JP2010053048A - Irbesartan-containing pharmaceutical composition having mitigated bitter taste - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an irbesartan oral pharmaceutical composition which improves the bitter taste and has an excellent feeling of taking, and an irbesartan oral pharmaceutical composition which is easy for a patient of dysphagia to take and can adjust the dosage. <P>SOLUTION: The oral pharmaceutical composition contains irbesartan and sucralose. The oral pharmaceutical composition further includes an organic acid and/or a flavor such as a flavor of citrus fruits such as a grapefruit, a coffee flavor, and a cherry flavor. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to an oral pharmaceutical composition containing irbesartan in which the unpleasant taste of irbesartan is reduced and the feeling of taking is improved.

  Irbesartan, ie 2-Butyl-3- {4- [2- (1H-tetrazol-5-yl) phenyl] benzyl} -1,3-diazaspiro [4.4] non-1-en-4-one It is an active angiotensin II receptor antagonist and is particularly useful for the treatment of hypertension. Irbesartan has the formula:

The details thereof are described in Patent Document 1.

  Irbesartan is administered in a relatively large amount, for example, 50 to 300 mg for the treatment of the above diseases. In order to have a strong bitterness as a characteristic of the drug, there are cases where preparations such as film coating are applied to tablets.

  On the other hand, generally, dosage forms such as liquids (including suspensions), syrups, powders, granules, and dry syrups are used to improve ease of swallowing and adjust the dose according to patient characteristics. . Recently, many techniques relating to a preparation that rapidly disintegrates in the oral cavity have been disclosed as dosage forms suitable for the elderly and children.

  However, since these dosage forms tend to express a taste in the oral cavity when taken, they are difficult to take if the drug has an unpleasant taste and easily lead to a decrease in patient compliance. For this reason, many methods have heretofore been proposed as methods for blocking or reducing the unpleasant taste of drugs. For example, in liquids, syrups, powders, fine granules, granules, dry syrups, etc., a method of adding sweeteners or fragrances is known. Encapsulation, coating, spray drying, etc. are used.

In order to produce a preparation that contains an effective amount of irbesartan and is easy to drink and excellent in dosage, there has been a problem to be solved in reducing bitterness. Therefore, it is considered that an oral pharmaceutical composition having a good dosage with reduced bitterness and easy to swallow will help improve patient compliance.
US Pat. No. 5,270,317

  The problem to be solved by the present invention is to provide a preparation with little bitterness of irbesartan, particularly a preparation that is easy to take with little discomfort even at a high concentration.

  As a result of intensive studies, the present inventors have found that the bitterness of irbesartan is hardly alleviated by the addition of a high-intensity sweetener (especially thaumatin having a higher sweetness than sucralose), but the addition of sucralose leads to the addition of irbesartan. It was found for the first time that the bitter taste of can be reduced to a level that can be taken. In general, when the addition of sucralose does not improve the bitterness of the drug, it is considered that the addition of sweeter thaumatin is effective.In fact, in the experiments conducted by the present inventors, acetaminophen having a bitter taste is The bitterness was not improved by addition, and bitterness was reduced by adding the same amount of sweeter thaumatin. From this it is surprising that the addition of sucralose is effective even though the addition of thaumatin with a higher sweetness is not effective with irbesartan. Based on this viewpoint, the present inventors have found that an oral pharmaceutical composition in which the feeling of administration is greatly improved can be obtained by making an oral pharmaceutical composition in which sucralose is added to irbesartan. Furthermore, it was found that the bitterness was reduced by adding an organic acid, and that the bitterness was reduced by adding a citrus flavor such as coffee flavor, grapefruit, or cherry flavor, and completed the present invention. .

