WO2001028541A2

WO2001028541A2 - Composition comprising sildenafil and l-arginine

Info

Publication number: WO2001028541A2
Application number: PCT/IL2000/000622
Authority: WO
Inventors: Shlomo Laniado; Naftali Stern; Gad Keren
Original assignee: Shlomo Laniado; Naftali Stern; Gad Keren
Priority date: 1999-10-19
Filing date: 2000-10-05
Publication date: 2001-04-26
Also published as: AU7682600A; IL132460A0; WO2001028541A3

Abstract

The present invention relates to a synergistic composition for the treatment of erectile dysfunction comprising suitable amounts of Sildenafil and of L-Arginine or of pharmaceutically acceptable salts thereof. The composition comprises preferably 25 - 100 mg of Sildenafil and 0.5 - 1.5 g of L-Arginine. The composition may comprise suitable excipients and advantageously in oral dosage form. The composition is also for the use of said composition and for the method of treatment for the treatment of erectile dysfunction.

Description

SILDENAFIL PREPARATION

The present invention relates to a Sildenafil preparation having an extended activity.

The filling of the cavernous sinusoidal spaces is a tightly regulated process depending not merely on the inflow of penile arterial blood but also on the relaxation of the vascular smooth muscle cells of these sinusoidal spaces. This relaxation process is largely mediated by the local release of nitric oxide, i.e. of NO.

Sildenafil is a type 5-CGMP phosphodiesterase inhibitor which has been approved for the treatment of erectile dysfunction of various etiologies of men. The preparation is administered orally usually about one hour prior to the intended intercourse and is effective for about 4 hours post-ingestion . It has been shown that doses of 25 -100 g are both efficacious and safe.

Sildenafil-amplified erection depends on sexual arousal and neural transmission to the penis and subsides post-coitally . Thus in addition Sildenafil-assisted erection frees individuals from the embarassement of unwanted or protracted erection generated often by the use of alternative means such as of intravenous injection of vasoactive drugs or of external vacuum pumps.

However, it has been shown that many people do not respond satisfactorily even to a high dose (100 mg) of Sildenafil; and the effective time of activity and/or the degree of attained erection are not always sufficient.

It has thus been desirable to find a preparation which would overcome the above disadvantages, i.e. would enable the use of various doses of Sildenafil with improved efficacy in terms of extended effective time of activity; and improved erection. Naturally, said preparation should be safe to use, not too difficult to manufacture and not to be too expensive.

It has now surprisingly been found that the addition of a certain amount of L-Arginine to the Sildenafil has the desired effect. Moreover, it enables the erections with maximal doses of Sildenafil without causing any headache and for a longer time of activity. The terms Sildenafil and L-Arginine herein comprise the pharmaceutically acceptable salts thereof.

This effect was rather unexpected in view of the following statement in Circulation-Cheitlin et al . 99 (1) :168:

" Dietary sources of nitrites, nitrates, and L-arginine (the substrate from which NO is synthesized) do not contribute to the circulating levels of NO in humans and therefore are unlikely to interact with Sildenafil."

Later works showed that in spite of said publication L- Arginine showed some activity but this was quite low and one could not envisage that the activity of L-arginine would have any influence on the activity of Sildenafil.

It has now been surprisingly be found that L-Arginine has a synergistic effect on the activity of Sildenafil in the treatment of erectile dysfunction.

The present invention thus consists in a synergistic composition for the treatment of erectile dysfunction comprising suitable amounts of Sildenafil and of L-Arginine.

The amounts of Sildenafil should be advantageously 25 - 100 mg and that of L-Arginine 0.5 - 1.5 g.

The composition according to the present invention may be in the form of oral dosage forms as tablets, coated tablets, dispersible tablets, effervescent tablets, capsules, granules, suspensions, solutions, etc. These compositions may be prepared common known techniques by common known techniques . Said compositions may contain in addition to the active ingredients excipients such as carriers, disentegrants , lubricants, stabilizers, flavoring agents, solvents, etc.

The composition according to the present invention may comprise both active ingredients in one dosage form or may be in two separate dosage forms. Both separate dosage forms, if present, should be administered together or within short intervals, preferably starting with the L-Arginine dosage form.

Both possibilities are within the scope of the present invention.

The preferred composition comprises 100 mg of Sildenafil and 1 g of L-Arginine.

The present invention also consists in the use of a syner- gistic composition comprising Sildenafil and L-Arginine for the treatment of erectile dysfunction.

The present invention also consists in a method for the treatment of erectile dysfunction by administering a composition comprising Sildenafil and L-Arginine.

The present invention will now be illustrated with reference to the following Example without being limited by same.

The people treated in the following Examples were treated also with certain amounts of L-Arginine. However there was shown no a low activity. Example 1

To two individuals not responding to 100 mg of Sildenafil were administered together with the Sildenafil 1 g of L-Arginine. About 1 hour after the application of the preparation said individuals had satisfactory erections. Example 2

Two individuals suffering from diabetes were unable to tolerate 100 mg of Sildenafil due to headache. They were administered a lower dose of Sildenafil (50 mg) together with 1 g of L-Arginine. They had satisfactory erections, 1 hour after the application of the preparation, without suffering from any headache . Example 3

A man 60 years old having slight diabetes was impotent for many years. When taking 50 mg of Sildenafil he had an ejection. However the effect terminated after about 4 hours. When taking together with the Sildenafil 2 capsules (500 mg each) of L- Arginine the activity continued for up to 20 hours. Example 4

To 6 individuals (age 54-68) who did not respond to a treatment with 100 mg of Sildenafil and to a treatment with 1500 -2500 mg of L-Arginine a combined dosage of 50 mg of Sildenafil and of 1000 mg of L-Arginine was administered. The combined dosage resulted in satisfactory erections within 6-15 hours.

Claims

1. A synergistic composition for the treatment of erectile dysfunction comprising suitable amounts of Sildenafil and of L-Arginine or of pharmaceutically acceptable salts thereof.

2. A composition according to Claim 1 comprising 25 - 100 mg of Sildenafil and 0.5 - 1.5 g of L-Arginine.

3. A composition according to Claim 2 comprising 100 mg of Sildenafil and 1 g of L-Arginine.

4. A composition according to any of Claims 1 to 3 , comprising suitable excipients selected among carriers, disintegrants , lubricants, stabilizers, flavoring agents and solvents.

5. A composition according to any of Claims 1 to 4 being in oral dosage forms being selected among tablets, coated tablets, dispersable tablets, effervescent tablets, capsules, granules suspensions and solutions.

6. A composition according to any of Claims 1 to 5, which consists of two separate oral dosage forms, one comprising the Sildenafil and one comprising the L-Arginine.

7. A synergistic composition for the treatment of erectile dysfunction, as defined in Claim 1, substantially as herein before described with reference to the Examples.

8. Use of a composition comprising Sildenafil and L-Arginine for the treatment of erectile dysfunction.

9. A method for the treatment of erectile dysfunction by the administering a composition comprising Sildenafil and L- Arginine .

10. A method according to Claim 9, wherein the composition is administered simultaneously or within short intervals by two separate oral dosage forms one comprising the Sildenafil and one comprising the L-Arginine.