JP2001072578A - Tablet quickly disintegrable in oral cavity - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject tablets takable without substantially sensing the bitterness of a medicinal ingredient therein even if taken without water despite uncoating the medicinal ingredient. SOLUTION: This tablet comprises a medicinal ingredient with bitterness, an essential oil and a high-sweetness sweetener and/or a bitterness-mitigating ingredient consisting of an acid phospholipid or lyso-modification thereof; wherein, in particular, the medicinal ingredient is acetaminophen, the essential oil is peppermint oil, the high-sweetness sweetener is stevia or aspartame, and the acid phospholipid or lyso-modification thereof is soybean lecithin.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a rapidly disintegrating tablet in the oral cavity with reduced bitterness, and more particularly, to blend a bitterness reducing component without coating a pharmaceutical component having bitterness. To a rapidly disintegrating tablet in the mouth.

[0002]

2. Description of the Related Art In recent years, the quality of life (QOL) of patients has been increasing.
e) Oral quick disintegrating tablets are attracting attention as a dosage form that can be easily taken by elderly people and children with low swallowing ability for improvement. However, when a pharmaceutical ingredient having a bitter taste is incorporated into a rapidly disintegrating tablet in the oral cavity, the tablet immediately disintegrates in the oral cavity, so that the pharmaceutical ingredient having a bitter taste is exposed in the oral cavity.
In addition, at this time, since it is taken without water, the bitter taste will be felt more strongly for a long time than ordinary internal tablets,
This is a major disadvantage of a rapidly disintegrating tablet in the oral cavity, which is characterized by being easy to take. In order to solve the above-mentioned problems, a pharmaceutical ingredient having a bitter taste to be blended into an orally rapidly disintegrating tablet is coated with a polymer such as ethyl cellulose and Eudragit,
A method has been proposed in which the pharmaceutical component is not directly exposed even if the tablet disintegrates in the oral cavity (Japanese Patent Publication No. Hei 6-502194). However, in the above method, even if the pharmaceutical component having a bitter taste is coated with an aqueous coating agent, a sufficient coating effect cannot be obtained because the strength of the film is weak. On the other hand, coating with an organic solvent can provide a sufficient coating effect, but the residual solvent of the coating and the working environment during production,
For example, inhalation of the organic solvent by a worker, danger of ignition and explosion at the time of work, and the like become problems. In addition, these coatings have the disadvantage of requiring a long operation and equipment. Furthermore, when the coating layer is thickened to sufficiently suppress bitterness and prevent breakage of the film at the time of tableting, the dissolution of the pharmaceutical component is delayed. Will not elute.

On the other hand, in the fields of granules, powders, liquids and the like, techniques for reducing bitterness have been developed.
For example, in order to reduce bitterness, those containing stevia (Japanese Patent Application Laid-Open No. 10-101582) or aspartame (Japanese Patent Application Laid-Open No. 2-56416) classified as so-called high-intensity sweeteners, flavors and sweeteners (For example, JP-A-10-273435) and a combination of a sugar alcohol and thaumatin which is one of high-intensity sweeteners (for example, JP-A-10-3060).
No. 38), those based on sugar alcohols (for example, JP-A-10-53538), those based on essential oils or essential oil components (for example, JP-A-5-255126), those based on acidic phospholipids (e.g. 62-2652
No. 34, JP-A-8-9897, JP-A-7-6
Numerous proposals have been made.
However, these are techniques for reducing bitterness in general preparations on the premise that they are taken together with water, and these techniques are directly applied to intraorally rapidly disintegrating tablets that are scheduled to be taken without water. However, the effect of reducing bitterness was not sufficient, and a rapidly disintegrating tablet in the oral cavity could not be obtained.

[0004]

SUMMARY OF THE INVENTION As described above, the present invention relates to an intraoral speed which can be easily taken without coating a pharmaceutical ingredient having a bitter taste and without feeling the bitter taste even when taken without water. It is an object to provide a disintegrating tablet.

