OA16802A - Pharmaceutical composition for treating premature ejaculation and method for treating premature ejaculation. - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for treating, preventing or improving premature ejaculation, which is taken on demand prior to sexual activity, the composition comprising clomipramine hydrochloride in an amount of 14 to 16 mg, preferably about 15 mg, as an active ingredient. More preferably, the composition of the present invention further comprises pregelatinized starch and sodium starch glycolate. The pharmaceutical composition of the present invention can provide rapid onset of efficacy, reduce a dissolution (absorption) deviation according to the patient's gastrointestinal pH and minimize side effects.

Description

The présent invention relates to a pharmaceutical composition for treating prématuré éjaculation, which provicies rapid-onset of efficacy, exhibits less uptake déviation according to the patient’s conditions and has reduced side effects. Also, the présent invention relates to a mcthod for treating, preventing or improving prématuré éjaculation by using the pharmaceutical composition. Further, the présent invention relates to a medical use of the pharmaceutical composition in the treatment, prévention or improvement of prématuré éjaculation.

This application daims priority to Korean Patent Application No. 10-20110062620 fïled on June 28, 2011, the disclosure thereof is incorporated herein by reference.

BACKGROUND ART

Prématuré éjaculation is one of the common sexual complaints and is estimated to affect approximately 30 to 40% of men. Prématuré éjaculation means persistent or récurrent éjaculation with minimal sexual stimulation before, upon, or shortly after sexual activity, and before the person wishes it. Such éjaculation that occurs sooner than desired is often disappointing and can lead to other sexual dysfunctions including erectile difficulties, female inorgasmia, low sexual desire, and sexual aversion.

It is known that prématuré éjaculation may be treated by using antidepressants comprising fluoxetine, paroxetine or sertraline. However, the antidepressants cause side effects such as nausea, headache, dizziness, asomnia, xerostama and anxiety, and side effect associated with sédation, anticholinergic actions and cardiovascular responses. Also, considering that the antidepressants affect the nervous System, it is necessary to finely control their dosages to ensure safety. That is, unlike other drugs, since a drug for improving prématuré éjaculation affect the cardiovascular System and/or the nervous System which may cause severe side effects, its dosage must be carefully controlled.

I

PHARMACEUTICAL COMPOSITION FOR TREATING PREMATURE EJACULATION AND MEHTOD FOR TREATING PREMATURE EJACULATION

TECHNICAL FIELD

The présent invention relates to a pharmaceutical composition for treating prématuré éjaculation, which provides rapid-onset of efficacy, exhibits less uptake déviation according to the patient’s conditions and has reduced side effects. Also, the présent invention relates to a method for treating, preventing or improving prématuré éjaculation by using the pharmaceutical composition. Further, the présent invention relates to a medical use of the pharmaceutical composition in the treatment, prévention or improvement of prématuré éjaculation.

This application ciaims priority to Korean Patent Application No. 10-20H0062620 fded on June 28, 20ll, the disclosure thereof is incorporated herein by reference.

BACKGROUND ART

Prématuré éjaculation is one of the common sexual complaints and is estimated to affect approximately 30 to 40% of men. Prématuré éjaculation means persistent or récurrent éjaculation with minimal sexual stimulation before, upon, or shortly after sexual activity, and before the person wishes it. Such éjaculation that occurs sooner than desired is often disappointing and can iead to other sexual dysfonctions including erectile difficulties, female inorgasmia, low sexual desire, and sexual aversion.

It is known that prématuré éjaculation may be treated by using antidepressants comprising fluoxetine, paroxetine or sertraiine. However, the antidepressants cause side effects such as nausea, headache, dizziness, asomnia, xerostama and anxiety, and side effect associated with sédation, anticholinergic actions and cardiovascular responses. Also, considering that the antidepressants affect the nervous system, it is necessary to finely control their dosages to ensure safety. That is, unlike other drugs, since a drug for improving prématuré éjaculation affect the cardiovascular system and/or the nervous system which may cause severe side effects, its dosage must be carefolly controlled.

Furthermore, for purposes of treating prématuré éjaculation, it must demonstrate a rapid onset.

