JPH0296516A - Granule and production thereof - Google Patents

Abstract

PURPOSE:To obtain rapidly soluble granule for oral administration having several properties, requiring a small amount of organic solvent used, having a concealed unpleasant taste, containing a powdery drug of unpleasant taste, lipidal substance having a specific melting point, slightly water-soluble polymer substance and substance swelling in water. CONSTITUTION:Mixed powder at least containing <=40wt.% powdery drug of unpleasant taste such as pyridone carboxylic acid-based antimicrobial agent or antiepiletic, 2-40wt.% lipidal substance such as sucrose fatty acid ester having >=30 deg.C melting point, 3-20wt.% slightly water-soluble polymer such as methyl acrylate-methacrylic acid chloride trimethylammonium copolymer and 20-55wt.% substance swelling in water, such as hydroxypropyl cellulose having low substitution degree is blended with an organic solvent such as ethanol, granulated, the molecular weight solvent is removed and then the granules are heat-treated to efficiently give the aimed granule. The granule has properties wherein matrix is formed as a whole and the lipidal substance exists in a homogeneous and almost continuous state in the granule.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to fast-dissolving oral granules with masked unpleasant taste.

PRIOR ART AND PROBLEMS TO BE SOLVED Various methods have been reported for formulating oral drugs with unpleasant taste into easy-to-take forms. For example, a method for manufacturing solid pharmaceuticals in which a slurry containing a film-forming polymer compound and a drug is sprayed onto a carrier (Japanese Unexamined Patent Publication No. 51-797g0), a drug is dispersed in a solution in which a coating material is dissolved at a high C degree; A method for producing an oral pharmaceutical composition in which a powdering agent is added to powder (Japanese Patent Publication No. 58-401), a bitter masking substance is dissolved in a non-flammable chlorinated organic solvent at a high concentration, a drug is added thereto, and the mixture is stirred. A method for manufacturing oral preparations (Japanese Patent Publication No. 58-40
529), Solid drug coating method in which drugs are coated with a slurry obtained by dispersing powder of low-substituted cellulose ethers in a solution of cellulose ether (Special [1, 1973-
13117g5), a coating method in which a drug is dissolved in a W-containing solvent in which a styrene-maleic acid copolymer and a wall material are dissolved or dispersed, and then this is spray-dried (Japanese Patent Laid-Open No. 4
9-132210), a method in which a melt of a waxy substance in which drugs and substances that swell but do not dissolve in water are dispersed is ejected from a nozzle and cooled and solidified (Special Publication Sho GO-29082
), etc. have been reported. These methods mask unpleasant tastes of drugs, such as bitterness.

All of the above methods have in common that the unpleasant taste masking substance is used in the form of a solution, dispersion or melt. Since substances that mask unpleasant tastes are generally polymer film-forming substances, the use of solutions, dispersions, or melts thereof causes various problems. For example, clogging of equipment such as sprayer, equipment used, etc.
Problems include poor work efficiency due to difficulty in cleaning instruments and a significant increase in the amount of solvent used. The use of large amounts of organic solvents is not at all preferable from the viewpoint of pollution prevention or fire prevention.

The present inventors previously discovered a method for solving these problems all at once by mixing a powdered drug with an unpleasant taste with a powdered substance that can mask the unpleasant taste, and adding the powdered substance to the mixture. A method for manufacturing an oral solid preparation with masked unpleasant taste was developed, which comprises adding a soluble organic solvent and removing the organic solvent after granulation (Japanese Patent Laid-Open No. 150220/1989).

This time, the present inventors have discovered the contradictory aspects of masking unpleasant taste and rapid elution of the drug! The present invention was completed after conducting various studies to solve the problem at the same time and more advantageously than the method disclosed in Japanese Patent Application Laid-Open No. 03-150220.

Components of the present invention The present invention is a powdered drug with an unpleasant taste that is less than 40 tnffi% (hereinafter simply referred to as %) and a lipid substance with a melting point of 30°C or more*
2-40%, a water-soluble polymeric substance 3-20%, and a water-swellable substance 20-559 (at least), and has various unpleasant tastes listed in (1) to (0) below.Fast-dissolving oral use. This invention relates to granules and their manufacturing method.

(2) The granules of the present invention form a matrix as a whole.

(2) The lipid substance in the granules of the present invention exists in a uniform and substantially continuous state within the particles.

■ The apparent specific gravity of the granules of the present invention is about 0.5 to about 0.
．． It is within the range of 1 g/ml.

■ The granules of the present invention! Substantially no fine powder passes through a 50 mesh sieve.

■ The particle size of the granules of the present invention is mainly about 100 to about 10
00 μm, (1) A dissolution test is conducted on the granules of the present invention in an amount equivalent to 50 mg of drug using the paddle method (test solution: 900 ml of water, rotation speed: 50 rpm, 1 temperature: 37°C). At this time, more than 85% of the drug is eluted in 15 minutes.

Examples of powdered drugs with unpleasant tastes include 5-
Amino-1-cyclopropyl-6,8-difluoro-7
-(3,5-dimethyl-1-piperazinyl)-1,4-
dihydro-4-oxoquinoline-3-carboxylic acid (hereinafter referred to as pyridonecarboxylic ff1A) or its hydrate, enoxacin, ofloxacin, pefloxacin,
Examples include pyridonecarboxylic acid antibacterial agents such as Sibroa 0xasif, antiepileptic agents such as zonisamide, macrolide antibiotics such as erythromycin, and β-lactam antibiotics such as Beniciri/ and Cef 10 Subori/v#4. It will be done. As the lipid substance, any substance with a melting point of 30°C or higher can be used, such as lyoto sugar ester S.
Silosaccharide fatty acid esters commercially available under the trade names of -370 and S-170, higher fatty acids such as Steary 7W1, higher alcohols such as stearyl alcohol, waxes such as Sarashimiro, and mixtures thereof are used.

Also, water! As the 1i8a polymer substance, any substance can be used as long as it is soluble in a1M medium such as ethanol, inpropar/-al, dichloromethano, etc. For example, methyl methacrylate commercially available under the trade name Eudragifu) R3 or RL. Specific examples thereof include trimethylammonium methacrylate copolymer, ethylcellulose, and hydroxypropyl methylcellulose phthalate commercially available under the trade names of HP-55. Furthermore, examples of water-swellable substances include low-substituted hydroxypropylcellulose, abbreviated as L-111'C, and EC.
Examples include carboxymethylcellulose calcium, which is commercially available under the trade name G505, and polyvinylpolypyrrolidone, which is commercially available under the trade name Polyplaston XL.

Each ingredient contains 4 unpleasant-tasting powdered drugs per final granule.
0% or less, preferably 25% or less, lipid substances 2-4
0%, preferably 5-20%, 3-20%, preferably 5-15% of water lIl-soluble polymeric substances and 20-55%, preferably 30-50% of water-swellable substances.

The granules of the present invention are prepared by adding a solvent such as ethanol, isopropanol, or dichloromethane to a mixed powder consisting of a powdered drug having an unpleasant taste, a lipid substance, a water-Ni-soluble polymer substance, and a water-swellable substance. After granulation, the organic solvent is removed and then heat treatment is performed to efficiently produce the product. Mixing of each powder component, addition of the organic solvent, granulation, and removal of the organic solvent can be carried out according to conventional methods. For example, A W-containing solvent is added to the powder mixture, kneaded, extruded, granulated, dried to remove the organic solvent, or each powder component is placed in a high-speed stirrer and the organic solvent is removed while stirring. This can be easily carried out by spraying, further stirring and granulation, and then drying to remove the solvent.The method using a high-speed stirrer allows mixing, addition of a vA solvent, and granulation to be carried out all at once. Moreover, this is the most preferred method because it allows the organic solvent to be sprayed while clearly observing the degree of granulation.In addition, binders such as hydroxypropyl cellulose and methyl cellulose, and excipients such as lactose may be further mixed as desired. You may perform an operation.

Thus, the granules obtained in the intermediate step of the method of the present invention (hereinafter referred to as
- Sometimes referred to as secondary granules), the poorly water-soluble polymeric substance as a component is once dissolved in an aqueous solvent, and the other components are embedded in a matrix formed by removing the organic solvent. In addition, lipid substances are hardly affected by organic solvents;
It is estimated that it is dispersed and embedded in the matrix.

Such secondary granules are then subjected to heat treatment. This step is carried out at 30° C. or higher for 0.5 to 12 hours. Heating may be column drying (1 to 12 hours), but heating with a fluidized bed dryer (0.5 to 3 hours) is preferred. By this treatment, the lipidic substances dispersed in the matrix are melted and, after cooling, solidify in a uniform and substantially continuous surface.

Therefore, the heating temperature varies depending on the melting point of the lipid substance.

As the lipidic substance, preferably used is one that melts at 40 to 90°C, particularly preferably 60 to 75°C, and examples of such particularly preferred lipidic substances include I(L 1
Examples include sid sugar fatty acid esters in which 1 is 3 or less. Apparent specific gravity is approximately 0.45 to approximately 0.55g due to heat treatment
/m1 becomes about 0.5 to about 0.7g/m#, and 1
The fine powder that passes through the 50-mesh sieve is fused with or attached to larger particles, and has a sharp particle size distribution, with the particle size mainly in the range of about 100 to about 1000 μm, and the surface of the particles is smooth and has no pores. It becomes less.

The granules of the present invention can be efficiently produced by cooling after heating. During or before or after cooling, 0
．． Addition of 1 to 5%, preferably about 1%, of magnesium stearate improves flowability and prevents static electricity, and may also enhance masking of unpleasant tastes and improve dissolution rate.

Effects of the present invention The method of the present invention requires only a very small amount of Ia solvent, and has a good yield (95% or more) in syringe. The distribution is sharp and usually does not require sizing.

The granules of the present invention have masked unpleasant tastes.

The intensity of the unpleasant taste caused by a drug depends on the initial dissolution rate of the drug during the day (in saliva), and when the initial dissolution rate is low, the unpleasant taste is weak.

In the following, an amount equivalent to 50 mg of the granules of the present invention as a drug was placed in a syringe, 10 ml of water was added, and the injection tube was rotated up and down for 30 seconds with a membrane filter (pore size: 0.45 μm). Drug concentration in the filtrate obtained by filtration [D 30sec; mg/ml
] This is one measure of the intensity of unpleasant taste.

As a drug with an unpleasant taste, when a pyridonecarboxylic acid antibacterial agent is prepared according to the method of the present invention, the D3Osec value is 0.
．． 15mg/mj or less, and 0.1mg/mj when prepared under favorable conditions! The following is true.

In this way, the granules of the present invention have a low solubility in the initial stage and mask unpleasant taste, but thereafter the drug is rapidly eluted. Dissolution test by method (test solution; 90
0ml water, rotation speed; 50rf) m1 temperature = 37℃
), the drug dissolution rate (D l
5m1n ) is 85% or more, and the dissolution rate of 4J in 30 minutes (D 30m1n ) is 90% or more.

Specific Examples Next, the present invention will be explained in more detail with reference to Examples and Comparative Examples.

(Left below) Example prescription pyrido 7 carbon i! IA 20
% 1000 g sucrose fatty acid ester
15% 750g (Ryoto Sugar Ester 170) Methyl methacrylate - Methacrylic M
7.5% 375g Trimethylammonium chloride (Eudragifud RL) Low degree of substitution Upper droxypropylcellulose 45%
225Off lactose 12.5% 625g
(Dish) -Next granule (granulator n) Pyridone carbo 7mA was crushed in advance with a crusher (Valverizer Nihon Riki Wamicron), and each component other than magnesium stearate was extracted with high i! l! fR stirrer (vertical granulator-FM-VG-25 type; Fuji Sangyo ■
) and mix for 1 minute. Pour 1250g (25%) of 89.5% ethanol into this through the funnel and
Stone making for 5 minutes. Place the granulated product in a box-type blow dryer at 40°C.
Dry for 12 hours. 3 at Rai/Rotor (Kan Iron Works)
2 meshes to obtain 4980 g of secondary granules.

■ Secondary granules (heating process) The primary granules are dried using a fluidized bed dryer (Flow Coater FLO-5).
The mixture was poured into a mold made by Tomo Okawa and allowed to flow for 1 hour at a temperature of 00 to 70°C to obtain 4970 g of secondary granules.

(3) Tertiary granules (stearin ff1Mgm processing process)
V=Kisa-VMloM:! Secondary granules and magnesium stearate were added to (Fuji Paudal ■) and mixed at 50 rpm for 30 minutes to obtain 5000 g of tertiary granules.

The sex of each granule is as follows.

(Left below) indicates the time (in seconds) until bitterness is felt when one tablet (250 mg) is taken into the mouth.

As shown in Table 1, the granules of the present invention (secondary and tertiary granules) have a D 30sec value (dissolution amount after 30 seconds as an index of bitterness) and a dissolution rate after 15 minutes and 30 minutes (
D 15m1n and D30min) are excellent.

In addition, 9% of the fine particles passing through 80 meshes of the secondary granules
However, the secondary granules of the present invention do not contain it at all.

Example 2 Granules of zonisamide having the following formulation were prepared in the same manner as in Example 1.

Prescription Zodismid Sucrose Fatty Acid Ester (Ryoto Sugar Ester S-170) Methyl methacrylate - Methacrylate Trimethylammonium Chloride (Oi V Lagibuto RL) 20% 1000 g 20% Weight 000g 15% 750g Comparative Example l JP-A A dissolution test and a bitterness test were conducted on the powder prepared using ethyl cellulose that passes through a 200-mesh sieve as disclosed in Example 1 of Publication No. 150220, and the granules prepared in Example 2. I got the result.

As shown in Table 2, the granules of the present invention are
It dissolves more quickly than the powder disclosed in Japanese Patent No. 220, and has a better bitter taste masking effect.

