WO2003026619A1

WO2003026619A1 - Granules having improved dosing properties

Info

Publication number: WO2003026619A1
Application number: PCT/JP2002/009910
Authority: WO
Inventors: Kouji Murai; Akihiro Uchida; Masaharu Aimoto; Yasuki Kato
Original assignee: Kyowa Hakko Kogyo Co., Ltd.
Priority date: 2001-09-26
Filing date: 2002-09-26
Publication date: 2003-04-03
Also published as: JPWO2003026619A1

Abstract

It is intended to provide granules having relieved coarseness in the oral cavity in dosing, characterized by containing a component which is hardly soluble in water or saliva and a component which is converted into a viscous liquid upon the addition of water.

Description

Specification

Granules with improved ingestibility

The present invention relates to granules having improved ingestibility.

In pharmaceuticals, granules are widely used as highly versatile dosage forms, and are especially useful when the swallowing ability is low and it is difficult to take tablets and other molded products, such as elderly people and children. Even for adults, granules are easier to take than other dosage forms when the dose is increased. In addition, granules have the advantage that the dosage can be adjusted accurately depending on the disease state and age, and are suitable for preparation.

However, when taking granules, it is necessary to flush out all of the granules scattered in the oral cavity from the oral cavity, and therefore generally requires more water than when taking tablets or forceps. If the granules are taken with a small amount of water, the granules will remain in the oral cavity and the bitterness of the drug will continue and the sublingual and gums will continue to feel rough. 'For this reason, users often have the impression that granules are difficult to take. Particularly children may resist taking granules. As mentioned above, granules tend to have the impression that they are difficult to take because they require a large amount of water when taken, even though they are originally a dosage form that is highly ingestible. This is a very worrisome problem for pharmaceuticals that need to take the required amount when needed, and there is an urgent need for a solution.

In particular, granules containing active ingredients or excipients that are sparingly soluble in water or saliva, or active ingredients that become sparingly soluble in water or saliva by coating or matrixing the active ingredient with a coating material Granules containing liquor are likely to produce a rough feeling due to the feeling of the hardness of the particles in the oral cavity, greatly reducing the ingestibility.

Conventionally, attempts have been made to improve the ingestibility of granules by adding sweeteners and flavors.However, it is difficult to take even if the taste discomfort is improved by imparting palatability. There is no substantial improvement in the problem of granules. As an alternative to granules, for example, dry syrups have been used. Because they are bulkier than granules and require more water to take, users may have the impression that they are more difficult to take. Also, dry syrups are premised on dissolving or suspending in a certain amount of water, so if they are taken in the form of condyles, they will not disintegrate or elute in the digestive tract properly. However, there is a risk that sufficient medicinal effects may not be obtained or side effects may occur. In some cases, taking granules together with jelly drinks has improved the ingestibility by removing the roughness caused by feeling the hardness of the particles. However, the need for jelly drinks several times the volume of granules requires time and effort to prepare and take. In addition, when taken with jelly, there is a risk that the drug may block contact between saliva and gastric juice and the drug, affect its absorption and onset of drug effects, and cause side effects.

On the other hand, rapidly disintegrating tablets in the oral cavity, which are a form of molded preparations such as tablets, are tablets that dissolve or disintegrate quickly in the oral cavity after being taken, and can be easily taken by elderly people and children. Kaihei 5-271054, JP-A-8-291051). Similarly, oral rapidly disintegrating granules that dissolve or disintegrate rapidly in the oral cavity after ingestion are also known (JP-A-11-343231, Patent No. 3018318). However, the active ingredient or excipient or the active ingredient that is hardly soluble in water or saliva is one or two selected from the group consisting of acryl polymers, cellulose polymers, natural polymers, oils and fats, and oil salts. By coating or matrixing with the above coating agent, granules containing an active ingredient that has become sparingly soluble in water or saliva must be dissolved or disintegrated into particles that are sufficiently small in the oral cavity. This causes a feeling of sensation, which greatly reduces the feeling of taking.闘 's war

An object of the present invention is to eliminate the graininess caused by feeling the scattering in the oral cavity and the hardness of the particles when a granule containing a component that is hardly soluble in water or saliva is taken. To improve the ingestibility of the drug.

The present invention relates to the following (1) to (40).

(1) A feeling of roughness in the oral cavity when ingested, characterized by containing a component that is hardly soluble in water or saliva and a component that becomes a viscous liquid when water is added. Granules with reduced content.

(2) The granule according to the above (1), wherein the component that is hardly soluble in water or saliva is an active ingredient and / or an excipient.

