JP2002338500A - Rapidly decaying oral tablet having reduced bitterness and method for reducing bitterness - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method having high practicality for reducing the bitterness of a bitter medical agent by using an additive free from retardation of a releasing speed, exhibiting no loss of bioavailability when compared with a common preparation and commonly used in the pharmaceutical field, and an oral medicinal composition having reduced bitterness. SOLUTION: The oral medicinal composition having reduced bitterness comprises a bitter medical agent and a water-insoluble substance having an average particle diameter of <=30 μm, and it has such a shape that the release of the bitter medical agent is preceded by the dispersion of the water-insoluble substance on the surface of the tong as particles.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a rapidly disintegrating tablet in the oral cavity which reduces the bitterness of a drug having a bitter taste (hereinafter, a bitter drug) and the use of the rapidly disintegrating tablet in the oral cavity for reducing the bitterness. In particular, the present invention relates to a bitter drug and an average
(1) a layer containing the water-insoluble substance is disposed at a site where the layer containing the water-insoluble substance elutes earlier than a layer having a bitter taste, or (2)
The present invention relates to an orally rapidly disintegrating tablet containing a site having the feature of (1), and a use of the orally rapidly disintegrating tablet for reducing bitterness.

[0002]

2. Description of the Related Art In recent years, various drugs have been applied to rapidly disintegrating tablets in the oral cavity. However, drugs having a bitter taste are limited to those with a weak bitter taste. Therefore, there is no known bitterness reducing technology that is widely used for various bitter drugs and does not impair the properties of the rapidly disintegrating tablet in the oral cavity and does not reduce the bioavailability.

[0003] There are many bitter drugs, but when considering their application to pharmaceutical preparations, it is common to select a technique according to the degree of bitterness of the drug. Specifically, flavor,
A method of adding a sweetener and the like, a film coating method using a polymer base, and the like are known. In the method of adding a flavor and a sweetener, it is difficult to mask bitterness only by that method, and it can be applied only to a very limited number of drugs.

[0004] A generally known film coating method using a polymer base is often selected for the purpose of controlling the release of a drug. Therefore, when reducing the bitterness of a bitter drug, the significance of selecting this method is to suppress the release of the drug in the oral cavity below the threshold value of the drug. Here, the threshold value is a limit concentration at which the bitterness of the drug is felt, and if the concentration is lower than this concentration, no bitterness is felt. In general, a drug with a high threshold value, that is, a drug with a high threshold concentration at which bitterness is felt, has a low bitterness degree, and a drug with a low threshold value has a high bitterness degree.

[0005] However, when the film coating method is applied to a drug having a low threshold value and formulation is considered, particularly when formulation into a dosage form without taking water such as a rapidly disintegrating tablet in the oral cavity is considered. In order to minimize the amount of drug released in the blood, the amount of coating must be increased, and as a result, sufficient release of the drug in the gastrointestinal tract cannot be ensured. Inviting is a problem.

Further, besides the above method, Japanese Patent Laid-Open No. 6-28
Japanese Patent No. 4866 discloses a protein-lipid complex as a taste improver, and Japanese Patent Application Laid-Open No. 8-9897 discloses an acidic phospholipid or a lyso form thereof as a coating composition of a bitter-containing substance. They focus on the bitter taste receiving mechanism performed by the taste organ in the oral cavity and the interaction between the bitter drug and lipid, and it is described that these substances are effective in reducing bitterness. However, since these substances contain phospholipids, they are unstable to temperature and heat, and inevitably decrease the stability during preparation or storage of the preparation.

[0007]

Accordingly, it is an object of the present invention to provide a method which does not cause a delay in the release rate, does not show a decrease in bioavailability in comparison with conventional preparations, and is generally used in the field of preparations. The method of reducing the bitterness of a bitter drug and the intraoral cavity with reduced bitterness, which have high practicality by using additives, can be applied to various drugs, and do not impair the properties of the rapidly disintegrating tablet in the oral cavity It is to provide a fast disintegrating tablet.

[0008]

Under such a state of the art, the inventors of the present invention conceived of dispersing various substances on the tongue surface and reducing bitterness due to stagnation, and solved the above-mentioned problems based on this idea. I studied how to do it. As a result, pigments known as a kind of pigments, coloring agents, particularly titanium oxide, talc, iron oxide, etc., which are generally used as excipients for pharmaceutical preparations, are used to precede the release of bitter drugs. By disintegrating, dispersing and dispersing a part or all of the preparation containing the excipient of the present invention on the surface of the tongue, a kind of water repellent environment is formed on the surface of the tongue, thereby reducing the bitter taste of the bitter drug. It has been found that this can be achieved.

Further, the present inventors pulverize a water-insoluble excipient generally used in the field of pharmaceutical preparations, which had no effect in a non-pulverized state, and pulverize it into fine particles (fine particles). The present inventors have found that it is possible to provide the same effect, and that the method of preparing a rapidly disintegrating tablet in the oral cavity by this method does not impair the properties, and completed the present invention. Was. For preparations containing bitter drugs, such as tablets or granules, it is customary to minimize disintegration of the preparation in the oral cavity and to promptly transfer the preparation into the gastrointestinal tract so as not to feel bitterness. However, the preparation containing the bitter drug provided by the present invention is characterized by including a step of intentionally disintegrating a part or all of a layer containing a water-insoluble excipient in the oral cavity.