[0005]

As a result of diligent studies to solve the above-mentioned problems, the present inventors have found that essential oils which have been known to reduce bitterness, high-potency sweeteners and / or acidic sweeteners The present inventors have found that a combination of a phospholipid or a lyso form thereof specifically exhibits a remarkable bitterness reducing effect, and have completed the present invention based on such findings.

That is, the present invention is characterized by comprising (1) a pharmaceutical ingredient having a bitter taste, and an essential oil and a bitterness reducing ingredient comprising a high-intensity sweetener and / or an acidic phospholipid or a lyso-form thereof. An orally rapidly disintegrating tablet, (2) an orally rapidly disintegrating tablet according to the above (1), wherein the bitterness reducing component comprises an essential oil and a high-intensity sweetener, and (3) an essential oil and an acidic phospholipid or a lysozoate thereof. (1) the intraoral rapid disintegrating tablet according to the above (1), (4) the intraoral rapid dissolving tablet according to the above (1), wherein the bitterness-reducing component comprises an essential oil, a high-intensity sweetener and an acidic phospholipid or a lyso-form thereof. Disintegrating tablets,
(5) The orally rapidly disintegrating tablet according to the above (1), wherein the pharmaceutical ingredient having a bitter taste is not coated.
(8) the orally rapidly disintegrating tablet according to (1), wherein the pharmaceutical ingredient having bitterness is acetaminophen, (7) the essential oil is peppermint oil, The orally rapidly disintegrating tablet according to the above (1), wherein the high-sweetness sweetener is one or two selected from stevia and aspartame,
And (9) The intraoral rapidly disintegrating tablet according to the above (1), wherein the acidic phospholipid or its lyso form is soy lecithin.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail. In the specification of the present application, a rapidly disintegrating tablet in the oral cavity means, for about 90 seconds, preferably about 60 seconds without chewing in the presence of saliva in the oral cavity. A solid pharmaceutical formulation that disintegrates in a shorter time.

[0008] The bitter medicinal ingredients used in the present invention include those that have a bitter taste among the medicinal ingredients generally administered orally. Above all, as-needed pharmaceutical ingredients that are supposed to be taken under the condition that you cannot drink water, for example, antipyretic analgesics, antihistamines, antiallergic agents, sympathetic stimulants, parasympathetic blockers, central stimulant, H ₂ blockers, antacids, anti-inflammatory enzyme agents, anti-inflammatory agents, bronchodilators, anti-microbial agents, antitussives, expectorants, anticholinergic agents, if antidiarrheal agents, hypnotic sedatives, cholagogues, antihypertensive agents , Skeletal muscle relaxants, motion sickness prevention and treatment drugs, or osteoporosis treatment drugs expected to be able to be taken easily and easily on a daily basis, vitamins, those having a bitter taste among crude drugs are preferable, for example, Acetaminophen,
Antipyretic analgesics such as ibuprofen and ketoprofen; chlorpheniramine maleate, d-chlorpheniramine maleate, diphenhydramine or salts thereof, promethazine hydrochloride, isotipendyl hydrochloride, clemastine fumarate, iproheptin hydrochloride, cyproheptadine hydrochloride, diphenylpyraline or salts thereof, Dimethindene maleate, triprolidine hydrochloride, homochlorcyclidine hydrochloride,
Azelastine hydrochloride, ibudilast, sodium cromoglicate or salts thereof, oxatomide, amlexanox, carbinoxamine maleate, mequitazine, tranilast, repirinast, emedastin fumarate, ozagrel hydrochloride, tazanolast, pemirolast or salts thereof, anti-allergic agents such as anti-allergic agents such as suplatast tosilate, etc. Sympathomimetics such as phenylpropanolamine hydrochloride; parasympathomimetics such as belladonna (total) alkaloids and isopropamide iodide; central stimulants such as caffeine and anhydrous caffeine; famotidine, cimetidine;
Ranitidine hydrochloride, nizatidine, H ₂ blockers such as hydrochloric acid roxatidine acetate; magnesium carbonate, light anhydrous silicic acid, magnesium aluminometasilicate, antacids such as synthetic hydrotalcite; lysozyme chloride, anti-inflammatory enzyme agents such as serrapeptase Anti-inflammatory agents such as tranexamic acid; bronchodilators such as methylephedrine hydrochloride (including d- and dl-forms) and ephedrine hydrochloride; codeine, codeine phosphate, dihydrocodeine phosphate, dextromethorphan hydrobromide, noscapine, Antitussives such as dimemorphan, guaiacolsulfonic acid and guaifenesin; expectorants such as potassium guaiacolsulfonic acid and bromhexine hydrochloride; bile drugs such as ursodeoxycholic acid and chenodeoxycholic acid; antiseptic agents such as loperamide hydrochloride; hypnotics such as bromvaleryl urea. ; Anti-anxiety agents such as Zepamu; motion sickness prophylactic or therapeutic drug, such as dimenhydrinate; thiamine hydrochloride,
Thiamine nitrate, bisthiamine nitrate, thiamine disulfide, thiamine dicetyl sulfate, dicetiamine hydrochloride, fursultiamine, fursultiamine hydrochloride, octiamine, shicotiamine, bisibutiamine, bisbenthamine, prosultiamine, benfotiamine, diamine Vitamin B such as benzoylthiamine and thiamine pyrophosphate
Class ₁ ; Vitamin B such as sodium riboflavin phosphate
Class _2; vitamin B ₆ such as pyridoxine hydrochloride; calcium pantothenate; phytonadione, vitamin K, such as menatetrenone; Scutellaria, like crude drugs powder and extract such as Phellodendron bark.

