 / 12769 describes an orally disintegrating preparation obtained by suspending a pharmaceutical substance, lactose and mannitol in an agar solution, filling a PTP pocket or the like to solidify in a jelly, and drying under reduced pressure. However, this molded product has weak tablet strength and is difficult to apply to packaging forms other than PTP packaging such as bottle packaging. In addition, industrial productivity is inferior because it takes a long time to produce.

  JP-A-6-218028 and JP-A-8-19589 disclose molding using a wet tablet in which a wet kneaded product is filled into a mold, compressed and molded, and then dried to produce a tablet. A method is described. These methods are wet tablet methods, and are molded at a low pressure, so that after drying, they become porous tablets having an appropriate porosity and are soft and excellent in disintegration. However, since the wet powder having poor fluidity is filled and compressed, there is a large variation in filling, and sticking is likely to occur. In addition, a special molding machine is required, and a special dryer that dries while maintaining the shape of the soft molded product may be necessary, which is inferior in industrial productivity.

  Therefore, as a method for producing a tablet having strong tablet strength, good solubility and disintegration, International Publication No. WO97 / 47287 is combined with a sugar or sugar alcohol having an average particle size of 30 μm or less, a pharmaceutically active ingredient and a disintegrating agent in the oral cavity. A method for producing tablets that disintegrate rapidly is described. According to this, for example, a compression molded product obtained by pulverizing sugar alcohol and then adding a disintegrant or the like has a certain degree of hardness, and it is said that rapid disintegration is obtained. Finely pulverizing alcohol requires labor, and pulverized mannitol increases the friction generated between the mortar wall during compression molding and reduces the fluidity during tablet production. There is a problem of decline.

  Japanese Patent Laid-Open No. 2000-273039 discloses an orally disintegrating tablet that disintegrates within 60 seconds, containing mannitol, a disintegrant, celluloses, a lubricant, and at least one of starches and lactose. The range of the manufacturing method is vague, and the disintegration time in the oral cavity is slightly long within 60 seconds.

  As described above, there are many ways to develop a tablet that has rapid disintegration and solubility when placed in the oral cavity or in water, and has strong strength that does not collapse in the manufacturing process and distribution process. It is necessary and cannot be easily produced by conventional manufacturing methods.

  The object of the present invention is to provide an intraoral dissolution type compression-molded product having the above-mentioned (1) rapid disintegration property, solubility in the oral cavity, and hardness that does not break immediately after taking, (2) Providing a production method for obtaining the above-mentioned intraoral dissolution type compression molding by a general formulation process, (3) Providing an oral dissolution type compression molding that can be taken without water, and a production method thereof (4) ) It is to provide a useful intraoral dissolution type compression-molded product having excellent industrial production, content uniformity of active pharmaceutical ingredients, and uniformity of dosage form.

  The inventors of the present invention studied an orally disintegrating tablet that can be prepared easily and easily using a general facility without requiring a special preparation technique. As a result, based on D-mannitol, one or more disintegrating agents selected from starch, low-substituted hydroxypropyl cellulose, fibrin glycolic acid and hydroxypropyl starch are mixed, and the indicated viscosity is 25 mPa · s or less. In addition to having a rapid disintegration and solubility by compressing and molding a wet granulated and dried product with an organic solvent or water, using the above binder in an amount of 2 parts by weight or less of the total amount of the solid agent composition The present inventors have found that an intraoral rapidly disintegrating solid preparation having strong strength that does not collapse in the production process and distribution process can be produced, and the present invention has been completed based on this finding.

  The intraoral quick disintegrating tablet referred to in the present invention refers to a tablet composition that finely disintegrates and disperses within 30 seconds in the oral cavity when taken without using water in the oral cavity.

  The present invention is based on D-mannitol, mixed with one or more disintegrants selected from starch, low-substituted hydroxypropylcellulose, fibrin glycolic acid and hydroxypropyl starch, and has a displayed viscosity of 25 mPa · s. The following binder is used in an amount of 2 parts by weight or less based on the total amount of the solid agent composition, and it is characterized by compression molding a wet granulated and dried product, and has a rapid disintegration time in the oral cavity of 30 seconds or less. It is a solid preparation that rapidly disintegrates in the oral cavity and has strong disintegration and solubility.

  The present inventors blended saccharides or sugar alcohols that are generally used in general, disintegrants, binders, etc., do not require special pharmaceutical technology, and are prepared simply and easily using general equipment. We conducted intensive research to develop a method for producing orally disintegrating tablets.

