JP5587671B2 - Pharmaceutical composition containing PDE5 inhibitor and antinasal - Google Patents

Description

The present invention relates to a pharmaceutical composition mainly for treating or improving penile erection dysfunction, comprising a phosphodiesterase 5 inhibitor and an antinasal.

Phosphodiesterase (hereinafter referred to as PDE) is an enzyme that hydrolyzes cyclic AMP (hereinafter referred to as cAMP) and cyclic GMP (hereinafter referred to as cGMP) phosphate esters. I know it exists. In many cases, the PDE activity is increased in the state in which the cell function is impaired, and it is estimated that cGMP and cAMP are deficient as a result, and drugs that inhibit PDE increase these. Useful.
PDE5, which is a kind of PDE, is an enzyme that is abundant in the corpus cavernosum and lung tissue, and is known to be involved in penile erection. The mechanism of erection can be explained as follows by integrating the known literatures so far.
By sexual stimulation, nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS) in peripheral nerves in the penile cavernous body activates guanylate cyclase in the penile cavernous body to synthesize cGMP. . As the cGMP concentration rises, the smooth muscle of the cavernous cavernous body relaxes and blood flows from the penile artery. The blood inflow into the penile cavernous body causes an increase in penis volume and size, and penile hardening due to an increase in internal pressure. As a result, the penile veins are compressed, blood outflow from the cavernous corpus cavernosum is suppressed, and the erection is completed. Thereafter, when the supply of NO is interrupted due to completion of ejaculation or attenuation of sexual stimulation, cGMP is decomposed by PDE5 present in the cavernous corpus cavernosum, blood inflow from the penile artery is stopped, and the state before the erection is eventually restored.

  When any of these, or a combination of these, such as blockage of cavernous blood inflow due to penile artery contraction due to sympathetic nerve tension due to stress, decrease in nNOS activity, decrease in guanylate cyclase activity, increase in PDE5 activity, etc. Does not erection or does not continue even if erection, sexual intercourse can not be done. Such a pathological condition is called erectile dysfunction, erectile dysfunction, or erectile dysfunction, but recently "ED", which is an abbreviation for the English name Erectile Dysfunction, has been widely used due to psychological considerations.

  In recent years, PDE5 inhibitors have been found and revolutionized ED treatment. This inhibits the activity of PDE5, a cGMP-degrading enzyme in the corpus cavernosum, maintains and increases the amount of cGMP in the corpus cavernosum caused by peripheral NO nerves in the penis, and maintains the increased intracavernosal pressure (erection) state (For example, refer nonpatent literature 1). PDE5 inhibitors saved the majority of patients suffering from ED.

  When the world's first PDE5 inhibitor (sildenafil citrate, trade name Viagra) was released, it was used in combination with an angina treatment drug (nitric acid drugs such as nitroglycerin, amyl nitrite, and isosorbide nitrate) that are NO donors. Due to numerous reports of deaths due to, both are now contraindicated. The reason for this is that NO hypotensive action through the increase of cGMP is enhanced by the NO donor stimulating the production of cGMP and the PDE5 inhibitor inhibiting the degradation of cGMP. At present, concomitant attention has been given to drugs that increase cGMP, antihypertensives, α-blockers, and the like (see, for example, Non-Patent Document 2).

  On the other hand, the anti-nose (hampi) is a viper that has been taken out of the viscera, peeled off, stretched and dried. Ingredients include fatty acids, taurine, cholesterol, amino acids, vitamin B group and the like. Pharmacological effects include smooth muscle contraction, weight gain, mild increase in estrus, anti-fatigue, anti-cold stress, etc. Applicable for nourishing tonic and recovery from fatigue (above) For example, refer nonpatent literature 3). Moreover, in the pharmaceutical, it is mix | blended with the nourishing tonic (for example, refer nonpatent literature 4).

  At present, there has been no literature which describes that the antinasal itself has an effect of treating or improving erectile function. Furthermore, no combination of PDE5 inhibitor and antinasal is known or suggested.

Collection of ethical drugs 2009 edition JAPIC 2008 Viagra package insert 14th edition Pfizer 2008 Wanhan Pharmacy Nanzan-do 1983 p. 202-203 OTC Pharmaceutical Dictionary 11th edition Jiho 2008

  People who are afflicted with ED are overwhelmingly older than younger people, and since the age of taking angina and antihypertensive drugs is high, there is a problem that some patients cannot take advantage of PDE5 inhibitors. It was. Accordingly, it is an object of the present invention to provide a pharmaceutical composition that exhibits sufficient and excellent penile erection function by administration of a PDE5 inhibitor at a low dose with few side effects.

