JP5337430B2 - Orally disintegrating tablets - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To develop a tablet quickly disintegrating in oral cavity which shows high initial elution property, shows good disintegrability, ensures practical tablet hardness and is palatable at taking. <P>SOLUTION: The tablet quickly disintegrating in oral cavity contains a pharmaceutically active ingredient, polyvinyl alcohols and water-soluble polyoxyethylenes such as polyoxyl stearate. <P>COPYRIGHT: (C)2010,JPO&amp;INPIT

Description

  The present invention has an improved dissolution property and exhibits good disintegration in the oral cavity, ensures a practical tablet hardness, and has a good mouthfeel when taken, especially glimepiride oral disintegration in the oral cavity The present invention relates to a lock and a method for producing the same.

In recent years, an aging society has progressed, and the number of elderly people with reduced or impaired food intake functions (such as mastication and swallowing) due to decreased physiological functions or senile dementia is increasing. In addition, there are many patients with nocturnal enuresis among elderly people, and when taking such patients with water, problems such as difficulty in taking or concern about nocturnal urine have arisen. On the other hand, because of the advantage that it can be taken at any time and place in a busy modern society, development of an oral preparation that does not require water at the time of taking is required.
Therefore, various oral preparations that can be taken without water have been developed, and as one of them, orally disintegrating tablets have been actively developed.

  Intraoral quick disintegrating tablets need to disintegrate quickly when taken, but they need to have a moderate hardness that will not break during storage and transportation before taking, and storage stability is also required. . Orally rapidly disintegrating tablets containing a drug such as famotidine, saccharides and polyvinyl alcohol as an intraoral quick disintegrating tablet with excellent storage stability, especially storage stability under humidified conditions. It is disclosed in Patent Document 1.

In Patent Document 2, pravastatin sodium and a saccharide such as D-mannitol are mixed, and water and / or a water-soluble organic solvent in which a binder such as polyvinyl alcohol is dissolved are kneaded and filled in the filling hole. A fast disintegrating tablet that is compression molded through a film after filling is disclosed.
Republished patent WO01 / 064190 JP2002-20282

  The inventors of the present invention have made various studies in order to develop an orally rapidly disintegrating tablet with improved dissolution, good mouthfeel when taken, practical tablet hardness, excellent storage stability, etc. When polyvinyl alcohols were used as binders, it was found that increasing the number of polyvinyl alcohols improved the drug dissolution, while the rapid disintegration required for intraoral quick disintegrating tablets tended to be impaired. . Therefore, the present inventors have completed the present invention as a result of various investigations on methods that can satisfy the dissolution property, particularly the dissolution property at the initial stage of administration, without impairing the rapid disintegration property.

  That is, as a result of intensive studies on the above problems, the present inventors solved the above problems by using water-soluble polyoxyethylenes, in particular, polyoxyl stearate, when polyvinyl alcohols are used as a binder. The present invention has been completed by finding out what can be done.

That is, the present invention
(1) pharmaceutically active ingredient, at least one polyvinyl alcohol selected from the group consisting of polyvinyl alcohol and polyvinyl alcohol copolymers, and polyethylene glycol, polyoxyethylene polyoxypropylene glycol, the group consisting of polyethylene glycol ethers and polyethylene glycol fatty acid esters At least one water-soluble polyoxyethylene selected from the group consisting of 0.1 to 3% by mass of polyvinyl alcohol and 0.1% by mass of water-soluble polyoxyethylene based on the total amount of the orally rapidly disintegrating tablet 0.05 to 1% by mass , rapidly disintegrating tablet in the oral cavity that disintegrates within 30 seconds in the oral cavity (excluding those containing erythritol) ,
(2) The intraoral quick disintegrating tablet according to (1), further comprising an excipient and a disintegrant;
(3) The intraoral rapidly disintegrating tablet according to the above (2 ), wherein the excipient content is 50 to 80% by mass with respect to the total amount of the orally rapidly disintegrating tablet,
(4) The intraoral rapidly disintegrating tablet according to (3) above, wherein the content of polyvinyl alcohol is 0.3 to 1% by mass,
(5) The above ( the disintegrant content is 0.5 to 7% by mass and the total content of the excipient and the disintegrant is 50 to 98% by mass with respect to the total amount of the orally rapidly disintegrating tablet ( 2 ) -orally fast disintegrating tablet according to any one of (4),

