KR101421330B1 - A disintegrating tablet - Google Patents

Abstract

The present invention provides tablets that contain hygroscopic drugs and are excellent in collapsibility, strength, and drug stability. Specifically, the present invention relates to a pharmaceutical composition comprising a drug having an equilibrium moisture content of 10 to 20% at 25 DEG C and a relative humidity of 75%, erythritol and mannitol, and an equilibrium moisture content at 25 DEG C and a relative humidity of 75% And 20% by mass of a hydroxypropyl cellulose having a viscosity of 100 to 2000 cps at 37 캜, wherein the disintegrating tablet contains 15 to 50% by mass of the drug relative to the total amount of the disintegrating tablet , And a porosity of 10 to 40%.

Description

A DISINTEGRATING TABLET}

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

Conventionally, various drugs are used in pharmaceuticals, but hygroscopic drugs having hygroscopicity of these drugs are known to cause deliquescence often at high temperatures in the summer, and their handling has become a problem.

Further, a disintegrating tablet which is easily collapsed in the body (for example, in the oral cavity) after conventional administration is known. Currently there is no unified definition of "collapsing tablet", but it is generally a tablet that has the ability to rapidly disintegrate in the body after taking it. Oral Intraoral Decay In the case of definition, the expected decay time is generally within 5 to 60 seconds without chewing in the mouth. Disintegrating tablets (especially oral disintegrating tablets) are very useful tablets for users (especially infants and elderly people with low swallowing ability) because they can be taken without water.

As the collapsing tablet, for example, by increasing the porosity of the tablet and / or by adding a disintegrant to the tablets, when the tablet is contacted with a body fluid (for example, saliva at the time of taking it) at the time of taking it, (For example, Patent Documents 1 to 4).

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

However, when the porosity of the tablet is increased, the strength of the tablet itself is lowered. Therefore, there is a problem that handling becomes inconvenient, such as breakage of the tablet when it is transported or removed from the storage container.

In addition, when a disintegrant is added, since the disintegrant itself has a large water absorption property, there is a restriction in handling that the contact with moisture should be avoided as much as possible until the time of ingestion in order to prevent the strength of the tablets from lowering due to moisture absorption.

These problems are more serious problems in tablets containing a hygroscopic drug which is liable to soften and deteriorate by absorbing moisture in the air.

Under these circumstances, a problem to be solved by the present invention is to provide a disintegrating tablet that combines a hygroscopic drug with a disintegration property, a strength and a drug stability.

In order to achieve the above object, the inventors of the present invention have made intensive investigations on a disintegrating tablet containing a hygroscopic drug. As a result, it has been found that when erythritol and mannitol are mixed with a predetermined hydroxypropylcellulose in a hygroscopic drug, A disintegrating tablet was obtained. The present invention is based on this finding.

That is,

(1) a drug having an equilibrium water content of 10 to 20% at 25 DEG C and a relative humidity of 75%, erythritol and mannitol, an equilibrium moisture content at 25 DEG C and a relative humidity of 75% of 5 to 20% Wherein the disintegrating tablet contains 15 to 50% by mass of the drug relative to the total amount of the disintegration tablet, the porosity is 10 to 10% by mass based on the total amount of the disintegration tablet, To 40%;

(2) The disintegrating tablet according to the above item (1), wherein the drug has an equilibrium moisture content of 10 to 18% at a relative humidity of 75%;

(3) The disintegrating tablet according to (1) or (2), wherein the drug is an acarbose;

(4) The disintegrating tablet according to any one of (1) to (3) above, wherein the disintegrating tablet is an intraoral disintegration tablet;

(5) A disintegrating tablet according to any one of (1) to (4), wherein the disintegrating tablet does not contain a water-insoluble disintegrant;

(6) The pharmaceutical composition according to the above (5), wherein the water-insoluble disintegrant is crospovidone, croscarmellose sodium, carmellose calcium, carmellose, carboxymethylstarch sodium, disintegrating tablet selected from the group consisting of pregelatinized starch, corn starch, hydroxypropyl starch, crystalline cellulose and gelatin;

(7) a step of mixing (i) a drug having an equilibrium water content of 10 to 20% at 25 DEG C and a relative humidity of 75%, erythritol and mannitol,

(ii) a non-aqueous solution of hydroxypropylcellulose having an equilibrium moisture content of 5 to 20% at 25 DEG C and a relative humidity of 75% and a viscosity of 20 mass% aqueous solution at 37 DEG C of 100 to 2000 cps, (i) wetting and drying the mixture obtained in

(iii) molding the mixture obtained in (ii) into a collapse tablet, wherein the collapse tablet comprises 15 to 50% by mass of the drug relative to the total amount of the collapse definition, and having a porosity of 10 to 40% Way.

