JP5704853B2 - Pharmaceutical composition containing a PDE5 inhibitor and jacho cow - 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 jacho cow.

  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, Jachoushi (snake bed) is a dried fruit of the celery family Okazeri or Yabujirami. As a pharmacological action, an aphrodisiac action, a sex hormone enhancement action, etc. are reported, and as an application, there are serpentine baths externally used for eczema / cutaneous pruritus and vulvular colic. Moreover, as an internal use, it mix | blends with other herbal medicines for the purpose of an anthelmintic agent or a strong, tonic and aphrodisiac (for example, refer nonpatent literature 3). Moreover, in the pharmaceutical, it is mix | blended with the nourishing tonic (for example, refer nonpatent literature 4).

  So far, it has been disclosed that Jacho cattle have human lung-derived phosphodiesterase inhibitory activity (see Patent Document 1). However, at present, there is no known combination of a PDE5 inhibitor and Jasho cow.

JP 2000-319191 A

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, it has been found that the erection action of a PDE5 inhibitor, which cannot be predicted from a single agent, is remarkably enhanced when a plant herbal medicine jasho beef (snake bed) is used in combination with a PDE5 inhibitor, thereby completing the present invention. It came to.

That is, the present invention is as described below.
(1)
A pharmaceutical composition comprising a phosphodiesterase 5 inhibitor and jacho cow as active ingredients.
Further, the present invention is preferably 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 the phosphodiesterase 5 inhibitor is enhanced by containing Jacho cattle.
(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 Jacho cattle.
(5)
The pharmaceutical composition as described in (1) for shortening the penile erection onset time in the administration of a phosphodiesterase 5 inhibitor by containing jacho cows.
(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 or tadalafil.

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), which comprises a phosphodiesterase 5 inhibitor and a jacho cow in the same pharmaceutical composition.
(10)
Use of a phosphodiesterase 5 inhibitor and Jacho cattle for producing a pharmaceutical composition for treating penile erection dysfunction or for improving penile erection dysfunction.
(11)
A method of administering a phosphodiesterase 5 inhibitor and a jacho cow simultaneously, sequentially or separately.
(12)
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 .

  When the pharmaceutical composition of the present invention is administered, the pharmaceutical composition containing each phosphodiesterase 5 inhibitor and the pharmaceutical composition containing Jasho cattle 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.

  According to the present invention, when a pharmaceutical composition containing a PDE5 inhibitor and a jacho cow 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.

  `` 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. Specifically, it refers to sildenafil citrate, vardenafil hydrochloride, tadalafil, udenafil and the like.

  Sildenafil citrate, vardenafil hydrochloride, tadalafil, and udenafil are known compounds and are available as PDE5 inhibitors because they are commercially available. Jashoushi is listed in the 15th revised Japanese Pharmacopoeia, and extracts, powders, tinctures and fluid extracts are commercially available and can be easily obtained.

  The content of the PDE5 inhibitor in the daily dose of the pharmaceutical composition of the present invention is 1 mg to 150 mg, preferably 5 mg to 100 mg. In addition, the content of jasho cow varies depending on the extract, powder, tincture, and flow extract, but is, for example, 100 mg to 10,000 mg, preferably 200 mg to 5000 mg.

  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.

  When administered "sequentially or separately", the PDE5 inhibitor and Jasho beef should be taken about 1 hour before sexual activity, but the time interval is preferably within 30 minutes even when taken separately. .

Examples of the present invention are described below, but are not limited thereto.
(Example) Tablet (component)
(Table 1)
4 tablets (mg) a b c d
――――――――――――――――――――――――――――――――――――
Sildenafil citrate 25---
Vardenafil hydrochloride-10--
Tadalafil − − 10 −
Udenafil---100
Jasho beef extract powder 1g 1g 1g 1g
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 is a commercially available Viagra tablet (registered trademark, manufactured by Pfizer), Tadalafil is a commercially available medical Cialis tablet (registered trademark, manufactured by Eli Lilly) Crushed in a mortar and used. As for Jashoushi, a commercially available Jashoushi extract (manufactured by Matsuura Pharmaceutical Co., Ltd.) was used.

