JP2011184433A - Vardenafil-containing oral liquid medicine composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an oral liquid medicine containing a vardenafil hydrochloride which is excellent in stability and internal applicability. <P>SOLUTION: This oral liquid medicine contains the vardenafil hydrochloride with a pH of 4 or less, using a pH adjuster excepting hydrochloric acid. Preferably, this oral liquid medicine has the pH adjuster that comprises lactic acid, tartaric acid, or malic acid. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a liquid preparation containing vardenafil hydrochloride, mainly for treatment or improvement of penile erectile dysfunction and excellent in storage stability and convenience in use, and a container containing the liquid preparation.

  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 type of PDE, is an enzyme that is abundant in the corpus cavernosum and lung tissue, and is known to be involved in penile erectile dysfunction and pulmonary hypertension. The mechanism of erection can be explained as follows by integrating 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.

  On the other hand, blockage of cavernous blood inflow due to penile arterial contraction due to sympathetic nerve tension due to stress, etc., a decrease in nNOS activity or a decrease in guanylate cyclase activity, an increase in PDE5 activity, etc. If this happens, the penis will not erection, or it will not persist after erection, making it impossible to have intercourse. Such a pathological condition is called erectile dysfunction, erectile dysfunction, or erectile dysfunction. For psychological considerations, the expression “ED”, which is an abbreviation for the English name Erectile Dysfunction, is widely used.

  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). This PDE5 inhibitor saved the majority of patients suffering from ED.

  To date, several types of PDE5 inhibitors have been put on the market, but all are solid preparations (tablets), and little is known about techniques related to liquids. To date, for intranasal administration of sildenafil methanesulfonate Only an aqueous solution is disclosed (see Patent Document 1). However, this is not an internal solution.

  Patent Document 2 describes tablets, capsules, solutions, suspensions, ointments, sprays, creams, gels, and the like as dosage forms of sildenafil citrate combination formulations. However, this document does not disclose any specific formulation example or production technique of a solution or suspension (see Patent Document 2).

  Thus far, a tablet of vardenafil hydrochloride, which is one of PDE5 inhibitors, has been put on the market for the efficacy of erectile dysfunction, but the internal solution is completely unknown.

Japanese Patent No. 3263379 JP 2001-233770 A

Collection of ethical drugs 2009 edition JAPIC 2008

  So far, there has been no technical information about PDE5 inhibitor-containing internal liquids, but the present inventors have conducted intensive research for many years focusing on the usefulness of PDE5 inhibitor-containing internal liquids. It was.

  That is, the present inventors, in particular, taking into account the usage form of the PDE5 inhibitor, makes the dosage form a liquid agent under circumstances different from that of a normal solid agent, so that the convenience of taking is particularly improved. Focusing on the fact that this would be the case, the present inventors completed the present invention by investigating a PDE5 inhibitor-containing internal solution with excellent stability.

  In general, it is known that an internal liquid preparation can be used only with a very limited drug because it is difficult to ensure the stability of the internal liquid preparation, unlike a solid preparation. In that respect, the internal liquid preparation of the present invention can be said to be a great feature in that its stability is very excellent.

  That is, the object of the present invention is to determine whether it is possible to make a PDE5 inhibitor into an internal solution, and not only the contents (solution) but also the storage conditions and other ideal PDE5 inhibitors It is to provide a stable PDE5 inhibitor-containing liquid agent by elucidating whether or not an internal liquid agent can be obtained.

  In order to elucidate and solve such problems, the present inventors have made extensive studies on a solution containing vardenafil hydrochloride. As a result, it was found that when the pH was not adjusted or the pH was adjusted with hydrochloric acid, the pH of the solution increased with time, the content decreased or colored, and the formulation was unstable.

  As the investigation further progressed, it was found that a vardenafil hydrochloride-containing internal liquid preparation could be obtained by producing an internal liquid preparation within a specific pH range using a pH adjuster other than hydrochloric acid.

  Also, under such conditions, the liquid agent of the present invention has found a surprising result that it can realize sufficient storage stability without requiring light-shielding storage even without adding a stabilizer, and completes the present invention. It came to.

That is, the present invention is as described below.
(1) An oral solution characterized by containing vardenafil hydrochloride and a pH adjusting agent other than hydrochloric acid and containing no preservative.
As the present invention, preferably,
(2) The oral solution according to (1) above, wherein the pH adjuster is lactic acid, tartaric acid, or malic acid.
(3) The internal liquid preparation according to any one of (1) to (2), wherein the internal liquid preparation has a pH of 2.5 to 4.0,
(4) The internal liquid preparation according to any one of (1) to (2), wherein the internal liquid preparation has a pH of 3.0 to 3.5,
(5) The internal liquid preparation according to any one of (1) to (4), further comprising a sweetener and / or a fragrance,
(6) The internal liquid preparation according to any one of (1) to (5), for treatment or improvement of penile erectile dysfunction, and
(7) The internal use liquid according to any one of (1) to (6), wherein the medicinal effect develops earlier than the solid preparation.

