JP3130058B2 - Masked granules - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a granular substance which is masked for an unpleasant taste of a drug.

[0002]

2. Description of the Related Art The role of granular preparations such as granules and fine granules in various dosage forms such as tablets and capsules in pharmaceuticals is extremely important, especially in improving the ingestibility and compliance of children and the elderly. It is. And, in recent years, as the aging of patients has progressed rapidly, the demand has been increasing more and more. However, even in the case of a granular preparation, when a drug having an unpleasant taste such as bitterness, acidity or irritation is contained, the preparation is not necessarily easy to take.

[0003] For this reason, generally, granular preparations having an unpleasant taste are usually devised with a formulation for masking the unpleasant taste. The most commonly used formulation technique is to coat the surface of the granular material with a coating agent that does not dissolve in the mouth, such as a wax or a water-insoluble polymer. In this case, conventionally, a method of dissolving the coating agent in an organic solvent or suspending the coating agent in water to perform spray coating has been used. However, the use of the organic solvent has many problems such as adverse effects on hygiene to workers, environmental pollution, and residues in the preparation. For this reason, recently, a method of applying a coating by dispersing a coating agent in water together with a plasticizer has been found, and has been widely used. However, this method is also unsuitable for water-unstable drugs, and when applied to a water-soluble drug, the drug is easily dissolved in the coating solution. It has drawbacks such as generation of substances and poor film formation. Further, in the case of spray coating, since there are many fluctuation factors of manufacturing conditions such as coating speed and temperature, it is necessary to control conditions with high accuracy to always obtain a preparation of constant quality. In particular, since water-insoluble coating agents are used in the masking of granular preparations, it is important to note that variations in film formation due to changes in conditions and slight fluctuations in the amount of films have a significant effect on the elution characteristics of drugs that are important in quality. You have to be careful.

[0004]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a granular material which effectively masks drug blemishes and the like.

[0005]

DISCLOSURE OF THE INVENTION The present invention provides a method of melting and granulating a powder of a drug having an unpleasant taste, a granular disintegrant, and a granular water-insoluble low-melting substance. It was made based on the finding that an unpleasant taste can be effectively masked by melt granulation with a fine powder additive at a temperature equal to or higher than the melting point of the low melting point substance.

[0006] That is, the present invention provides a granulated material obtained by melting and granulating a powdery water-insoluble low-melting substance, a powdered disintegrant and a drug powder at a temperature not lower than the melting point of the low-melting substance. The present invention relates to a granular material obtained by melting under the flow of a fine powdery additive, characterized in that a film comprising a water-insoluble low-melting substance and the above additive is formed on the surface of the granular material.

[0007] In the present invention, as a molten granulated product using a water-insoluble low melting point substance (hereinafter, referred to as a coated granular material), a granular material disclosed in JP-A-58-214333, that is, A drug powder having an unpleasant taste, a powdery water-insoluble low-melting substance and a powdery disintegrant are heated under fluid mixing at a temperature equal to or higher than the melting point of the low-melting substance, and the drug is melted in the melting process of the low-melting substance. Granules obtained by adhering powder to the low-melting substance are mentioned.
1400 μm is used. It is desirable that the coated granules have a smooth surface for efficient coating, but according to the granulation method disclosed in the above publication, it is possible to produce coated granules having an almost spherical and smooth surface. it can.

The water-insoluble low melting point substance used in the present invention preferably has a melting point of 40 to 90 ° C., preferably 50 to 80 ° C., for example, fatty acids such as stearic acid, palmitic acid and myristic acid; Examples include higher alcohols such as cetanol and stearyl alcohol, oils and fats such as hardened oil and wood wax, surfactants such as glycerin fatty acid ester, hydrocarbons such as paraffin and microcrystalline wax, and mixtures thereof. Further, even the above-mentioned water-insoluble low-melting point substance, a mixture obtained by eutectic with a water-soluble low-melting point substance such as macrogol can be used. It is preferable to use a powdery and granular material, and the particle size may be determined according to the particle size of the target granular material, and it is generally preferable to use a particle size in the range of 100 to 840 μm.