That is, the present invention is as follows.
[1] An oral pharmaceutical composition containing irbesartan and sucralose (hereinafter also referred to as the oral pharmaceutical composition of the present invention).
[2] The oral pharmaceutical composition according to the above [1], further comprising an organic acid or a salt thereof or a solvate thereof.
[3] The oral pharmaceutical composition according to the above [2], wherein the organic acid is one or more selected from malic acid, citric acid and tartaric acid.
[4] The oral pharmaceutical composition according to any one of [1] to [3], further comprising a water-soluble excipient.
[5] The oral pharmaceutical composition according to the above [4], wherein the water-soluble excipient is D-mannitol.
[6] The oral pharmaceutical composition according to any one of [1] to [5], further including a fragrance.
[7] The oral pharmaceutical composition according to the above [6], wherein the fragrance is a citrus fragrance, a coffee fragrance, or a cherry fragrance.
[8] The oral pharmaceutical composition according to any one of [1] to [7] above, wherein the weight ratio of sucralose to irbesartan is 1: 0.05 to 1: 0.3.
[9] The oral pharmaceutical composition according to any one of [1] to [8] above, wherein the sucralose content per dosage unit is 5 to 30 mg.
[10] The above [1] to [9], wherein the dosage form is liquid, jelly, gummi, dry syrup, powder, granule, fine granule, chewable preparation, orally disintegrating fine granule or orally disintegrating tablet An oral pharmaceutical composition according to any one of the above.
[11] The oral pharmaceutical composition according to the above [10], wherein the dosage form is liquid, dry syrup, powder, granule, fine granule, chewable preparation, orally disintegrating fine granule or orally disintegrating tablet.
[12] A method of masking the unpleasant taste of irbesartan by adding (1) sucralose and (2) a fragrance.

ADVANTAGE OF THE INVENTION According to this invention, the bitterness of irbesartan can be improved and the oral pharmaceutical composition of irbesartan excellent in the ingestion feeling can be provided. This makes it possible to easily take a sufficient amount of irbesartan not only for adults but also for patients of all ages such as the elderly and children.
According to the present invention, solution, jelly, gummi, syrup, dry syrup, powder, granule, fine granule, chewable preparation, orally disintegrating powder, orally disintegrating granule, orally disintegrating fine granule, Even if the dosage form is easy to express in the oral cavity, such as orally disintegrating tablets, the bitterness of irbesartan can be improved, so it can be taken by patients with difficulty swallowing, the elderly, children, etc. It is possible to provide an oral pharmaceutical composition that is easy and can be dose-adjusted and has improved irbesartan bitterness.

  In the oral pharmaceutical composition of the present invention, the amount of irbesartan, which is an active ingredient, is not particularly limited and varies depending on the dosage form. Usually, 10 to 300 mg is included in one preparation, preferably 25. -200 mg is mentioned. The concentration of irbesartan in the present invention is not particularly limited, but in the case of a suspension, for example, preferably 5 to 350 mg / mL. For example, in the case of an orally disintegrating preparation that can be taken without water, 50 to 700 mg / g may be mentioned.

The oral pharmaceutical composition of the present invention contains sucralose.
In the present invention, the weight ratio of irbesartan to sucralose is, for example, 1: 0.01 to 1: 5, preferably 1: 0.01 to 1: 1, and particularly preferably 1: 0.05. ˜1: 0.3. Moreover, the compounding quantity of the sucralose per 1 dosage unit (1 tablet, 1 packet, or 1) is 1-50 mg, for example, Preferably it is 2.5-30 mg, More preferably, 5-30 mg is mentioned.

The oral pharmaceutical composition of the present invention preferably contains an organic acid or a salt thereof or a solvate thereof.
Examples of the organic acid in the present invention include malic acid, citric acid, tartaric acid, ascorbic acid, adipic acid, succinic acid, fumaric acid, maleic acid, gluconic acid, glucuronic acid, and mixtures thereof. The salt of the organic acid is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include sodium salt, potassium salt, calcium salt, magnesium salt, or a double salt thereof, and acidic hydrogen remains. It may be an acidic salt (for example, disodium citrate). Examples of solvates of organic acids or salts thereof include hydrates. Preferred organic acids include organic acids having 2 or 3 carboxyl groups such as malic acid, citric acid, tartaric acid, and particularly preferred are malic acid and citric acid.
The weight ratio of sucralose to an organic acid or a salt thereof or a solvate thereof is not particularly limited, but may be, for example, 1: 0.01 to 1: 1, preferably 1: 0.01 to 1: 0.5 is mentioned, More preferably, 1: 0.05-1: 0.5 is mentioned, More preferably, 1: 0.1-1: 0.5 is mentioned.
In the present invention, the weight ratio of irbesartan to organic acid or salt thereof or solvate thereof is, for example, 1: 0.0005 to 1: 0.15, and preferably 1: 0.001 to 1: 0. 0.1, particularly preferably 1: 0.005 to 1: 0.05. Moreover, 0.05 mg-15 mg are mentioned, for example as for the compounding quantity of the organic acid per taking unit (1 tablet, 1 packet, or 1), Preferably 0.5 mg-5 mg are mentioned.