DISCLOSURE

Technical Problem

Accordingly, it is an object of the présent invention to provide a pharmaceutîcal composition for treating prématuré éjaculation, which can be conveniently taken just prior to sexual activity, not for a certain period of time, to provide rapid-onset of efficacy and exhibit outstanding effectiveness for prématuré éjaculation.

It is another object of the présent invention to provide an optimum content, i.e. dosage of an active ingrédient contained in the pharmaceutîcal composition.

It is yet another object of the présent invention to provide a pharmaceutîcal composition for treating prématuré éjaculation, which can provide a rapid release or dissolution of an active ingrédient, thereby allowing rapid uptake even if taken just prior to sexual activity and eventually exhibiting rapid-onset in its efficacy, as well as reduce an uptake déviation according to a patient and the gastrointestinal condition of the patient.

It is still another object of the présent invention to provide a medical use of the pharmaceutîcal composition in the treatment, prévention or improvement of prématuré éjaculation.

It is still another object of the présent invention to provide a method for treating, preventing or improving prématuré éjaculation, comprising administering the pharmaceutîcal composition to a patient being in need of the treatment, prévention or improvement of prématuré éjaculation.

Technical Solution

In order to achieve the above objects, the présent invention provides a pharmaceutîcal composition for treating, preventing or improving prématuré éjaculation, comprising clomipramine hydrochloride in an amount of 14 to 16 mg, preferably about I5mg, as an active ingrédient, the composition being taken on an asneeded or on demand basis prior to sexual activity.

Also, the présent invention provides a method for treating, preventing or improving prématuré éjaculation, comprising admînistering clomipramine hydrochloride in an amount of 14 to 16 mg to a male patient in need of the treatment of prématuré éjaculation. Preferably, the présent invention provides a method for treating, preventing or improving prématuré éjaculation, comprising admînistering clomipramine hydrochloride to a male patient in need of the treatment of prématuré éjaculation, wherein clomipramine hydrochloride is administered in an amount of about 15 mg based on a 70 kg male.

In addition, the présent invention provides a medical use of clomipramine hydrochloride in the préparation of a medicine for treating, preventing or improving prématuré éjaculation, which comprises clomipramine hydrochloride in an amount of 14 to 16 mg, preferably about 15mg.

Clomipramine hydrochloride is a drug which has been long used in the treatment of dépréssion. It is recommended that clomipramine hydrochloride is oraily administered in an initial amount of lOmg/day for adults in the treatment of dépréssion and its daily dose can gradually increase by 30 to 150 mg in divided doses for further enhanced effects. The typical daily dosage of clomipramine hydrochloride is 30 to 50 mg.

Although such a dosage of clomipramine hydrochloride is effective in the treatment of dépréssion, it is very surprising that the use of clomipramine hydrochloride in an amount greater than about 15 mg has little to no effects in the treatment of prématuré éjaculation, but rather increases in side effects.

As used herein, the term “prior to sexual activity” in the directions for use of the pharmaceutical composition of the présent invention, means 0.5 to 10 hours prior to sexual activity, preferably 2 to 6 hours prior to sexual activity.

Preferably, considering the directions for use of the composition of the présent invention taken prior to sexual activity on demand, in order to provide a rapidlydissolved pharmaceutical composition, the composition of the présent invention further comprises pregelatinized starch and sodium starch glycolate as an excipient for very rapid dissolution of clomipramine hydrochloride. More preferably, the pharmaceutical composition of the présent invention comprises clomipramine hydrochloride, lactose, pregelatinized starch and sodium starch glycolate. Most preferably, the pharmaceutical composition of the présent invention comprises 7 to 13 wt% of clomipramine hydrochloride, 70 to 80 wt% of lactose, 7 to 13 wt% of pregelatinized starch and 1 to 5 wt% of sodium starch giycolate based on the total weight of the composition.

Preferably, when the pharmaceutical composition comprising clomipramine hydrochloride according to the présent invention is subject to conventional dissolution tests (using a paddle and a 900 ml dissolution medium), it exhibits a dissolution rate of 90 wt% or more, preferably 95 wt% or more at 15 minutes of testing time in ail of a buffer solution of pH 1.2, a buffer solution of pH 4.0, purified water and a buffer solution of pH 6.8.

