JPH11322604A - Pharmaceutical preparation containing diphenylpiperazine compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a pharmaceutical preparation useful for treatment and prevention of diseases such as Parkinson's disease or Parkinson syndrome caused by dopamine deficiency of synaptic cleft and diseases such as narcotic poisoning by including a compound (salt) having specific three partial structures and sugar alcohol, etc. SOLUTION: This pharmaceutical preparation comprises a compound having all of partial structures represented by formula I (R1 and R2 are each H or a halogen), formula II and formula III [R3 to R5 are each H a (substituted) aromatic or 1-4C aliphatic alkyl or the like and at least either one of R4 and R5 is (substituted)aromatic alkyl] of formula IV [(m) is 0-3] and/or its salt, preferably 1-[4,4-bis(4-fluorophenyl)butyl]-4-(2-hydroxy-3-phenylamino)- propylpiperazine or the like and sugar alcohol, preferably D-mannitol and/or lactic acid.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to Parkinson's disease,
The present invention relates to a pharmaceutical preparation containing a compound having a diphenylmethyl structure and a piperazine structure, which is useful for treating and preventing diseases caused by intersynaptic dopamine deficiency such as Parkinson's syndrome and diseases such as drug addiction.

[0002]

2. Description of the Related Art Compounds represented by the general formula (4) and having all of the partial structures represented by the general formulas (1), (2) and (3) and / or salts thereof are excellent. Have dopamine reuptake inhibitory activity, so Parkinson's disease,
It is expected to be applied to pharmaceuticals as therapeutic or preventive drugs for diseases caused by inter-synaptic dopamine deficiency such as Parkinson's syndrome and drug addiction. 1-
[4,4-bis (4-fluorophenyl) butyl] -4
The present inventors have found that-(2-hydroxy-3-phenylamino) propylpiperazine (hereinafter, compound 1) and its salt are colored and decomposed with time. Therefore, the present inventors have found that, when formulated, there is a concern about the coloring of the formulation and the stability of Compound 1 or a salt thereof in the formulation, and it is necessary to study stabilization. In general, light, moisture, oxygen, pH and the like can be considered as factors affecting the stability of a drug. On the other hand, stabilization by a method using additives such as antioxidants such as ascorbic acid and EDTA, and pH regulators such as organic acids and salts thereof, mineral acids and salts thereof, and the like is generally known. . But,
According to the study of the present inventors, additives such as an antioxidant and a pH regulator could not suppress the coloring and decomposition of Compound 1 or a salt thereof.

[0003] On the other hand, it is widely known that saccharides can be used as excipients in pharmaceutical preparations. Among them, sugar alcohols such as D-mannitol, maltitol, erythritol and / or lactose are considered to be the stability of the above compounds. It was not known to contribute, nor could it be speculated.

[0004]

Embedded image General formula (4) (However, R1, R2, R3, R4, and R5 represent the same as above, respectively, and m represents an integer of 0 to 3.)

[0005]

Embedded image General formula (1) (However, R1 and R2 each independently represent a hydrogen atom or a halogen atom.)

[0006]

Embedded image General formula (2)

[0007]

Embedded image Formula (3) (wherein, R3, R4, and R5 each independently represent a hydrogen atom, an aromatic group which may have a substituent,
4 represents an aliphatic alkyl group, an aromatic group which may have a substituent or an aliphatic alkylcarbonyl group having 1 to 4 carbon atoms, and at least one of R4 and R5 may have a substituent. It should be a good aromatic alkyl group. )

[0008]

DISCLOSURE OF THE INVENTION The present invention has been made under such circumstances, and is intended to stabilize a compound having a partial structure represented by the above general formulas (1) to (3) and / or a salt thereof. It is an object of the present invention to mix it into

[0009]

In view of such a situation, the present inventors have considered that
After extensive research efforts, the general formulas (1), (2),
The invention has been found that a solid pharmaceutical preparation comprising a compound having all of the partial structures shown in (3) and / or a salt thereof and a sugar alcohol and / or lactose has excellent stability. Was completed. Hereinafter, the present invention will be described in detail focusing on embodiments.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION (1) Compound which is an essential component of the pharmaceutical preparation of the present invention The pharmaceutical preparation of the present invention comprises a compound having a partial structure represented by the above general formulas (1) to (3) and / or Or its salt is contained as an essential active ingredient. Here, as the salt of the compound of the essential component of the present invention, any physiologically acceptable salt that is usually used in medicine can be used without any particular limitation, for example, hydrochloric acid, sulfuric acid, and the like. And mineral acid salts such as phosphoric acid, organic acid salts such as citric acid, oxalic acid, and maleic acid, and carbonates. Of these, hydrochloride is particularly preferable in terms of stability and economy. Further, as such a compound, a compound represented by the above general formula (4) is preferable, and a compound represented by the general formula (4) is preferably 1- [4,4-bis (4
-Fluorophenyl) butyl] -4- (2-hydroxy-3-phenylamino) propylpiperazine is particularly preferred. This is because of its great utility as a pharmaceutical. Although this compound has an asymmetric carbon, in the pharmaceutical preparation of the present invention, this compound can be used in a racemic form or as an optically active substance. It is preferable to use an optically active substance. This is because there is a difference in pharmacological action between optical isomers. These compounds and / or salts thereof may be contained alone or in combination of two or more. Preference is given to containing only one. The preferred content of these compounds, which are essential components of the present invention, is 1 to 30 parts by weight, more preferably 5 to 20% by weight, based on the efficacy of dopamine uptake inhibitory action, the moldability and stability of the preparation. .

