JPH0776517A - Composition for medicine - Google Patents

Abstract

PURPOSE:To obtain a composition for medicine useful for masking of a taste for many hours.long period of time of several hours to several days after suspen sion in water, having excellent elution in digestive tubes and bioavailability. CONSTITUTION:This composition for medicine is obtained by coating very small spherical particles containing a readily water-soluble and unpleasant taste, having uniform particle diameter, with a coating film comprising a hydrophobic substance and/or a water-insoluble polymer.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention reduces the unpleasant taste of a drug and prevents the unpleasant taste of the drug from leaking out for a long time even after being suspended in water before use, and when it is transferred to the digestive tract. The present invention relates to a medicinal composition which does not impair the bioavailability (bioavailability) of a drug by rapidly achieving the dissolution of the drug.

[0002]

2. Description of the Related Art When a drug has an unpleasant taste such as bitterness, it is a great pain for a patient to take it as a powder, granules, or dry syrup, and especially children can be vomited, which is not preferable for compliance. .

The dry syrup formulation is selected as a pediatric dosage form because of its ease of prescribing and taking, but it suppresses unpleasant taste leakage of the drug for a long time after being suspended in water before use,
At present, no drug that has achieved rapid drug elution when transferred to the digestive tract has been developed so far. Conventionally, in pharmaceuticals, as a method for reducing the bitterness of a substance having a bitterness, a composition of hydrogenated oil and macrogol or a surfactant added thereto is melted, and a substance having a bitterness is suspended therein, and sprayed, It is described in JP-A-54-95719 that fine particles obtained by solidification can suppress bitterness without lowering the dissolution property of the main drug. Further, a method in which a drug is dispersed in molten stearic acid and sprayed and solidified by using a double nozzle is disclosed in JP-A-63-63.
It is disclosed in Japanese Patent Publication No. 303928.

However, in the conventional techniques represented by these techniques, masking in the mouth for about 1 minute is possible, and although it can be used as a powder or granule, it is easily soluble in water and has an unpleasant taste. It was difficult to say that this is the most suitable technology for making powders, granules, and dry syrups for the drugs that they have. Particularly, in the prior art, the granules obtained by spraying and solidifying are usually non-uniform in size and shape, and also have projections, depressions (large surface area),
A large amount of masking base (coating agent) is required to cover the entire surface of the granulated product, which is not suitable for making a high dose of a dry syrup preparation. In addition, if the granules are coated with a large amount of coating agent for sufficient masking, the drug is not rapidly eluted in the digestive tract,
There was a problem that bioavailability was lowered. As described above, hitherto, in a dry syrup preparation to be taken after suspension in water, no technique has been developed in consideration of bitterness masking for a long time after suspension in water and rapid dissolution of a drug in the digestive tract.

[0005]

DISCLOSURE OF THE INVENTION The present invention reduces the unpleasant taste of a drug and can be taken by suspending it in water before use.
Moreover, it is an object of the present invention to provide a pharmaceutical composition having excellent dissolution properties in the digestive tract.

[0006]

In order to achieve the above-mentioned object, according to the present invention, a fine spherical particle having a uniform particle size containing a drug having a water-soluble and unpleasant taste is provided with a hydrophobic substance and And / or a pharmaceutical composition characterized by being coated with a film comprising a water-insoluble polymer.

The pharmaceutical composition of the present invention sufficiently masks the unpleasant taste of the drug for several hours to several days after being dispersed in water, and the pH-dependent soluble polymer coating does not impair the bioavailability of the drug. It rapidly elutes in acidic or alkaline solutions. In the present invention, by using fine spherical particles having a uniform particle diameter, it becomes possible to obtain a pharmaceutical composition having an optimum particle diameter for a dosage form such as a powder, granules and dry syrup. Furthermore, by using fine spherical particles having a uniform particle diameter, it becomes possible to coat a coating layer having a uniform thickness, and it is possible to obtain a pharmaceutical composition having uniform and efficient quality with uniform coating. It will be possible. Further, during the process of formulating the pharmaceutical composition of the present invention, the drug is prevented from coming into contact with water or an organic solvent, and therefore, it is useful for a drug that is easily decomposed or changed by water or an organic solvent.

Hereinafter, the pharmaceutical composition of the present invention will be described in detail. Drugs applicable and preferably applicable in the present invention include those which are easily soluble in water and have an unpleasant taste, or those which are easily decomposed or changed by water or an organic solvent, and have the disadvantages of both of them. Such as berberine chloride, digitoxin, sulpiline, etilefrine hydrochloride, diltiazem hydrochloride, propranolol hydrochloride, chloramphenicol, aminophylline, erythromycin, josamycin, clarithromycin, phenobarbital, calcium pantothenate, inderoxazine hydrochloride, aminoguanidine hydrochloride. ,
3,4'-dideoxy-mycaminosyl tylonolide (see JP-A-2-275894) and the like.

