WO2012000634A1 - Composition pharmaceutique pour le traitement de dysfonction érectile - Google Patents

Composition pharmaceutique pour le traitement de dysfonction érectile Download PDF

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Publication number
WO2012000634A1
WO2012000634A1 PCT/EP2011/003145 EP2011003145W WO2012000634A1 WO 2012000634 A1 WO2012000634 A1 WO 2012000634A1 EP 2011003145 W EP2011003145 W EP 2011003145W WO 2012000634 A1 WO2012000634 A1 WO 2012000634A1
Authority
WO
WIPO (PCT)
Prior art keywords
quinine
sildenafil
pharmaceutically acceptable
erectile dysfunction
pharmaceutical composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2011/003145
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German (de)
English (en)
Inventor
Georg Bambach
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Individual
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Individual
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Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of WO2012000634A1 publication Critical patent/WO2012000634A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/49—Cinchonan derivatives, e.g. quinine
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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 invention relates to a pharmaceutical agent for the treatment of erectile
  • Erectile dysfunction is known to cause a patient to be unable to achieve the erection necessary for sexual intercourse.
  • This dysfunction can be age-related, with a significant percentage of men becoming impotent as they age.
  • impotence may also be produced by surgical procedures such as radical retropubic prostatectomy and destruction of neurovascular bundles of nerves passing through the small basin, rectal surgery, or prostate radiation in prostate cancer.
  • potentiating agents such as sildenafil
  • INN SILDAFENIL commercially and from the European patents EP 463756 and
  • Combination agents which treat sildenafil with a further active ingredient can be taken from WO 00/54774 and EP 1 81 1 988.
  • the present invention has for its object to provide a further drug with which the effect of already known drugs for the relief of erectile dysfunction can be increased.
  • Drugs for the relief of erectile dysfunction can increase.
  • salts with acids are meant the following salts: salts of organic and inorganic acids, such as chloride, dichloride, hydrochloride, sulphate, disulphate, hydrosulphate and the corresponding hydrate forms for this purpose, for example hydrochloride dihydrate, sulphate dihydrate, disulphate heptahydrate, bromides, citrates, hydrocitrates, magnesium citrates, phosphates, acid phosphates, lactates, tartrates, acid tartrates and other salts of acids which are usually used pharmaceutically to form salts with acids.
  • organic and inorganic acids such as chloride, dichloride, hydrochloride, sulphate, disulphate, hydrosulphate and the corresponding hydrate forms for this purpose, for example hydrochloride dihydrate, sulphate dihydrate, disulphate heptahydrate, bromides, citrates, hydrocitrates, magnesium citrates, phosphates, acid phosphates, lactates, tartrates,
  • hydrochloride dihydrate and the sulfate dihydrate of quinine are preferably used according to the invention.
  • Sildenafil is the chemical compound 1 - ⁇ [3- (1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) 4-ethoxyphenyl] sulfonyl-4-methylpiperazine and its salts with acids as defined above Sildenafil citrate is preferred.
  • Tadalafil means (6R, 12aR) -6- (1,3-benzodioxol-5-yl) -2-methyl-1,2,3,4,6,7,12,12a, octahydropyrazino [2 ', 1 ': 6, 1] pyrido [3,4-b] indole-1,4-dione.
  • this compound can be used as a salt with an acid as mentioned above.
  • Vardenafil has the following IUPAC nomenclature: l - ⁇ [3- (5-Methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5, 1-fj [1,2,4] triazine-2-one) yl) -4-ethoxyphenyl] sulfonyl ⁇ -4-ethylpiperazine.
  • this compound can be advantageously used in the form of a salt with an acid as defined above.
  • the three drugs mentioned can be used in erectile dysfunction to adjust the erection for sexual intercourse during sexual arousal of the patient.
  • the degree and duration of the erection essentially depends on how much blood flows into or drains out to the erectile tissue of the penis.
  • the effect of the blood supply to the penis, ie to the corpus cavernosum, has been described in a large number of publications, so that it need not be discussed further here.
  • Essential in the Control is the cyclic guanosine monophosphate cGMP, which is formed in the state of erection and cleaved by the enzyme phosphodiesterase-5 (PDE-5). This cleavage is prevented by blocking the enzyme PDE-5 by the three drugs mentioned above, so that the cGMP can freely control the erection of the penis by the inflow of blood to the corpus cavernosum.
  • the three aforementioned active substances sildenafil, tadalafil and vardenafil are usually used in doses of 20-25 mg, 50 mg and 100 mg according to the needs of the patient.
  • quinine or quinine dihydrochloride can reduce the dosage amount by up to 50% without limiting the effect of the drug to remedy erectile dysfunction.
  • quinine itself is in pharmacy more than 100 years ago known pharmaceutical agent for the control of malaria or even today for combating leg cramps. It acts as a muscle-tonic in calf cramps and is usually without effect in the fight against erectile dysfunction. Only the inventive combination of quinine or its chloride or sulfate salts with sildenafil, tadalafil and vardenafil leads to the unexpected
  • the active ingredient ratio based on the weight of quinine / ED removal agent, is in a range from 1: 100 to 10: 1, preferably 1: 5 to 5: 1, in particular 0.5: 1 to 2.5: 1.
  • the combination of quinine / sildenafil uses 1-200 mg of quinine and 10-100 mg of sildenafil per dosage form (tablet). Quinine levels of 10-150 mg and sildenafil levels of 10-80 mg are preferred.
  • the following quantities of quinine and vardenafil can be used in one tablet as a dosage form: 1 -200 mg quinine and 10-100 mg vardenafil. Quinine levels of 10-150 mg and vardenafil levels of 10-80 mg are preferred.
  • a pharmaceutically acceptable carrier may be present in the compositions.
  • carrier materials include binders, auxiliaries or carrier materials themselves.
  • the carrier is chosen according to the purpose, d. H. in the form of oral tablets, capsules, either solid-filled, semi-solid or liquid-filled, powders, oral gels, elixirs, solutions, syrups, suspensions and the like.
