JP2000281561A - New solid dispersion preparation by solvent method - Google Patents

Abstract

PROBLEM TO BE SOLVED: To industrially produce a solid dispersion preparation by a solvent method using a low toxic solvent scarcely liable to cause explosion without deteriorating the qualities, such as elusiveness, of the preparation. SOLUTION: This solid dispersion preparation is prepared by a solvent method. Therein, a homogeneous phase mixture solvent comprising water and an organic solvent is used as the solvent for the solvent method. Thus, the solid dispersion preparation can profitably be produced using the low toxic and low cost solvent scarcely having a danger of explosion substantially without affecting the quality of the obtained solid dispersion preparation.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a preparation by a solvent-based solid dispersion using a novel solvent, and more particularly, to a solid obtained by using a homogeneous mixed solvent containing water and an organic solvent as a solvent in the solvent method. The present invention relates to a dispersion-based preparation and a method for producing the same, which makes it possible to use a low-toxicity and low-cost solvent with a low risk of explosion at the production stage, thereby reducing the production cost.

[0002]

2. Description of the Related Art In the manufacture of pharmaceutical preparations, when preparing oral preparations, solid dispersions are widely used as a means for improving the solubility of poorly soluble drugs, and many poorly soluble drugs are used as solid dispersion preparations. It has been put to practical use. Solid dispersion (Soli
d Dispersion) is defined as `` one or more active ingredients dispersed in a solid inert carrier or its matrix, prepared by a melt method, a solvent method, or a melt-solvent method. '' (WL Chiou and S. Riegelma
n: Pharmaceutical application of solid dispersion
systems, J. Pharm. Sci., vol. 60, 1281-1302, 1971
reference. ). That is, a solid mixture obtained by the operation of forming a uniform liquid phase by melting or dissolving both the drug and the carrier, and then solidifying, and the drug is uniformly dispersed in the carrier matrix in the form of microcrystals or molecules. are doing.

[0003] Solid dispersions can increase the dissolution rate and the drug concentration in an aqueous solution, resulting in an increase in absorption and an increase in blood concentration.

[0004] Among the melting method, the solvent method and the melting-solvent method, the solvent method is suitable for a drug which can be prepared at a low temperature and is unstable at a high temperature or a drug having a high melting point. Although it is preferably used because it is not so limited, organic solvents such as alcohols and chlorinated hydrocarbons are generally used as the solvent. However, many of the organic solvents that can be used in this method have a low flash point, and there is a danger of explosion, so handling is nervous. The use of chlorinated hydrocarbons is not preferred in terms of toxicity. On the other hand, although water does not pose a risk of explosion, the solid dispersion state of the drug is often unstable with respect to moisture, and the drug recrystallizes under humidified conditions, resulting in poor solubility. Therefore, water has been avoided as much as possible for the preparation of solid dispersion formulations.

[0005]

In the production of solid dispersions by the solvent method, there is a need to select a solvent having low risk of explosion, low toxicity and low cost while maintaining the quality of the preparation.

An object of the present invention is to provide a solid dispersion preparation by a solvent method, which uses a low-toxic and low-cost solvent to reduce the risk of explosion without lowering the quality of the preparation such as dissolution. To obtain a body preparation.

[0007]

The present inventors have conducted intensive studies to solve the above-mentioned problems. As a result, the solid dispersion is unstable with respect to moisture, the drug recrystallizes under humidified conditions, and the elution is difficult. Although the use of water was considered to be extremely difficult because of its poor quality, an attempt was made to produce a solid dispersion using a mixed solvent that formed a uniform phase by mixing water with an organic solvent. Contrary to the prediction, the present inventors have found that an excellent solid dispersion substantially equivalent to that obtained by a conventional organic solvent can be obtained, and have completed the present invention based on this finding.