According to the present invention, a layer containing a water-insoluble substance, which is fine particles, is formed by a different idea from the conventional idea of achieving a reduction in bitterness by not disintegrating or releasing a preparation containing a bitter drug in the oral cavity. Prior to the release of the bitter drug, it disintegrates, disperses as particles, and stays on the surface of the tongue to form a kind of water-repellent environment, avoiding contact, adsorption, and permeation of the drug to the tongue, To reduce the bitterness of the rice.

Although the mechanism of retention of the water-insoluble substance on the surface of the tongue is not yet clear, the results of experiments conducted by the present inventors and the measurement of the particle size of the water-insoluble substance that showed an effect showed that the particle size of the substance was small. Seems to be involved. Further, the embodiment of the rapidly disintegrating tablet in the oral cavity of the present invention is based on the experimental results that the time difference between the bitter drug and the water-insoluble substance appearing in the oral cavity is related to the reduction of bitter taste. This is considered in order to sufficiently bring out the effect of reduction.

That is, the present invention provides: An orally rapidly disintegrating tablet containing a drug and a saccharide, which comprises a drug having a bitter taste and a water-insoluble substance having an average particle size of 30 μm or less, and (1) a layer containing the water-insoluble substance has a bitter taste. A rapidly disintegrating tablet in the oral cavity, wherein the tablet is arranged at a site that can be eluted at an earlier stage than the drug layer having (2) or (1).

2. Drug is 0.5-85% by weight of the whole tablet
Wherein the water-insoluble substance is 5-1000 mg.
2. a rapidly disintegrating tablet in the oral cavity according to The water-insoluble substance is at least one selected from the group consisting of pharmaceutically acceptable pigments, coloring agents, metal compounds, cellulose and its derivatives, starch and its derivatives, natural polymers and their derivatives, and synthetic polymers. An oral rapidly disintegrating tablet according to the above 2,

4. 4. the orally rapidly disintegrating tablet according to the above item 3, wherein the water-insoluble substance is titanium oxide or / and talc; 2. The orally rapidly disintegrating tablet according to the above item 1, containing particles, wherein the layer containing the water-insoluble substance is arranged at a site where the layer can be eluted earlier than the layer having a bitter taste.

6. 6. the orally rapidly disintegrating tablet according to the above 1, wherein the tablet is a three-layer tablet; 2. The orally rapidly disintegrating tablet according to the above 1, wherein the saccharide is in the form of a granulated product obtained by spraying a saccharide having low moldability with a saccharide having high moldability as a binder, and coating and / or granulating the saccharide.

8. 8. The orally rapidly disintegrating tablet according to the above 7, which comprises a step of humidifying and drying the compression molded product in the production process. The orally rapidly disintegrating tablet according to the above 8, wherein the low-formability saccharide is one or more selected from the group consisting of lactose, mannitol, glucose, sucrose, xylitol, and erythritol,

10. 10. The orally rapidly disintegrating tablet according to the above item 8, wherein the saccharide having high moldability is one or more selected from the group consisting of maltose, maltitol, sorbitol, and trehalose. 2. A method for reducing bitterness by dispersing a water-insoluble substance having an average particle diameter of 30 μm or less as particles in the tongue surface prior to the release of a bittering drug in the oral cavity and retaining the same, thereby reducing bitterness. Use of an orally rapidly disintegrating tablet according to

[12] 12. The use of the orally rapidly disintegrating tablet according to the above item 11, wherein the saccharide having low moldability is one or more selected from the group consisting of lactose, mannitol, glucose, sucrose, xylitol, and erythritol. Highly moldable sugars are maltose, maltitol,
Use of the orally rapidly disintegrating tablet according to the above item 11, which is one or more selected from the group consisting of sorbitol and trehalose,

14. The water-insoluble substance is at least one selected from the group consisting of pharmaceutically acceptable pigments, coloring agents, metal compounds, cellulose and its derivatives, starch and its derivatives, natural polymers and their derivatives, and synthetic polymers. 14. Use of the orally rapidly disintegrating tablet according to 11 above, 15. The use of the orally rapidly disintegrating tablet according to the above 14, wherein the water-insoluble substance is titanium oxide and / or talc.

The "orally disintegrating tablet in the oral cavity" in the present invention is
A tablet or a formulation in a form similar to a tablet that disintegrates in the oral cavity within a predetermined time when taken, and the specific time is specifically within 2 minutes, preferably within 1 minute. As an example of such an orally rapidly disintegrating tablet, an international publication pamphlet
WO98 / 02185, International Publication Pamphlet WO95 / 20380,
Examples include, but are not limited to, those disclosed in JP-A-10-182436.

