JP2010163428A - Disintegrating tablet - Google Patents

Abstract

Disclosed is a tablet containing a hygroscopic drug and having excellent disintegration, strength and drug stability.
A drug having an equilibrium water content of 10 to 20% at 25 ° C. and a relative humidity of 75%, erythritol and mannitol, and an equilibrium water content of 5 to 20% at a relative humidity of 75% at 25 ° C. And a disintegrating tablet comprising a 20% by mass aqueous solution of hydroxypropylcellulose having a viscosity at 37 ° C. of 100 to 2000 cps,
Containing 15-50% by mass of the drug with respect to the total mass of the disintegrating tablet, and
A disintegrating tablet, wherein the disintegrating tablet has a porosity of 10 to 40%.
[Selection figure] None

Description

  The present invention relates to a disintegrating tablet and a method for producing the same. More specifically, the present invention relates to a disintegrating tablet excellent in disintegration, strength and stability while containing a hygroscopic drug, and a method for producing the disintegrating tablet.

  Conventionally, various drugs have been used in preparations. Among these drugs, hygroscopic drugs having hygroscopicity are known to frequently cause deliquescence at high temperatures in summer, and their handling becomes a problem. ing.

  Conventionally, disintegrating tablets that are easily disintegrated in the body (for example, in the oral cavity) after taking are known. Although there is no unified definition for disintegrating tablets at present, it is generally said to refer to tablets having a function of rapidly disintegrating in the body after taking. In the case of orally disintegrating tablets taken orally, the expected disintegration time is generally considered to be within 5 to 60 seconds without chewing in the oral cavity. Disintegrating tablets (especially orally disintegrating tablets) can be taken without water, and are very useful tablets for users (especially infants and elderly people with low swallowing ability).

  As a disintegrating tablet, for example, by increasing the porosity of the tablet or by adding a disintegrant to the tablet, water in the bodily fluid is rapidly removed when it comes into contact with bodily fluid (eg, saliva during swallowing). The thing etc. which are made to absorb and exhibit disintegration etc. are devised (for example, patent documents 1-4).

Japanese Patent Laid-Open No. 2004-2326 International Publication No. WO95 / 20380 Pamphlet Japanese Patent No. 2919771 Japanese Patent Publication No. 7-39340

However, when the void ratio of the tablet is increased, the strength of the tablet itself is lowered, so that there is a problem that handling is inconvenient because the tablet is missing during transportation or removal from the storage container.
In addition, when a disintegrant is blended, the disintegrant itself has a high water absorbability, so there is a restriction in handling that contact with moisture should be avoided as much as possible until taking to prevent tablet strength reduction due to moisture absorption. .

  These problems are more serious in tablets containing hygroscopic drugs that are easily softened and altered by absorbing moisture in the atmosphere.

  Under such circumstances, the problem to be solved by the present invention is to provide a disintegrating tablet having disintegration, strength and drug stability while containing a hygroscopic drug.

In order to achieve the above-mentioned problems, the present inventors have intensively studied a disintegrating tablet containing a hygroscopic drug, and as a result, when erythritol, mannitol, and a predetermined hydroxypropyl cellulose are blended with the hygroscopic drug, It has been found that a disintegrating tablet having drug stability is obtained. The present invention has been made based on this finding.
That is, the present invention has (1) a drug having an equilibrium water content of 10 to 20% at 25 ° C. and a relative humidity of 75%, erythritol and mannitol, and an equilibrium water content of 75% relative humidity at 25 ° C. 5-20%, and a 20 mass% aqueous solution of hydroxypropyl cellulose having a viscosity of 100-2000 cps at 37 ° C. in an aqueous 20 mass% solution, A disintegrating tablet comprising 50% by mass, wherein the disintegrating tablet has a porosity of 10 to 40%;
(2) The disintegrating tablet according to (1), wherein the drug is a drug having an equilibrium water content of 10 to 18% under a relative humidity of 75%;
(3) The disintegrating tablet according to (1) or (2), wherein the drug is acarbose;
(4) The disintegrating tablet according to any one of (1) to (3), which is an orally disintegrating tablet;
(5) The disintegrating tablet according to any one of (1) to (4), which does not contain a water-insoluble disintegrant;
(6) The water-insoluble disintegrant is crospovidone, croscarmellose sodium, carmellose calcium, carmellose, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, starch, partially pregelatinized starch, corn starch, hydroxypropyl starch, crystals The disintegrating tablet according to (5), selected from the group consisting of cellulose and gelatin;
(7) A method for producing a disintegrating tablet, comprising the following steps:
(I) a step of mixing a drug having an equilibrium water content of 10 to 20% under a relative humidity of 75% at 25 ° C., erythritol, and mannitol;
(Ii) A non-aqueous solution of hydroxypropylcellulose having an equilibrium water content of 5 to 20% under a relative humidity of 75% at 25 ° C. and a viscosity of 100 to 2000 cps at 37 ° C. of a 20 mass% aqueous solution is used. A step of wetting the mixture obtained in (i) and then drying, and (iii) a step of forming the mixture obtained in (ii) into a disintegrating tablet, wherein the disintegrating tablet comprises the disintegrating tablet The production method comprising 15 to 50% by mass of the drug with respect to the total mass of the tablet, and wherein the disintegrating tablet has a porosity of 10 to 40%.
(8) The present invention relates to a disintegrating tablet obtained according to the production method described in (7) above.

