WO2013062073A1 - 低用量ラモセトロン含有口腔内崩壊錠 - Google Patents
低用量ラモセトロン含有口腔内崩壊錠 Download PDFInfo
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- WO2013062073A1 WO2013062073A1 PCT/JP2012/077687 JP2012077687W WO2013062073A1 WO 2013062073 A1 WO2013062073 A1 WO 2013062073A1 JP 2012077687 W JP2012077687 W JP 2012077687W WO 2013062073 A1 WO2013062073 A1 WO 2013062073A1
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- Prior art keywords
- orally disintegrating
- disintegrating tablet
- ramosetron
- tablet according
- less
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
Definitions
- the present invention relates to an orally disintegrating tablet containing a low dose of ramosetron or a pharmaceutically acceptable salt thereof.
- the present invention relates to an orally disintegrating tablet with improved absorbability for the treatment of irritable bowel syndrome, containing a low dose of ramosetron or a pharmaceutically acceptable salt thereof.
- Ramosetron has the chemical name (-)-(R) -5-[(1-methyl-1H-indol-3-yl) carbonyl] -4,5,6,7-tetrahydro-1H-benzimidazole.
- Patent Document 1 discloses that a series of tetrahydrobenzimidazole derivatives including ramosetron and a pharmaceutically acceptable salt thereof have a 5HT 3 receptor antagonistic action. Based on this effect, it is suggested that cancer drugs such as cisplatin and the prevention and treatment of vomiting due to radiation may be prevented. Clinical dosage is usually 0.1 mg to 10 mg intravenously per day for adults, 0.5 mg or more orally It is 50 mg or less, and it is described that this is administered once or divided into several times.
- Non-Patent Documents 1 and 2 an orally disintegrating tablet containing 0.1 mg of ramosetron hydrochloride, which is effective and effective for digestive symptoms (nausea, vomiting) associated with administration of an antineoplastic agent (cisplatin, etc.), is “Nazea ( (Registered trademark) OD tablet 0.1 mg "is described in Japan.
- the orally disintegrating tablet contains lactose hydrate, D-mannitol, aspartame, agar powder, yellow ferric oxide and ferric oxide in addition to ramosetron hydrochloride.
- Patent Document 2 discloses a density of 400 mg / ml to 1000 mg / ml of an active ingredient, a saccharide comprising lactose and / or D-mannitol, and a solid content of 0.12 w / w% to 1.2 w / w%.
- An invention relating to an orally disintegrating solid preparation having sufficient strength for handling the preparation is disclosed, and in claim 4, the active ingredient is (R) -5-[(1-methyl-3-indolyl)
- An invention relating to an orally disintegrating solid preparation containing carbonyl] -4,5,6,7-tetrahydro-1H-benzimidazole hydrochloride (ramosetron hydrochloride) is described.
- the solid preparation has a structure mainly composed of sugar, and is rapidly weakened by saliva in the oral cavity and gradually disintegrates or dissolves.
- Kanten which is an additive other than sugar, facilitates the handling of the preparation in the production process, ensures uniformity of content, does not lose its shape, and has an orally disintegrating solid that has sufficient strength for handling. It has been added to provide a formulation.
- Patent Document 3 a preparation containing ramosetron hydrochloride of 0.002 mg or more and 0.02 mg or less, or equimolar amount of ramosetron or 0.002 mg or more and 0.02 mg or less of ramosetron or other pharmaceutically acceptable salt is a diarrhea type. It is described as being useful as a therapeutic agent for irritable bowel syndrome. Further, Example 2 of Patent Document 3 describes an orally disintegrating tablet containing ramosetron hydrochloride.
- Non-Patent Documents 3 and 4 tablets containing 2.5 ⁇ g or 5 ⁇ g of ramosetron hydrochloride, which are effective for diarrhea-type irritable bowel syndrome, are “Iribo (registered trademark) 2.5 ⁇ g” and “Iribo (registered trademark)”. ) Tablets 5 ⁇ g ”.
- Nazea OD pharmaceutical package insert Nazea OD pharmaceutical interview form Iribo Tablets package insert Iribo Tablets Drug Interview Form
- An object of the present invention is to provide an orally disintegrating tablet containing a low dose of ramosetron or a pharmaceutically acceptable salt thereof.
- Another object of the present invention is to provide an orally disintegrating tablet containing a low dose of ramosetron or a pharmaceutically acceptable salt thereof and useful as a therapeutic agent for diarrhea-type irritable bowel syndrome.
- Still another object of the present invention is to provide an orally disintegrating tablet containing a low dose of ramosetron or a pharmaceutically acceptable salt thereof and having bioequivalence with Iribo (registered trademark) tablets (ordinary tablets). It is to provide.
- Iribo (registered trademark) tablets normal tablets containing 2.5 ⁇ g or 5 ⁇ g of ramosetron hydrochloride are used for diarrhea-type irritable bowel syndrome.
- Nazea OD an orally disintegrating tablet containing a high dose of ramosetron already has bioequivalence (BE) to a normal tablet.
- Nazea OD is an orally disintegrating tablet disclosed in Patent Document 2, but after that, a simpler production method considering mass production has been selected, and orally disintegrating tablets of other drugs have been marketed.
- the amount of ramosetron or a pharmaceutically acceptable salt thereof is smaller than that of josea OD and stability is lowered.
- an orally disintegrating tablet containing a low dose of ramosetron the present inventors first included a low dose of ramosetron hydrochloride (20 ⁇ g as ramosetron) in the preparation,
- An orally disintegrating tablet comprising a known formulation (Production Example 1 described later) containing the same stabilizer contained in a registered trademark (refer to Japanese Patent No. 3689104 for a method for preparing an orally disintegrating tablet).
- a known formulation Production Example 1 described later
- a registered trademark reference to Japanese Patent No. 3689104 for a method for preparing an orally disintegrating tablet
- an orally disintegrating tablet composed of a known formulation (Production Example 1 described later) is orally administered to dogs (for gastrointestinal movement, oral gastric forced administration that disintegrates and dissolves in the stomach and moves to the small intestine).
- dogs for gastrointestinal movement, oral gastric forced administration that disintegrates and dissolves in the stomach and moves to the small intestine.
- a suspension in which the orally disintegrating tablet is dispersed in water is orally administered to a dog.
- Pharmacokinetics-Parameters compared with normal tablets were compared.
- Cmax is equivalent in the method in which the normal tablet and the orally disintegrating tablet are orally administered (oral intragastric forced administration), and in the method in which the orally disintegrating tablet is orally administered (oral administration) as a suspension, It was found that it decreased compared to the tablet.