(3) A component that is hardly soluble in water or saliva, and the active ingredient is coated with one or more coating agents selected from the group consisting of acrylic polymers, cellulose polymers, natural polymers, oils and fats and oils and salts. Alternatively, the granule according to the above (1), which is a matrixed active ingredient.

(4) Insoluble components in water or saliva are active nervous system drugs, somatic nervous system drugs, smooth muscle drugs, antihistamines アレルギー allergic drugs, central nervous system drugs, cardiovascular system Agonists, Diuretics, Antidiuretics, Respiratory drugs, Gastrointestinal drugs, Blood and hematopoietic organ drugs, Hormones, Vitamins, Antidotes, Antiinfectives, Antineoplastic drugs, Immunological drugs, The granule according to the above (1), which is one or more active ingredients selected from the group consisting of diagnostic agents and narcotics' stimulants.

(5) Insoluble ingredients in water or saliva: acetilsviramycin, amoxicillin, ethyl icosapentate, traconazole, oxatomide, gribuzole, gluyuthione, ketofenylbuzozon, copamamid, cisapuri , Todolalazine hydrochloride, tropisetron hydrochloride, domperidone, sodium valproate, fluorouracil, flunarizine hydrochloride, flurazepam hydrochloride, benidipine hydrochloride, minocycline hydrochloride, mebendazol, medroxyprogesterone, ubidecarenone, pyridoxalone and pyridoxal phosphate The granule according to the above (1), which is one or more active ingredients selected from the group consisting of Lepodova.

(6) The granule according to any one of the above (1) to (5), wherein the component which becomes a viscous liquid when water is added is a binder and / or a disintegrant.

(7) The components that become a viscous liquid when water is added are hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, polyvinyl alcohol, polyethylene oxide, pullulan, sodium alginate, gelatin, agar, and copolydon. One or more binders and / or disintegrators selected from the group consisting of corn starch, potato starch, pregelatinized starch, carboxymethyl starch sodium and hydroxypropyl starch (1) The granules according to any one of (1) to (5). (8) Oxatomide is a component that is hardly soluble in water or saliva, and a component that becomes a viscous liquid when water is added is hydroxypropylmethylcellulose, hydroxypropylcellulose, and hydroxypropyl starch. The granule according to the above (1), which is two or more kinds selected from the group consisting of:

(9) The granule according to any one of the above (1) to (8), containing a soluble additive.

(10) A tablet obtainable by compression-molding the granule according to any one of the above (1) to (9) using a tableting machine.

(11) An agent for improving the ingestibility of granules containing a component which is hardly soluble in water or saliva, comprising a component which becomes a viscous liquid when water is added.

(12) The agent for improving the ingestibility of granules according to the above (11), wherein the component hardly soluble in water or saliva is an active ingredient and / or an excipient.

(13) The agent for improving the ingestibility of granules according to the above (11) or (12), wherein the components that become a viscous liquid when water is added are a binder and Z or a disintegrant.

(14) Reduces the feeling of roughness in the oral cavity when taking granules containing components that are hardly soluble in water or saliva, characterized by containing a component that becomes a viscous liquid when water is added. Agent.

(15) The graininess reducing agent according to the above (14), wherein the component hardly soluble in water or saliva is an active ingredient and / or an excipient.

(16) A component which is hardly soluble in water or saliva, the active component is coated with one or more coating agents selected from the group consisting of acrylyl polymer, cellulose polymer, natural polymer, fats and oils and fats or salts. The roughness reducing agent according to the above (14), which is a matrix-forming active ingredient.

(17) Insoluble or soluble components in water or saliva: autonomic nervous system drugs, somatic nerve system drugs, smooth muscle drugs, antihistamines, allergy drugs, central nervous system drugs, cardiovascular system Agonists, diuretics 'Antidiuretics, Respiratory drugs, Gastrointestinal drugs, Blood' Hematopoietic organ drugs, hormones, vitamins, antidote drugs, anti-infective drugs, anti-neoplastic drugs, immunological drugs, The agent for reducing sensation of roughness described in the above (14), which is one or more active ingredients selected from the group consisting of a diagnostic drug and a drug and a stimulant.

(18) Insoluble components in water or saliva include acetilsviramycin, amoxicillin, ethyl ethyl icosapentate, itraconazole, oxatomid, Gribzol, Guluyethione, Ketofenilbudin, Cobamamide, Cisapride, Todolalazine hydrochloride, Tropisetron hydrochloride, Domperidone, Sodium valproate, Fluorouracil, Flunarizine hydrochloride, Flurazepam hydrochloride, Bendipine hydrochloride, Hydrochloride The agent according to the above (14), which is one or more active ingredients selected from the group consisting of minocycline, mebendazole, medroxyprogesterone, ubidecarenone, pyridoxal phosphate and repodova.

