WO2000053184A1

WO2000053184A1 - Drug composition for percutaneous absorption

Info

Publication number: WO2000053184A1
Application number: PCT/JP2000/001429
Authority: WO
Inventors: Hitoshi Yamauchi; Noriko Nakajima; Hiroyoshi Nishi; Yoshinori Matsuoka; Shinji Yano
Original assignee: Saitama Daiichi Pharmaceutical Co., Ltd.; Mitsubishi Chemical Corporation
Priority date: 1999-03-11
Filing date: 2000-03-09
Publication date: 2000-09-14
Also published as: AU2940000A

Abstract

A drug composition for percutaneous absorption, comprising (a) an active ingredient selected from the group consisting of quinazoline derivatives having a α1-receptor blocking effect and salts thereof, (b) a substance selected from the group consisting of C8-C15 fatty acids, C8-C16 fatty acid esters, C8-C12 higher alcohols, and geraniol, (c) a substance selected from the group consisting of polyhydric alcohols and ethanol and, if necessary, (d) benzyl alcohol. This composition enables efficient percutaneous absorption of terazosin or other drugs.

Description

Description Pharmaceutical composition for transdermal absorption Technical field

The present invention relates to a pharmaceutical composition for percutaneous absorption useful for treating hypertension or dysuria, which contains a quinazoline derivative having a 1 receptor blocking action or a salt thereof as an active ingredient. Background art

A quinazoline derivative or its salt having a 1-receptor blocking effect such as terazosin hydrochloride is clinically used as a therapeutic agent for hypertension or dysuria. The drug may cause side effects, such as orthostatic hypotension, when taken orally, and this is thought to be due to the highest blood concentration in the first dose. As a preparation which can avoid such problems and achieve a constant blood concentration over a long period of time, a pharmaceutical composition for transdermal absorption containing this drug as an active ingredient has been proposed (JP-A-10-45597). Gazette, International Publication W095 / 31190, International Publication W098 / 37870). Disclosure of the invention

An object of the present invention is to provide a quinazoline derivative having a 1-receptor blocking action such as terazosin hydrochloride or a salt thereof as an active ingredient, which is capable of efficiently transdermally absorbing the active ingredient. It is to provide a pharmaceutical composition.

The present inventors have conducted intensive research to solve the above-mentioned problems, and as a result, have found that esters of fatty acids having 8 to 15 carbon atoms such as chlorophyllic acid and esters of fatty acids having 8 to 16 carbon atoms such as methyl propyl phosphate etc. It has been found that a pharmaceutical composition having extremely excellent transdermal absorbability can be provided by combining a quinazoline derivative or a salt thereof with a component such as a polyhydric alcohol or a component such as a polyhydric alcohol. In addition, benzyl alcohol is added to the above pharmaceutical composition. It has also been found that by blending, a pharmaceutical composition with further improved transdermal absorbability can be provided. The present invention has been completed based on these findings.

That is, the present invention provides a pharmaceutical composition for transdermal absorption, comprising the following components:

(a) an active ingredient selected from the group consisting of quinazoline derivatives having a 1 receptor blocking action and salts thereof;

(b) One or more substances selected from the group consisting of fatty acids having 8 to 15 carbon atoms, esters of fatty acids having 8 to 16 carbon atoms, higher alcohols having 8 to 12 carbon atoms, and geraniol ;as well as

(c) a pharmaceutical composition comprising one or more selected from the group consisting of polyhydric alcohols and ethanol.

According to a preferred embodiment of the present invention, the above-mentioned pharmaceutical composition further comprising benzyl alcohol as the component (d); the quinazoline derivative or a salt thereof is selected from the group consisting of terazosin, prazosin, doxazosin, bunazosin, and salts thereof. The above-mentioned pharmaceutical composition, wherein the quinazoline derivative or a salt thereof is terazosin or a salt thereof; the above-mentioned pharmaceutical composition, wherein the salt of the quinazoline derivative is terazosin hydrochloride; The above pharmaceutical composition, which is one or more fatty acids selected from the group consisting of acid, lauric acid, myristic acid, and pen-decanoic acid; wherein the fatty acid ester is methyl caprate, ethyl caprylate, capric acid Sopropyl, methyl caprylate, ethyl caprylate, isopropyl caprylate, lauri The above pharmaceutical composition is provided which is one or more esters selected from the group consisting of methyl phosphate and ethyl laurate.