(8) A disintegrating tablet obtained according to the production method described in (7)

.

The disintegrating tablet of the present invention combines disintegration, strength and drug stability even when a hygroscopic drug is formulated, as shown in Examples described later. Therefore, the present invention can solve the inconvenience of handling in the conventional collapsing collapse, and further increase the use of collapse collapse.

Hereinafter, the present invention will be described in detail.

The drug used in the collapsing tablet of the present invention is a drug having an equilibrium water content of 10 to 20% at 25 DEG C and a relative humidity of 75%.

The equilibrium moisture content of the drug is 10 to 20%, preferably 10 to 18% at 75% relative humidity at 25 ° C. A drug having an equilibrium moisture content of 10 to 20% at 25% relative humidity at 75% is generally understood to be a hygroscopic drug, and the present invention relates to a pharmaceutical composition comprising a hygroscopic drug having a disintegration property, strength and drug stability Can be provided.

As used herein, the "equilibrium moisture content" at 25 DEG C and a relative humidity of 75% refers to a value determined according to the following procedure.

The drug to be measured is dried at 105 DEG C for 2 hours, then about 5 g is taken and its mass (W1) is measured. After the mass measurement, the drug to be measured is left in a desiccator adjusted to a relative humidity of 75% at 25 캜 for 72 hours by using a saturated saline solution, and its mass (W2) is measured. Based on W1 and W2, the equilibrium water content (%) is calculated by the following equation.

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

The drug to be used in the present invention may be any of solid, crystalline, oil, and liquid, and may be, for example, a nourishing tonic medicine, a paracetamol antiinflammatory drug, a psychotropic drug, an anxiolytic drug, , Anticonvulsant, anti-ulcer agent, eukaryotic expectorant, pneumoperitoneum, respiratory stimulant, bronchodilator, allergy medicine, dental oral medicine, antihistamine An antidiabetic agent, an antihypertensive agent, an antibiotic, a chemotherapeutic agent, a diabetic drug, an osteoporosis drug, an anti-rheumatic drug, an anti-rheumatic drug, Skeletal muscle relaxants, antispasmodics, hormones, alkaloids, sulphides, gout remedies, blood coagulation inhibitors, anti-malignant agents, and the like.

Of these, diabetic drugs are preferred. Diabetic drugs include alpha glucosidase inhibitors. Specific examples of the alpha glucosidase inhibitor include acarbose and voglibose. Acarbose is particularly preferred.

The drug used in the present invention is a known compound and is easily available on the market or can be synthesized.

The drugs may be used alone or in combination of two or more.

The content of the drug in the collapsing tablet of the present invention varies depending on the type of the drug to be used and the like, and is from 15 to 50 mass%, preferably from 15 to 30 mass%, based on the total amount of the collapse. If it is in the range of 15 to 50 mass%, a disintegrating tablet having collapsibility, strength and stability can be obtained.

The erythritol used in the collapsing tablet of the present invention is not particularly limited as long as it can be compounded into the collapsing 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 is 40 to 84 mass%, preferably 60 to 84 mass%, based on the total amount of the disintegration tablet. If it is in the range of 40 to 84 mass%, a disintegrating tablet having both disintegration and strength and drug stability can be obtained.

The mannitol used in the collapsing tablet of the present invention is not particularly limited as long as it is compoundable in the collapsing tablet.

Mannitol is a known compound and is readily available on the market.

The content of mannitol in the collapsing tablet of the present invention varies depending on the moldability of the drug and the like, and is 0.5 to 44.5 mass%, preferably 1 to 20 mass%, based on the total amount of the collapse. 0.5 to 44.5 mass%, a disintegrating tablet having both disintegration resistance and strength and drug stability can be obtained.

The hydroxypropyl cellulose used in the disintegrating tablet of the present invention has an equilibrium moisture content of 5 to 20% at 25 DEG C and a relative humidity of 75% and a viscosity of 20% by mass aqueous solution at 37 DEG C of 100 to 2000 cps Hydroxypropylcellulose.

The equilibrium water content of the hydroxypropyl cellulose is 5 to 20%, preferably 5 to 15% at 25 DEG C and a relative humidity of 75%. When the equilibrium moisture content is 5 to 20%, even when a hygroscopic drug is added, it is possible to provide collapsing tablets having both disintegration and strength and drug stability.