(19) The roughness reducing agent according to any one of the above (14) to (18), wherein the component which becomes a viscous liquid when water is added is a binder and Z or a disintegrant.

(20) The components that become viscous liquids when water is added are hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, polyvinyl alcohol, polyethylene oxide, pullulan, sodium alginate, gelatin, agar, and copolydon. , One or more binders selected from the group consisting of corn starch, potato starch, pregelatinized starch, sodium carboxymethyl starch and hydroxypropyl starch, and Z or a disintegrant ( 14) The reducer according to any one of claims 18 to 18.

(21) The component that is hardly soluble in water or saliva is oxatomide, and the component that becomes a viscous liquid when water is added consists of hydroxypropylmethylcellulose, hydroxypropylcellulose, and hydroxypropylstarch. The roughness reducing agent according to the above (14), which is at least two members selected from the group consisting of:

(22) The roughness reducing agent according to any one of the above (14) to (21), which comprises a soluble additive.

(23) A granule containing a component which is hardly soluble in water or saliva, characterized by containing a component which becomes a viscous liquid when water is added, and obtained by compression molding with a tableting machine. A roughening agent for tablets that can be used.

(24) The graininess reducing agent for tablets according to the above (23), wherein the component that is hardly soluble in water or saliva is an active ingredient and / or an excipient.

(25) The roughness reducing agent for tablets according to the above (23) or (24), wherein the component which becomes a viscous liquid when water is added is a binder and / or a disintegrant.

(26) Add water to granules containing ingredients that are hardly soluble in water or saliva And a component which becomes a viscous liquid.

(27) The method for improving the ingestibility of granules according to the above (26), wherein the component hardly soluble in water or saliva is an active ingredient and Z or an excipient.

(28) The method for improving the ingestibility of granules according to the above (26) or (27), wherein the component which becomes a viscous liquid when water is added is a binder and / or a disintegrant.

(29) A granule containing a component that is hardly soluble in water or saliva, which contains a component that becomes a viscous liquid when water is added. How to reduce the feeling of roughness.

(30) The method for reducing roughness as described in (29) above, wherein the component that is hardly soluble in water or saliva is an active ingredient and Z or an excipient.

(31) An ingredient that is hardly soluble in water or saliva, and the active ingredient is coated with one or more coating agents selected from the group consisting of acrylic polymers, cellulose polymers, natural polymers, oils and fats and oils and salts. Alternatively, the method for reducing roughness as described in the above item (29), which is an active ingredient in a matrix form.

(32) Poorly soluble components in water or saliva include autonomic nervous system drugs, somatic nervous system drugs, smooth muscle drugs, antihistamines, allergy drugs, central nervous system drugs, cardiovascular system Agonists, diuretics * Antidiuretics, respiratory drugs, digestive drugs, blood and hematopoietic organ drugs, hormones, vitamins, antidote drugs, anti-infective drugs, anti-neoplastic drugs, immunological drugs, (29) The method according to the above (29), which is one or more active ingredients selected from the group consisting of diagnostic agents and narcotics' stimulants.

(33) The components that are hardly soluble in water or saliva are acetilsviramycin, amoxicillin, ethyl icosapentate, itraconazole, oxatomide, gribuzole, gluethione, ketofenilpuzone, kobamamide, cisapuri , Todolalazine hydrochloride, tropisetron hydrochloride, domperidone, sodium valproate, fluorouracil, flunarizine hydrochloride, flurazepam hydrochloride, penidipine hydrochloride, minocycline hydrochloride, mebendazole, medroxyprogesterone, ubidecarenone, pyridoxal phosphate (30) The method for reducing a feeling of roughness according to the above (29), which is one or more active ingredients selected from the group consisting of levodoba.

(34) The component that becomes a viscous liquid when water is added is a binder and / or The method for reducing graininess according to any one of the above (29) to (33), which is a disintegrant.

(35) The components that become viscous liquids when water is added are hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, polyvinyl alcohol, polyethylene oxide, pullulan, sodium alginate, gelatin, agar, and copolydon. (29) to (28) to which are one or more binders and / or disintegrators selected from the group consisting of corn starch, potato starch, pregelatinized starch, carboxymethyl starch sodium and hydroxypropyl starch. (33) The method for reducing a feeling of roughness according to any one of (33).

(36) The component that is hardly soluble in water or saliva is oxatomide, and the component that becomes a viscous liquid when water is added is hydroxypropylmethylcellulose, hydroxypropylcellulose, and hydroxypropyl starch. (29) The method for reducing a feeling of roughness according to the above (29), which is at least two kinds selected from the group consisting of:

(37) The method for reducing roughness as described in any of (29) to (36) above, further comprising a soluble additive.