- the present inventors conducted extensive studies focusing on the effect of not lowering Cmax of ramosetron compared to ordinary tablets when orally administering a low dose ramosetron orally disintegrating tablet, Surprisingly, it has been found that kantene powder added as a suspending agent to Nazea OD tablets (high dose ramosetron-containing orally disintegrating tablets) has this action. It was also found that orally disintegrating tablets containing low-dose ramosetron hydrochloride and agar powder form normal tablets and BE in humans. As a result of further investigations, the present inventors have completed the present invention.
- the present invention [1] (a) 0.001 mg to 0.05 mg of ramosetron hydrochloride, or (b) 0.001 mg to 0.05 mg of ramosetron hydrochloride and an equimolar amount of ramosetron or a pharmaceutically acceptable salt thereof, and agar and / or Orally disintegrating tablets containing agar powder, [2] containing (a) 0.00125 mg or more and 0.025 mg or less of ramosetron hydrochloride, or (b) 0.00125 mg or more and 0.025 mg or less of ramosetron hydrochloride and an equimolar amount of ramosetron or a pharmaceutically acceptable salt thereof, Orally disintegrating tablet according to 1], [3] The oral cavity according to [1] or [2], wherein the amount of kantene and / or kanteng powder is 10% by weight or more and 500,000% by weight or less based on ramosetron or a pharmaceutically acceptable
- Disintegrating tablets [4] The orally disintegrating tablet according to [1] or [2], wherein the amount of agar and / or agar powder is 0.001 wt% or more and 70 wt% or less per unit preparation, [5] An orally disintegrating tablet according to any one of [1] to [4] for the treatment of diarrhea-type irritable bowel syndrome, [6] The orally disintegrating tablet according to any one of [1] to [5], which is bioequivalent to 2.5 ⁇ g of Iribo (registered trademark) tablet or 5 ⁇ g of Iribo (registered trademark) tablet, [7] The orally disintegrating tablet according to any one of [1] to [6], further comprising a stabilizer, [8] The orally disintegrating tablet according to [7], wherein the stabilizer is hydroxycarboxylic acid, [9] The orally disintegrating tablet according to [8], wherein the hydroxycarboxylic acid is one or more substances selected from the group consisting of tartaric acid, malic
- Tablets [12] The orally disintegrating tablet according to any one of [1] to [11], further comprising a saccharide, [13] The orally disintegrating tablet according to [12], wherein the saccharide is a saccharide having a high moldability and / or a saccharide having a low moldability.
- saccharide having high moldability is one or two or more substances selected from the group consisting of maltose, maltitol, sorbitol, and trehalose
- saccharide having low formability is one or two or more substances selected from the group consisting of lactose, D-mannitol, glucose, sucrose, xylitol, and erythritol.
- Iribo containing (a) 0.001 mg or more and 0.05 mg or less of ramosetron hydrochloride, or (b) 0.001 mg or more and 0.05 mg or less of ramosetron hydrochloride and an equimolar amount of ramosetron or a pharmaceutically acceptable salt thereof.
- Kanten and / or Kanten powder for the production of orally disintegrating tablets that are bioequivalent to 2.5 ⁇ g of (R) tablets or 5 ⁇ g of Iribo® tablets, [17]
- An orally disintegrating tablet containing at least 0.00125 mg to 0.025 mg of ramosetron hydrochloride, agar and / or agar powder, D-mannitol, and maltose per unit preparation, I will provide a.
- the present invention can provide an orally disintegrating tablet containing a low dose of ramosetron or a pharmaceutically acceptable salt thereof and useful as a therapeutic agent for diarrhea-type irritable bowel syndrome.
- the present invention also provides an orally disintegrating tablet containing ramosetron or a pharmaceutically acceptable salt thereof and having bioequivalence to a normal tablet containing ramosetron hydrochloride. Play.
- low dose means that ramosetron or a pharmaceutically acceptable salt thereof is contained and the dose is low (small). Specifically, it means lower (smaller) than the dose of josea, 0.1 mg.
- the “orally disintegrating tablet” means a tablet that disintegrates or disintegrates / dissolves in the oral cavity.
- an oral disintegration time for example, when a tablet is taken without ingesting water, it is within 3 minutes by saliva only in the oral cavity, within 2 minutes as another embodiment, within 1 minute as another embodiment, and further As an embodiment, it is defined as a tablet that disintegrates within 45 seconds, or a preparation similar to a tablet.
- the “orally disintegrating tablet” is actually an “orally disintegrating tablet”, but also includes tablets described as orally administered as a usage. Embodiments also include tablets described as oral gastric gavage.
- “ordinary tablet” means a tablet that disintegrates and dissolves in the stomach after oral administration with a liquid such as water, for example, as gastrointestinal movement.
- “Iribo (registered trademark) tablets” containing 2.5 ⁇ g or 5 ⁇ g of ramosetron hydrochloride are “ordinary tablets”.
- bioequivalent means that the ratio of geometric average values of AUC and Cmax of ramosetron to the control preparation (eg, normal tablet) of the preparation to be tested is 0.80 or more and 1.25 or less, respectively, in the in vivo test. (80% or more and 125% or less).
- Ramosetron and pharmaceutically acceptable salts thereof can be easily obtained by the production method described in Patent Document 1 or according thereto.
- salts of ramosetron include mineral acid salts such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid, acetic acid, oxalic acid, succinic acid, citric acid, maleic acid, and apples.
- mineral acid salts such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid
- acetic acid oxalic acid
- succinic acid citric acid, maleic acid, and apples.
- salts with acids fumaric acid, tartaric acid, organic acids such as methanesulfonic acid
- salts with acidic amino acids such as glutamic acid and aspartic acid.
- commercially available ramosetron hydrochloride is preferred. These salts can be used alone or in combination of two or more.
- the orally disintegrating tablet of the present invention is 0.001 mg to 0.05 mg, or 0.00125 mg to 0.025 mg, or 0.00125 mg to 0.005 mg, or 0.002 mg to 0.005 mg, or 0.00125 mg per tablet (unit preparation). Or 0.0025 mg, or 0.005 mg, or 0.0226 mg of ramosetron or a pharmaceutically acceptable salt thereof.
- the content of ramosetron or a pharmaceutically acceptable salt thereof per unit preparation can be 0.0001 wt% or more and 0.01 wt% or less.
- the dose of ramosetron or a pharmaceutically acceptable salt thereof is appropriately determined according to individual cases in consideration of the administration route, the symptoms of the disease, the age, race, sex, etc. of the administration subject.
