JPS62148423A - Mobenzoxamine solution pharmaceutical - Google Patents

Abstract

PURPOSE:The titled solution pharmaceutical containing a clathrate compound of mobenzoxamine with heptakis(2,6-di-0-methyl)-beta-cyclodextrin (DM-beta-CydD). CONSTITUTION:A mobenzoxamine solution pharmaceutical obtained by dissolving 1-[2-(4-methoxybenzhydryloxy)ethyl]-4-[3-(4-fluorobenzoyl)propyl]piper azine (mobenzoxamine) in methanol, adding the solution to heptakis(2,6-di-0-methyl)-beta- cyclodextrin (DM-beta-CyD), thoroughly mixing both, distilling away the methanol, adding purified water to dissolve the residue and freeze-drying the solution. In the process,the molar ratio of the mobenzoxamine to DM-beta-CyD is preferably 1:3-1:10. Although the mobenzoxamine has low solubility in water, the above- mentioned clathrate compound increases the solubility and the formulation into the solution pharmaceutical, e.g. injection, syrup, etc., can be carried out and the pharmaceutical is stable even in preservation for a long period. A dry syrup may be, formulated, as necessary.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to a liquid preparation of mobenzoxamine, more specifically, a liquid preparation of mobenzoxamine and heptakis (2,6-/-0-methyl)-β-cyclodextrin (hereinafter referred to as DM). -β-CyD
The present invention relates to a stable mobenzoxamine liquid preparation containing all clathrate compounds (referred to as ).

[Conventional technology and its problems]

1-(2-(4-methoxybenzhydryloxy)ethyl]-4-[3-(4-fluorobenzoyl)f-ropyl]biperazone (mobenzoxamine) has excellent antiemetic effects,
It has an antispasmodic effect (British Patent No. 1,529,782), and is currently being studied for clinical application.

However, mobenzoxamine has very low solubility in water, is unstable, and its activity decreases significantly when stored for a long period of time.

It was difficult to make it into a liquid formulation.

[Means for solving problems]

Under such circumstances, the present inventor conducted intensive research to solve the above-mentioned drawbacks and found that Mobe/zoxamine was converted into DM-β-
We discovered that when made into an inclusion compound with CFD, the solubility of mobenzoxamine in water increases, making it possible to form liquid formulations such as injections and syrups, and that this liquid formulation is stable even when stored for a long period of time. The invention has been completed.

That is, the present invention provides mobenzoxamine and DM-β-C.
The present invention provides a mobenzoxamine solution containing a clathrate compound with 7D.

The clathrate compound of mobenzoxamine and DM-β-CFD can be prepared, for example, by dissolving mobenzoxamine in methanol, adding this to 1 kDM-β-cyo, mixing well, distilling off the methanol, then adding Nli water to dissolve, and freeze-drying. Manufactured by a method. At this time, the molar ratio of mobenzoxamine and DM-β-cyo is 1=3 to 1:1.
0 is preferred.

The mobenzoxamine liquid preparation of the present invention is prepared by dissolving the clathrate compound alone or together with a suitable excipient in a solvent according to a conventional manufacturing method for liquid preparations 1 such as injections and syrups. It can also be made into a dry syrup if necessary.

〔Effect of the invention〕

As described above, by using the clathrate compound of mobenzoxamine and DM-β-cyo, mobenzoxamine can be made into a liquid preparation, and the liquid preparation is stable for a long period of time.

〔Example〕

Next, an example will be given and explained.

Example 1 Mobenzoxamine (M) was dissolved in methanol, added to DM-β-C7D, mixed well, methanol was distilled off, purified water was added, dissolved, and lyophilized to prepare the next clathrate. The compound was obtained.

Example 2 The following sample prepared by the method of Example 1 was placed in a flask in an amount equivalent to 0.409 mobenzoxamine (M), and distilled water for injection was added to it, dissolved and tightly closed at 200 mm, and this solution 25 was colorless. The mixture was filled into a 25-mm ampoule made of transparent glass and sealed, and an accelerated test was conducted at 40° C. under light shielding to measure the appearance, pH, and M residual rate.

The solubility of M in water is 0.019/1 at 25°C.
Because it is very low at 00- or less.

Prepare a pH 2.0 hydrochloric acid/potassium chloride buffer i, weigh out exactly 0.409 of M, then add and dissolve this buffer to make exactly 200 ml! Closed. This solution 25rILl was filled into a 25ml ampoule made of colorless transparent glass and sealed, and an accelerated test was conducted at 40°C under light shielding.
The residual rate was measured. The results are shown in Table 1.

Sample A: M/DM-β-c) rD=1/3 Sample B
: M/DM-β-C7D=1/4 Sample C:M Table 1 Table 2 Example 3 The following sample produced by the method of Example 1 was placed in a flask in an amount equivalent to 1.0 g as mobenzoxamine (M).
Granulated sugar 1002 was added to this, and purified water was added to dissolve it to make it exactly 500. After putting this syrup liquid 50. Do it.

The M residual rate was measured. The results are shown in Table 2.

Sample D: M/DM-β-Cy D = 1/3
Sample E: M/DM-β-cyo=1/4 or less, margin or more

Claims (1)

[Claims] 1. Mobenzoxamine and heptakis (2,6-di-O-
1. A mobenzoxamine liquid preparation containing a clathrate compound with methyl)-β-cyclodextrin.