KR20140102939A - Pharmaceutical composition for intravaginal administration comprising phosphodiesterase-5 inhibitor or pharmaceutically acceptable salt thereof - Google Patents

Abstract

The present invention relates to a pharmaceutical composition comprising a phosphodiesterase-5 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient; And a hard fat as a base for suppositories. The pharmaceutical composition for vaginal administration according to the present invention is excellent in stability and can be used for a desired organ 5 inhibitors, thereby reducing the systemic side effects of PDE-5 inhibitors and maximizing the drug concentration in the reproductive and uterine glands. Thus, the present invention provides a method for improving women's menopausal disorders, treating sexual arousal disorder, And the probability of fertilization and the increase of pregnancy rate.

Description

[0001] PHARMACEUTICAL COMPOSITION FOR INTRAVAGINAL ADMINISTRATION COMPRISING PHOSPHODIESTERASE-5 INHIBITOR OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF [0002] The present invention relates to a pharma- ceutical composition comprising a phosphodiesterase-5 inhibitor or a pharma- ceutically acceptable salt thereof,

The present invention relates to a pharmaceutical composition for intravaginal administration comprising a phosphodiesterase-5 inhibitor or a pharmaceutically acceptable salt thereof, and more particularly to a pharmaceutical composition for the prevention of systemic adverse effects of a female genital / The present invention relates to a pharmaceutical composition exhibiting an improved pharmacological effect by maximizing the concentration and a suppository formulated therefrom.

The phosphodiesterase-5 inhibitor (hereinafter referred to as' PDE-5 ') is a selective inhibitor of cyclic guanosine 3', 5'-monophosphate phosphodysterase type 5 (cGMP PDE-5) And is used as a remedy for erectile dysfunction. Sildenafil, Tadalafil, Vardenafil and Udenafil are currently being developed as drugs.

For example, when sildenafil (chemical formula: 5- [2-ethoxy-5 (4-methyl-1-piperazinylsulfonyl) phenyl] 7H-pyrazolo [4,3-d] pyrimidin-7-one) is known to be used in various cardiovascular treatments such as hypertension, heart failure and atherosclerosis (Korean Patent No. 78931) (Korean Patent No. 262926).

(6R-trans) -6- (1,3-benzodioxol-5-yl) -2,3,6,7,12,12a-hexahydro- [1, 2 ': 1,6] pyrido [3,4-b] indole-1,4-dione) is commercially available from Lilly under the trade name "Cialis" and can be used as an erectile dysfunction agent (Korean Patent No. 10-0577057). Vardenafil (formula: 4- [2-ethoxy-5- (4-ethylpiperazin-1-yl) sulfonyl-phenyl] -9-methyl-7-propyl-3,5,6,8- [4.3.0] nona-3,7,9-trien-2-one) is commercially available from Bayer under the trade name "Levitra" and is known to be used as an erectile dysfunction treatment (Korean Patent No. 10-0430355 Pyrazolo [4,3-d] pyrimidin-5-yl) - N (N, N-diethylamino) - [2- (1-methylpyrrolidin-2-yl) ethyl] -4-propoxybenzenesulfonamide) is commercially available under the trade name "Zydena" from Dong Ah Pharmaceutical and can be used as an erectile dysfunction drug (Korean Patent No. 10-0353014).

The PDE-5 inhibitors are commercially available in the form of free bases or water-soluble salts thereof, for example, sildenafil is commercially available (Viagra) in the form of a citrate salt. Korean Patent No. 435514 discloses a method of increasing the bioavailability of sildenafil in the form of lactate. On the other hand, in terms of formulation, foaming tablets (Korean Patent Application Laid-Open No. 2001-36527), oral tablets using sildenafil free base for improving bitterness (Korean Published Application No. 1999-0088249) have. However, there has not yet been studied a composition for vaginal administration targeting women.

In the case of tablets containing PDE-5 inhibitors, side effects such as headache, facial flushing, rhinitis, and digestive disorders were reported during oral administration. Korean Journal of Urology, 48, 2, 2007, Clinical efficacy, safety, and patient preference of 5-phosphodiesterase inhibitors were tested in a clinical trial using sildenafil, vardenafil, and tadalafil in commercial oral formulations, The frequency of adverse events occurred in approximately 1/5 of the test groups, and the difference in drug side-effects ratio was not reported to be large. Specifically, Pfizer's "Viagra Tablets", a commercial drug of sildenafil citrate salt, reports side effects such as flushing, headache, dyspepsia, dizziness, palpitations, eyeball redness, and visual anomalies. In addition, side effects such as facial flushing, headache, fever, chest discomfort, eye irritation, nasal congestion, and indigestion have been reported in Donga Pharmaceutical's "Zydena Chung", a commercial oral formulation of Udenapil.