Thus, since the pharmaceutical composition comprising clomipramine hydrochloride according to the présent invention comprises particular excipients in a certain amount to provide rapid drug dissolution, the efficacy of the composition taken prior to sexual activity on demand can be rapidly exhibited, and since the dissolution rate of the composition is uniform without a decrease under various pH conditions, an efficacy déviation is surprisingly reduced according to the patient’s conditions.

The pharmaceutical composition of the présent invention may further comprise a binder or a lubricant which are well known in the art for various purposes within the range without deteriorating the présent invention. For the dissolution purpose of the présent invention, povidone is preferably used as the binder.

Further, the présent invention provides a medical use of the pharmaceutical composition in the treatment, prévention or improvement of prématuré éjaculation.

Furthermore, the présent invention provides a method for treating, preventing or improving prématuré éjaculation, comprising administering the pharmaceutical composition to a patient in need of the treatment, prévention or improvement of prématuré éjaculation.

Advantaeeous Effects

The présent invention provides a pharmaceutical composition for treating, preventing or improving prématuré éjaculation, characterized by comprising clomipramine hydrochloride in an amount of 15 mg, which can provide rapid onset of efficacy, reduce a dissolution (uptake) déviation according to the patient’s gastrointestinal pH conditions and minimize side effects.

Also, the présent invention provides a method for treating, preventing or improving prématuré éjaculation, characterized by administering clomipramine hydrochloride in an amount of about 15 mg based on a 70 kg male in need of the treatment of prématuré éjaculation.

BEST MODE

Hereinafter, various preferred examples of the présent invention will be described in detail for better understanding. However, the examples of the présent invention may be modified in various ways, and they should not be interpreted as limiting the scope of the invention. The examples of the présent invention are just for better understanding of the invention to persons having ordinary skill in the art.

<Preparation of Immcdiatc-Dissolution Formulation Comprising Clomipramine Hydrochloride >

In order to provide the desired effect immediately after intake prior to sexual activity on demand, the dissolution of a clomipramine-containing formulation should be rapidly made. Accordingly, the présent inventors hâve endeavored to develop a formulation capable of achieving almost 100% dissolution rate within 15 minutes and found that the following prescriptions can provide very rapid dissolution and are not influenced by pH changes of a dissolution medium, thereby maintaining a high dissolution rate, through various expérimentations.

Specifically, clomipramine hydrochloride-containing formulations (tabiets) were prepared by the prescriptions shown in Table 1, in which povidone was used as a binder after being dissolved in purified water.

Table 1

Ingrédients (Amount (mg) of each ingrédient contained in a tablet)	Formulation containing 15 mg of active ingrédient	Formulation containing 30 mg of active ingrédient
Clomipramine hydrochloride	15.0	30.0
Lactose	111.5	101.1
Pregelatinized starch	14.5	9.5
Povidone	4.5	4.5
Sodium starch glycolate	3.0	3.0
Magnésium stéarate	1.5	1.5
Total weight	150.0	150.0

Then, the clomîpramine formulation of the présent invention using the ingrédients listed in Table l were measured for its dissolution rate according to the dissolution test method presented in the Korean Pharmacopoeia and compared with clomîpramine hydrochloride-containing products which hâve been commercially available as antidepressants, e.g., clomîpramine HCl 25 mg formulation (Myung In Pharmaceutical Co., Ltd., South Korea), clomîpramine HCl 10 mg formulation (Pharmaceutical Co., Ltd., South Korea) and clomîpramine HCl 25 mg formulation (Whan In Pharm. Co., Ltd., South Korea).

Dissolution rates (%) in each dissolution medium (900 ml) were represented by the proportion of clomîpramine (mg) dissolved for the testing time relative to clomîpramine (mg) contained in each Test Drug, and the results thereof are shown in Tables 2 to 5.