  • the active ingredients, quinine and sildenafil may be combined with any oral non-toxic pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, cellulose, Magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, ethyl alcohol (for liquid forms) and the like.
  • any oral non-toxic pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, cellulose, Magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, ethyl alcohol (for liquid forms) and the like.
  • binders binders, lubricants, disintegrating agents,
  • Disinfectants and coloring matters are also incorporated into the mixture.
  • binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate,
  • Carboxymethyl cellulose polyethylene glycols and waxes.
  • Suitable lubricants are, for example, boric acid, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include starch, methyl cellulose, guar gum and the like.
  • Disinfectants include benzalkonium chloride and the like.
  • Oral administration of the agent of the invention is preferred.
  • tablets or capsules are used.
  • agents of the invention may be formulated in sustained-release form. Accordingly, coated tablets are formulated which permit sustained release of the drug.
  • the human oral dose containing the agent according to the invention is max. Administered 1 x / day.
  • the dosage form refers to an agent formulated in a delivery system, for example, tablet, capsule, oral gel, powder for dissolution or suspension in conjunction with inactive ingredients.
  • Capsule refers to a particular container or enclosure made of methylcellulose, polyvinyl alcohol, denatured gelatins or starches. It can be used equally hard capsules and soft capsules for the purposes of the invention.
  • Tablet relates to a compressed or shaped solid dosage form containing the active
  • the tablet is usually prepared by compressing the ingredients of the invention or granulated mixtures previously obtained by wet granulation, dry granulation or by
  • Oral gels refer to the active ingredients and a carrier that is dispersed or solubilized in a hydrophilic semi-solid matrix.
  • Powders for dissolving concern powder mixtures containing the active ingredients and the carrier as well as suitable diluents which can be suspended in water or juices.
  • Diluents are substances that usually make up the major proportion of the dosage form. Common diluents include sugars such as lactose, sucrose, mannitol and sorbitol.
  • Starches can be derived from wheat, corn, rice and potatoes. As cellulose microcrystalline cellulose can be used.
  • the amount of such diluents in the mixture may range from about 2 to about 98 percent by weight based on the total agent.
  • Disintegrating substances which are added to the mixture according to the invention help in breaking up (disintegrating) the mixture and in releasing the substances.
  • Such disintegrants include starches, cold water-soluble modified starches such as sodium carboxymethyl starch, natural and synthetic gums such as guar, karaya, tragacanth and agar, cellulose derivatives such as methyl cellulose and
  • alginates such as alginic acid and sodium alginate
  • lime substances such as bentonites or effervescent mixtures.
  • the proportion of these disintegrants in the mixture may range from about 1 to about 15 percent by weight based on the mixture.
  • Binders concern substances which have a binding effect on the substances usually present in granules and hold them together in the mixture.
  • Binders add binding forces to those already present in the mixture
  • Suitable binders include sugars such as sucrose, starches derived from wheat, corn, rice and potato, natural gums such as acacia, gelatin and
  • tragacanth derivatives derived from algae, such as alginic acid, sodium alginate,
  • Ammonium calcium alginate cellulosic materials such as cellulose, methylcellulose,
  • the amount of binder in the mixture may be in a range of 2-98% by weight based on the
  • Lubricants are those substances that help release the finished tablet from the tablet press by reducing friction.
  • Suitable lubricants include metallic stearates such as magnesium stearate,
  • Calcium stearate or potassium stearate, stearic acid, refractory waxes and water-soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate,
  • Sodium oleate, PEGs These lubricants are usually used in the last step before compression, since they must be present on the surface of the granules.
  • the amount of lubricant ranges from 0.5 to about 5 percent by weight based on the total mixture.
  • “Therapeutically effective amount” means the amount of active ingredients sufficient for the desired therapeutic effect.
  • the amount of therapeutic dose of the active ingredients may vary depending on the condition of the patient and the route of administration.
  • the dosage form as well as the dose and the dose frequency may vary depending on the age,
  • the dose may be administered orally in one or more dosage units.
  • Compressed tablets can be made by pressing in a machine, the active ingredients in free-flowing form, such as powders or granules, optionally mixed with a binder, lubricants, inert
  • Molded tablets can be made by molding in a special machine by moistening a mixture of powdered active ingredients with an inert liquid diluent.
  • microcrystalline cellulose, gelatin, magnesium stearate, fumed silica, cross carmelose and sodium magnesium stearate are used as auxiliaries, the tablets usually consisting of a core and a film coating.
  • the amounts mentioned in the examples are each based on the pure active substance, but not on the salt of the acid.
  • Example 1 further tablets are formulated containing 50 and 100 mg
  • a 40 mg tablet of tadalafil is formulated with 20 mg of quinine.
  • Example 3 the amount of vardenafil remains the same, the amount of quinine is increased to 30 mg per tablet.
  • Examples 1-5 are repeated in place of quinine, each with the same amount of quinidine.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Reproductive Health (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Endocrinology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Gynecology & Obstetrics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un agent pharmaceutique destiné au traitement de dysfonction érectile, comprenant de la quinine et du sildénafil, du vardénafil ou du tadalafil comme principe actif d'augmentation de la puissance.
PCT/EP2011/003145 2010-06-29 2011-06-27 Composition pharmaceutique pour le traitement de dysfonction érectile Ceased WO2012000634A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102010025535.1 2010-06-29
DE102010025535 2010-06-29

