JP2005060310A - Preparation for oral administration with masked unpleasant taste - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To make both of masking effects and properties for eluting a medicament coexist in a preparation for oral administration having unpleasant taste masked by coating a medicament having the taste. <P>SOLUTION: The preparation for the oral administration is obtained by coating medicament particles having the unpleasant taste and optionally mixed with a vehicle, with a mixture of a polymer soluble in the stomach with a water-insoluble polymer soluble in a solvent used for the coating of a medicinal preparation. A coating layer of the polymer soluble in the stomach may be formed in the middle. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to pharmaceutical preparations, and more particularly to oral dosage forms that mask unpleasant taste.

  In order to facilitate oral administration of drugs having an unpleasant taste, pharmaceutical techniques for masking the unpleasant taste of drugs are known. For example, JP-A-49-81526 discloses a wall material polymer selected from polyvinyl acetal diethylaminoacetate, cellulose acetate dibutylaminohydroxypropyl ether, dimethylaminoethyl methacrylate copolymer, or ethylcellulose, and a wax-like substance as an organic solvent. Dissolved or dispersed, a macrolide antibiotic is dissolved in this solution, and spray-dried to obtain a preparation with masked bitterness. This method requires a large amount of a solvent such as methylene chloride, and requires a great investment in the spray dryer apparatus and solvent recovery.

  Japanese Patent Laid-Open No. 2000-53563 uses, as a core, a spherical molded product of crystalline cellulose, optionally mixed with saccharide, and coats or molds and coats a drug having a bitter taste with a formulation aid on its surface, and a bitterness suppressing layer thereon. Disclosed is a fine granule formulation coated with ethyl cellulose containing a water-soluble plasticizer. When this preparation is administered orally, the core remains in the mouth, giving a rough feeling.

  In general, when masking a drug insoluble in saliva and water for masking unpleasant tastes such as bitterness, the masking effect and drug elution are not compatible, and both must be balanced appropriately.

  An object of the present invention is to provide a preparation for oral administration which has both a masking effect and a drug dissolution property when a drug having an unpleasant taste is coated with a masking substance.

  According to the present invention, drug particles having an unpleasant taste, optionally mixed with an excipient, are coated with a mixture of a gastric soluble polymer and a water-insoluble polymer soluble in a solvent used for pharmaceutical formulation coating. A preparation for oral administration is provided.

  In another aspect, the present invention is applicable to gastric soluble polymers and solvents used in pharmaceutical formulation coatings, which are coated with gastric soluble polymers, which have an unpleasant taste, optionally mixed with excipients. Disclosed is a preparation for oral administration which is coated with a mixture with a soluble water-insoluble polymer.

  In the present invention, the masking polymer mixture can be coated as a solution and coated as a continuous film. Since the polymer mixture contains a gastric polymer, both the masking effect of the unpleasant taste of the drug and the dissolution of the drug can be achieved. . The formulation can be manufactured by routine operations using a fluidized bed granulation coating apparatus.

  The present invention can be applied to all drugs having an unpleasant taste such as a bitter taste. The drug is used by optionally mixing with an excipient depending on its state and unit dosage. Mixing with excipients weakens the chargeability of the drug particles and facilitates coating. The term “excipient” as used herein refers to sugar, sugar alcohol, crystalline cellulose, crystalline cellulose / sodium carboxymethylcellulose, sodium carboxymethylcellulose, low-substituted hydroxypropylcellulose, corn starch, potato starch, ethyl cellulose, aminoalkyl Contains methacrylate copolymers, light anhydrous silicic acid, titanium oxide, talc and the like. Ethyl cellulose and aminoalkyl methacrylate copolymers are preferred. When mixed, the excipient is preferably used in an amount of 1 to 80% by weight, particularly 1 to 50% by weight of the drug.

  Drug particles optionally mixed with excipients are sprayed with a solution of a mixture of a gastric soluble polymer and a water-insoluble polymer soluble in a solvent used in pharmaceutical formulation coatings to form a masking layer, dry. The solvent of this polymer mixture solution is an organic solvent used for pharmaceutical preparation coating. Environmentally friendly solvents are preferred, especially ethanol and hydrous ethanol.

  Typical examples of gastric polymers are polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer (Eudragit E) and mixtures thereof.

