JP3466921B2 - Taste masking pharmaceutical formulation - Google Patents

Description

Description: BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a pharmaceutical preparation masking an unpleasant taste, and more particularly, to a core particle containing a drug having an unpleasant taste, a low melting substance and a low melting point. The present invention relates to a taste-masking pharmaceutical preparation comprising a coated powder or a coated granule, which is coated with a coating made of a water-soluble substance having a molecular weight. An object of the present invention is to mask the unpleasant taste of a drug when taking it, excel in taking the drug, and dissolve the drug quickly in the gastrointestinal tract without depending on the acidity in the stomach to dissolve the drug. It is an object of the present invention to provide a coated powder or a coated granule which does not impair the bioavailability (bioavailability). 2. Description of the Related Art Drugs having an unpleasant taste such as bitterness are difficult to take, but in the case of tablets, bitterness can be easily shielded by coating a simple film such as a water-soluble polymer. It can also ensure rapid release elution. On the other hand, when the drug having an unpleasant taste is made into small solid particles such as granules and powders,
It is difficult to achieve both rapid release elution and bitterness masking.
In powders, granules, etc., it is common to coat a water-insoluble polymer, a gastric-soluble polymer, and a film of an enteric polymer, but in the case of a drug whose absorption site is limited to the upper gastrointestinal tract, It is necessary to rapidly elute the drug in the digestive tract, especially in the stomach, in which case the coating cannot be thickened,
The more bitter the drug, the more difficult it is to achieve both bitterness masking and immediate release. In order to release the drug quickly in the stomach, the enteric polymer coating is not preferable, and
If the administered patient is middle-aged or elderly, coating gastric-soluble polymers is likely to reduce bioavailability, because on average gastric acidity is low and pH is high. In addition, when the drug having an unpleasant taste is hardly soluble in water and the bitterness is extremely strong, it is necessary to thicken those coatings in order to achieve a sufficient bitterness masking effect, and to ensure quick release. Even in a mixed film composed of a film obtained by adding a water-soluble polymer to a water-insoluble polymer, there is a possibility that the drug is gradually released. In view of such circumstances, Japanese Patent Application Laid-Open No. 62-258327 discloses a method of masking bitterness at the time of administration and rapidly disintegrating and dissolving in the digestive tract, including a coating composition comprising a hardened oil and a water-soluble coating base. A method for producing a coated powder and a coated granule, characterized in that they are used for coating. However, since this method uses a water-soluble polymer as a water-soluble coating base, the viscosity of the coating liquid is high,
Since the solid content concentration in the coating liquid cannot be increased, the amount of the solvent used increases, and disadvantages such as a long time required for coating occur. JP-A-57-58631 discloses a coating composition comprising a polymer coating insoluble in gastric and intestinal fluids and a water-soluble polymer coating. However, this composition has problems such as poor feeling of taking, difficulty in controlling dissolution for making a quick release preparation for bitterness masking, and susceptibility to gastric acidity. JP-A-3-130214 discloses a preparation in which core particles containing a large amount of a water-swellable substance are coated with a film composed of ethylcellulose and a water-soluble substance. But,
This preparation has a poor feeling of taking and has a high viscosity due to the use of ethylcellulose and a water-soluble polymer as a water-soluble substance, so that a coating agent having a sufficient total solid concentration cannot be obtained. In addition, since elution is delayed with an increase in the amount of coating,
In order to mask bitterness and obtain quick release, there are drawbacks such as a narrow range of the optimum coating amount. JP-A-5-255075
Japanese Patent Application Laid-Open Publication No. H11-146,086 discloses a method of melting a low-melting substance by heating and dispersing a gastric-soluble polymer compound therein, and a method of melt-granulating a drug having an unpleasant taste. But,
Since this method uses a gastric-soluble polymer, it has a drawback that rapid release cannot be ensured in patients with low gastric acidity, and furthermore, if the drug is hardly soluble, elution will be delayed more and more. in this way,
Heretofore, in the screening of unpleasant tastes by powders and granules, no technology has been developed that completely satisfies all of short-term complete bitterness screening and rapid disintegration in the digestive tract, elution, and feeling of taking. Was. DISCLOSURE OF THE INVENTION [0004] The present invention masks unpleasant tastes regardless of the degree of unpleasant taste of the drug, is excellent in taking sensation, rapidly dissolves in the digestive tract, and It is an object of the present invention to provide a granular pharmaceutical composition that does not impair bioavailability. [0005] In order to achieve the above object, the present inventors have conducted various studies on coating agents suitable for coating pharmaceuticals and granules. The present inventors have found that the object can be achieved by coating drug-containing core particles with a coating base comprising a combination with a water-soluble substance, and completed the present invention. That is,
The present invention relates to core particles containing a drug having an unpleasant taste,
It is intended to provide a taste-masking pharmaceutical preparation selected from coated powders and coated granules characterized by being coated with a coating comprising a low-melting-point substance and a low-molecular-weight water-soluble substance. [0006] The pharmaceutical preparation of the present invention includes the following embodiments. (1) A coated powder or a coated granule, wherein core particles containing a drug having an unpleasant taste are coated with a coating comprising a low-melting substance and a low-molecular-weight water-soluble substance. (2) The coated powder or coated granule according to (1), wherein the core particles have a particle size of 50 to 2000 μm. (3) The coated powder or coated granule according to (2), wherein the coating component is 1 to 200% by weight based on the core particles. (4) The coated powder or coated granule according to (1), wherein the low-melting-point substance and the low-molecular-weight water-soluble substance are mixed in a weight ratio of 1: 100 to 100: 1. (5) The low-melting substance used for the film is a higher alcohol, a higher fatty acid or a glycerin ester thereof, an ester of an organic acid and a higher fatty acid glycerin ester, an oil or a fat, a wax, or a mixture thereof (1) to (4). Coated powder or coated granules. (6) The coated powder or coated granule according to (5), wherein the low-melting substance has a melting point of about 40 ° C to about 110 ° C. (7) The coated powder and coated granules according to (6), wherein the low-melting substance used for the coating is a higher fatty acid glycerin ester and / or an ester of an organic acid and a higher fatty acid glycerin ester. (8) The molecular weight of the low molecular weight water-soluble substance is from about 50 to about 10
The coated powder or the coated granule according to (1) to (6), which is 00. (9) The coated powder or coated granule according to (8), wherein the low molecular weight water-soluble substance is a saccharide, a sugar alcohol, or a mixture thereof. (10) The particle diameter of the core particles is 75 to 1400 μm,
The coating component is 5 to 100% by weight based on the core particles, and the low melting point substance and the low molecular weight water-soluble substance are in a weight ratio of 20 to 100.
The coated powder or coated granule according to (1), wherein the mixing ratio is from 100 to 20. (11) The low-melting substance has a melting point of about 40 ° C to about 110 ° C, and the low-molecular weight water-soluble substance has a molecular weight of about 50 to about 10 ° C.
(10) The coated powder and the coated granule according to (10), which are 00. (12) The melting point of the low melting point substance is about 45 ° C. to about 80 ° C., and the molecular weight of the low molecular weight water soluble substance is about 70 to about 800.
(11) The coated powder or coated granule according to (11). (13) The coating powder of (12), wherein the low-melting substance used in the coating is a higher fatty acid glycerin ester and / or an ester of an organic acid and a higher fatty acid glycerin ester, and the low molecular weight water-soluble substance is a sugar alcohol. Coated granules. (14) The coated powder or coated granule according to (1) to (13), wherein the drug having an unpleasant taste is rebamipide. [0007] The pharmaceutical preparation of the present invention has a coating of a low-melting-point substance and a low-molecular-weight water-soluble substance, which masks unpleasant taste when taken without impairing bioavailability, has an excellent feeling on taking, and has a gastric acidity in the digestive tract. It elutes the drug quickly without any effect. The core particles to be coated by the method of the present invention are substances commonly used in the manufacture of solid preparations, such as crystalline cellulose, potato starch, dextrin, corn starch, lactose, sucrose, mannitol, talc, and calcium carbonate. Agents, magnesium stearate, calcium stearate, lubricants such as aluminum stearate, sodium carboxymethyl starch, sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, hydroxypropyl starch, potato starch Disintegrants such as gum arabic, hydroxypropylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, binders such as gelatin, sodium lauryl sulfate Surfactants such as polysorbate 80, cetyl alcohol,
Esters of higher alcohols such as stearyl alcohol, higher fatty acids such as myristic acid, palmitic acid, stearic acid and behenic acid, or glycerin esters thereof, and organic acids such as acetic acid, citric acid and succinic acid with glycerin mono- or di-higher fatty acid esters. Oils such as hardened soybean oil, hardened castor oil, mocro, hardened tallow, carnauba wax,
It can be produced from waxes such as beeswax, higher hydrocarbons such as paraffin, ceresin, and microcrystalline wax, or mixtures thereof, but is not limited thereto.
