WO2010087358A1

WO2010087358A1 - Novel composition

Info

Publication number: WO2010087358A1
Application number: PCT/JP2010/051017
Authority: WO
Inventors: 弘一坂本; 真裕小川; 宏治鵜飼
Original assignee: エーザイ・アール・アンド・ディー・マネジメント株式会社
Priority date: 2009-01-29
Filing date: 2010-01-27
Publication date: 2010-08-05
Also published as: JP2012072061A

Abstract

Provided is a solid preparation which has excellent disintegration properties and suspension properties in water, allows homogeneous dispersion of drug granules in a small amount of water, exhibits good extrudability from a glass syringe and, therefore, can minimize the amount of the drug remaining in the glass syringe while preventing a feeding tube from blocking up with the drug granules. A solid preparation which comprises two or more kinds of disintegrating agents selected from the group consisting of crospovidone, croscarmellose sodium, croscarmellose calcium, low-substituted hydroxypropyl cellulose, low-substituted sodium carboxymethyl starch, crystalline cellulose, pregelatinized starch, starch and povidone.

Description

New composition

The present invention relates to a novel pharmaceutical preparation and a pharmaceutical composition. More specifically, the present invention relates to a novel formulation and a pharmaceutical composition for tube administration.

Conventionally, various pharmaceutical preparations that are easy to be taken by patients who are difficult to swallow such as elderly people and infants have been developed. Such patients are often taken with disintegrating tablets that exhibit rapid disintegration in the mouth.

However, even when administered to infants, even administration with disintegrating tablets may be difficult. Therefore, in such a case, an administration method by nasal tube administration using a nasogastric tube (hereinafter also referred to as “transtube tube” or “NG tube”) is selected.

In the nasal tube administration, it is necessary to disperse the pharmaceutical substance in water at the time of taking it even if the purpose is to administer a small amount of drug.

However, preparations that are difficult to disperse in water at room temperature are undesirable from the viewpoint of drug compliance because they require dissolution with warm water and the preparation process at the time of administration becomes complicated. In addition, if dispersed in a large amount of water, it may be a burden on the patient during administration.

Furthermore, if the dispersed preparation is clogged or remains in the syringe barrel or tube, it may be impossible to administer an accurate dose of the drug.

Therefore, it is desirable that such a preparation containing a drug used for tube administration has good disintegration and suspendability in water at room temperature from the viewpoint of the work efficiency of the preparation process at the time of administration. Furthermore, it is desired that the preparation has a property of being uniformly dispersible in a small amount of water. In addition, when administered via tube, a preparation that exhibits good extrudability from the syringe barrel of the formulation and that does not clog the tube tube with the formulation and does not remain in the syringe barrel is required. It has been.

Until now, various studies have been made to obtain such a preparation.

WO99 / 55311 describes an orally disintegrating tablet composed of sugar alcohol, crystalline cellulose, crospovidone, hydroxypropylcellulose (HPC) and the like.

JP-A 2008-150364 discloses a disintegrating tablet for tube administration containing a polyvinyl binder such as polyvinyl pyrrolidone or polyvinyl alcohol and having disintegration / suspension properties at room temperature and in water.

WO2005 / 011637 describes a time-dispersed preparation that exhibits an appropriate viscosity and fluidity when dispersed in a small amount of water before administration, and a main drug granule having an average particle diameter of 2 mm or less containing a pharmaceutical ingredient, and A time-dispersed formulation containing a thickener such as propylene glycol alginate is described. It is described that the preparation can be dispersed through addition of water at the time of administration and administered through a tube tube.

WO99 / 55311 JP 2008-150364 A WO2005 / 011637

However, in the conventional techniques described in these documents, it is not sufficient to keep the drug uniformly dispersed in water. In addition, the tube does not have excellent extrudability from the syringe barrel, and the tube tube is clogged with the main drug granule, and further, it is not sufficient to keep the remaining drug in the syringe barrel small.

Therefore, it is excellent in disintegration and suspension in water, can disperse the drug uniformly in water, has good extrudability of the drug solution from the syringe, and the tube tube is clogged with drug granules. There is a need for a solid preparation for tube administration that has no residual drug in the syringe.

In view of such a situation, the present inventors have intensively studied to solve the problem, and as a result, the solid preparation containing the drug and the solid preparation not containing the drug are supplementarily dispersed in water. The inventors have found that this can be solved, and have completed the present invention.

That is, the present invention is (1) a solid preparation for use in dispersion in water together with a solid preparation containing a drug, and is a solid preparation containing no more than one disintegrant and containing no drug.