[0009] Pharmaceutical ingredients which show a particularly remarkable effect of reducing bitterness in the orally rapidly disintegrating tablet of the present invention include acetaminophen, tranexamic acid, noscapine and bromhexine hydrochloride. When acetaminophen is used as a pharmaceutical ingredient having a bitter taste, its crystal particle size is about 50 to about 800 μm, preferably about 100 to 500 μm.
Those in the range of μm can be selected. When the crystal particle diameter of acetaminophen is in the above range, the effect of reducing bitterness is particularly remarkable. There is no particular limitation on the amount of the pharmaceutical ingredient having such a bitter taste, which can be appropriately selected depending on the purpose of administration. Generally, about 0.01 to 80 parts by weight, preferably about 100 parts by weight of the preparation, preferably About 0.
It can range from 0.5 to 70 parts by weight, particularly preferably from about 0.1 to 60 parts by weight.

The orally rapidly disintegrating tablet of the present invention contains an essential oil and a high-intensity sweetener and / or an acidic phospholipid or a lyso-form thereof as a bitterness reducing component. The essential oils that can be used in the present invention include mint oil, eucalyptus oil, cinnamon oil, fennel oil, clove oil, orange oil, lemon oil, rose oil, preferably mint oil, cinnamon oil, fennel oil, Clove oil, particularly preferably mint oil. The amount of these essential oils depends on the amount of the pharmaceutical ingredient having bitterness and the degree of the bitterness,
It can be appropriately selected depending on the amount of the high-intensity sweetener and the acidic phospholipid or the lyso form thereof to be added together, but generally about 0.01 part by weight per 100 parts by weight of the preparation.
It can range from 10 to 10 parts by weight, preferably from about 0.02 to 8 parts by weight, particularly preferably from about 0.05 to 5 parts by weight.

The so-called high-intensity sweetener used in the present invention refers to an artificially synthesized sweetener whose sweetness is several times or more, preferably about 100 times or more that of sugar. Specific examples include aspartame, stevia, saccharin, dipotassium glycyrrhizin, thaumatin, sucralose, acesulfame K, and the like, with aspartame and stevia being particularly preferred. The compounding amount of these high-sweetness sweeteners is appropriately selected depending on the compounding amount of the pharmaceutical ingredient having a bitter taste, the degree of the bitterness thereof, and the compounding amount of the essential oil, the acidic phospholipid, or the lyso-form thereof in combination. In general, about 0.01 to 20 parts by weight, and preferably about 0.05 to
It can range from 15 parts by weight, particularly preferably from about 0.1 to 10 parts by weight.

