JP7391521B2 - Pharmaceutical composition for treating erectile dysfunction - Google Patents

Description

The present invention relates to a pharmaceutical composition for treating erectile dysfunction that has excellent stability.

Vardenafil (chemical name: 1-{[3-(3,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-f][1,2,4] Triazin-2-yl)-4-ethoxyphenyl]sulfonyl}-4-ethylpiperazine) is an active ingredient of a therapeutic agent for erectile dysfunction.
Various forms of vardenafil are known, but since a solid drug can be obtained in a uniform and reproducible form by using the trihydrate of vardenafil hydrochloride, the invention described in Patent Document 1 During the manufacture of the vardenafil hydrochloride formulation, vardenafil hydrochloride is converted into the trihydrate by contacting it with a humid gas having a specific relative humidity.
Additionally, Patent Document 2 discloses a formulation containing vardenafil hydrochloride trihydrate that rapidly disintegrates in the mouth.

Patent No. 5173113 Patent No. 5122984

As mentioned above, preparations for treating erectile dysfunction containing vardenafil hydrochloride have already been developed.
However, the present inventors have experimentally discovered that vardenafil is easily decomposed by heat, light, etc., and is by no means a stable compound.
Therefore, an object of the present invention is to provide a pharmaceutical composition for treating erectile dysfunction containing vardenafil with excellent stability.

The present inventors have conducted extensive research in order to solve the above problems. As a result, the preparations for treating erectile dysfunction containing vardenafil described in Patent Documents 1 and 2 contain cross-linked polyvinylpyrrolidone as a disintegrant, but since this causes loss of stability of vardenafil, the disintegrant has a low degree of substitution. The present invention was completed by discovering that the stability of vardenafil in a pharmaceutical composition can be enhanced by using hydroxypropylcellulose.
The present invention will be described below.

[1] An active ingredient selected from the group consisting of vardenafil, a salt thereof, a hydrate thereof, and a hydrate of a salt thereof, and
A pharmaceutical composition for treating erectile dysfunction, comprising low-substituted hydroxypropyl cellulose.
[2] The pharmaceutical composition for treating erectile dysfunction according to [1] above, wherein the active ingredient is vardenafil hydrochloride.
[3] The pharmaceutical composition for treating erectile dysfunction according to [1] above, wherein the active ingredient is vardenafil hydrochloride hydrate.
[4] The pharmaceutical composition for treating erectile dysfunction according to any one of [1] to [3] above, further comprising a coloring agent.
[5] The pharmaceutical composition for treating erectile dysfunction according to [4] above, wherein the coloring agent is a yellow coloring agent.
[6] The pharmaceutical composition for treating erectile dysfunction according to any one of [1] to [5] above, which does not contain cross-linked polyvinylpyrrolidone.
[7] The pharmaceutical composition for treating erectile dysfunction according to any one of [1] to [6] above, which is in the form of a tablet.
[8] The pharmaceutical composition for treating erectile dysfunction according to any one of [1] to [7] above, which does not have a coating layer.
[9] Incorporating low-substituted hydroxypropylcellulose into a pharmaceutical composition for treating erectile dysfunction containing an active ingredient selected from the group consisting of vardenafil, a salt thereof, a hydrate thereof, and a hydrate of a salt thereof. A method for stabilizing the active ingredient, characterized in that:

In the pharmaceutical composition for treating erectile dysfunction according to the present invention, the active ingredient vardenafil has high stability. Therefore, the pharmaceutical composition for treating erectile dysfunction according to the present invention is industrially very excellent as one form of a pharmaceutical composition for treating erectile dysfunction containing vardenafil.

The pharmaceutical composition for treating erectile dysfunction according to the present invention contains an active ingredient selected from the group consisting of vardenafil, a salt thereof, a hydrate thereof, and a hydrate of a salt thereof, and low-substituted hydroxypropyl cellulose. .

Vardenafil has the chemical name 1-{[3-(3,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-f][1,2,4]triazin-2-yl )-4-ethoxyphenyl]sulfonyl}-4-ethylpiperazine, which is a cGMP phosphodiesterase inhibitor having the following chemical structure. Vardenafil increases the amount of cGMP by selectively inhibiting PDE5 (phosphodiesterase 5), and has the effect of causing penis erection.

