JP2010163425A - Medicinal composition containing phosphodiesterase-5 inhibitor and pantethine - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To find and provide a medicinal composition which is safe and has a reinforced action for penis-erection. <P>SOLUTION: The medicinal composition contains a phosphodiesterase-5 inhibitor and pantethine. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

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

  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. Phosphodiesterase 5 (PDE5) is known as a kind of PDE.

  In many cases, the PDE activity is increased in the state in which the cell function is impaired, and it is presumed that cGMP and cAMP are deficient as a result, and drugs that inhibit PDE increase these. Useful. For example, PDE5 is an enzyme that is abundant in the penile cavernous body.

The mechanism of penile erection can be explained as follows from the information disclosed in the conventional literature.
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 agent (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 1).

  On the other hand, pantethine is a precursor of CoA (coenzyme A), and includes (1) atherosclerotic progress inhibitory action, (2) total cholesterol lowering action, (3) triglyceride lowering action, (4) HDL cholesterol increasing action, 5) Fatty acid oxidation promoting action, (6) vascular wall cholesterol metabolism promoting action, (7) platelet count improving action, (8) intestinal motility promoting action, etc. are known (for example, see Non-Patent Document 1). Therefore, in a broad sense, it may be said that it is effective for ED patients having penile arteriosclerosis, but it is natural that immediate effect cannot be expected. In addition, there are no reports that pantethine is effective for ED at present.

In addition, useful combinations with PDE5 inhibitors include (1) antidiabetic agents, (2) HMG-CoA reductase inhibitors, (3) antihypertensive agents, (4) serotonin reuptake inhibitors (SSRI), Etc. have been disclosed so far (see Patent Document 1).
However, there is no document that describes or suggests a combination use of a PDE5 inhibitor and pantethine.

JP 2005-504113 A

Collection of ethical drugs 2009 edition JAPIC 2008

  To find and provide a safe pharmaceutical composition with enhanced penile erection effect.

  The present inventors are not a contraindicated or cautionary ingredient for concomitant use with a PDE5 inhibitor, that is, not a drug that increases cGMP, an antihypertensive agent, an α blocker, or a component that is not known to be used with a PDE5 inhibitor In order to find a safe pharmaceutical composition that exhibits an excellent anti-ED effect, research has been conducted eagerly. As a result, it was found that the penile erection action was remarkably enhanced by the combined use of a PDE5 inhibitor and pantethine, and the present invention was completed.

That is, the present invention is as described below.
(1)
A pharmaceutical composition comprising a phosphodiesterase 5 inhibitor and pantethine.
The present invention is preferably as described below.
(2)
The pharmaceutical composition according to (1) for treating penile erection dysfunction or for improving penile erection dysfunction.
(3)
A pharmaceutical composition for treating penile erection dysfunction or improving penile erection dysfunction for enhancing the penile erection effect obtained by administration of a phosphodiesterase 5 inhibitor by containing pantethine.
(4)
A pharmaceutical composition for treating penile erection dysfunction or for improving penile erection dysfunction, wherein the duration of penile erection obtained by administration of a phosphodiesterase 5 inhibitor is prolonged by containing pantethine.
(5)
The phosphodiesterase 5 inhibitor is any one selected from the group consisting of sildenafil, vardenafil, tadalafil and pharmacologically acceptable salts thereof, any one selected from (1)-(4) The pharmaceutical composition as described.
(6)
The pharmaceutical composition according to any one of (1) to (4), wherein the phosphodiesterase 5 inhibitor is sildenafil citrate, vardenafil hydrochloride hydrate, or tadalafil.
(7)
The pharmaceutical composition according to any one of (1) to (4), wherein the phosphodiesterase 5 inhibitor is sildenafil citrate.