- the orally disintegrating tablet of the present invention is used, and 0.001 mg to 0.05 mg or less of ramosetron hydrochloride and equimolar amount of ramosetron or a pharmaceutically acceptable product thereof per day Salt can be administered.
- Ramosetron hydrochloride can be administered at a daily dose of 0.001 mg to 0.05 mg, preferably 0.00125 mg to 0.025 mg, or 0.0025 mg to 0.01 mg, or 0.005 mg to 0.01 mg per adult. It is preferable to administer once a day after meals.
- the orally disintegrating tablet of the present invention contains agar and / or agar powder.
- Kanten (agar) is composed of polysaccharides with galactose as the basic skeleton, and is classified into agarose rich in neutral gelling ability and agaropectin without ionic gelling ability.
- the structure of agarobiose which is a repeating unit of agarose, consists of ⁇ -D-galactopyranose bonded at the 1st and 3rd positions and 3,6 anhydro- ⁇ -L-galactobilanose bonded at the 1st and 4th positions.
- Agaropectin contains all ionic polysaccharides other than agarose in agar and / or agar powder, and its structure is the same as that of agarose, but is partially sulfated, methoxyl, pyruvate, carboxyl Contains groups.
- the molecular weight of kanteng and / or kanteng powder varies depending on the degree of hydrolysis when extracted from seaweed, but is generally several thousand or more and tens of thousands or less.
- Kanten powder is powdered Kanten powder and is not particularly limited in shape, particle size and the like.
- the agar and / or agar powder used in the present invention can be used singly or in combination.
- the content of agar and / or agar powder in the orally disintegrating tablet of the present invention is not particularly limited as long as it can be added pharmaceutically.
- the content of agar and / or agar powder is 0.001% to 70% by weight per unit preparation, 0.01% to 30% by weight in another embodiment, 0.05% to 10% in a further embodiment. It can be less than wt%.
- various pharmaceutical additives are appropriately blended as desired to prepare a preparation.
- a pharmaceutical additive is not particularly limited as long as it is pharmaceutically acceptable and pharmacologically acceptable.
- excipients for example, excipients, stabilizers, binders, disintegrants, acidulants, foaming agents, artificial sweeteners, fragrances, lubricants, colorants, buffers, antioxidants, surfactants Etc.
- excipients examples include D-mannitol and lactose hydrate.
- the stabilizer for example, a compound having a carbonyl group, which stabilizes ramosetron or a pharmaceutically acceptable salt thereof.
- the compound having a carbonyl group include aliphatic carboxylic acids (specifically, saturated or unsaturated, linear or branched aliphatic mono-, di- or tri-carboxylic acids.
- a hydroxycarboxylic acid having 3 to 36 carbon atoms or an ester thereof, an acidic amino acid, an enolic acid, an aromatic carboxyl compound (specifically, an alkyl or hydroxy group having 1 to 4 carbon atoms is substituted)
- Aromatic mono-, di- or tri-carboxylic acids, especially aromatic carboxylic acids having 7 to 20 carbon atoms) or their esters, polymeric substances having a carboxyl group The recited, these compounds may be appropriately used in combination of two or more.
- the specific compound having a carbonyl group is preferably a hydroxycarboxylic acid or an ester thereof, a polymer substance having a carboxyl group, an aromatic carboxyl compound or an ester thereof, or an enolic acid, particularly a hydroxycarboxylic acid or an ester thereof, a carboxyl
- a polymer substance having a group, an aromatic carboxyl compound or an ester thereof is preferable, and a hydroxycarboxylic acid or an ester thereof or a polymer substance having a carboxyl group is more preferable.
- the aliphatic carboxylic acid is preferably maleic acid, malonic acid, succinic acid, or fumaric acid.
- hydroxycarboxylic acid tartaric acid, malic acid and citric acid are preferable, and tartaric acid and citric acid are more preferable. More preferred is citric acid.
- the acidic amino acid is preferably glutamic acid or aspartic acid.
- the aromatic carboxyl compound is preferably phthalic acid or propyl gallate, and more preferably propyl gallate.
- Preferred as the polymer substance having a carboxyl group is carboxymethyl cellulose or alginic acid, and more preferred is carboxymethyl cellulose.
- enolic acid is preferably ascorbic acid or erythorbic acid, and more preferably ascorbic acid.
- hydrates and anhydrides having no water of crystallization such as citric acid hydrate or citric acid anhydride
- a hydrate, an anhydride, or a mixture thereof is included.
- the degree of polymerization and the molecular weight of the polymer substance are not particularly limited, but in the case of carboxymethyl cellulose, a weight average molecular weight of about 110,000 is particularly preferable, and that of alginic acid is preferably about 200,000.
- binder examples include gum arabic, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, maltose and the like.
- disintegrant examples include corn starch, potato starch, carmellose calcium, carmellose sodium, and low-substituted hydroxypropylcellulose.
- sour agent examples include citric acid, tartaric acid, malic acid and the like.
- foaming agents examples include baking soda.
- artificial sweetener examples include saccharin sodium, dipotassium glycyrrhizin, aspartame, stevia and thaumatin.
- fragrances include lemon, lemon lime, orange and menthol.
- lubricant examples include light anhydrous silicic acid, magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene glycol, talc, stearic acid and the like.
- colorant examples include yellow ferric oxide, red ferric oxide, black iron oxide, titanium oxide, edible yellow No. 4, No. 5, edible red No. 3, No. 102, and edible blue No. 3.
- yellow iron sesquioxide, red iron sesquioxide, black iron oxide, and titanium oxide also act as light stabilizers.
- Preferred light stabilizers are yellow ferric oxide and red ferric oxide.
- Buffers include citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid or salts thereof, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine or salts thereof, magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid Boric acid or a salt thereof.
- antioxidants examples include ascorbic acid, dibutylhydroxytoluene, propyl gallate and the like.
- surfactant examples include polysorbate 80, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil, and the like.
- Pharmacological additives can be appropriately added in an appropriate amount by combining one or more kinds.
- the blending amount of the stabilizer is not limited as long as it stabilizes ramosetron or a pharmaceutically acceptable salt.
- it is 0.01 wt% or more and 90 wt% or less per unit preparation, preferably 0.01 wt% or more and 50 wt% or less, more preferably 0.1 wt% or more and 10 wt% or less.
- the amount of light stabilizer to be blended is determined according to the type of colorant and the method of addition. For example, it is usually 0.1 to 20% by weight, preferably 0.2 to 10% by weight, more preferably 0.2 to 5% by weight, based on the entire composition.