Vardenafil may be incorporated into the pharmaceutical composition in salt form. The acid that forms a salt with vardenafil is not particularly limited as long as it is pharmaceutically acceptable, but examples include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, perchloric acid, and phosphoric acid. Acids; oxalic acid, malonic acid, maleic acid, fumaric acid, lactic acid, malic acid, citric acid, tartaric acid, benzoic acid, trifluoroacetic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, glutamic acid, etc. Examples include organic acids such as acidic amino acids such as aspartic acid. As the salt, hydrochloride and methanesulfonate are preferred, and hydrochloride is more preferred.

Vardenafil and its salts may be incorporated into the pharmaceutical composition in the form of a hydrate. Hydrates include monohydrates and trihydrates, with trihydrates being preferred. Hereinafter, vardenafil, its salt, its hydrate, and the hydrate of its salt will be referred to as "vardenafil, etc."

The size of the raw material, such as vardenafil, may be adjusted as appropriate. For example, the average particle diameter can be set to 5 μm or more and 20 μm. Therefore, it is preferable that vardenafil and the like be crushed in advance. Note that in the present disclosure, the average particle diameter is measured using a laser diffraction particle size distribution measuring device.

The amount and proportion of vardenafil, etc. in the pharmaceutical composition for treating erectile dysfunction according to the present invention may be adjusted as appropriate within a range where vardenafil can exert its effects. For example, in the case of tablets, the amount of vardenafil, etc. per tablet can be 1 mg or more and 30 mg or less, preferably 5 mg or more and 25 mg or less. Furthermore, the proportion of vardenafil and the like in the pharmaceutical composition is preferably 1% by mass or more and 25% by mass or less, more preferably 5% by mass or more and 15% by mass or less.

Low-substituted hydroxypropylcellulose refers to a cellulose derivative in which some of the hydroxyl groups in the glucose ring are substituted with hydroxypropoxy groups. There are three hydroxyl groups in the glucose ring that constitutes cellulose, and the number of hydroxypropoxy groups per glucose ring is called the molar substitution degree (MS), and the molar substitution degree of low-substituted hydroxypropyl cellulose is 0.2. Above, it is 0.4 or less.

In the pharmaceutical composition for treating erectile dysfunction according to the present invention, low-substituted hydroxypropylcellulose is blended as a disintegrant. A disintegrant is a component added to promote disintegration of a preparation by taking in water, thereby facilitating release of the active ingredient. Since low-substituted hydroxypropyl cellulose is insoluble in water but swells with water, the presence of water can promote disintegration of the pharmaceutical composition. In the present invention, low-substituted hydroxypropyl cellulose is added to a pharmaceutical composition for treating erectile dysfunction containing vardenafil or the like as an active ingredient as a disintegrant that does not impair the stability of vardenafil or the like.

The size of the low-substituted hydroxypropylcellulose may be adjusted as appropriate. For example, the average particle diameter can be set to 10 μm or more and 60 μm or less. Further, the low-substituted hydroxypropyl cellulose may be in the form of powder or fiber.

The amount and proportion of the disintegrant in the pharmaceutical composition for treating erectile dysfunction according to the present invention may be adjusted as appropriate within a range that allows the composition to disintegrate well after being taken. For example, the amount of disintegrant per tablet can be 1 mg or more and 50 mg or less. The amount is preferably 30 mg or less or 20 mg or less, more preferably 10 mg or less. Furthermore, the proportion of the disintegrant in the pharmaceutical composition is preferably 1% by mass or more and 30% by mass or less. The ratio is preferably 20% by mass or less or 10% by mass or less, more preferably 5% by mass or less.

The pharmaceutical composition for treating erectile dysfunction according to the present invention only needs to contain low-substituted hydroxypropyl cellulose, and may be combined with low-substituted hydroxypropyl cellulose and other disintegrants, but may not contain cross-linked polyvinylpyrrolidone. Preferably one without. According to the experimental findings of the present inventors, cross-linked polyvinylpyrrolidone impairs the stabilization of vardenafil and the like. Crosslinked polyvinylpyrrolidone is sometimes abbreviated as crospovidone. Furthermore, the pharmaceutical composition for treating erectile dysfunction according to the present invention preferably contains only low-substituted hydroxypropyl cellulose as a disintegrant, in addition to inevitable impurities and unavoidable contaminants.

The pharmaceutical composition for treating erectile dysfunction according to the present invention preferably contains a coloring agent. The color of vardenafil and the like is said to range from white to slightly yellow or slightly brown, but this slightly yellow and slightly brown color is also thought to be due to the decomposition products of vardenafil. Therefore, it is preferable to incorporate a coloring agent into the composition to reduce the influence of light on vardenafil and to make the coloring of the composition caused by the decomposition of vardenafil less noticeable.