According to another preferred embodiment, the higher alcohol is one or more higher alcohols selected from the group consisting of octanol, nonanol, decanol, pendanol, and dodecanol. The above-mentioned pharmaceutical composition, wherein the polyhydric alcohol is propylene glycol, 1,3-butylene glycol, ethylene glycol, diethylene glycol, 1,3-propylene glycol, triethylene glycol, dipropylene glycol. The above pharmaceutical composition is provided which is one or more polyhydric alcohols selected from the group consisting of glycol, 1,4-butanediol, and glycerin.

According to a particularly preferred embodiment, there is provided a pharmaceutical composition for transdermal absorption, comprising:

(b-1) a fatty acid having 8 to 15 carbon atoms or a fatty acid ester having 8 to 16 carbon atoms;

(b-2) a higher alcohol having 8 to 12 carbon atoms;

(c-1) ethanol;

(c-2) polyhydric alcohol;

(d) benzyl alcohol, and

(e) water

Is provided by the present invention, wherein the active ingredient selected from the group consisting of quinazoline derivatives having a 1 receptor blocking action and salts thereof is an active ingredient selected from the group consisting of terazosin and salts thereof. The above pharmaceutical composition is the most preferred embodiment.

In another aspect, the present invention relates to a composition for promoting transdermal absorption of a drug selected from the group consisting of quinazoline derivatives having a 1 receptor-blocking action and salts thereof, comprising the following components:

(c) One or more substances selected from the group consisting of polyhydric alcohols and alcohols

According to a preferred embodiment of the present invention, there are provided the above composition further comprising benzyl alcohol, and the above composition for promoting percutaneous absorption of terazosin hydrochloride.

In still another aspect, the present invention relates to a method for producing the above-mentioned pharmaceutical composition for transdermal absorption. (b) One or more substances selected from the group consisting of fatty acids having 8 to 15 carbon atoms, esters of fatty acids having 8 to 16 carbon atoms, higher alcohols having 8 to 12 carbon atoms, and geraniol And (c) the use of one or more substances selected from the group consisting of polyhydric alcohols and ethanol. BEST MODE FOR CARRYING OUT THE INVENTION

Examples of the active ingredient, a quinazoline derivative having a 1-receptor blocking effect or a salt thereof include, for example, terazosin: 4-amino-2- [4- (tetrahydro-2-furoyl)-1-piperazinylj-6, 7-dimethoxyquinazoline], prasosin: 1- (4-amino-6,7-dimethoxy-2-2-quinazolinyi-4-1 (2-furoyl) piperazinej, doxazo,

Caoxazosin: to (4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(1,4-benzodioxan -2-ylcarbonyl) piperazme bunazosin bunazosin: 4-amino-2-(4-butyry to hexahydro-lH -1,4-diazepin-tolyl) -6,7-dimethoxyquinazoline] or a salt thereof, and a hydrate or solvate thereof may be used. When these components have an asymmetric carbon, an optical isomer, an arbitrary mixture of optical isomers, or a racemate may be used as an active ingredient. Of these, terazosin or a salt thereof or a hydrate thereof is preferably used, and terazocin hydrochloride is preferably used.

(terazosin hydrochloride: racemic hydrochloride, dihydrate) is more preferable.

The pharmaceutical composition of the present invention comprises, together with the active ingredient (component (a)), a fatty acid having 8 to 15 carbon atoms, an ester of a fatty acid having 8 to 16 carbon atoms, and a higher alcohol having 8 to 12 carbon atoms. Or two or more substances (component (b)) selected from the group consisting of alcohol and geraniol, and one or more substances (components (component (b)) selected from the group consisting of polyhydric alcohols and ethanol. c))) is included. The pharmaceutical composition of a preferred embodiment of the present invention further comprises benzyl alcohol (component ()) in addition to the above components.

Fatty acids used as component (b) should have 8 to 15 carbon atoms However, the structure is not particularly limited, and any structure may be used. For example, either a straight-chain or branched-chain fatty acid may be used, and it may have one or more unsaturated bonds. Of these, saturated and linear fatty acids are preferred. For example, force-puric acid, force-prillic acid, pendecanoic acid, lauric acid, myristic acid, or penic acid decanoic acid can be suitably used, and force-puric acid or lauric acid is more preferable.