The "water-insoluble substance" in the present invention is a drug substance generally used in the field of oral preparations of pharmaceuticals, and means a solid substance which is insoluble in water. For example, water-insoluble and solid substances listed in the Japanese Pharmacopoeia (13th revision, Hirokawa Shoten) and the Pharmaceutical Excipients Dictionary (Recommended by the Pharmaceutical Affairs Bureau, Ministry of Health and Welfare, edited by the Japan Pharmaceutical Excipients Association) It is. The term "water-insoluble" refers to the term "almost insoluble" indicating the solubility described in the general rules of the Japanese Pharmacopoeia, i.e., the degree of dissolution within 30 minutes when shaking vigorously at 20 ± 5 ° C every 5 minutes for 30 seconds. Of these, the property requires a solvent amount of 10,000 mL or more to dissolve 1 g of solute.

Further, the average particle size refers to the average particle size of the primary particles of the excipient, and is generally a laser diffraction type particle size distribution measuring device used for measuring the average particle size (for example, HORIBA laser diffraction / scattering). Formula particle size distribution measuring device). In the present invention, the average particle diameter of the excipient determined based on the method, 30μm
The following are defined as fine powder (fine particles), and those exceeding 30 μm are defined as large particles.

The "layer" in the description that "the layer containing the water-insoluble substance is disposed at a site where it can be eluted earlier than the drug layer having a bitter taste" means the portion containing the water-insoluble substance or the drug. Means For example, in a three-layer tablet,
One to three layers are shown. In the case of a dry-coated tablet, an outer layer or a core tablet is shown. In the case of particles or granules, it indicates a coating layer or a layer stack containing a water-insoluble substance, and indicates a coating layer or a particle itself or a granule itself containing a drug.

The phrase "can be eluted at an early stage" means that the layer containing the water-insoluble substance disintegrates and elutes faster than the elution of the drug layer having a bitter taste. Therefore, `` the layer containing the water-insoluble substance was arranged at a site where it can be eluted earlier than the drug layer having a bitter taste '' means that the layer containing the water-insoluble substance elutes and disintegrates faster than the drug layer having a bitter taste. Means the formulation form. Specifically, three-layer tablets, dry coated tablets, and particles or granules. As long as these forms are taken, the dissolution and dissolution of the layer containing the water-insoluble substance inevitably occurs rather than the release of the drug layer. For example, when the preparation is put into a flask containing water and stirred, 1 to 30 When the elution of the water-insoluble substance is visually observed in seconds, the condition can be confirmed.

The expression "the layer containing the water-insoluble substance contains a portion having a characteristic arranged at a site which can be eluted earlier than the drug layer having a bitter taste" contains the above-mentioned particles or granules. Means that. Furthermore, “prior to the release of the bitter drug” means that the time at which the layer containing the water-insoluble substance starts to disintegrate or disperse earlier than the time at which the release of the bitter drug starts. Specifically, 1 to 1 after the collapse and dispersion of the layer containing the water-insoluble substance has started.
It is desirable that the release of the bitter drug starts after 0 seconds, preferably 5 to 10 seconds, and therefore “before the release of the bitter drug” specifically means “one bit more than the release of the bitter drug”.
It is preferred that the disintegration and dispersion of the layer containing the water-insoluble substance starts "before 10 seconds or more". The description of disintegration, dispersion, and retention on the surface of the tongue does not require that these processes occur in a stepwise manner; disintegration and dispersion on the surface of the tongue occur simultaneously, and dispersion and retention on the surface of the tongue occur simultaneously. Is also good.

Regarding the retention on the surface of the tongue, a factor closely related to the retentivity is not always clear, but it is presumed that the particle size of the water-insoluble substance is one factor. . Therefore, “as particles” means being in the form of powder or primary particles in the oral cavity, and indicates a mode for maximizing the effect of a water-insoluble substance having a size of 30 μm or less. The time required for the water-insoluble substance to stay on the surface of the tongue is the time required for the bitter drug to pass into the stomach, and is 1 to 5 minutes, preferably 2 to 5 minutes, and more preferably 3 to 5 minutes. It is.

Such a form has a remarkable effect when applied to a rapidly disintegrating tablet in the oral cavity without taking water, as well as a preparation to be taken with water. Further, in the conventional method for reducing bitterness, it is necessary to adjust the amount of the excipient according to the bitterness and amount of the drug (for example, the amount of film coating). No adjustment is necessary for the insoluble substance, and the amount is sufficient to disperse sufficiently on the surface of the tongue, for example, 5-1000 mg, preferably 10-5.
00 mg, more preferably 20-250 mg. That is, these amounts correspond to the blending amount of the water-insoluble substance.

The expression "does not show a decrease in bioavailability" in comparison with the conventional preparation in the present invention refers to the release of the normal preparation (or the release of the bitter drug itself) in an in vitro dissolution test. In this case, not showing any delay in release means that in vivo release is indirectly assured, and it is expected that no bioavailability is reduced.