- Orally disintegrating tablets are generally roughly classified into a mold type, a wet type, and a normal tableting type, but the orally disintegrating tablet of the present invention may be any type.
- the mold-type orally disintegrating tablet is prepared by filling a mold with a solution or suspension such as an excipient as disclosed in, for example, Japanese Patent No. 2807346 (US Patent No. 5466464). Can be manufactured by drying.
- the mold-type orally disintegrating tablet comprises, for example, a solution or suspension containing ramosetron or a pharmaceutically acceptable salt thereof, agar or agar powder, and various pharmaceutical additives blended as necessary.
- a solution or suspension containing ramosetron or a pharmaceutically acceptable salt thereof agar or agar powder, and various pharmaceutical additives blended as necessary.
- After filling the PTP pocket it can be produced by removing moisture by a method such as freeze drying, drying under reduced pressure, or low temperature drying.
- Wet type orally disintegrating tablets are moistened with excipients such as saccharides as shown in Patent No. 3069458 (U.S. Pat. No. 5,018,618, U.S. Pat. No. 5,720,974).
- the tablet is produced by tableting under low pressure and then drying.
- ramosetron or a pharmaceutically acceptable salt thereof, an excipient such as a saccharide, and agar and / or agar powder are moistened with a small amount of water or a mixture of water and alcohol, and the moist mixture is subjected to low pressure. After molding, it can be produced by drying.
- a pharmaceutically acceptable salt, agar and / or agar powder, and an excipient such as a low moldability saccharide, and a solution or suspension of a high moldability saccharide or a water-soluble polymer are used.
- the granulated product can be compression-molded to form a compressed molded product, or the compressed molded product can be further humidified and dried to produce an orally disintegrating tablet.
- a normal tablet type orally disintegrating tablet as shown in International Publication No.
- WO99 / 47124 (US Pat. No. 6,658,954), for example, ramosetron or its pharmaceutical Orally-acceptable salts, sugar and / or agar powder, saccharides such as D-mannitol, maltitol, erythritol, and xylitol, and amorphous saccharides. Can be made.
- a normal tablet-type orally disintegrating tablet as disclosed in WO 2002/92057 pamphlet (US 2003/099701 specification), for example, ramosetron or A mixture of the pharmaceutically acceptable salt, agar and / or agar powder, and an excipient and a saccharide having a “melting point having a lower melting point” than that of the excipient is compression-molded and heated.
- An orally disintegrating tablet can be prepared by forming a crosslink by melting and solidifying a saccharide having a low melting point. By such humidification drying or heat treatment, the tablet strength of the orally disintegrating tablet can be improved.
- a normal tablet type orally disintegrating tablet as disclosed in International Publication No.
- WO2008 / 032767 (U.S. Patent Application Publication No. 2008/0085309), for example, ramosetron or Oral disintegration by compression molding a mixture of the pharmaceutically acceptable salt, agar and / or agar powder, and excipients and processed starches having a pregelatinization degree of 30% to 60% Tablets can be prepared.
- a general excipient can be used, but it is particularly preferable to use a pharmaceutically acceptable saccharide, and a technique utilizing the moldability of the saccharide.
- a pharmaceutically acceptable saccharide In the case of using saccharides with low moldability, crystalline / amorphous saccharides, and tablet strength improvement technology by humidification drying, it is common to use cross-linking technology with crystalline saccharides and saccharide melt-solidified products.
- high melting point saccharides can be used.
- the saccharide having low moldability means, for example, when tableting 150 mg of saccharide with a punch having a diameter of 8 mm at a tableting pressure of 10 kg / cm 2 or more and 50 kg / cm 2 or less, the hardness of the tablet is 0 kp or more and 2 kp or less.
- the term “highly moldable saccharide” means that the hardness by the same method is 2 kp or more.
- Saccharides with low moldability are pharmaceutically acceptable, and examples thereof include lactose, D-mannitol, glucose, sucrose, xylitol, erythritol and the like. One or more of these may be used in appropriate combination.
- Saccharides with high moldability are pharmaceutically acceptable, and examples thereof include maltose, maltitol, sorbitol, oligosaccharides and trehalose. These saccharides can also be used alone or in combination of two or more.
- Amorphous saccharides are pharmaceutically acceptable and include, for example, lactose, sucrose, glucose, sorbitol, maltose, trehalose and the like, and these saccharides may be used alone or in combination of two or more. It is also possible to use it.
- the “sugar having a low melting point” is pharmaceutically acceptable, and examples thereof include xylitol and trehalose. These saccharides can also be used alone or in combination of two or more.
- binders for orally disintegrating tablets include maltitol and copolyvidone. Such binders can be used alone or in combination of two or more.
- a water-soluble polymer for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, polyvinyl alcohol, gum arabic powder, gelatin, pullulan and the like are suitable.
- ⁇ -ized means that when physical treatment is applied to starch, water enters between the molecules and swells (gelatinizes). Become.
- processed starch include corn starch, wheat starch, potato starch, rice starch, tapioca starch and the like.
- the amount of excipient used in the orally disintegrating tablet of the present invention is appropriately adjusted. For example, it is usually 20 mg to 1000 mg per tablet, 50 mg to 900 mg as another embodiment, and 70 mg to 800 mg as a further embodiment. Hereinafter, it is 35 mg or more and 400 mg or less as another aspect.
- the blending amount of highly moldable saccharides, water-soluble polymers, amorphous saccharides, and saccharides with a low melting point is 0.5 wt. % Or more and 40% by weight or less is preferable, and in another aspect, it is 2% by weight or more and 30% by weight or less, and in a further aspect, it is 5% by weight or more and 20% by weight or less, or % Or less is preferred.
- Kanten and / or Kanten powder there is no particular limitation on the timing of adding Kanten and / or Kanten powder as long as it can produce a preparation that achieves the desired effect of the present invention.
- a pulverization process, a mixing process, or a granulation process is preferred.
- the pulverization step is not particularly limited as long as it is a pharmaceutically pulverization method, as long as it is a pharmaceutically pulverization method.
- the pulverizer include a hammer mill, a ball mill, and a jet mill.
- the grinding conditions are not particularly limited as long as they are appropriately selected.
- the mixing method is not particularly limited as long as it is a method in which each component is generally uniformly mixed pharmacologically.
- Examples of the mixing apparatus include a V-type mixer, a ribbon-type mixer, a container mixer, and a high-speed stirring mixer.
- the mixing conditions are not particularly limited as long as they are appropriately selected.
- Examples of the granulating step granulator include a fluidized bed granulator.