As the coloring agent, a yellow coloring agent is preferable because of the color of vardenafil and the like. The yellow colorant is not particularly limited as long as it is pharmaceutically acceptable, but examples include yellow No. 4 aluminum lake, yellow No. 5 aluminum lake, and yellow iron sesquioxide, with yellow iron sesquioxide being preferred. .

The amount and proportion of the coloring agent in the pharmaceutical composition for treating erectile dysfunction according to the present invention may be adjusted as appropriate. For example, in the case of tablets, the amount of coloring agent per tablet can be 0.01 mg or more and 1 mg or less, preferably 0.05 mg or more and 0.5 mg or less. Furthermore, the proportion of the colorant in the pharmaceutical composition is preferably 0.05% by mass or more and 0.5% by mass or less.

Examples of the dosage form of the pharmaceutical composition for treating erectile dysfunction according to the present invention include solid preparations such as tablets, granules, powders, and capsules, with tablets being more preferred. Powders are powder preparations, and granules have larger grains and are uniform in size than powders.

The pharmaceutical composition for treating erectile dysfunction according to the present invention may contain commonly used ingredients depending on its dosage form. For example, in the case of solid preparations, excipients such as lactose, sucrose, mannitol, crystalline cellulose, and starch; binders such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, and ethyl cellulose; fluidizing agents such as light silicic anhydride; stearin A lubricant such as magnesium acid, calcium stearate, talc, or hydrogenated vegetable oil may be added. Although lactose, crystalline cellulose, light anhydrous silicic acid, etc. are sometimes incorporated into tablets as disintegrants, this is not common, and in the present invention, these are incorporated in relatively large amounts as excipients.

The amount of excipients in the pharmaceutical composition for treating erectile dysfunction according to the present invention can be, for example, 50 mg or more and 150 mg or less per tablet in the case of tablets, and the proportion of excipients in the pharmaceutical composition is , preferably 50% by mass or more and 90% by mass or less. Further, when the pharmaceutical composition for treating erectile dysfunction according to the present invention is a tablet, the amount of lubricant per tablet can be, for example, 0.5 mg or more and 5 mg or less, The proportion of the brightener is preferably 0.5% by mass or more and 5% by mass or less.

The pharmaceutical composition for treating erectile dysfunction according to the present invention can be manufactured by a conventional method. For example, in the case of tablets, the components may be mixed and then compressed using a tablet machine. If the tablet is to be colored, it may be colored in advance by, for example, spraying a solution or dispersion of a coloring agent onto one or more excipients in a relatively large amount and then drying. Further, during the mixing of the components, the particles may be sized to a desired particle size by sieving or the like at any time.

The size of the pharmaceutical composition for treating erectile dysfunction according to the present invention may be adjusted as appropriate depending on the amount of vardenafil and the like. For example, in the case of a tablet, the shape can be a disc or lens shape that is easy to take orally, the diameter can be 3 mm or more and 10 mm or less, and the maximum thickness can be 2 mm or more and 5 mm or less.

It is preferable that the tablet for treating erectile dysfunction according to the present invention does not have a coating layer. Formation of the coating layer requires a process of spraying a coating solution onto the uncoated tablet and drying it, but the tablet for treating erectile dysfunction according to the present invention is highly stable even without a coating layer. There is no need to provide a coating layer.

Hereinafter, the present invention will be explained in more detail with reference to examples, but the present invention is not limited by the examples below, and changes may be made as appropriate within the scope of the spirit of the above and below. Of course, other implementations are also possible, and all of them are included within the technical scope of the present invention.

Example 1
Vardenafil hydrochloride hydrate, crystalline cellulose, low-substituted hydroxypropyl cellulose, and light anhydrous silicic acid having the composition shown in Table 1 were placed in a polyethylene bag and thoroughly mixed. Next, magnesium stearate was mixed to obtain a powder for tabletting. The tableting powder was compressed using a rotary tablet machine to obtain tablets with a diameter of 8 mm. The amounts of each component shown in Table 1 are per tablet.

Comparative example 1
Tablets with a diameter of 8 mm were obtained in the same manner as in Example 1 with the composition shown in Table 1, except that crospovidone was used as a disintegrant instead of low-substituted hydroxypropylcellulose.