It is known that the acidic phospholipid or lyso form thereof used in the present invention has a bitterness reducing action by itself (JP-A-7-67552), and phosphatidylserine, phosphatidic acid, phosphatidylinositol, Phosphatidylglycerol, acid phospholipids such as cardiolipin and lysophosphatidylserine,
It is a lyso-form such as lysophosphatidic acid, lysophosphatidylinositol and lysophosphatidylglycerol. These acidic phospholipids or lyso forms thereof can be obtained by extracting and separating soybean lecithin, egg yolk lecithin and the like from various animals and plants according to the method described in JP-A-8-9896. Further, as the acidic phospholipid or lyso form thereof used in the present invention, for example, those commercially available as VENCOOTE BMI-60 (trade name, Kao) can also be used. The amount of the acidic phospholipid or its lyso form can be appropriately selected depending on the amount of the pharmaceutical ingredient having bitterness, the degree of the bitterness, and the amount of the essential oil or high-intensity sweetener to be added together. ,
Generally, about 0.01 to 20 parts by weight per 100 parts by weight of the preparation.
It can range from about 0.05 to 15 parts by weight, particularly preferably from about 0.1 to 10 parts by weight.

The orally rapidly disintegrating tablet of the present invention comprises the above-mentioned essential components of the present invention, a pharmaceutical ingredient having a bitter taste, an essential oil, a high-intensity sweetener and / or an acidic phospholipid or a lyso-form thereof. Can be produced by a method for producing a rapidly disintegrating tablet in the mouth, specifically, for example, a method described in JP-A-10-182436, that is, erythritol in addition to the above essential components of the present invention. , Microcrystalline cellulose and a disintegrant (see Examples 1 to 5 below). Further, the rapidly disintegrating buccal tablet of the present invention can also contain various additives used in the production of general solid preparations, as long as the effects of the present invention are not hindered.

When essential oil, a high-intensity sweetener and / or an acidic phospholipid or its lyso-form is simultaneously added to the orally rapidly disintegrating tablet of the present invention, porous calcium silicate is used to prevent the tablet from decreasing in hardness. Can also be blended. The amount of the porous calcium silicate in this case is about 0.5 to about 100 parts by weight of the orally rapidly disintegrating tablet of the present invention.
It is preferable to mix in a range of 30 parts by weight. The porous calcium silicate used here is FLORITE RE
(Commercial name, Soda Tokuyama) can be easily obtained from the market.

The essential oil (eg, peppermint oil) formulated in the present invention volatilizes during the storage period when left unpackaged. As the amount of essential oil (eg, peppermint oil) is reduced, the bitter masking effect of the present invention is reduced and the bitter taste is felt. Moreover, the tablet of the present invention causes a decrease in moisture absorption hardness when stored under high humidity. Therefore,
The packaging form of the orally rapidly disintegrating tablet of the present invention is preferably an airtight container such as a strip package, a blister package, and a bottle package. Particularly, a highly airtight aluminum strip package or a blister package is preferably used in an inner bag (for example, aluminum foil, polyethylene film). )) Are especially preferred.

[0016]

EXAMPLES The present invention will be described more specifically with reference to examples, comparative examples and comparative tests of the present invention. Example 1: Essential oil + high-intensity sweetener + soy lecithin + porous calcium silicate 30 g erythritol, crystalline cellulose (Seolas KG
801) 8.41 g, crospovidone 2.45 g, soy lecithin (Benecote BMI-60) 1.0 g, porous calcium silicate (Fluorite RE) 2 g, stevia 0.25 g, and aspartame 0.5 g in a mortar. Add 100 μl of light oil and spread with pestle. 15 g of acetaminophen and 0.3 g of magnesium stearate were mixed with the obtained powder, and an autograph (AG-
5000B, Shimadzu Corporation) at a tablet weight of 600 mg.

Example 2: Essential oil + high-intensity sweetener + soybean lecithin erythritol 30 g, crystalline cellulose (Ceolas KG)
801) 9.91 g, crospovidone 2.45 g, soy lecithin (Benecote BMI-60) 1.5 g, stevia 0.25 g, aspartame 0.5 g are placed in a mortar,
Add 100 μl of light oil and spread with a pestle. 15 g of acetaminophen and 0.3 g of magnesium stearate were mixed with the obtained powder, and an autograph (AG-
5000B, Shimadzu Corporation) at a tablet weight of 600 mg.

Example 3: Essential oil + high sweetness sweetener 15 g of acetaminophen, 39.7 erythritol
g, crystalline cellulose (CEOLUS KG801) 7.16
g, crospovidone 2 g, stevia 0.25 g, and aspartame 0.5 g are placed in a mortar, 100 μl of thin oil is added, and spread with a pestle. Then, add an appropriate amount of purified water,
After kneading, it was vacuum dried at 40 ° C. for 16 hours. The obtained granulated powder was sized with 16 mesh, and 0.03 g of magnesium stearate was mixed with 6.47 g of the sized powder, and a tableting pressure of 1400 k was applied using a 13 mm die and a flat punch.
The tablet weight was 650 mg with an autograph (AG-5000B, Shimadzu Corporation) using a g / punch.

Example 4: Essential oil + high-intensity sweetener + soy lecithin + porous calcium silicate 30 g of erythritol, crystalline cellulose (Ceolas KG)
801) 8.41 g, crospovidone 2.45 g, soy lecithin (Benecote BMI-60) 1.0 g, special calcium silicate (Fluorite RE) 2 g, stevia 0.25 g, aspartame 0.5 g are placed in a mortar, Add 100 μl of light oil and spread with a pestle. To the obtained powder, 12.5 g of tranexamic acid and 0.3 g of magnesium stearate were mixed, and using a 13 mm die and a flat punch, an autograph (AG-
5000B, Shimadzu Corporation) at a tablet weight of 575 mg.

Example 5: Essential oil + high-intensity sweetener + porous calcium silicate 900 g of erythritol, crystalline cellulose (Seolas K)
G801) 160.5 g, crospovidone 72 g, porous calcium silicate (Fluorite RE) 18 g, yellow No. 5 aluminum lake 0.36 g were charged with a fluid bed granulator (F).
D-3SN, Powrex) to granulate by spraying purified water, followed by drying in a fluidized bed to obtain a granulated powder.
After sizing with a power mill (Showa Machine Works), sieved powder is obtained. Separately, crystalline cellulose (Ceolas KG801)
98 g, stevia 2.5 g, and aspartame 5 g are placed in a mortar, 1 ml of thin oil is added, and spread with a pestle to obtain a thin oil double powder. The sized powder 383.
62 g, 150 g of acetaminophen and 3 g of magnesium stearate are mixed to obtain a mixed powder. This mixed powder was tableted with a rotary tableting machine using a 13 mm die and a flat punch at a tableting pressure of 1400 kg / punch and a tablet weight of 600 m.
g.

Comparative Example 1: 15 g of a high-potency sweetener, acetaminophen, 30 g of erythritol, 1.15 g of crystalline cellulose (Ceolas KG801), 2.5 g of crospovidone, 0.25 g of stevia, 0.5 g of aspartame, and 0.5 g of magnesium stearate 0.3 g and mixed with a 13 mm die and a flat punch.
Tablets were produced at a tablet weight of 600 mg with an autograph (AG-5000B, Shimadzu Corporation) using 0 kg / punch.

Comparative Example 2: 30 g of erythritol essential oil, crystalline cellulose (Seolas KG)
801) 12.16 g of crospovidone and 2.45 g of crospovidone are placed in a mortar, 100 μl of light oil is added, and spread on a pestle. 15 g of acetaminophen and 0.3 g of magnesium salitenate were mixed with the obtained powder, and using a 13 mm die and a flat punch, an autograph (AG-5000B, Shimadzu Corporation) was used at a tableting pressure of 1400 kg / punch. Tablet weight 6
Tablets were made at 00 mg.