  The disintegrating tablet of the present invention combines disintegration, strength, and drug stability even when a hygroscopic drug is blended, as shown in the examples described later. Therefore, the present invention can eliminate the inconvenience in handling that has existed in conventional disintegrating tablets, and can further expand the use of disintegrating tablets.

The present invention is described in detail below.
The drug used for the disintegrating tablet of the present invention is a drug having an equilibrium water content of 10 to 20% under a relative humidity of 75% at 25 ° C.
The equilibrium moisture content of the drug is 10-20%, preferably 10-18%, under 75% relative humidity at 25 ° C. It is understood that a drug having an equilibrium water content of 10 to 20% under a relative humidity of 75% at 25 ° C. is generally a hygroscopic drug, and the present invention can be disintegrated even when such a hygroscopic drug is blended. Disintegrating tablets having both strength and drug stability can be provided.
In this specification, the equilibrium water content at 25 ° C. and 75% relative humidity is a value determined according to the following procedure.
After the drug to be measured is dried at 105 ° C. for 2 hours, about 5 g is taken and its mass (W1) is measured. The measurement target drug after mass measurement is allowed to stand for 72 hours in a desiccator in which the relative humidity at 25 ° C. is adjusted to 75% using saturated saline, and then its mass (W2) is measured. Based on W1 and W2, the equilibrium water content (%) is calculated from the following formula.
Equilibrium moisture content (%) = (W2−W1) / W1 × 100

  The drug used in the present invention is not particularly limited as long as it satisfies the above-mentioned conditions of relative humidity and can be administered by tablets. The drug may be systemic or local.

The drug used in the present invention may be any of solid, crystalline, oily, solution and the like, for example, nourishing tonic health drug, antipyretic analgesic / antiinflammatory drug, psychotropic drug, anxiolytic drug, antidepressant drug, hypnosis Sedative, antispasmodic, central nervous system drug, cerebral metabolism improving agent, cerebral circulation improving agent, antiepileptic agent, sympathomimetic agent, gastrointestinal drug, antacid, anti-ulcer agent, antitussive expectorant, antiemetic, respiratory enhancement Agents, bronchodilators, allergic agents, dental and oral agents, antihistamines, cardiotonic agents, arrhythmic agents, diuretics, antihypertensive agents, vasoconstrictors, coronary vasodilators, peripheral vasodilators, hyperlipidemia agents , Antibacterials, antibiotics, chemotherapeutics, antidiabetics, osteoporosis, antirheumatic, skeletal muscle relaxant, antispasmodic, hormone, alkaloid narcotic, sulfa, gout, blood coagulation Ingredients selected from blocking agents, antineoplastic agents, etc. It is.
Of these, antidiabetic drugs are preferred. Examples of antidiabetic drugs include alpha glucosidase inhibitors. Specific examples of the alpha glucosidase inhibitor include acarbose and voglibose. Acarbose is particularly preferred.

The drugs used in the present invention are known compounds and can be easily obtained on the market or synthesized.
Moreover, a drug can be used individually or in combination of 2 or more types.

