WO2001028541A2 - Composition comprising sildenafil and l-arginine - Google Patents
Composition comprising sildenafil and l-arginine Download PDFInfo
- Publication number
- WO2001028541A2 WO2001028541A2 PCT/IL2000/000622 IL0000622W WO0128541A2 WO 2001028541 A2 WO2001028541 A2 WO 2001028541A2 IL 0000622 W IL0000622 W IL 0000622W WO 0128541 A2 WO0128541 A2 WO 0128541A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- sildenafil
- arginine
- composition
- treatment
- erectile dysfunction
- Prior art date
Links
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 title claims abstract description 70
- 229960003310 sildenafil Drugs 0.000 title claims abstract description 35
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 title claims abstract description 28
- 239000000203 mixture Substances 0.000 title claims abstract description 24
- 229930064664 L-arginine Natural products 0.000 claims abstract description 24
- 235000014852 L-arginine Nutrition 0.000 claims abstract description 24
- 208000010228 Erectile Dysfunction Diseases 0.000 claims abstract description 12
- 201000001881 impotence Diseases 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 8
- 230000002195 synergetic effect Effects 0.000 claims abstract description 6
- 239000006186 oral dosage form Substances 0.000 claims abstract description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 3
- 150000003839 salts Chemical class 0.000 claims abstract description 3
- 239000003826 tablet Substances 0.000 claims description 5
- 239000002775 capsule Substances 0.000 claims description 3
- 239000000969 carrier Substances 0.000 claims description 2
- 239000007938 effervescent tablet Substances 0.000 claims description 2
- 239000000796 flavoring agent Substances 0.000 claims description 2
- 235000013355 food flavoring agent Nutrition 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 239000000314 lubricant Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 239000003381 stabilizer Substances 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims description 2
- 239000007884 disintegrant Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 7
- 239000002552 dosage form Substances 0.000 description 4
- 206010019233 Headaches Diseases 0.000 description 3
- 231100000869 headache Toxicity 0.000 description 3
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 229940099471 Phosphodiesterase inhibitor Drugs 0.000 description 1
- 230000037007 arousal Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- -1 disentegrants Substances 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 150000002826 nitrites Chemical class 0.000 description 1
- 210000003899 penis Anatomy 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
- 230000002227 vasoactive effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
Definitions
- 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 .
- 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.
- 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.
- 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.
- 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.
- 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.
- Example 1 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 The people treated in the following Examples were treated also with certain amounts of L-Arginine. However there was shown no a low activity.
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Gynecology & Obstetrics (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU76826/00A AU7682600A (en) | 1999-10-19 | 2000-10-05 | Sildenafil preparation |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IL132460 | 1999-10-19 | ||
| IL13246099A IL132460A0 (en) | 1999-10-19 | 1999-10-19 | Sildenafil preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2001028541A2 true WO2001028541A2 (en) | 2001-04-26 |
| WO2001028541A3 WO2001028541A3 (en) | 2002-03-14 |
Family
ID=11073348
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IL2000/000622 WO2001028541A2 (en) | 1999-10-19 | 2000-10-05 | Composition comprising sildenafil and l-arginine |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU7682600A (en) |
| IL (1) | IL132460A0 (en) |
| WO (1) | WO2001028541A2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005018620A3 (en) * | 2003-08-26 | 2005-07-28 | Cell Ct Cologne Gmbh | Use of nitric oxide synthase (nos) cofactor for the treatment of sexual dysfunction |
| WO2023152500A1 (en) * | 2022-02-09 | 2023-08-17 | Future Pharmtech Inc. | Combination of compounds for treating vascular diseases comprising pde5 inhibitor, arginine and n-acetylcysteine |
| WO2025023901A1 (en) * | 2023-07-26 | 2025-01-30 | Montero Gida Sanayi Ve Ticaret Anonim Sirketi | The pharmaceutical combination comprising phosphodiesterase type-5 inhibitor and l-arginine |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5958926A (en) * | 1996-11-01 | 1999-09-28 | Nitromed, Inc. | Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses |
| WO1999051252A1 (en) * | 1998-04-03 | 1999-10-14 | The Daily Wellness Company | Compositions comprising l-arginine, ginseng and gingko biloba for enhancing blood circulation |
| AU4699299A (en) * | 1998-06-26 | 2000-01-17 | Nutracorp Scientific, Inc. | Promoting nitric oxide and cyclic gmp activity |
-
1999
- 1999-10-19 IL IL13246099A patent/IL132460A0/en unknown
-
2000
- 2000-10-05 AU AU76826/00A patent/AU7682600A/en not_active Abandoned
- 2000-10-05 WO PCT/IL2000/000622 patent/WO2001028541A2/en active Application Filing
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005018620A3 (en) * | 2003-08-26 | 2005-07-28 | Cell Ct Cologne Gmbh | Use of nitric oxide synthase (nos) cofactor for the treatment of sexual dysfunction |
| WO2023152500A1 (en) * | 2022-02-09 | 2023-08-17 | Future Pharmtech Inc. | Combination of compounds for treating vascular diseases comprising pde5 inhibitor, arginine and n-acetylcysteine |
| WO2025023901A1 (en) * | 2023-07-26 | 2025-01-30 | Montero Gida Sanayi Ve Ticaret Anonim Sirketi | The pharmaceutical combination comprising phosphodiesterase type-5 inhibitor and l-arginine |
Also Published As
| Publication number | Publication date |
|---|---|
| IL132460A0 (en) | 2001-03-19 |
| AU7682600A (en) | 2001-04-30 |
| WO2001028541A3 (en) | 2002-03-14 |
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