As the fatty acid ester used as the component (b), an ester composed of a fatty acid having 8 to 16 carbon atoms can be used. The structure of the fatty acid moiety is not particularly limited, and any structure may be used. For example, it may be linear or branched, and may have one or more unsaturated bonds. Preferably, straight-chain saturated fatty acid esters can be used. Although the structure of the ester moiety is not particularly limited, a linear or branched alkyl group having 1 to 6 carbon atoms, or an aralkyl group such as a benzyl group can be used, and preferably 1 to 6 carbon atoms. A single linear or branched alkyl group can be used. Further, an ester composed of a fatty acid having 8 to 16 carbon atoms can be used.More preferably, a fatty acid ester having 8 to 12 carbon atoms is used, and more specifically, as a fatty acid ester, For example, methyl caprate, ethyl caprylate, isopyl porphyrate, methyl caprylate, ethyl caprylate, isopropyl caprylate, methyl laurate, or ethyl laurate can be used, and cabril is more preferable. Methyl acid or ethyl ethyl prillate can be used.

As the higher alcohol used as the component (b), a monohydric alcohol having about 8 to 12 carbon atoms can be used. The structure of the higher alcohol is not particularly limited, may be linear or branched, and may contain one or more unsaturated bonds. Preferably, a linear, saturated alcohol can be used. More specifically, for example, octanol, nonanol, decanol, pendecanol, or dodecanol can be used, and nonanol, decanol, or pendeol can be more preferably used. In addition, as the component (b), carbon One or two or more substances selected from the group consisting of fatty acids having 8 to 15 carbon atoms, fatty acid esters having 8 to 16 carbon atoms, higher alcohols having 8 to 12 carbon atoms, and geraniol are selected. Preferred combinations include:

(b-1) a fatty acid having 8 to 15 carbon atoms or a fatty acid ester having 8 to 16 carbon atoms,

(b-2) A combination of higher alcohols having 8 to 12 carbon atoms is used.

As the polyhydric alcohol used as the component (c), a dihydric or trihydric alcohol can be used, but the structure is not particularly limited. For example, propylene glycol, 1,3-butylene glycol, ethylene glycol, diethylene glycol, 1,3-propylene glycol, triethylene glycol, dipropylene glycol, 1,4-butanediol, or glycerin And more preferably propylene glycol or 1,3-butylene glycol. As the component (c), one or more substances selected from the group consisting of polyhydric alcohols and ethanol are selected. More preferably, (c-1) ethanol and (c- 2) A combination of polyhydric alcohols is used.

The amount of each component in the pharmaceutical composition of the present invention can be appropriately selected according to conditions such as the type of the active ingredient and a desired transdermal absorption rate. The above quinazoline derivative or a salt thereof is 0.01 to 15 wt%, preferably 0.05 to about 10 wt%, and component (b) is 0.1 to 80 wt%, preferably 5 to 70 wt%, and more preferably 5 to 20 wt%. Component (c) can be blended at about 0.5 to 95 wt%, preferably about 1 to 90 wt%. When benzyl alcohol is blended as component (d), the blending amount is about 0.5 to 20 wt%.

The pharmaceutical composition of the present invention may contain water, and in order to reduce skin irritation, a water-containing composition may be suitably used. When prepared as a water-containing composition, the above-mentioned quinazoline derivative or a salt thereof as an active ingredient is 0.01 to 15 wt%, preferably about 0.05 to 10 wt%, and the component (b) is 0.1 to 10 wt%, preferably 0.5 to 2 wt%. The component (c) may be added in an amount of 0.5 to 60 w%, preferably about 1 to 45 wt%. When blending benzyl alcohol as component (d), the blending amount should be 0.5 to 20. It is about.

