JP2001220349A - Erectile dysfunction improvement agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an erectile dysfunction improvement agent that has high safety and excellent effect against the dysfunction. SOLUTION: The erectile dysfunction improvement agent includes (A) L- arginine or the salt thereof and (B) theobromine or the salt thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an agent for improving penile erectile dysfunction.

[0002]

2. Description of the Related Art It is said that the number of male patients with penile erectile dysfunction is rapidly increasing with an increase in the elderly population. Erection is caused by relaxation of the corpus cavernosum tissue, increased blood flow in the penile artery and suppression of blood leakage from the penile vein. It is clear that this will happen. That is, NO synthesized by nitric oxide (NO) synthase in endothelial cells or nerve endings diffuses into smooth muscle cells existing in the corpus cavernosum of the penis. The NO is then activated by the binding of NO to the heme component of guanylate cyclase, whereby cyclic guanosine monophosphate (cGMP) is synthesized from guanosine triphosphate. cGMP is
CGMP to reduce calcium levels in smooth muscle cells
As the concentration increases, relaxation of smooth muscle progresses, and blood flow in the penile artery increases. Therefore, erectile dysfunction may result if any of the above steps are inhibited.

[0003] Phosphodiesterase-5 (PDE-5) localized in the corpus cavernosum of the penis is a cGMP-degrading enzyme, and activation of PDE-5 is considered to be one of the causes of erectile dysfunction. From this viewpoint, the PDE-5 inhibitor sildenafil citrate (hereinafter abbreviated as “sildenafil”) has been manufactured and approved by the FDA as an orally administrable therapeutic agent for erectile dysfunction. However, side effects are also problematic because sildenafil has an efficacy rate of only about 50% and lacks vascular selectivity to increase blood flow.

[0004] On the other hand, since L-arginine is a substrate for nitric oxide synthase, clinical tests have been carried out with the expectation of an effect of improving erectile dysfunction by promoting NO production. Development has been discontinued.

[0005]

Accordingly, an object of the present invention is to provide an agent for improving erectile dysfunction which is safe and has excellent effects.

[0006]

Accordingly, the present inventors have conducted various studies focusing on highly safe L-arginine.
If L-arginine or a salt thereof is used in combination with theobromine or a salt thereof, unexpectedly, the corpus cavernosum blood flow is synergistically increased, and it has been found that a drug containing these is useful as an erectile dysfunction ameliorating agent. Was completed.

That is, the present invention provides an agent for ameliorating erectile dysfunction, comprising the components (A) and (B) (A) L-arginine or a salt thereof, and (B) theobromine or a salt thereof.

[0008]

DETAILED DESCRIPTION OF THE INVENTION As mentioned above, L-arginine is
Although it was known to have an effect of improving erectile dysfunction to a certain extent, its effect alone was not always sufficient, and its development as a drug was discontinued. However, theobromine is known to have a diuretic effect and a cardiotonic effect, but is not known at all for the effect of improving erectile dysfunction.

The salts of L-arginine and theobromine used in the present invention include mineral salts such as hydrochloride, sulfate and nitrate, and organic acid salts such as acetate and citrate.

The agent for ameliorating erectile dysfunction of the present invention only needs to contain L-arginine or a salt thereof and theobromine or a salt thereof. In addition, the above-mentioned sildenafil citrate may be used in combination. .

The agent for improving erectile dysfunction of the present invention can be formulated into various dosage forms by blending necessary additives in addition to the above-mentioned components (A) and (B). When preparing a solid oral preparation, components (A) and (B) are mixed with excipients and, if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring agent, a flavoring agent, and the like. Depending on the method, it can be in the form of tablets, granules, powders, capsules and the like, and also in the form of confectionery such as chocolate. When preparing a liquid preparation for oral use, a flavoring agent, a buffer, a stabilizer, a deodorant, etc. are added to the components (A) and (B), and an oral solution, a syrup, a jelly, an elixir, etc. are prepared in a usual manner. can do.
When preparing an injection, a pH adjuster, a buffer, a stabilizer, an isotonic agent, a local anesthetic, etc. are added to the components (A) and (B), and subcutaneous, intramuscular, and intravenous in a conventional manner. And an injection for intracavernous injection. When preparing an ointment, a base, a stabilizer, a wetting agent, a preservative, and the like usually used for the components (A) and (B) may be blended as necessary, and then mixed and formulated by a conventional method. . When preparing a patch, the above-mentioned ointment, cream, gel, paste or the like may be applied to a usual support in a conventional manner. The agent for improving erectile dysfunction of the present invention may be prepared in the form of a kit by separately preparing L-arginine or a salt thereof and theobromine or a salt thereof.