- granulation methods for example, fluidized bed granulation method, melt granulation method, high speed stirring granulation method, crushing (pulverization) granulation method, extrusion granulation method, rolling granulation method, spray granulation method, dry method Examples include granulation methods.
- Another embodiment is a fluidized bed granulation method.
- the method includes a method of dissolving citric acid in a binder solution for drug stabilization (see WO2004 / 066998 for stabilization of ramosetron with citric acid).
- the binder solution is prepared by dissolving or dispersing the binder in a solvent such as water, ethanol or methanol. Further, these solvents can be appropriately mixed and used.
- the preparation conditions of the spray liquid are not particularly limited as long as they are appropriately selected.
- the drying method is not particularly limited as long as it is a pharmaceutically drying method.
- ventilation drying and reduced pressure drying are mentioned.
- a granulated product or a mixture of granulated products mixed with various pharmaceutical additives is filled into capsules to form capsules, or compressed into tablets using a rotary tableting machine. be able to.
- the compression step is not particularly limited as long as it is a method for molding the pharmaceutical composition of the present invention. Specifically, for example, a direct tableting method in which a tablet is obtained by compression molding after mixing a drug and an appropriate pharmaceutical additive, and a method in which a lubricant is further mixed with the granulated product and then compression molding is performed to produce a tablet. It is done.
- Examples of the tableting device include a rotary tableting machine, a single-shot tableting machine, and an oil press. Tableting conditions such as tableting pressure are not particularly limited as long as the tablet can be molded and the tableting pressure does not damage the tablet during the production process.
- Humidification and drying process As described in International Publication No. WO95 / 20380 pamphlet (US corresponding patent No. 5576014), when an orally disintegrating tablet is produced using a sugar having low moldability, In order to increase the hardness, humidification and drying processes can be employed. “Humidification” is determined by the apparent critical relative humidity of the saccharides contained, but usually humidifies above its critical relative humidity. For example, the humidity is 30 RH% or more and 100 RH% or less, and in another aspect, it is 50 RH% or more and 90 RH% or less. The temperature at this time is preferably 15 ° C. or more and 50 ° C. or less, and in another embodiment, it is 20 ° C. or more and 40 ° C. or less.
- the treatment time is 1 hour or more and 36 hours or less, and in another aspect, it is 12 hours or more and 24 hours or less.
- “Drying” is not particularly limited as long as it is a step of removing moisture absorbed by humidification.
- the temperature condition for drying can be set to 10 ° C. or higher and 100 ° C. or lower, and as another mode, 20 ° C. or higher and 60 ° C. or lower can be set, and as a further mode, 25 ° C. or higher and 40 ° C. or lower can be set.
- the treatment time can be 0.5 hours or more and 6 hours or less, and in another aspect, it can be 1 hour or more and 4 hours or less.
- an orally disintegrating tablet is produced using an excipient with a high melting point and a low sugar.
- a heating step can be employed to increase the hardness of the prepared molded product. “Heating” is determined by the melting point of the saccharide having a low melting point, and is usually heated to a temperature not lower than the melting point of the excipient having a high melting point and not lower than the melting point of the saccharide having a low melting point.
- the treatment time can be 0.5 minutes or more and 120 minutes or less, and in another aspect, it can be 1 minute or more and 60 minutes or less.
- agar and / or agar powder is used in the orally disintegrating tablet of the present invention.
- an orally disintegrating tablet having bioequivalence to a normal tablet can be provided. This is thought to be because Kanten and / or Kanten powder have a function of suppressing the delay of movement speed and absorption of ramosetron or a pharmaceutically acceptable salt thereof in the oral cavity or esophagus.
- Ramosetron used was produced by the method described in Example 44 of JP-B-6-25153.
- D-mannitol (Pearlitol 50C, made by rocket, the same thing was used unless otherwise specified) 8 parts, maltose 3 parts, red iron sesquioxide (iron sesquioxide S, made by Hatake Kasei, especially hereafter) When there is no description, the same one was used.) After mixing and grinding 1 part, 79.8 parts of D-mannitol was charged into a fluidized bed granulator (FLOW COATER, manufactured by Freund) and sprayed with the spray solution. Fluidized bed granulated.
- FLOW COATER manufactured by Freund
- the granulated product was dried until the product temperature reached 40 ° C, and then 1 part of magnesium stearate (Parteck LUB MST, manufactured by Merck, unless otherwise specified) was used.
- the mixed powder was tableted at 120 mg per tablet using a rotary tableting machine (X-20, manufactured by Hata Iron Works) to obtain a tablet having an initial hardness of about 10N.
- the tablet was stored at 25 ° C. and 62% relative humidity for 15 hours, and then stored at 30 ° C. for 3 hours to obtain an orally disintegrating tablet containing 22.6 ⁇ g of ramosetron hydrochloride as a comparative example.
- a spray solution was prepared by stirring and dissolving 7 parts maltose, 0.0028 parts ramosetron hydrochloride and 0.2 parts anhydrous citric acid in 28 parts water using a magnetic stirrer.
- GPCG15 fluidized bed granulator
- the granulated product was dried until the product temperature reached 40 ° C., and then 1 part of magnesium stearate was mixed.
- the mixed powder was tableted at 180 mg per tablet using a rotary tableting machine (X-20, manufactured by Hata Iron Works) to obtain a tablet having an initial hardness of about 10N.
- the tablet was stored at 25 ° C. and 62% relative humidity for 15 hours, and then stored at 30 ° C. for 3 hours to obtain an orally disintegrating tablet containing 5 ⁇ g of ramosetron hydrochloride of the present invention.
- the mixed powder was tableted at 180 mg per tablet using a rotary tableting machine (X-20, manufactured by Hata Iron Works) to obtain a tablet having an initial hardness of about 10N.
- the tablet was stored at 25 ° C. and 62% relative humidity for 15 hours, and then stored at 30 ° C. for 3 hours to obtain an orally disintegrating tablet containing 5 ⁇ g of ramosetron hydrochloride of the present invention.
- Production Example 6 The mixed powder of Production Example 3 was tableted at 90 mg per tablet using a rotary tableting machine (X-20, manufactured by Hata Iron Works) to obtain a tablet having an initial hardness of about 10N. The tablet was stored at 25 ° C. and 62% relative humidity for 15 hours, and then stored at 30 ° C. for 3 hours to obtain an orally disintegrating tablet containing 2.5 ⁇ g of ramosetron hydrochloride of the present invention.
- a rotary tableting machine X-20, manufactured by Hata Iron Works
- the granulated product was dried until the product temperature reached 40 ° C., and then 1 part of magnesium stearate was mixed.