[0009] Drugs that are melt-granulated using the water-soluble low-melting substance include cetraxate hydrochloride, ofloxacin, indomethacin, aspirin and the like, which have unpleasant tastes. These are usually 8 parts by weight or less, preferably 0.5 to 1 part by weight of the low-melting substance.
It is preferred to use 5 parts by weight. Examples of the disintegrant according to the present invention include croscarmellose sodium, carboxymethylcellulose calcium, carboxymethylcellulose, low-substituted hydroxypropyl cellulose, crystalline cellulose, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, and the like. The disintegrant is preferably used in an amount of 0.01 to 0.2 part by weight per 1 part by weight of the granular material to be coated, and usually has a particle size of 150 μm or less, preferably 100 μm or less.
The above-mentioned molten granules can be formed only with a water-insoluble low-melting substance, a drug and a disintegrant, but corn starch, lactose, etc. can be used as an excipient, and the amount of the low-melting substance is 1 weight. The amount is usually 0.05 to 4 parts by weight per part by weight. Excipients usually have a particle size of 1 to 150μ
It is better to use m.

[0010] Examples of the fine powdery additives to be coated on the surface of the above-mentioned granular material to be coated include talc, light anhydrous silicic acid, magnesium aluminate metasilicate, calcium stearate, magnesium stearate, titanium oxide, synthetic aluminum silicate or the like. These mixtures and the like can be mentioned. Of these, inorganic powders are preferably used. Its size can be arbitrary, but 2
It is preferable to use one having a size of 0 μm or less. The amount to be used is usually 0.05 to 1 part by weight of the granular material to be coated.
The content is preferably 0.5 parts by weight.

The granular material of the present invention can be produced, for example, by the following method. First, a powdery, water-insoluble low-melting substance is used to give an unpleasant taste, usually with a particle size of 0.1 to 150 μm.
Granules to be coated by granulating while heating at a temperature not lower than the melting point of the low-melting substance, usually for 5 to 30 minutes, under fluid mixing with a drug powder and a powdered disintegrant, and in some cases suitable excipients Get. The obtained granules to be coated and the fine powdery additives, if necessary, are usually put into a rotary mixer or a fluidized dryer together with the excipients described above, usually 0.1 parts by weight or less per 1 part by weight of the granules to be coated,
It is possible to form a film composed of the water-insoluble low-melting substance and the above-mentioned additive by adhering the finely powdered additive to the coated granular material by fluid-mixing while maintaining the temperature at or above the melting point of the used low-melting substance. Thereafter, by cooling the mixture without stopping the mixing operation, the target granular material can be produced.

The heating operation is usually performed with hot water or hot air, and the temperature is generally preferably 5 to 30 ° C. higher than the melting point of the water-insoluble low-melting substance to be used. Depends on the scale, but usually on a scale of about 1 to 10 kg
20 minutes.

[0013]

EFFECTS OF THE INVENTION The granules of the present invention have excellent quality as granular preparations, such as taste masking properties in the mouth, dissolution properties, appearance, and strength stability. In addition, it has the following very useful advantages. (1) Compared to coating for general masking,
There is no need to prepare a coating solution, the coating time can be greatly reduced, and a product of constant quality can be produced with a simple apparatus at a high yield without the need for complicated conditions. (2) Since there is no need to use a solvent, there is no danger such as safety, hygiene, pollution, or residue in the product, and the stability of the drug is not impaired. (3) The particle size of the product can be easily controlled by changing the particle size of the water-insoluble low-melting substance. For example, when a water-insoluble low-melting substance having a particle size of 150 to 250 μm is used during granulation, a fine granule having a particle size of 250 to 500 μm can be obtained.
When a water-soluble low melting point substance having a particle size of 300 to 850 µm is used, a granule having a particle size of 500 to 1400 µm can be obtained. (4) The degree of masking in the mouth and dissolution in the body can be freely controlled by adjusting the type and amount of the water-insoluble low-melting substance, disintegrant and fine powder additive.

Next, the present invention will be specifically described with reference to examples.

EXAMPLE 1 2.8 kg of cetraxate hydrochloride (particle size: 150 μm or less), 0.5 kg of corn starch (particle size: 10 μm or less), croscarmellose sodium 0 in a fluidized bed granulator (Grat WSG-5). 2.5 kg (particle size: 20-50 μm) and 1.2 kg of glyceryl monostearate (150-250 μm, manufactured by NOF Corporation) are granulated while heated and fluidized at an intake temperature of 85 ° C., and then cooled, and then sieved to a 500 μm sieve. To obtain granules to be coated (average particle size of about 40
0 μm). Next, 2.1 kg of the coated granular material and 0.9 kg of talc (particle size: about 10 μm or less) are put into a jacketed cross rotary mixer (CM-10 type), and the mixture is heated to 80 ° C.
Of warm water is circulated in the jacket at a speed of 20 revolutions per minute, and after 10 minutes, the circulating water is switched to tap water and cooled to a sample temperature of 40 ° C., and the masked granular preparation (fine granules, average particle size) : About 400 µm).