  In order to solve such a problem, the present inventors have been diligently researching to date while repeating trial and error for a large number of combined components. As a result, when an antinasal (hampi) that is an animal herbal medicine is used in combination with a PDE5 inhibitor, the erection action of the PDE5 inhibitor is remarkably enhanced and the present invention has been completed.

That is, the present invention is as described below.
(1)
A pharmaceutical composition comprising a phosphodiesterase 5 inhibitor and an antinasal as active ingredients.

Further, preferred embodiments of the present invention are as described below.
(2)
The pharmaceutical composition according to (1), which is used for treating penile erectile dysfunction or for improving penile erectile dysfunction.
(3)
The pharmaceutical composition according to (1), wherein the penile erection action obtained by administration of a phosphodiesterase 5 inhibitor is enhanced by containing an antinasal.
(4)
The pharmaceutical composition according to (1), wherein the duration of penile erection obtained by administration of the phosphodiesterase 5 inhibitor is prolonged by including an antinasal.
(5)
The pharmaceutical composition according to (1), wherein the penile erection onset time in administration of the phosphodiesterase 5 inhibitor is shortened by including an antinasal.
(6)
The phosphodiesterase 5 inhibitor is one selected from the group consisting of sildenafil, vardenafil, tadalafil, udenafil and pharmacologically acceptable salts thereof, any one selected from (1)-(5) Pharmaceutical composition.
(7)
The pharmaceutical composition according to any one of (1) to (5), wherein the phosphodiesterase 5 inhibitor is sildenafil citrate, vardenafil hydrochloride hydrate, tadalafil or udenafil.
(8)
The pharmaceutical composition according to any one of (1) to (5), wherein the phosphodiesterase 5 inhibitor is sildenafil citrate.

Furthermore, this invention also includes the invention described below.
(9)
The method for producing a pharmaceutical composition according to any one of (1) to (8), wherein the phosphodiesterase 5 inhibitor and the antinasal are contained in the same pharmaceutical composition.
(10)
Use of a phosphodiesterase 5 inhibitor and an antinasal for producing a pharmaceutical composition for treating penile erectile dysfunction or for improving penile erectile dysfunction.
(11)
A method for treating penile erection dysfunction or a method for improving penile erection dysfunction, comprising administering an effective amount of the pharmaceutical composition according to any one of (1) to (8) selected from mammals .

  According to the present invention, when a pharmaceutical composition containing a PDE5 inhibitor and an antinasal is used at the same time approximately 1 hour before sexual activity, the penile erection effect is remarkably enhanced and safe. This is useful because the content of the PDE5 inhibitor can be reduced.

When administering the pharmaceutical composition of the present invention, the pharmaceutical composition containing each phosphodiesterase 5 inhibitor and the pharmaceutical composition containing the antinasal can be administered simultaneously or sequentially.
“Simultaneous” administration includes administration at exactly the same time, as well as administration at a time that is pharmacologically acceptable. The dosage form is not particularly limited as long as it can be administered at approximately the same time, but is preferably a single pharmaceutical composition.

  “Sequentially or separately” administration is not particularly limited as long as it can be administered separately at different times. For example, one composition is administered and then another composition is administered after a predetermined time. There are ways to administer things.

  “Treatment” means curing or ameliorating a disease or condition or suppressing a symptom.

  `` Penis erection dysfunction '' refers to a condition where, for some reason, penile erection is not enough to be required for sexual intercourse, or it does not persist even after erection and normal sexual intercourse cannot be performed, “Improving penile erection dysfunction” refers to improving such a condition.

  The “PDE5 inhibitor” is not particularly limited as long as it has an action of inhibiting PDE5, and specifically refers to sildenafil citrate, vardenafil hydrochloride hydrate, tadalafil, udenafil and the like.

  As a PDE5 inhibitor, sildenafil citrate, vardenafil hydrochloride hydrate, tadalafil and udenafil are known compounds and are commercially available. Also, anti-nasal, tincture and flow extract are commercially available and easily available.

  The content of the PDE5 inhibitor in the daily dose of the pharmaceutical composition of the present invention is 1 mg to 120 mg, preferably 5 mg to 70 mg. The content of the antinas is different depending on the antinasal powder, antinasal tincture and antinasal flow extract, but is 10 mg to 1600 mg, preferably 100 mg to 800 mg, in terms of the active ingredient.