  The content of the drug in the disintegrating tablet of the present invention varies depending on the type of drug used and the like, but is 15 to 50% by mass, preferably 15 to 30% by mass with respect to the total mass of the disintegrating tablet. When it is 15 to 50% by mass, a disintegrating tablet in which disintegration, strength and stability are arranged side by side can be obtained.

The erythritol used for the disintegrating tablet of this invention will not be restrict | limited especially if it can mix | blend with a disintegrating tablet.
Erythritol is a known compound and is readily available on the market.
The content of erythritol in the disintegrating tablet of the present invention varies depending on the moldability of the drug and the like, but is 40 to 84% by mass, preferably 60 to 84% by mass with respect to the total mass of the disintegrating tablet. When it is 40 to 84% by mass, a disintegrating tablet having disintegration, strength, and drug stability can be obtained.

The mannitol used for the disintegrating tablet of this invention will not be restrict | limited especially if it can mix | blend with a disintegrating tablet.
Mannitol is a known compound and is readily available on the market.
The content of mannitol in the disintegrating tablet of the present invention varies depending on drug moldability and the like, but is 0.5 to 44.5% by mass, preferably 1 to 20% by mass, based on the total mass of the disintegrating tablet. is there. When it is 0.5 to 44.5% by mass, a disintegrating tablet having disintegration properties, strength, and drug stability can be obtained.

Hydroxypropyl cellulose used in the disintegrating tablet of the present invention has an equilibrium water content of 5 to 20% under a relative humidity of 75% at 25 ° C., and a viscosity at 37 ° C. of a 20 mass% aqueous solution of 100 to 2000 cps. Hydroxypropyl cellulose.
The equilibrium water content of hydroxypropylcellulose is 5 to 20%, preferably 5 to 15% under 75% relative humidity at 25 ° C. When the equilibrium water content is 5 to 20%, even when a hygroscopic drug is blended, a disintegrating tablet having disintegration, strength, and drug stability can be provided.
In this specification, the equilibrium water content at 75 ° C. relative humidity at 25 ° C. refers to a value determined by the same procedure as the above-mentioned “equilibrium water content of drug”.

The viscosity of hydroxypropyl cellulose is 100 to 2000 cps, preferably 100 to 500 cps, in a 20% by mass aqueous solution at 37 ° C. When the viscosity at 37 ° C. of the 20 mass% aqueous solution is 100 to 2000 cps, a disintegrating tablet having disintegration, strength and drug stability can be provided even when a hygroscopic drug is blended.
In this specification, the viscosity at 37 ° C. of a 20% by mass aqueous solution of hydroxypropylcellulose is a value measured according to “Viscosity Measurement Method 2 Method Rotational Viscometer Method” described in the 15th revised Japanese Pharmacopoeia General Test Method. Say.

The hydroxypropyl cellulose used in the present invention is not particularly limited as long as it satisfies the above-mentioned equilibrium water content and viscosity conditions and can be administered by tablets.
As a specific example of hydroxypropyl cellulose having the above properties, a product name from Nippon Soda: HPC-SSL (equilibrium water content at 75% relative humidity at 25 ° C. under 10%, viscosity of 20% by weight aqueous solution at 37 ° C .: 200 cps) and the like.

The above hydroxypropyl cellulose is a known compound and can be easily obtained in the market or synthesized.
Hydroxypropyl cellulose can be used alone or in combination of two or more.

  The content of hydroxypropylcellulose in the disintegrating tablet of the present invention varies depending on the moldability of the drug and the like, but is 0.5 to 5% by mass, preferably 0.8 to 2% by mass with respect to the total mass of the disintegrating tablet. %. When the content is 0.5 to 5% by mass, a disintegrating tablet having disintegration, strength, and drug stability can be obtained.

The disintegrating tablet of the present invention preferably does not contain a water-insoluble disintegrant.
Water-insoluble in water-insoluble disintegrant is the amount of purified water required to shake and dissolve 1 g of water-insoluble disintegrant in purified water at 20 ° C. for 30 minutes according to the measurement method described in the 15th revised Japanese Pharmacopoeia. Means 1000 mL or more.
Disintegration in a water-insoluble disintegrant means that the preparation disintegrates when the prepared preparation is tested under specified conditions in accordance with the “Disintegration Test Method” described in the 15th Amendment of the Japanese Pharmacopoeia General Test Method. Say.