m, preferably in the range of 75 to 1400 μm. If the core particles have an appropriate size, they may be crystals of the drug itself. In the case of a preparation containing a drug having a strong unpleasant taste such as rebamipide and / or a poorly soluble drug, sodium carboxymethyl starch, sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose, croscarme It is preferable to add a water-swellable disintegrant, such as loin sodium, hydroxypropyl starch and potato starch. More specifically, core particles suitable for the present invention include excipients such as crystalline cellulose, dextrin, corn starch and lactose, water-swellable disintegrants such as sodium carboxymethyl starch and croscarmellose sodium, polysorbate 80 and the like. Can be produced by mixing with a surfactant or the like. The method for producing core particles is a method known per se, for example, extrusion granulation, pulverization granulation, fluidized bed granulation, tumbling granulation, high speed stirring granulation, spray cooling with a low melting point substance, melt granulation method. However, in order to provide a more uniform coating, it is preferable that the particle diameter of the core particles is as uniform as possible and the particle surface is smooth. More specific preferred methods for producing core particles include the above-mentioned excipients such as crystalline cellulose, dextrin, corn starch, lactose, water-swellable disintegrants such as sodium carboxymethyl starch and croscarmellose, and interfaces such as polysorbate 80. This is a method in which a composition comprising an active agent and the like and a drug to be masked is kneaded with water and / or alcohol, and then extruded and granulated. The low-melting substances used in the present invention include, for example, higher alcohols such as cetyl alcohol and stearyl alcohol, higher fatty acids such as myristic acid, palmitic acid, stearic acid and behenic acid, and glycerin esters, acetic acid and citric acid thereof. , Esters of organic acids such as succinic acid and glycerin mono- or di-higher fatty acid esters, oils and fats such as hardened soybean oil, hardened castor oil, mocro, hardened tallow, waxes such as carnauba wax, beeswax, paraffin, ceresin, microcrystalline Higher hydrocarbons such as waxes, and mixtures thereof are mentioned. More preferred low-melting substances include myristic acid,
Glycerin esters of higher fatty acids such as palmitic acid, stearic acid and behenic acid, and esters of organic acids such as acetic acid, citric acid and succinic acid with glycerin mono- or di-higher fatty acid esters are exemplified. The low melting point material has a melting point of about 40 ° C to about 110 ° C, preferably about 45 ° C to about 100 ° C.
° C, more preferably from about 45 ° C to about 80 ° C. As the low molecular weight water-soluble substance used in the present invention, sugars such as sucrose and fructose, sugar alcohols such as mannitol, sorbitol and xylitol, and mixtures thereof are used. More preferred low molecular weight water-soluble substances include mannitol, sorbitol,
Sugar alcohols such as xylitol; The molecular weight of the low molecular weight water soluble material is from about 50 to about 1000, preferably from about 60 to about 900, more preferably from about 70 to about 800. The solubility of the low molecular weight water-soluble substance is from about 0.01 g / ml to about 2 g / ml. The low-melting substance and the low-molecular-weight water-soluble substance are mixed at a weight ratio of 1: 100 to 100: 1, preferably 10: 1.
Pairs 100 to 100: 10, more preferably 20: 100
1 to 70%, preferably 5 to 60% as a solid part in an organic solvent or a mixed solvent of an organic solvent and water in a ratio of 100 to 20.