(38) Contains a component that becomes a viscous liquid when water is added to a tablet that can be obtained by compression-molding a granule containing a component that is hardly soluble in water or saliva with a tableting machine. A method for reducing roughness in the oral cavity when taking the tablet.

(39) The method for reducing a feeling of roughness according to the above (38), wherein the component hardly soluble in water or saliva is an active ingredient and a vehicle.

(40) The method for reducing a feeling of roughness according to the above (38) or (39), wherein components that become a viscous liquid when water is added are a binder and Z or a disintegrant.

The granules of the present invention contain a component that is hardly soluble in water or saliva and a component that becomes a viscous liquid when water is added. When taken, the oral cavity (on the tongue, sublingual, gums, maxilla, There are no particular limitations on the granules that have a reduced feeling of roughness in the throat, etc., and have improved takeability. The granules include pills, granules, fine granules, and the like described in the Japanese Pharmacopoeia. Powders and the like.

The water- or saliva-insoluble component used in the present invention means that it is insoluble or partially soluble in the amount of water used when taking the drug, Or, those that do not dissolve or remain partially soluble in saliva in the oral cavity. As the component that is hardly soluble in water or saliva, the active ingredient that is hardly soluble in water or saliva, water or Excipients that are hardly soluble in saliva are exemplified.

For the active ingredient that is hardly soluble in water or saliva, the active ingredient is one or two or more kinds of coating agents selected from the group consisting of acryl polymer, cellulose polymer, natural polymer, oil and fat, oil and fat salt, etc. Also included are active ingredients which are coated or matrixed to render them poorly soluble in water or saliva. At this time, there is no limitation on the solubility of the active ingredient, and depending on the characteristics of the active ingredient, the active ingredient that has become hardly soluble in water or saliva as a result of being coated or matrixed with an appropriate coating agent is used. Point. Examples of the purpose of coating or matrix formation include masking of taste and odor, enteric coating or sustained release, stabilization such as light shielding and moisture proofing, and the like, and coating or matrix formation can be performed by a known method. Above all, masking of taste and odor is preferably considered in order to improve ingestibility.

Specific examples of the coating agent used in the present invention include acrylic polymers such as copolymers of methacrylic acid, aminoalkyl methacrylate copolymers and carboxyvinyl polymers (the acrylic polymers include acrylic acid derivatives and Z Or methacrylic acid derivatives are polymerized), ethylcellulose, cellulose polymers such as hydroxypropylmethylcellulose, hydroxypropylcellulose and cellulose acetate phthalate, gum arabic, pullulan, alginic acid, agar, gelatin, etc. And one or more kinds of coating agents selected from oils and fats and oils such as stearic acid, magnesium stearate, hardened oil, paraffin, carnavalo-glycerin fatty acid ester, and the like. These coatings may optionally be used with plasticizers or soluble additives, for example, polyethylene glycol, polyoxyethylenepolyoxypropylene glycol, polyoxyethylene hydrogenated castor oil, triethyl citrate, It may be used by mixing with polysorbate, sugar, sugar alcohol, oligosaccharide and the like.

The active ingredient that is hardly soluble in water or saliva may be, for example, any of solid, powder, crystal, oil, and solution, and specific examples thereof include, for example, an autonomic nervous system drug, Somatic nervous system drug, smooth muscle drug, antihistamine, are Lugi Ichii, Central nervous system drugs, Cardiovascular drugs, Diuretics * Anti-diuretics, Respiratory drugs Ji, Gastrointestinal drugs, Blood and hematopoietic organ drugs, Hormones, Vitamin, Antidote, One or more active ingredients selected from anti-infectives, antineoplastics, immunological drugs, diagnostics, narcotics, stimulants, and the like. More specifically, for example, acetilsviramycin, amoxicillin, ethyl icosapentate, itraconazole, oxatomide, gribzol, guru thione, ketophenyl buzon, cobamamide, cisapride, todralazine, tropisetron , Doveridone, valproic acid, pyridoxal, fluorouracil, flunarizine, flurazepam, benidipine, minocycline, mebendazole, medroxyprogesterone, ubidecarenone, levodoba and pharmaceutically acceptable salts thereof. One or more active ingredients and the like can be mentioned.

Pharmaceutically acceptable salts include pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like. Examples of the acid addition salts include inorganic acid salts such as hydrochloride, sulfate, and phosphate, and organic acid salts such as acetate, maleate, fumarate, tartrate, citrate, and lactate. Examples of the metal salt include alkali metal salts such as a lithium salt, a sodium salt, and a potassium salt; alkaline earth metal salts such as a magnesium salt and a calcium salt; an aluminum salt; a zinc salt; and the like. Salts such as ammonium and tetramethylammonium; organic amine addition salts include addition salts such as morpholine and piperidine; amino acid addition salts include glycine, phenylalanine, aspartic acid, and the like. Additional salts such as glutamic acid and lysine are exemplified.

