WO2001091761A1

WO2001091761A1 - Matrices for oral preparations

Info

Publication number: WO2001091761A1
Application number: PCT/JP2001/004593
Authority: WO
Inventors: Kenichi Abe; Keijiro Kawahara; Toshio Yajima
Original assignee: Taisho Pharmaceutical Co.,Ltd.
Priority date: 2000-06-01
Filing date: 2001-05-31
Publication date: 2001-12-06
Also published as: AU6068001A

Abstract

Matrices obtained by granulating the following components by spray solidifying: (A) clarithromycin; (B) a glycerol fatty acid ester or stearyl alcohol; and (C) one or more members selected from among hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S. These matrices make it possible to provide oral preparations which are free from any offensive taste of clarithromycin, in particular, the offensive taste evolving when taken together with acidic drinks (orange juice, yogurt, etc.).

Description

Specification

Matrix for oral formulation Technical field

The present invention relates to a matrix for oral preparations which does not cause bitterness when taken simultaneously with the unpleasant taste of clarithromycin, especially acidic beverages (orange juice, yogurt, etc.).

Background art

Clarithromycin is known as an antibiotic that has excellent effects, but has the disadvantage that it cannot be formed into granules, powders, dry syrups, etc. that are easy to take with conventional methods due to its strong bitterness .

Conventionally, various formulation methods have been disclosed for masking the taste of a drug exhibiting an unpleasant taste.

Japanese Patent Application Laid-Open No. 49-8181526 discloses that a macrolide antibiotic is spray-dried using an inert volatile organic solvent such as polyvinyl acetal acetylaminoacetate (AEA), and the coated macro is coated. A method has been disclosed for collecting ride-type antibiotic particles, but this method is not preferred because of concerns about the effect of the organic solvent on the environment and remaining in the drug product.

Japanese Patent Application Laid-Open No. 56-140915 discloses a technique for coating a powdery or granular drug with waxes, which can be applied to masking of unpleasant tastes. The dissolution after ingestion is inadequate because masking is performed only with the genus.

JP-A-58-4714 and JP-A-59-16822 disclose techniques for encapsulating drugs having an unpleasant taste, respectively. Poor.

Japanese Patent Application Publication No. Hei 8-5505841 discloses a matrix composed of a wax core agent and a hydrophobic polymer agent, but does not disclose the improvement of the strong bitterness of Clarice's mouth mycin.

Macrolides are generally offered as dry syrups for children There are many. However, children often dislike taking the drug, and are often given a suspension in their favorite orange juice or yogurt. However, the conventionally known dry syrup containing clarithromycin has the property of rapidly releasing a drug when it is in an acidic state.Therefore, when it is suspended in orange juice etc., it becomes bitter when it becomes acidic. was there.

Disclosure of the invention

DISCLOSURE OF THE INVENTION The present inventors have aimed at providing an oral preparation having an improved unpleasant flavor of Clarice Mouthmycin, particularly an improved flavor when taken together with an acidic liquid beverage (orange juice, yogurt, etc.). As a result of the study, it was found that a certain kind of matrix could mask the strong bitterness of Clarice's mouth mycin, and that the masking effect was maintained even when taken with an acidic beverage, thus completing the present invention. That is, the present invention

(A) Clarithromycin

(B) glycerin fatty acid ester or stearyl alcohol, and

(C) selected from hydroxypropyl methylcellulose monohydrate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S One or more

Is a matrix obtained by spray coagulation and granulation.

In the present invention, the glycerin fatty acid ester is one in which glycerin and a fatty acid are ester-bonded, and is preferably monoglyceride or triglyceride. Fatty acids constituting the ester are preferably behenic acid, stearic acid, oleic acid, palmitic acid, myristic acid, lauric acid and the like.

The component (C) of the present invention is selected from hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, methacrylic acid copolymer L, methacrylic acid copolymer LD, and methacrylic acid copolymer S. One or more types. Here, when stearyl alcohol is used as the component (B), from the viewpoint of the solubility of the heated and dissolved component (B), the component (C) is hydroxypropylmethylcellulose acetate succinate or carboxymethyl. The ethylcell mouth is most preferred.

In the present invention, the blending amount of the component (B) is preferably 0.5 times or more, more preferably 1 time or more, and even more preferably 2 times or more in terms of mass ratio with respect to clarithromycin. If the ratio is less than 0.5, not only the masking of a sufficiently unpleasant taste cannot be achieved, but also the viscosity of the dispersion becomes high and the work becomes difficult. On the other hand, if the amount of the component (B) is too large, the dissolution of clarithromycin from the preparation deteriorates. Therefore, the blending amount of the component (B) is preferably 20 times or less of clarithromycin, and more preferably 10 times or less. preferable.