Example 3 Granules with the following formulation (D30sec=0.
05mg/mA' 1 D15 win =93%
) 4%0g was obtained.

(Left below) Prescription pyrido/carboxylic acid A 5% 2
50g Sucrose fatty acid ester 15%
750g (Riyana-Tosu Sugar Ester S-170
) Methyl methacrylate-methacrylic a 10%
500g Trimethylammonium chloride (Eudoragift RL Low 11-hydroxypropylcellulose 45%
2250 g lactose
5% 1250g Example 4 Same as Example 1 except that Ryoto Sugar Ester S-370 was used as the 9-saccharide fatty acid ester.
D30sec =0.08 mg/ml, D15m
5010 g of granules having a sexiness of +n=%% were obtained.

Example 5 D30sec = 43 in the same manner as in Example 2 except that Eudragibut R8 was used as the methyl methacrylate-trimethylammonium methacrylate chloride copolymer.
4937 g of granules with a sexiness of μg/mjs D15min = 98% were obtained.

Example 6 Granules with the following formulation were prepared in the same manner as in Example 1, and D3
0sec=0.11m g/mes D 15
A result of sin = 98% was obtained.

Prescription pyrido/carvone 1! IA 2
0% 1000 g stearyl alcohol
15% 750g Ethyl cellulose 1115%
750ff Carboxymethylcellulose Ca
50% 2500 g (ECG505) Magnesium stearate 1% 5
0 g total 1% 5050 g A solution of 5% of this ethyl cellulose dissolved in Un consisting of toluef-ethanol (8:2) has a viscosity of 10 cps at 5°C.

Example 7 Granules with the following formulation were prepared in the same manner as in Example 1, and D3
0sec=O, 12mg/ml, D 15ml
A result of n = 95% was obtained.

(Left below) Prescription Pyridonecarvone ff1A Beeswax Hydroxyprobil Methylcellulose phthalate (I
P-55) Polyvinyl polypyrrolidone (Polyplaston XL 10) Methylcellulose 20% 1000g 5% 250g 7.5% 375g 45% 2250g 3% 150g Total 100% 5000g

Claims (5)

[Claims] (1) 40% by weight of powdered drug with unpleasant taste (hereinafter simply %)
2 to 40 lipid substances with a melting point of 30°C or higher
%, contains at least 3 to 20% of a poorly water-soluble polymeric substance and 20 to 55% of a water-swellable substance, and contains the following [1] to [
6] Fast-dissolving oral granules that mask unpleasant taste and have the following properties: [1] The granules as a whole form a matrix; [2] The lipid substance in the granules is exist in a uniform and almost continuous state within the particles; [3] the apparent specific gravity of the granules is about 0.5 to about 0.7 g;
/ml, [4] The granules do not substantially contain fine powder that passes through a 150 mesh sieve, [5] The particle size of the granules is mainly about 100 to about 1000.
[6] The granules in an amount equivalent to 50 mg of the drug were tested using the paddle method (test solution: 900 ml of water, rotation speed: 50 rpm).
)Temperature: 37°C) When performing a dissolution test, more than 85% of the drug is eluted in 15 minutes. (2) the powdered drug with an unpleasant taste is a pyridonecarboxylic acid-based antibacterial agent or an antiepileptic agent; the lipid substance is a sucrose fatty acid ester, a higher fatty acid, hydrogenated castor oil, a higher alcohol and/or a wax; The poorly water-soluble polymeric substance is ethyl methacrylate-trimethylammonium methacrylate chloride copolymer, ethylcellulose and/or hydroxypropylmethylcellulose phthalate, and the water-swellable substance is low-substituted hydroxypropylcellulose, carboxymethylcellulose calcium and/or The granule according to claim 1, which is polyvinylpolypyrrolidone. (3) Powdered drug with unpleasant taste is 5-amino-1-cyclopropyl-6,8-difluoro-7-(3,5-dimethyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline -3-carboxylic acid or its hydrate, enoxacin or zonisamide, the lipid substance is sucrose fatty acid ester, and the poorly water-soluble polymer substance is ethyl methacrylate-trimethylammonium methacrylate copolymer. The granules according to claim 1 or 2, wherein the water-swellable substance is low-substituted hydroxypropyl cellulose. (4) A mixture consisting of at least 40% of a powdered drug with an unpleasant taste, 2 to 40% of a lipid substance with a melting point of 30°C or higher, 3 to 20% of a poorly water-soluble polymeric substance, and 20 to 55% of a water-swellable substance. Claim 1, characterized in that an organic solvent is added to the powder, the organic solvent is removed after granulation, and then heat treatment is performed.
Method for producing the granules described. (5) The manufacturing method according to claim 4, wherein the organic solvent is ethanol, isopropanol and/or dichloromethane.