The type of excipient that is hardly soluble in water or saliva is not particularly limited, and examples thereof include light anhydrous silicic acid, hydrated silicon dioxide, magnesium aluminate metasilicate, hydrotalcite, calcium carbonate, and the like.

The content of the active ingredient that is hardly soluble in water or saliva in the granules of the present invention is preferably 0.001% to 80%, more preferably 0.1% to 50%. The content of the poorly soluble excipient is preferably 0.1% to 95%, more preferably 1% to 50%.

The components used in the present invention that become a viscous liquid when water is added include those that dissolve or swell when water is added, and are transparent or suspended viscous liquids or viscous liquids. It is not particularly limited as long as it becomes a liquid, but preferably, a binder which becomes a viscous liquid when water is added, a disintegrating agent which becomes a viscous liquid when water is added, and the like are preferable. More preferably, for example, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, polyvinyl alcohol, polyethylene oxide, pullulan, sodium alginate, gelatin, agar, copperidone, corn starch, potato starch, pregelatinized starch, carboxymethyl starch Examples include one or more binders and / or disintegrators selected from the group consisting of mono-tinadium and hydroxypropyl starch. The component that becomes a viscous liquid when added to water is brought into contact with the water used at the time of ingestion and the saliva in the oral cavity to bring the granules into a resilient and plastic state, and the granules are unnecessary. It has the effect of preventing it from being scattered in the oral cavity, and after the granules disintegrate in the oral cavity, it becomes viscous around components that are hardly soluble in water or saliva, which cause a feeling of roughness. It is surrounded by liquid and has the effect of preventing physical irritation on the tongue and throat.

The components used in the present invention that become a viscous liquid when water is added include those that become partially or wholly viscous when 0.1 mg to 10 g are added to 1 mL of water. The content in the granules of the present invention is preferably 0.01% to 95%, more preferably 0.1% to 50%.

The granules of the present invention may be granules containing a soluble additive as an excipient. The soluble additive is an additive which is soluble in water and has a property of binding particles by physical or electrostatic action, and specific examples thereof include sugars, sugar alcohols, and amino acids. And derivatives thereof, polyols such as polyethylene glycol, solubilized cellulose derivatives, and soluble epoxy or acrylic polymers. The soluble acryl polymer in the examples of the soluble additive means a polymer in which an acrylic acid derivative and / or a methacrylic acid derivative is polymerized and is soluble. Among the soluble additives, sugars and sugar alcohols having preferably less than 24 carbon atoms are mentioned, more preferably mannitol, xylitol, sorbitol, erythritol and trehalose. By preparing granules using soluble additives, it has the characteristic of rapidly dissolving or disintegrating in the oral cavity and has the necessary strength. The active ingredient, excipient or active ingredient, which does not dissolve or disintegrate sufficiently even if it contains a component which becomes a viscous liquid when water is added according to the present invention, although it is easy to prepare granules that Is coated or matrixed with one or more coating agents selected from the group consisting of acrylic polymers, cellulose polymers, natural polymers, fats and oils, fats and oils, etc. Even in the case of granules containing the active ingredient that has become soluble, the ingestion can be improved to a higher degree without causing a feeling of roughness. Furthermore, the strength of the granules is increased by the binding force of the components that become a viscous liquid when water is added, and when a disintegrant that becomes a viscous liquid when water is used, Faster dissolution or disintegration rate. As a soluble additive, a powder or crystal having an average particle size of less than 50 zm, or a powder or crystal having an average particle size of less than 50 zm collected as primary particles, and having a mean particle size of 30 to 500 m. When a soluble additive in one of the following particle forms is used, its ingestibility is better, but the powder or crystal form has an average particle diameter of 50 m or more, and the powder or crystal has a mean particle diameter of less than 50 m. Even if the soluble additive is in the form of secondary particles having an average particle diameter of 500 zm or more, which are collected as primary particles, the ingestibility is good. Further, the soluble additive has an effect of rapidly dissolving or swelling a component which becomes a viscous liquid when water is added, and this combination is more preferable.

The granules of the present invention may contain various additives used for the production of general preparations, and the amount of addition may be the amount used for production of general preparations. Examples of such additives include sour agents, foaming agents, artificial sweeteners, flavors, lubricants, coloring agents, stabilizers, and solubilizers.