  Examples of water-insoluble polymers that are soluble in solvents used in pharmaceutical formulation coatings are ethyl cellulose, ethyl acrylate / methyl methacrylate copolymers, and the like. Ethyl cellulose soluble in ethanol is preferred.

  The ratio of the gastric polymer to the other polymer is preferably 1: 4 to 4: 1, particularly 1: 3 to 3: 1 by weight.

  Prior to forming the masking layer, the drug particles, optionally mixed with excipients, may be intermediate coated with the gastric polymers described above.

  Coating of the drug particles, optionally mixed with excipients, with the masking layer and the intermediate coating with the gastric polymer is preferably carried out using a fluidized bed granulation coating apparatus.

  The granulated material coated with the masking layer can be orally administered as it is, but can be formulated into oral preparations such as granules, capsules, dry syrups, tablets and orally disintegrating tablets together with usual auxiliary components. The auxiliary components used are well known in the art and include, for example, disintegrants, binders, dispersants, sweeteners, lubricants, fluidizers, flavors, colorants and the like.

  The invention is illustrated by the following non-limiting examples and comparative examples. In these examples, theophylline and clarithromycin are used as drugs, but it will be apparent that the present invention can be widely applied to other drugs having an unpleasant taste.

Example 1
Ethanol was added to 250 g of theophylline and 125 g of ethyl cellulose, kneaded with a high speed mixer, and dried. The obtained granule was pulverized with a hammer mill, and 300 g of the obtained fine powder was used for coating.
In 3680 g of 95% ethanol, 60 g of ethyl cellulose and 140 g of aminoalkyl methacrylate copolymer (Eudragit E) were dissolved, and 120 g of talc was dispersed therein to prepare a coating solution.
300 g of fine powder was put into a fluidized bed granulation coating apparatus (multiplex MP-01), and the above coating solution was sprayed to obtain a granulated product. To 310 g of this granulated product, 615 g of mannitol and 50 g of crystalline cellulose / sodium carboxymethylcellulose were added and mixed uniformly, and this was granulated in a fluidized bed using an aqueous solution of 20 g of hydroxypropyl cellulose as a binder solution to obtain granules.

Example 2
300 g of clarithromycin and 60 g of aminoalkyl methacrylate copolymer (Eudragid RS) were mixed and ground with a hammer mill.
274 g of aminoalkyl methacrylate (Eudragit E) was dissolved in 2500 g of 85% ethanol, and 96 g of magnesium stearate was dispersed to prepare an intermediate coating solution.
329 g of mixed fine powder of clarithromycin and Eudragit RS was put into a fluidized bed granulation coating apparatus (multiplex MP-01), and an intermediate coating solution was sprayed to obtain an intermediate coated granulated product.
In 1200 g of 90% ethanol, 60 g of ethyl cellulose and 24 g of Eudragit E were dissolved, and 24 g of magnesium stearate was dispersed to prepare a final coating solution.
296 g of the intermediate coated granulated product was put into multiplex MP-01, and granulated by spraying the final coating solution. 186.75 g of mannitol, 17.5 g of corn starch, 7 g of sodium carboxymethylcellulose, 7 g of magnesium oxide, and 1.75 g of saccharin sodium were uniformly mixed with 123 g of the obtained granulated product, and a fluidized bed was prepared using an aqueous solution of 7 g of hydropropylcellulose as a binding solution. Granules were obtained.

Example 3
300 g of clarithromycin and 60 g of Eudragit RS were mixed and ground with a hammer mill to obtain a fine powder.
Eudragit E 274 g was dissolved in 2500 g of 85% ethanol, and 96 g of magnesium stearate was dispersed to prepare an intermediate coating solution.
The fine powder 329g was put into multiplex MP-01, and the intermediate coating liquid was sprayed to obtain an intermediate coated granulated product.
The final coating solution was prepared by dissolving 75 g of ethyl cellulose and 37.5 g of Eudragit E in 1500 g of 90% ethanol and dispersing 37.5 g of magnesium stearate.
300 g of the intermediate coated granule was put into multiplex MP-01, the final coating solution was sprayed, and the masking layer was coated.
172.75 g of mannitol, 17.5 g of corn starch, 7 g of sodium carboxymethylcellulose, 7 g of magnesium oxide, 1.75 g of saccharin sodium were uniformly mixed with 132 g of the obtained granulated product, and an aqueous solution of 7 g of hydroxypropylcellulose was used as the granulating liquid. And fluidized bed granulation to obtain granules.