In the present invention, the microspherical particles contain a drug, but it is preferable to use a wax-like substance as a base constituting the microspherical particles together with the drug. The wax-like substance used is not particularly limited as long as it has a melting point of 40 to 90 ° C., which is usually used as a pharmaceutical additive, and can be formed into fine spherical particles after melting or dispersing a drug. For example, hydrogenated castor oil, hydrogenated soybean oil,
Various hydrogenated oils such as hydrogenated rapeseed oil; stearyl alcohol,
Higher alcohols such as cetanol; higher fatty acids such as stearic acid and palmitic acid; vegetable or animal fats or waxes such as carnauba wax, beef tallow, beeswax, bleached beeswax; Macrogol 2000, Macrogol 4000, Macrogol 6000, Macro Polyethylene glycols such as Goal 20000; sorbitan fatty acid ester, sucrose fatty acid ester, higher fatty acid monoglyceride, polyoxypropylene glycol, polyoxyethylene,
Examples thereof include surfactants such as polyoxypropylene glycol and sodium lauryl sulfate.

In the present invention, the amount of the wax-like substance used as the base material for the fine spherical particles is not particularly limited as long as it is an amount capable of melting or dispersing the drug. However, when a large amount of a wax-like substance is used, the dose per dose also increases, which is unsuitable for a drug that requires a large amount of dose. Preferably, 0.25 to 10 parts by weight, more preferably 0.5 to 2 parts by weight, of the waxy substance is suitable for 1 part by weight of the drug. When the wax-like substance is less than 0.25 part by weight, it cannot be said that the amount is sufficient to melt or disperse the drug. On the other hand, if the amount of the wax-like substance exceeds 10 parts by weight, it is not preferable for the above reason.

In the present invention, the water-insoluble polymer used as a coating component for coating the microspherical particles is a gastric or enteric pH-dependent soluble polymer which is usually used as a pharmaceutical additive. There is no particular limitation as long as it is soluble in an organic solvent. For example, gastric-soluble polymers such as methacrylic acid copolymer E and polyvinyl acetal diethylaminoacetate; enteric-soluble polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, methacrylic acid copolymer L, and methacrylic acid copolymer LD. Polymers can be mentioned.

Similarly, the hydrophobic substance used as the coating component of the present invention is not particularly limited as long as it is usually used as a pharmaceutical additive and soluble in an organic solvent. Examples include various hydrogenated oils such as hydrogenated castor oil, hydrogenated soybean oil and hydrogenated rapeseed oil; higher fatty acids such as stearic acid and palmitic acid; and higher alcohols such as stearyl alcohol and cetanol.

The organic solvent used here is not particularly limited as long as it dissolves the water-insoluble polymer and the hydrophobic substance. For example, dichloromethane, dichloroethane, chloroform, methanol, ethanol, isopropanol, butanol, diethyl ether, acetone,
Tetrahydrofuran, ethyl acetate and the like can be mentioned. Furthermore, since the solubility varies depending on the water-insoluble polymer and hydrophobic substance used, it is necessary to select an appropriate organic solvent.
Since the amount of the organic solvent to be used must be suppressed as much as possible from the viewpoint of protecting the natural environment, one having a solubility of 5% or more in the organic solvent is preferable.

In the present invention, it is preferable to include a surfactant as a coating component. The surfactant is not particularly limited as long as it is one that is usually used as a pharmaceutical additive. Examples thereof include sorbitan fatty acid ester, sucrose fatty acid ester, higher fatty acid monoglyceride, polyoxypropylene glycol, polyoxyethylene polyoxypropylene glycol, sodium lauryl sulfate and the like. The purpose of adding these surfactants is to prevent the deposition of hydrophobic substances from the high-concentration coating component liquid, improve the coating properties on fine spherical particles (prevention of scraping due to uniform film thickness), and spray gun in the coating process by the spray method. To prevent clogging.

The amount of the surfactant used as the coating component is not particularly limited as long as it can achieve the above object. However, in consideration of the coating property and the like, the surfactant is preferably 0.01 to 10% by weight with respect to the amount of the coating film made of the hydrophobic substance and / or the water-insoluble polymer. Further 0.1
~ 1.0 wt% is preferred, and 0.25-0.75 wt% is optimal. If the amount of the surfactant is less than 0.01% by weight or more than 10% by weight, there is a problem in the above-mentioned target film formability.