Examples of the sour agent include cunic acid, tartaric acid, malic acid and the like. Examples of the foaming agent include baking soda and the like. Artificial sweeteners include, for example, sodium saccharin, glycyrrhizin double-strength lime, aspartame, stevia,

—Matin and the like. Examples of the flavor include lemon, lemon lime, orange, beriichi stoguchi, vanilla, and menthol. Examples of the lubricant include magnesium stearate, sucrose fatty acid ester, polyethylene glycol, talc, stearic acid and the like. Coloring agents include, for example, food colors such as Food Yellow No. 5, Food Red No. 2, Food Blue No. 2, etc. Gala and the like. Examples of the stabilizer include antioxidants such as tocopherol and sodium sulfite, basic substances when the active ingredient is basic, and acidic substances when the active ingredient is acidic. Examples of the solubilizer include cyclodextrin, polysorbate, and sodium lauryl sulfate. The granules of the present invention can be produced by any of the methods generally used in the production of granules, such as fluidized bed granulation, stirring granulation, tumbling granulation, tumbling fluidized bed granulation, and extrusion granulation. I just need.

It is preferable to add a component that is hardly soluble in water or a sleeping liquid, a component that becomes a viscous liquid when water is added, and other components as necessary, and mix well. After mixing, granulate using purified water, ethanol, etc. When performing granulation by fluidized bed granulation, stirring granulation, tumbling granulation, tumbling fluidized bed granulation, extrusion granulation, etc., add the required amount of purified water, ethanol, etc. to the desired size. Granulate. At this time, purified water, ethanol and the like may be added together with the binder. After granulation, it is dried by a commonly used method. After granulation or drying, it is not always necessary to store in a special environment such as a humid environment. Granules can be obtained by classifying the dried granules with a desired sieve or the like. At this time, the pills, granules, fine granules and powders described in the Japanese Pharmacopoeia can be obtained by adjusting the aperture of the sieve. An antistatic agent or a flavoring / flavoring agent may be added to the obtained granules. It may be filled in a bottle or packed as a package.

Further, the granules thus obtained may be compression-molded with a tableting machine to produce tablets.

Hereinafter, the present invention will be described specifically with reference to Examples. Sun »Assault 暴开

Example 1

2 g of oxatomide, 0.5 g of hydroxypropyl methylcellulose 2910 (Shin-Etsu Chemical: TC-5E), 5.5 g of hydroxypropyl starch and 91.5 g of D-mannitol in a mortar, kneading with 15 mL of purified water I combined. The kneaded product is extruded and granulated by a granulator (Fuji Baudal: Dome Gran), and then dried (Ikeda The product was dried in a drying oven (Rikasha Co., Ltd.) to obtain granules.

Example 2

2 g of oxatomide, 2 g of hydroxypropyl cellulose (Nippon Soda: HPC-SSL), 5.5 g of hydroxypropyl starch and 90 g of: D-mannitol were mixed in a mortar, and kneaded by adding 15 mL of purified water. The kneaded product was granulated with an extrusion granulator (Dome Gran, manufactured by Fuji Baudal) and dried with a dryer (dried oven, manufactured by Ikeda Rika) to obtain granules.

Next, the strength and disintegration of the granules of the present invention will be described with reference to test examples.

Test example 1

The following tests were conducted on the strength and disintegration of the granules.

The strength of the granules is evaluated from the particle generation rate (%) when 1 g of the granules is placed in a test tube with a diameter of 15 mm and shaken up and down at 40 mm and shaken 300 times per minute for 60 minutes. Conducted a disintegration test according to the Japanese Pharmacopoeia13, and evaluated from the average disintegration time (sec).

As a result, the incidence of fine particles of the granules obtained in Examples 1 and 2 was less than 5%, respectively, and the average disintegration time was less than 15 seconds.

From the above, it was shown that the granules of the present invention had sufficient strength and good disintegration properties, and were granules that were free of roughness and easy to take.卜 available

According to the present invention, it is possible to obtain granules containing a component that is hardly soluble in water or saliva and that is easy to take without a feeling of roughness.

Claims

The scope of the claims

1. Granules with reduced roughness in the mouth when taken, characterized by containing a component that is hardly soluble in water or saliva and a component that becomes a viscous liquid when water is added.

2. The granule according to claim 1, wherein the component that is hardly soluble in water or saliva is an active ingredient and / or an excipient.

3. An ingredient that is hardly soluble in water or saliva, and the active ingredient is coated with one or more kinds of coating agents selected from the group consisting of acrylic polymers, cellulose polymers, natural polymers, oils and fats and oils or salts. 2. The granule according to claim 1, which is a matrixed active ingredient.