(6) The above (1) to (5), wherein the total content of polyvinyl alcohols and water-soluble polyoxyethylenes is 0.3 to 1% by mass with respect to the total amount of the rapidly disintegrating tablet in the oral cavity. Orally rapidly disintegrating tablet according to any one of
(7) 0.5 to 5% by mass of pharmaceutically active ingredient, 0.1 to 3% by mass of polyvinyl alcohols, and 0.05 to 1% by mass of water-soluble polyoxyethylenes with respect to the whole preparation In addition, the intraoral rapidly disintegrating tablet according to any one of the above (1) to (5) , wherein the balance is an excipient, a disintegrant and other pharmaceutical additives,
(8) The intraorally rapidly disintegrating tablet according to any one of (1) to (7), wherein the polyvinyl alcohol is partially saponified polyvinyl alcohol,
(9) The intraorally rapidly disintegrating tablet according to (8), wherein the partially saponified polyvinyl alcohol is a partially saponified polyvinyl alcohol having a viscosity of 3 to 8 mPa · S (4%, 20 ° C.),
(10) The intraorally rapidly disintegrating tablet according to any one of (1) to (9), wherein the water-soluble polyoxyethylene is polyoxyl stearate,
(11) The intraorally rapidly disintegrating tablet according to any one of (1) to (10), wherein the pharmaceutically active ingredient is glimepiride,
(12) The intraorally rapidly disintegrating tablet according to any one of (2) to (11), wherein the excipient is lactose hydrate.
(13) A dispersion liquid in which a water-insoluble pharmaceutically active ingredient is uniformly dispersed in a polyvinyl alcohol-containing solution is sprayed on the excipient, and fluidized bed granulation is carried out. Water-soluble polyoxyethylenes and other pharmaceutical additives, excluding the form and the lubricant to be added later, are mixed uniformly, and the resulting mixture is mixed with a lubricant and then tableted. the resulting (1) to (12) either orally fast disintegrating tablet according to one of,
It is about.

  The intraoral quick disintegrating tablet obtained by the present invention has excellent storage stability and the like of the tablet itself, has improved initial dissolution properties, and also has quick disintegrating properties.

  The present invention relates to an orally rapidly disintegrating tablet containing a pharmaceutically active ingredient as an active ingredient, polyvinyl alcohol as a binder, and water-soluble polyoxyethylenes such as polyoxyl stearate as an initial dissolution improving agent. Most preferably, it relates to an orally rapidly disintegrating tablet containing polyvinyl alcohols and polyoxyl stearate together with pharmaceutically active ingredients.

In the present invention, “orally disintegrating tablet in the oral cavity” means disintegrating within 90 seconds, preferably within 60 seconds, more preferably within 30 seconds, with only saliva in the oral cavity, and disintegrating in the oral cavity without ingesting water. It means tablets that can be taken. Further, this “orally-fast disintegrating tablet” preferably has a tablet hardness that does not cause cracking or chipping when the PTP is taken out of the tablet.
Specifically, in tablets having a diameter of 6 to 8 mm, an orally rapidly disintegrating tablet having a hardness of 20 N or more, preferably 30 N or more, more preferably 40 N or more, and most preferably 45 N or more can be mentioned. Furthermore, an orally rapidly disintegrating tablet having a hardness after storage of 20 N or more, preferably 30 N or more, more preferably 40 N or more, and most preferably 45 N or more under the conditions of 25 ° C. and 75% relative humidity for 1 week.
In the following description, “part” represents part by mass unless otherwise specified.

As the pharmaceutically active ingredient in the intraoral rapidly disintegrating tablet of the present invention, a water-insoluble drug is usually used. For example, antipyretic analgesics, antipsychotics, anti-anxiety drugs, antidepressants, hypnotic sedatives, antispasmodic drugs, central nervous system drugs, brain metabolism improving agents, cerebral circulation improving agents, antiepileptic agents, sympathomimetic drugs, Gastrointestinal, Antacid, Antiulcer, Antitussive, Antiemetic, Antiemetic, Respiratory, Bronchodilator, Allergy, Dental Oral, Antihistamine, Cardiotonic, Arrhythmic, Diuretic, Antihypertensive, Vasoconstrictor, Coronary vasodilator, Peripheral vasodilator, Hyperlipidemia, Biliate, Antibiotic, Chemotherapy, Diabetes, Osteoporosis, Antirheumatic, Skeletal muscle relaxant One or more components selected from antispasmodic agents, hormonal agents, alkaloid narcotics, sulfa drugs, anti-gout drugs, anticoagulants, anti-neoplastic agents and the like are used.
The content of the pharmaceutically active ingredient in the intraoral quick disintegrating tablet of the present invention is not particularly limited as long as the effect of the present invention can be achieved. Usually, about 0.5 to 10% by mass, more preferably about 0.5 to 5% by mass, and still more preferably about 0.5 to 3% by mass is used with respect to the total amount of the orally rapidly disintegrating tablet. preferable.