As a more preferred composition,

(a) 0.01 to 15 wt. of the quinazoline derivative or a salt thereof

(b-1) 0.1 to 5 wt% of a fatty acid having 8 to 15 carbon atoms or a fatty acid ester having 8 to 16 carbon atoms,

(b-2) 0.1 to 5 w of a higher alcohol having 8 to 12 carbon atoms,

(c-1) 0.5 to 60 wt% ethanol,

(c-2) 1 to 40 wt% polyhydric alcohol,

(d) benzyl alcohol 0.5 ~ 20 wt%

(e) 1-70 wt¾ water

And a composition comprising:

When water is not contained, the quinazoline derivative or a salt thereof as the active ingredient is 0.01 to 15 wt%, preferably about 0.05 to 10 wt%, and the component (b) is 0.1 to 80 wt%, preferably Can be blended in an amount of 1 to 70 wt% _N, more preferably 5 to 20 wt%, and the component (c) in an amount of 10 to 95 wt%, preferably about 20 to 90 wt%. When benzyl alcohol is blended as component (d), the blending amount is about 0.5 to 20 wt%.

The form of the pharmaceutical composition of the present invention is not particularly limited as long as it is a form suitable as a preparation for transdermal absorption. For example, general external applications such as ointments, creams, solutions, lotions, liniments, cataplasms, plasters (plus plasters), tapes, patches, gels, or reservoirs It can be prepared as a formulation. In addition, the method for preparing the pharmaceutical composition is not particularly limited, and a conventional preparation method well-known to those skilled in the art can be adopted according to the formulation form. In the production of the pharmaceutical composition part of the present invention, one or more kinds of pharmaceutical additives can be used, and the necessity and type thereof are appropriately determined by those skilled in the art according to the type of the pharmaceutical form. It is possible to choose.

For example, aqueous bases such as macrogol; oily bases such as petrolatum, liquid paraffin; gum arabic, gelatin, methylcellulose, ethylcellulose, carbohydrate Water-soluble polymers such as xymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyacrylic acid, polyvinyl alcohol, and polyvinylpyrrolidone; Agents, preservatives, coloring agents and the like can be used as additives for the preparation, but are not limited thereto. It should be noted that these excipients for pharmaceutical preparations need to be selected so as not to impair the transdermal absorbability of the pharmaceutical composition of the present invention, but the skin absorbability test specifically described in the Examples of the present specification is required. By doing so, it is possible to select the desired pharmaceutical excipient. Further, terazosin hydrochloride and the like are slightly unstable in an acid or an alkaline solution, so that it is preferable to select the pH to be 3.5 to 8.0.

Although the pharmaceutical composition of the present invention is excellent in transdermal absorbability, not only that, but also the above-mentioned quinazoline derivative and its salts which are effective components are extremely stable in the present composition, and from the viewpoint of drug stability, It is an excellent composition that does not cause any problems and has little skin irritation. Example

Hereinafter, the present invention will be described more specifically with reference to Examples, but the scope of the present invention is not limited to the following Examples.

Example 1

The isolated skin of Yucatan micropig is sandwiched between vertical diffusion cells (Franz type diffusion cells, application area: 0.95 cm ² ) circulating water at 37 ° C, and phosphate buffered saline (pH 7.4) is placed on the receiver (dermis) side. ) 4 ml was added, and the mixture was stirred with a magnetic mixer. Apply 200〃1 of each sample to the donor (keratin) side, sample the solution in the receiver over time, measure the drug concentration in the solution by high-performance liquid chromatography, and determine the amount of drug that has permeated the skin. I asked. Each sample was prepared as a suspension composition by adding terazosin hydrochloride to the components shown in Table 1.

Table 1 shows the results. In Table 1, BA is benzyl alcohol; PG is propylene glyco BG is 1,3-butylene glycol; S-318 is monoglyceride of prillic acid; IPM is isoprovir myristate; IPA is isopropyl alcohol, and the permeation rate is the skin permeation rate of the drug per unit area. The maximum permeation (g / cm ² / hr) is shown, and the cumulative permeation is the cumulative permeation of the drug per unit area (g / cm ² ) after 48 hours.