The present invention also includes the following aspects.
(2) A solid preparation for use by dispersing in water together with a solid preparation containing a drug, crospovidone, croscarmellose sodium, croscarmellose calcium, low-substituted hydroxypropylcellulose, low-substituted carboxymethyl starch A drug-free solid preparation comprising two or more disintegrants selected from the group consisting of sodium, crystalline cellulose, pregelatinized starch, starch and povidone.
(3) The solid preparation containing no drug according to (1) or (2), wherein the solid preparation containing the drug is sparingly soluble in water.
(4) A solid preparation containing no drug according to any one of (1) to (3), wherein one of the disintegrants is crospovidone.
(5) The solid preparation containing no drug according to any one of (1) to (4), wherein the disintegrant is crospovidone and croscarmellose sodium.
(6) A solid preparation containing no drug according to any one of (1) to (5), comprising 20% by mass or more of a disintegrant based on the total amount of the solid preparation containing no drug.
(7) A solid preparation containing no drug according to any one of (1) to (6), comprising 40% by mass or more of a disintegrant based on the total amount of the solid preparation containing no drug.
(8) A solid preparation containing no drug according to any one of (1) to (7), comprising 42% by mass or more of a disintegrant based on the total amount of the solid preparation containing no drug.
(9) The solid preparation containing no drug according to any one of (1) to (8), comprising 30% by mass or more of crospovidone based on the total amount of the disintegrant contained in the solid preparation containing no drug.
(10) The solid preparation containing no drug according to any one of (1) to (9), comprising 50% by mass or more of crospovidone based on the total amount of the disintegrant contained in the solid preparation containing no drug.
(11) The composition according to any one of (1) to (7), comprising 40% by mass or more of a disintegrant based on the total amount of the solid preparation containing no drug and 30% by mass or more of crospovidone based on the total amount of the disintegrant. A solid preparation containing no drug.
(12) A pharmaceutical composition comprising a solid preparation containing a drug and a solid preparation containing no drug according to any one of (1) to (11).
(13) The pharmaceutical composition according to (12), wherein the solid preparation containing no drug and the solid preparation containing the drug are granules.
(14) The pharmaceutical composition according to (13), wherein a solid preparation containing a drug as a granule and a solid preparation not containing a drug as a granule are mixed and then tableted.
(15) The pharmaceutical composition according to any one of (12) to (14), wherein the drug is a benzimidazole compound.
(16) The pharmaceutical composition according to (15), wherein the benzimidazole compound is a proton pump inhibitor.
(17) The proton pump inhibitor is rabeprazole, omeprazole, esomeprazole, pantoprazole, lansoprazole, dexlansoprazole, nepaprazole, leminoprazole, tenatoprazole, pumaprazole, 2-[[[[4-((2,2-dimethyl- 1,3-dioxane-5-yl) methoxy) -3,5-dimethylpyridin-2-yl] methyl] sulfinyl] -1H-benzimidazole and their pharmacologically acceptable salts The pharmaceutical composition according to (16), which is one or more kinds.
(18) The pharmaceutical composition according to any one of (12) to (14), wherein the drug is a therapeutic or prophylactic agent for diseases or symptoms caused by gastric acid.
(19) Diseases or symptoms caused by gastric acid are gastric ulcer, duodenal ulcer, anastomotic ulcer, reflux esophagitis, Zollinger-Ellison syndrome, symptomatic reflux esophagitis, endoscopic negative reflux esophagitis, non-erosive Reflux esophagitis, gastroesophageal reflux disease, NUD (Non-Ulcer Dyspepsia), abnormal throat, Barrett esophagus, NSAID ulcer, gastritis, gastric bleeding, hemorrhagic gastritis, gastrointestinal bleeding, peptic ulcer, hemorrhagic ulcer, stress Ulcer, gastric hyperacidosis, indigestion, gastric failure, elderly ulcer, refractory ulcer, acute gastric mucosal lesion, heartburn, heartburn during sleep apnea, bruxism, stomach pain, stomach upset, nausea, nausea, temporomandibular joint (18) The pharmaceutical composition according to (18)
(20) The pharmaceutical composition according to any one of (12) to (14), wherein the drug is a disinfectant or disinfectant auxiliary agent for gastric Helicobacter pylori.
(21) A method for administering a solid preparation containing a drug, wherein the solid preparation containing no drug according to any one of (1) to (11) is used.
(22) Administration of a solid preparation containing a drug, wherein the solid preparation containing a drug and the solid preparation containing no drug according to any one of (1) to (11) are dispersed in water and administered by tube Method.
(23) The administration method according to (22), wherein the method is dispersed in 1 ml to 15 ml of water or milk.
(24) The administration method according to any one of (21) to (23), which is oral or nasal administration.

According to the present invention, when two or more disintegrants are blended in the composition at 40% by mass or more, they rapidly disintegrate into water and become granules, and a solid preparation containing the drug is uniformly dispersed in a small amount of water. It is possible to obtain a solid preparation having good extrudability from a syringe barrel and having a tube tube not clogged with drug granules.

The result of the syringe passage performance confirmation test by the material testing machine using the tablet which does not contain the drug obtained by the method of Production Example 1 and the granules containing the drug obtained by the method of Production Example 4 is shown. When the disintegrant was 40% by mass or more based on the total amount of the solid preparation, good extrudability was exhibited. Using a granule containing no drug obtained by the method of Production Example 2 and a granule containing the drug obtained by the method of Production Example 4, a syringe passing performance confirmation test was conducted in the same manner as in Example 1. The results are shown. When the disintegrant was 40% by mass or more based on the total amount of the solid preparation, good extrudability was exhibited. The friability of the tablet was shown when the amount of crospovidone relative to the total amount of disintegrant was changed.

In the present invention, the dosage form of a solid preparation containing no drug and a solid preparation containing a drug is a granule, fine granule, powder, tablet or the like, preferably a granule or a tablet.