The present invention can be applied to any water-insoluble pharmaceutically active ingredient, but glimepiride is most preferred, and glimepiride will be described in detail below as a representative example.
Glimepiride has the chemical name 1-[[4- [2-[(3-ethyl-4-methyl-2-oxo-3-pyrrolin-1-ylcarbonyl) amino] ethyl] phenyl] sulfonyl] -3- ( 4α-methylcyclohexane-1β-yl) urea, which is particularly effective as a sulfonylurea oral hypoglycemic agent for non-insulin dependent diabetes.

The polyvinyl alcohol used for this invention will not be restrict | limited especially if mix | blending in the field | area of a pharmaceutical is recognized, It can use individually or in combination of 2 or more types.
The polyvinyl alcohols used as the binder in the intraoral rapidly disintegrating tablet of the present invention are classified into polyvinyl alcohols, and any of them may be used as the binder, and preferable ones are polyvinyl alcohol or polyvinyl alcohol. Examples thereof include polyvinyl alcohol copolymers such as (meth) acrylic acid. Usually, polyvinyl alcohol which is a partial hydrolyzate (partially saponified product) or a complete hydrolyzate obtained by hydrolyzing polyvinyl acetate with an acid or an alkali is preferred.
In the present invention, polyvinyl alcohol having a viscosity of about 1 to 50 mPa · S (4% aqueous solution, 20 ° C .: hereinafter the same) is preferable. More preferably, polyvinyl alcohol having a viscosity of about 3 to 30 mPa · S, more preferably about 3 to 8 mPa · S, and most preferably about 4.8 to 5.8 mPa · S is used.
The polyvinyl alcohol used in the present invention may be either a completely saponified product or a partially saponified product. Preferred polyvinyl alcohol has a saponification degree of usually 70% or more, more preferably 80% or more, more preferably 85% or more, and more preferably partially saponified polyvinyl alcohol having a saponification degree of 70% or more. Most preferably, the saponification degree is 85% or more and 90% or less.
These polyvinyl alcohols are about 0.1 to 3% by mass, preferably about 0.1 to 1% by mass, more preferably about 0.3 to 0.6% by mass, based on the total amount of the rapidly disintegrating tablet. It is preferable to use it.
In the intraoral quick disintegrating tablet of the present invention, other binders other than polyvinyl alcohols can be used in combination, but usually it is preferably mainly polyvinyl alcohols, for example, 60% or more, more preferably 80%, More preferably, it is 90% or more, and alone is most preferable.

The water-soluble polyoxyethylenes used in combination with polyvinyl alcohol in the oral cavity rapid disintegrating tablet of the present invention, in general, the formula _{:-( CH 2 CH 2 O) n} - refers to a polymer having a polyoxyethylene skeleton represented by .
The water-soluble polyoxyethylenes used in the present invention are not particularly limited as long as they can achieve the effects of the present invention and are recognized to be blended in the pharmaceutical field. It can be used alone or in combination of two or more. Examples of such water-soluble polyoxyethylenes include polyethylene glycols (preferably having an average molecular weight of about 190 to 25,000) and polyoxyethylene polyoxypropylene glycols (preferably, the average degree of polymerization of propylene oxide: 5 to 5). 67 and an average degree of polymerization of ethylene oxide: about 42 to 196), polyethylene glycol ethers (for example, polysorbate 80 described in Japanese Pharmacopoeia 15th (anhydrous partially esterified with oleic acid) And polyethylene glycol fatty acid esters (for example, polyoxyl 40 stearate described in the 15th revision Japanese Pharmacopoeia) and the like.
Among them, preferable water-soluble polyoxyethylenes are the above polyethylene glycols, polyethylene glycol ethers, polyethylene glycol fatty acid esters, more preferably polyethylene glycol fatty acid esters, and particularly preferably polyoxyl stearate (polyoxyl stearate). Among them, polyoxyl stearate 40 is more preferable.
Moreover, these water-soluble polyoxyethylenes are about 0.01-1 mass% with respect to the total amount of an intraoral quick disintegrating tablet, More preferably, it is about 0.05-1 mass%, More preferably, 0.05- It is preferable to use about 0.2% by mass.
In the present invention, balance with water-soluble polyoxyethylenes (preferably polyoxyl stearate) used in combination with polyvinyl alcohols is important. For example, the polyvinyl alcohol is 0.1 to 3% by mass, more preferably 0.3 to 1% by mass, and still more preferably 0.3 to 0.6% by mass with respect to the total amount of the orally rapidly disintegrating tablet. In some cases, it is preferable to contain water-soluble polyoxyethylenes (preferably polyoxyl stearate) in an amount of 0.05 to 0.3% by mass, more preferably 0.08 to 0.2% by mass. And when both total is 0.3-1 mass% with respect to the total amount of an intraoral quick disintegrating tablet, it is more preferable.

Examples of the excipient used in the intraoral quick disintegrating tablet of the present invention include saccharides such as sucrose, lactose, mannitol and glucose, crystalline cellulose, calcium citrate, calcium hydrogen phosphate and calcium sulfate. These excipients may be used alone or in admixture of two or more. Among these, lactose or mannitol can be mentioned as preferred, and lactose is most preferred. As lactose, lactose hydrate is usually used. The content of the excipient in the intraoral quick disintegrating tablet is the remainder of the other additives, but is usually about 50 to 80%, more preferably about 60 to 75% with respect to the total amount of the intraoral quick disintegrating tablet. . When using lactose (lactose hydrate) as an excipient, it is sometimes preferable to use a small amount of crystalline cellulose. The blending amount of the crystalline cellulose is about 5 to 20%, more preferably about 10 to 15% with respect to the total amount of the intraoral quick disintegrating tablet.
Examples of the disintegrant used in the orally rapidly disintegrating tablet of the present invention include crospovidone, carmellose, carmellose calcium, croscarmellose sodium, carboxymethyl starch sodium, low-substituted hydroxypropylcellulose, corn starch and the like. Preferred are crospovidone, corn starch and the like, most preferably crospovidone. These disintegrants can be used in combination of two or more, but are usually used alone. Although the amount of the disintegrant used depends on the disintegrant used, it cannot be generally specified, but it is about 0.5 to 7%, more preferably about 1 to 5% with respect to the total amount of the intraoral quick disintegrating tablet.
In the intraoral quick disintegrating tablet of the present invention, the excipient and the disintegrant are usually about 50 to 98% by mass, preferably about 70 to 97% by mass, based on the total amount of the intraoral quick disintegrating tablet. More preferably, the combined amount is about 90 to 97% by mass.

The intraoral quick disintegrating tablet of the present invention may further contain various pharmaceutical additives other than those generally used for tablet production, if necessary. For example, 0 to 10% by mass, preferably 0.1 to 5% by mass, and more preferably 0.5 to 4% by mass of an additive may be included with respect to the total mass of the tablet. These substances may be used alone or in admixture at any ratio.
Examples of various pharmaceutical additives other than the above include sweeteners, flavoring agents, fragrances, lubricants, fluidizing agents, and coloring agents.

  The sweetener used in the intraoral quick disintegrating tablet of the present invention is preferably a non-saccharide natural sweetener or a synthetic sweetener. Examples thereof include acesulfame potassium, aspartame, saccharin or a salt thereof, glycyrrhizic acid or a salt thereof, stevia or a salt thereof, sucralose, thaumatin and the like.

Examples of the corrigent include ascorbic acid and its salt, glycine, sodium chloride, magnesium chloride, hydrochloric acid, dilute hydrochloric acid, citric acid and its salt, anhydrous citric acid, L-glutamic acid and its salt, succinic acid and its salt, acetic acid, Examples thereof include tartaric acid and its salt, sodium hydrogen carbonate, fumaric acid and its salt, malic acid and its salt, glacial acetic acid, disodium inosinate, honey and the like.
Perfumes include what are called flavoring agents, such as orange essence, orange oil, caramel, camphor, cinnamon oil, spearmint oil, strawberry essence, chocolate essence, cherry flavor, spruce oil, pine oil, mint oil, vanilla flavor. , Bitter essence, fruit flavor, peppermint essence, mixed flavor, mint flavor, menthol, lemon powder, lemon oil, rose oil and the like.

Examples of the lubricant include magnesium stearate, calcium stearate, talc, and sucrose fatty acid ester. Usually magnesium stearate is used.
Examples of the fluidizing agent include hydrous silicon dioxide, light anhydrous silicic acid, heavy anhydrous silicic acid, titanium oxide and the like.
Examples of the colorant include food colors such as food red No. 3, food yellow No. 5, food blue No. 1, yellow ferric oxide, ferric oxide, brown iron oxide, black iron oxide, copper chlorophyll, copper chlorophyllin sodium, Examples include riboflavin and powdered green tea.
Any amount of these components can be used alone or in combination as long as they do not impair the disintegration property and moldability of the intraoral rapidly disintegrating tablet of the present invention.

The intraoral quick disintegrating tablet of the present invention can be produced by the following method.
As a specific production method, the active ingredient (preferably glimepiride) and production raw material are weighed, and mixed with a suitable mixer such as a V-type mixer, and directly mixed with a tableting machine to be described later. Examples of the method include tableting and manufacturing. Also, a dry granulation method using a roll compressor to obtain a mixed powder for tablets, or wet granulation using water, acetone, ethyl alcohol, propyl alcohol or a mixture thereof in which a binder is dispersed or dissolved as necessary. A method of granulating, or a method of producing a mixed powder for tablets by dividing into two or more separate groups may be used. When producing a mixed powder for tablets, a binder, a corrigent, a fluidizing agent, a lubricant, a fragrance, a sweetener, a coloring agent, and the like may be mixed as necessary.
Further, as described in the examples, a more preferable method for producing the intraoral rapidly disintegrating tablet of the present invention is to spray a dispersion in which fine particles of a water-insoluble drug are uniformly dispersed in a polyvinyl alcohol-containing solution, thereby forming a fluidized bed structure. The resulting granulated product was uniformly mixed with water-soluble polyoxyethylenes and other pharmaceutical additives, excluding blended excipients and lubricants added later. In this method, a lubricant is added to and mixed with the mixture, followed by tableting.
In the present invention, the particle size of the pharmaceutically active ingredient or pharmaceutically acceptable salt and additive thereof is not particularly limited, but the smaller the particle size, the better the feeling of dosing.

The mixed powder for tablets thus obtained is compressed by applying a pressure of 200 kg to 1000 kg / kg, preferably 400 kg to 800 kg / kg, using a single tableting machine, a rotary tableting machine or the like. If the pressure is lower than this, the tablet hardness is insufficient and sufficient hardness for handling cannot be secured, and if the pressure is high, disintegration is delayed, which is not preferable.
For compression molding, a normal tableting method can be used, but an external lubrication tableting method can also be used. By the external lubricant tableting method, the amount of lubricant added can be reduced, the disintegration rate can be increased, and the tablet hardness can be improved. The usual method of mixing a lubricant with a powder mixture for tablets requires 0.1 to 1 mg of lubricant per 100 mg tablet, but the external lubricant tableting method requires 0.5 mg or less. Tableting with a use amount of 0.1 mg or less is possible. As an apparatus for external lubricant tableting, there is ELS-P1 type III manufactured by Kikusui Seisakusho Co., Ltd.

  The intraoral quick disintegrating tablet of the present invention can adopt any shape, such as a round shape, an oval shape, a spherical shape, a cylindrical shape, a rod shape, a donut shape, a laminated tablet, and a dry-coated tablet. It may also be coated with a coating. Further, marks for improving the identification, characters, etc., or dividing lines for division may be added. Usually, cylindrical tablets are used.

  The intraoral quick disintegrating tablet of the present invention is rapidly disintegrated in the oral cavity by saliva and can be taken smoothly without leaving a rough surface. The dissolution of the intraoral rapidly disintegrating tablet of the present invention is usually 1 to 90 seconds, preferably 1 to 60 seconds, and more preferably about 1 to 30 seconds.

Moreover, it is generally known that the hardness (measured by a tablet hardness meter) of an orally rapidly disintegrating tablet is a value having no problem as long as it is at least 20 N (2 kgf) or more. Fast disintegrating tablets exhibit good intraoral rapid disintegration even at 30 N (3 kgf) or more, and even 40 N (4 kgf) or more.
In addition, this preparation can be taken without being disintegrated in the oral cavity or taken with water.

  EXAMPLES Hereinafter, although an Example and a test example demonstrate this invention concretely, this invention is not limited to these Examples.