Furthermore, the present invention includes the following inventions.
(8)
The method for producing a pharmaceutical composition according to any one of (1) to (7), wherein the phosphodiesterase 5 inhibitor and pantethine are contained in the same pharmaceutical composition.
(9)
Use of a phosphodiesterase 5 inhibitor and pantethine for producing a pharmaceutical composition for treating penile erectile dysfunction or for improving penile erectile dysfunction.
(10)
A method of administering a phosphodiesterase 5 inhibitor and pantethine simultaneously, sequentially or separately.
(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 claims 1 to 7 selected to a mammal.

  When administering the pharmaceutical composition of the present invention, a pharmaceutical composition containing a phosphodiesterase 5 inhibitor and a pharmaceutical composition containing pantethine 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 it is preferably a single composition.

  “Sequential or separate” administration is not particularly limited as long as it can be administered separately at different times. For example, one component is administered, and then the other components are administered after a predetermined time. There is a method of administration.

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

  According to the present invention, it has been found that the penile erection action of a PDE5 inhibitor is enhanced by the combined use with pantethine. Therefore, for example, a combination is useful because the amount of the PDE5 inhibitor can be reduced, and the side effects of the PDE5 inhibitor can be reduced. Furthermore, since pantethine has no cGMP increasing action, α blocking action, PDE5 inhibitory action, etc., even if used in combination, it does not cause harmful side effects and is safe.

Test result 1: Rabbit penis length measurement results at each time after test drug administration Additional test results: Rabbit penis length measurement results at each time after administration of test drug

  `` 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, tadalafil and the like.

  “Panthetine” is N, N ′-[dithiobis (ethyleneiminocarbonylethylene)] bis (2,4-dihydroxy-3,3-dimethylbutyramide).

  Sildenafil hydrochloride, vardenafil hydrochloride, and tadalafil are known compounds and are available as PDE5 inhibitors because they are commercially available. Pantethine is listed in the 15th revised Japanese Pharmacopoeia.

  The content of the PDE5 inhibitor in the daily dose of the pharmaceutical composition of the present invention is 1 mg-120 mg, preferably 5 mg-70 mg. Moreover, content of pantethine is 10 mg-800 mg, Preferably, it is 30 mg-600 mg. Take these once a day, approximately 1 hour before sexual activity.

  When administered “sequentially or separately”, the PDE5 inhibitor is still taken about 1 hour before sexual activity, but rather it is preferred to administer pantethine first.

Examples of the invention are described below.
(Example) Tablet (component)
(Table 1)
In 1 tablet (mg) a b c
―――――――――――――――――――――――――――――――
Sildenafil citrate 25--
Vardenafil hydrochloride-10-
Tadalafil − − 10
Panthetin 125 100 100
Crystalline cellulose 80 80 80
Lactose 60 60 60
Magnesium stearate 2 2 2
Hydroxypropylcellulose 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 extracting commercially available Viagra (registered trademark) tablets (manufactured by Pfizer Inc.) and then converting it to citrate again. As pantethine, a commercially available medical pantocin injection 5% (Daiichi Sankyo Co., Ltd.) was used.
Sildenafil citrate was dissolved in a solvent (DMSO: saline = 30: 70) so as to be 10 mg / mL. For pantethine, a pantocin injection of 5% concentration (50 mg / mL) was used as it was. A combination of pantethine and sildenafil citrate was prepared by adding the pantocin injection 5% so that the concentration of sildenafil citrate was 10 mg / mL.

(2) Animals used JW male rabbits 16 weeks old were purchased from Japan SLC Co., Ltd., and used for rabbits in a rabbit breeding room controlled at a temperature of 20-26 ° C, humidity of 30-70%, and lighting time of 6: 00-18. 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 administered into the ear vein. The administration volume of any test substance is 0.1 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.
After administration of the test drug, the penis exposure length (mm) was measured with calipers at intervals of 1, 3, 5, 10, 15, 30, and 60 minutes.

(4) Test result 1
The measurement results of the rabbit penis length at each time after administration of the test drug are shown in Table 2 and FIG.
Here, S is sildenafil citrate and P is pantethine. Moreover, each value is an average value of 3 animals per group.