That is, the present invention relates to a solid dispersion preparation by a solvent method, wherein the solvent in the solvent method is a homogeneous mixed solvent containing water and an organic solvent, and a method for producing the same.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION In the case of producing a solid dispersion preparation by the solvent method of the present invention, a drug and its components such as a carrier are uniformly dissolved in a solvent to be used, and then the solvent is distilled off. In practice, except for the composition of the solvent according to the characteristic part of the present invention, a method for producing a solid dispersion formulation by a conventionally known solvent method (Mitsuru Hashida, "Design and Evaluation of Oral Administration Formulation", The method may be carried out by using a method disclosed in Hososha, p. 173, 1995.) Of course, a method developed in the future as a solid dispersion method by a solvent method can be used.

[0010] As for the carrier to be used, those conventionally used in the method can be appropriately selected and used. Substances that are highly water-soluble and readily soluble in various organic solvents, such as highly water-soluble cellulose derivatives, polyethylene glycol, and polyvinylpyrrolidone are usually well selected.

The preparations obtained according to the present invention include various preparations for oral use such as granules, tablets, powders, capsules and the like used for pharmaceuticals.

The present invention is characterized by the solvent used in the solvent method, that is, by using a homogeneous mixed solvent of an organic solvent and water. As described above, there is no substantial difference in the quality required for the preparation such as dissolution and storage stability of the obtained solid dispersion as compared with the preparation using the organic solvent alone, and the water-containing organic The availability of the solvent was extremely difficult to predict. It was also found that the use of safer solvents with less risk of explosion enabled higher safety in the manufacturing stage, lower toxicity and lower cost, was extremely useful industrially, and could significantly reduce manufacturing costs. .

The mixed solvent used in the present invention is not particularly limited as long as it is a mixed solvent containing water and one or more organic solvents and forming a homogeneous phase.

As a usable organic solvent, a water-soluble or water-soluble organic solvent may be used, and examples thereof include alcohols such as methanol, ethanol and propanol, ketones such as acetone, and nitriles such as acetonitrile. No. Usually, it is sufficient to use one kind of organic solvent, but a plurality of organic solvents can be mixed and used for improving the solubility.

Further, even when an organic solvent which is insoluble in water or an organic solvent which is hardly soluble (for example, dichloromethane) is used together with the above water-soluble or water-soluble solvent, a uniform phase is formed. It is also possible to add and mix an organic solvent capable of being used. That is, any mixed solvent containing water and an organic solvent (one or more) that forms a homogeneous phase is included in the mixed solvent used in the present invention.

The content of water may be appropriately selected depending on the solubility of the drug to be used, the operating temperature of the mixed solvent, the drying efficiency, and the like. Generally, at most about 80% by volume of the total mixed solvent, that is, 80% by volume. % Or less, more preferably 30% or less.
About 50% by volume.

Preferred organic solvents are ethanol,
Alcohols such as 2-propanol;

The active ingredient of the preparation includes a drug which is hardly soluble in water. Examples of such poorly water-soluble drugs include cyproheptadines.

As cyproheptadines, for example,
4- (5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-[(E) -3- (3-methoxy-2-nitrophenyl) -2-propenyl] piperidine (JP-A-5-9780)
See No. 8 publication. ) And the like.

In the preparation of the preparation of the present invention, the granulation and drying methods may be in accordance with a conventional method.
Granulation and / or drying can be performed using a stirring granulator, a spray dryer and an evaporator.

When a granule preparation is produced, granulation by a fluidized bed granulator is preferred in the following points.

1. Since granulation and drying proceed simultaneously, granulation is possible even when a large amount of solvent is required.

2. Since the concentration of the solvent vapor in the system can be controlled by changing the spray speed, the risk of explosion can be reduced.

[0024]

The present invention will be described in detail below based on examples and comparative examples.

Example 1 4- (5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-[(E) -3- (3-methoxy-2-nitrophenyl) -2-propenyl] 1 g of piperidine (hereinafter referred to as “compound A”) and 8 g of hydroxypropylcellulose are mixed with 30 g of ethanol and 15 g of purified water.
And the solvent was distilled off under reduced pressure using a rotary evaporator. Crush the obtained solid,
After heating and vacuum drying overnight in a vacuum sample dryer, 8 g of a solid dispersion was obtained.