Specific examples of the water-insoluble disintegrant include crospovidone (1-ethenyl-2-pyrrolidinone homopolymer), croscarmellose sodium, carmellose calcium, carmellose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose (for example, hydroxy Propoxyl group content is 5 to 16% by weight), starch, partially pregelatinized starch, corn starch, hydroxypropyl starch, crystalline cellulose, gelatin and the like.
Since the water-insoluble disintegrant described above absorbs moisture and exhibits a disintegrating action, by not blending with a disintegrating tablet, denaturation of the hygroscopic drug can be further reduced and the tablet strength can be further increased.

The disintegrating tablet of the present invention has a porosity of 10 to 40%. The porosity is preferably 20 to 40%. When the disintegrating tablet has a porosity of 10 to 40%, it can rapidly absorb water in the body fluid when it comes into contact with body fluid (eg, saliva during swallowing) and can exhibit excellent disintegration properties. .
The porosity is a value determined according to the following formula.
Porosity (%) = (V−W / M) / V × 100
V: Volume of disintegrating tablet (cm ³ )
W: Mass of disintegrating tablet (g)
M: Density of disintegrating tablet (g / cm ³ )

The density (M) of the disintegrating tablet refers to a value determined according to the following procedure. The disintegrated tablet is transferred to a mortar and powdered. About 5 g of a powder sample is taken and its mass (W2) is measured. The volume (V2) of the powder sample after mass measurement is measured using a pycnometer (trade name: helium hydrometer 1302 manufactured by Shimadzu Corporation). Based on the measured values of W2 and V2, the density (M) is calculated from the following calculation formula.
Density of disintegrating tablet (g / cm ³ ) = W2 / V2

A lubricant, a coloring agent, and the like can be added to the disintegrating tablet of the present invention as necessary.
Examples of the additive include the following substances.
Lubricant Sodium stearyl fumarate, magnesium stearate, sucrose fatty acid ester The content of the lubricant varies depending on the moldability of the drug, etc., but is 0.001 to 10 mass relative to the total mass of the disintegrating tablet %.
Colorant yellow iron sesquioxide, iron sesquioxide, edible dye, edible lake dye

The disintegrating tablet of the present invention comprises the following steps (1) to (3):
(1) A step of mixing a drug having an equilibrium water content of 10 to 20% under a relative humidity of 75% at 25 ° C., erythritol, and mannitol.
(2) A non-aqueous solution of hydroxypropyl cellulose having an equilibrium water content of 5 to 20% at a relative humidity of 75% at 25 ° C and a viscosity of 100 to 2000 cps at 37 ° C of a 20% by mass aqueous solution is used. A step of moistening the mixture obtained in (1) and then drying, and (3) a step of molding the mixture obtained in (2) into a disintegrating tablet,
It can manufacture by the method containing.

Steps (1) to (2) can be performed using a granulator commonly used in the pharmaceutical field, for example, a fluidized bed granulation / coating apparatus or a stirring and mixing granulator.
The non-aqueous solution of hydroxypropyl cellulose used in step (2) is a solution obtained by dissolving hydroxypropyl cellulose in a non-aqueous solvent. Examples of the non-aqueous solvent include ethanol and methanol. Hydroxypropyl cellulose is also soluble in an aqueous solvent, but a non-aqueous solvent is used in the present invention in order to prevent denaturation and loss of strength of a disintegrating tablet due to absorption of moisture contained in the aqueous solvent by the hygroscopic drug. The hydroxypropylcellulose concentration in the non-aqueous solution is preferably 5-20%. The non-aqueous solvent can be dried at 30 to 90 ° C, preferably 60 ° C.
In the step (2), the surface of each component (drug, erythritol and mannitol) in the mixture obtained in the step (1) is wetted using a non-aqueous solution of hydroxypropylcellulose, and dried to dry the hydroxypropylcellulose. A mixture of each component (drug, erythritol and mannitol) coated with is obtained.
The obtained mixture may be adjusted to a particle size of, for example, 0.5 to 5 mm, preferably 0.8 to 2 mm using a granulator before being subjected to step (3). Moreover, you may add a lubricant before attaching | subjecting to a process (3).
Step (3) can be performed using a tableting machine commonly used in the pharmaceutical field, such as a single tableting machine or a rotary tableting machine. Molding from the mixture obtained in step (2) into a tablet can achieve a minimum pressure, for example, 0.1 to 10 kN / cm ² , so as to achieve the porosity (10 to 40%) of the disintegrating tablet described above. Preferably it carries out at 0.3-5 kN / cm < ² >. Moreover, although a normal tableting method can be used, an external lubrication tableting method can also be used. An apparatus for performing external lubricant tableting includes ELSP1 manufactured by Kikusui Seisakusho.
Optionally, the tablet obtained in step (3) is subjected to a humidification and drying step, which causes melting and solidification of hydroxypropylcellulose covering each component (drug, erythritol and mannitol), thereby increasing the strength of the disintegrating tablet. It may be further increased. However, the humidification process must be performed under conditions that do not cause denaturation of the hygroscopic drug due to moisture and decrease in strength of the disintegrating tablet (for example, the tablet is placed in a humidification tank at a temperature of 50 ° C. and a relative humidity of 90% for 2 minutes). Drying can be carried out using a conventional drying method in the pharmaceutical field, such as vacuum drying or fluidized bed drying.