In the present invention, a solid preparation containing a drug has a coating which is hardly soluble or insoluble in water and can be dispersed in water.

In addition, when the solid preparation containing a drug is a granule, it may be referred to as a main drug granule for convenience.

In the present invention, the amount of drug used can be changed depending on the effect exerted. For example, a small amount may be used if it exhibits a medicinal effect in a small amount. Thereby, the quantity of the disintegrating agent contained in the solid preparation of the present invention can be adjusted.

In the present invention, the drug is not particularly limited. For example, antipyretic analgesic agent, anti-inflammatory agent, antitussive agent, antiemetic, antidepressant, anticholinergic agent, antidementia agent, antimigraine agent, psychotropic agent , Hypnotic, antipruritic, antispasmodic, antitumor agent, muscle relaxant, antiarrhythmic agent, ulcer treatment, antiarteriosclerotic agent, antihypertensive agent, blood circulation promoter, cardiotonic agent, diuretic, antiasthma agent, antiallergic agent , Antidiabetics, antihistamines, antirheumatics, immunomodulators, anthelmintics, antibacterials, antifungals, antivirals, expectorants, lipid lowering agents, osteoporosis agents, astringents, vitamins, etc. be able to.

Preferably, it is a benzimidazole compound used as a gastroenteritis / ulcer treatment agent or the like.

In the present invention, the benzimidazole compound is not particularly limited, and for example, a proton pump inhibitor can be cited as a suitable example.

Examples of such proton pump inhibitors include rabeprazole, omeprazole, pantoprazole, lansoprazole, dexlansoprazole, nepaprazole, leminoprazole, esomeprazole, tenatoprazole, pumaprazole, 2-[[[[(((2,2,2 -Dimethyl-1,3-dioxane-5-yl) methoxy) -3,5-dimethylpyridin-2-yl] methyl] sulfinyl] -1H-benzimidazole sodium salt and the like. Further, pharmacologically acceptable salts of these compounds, for example, sodium salts, potassium salts, magnesium salts, calcium salts and the like and hydrates can also be mentioned as suitable examples. Preferably rabeprazole, 2-[[[[4-((2,2-dimethyl-1,3-dioxane-5-yl) methoxy) -3,5-dimethylpyridin-2-yl] methyl] sulfinyl] -1H- Benzimidazole or a pharmacologically acceptable salt thereof.

In the present invention, both a solid preparation containing a drug and a solid preparation containing no drug are dispersed in a small amount of water and administered. The amount of water to be dispersed is usually 1 to 15 ml, preferably 3 to 12 ml, more preferably 5 to 10 ml with respect to 1 g of the solid preparation containing no drug. When the subject to be administered is an infant, it is preferable to take the volume of the stomach into consideration so that the dose per administration is about 3 to 5 ml.
For administration to infants, milk, liquid milk dissolved or dispersed in water, or liquid milk may be used instead of water.

In the present invention, the amount of the solid preparation containing no drug is usually 1 to 12 parts by weight, preferably 3 to 10 parts by weight, more preferably 5 to 7 parts by weight with respect to 1 part by weight of the solid preparation containing the drug. It is.

In the present invention, suitable administration methods for drugs include nasal tube administration, oral tube administration such as oral tube administration, and the like. Nasal tube administration is preferable.

In the present invention, the solid preparation containing a drug refers to a solid preparation containing the above-mentioned drug component exhibiting pharmacological activity to a living body. Moreover, the solid formulation which does not contain a drug is a solid formulation which does not contain the above-mentioned drug component, and is composed of appropriate excipients and disintegrants. When the solid preparation containing no drug is dispersed in a solvent together with the solid preparation containing the drug, the uniformity of the drug solution can be increased. Furthermore, when the drug solution is administered by tube, the drug solution can be smoothly extruded from the syringe barrel.

The solid preparation in the present invention is not particularly limited as long as it is produced by a known method. For example, granules, fine granules, and powders can be obtained by the method described in the 15th revision Japanese Pharmacopoeia. In addition, general additives may be added to these granules or the like, or they may be filled into capsules or molded into tablets. A solid preparation containing a drug and a solid preparation containing no drug may be mixed in advance to form granules, capsules, and tablets, or may be separately manufactured and mixed at the time of administration. In addition, a solid preparation containing a drug and a solid preparation containing no drug may be the same dosage form, or may be different dosage forms. For example, one can be a granule and the other can be a tablet.

Examples of the additive include excipients, binders, lubricants, disintegrating agents, coloring agents, flavoring agents, emulsifiers, surfactants, solubilizers, suspending agents, etc. Examples include tonicity agents, buffering agents, preservatives, antioxidants, stabilizers, absorption promoters, pH adjusters, and the like, and these can be used in appropriate combinations as desired.

Examples of the excipient include lactose, sucrose, glucose, corn starch, mannitol, sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, light anhydrous silicic acid, aluminum silicate, calcium silicate, magnesium aluminate metasilicate, Examples thereof include calcium hydrogen phosphate.

It is preferable to blend a water-soluble excipient such as lactose, mannitol, xylitol.

Examples of the binder include corn starch, polyvinyl alcohol, methylcellulose, ethylcellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, macrogol and the like.