table 1

Sample components (b) L and d (d) Permeation speed Cumulative permeation amount

1 10% ke, Lanilol 20% BA 70¾ PG 106.83 810.82

2 10% Cuff ⁰ phosphate 90% PG 127.61 2677.08

3 20% cuff. Phosphoric acid 80% BG 103.60 1652.34

4 20% cuff. Methyl lylate 20% BA 60¾ PG 119.98 4110.28

5 20% cuff. Methyl lylate 20% BA 60% BG 114.59 3508.94

6 20% cuff. Ethyl lylate 20% BA 60¾ PG 75.29 2738.44

7 20% cuff. Lylic acid irif. Lohi. 20% BA 60¾ PG 63.53 2082.32

8 20% Cuff ° Methyl phosphate 20% BA 60¾ PG 72.63 2460.82

9 20% Methyl laurate 20% BA 60% PG 78.90 2625.68

10 20% Ethyl laurate 20% BA 60% PG 47.92 1543.60

11 10¾ Cuff. Phosphoric acid 20% BA 70% PG 258.96 5114.90

12 20% cuff. Phosphoric acid 20% BA 60% PG 203.59 6294.52

13 20% Pente, 20% BA 60% PG 270.00 8434.24

14 5% Lauric acid 20% BA 75% PG 191.28 4886.87

15 20% Lauric acid 20% BA 60% PG 232.45 6981.22

16 20% Lauric acid 20% BA 60% BG 52.20 1072.37

17 5% Myristic acid 20% BA 75% PG 35.87 833.95

18 to 5%. Sate, canic acid 20¾ BA 75% PG 32.79 811.31

19 20% Octanol 20% BA 60¾ PG 254.79 8408.74

20 20% Nonanol 20¾ BA 60¾ PG 232.23 7073.45

21 20% Nord 20% BA 60% PG 244.84 9070.71

22 20% Venote, power 20% BA 60% PG 281.97 9695.19

23 20% Dete, Canol 20% BA 60% PG 157.52 5315.59

24 PG only 0.08 0.30

25 BA only 4.63 84.80

26 20% BA 80¾ PG 0.65 0.27

27 60¾ S-318 / 40¾ PG 13.86 279.83

28 20% Cuff ⁰ Phosphoric acid 80¾ IPM 0.54 8.67

29 5% Cuff ⁰ phosphate 20% BA 75% IPA 6.41 50.15

30 5% c. Lumitic acid 20% BA 75% PG 2.17 31.12 Example 2

A skin permeation test was performed in the same manner as in Example 1 using the extirpated skin of Yucatan micropig. The water-containing composition shown in Table 2 was used as a sample, and the blending amount of terazosin hydrochloride was 5 Wt%. In Table 2, PG is propylene glycol; BG is 1,3-butylene glycol; BA is benzyl alcohol; EtOH is ethanol; GL is a 50% glycerin aqueous solution. The content is shown in wt%, the permeation rate indicates the maximum value of the skin permeation rate of the drug per unit area (〃g / cm ² / hr), and the cumulative permeation rate per unit area after 48 hours. The cumulative drug permeation (透過 g / cm ² ) is shown. Table 2

Cuff. Li cuff ⁰ Lil Te 1 PG BG BA EtOH water GL permeation rate accumulation;! ¾ peroxide charges phosphate m Bruno - Le

1 0.5 15 4 20 55.5 22.35 645.50

2 1 15 20 59.0 6.26 233.12

3 1 15 4 10 65.0 21.93 651.51

4 1 15 4 20 55.0 27.78 927.23

5 1 5 4 20 65.0 10.58 354.20

6 2 5 20 68.0 12.35 393.16

7 1 15 4 20 55.0 82.68 3231.83

8 1 45 4 20 25.0 36.31 639.76

9 2 15 4 20 54.0 69.80 2192.63

10 1 45 4 20 Z5.0 36.20 869.23

11 1 5 4 20 65 32.87 989.27

12 1 15 4 20 55.0 75.20 2721.93

13 15 4 20 56.0 0.31 6.71 Example 3

A drug permeation experiment was carried out in the same manner as in Example 1 except that the extirpated skin of a hairless mouse (female) was used instead of the extirpated Yucatan micropig skin. A composition was prepared by adding benzyl alcohol and propylene glycol to lauric acid, methyl caprylate, or decanol, and a sample was prepared by adding prazosin hydrochloride (10 wt%) to this composition. The content is shown in wt%, and the permeation rate is Indicates the maximum value (g / cm ² / hr) of the skin permeation rate of the drug _c

Table 3

si agent Drug lauric acid Cafyl methyl phosphate, phenol, BA PG Permeation rate

1 Furacin hydrochloride 10-20% 70% 62.89

2 // 10% 20% 70% 126.71

3 // 10% 20% 70% 92.18 Example 4

A skin permeation test was performed in the same manner as in Example 1 except that the application of each sample to one side of the donor was 100/1, and the amount of terazosin hydrochloride was 1%. In Table 4, PG indicates propylene glycol; BG indicates 1,3-butylene glycol; BA indicates benzyl alcohol; EtOH indicates ethanol. The content is expressed in wt%, the permeation rate is the maximum value of the skin permeation rate of the drug per unit area (/ g / cmVhr), and the cumulative permeation is the cumulative permeation of the drug per unit area after 48 hours. (/ G / cm ² ).