Although the thickness of the disintegrating tablet of this invention changes depending on the kind etc. of application object, when applying in an oral cavity, it is 1-8 mm, Preferably it is 3-6 mm. The foreign material feeling at the time of taking can be suppressed as it is 1-8 mm.
The shape of the disintegrating tablet of the present invention varies depending on the type of application target and the like, but is rectangular, round, elliptical, or the like. A round shape or an oval shape is preferable in that the feeling of foreign matter during ingestion is suppressed.
The disintegrating tablet of the present invention is generally applied to the oral cavity, but can also be applied to sites other than the oral cavity, such as the intestinal mucosa, conjunctival sac, nose, pharynx, and vagina.
Further, the disintegrating tablet of the present invention can be used for the purpose of both systemic action and local action depending on the nature of the drug contained.

  Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples, but these do not limit the present invention.

Examples Acarbose (measured according to the above measurement method (the same is true for the comparative example)) Equilibrium moisture content at 75% relative humidity at 25 ° C .: 17% (Bayer HealthCare) 75 g, Erythritol (Niken Kasei) 283.5 g and mannitol (Towa Kasei Kogyo Co., Ltd.) 9 g was charged into a stirring and mixing granulator (VG-1 manufactured by Paulec) and mixed. Next, the equilibrium moisture content at 25 ° C. and 75% relative humidity is 10% (measured according to the above measurement method (the same is true for the comparative example)), and the viscosity of a 20 mass% aqueous solution at 37 ° C. is 200 cps (the above measurement). In a mixture using a solution (solvent: ethanol; hydroxypropylcellulose concentration: 10%) containing 3.75 g of hydroxypropylcellulose (Nippon Soda, trade name: HPC-SSL), which is measured according to the method (the same is true for comparative examples) The surface of each component was moistened and dried by ventilation at 60 ° C., and then adjusted to a particle size of 1 mm using a 16 mesh screen. Next, 3.75 g of sodium stearyl fumarate (Kimura Sangyo) was added as a lubricant and mixed. Using the tableting machine CP-12HUK (manufactured by Kikusui Seisakusho) (杵 9 mmφ), the resulting mixed powder was tableted into a tablet mass of 250 mg, a tablet thickness of 4.2 mm, and a shape: round (tablet pressure: 1 kN / cm ² ), the tablets were left for 2 minutes in a humidification tank at a temperature of 50 ° C. and a relative humidity of 90%. Next, it was dried by ventilation at 60 ° C. The resulting tablet did not contain a water-insoluble disintegrant. The porosity of the tablet determined according to the above formula (same for the comparative example) was 23%.

Comparative Example 1
As hydroxypropylcellulose, 3.75 g of hydroxypropylcellulose (Nippon Soda) having an equilibrium water content of 9% under a relative humidity of 75% at 25 ° C. and a viscosity of 9000 cps at 37 ° C. of a 20% by mass aqueous solution A tablet was produced in the same manner as in Example except that it was used. The porosity of the obtained tablet was 22%.