  Take these once a day, approximately 1 hour before sexual activity. In the case of pulmonary arterial hypertension, take this amount in three divided doses.

  In addition, when administered “sequentially or separately”, the PDE5 inhibitor and the antinasal are still taken about 1 hour before sexual activity, but the time interval should not exceed 30 minutes even if taken separately. desirable.

Examples of the present invention are described below, but are not limited thereto.
(Example) Tablet (component)
(Table 1)
In 1 tablet (mg) a b c d
――――――――――――――――――――――――――――――――――――
Sildenafil citrate 25---
Vardenafil hydrochloride hydrate-10--
Tadalafil − − 10 −
Udenafil---100
Antinasal end 250 250 250 250
Crystalline cellulose 80 80 80 120
Lactose 60 60 60 90
Magnesium stearate 2 2 2 3
Hydroxypropyl cellulose Suitable amount Suitable amount Suitable amount Suitable amount ――――――――――――――――――――――――――――――――――――
(Manufacturing method)
Taking the above ingredients and amounts, tablets are produced according to the section “General Tablet Preparation Guidelines”.
(Test example) Penile erection effect confirmation test (1) Test substance Sildenafil citrate was used by grinding a commercially available medical Viagra tablet (registered trademark, manufactured by Pfizer) in a mortar. Similarly, vardenafil hydrochloride hydrate and tadalafil were also used by pulverizing commercially available medical Levitra tablets (registered trademark, manufactured by Bayer) and Cialis tablets (registered trademark, manufactured by Eli Lilly) in a mortar, respectively.

  In addition, commercially available Hampi tincture and carrot extract (both manufactured by Matsuura Pharmaceutical Co., Ltd.) were used for antinas and ginseng.

  Sildenafil citrate, vardenafil hydrochloride hydrate and tadalafil were diluted with distilled water to a concentration of 2 mg / Kg and administered at 5 mL / Kg.

Further, Hampi tincture and carrot flow extract were used as they were and administered at 5 mL / Kg (500 mg / Kg as an antinasal and 5 g / Kg as carrot in terms of crude drug). As a combination of sildenafil citrate and antinasal or ginseng, sildenafil citrate was administered at 10 mg / Kg, and then Hampi tincture or ginseng extract was administered at 5 mL / Kg.
(2) Animals used JW male rabbits 16 weeks old were purchased from Kitayama Labes Co., Ltd., and used for rabbits in a rabbit breeding room controlled at a temperature of 20 to 26 ° C, humidity of 30 to 70%, and lighting time of 6:00 to 18:00. The animal was placed in a bracket taper cage and freely fed with rabbit feed and tap water through a water filter.
(3) Test method The test substance was orally administered using a sonde or Neraton catheter No. 12. The administration volume of any test substance is 5 mL / Kg. Usually, the rabbit's penis is not exposed and is exposed at the time of erection, so the erection effect by administration of the test drug can be evaluated by the exposed penile length.

The penis exposure length (mm) was measured with calipers at intervals of 5, 15, 30, 45, 60, 90, 120 and 180 minutes after administration of the test drug.
(4) Test results Tables 2 to 5 show the measurement results of the rabbit penis length at each time after administration of the test drug. Moreover, each value is an average value of three per group.

In the following tables, “sildenafil” represents sildenafil citrate, and “vardenafil” represents vardenafil hydrochloride hydrate.
(Table 2) Penis length (mm)
Time after administration Sildenafil Antinasal Sildenafil (10mg / kg)
(Min) (10mg / Kg) (500mg / Kg) + Antinasal (500mg / kg)
――――――――――――――――――――――――――――――――
5 0.0 0.0 0.0
15 3.4 0.0 8.6
30 3.2 0.0 5.8
45 5.0 0.0 4.8
60 4.7 0.0 5.0
90 0.7 0.0 2.6
120 0.7 0.0 3.0
180 0.0 0.0 2.5
――――――――――――――――――――――――――――――――
AUC 327 0 669

(Table 3) Penis length (mm)
Time after administration Sildenafil Ginseng Sildenafil (10mg / kg)
(Min) (10mg / Kg) (5g / Kg) + carrot (5g / kg)
――――――――――――――――――――――――――――――――
5 0.0 0.0 0.0
15 2.5 0.0 1.8
30 5.8 0.0 3.4
45 6.0 0.0 2.7
60 6.2 0.0 3.0
90 4.2 0.0 0.0
120 2.0 0.0 0.6
180 0.7 0.0 0.5
――――――――――――――――――――――――――――――――
AUC 584 0 224

From the results in Table 2, erectile action was observed for sildenafil citrate alone. Moreover, it was confirmed that the antinasal single agent has no erection action. However, it was found that when silnasafil citrate is used in combination with an antinasal, the effect of sildenafil citrate is enhanced and sustained.