  As a result, in order to produce tablets with good moldability and solubility in general equipment, it is essential to select D-mannitol as a saccharide or sugar alcohol, which is limited to D-mannitol. Only by using a disintegrant and a limited binder and blending these limited amounts, the oral speed has a high strength and has rapid disintegration and solubility within about 30 seconds. A disintegrating solid tablet could be easily and easily produced.

  The present inventors first examined saccharides or sugar alcohols that are excellent in moldability as a solid agent, rich in solubility in the oral cavity, and satisfy human taste, and D-mannitol is the only property of these. (See Experimental Example 1). However, D-mannitol has a handling problem such as a decrease in fluidity during tablet production and an increase in friction between the mortar wall during compression molding. This problem is solved by dissolving D-mannitol in the oral cavity. Therefore, it was necessary to find a simple and easy improvement method without impairing the performance.

  As a result of diligent examination of a method for improving the defects without impairing the advantages of D-mannitol, one or more kinds selected from starch, low-substituted hydroxypropyl cellulose, fibrin glycolic acid and hydroxypropyl starch as disintegrants were used. By blending, using a binder with a displayed viscosity of 25 mPa · s or less and a relatively fast dissolution rate in water, and performing a granulation operation that also serves as a surface treatment to improve the handling of D-mannitol And found a method for producing the desired tablet.

  That is, the present invention is based on D-mannitol, mixed with one or more disintegrants selected from starch, low-substituted hydroxypropyl cellulose, fibrin glycolic acid and hydroxypropyl starch, and has a display viscosity of Using a binder of 25 mPa · s or less in an amount of 2 parts by weight or less based on the total amount of the solid agent composition, wet granulation and drying are compression-molded. It is an intraoral rapidly disintegrating solid preparation having strong strength and having no problem in content uniformity.

  The additive used as the base of the present invention is D-mannitol, but there is no limitation on the particle size of D-mannitol, and it has sufficient strength and is rapidly disintegrated without being pulverized to a particle size smaller than necessary. It is possible to produce an intraoral rapidly disintegrating solid preparation having the property and solubility.

  About the disintegrating agent to be blended, one or more selected from starch, low-substituted hydroxypropyl cellulose, fibrin glycolic acid and hydroxypropyl starch, which are very compatible with D-mannitol, should be used. Is essential (see Experimental Example 2). Moreover, the blending ratio of D-mannitol and the disintegrant is such that the manufactured tablet has sufficient strength and needs to disintegrate within 30 seconds in the oral cavity, and the strength reduction degree after moisture absorption of the tablet is small. Taking this into consideration, the weight ratio is 10: 1 to 1: 1, preferably 10: 1 to 10: 6, and most preferably 10: 1 to 10: 3.

  The binder used in the present invention is blended mainly for the purpose of surface modification of D-mannitol and the improvement of the fluidity of the granules to be produced. In order to achieve both oral disintegration time within 30 seconds and modification of powder properties, starch, low-substituted hydroxypropylcellulose, fibrin glycolic acid and hydroxypropyl used as disintegrants Polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose or polyvinyl alcohol having a displayed viscosity of 25 mPa · s or less based on a combination with starch, and 2 wt% or less of the total amount of the solid agent composition, preferably Used in an amount of 1.5% by weight or less, wet granulation / drying It has been found that there is a need.

  Thus, by combining D-mannitol, a disintegrant, and a binder, a compressed solid preparation that can be easily dissolved in the oral cavity within 30 seconds can be produced, but a display viscosity is 25 mPa · s or less. About 20 seconds more ideal by compressing the wet granulated and dried product using 1.5 wt% or less, more preferably 1 wt% or less of the total amount of the solid agent composition. It is also possible to obtain an intraorally rapidly disintegrating solid preparation that disintegrates within a range.

  The active pharmaceutical ingredient applied to the present invention is any antihistamine, allergic agent, gastric mucosal repair agent, hypnotic sedative, H2 receptor antagonist, arrhythmia agent, etc. Good. The compounding amount of the pharmaceutically active ingredient when using the present invention depends on the compounding purpose and its physicochemical properties, but in order to achieve an oral disintegration time of 30 seconds or less, the total amount of the solid composition is Therefore, it is usually 30% or less, preferably 20% or less.

  The fast disintegrating tablet of the present invention has excipients, disintegrants, lubricants, surfactants, sour agents, foaming agents, flavoring agents, dissolution agents, and the like used in general preparations, as long as there is no hindrance to fast disintegration and tablet strength An adjuvant etc. can be mix | blended.

  The preparation of the present invention can be produced by a conventional preparation production technique. That is, a pharmaceutical active ingredient, D-mannitol, a disintegrating agent, and the like are mixed, a solution in which a binder is dissolved in water or an organic solvent is used, and a lubricant is mixed in a wet granulated, dried, and sieved product. It is possible to manufacture by compression molding. Further, when wet granulation is performed, the active pharmaceutical ingredient can be dissolved or suspended in a binder solution and added, and the binder can be added together with a disintegrant or the like in powder form.

  For granulation operations related to the above formulation method, stirring granulator, fluidized bed granulator, kneader, rolling granulator, vacuum granulator, etc. can be used, and it is also merit that any granulation model can be selected It is.

  According to the present invention, special preparation technology is not required, and when it is put into the oral cavity or water using general equipment, it has rapid disintegration and solubility, and does not collapse in the manufacturing process and distribution process. It has become possible to easily produce tablets having such strong strength.

  The invention is illustrated by the following non-limiting examples.

Experimental example 1
(A) D-mannitol, (b) erythritol, (c) trehalose, (d) lactose, (e) maltitol, (f) amalty, (g) xylitol as a saccharide or sugar alcohol 90 g of alcohol and 20 g of corn starch were mixed, kneaded and granulated with an appropriate amount of water, then dried at 60 ° C. and sieved, and 0.6 g of magnesium stearate was mixed. A tablet of 110 mg was made using a 5 mm punch. Table 1 shows the tablet compression pressure, tablet strength, and oral disintegration time.

  Those with disintegration time in the oral cavity of 30 seconds or less were (a), (b) and (d), but (b) had weak tablet strength, and (d) had proper sweetness in the oral cavity. Therefore, (a) was the most suitable because it was unsuitable for base shaping as an orally disintegrating tablet.

Experimental example 2
Disintegrants include (h) corn starch, (i) partially pregelatinized starch (PCS), (j) low-substituted hydroxypropyl cellulose (LH-31), (k) carmellose (NS-300), (l) carmellose Sodium (ECG-505), (m) croscarmellose sodium (Akizol), (n) crospovidone (Collidon), (o) sodium carboxymethyl starch (primogel), (p) hydroxypropyl starch (HPS) and ( q) Using partially pregelatinized starch (START-1500), mixing 90 g of D-mannitol and 20 g of disintegrant, kneading and granulating with an appropriate amount of water, drying at 60 ° C. and sieving 0.5 g of magnesium stearate is mixed with the resulting product, and 1 tablet of 110 mg is made using a bowl with a diameter of 7.5 mm. It was. Table 2 shows the tablet compression pressure, tablet strength, and oral disintegration time.

  D-mannitol has compatibility with disintegrants, and super disintegrants are not always good, and (h), (j), (k) and (p) have the effect of greatly improving the loosening of D-mannitol. I found out that

Example 1
90 g of D-mannitol and 20 g of corn starch were mixed, kneaded and granulated using a solution of 2.2 g of Kollidon 30 and dissolved in 30 g of water, then dried at 60 ° C. and sieved. 0.5 g of magnesium acid was mixed, and one tablet of 110 mg was made using a punch with a diameter of 7.5 mm.

Example 2
90 g of D-mannitol and 20 g of corn starch were mixed, kneaded and granulated using a solution of 1.1 g of Kollidon 30 and dissolved in 30 g of water, then dried at 60 ° C. and sieved. 0.5 g of magnesium acid was mixed, and one tablet of 110 mg was made using a punch with a diameter of 7.5 mm.

Example 3
90 g of D-mannitol and 20 g of corn starch were mixed, kneaded and granulated using a solution of 1.1 g of TC-5 dissolved in 30 g of water, then dried at 60 ° C. and sieved. 0.5 g of magnesium stearate was mixed, and one tablet of 110 mg was made using a punch with a diameter of 7.5 mm.

Example 4
90 g of D-mannitol and 20 g of LH-31 mixed, kneaded and granulated using a solution of 1.1 g of TC-5 dissolved in 30 g of water, dried at 60 ° C. and sieved In addition, 0.5 g of magnesium stearate was mixed, and one tablet of 110 mg was manufactured using a punch having a diameter of 7.5 mm.