"Does not impair the properties of a rapidly disintegrating tablet in the oral cavity" means that when the technique of the present invention is applied to a rapidly disintegrating tablet in the oral cavity, the two properties of the rapidly disintegrating tablet in the oral cavity are not impaired. It means that it is in the state. Specifically, it means that the hardness of the orally rapidly disintegrating tablet is 2 kp or more and the disintegration time in the oral cavity is within 2 minutes.

[0030]

DETAILED DESCRIPTION OF THE INVENTION The present invention will be described in more detail.
The water-insoluble substance used in the present invention has the water-insoluble property, is pharmaceutically acceptable and can achieve the object of the present invention, and has an average particle diameter of 30 μm or less, preferably 20 μm or less. It is not particularly limited as long as it is a solid substance of 10 μm or less. Among them, water-insoluble materials often used in normal formulation, such as pigments, colorants,
Examples include metal compounds, cellulose and its derivatives, starch and its derivatives, natural polymers and their derivatives, and synthetic polymers. In particular, pigments and colorants are the most suitable water-insoluble materials for the present invention. Also, if necessary, a suitable particle size such as a hammer mill, a sample mill, a jet mill, or the like, or a water-insoluble substance is dissolved in a suitable solvent and then spray-dried to obtain a desired particle size. It is also possible.

The pigment used in the present invention is preferably a colored pigment such as iron sesquioxide, a white pigment such as titanium oxide, and extenders such as talc, kaolin, calcium carbonate and magnesium carbonate. ,
Talc is particularly preferred. Particularly suitable pigments include
Titanium oxide which is excellent in dispersibility, retention property, and operability in production in the oral cavity and is advantageous for achieving the object of the present invention is exemplified.

As coloring agents, yellow iron sesquioxide, yellow 4
No. aluminum lake and the like, particularly preferably yellow iron sesquioxide. The metal compound of the water-insoluble substance can also be used by gelling the metal compound. Specifically, for example, a dried aluminum hydroxide gel, synthetic aluminum silicate, aluminum magnesium hydroxide, aluminum hydroxide gel, etc. Aluminum compounds, calcium silicates, calcium compounds such as calcium stearate, magnesium oxide, magnesium silicate, magnesium compounds such as magnesium stearate, light silicic anhydride, and silicic acid compounds such as synthetic hydrotalcite are particularly suitable metal compounds. It is listed as. Particularly preferred is a dried aluminum hydroxide gel.

As cellulose and its derivatives, crystalline cellulose, ethylcellulose, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose and the like are particularly preferred specific examples. As starch and derivatives thereof, for example, corn starch, potato starch and the like are particularly preferred.

As natural polymers and derivatives thereof, for example, gelatin, shellac and the like are particularly preferred. Methacrylic acid copolymer as synthetic polymer
L, S, aminoalkyl methacrylate copolymer
E, RS, dimethylpolysiloxane and the like.

The water-insoluble substance may be one or more of the substances shown here.
More than one kind of substance can be used in appropriate combination. The amount of the water-insoluble substance is as described above. The drug used in the present invention is not particularly limited as long as it is used as a pharmaceutically active ingredient and exhibits a bitter taste exceeding the limit concentration at which bitter taste is felt, that is, a threshold value, in an effective amount per formulation unit.

Examples of such pharmaceutically active ingredients include hypnotic sedatives, hypnotic inducers, anxiolytics, antiepileptics, antipyretic analgesics and anti-inflammatory agents, antidepressants, antiparkinson agents, agents for the psychiatric nerve, and other agents for the central nervous system. , Skeletal muscle relaxants, agents for autonomic nerves, antispasmodics, inotropic agents, agents for arrhythmias, diuretics, antihypertensive agents, vasoconstrictors, coronary vasodilators, peripheral vasodilators, agents for hyperlipidemia, and other circulatory organs Preparations, antitussive expectorants, bronchodilators, other allergy agents, antidiarrheals, intestinal medicines, peptic ulcer treatments, gastric digestives, antacids, other fire-fighting organs, pituitary hormones, thyroid hormones Agents, hormones such as antithyroid hormones, urological agents, vitamins,
Hemostatic, anticoagulant, liver disease agent, antidote, habitual addiction agent, gout treatment agent, diabetes agent, antineoplastic agent,
Antihistamines, crude drugs, Chinese medicine, antibiotics, chemotherapeutics,
Insecticides, antiprotozoal agents, and the like. Specifically, meclofenoxate hydrochloride, chloramphenicol, aminophylline, erythromycin, josamycin, calcium hopatenate, phenobabital, cimetidine, famotidine, ethylephrine hydrochloride, diltiazem hydrochloride, propranolol hydrochloride, flufenamic acid, atorvastatin calcium, digitoxin , Theophylline, promethazine hydrochloride, quinine hydrochloride, sulpyrine, ibuprofen and the like. These drugs can be used alone or in appropriate combination of two or more kinds.

The compounding amount of the drug is usually appropriately selected depending on the kind of the drug or the medical use (indication), but is not particularly limited as long as it is a therapeutically effective amount or a prophylactically effective amount. Preferably, it is 0.5-85% by weight of the whole preparation, more preferably 0.5-80% by weight. More preferably, it is 0.5-50% by weight, even more preferably 0.5-10% by weight. When the lower limit of the compounding amount is 0.5% by weight, the range in which bitterness is not usually felt is reached. However, there are cases in which a drug that feels bitterness can be commercialized with a smaller amount, and this amount is limited. Should not be interpreted.

The preparation form of the present invention is not particularly limited and can be applied to various dosage forms widely used as pharmaceuticals. However, prior to the release of the bitter drug, the layer containing the water-insoluble substance is disintegrated. It is necessary to consider a form that can be dispersed and retained on the surface of the tongue. Further, the water-insoluble substance needs to be dispersed as particles in the oral cavity, that is, to return to a powder state or a primary particle state. In the physical mixture of the bitter drug and the water-insoluble substance, the drug particles and the water-insoluble substance particles reach the taste cells at the same time, and sufficient suppression of bitterness cannot be achieved, but according to the formulation disclosed in the present invention, Alternatively, bitterness suppression is achieved by a water-repellent environment formed by a water-insoluble substance which is fine particles existing as primary particles.

As a specific formulation, a three-layer tablet containing a water-insoluble substance in the upper and lower layers and a bitter drug in the middle layer, or a water-insoluble substance in the outer layer and a bitter drug in the core part Dry syrup, capsule, tablet, troche containing particles or granules obtained by laminating or coating a water-insoluble substance layer on a core portion containing a dry-coated tablet or a bitter drug, or containing these granules by a known method. And solid preparations such as chewable tablets. When these preparations are orally administered, water-insoluble substances, which are fine particles contained in the preparation, are dispersed as particles, that is, return to the state of powder or primary particles. This achieves the object of the present invention.

In addition, as described in, for example, WO 95-20380, a rapidly disintegrating tablet in the mouth can be prepared. Specifically, a rapidly disintegrating tablet in the oral cavity containing a saccharide is a preferred embodiment. As the saccharide, a general saccharide, a combination of a saccharide with a low moldability and a saccharide with a high moldability, a combination of a crystalline saccharide and an amorphous saccharide, a combination of a saccharide with a high melting point and a saccharide with a low melting point as appropriate are used. It is possible to choose. As an example, a saccharide having low moldability is sprayed using a saccharide having high moldability as a binder to prepare a granulated product obtained by coating and / or granulating, and the granulated product is prepared by compression molding. be able to. However, the orally rapidly disintegrating tablet of the present invention is not limited to these.

The sugar having low moldability is, for example, a tablet pressure of 10 to 50 mg obtained by using a punch having a diameter of 8 mm.
When compressed at kg / cm ² , the hardness of the tablet is 0-2 kp
And a saccharide having high moldability indicates a saccharide having a hardness of 2 kp or more by the same method.
Low formability saccharides are pharmaceutically acceptable,
For example, lactose, mannitol, glucose, sucrose, xylitol, erythritol and the like can be mentioned. One or two or more of these can be used in appropriate combination.

The saccharides having high moldability are pharmaceutically acceptable and include, for example, maltose, maltitol,
Sorbitol, trehalose and the like can be mentioned.
Such saccharides can be used alone or in combination of two or more.

In order to further increase the hardness of the prepared tablet, humidification and drying steps can be adopted. “Humidification” is determined by the apparent critical relative humidity of the contained saccharide, and is usually humidified above the critical relative humidity. For example, the humidity is 30 to 100 RH%, preferably 50 to 90 RH%. The temperature at this time is 15-5
It is preferably 0 ° C, more preferably 20-40 ° C. Processing time is 1-36 hours, preferably 12-36 hours.
24 hours. “Drying” is not particularly limited as long as it is a step of removing moisture absorbed by humidification. For example, as the drying temperature condition, 10-100 ° C can be set, preferably 20-60 ° C, more preferably 25-40 ° C. The processing time can be 0.5-5 hours, preferably 1-3 hours.

In preparing the preparation of the present invention, known methods can be used, and one type of additive conventionally used and / or
Alternatively, two or more kinds can be used in appropriate combination. Such additives include binders, disintegrants, thickeners, extenders,
Excipients, lubricants, flavoring agents, flavors and the like can be mentioned. Also, after taking the product of the present invention, depending on the water-insoluble substance,
The surface of the tongue is colored by the color of the substance. If necessary, a water-soluble pigment such as food blue 1
No., Food Yellow No. 4, Food Yellow No. 5, Food Red No. 102,
Food Red No. 2 and Food Red No. 3 can be appropriately added to obtain a desired color.

In the case of a three-layer tablet, there is known a technique in which a bitter drug is positioned in the middle second layer to suppress bitterness. However, in the present invention, most of the components constituting the tablet are contained in the oral cavity. Therefore, the technical idea is completely different. The production method of the present invention will be described.