Table 2

pH12	Whan In 25mg	Myung In 25m;	Myung In lûmp	Test Drug 15mg	Test Drug 30mg
5 minutes	51.0	46.7	38.6	60.6	53.4
10 minutes	85.6	73.7	61.1	90.7	91.7
15 minutes	96.6	90.0	79.7	99.4	99.5

Table 3

pH4.0	Whan In 25mg	Myung In 25m$	Myung In lOmg	Test Drug 15mg	Test Drug 30mg
5 minutes	51.4	54.5	47.7	61.7	49.1
10 minutes	88.5	91.7	83.3	94.2	91.8
15 minutes	98.1	94.3	84.8	100.9	993

Table 4

Purified Water	Whan In 25mg	Myung In 25mj	Myung In 10mf	Test Drug 15mg	Test Drug 30mg
5 minutes	48.9	45.0	54.4	55.4	47.3
10 minutes	85.5	83.8	56.6	88.2	88.7
15 minutes	87.7	88.7	61.6	99.4	97.8

Table 5

pH6.8	Whan In 25mg	Myung In 25m$	Myung In lOmj	Test Drug 15mg	Test Drug30mg
5 minutes	44.8	30.1	12.6	46.0	39.5
10 minutes	72.3	54.6	322	95.9	73.9
15 minutes	86.9	61.8	39.7	95.0	92.2

As shown in Tables 2 to 5, the clomîpramine hydrochloride-containing formulations according to the présent invention exhibited a very rapid dissolution rate and a high dissolution rate irrelevant to pH changes, as compared with other clomipramine hydrochloride-containing products available as antidepressants. Thèse results mean that the formulations of the présent invention can provide uniform efficacy irrelevant to a pH déviation in the gastrointestinal tract of the patient taking clomipramine hydrochloride.

<Clinical Study of Rapid-Acting Clomipramine Formulation>

Male patients suffering from prématuré éjaculation were subject to the following parallel clinical study (Phase 2b) (randomized, double-blind, placebocontrolled and fixed dose study) for evaluating tolérance and determining a proper therapeutic capacity.

Test Drug:

Test drugs were of 3 types, i.e., clomipramine hydrochloride 15 mg-containing formulation (PED-l) and clomipramine hydrochloride 30 mg-containing formulation (PED-2), which were prepared as shown in Table 1, and placebo with lactose as an excipient, instead of clomipramine.

Place:

The clinical study was conducted at Séoul St. Mary’s Hospital, Catholic University and Mok-dong Hospital, Ehwa Womans University.

Purpose:

- PED-l (clomipramine hydrochloride 15 mg), PED-2 (clomipramine hydrochloride 30 mg) and placebo were orally administered by on-demand therapy to male patients suffering from prématuré éjaculation , and each therapeutic capacity of PED-l and PED-2 can be determined, relative to placebo, via the clinical study.

Clomipramine hydrochloride 15 mg, 30mg and placebo can be compared for their effectiveness in the treatment of prématuré éjaculation.

Clomipramine hydrochloride 15 mg, 30mg and placebo can be compared for their safety.

Method:

Subjects who passed screening entered a 4-week run-in period, and were randomized in l:l:l ratio of 2 groups with clomipramine and l group with placebo and subject to a double blind experiment. The randomized subjects showed intravaginal éjaculation latency time (1ELT) of 2 minutes or less in 75% of intercourse for the run-in period. Each subject visited the hospital after taking the test drugs for 4 weeks by on-demand therapy.

Number of Patients:

ITT (Intent to Treatment)

- 95 patients (32 patients of placebo group, 33 patients of 15 mg group, 20 patients of 30 mg group)

PP (Per protocol) patients (29 patients of placebo group, 32 patients of 15 mg group, 25 patients of 30 mg group)

Safety Population patients (31 patients of placebo group, 33 patients of 15 mg group, 28 patients of 30 mg group)

Bodv Weight and Height of Patients:

Patients had a mean body weight of 71.26+9.42 kg, and a mean height of 170.26±5.66 cm. More specifically, the placebo-administered group had a mean body weight of 71.11 kg, the 15 mg-administered group had a mean body weight of 70.85 kg, and the 30 mg-administered group had a mean body weight of 71.80 kg. Ail subjects were Asian.

Patienfs Conditions:

1) Patient showing IELT of 2 minutes or less in at least 75% of intercourse (on average of more than 3 times out of 4 attempts of sexual activity)

2) Male

3) Age of 20 to 65

4) Patient having a steady sexual relationship with the opposite sex of at least 6 months duration and with the intent to maintain such a relationship during the test period.