Comparative Example 1
Ethanol was added to 300 g of clarithromycin and 60 g of ethyl cellulose, kneaded with a high speed mixer, dried and pulverized with a hammer mill to obtain a fine powder.
A solution obtained by dissolving 165 g of Eudragit E in 1435 g of 80% ethanol and dispersing 49.5 g of magnesium stearate in 300 g of the above fine powder was fluid bed coated, and 1161.5 g of the resulting granulated product was subjected to 191.5 g of mannitol, 17.5 g of crystalline cellulose / sodium carboxymethylcellulose, 11 g of magnesium oxide and 7 g of aspartame were uniformly mixed, and fluidized-bed granulated using an aqueous solution of 7 g of hydroxypropylcellulose to obtain granules.

Comparative Example 2
250 g of the intermediate coated granulated product of Example 3 was fluid bed coated with a final coating solution in which 35 g of talc was dispersed in a solution of 50 g of ethyl cellulose in 1000 g of 80% ethanol to obtain a granulated product. To this granulated product 128g, mannitol 181.75g, carboxymethylcellulose sodium 7g, magnesium oxide 7g, saccharin sodium 1.75g were mixed together, and fluidized bed granulated using an aqueous solution of hydroxypropylcellulose 7g, granule Got.

Dissolution test The granules of Examples 1, 2, 3 and Comparative Example 3 were subjected to a dissolution test according to the 13th revised JP Dissolution Test Method. 1 g of each specimen was taken and the granules of Example 1 were tested at pH 1.2, pH 6.8 and water. The results are shown in the graph of FIG.
The granules of Examples 2 and 3 and Comparative Example 2 were tested on the acidic side (pH 5.0) and the neutral side (pH 6.8). The results are shown in the graphs of FIGS.

Sensory test A bitter sensory test was performed on the granules of Examples 2 and 3 and Comparative Examples 1 and 2.
1 g of each specimen was suspended in 25 ml of water, and this was taken by 7 healthy adults, and the degree of bitterness was evaluated by a score according to the evaluation criteria shown in Table 1. In addition, the same test was performed on the suspension of each specimen that was allowed to stand at 4 ° C. for 1 day. The results immediately after preparation are shown in Table 2, and the results after standing at 4 ° C. for 1 day are shown in Table 3.

  Next, in order to compare the bitterness of the granule of Example 3 and the commercially available clarithromycin preparation, a solution obtained by suspending 1 g of each sample in 25 ml of a commercially available sports drink (Pocaris wet manufactured by Otsuka Pharmaceutical Co., Ltd.) It was allowed to be taken by a person, and scored as before, after 1 minute, 3 minutes, and 5 minutes. However, if the subject was determined to be bitter and unable to drink, the study was stopped at that stage. The results are shown in Table 4.

Discussion From the results of the dissolution test and the bitter evaluation test, it is clear that the preparation of the present invention satisfies both the drug dissolution rate and the bitterness masking effect.

  The present invention is useful in the pharmaceutical industry because it is easy to take a drug having an unpleasant taste and forms a dosage form.

The elution graph of the granule of Example 1. The elution graph of the granule of Examples 2, 3 and Comparative Example 2 on the acidic side. The elution graph of the granules of Examples 2 and 3 and Comparative Example 2 on the neutral side.

Claims (5)

  For oral administration, drug particles with an unpleasant taste, optionally mixed with excipients, are coated with a mixture of a gastric soluble polymer and a water-insoluble polymer that is soluble in a solvent used in pharmaceutical formulation coating Formulation.   A drug particle having an unpleasant taste, optionally mixed with an excipient, is coated with a gastric polymer, and a mixture of the gastric polymer and a water-insoluble polymer soluble in a solvent used for pharmaceutical preparation coating Preparation for oral administration coated with   The formulation according to claim 1 or 2, wherein the gastric polymer is a polyvinyl acetal diethylaminoacetate or aminoalkyl methacrylate copolymer.   The formulation according to claim 1 or 2, wherein the water-insoluble polymer soluble in the solvent used in the pharmaceutical formulation coating is ethyl cellulose or ethyl acrylate / methyl methacrylate copolymer.   The preparation according to any one of claims 1 to 4, wherein the mixing ratio by weight of the gastric soluble polymer and the water-insoluble polymer soluble in the solvent used for the pharmaceutical preparation coating is from 1: 4 to 4: 1.

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