The drug is mixed with excipients such as lactose and corn starch, and hydroxypropyl cellulose (HPC-
SL) or the like, and a disintegrant or the like is blended to form first granules. In order to prepare a rapidly disintegrating tablet in the oral cavity, a drug is mixed with a sugar having low moldability such as mannitol and granulated with a sugar having high binding properties such as maltose as a binder (first granule). While lactose,
Corn starch is granulated in the same manner as the first granule, and the mixture with the water-insoluble substance shown in the present invention is used as the second granule. In the case of a rapidly disintegrating tablet in the oral cavity, mannitol or the like is granulated with maltose or the like, and mixed with a water-insoluble substance to prepare second granules. When a three-layer tablet, the second granules as the first and third layers,
The first granules are compressed as a second layer using a three-layer tableting machine. Further, in order to obtain a dry coated tablet, the first granule is tableted in advance as a core tablet, and thereafter, the second granule is formed as an outer layer and pressed by a dry tableting machine.

The tablet produced by the method is orally administered, and firstly, part or all of the layer containing the water-insoluble substance disintegrates in the oral cavity, and simultaneously or afterwards, the water-insoluble substance is dispersed on the tongue surface. Disperse and stay as. Therefore, in this state, the tongue surface has a water-repellent environment. After passing through this process, the layer containing the bitter drug collapses and moves into the digestive tract while the water-insoluble substance is retained, and the present method for reducing bitterness is achieved.

[0048]

The present invention does not cause a delay in the release rate,
It does not show a decrease in bioavailability in comparison with conventional preparations, and can also use additives commonly used in the field of preparation, and has excellent stability, operability, and extremely practicality This is a remarkable effect in that it is possible to provide an orally disintegrating tablet in which the bitterness of a highly bitter drug is reduced.

[0049]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the present invention is limited thereto. Measurement of the average particle size in the examples, evaluation of bitterness,
Measurement of hardness of the intraorally rapidly disintegrating tablet, measurement of disintegration time in the oral cavity,
Was performed according to the test method shown below.

Measurement of average particle diameter A sample to be measured is taken with a microspatula (approximately 30-5
0 mg), dispersed in a suitable dispersion medium (eg, n-hexane, water, etc.) in which each sample is not dissolved, and then subjected to a HORIBA laser diffraction / scattering particle size distribution analyzer (Horiba, LA-91).
Measure at 0). The results are automatically analyzed by a computer.

Evaluation Test Method of Bitterness Before conducting the test, the panelist thoroughly rinses the mouth with water. When the water-insoluble substance is dispersed in the tongue in advance, the amount of water-insoluble substance shown in each example is placed on the tongue and dispersed, and after 3 seconds, the drug solution is contained in the oral cavity for 3 seconds and then exhaled. Thereafter, the mouth is thoroughly rinsed with water. In the case of evaluation of a liquid in which a water-insoluble substance is dispersed in a drug solution, the liquid is contained in the oral cavity for 3 seconds, then spit out, and the oral cavity is thoroughly rinsed with water. In the case of evaluation of the tablet, the tablet is contained in the oral cavity, and after the tablet is contained in the oral cavity until it disintegrates (approximately 20 seconds), the tablet is exhaled, and the oral cavity is thoroughly rinsed with water. The degree of bitterness when the solution or tablet is contained in the oral cavity is indicated by the following symbols. -: No bitterness is felt, ±: Almost no bitterness is felt, +: Bitterness is felt but can be put up, ++: Bitterness can be put up and cannot be put up. If the same panelist repeats the test, the taste of the previous test remains. Take enough time (not less than one hour) to perform the test.

Measurement of Hardness of Orally Rapidly Disintegrating Tablets The hardness was measured using a Schleuniger tablet hardness tester (Schleunigel). The test was performed with three tablets, and the average value is shown. The hardness of a tablet indicates the force (unit: kp) required to break the tablet. Measurement of Oral Disintegration Time The time from when the tablet was contained in the mouth until the tablet completely disintegrated in the oral cavity was measured.

Example 1 50 mg of titanium oxide (a product conforming to the Japanese Pharmacopoeia) was previously dispersed on the tongue, and then 5 ml of a 20 mM theophylline (manufactured by Nacalai Tesque) aqueous solution was contained in the oral cavity. ) (Table 1).

Example 2 50 mg of talc (a product conforming to the Japanese Pharmacopoeia, manufactured by Kihara Kasei) was previously dispersed on the tongue, and then 5 ml of an aqueous solution of 20 mM theophylline (manufactured by Nacalai Tesque) was contained in the oral cavity. n = 2) and evaluated in the same manner as in Example 1 (Table 1).

Example 3 50 mg of dried aluminum hydroxide gel (a product conforming to the Japanese Pharmacopoeia, manufactured by Kyowa Chemical) was dispersed on the tongue in advance, and then 20 mg
5 ml of an aqueous solution of mM theophylline (manufactured by Nacalai Tesque) was contained in the oral cavity, and its bitterness was evaluated by a healthy person (n = 2) in the same manner as in Example 1 (Table 1).