The core particles are dissolved and dispersed at a concentration of% by weight, and coated while flowing the core particles. The coating solution may be dissolved by heating if necessary. As the organic solvent, methanol, ethanol, isopropanol, butanol, diethyl ether, dichloromethane, dichloroethane, chloroform, acetone or the like is used, and it can be appropriately selected depending on the type of the low-melting substance used. Alternatively, a low-melting substance and a water-soluble substance may be directly heated and melted without using an organic solvent. Further, in order to control the dissolution, a water-repellent lubricant such as magnesium stearate, calcium stearate, aluminum stearate or the like can be incorporated in the coating material. As the method of flowing the core particles in the present invention, a fluidized bed, centrifugal flow, sugar coating pan, aeration type coating pan, vacuum type coating pan, high-speed stirring or a combination thereof is used. Now, a device suitable for a manufacturing method or the like is selected. In the present invention, the amount of the coating on the core particles is not particularly limited. However, it is desirable that the amount of the coating be suitable to shield the unpleasant taste of the drug and to ensure quick elution in the digestive tract, and the amount is the degree of unpleasant taste, the size, shape, and smoothness of the core particles. Although it depends on the degree, the coating component is preferably 1 to 200% by weight, more preferably 1 to 100% by weight, more preferably 5 to 10% by weight based on the core particles.
0% by weight is more preferred. As the drug in the present invention, various drugs can be applied regardless of the degree of discomfort, and examples thereof include antibiotics, antibacterial drugs, antipyretic analgesics, antitussive expectorants, antihistamines, and peptic ulcer drugs. Can be Since the formulation of the present invention has an excellent unpleasant taste shielding effect, it can be advantageously applied to drugs having a strong unpleasant taste. Further, since the drug elutes quickly in the digestive tract, it can be advantageously applied to poorly soluble drugs. It can be suitably applied to drugs having a strong unpleasant taste and poor solubility, and more specifically, to drugs such as rebamipide. [0014] The pharmaceutical preparation of the present invention masks the unpleasant taste of the drug when taken, is excellent in taking feeling, and elutes the drug quickly in the digestive tract without depending on the acidity in the stomach.
Does not reduce bioavailability. Further, since the amount of the organic solvent used is small and the total solid content concentration in the coating solution can be increased, a sufficient amount of coating can be performed in a short time. Next, the present invention will be described with reference to examples and reference examples, but the present invention is not limited to these examples. still,
The following commercially available products were used as base materials in Examples and Reference Examples. Glycerin citrate fatty acid ester (Sunsoft No.621
G / Taiyo Chemical) Glycerin monostearate (Poem S-100 /
RIKEN Vitamin) Glycerin behenate (Sunsoft No.1030 /
Taiyo Kagaku) D-mannitol (Kyowa Hakko) Dextrin (Amicol No. 10 / Nisseki Chemical Industry) Corn starch (Nihon Shokuhin Cornstarch XX16 / Nippon Shokuhin Kako) Polysorbate 80 (TO-10M / Nikko Chemicals) Reference Example 1 Rebamipide 920 g, dextrin 315 g and corn starch 2650 g were mixed in ethanol 5 with a high-speed stirring granulator.
0 g, 750 g of purified water and 252 of polysorbate 80
g of the mixture, and kneaded with a binding liquid obtained by mixing with a binder having a pore diameter of 0.6 mmφ to form a noodle-like shape using an extruder granulator Dome Gran (DG-L1 / Fuji Paudal). After being subjected to malm treatment with a riser (QJ-400 / Fuji Paudal), it was fluid-dried to obtain spherical or bale-shaped core granules. Reference Example 2 920 g of rebamipide, 630 g of dextrin, 460 g of corn starch, 126 g of crystalline cellulose, 165 lactose
0 g, sodium carboxymethyl starch 135 g,
81 g of croscarmellose sodium was kneaded by a high-speed stirring granulator with a binding solution obtained by mixing 95 g of ethanol, 830 g of purified water and 126 g of polysorbate 80, and the mixture was mixed with 0.1 g.