Examples of the lubricant include sodium stearyl fumarate, magnesium stearate, calcium stearate, talc, synthetic magnesium silicate, carnauba wax, hardened oil, and microcrystalline wax.

Examples of the disintegrant include crystalline cellulose, agar, gelatin, pregelatinized starch, starch, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, crystalline cellulose, low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose. Calcium, croscarmellose sodium, croscarmellose calcium, carboxymethyl starch, carboxymethyl starch sodium, crospovidone, povidone and the like can be mentioned.

Disintegrants to be incorporated into the solid preparation containing no drug in the present invention include crospovidone, croscarmellose sodium, croscarmellose calcium, low-substituted hydroxypropylcellulose, sodium carboxymethyl starch, crystalline cellulose, pregelatinized starch, starch Povidone and the like are preferable.

The disintegrant contained in the whole solid preparation not containing the drug of the present invention is 40% by mass or more, more preferably 42% by mass or more, further preferably 50% by mass or more, more preferably 60% by mass of the whole solid preparation containing no drug. It is good to contain 70 mass% or more, 80 mass% or more still more preferably 70 mass% or more. More specifically, it preferably contains 30% by mass of crospovidone, more preferably 40% by mass of crospovidone, and even more preferably 50% by mass of crospovidone based on the total amount of the disintegrant.

Examples of the colorant include those allowed to be added to pharmaceuticals such as iron sesquioxide, yellow sesquioxide, carmine, caramel, β-carotene, titanium oxide, talc, riboflavin sodium phosphate, yellow aluminum lake, etc. Can be mentioned.

Examples of the flavoring agent include cocoa powder, mint brain, fragrance powder, mint oil, menthol, dragon brain, and cinnamon powder.

Examples of the emulsifier or surfactant include stearyl triethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, glyceryl monostearate, sucrose fatty acid ester, and glycerin fatty acid ester.

Examples of the solubilizer include polyethylene glycol, propylene glycol, benzyl benzoate, ethanol, cholesterol, triethanolamine, sodium carbonate, sodium citrate, polysorbate 80, nicotinamide, and the like.

Examples of the suspending agent include hydrophilic polymers such as polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, and hydroxypropyl cellulose in addition to the surfactant.

Examples of the isotonic agent include glucose, sodium chloride, mannitol, sorbitol and the like.

Examples of the buffer include buffer solutions such as phosphate, acetate, carbonate, and citrate.

Examples of the preservative include methyl paraben, propyl paraben, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.

Examples of the antioxidant include sulfite, ascorbic acid, α-tocopherol and the like.

Examples of the stabilizer include ascorbic acid, sodium edetate, erythorbic acid, and tocopherol.

Examples of the absorption promoter include isopropyl myristate, tocopherol, calciferol and the like.

The pH adjuster is not particularly limited, and examples thereof include organic acids such as citric acid and tartaric acid.

When a solid preparation containing a drug according to the present invention or a solid preparation not containing a drug is made into granules or fine granules, the particle size is usually 50 to 1500 μm, preferably 100 to 1000 μm, more preferably 400. ~ 800 μm.

In the present invention, diseases or symptoms caused by gastric acid include gastric ulcer, duodenal ulcer, anastomotic ulcer, reflux esophagitis, Zollinger-Ellison syndrome, symptomatic reflux esophagitis, endoscopic negative reflux esophagitis, non- Erosive reflux esophagitis, gastroesophageal reflux disease, NUD (Non-Ulcer Dyspepsia), abnormal throat, Barrett esophagus, NSAID ulcer, gastritis, gastric bleeding, hemorrhagic gastritis, gastrointestinal bleeding, peptic ulcer, hemorrhagic ulcer , Stress ulcer, gastric hyperacidity, indigestion, gastric failure, elderly ulcer, refractory ulcer, acute gastric mucosal lesion, heartburn, heartburn during sleep apnea, bruxism, stomach pain, stomach upset, nausea, nausea, Examples include temporomandibular disorders and gastric erosions.

Production Example 1 Solid preparation (tablet) containing no drug of the present invention
Lactose hydrate 500g (trade name: Pharmamatose 200M, DMV), corn starch 225g (trade name: eclipse corn starch, Nippon Shokuhin Kako Co., Ltd.), crospovidone 375g (trade name: polyplastidone, ISP) ), Croscarmellose sodium 375 g (trade name: Ac-Di-Sol, FMC International Inc.) was placed in a high-speed stirring granulator (trade name: Supermixer, Kawata) and mixed for 3 minutes.

Next, 10 g of citric acid hydrate (trade name: Citric Acid Monohydrate, Granular, USP, J. T. Baker) was added in an appropriate amount and purified for 5 minutes.

After drying with a fluid bed granulator (trade name: FLO-5, Freund Sangyo), it was sized with a 1 mm screen using a granulator (trade name: Power Mill, Showa Giken).

15 g of sodium stearyl fumarate (trade name: Pruv, JRS Pharma LP) was added to the obtained granules and mixed for 15 minutes with a mixer (trade name: tumbler mixer, Showa Chemical Machinery). This mixture was molded using a tableting machine (trade name: AP-15, manufactured by Hata Seiko Co., Ltd.) to obtain tablets for tube administration.