  According to the present invention, an extremely stable vardenafil hydrochloride-containing internal liquid can be realized without adding a stabilizer. It is useful because it is a liquid for treating or improving penile erection dysfunction that is convenient for taking.

  “Penis erection dysfunction treatment” is a disease or symptom that, for some reason, penile erection does not occur to the extent necessary for sexual intercourse, or it does not persist even after erection and normal sexual intercourse cannot be performed. The term “improvement of penile erection dysfunction” means to reduce or suppress such a disease or symptom.

  Vardenafil hydrochloride is a known compound and is available on the market. The pH adjuster is not particularly limited as long as it is other than hydrochloric acid. For example, pH adjusters such as lactic acid, tartaric acid, malic acid, citric acid and sodium hydroxide are listed in the Pharmaceutical Additives Dictionary 2005.

  “PH adjuster” is usually a pH adjuster described in an additive dictionary or the like, and preferably malic acid, lactic acid, tartaric acid, acetic acid, fumaric acid, succinic acid, maleic acid, adipic acid And more preferably malic acid, lactic acid or tartaric acid.

  The pH of the internal solution is preferably 2.5 to 4.0, more preferably 3.0 to 3.5.

  The “sweetener” is a sweetener usually used as a food. Preferably, glucose, fructose, sucrose, etc. are used as general sweeteners, and reduced maltose water candy, xylitol is used as a sugar alcohol. -Such as acesulfame K, sclarose, aspartame, stevia, etc. as artificial sweeteners.

  “Preservatives” and “fragrances” are generally preservatives and fragrances described in the food additive dictionary.

  The content of vardenafil hydrochloride in the daily dose of the liquid preparation of the present invention is 1 mg to 70 mg, preferably 3 mg to 40 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. The volume of the liquid agent is not particularly limited, but the amount of liquid per one time is preferably 100 mL or less, and more preferably 50 mL or less.

  The liquid preparation of the present invention may further contain an appropriate amount of sweeteners and / or fragrances in order to provide ingestion and palatability.

  The liquid preparation of the present invention may further contain an appropriate amount of sweeteners and / or fragrances in order to provide ingestion and palatability.

  Furthermore, the container for internal use liquid preparations of the present invention is a polyethylene drinking-out container that is designed to open a drinking mouth part by screwing a knob part in order to combine convenience for taking a scene and convenience for disposal. A disposable container is desirable. Such a container is molded using, for example, a normal blow fill seal (BFS) molding machine. In BFS molding, a resin container is molded by a molding machine, and immediately filled with a chemical solution and sealed.

Examples of the present invention will be described below, but the present invention is not limited thereto.
(Comparative Example 1)
Vardenafil hydrochloride was dissolved in purified water, and then a hydrochloric acid solution was added to prepare a solution of 10 mg / 20 mL, pH 4 as vardenafil.
(Comparative Example 2)
Vardenafil hydrochloride was dissolved in purified water to prepare a 10 mg / 20 mL solution as vardenafil (pH 5.14).

Example 1
After dissolving vardenafil hydrochloride in purified water, a lactic acid solution was added to prepare a solution of 10 mg / 20 mL, pH 3.5 as vardenafil.
(Example 2)
After dissolving vardenafil hydrochloride in purified water, a lactic acid solution was added to prepare a solution of 10 mg / 20 mL, pH 3 as vardenafil.
(Example 3)
After dissolving vardenafil hydrochloride in purified water, a tartaric acid solution was added to prepare a solution of 10 mg / 20 mL, pH 3.5 as vardenafil.
Example 4
After dissolving vardenafil hydrochloride in purified water, a tartaric acid solution was added to prepare a solution of 10 mg / 20 mL, pH 3 as vardenafil.
(Example 5)
After dissolving vardenafil hydrochloride in purified water, a malic acid solution was added to prepare a solution of 10 mg / 20 mL, pH 3.5 as vardenafil.
(Example 6)
After dissolving vardenafil hydrochloride in purified water, a malic acid solution was added to prepare a solution of 10 mg / 20 mL, pH 3 as vardenafil.