5) Male showing prématuré éjaculation for at least 6 months before attending the clinical study.

6) Score of more than 9 (including potential prématuré éjaculation) in prématuré éjaculation diagnostic tool (PEDT) of Korean version.

7) Healthy person having no history of a medical disorder, or any abnormalities found in a physical examination, laboratory examination, radiographie examination and electrocardiogram examination, or someone whose results departed from the reference range in a laboratory examination or electrocardiogram examination but was clearly recorded as not being clinically sîgnificant in an official document.

8) Subject whose sexual partners are women of childbearing âge and agréé to use contraception.

9) Patient having the will to try at least 4 attempts of sexual activity for 4 days during the baseline period without treatment.

10) Patient having the will to stop other kinds of conventional thérapies (medicines, behavioral thérapies or topical treatment) of prématuré éjaculation.

Dosage and Method of Administration:

Group 0 was administered with a tablet of 15 mg placebo and a tablet of 30 mg placebo, Group l was administered with a tablet of 15 mg clomipramine HCl and a tablet of 30 mg placebo, and Group 2 was administered with a tablet of 30 mg clomipramine HCl and a tablet of 15 mg placebo for 4 weeks on-demand at about 2 hours to 6 hours prior to sexual activity. The tablets were orally taken with a glass of water.

Evaluation of Effects:

l ) Primary Endpoint

Primary effectiveness évaluation variables in this clinical study inciude an 1ELT fold change at visit 3 (measuring between 0 and 4 weeks) relative to baseline values (i.e., IELT fold change = Value of lELT ineasured at visit 3 (0 to 4 weeks) / Value of IELT measured at baseline) in each of Group 0 (with treatment of placebo), Group l (with treatment of 15 mg clomipramine HCl) and Group 2 (with treatment of 30 mg clomipramine HCl). Also, a différence between Group l and Group 0, and a différence between Group 2 and Group 0 were confirmed by a T assessment according to the Williams method.

2) Secondary Endpoint (D Afler administering placebo and 15 mg of clomipramine, and placebo and 30 mg of clomipramine for the period of 4 weeks, a change (%) of IELT values between 0 to 4 weeks after administration, relative to before administration, was calculated by the équation [Change (%) of IELT Values = (Value of IELT measured at 0 to 4 weeks - Value of IELT measured at baseline)xl00 / Value of IELT measured at baseline].

© After administering placebo and 15 mg of clomipramine, and placebo and 30 mg of clomipramine for the period of 4 weeks, a mean change of IELT values between 0 to 4 weeks after administration was calculated.

(3) Drug coitus interval time (DCIT) was determined by a différence between the time of dosing and the time of intercourse attempt, and the DCIT was calculated at every intercourse attempt after dosing.

Evaluation of Safetv:

1) Abnormal Réaction

Each group was compared for a différence in the génération of abnormal reactions according to the nature of variables through a proper statistical analysis. Also, this évaluation includes confirming the effect of a dose increase on the abnormal reactions. The abnormal reactions were summarized by encoding according to the medical dictionary for regulatory activities (MedDRA), with presenting the proportion of subjects undergoing abnormal reactions in each group and 90% confidence interval thereof. Ail abnormal reactions were represented according to their severity and summarized into those relevant to a test drug, those causing death or the stop of clînical trials, and those with significance. Also, if a follow-up study can be done, the results of treatment were presented. The évaluation of abnormal reactions was conducted based on abnormal reactions confïrmed during the randomized treatment period.

2) Abnormal Change in Laboratory Examination Values

Among laboratory data obtained in this study, data which were regarded as being an abnormal value were summarized on the basis of the test group and visit order. Successive data such as blood and biochemical test résulte were presented by descriptive statistics based on each test group and visit order, and categorical data such as urinary test results were presented by the frequency and proportion of each category. Also, if there was a différence in test groups before and after administration of a test drug, the différence was suitably analyzed by a proper statistical method.

3) Abnormal Change in Physical Examination such as Electrocardiography (ECG)

Among ECG data obtained in this study, data which were regarded as being an abnormal value were summarized on the basis of the test group and visit order.