The PDE-5 inhibitor induces an action such as erection by suppressing PDE-5, which is mainly distributed in the genital area. The above-described side effects are caused by a drug other than PDE-5 or PDE-5 It has been reported to occur on up to 11 species of PDE (Phosphodiesterase) ( Nature , 425, 98-102, 2003).

Therefore, the inventors of the present invention have been studying a method for reducing side effects that may occur when orally administered, and have found that a composition for vaginal administration containing a PDE-5 inhibitor locally acts on a desired organs, thereby reducing side effects And that the effect of the drug can be enhanced. Further, by confirming a method for improving the stability of the composition, the present invention has been completed.

Accordingly, it is an object of the present invention to provide a pharmaceutical composition for vaginal administration in which the maximum drug concentration and the blood concentration curve (AUC) increase in female genitalia and uterus and the stability are improved while the systemic drug concentration is decreased .

In order to achieve the above objects, the present invention provides a pharmaceutical composition comprising a phosphodiesterase-5 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient; And a hard fat as a base for suppositories.

The present invention also provides a suppository for intravaginal administration formulated from the composition.

The pharmaceutical composition for vaginal administration according to the present invention is excellent in stability, rapidly absorbs drugs, acts locally on a desired organ to reduce systemic side effects caused by PDE-5 inhibitors, 5 inhibitor, thereby improving the menopausal symptoms of women, treating sexual arousal disorder, and increasing the fertility rate and pregnancy rate.

1 is a graph showing dissolution rates of a tablet of Example 6 and a tablet of Comparative Example 5. Fig.
FIG. 2 is a graph showing the plasma concentration of sildenafil over time after administration of the tablets of Comparative Example 5 to male and female rats.
3 is a graph showing the plasma concentration of sildenafil over time after administering tablets of Comparative Example 5 and suppositories of Example 6 to rats (n = 6), respectively.
4 is a graph showing plasma concentrations of sildenafil over time after administering tablets of Comparative Example 5 and suppositories of Example 6 to females (n = 4), respectively.

The present invention relates to a pharmaceutical composition comprising a phosphodiesterase-5 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient; And a hard fat as a base for suppositories.

Examples of phosphodiesterase-5 inhibitors in the present invention include, but are not limited to, Sildenafil, Tadalafil, Vardenafil or Udenafil. In addition, the pharmaceutically acceptable salts of phosphodiesterase-5 inhibitors include maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid Benzenesulfonic acid, salicylic acid, citric acid, gluconic acid, lactic acid, mandelic acid, mandelic acid, citric acid, It is also possible to use cinnamic acid, aspartic acid, stearic acid, palmitic acid, formic acid, glycollic acid, glutamic acid, hydrochloric acid, Examples of the salt include salts of hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, phosphoric acid or nitric acid, But are not limited thereto, and various other salts commonly known in the art Can be used.

The pharmaceutical composition for vaginal administration according to the present invention can be formulated as a suppository for intravaginal administration (vaginal suppository) and can be applied topically to the intravaginal route of the woman to reduce systemic side effects, / Maximize the drug concentration near the uterus to increase the drug effect.

Vaginal suppositories are less likely to cause gastrointestinal disturbances than oral dosage forms, and are suitable for patients who are applied to drugs that are degraded when passing through the gastrointestinal tract, or who refuse oral administration, and because the absorbed drug does not pass through the liver, It is known that there is no loss of drug distribution due to. On the other hand, there are not many drugs developed as suppositories, which can lead to foreign sensation, discomfort, mucous membrane irritation or damage.

In the case of suppositories, semi-solid excipients are mainly used to reduce the foreign body sensation in the human body, to protect the mucous membranes weak or to accelerate the disintegration. The main process of suppositories using such semi-solid excipients is primarily It is customary to dissolve excipients using high heat. The stability of a pharmaceutical composition greatly affects the shelf life and therapeutic efficacy of the product. In general, heat, moisture, compatibility between adjuvants and residual solvent are widely known as important factors affecting stability.

As described above, since the excipient liquefied by heat during the usual suppository production process has a liquid property, it can dissolve all or a part of the main ingredient. When the main ingredient in the dissolved state is exposed to heat, Which can lead to even greater chemical changes. Therefore, since these chemical changes during the pharmaceutical manufacturing process can have a great influence on commercial product development, compared with the tablet formulations, which are most frequently marketed as commercial pharmaceutical products in the production process, More consideration should be given.

For the above reasons, the composition of the present invention is characterized in that it contains hard fat as a base for suppositories.