4. Poorly soluble components in water or saliva include autonomic nervous system drugs, somatic nervous system drugs, smooth muscle drugs, antihistamines, allergic drugs, central nervous system drugs, cardiovascular effects Drugs, diuretics, antidiuretics, drugs for the respiratory system, drugs for the digestive system, drugs for the blood and hematopoietic organs, hormones, vitamins, antidote, anti-infectives, antineoplastic drugs, immunological drugs, diagnostics 2. The granule according to claim 1, wherein the granule is one or more active ingredients selected from the group consisting of drugs and narcotics stimulants.

5. Insoluble components in water or saliva: acetilsviramycin, amoxicillin, ethyl icosapentate, itraconazole, oxatomide, gripzol, gluyuthione, ketofenilpuxone, cobamamide, cisapuri , Todolalazine hydrochloride, Trobisetron hydrochloride, Domperidone, Sodium valproate, Fluorouracil, Flunarizine hydrochloride, Flurazepam hydrochloride, Bendizipine hydrochloride, Minocycline hydrochloride, Mebendazole, Medroxyprogesterone, Ubidecarenone, Pyridoxalole 2. The granule according to claim 1, which is one or more active ingredients selected from the group consisting of:

6. The granule according to any one of claims 1 to 5, wherein the components that become a viscous liquid when water is added are a binder and a disintegrant.

7. The components that become viscous liquids when water is added include hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, polyvinyl alcohol, polyethylene oxide, pullulan, sodium alginate, gelatin, agar, copolydon, Corn starch, potato starch, The binder according to any one of claims 1 to 5, wherein the binder is one or more binders and / or disintegrators selected from the group consisting of pregelatinized starch, carboxymethyl starch sodium, and hydroxypropyl starch. The granules as described.

8. The component that is hardly soluble in water or saliva is oxatomide, and the component that becomes a viscous liquid when added to water is from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, and hydroxypropylstarch. 2. The granule according to claim 1, which is at least two kinds selected.

9. The granule according to any one of claims 1 to 8, comprising a soluble additive.

10. A tablet obtainable by compression-molding the granule according to any one of claims 1 to 9 with a tableting machine.

11. An agent for improving the ingestibility of granules containing a component that is hardly soluble in water or saliva, characterized by containing a component that becomes a viscous liquid when water is added.

12. The agent for improving the ingestibility of granules according to claim 11, wherein the component that is hardly soluble in water or saliva is an active ingredient and a diluent.

13. The ingestibility improving agent for granules according to claim 11 or 12, wherein the components that become a viscous liquid when water is added are a binder and Z or a disintegrant.

14. An agent for reducing roughness in the oral cavity when taking granules containing a component that is hardly soluble in water or saliva, characterized by containing a component that becomes a viscous liquid when water is added. .

15. The roughness reducing agent according to claim 14, wherein the component that is hardly soluble in water or saliva is an active ingredient and Z or an excipient.

16. A component that is hardly soluble in water or saliva, the active component is coated with one or more coating agents selected from the group consisting of acryl polymers, cellulose polymers, natural polymers, fats and oils and fats or salts. 15. The roughness reducing agent according to claim 14, which is a matrix-forming active ingredient.

17. Poorly soluble components in water or saliva include autonomic nervous system drugs, somatic nervous system drugs, smooth muscle drugs, antihistamines, allergic drugs, central nervous system drugs, cardiovascular effects Drugs, diuretics, antidiuretics, respiratory drugs, digestive drugs, blood and hematopoietic organ drugs, hormones, vitamins, antidote drugs, anti-infective drugs, antineoplastic drugs, immunological drugs, diagnostics One selected from the group consisting of drugs and narcotics' stimulants Or the zarakki sensation reducing agent according to claim 14, which is two or more active ingredients.

18. Insoluble ingredients in water or saliva: acetilsviramycin, amoxicillin, ethyl icosapentate, traconazole, oxatomid, gribzol, gluduthione, ketofenylbuzozon, kobamamid, Cisapride, Todralazine hydrochloride, Tropisetron hydrochloride, Domperidone, Sodium valproate, Fluorouracil, Flunarizine hydrochloride, Flurazepam hydrochloride, Bendizipine hydrochloride, Minocycline hydrochloride, Mebendazol, Medroxyprogesterone, Ubidecarenone, Phosphate 15. The roughness reducing agent according to claim 14, which is one or more active ingredients selected from the group consisting of pyridoxal and lepodova.

19. The graininess reducing agent according to any one of claims 14 to 18, wherein the components that become a viscous liquid when water is added are a binder and Z or a disintegrant.

20. The components that become a viscous liquid when water is added are hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, polyvinyl alcohol, polyethylene oxide, pullulan, sodium alginate, gelatin, agar, copolydon, One or more binders selected from the group consisting of corn starch, potato starch, pregelatinized starch, carboxymethyl starch sodium and hydroxypropyl starch, and Z or a disintegrant. -: The sarazuki sensitizer according to any of 18 above.

