JPS61225122A - Composition containing quinazoline compound - Google Patents

Abstract

PURPOSE:To provide the titled composition for promoting the absorption of a drug, by using lecithin as an essential component. CONSTITUTION:A pharmaceutical composition containing a quinazoline compound (e.g. the compound of formula I, the compound of formula II, etc.) and useful as a remedy for hypertension is produced by using lecithin (preferably the one extracted from albumen or soybean, etc., and having a phase transition temperature of <=37 deg.C) as an essential component. It is administered in the form to effect the transcutaneous or rectal absorption, i.e. as an ointment or suppository.

Description

[Detailed description of the invention] The present invention relates to a composition containing a quinatuolin compound.

More specifically, the present invention relates to a composition containing a quinazoline compound for the purpose of promoting absorption of the quinazoline compound.

In the pharmaceutical field, quinatuolin compounds are useful substances, such as prazosin as a therapeutic agent for hypertension and methaqualone as a hypnotic agent. Usually, these substances are administered orally and absorbed through the intestinal tract to reach a predetermined blood concentration. However, if these substances can be administered directly to the skin and reach a specified blood concentration through skin absorption, or if they are administered to the rectum and can reach a specified blood concentration through rectal absorption. , quinatuolin-based compounds can be used more safely.

The present inventors have conducted research on the absorption of quinatuolin compounds, particularly through dermal and rectal administration of the compounds, with the aim of safe use of quinatuolin compounds, particularly as antihypertensive agents. the result,
The inventors discovered that the absorption of this compound is promoted when it is administered together with lecithin, leading to the completion of the present invention.

That is, the object of the present invention is to promote the absorption of guinazoline compounds, and in order to achieve the object, the present invention discloses a composition containing a quinazoline compound characterized in that it contains lecithin as an essential component.

In the field of pharmaceuticals, techniques for adding lecithin to effectively express the effects of drugs have been known.

For example, JP-A-56-135416. 58-150
508, 55-47608. What is seen in the invention related to No. 57-75916 (However, it was not known that adding lecithin to quinazoline compounds greatly increases absorption. In other words, adding lecithin to quinazoline compounds In particular, the addition of lecithin having a phase transition temperature of 37° C. or lower is new, a technique that could not be imagined based on conventional knowledge, and its effects are unpredictable.

The present invention will be explained in detail below.

In the present invention, a guinatuolin-based compound is a compound having a guinatuolin skeleton, and those that are particularly important in the pharmaceutical field are antihypertensive agents, representative examples of which are prazosin and bunazosin, each represented by the following formula 4114.

These substances are generally available as hydrochloride salts.

The use of the hydrochloride salts of these substances is therefore a specific embodiment of the invention.

The lecithin according to the present invention is extracted from egg yolk or soybean, and in some cases, further purified phospholipid-containing substances, hydrogenated products thereof, or synthetic glycerophosphate esters can be used. Among lecithins, lecithins having a phase transition temperature of 37° C. or lower are particularly preferred. Here, the phase transition temperature is the temperature at which the solid phase transitions to the liquid phase, and in lecithin, it is determined by the number of carbon atoms and the degree of unsaturation of the hydrocarbon moiety of lecithin. According to the experimental example described later.

A study of lecithin in which the hydrocarbon moiety is saturated revealed that the lower the number of carbon atoms in the hydrocarbon moiety, the higher the membrane permeation rate of the drug, and therefore the absorption is promoted. From the results of this experimental example, the phase transition temperature is 37
It has been found that preferred embodiments are obtained when lecithin below 0.degree. C. is used.

The composition of the present invention is not particularly limited as long as it is a composition in the form of a preparation in which the quinatuolin compound is absorbed through membrane permeation.

However, dosage forms intended for dermal absorption and dosage forms intended for rectal absorption are particularly preferred formulation forms, and therefore emollients and suppositories are preferred embodiments of the invention.

Components such as excipients necessary for producing the composition of the present invention can be arbitrarily selected and added, and the present invention is not limited thereto. Moreover, the composition of the present invention may be manufactured according to a conventional method depending on the selected formulation form.

The present invention will be specifically explained by the following examples.

Example 1 10 g of bunazosin hydrochloride and 15 g of egg yolk lecithin were dissolved in 500 g of propylene glycol to prepare a drug solution of the present invention for skin absorption.

Example 2 Bunazosin hydrochloride 3II and egg yolk lecithin 15.9 g were mixed with 500 g of cocoa butter to prepare a suppository of the present invention for rectal absorption.

Example 3 The procedure was carried out in the same manner as in Example 1 except that prazosin hydrochloride was used instead of bunazosin hydrochloride in Example 1.
The chemical solution of the present invention was prepared.

The present invention will be explained in detail using the following experimental examples.

Experimental Example 1 Sample and Method The chemical solution of Example 1 was used as a specimen sample. Separately, a drug solution was prepared in Example 1 except that the egg yolk lecithin was removed.

This was prepared as a control sample. The hair on the back of the rabbit was removed, and 5 g of each specimen or control sample was randomly administered.

Bunazosin concentration in blood was measured over time. In addition.

Quantification was performed by fluorometry.

Results Regarding the control sample, the blood bunazosin concentration was below the quantitative detection limit of bunazosin at any time after administration. On the other hand, for the specimen sample, it was (Figure 1). Figure 1 shows the results of the average value of n = 3. Figure 1
It is clear from these results that the drug solution of the present invention exhibits the effect of significantly promoting absorption.

Experimental Example 2 Sample and Method The inhibitor of Example 2 was used as a test sample. Separately, a detergent was prepared in Example 2 except that egg yolk lecithin was removed.

This was prepared as a control sample. 500+ng of each test sample or control sample was administered into the rectum of male rats weighing approximately 300 g, and the bunazosin concentration in the blood was measured over time.

Note that quantification was performed by fluorescence photometry.

The results are shown in Figure 2. Figure 2 shows the results of the average value of n-2. In the figure, the e-marked line shows the results for the specimen sample, and the ○ mark line shows the results for the control sample.

It is clear from FIG. 2 that the suppository of the present invention exhibits the effect of promoting absorption.

Experimental Example 3 Sample bunazosin hydrochloride 20 mg and phospholipid 8 in Table 1 below
The phospholipid 5n9 described in the column was mixed with propylene glycol 0.
A drug solution dissolved in 5 g was prepared and used as a sample.

Table 1 Method: The skin removed from a hairless mouse was attached to a membrane permeation test device, and the sample was placed on the epidermis side and water was placed on the dermis side.The aqueous phase was stirred and bunazosin in the aqueous phase was measured. I found the speed.

The results are shown in Figure 3. Figure 3 shows that as the number of carbon atoms in the hydrocarbon moiety of the phospholipids that make up lecithin increases, the membrane permeation rate decreases, and the phase transition temperature is 37°C, which is the normal body temperature of animals.
It is known that when using phospholipids exceeding Therefore, it has been found that it is preferable to use lecithin having a phase transition temperature of 37° C. or lower.

Experimental Example 4 A sample was prepared in the same manner as in Experimental Example 3, except that egg yolk lecithin was used at a concentration of 0.1% to 3.0% instead of phospholipid 5 rn9 in the sample of Experimental Example 3. Then, the membrane permeation rate was determined in the same manner as in the same experimental example. The results are shown in Figure 4. It is clear from FIG. 4 that as the lecithin concentration increases, the membrane permeation rate increases up to a certain concentration. It is presumed that this constant concentration is related to the micelle-forming concentration of lecithin in the composition. Therefore, lecithin is
Although it may be blended without any particular concentration limitation, it is considered that up to 5% is practically sufficient.

Experimental Example 5 Sample and Method A drug solution was prepared by dissolving 20 mg of prazosin hydrochloride and 5 mg of phospholipid in 0.5 g of propylene glycol.

It was used as a specimen sample. Prepare a drug solution prepared in the same way as the test sample, except that phospholipids are not added.

This was used as a control sample. A membrane permeation experiment was conducted in the same manner as in Experimental Example 3, and changes over time in the cumulative amount of prazosin permeated were determined.

The results are shown in FIG. In the figure, the marked lines indicate the results for the specimen sample, and the ○ marked lines indicate the results for the control sample. It is clear from FIG. 5 that the phospholipids constituting lecithin promote membrane permeation for absorption of prazosin.

[Brief explanation of drawings]

FIG. 1 is Time 1 described in the results section of Experimental Example 1, and is a graph showing the change over time in blood concentration in skin administration. FIG. 2 is the one described in the section of results of Experimental Example 2. It is a graph showing the change in blood concentration over time during rectal administration. FIG. 3 is shown in the section of results of Experimental Example 3, and is a graph showing the relationship between the number of carbon atoms in the hydrocarbon portion of a phospholipid and the membrane permeation rate. FIG. 4 is described in Experimental Example 4, and is a graph showing the relationship between lecithin concentration and membrane permeation rate. FIG. 5 is described in the section of results of Experimental Example 5, and is a graph showing the change over time in the cumulative amount of drug permeation.

Claims (4)

[Claims] (1) Quinatuolin-based compound-containing composition containing lecithin as an essential component (2) The quinazoline compound-containing composition according to claim 1, wherein the quinazoline compound is prazosin hydrochloride or bunazosin hydrochloride. (3) The quinatuolin compound-containing composition according to claim 1 or 2, wherein the composition is a composition for skin absorption or a composition for rectal absorption. (4) The quinatuolin compound-containing composition according to claims 1 to 3, wherein the lecithin has a phase transition temperature of 37°C or lower.