JP4731941B2 - Oral formulation particles - Google Patents

Description

  The present invention relates to particles for oral preparation, and more particularly to particles for oral preparation containing a drug having an unpleasant taste as an active ingredient.

  For drugs having an unpleasant taste, various contrivances have been made on the formulation in order to mask an unpleasant taste such as a bitter taste or astringency, or to have good bioavailability.

  For example, Patent Document 1 discloses a drug having an unpleasant taste (such as erythromycin), a carrier for spray coagulation granulation (such as glycerin fatty acid ester and hydrogenated oil) having a melting point of 40 ° C. to 120 ° C., and an enteric or gastric polymer. Disclosed are particles for oral preparations having an average particle size of 160 μm or less obtained by spray coagulation granulation of components composed of (Eudragit E, carboxymethyl ethyl cellulose, hydroxypropyl methyl cellulose acetate succinate, etc.).

  Patent Document 2 discloses that a complex having an average particle size of 80 μm obtained by spray coagulation granulation of a component having an unpleasant taste (erythromycin), glycerin fatty acid ester, and Eudragit E, mannitol, magnesium oxide and starch. And particles for oral preparations, in which a sweetener is further mixed.

However, when these particles for oral preparation are suspended at the time of use and taken orally, the particle diameter is as small as 160 μm or less, so that they remain in the gaps of the teeth and have an unpleasant taste.
JP 2000-169364 A JP 2002-128705 A

  An object of the present invention is a particle for an oral preparation containing a drug having an unpleasant taste as an active ingredient, and when taken in suspension during use, an unpleasant taste remains due to remaining in the gaps of teeth, etc. It is providing the particle | grains for oral preparations which do not show a rough feeling.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have coated an elementary particle containing a drug having an unpleasant taste as an active ingredient in two layers with different gastric coating agents, and the average particle size is When particles for oral preparations composed of a mixture of active ingredient-containing particles having an average particle size of 200 to 800 μm and sweet component-containing particles having an average particle diameter of 200 to 800 μm are taken in suspension during use, they exhibit an unpleasant taste. In addition, they found that it did not show a rough feeling. Thereafter, further research was conducted to complete the present invention.

That is, the present invention
[1] Oral preparation particles composed of active ingredient-containing particles (A) and sweetener-containing particles (B), wherein the active ingredient-containing particles (A) are elementary particles containing a drug having an unpleasant taste ( a1) particles having an average particle size of 200 to 800 [mu] m coated on two layers comprising a first coating layer (b1) and a second coating layer (b2) by gastric soluble coating agents having different surfaces; (B) is a particle for oral preparations characterized by being particles having an average particle diameter of 200 to 800 μm containing a sweetener,
[2] Particles for oral preparation according to the above [1], wherein the elementary particles (a1) further contain D-mannitol, crystalline cellulose and hydroxypropyl cellulose,
[3] Gastric soluble coating agent is hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, polyvinyl acetal ethylaminoacetate, ethyl methacrylate / methacrylated trimethylammonium ethyl copolymer, dimethylaminoethyl methacrylate / methyl methacrylate Particles for oral preparation according to the above [1] or [2], selected from a copolymer, a methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer, and a combination of two or more thereof,
[4] The surface of the elementary particles (a1) is coated with a first coating layer (b1) containing polyvinyl acetal diethylaminoethylaminoacetate, and the first coating layer (b1) is further methyl methacrylate / methacrylic acid The particles for oral preparation according to any one of [1] to [3], which are coated with a second coating layer (b2) containing a butyl / dimethylaminoethyl methacrylate copolymer,
[5] The particles for oral preparation according to any one of [1] to [4], wherein the weight ratio of the active ingredient-containing particles (A) to the sweetener-containing particles (B) is 1: 9 to 9: 1. ,
[6] The particles for oral preparation according to any one of [1] to [5], wherein the sweetener is a combination of a saccharide sweetener and a high-intensity sweetener,
[7] A combination of a saccharide sweetener selected from xylitol, erythritol, trehalose, D-mannitol, xylitol, lactitol, and reduced palatinose and a high-intensity sweetener selected from sodium saccharin, aspartame, stevia, and sucralose. Orally formulated particles according to any one of [1] to [6],
[8] The oral preparation particles according to any one of [1] to [7], wherein the drug having an unpleasant taste is clarithromycin, and [9] the dry syrup particles according to the above [8]. Oral formulation particles,
About.

  The particles for oral preparation of the present invention have excellent effects that no unpleasant taste remains and no graininess when taken in suspension during use, and are particularly excellent as dry syrup particles.