Production Example 2 Solid preparation (granule) containing no drug of the present invention
Lactose hydrate 515g (trade name: Pharmatose 200M, DMV), corn starch 225g (trade name: eclipse corn starch, Nippon Food & Chemicals Co., Ltd.), crospovidone 375g (trade name: polyplastidone, ISP) ), Croscarmellose sodium 375 g (trade name: Ac-Di-Sol, FMC International Inc.) was placed in a high-speed stirring granulator (trade name: Supermixer, Kawata) and mixed for 3 minutes.

After drying with a fluidized bed granulator (trade name: FLO-5, Freund Sangyo), it is sized with a 1 mm screen using a granulator (trade name: Power Mill, Showa Giken), and granules for tube administration Got.

The formulation per tablet of Production Example 1 and the formulation per capsule of Production Example 2 are as shown in Table 1 below.

Production Example 3 Solid preparation containing drug (granule)
12.5 g of rabeprazole sodium, 502.5 g of lactose hydrate (trade name: Pharmatose 200M, DMV), 225 g of corn starch (trade name: eclipse corn starch, Nippon Shokuhin Kako Co., Ltd.), 375 g of crospovidone (trade name: Polyplastone, ISP), 375 g of croscarmellose sodium (trade name: Ac-Di-Sol, FMC International Inc.)) is placed in a high-speed stirring granulator (trade name: Supermixer, Kawata) for 3 minutes. Mixed.

Next, an appropriate amount of ethanol in which 10 g of citric acid hydrate (trade name: Citric Acid Monohydrate, Granular, USP, J.T.Baker) was dissolved was added and granulated for 5 minutes.

Production Example 4 Solid preparation containing drug (granule)
3480.0 g of rabeprazole sodium, 1113.6 g of magnesium oxide (manufactured by Tomita Pharmaceutical Co., Ltd.) and 835.2 g of ethyl cellulose (trade name: Etocel, Dow Chemical Company) were dissolved in 38470 g of absolute ethanol. Using a fine particle coating device (model: FD-GPCG-15SPC, POWREC Co., Ltd.), this solution is coated on 5846.4g of non-parrel 108 (trade name, Freund Sangyo), which is a nuclear material, and dried to obtain granules. It was.

Next, 974.4 g of ethyl cellulose (trade name: etosel, Dow Chemical) and 5985.6 g of hydroxypropyl cellulose (trade name: HPC-L, Shin-Etsu Chemical) are dissolved in 140265 g of absolute ethanol, and magnesium stearate (Marincklot) 2) A coating solution in which 2784 g was dispersed was coated on half of the above granules and dried to obtain intermediate layer coated granules.

Furthermore, 6960 g of hydroxypropylmethylcellulose phthalate (trade name: HP-55S, Shin-Etsu Chemical Co., Ltd.) and 696 g of diacetylated monoglyceride (trade name: Mybasset, Quest International) are dissolved in 167111 g of 80% ethanol aqueous solution, and then talc. After dispersing 661.2 g (Matsumura Sangyo Co., Ltd.) and 348 g of titanium oxide (Merck), the intermediate layer-coated granules were coated and dried to obtain enteric granules.

The enteric granules were classified with a 355 μm and 557 μm Dalton vibrating sieve (Dalton) and dried with a shelf-type vacuum dryer (Nippon Industries Co., Ltd.). Thereafter, 174 g of light anhydrous silicic acid (trade name: AEROSIL, Nippon Aerosil Co., Ltd.) and 174 g of talc (Matsumura Sangyo Co., Ltd.) are added to 16356 g of the dried granules, and a 50 L tumbler mixer (model: TM-50S, Showa) And mixed with Giken Co., Ltd. to obtain granules for tube administration.

Production Example 5 Preparation for tube administration to infants (packaging)
The granules produced by the method of Production Example 2 were vacuum dried. 48 mg of the granules produced by the method of Production Example 4 were mixed uniformly with 300 mg of these granules, and placed in an aluminum bag to produce a package.

Production Example 6 Preparations for tube administration to infants (capsules)
The granules produced by the method of Production Example 2 were vacuum dried. To 300 mg of the granules, 48 mg of the granules produced by the method of Production Example 4 were mixed uniformly and filled into hard capsules.

Production Example 7 Preparation for tube administration (tablet)
The mixed granule obtained by the method of Production Example 1 was vacuum dried. 48 mg of the granule produced by the method of Production Example 4 was added to 300 mg of this granule, mixed, and tableted with a material testing machine (device name: Autograph, model: AG-5000A, manufactured by Shimadzu Corporation) for tube administration. Tablets were obtained.

Production Example 8 Preparations for tube administration (tablets)
The granules produced by the method of Production Example 2 were vacuum dried. 48 mg of the granule produced by the method of Production Example 4 was added to 300 mg of the granule, mixed, and tableted with a nucleated tableting machine to obtain a tablet for tube administration.

Production Examples 9 to 11 Preparation of Formulation for Infants Administration The sachets, capsules or tablets produced by the methods of Production Examples 5 to 7 are placed in syringes into which 2 ml of purified water has been injected, and are sufficiently stirred. A drug dispersion for tube administration was obtained.