- the mixed powder was tableted at 90 mg per tablet using a rotary tableting machine (X-20, manufactured by Hata Iron Works) to obtain a tablet having an initial hardness of about 10N.
- the tablet was stored at 25 ° C. and 62% relative humidity for 15 hours and then stored at 30 ° C. for 3 hours to obtain an orally disintegrating tablet containing 1.25 ⁇ g of ramosetron hydrochloride of the present invention.
- Experimental example 2 The oral disintegrating tablet containing 22.6 ⁇ g of ramosetron hydrochloride produced in Production Example 1 was forcibly orally administered to the beagle dog fasted for 18 hours or more together with 50 mL of water.
- pentagastrin (0.015 mg / kg) was intravenously administered 30 minutes before, 30 minutes, and 90 minutes after oral gavage administration of the tablets, and the gastric pH of the beagle dog was treated to be acidic.
- blood was collected over time, and the plasma ramosetron concentration obtained by centrifugation was measured. The results are shown in Table 1.
- Experimental example 3 The orally disintegrating tablet containing 22.6 ⁇ g of ramosetron hydrochloride produced in Production Example 1 was placed in a syringe for injection together with 2 mL of water, and then uniformly dispersed by pumping. The suspension was administered orally to beagle dogs that had been fasted for at least 18 hours.
- pentagastrin (0.015 mg / kg) was intravenously administered 30 minutes before, 30 minutes, and 90 minutes before oral administration of the tablet, and the gastric pH of the beagle dog was treated to be acidic. After intraoral administration, blood was collected over time, and the plasma ramosetron concentration obtained by centrifugation was measured. The results are shown in Table 1.
- Experimental Example 4 An agar powder suspension (0.05 mg / mL) was prepared. Next, the orally disintegrating tablet containing 22.6 ⁇ g of ramosetron hydrochloride produced in Production Example 1 was placed in a syringe for injection together with 2 mL of the above Kanteng powder suspension, and then uniformly dispersed by pumping. The suspension was administered orally to beagle dogs that had been fasted for at least 18 hours. In addition, pentagastrin (0.015 mg / kg) was intravenously administered 30 minutes before, 30 minutes, and 90 minutes before oral administration of the tablet, and the gastric pH of the beagle dog was treated to be acidic. After intraoral administration, blood was collected over time, and the plasma ramosetron concentration obtained by centrifugation was measured. The results are shown in Table 1.
- Experimental Example 5 The usual tablet containing 5 ⁇ g of ramosetron hydrochloride produced in Production Example 4 was forcibly orally administered to a beagle dog fasted for 18 hours or more together with 50 mL of water.
- pentagastrin (0.015 mg / kg) was intravenously administered 30 minutes before, 30 minutes, and 90 minutes before oral administration of the tablet, and the gastric pH of the beagle dog was treated to be acidic.
- blood was collected over time, and the plasma ramosetron concentration obtained by centrifugation was measured. The results are shown in Table 2.
- orally disintegrating tablets containing ramosetron or a pharmaceutically acceptable salt thereof achieved BE with normal tablets by containing agar powder.
- an orally disintegrating tablet with improved absorbability comprising a low dose of ramosetron or a pharmaceutically acceptable salt thereof and having bioequivalence to a normal tablet. it can.