Table 4

Try Te Cuff Hydrochloride. Re cuff. Lil ΐ 、、 Kano PG BG BA EtOH Water applied too much

Materials Lasso, methyl phosphate 1)

3 £ degree

1 1.0 0.25 0, 75 20 4 30 44.0 100 11.34 413.54

2 1.0 0.25 0.75 20 4 30 44.0 100 10.75 410.42

3 1.0 0.5 0.5 20 4 30 44.0 100 11.82 444.26

4 1.0 0.5 0.5 20 4 50 24.0 100 13.99 392.64

5 1.0 0.5 0.5 20 4 50 24.0 100 11.06 394.41

6 1.0 0.5 0.75 20 4 30 43.75 100 10.59 330.51

7 1.0 1.0 10 4 40 44.0 100 10.18 354.17

8 ²⁾ 1.0 10 40 48.0 100 3.28 83.16

9 ³⁾ 1.0 10 40 48.0 100 2.57 63.60

10 ⁴⁾ 1.0 10 40 48.0 100 1.20 23.36

1) Application amount (ul / cm ² )

2) _c containing 1 w of lauric monoglyceride

3) Contains 1 wt% of oleic acid monoglyceride c

4) Contains 1 wt% caprylic acid monoglyceride c Industrial applicability

Since the pharmaceutical composition of the present invention contains a quinazoline derivative having a 1 receptor blocking action or a salt thereof as an active ingredient, and can efficiently transdermally absorb the active ingredient, it can be used as an external preparation. Excellent drug efficacy in urination disorders and hypertension treatment.

Claims

The scope of the claims

1. A pharmaceutical composition for transdermal absorption, comprising:

(c) one or more substances selected from the group consisting of polyhydric alcohols and ethanol

A pharmaceutical composition comprising:

2. The pharmaceutical composition according to claim 1, further comprising (d) benzyl alcohol.

3. The pharmaceutical composition according to claim 1, wherein the active ingredient is selected from the group consisting of terazosin, prazosin, doxazosin, bunazosin, and salts thereof.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the active ingredient is terazosin hydrochloride.

5. The fatty acid according to claim 1, wherein the fatty acid is one or more fatty acids selected from the group consisting of hydropric acid, hydroprilic acid, pendenoic acid, lauric acid, myristic acid, and pennodecanoic acid. Item 5. The pharmaceutical composition according to any one of Items 4 to 4.

6. An ester of a fatty acid selected from the group consisting of methyl caprate, ethyl caprylate, isopropyl caprate, methyl caprylate, ethyl caprylate, isopropyl caprylate, methyl paraphosphate, and ethyl laurate. Or the pharmaceutical composition according to any one of claims 1 to 5, which is two or more esters.

7. Claims 1 to 6 wherein the higher alcohol is one or more higher alcohols selected from the group consisting of octanol, nonanol, decanol, decanol, and dodecanol. Item 14. The pharmaceutical composition according to any one of the above items.

8. The polyhydric alcohol consists of propylene glycol, 1,3-butylene glycol, ethylene glycol, diethylene glycol, 1,3-propylene glycol, triethylene glycol, dipropylene glycol, 1,4-butanediol, and glycerin The pharmaceutical composition according to any one of claims 1 to 7, which is one or more polyhydric alcohols selected from the group.

9. A pharmaceutical composition for transdermal absorption, comprising:

(b-2) a higher alcohol having 8 to 12 carbon atoms;

(c-1) ethanol;

(c-2) a polyhydric alcohol; and

(d) benzyl alcohol

(e) 7k

A pharmaceutical composition comprising:

10. The pharmaceutical composition according to claim 9, wherein the active ingredient selected from the group consisting of a quinazoline derivative having a receptor blocking action and salts thereof is an active ingredient selected from terazosin and salts thereof.