Test Example 1: Stability Test The tablets manufactured in Example 1 and Comparative Example 1 were placed in a sealed container and stored at 70°C. Sample tablets were obtained on the 3rd, 6th, and 9th day from the start of the test, and the amount of substances related to vardenafil, the active ingredient, was measured under the following conditions. In addition, the tablets before the start of the test were also measured in the same way.
Each sample tablet was suspended in a mixed solvent (80 mL) of water:acetonitrile=4:1 (volume ratio), filtered through a membrane filter to obtain a sample solution, and analyzed by liquid chromatography under the following conditions.
Column: "XTerra RP18" manufactured by Waters, 3.0 mm x 25 cm, 5 μm
Column temperature: Approximately 40℃
Detector: Ultraviolet absorption photometer Measurement wavelength: 242 nm
Mobile phase: The concentration gradient was controlled by changing the mixing ratio of acetonitrile and a solution prepared by dissolving 1.3 g of potassium dihydrogen phosphate and 0.56 g of anhydrous disodium hydrogen phosphate in water to make 1000 mL.
The area of each peak in the obtained chromatogram was calculated by automatic integration method, and the proportion of vardenafil related substances was determined by area percentage method. The results are shown in Table 2.

As shown in Table 2, in the tablet of Comparative Example 1 containing crospovidone as a disintegrant, the active ingredient vardenafil decomposed over time, and especially the N-oxide form increased, and the total amount of vardenafil related substances increased. is also increasing over time.
On the other hand, in the tablet of Example 1 containing low-substituted hydroxypropyl cellulose as a disintegrant, the amount of vardenafil related substances produced, including the N-oxide form, was clearly lower, and the total amount of vardenafil related substances was lower than that of the tablet of Comparative Example 1. It is significantly suppressed compared to
The above results showed that the stability of vardenafil tablets was significantly increased simply by using low-substituted hydroxypropyl cellulose as a disintegrant.

Example 2
With the composition shown in Table 3, vardenafil hydrochloride hydrate, crystalline cellulose, lactose hydrate, low-substituted hydroxypropyl cellulose, and light silicic anhydride were charged into a container mixer and thoroughly mixed. Next, magnesium stearate was mixed to obtain a powder for tabletting. The tableting powder was compressed using a rotary tablet machine to obtain tablets with a diameter of 8 mm. The amounts of each component shown in Table 3 are per tablet.

Example 3
The lactose hydrate was put into a fluidized bed granulator, and a dispersion of yellow iron sesquioxide dispersed in purified water was sprayed thereon, and then dried and sized to obtain a colored lactose sized powder. As shown in Table 3, the ratio of yellow iron sesquioxide to 65.00 mg of lactose hydrate was 0.17 mg.
Tablets with a diameter of 8 mm were obtained in the same manner as in Example 2, except that the colored lactose granulated powder described above was used instead of the white lactose hydrate.

Test Example 2: Photostability Test The tablets of Examples 2 and 3 were irradiated with 1.2 million Lux of light using a D2 lamp or a xenon lamp. Next, the proportion of vardenafil related substances was determined under the same conditions as in Test Example 1. Note that the D2 lamp is also called a deuterium lamp and emits visible light from ultraviolet light, and the xenon lamp also emits visible light from ultraviolet light, but the light is extremely close to natural daylight. The results are shown in Table 4.

As shown in Table 4, it was shown that by coloring the tablets, the stability of vardenafil was further increased even against high energy light such as ultraviolet light.

Example 4
Tablets were obtained in the same manner as in Example 3 except that the composition was changed to that shown in Table 5. However, the diameter of the 20 mg tablet was 8 mm, but the diameter of the 10 mg tablet was 6.5 mm.

Claims (7)

an active ingredient selected from the group consisting of vardenafil, a salt thereof, a hydrate thereof, and a hydrate of a salt thereof ;
low- substituted hydroxypropyl cellulose , and
A pharmaceutical composition for treating erectile dysfunction, comprising a yellow coloring agent . The pharmaceutical composition for treating erectile dysfunction according to claim 1, wherein the active ingredient is vardenafil hydrochloride. The pharmaceutical composition for treating erectile dysfunction according to claim 1, wherein the active ingredient is vardenafil hydrochloride hydrate. The pharmaceutical composition for treating erectile dysfunction according to any one of claims 1 to 3 , which does not contain cross-linked polyvinylpyrrolidone. The pharmaceutical composition for treating erectile dysfunction according to any one of claims 1 to 4, which is in the form of a tablet. The pharmaceutical composition for treating erectile dysfunction according to any one of claims 1 to 5 , which does not have a coating layer. Low-substituted hydroxypropylcellulose and a yellow colorant are blended into a pharmaceutical composition for treating erectile dysfunction containing an active ingredient selected from the group consisting of vardenafil, a salt thereof, a hydrate thereof, and a hydrate of a salt thereof. A method for stabilizing an active ingredient, characterized in that: