JPS59130866A - Production of pindolol preparation - Google Patents

Abstract

PURPOSE:Pindolol hardly soluble in water (used for treating hypertension and arrhythmia) is solubilized in water using heptakis(2,6-di-O-methyl)beta-cyclodextrin to give a pindolol preparation with a wide range of application as a drug. CONSTITUTION:Pindolol of the formula is dispersed and dissolved in an aqueous solution of keptakis(2,6-di-O-methyl)-beta-cyclodextrin by applying ultrasonic waves to produce the water-based pindolol preparation. The preparation is not only directly applicable as an injection solution but also orally, because the absorption is increased, thus its application range is expanded. The resultant preparation is diluted into a variety of concentrations of solutions for injection or internal use or subjected to freeze-drying to a powder for solid drugs.

Description

[Detailed description of the invention] The present invention relates to a method for producing a pindolol formulation.

For more information, see Heptakis (2,6-G〇-Medyl)
- A method for producing a pindolol formulation that uses β-cyclodextrin (hereinafter abbreviated as DM-β-CyD) to make pindolol, which is poorly soluble in water, water-soluble and expands the scope of its application as a pharmaceutical product. This applies to

Pindolol has the structure shown in the formula below, and it blocks the β-receptors in the heart, suppresses the increase in heart rate and increase in cardiac contractility caused by abnormal activation of the sympathetic nervous system, and increases the demand for oxygen in the myocardium. It is a substance that prevents oxygen and normalizes the supply and demand balance of oxygen.

Pindolol has a weak effect on suppressing cardiac contractility at doses that reduce heart rate, so it has a wide therapeutic range and has been put into practical use as a drug for hypertension and irregularities.

However, pintrol is H-soluble in water, and when granules or tablets formed with ordinary pharmaceutical excipients are orally administered, it is difficult to absorb in the gastrointestinal tract, and liquid formulations (oral solutions, injections) When used as a surfactant, it is solubilized by a certain type of surfactant, but the side effects of the surfactant itself pose a problem.

In view of the above-mentioned circumstances, the present inventors conducted research on the water solubilization of pindolol, and as a result, they obtained pindolol by DM-β-CVD.
The present invention was completed based on the discovery that when dissolved in an aqueous solution/liquid, the aqueous solution has a concentration that can be used as an injection and has a therapeutic effect.

1. In other words, the present invention provides therapeutically effective injections, oral liquid preparations, and solid preparations that are expected to increase the absorption rate when water-soluble pindolol is administered in the form of a liquid or solid preparation. This invention relates to a method for manufacturing pindolol preparations in various dosage forms such as pharmaceutical preparations.

The method for producing the pindolol formulation of the present invention will be described.

Pindolol is added to the DM-β-CVD aqueous solution, and dispersed and dissolved using ultrasound for about 2 hours.

This dissolution operation is performed at room temperature or under heated conditions, e.g.
It may be ℃. After dissolving, filter the solution through a membrane filter.
(pore size 0.22 um)) to obtain a pindolol aqueous solution.

The aqueous pindolol solution obtained according to the present invention can be diluted with water to various concentrations and formulated into pharmaceutical preparations. It is also possible to freeze-dry the pindolol aqueous solution and store it as a powder, and this powder can be used to formulate a pharmaceutical preparation. Examples of pharmaceutical preparations include injections, internal solutions, powders, fine granules, and granules. During formulation, conventional pharmaceutical excipients, diluents, stabilizers, or desired pH adjusters and osmotic pressure adjusters can be added.

The osmotic pressure ratio of the pindolol aqueous solution produced by the present invention is as low as 0.24 when solubilized with 10 (W/V)% DM-β-cyD, and is stable against light and heat. β-CVD has almost no toxicity, is safe even when used at high concentrations, and can make pindolol, which is sparingly soluble in water, solubilized to a therapeutically effective St degree. This solubilization phenomenon of pindolol is explained as follows. That is, an aqueous solution of pindolol (11 degrees 7.06
10-5 M) shows an ultraviolet absorption spectrum as shown by the solid line in the figure, and the maximum absorption wavelength is around 263 nm, but when DM-β-CVD was added to this aqueous solution (concentration 2
．． 00'
As shown by the broken line, the maximum absorption wavelength is around the same <263 nm, but it shifts slightly to the longer wavelength side. DM
- Such a spectral change due to the addition of β-QyD is
It was shown that pindolol forms an clathrate compound with DM-β-CVD in an aqueous solution, and it is assumed that the clathration increases the water solubility of pindolol and also increases its stability against light and heat. be done.

As mentioned above, the pindolol preparation produced by the present invention is water-soluble and can not only be applied as an injection as it is, but also when used as an oral preparation, it is likely to be water-soluble, increasing the absorption rate. Wide range of application. Moreover, the invention of the manufacturing method is an epoch-making manufacturing method that can make pindolol, which is poorly soluble in water, water-soluble, and is excellent as an industrial manufacturing method.

Below, experimental examples and examples of the present invention will be given to explain more specifically.

Example 0.1 1 g of Pintolu 50Il was added to 1011 of each DM-β-cyD aqueous solution of 0.20 (W/V)%, and 3
After dispersing and dissolving using ultrasonic waves at 0° C. for 2 hours, the mixture is filtered using a membrane filter (pore size: 0.223 Ill). The absorbance of the first solution was measured at the maximum absorption wavelength around 263 nm, and the concentration of dissolved pindolol was determined. The results are shown in Table 1 above.

Table 1 Example 1 DM-β-cyoiooo was added to distilled water for injection 1! Add 0.6 g of pintolu to this, disperse and dissolve using ultrasonic waves for 2 hours at 30°C, and filter with a membrane filter (pore size 0.22 Jl) C'.
(W/V)% pindolol aqueous solution is obtained.

Add sodium chloride to 100 xl of the pindolol aqueous solution.
Add 1.26 () and 200 xi of distilled water for injection, stir to dissolve. This solution is sterilized by filtration, and 0.02<
W/V)% pindolol injection.

This injection was stable even when stored at 40°C for one month.

Example 2 100 x I of the pinto[]-le aqueous solution obtained in Example 1 was freeze-dried to obtain powder 101J. Distilled water for injection was added to the powder 10Q and sodium chloride 1,260 mt.
fi 300yJ' 0.02 (W/V
) % h> g.

- Injections and injections.

Example 3 50 parts of the freeze-dried powder obtained in Example 2, 9 parts of lactose and 1 part of magnesium stearate are uniformly mixed to form a powder containing C and 0.5 (W/W)% of pindolol.

Example 4 9 parts of lactose and 1 part of magnesium stearate were uniformly mixed with 50 parts of the freeze-dried powder obtained in Example 2, and the mixture was made into fine granules by normal dry granulation, and classified to yield 0.5 pindolol.
(W/W)%.

Example 5 9 parts of crystalline cellulose was added to 50 parts of the freeze-dried powder obtained in Example 2.
1 part and 1 part of methylcellulose are mixed uniformly, kneaded, crushed, granulated, dried, classified, and made into pindolol 0.5 (W/
W) %.

[Brief explanation of drawings]

The figure shows an ultraviolet absorption spectrum of an aqueous pindolol solution obtained by the production method of the present invention. In the figure, the solid line is pindolol aqueous solution, and the broken line is pindolol hebutakis (
2 is an ultraviolet absorption spectrum of an aqueous solution of 2,6-di〇-methyl)-β-cyclodextrin clathrate. F Continuation Lottery (Method) May 9, 1982] Special, '[Agency Commissioner Kazuo Wakasugi 1+c?
Indication of t1, -Ji 11 1981 Special Edition 1 Incline No. 5743 2 Name of the invention 3 Process for manufacturing pindolol preparation 3 Applicant for cuffs Patent applicant 10 tr 11 Motohashi Kobune-cho, Chuo-ku, Tokyo Seria Shinyaku Kogyo Co., Ltd. 4. Agent: Chiyo, Tokyo 1)] Ward Uchigami EE 3-5-3-5, Sode l
Date of order: 1984 47i 61J (Shipping date: 58.4.2
6) 6. Clarification of the subject of amendment ζ111 rjJ 7. Contents of amendment Submission of specification clearly written in type 8. List of documents discussed

Claims (1)

[Claims] 1) Heptakis (2,6-G-O-
1. A method for producing a pindolol preparation, which comprises dispersing and dissolving pindolol in an aqueous solution of medyl)-β-cyclodextrin using ultrasound.