(Comparative Example 1) A solid dispersion was produced by repeating Example 1 described above, except that 45 g of ethanol was used instead of the mixed solvent, and no other changes were made.

(Evaluation of Solid Dispersion) The solid dispersion obtained in Example 1 was almost insoluble in comparison with the product of the conventional method (Comparative Example 1), as apparent from the results in Table 1 below. Were identical.

The results of a dissolution test performed on the solid dispersion preparation are shown in Table 1.

[0029]

[Table 1] Dissolution characteristics of solid dispersion preparation [Numerical value: dissolution rate (%)]

The above test was performed according to the dissolution test paddle method of the Japanese Pharmacopoeia. Temperature: 37 ° C .; Paddle: 50 rpm; Test solution: 900 ml of water; 10 mg equivalent of compound A was charged.

Example 2 25 g of Compound A and 200 g of polyvinylpyrrolidone were dissolved in a mixed solvent of 700 g of ethanol and 600 g of purified water, and this mixed solution was sprayed on 450 g of lactose using a fluidized bed granulator. 650 g of body granules were obtained. The granules thus obtained were tableted to produce tablets.

As a result of a dissolution test, the obtained granules and tablets were almost the same as those obtained by the conventional method, and it was found that the solid dispersion state was maintained.

Example 3 25 g of Compound A and 200 g of hydroxypropylmethylcellulose were dissolved in a mixed solvent of 700 g of ethanol and 600 g of purified water, and dried using a spray drier to obtain 215 g of a solid dispersion powder.

The solid dispersion powder obtained here was also of the same quality as that obtained by the conventional method.

[0035]

EFFECT OF THE INVENTION In a solid dispersion preparation by a solvent method,
By using a homogeneous phase mixed solvent containing water and an organic solvent as a solvent in the solvent method, the quality of the obtained formulation is not degraded, and the solvent used is less likely to explode, and is low toxic and inexpensive. Therefore, the cost can be reduced, and it is possible to industrially manufacture and provide a solid dispersion formulation extremely advantageously.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Kobuchi Kobuchi 1-1, Suzukicho, Kawasaki-ku, Kawasaki-shi, Kanagawa Prefecture Ajinomoto Co., Inc. Pharmaceutical Research Laboratories (72) Kuniwazu Suzuki 1, Suzukicho, Kawasaki-ku, Kawasaki-shi, Kanagawa -1 Inside the Pharmaceutical Research Laboratories of Ajinomoto Co., Ltd. (72) Masato Narujima 1-1, Suzukicho, Kawasaki-ku, Kawasaki-shi, Kanagawa Prefecture Inside the Pharmaceutical Research Laboratories of Ajinomoto Co., Inc. 1-1 Suzukicho Ajinomoto Co., Inc. Pharmaceutical Research Laboratory F-term (reference) 4C076 AA29 AA36 BB01 CC03 DD37 EE16 EE32 FF02 GG09 GG12 GG14 GG50 4C086 AA01 AA02 BC21 MA01 MA05 MA35 MA43 NA20 ZB13

Claims (8)

[Claims] 1. A solid dispersion preparation according to a solvent method, wherein the solvent used in the solvent method is a homogeneous phase mixed solvent containing water and an organic solvent. 2. The preparation according to claim 1, wherein the organic solvent is an alcohol. 3. The preparation according to claim 1, wherein the active ingredient of the preparation is hardly soluble in water. 4. The preparation according to claim 1, wherein the active ingredient of the preparation is at least one compound selected from cyproheptadines. 5. The method according to claim 1, wherein the cyproheptadines are 4- (5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-[(E)-.
The preparation according to claim 4, which is 3- (3-methoxy-2-nitrophenyl) -2-propenyl] piperidine. 6. The preparation according to claim 1, wherein the content of water in the mixed solvent is at most 80% by volume. 7. The preparation according to claim 1, which has been granulated and / or dried by at least one of a fluidized bed granulator, a stirring granulator, a spray dryer and an evaporator. 8. A method for producing a solid dispersion preparation according to claim 1, wherein the solvent used in the solvent method is a homogeneous mixed solvent containing water and an organic solvent.