<Test Example 1> Solution stability test 1
(1) Test substance Vardenafil hydrochloride was used as a hydrochloride after extracting a commercially available Levitra tablet (registered trademark, manufactured by Bayer Yakuhin Co., Ltd.).
The pH adjuster lactic acid used was a commercially available product from Musashino Chemical Laboratory, and the tartaric acid, malic acid and hydrochloric acid used were commercially available products from Wako Pure Chemical Industries, Ltd.
(2) Test method The liquid agent obtained in Comparative Example 1-2 and Example 1-6 was put in a transparent glass bottle, stored under a temperature condition of 50 to 60 degrees, and the property was observed over a certain period.
(3) Test result 1 (pH adjuster is hydrochloric acid or not used)
Table 1 shows the results of changes over time when the storage conditions were 60 degrees. From Table 1, it turned out that the raise of pH was recognized and it was unstable in Comparative Example 1-2. Further, coloring was observed in Comparative Example 1, and a decrease in content was also observed in Comparative Example 2.

  Next, Table 2 shows the results of changes over time when the storage conditions were 50 degrees. Similar to the results shown in Table 1, in Comparative Example 1-2, it was found that the pH was increased and was unstable, coloring was observed in Comparative Example 1, and a decrease in content was observed in Comparative Example 2.

  As described above, it was found that the storage stability was insufficient in any of the comparative examples.

(4) Test result 2 (pH adjuster is lactic acid)
Table 3 shows the results of changes over time when the storage conditions were 60 degrees. From Table 3, it was found that excellent storage stability was obtained in both cases of Examples 1 and 2.

  Next, Table 4 shows the results of changes over time when the storage conditions were 50 degrees. Similar to the results in Table 3, it was found that excellent storage stability was obtained in both cases of Examples 1 and 2.

  As described above, it has been found that when lactic acid is used as a pH adjuster, it is stable.

(5) Test result 3 (pH adjuster is tartaric acid)
Table 5 shows the results of changes over time when the storage conditions were 60 degrees. From Table 5, it was found that excellent storage stability was obtained in any of Examples 3 and 4.

  Table 6 shows the results of changes over time when the storage conditions were 50 degrees. Similar to the results in Table 5, it was found that excellent storage stability was obtained in both cases of Examples 1 and 2.

  As mentioned above, when tartaric acid was used as a pH adjuster, it turned out that it is stable.

(6) Test result 4 (pH adjuster is malic acid)
Table 7 shows the results of changes over time when the storage conditions were 60 degrees. From Table 7, it was found that excellent storage stability was obtained in any of Examples 5 and 6.

  Table 8 shows the results of changes over time when the storage conditions were 50 degrees. Similar to the results in Table 7, it was found that excellent storage stability was obtained in any of Examples 5 and 6.

  As mentioned above, when malic acid was used as a pH adjuster, it turned out that it is stable.

<Test Example 2> Solution stability test 2
(1) Test substance Vardenafil hydrochloride was used as a hydrochloride after extracting a commercially available Levitra tablet (registered trademark, manufactured by Bayer Yakuhin Co., Ltd.).
The pH adjuster lactic acid used was a commercially available product from Musashino Chemical Laboratory, and the tartaric acid, malic acid and hydrochloric acid used were commercially available products from Wako Pure Chemical Industries, Ltd.
(2) Test Method Each specimen filled with the liquid preparation obtained in Comparative Example 1-2 and Example 1-6 in a transparent glass bottle was placed in a 3000 Lux / hr light stability tester and subjected to a light stability test. . The properties of the solution were observed 200 hours after irradiation (600,000 Lux).
(3) Test results Table 9 shows the results of examination of property changes. From Table 9, it turned out that the raise of pH and the fall of the content were recognized in Comparative Example 1-2, and it was unstable. Further, in Comparative Example 1, coloring was also observed. On the other hand, in Example 1-6, it turned out that the storage stability is excellent.

According to the present invention, an extremely stable vardenafil hydrochloride-containing internal liquid can be realized without adding a stabilizer. It is useful because it is a liquid for treating or improving penile erection dysfunction that is convenient for taking.

Claims (6)

An oral solution characterized by containing vardenafil hydrochloride and a pH adjusting agent other than hydrochloric acid and containing no preservative. The internal use liquid agent of Claim 1 whose pH adjuster is lactic acid, tartaric acid, or malic acid. The internal use liquid agent of any one selected from Claim 1-2 whose pH of an internal use liquid agent is 2.5-4.0. The internal liquid preparation according to any one of claims 1-2, wherein the internal liquid preparation has a pH of 3.0 to 3.5. Furthermore, the internal use liquid agent of any one selected from Claims 1-4 containing a sweetener and / or a fragrance | flavor. The internal use liquid agent of any one selected from Claim 1-5 for penis erectile dysfunction treatment or improvement.