Production Example 12 Solid preparation (tablet) containing no drug of the present invention
Lactose hydrate 25.05 kg (trade name: Pharmatose 200M, DMV), corn starch 13.5 kg (trade name: eclipse corn starch, Nippon Shokuhin Kako Co., Ltd.), crospovidone 22.5 kg (trade name: polyplastidone ISP)), croscarmellose sodium 22.5kg (trade name: Ac-Di-Sol, FMC International Inc.), light anhydrous silicic acid 900g (trade name: AEROSIL, Aerosil Japan) : Super mixer, Kawata) and mixed for 3 minutes.

Next, an appropriate amount of purified water in which 600 g of citric acid hydrate (trade name: Citric Acid Monohydrate, Granular, USP, J.T.Baker) was dissolved was added and granulated for 4 minutes.

After drying with a fluidized bed granulator (trade name: WST-120, Powrec Co., Ltd.), it is sized with a 1 mm screen using a granulator (trade name: Power Mill, Showa Giken) for tube administration. Granules were obtained.

450 g of sodium stearyl fumarate (trade name: Pruv, JRS Pharma LP) and 4.5 kg of crystalline cellulose (trade name: Theolas KG-1000, Asahi Kasei) are added to the resulting granules, and a blender (trade name: tumbler blender, Showa) For 10 minutes. This mixture was molded using a tableting machine (trade name: FETTE P1200, manufactured by Bosch) to obtain tablets for tube administration.

The prescription per tablet of Production Example 12 is as shown in Table 2.

For these tablets, the hardness of 10 tablets was measured using a Kiya digital hardness tester (Fujiwara Seisakusho), and the average value was calculated. Moreover, the disintegration time of 6 tablets was measured by the method described in the 15th revision Japanese Pharmacopoeia, and the average value was calculated. The results are shown in Table 3.

Production Examples 13-15
To the granules produced by the same method as in Production Example 12, sodium stearyl fumarate (trade name: Pruv, JRS Pharma LP), light anhydrous silicic acid and crystalline cellulose (trade name: Theolas KG-1000) shown in Table 4 Asahi Kasei) was added, and tableting was performed in the same manner as described above to obtain tablets for tube administration.

The prescription per tablet of Production Examples 13 to 15 is as shown in Table 4.

Light Silica (1) Product name: AEROSIL (Nippon Aerosil)
Light Silicic Anhydride (2) Product Name: Silysia (Fuji Silysia)

About these tablets, the hardness of the tablets was measured using a Kiya-type digital hardness meter (Fujiwara Seisakusho). Moreover, disintegration time was measured by the method described in the 15th revision Japanese Pharmacopoeia. Table 5 shows the average of the measured values of 10 tablets each.

Example 1 Syringe passing performance confirmation test using a material testing machine Test method An appropriate amount of purified water was placed in a syringe with a 10 ml tip cup (manufactured by Baxa). The tablet obtained by the method similar to manufacture example 1 and the granule obtained by the method of manufacture example 4 were thrown into the said syringe, and the syringe was turned upside down. Thereafter, a 40 cm, 6 Fr nasogastric tube (manufactured by Vygon) was attached, and the contents were extruded from the tube using a material testing machine (trade name: Autograph, AG-5000A, manufactured by Shimadzu Corporation). The pressure when the extrusion speed was 100 mm / min was measured. In addition, the control method of the extrusion end point was controlled by measuring the point of importance of the syringe and inputting the stroke into the extrusion distance. Extrusion pressure was measured when 0, 20, 40, 60, 80, and 100 mass% of the disintegrant was blended with respect to the total amount of the solid preparation.

Results The results of the test are as shown in Table 6. When the disintegrant was 40% by mass or more based on the total amount of the solid preparation, good extrudability was shown (FIG. 1).

Example 2 Syringe passing performance confirmation test using a material testing machine Test method An appropriate amount of purified water was put into a syringe with a 10 ml tip cup (manufactured by Baxa). The tablet obtained by the method similar to manufacture example 1 and the granule obtained by the method of manufacture example 4 were thrown into the said syringe, and the syringe was turned upside down. Thereafter, a 40 cm, 6 Fr nasogastric tube (manufactured by Vygon) was attached, and the contents were extruded from the tube using a material testing machine (trade name: Autograph, AG-5000A, manufactured by Shimadzu Corporation). The pressure when the extrusion speed was 100 mm / min was measured. In addition, the control method of the extrusion end point was controlled by measuring the point of importance of the syringe and inputting the stroke into the extrusion distance. Extrusion pressures when 42, 45, 50, 55, 65, 70, and 75 mass% of the disintegrant were blended with respect to the total amount of the solid preparation were measured.

Results The results of the test are as shown in Table 7. Good extrudability was exhibited when the disintegrant was 42% by mass or more based on the total amount of the solid preparation.

Example 3 Syringe passing performance confirmation test using a material testing machine Conducted using a granule not containing a drug obtained by the same method as in Production Example 2 and a granule containing a drug obtained by the method of Production Example 4. A syringe passing performance confirmation test was performed in the same manner as in Example 1. The extrusion pressure when the disintegrant was blended at 5, 10, 15, 20, 40, 50, 60, 80 and 100% by mass with respect to the total amount of the solid preparation was measured three times for each sample.

Results The results of the test are as shown in Table 8.