Sildenafil citrate or tadalafil was diluted with distilled water to a concentration of 2 mg / Kg and administered at 5 mL / Kg. Jasho beef extract was administered at 5 mL / Kg. As for the combination of sildenafil citrate and jasho beef extract, 10 mg / kg of sildenafil citrate or tadalafil was administered, and then 5 ml / kg of jasho beef extract was administered.
(2) Animal used JW male rabbit 16-week-old was purchased from Japan SLC Co., Ltd. or Kitayama Labes Co., Ltd., temperature 20-26 ° C., humidity 30-70%, lighting time 6: 00-18: 00. The rabbit was placed in a rabbit bracket taper cage in a rabbit breeding room, and feed water for rabbit breeding and tap water passed through a water filter were freely ingested.
(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 Table 2 and Table 3 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 table, “sildenafil” refers to sildenafil citrate.
(Table 2) Penis length (mm)
Time after administration Sildenafil Jasho cow extract Sildenafil (10 mg / Kg)
(Min) (10mg / Kg) (5mL / Kg) + Jashou bovine extract (5 mL / Kg)
―――――――――――――――――――――――――――――――――――――――
5 0.0 0.0 2.3
15 0.0 0.0 5.1
30 0.8 0.0 5.4
45 2.5 0.0 6.5
60 1.2 0.0 6.8
90 3.7 0.0 4.2
120 1.2 0.0 2.4
180 2.7 0.0 3.5
―――――――――――――――――――――――――――――――――――――――
AUC 288 0 751
From the results in Table 2, the erectile action of sildenafil citrate alone was observed. It was also found that jachobull alone has no erection effect at least at this dose. However, it has been found that the surprising fact that sildenafil citrate is combined with jasho calf significantly shortens the onset time, enhances the effect of erection and increases the duration of sildenafil.

It is clear that this result cannot be predicted from the results for each single agent. In addition, when the jasho cow was used together, the enhancement effect was 2.6 times that of sildenafil alone when evaluated by AUC (mm · min).
(Table 3) Penis length (mm)
Time after administration Tadalafil Jasho cow extract Tadalafil (10 mg / Kg)
(Min) (10mg / Kg) (5mL / Kg) + Jashou bovine extract (5 mL / Kg)
―――――――――――――――――――――――――――――――――――――――
5 0.0 0.0 0.0
15 0.0 0.0 0.9
30 0.0 0.0 2.0
45 0.0 0.0 2.1
60 0.9 0.4 2.9
90 1.7 0.0 4.0
120 1.3 0.0 4.0
180 1.4 0.0 1.8
―――――――――――――――――――――――――――――――――――――――
AUC 168 8 491
From the results in Table 3, the erectile action of tadalafil alone was observed. It was also found that jachobull alone had little erection effect at least at this dose. However, when Tadalafil is used in combination with Jasho beef, it has been found that tadalafil's erection action is shortened, enhanced, and prolonged.

  It is clear that this result cannot be predicted from the results for each single agent. In addition, when Jachoushi was used in combination, the enhancement effect was 2.8 times the expected value from Tadalafil and Jashobo single agent when evaluated by AUC (mm · min).

  According to the present invention, when a pharmaceutical composition containing a PDE5 inhibitor and a jacho cow 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.

Claims (5)

A pharmaceutical composition comprising sildenafil citrate or tadalafil for treating penile erection dysfunction or improving penile erection dysfunction and jacho cow as active ingredients. A pharmaceutical composition comprising sildenafil citrate or tadalafil and jasho cow as active ingredients for enhancing the penile erection effect obtained by administration of sildenafil citrate or tadalafil by containing jasho cow. A pharmaceutical composition comprising sildenafil citrate or tadalafil and jasho calf as active ingredients for prolonging penile erection duration obtained by administration of sildenafil citrate or tadalafil by containing jasho cattle. A pharmaceutical composition comprising sildenafil citrate or tadalafil and jasho cow as active ingredients for shortening the onset time of penile erection in the administration of sildenafil citrate or tadalafil by including jasho cow. Use of sildenafil citrate or tadalafil and jasho cattle for producing a pharmaceutical composition for treating penile erectile dysfunction or for improving penile erectile dysfunction.