Comparative Test The orally rapidly disintegrating tablet of the present invention obtained in Examples 1 to 4 above,
The hardness and dissolution time in the mouth of each of the oral preparations of Comparative Formulations 1 and 2 were examined, and the bitterness was evaluated. The following score was used for the evaluation of bitterness, and the evaluation was made separately for the bitterness 10 seconds after ingestion and the bitterness 60 seconds after ingestion. Bitter taste evaluation score Bitter taste is hardly felt: 0 Bitterness is slightly felt: 1 Bitterness is felt: 2 Bitterness is strongly felt: 3 When the score is 0 to 1, there is no problem in taking the bitterness. When it is ３3, it is difficult to take it due to bitterness. The results are shown in Table 1 below.

[0024]

[Table 1]

According to Table 1 above, the bitterness reducing effect of the orally rapidly disintegrating tablet containing only one of the essential oil and the high-sweetness sweetener (Comparative Examples 1 and 2) is not sufficient. In the rapid disintegration in the oral cavity of the present invention (Examples 1 to 5), the bitterness was reduced to such an extent that there was no problem at all in taking it. In particular, the excellent effect of the orally rapidly disintegrating tablet of the present invention is apparent in that bitterness is reduced 60 seconds after ingestion.

Example 6 The tablets obtained in Example 5 were packaged in aluminum strips,
The hardness, dissolution time in mouth, and bitterness of the tablets stored at 6 ° C. and 75% relative humidity for 6 months were evaluated. The evaluation of bitterness is the same as in Table 1.

Comparative Example 3 The tablets obtained in Example 5 were placed in a glass bottle,
The hardness, dissolution time in mouth, and bitterness of the tablets stored at 6 ° C. and 75% relative humidity for 6 months were evaluated. The evaluation of bitterness is the same as in Table 1. Table 2 shows the evaluation results of Example 6 and Comparative Example 3.
Shown in

[0028]

[Table 2]

As is clear from Table 2, the rapidly disintegrating tablet in the oral cavity of the present invention is preferably in a highly airtight package such as an aluminum strip package.

[0030]

The orally rapidly disintegrating tablet of the present invention can be taken with almost no bitterness even when taken without water, even though it is not coated with a bitter pharmaceutical ingredient. Therefore, in addition to being able to be manufactured at a lower cost than in the case of coating with a pharmaceutical component, it is a very useful formulation in the medical field in that the required pharmaceutical component can be taken at any time and place. .

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Claims (9)

[Claims] An orally rapidly disintegrating tablet comprising a pharmaceutical ingredient having a bitter taste and an essential oil and a bitterness-reducing component comprising a high-intensity sweetener and / or an acidic phospholipid or a lyso-form thereof. 2. The orally rapidly disintegrating tablet according to claim 1, wherein the bitterness reducing component comprises an essential oil and a high-sweetness sweetener. 3. The orally rapidly disintegrating tablet according to claim 1, wherein the bitterness reducing component comprises an essential oil and an acidic phospholipid or a lyso form thereof. 4. The bitterness-reducing component comprises an essential oil, a high-intensity sweetener, and an acidic phospholipid or a lyso-form thereof.
2. The rapidly disintegrating tablet in the oral cavity according to item 1. 5. The orally rapidly disintegrating tablet according to claim 1, wherein the pharmaceutical ingredient having a bitter taste is not coated. 6. The orally rapidly disintegrating tablet according to claim 1, wherein the pharmaceutical ingredient having a bitter taste is acetaminophen. 7. The orally rapidly disintegrating tablet according to claim 1, wherein the essential oil is peppermint oil. 8. The orally rapidly disintegrating tablet according to claim 1, wherein the high-intensity sweetener is one or two selected from stevia and aspartame. 9. The orally rapidly disintegrating tablet according to claim 1, wherein the acidic phospholipid or its lyso form is soy lecithin.