As used herein, the "equilibrium moisture content at 25 DEG C under 75% relative humidity" refers to a value determined by the same procedure as the aforementioned "equilibrium moisture content of the drug ".

The viscosity of hydroxypropyl cellulose is 100 to 2000 cps, preferably 100 to 500 cps, at a viscosity of 20 mass% aqueous solution at 37 캜. When the 20% by mass aqueous solution has a viscosity of 100 to 2000 cps at 37 캜, it is possible to provide collapsing tablets having both disintegration and strength and drug stability even when a hygroscopic drug is added.

In the present specification, the viscosity of a 20 mass% aqueous solution of hydroxypropyl cellulose at 37 캜 refers to a value measured according to the " Viscosity Measurement Method 2 Method Rotor Viscometer Method "described in the 15th General Japanese Pharmacopoeia.

The hydroxypropyl cellulose used in the present invention is not particularly limited as long as it satisfies the above equilibrium moisture content and viscosity conditions and can be administered by tablet.

Specific examples of hydroxypropylcellulose having the above properties include Nippon Soda Co., Ltd. under the trade name of HPC-SSL (equilibrium moisture content at 25 ° C under a relative humidity of 75% of 10%, 20 mass% % Aqueous solution at 37 캜: 200 cps).

The above-mentioned hydroxypropylcellulose is a known compound and is easily available on the market or can be synthesized.

The hydroxypropyl cellulose may 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 formability of the drug and the like, and is from 0.5 to 5 mass%, preferably from 0.8 to 2 mass%, based on the total amount of the decay. If it is 0.5 to 5% by mass, a disintegrating tablet having both disintegration and strength and drug stability can be obtained.

The disintegrating tablet of the present invention preferably does not contain a water-insoluble disintegrant.

The water insolubility in the water insoluble disintegrator means that when 1 g of the water insoluble disintegrant is vibrated strongly in purified water at 20 캜 for 30 minutes in accordance with the measurement method described in the general rules of Japanese Pharmacopoeia of 15th Edition, And the amount of purified water required for dissolving is 1000 ml or more.

The disintegration property in the water-insoluble disintegrating agent means that the formulation is collapsed when the formulation is tested under the predetermined conditions according to the "disintegration test method "

Specific examples of the water-insoluble disintegrators include crospovidone (1-ethenyl-2-pyrrolidinone homopolymer), croscarmellose sodium, carmellose calcium, carmellose, carboxymethylstarch sodium, (For example, a hydroxypropoxyl group content of 5 to 16% by weight), starch, partially pregelatinized starch, corn starch, hydroxypropyl starch, crystalline cellulose and gelatin.

The water-insoluble disintegrating agent described above absorbs water and exerts a disintegrating action. Therefore, the water-insoluble disintegrant does not contain the water-insoluble disintegrant in the disintegrating tablet, thereby further reducing denaturation of the hygroscopic drug and increasing the tablet strength.

The disintegration tablet of the present invention has a porosity of 10 to 40%. The porosity is preferably 20 to 40%. When the disintegration definite porosity is 10 to 40%, it can rapidly absorb moisture in body fluids when contacted with a body fluid (for example, saliva at the time of swallowing) at the time of taking it, and exhibit excellent collapsibility. The porosity is a value obtained by the following equation.

V: Decomposition definition volume (㎤)

W: Deflection mass (g)

M: Decomposition definition density (g / cm3)

Decomposition Definition Density (M) refers to a value determined according to the following procedure:

Disintegration tablets are transferred to trigger and used as a sample. Approximately 5 g of the powder sample is taken, and its mass (W2) is measured. The volume (V2) of the powder sample is measured after mass measurement using a pycnometer (Helium Pycnometer 1302, manufactured by SHIMADZU CORPORATION). Based on the measured values of W2 and V2, the density (M) is calculated from the following equation.

To the collapsing tablet of the present invention, a lubricant, a coloring agent, and the like may be added as needed.

As the additive, the following substances can be mentioned.

Lubricant

The content of sodium stearyl fumarate, magnesium stearate and sucrose fatty acid ester lubricant varies depending on the moldability of the drug and is 0.001 to 10% by mass based on the total amount of the collapse.

coloring agent

Yellow ferric oxide, ferric oxide red, edible pigment, edible lake pigment.

The disintegrating tablet of the present invention can be produced by a method including the following steps (1) to (3).