In the present invention, the amount of the component (C) is preferably 1% by mass or more of the component (B), more preferably 5% by mass or more. Although the maximum amount of the component (C) varies depending on the amount of the clarithromycin, the amount is preferably such that the total mass of the clarithromycin and the component (C) is 70% by mass or less of the whole matrix, and the mass is 60%. % Is more preferable.

In the present invention, the blending amount of clarithromycin is preferably 60% by mass or less, more preferably 45% by mass or less, and still more preferably 30% by mass or less in terms of workability. However, when the amount of clarithromycin is reduced, a large amount of the drug must be administered in order to administer a sufficient amount to exert a drug effect. Therefore, the amount of clarithromycin is 5% by mass. Or more, more preferably 10% by mass or more.

In the matrix of the present invention, a plasticizer such as Macrogol 600, triethyl quenate, triacetin, propylenedaricol, Macrogol 00 or the like can be added to the matrix component.

In the matrix of the present invention, additives used in the production of general matrix preparations can be appropriately used within a quantitative and qualitative range that does not impair the effects of the present invention.

The matrix of the present invention provides good masking of unpleasant taste, It must be manufactured by spray coagulation granulation in order to obtain particles for oral preparations with excellent bioavailability.

Here, spray coagulation granulation can be classified as one of the granulation methods generally called melt granulation, and the droplets formed by spraying a liquid or suspension are cooled to form spherical or granular particles. Is a method for obtaining solid particles of This method is characterized in that it does not use an organic solvent, and differs from spray drying, which is a typical example of the melt granulation method, in that it is cooled.

The matrix of the present invention is usually produced as follows. First, the component (C) is mixed with the component (B) heated and dissolved above the melting point, clarithromycin is dispersed in the mixture, and the mixture is spray-coagulated and granulated under preset spraying conditions to form a matrix. Obtainable.

In the case of manufacturing by spray coagulation granulation, the suspension in the manufacturing components is heated and suspended because if the particle size is large, it will not be clogged in the piping during spraying and will not be uniformly dispersed in the manufactured matrix. The particle diameter of the particles in the component is usually 20 m or less, preferably 10 m or less. For this reason, solids that do not dissolve upon heating or do not dissolve in the spray-solidified granulation carrier that has been heated and dissolved need to be pulverized to reduce the particle size. Therefore, from the viewpoint of operability and uniformity, it is preferable to incorporate an enteric base and a plasticizer which are easily dissolved in the carrier for spray coagulation and granulation having a melting point of 40 to 120 ° C.

The matrix thus obtained can be used as it is or as required with additives such as excipients, disintegrants, binders, lubricants, antioxidants, coating agents, coloring agents, flavoring agents, surfactants Oral solid preparations such as powders, granules, capsules, tablets, and dry syrups can be obtained by adding a powder, a plasticizer and the like, and going through a usual preparation process.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples. The glycerin fatty acid ester used was one having stearic acid as a main fatty acid and a monoglyceride content of 90% or more. Example 1

600 g of glycerin fatty acid ester was dissolved at about 100 ° C., and 100 g of carboxymethylethylcellulose was dispersed and dissolved therein. Clarithromycin (300 g) was further dispersed in the mixture. This dispersion was spray-coagulated and granulated using a spray dryer under the conditions of an inlet temperature of 100 ° C and a rotating disk of 2000 O rpm, and particles for oral preparation having an average particle size of 94.2 m were obtained. I got Example 2

Glycerin fatty acid ester (600 g) was dissolved at about 100 ° C., and hydroxypropylmethylcellulose acetate succinate (100 g) was dispersed and dissolved therein. Further, 300 g of clarithromycin was dispersed in the mixture. This dispersion was spray-coagulated and granulated using a spray-drying device under the conditions of an inlet temperature of 100 ° C. and a rotating disk of 2000 rpm, and particles for oral preparation having an average particle size of 91.2 m were obtained. I got

Example 3

600 g of glycerin fatty acid ester was dissolved at about 100 ° C., and 100 g of a methacrylic acid copolymer L D 100 g ground to a particle diameter of 20 m or less using a pin mill was dispersed therein. Further, 300 g of clarithromycin was dispersed in the mixture. This dispersion was spray-coagulated and granulated using a spray-drying device under the conditions of an inlet temperature of 100 and a rotating disk of 2000 rpm to obtain particles for oral preparation having an average particle size of 88.3 m. Was.

Example 4

500 g of glycerin fatty acid ester was dissolved at about 100, and 100 g of carboxymethylethylcellulose was dispersed and dissolved therein. To the mixture, 100 g of hardened oil dissolved in about 120 was separately added, and then 300 g of clarithromycin was added and dispersed. This dispersion was spray-coagulated and granulated using a spray-drying device under the conditions of an inlet temperature of 100 ° C and a rotating disk of 2000 rpm, and was used for oral preparations having an average particle size of 90.4 m. Particles were obtained.

