JPH06217716A - Additive for pharmaceutical preparation - Google Patents

Abstract

PURPOSE:To obtain an additive for a pharmaceutical preparation, composed of a trehalose, readily soluble in water, capable of providing a colorless, transparent and low-viscosity aqueous solution and manifesting good fluidity and low reactivity and excellent in mixability, granulating properties, compression moldability and feeling of administration without causing a change in blending. CONSTITUTION:This additive for formulating a pharmaceutical preparation is obtained by using a trehalose as an excipient, mixing the trehalose with hydroxypropyl cellulose and corn starch and granulating or spray-drying the resultant mixture. Otherwise, powder of 1,6-dihydro-2-{2-(2-methylpropoxy)anilino}-6-oxo-5-pyrimidinecarboxylic acid which is a sparingly water-soluble compound having antiallergic and antiulcer action as a medicinal ingredient is added to the trehalose, hydroxypropyl cellulose and corn starch and the obtained mixture is charged into a fluidized granulating coater. A solvent is sprayed thereon while fluidizing the mixture in air at 55 deg.C inlet temperature to dry the prepared granulated material. The prepared dried granulated material is directly tableted to provide the pharmaceutical preparation such as a tablet. The additive is readily soluble in water, capable of providing a colorless, transparent and low-viscosity aqueous solution and feeling of administration with slight sweetness and excellent in mixability, granulating properties, compression moldability and fluidity.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a pharmaceutical additive in the fields of foods, pharmaceuticals, feeds, etc., and more particularly to a pharmaceutical additive comprising trehalose.

[0002]

2. Description of the Related Art Solid preparations such as tablets, pills, granules, powders (including fine granules), troches and chewable agents, injections, suspensions, emulsions in the fields of foods, pharmaceuticals, feeds, etc. In the production of liquid preparations such as elixirs and syrups, excipients, stabilizers, preservatives, buffers are used in order to secure the criteria for properties and quality during storage of active ingredients and their usefulness, or to enhance their usefulness. Appropriate additives such as The additive must be harmless in the dosage of the formulation and should not interfere with the therapeutic effect of the formulation or interfere with testing.

Conventionally, solid excipients include various excipients such as starches such as potato starch and corn starch, sugars such as lactose, sucrose, glucose and mannitol, inorganic salts such as calcium phosphate and precipitated calcium carbonate. It is used for the purpose of dilution. Also, various sugars and cellulose derivatives, and polymeric substances such as polyvinylpyrrolidone are used as additives for increasing the solubility of poorly soluble drugs, for example, carriers used in the solid solution method and the mixed pulverization method. (Japanese Patent Laid-Open No. 58-77811, etc.)

On the other hand, tablets have been conventionally manufactured by a wet tableting method (indirect tableting method), but in recent years, a direct tableting method for the purpose of simplifying the manufacturing process and omitting the granulation process has been adopted. Widely used. In this direct compression method, the mixed powder consisting of the active ingredient and various additives needs to show good flowability and compression moldability, and further, in order to obtain good disintegration after administration, it is suitable for direct compression. It is necessary to use excipients. As the excipient for direct compression, microcrystalline cellulose, calcium hydrogen phosphate and sorbitol have been used for a long time. In addition to the tableting excipient, for example,
Excipients for tableting consisting of xylan and glucomannan (JP-A-51-15611), excipients for compression molding obtained by spray drying a dispersion of cellulose powder and hydroxypropyl starch powder (JP-A-60-97919). JP-A-59-130821), and water-soluble glucan (JP-A-59-130821). In addition, as an excipient for direct compression,
Lactose that has been spray dried or fluidized bed granulated is commercially available (Fast Flow-Hydrous NFSpray Dryed Foremo)
manufactured by St., product name Dilactos Freund Sangyo, product name Tabretoze Taiyo Kagaku).

[0005] In troches, chewing agents or sublingual tablets, it is desirable that both the active ingredient and the additive are water-soluble, and it is necessary to add a completely soluble excipient, and conventionally, sucrose, lactose,
Sugars such as mannitol and xylitol are used (JP-A-3-56413 and JP-A-4-2109).
No. 24). Thus, water-insoluble starches, inorganic salts and microcrystalline cellulose are limited in their use as excipients in the formulation.