  The present invention relates to particles for oral preparation comprising active ingredient-containing particles (A) and sweetener-containing particles (B), wherein the active ingredient-containing particles (A) are elementary particles containing a drug having an unpleasant taste. (A1) is a particle having an average particle diameter of 200 to 800 μm and coated with two layers consisting of a first coating layer (b1) and a second coating layer (b2) by a gastric soluble coating agent having a different surface, the sweetener containing The particles (B) are particles for oral preparations containing a sweetener and having an average particle size of 200 to 800 μm.

  In the present invention, “unpleasant taste” in a drug having an unpleasant taste is a general term for unpleasant discomfort including bitterness and astringency felt in the oral cavity and pharynx. Drugs having such an unpleasant taste include macrolide antibiotics (for example, erythromycin, clarithromycin, taxamycin, josamycin, midecamycin, roxistamycin, azithromycin, etc.), β-lactam antibiotics (for example, penicillin derivatives, Cephalosporin derivatives), tetracycline antibiotics (eg, tetracycline), neuropsychiatric agents (eg, chlorpromazine), cardiotonic agents (eg, digitoxin), antipyretics (eg, sulpyrine), anti-ulcer agents (eg, , Cimetidine, etc.).

  The component contained in the elementary particles (a1) of the active ingredient-containing particles (A) can further contain an excipient, a binder and the like in addition to a drug having an unpleasant taste that is an active ingredient. For example, D-mannitol Crystalline cellulose and hydroxypropyl cellulose can be suitably included. The mixing ratio of these components varies slightly depending on the kind of the drug. However, when the drug having an unpleasant taste is clarithromycin, 1 to 10 parts by weight of D-mannitol, 1 part by weight of crystal with respect to 1 part by weight of clarithromycin. It is preferable that they are 1 to 10 parts by weight of cellulose and 0.1 to 1 parts by weight of hydroxypropyl cellulose.

  Examples of the gastric soluble coating agent for coating the elementary particles (a1) include hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, polyvinyl acetal ethylaminoacetate, ethyl methacrylate / methacrylated trimethylammonium ethyl copolymer, and dimethyl methacrylate. Aminoethyl-methyl methacrylate copolymer, methyl methacrylate-butyl methacrylate-dimethylaminoethyl copolymer (generic name: aminoalkyl methacrylate copolymer E; trade name: Eudragit E), or two or more of these Examples include combinations. The surface of the elementary particles (a1) is coated with two layers of the first coating layer (b1) and the second coating layer (b2) by using two different types of gastric coating agents or different combinations. As a coating agent used for providing the first coating layer (b1) on the surface of the elementary particles (a1), polyvinyl acetal diethylaminoacetate is particularly preferable. As the coating agent used for further forming the second coating layer (b2) on the surface of the first coating layer (b1), a methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer is particularly preferable. These coating agents can be used in combination with an anti-adhesive agent, a lubricant, a fluidizing agent, a colorant and the like. Specifically, for example, talc, titanium oxide, magnesium stearate and the like can be used in combination.

  The coating amount of the first coating layer (b1) and the second coating layer (b2) is 0.05 to 0.5 parts by weight of the first coating layer (b1) with respect to 1 part by weight of the elementary particles (a1). It is preferable that it is 0.1-1.0 weight part of 2 coating layers (b2).

  The average particle diameter of the active ingredient-containing particles (A), that is, the particles obtained by coating the surfaces of the elementary particles (a1) with the two layers of the first coating layer (b1) and the second coating layer (b2) is 200 to 800 μm. . When the average particle diameter is less than 200 μm, the particles are likely to remain in the gaps of the teeth, and an unpleasant taste is exhibited. On the other hand, if it exceeds 800 μm, it feels rough when taken, which is not preferable.

  The other sweetener-containing particles (B) constituting the particles for oral preparation of the present invention are particles containing a sweetener. Examples of the sweetener include erythritol, trehalose, D-mannitol, xylitol, Examples include saccharide sweeteners such as lactitol and reduced palatinose, and high-intensity sweeteners such as sodium saccharin, aspartame, stevia, and sucralose. Combination with sodium saccharin) is preferred. The sweetener-containing particles (B) may further contain other components (such as excipients and binders), such as crystalline cellulose, crystalline cellulose / carmellose sodium, magnesium carbonate, Examples include carmellose sodium. The average particle size of the sweetener-containing particles (B) is preferably matched with the average particle size of the active ingredient-containing particles (A).

The weight ratio of the active ingredient-containing particles (A) to the sweetener-containing particles (B) is preferably 1: 9 to 9: 1, particularly 3: 7 to 7: 3.
If necessary, a fragrance, a fluidizing agent (for example, light anhydrous silicic acid) or the like may be blended in the mixed particles of both.