The oral pharmaceutical composition of the present invention preferably contains a fragrance. By blending a fragrance, a more preferable dosing feeling can be obtained.
Examples of the fragrance in the present invention include citrus fragrances such as lemon, orange, and grapefruit, cherry fragrance, pine fragrance, fruit fragrance, yogurt mixed fruit fragrance, and coffee fragrance. Of these, citrus flavor (especially grapefruit flavor), cherry flavor, and coffee flavor are preferred.
The blending amount of the fragrance is not particularly limited, and an appropriate amount may be appropriately selected from the amount usually used in the pharmaceutical preparation field (for example, 0.1 w / w% or less in the preparation). Although the minimum of a compounding quantity is not specifically limited, Preferably it is 0.01 w / w% or more.

  The oral pharmaceutical composition of the present invention is not particularly limited as long as it is a dosage form that can be administered orally, but it is a liquid, jelly, gummi, syrup, dry syrup, tablet, powder, granule, fine granule, chewable preparation, Examples of the dosage form include orally disintegrating powders, orally disintegrating granules, orally disintegrating fine granules, and orally disintegrating tablets. Here, in the present specification, the liquid agent includes a suspension. More preferably, since water is not required at the time of taking, it can be taken at any time and place, liquid, jelly, gummi, chewable preparation, orally disintegrating powder, orally disintegrating granules, orally disintegrating fine particles Granules or orally disintegrating tablets. From the standpoint of possible dose adjustment according to patient characteristics, liquids, syrups, dry syrups, powders, granules, fine granules, orally disintegrating powders, orally disintegrating granules, orally disintegrating fine granules, etc. preferable. In addition, from the viewpoint that it is easy to take for patients who have difficulty swallowing, elderly people, and children, liquids, syrups, jellies, gummi, dry syrups, powders, granules, fine granules, chewable preparations, orally disintegrating type Powders, orally disintegrating granules, orally disintegrating fine granules, orally disintegrating tablets and the like are preferable.

  In the oral pharmaceutical composition of the present invention, in addition to the above, nontoxic and inert additives usually used in the pharmaceutical field can be added. These additives include those that are substantially added as pharmaceutical additives without substantially affecting the effects of the present invention. For example, excipients such as D-mannitol, xylitol, sorbitol, erythritol, maltitol, reduced starch saccharified, reduced palatinose, talc, kaolin, calcium hydrogen phosphate, calcium sulfate, calcium carbonate, crystalline cellulose, stearic acid, stearin Lubricants such as magnesium oxide, calcium stearate, sodium stearyl fumarate, fluidizing agents such as light anhydrous silicic acid, disintegrants such as crospovidone, carboxymethylcellulose calcium, low-substituted hydroxymethylcellulose, hydroxypropylcellulose, hypromellose (hydroxy Propylmethylcellulose), povidone (polyvinylpyrrolidone), gelatin, methylcellulose, gum arabic powder, polyvinyl alcohol, alkylhydroxyethylcellulose Binding agents, coloring agents such as yellow ferric oxide, sweeteners other than sucralose, flavoring agents, adsorbents, preservatives, stabilizers, wetting agents, antistatic agents, pH adjusting agents, polysorbates (for example, polysorbate 80) ), A starch such as corn starch, a solvent such as water, and a suspending agent. Especially in the case of oral solid preparations that can be taken without water, such as dry syrup, orally disintegrating powder, orally disintegrating granules, orally disintegrating fine granules, orally disintegrating tablets, The disintegration property and solubility in the oral cavity are improved, and the feeling of taking is further improved.