In general, as a base for suppositories, cacao butter, lanolin, polyethylene glycol, hard fat, glycerogelatin, cottonseed oil, palm oil, glycerin soap, propylene glycol and the like may be used. However, the phosphodiester- Surprisingly, the use of hard fat in suppositories containing the active ingredient showed significantly better stability under severe conditions (60 < 0 > C) than other bases.

The above range is contained in the NF port of USP Pharmacopoeia and is defined as a mixture of glycerides of saturated fatty acids.

The hard fat used as a suppository base in the present invention is a mixture of triglyceride esters of higher saturated fatty acids containing various mono- and diglycerides and is preferably a triglyceride ester of saturated fatty acids having 8 to 18 carbon atoms Can be used.

In addition, suppository bases usable in the compositions according to the invention may have the following characteristics:

- Melting point: 27 ~ 44 ℃;

- hydroxyl value: up to 30 mg potassium hydroxide per gram;

- acid value: up to 1.3 mg of potassium hydroxide per gram;

- iodine: up to 7.0 mg iodine per 100 g;

- Saponification: up to 215 - 255mg of potassium hydroxide per gram.

Specific examples of the state which can be used in the present invention the creamer Oreo (Cremer Oleo GmbH & Co. KG, Standort Witten) four or Sasol (Sasol Olefins & Surfactans GmbH, Hamburg , Germany) 's WITEPSOL, Sasol's MASSA ^ESTARIUM, Stephan Company, (Stepan Company, Northfield, Illinois), and more specifically WitePSOL H, W, or E grade products. WITEPSOL H5, H12, H15, H19, H175, H32, H35, H37 , W25, E75, E85 and MASSA ESTARIUM B, and MASSA ESTARIUM C.

The bases usable in the present invention can be produced by any conventional method. For example, a base may be produced by mixing saturated fatty acids, preferably derived from coconut and palm oil, and then esterifying this mixture with glycerol. At this time, the characteristics of the base can be changed by changing the esterification conditions.

The ground medium as the suppository base may be used in an amount of 60 to 99% by weight based on the total amount of the composition. Since the suppository is used in direct contact with the vagina, it is necessary for the user to have a size that is convenient for handling, and if it is too small or too large, it may cause difficulties in use. Therefore, the composition of the present invention has an advantage of being able to produce suppositories having an excellent stability and a size advantageous to use as a vaginal suppository by using a ground level in the above range.

The composition of the present invention may also contain surfactants such as poloxamer, polysorbate (Tween) 80, sorbitan ester (Span) and the like in order to facilitate absorption or facilitate absorption of the drug. PH adjusters such as lactic acid, phosphoric acid, and citric acid to promote absorption and reduce mucous membrane irritation; Or an additive such as bees wax, lecithin, ethoxylated fatty alcohols, ethoxylated fatty glycerides, and the like.

The pharmaceutical composition for vaginal administration according to the present invention not only has the advantages of the existing vaginal suppositories but also has excellent stability and quickly absorbs the drugs and can specifically increase the concentration of the drug particularly in the female genital / And can be effectively used for topical treatment of the site and improvement of menopausal disorder, treatment of sexual arousal disorder, correction probability and increase of pregnancy duration rate.

As used herein, "C" is the concentration of a pharmaceutically active ingredient (drug) in a biological sample (e.g., blood, serum and each organ). The concentration of the drug in the biological sample may be determined by any standard assay method known in the art. The term " _Cmax " refers to the highest concentration reached by the dose of the drug given in the biological sample. More specifically, " _{Cmax - org} " refers to the highest concentration in the organs, for example the highest drug concentration in the _{uterus and genitalia is} referred to as " _{Cmax - uterus and genitalia} ". The terms used in the present invention, "C _{max - sys"} represents the maximum density reached by the capacity of the whole body blood drug. In addition, the term "AUC" used in the present invention refers to the serum concentration "C""AUC _org " refers to the AUC in the organ, for example the AUC of the _{uterus and genitalia} is denoted "AUC _{uterus and genitalia} "."AUC _sys " refers to the systemic blood drug concentration-time curve as the enemy.

Vaginal administration composition of the present invention the C _max and AUC of the cervical and genital upon vaginal administration 10 times to 20 times higher than for oral administration, more than 1/5 times the C _max and AUC compared to the oral administration of the blood flow in the systemic Respectively. Specifically, the composition of the present invention has a C _max in the uterus and genitalia of 5 to 20 times higher than that of the oral administration, and the AUC of the uterus and genitalia is 5 to 7 times higher than that of the oral administration. In addition, the composition of the present invention shows a C _max of about 1/5 to 1/7 times the C _max in the systemic bloodstream when administered intravaginally, and the drug AUC in the systemic bloodstream is about 1/5 times that of the oral administration.

A PDE-5 inhibitor is used in the present invention surprisingly high C _max in women than men oral administration _- represents a _{sys sys} and AUC results. This fact shows that when the substance is orally administered to a woman, a side effect can be expressed at a higher rate than that of a male, and thus it is considered to be difficult to use commercially. However, the composition of the present invention shows a high _Cmax and AUC in certain organs, particularly in genitalia and uterus, when administered as vaginal suppository in vivo, compared to oral administration to women, Low drug concentration. In addition to reducing systemic side effects, it is also possible to use positional selective medication to improve the sexual satisfaction of women, alleviate women's menopausal symptoms, or improve the pregnancy success rate. And to maximize the effectiveness of drug treatment.

The present invention provides a suppository for vaginal administration made from the composition. The suppositories may be formulated using conventional methods known in the art (for example, cold method, melting method, etc.).

Hereinafter, the present invention will be described in more detail with reference to the following examples. The following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Examples 1 to 5 and Comparative Examples 1 to 4: Stability test by suppository base

In order to examine the effect of the suppository base on the stability of the composition for vaginal administration comprising the phosphodiesterase-5 inhibitor as an active ingredient, compositions for vaginal administration were prepared using various suppository bases. Examples 1 to 5 were prepared using ground paper as suppository bases, and Comparative Examples 1 to 4 used cacao paper, polyethylene glycol 4000, glycerogelatin and propylene glycol as suppository bases, respectively.

Specifically, according to the composition shown in Table 1 below, hard fat (Wettesol E75, Sasol, Germany), hard fat (WitapeSol S58, Sasol, Germany) (Hard fat, Wittesol H15, Sasol, Germany), hard fat (Wittesol W35, Sasol, Germany) and hard fat (Wittesol H19, Sasol, Germany) 500 g of cacao paper, polyethylene glycol 4000, glycerogelatin and propylene glycol were each put into a container and melted in a homogeneous solution state by heating at about 60 ° C. After adjusting the temperature of each base to about 40 ° C, 50 g of sildenafil base (Sildenafil base, Dongwoo Sinsech, Korea) was added, and homomixer (2500 rpm) and paddle mixer For about 120 minutes. The composition of the above-prepared composition is shown in Table 1 below.

Example 1 Example 2 Example 3 Example 4 Example 5 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Sildenafil free base 50 50 50 50 50 50 50 50 50 Hard fat (E75) 500 - - - - - - - - Hard fat (S58) - 500 - - - - - - - Hard fat (H15) - - 500 - - - - - - Hard fat (W35) - - - 500 - - - - - Hard fat (H19) - - - - 500 - - - - Cacao - - - - - 500 - - - Polyethylene glycol 4000 - - - - - - 500 - - Glycerol gelatin - - - - - - - 500 - Propylene glycol - - - - - - - - 500

The composition was sealed in an HDPE bottle and stored under the conditions of 60 ° C, respectively. Then, at 1, 2 and 4 weeks, the amount of the resulting flexible substance was measured by the following analysis method.

<Analysis method>

25 mg of sildenafil is precisely weighed into a 250-mL volumetric flask and dissolved in 20 mL of methylene chloride. After centrifuging this solution, accurately collect 10 mL of the supernatant, place it in a 50 mL volumetric flask, mix well with methanol, adjust to the marking, and filter it through a 0.45 um membrane filter and analyze it by the following HPLC analysis method.

Detector: ultraviolet absorption spectrophotometer (measurement wavelength: 290 nm)

Column: Reversed phase C18 column, 4.6 X 150 mm, 3 um

Flow rate: 1.0 ml / min

Column temperature: 35 ° C

Mobile phase: 0.05 M Triethylamine phosphate: methanol: acetonitrile = 580: 250: 170 (v / v / v)

The amounts of the resulting flexible materials (RRT 1.26) for the compositions of Examples 1 to 5 and Comparative Examples 1 to 4 are shown in Table 2 below.

Example 1 Example 2 Example 3 Example 4 Example 5 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Early 0.05 0.03 0.04 0.04 0.03 0.17 0.20 0.05 0.09 1 week 0.10 0.31 0.06 0.23 0.07 0.23 3.30 2.34 1.98 2 weeks 0.15 0.97 0.09 0.87 0.10 1.12 5.37 3.44 2.32 4 weeks 0.34 1.15 0.12 1.63 0.11 2.84 9.15 5.87 2.88

As shown in Table 2, when the peaks of the flexible substance appearing at the RRT (relative peak retention time) 1.26 relative to the peak area of the main component are observed in the order of the initial, 1, 2 and 4 weeks, the hard fat ) In Comparative Examples 1 to 5, while the compositions of Comparative Examples 1 to 4 using suppository bases other than the ground were produced in a remarkably large amount. The results show that the use of ground pads for vaginal administration using the phosphodiesterase-5 inhibitor is desirable from the standpoint of stability. Based on the above results, suppositories were prepared using ground.

Example 6: Preparation of suppositories containing sildenafil

1500 g of Wittesol H19 (Hard fat, Sasol, Germany) was placed in a vessel and heated at about 60 ° C to melt in a homogeneous solution state. 25 g of sildenafil free base (Dongwoo Sinsech, Korea) was added to the solution and homogenized for about 120 minutes using a homomixer (2500 rpm) and a paddle mixer (17 rpm) at the same time.

Separately, the PVC film was molded into a hollow shell-like suppository using a mold, and the composition prepared above was divided and charged at 15O &lt; 0 &gt; C at a temperature of about 38 [deg.] C. The filled PVC film was sealed quickly and then solidified at a temperature of about 12 캜 to prepare 1000 suppositories for vaginal administration.

Example 7: Preparation of suppositories containing tadalafil

The procedure of Example 6 was repeated, except that 1550 mg of PVC film was filled with 50 g of tadalafil free base instead of sildenafil free base using Witepsol H15 instead of Witepsol H19 in Example 6, 6 was repeated to prepare 1000 suppositories for vaginal administration.

Example 8: Preparation of suppositories containing udenafil

2600 g of Wittesol H15 (Hard fat, Sasol, Germany) was placed in a vessel and heated at about 60 ° C to melt in a homogeneous solution state. 100 g of polysorbate 80 and 26 g of lactic acid were added to the solution. Thereafter, 100 g of Yudenafil free base (Hanmi Precision, Korea) was added and mixed homogeneously for about 120 minutes using a homomixer (2500 rpm) and a paddle mixer (17 rpm) at the same time.

Separately, the PVC film was molded into a hollow shell-like suppository using a mold, and the composition prepared above was divided into 2826 mg portions at about 40 캜. The filled PVC film was sealed quickly and then solidified at a temperature of about 8 캜 to prepare 1000 suppositories for vaginal administration.

Example 9: Preparation of suppositories containing vardenafil

The procedure of Example 8 was repeated except that 2776 mg of a vinyl film was filled with 50 g of vardenafil free base (Dongwu ShinTech, Korea) in place of Uptepsol H75 and Uptepsol E75 in place of Udenapil free base. 8 was repeated to prepare 1000 suppositories for vaginal administration.

The compositions of suppositories prepared in Examples 6 to 9 are shown in Table 3 below.

Component (g) Example 6 Example 7 Example 8 Example 9 Sildenafil 25 - - - Tadalafil - 50 - - Udena Phil - - 100 - Vardenafil - - - 50 Witepsol H19 1500 - - - Uittesol H15 - 1500 2600 - Witepsol E75 - - - 2600 Polysorbate 80 - - 100 100 Lactic acid - - 26 26 Total amount 1525 1550 2826 2776

Comparative Example 5: Preparation of tablets for oral administration containing sildenafil

(Avicel pH-102, FMC, USA), crospovidone (Polyplasdone XL-10, available from ISP Company, USA) and magnesium stearate (manufactured by Mitsubishi Chemical Corporation) according to the composition shown in Table 4 below. NOF, Japan) was used to prepare tablets containing sildenafil as an active ingredient.

After mixing the ingredients, tablets with a hardness of about 15 kp were prepared using a refiner (MRC-45, Sejong Pharmatech, Korea) at a force of about 5 kN.

Comparative Example 5 Weight (mg) Sildenafil 25 Microcrystalline cellulose 200 Crospovidone 15 Magnesium stearate 2.5 Total amount 242.5

Experimental Example  One: Disintegration test

The suppositories of Examples 6 to 9 were subjected to the disintegration test as described below by the suppository test method in the disintegration test item of the General Test Methods among the Korean Pharmacopoeia 9 revision.

<Test Conditions>

Equipment: Disintegration test equipment for suppositories (SDT-300, Fine Scientific Instruments, Korea)

Temperature: 36 ° C

Disintegration test solution: 4 L or more (distilled water)

Rotation speed: 1/2 revolution every 10 minutes

In addition, the disintegration test was conducted as described below by the general release formulation-tablet test method in the disintegration test item of the General Test Methods in the Korean Pharmacopoeia 9 revision of the tablets for oral administration of Comparative Example 5.

<Test Conditions>

Equipment: Disintegration tester (DIT-400, Lab fine, Korea)

Temperature: 37 ° C

Disintegration Test Solution: 1 L (the second solution of the pharmacological disintegration test solution)

Rotation speed: 1/2 revolution every 10 minutes

The results of the above tests are shown in Table 5.

Example 6 Example 7 Example 8 Example 9 Comparative Example 5 Disintegration time (minutes) 12 13 13 11 11

As shown in the above table, the suppositories of Examples 6 to 9 according to the present invention were all disintegrated within 13 minutes, and no foreign matter remained in the container in the testing machine. This was within 30 minutes of the test for disintegration of suppositories in the Disintegration Tests of the KP General Test.

In addition, the tablet for oral administration of Comparative Example 5 also disintegrated in about 11 minutes, which was within 30 minutes of the disintegration test of the general release formulation in the Disintegration Test Portion of the Korean Pharmacopoeia (KP) General Test Methods.

Therefore, the suppositories of Examples 6 to 9 of the present invention are expected to be liquefied completely without disintegration upon vaginal administration, and the tablet for oral administration of Comparative Example 5 is also expected to disintegrate in the gastrointestinal tract in a short time.

Experimental Example 2: Melting point measurement

The suppositories of Example 6 and Example 9 were measured for their melting points using DSC (Differential Scanning Calorimeter, Sinco, Korea). The measurement results are shown in Table 6 below.

Example 6 Example 9 Melting point (캜) 31.2 to 35.8 35 to 35.6

As shown in the above table, the suppositories of the present invention exhibited melting points ranging from 25 ° C to 36 ° C, indicating that the suppositories of the present invention are in a solid state at room temperature, but are easily melted at body temperature.

Experimental Example 3: Elution test

The supernatant of Example 6 and the tablet of Comparative Example 5 were subjected to a dissolution test under the conditions of 50 rpm, 900 mL, and 36.5 DEG C using an elution solution of pH 4.4 by the second method (paddle method) of the pharmacokinetic (KP) Respectively. 5 mL of each sample was taken at 5, 10, 15, 30, 45, 60, 90, 120 and 180 minutes and filtered through a 0.45 μm membrane filter. Thereafter, it was analyzed using UV (Hitachi, Japan) under the following conditions, and the results are shown in Fig.

<Analysis condition>

Analytical Instruments: UV

Analysis wavelength: 290 nm

As shown in FIG. 1, the supernatant of Example 6 and the tablet of Comparative Example 5 showed about 85% elution after 45 minutes of elution.

To determine the similarity of the two compositions, a similarity factor (f2), the FDA recommended method, was calculated.

Specifically, Table 6 of the &quot; Drug Equivalence Test Standard &quot; of Notification No. 2011-57 of the Food and Drug Administration, and JW Moore and HH Flanner. Pharm. Tech. , The similarity factor (f2) of the supernatant of Example 6 and the elution of the tablets of Comparative Example 5 (f2) were calculated according to the method disclosed in the above-mentioned Example, 20 (6): 64-74 Was 51.7 and was judged to be equivalent according to the criteria.

Experimental Example 4: Measurement of Drug Parameters of Tablets of Comparative Example 5 in vivo  Experiment)

The tablets of Comparative Example 5 were orally administered to rats under the following conditions, and drug parameters such as C _max , AUC, and T _max were measured. At this time, the rats were divided into male and female to compare the difference in drug parameters between male and female. The specific animal test protocol, animal test procedure, analytical sample pretreatment method, and instrumental analysis conditions are shown in Tables 7 to 10, and the results are shown in Table 11 and FIG.

Animal Test Protocol Used animal SD rats weight 220 ± 10 g gender Female 5, Male 6 Sample collection time 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8 and 24 hours Sample weight 0.5 mL blood collection Sample preparation 1. Blood was collected by centrifugation (12,000 rpm, 3 minutes).
2. Spray on Eppendorf tubes
3. Storage at -70 ° C

Animal testing course a. Adapt the rats for 5 days
b. Weigh the rats immediately before drug administration.
c. Sildenafil was prepared by grinding and dispersing in distilled water, and placed in a 1 mL syringe with needle removed.
d. The drug is administered orally.
e. At a certain point, 0.5 mL of blood is collected and centrifuged, and the plasma is transferred to an Eppendorf tube and stored at -70 ° C.

Analytical sample pretreatment method 1) Take 200 μL of the plasma sample obtained at each time point.
2) Add 1 ml of the internal standard solution (telmisartan solution of 1 ppm in MeOH: ACN (50:50) dilution) to the sample.
3) Add 1 mL of dichloromethane to the above sample, and homogeneously mix for 10 minutes.
4) Centrifuge the mixture at 12,000 rpm for 3 minutes.
5) After separating the organic solvent layer, the solvent is evaporated at 40 ° C with nitrogen gas.
6) Add 100 μL of mobile phase, mix for 30 seconds, and centrifuge at 12,000 rpm for 3 minutes.
7) Take the supernatant and use this as the sample solution and inject 5 μL of the sample solution.

Comparison of pharmacokinetics in male and female rats The male (R) Female (T) T / R AUC ^{0 -24} (ng · hr / mL) 875.4 ± 574.2 19770.5 ± 7843.7 22.59 C _max (ng / mL) 728.7 ± 768.6 6666.5 ± 3598.3 9.15 T _max (hr) 0.2 ± 0.1 0.6 ± 0.2 2.53

As a result, the AUC _sys in female rats was about 22.6 times higher than that of male rats and the C _{max - sys} was about 9.2 times higher in sildenafil (oral administration). These results show that sildenafil tablets can achieve higher therapeutic effects in women than men, but high drug concentrations in the systemic bloodstream are expected to cause many side effects in women because they lead to side effects. Therefore, it was judged that sildenafil tablets could not be commercially applied to women.

Experimental Example 5: Comparison of tissue distribution of sildenafil according to sex

When the suppository of Example 6 and the tablet of Comparative Example 5 were applied to rats, an animal test was conducted under the following conditions to determine the concentration of sildenafil distributed in each organ. Animal tests were carried out using 6 male rats and 8 female rats, the male rats were orally administered the tablets of Comparative Example 5 and the 5 rats of the female rats were orally administered the tablets of Comparative Example 5 while the remaining 3 The horses were vaginally administered the suppositories of Example 6. The specific animal test protocol, animal test procedure, and analytical sample pretreatment method are shown in Tables 12 to 14, and the results are shown in Table 15.

Animal Test Protocol Used animal SD rats weight 220 ± 10 g gender Female 8, Male 6 Sample collection time 0, 0.5, 1, 2, 4, 8, and 24 hours Sampling The abdominal aorta was cut at each time point to extract liver, kidney, lung, genital and vagina after bleeding Number of animals per group Female 3 (vaginal), female 5 (oral), male 6 (oral)
Sample preprocessing method 1. Extracted organ weighing
2. Diluted with 4% BSA (bovine serum albumin) (liver X3, kidney X3, lung X5, genitalia + vaginal X10)
3. Homogenization at 20,000 rpm
4. Spray on Eppendorf tubes
5. Storage at -70 ° C

Animal testing course a. Rats are adapted for 5 days.
b. The rats were weighed immediately before drug administration and randomly grouped and labeled on the tail.
c. The tablets of Comparative Example 1 were thoroughly ground and dispersed in distilled water. The supernatant of Example 6 was dissolved by warming to 50 占 폚, and the tablets were fixed in a 1 mL syringe from which the needles had been removed.
d. The tablets and suppositories of Comparative Example 5 were administered orally and vaginally, respectively.
e. The rats were anesthetized with ether and lavaged, followed by cutting the celiac artery and bleeding.
f. Liver, lungs, kidneys, genitalia and vagina are removed to remove fat.
g. Weigh each of the extracted organs and put them in a falcon tube.
h. Each organ was diluted with 4% BSA (bovine serum albumin) (liver X3, kidney X3, lung X5, genitalia + vaginal X10)
i. Homogenize at 20,000 rpm.
j. Dispense into Eppendorf tubes.
k. Storage at -70 ° C.

Analytical sample pretreatment method 1) Take 100 μL of the long sample.
2) Add 1 ml of the internal standard solution (telmisartan solution with 1ppm concentration of MeOH: ACN (50:50) diluent) to the sample.
3) Dichloromethane (1 mL) was added to the sample and mixed homogeneously for 10 minutes.
4) Centrifuge the mixture at 12,000 rpm for 3 minutes.
5) After separating the organic solvent layer, the solvent is evaporated at 40 ° C with nitrogen gas.
6) Add 200 μL of mobile phase, mix for 30 seconds, and centrifuge at 12,000 rpm for 3 minutes.
7) Take the supernatant and use this as the sample solution and inject 5 μL of the sample solution.

Comparison of Sildenafil Tissue Distribution by Gender Example 6 Comparative Example 5 Comparative Example 5 group parameter female
Vagina female
oral- cock
oral- Tissue / plasma (oral) Tissue / plasma (oral) Tissue / plasma (oral) liver AUC _{0 -24} (ng · hr / mL) 0.23 0.46 2.75 C _max (ng / mL) 2.28 4.17 3.04 lungs AUC _{0 -24} (ng · hr / mL) 0.37 0.82 0.06 C _max (ng / mL) 3.26 5.94 0.11 kidney AUC _{0 -24} (ng · hr / mL) 0.19 0.60 5.69 C _max (ng / mL) 1.94 5.86 5.45 Uterus + vagina AUC _{0 -24}
(ng · hr / mL) 8.96 0.46 - C _max (ng / mL) 105.48 2.67 - Testicle + penis AUC _{0 -24} (ng · hr / mL) - - 43.97 C _max (ng / mL) - - 11.00

As shown in Table 15 above, surprising results were obtained for each male and female parts. Firstly, when oral administration was carried out, the AUC and _Cmax values in the organs of female rats were generally high when compared by male and female sex, but the male reproductive / testicular levels were very high. This implies that PDE-5 inhibitors may have a higher local effect on male rats compared to female rats and that the side effects of other organs are less. On the other hand, when compared with the results of oral administration versus intramuscular administration, the AUC and _Cmax values of female rats were lower in other organs when vaginal administration, but the AUC and _Cmax values were higher in toxic genital / uterus. Therefore, it is considered that PDE-5 inhibitor can be administered in vaginal suppository form to minimize systemic side effects and to maximize drug bioavailability in specific organs (genital and uterine).

Experimental Example 6: Comparison of sildenafil pharmacokinetics (rats)

The suppositories of Example 6 and the tablets of Comparative Example 5 were administered to the rats in vaginally and orally, respectively, and plasma drug concentrations and drug parameters were measured in the same manner as in Experimental Example 4. The measurement results are shown in Table 16 and FIG.

parameter Comparative Example 5
(Oral administration) Example 6
(Vaginal administration) T / R ratio AUC _sys ^{0 -24} (ng · hr / mL) 11907.76 ± 8499.20 1497.77 ± 745.06 0.126 C _{max - sys} (ng / mL) 1684.86 ± 589.40 155.55 ± 98.84 0.092 T _max (hr) 0.65 + 0.14 10.00 ± 11.01 15.385

Table 16 and, as shown in Figure 3, in the case of vaginal administration of sildenafil C _max as compared to oral _{administration-were} that the _{sys sys} and AUC ^{0 -24} low as about 1/10. Comparing the results with the results of the drug distribution in the organ obtained in Experimental Example 5, it has been found that the vaginal administration of the PDE-5 inhibitor maintains the drug concentration in the target organ, that is, the genital and uterus, It can be seen that

Experimental Example 7: Comparison of sildenafil pharmacokinetics (human)

Four subjects (female, 25 to 40 years old) were divided into two groups and the tablets of Comparative Example 5 were orally administered to the first group by the double blind method, and the suppositories of Example 6 were administered to the second group. Thereafter, the pharmacokinetics of sildenafil were compared in the same manner as in Experimental Example 4. The results of the above experiment are shown in Table 17 and FIG.

parameter Comparative Example 5 Example 6 T / R ratio AUC _{0 -24} (ng · hr / mL) 891.3 + - 182.3 165.1 ± 78.0 0.185 C _max (ng / mL) 282.0 ± 69.6 9.5 ± 2.6 0.034 T _max (hr) 1.4 ± 0.3 7.0 ± 2.0 5.091

As shown in Table 17 and FIG. 4, similar to Experimental Example 6, vaginal administration showed C _max and AUC lower than about 1/5 of that of oral administration. Therefore, it is considered that PDE-5 inhibitor can reduce the systemic side effects and maximize the drug concentration in specific organs, thereby increasing the bioavailability of the drug, thereby maximizing the therapeutic effect of the drug.

Claims (10)

A phosphodiesterase-5 inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient; And a hard fat as a base for suppositories.
The pharmaceutical composition according to claim 1, wherein the phosphodiesterase-5 inhibitor is sildenafil, tadalafil, vardenafil, or udenafil.
The method of claim 1, wherein said pharmaceutically acceptable salt of said phosphodiesterase-5 inhibitor is selected from the group consisting of maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, salicylic acid, Hydroxamic acid, hydroiodic acid, citric acid, formic acid, glycolic acid, glutamic acid, hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, acid, sulfuric acid, phosphoric acid or nitric acid.
The pharmaceutical composition for vaginal administration according to claim 1, wherein said ground is a mixture of triglyceride esters of saturated fatty acids having 8 to 18 carbon atoms.
The pharmaceutical composition for vaginal administration according to claim 1, wherein the ground is included in an amount of 60 to 99% by weight based on the total amount of the composition.
The pharmaceutical composition for vaginal administration according to claim 1, wherein the composition further comprises at least one surfactant, a pH adjuster or an additive.
The pharmaceutical composition for vaginal administration according to claim 1, wherein the C _max and the AUC in the uterus and genitalia when the composition is administered in vagina are 5 to 20 times higher than in oral administration.
The pharmaceutical composition for vaginal administration according to claim 1, wherein C _max and AUC in the systemic bloodstream when the composition is administered in vagina are as low as 1/5 or less as compared with oral administration.
The pharmaceutical composition for vaginal administration according to claim 1, wherein the composition is used for improving a woman's menopausal disorder, for treating sexual arousal disorder, and for increasing the fertility and fertility rate.
 A suppository for vaginal administration formulated from the composition of claim 1.

Images