Statistical Processing:

l ) Primary Endpoint in Effect

Primary effectiveness évaluation variables in this clînical study include an 1ELT fold change relative to baseline values, which was measured before drug administration (visit 2) (the IELT fold change = IELT measured after drug administration (visit 3) / IELT measured at baseline) in each of the group with treatment of placebo, the group with treatment of 15 mg clomipramine HCl and the group with treatment of 30 mg clomipramine HCl. Also, a différence between the 15 mg clomipramine HCl group and the placebo group, and a différence between the 30 mg clomipramine HCl group and the placebo group were confïrmed by the Williams test.

The results of Effective évaluation were presented by separating each of ITT and PP groups into 3 types because one subject (ID 2004) of the 15 mg clomipramine HCl group exhibited a very high value of IELT (2865.46 seconds) after 4 weeks. It was confïrmed that this subject failed to ejaculate in most attempts, and thus such time was estimated as an outlier which was generated from the time to éjaculation being determined by the time until intercourse ends. Nevertheless, the time to éjaculation and the number of intercourse attempts should be recorded according to the requirements of the executed program. Owing to such an outlier, there is a high

I l possibility that the analysis results are severely biased. For this reason, the ÎTT group and the PP group were each analyzed into 3 ways, i.e, l) the analysis that the study was conducted according to the executed program (there is no change in the results of the subject of ID 2004), 2) the analysis that the value of IELT after 4 weeks corresponds to 494.690 which is the second highest score, in the 15 mg clomipramine HCl group including the subject of ID 2004, and 3) the analysis excluding the results of the subject oflD 2004.

2) Secondary Endpoint in Effect of Drug

Secondary effectiveness évaluation variables in this clinical study include l) an IELT change (%) relative to baseline values, which was measured before drug administration (visit 2) (the IELT change (%) = (IELT measured after drug administration (visit 3) - IELT measured at baseline)x 100 / IELT measured at baseline) in each of 3 groups, 2) a mean IELT change relative to baseline values, which was measured before drug administration (visit 2) (the mean IELT change = IELT measured after drug administration (visit 3) - IELT measured at baseline) in each of 3 groups, and

3) drug coitus interval time (DCIT) determined by a différence between the time of dosing and the time of intercourse attempt, which was presented in patient’s record. In the l) and 2) cases using IELT values, the analysis of the primary effectiveness évaluation variables was identîcally applied, and the 3) case using DCIT was conducted by taking account of ANOVA model so as to compare a mean value of each group.

3) Safety

The safety of a test drug was evaluated on the basis of all abnormal reactions, clinical laboratory results, chest X-ray results, 12-lead ECG results and vital signs (blood pressure and puise frequency) of test subjects. All of such safety variables were obtained from baseline through randomization for the treatment period and these variables of each subject were presented and summarized by a statistical method.

For comparison of an outlier of laboratory results, chest X-ray results, 12-lead ECG results which were generated in each group, analysis was performed using chisquared test, Fisher’s exact test or Poisson test. For vital signs, the summary statistics of the successive data were presented, and assessment was performed using F-test of ANOVA.

Results of Effect Evaluation:

The results of effect évaluation are shown in Table 6.