Example 5
139.5g of D-mannitol, 20g of corn starch, 20g of NS-300, 2g of Adsolider 101, 0.4g of aspartame, 0.1g of thaumatin, 4g of HPC-L, mix well, and 10g of ebastine A solution dissolved in 46 g of ethanol was added and kneaded, and after fluid drying at 50 ° C., 2 g of Adsolider 101 and 2 g of magnesium stearate were mixed with the sieved 1 Tablets of 200 mg were made.

Example 6
EPCTIN 5g, D-mannitol 65.2g, corn starch 20g, NS-300 2.5g, LH-31 2.5g, Adsolider 101 1g, aspartame 0.2g, mix well, HPC-L After adding 0.6 g of a solution dissolved in water and kneading, fluidizing and drying at 70 ° C., 2 g of adsorber 101 and 1 g of magnesium stearate were mixed with the sieved mixture, A tablet of 200 mg was made using

Example 7
1 g of zolpidem tartrate, 90 g of D-mannitol, 40 g of corn starch, 2 g of aspartame, 30 g of Kollidon, kneaded and granulated with 30 g of water, dried at 60 ° C. and sieved. -0.25 g of menthol, 0.2 g of Adsolider 101 and 0.5 g of magnesium stearate were mixed, and a tablet of 144 mg was produced using a 7.5 mm diameter punch.

Example 8
Mix with 0.5 g of etizolam, 90 g of D-mannitol, 10 g of corn starch, 10 g of NS-300, 0.5 g of aspartame and mix with 1 g of HPC-L in 30 g of water. After granulation, dried at 60 ° C. and sieved, 0.25 g of 1-menthol, 0.25 g of adsolider, 0.5 g of magnesium stearate are mixed, and 1 mm using a 7.5 mm diameter koji. A 112 mg tablet was produced.

Example 9
20 g of famotidine, 73.8 g of D-mannitol, 24 g of corn starch, 10 g of NS-300, 10 g of LH-31, 1.2 g of aspartame, and 1 g of Kollidon 30 are mixed and mixed with water. After granulation, 1 g of magnesium stearate was mixed with what was dried at 60 ° C. and sieved, and 1 tablet of 140 mg was made using a 7.5 mm diameter punch.

Comparative Example 1
Using (i) Kollidon 30, (ii) TC-5 (another name for hydroxypropylmethylcellulose) and (iii) HPC-L as a binder, 90 g of D-mannitol and 20 g of corn starch are mixed, and 3 g of binder is mixed. After kneading and granulating using a solution dissolved in 30 g of water, 0.6 g of magnesium stearate is mixed with what is dried and sieved at 60 ° C., and 1 tablet 110 mg using a 7.5 mm diameter punch. Made tablets.

Comparative Example 2
Pranlukast hydrate 112.5 g, D-mannitol 110 g, corn starch 70 g, LH-31 6 g, aspartame 0.3 g, HPC-L 1.5 g and mixed, using 70 g water After kneading and granulating, 1.5 g of magnesium stearate was mixed with what was dried and sieved at 60 ° C., and a tablet of 301.8 mg was produced using a 9 mm diameter punch.

Test Results Table 3 shows the tablet strength and oral disintegration time of the tablets produced in Examples 1-9 and Comparative Examples 1-2. The tablets of Examples 1 to 9 were free from obstructions during compression molding such as adhesion to creases and dies and squeaks, and good tablets having a hardness of 30 N or more were obtained. The oral disintegration time was within 30 seconds.

  On the other hand, in the comparative example, there was no problem in compression moldability, but the oral disintegration time required 40 seconds or more.

Claims (4)

  a) active pharmaceutical ingredient, b) D-mannitol, c) starch, low-substituted hydroxypropylcellulose, fibrin glycolic acid and hydroxypropyl starch, mixed with one or more disintegrants to give a 2% aqueous solution Oral formed by compression molding a wet granulated and dried product using a binder having a viscosity of 25 mPa · s or less (hereinafter referred to as the indicated viscosity) in an amount of 2% by weight or less of the total amount of the solid agent composition Fast disintegrating solid preparation.   The intraoral rapidly disintegrating solid preparation according to claim 1, wherein the mixing ratio of D-mannitol and the disintegrant is 10: 1 to 1: 1.   The solid preparation according to claim 1 or 2, wherein the binder is polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose or polyvinyl alcohol.   The solid preparation according to claim 1, 2, or 3, wherein the content of the active pharmaceutical ingredient is 30% by weight or less.