(1) a step of mixing a drug having an equilibrium water content of 10 to 20% at 25 DEG C and a relative humidity of 75%, erythritol and mannitol,

(2) Using a non-aqueous solution of hydroxypropylcellulose having an equilibrium moisture content of 5 to 20% at 25 DEG C and a relative humidity of 75% and a viscosity of 20 mass% aqueous solution at 37 DEG C of 100 to 2000 cps, Wetting the mixture obtained in (1), followed by drying, and

(3) a step of molding the mixture obtained in (2) into a collapsing tablet

The steps (1) to (2) can be carried out by using a pelletizing machine in the field of pharmaceuticals, for example, a fluidized bed granulating / coating machine or a stirring / mixing granulating machine.

The non-aqueous solution of hydroxypropylcellulose used in the step (2) is a solution obtained by dissolving hydroxypropylcellulose in a non-aqueous solvent. Examples of the non-aqueous solvent include ethanol and methanol. Hydroxypropylcellulose is also dissolved in an aqueous solvent. In order to prevent degradation of denaturation or degradation of strength due to absorption of moisture contained in an aqueous solvent by a hygroscopic drug, a non-aqueous solvent is used in the present invention. The concentration of hydroxypropylcellulose in the non-aqueous solution is preferably 5 to 20%. The drying of the non-aqueous solvent can be carried out at 30 to 90 占 폚, preferably at 60 占 폚.

In the step (2), the surface of each component (drug, erythritol and mannitol) in the mixture obtained in the step (1) is wetted with a non-aqueous solution of hydroxypropyl cellulose and dried to coat the hydroxypropylcellulose with hydroxypropylcellulose A mixture of each of the components (drug, erythritol and mannitol) is obtained.

The obtained mixture may be adjusted to a particle size of 0.5 to 5 mm, preferably 0.8 to 2 mm, for example, using a sizing device before adding to the step (3). In addition, a lubricant may be added before adding to the step (3).

Step (3) can be carried out using a tableting machine, for example, a single-tablet refiner or a rotary tablet machine in the field of pharmaceuticals. The molding from the mixture obtained in the step (2) to the refining furnace is carried out at a minimum pressure, for example, 0.1 to 10 kN / cm 2, preferably 0.3 to 5 kN (10 to 40 kN), so as to achieve the above- / Cm < 2 >. In addition, a conventional tattoo method can be used, but an external satin tattoo method can also be used. A device for external contact sticking is ELSP1 manufactured by Kikusui Seisakusho Ltd. and the like.

Optionally, the tablets obtained in step (3) are added to a humidifying and drying step to cause melting and solidification of the hydroxypropyl cellulose covering each component (drug, erythritol and mannitol), and the strength of the disintegrating tablet may be further increased . The humidification step should be carried out under the conditions that denaturation of the hygroscopic drug by moisture and / or degradation of the corroded proof strength do not occur (for example, refining in a humidification tank at a temperature of 50 DEG C and a relative humidity of 90% for 2 minutes). Drying can be carried out by a conventional drying method in the field of formulation, for example, vacuum drying or fluidized bed drying.

The thickness of the collapsing definition of the present invention varies depending on the kind of the object to be applied and is 1 to 8 mm, preferably 3 to 6 mm when applied in the oral cavity. 1 to 8 mm, it is possible to suppress a foreign body feeling upon administration.

The shape of the collapse definition of the present invention varies depending on the type of the object to be applied and the like, and is a rectangle, a circle, an ellipse, and the like. Circular, and elliptical, it is preferable in that the foreign body feeling is suppressed at the time of ingestion.

The disintegrating tablet of the present invention is generally applied in the oral cavity, but may be applied to areas other than the oral cavity, such as intestinal membrane, conjunctival sac, nose, pharynx, vagina, and the like.

Also, the collapsing tablet of the present invention can be used either as a systemic action or as a local action, depending on the nature of the drug contained.