Table 6

Clomipramine

	Placebo	15 mg	30 ma
ΓΤΤ&ΡΡ*	VtA	(N=32, 29)	(N=33, 32)	(N=30, 25)	p-value1)
	baseline	76.70±23.31	70.3114.58	69.1712623	0.4968
	Week 4	138.15183.37	267.561479.80	186.991148.42
ΓΤΠ	Fold Change	1.7510.84	4.5818.40	2.8911.98	0.0318, 0.0030
	% Change	75.44184.12	357.661840.06	189.351197.81	0.0318, 0.0590
	change	61.45170.87	197.251479.35	117.821142.88	0.0030, 0.0291
	baseline	76.70123.31	70.3114.58	69.1712623	0.4968
	Week 4	138.15183.37	195.721124.84	186.991148.42
ΠΤ2	Fold Change	1.7510.84	3.3913.48	2.8911.98	0.0064, 0.0030
	% Change	75.44184.12	238.711347.73	189.351197.81	0.0064, 0.0050
	change	61.45170.87	125.401117.01	117.821142.88	0.0030, 0.0291
	baseline	76.70123.31	70.62131.08	69.1712623	0.5125
	Week 4	138.15183.37	186.381114.52	186.991148.42
ΓΤΤ3	Fold Change	1.7510.84	3.2413.42	Z891L98	0.0115, 0.0030
	% Change	75.44184.12	223.701342.25	189.351197.81	0.0115, 0.0092
	change	61.45170.87	115.751104.68	117.821142.88	0.0030, 0.0291
	baseline	75.66123.98	70.63131.07	67.92126.13	0.5720
	Week 4	137.43187.68	271.191487.01	203.961155.63
PP1	Fold Change	1.7610.88	4.6418.53	3.0811.93	0.0330, 0.0018
	% Change	75.91188.02	364.091852.68	207.851193.30	0.0330, 0.0604
	change	61.77174.40	200.551486.64	136.0S1147.95	0.0018, 0.0147
	baseline	75.66123.98	70.63131.07	67.92126.13	0.5720
	Week 4	137.43187.68	197.101126.58	203.961155.63
PP2	Fold Change	1.7610.88	3.4113.53	3.0811.93	0.0074, 0.0018
	% Change	75.91188.02	241.421118.72	207.851193.30	0.0074, 0.0065
	change	61.77174.40	126.471118.72	136.051147.95	0.0018, 0.0147
	baseline	75.66123.98	70.9613153	67.92126.13	0.5818
	Week 4	137.43187.68	187.501116.23	203.961155.63
PP3	Fold Change	1.76+0.88	3.2613.48	3.0811.93	0.0131, 0.0018
	% Change	75.91188.02	226.011347.66	207.851193.30	0.0131, 0.0127
	change	61.77174.40	116.541106.32	136.051147.95	0.0018, 0.0147

ITT(PP)l : Case defmed according to the disclosure of the executed program.

ITT(PP)2: Case that after the subject of ID 2004 takes a test drug, the time of intercourse applied is the maximum (494.690) of the corresponding group.

ITT(PP)3: Case excluding the subject of ID 2004.

I) Comparison of Baseline IELT: F-Test (two sided); William’s Test for foid change between placebo and 15 mg: one sided test with significance level 0.0250; William’s Test for fold change between placebo and 30 mg: one sided test with significance level 0.0250; William’s Test for change and % change between placebo and 15 mg: one sided test with significance level 0.0250; William’s Test for change and % change between placebo and 30 mg: one sided test with significance level 0.0250.

As a resuit of this clinical study for prématuré éjaculation patients who ejaculated within 2 minutes after vaginal insertion, ail dosing group (15 mg, 30mg ) of clomipramine exhibited the extended time of éjaculation after vaginal insertion. In particular, when a degree of extended éjaculation time after vaginal insertion is represented by the value of IELT fold change after the treatment period of 4 weeks relative to before a test drug-treatment (baseline), the analysis of ITT groups showed that the value of IELT fold change was estimated to 4.58±8.40, 3.39±3.48, and 3.24±3.42 in the clomipramine 15 mg group according to the treatment resuit of each outlier, while l.75±0.84 in the placebo group, and also the value of IELT fold change in the clomipramine 30 mg group was 2.89±l,98. In the case of ITTl, it was confirmed that there is no significant différence (p=0.0318) between the placebo group and the clomipramine 15 mg group at one sided test with a significant level of 2.5%. However, in the cases of 1TT2 and ITT 3, it was confirmed that there is a notable increase (p=0.0064, 0.0115) in the value of IELT fold change of the clomipramine 15 mg group, as compared with that of the placebo group. Also, comparing the clomipramine 30 mg group with the placebo group, there is a notable différence (p=0.0030) at one sided test with a significant level of 2.5%. In conclusion, the minimum effective dose in the case of 1TT1 was 30 mg of clomipramine, while each minimum effective dose in the cases of ITT2 and ITT3 was 15 mg of clomipramine. When considering overall situations including these results and the fact that an outlier fails to reflect the nature of disorders well, 15 mg of clomipramine can be determined as the minimum effective dose, and it would be understood that there is no différence between 15 mg of clomipramine and 30 mg of clomipramine in tenus of IELT fold change being an évaluation base of the primary effectiveness.

Results of Safety Evaluation:

The results of safety (regarding abnormal reactions) évaluation are shown in Tables 7 to 9.