In the present invention, the coating amount of the fine spherical particles is not particularly limited as long as it is the minimum amount of the fine spherical particles. However, after suspending in water, the amount that suppresses the unpleasant taste of the drug, further achieves the rapid dissolution of the drug in the digestive tract, and achieves a uniform coating thickness of the coating, relative to the microspherical particles. Coating component 10-100% by weight
Is preferable, and further 20 to 50% by weight is preferable.

As described above, the present invention uses fine spherical particles containing a drug, but the fine spherical particles are not particularly limited as long as they have a uniform particle diameter. Here, the uniform particle size may be substantially uniform, and in consideration of the subsequent formulation step, the particle size and the particle size distribution are preferably in the range of 50 to 250 μm,
100 to 200 μm is more preferable. With this particle size, it is possible to avoid a feeling of strangeness in the mouth.

In the present invention, it is extremely important to use fine spherical particles having a uniform particle size. That is,
When coating a coating of a hydrophobic substance and / or a water-insoluble polymer on a fine spherical particle using a granulator, particularly a fluidized bed granulator, if the particle diameter of the fine spherical particle is not uniform, The thickness tends to be non-uniform, and as a result, the degree of bitterness masking and the elution rate vary among particles.

The formulation of the present invention can be carried out, for example, by the following method. First, the drug is melted or dispersed in a molten wax-like substance having a melting point of 40 to 90 ° C. Next, this molten liquid is dropped on a disk rotating at high speed by using an appropriate liquid feed pump. The dropped liquid scatters due to the centrifugal force of the disc, and is cooled and solidified during the fall to obtain fine spherical particles. Next, while the fine spherical particles are being fluidized in a fluidized bed granulator, a liquid containing a coating component is sprayed from a spray gun. After coating the coating components on the fine spherical particles, various additives which are usually used as pharmaceutical additives are further added and granulated to obtain various preparations.

[0020]

EFFECT OF THE INVENTION The pharmaceutical composition of the present invention is capable of masking taste for a long time or a long time of several hours to several days after suspension in water.
It excels in dissolution and bioavailability in the digestive tract. In addition, the following excellent effects are exhibited. (1) Since the drug is contained in the microspherical particles without using water or an organic solvent, it can be applied to drugs unstable to these solvents. (2) The particle size of the microspherical particles can be arbitrarily adjusted, and it can be applied to various preparations such as powders, granules and dry syrups. (3) In order to use fine spherical particles having a uniform particle size,
It is possible to efficiently obtain a pharmaceutical composition having uniform quality without uneven coating. (4) The degree of masking after water suspension (how many hours after suspension) and elution in the digestive tract can be freely adjusted by adjusting the type, ratio and coating amount of the components that coat the microspherical particles. It is adjustable. Therefore, it is possible to select and control the optimum particle size, coating thickness, etc., corresponding to various preparations such as dry syrup, powder and granules. (5) The particle size of the fine spherical particles is preferably 250 μm or less, and it is possible to avoid a feeling of strangeness in the mouth.

[0021]

[Examples] Hereinafter, the production method of various preparations of the present invention will be specifically described with reference to Examples, but the present invention is not limited to these Examples.

[Preliminary test] In order to pursue a method for producing a dry syrup preparation capable of achieving the object of the present invention, first, a threshold of bitterness was determined by a sensory test.

(In vitro evaluation of bitterness) 1) Bitterness threshold test with 3,4'-dideoxy-mycaminosyltylonolide (hereinafter abbreviated as drug X) alone After thoroughly rinsing the mouth with purified water , An aqueous solution of drug X (25
˜200 μg / ml) 10 ml in mouth. After about 10 seconds, the contents in the mouth were exhaled and the mouth was rinsed. A sensory evaluation was conducted on the taste at this time. The evaluation was divided into the following stages. The results are shown in Table 1. 1: Same taste as water. 2: A difference from water is recognized. 3: I feel a little bitterness. 4: Feel bitterness. 5: I strongly feel bitterness. Threshold test results: From the results in Table 1, the bitterness threshold for Drug X alone was determined to be about 50 μg / ml.

[0024]

[Table 1]

2) Bitterness threshold test when a corrigent is added 8 ml of an aqueous solution of drug X (200 to 1000 μg / ml)
2.5 g of purified sucrose and 1 mg of saccharin sodium were added to and the same experiment as in 1) was performed. The evaluation was performed in the following 5 stages. The results are shown in Table 2. 1: Extremely sweet. 2: Sweet. 3: I feel a little bitterness. 4: I feel bitterness but can endure. 5: I can't stand it. Threshold test result: Bitterness threshold is 300 when flavoring agent is added
It was determined to be about μg / ml.