Comparative Example 1 50 mg of titanium oxide (a product conforming to the Japanese Pharmacopoeia) was added to 5 ml of an aqueous solution of 20 mM theophylline (manufactured by Nacalai Tesque), dispersed and then contained in the oral cavity.
2) (Table 1).

Comparative Example 2 50 mg of talc (a product conforming to the Japanese Pharmacopoeia, manufactured by Kihara Kasei) was added to a 5 mM aqueous solution of 20 mM theophylline (manufactured by Nacalai Tesque).
After dispersing in addition to l, it was contained in the oral cavity and its bitterness was evaluated by a healthy person (n = 2) (Table 1).

COMPARATIVE EXAMPLE 3 50 mg of a dried aluminum hydroxide gel (a product conforming to the Japanese Pharmacopoeia, manufactured by Kyowa Chemical Co., Ltd.) was added to 5 ml of an aqueous solution of 20 mM theophylline (manufactured by Nacalai Tesque), dispersed, and then contained in the oral cavity. (N = 2) (Table 1). Table 1 Bitterness-suppressing effects of various dispersing excipients on the bitterness of theophylline aqueous solution Discussion As a result, it was presumed that the reduction of the bitter taste of the water-insoluble substance was not due to the dilution effect, but was apparently due to the spread to the tongue surface prior to the bitter drug.

Test Example 1 The following results were obtained by measuring the average particle size of the above-mentioned excipients. Table 2 Average particle size of excipient Discussion From these results, it was confirmed that the water-insoluble substance used was fine particles.

Example 4 Cumulite (aluminum hydroxide: sodium hydrogen carbonate coprecipitate, manufactured by Kyowa Chemical Co., Ltd., measured average particle diameter 72 μm) was taken in a mortar, sufficiently pulverized, and the average particle diameter was measured to be about 9 μm. Met. The bitterness of the unmilled mullite product and the mortar crushed product was evaluated (Table 3). Table 3 Influence of particle size of cumulite on bitterness of theophylline aqueous solution Discussion The above experimental results suggest that the bitterness of the drug can be reduced by dispersing the water-insoluble substance, which is fine particles, as particles on the surface of the tongue in advance and retaining the particles.

Example 5 For each of the following excipients, the bitterness of the drug solution was evaluated by the following three methods. The average particle size of each excipient was measured (Table 4). A water-insoluble substance is dispersed in 5 ml of a 20 mM theophylline aqueous solution, and the bitterness of the solution is evaluated. ) And evaluated in the same manner as with the crushed product. Table 4 Differences in the degree of bitterness suppression and differences in average particle size due to differences in excipient evaluation methods Consideration From the above results, the particle size effective for suppressing bitterness is about 3
It can be estimated to be 0 μm or less.

Example 6 Granules obtained by granulating 380 g of mannitol (Towa Kasei Kogyo Co., Ltd.) with an aqueous solution containing 20 g of maltose (Hayashibara Shoji, San Malt Midori) using a fluidized bed granulator (manufactured by Okawara Kakoki Co., Ltd., UNI-GLATT). I got After measuring 80 mg of the granules and 20 mg of titanium oxide (Freund Industrial Co., Ltd., Japan), after mixing,
It was filled in a 9 mm diameter die and pressed lightly with a pestle to form the first layer. 20 mg of theophylline (manufactured by Nacalai Tesque) and 80 mg of granules are measured and mixed, and then filled on the first layer,
It was lightly pressed with a pestle to form the second layer. A mixture having the same composition as the first layer was prepared, filled on the second layer, and compressed with a pestle to obtain a rapidly disintegrating three-layer tablet in the oral cavity in a total amount of 300 mg (oil
press use). Separately, an excipient and a granule having the same composition as the orally rapidly disintegrating three-layer tablet were measured and mixed, and the mixture was mixed to have a diameter of 9 mm.
The tablets were compressed with an oil press using a pestle to obtain a control oral rapidly disintegrating tablet. The bitterness of the obtained three-layer tablet and control tablet was evaluated. The hardness of the three-layer tablet was 4 kp, and the oral disintegration time was 25 seconds. Table 5 Comparison of bitterness between three-layer tablets and control tablets

Example 7 30 g of josamycin (Yamanouchi Pharmaceutical) was added to a mixed solution of 90 g of Aquacoat (Asahi Kasei, ECD-30) and 3 g of triacetin (Organic Synthetic Chemical Industry, local regulations) and uniformly dispersed. . This liquid was spray-dried using a spray drier (Okawara Kakoki, L-8 type) to obtain spherical granules. 100 mg of the granules shown in Example 6 and 30 mg of titanium oxide (manufactured by Freund Corporation, Japan Pharmaceutical Co., Ltd.) were mixed to form a first layer of a three-layer tablet. The spherical granules 100 mg were measured and mixed with the granules 100 mg shown in Example 6 to form a second layer. Finally, a mixture of the granules 100 mg and titanium oxide 30 mg shown in Example 6 was used as a third layer to obtain a total amount of 460 mg. Was prepared using an oil press. The hardness of the three-layer tablet was 3 kp, and the oral disintegration time was 22 seconds.