  The particles for oral preparation of the present invention can be produced by a method known per se. For example, the active ingredient-containing particles (A) elementary particles (a1) are kneaded by kneading a mixture of a drug having an unpleasant taste and other components (D-mannitol, crystalline cellulose, hydroxypropyl cellulose, etc.). The product can be produced by granulating with a granulator (for example, an extrusion granulator), adjusting the size with a malmerizer, and then drying. In order to make the average particle diameter of the particles 200 to 800 μm, for example, it can be carried out by adjusting the opening of a screen (screen) attached to the extrusion granulator.

The elementary particles (a1) thus obtained are then coated in two layers using a coating agent. The coating can be performed according to a conventional method. For example, the surface of the elementary particles ((a1) is first formed using a mixture of polyvinyl acetal diethylaminoacetate and talc, and a first coating layer (b1) is formed by a fluid coating machine, and then, for example, methyl methacrylate / methacrylic acid. The active ingredient-containing particles (A) can be produced by forming the second coating layer (b2) with a fluid coating machine using a butyl acid / dimethylaminoethyl methacrylate copolymer.

On the other hand, the sweetener-containing particles (B) are prepared by kneading a mixture of a sweetener and other ingredients in the same manner as the elementary granules (a1) and granulating the kneaded product (for example, an extruding granulator). After granulation, the particles can be sized with a Malmerizer and then dried.
Oral preparation particles can be obtained by mixing the active ingredient-containing particles (A) obtained above and the sweetener-containing particles (B) by a conventional method.

  The particles for oral preparation thus obtained can be made into an oral solid preparation such as a dry syrup by adding a fragrance or a fluidizing agent as it is or if necessary.

Example 1
50 g of clarithromycin, 125 g of crystalline cellulose, 55 g of D-mannitol, and 20 g of hydroxypropylcellulose are mixed and then kneaded. The kneaded product is granulated with an extrusion granulator equipped with a screen (0.4 mm), then sized with a Malmerizer and dried. Polyvinyl acetal diethylaminoethylaminoacetate was coated with 5.0% of the granules with a coating solution having a composition of 5% and ethanol (95) 95%. Further, the coating solution having a composition of 15% aminoalkyl methacrylate copolymer E, 2% magnesium stearate, 66.4% ethanol (95), and 16.6% purified water was applied to the granules, and 4.0 to the grains. % Coating to give coated grains (average particle size: 400 μm).

Separately, 190 g of xylitol, 33 g of crystalline cellulose, 10 g of crystalline cellulose / carmellose sodium, 10 g of magnesium carbonate, 5 g of sodium saccharin, and 2 g of carmellose sodium are mixed and kneaded. The kneaded product was granulated with an extrusion granulator equipped with a screen (0.4 mm), then sized with a malmerizer, and dried to obtain sweetened granules (average particle size: 400 μm).
Coated grains and sweetened grains were mixed so that clarithromycin was 10% to obtain a dry syrup preparation.

(Example 2)
50 g of clarithromycin, 125 g of crystalline cellulose, 55 g of D-mannitol, and 20 g of hydroxypropylcellulose are mixed and then kneaded. The kneaded product is granulated with an extrusion granulator equipped with a screen (0.6 mm), then sized with a Malmerizer and dried. Polyvinyl acetal diethylaminoethylaminoacetate was coated with 3.0% of the granules with a coating solution having a composition of 5% and ethanol (95) 95%. Furthermore, with respect to this grain, in the coating liquid of the composition of aminoalkyl methacrylate copolymer E15%, magnesium stearate 2%, titanium oxide 1%, ethanol (95) 66.4%, purified water 15.6%, On the other hand, 4.0% coating was performed to obtain coated particles (average particle size: 600 μm).

Separately, 190 g of xylitol, 33 g of crystalline cellulose, 10 g of crystalline cellulose / carmellose sodium, 10 g of magnesium carbonate, 5 g of sodium saccharin, and 2 g of carmellose sodium are mixed and kneaded. The kneaded product was granulated with an extrusion granulator equipped with a screen (0.6 mm), then sized with a Malmerizer, and dried to obtain sweetened granules (average particle size: 600 μm).
Coated grains and sweetened grains were mixed so that clarithromycin was 10% to obtain a dry syrup preparation.

(Example 3)
50 g of clarithromycin, 125 g of crystalline cellulose, 55 g of D-mannitol, and 20 g of hydroxypropylcellulose are mixed and then kneaded. The kneaded product is granulated with an extruding granulator equipped with a screen (0.2 mm), then sized with a Malmerizer and dried. 4.4% coating was performed on the granules with a coating solution having a composition of 5% polyvinyl acetal diethylaminoethylaminoacetate and 95% ethanol (95). Furthermore, with respect to this grain, in the coating liquid of the composition of aminoalkyl methacrylate copolymer E15%, magnesium stearate 2%, titanium oxide 1%, ethanol (95) 66.4%, purified water 15.6%, On the other hand, it was coated with 8.0% to form coated particles (average particle size: 200 μm).

Separately, 190 g of xylitol, 33 g of crystalline cellulose, 10 g of crystalline cellulose / carmellose sodium, 10 g of magnesium carbonate, 5 g of sodium saccharin, and 2 g of carmellose sodium are mixed and kneaded. The kneaded product was granulated with an extrusion granulator equipped with a screen (0.2 mm), then sized with a Malmerizer, and dried to obtain sweetened granules (average particle size: 200 μm).
Coated grains and sweetened grains were mixed so that clarithromycin was 10% to obtain a dry syrup preparation.

(Comparative Example 1)
50 g of clarithromycin, 150 g of crystalline cellulose, 25 g of low-substituted hydroxypropyl cellulose and 25 g of hydroxypropyl cellulose are mixed and then kneaded. The kneaded product is granulated with an extrusion granulator equipped with a screen (0.4 mm), then sized with a Malmerizer and dried. In a coating solution of 3% ethylcellulose, 2% hydroxypropylmethylcellulose, 1% talc, 0.5% triethyl citrate, 74.7% ethanol (95) and 18.8% purified water, 6% of the particles .8% coating was made into coated grains (average particle size: 400 μm).

Separately, 190 g of xylitol, 33 g of crystalline cellulose, 10 g of crystalline cellulose / carmellose sodium, 10 g of magnesium carbonate, 5 g of sodium saccharin, and 2 g of carmellose sodium are mixed and kneaded. The kneaded product was granulated with an extrusion granulator equipped with a screen (0.4 mm), then sized with a malmerizer, and dried to obtain sweetened granules (average particle size: 400 μm).
Coated grains and sweetened grains were mixed so that clarithromycin was 10% to obtain a dry syrup preparation.

(Comparative Example 2)
50 g of clarithromycin, 125 g of crystalline cellulose, 50 g of low-substituted hydroxypropyl cellulose and 25 g of hydroxypropyl cellulose are mixed and then kneaded. The kneaded product is granulated with an extrusion granulator equipped with a screen (0.4 mm), then sized with a Malmerizer and dried. 8.8% of granules in a coating solution of 10% aminoalkyl methacrylate copolymer E, 5% magnesium oxide, 2% magnesium stearate, 66.4% ethanol (95) and 16.6% purified water Coating was performed to obtain coated grains (average particle diameter: 400 μm).

Separately, 190 g of xylitol, 33 g of crystalline cellulose, 10 g of crystalline cellulose / carmellose sodium, 10 g of magnesium carbonate, 5 g of sodium saccharin, and 2 g of carmellose sodium are mixed and kneaded. The kneaded product was granulated with an extrusion granulator equipped with a screen (0.4 mm), then sized with a malmerizer, and dried to obtain sweetened granules (average particle size: 400 μm).
Coated grains and sweetened grains were mixed so that clarithromycin was 10% to obtain a dry syrup preparation.

(Comparative Example 3)
50 g of clarithromycin, 125 g of crystalline cellulose, 55 g of D-mannitol, and 20 g of hydroxypropylcellulose are mixed and then kneaded. The kneaded product is granulated with an extrusion granulator equipped with a screen (0.6 mm), then sized with a Malmerizer and dried. Polyvinyl acetal diethylaminoethylaminoacetate was coated with 3.0% of the particles with a coating solution having a composition of 5% ethanol and 95% ethanol (95) to form coated particles (average particle size: 600 μm).

Separately, 190 g of xylitol, 33 g of crystalline cellulose, 10 g of crystalline cellulose / carmellose sodium, 10 g of magnesium carbonate, 5 g of sodium saccharin, and 2 g of carmellose sodium are mixed and kneaded. The kneaded product was granulated with an extrusion granulator equipped with a screen (0.6 mm), then sized with a Malmerizer, and dried to obtain sweetened granules (average particle size: 600 μm).
Coated grains and sweetened grains were mixed so that clarithromycin was 10% to obtain a dry syrup preparation.

(Comparative Example 4)
50 g of clarithromycin, 125 g of crystalline cellulose, 55 g of D-mannitol, and 20 g of hydroxypropylcellulose are mixed and then kneaded. The kneaded product is granulated with an extrusion granulator equipped with a screen (1.0 mm), then sized with a Malmerizer and dried. Polyvinyl acetal diethylaminoethylaminoacetate was coated with a coating solution having a composition of 5% and ethanol (95) 95%, and 2.8% of the granules were coated. Furthermore, 15% of aminoalkyl methacrylate copolymer E, 2% of magnesium stearate, and 1% of titanium oxide with respect to this grain. A coating solution having a composition of ethanol (95) 66.4% and purified water 15.6% was coated with 5.0% of the particles to form coated particles (average particle size: 1000 μm).

Separately, 190 g of xylitol, 33 g of crystalline cellulose, 10 g of crystalline cellulose / carmellose sodium, 10 g of magnesium carbonate, 5 g of sodium saccharin, and 2 g of carmellose sodium are mixed and kneaded. The kneaded product was granulated with an extrusion granulator equipped with a screen (1.0 mm), then sized with a malmerizer, and dried to obtain sweetened granules (average particle size: 1000 μm).
Coated grains and sweetened grains were mixed so that clarithromycin was 10% to obtain a dry syrup preparation.

(Test example) Sensory evaluation test 1 g of the dry syrup preparations of Examples 1 to 3 and Comparative Examples 1 to 4 were suspended in 10 ml of water. Each panelist contained the suspension in the mouth, and the mouthfeel and the bitterness after 1 minute were evaluated. Thereafter, the liquid was discharged, and after 30 minutes, the taste was evaluated and the remaining bitterness was evaluated by remaining in the gaps of the teeth. The results are as shown in Tables 1 to 3 below.
In addition, the rough feeling and the bitterness after 1 minute and after 30 minutes were evaluated in five stages according to the following criteria.

Evaluation of rough feeling:
I don't feel any roughness ... 5
I don't feel any roughness ... 4
I feel a little rough ... 3
Feel the roughness ... 2
A strong feeling of roughness

Evaluation of bitterness after 1 minute and after 30 minutes:
I do not feel any bitterness ... 5
Almost no bitterness ... 4
I feel a little bitter ... 3
I feel a bitter taste ... 2
I feel a strong bitterness ... 1

  From the experimental results shown in Tables 1 to 3, the preparations of the present invention (formulations of Examples 1 to 3) obtained high evaluation points in terms of roughness and bitterness after 1 and 30 minutes. It can be seen that it is remarkably superior to the preparations of Comparative Examples 1 to 4.

The particles for oral preparation of the present invention are excellent particles that do not have an unpleasant taste remaining due to remaining in the gaps of the teeth when taken in suspension during use, and do not exhibit a rough feeling. It can be used in the medical field.

Claims (7)

Particles for oral preparation comprising active ingredient-containing particles (A) and sweetener-containing particles (B), wherein the active ingredient-containing particles (A) have the surface of elementary particles (a1) containing clarithromycin , A second coating layer (b1) containing polyvinyl acetal diethylaminoacetate , wherein the first coating layer (b1) further contains a methyl methacrylate / butyl methacrylate / dimethyl methacrylate ethyl methacrylate copolymer . Oral particles characterized in that they are particles having an average particle diameter of 200 to 800 μm coated with the coating layer (b2) , and the sweetener-containing particles (B) are particles having an average particle diameter of 200 to 800 μm containing a sweetener. Formulation particles.   The particle for oral preparation according to claim 1, wherein the elementary particles (a1) further contain D-mannitol, crystalline cellulose and hydroxypropylcellulose. The particles for oral preparation according to claim 1 or 2 , wherein the weight ratio of the active ingredient-containing particles (A) to the sweetener-containing particles (B) is 1: 9 to 9: 1. The particle for oral preparation according to any one of claims 1 to 3 , wherein the sweetener is a combination of a saccharide sweetener and a high-intensity sweetener. The sweetener is a combination of a saccharide sweetener selected from xylitol, erythritol, trehalose, D-mannitol, xylitol, lactitol, reduced palatinose and a high-intensity sweetener selected from saccharin sodium, aspartame, stevia, and sucrose. Item 6. The oral preparation particle according to any one of Items 1 to 4 . The particle for oral preparation according to any one of claims 1 to 5, which is a particle for dry syrup. The coating amount of the first coating layer (b1) and the second coating layer (b2) is 0.05 to 0.5 parts by weight of the first coating layer (b1) with respect to 1 part by weight of the elementary particles (a1). The particles for oral preparation according to any one of claims 1 to 6, wherein the second coating layer (b2) is 0.1 to 1.0 part by weight.