Comparative Example 1

Dissolve 600 g of glycerin fatty acid ester at about 100 ° C, and add Eudragit E 100 g was dispersed and dissolved. 300 g of clarithromycin was further dispersed in the mixture. This dispersion was spray-coagulated and granulated using a spray-drying device under the conditions of an inlet temperature of 80 ° C and a rotating disk of 2000 rpm to obtain particles for oral preparation having an average particle size of 82.5 m. Obtained.

Test example 1

Approximately 33 mg of particles for oral preparation manufactured in Examples and Comparative Examples was precisely weighed and suspended in about 5 ml of orange juice for 10 healthy adults for about 10 seconds. After that, the suspension was spit out, and the oral cavity was thoroughly rinsed with purified water. The unpleasant taste felt at that time was evaluated based on the following five grades, and the results of the average numerical values of 10 persons are shown in Table 1.

0: no unpleasant taste is felt, 1; unpleasant taste is noticed, 2; a little unpleasant taste is felt, 3; unpleasant taste is felt, 4; 5; unpleasant taste and unbearable

Test example 2

Approximately 33 mg of the particles for oral preparation produced in Examples and Comparative Examples were precisely weighed and suspended in about 5 ml of orange juice. 30 minutes after the suspension, 10 healthy adults were put into the oral cavity and the time until they felt bitter was measured with a stopwatch. Table 1 also shows the results of the average values of the 10 persons.

As is clear from the table, it was confirmed that all of the oral preparations of the present invention had a high masking effect. Furthermore, it is more effective to use an enteric base which completely dissolves the carrier for spray coagulation and granulation, because the enteric base can be more uniformly dispersed when the matrix solidifies. Can be

Test example 1 Test example 2

Example 1 1.7 19 seconds

Example 2 1.18 15 seconds

Example 3 2. 4 11 seconds

Example 4 1-1 28 seconds

Comparative Example 1 4.4 2 seconds Example 5

650 g of stearyl alcohol was dissolved at about 90 ° C., and 50 g of hydroxypropylmethylcellulose acetate succinate was dispersed and dissolved therein. Further, 300 g of clarithromycin was dispersed in the mixture. This dispersion was spray-coagulated and granulated using a spray-drying device under the conditions of an inlet temperature of 90 ° C. and a rotating disk of 1,000,000 rpm to obtain particles for oral preparation.

Example 6

300 g of glycerin fatty acid ester was dissolved at about 120 ° C., and 80 g of hydroxypropylmethylcellulose acetate succinate was dispersed and dissolved therein. Further, 320 g of hardened oil dissolved at about 120 ° C. was added to the mixture, and 300 g of clarithromycin was dispersed. This dispersion was spray-coagulated and granulated using a spray-dry apparatus under the conditions of an inlet temperature of 120 and a rotating disk of 12,000 rpm to obtain particles for oral preparation.

Example 7

Glycerin fatty acid ester (500 g) was dissolved at about 100 ° C., and hydroxypropylmethylcellulose phthalate (2,208,240) g and triethyl citrate (30 g) were dispersed and dissolved therein. Further, 210 g of hardened oil dissolved at about 120 ° C. was added to the mixture, and 200 g of clarithromycin was dispersed. This dispersion was spray-coagulated and granulated using a spray-drying device under the conditions of an inlet temperature of 120 ° C. and a rotating disk of 1500 rpm, and the granules for oral preparation were prepared. Got a child.

Example 8

Glycerin fatty acid ester (650 g) was dissolved at about 100 ° C., and hydroxypropylmethylcellulose acetate succinate (70 g) and triethyl citrate (20 g) were dispersed and dissolved therein. Further, 200 g of stearic acid dissolved at about 100 ° C. was added to the mixture, and 150 g of clarithromycin and 10 g of magnesium oxide were dispersed. This dispersion was spray-coagulated and granulated using a spray drier under the conditions of an inlet temperature of 100 ° C. and a rotating disk of 8500 rpm to obtain particles for oral preparation.

Industrial applicability

ADVANTAGE OF THE INVENTION By this invention, it became possible to provide the matrix which is excellent in the masking property of the drug which shows an unpleasant taste, and has favorable bioavailability. At the same time, since the component (C) used in the present invention is an enteric polymer, it can also be expected to have the effect of transferring Clarice Mouthmycin to the intestine at a high concentration.

Further, even when the matrix of the present invention is suspended in an acidic liquid beverage and taken, it does not cause bitterness, so that it can be taken together with juices and the like, which is useful for pediatric preparations and the like.

Further, since the preparation of the present invention has excellent dissolution properties, it is also effective as a quick-acting preparation.

Claims

The scope of the claims

1. A matrix obtained by spray coagulation and granulation of the following components (A), (B) and (C).

(A) Clarithromycin

(B) glycerin fatty acid ester or stearyl alcohol

(C) One or two selected from hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethyl cellulose, methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S that's all

2. The matrix according to claim 1, wherein component (B) is contained in an amount of 0.5 to 20 times by mass the amount of clarithromycin.