Examples 1-3
Glimepiride was dispersed with a homogenizer in an aqueous solution (concentration: 11.3% w / w) in which polyvinyl alcohol was dissolved. Using a fluidized bed granulator, the dispersion was sprayed onto lactose hydrate and fluidized bed granulated. To the resulting granulated product, add the ingredients listed in the remaining table (crystalline cellulose, crospovidone, corn starch, iron sesquioxide, light anhydrous silicic acid, etc.) excluding the lubricant and mix evenly using a mixer. Finally, magnesium stearate was added, and then mixed again with a mixer to prepare tablets for tableting. Next, using a tableting machine, a circular tablet with a diameter of 6.0 mm was prepared. The hardness of the obtained tablet was 50N. Table 1 below shows the formulation of the obtained tablets of Examples 1 to 3.

In the above, the following components were used for each component of polyvinyl alcohol, polyoxyl 40 stearate, lactose hydrate, and crystalline cellulose.
Polyvinyl alcohol: Polyvinyl alcohol (partially saponified product), trade name EG-05, polyoxyl stearate 40 manufactured by Nippon Synthetic Chemical Industry Co., Ltd .: trade name MYS-40MV, lactose hydrate manufactured by Nikko Chemicals Co., Ltd .: lactose hydrate ( 200), DMV crystalline cellulose: trade name Theolas KG-1000, manufactured by Asahi Kasei Chemicals Corporation

In addition, lactose hydrate, crystalline cellulose, magnesium stearate and polyoxyl 40 in the above are those described in the 15th revision Japanese Pharmacopoeia, and crospovidone and polyvinyl alcohol are those described in Pharmaceutical Additive Standard 2003. It was used.
As a result of carrying out an oral disintegration test in humans on the preparations obtained in Examples 1 to 3, all disintegrated within 30 seconds and showed good disintegration properties.
In addition, the oral disintegration test in humans was performed as follows.
For the subjects (3 persons), the mouth was rinsed in advance by gargle, and after 30 seconds, the tablet was placed on the tongue, the mouth was closed, and the time until the shape completely disintegrated without chewing was measured.

Example 4 and Comparative Example 1
The intraoral quick disintegrating tablets of Example 4 and Comparative Example 1 were produced in the same manner as in Examples 1 to 3 except that the formulation was changed to that shown in Table 2 below.

It attached to both, and when the oral disintegration test was implemented similarly to Examples 1-3, all showed favorable oral disintegration property.
Moreover, it was as Table 3 when the elution test of the active ingredient was done by the method described after Table 3 with respect to the formulation obtained above.

Dissolution test method Using the intraorally rapidly disintegrating tablets obtained in Example 4 and Comparative Example 1, a dissolution test using the second solution of dissolution test described in the 15th revision Japanese Pharmacopoeia was performed.
That is, one tablet was taken, and the test was performed at 900 rpm with the paddle method using 900 mL of the test solution. The elution test was started, and after 10 minutes, 10 mL or more of the eluate was taken and filtered through a membrane filter having a pore size of 0.45 μm or less. Except for 3 mL of the first filtrate, 1 mL of the next filtrate was accurately weighed, and 1 mL of the internal standard solution L was accurately added to obtain a sample solution. Separately, glimepiride for quantification is dried at 105 ° C. for 4 hours, and about 22 mg thereof is accurately weighed and dissolved in the mobile phase to make exactly 200 mL. 1 mL of this liquid was accurately weighed and the mobile phase was added to make exactly 100 mL. 1 mL of this solution was accurately weighed and 1 mL of internal standard solution L was accurately added to obtain a standard solution. The sample solution and 50 μL of the standard solution were tested by liquid chromatography under the following conditions, and the ratios Q _T and Q _S of glimepiride peak area to the peak area of the internal standard substance were determined.

The dissolution rate (%) with respect to the displayed amount of glimepiride (C ₂₄ H ₃₄ N ₄ O ₅ S) at the time of collecting the eluate at the n-th time can be expressed by the following formula.