(Table 2) Penis length (mm)
Drug 1 minute later 3 minutes later 5 minutes later 10 minutes later 15 minutes later 30 minutes later 60 minutes later ――――――――――――――――――――――――――― ――――――――――
S single agent 2.0 4.6 5.7 5.4 5.8 6.1 5.0
P single agent 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
Mixture 1.5 6.4 7.5 9.3 8.0 8.0 7.6
――――――――――――――――――――――――――――――――――――――

  From the results shown in Table 2 and FIG. 1, the penile erection action can be confirmed in the sildenafil citrate monotherapy group, but no penile erection action is observed in the pantethine monotherapy group. It was found that sildenafil citrate combined with pantethine enhanced the penile erection effect of sildenafil. In addition, AUC (penis length mm × time min) for 60 minutes after administration is 328 for S single agent, 0 for P single agent, and 461 for combination (S and P combined use), 1.4 times enhancement The effect was obtained.

(5) Additional test results Table 3 and FIG. 2 show the results of the test performed again in the same kind of newly purchased rabbits on the same conditions as (1) and (2) at a later date. Here, S is sildenafil citrate and P is pantethine. Moreover, each value is an average value of 3 animals per group.

(Table 3) Penis length (mm)
Drug 1 minute later 3 minutes later 5 minutes later 10 minutes later 15 minutes later 30 minutes later ――――――――――――――――――――――――――――――― ―――
S single agent 0.0 2.4 3.3 3.1 3.1 2.7 2.9
P single agent 0.0 0.0 0.0 0.0 0.0 0.0 0.0
Mixture 2.6 5.7 6.8 7.3 6.6 5.8
――――――――――――――――――――――――――――――――――

  From the results shown in Table 3 and FIG. 2, the penile erection action was confirmed in the sildenafil citrate monotherapy group as in the test result 1, but no penile erection action was observed in the pantethine monotherapy group. In a follow-up study, it was reconfirmed that sildenafil citrate was combined with pantethine to enhance the penile erection effect of sildenafil. In addition, AUC (penis length mm × time min) for 30 minutes after administration was 81 for S single agent, 0 for P single agent, and 185 for combination (S and P combined use), 2.3 times enhancement The effect was obtained.

Claims (11)

A pharmaceutical composition comprising a phosphodiesterase 5 inhibitor and pantethine. The pharmaceutical composition according to claim 1 for treating penile erection dysfunction or for improving penile erection dysfunction. A pharmaceutical composition for treating penile erection dysfunction or improving penile erection dysfunction for enhancing the penile erection effect obtained by administration of a phosphodiesterase 5 inhibitor by containing pantethine. A pharmaceutical composition for treating penile erection dysfunction or for improving penile erection dysfunction, wherein the duration of penile erection obtained by administration of a phosphodiesterase 5 inhibitor is prolonged by containing pantethine. The phosphodiesterase 5 inhibitor is any one agent selected from the group consisting of sildenafil, vardenafil, tadalafil and pharmacologically acceptable salts thereof, according to any one of claims 1-4. Pharmaceutical composition. The pharmaceutical composition according to any one of claims 1-4, wherein the phosphodiesterase 5 inhibitor is sildenafil citrate, vardenafil hydrochloride hydrate or tadalafil. The pharmaceutical composition according to any one of claims 1 to 4, wherein the phosphodiesterase 5 inhibitor is sildenafil citrate. The method for producing a pharmaceutical composition according to any one of claims 1 to 7, wherein the phosphodiesterase 5 inhibitor and pantethine are contained in the same pharmaceutical composition. Use of a phosphodiesterase 5 inhibitor and pantethine for producing a pharmaceutical composition for treating penile erectile dysfunction or for improving penile erectile dysfunction. A method of administering a phosphodiesterase 5 inhibitor and pantethine simultaneously, sequentially or separately. 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 claims 1 to 7 selected to a mammal.