The compounding ratio (weight ratio) of L-arginine or a salt thereof and theobromine or a salt thereof in the erectile dysfunction improving agent of the present invention is 99.95 from the viewpoint of improving the effect of improving erectile dysfunction by using these together. : 0.05-33: 67 is preferred, and 9
9.5: 0.5 to 80:20 is particularly preferred. As a method of administering the erectile dysfunction ameliorating agent of the present invention, it is desired to erect the penis
It is preferred to administer minutes to 1 hour before. In addition, in the case of oral administration, the total amount of components (A) and (B) is suitably 0.2 to 5 g per dose. In the case of a patch, it is appropriate to use a tape or the like containing the components (A) and (B) in a total of 0.02 to 1 g per time. In the case of a coating agent, the total of components (A) and (B) is 0.02-
It is appropriate to use an ointment, cream or the like containing 1 g.

[0013]

EXAMPLES Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to the following examples.

Example 1 Investigation of the Effects of L-Arginine and Theobromine on the Rabbit Penis Cavernous Dilatation Response A Japanese white native male rabbit weighing about 2.5 kg was anesthetized with pentobarbital sodium (25 mg / kg, iv) under anesthesia. After exsanguination by exsanguinating the femoral artery, the penis was excised immediately. The corpus cavernosum was cut off in Krebs solution under ice cooling to prepare a columnar specimen about 7 mm in length and about 2 mm in diameter.
One end of the sample was fixed, and the other end was connected to a transducer for measuring tension (“TB-612T” manufactured by Nihon Kohden Corp.). 95
The specimen is held in Krebs heated to 37 ° C. saturated with 5% oxygen and 5% carbon dioxide, and the isometric tension change caused by the addition of various drugs is drawn with a pen and an oscillograph (“R-64” manufactured by Rika Electric Industry Co., Ltd.) "). The drug addition method is as follows (n = 5 for each group).

Group 1 (control): 10 ^-5 M phenylephrine was added. Group 2: ^10-5 M phenylephrine was added, and 15 minutes later (this 15 minutes is the time until the contraction due to the addition of phenylephrine was stabilized) and 3 × 10 ^-3 M L-arginine was added. Addition. Group 3: 10 ^-5 M phenylephrine was added and 15 minutes later 3
× 10 ^-5 M of theobromine was added. Group 4: 3 × 10 ⁻⁵ M theobromine was added and after 20 minutes
10 ⁻⁵ M phenylephrine was added, and 15 minutes later, 3 × 10 ⁻³ M L-arginine was added.

The corpus cavernosum of the first group to which 10 ^-5 M phenylephrine was added had a contractile force of 792 ± 72 mg (the value on the left side of ± indicates the average value of 5 animals, and the value on the right side indicates the standard error. .
The same applies hereinafter), and the contraction was remarkable. FIG. 1 shows the relaxation rates (%) of the second to fourth groups with respect to the phenylephrine-induced contraction of the corpus cavernosum of the first group. Relaxation rate of the second group is 6.0 ± 0.4
%, The relaxation rate of the third group was 3.5 ± 0.6%, and the addition of L-arginine or theobromine alone caused a slight relaxation reaction. In contrast, the relaxation rate of the fourth group was 24.0 ±
1.3%, confirming that the combined use of L-arginine and theobromine induces a remarkable relaxation reaction. The sum of the relaxation rates of the second and third groups (arithmetic sum) is 9.5 ±
It was 0.7% (shown as the predicted value of Group 4 in FIG. 1), and there was a highly significant difference between the actual relaxation rate of Group 4 (P <0.005). This result indicates that the combination of L-arginine and theobromine synergistically expands the corpus cavernosum.

[0017]

EFFECTS OF THE INVENTION The agent for improving erectile dysfunction of the present invention has a markedly superior effect when L-arginine or a salt thereof and theobromine or a salt thereof act synergistically and each is used alone. It shows erectile dysfunction improving effect. In addition, L-arginine and theobromine have been confirmed to be sufficiently safe, and the agent for ameliorating erectile dysfunction of the present invention has excellent safety.

[Brief description of the drawings]

BRIEF DESCRIPTION OF DRAWINGS FIG. 1 is a graph showing the relaxation rate of various cavities in the corpus cavernosum of penis contracted by addition of phenylephrine.

Claims (1)

[Claims] An agent for ameliorating erectile dysfunction, comprising the components (A) and (B) (A) L-arginine or a salt thereof, and (B) theobromine or a salt thereof.