[0026]

[Table 2]

(Example 1) Aminoguanidine hydrochloride 500
g was added to 500 g of stearic acid (63 stearin, manufactured by Kawaken Fine Chemical Co., Ltd.) melted at about 80 ° C., and dispersed using a homogenizer. This dispersion liquid was dripped and scattered on a disk rotating at high speed to generate about 95 microspherical particles.
0 g was obtained. Add 63 stearin 1 to these microspheres.
0% (hereinafter, all% represent% by weight), sucrose fatty acid ester (ryoto sugar ester S-370F
A methylene chloride solution containing 0.5% of two components was sprayed to obtain 25, 40 and 50% coated products.

According to Japanese Pharmacopoeia Dissolution Test Method 2, 500 ml of Disintegration Test Method Solution 2 (pH 6.8) was used as a test solution.
Was used and tested at 100 revolutions. Separately, 300 mg of the coated particles was taken as a drug, added with 10 ml of water, shaken and dispersed, and then stored in a refrigerator. After 1-3 days,
Millipore filter (φ = 0.45 μm)
And the absorbance was measured at a measurement wavelength of 210 nm to determine the drug elution amount. At the same time, the dispersion was contained in the mouth, and a sensory test of taste was performed. The results are shown in Table 3.

[0029]

[Table 3]

[Experimental Example] (Experimental Method) The fine spherical particles (uncoated product) obtained in Example 1 were tested by the Japanese Pharmacopoeia Dissolution Test Method No. 2. Disintegration test method 1st liquid (pH
1.2), the second liquid (pH 6.8) and purified water to 500
It was performed at 100 revolutions using ml. (Results / Discussion) As a result of the dissolution test, the drug dissolution amount was 100% in about 3 minutes in all the test solutions. From this experimental result, it was expected that an unpleasant taste would be exhibited in the mouth within a few minutes after suspension in water. However, as shown by the results of the sensory test of the taste of the fine spherical particles (coated product), no bitterness was observed in the present invention even after 3 days from the suspension in water, and it is clear that the present invention is highly useful. Is.

(Example 2) 2% of hydrogenated rapeseed oil (Lovely Wax 103 manufactured by Freund Sangyo) 9% and polyvinyl acetal diethylaminoacetate (AEA Sankyo) 1% were added to fine spherical particles produced by the same method as in Example 1.
A methylene chloride solution containing the components was sprayed to obtain a 100% coated product. Disintegration test method 1st liquid (pH 1.2) and water 500 as a test solution according to the Japanese Pharmacopoeia Dissolution Test Method 2
The test was performed at 100 revolutions using ml. The result is shown in FIG.

(Example 3) Drug X (500 g) was added at about 80 ° C.
The mixture was added to 750 g of 63 stearin melted in step 1, and dispersed using a homogenizer. Then, 50 and 55% coated particles were obtained in the same manner as in Example 1. Then, 10% dry syrup was prepared by the following recipe manufacturing method.

When 50% coated particles are used, 150 g of 50% coated particles (40 g of the drug X) is added to a light silicic acid anhydride (Adsolider 101) which is a fluidizing agent.
Freund Sangyo) 1.5g, excipient white sugar 2
33.9 g, 8 g of sodium salt of carboxymethyl cellulose (CMC-Na, manufactured by Dai-ichi Kogyo Seiyaku Co., Ltd.) which is a thickener
Add and mix. This mixed powder is granulated using a fluidized bed granulator. HPC-SL (Nippon Soda) as a binder 1
0 g, surfactant SLS (manufactured by Nikko Chemicals)
0.6g, sweetener aspartame (made by Ajinomoto)
1.6 g, 1.2 g of tartaric acid as a sour agent, 0.4 g of yellow No. 5 aluminum lake (manufactured by Sanei Chemical Industry Co., Ltd.) as a pigment
Is dissolved or decomposed in water to give 100 g. After drying, 0.4 g of light anhydrous silicic acid and 0.4 g of orange micron (manufactured by Takasago International Corporation), which is a fragrance, are mixed to obtain a total amount of 400 g of a 10% dry syrup.