Publications (1)

Publication Number Publication Date
WO2012000634A1 true WO2012000634A1 (fr) 2012-01-05

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PCT/EP2011/003145 Ceased WO2012000634A1 (fr) 2010-06-29 2011-06-27 Composition pharmaceutique pour le traitement de dysfonction érectile

Country Status (1)

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WO (1) WO2012000634A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0463756A1 (fr) 1990-06-20 1992-01-02 Pfizer Limited Pyrazolopyrimidones comme agents antiangineux
EP0702555A1 (fr) 1993-06-09 1996-03-27 Pfizer Limited Pyrazolopyrimidinones utilisees pour traiter l'impuissance
WO2000054774A1 (fr) 1999-03-16 2000-09-21 Pentech Pharmaceuticals, Inc. Composition d'apomorphine et de sildenafil
WO2004043365A2 (fr) * 2002-11-06 2004-05-27 Azaya Therapeutics, Inc. Methode de traitement de l'ejaculation precoce chez les humains
WO2007070779A2 (fr) 2005-12-13 2007-06-21 Trinity Laboratories, Inc. Procede de traitement de l'ejaculation precoce chez les humains
EP1811988A1 (fr) 2004-11-11 2007-08-01 SIGMA-TAU Industrie Farmaceutiche Riunite S.p.A. Emploi de l'acétyl-l-carnitine associée à la propionyl-l-carnitine et au sildenafil dans le traitement de troubles de l'érection

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0463756A1 (fr) 1990-06-20 1992-01-02 Pfizer Limited Pyrazolopyrimidones comme agents antiangineux
EP0702555A1 (fr) 1993-06-09 1996-03-27 Pfizer Limited Pyrazolopyrimidinones utilisees pour traiter l'impuissance
WO2000054774A1 (fr) 1999-03-16 2000-09-21 Pentech Pharmaceuticals, Inc. Composition d'apomorphine et de sildenafil
WO2004043365A2 (fr) * 2002-11-06 2004-05-27 Azaya Therapeutics, Inc. Methode de traitement de l'ejaculation precoce chez les humains
US7754767B2 (en) 2002-11-06 2010-07-13 Trinity Laboratories, Inc. Method for treatment of premature ejaculation in humans
EP1811988A1 (fr) 2004-11-11 2007-08-01 SIGMA-TAU Industrie Farmaceutiche Riunite S.p.A. Emploi de l'acétyl-l-carnitine associée à la propionyl-l-carnitine et au sildenafil dans le traitement de troubles de l'érection
WO2007070779A2 (fr) 2005-12-13 2007-06-21 Trinity Laboratories, Inc. Procede de traitement de l'ejaculation precoce chez les humains

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
J. PHARM. PHARMACOL., vol. 61, 2007, pages 1637
SOMMER F ET AL: "409 Which PDE5-inhibitor do patients prefer? A comparative study of 50 mg sildenafil, 10 mg tadalafil and 10 mg vardenafil", EUROPEAN UROLOGY SUPPLEMENTS, XX, XX, vol. 3, no. 2, 1 February 2004 (2004-02-01), pages 105, XP027535069, ISSN: 1569-9056, [retrieved on 20040201] *

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