[0006] Injectable preparations are used as solubilizing agents, or in freeze-dried preparations, polysaccharide additives such as dextran are used in order to enhance the solubility upon reconstitution. Examples of the special additive include, for example, a polymer prodrug in which an antitumor agent is bound to a polymer having an affinity for the cancer cell in order to specifically reach the cancer cell. Have been proposed, and polysaccharides such as dextran, proteins such as albumin, synthetic polymers such as peptides and polyethylene glycol have been used as carriers (Int.J.Pharmaceut.V).
ol.137.145-154.1987 etc.).

[0007] However, many of the additives, when mixed with the active ingredient, cause a change in the blending to cause deterioration of the quality of the active ingredient with the passage of time, although the degree of difference varies. For example, lactose, which is commonly used as an additive, cannot be used because of its reducing property when the active ingredient is highly sensitive to it, and the active ingredient having a primary amine causes a Maillard reaction to cause a brown reaction product. To generate. It is known that the vitamin D ₃ derivative is remarkably decomposed when blended with lactose (JP-A-4-13625). Calcium hydrogen phosphate and calcium fibrin glycolate cannot be used as an active ingredient reactive with calcium.
Additives with low reactivity with active ingredients such as potato starch, corn starch or microcrystalline cellulose have good mixability and fluidity, but have drawbacks such as poor compression moldability or poor fluidity. . Furthermore, the above-mentioned additives such as potato starch are insoluble in water, and when used in a troche or a chewable agent, the tongue feels unpleasant and the desired dose cannot be obtained.

As described above, there is no conventional additive that can be used for the above-mentioned various purposes including the dilution of the active ingredient and has a low reactivity with the active ingredient. The development of agents is desired.

[0009]

The object of the present invention is to provide a pharmaceutical composition which can be used for various purposes including the dilution of the active ingredient in the fields of foods, pharmaceuticals, feeds, etc., and which has low reactivity with the active ingredient. To provide an additive.

[0010]

[Means for Solving the Problems] Trehalose is obtained as columnar crystals soluble in water, and has a melting point of 203 ° C.
It is known to give molar D-glucose, non-reducing. In addition to the above-mentioned various properties of trehalose, the inventors of the present invention have tastes, viscosities and transparency of aqueous solutions, crushing properties of crystals, and further, color tone, fluidity, compression moldability, wetting properties, hygroscopic properties, and effectiveness of the powder. The presence or absence of changes in the composition with the ingredients was investigated in detail. As a result, they have found that trehalose has various properties useful as an additive, which have not been found in the additives known so far, and have completed the present invention. That is, the present invention provides a pharmaceutical additive comprising trehalose.

There are three types of trehalose, α, α-trehalose, α, β-trehalose and β, β-trehalose. Among these, as additives for the formulation,
The naturally occurring α, α-trehalose is preferred. The aqueous solution of trehalose is colorless and transparent, has low viscosity, and
It has a slight sweetness and is easy to take. Powdery trehalose that passes through a 200-mesh (74 μm) sieve shows excellent mixability as an excipient for the purpose of diluting the active ingredient, and can ensure the content uniformity of the preparation. The particle size of trehalose can be easily controlled by mechanical grinding or the like. Therefore, the convenience is further improved by processing trehalose into a particle size according to the purpose of use or the characteristics of the active ingredient.

Unlike the starch additives, trehalose exhibits excellent compression moldability. Further, the color tone of the compression molded product is high in whiteness unlike the molded product of lactose. In addition to the trehalose whose particle size is controlled, a mixture with other additives such as a cellulose derivative is granulated (rolling granulation, fluidized bed granulation, etc.) or spray-dried,
It can be a useful additive as an excipient for tableting, particularly as an additive for direct tableting. Furthermore, trehalose is an additive that is well soluble in water and has a slight sweetness and is excellent in ingestion feeling, and can be used as a water-soluble excipient in lozenges, sublingual tablets and chewable tablets.