Examples of water-soluble excipients include sorbitol, D-mannitol, maltitol, reduced starch saccharified product, xylitol, reduced palatinose, erythritol, and the like. Also good. Preferred water-soluble excipients include D-mannitol, xylitol, and erythritol, and more preferred examples include D-mannitol and erythritol.
Although it does not specifically limit as a compounding quantity of the water-soluble excipient | filler in the oral pharmaceutical composition of this invention, Usually 15-75 w / w% is mentioned, Preferably 25-50 w / w% is mentioned.
The blending amount of additives other than the above-described water-soluble excipient is not particularly limited, and a known amount may be appropriately selected according to the dosage form.

  The method for producing the oral pharmaceutical composition of the present invention is not particularly limited and includes known methods. In the case of a solid preparation, for example, as a granulation method, an extrusion granulation method, a crushing granulation method, a dry method, or the like. Consolidation granulation method, fluidized bed granulation method, rolling granulation method, rolling fluidized bed granulation method, high-speed stirring granulation method, kneading granulation method are mentioned. Examples thereof include a granule compression method and a direct compression method.

  When the oral pharmaceutical composition of the present invention is a tablet (orally disintegrating tablet), it can be produced, for example, by the following method. Irbesartan and optional additives (eg water soluble excipients (eg D-mannitol), disintegrants (eg crospovidone), starches (eg corn starch), colorants (eg yellow ferric oxide) etc. ), And granulated with an aqueous solution of a binder (e.g., hydroxypropyl cellulose) containing a surfactant (e.g., polysorbate 80) as necessary, and after drying, sucralose and optional additives (e.g., Fragrance (for example, coffee flavor, cherry flavor, grapefruit flavor), organic acid (for example, citric acid, malic acid), lubricant (for example, sodium stearyl fumarate), fluidizing agent (for example, light anhydrous silicic acid), etc. ) Can be mixed and compression molded to obtain a tablet.

The oral pharmaceutical composition of the present invention is useful as an angiotensin II receptor antagonist for the treatment of hypertension and the like.
The oral pharmaceutical composition of the present invention can be safely administered orally to mammals such as humans.
The dose can be appropriately selected depending on the age, body weight, severity of the disease, etc. For example, 50 to 300 mg per day is administered to an adult.

The invention also relates to a method of masking the unpleasant taste of irbesartan by adding (1) sucralose and (2) a fragrance.
Examples of the amount of sucralose added to irbesartan include the same ranges as those described above for the weight ratio of sucralose to irbesartan. Examples of the fragrance include the same as described above. The addition amount of the fragrance is not particularly limited, and an appropriate amount may be appropriately selected from the amount usually used in the pharmaceutical preparation field (for example, 0.1 w / w% or less in the preparation). The lower limit of the addition amount is not particularly limited, but is preferably 0.01 w / w% or more in the preparation.
The addition method is not particularly limited, and for example, irbesartan, sucralose, and a fragrance may be contained in the same preparation by a method known per se.
According to the method of the present invention, the unpleasant taste of irbesartan can be masked, and it becomes easy to take.

  Hereinafter, the present invention will be described more specifically with reference to Examples, Comparative Examples, and Test Examples, but the present invention is not necessarily limited thereto.

[Example 1]
According to the following prescription, irbesartan, D-mannitol and sucralose were mixed in a mortar to obtain irbesartan powder.

[Comparative Example 1]
Irbesartan powder was obtained by replacing sucralose of Example 1 with aspartame, acesulfame K, thaumatin, stevia, or saccharin Na.

[Comparative Example 2]
Irbesartan powder was obtained by replacing the sucralose of Example 1 with D-mannitol.

[Test Example 1]
The preparations of Example 1 and Comparative Examples 1 and 2 were discharged in the mouth for 1 minute, and the bitter taste felt at 1 minute and 5 minutes after the discharge was scored according to the following criteria.
1: Feel little bitterness 2: Feel bitterness 3: Feel strong bitterness 4: Feel unbearable bitterness

  The preparation of Example 1 containing sucralose was of a level that could be taken with reduced bitterness, but Comparative Example 1 containing other high-intensity sweeteners and Comparative Example 2 not containing high-intensity sweeteners. The formulation could not reduce the bitterness below acceptable levels.