Table 7

	Placebo (N=34)	Clomipramine	Total (N=1O1)
15 mg (N=34)	30 mg (N=33)
Number of Subjects showlng Abnormal Réactions	4(11.76)	11(32.35)	19(57.57)	34(34.00)
Génération Number of Abnormal Reactions	4	19	30	53(53%)
Mlfd	4	17	28	49
Moderato	0	2	2	4
Severe	0	0	0	0
Number of Subjects showing Serions Abnormal Reactions	0	0	0	0
Génération Number of Serious Abnormal Reactions	0	0	0	0

Table 8

System Organ Class	Placebo (N=33)	Clomipramine	Total (N=100)
15 mg (N =34)	30 mg (N =33)
Gastrointestinal disorders	1	6	8	15
General disorders		2	4	6
Infections			1	1
Investigations	1	1	2	4
Nervous System disorders		4	4	8
Psychiatrie disorders		3	8	11
Rénal and urinary disorders		2	1	3
Reproductive System and breast disorders	1		1	2
Skin and subeutaneous tissue disorders	1	1	1	3

Table 9

System Organ Class	Placebo (N-34)	Oomipramine	Total (N-100)
15 mg (N >34)	30 mg (N >33)
Number of Subjects Showlng Abnormal Reactions	3(8.82)	10(29.41)	17(5151)	30(30.00)
Number of Abnormal Reactions having Causal Relationship	3	15	26	44
Follow-up
No	3	12	16	31
Readministration After Temporary Suspension			1	1
Contlnuous Stop of Médication		3	9	12
Progresslng
Complote Disappearance	3	15	26	44

In the safety évaluation of subjects who were administered with a test drug or placebo after randomization, most of the subjects showed mild abnormal reactions, 5 without serious or severe abnormal reactions. Although the abnormal reactions were mild, the génération rate of abnormal reactions, which were estimated to hâve a causal relationship with a test drug, and the proportion of the corresponding subjects were shown to be dose-dependent.

Conclusion:

In conclusion, taking into considération ail the results of ITT groups and PP groups into account, since the 15mg dose groups exhibited an effect of extension in intravaginal éjaculation latency time (IELT) after insertion, as compared with the placebo groups, and also exhibited good drug tolérance, it is believed that a dose of 15 15mg would be suitable as a treatment dose.

Claims (10)

1. WH AT IS CLA1MED IS :

   1. A pharmaceutical composition for treating, preventing or improving prématuré éjaculation, comprising clomipramine hydrochloride in an amount of 14 to 16 mg as an active ingrédient, the composition being taken on demand prior to sexual activity.
2. 2. The pharmaceutical composition of claim 1, which comprises clomipramine hydrochloride in an amount of 15 mg.
3. 3. The pharmaceutical composition of claim 1, which is administered 2 to 6 hours prior to sexual activity.
4. 4. The pharmaceutical composition of any one of claims 1 to 3, which further comprises pregelatinized starch and sodium starch glycolate, and exhibits a dissolution rate of 90 wt% or more at 15 minutes of testing time in ail of a buffer solution of pH 1.2, a buffer solution of pH 4.0, purified water and a buffer solution of pH 6.8 when the composition is subject to a dissolution test using a paddle and a 900 ml dissolution medium.
5. 5. The pharmaceutical composition of any one of claims 1 to 3, which comprises clomipramine hydrochloride, lactose, pregelatinized starch and sodium starch glycolate.
6. 6. The pharmaceutical composition of claim 5, which comprises 7 to 13 wt% of clomipramine hydrochloride, 70 to 80 wt% of lactose, 7 to 13 wt% of pregelatinized starch and 1 to 5 wt% of sodium starch glycolate based on the total weight of the composition.
7. 7. The pharmaceutical composition of claim 6, which further comprises a binder or a lubricant.
8. 8. The pharmaceutical composition of claim 7, wherein the binder is povidone.
9. 9. Use of 14 to 16 mg of clomipramine hydrochloride for administration to a male patient in treating, preventing or iinproving prématuré éjaculation.
10. 10. The use of claim 9, wherein clomipramine hydrochloride is administered in an amount of 15 mg.