Trehalose is useful as an additive for improving the solubility of a poorly soluble drug, for example, by itself or in combination with polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, for example, a solid solution method or a mixed pulverization method. Is. When the pharmaceutical additive of the present invention is used as a sweetening agent for a syrup, a sweetener-containing pharmaceutical preparation with less sweetness than sucrose is obtained. It is also useful as a solubilizing agent for the active ingredient of an injection and an additive for a freeze-dried preparation in place of dextran.

[0014]

[Action] Trehalose is a pharmaceutically stable disaccharide and has low reactivity with the active ingredient. It also dissolves well in water,
It is a sugar that has a slight sweetness and is excellent in ingestion. further,
The powder has excellent mixability, granulation property and compression moldability, and exhibits good fluidity. Therefore, trehalose is a food,
It can be used for various purposes such as dilution of the active ingredient in the fields of pharmaceuticals, feeds, etc., and can be an additive for a formulation having a low reactivity with the active ingredient.

[0015]

EXAMPLES The present invention will be specifically described by the following examples. Example 1 Fluidized bed granulation using trehalose as an excipient 1,6-dihydro-2- {2- (2-methylpropoxy) anilino} -6-oxo-5-pyrimidinecarboxylic acid (hereinafter referred to as compound) It is a sparingly water-soluble compound that has anti-allergic and anti-ulcer effects. (Tokuhohei 3-368
No. 35, JP-A-62-267229) When producing a tablet containing the present compound, tableting troubles such as sticking, capping and laminating are likely to occur. In addition, this compound has strong water repellency and is difficult to be granulated by wet granulation, and tablets containing this compound have a long disintegration time. 120g of powder of the compound having the above characteristics
In addition, 48 g of hydroxypropyl cellulose SL (manufactured by Nippon Soda Co., Ltd.), 168 g of α, α-trehalose that passes through a 200 mesh (74 μm) sieve, and 96 g of corn starch (manufactured by Nippon Food Processing Co., Ltd.) are fluidized granulation coating equipment (FL). -10 type manufactured by Freund Sangyo Co., Ltd., while flowing in air with an inlet temperature of 55 ° C., a solvent (30%
The ethanol solution was sprayed for 106 minutes under the conditions of a spraying air pressure of 0.6 kg / cm ² , a spraying air amount of 180 NL / min, and a spraying liquid velocity of 12.5 ml / min. After spraying, the product was dried under the same flow conditions, and then the granulated product was sieved with a 24 mesh (710 μm) sieve to obtain a granulated product having an average particle diameter of 195 μm.

Comparative Preparation 1 As a comparative preparation, a granulated product having an average particle diameter of 185 μm was obtained in the same manner as in Example 1 except that trehalose in Example 1 was replaced with lactose.

Example 2 400 g of trehalose that passed through a 200-mesh sieve (74 μm) was fluidized and granulated with a coating apparatus (FL-10 type).
(Freund Sangyo Co., Ltd.), and while flowing in air at an inlet temperature of 55 ° C., 1450 ml of a solvent (30% ethanol solution) is sprayed at a spraying air pressure of 0.6 kg / cm ² and a spraying air amount of 180 NL / min for granulation. I got a thing.

Example 3 To 144 g (manufactured in-house) of the granules obtained by sieving the granules of Example 1, 8 g of crosslinked sodium carboxymethyl cellulose (trade name Acdisol, manufactured by Asahi Kasei Co., Ltd.) as a disintegrator, and in Example 2 Put 82g of granulated product (made in-house) into V-type mixer (made by Shinagawa Seisakusho), mix for 1 minute, and then add 3g of talc (made by Fuji Talc) and 3g of magnesium stearate (Taihei Kagaku) as lubricants. And mixed for 30 seconds. The mixed powder is tablet press Collect 12HUK (Kikusui Seisakusho)
With a pestle having a diameter of 7 mm, tablet each 120 mg (preload 0.3
t / cm ² , main pressure 0.8 t / cm ² , turntable rotation speed 40 rpm) to obtain a plain tablet containing about 20 mg of the compound.