W _S : Weighed amount of glimepiride for determination (mg)
C: Displayed amount of glimepiride (C ₂₄ H ₃₄ N ₄ O ₅ S) in 1 tablet (mg)
As the internal standard solution L, a mobile phase solution (diluted 500,000 times) of propyl paraoxybenzoate was used.
The test conditions in the dissolution test are shown below.
Detector: UV absorptiometer (measurement wavelength: 228 nm)
Column: A stainless steel tube having an inner diameter of 4.6 mm and a length of 15 cm is filled with 5 μm of octadecylsilylated silica gel for liquid chromatography.
Column temperature: Constant temperature around 25 ° C. Mobile phase: 500 mL of acetonitrile was added to a solution obtained by dissolving 0.5 g of sodium dihydrogen phosphate in 500 mL of water, and the pH was adjusted to 3.5 with a phosphoric acid aqueous solution diluted five times. solution.
Flow rate: Adjusted so that the retention time of glimepiride was about 10 minutes.
In the dissolution test, when operating with 50 μL of the standard solution under the above conditions, the internal standard substance and glimepiride were eluted in this order, and the degree of separation was 10 or more. When the test was repeated 6 times with 50 μL of the standard solution under the above conditions, the relative standard deviation of the ratio of the peak area of glimepiride to the peak area of the internal standard substance was 1.0% or less.

  Since the initial dissolution property of the intraoral quick disintegrating tablet of the present invention is improved as described above, it is possible to accelerate the onset of the effect after taking. Therefore, it is an intraoral quick disintegrating tablet suitable for diabetics and the like that need to be effective early after taking.

Claims (13)

Pharmaceutically active ingredient at least one polyvinyl alcohol selected from the group consisting of polyvinyl alcohol and polyvinyl alcohol copolymers, and is selected from polyethylene glycol, polyoxyethylene polyoxypropylene glycol, the group consisting of polyethylene glycol ethers and polyethylene glycol fatty acid esters It contains at least one water-soluble polyoxyethylene, and the content of polyvinyl alcohol is 0.1 to 3% by mass and the content of water-soluble polyoxyethylene is 0.05 with respect to the total amount of the orally rapidly disintegrating tablet. An intraoral rapidly disintegrating tablet (excluding those containing erythritol) that is ˜1% by mass and disintegrates within 30 seconds in the oral cavity. The intraoral quick disintegrating tablet according to claim 1, further comprising an excipient and a disintegrant. The intraoral quick disintegrating tablet according to claim 2, wherein the excipient content is 50 to 80% by mass with respect to the total amount of the intraoral quick disintegrating tablet. The intraoral quick disintegrating tablet according to any one of claims 1 to 3, wherein the content of polyvinyl alcohol is 0.3 to 1 % by mass. The disintegrant content is 0.5-7% by mass and the total content of the excipient and the disintegrant is 50-98% by mass with respect to the total amount of the intraoral quick disintegrating tablet. Orally disintegrating tablet according to any one of the above. The total content of polyvinyl alcohols and water-soluble polyoxyethylenes is 0.3 to 1% by mass with respect to the total amount of the intraoral rapidly disintegrating tablet, according to any one of claims 1 to 5, The intraorally rapidly disintegrating tablet described. It contains 0.5 to 5% by mass of pharmaceutically active ingredient, 0.1 to 3% by mass of polyvinyl alcohols, and 0.05 to 1% by mass of water-soluble polyoxyethylenes, with the remainder being based on the whole formulation It is an excipient | filler, a disintegrating agent, and another pharmaceutical additive, The intraoral quick disintegrating tablet as described in any one of Claims 1-5 characterized by the above-mentioned. The intraoral quick disintegrating tablet according to any one of claims 1 to 7, wherein the polyvinyl alcohol is partially saponified polyvinyl alcohol. The intraorally rapidly disintegrating tablet according to claim 8, wherein the partially saponified polyvinyl alcohol is a partially saponified polyvinyl alcohol having a viscosity of 3 to 8 mPa · S (4%, 20 ° C). The water-soluble polyoxyethylene is a polyoxyl stearate, The intraoral quick disintegrating tablet according to any one of claims 1 to 9. The intraoral quick disintegrating tablet according to any one of claims 1 to 10, wherein the pharmaceutically active ingredient is glimepiride. The intraoral quick disintegrating tablet according to any one of claims 2 to 11, wherein the excipient is lactose hydrate . Spray a dispersion liquid in which a water-insoluble pharmaceutically active ingredient is uniformly dispersed in a polyvinyl alcohol-containing solution, and fluid bed granulation is performed on the excipient. excluding lubricant to be added later, and uniformly mixing a water soluble polyoxyethylenes and other pharmaceutical additives to the resulting mixture, after adding and mixing a lubricant, obtained by tableting The intraoral quick disintegrating tablet according to any one of claims 1 to 12 .