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Abstract
Description
[1](a)0.001mg以上0.05mg以下の塩酸ラモセトロン、又は(b)0.001mg以上0.05mg以下の塩酸ラモセトロンと等モル量のラモセトロン若しくはその製薬学的に許容される塩、並びにカンテン及び/またはカンテン末を含有する口腔内崩壊錠、
[2](a)0.00125mg以上0.025mg以下の塩酸ラモセトロン、又は(b)0.00125mg以上0.025mg以下の塩酸ラモセトロンと等モル量のラモセトロン若しくはその製薬学的に許容される塩を含有する、[1]に記載の口腔内崩壊錠、
[3]カンテン及び/またはカンテン末の量が、ラモセトロンまたはその製薬学的に許容される塩に対して10重量%以上500000重量%以下である、[1]または[2]に記載の口腔内崩壊錠、
[4]カンテン及び/またはカンテン末の量が、単位製剤あたり0.001重量%以上70重量%以下である、[1]または[2]に記載の口腔内崩壊錠、
[5]下痢型過敏性腸症候群の治療のための、[1]乃至[4]のいずれか一つに記載の口腔内崩壊錠、
[6]イリボー(登録商標)錠2.5μgまたはイリボー(登録商標)錠5μgと生物学的同等である、[1]乃至[5]のいずれか一つに記載の口腔内崩壊錠、
[7]更に安定化剤を含む、[1]乃至[6]のいずれか一つに記載の口腔内崩壊錠、
[8]安定化剤が、ヒドロキシカルボン酸である、[7]に記載の口腔内崩壊錠、
[9]ヒドロキシカルボン酸が、酒石酸、リンゴ酸、及びクエン酸からなる群から選択された1種または2種以上の物質である、[8]に記載の口腔内崩壊錠、
[10]更に光安定化剤を含む、[1]乃至[9]のいずれか一つに記載の口腔内崩壊錠、
[11]光安定化剤が、黄色三二酸化鉄、赤色三二酸化鉄、及び酸化チタンからなる群から選択された1種または、2種以上の物質である、[10]に記載の口腔内崩壊錠、
[12]更に糖類を含む、[1]乃至[11]のいずれか一つに記載の口腔内崩壊錠、
[13]糖類が、成形性の高い糖類、及び/または成形性の低い糖類である、[12]に記載の口腔内崩壊錠、
[14]成形性の高い糖類が、マルトース、マルチトール、ソルビトール、及びトレハロースからなる群から選択された1種、または2種以上の物質である、[13]に記載の口腔内崩壊錠、
[15]成形性の低い糖類が、乳糖、D-マンニトール、ブドウ糖、白糖、キシリトール、及びエリスリトールからなる群から選択された1種、または2種以上の物質である、[13]に記載の口腔内崩壊錠、
[16](a)0.001mg以上0.05mg以下の塩酸ラモセトロン、又は(b)0.001mg以上0.05mg以下の塩酸ラモセトロンと等モル量のラモセトロン若しくはその製薬学的に許容される塩を含有する、イリボー(登録商標)錠2.5μgまたはイリボー(登録商標)錠5μgと生物学的同等性を有する口腔内崩壊錠の製造のためのカンテン及び/またはカンテン末の使用、
[17]成人1人当たり1日量として0.00125mg以上0.025mg以下の塩酸ラモセトロンを投与して下痢型過敏性腸症候群を治療するために使用される口腔内崩壊錠であって、
単位製剤当たり、0.00125mg以上0.025mg以下の塩酸ラモセトロン、カンテン及び/またはカンテン末、D-マンニトール、並びにマルトースを少なくとも含有する、口腔内崩壊錠、
を提供する。
粉砕方法としては、通常製薬学的に粉砕する方法であれば、装置・手段とも特に制限されない。粉砕装置としては、例えば、ハンマーミル、ボールミル、ジェットミルなどが挙げられる。粉砕条件は適宜選択されれば特に制限されない。
混合方法としては、通常製薬学的に各成分を均一に混合する方法であれば、装置・手段とも特に制限されない。混合装置としては、例えば、V型混合機、リボン型混合機、コンテナミキサー、高速攪拌混合機などが挙げられる。混合条件は適宜選択されれば特に制限されない。
造粒機として、例えば流動層造粒機等が挙げられる。造粒方法として、例えば、流動層造粒法、溶融造粒法、高速攪拌造粒法、解砕(粉砕)造粒法、押出造粒法、転動造粒法、噴霧造粒法、乾式造粒法などが挙げられる。他の態様として流動層造粒法である。
成形工程では、造粒品、または造粒品に各種医薬添加剤を混合した混合品をカプセルに充填してカプセル剤としたり、回転式打錠機を用いて圧縮成形し、錠剤とすることができる。
国際公開第WO95/20380号パンフレット(米国対応特許第5576014号明細書)に記載のように、成形性の低い糖類を用いて口腔内崩壊錠を製造した場合、調製した成形物の硬度を高めるために、加湿、乾燥の工程を採用することができる。「加湿」は、含まれる糖類の見かけの臨界相対湿度により決定されるが、通常その臨界相対湿度以上に加湿する。例えば、湿度として30RH%以上100RH%以下であり、他の態様として50RH%以上90RH%以下である。このときの温度は15℃以上50℃以下であることが好ましく、他の態様として20℃以上40℃以下である。処理時間は1時間以上36時間以下であり、他の態様として12時間以上24時間以下である。「乾燥」は、加湿により吸収した水分を除去する工程であれば特に限定されない。例えば乾燥の温度条件として、10℃以上100℃以下を設定でき、他の態様として20℃以上60℃以下、更なる態様として25℃以上40℃以下を設定することができる。処理時間は、0.5時間以上6時間以下とすることができ、他の態様として1時間以上4時間以下とすることができる。
製造例1
塩酸ラモセトロン 0.01883部(0.0226mg)
D-マンニトール 87.8部(105.3374mg)
無水クエン酸 0.2部(0.24mg)
マルトース 10部(12.0mg)
赤色三二酸化鉄 1部(1.20mg)
ステアリン酸マグネシウム 1部(1.20mg)
塩酸ラモセトロン 0.0226部(0.0226mg)
無水クエン酸 0.5部(0.5mg)
ヒドロキシプロピルセルロース 3部(3.0mg)
結晶セルロース 86部(86.0mg)
低置換度ヒドロキシプロピルセルロース 10部(10.0mg)
ステアリン酸マグネシウム 0.5部(0.5mg)
塩酸ラモセトロン 0.0028部(0.005mg)
D-マンニトール 87.9部(158.215mg)
無水クエン酸 0.2部(0.36mg)
マルトース 10部(18.0mg)
カンテン末 0.1部(0.18mg)
赤色三二酸化鉄 0.8部(1.44mg)
ステアリン酸マグネシウム 1部(1.80mg)
塩酸ラモセトロン 0.005部(0.005mg)
無水クエン酸 0.5部(0.5mg)
ヒドロキシプロピルセルロース 3部(3.0mg)
結晶セルロース 86部(86.0mg)
低置換度ヒドロキシプロピルセルロース 10部(10.0mg)
ステアリン酸マグネシウム 0.5部(0.5mg)
塩酸ラモセトロン 0.0028部(0.005mg)
D-マンニトール 87.9部(158.215mg)
無水クエン酸 0.2部(0.36mg)
マルトース 10部(18.0mg)
カンテン末 0.1部(0.18mg)
赤色三二酸化鉄 0.5部(0.90mg)
黄色三二酸化鉄 0.3部(0.54mg)
ステアリン酸マグネシウム 1部(1.80 mg)
製造例3の混合粉末を、ロータリー打錠機(X-20、畑鉄工所製)を用いて一錠当たり90mgで打錠し、初期硬度約10Nを有する錠剤とした。該錠剤を25℃、相対湿度62%で15時間保存した後、30℃で3時間保存し、本発明の塩酸ラモセトロン2.5μg含有口腔内崩壊錠を得た。
塩酸ラモセトロン 0.00139部(0.00125mg)
D-マンニトール 87.9部(79.1088mg)
無水クエン酸 0.2部(0.18mg)
マルトース 10部 (9.0mg)
カンテン末 0.1部(0.09mg)
赤色三二酸化鉄 0.5部(0.45mg)
黄色三二酸化鉄 0.3部(0.27mg)
ステアリン酸マグネシウム 1部(0.90mg)
実験例1