Comparative Preparation 2 As a comparative preparation, the granulated product of Comparative Preparation 1 was used in place of the granulated product of Example 1, and the granulated lactose (trade name of Diractos, Freund Sangyo Co., Ltd.) was used in place of the granulated product of Example 2. A plain tablet containing about 20 mg of the compound was obtained in the same manner as in Example 3 except that the manufactured tablet was used.

[0020]

[Test example]

1. The particle size distributions of the granulated products of Example 1 and Comparative Preparation 1 were measured by a sieving method, and the results are shown in FIG.
It was revealed that Example 1 and Comparative Formulation 1 have almost the same particle size distribution, and that the additive of the present invention and lactose have no difference in granulation property. Therefore, it was found that it can be formulated as an excipient for an active ingredient that is compounded and changed with lactose without lowering the granulation property.

2. With respect to the plain tablets of Example 3 and Comparative Preparation 2, the compound content of each tablet was measured (high performance liquid chromatogram method), and the results are shown in Table 1. Content segregation was not observed in a bare tablet using the pharmaceutical additive of the present invention, and it was found that the pharmaceutical additive of the present invention can obtain the same mixing property (content uniformity) as when lactose is used. It was

[0022]

[Table 1]

3. The tablet quality (tablet weight, tablet hardness and disintegration time) of each of the bare tablets of Example 3 and Comparative Formulation 2 was measured, and the results are shown in Table 2. The additive for formulation of the present invention has the same tablet quality as that when powdered lactose is used as the granulation excipient and granulated lactose (excipient for direct compression) is used as the tableting additive. It turns out that you can get

[0024]

[Table 2]

4. Plain tablet prepared in Example 3, comparative formulation 2
The dissolution test (900 ml of buffer solution at pH 5.6 (37 ° C., paddle rotation speed 100 rpm)) was performed using the uncoated tablet of No. 1 and the powder of the compound as a test drug, and the results are shown in FIG. As is clear from FIG. 2, the bare tablet using the additive for formulation of the present invention shows the same dissolution property as the case of using water-soluble lactose, and has preferable properties as an excipient for a poorly soluble drug. I knew that.

5. L-arginine, which reacts with saccharides, 10 g and α
An aqueous solution was prepared by adding purified water to 10 g of α-trehalose to make 100 ml, and as a control, an aqueous solution using lactose instead of α, α-trehalose in the above aqueous solution.
Each kind of aqueous solution was dispensed into a vial and stored in a thermostat at 60 ° C and in a cool place (5 ° C) for 23 hours. 2 above
After storing under various conditions, the appearance of each aqueous solution was observed, and the transmittance (%) at 430 nm was measured using purified water as a control. The results are shown in Table 4. L
-The aqueous solution containing arginine and lactose turned brown due to the abuse of heat and showed a significant decrease in transmittance. However, when the additive of the present invention was used under the same conditions, no change in appearance was observed and the decrease in transmittance was slight. As described above, the pharmaceutical additive of the present invention can be used as an active ingredient in which there is a fear of a change in compounding with the additive.

[0027]

[Table 3]

[0028]

As described above, the pharmaceutical additive of the present invention is an aqueous solution which dissolves well in water, is colorless and transparent, has a slight sweetness, and has a low viscosity, and is excellent in ingestion feeling. Further, the pharmaceutical additive of the present invention has excellent mixability, granulation property and compression moldability, and exhibits good fluidity. Furthermore, the pharmaceutical additive of the present invention is pharmaceutically stable and has low reactivity with the active ingredient. The pharmaceutical additive of the present invention, which has the above-mentioned advantages and can be used for various additives, makes a great contribution to the industry.

[Brief description of drawings]

FIG. 1 is a diagram showing the results of particle size distribution measurement.

FIG. 2 is a diagram showing the results of a dissolution test.

Claims (1)

[Claims] 1. A pharmaceutical additive comprising trehalose.