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

Example

(Equilibrium moisture content at 75% relative humidity at 25 ° C: 17%) (Bayer Health Care) 75 g, erythritol (available from Nikken Co., (Nikkenkasei Corporation) and 9 g of mannitol (Towa-Kasei Co., Ltd.) were added to a stirring mixer (VG-1, manufactured by Paurex Corporation) and mixed. Then, the equilibrium moisture content at 25 DEG C under a relative humidity of 75% was 10% (measured according to the above measurement method (also in the comparative example)), and the viscosity at 37 DEG C of the 20 mass% aqueous solution was 200 cps (Solvent: ethanol: hydroxypropylcellulose concentration: 10%) containing 3.75 g of hydroxypropylcellulose (Nippon Soda, trade name: HPC-SSL) The surface of the component was wetted, ventilated and dried at 60 占 폚, and then assembled to a particle size of 1 mm using a 16 mesh screen. Subsequently, 3.75 g of sodium stearyl fumarate (Kimura Sangyo Co., Ltd.) as a lubricant was added and mixed. The resultant mixed powder was tableted (tablet pressure: 1 kN / cm 2) in the form of a tablet having a mass of 250 mg, a tablet thickness of 4.2 mm, and a shape of a circular shape using a tablet machine CP-12HUK (manufactured by Kikusui Seisakusho; punch diameter 9 mm) After that, the tablets were allowed to stand in a humidification chamber at a temperature of 50 캜 and a relative humidity of 90% for 2 minutes. Then, it was blow-dried at 60 占 폚. The tablets obtained did not contain a water-insoluble disintegrant. The porosity of the tablets obtained in accordance with the above-mentioned formula (also in the comparative example) was 23%.

Comparative Example  One

As hydroxypropyl cellulose, 3.75 g of hydroxypropyl cellulose (Nippon Soda Co., Ltd.) having an equilibrium moisture content of 9% at 25 DEG C and a relative humidity of 75% and a viscosity of 9000 cps at a temperature of 37 DEG C of an aqueous solution of 20 mass% The tablets were prepared in the same manner as in Example. The porosity of the obtained tablets was 22%.

Comparative Example  2

Except that 3.75 g of maltose (having an equilibrium moisture content of 7% at 25 DEG C and a relative humidity of 75% and a viscosity of 2 cps at a temperature of 37 DEG C of a 20 mass% aqueous solution at 25 DEG C) instead of hydroxypropyl cellulose (Hayashibara Shoji, INC. )) Was used instead of the above-mentioned solution. The porosity of the obtained tablets was 21%.

The tablets of Examples and Comparative Examples were evaluated for hardness (index of strength of decay justice strength) under two conditions of (1) immediately after preparation and (2) under the condition of being left standing after opening (25 DEG C, 75% And the intraoral disintegration time (index of disintegration decay) were measured. The test method is as follows.

Hardness (N)

The measurement was conducted under a relative humidity of 45 to 55% at 25 DEG C using a rainfall hardness tester (manufactured by KIYA Corporation). The measurement was carried out with respect to 10 tablets, and the average value thereof was taken as the hardness (N).

Oral  Decay time (sec)

One panelist measured the time from when the tablets were sandwiched between the tongue and the upper jaw, until the shape of the tablets became unrecognizable. The measurements were performed on the tablets of 3 tablets, and the average value thereof was defined as the intraoral disintegration time (seconds).

The measurement results are shown in Table 1 below.

Table 2 shows the results when the hardness is set to 20 N or higher and the disintegration time in the mouth is set to 30 seconds or less, as a criterion of acceptance of the strength and collapse property required for the collapsing tablet.

○: Passed

×: Failed

The stability of the hygroscopic drug was evaluated by measuring the content of acarbose after (1) immediately after preparation, (2) 1 month, (3) 3 months and (4) 6 months of storage. The storage container was a PTP + aluminum bag. The storage was carried out at a relative humidity of 75% at 40 ° C. The measurement of the acarbose content was carried out in accordance with the "liquid chromatography" described in the 15th General Japanese Pharmacopoeia General Test Methods. The results are shown in Table 3 below. The values in Table 3 are the content of acarbose (average value obtained by performing measurement three times using 20 tablets in tablets) (250 mg).

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

Claims (14)

delete delete delete delete delete delete (1) a step of mixing acarbose, erythritol and mannitol,
(2) Using an ethanol solution of hydroxypropylcellulose having an equilibrium moisture content of 5 to 20% at 25 DEG C and a relative humidity of 75% and a viscosity of 20 mass% aqueous solution at 37 DEG C of 100 to 2000 cps, Wetting and drying the mixture obtained in 1), and
(3) a step of molding the mixture obtained in (2) into an intraoral disintegrating tablet
Wherein the disintegrating tablet comprises 15 to 50% by mass of acarbose with respect to the total amount of the disintegration tablet, the porosity is 10 to 40%, and the disintegration time in the decaying oral cavity is 30 seconds or less. Gt; delete delete delete delete delete delete delete