When using 55% coated particles, 55% of 55% coated particles (equivalent to 40 g of drug X), 1.55 g of light anhydrous silicic acid, 227.85 g of purified sucrose,
Other additives are added in the same amount as above and the total amount is 400g.
Use 0% dry syrup. Japanese Pharmacopoeia Dissolution Test Method 2
Disintegration test method second liquid (pH 6.
The test was conducted at 100 revolutions using 500 ml of 8).
Separately, 1 g of 10% dry syrup was added, 4 ml of water was added, and the mixture was shaken, dispersed, and stored in a refrigerator. After 1 to 14 days, the dispersion was added to a Millipore filter (φ = 0.45μ
m), and the absorbance is measured at a measurement wavelength of 281 nm,
The drug elution amount was determined. At the same time, the dispersion was contained in the mouth, and a sensory test of taste was performed. The results are shown in Table 4.

[0035]

[Table 4]

Example 4 Microspherical particles were produced in the same manner as in Example 3, and then 63 stearin 10%, sucrose fatty acid ester 0.5%, and methacrylic acid copolymer L were prepared.
(Eudragit L, manufactured by Rohm Pharma) 2% 3
A 40% coated product was obtained by spraying a methanol solution containing the components. Then, a 10% dry syrup was produced in the same manner as in Example 3. Disintegration test method 2nd liquid (pH 6.8) as a test liquid according to the Japanese Pharmacopoeia Dissolution Test Method 2
Was tested at 100 revolutions using 500 ml. Separately, 1 g of 10% dry syrup was added, 4 ml of water was added, and the mixture was shaken, dispersed, and stored in a refrigerator. After 1 to 12 hours,
Millipore filter (φ = 0.45 μm)
And the absorbance was measured at a measurement wavelength of 281 nm to determine the drug elution amount. At the same time, the dispersion was contained in the mouth, and a sensory test of taste was performed. The results are shown in Table 5.

[0037]

[Table 5]

As shown in the above Examples, from the measurement results of the drug elution amount after the preparation was dispersed in water, the preparation of the present invention, when prepared as a syrup, can mask bitterness for 12 hours to 2 weeks after preparation. Became clear. This shows that it is possible to prepare and store several days at a time without having to prepare the syrup for each dose.
This is very useful when considering practicality.

(Example 5) To 140 g of a 40% coated product obtained by the same method as in Example 4, 1.4 g of light anhydrous silicic acid as a fluidizing agent and 238.8 g of lactose as an excipient were added.
Then a 10% aqueous solution of hydroxypropyl cellulose 1
Fluidized bed granulation was performed at 00 g to obtain a total amount of 400 g of 10% powder.

Example 6 To 140 g of a 40% coated product obtained in the same manner as in Example 4, 1.4 g of light anhydrous silicic acid as a fluidizing agent and 228.8 g of sucrose as an excipient were added,
Then 10% aqueous solution of hydroxypropyl cellulose 2
Fluidized bed granulation was performed at 00 g to give a total amount of 400 g of 10% granules.

Example 7 To 140 g of a 40% coated product obtained in the same manner as in Example 4 was added 250 g of lactose as an excipient, and a 10% aqueous solution of hydroxypropyl cellulose was added using a vertical granulator. Granulated at 100 g. Then, it was sieved with a 20 mesh sieve and dried to obtain 10% granules.

[Brief description of drawings]

FIG. 1 is a graph showing the amount of dissolution in Example 2.

Claims (10)

[Claims] 1. A microspherical particle having a uniform particle size and containing a drug which is easily soluble in water and has an unpleasant taste is coated with a film made of a hydrophobic substance and / or a water-insoluble polymer. A pharmaceutical composition comprising: 2. The pharmaceutical composition according to claim 1, wherein after suspending in water, the unpleasant taste is masked for a long time and the drug is rapidly eluted in the digestive tract. 3. The pharmaceutical composition according to claim 1, wherein the fine spherical particles are composed of a wax-like substance containing a drug. 4. The pharmaceutical composition according to claim 1, wherein the water-insoluble polymer is a gastric-soluble polymer or an enteric-soluble polymer. 5. The pharmaceutical composition according to claim 1, which contains a surfactant as a component of the coating film. 6. A coating of 10 parts by weight based on the weight of the fine spherical particles.
The pharmaceutical composition according to claim 1, which is uniformly coated in an amount of -100% by weight. 7. The particle size of the fine spherical particles is 50 to 250 μm.
The pharmaceutical composition according to claim 1, which is m. 8. The particle size of the fine spherical particles is 100 to 200.
The pharmaceutical composition according to claim 7, which has a thickness of μm. 9. The pharmaceutical composition according to claim 1, wherein the drug which is easily soluble in water and has an unpleasant taste is selected from the group consisting of antibiotics, antibacterial agents, antipyretic and analgesic and antiphlogistic agents, antitussive and expectorant agents, and antihistamine agents. 10. The pharmaceutical composition according to claim 1, which is used as a dry syrup, powder, fine granule or granule.