製造例2で製造した塩酸ラモセトロン22.6μg含有通常錠を水50mLとともに18時間以上絶食したビーグル犬に経口胃内強制投与した。なお、錠剤の経口胃内強制投与30分前、30分及び90分後にペンタガストリン(0.015 mg/kg)を静脈内投与し、ビーグル犬の胃内pHが酸性となるように処置した。経口胃内強制投与後、経時的に採血し遠心分離により得られた血漿中ラモセトロン濃度を測定した。結果を表1に示す。
製造例1で製造した塩酸ラモセトロン22.6μg含有口腔内崩壊錠を水50mLとともに18時間以上絶食したビーグル犬に経口胃内強制投与した。なお、錠剤の経口胃内強制投与30分前、30分及び90分後にペンタガストリン(0.015 mg/kg)を静脈内投与し、ビーグル犬の胃内pHが酸性となるように処置した。経口胃内強制投与後、経時的に採血し遠心分離により得られた血漿中ラモセトロン濃度を測定した。結果を表1に示す。
製造例1で製造した塩酸ラモセトロン22.6μg含有口腔内崩壊錠を注射用シリンジに水2mLとともに入れた後、ポンピングにより均一に分散させた。該懸濁液を18時間以上絶食したビーグル犬に口腔内投与した。なお、錠剤の口腔内投与30分前、30分及び90分後にペンタガストリン(0.015 mg/kg)を静脈内投与し、ビーグル犬の胃内pHが酸性となるように処置した。口腔内投与後、経時的に採血し遠心分離により得られた血漿中ラモセトロン濃度を測定した。結果を表1に示す。
カンテン末懸濁液(0.05mg/mL)を調製した。次に製造例1で製造した塩酸ラモセトロン22.6μg含有口腔内崩壊錠を注射用シリンジに上記カンテン末懸濁液2mLとともに入れた後、ポンピングにより均一に分散させた。該懸濁液を18時間以上絶食したビーグル犬に口腔内投与した。なお、錠剤の口腔内投与30分前、30分及び90分後にペンタガストリン(0.015 mg/kg)を静脈内投与し、ビーグル犬の胃内pHが酸性となるように処置した。口腔内投与後、経時的に採血し遠心分離により得られた血漿中ラモセトロン濃度を測定した。結果を表1に示す。
製造例4で製造した塩酸ラモセトロン5μg含有通常錠を水50mLとともに18時間以上絶食したビーグル犬に経口胃内強制投与した。なお、錠剤の口腔内投与30分前、30分及び90分後にペンタガストリン(0.015 mg/kg)を静脈内投与し、ビーグル犬の胃内pHが酸性となるように処置した。経口胃内強制投与後、経時的に採血し遠心分離により得られた血漿中ラモセトロン濃度を測定した。結果を表2に示す。
製造例3で製造したカンテン末入り塩酸ラモセトロン5μg含有口腔内崩壊錠を注射用シリンジに水2mLとともに入れた後、ポンピングにより均一に分散させた。該懸濁液を18時間以上絶食したビーグル犬に口腔内投与した。なお、錠剤の口腔内投与30分前、30分及び90分後にペンタガストリン(0.015 mg/kg)を静脈内投与し、ビーグル犬の胃内pHが酸性となるように処置した。口腔内投与後、経時的に採血し遠心分離により得られた血漿中ラモセトロン濃度を測定した。結果を表2に示す。
製造例5で製造したカンテン末含有塩酸ラモセトロン5μg含有口腔内崩壊錠、及びイリボー錠5μg(市販品、通常錠)をヒトへ口腔内投与したところ、AUC、Cmaxの幾何学平均値の比は80%以上125%以下となった。以上より、製造例5で製造した口腔内崩壊錠は通常錠とBEを達成した。
Claims (17)
- (a)0.001mg以上0.05mg以下の塩酸ラモセトロン、又は(b)0.001mg以上0.05mg以下の塩酸ラモセトロンと等モル量のラモセトロン若しくはその製薬学的に許容される塩、並びにカンテン及び/またはカンテン末を含有する口腔内崩壊錠。
- (a)0.00125mg以上0.025mg以下の塩酸ラモセトロン、又は(b)0.00125mg以上0.025mg以下の塩酸ラモセトロンと等モル量のラモセトロン若しくはその製薬学的に許容される塩を含有する、請求項1に記載の口腔内崩壊錠。
- カンテン及び/またはカンテン末の量が、ラモセトロンまたはその製薬学的に許容される塩に対して10重量%以上500000重量%以下である、請求項1または2に記載の口腔内崩壊錠。
- カンテン及び/またはカンテン末の量が、単位製剤あたり0.001重量%以上70重量%以下である、請求項1または2に記載の口腔内崩壊錠。
- 下痢型過敏性腸症候群の治療のための、請求項1乃至4のいずれか1項に記載の口腔内崩壊錠。
- イリボー(登録商標)錠2.5μgまたはイリボー(登録商標)錠5μgと生物学的同等である、請求項1乃至5のいずれか1項に記載の口腔内崩壊錠。
- 更に安定化剤を含む、請求項1乃至6のいずれか1項に記載の口腔内崩壊錠。
- 安定化剤が、ヒドロキシカルボン酸である、請求項7に記載の口腔内崩壊錠。
- ヒドロキシカルボン酸が、酒石酸、リンゴ酸、及びクエン酸からなる群から選択された1種または2種以上の物質である、請求項8に記載の口腔内崩壊錠。
- 更に光安定化剤を含む、請求項1乃至9のいずれか1項に記載の口腔内崩壊錠。
- 光安定化剤が、黄色三二酸化鉄、赤色三二酸化鉄、及び酸化チタンからなる群から選択された1種または、2種以上の物質である、請求項10に記載の口腔内崩壊錠。
- 更に糖類を含む、請求項1乃至11のいずれか1項に記載の口腔内崩壊錠。
- 糖類が、成形性の高い糖類、及び/または成形性の低い糖類である、請求項12に記載の口腔内崩壊錠。
- 成形性の高い糖類が、マルトース、マルチトール、ソルビトール、及びトレハロースからなる群から選択された1種、または2種以上の物質である、請求項13に記載の口腔内崩壊錠。
- 成形性の低い糖類が、乳糖、D-マンニトール、ブドウ糖、白糖、キシリトール、及びエリスリトールからなる群から選択された1種、または2種以上の物質である、請求項13に記載の口腔内崩壊錠。
- (a)0.001mg以上0.05mg以下の塩酸ラモセトロン、又は(b)0.001mg以上0.05mg以下の塩酸ラモセトロンと等モル量のラモセトロン若しくはその製薬学的に許容される塩を含有する、イリボー(登録商標)錠2.5μgまたはイリボー(登録商標)錠5μgと生物学的同等性を有する口腔内崩壊錠の製造のためのカンテン及び/またはカンテン末の使用。
- 成人1人当たり1日量として0.00125mg以上0.025mg以下の塩酸ラモセトロンを投与して下痢型過敏性腸症候群を治療するために使用される口腔内崩壊錠であって、
単位製剤当たり、0.00125mg以上0.025mg以下の塩酸ラモセトロン、カンテン及び/またはカンテン末、D-マンニトール、並びにマルトースを少なくとも含有する、口腔内崩壊錠。
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JP2000119175A (ja) * | 1998-10-13 | 2000-04-25 | Taisho Yakuhin Kogyo Kk | 口腔内速崩壊性固形製剤 |
JP2002138055A (ja) * | 2000-10-31 | 2002-05-14 | Nipro Corp | 口腔内速崩壊性圧縮成型物およびその製造方法 |
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JP2807346B2 (ja) * | 1991-12-24 | 1998-10-08 | 山之内製薬株式会社 | 口腔内崩壊製剤及びその製造法 |
JP2000119175A (ja) * | 1998-10-13 | 2000-04-25 | Taisho Yakuhin Kogyo Kk | 口腔内速崩壊性固形製剤 |
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JP2018123146A (ja) * | 2015-04-28 | 2018-08-09 | 大原薬品工業株式会社 | 光安定性を向上したシロドシン含有着色錠剤 |
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