Example 2 Coated granules obtained in the same manner as in Example 1.
2 kg together with 1.56 kg of talc (particle size: about 10 μm or less) was again put into a fluidized bed granulator, and was made to flow while heating at an intake air temperature of 80 ° C., so that all the powder adhered to the granules to be coated (about 20). After that, the hot air was replaced with room air by a damper operation and cooled to a sample temperature of 40 ° C. to obtain a masked granular preparation (fine granules, average particle size: about 400 μm).

Example 3 1.4 kg of ofloxacin (particle size: 10 μm) was added to a fluidized bed granulator.
Below), low-substituted hydroxypropylcellulose 0.5 kg
(Particle size: 20-50 μm), lactose 1.5 kg (particle size: 150
μm or less), 0.3 kg of corn starch (particle size: 10
μm or less) and stearic acid (150-250 μm) 1.
3 kg, and a granular material to be coated was obtained in the same manner as in Example 1 at an intake air temperature of 85 ° C. (average particle size: about 400 μm).
). Next, 2.1 kg of the coated granules and 0.8 kg of talc (particle size:
About 10 μm), and a masked granular preparation (fine granules, average particle size: about 400 μm) was obtained in the same manner as in Example 1.

Test Example 1 The masked granular preparations obtained in Examples 1, 2 and 3 were subjected to a mouth masking test and a dissolution test. The same test was performed for each of the coated granular materials as comparative samples. In the mouth masking test, 0.5 g of each of the samples was contained in the mouth, and the time until bitterness or sourness was felt was measured and defined as masking time. The number of testers was five.

The dissolution test is performed according to the Japanese Pharmacopoeia General Test
5 minutes after the start of the test using JP
Sample the test solution for up to 30 minutes
Measure the absorbance of xate or ofloxacin and dissolve
Time to reach 75% output rate (T ₇₅%) By calculation
Was. Table 1 shows the results.

Table 1 Test results Masking time Elution time (T ₇₅ %) Example 1 Coated material (granular material) 2-3 seconds 2.5 minutes Maskinque (granulated material) 30-60 seconds 5.2 minutes Example 2 Coated material (granular material 1) ２2 seconds 1.5 minutes Maskinque granules 20-40 seconds 3.4 minutes Example 3 Coated material 3-5 seconds 4.6 minutes Maskinque granules 40-60 seconds 9.2 minutes

As is evident from Table 1, the masked granules of the present invention had sufficient mouth masking properties and exhibited rapid elution characteristics.

 ──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-63-27423 (JP, A) JP-A-58-214333 (JP, A) JP-A-62-181214 (JP, A) JP-B-42 17324 (JP, B1) JP-B 39-17168 (JP, B1)

Claims (3)

(57) [Claims] 1. A particulate water-insoluble low melting point substance, a granulate and a powder of a drug with a disintegrant and unpleasant taste of the powdered obtained by melt granulation, above the melting point of the low melting point materials At the temperature, the unpleasant taste of the drug, which is characterized by melting with the fine powder additive under flow, is masked and has a rapid dissolution property.
Preparation of granules to be. 2. The disintegrant is croscarmellose sodium,
Carboxymethylcellulose calcium, carboxymethylcellulose, low-substituted hydroxypropylcellulose, crystalline cellulose, carboxymethylstarch sodium, cross-linked polyvinylpyrrolidone and mixtures thereof, and the finely powdered additive is talc, light anhydrous silicic acid The method according to claim 1, wherein the method is selected from the group consisting of magnesium aluminate metasilicate, calcium stearate, magnesium stearate, titanium oxide, synthetic aluminum silicate and a mixture thereof. 3. The water-insoluble low-melting substance has a particle size of 100 to 840.
μm, and the particle size of the powdery disintegrant is 150 μm or less, and the particle size of the drug powder having an unpleasant taste is 0.1 to 150 μm, and the particle size of the fine powder additive. Is 2
3. The method according to claim 2, wherein the thickness is 0 μm or less.