Comparative Example Josamycin drug substance was weighed out in an amount of 50 mg and mixed with the same excipient as the composition of the three-layer tablet (all excipients except spherical granules). A total of 410 mg tablets were prepared by an oil press. Tablets. Table 6 Comparison of bitterness between three-layer tablets and control tablets Consideration From Examples 6 and 7, it was considered that the bitter taste was suppressed because titanium oxide was dispersed on the surface of the tongue before the drug was released. It was also confirmed that the properties of the orally rapidly disintegrating tablet were not impaired.

Example 8 The spherical granules shown in Example 7 were applied to Aquacoat (Asahi Kasei, EC
D-30) and a mixture of triacetin (organic synthetic chemical industry, local regulations) (composition ratio 9: 1) using a fluidized bed granulator (Glatt GmbH,
GPCG). In addition, titanium oxide (Freund Sangyo, Japan), Aquacoat,
Triacetin mixed solution (composition ratio 9: 0.9: 0.1) was added to 4
0% coating was performed to prepare titanium oxide coated granules. The granules not coated with titanium oxide and the granules not coated with titanium oxide (the spherical granules shown in Example 7 were coated with aqua coat and triacetin at 5%, comparative examples) were eluted using 500 mL of the Japanese Pharmacopoeia disintegration test solution (500 mL). When a test (paddle method, 100 rotations) was performed, the dissolution of both was equivalent. Further, the bitterness of the two was evaluated. Table 7 Comparison of bitterness between titanium oxide coated granules and comparative example Discussion The elution in vitro was comparable between the comparative example and the titanium oxide coated granules, but the coated granules reduced bitterness. Therefore, the reduction of bitterness by this preparation was achieved by the titanium oxide layer being dispersed on the tongue surface, and it was presumed that the bioavailability did not decrease.

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Claims (15)

[Claims] 1. A rapidly disintegrating buccal tablet comprising a drug and a saccharide, wherein the tablet having a bitter taste and an average particle size of 30
μm or less, and (1) the layer containing the water-insoluble substance is arranged at a site where the layer can be eluted earlier than the drug layer having a bitter taste,
Or (2) an orally rapidly disintegrating tablet containing a site having the characteristics of (1). 2. The orally rapidly disintegrating tablet according to claim 1, wherein the drug is 0.5 to 85% by weight or less of the whole tablet and the water-insoluble substance is 5 to 1000 mg. 3. The water-insoluble substance is selected from the group consisting of pharmaceutically acceptable pigments, colorants, metal compounds, cellulose and derivatives thereof, starch and derivatives thereof, natural polymers and derivatives thereof, and synthetic polymers. The orally rapidly disintegrating tablet according to claim 2, which is one or more kinds of tablets to be disintegrated. 4. The orally rapidly disintegrating tablet according to claim 3, wherein the water-insoluble substance is titanium oxide and / or talc. 5. The orally rapidly disintegrating tablet according to claim 1, wherein the layer containing the water-insoluble substance is arranged at a site where the layer can be eluted earlier than the layer having a bitter taste. 6. The orally rapidly disintegrating tablet according to claim 1, wherein the tablet is a three-layer tablet. 7. The oral cavity according to claim 1, wherein the saccharide is in the form of a granulated substance obtained by spraying a saccharide having low moldability with a saccharide having high moldability as a binder, and coating and / or granulating the saccharide. Quick disintegrating tablets. 8. The orally rapidly disintegrating tablet according to claim 7, wherein the production step includes a step of humidifying and drying the compression molded product. 9. The saccharide having low moldability is lactose, mannitol,
The orally rapidly disintegrating tablet according to claim 8, which is one or more selected from the group consisting of glucose, sucrose, xylitol, and erythritol. 10. The orally rapidly disintegrating tablet according to claim 8, wherein the saccharide having high moldability is one or more selected from the group consisting of maltose, maltitol, sorbitol, and trehalose. 11. The oral cavity has an average particle diameter of 30 μm.
The intraorally fast disintegrating tablet according to claim 1, wherein the following water-insoluble substance is dispersed as particles on the tongue surface prior to the release of the drug having a bitter taste, and is retained to reduce the bitter taste. use. 12. The tablet according to claim 11, wherein the saccharide having low formability is one or more selected from the group consisting of lactose, mannitol, glucose, sucrose, xylitol, and erythritol. use. 13. The use of the orally rapidly disintegrating tablet according to claim 11, wherein the saccharide having high moldability is one or more selected from the group consisting of maltose, maltitol, sorbitol, and trehalose. 14. The water-insoluble substance is selected from the group consisting of pharmaceutically acceptable pigments, coloring agents, metal compounds, cellulose and derivatives thereof, starch and derivatives thereof, natural polymers and derivatives thereof, and synthetic polymers. Use of the orally rapidly disintegrating tablet according to claim 11, which is one or more kinds of tablets. 15. The use of an orally rapidly disintegrating tablet according to claim 14, wherein the water-insoluble substance is titanium oxide and / or talc.