21. The component that is hardly soluble in water or saliva is oxatomide, and the component that becomes a viscous liquid when added to water is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropyl cellulose, and hydroxypropyl starch. 15. The roughness reducing agent according to claim 14, which is at least two members selected.

22. The roughness reducing agent according to any one of claims 14 to 21, comprising a soluble additive.

23. A granule containing a component that is hardly soluble in water or saliva, characterized by containing a component that becomes a viscous liquid when water is added, and can be obtained by compression molding with a tableting machine. A roughening agent for tablets that can be used.

24. The ingredient that is hardly soluble in water or saliva contains the active ingredient and 24. The agent for reducing roughness of tablets according to claim 23, which is a form.

25. The agent of claim 23 or 24, wherein the component that becomes a viscous liquid when water is added is a binder and / or a disintegrant.

26. A method for improving the ingestibility of a granule, comprising adding a component which becomes a viscous liquid when water is added to a granule containing a component which is hardly soluble in water or saliva.

27. The method for improving the ingestibility of granules according to claim 26, wherein the component that is hardly soluble in water or saliva is an active ingredient and Z or an excipient.

28. The method for improving the ingestibility of granules according to claim 26 or 27, wherein the component which becomes a viscous liquid when water is added is a binder and / or a disintegrant.

29. Granules containing a component that is hardly soluble in water or saliva, and a component that becomes a viscous liquid when water is added to the granule, wherein the granules in the oral cavity are taken when the granule is taken. Feeling reduction method.

30. The method according to claim 29, wherein the component that is hardly soluble in water or saliva is an active ingredient and Z or an excipient.

31. A component which is hardly soluble in water or saliva, the active component is coated with one or more coating agents selected from the group consisting of acrylic polymers, cellulose polymers, natural polymers, fats and oils and fat salts. 30. The method for reducing roughness feeling according to claim 29, wherein the active ingredient is a matrix.

32. Poorly soluble components in water or saliva include autonomic nervous system drugs, somatic nervous system drugs, smooth muscle drugs, antihistamines, allergic drugs, central nervous system drugs, cardiovascular effects Drugs, diuretics, antidiuretics, respiratory drugs, digestive drugs, blood and hematopoietic organ drugs, hormones, vitamins, antidote drugs, anti-infective drugs, antineoplastic drugs, immunological drugs, diagnostics 30. The method according to claim 29, wherein the method is one or more active ingredients selected from the group consisting of drugs and narcotics' stimulants.

33. Insoluble components in water or saliva: acetilsviramycin, amoxicillin, ethyl icosapentate, itraconazole, xanthoxamide, gribuzole, guruzion, ketofenerupuzon, kobamamid, cisapuri Tolralazine hydrochloride, tropisetron hydrochloride, domperidone, sodium valproate, fluorouracil, flunarizine hydrochloride, flurazepam hydrochloride, benix hydrochloride 30. The method according to claim 29, wherein the active ingredient is one or more active ingredients selected from the group consisting of dipine, minocycline hydrochloride, mebendazole, medroxyprogesterone, ubidecarenone, pyridoxal phosphate, and lepodova. .

34. The method for reducing graininess according to any one of claims 29 to 33, wherein the components that become a viscous liquid when water is added are a binder and Z or a disintegrant.

35. The components that become viscous liquids when water is added are hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, polyvinyl alcohol, polyethylene oxide, pullulan, sodium alginate, gelatin, agar, copolydon, Claims 29 to 33 which are one or more binders and / or disintegrators selected from the group consisting of corn starch, potato starch, pregelatinized starch, carboxymethyl starch sodium and hydroxypropyl starch. The method for reducing a feeling of roughness described in any one of the above.

36. Oxatomid is a component that is hardly soluble in water or saliva, and components that become a viscous liquid when water is added are hydroxypropylmethylcellulose, hydroxypropylcellulose, and hydroxypropylstarch. 30. The roughness reducing method according to claim 29, wherein the method is two or more selected from the group consisting of:

37. The method for reducing roughness as described in any one of claims 29 to 36, further comprising a soluble additive.

38. Tablets that can be obtained by compression-molding granules containing components that are hardly soluble in water or saliva with a tableting machine are added with components that become viscous liquids when water is added to tablets. A method for reducing roughness in the oral cavity when taking the tablet.

39. The method according to claim 38, wherein the component that is hardly soluble in water or saliva is an active ingredient and an excipient.

40. The method according to claim 38 or 39, wherein the component that becomes a viscous liquid when water is added is a binder and / or a disintegrant.