Comparative Example 2
Instead of hydroxypropylcellulose, 3.75 g of maltose (equilibrium water content at 25 ° C. under 75% relative humidity of 7%, viscosity of 20 mass% aqueous solution at 37 ° C. of 2 cps) (Hayashibara Shoji) Except for the above, tablets were produced in the same manner as in the Examples. The porosity of the obtained tablet was 21%.

About the tablet of an Example and a comparative example, the hardness (index of strength of a disintegrating tablet) and the oral disintegration time (disintegration tablet of the disintegrating tablet) in conditions (25 ° C., 3 hours at 75% relative humidity) assumed to be left immediately after production and after opening. Disintegration index). The test method is as follows.

Hardness (N)
Using a Kiyama-type hardness meter (manufactured by Kiyama Seisakusho Co., Ltd.), the measurement was performed at a relative humidity of 45 to 55% at 25 ° C. Measurement was performed on 10 tablets, and the average value was defined as hardness (N).

Oral disintegration time (seconds)
One panelist put the tablet between the tongue and the upper jaw and measured the time until the tablet shape was not recognized without chewing. Three tablets were measured, and the average value was defined as the oral disintegration time (seconds).

The measurement results are shown in Table 1 below.

○：合格
×：不合格 Table 2 below shows the results when the hardness and disintegration criteria required for disintegrating tablets are set to a hardness of 20 N or more and an oral disintegration time of 30 seconds or less.

○: Pass ×: Fail

About the tablet of an Example, the acarbose content was measured immediately after manufacture and after 1 month, 3 months, and 6 months storage, and the stability of the hygroscopic drug was evaluated. The storage container was a PTP + aluminum bag. Storage was performed at a relative humidity of 75% and 40 ° C. The acarbose content was measured according to “Liquid Chromatography” described in the 15th Amendment Japanese Pharmacopoeia General Test Method. The results are shown in Table 3 below. The values in Table 3 are acarbose contents (average value measured three times using 20 tablets) in one tablet (250 mg).

  The disintegrating tablet of the present invention can be used as a medicine.

Claims (8)

A drug with an equilibrium water content of 10-20% at 25 ° C. and 75% relative humidity;
With erythritol,
With mannitol,
A disintegrating tablet comprising hydroxypropyl cellulose having an equilibrium water content of 5 to 20% under a relative humidity of 75% at 25 ° C and a viscosity of 100 to 2000 cps at 37 ° C of a 20 mass% aqueous solution,
Containing 15-50% by mass of the drug with respect to the total mass of the disintegrating tablet, and
A disintegrating tablet, wherein the disintegrating tablet has a porosity of 10 to 40%.   The disintegrating tablet according to claim 1, wherein the drug is a drug having an equilibrium water content of 10 to 18% under a relative humidity of 75%.   The disintegrating tablet according to claim 1 or 2, wherein the drug is acarbose.   The disintegrating tablet according to any one of claims 1 to 3, which is an orally disintegrating tablet.   The disintegrating tablet according to any one of claims 1 to 4, which does not contain a water-insoluble disintegrant.   The water-insoluble disintegrant is crospovidone, croscarmellose sodium, carmellose calcium, carmellose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, starch, partially pregelatinized starch, corn starch, hydroxypropyl starch, crystalline cellulose and gelatin The disintegrating tablet according to claim 5, which is selected from the group consisting of: A method for producing a disintegrating tablet, comprising the following steps:
(1) A step of mixing a drug having an equilibrium water content of 10 to 20% under a relative humidity of 75% at 25 ° C., erythritol, and mannitol.
(2) A non-aqueous solution of hydroxypropyl cellulose having an equilibrium water content of 5 to 20% at a relative humidity of 75% at 25 ° C and a viscosity of 100 to 2000 cps at 37 ° C of a 20% by mass aqueous solution is used. A step of moistening the mixture obtained in (1) and then drying, and (3) a step of molding the mixture obtained in (2) into a disintegrating tablet,
Including
The production method, wherein the disintegrating tablet contains 15 to 50% by mass of the drug with respect to the total mass of the disintegrating tablet, and the porosity of the disintegrating tablet is 10 to 40%.   A disintegrating tablet obtained according to the production method of claim 7.