As a result of the test, good extrudability was shown when the disintegrant was 40% by mass or more based on the total amount of the solid preparation (FIG. 2).

Example 4 Syringe passing performance confirmation test by hand test Test method An appropriate amount of purified water was put into a syringe with a 10 ml tip cup. The tablet obtained by the method similar to manufacture example 1 and the granule obtained by the method of manufacture example 4 were thrown into the said syringe, and the said syringe was turned upside down. Thereafter, a 6Fr NG tube was attached, and the contents were extruded from the tube by hand. The active ingredient granules in the syringe were flushed with 2 ml of water. The transmittance when the disintegrant was blended at 0, 20, 40, 60, 80, 100 mass% with respect to the total amount of the solid preparation was measured three times for each sample.

Results The results of the test are as shown in Table 9. When the main drug granule was clogged in the NG tube, it was evaluated that the sample did not pass through the tube.

As a result of the test, when the disintegrant was 40% by mass or more based on the total amount of the solid preparation, the sample could be easily extruded from the NG tube. It was found that the pushability from the syringe barrel was good even by hand pressing in a situation similar to administration in actual medical practice.

Example 5 Test for confirming passing performance of syringe barrel by hand Test method An appropriate amount of purified water was put into a syringe with a 10 ml tip cup. The tablet obtained by the method similar to manufacture example 1 and the granule obtained by the method of manufacture example 4 were thrown into the said syringe, and the said syringe was turned upside down. Thereafter, a 6Fr NG tube was attached, and the contents were extruded from the tube by hand. The active ingredient granules in the syringe were flushed with 2 ml of water. Extrusion pressure when 42, 45, 50, 55, 65, 70 and 75 mass% of the disintegrant was blended with respect to the total amount of the solid preparation was measured three times for each sample.

Results The results of the test are as shown in Table 10. When the main drug granule was clogged in the NG tube, it was evaluated that the sample did not pass through the tube.

As a result of the test, when the disintegrant was 42% by mass or more based on the total amount of the solid preparation, the sample could be easily extruded from the NG tube. It was found that the pushability from the syringe barrel was good even by hand pressing in a situation similar to administration in actual medical practice.

Example 6 Syringe passing performance confirmation test by hand pressing Similar to Example 3 using granules containing no drug obtained by the method of Production Example 2 and granules containing the drug obtained by the method of Production Example 4 The syringe passing performance confirmation test was carried out by pushing this method. The extrusion pressure when the disintegrant was blended at 5, 10, 15, 20, 40, 50, 60, 80 and 100% by mass with respect to the total amount of the solid preparation was measured three times for each sample.

Results The results of the test are as shown in Tables 11-19. When the disintegrant was 40% by mass or more of the entire solid preparation, the sample could be easily extruded from the NG tube. It was found that the pushability from the syringe barrel was good even by hand pressing in a situation similar to administration in actual medical practice.

Example 7 Test for confirming passing performance of syringe barrel by

hand

2 or 3 ml of purified water was placed in a syringe with a 10 ml tip cup. One 300 mg tablet obtained by the method of Production Example 12 and 48 mg of the granule obtained by the method of Production Example 4 were put into the syringe, and the syringe was turned upside down. Thereafter, a 6Fr NG tube was attached, and the contents were extruded from the tube by hand. Further, the main drug granules in the syringe were flushed with 2 ml of purified water. The ratio of the granules of Production Example 4 remaining in the syringe to the number of granules of Production Example 4 charged into the syringe was calculated. The average value of 9 times is shown in Table 20.

Example 8 Syringe Passage Performance Confirmation Test Using a Material Testing Machine Test Method An appropriate amount of purified water was placed in a syringe with a 10 ml tip cup (manufactured by Baxa). The tablet obtained by the method similar to manufacture example 1 and the granule obtained by the method of manufacture example 4 were thrown into the said syringe, and the syringe was turned upside down. Thereafter, a 40 cm, 6 Fr nasogastric tube (manufactured by Vygon) was attached, and the contents were extruded from the tube using a material testing machine (trade name: Autograph, AG-5000A, manufactured by Shimadzu Corporation). The pressure when the extrusion speed was 100 mm / min was measured. In addition, the control method of the extrusion end point was controlled by measuring the point of importance of the syringe and inputting the stroke into the extrusion distance. Extrusion pressures when 0, 20, 40, 50, 60, 80, and 100% by mass of crospovidone were blended with respect to the total of crospovidone and croscarmellose sodium were measured. Tables 21 and 22 show prescriptions per tablet.

Results The results of the test are as shown in Table 23. Good extrudability was exhibited when 40 mass% or more of crospovidone was included relative to the total amount of the disintegrant. Further, when the ratio of crospovidone to the total amount of the disintegrant was 20% by mass or less, the friability of the tablet was 0.5% or more (FIG. 3). On the other hand, when crospovidone was contained in an amount of 40% by mass or more, the friability of the tablets was 0.5% or less (FIG. 3).