(2) Sugar alcohol and lactose which are essential components of the pharmaceutical preparation of the present invention Examples of the sugar alcohol which is an essential component of the pharmaceutical preparation of the present invention include D-mannitol, xylitol, sorbitol, maltitol, Although there is erythritol, D-mannitol, maltitol, and erythritol having low hygroscopicity, for example, having a loss on drying of 0.5% or less are preferable, and D-mannitol is particularly preferable from the stabilizing effect of compound 1. Lactose is not particularly limited as long as it is usually used in a pharmaceutical composition. These sugar alcohols and lactose may be used in combination, and a combination of D-mannitol and lactose is preferred. When sugar alcohol or lactose is used alone in the pharmaceutical preparation of the present invention, the preferred content is 20 to 90% by weight, more preferably 6 to 90% by weight.
When the sugar alcohol and lactose are used in combination, the total content of the two is preferably 50 to 90% by weight, more preferably 60 to 80% by weight. This is to ensure the physical properties of the preparation such as the stabilizing effect of Compound 1 and the moldability and fluidity.

(3) Pharmaceutical preparation of the present invention The pharmaceutical preparation of the present invention is characterized by containing any of the above essential components and being a solid preparation. Preferred dosage forms for the pharmaceutical preparation of the present invention are, for example, granules, powders, capsules, and tablets, and tablets are particularly preferred from the viewpoint of ease of administration and production cost. The pharmaceutical preparation of the present invention may contain, in addition to the above-mentioned essential ingredients, optional components usually used in pharmaceutical preparations. Preferred examples of such optional components include excipients, binders, coating agents, lubricants, disintegrating agents, flavoring agents, solubilizing agents, and the like. The pharmaceutical preparation of the present invention can be obtained by treating these components according to a conventional method.

[0013]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples, but it goes without saying that the present invention is not limited to only these Examples.

<Examples 1 to 5, Comparative Examples 1 to 3> [Preparation of Formulation] Tablets were prepared according to the formulation shown in Table 1 and the production method shown in FIG.

[Production method] The production was carried out according to FIG. That is, trihydrochloric acid, excipient, crystalline cellulose, croscarmellose sodium and hydroxypropylmethylcellulose of Compound 1 are sufficiently mixed using a V-type mixer, granulated using a vertical granulator, dried and sieved. Thus, granules for tableting were obtained. The granules for tableting and magnesium stearate were mixed and tabletted to obtain tablets (* 1 in the table represents an excipient).

[0016]

[Table 1]

[Evaluation of stability] Based on the coloring of the tablet and the residual ratio of trihydrochloric acid of Compound 1 in the tablet, the stability was determined at 40 ° C. and 75% RH for 6 hours.
The stability of the formulation at months was evaluated.

1) Coloring of tablets The whiteness of the tablets was measured using a color difference meter, and the color difference from the start was determined. Table 2 shows the results. According to this table, in Examples 1 to 5 containing sugar alcohol and / or lactose, the coloring of the tablets was remarkably suppressed, and in Examples 2 to 5 containing sugar alcohol, especially Examples 2 to 5 containing D-mannitol. In, coloring was most suppressed. This indicates that the pharmaceutical preparation of the present invention can stably contain a compound having a partial structure represented by the above general formulas (1) to (3) and / or a salt thereof.

[0019]

[Table 2]

2) Stability of Trihydrochloride of Compound 1 in Tablets Tablets were sufficiently pulverized and mixed, methanol was added, and the mixture was shaken. The methanol extract was subjected to high performance liquid chromatography. The residual ratio was determined from the quantitative value of the trihydrochloride of Compound 1 at the beginning with respect to the quantitative value at the start of the treatment for 6 months. Table 3 shows the results. According to this table, Examples 1 to 5 containing sugar alcohol and / or lactose have a residual rate of 95% or more. Among Examples 2 to 5 containing sugar alcohol, examples containing D-mannitol are particularly preferred. In Example 2, the residual ratio was high. This indicates that the pharmaceutical preparation of the present invention can stably contain a compound having a partial structure represented by the above general formulas (1) to (3) and / or a salt thereof.

[0021]

[Table 3]

[0022]

According to the present invention, the general formulas (1) to (3)
A compound having a partial structure represented by formula (1) and / or a salt thereof can be stably compounded.

[Brief description of the drawings]

FIG. 1 is a diagram showing a production flow of a tablet.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 47/26 A61K 47/26 J

Claims (4)

[Claims] 1. General formulas (1), (2), and
A solid pharmaceutical preparation comprising a compound having all of the partial structures shown in (3) and / or a physiologically acceptable salt thereof and a sugar alcohol and / or lactose. Embedded image General formula (1) (wherein, R1 and R2 each independently represent a hydrogen atom or a halogen atom.) General formula (2) Formula (3) (wherein, R3, R4, and R5 each independently represent a hydrogen atom, an aromatic group which may have a substituent,
4 represents an aliphatic alkyl group, an aromatic group which may have a substituent or an aliphatic alkylcarbonyl group having 1 to 4 carbon atoms, and at least one of R4 and R5 may have a substituent. It should be a good aromatic alkyl group. ) 2. The compound having all of the partial structures represented by the general formulas (1), (2) and (3) is a compound represented by the following general formula (4). A solid pharmaceutical preparation according to claim 1. Embedded image General formula (4) (However, R1, R2, R3, R4, and R5 represent the same as above, respectively, and m represents an integer of 0 to 3.) 3. A compound represented by the general formula (4):
[4,4-bis (4-fluorophenyl) butyl] -4
The pharmaceutical preparation according to claim 1 or 2, which is-(2-hydroxy-3-phenylamino) propylpiperazine. 4. The pharmaceutical preparation according to claim 1, wherein the sugar alcohol is D-mannitol.