  In addition, the enhancement effect by combined use was twice that of sildenafil citrate single agent when evaluated by AUC (mm · min).

  On the other hand, from the results shown in Table 3, the ginseng single agent, which is a herbal medicine that is widely used as a nourishing tonic component as well as the antinasal, did not show an erection effect like the antinasal single agent. It was also found that when sildenafil citrate was combined with ginseng, sildenafil citrate attenuated the erection effect. From this, it became clear that the enhancement effect of sildenafil citrate erection by antinasal is a useful phenomenon peculiar to antinasal among herbal medicines widely used as a nourishing tonic component.

(Table 4) Penis length (mm)
Time after administration Vardenafil Antinasal Vardefir (1 mg / kg)
(Min) (1mg / Kg) (500mg / Kg) + Antinasal (500mg / kg)
――――――――――――――――――――――――――――――――
5 0.0 0.0 0.0
15 0.0 0.0 0.0
30 3.2 0.0 1.6
45 4.2 2.7 4.5
60 5.0 0.0 6.9
90 2.3 0.0 7.2
120 3.2 0.0 5.2
180 1.4 0.0 2.3
――――――――――――――――――――――――――――――――
AUC 478 41 768
From the results shown in Table 4, it was confirmed that the erection effect was observed in the vardenafil hydrochloride hydrate single agent, and the anti-nasal single agent had almost no erection effect. And when anti-nasal was used together with vardenafil hydrochloride hydrate, it was confirmed that the effect of enhancing the erection action was developed as in the case of sildenafil citrate. In addition, the enhancement effect by combined use was 1.6 times that of vardenafil hydrochloride hydrate single agent when evaluated by AUC (mm · min).

(Table 5) Penis length (mm)
Time after administration Tadalafil Antinasal Tadalafil (10mg / kg)
(Min) (10mg / Kg) (500mg / Kg) + Antinasal (500mg / kg)
――――――――――――――――――――――――――――――――
5 1.4 0.0 0.0
15 1.0 0.0 4.4
30 0.0 0.0 0.9
45 1.6 0.0 0.0
60 1.7 0.0 2.0
90 0.0 0.0 2.1
120 0.0 0.0 4.9
180 0.0 0.0 3.6
――――――――――――――――――――――――――――――――
AUC 86 0 504
From the results in Table 5, it was confirmed that the tadalafil single agent had an erection effect and the antinasal single agent had no erection effect. And when anti-nasal was used together with tadalafil, it was confirmed that the effect of enhancing and sustaining the erectile action was exhibited as in the case of sildenafil citrate. In addition, the enhancement effect by combined use was 5.9 times that of vardenafil hydrochloride hydrate single agent when evaluated by AUC (mm · min).

Claims (5)

A medicament for treating penile erectile dysfunction or for improving penile erectile dysfunction, comprising 1 selected from the group consisting of sildenafil, vardenafil, tadalafil and pharmacologically acceptable salts thereof and an antinasal as an active ingredient Composition. The medicament according to claim 1, for enhancing the penile erection effect obtained by administration of one selected from the group consisting of sildenafil, vardenafil, tadalafil and pharmacologically acceptable salts thereof by containing an antinasal. Composition. 2. The penile erection duration obtained in one administration selected from the group consisting of sildenafil, vardenafil, tadalafil and their pharmacologically acceptable salts, for sustained extension by containing an antinasal. Pharmaceutical composition. 1 selected from the group consisting of sildenafil, vardenafil, tadalafil and pharmacologically acceptable salts thereof, and any one selected from claims 1-3 comprising an antinasal in the same pharmaceutical composition A method for producing the pharmaceutical composition described. 1. Use of antinasal and 1 selected from the group consisting of sildenafil, vardenafil, tadalafil and their pharmacologically acceptable salts for producing a pharmaceutical composition for treating penile erectile dysfunction or improving penile erectile dysfunction .