Example 9 Syringe passing performance confirmation test by hand test Test method Milk (prepared by dispersing powdered milk (trade name: Snow Brand Pure, Snow Brand Milk Products Co., Ltd.) in water in a syringe with a 10 ml tip cup (manufactured by Baxa). We put an appropriate amount. The tablet obtained by the method of Production Example 12 and the granule obtained by the method of Production Example 4 were put into the syringe, and the syringe was turned upside down. Thereafter, a 6Fr NG tube was attached, and the contents were extruded from the tube by hand. In addition, 2 ml of milk was used to flush the main drug granules in the syringe.

Results Even when milk was used, the syringe passing performance was good as in the case of using water. Moreover, the viscosity of the suspension prepared using powdered milk was almost the same as that of the suspension prepared with water (Table 24).

Claims

A solid preparation for use by dispersing in water together with a solid preparation containing a drug, crospovidone, croscarmellose sodium, croscarmellose calcium, low substituted hydroxypropylcellulose, low substituted sodium carboxymethyl starch, crystals A solid preparation containing no drug, comprising two or more disintegrants selected from the group consisting of cellulose, pregelatinized starch, starch and povidone.
The solid preparation containing no drug according to claim 1, wherein the solid preparation containing the drug is sparingly soluble in water.
3. A solid preparation containing no drug according to claim 1 or 2, wherein one of the disintegrants is crospovidone.
The solid preparation containing no drug according to any one of claims 1 to 3, wherein the disintegrant is crospovidone or croscarmellose sodium.
5. The solid preparation containing no drug according to any one of claims 1 to 4, which comprises 20% by mass or more of a disintegrant based on the total amount of the solid preparation containing no drug.
6. The solid preparation containing no drug according to any one of claims 1 to 5, comprising 40% by mass or more of a disintegrant based on the total amount of the solid preparation containing no drug.
The solid preparation containing no drug according to any one of claims 1 to 6, comprising 42% by mass or more of a disintegrant based on the total amount of the solid preparation containing no drug.
The solid preparation containing no drug according to any one of claims 1 to 7, comprising 30% by mass or more of crospovidone based on the total amount of the disintegrant contained in the solid preparation containing no drug.
9. The solid preparation containing no drug according to any one of claims 1 to 8, comprising 50% by mass or more of crospovidone based on the total amount of the disintegrant contained in the solid preparation containing no drug.
The drug according to any one of claims 1 to 6, comprising 40% by mass or more of a disintegrant based on the total amount of the solid preparation not containing the drug, and 30% by mass or more of crospovidone based on the total amount of the disintegrant. Solid formulation not containing.
A pharmaceutical composition comprising a solid preparation containing a drug and a solid preparation containing no drug according to any one of claims 1 to 10.
12. The pharmaceutical composition according to claim 11, wherein the solid preparation containing no drug and the solid preparation containing the drug are granules.
The pharmaceutical composition according to claim 12, wherein a solid preparation containing a drug as a granule and a solid preparation not containing a drug as a granule are mixed and then tableted.
The pharmaceutical composition according to any one of claims 11 to 13, wherein the drug is a benzimidazole compound.
The pharmaceutical composition according to claim 14, wherein the benzimidazole compound is a proton pump inhibitor.
Proton pump inhibitors are rabeprazole, omeprazole, esomeprazole, pantoprazole, lansoprazole, dexlansoprazole, nepaprazole, leminoprazole, tenatoprazole, pumaprazole, 2-[[[4-((2,2-dimethyl-1, 3-Dioxane-5-yl) methoxy) -3,5-dimethylpyridin-2-yl] methyl] sulfinyl] -1H-benzimidazole and one pharmacologically acceptable salt thereof The pharmaceutical composition according to claim 15, which is as described above.
The pharmaceutical composition according to any one of claims 11 to 13, wherein the drug is a therapeutic or prophylactic agent for diseases or symptoms caused by gastric acid.
Diseases or symptoms caused by gastric acid are gastric ulcer, duodenal ulcer, anastomotic ulcer, reflux esophagitis, Zollinger-Ellison syndrome, symptomatic reflux esophagitis, endoscope-negative reflux esophagitis, non-erosive reflux esophagus Inflammation, gastroesophageal reflux disease, NUD (Non-Ulcer Dyspepsia), throat and laryngeal abnormalities, Barrett esophagus, NSAID ulcer, gastritis, gastric bleeding, hemorrhagic gastritis, gastrointestinal bleeding, peptic ulcer, hemorrhagic ulcer, stress ulcer, stomach Hyperacidity, dyspepsia, gastric failure, elderly ulcers, refractory ulcers, acute gastric mucosal lesions, heartburn, heartburn during sleep apnea, bruxism, stomach pain, stomach upset, nausea, nausea, temporomandibular disorder or stomach 18. A pharmaceutical composition according to claim 17 which is eroded.
The pharmaceutical composition according to any one of claims 11 to 13, wherein the drug is a disinfectant or disinfectant auxiliary agent for gastric Helicobacter pylori.
A method for administering a solid preparation containing a drug, wherein the solid preparation containing no drug according to any one of claims 1 to 10 is used.
A method for administering a solid preparation containing a drug, which comprises dispersing the solid preparation containing a drug and the solid preparation containing no drug according to any one of claims 1 to 10 in water and administering by tube.
The administration method according to claim 21, wherein the method is dispersed in 1 ml to 15 ml of water or milk.
The administration method according to any one of claims 20 to 22, wherein the administration method is oral or nasal administration.