[Example 2]
In accordance with the following formulation, corn starch (for granulation) and yellow ferric oxide are premixed and then a small universal mixer (dispensing mixer) together with irbesartan, D-mannitol, crospovidone (Polyplastidone XL-10, manufactured by ISP) , Manufactured by Shinagawa Kogyo Co., Ltd.), and after mixing, an aqueous solution of hydroxypropyl cellulose (HPC-L, manufactured by Nippon Soda) was added and kneaded. The kneaded product was dried and sized. After mixing sucralose, corn starch (for powder mixing), coffee flavor, light anhydrous silicic acid and sodium stearyl fumarate (PRUV, manufactured by JRS PHARMA) to the obtained granulated product, a single tableting machine (EK0, KORSCH) Was used to form tablets with a compression force of about 4 kN in a circular tablet mold having a diameter of 8 mm and a curvature radius of 12 mm.

[Example 3]
In accordance with the following formulation, corn starch (for granulation) and yellow ferric oxide are premixed and then a small universal mixer (dispensing mixer) together with irbesartan, D-mannitol, crospovidone (Polyplastidone XL-10, manufactured by ISP) , Manufactured by Shinagawa Kogyo Co., Ltd.), and after mixing, an aqueous solution of hydroxypropyl cellulose (HPC-L, manufactured by Nippon Soda) was added and kneaded. The kneaded product was dried and sized. After mixing sucralose, corn starch (for powder mixing), coffee flavor, light anhydrous silicic acid and sodium stearyl fumarate (PRUV, manufactured by JRS PHARMA) to the obtained granulated product, a single tableting machine (EK0, KORSCH) Was used to form tablets with a compression force of about 4 kN in a circular tablet mold having a diameter of 8 mm and a curvature radius of 12 mm.

[Example 4]
In accordance with the following formulation, corn starch (for granulation) and yellow ferric oxide are premixed, and then a small universal mixer (dispensing mixer) with irbesartan, D-mannitol, crospovidone (Polyplastidone XL-10, manufactured by ISP) , Manufactured by Kogyo Kogyo Co., Ltd.), and after mixing, an aqueous solution of hydroxypropylcellulose (HPC-L, manufactured by Nippon Soda) was added and kneaded. The kneaded product was dried and sized. After mixing sucralose, corn starch (for powder mixing), citric acid, cherry flavor, light anhydrous silicic acid and sodium stearyl fumarate (PRUV, manufactured by JRS PHARMA) to the obtained granulated product, a single tableting machine ( EK0, manufactured by KORSCH) was molded with a compressive force of about 4 kN in a circular tablet mold having a diameter of 8 mm and a curvature radius of 12 mm to obtain tablets.

[Example 5]
In accordance with the following formulation, corn starch (for granulation) and yellow ferric oxide are premixed and then a small universal mixer (dispensing mixer) together with irbesartan, D-mannitol, crospovidone (Polyplastidone XL-10, manufactured by ISP) , Manufactured by Shinagawa Kogyo Co., Ltd.), mixed, and then added a solution of hydroxypropylcellulose (HPC-L, manufactured by Nippon Soda) and polysorbate 80 (NIKKOL TO-10MV, manufactured by Nikko Chemicals) in water. Kneaded. The kneaded product was dried and sized. After mixing sucralose, corn starch (for powder mixing), malic acid, grapefruit fragrance, light anhydrous silicic acid and sodium stearyl fumarate (PRUV, manufactured by JRS PHARMA) into the obtained granulated product, a single tableting machine ( EK0, manufactured by KORSCH) was molded with a compressive force of about 4 kN in a circular tablet mold having a diameter of 8 mm and a curvature radius of 12 mm to obtain tablets.

[Example 6]
In accordance with the following formulation, corn starch (for granulation) and yellow ferric oxide are premixed and then a small universal mixer (dispensing mixer) together with irbesartan, D-mannitol, crospovidone (Polyplastidone XL-10, manufactured by ISP) , Manufactured by Shinagawa Kogyo Co., Ltd.), and after mixing, an aqueous solution of hydroxypropyl cellulose (HPC-L, manufactured by Nippon Soda) was added and kneaded. The kneaded product was dried and sized. After mixing sucralose, corn starch (for powder mixing), coffee flavor, light anhydrous silicic acid and sodium stearyl fumarate (PRUV, manufactured by JRS PHARMA) to the obtained granulated product, a single tableting machine (EK0, KORSCH) Was used to form tablets with a compression force of about 4 kN in a circular tablet mold having a diameter of 8 mm and a curvature radius of 12 mm.

[Example 7]
In accordance with the following formulation, corn starch (for granulation) and yellow ferric oxide are premixed and then a small universal mixer (dispensing mixer) together with irbesartan, D-mannitol, crospovidone (Polyplastidone XL-10, manufactured by ISP) , Manufactured by Shinagawa Kogyo Co., Ltd.), and after mixing, an aqueous solution of hydroxypropyl cellulose (HPC-L, manufactured by Nippon Soda) was added and kneaded. The kneaded product was dried and sized. After mixing sucralose, corn starch (for powder mixing), coffee flavor, light anhydrous silicic acid and sodium stearyl fumarate (PRUV, manufactured by JRS PHARMA) to the obtained granulated product, a single tableting machine (EK0, KORSCH) Was used to form tablets with a compression force of about 4 kN in a circular tablet mold having a diameter of 8 mm and a curvature radius of 12 mm.

[Comparative Example 3]
Tablets were produced by changing the sucralose of Example 3 to aspartame.

[Comparative Example 4]
Tablets were prepared by changing sucralose of Example 4 to acesulfame K.

[Comparative Example 5]
Tablets were produced by changing the sucralose of Example 5 to thaumatin.

[Test Example 2]
The sensory test was implemented about the formulation prepared in Examples 2-7 and Comparative Examples 3-5. The formulation was discharged in the mouth for 1 minute, and the bitter taste felt at 1 minute and 5 minutes after the discharge was scored according to the following criteria.
1: Feel little bitterness 2: Feel bitterness 3: Feel strong bitterness 4: Feel unbearable bitterness Table 9 shows the results. In the preparations of Examples 2 to 7 of the present invention, the bitterness was reduced, whereas the preparations of Comparative Examples 3 to 5 were very bitter and the bitterness persisted.

  INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide an irbesartan oral pharmaceutical composition with improved bitterness and excellent feeling of administration. Not only is it difficult for patients with swallowing to take, but also dose adjustment is possible, so that medication tailored to the patient becomes possible.

Claims (12)

  An oral pharmaceutical composition comprising irbesartan and sucralose.   Furthermore, the oral pharmaceutical composition of Claim 1 containing an organic acid or its salt, or those solvates.   The oral pharmaceutical composition according to claim 2, wherein the organic acid is at least one selected from malic acid, citric acid and tartaric acid.   Furthermore, the oral pharmaceutical composition in any one of Claims 1-3 containing a water-soluble excipient | filler.   The oral pharmaceutical composition according to claim 4, wherein the water-soluble excipient is D-mannitol.   Furthermore, the oral pharmaceutical composition in any one of Claims 1-5 containing a fragrance | flavor.   The oral pharmaceutical composition according to claim 6, wherein the fragrance is a citrus fragrance, a coffee fragrance or a cherry fragrance.   The oral pharmaceutical composition according to any one of claims 1 to 7, wherein the weight ratio of sucralose to irbesartan is 1: 0.05 to 1: 0.3.   The oral pharmaceutical composition according to any one of claims 1 to 8, wherein the sucralose content per dosage unit is 5 to 30 mg.   The dosage form according to any one of claims 1 to 9, wherein the dosage form is a liquid, jelly, gummi, dry syrup, powder, granule, fine granule, chewable preparation, orally disintegrating fine granule, or orally disintegrating tablet. Oral pharmaceutical composition.   The oral pharmaceutical composition according to claim 10, wherein the dosage form is liquid, dry syrup, powder, granule, fine granule, chewable preparation, orally disintegrating fine granule or orally disintegrating tablet. A method of masking the unpleasant taste of irbesartan by adding (1) sucralose and (2) a fragrance.