Extruded granulator Domegran (DG-L1 / Fuji Paudal) equipped with a screen having a hole diameter of 6 mmφ to make a noodle-like shape, and the extruded noodle-like substance is subjected to Malmé treatment with a marmizer (QJ-400 / Fuji Paudal). After that, it was fluid-dried to obtain bale-shaped core granules. EXAMPLE 1 100 g of glycerin citrate fatty acid ester and 100 g of D-mannitol were added to a mixture of 240 g of ethanol and 60 g of purified water, and the mixture was stirred for about 7 hours using a heating device.
The mixture was heated to 0 ° C. and dissolved and dispersed to obtain a coating liquid. 600 g of the core granules obtained in Reference Example 1 were charged into a fluidized bed granulator, and 200 g of the coating liquid was sprayed while flowing at an air supply temperature of 55 ° C. to obtain coated granules. Test Example 1 The coated granules obtained in Example 1 were subjected to a panel test. That is, about 0.5 g of the preparation is given to 10 healthy persons.
Was taken and a taste test was performed, and none of the panelists felt bitterness. On the other hand, when a taste test was similarly performed on the core granules of Reference Example 1, all panelists complained of the bitterness of the active ingredient rebamipide. Test Example 2 Regarding the core granules of Reference Example 1 and the coated granules of Example 1,
A drug dissolution test was performed according to the 13th revised Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method). As a test solution,
That is, a disodium hydrogen phosphate / citrate buffer having a pH of 5.4 described in the pharmacopoeia (1.05 g of citric acid and 2.92 g of disodium hydrogen phosphate dodecahydrate in water 20) was used.
0 mL and adjust to pH 5.4 with phosphoric acid or sodium hydroxide TS if necessary), add 0.46 g of nuclear granules to be tested and 0.5 g of coated granules to 900 ml of the test solution Paddle the mixture,
The mixture was eluted with stirring at 37 ° C. at 100 rpm. Drug eluted by sampling the test solution every 2 minutes (Rebamipide)
Was measured, and the dissolution rate (%) was calculated from the charged content. Table 1 shows the results. [Table 1] As is clear from the data in Table 1 above, the coated granules of Example 1 showed that the elution of the drug was suppressed at the beginning, the bitterness at the time of ingestion was masked, and thereafter the elution was rapid. It is shown that it is secured. In contrast, a large amount of drug was eluted from the initial stage in the uncoated nuclear granules, indicating that no masking was performed. Examples 2 to 4 The core granules obtained in Reference Example 1 were coated with various coating bases shown in Table 2 by the same operation to obtain coated granules. [Table 2] Test Example 3 The coated granules of Examples 2 to 4 above were tested in Test Example 1.
A taste test was conducted by 10 taste panelists in the same manner as in the above. As a result, no bitterness was felt for any of the coated granules, indicating that the bitterness at the time of administration was sufficiently masked. Examples 5 to 8 The coated granules of the present invention were prepared in the same manner as in Examples 1 to 4, except that 600 g of the core granules obtained in Reference Example 1 was changed to 600 g of the core granules obtained in Reference Example 2. I got

Continuation of the front page (72) Inventor Toshio Nakamura 2-115, Shinkirai, Kitajima-cho, Itano-gun, Tokushima Prefecture (72) Inventor Masaaki Kotomi 3-19-1-603, Nakasu-cho, Tokushima-shi, Tokushima Prefecture (56) References JP-A-4-217913 (JP, A) JP-A-2-240016 (JP, A) JP-A-5-310599 (JP, A) JP-A-6-116138 (JP, A) JP-A-9-52850 (JP, A) JP-A-11-35486 (JP, A) WO 97/018798 (WO, A1) (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 9/14 A61K 9/16 A61K 47/10 A61K 47/14 A61K 31/4704 CAPLUS (STN)

Claims (1)

(57) [Claim 1] A coated powder characterized by comprising core particles containing rebamipide having an unpleasant taste coated with a coating made of a fatty acid ester of glycerin citrate and mannitol. A taste-masking pharmaceutical preparation comprising coated granules.