WO2019142015A1 - Composition pharmaceutique d'administration transdermique par voie urétrale en gouttes pour le traitement de la dysfonction érectile - Google Patents

Composition pharmaceutique d'administration transdermique par voie urétrale en gouttes pour le traitement de la dysfonction érectile Download PDF

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Publication number
WO2019142015A1
WO2019142015A1 PCT/IB2018/050324 IB2018050324W WO2019142015A1 WO 2019142015 A1 WO2019142015 A1 WO 2019142015A1 IB 2018050324 W IB2018050324 W IB 2018050324W WO 2019142015 A1 WO2019142015 A1 WO 2019142015A1
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WO
WIPO (PCT)
Prior art keywords
amount
pharmaceutical composition
erectile dysfunction
present
ddaip
Prior art date
Application number
PCT/IB2018/050324
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English (en)
Spanish (es)
Inventor
Ciro Eduardo SILVA RIAÑO
Original Assignee
Caicedo Pinto, David Felipe
Priority date (The priority date 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 date listed.)
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Publication date
Application filed by Caicedo Pinto, David Felipe filed Critical Caicedo Pinto, David Felipe
Priority to PCT/IB2018/050324 priority Critical patent/WO2019142015A1/fr
Publication of WO2019142015A1 publication Critical patent/WO2019142015A1/fr

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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
    • A61K31/435—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
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • 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
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides

Definitions

  • the present invention relates to compositions and their form of transdermal administration for the treatment of sexual dysfunction in humans by the urethral route.
  • the present invention comprises an aqueous pharmaceutical composition of transdermal absorption and urethral application by drops.
  • this invention relates to the use of compositions comprising the assets of alprostadil, phentolamine, papaverine and atropine in their pharmaceutically acceptable salts on a pharmaceutical support based on a DDAIP hydrochloride salt (DDAIP-HCI) for transdermal administration.
  • DDAIP-HCI DDAIP hydrochloride salt
  • urethral route The object and purpose of the present invention comprises a pharmaceutical composition for erectile dysfunction that also includes an active ingredient that increases its penetration through the skin by application via the urethra, guaranteeing rapidity of action of the drugs and their effectiveness avoiding adverse effects.
  • the present invention relates to compositions and their dosage form for the treatment of sexual dysfunction in humans of rapid absorption. More particularly, this invention relates to the use of compositions comprising a DDAIP hydrochloride salt (DDAIP-HCI) as a rapid and long-lasting pharmacological action for pain-sensitive individuals during the application of assets for the treatment of male erectile dysfunction based on the assets of alprostadil, phentolamine, Papaverine and atropine in their pharmaceutically acceptable salts.
  • DDAIP-HCI DDAIP hydrochloride salt
  • the routes of drug administration are the routes of entry of the drug into the body, which influences the latency, intensity and duration of the effect, for this reason it is very important to know its advantages and disadvantages in addition to which of the routes of administration of Drugs is used in a particular situation.
  • the advantages of transdermal drug administration over other methods of drug administration are well known.
  • Most drugs do not permeate the skin sufficiently to provide therapeutic levels of drug delivery.
  • the skin especially the outer layer provides a barrier to the penetration of most substances.
  • the Topical drug formulations typically include a skin penetration enhancer.
  • Skin penetration enhancers can also be called absorption enhancers, accelerators, adjuvants, solubilizers, absorption promoters, etc. Whatever the name, such agents serve to improve the absorption of the drug through the skin.
  • Ideal penetration enhancers not only increase the flow of drugs through the skin, but do so without irritating, sensitizing or damaging the skin.
  • ideal penetration enhancers should not adversely affect the stability of the active drug, or the quality of the composition. Particularly in the matter of water-based formulations to form drops.
  • impotence or male erectile dysfunction is defined as the inability to achieve and maintain an erection sufficient for a satisfactory sexual act and intercourse.
  • Impotence in a given case can come from psychological disorders, physiological abnormalities in general, neurological disorders, hormonal deficiencies or a combination of the above.
  • psychogenic impotence is defined as functional impotence without a determining and apparent functional organic basis.
  • a diagnostic method uses oral medication as a means to distinguish dysfunctional patients who can respond to oral medications from those who need more direct intervention, that is, such as intracavernous injection or surgery.
  • the treatment of dysfunction is usually carried out mainly orally, with medications such as sildenafil, this being a selective phosphodiesterase inhibitor with positive results, but with systemic side effects (headache, easy redness, indigestion). among others) and waiting for the drug to reach the site of action after its systemic distribution It also involves all the problems associated with blood pressure, since in all patients it cannot be administered.
  • medications such as sildenafil, this being a selective phosphodiesterase inhibitor with positive results, but with systemic side effects (headache, easy redness, indigestion). among others) and waiting for the drug to reach the site of action after its systemic distribution It also involves all the problems associated with blood pressure, since in all patients it cannot be administered.
  • nitric oxide is released from parasympathetic post-synaptic neurons and, to a lesser extent, endothelial cells and a-adrenergic neurons are inhibited in arterial and trabicular smooth muscle.
  • Nitric oxide which diffuses easily, stimulates the increased formation of cyclic guanosine monophosphate (GMP) in the corpus cavernosum by guanylate cyclase to relax smooth muscle cells.
  • GMP cyclic guanosine monophosphate
  • an effective solution is the direct administration that allows an immediate interaction of the assets and therefore their effective treatment.
  • Alprostadil is a protagladin E1 (PGE1, alprostadil) that belongs to the family of eicosanoids, which represent a large group of oxygenated metabolites of fatty carbon polyunsaturated acids, including prostagladins, thromboxanes, leukotrienes, lipoxins, epoxyecosatrienic acids, hepoxylin, leukotrienes, lipoxins, epoxyeicosatrienic acids, hepoxylin and other compounds.
  • the natural precursor of eicosanoids is free arachidonic acid that binds phospholipids from the adherent membrane and released by the enzyme phospholipase A2.
  • Physiological eicosanoids that exist in almost all tissues and are shown to be modulators or mediators of a considerable number of physiological processes. All these effects are mid eicosanoids attributed through specific cell receptors, which have been identified in platelets and smooth muscle cells. In the field of urology and andrology, they are especially used in impotence management.
  • compositions containing alprostadil on the market such as in US Patent US6124461 N s Shoemaker, these are an emulsifier which can be polyethylene glycol, its dose not readily standardized and have a pH between 4 5-5.2; producing irritation at the time of administration to the patient.
  • Other formulations such as US application US20040102475 N s Podolski used as arginine or glycine buffer with mannitol and benzyl alcohol, with a pH between 3-7 and preferably 3-5, producing irritation and pain to the patient.
  • these developments of the new intracavernous injection compositions produce certain pains in sensitive individuals, making it necessary to look for new compositions for erectile dysfunction that also includes an active that prevents pain.
  • the object and purpose of the present invention comprises a pharmaceutical composition for erectile dysfunction which also includes an active that facilitates the absorption of the skin for a topical application via the urethra.
  • a first object of the present invention is to avoid the disadvantages of the prior art.
  • the main object of the present invention is to create a pharmaceutical composition for erectile dysfunction which also includes an active that facilitates the absorption of the skin for a topical application via the urethra.
  • the pharmaceutical composition according to the present invention comprises an aqueous pharmaceutical form of transdermal absorption and urethral application by drops.
  • the present invention meets these needs and provides other advantages related to the administration of the product, which includes an active ingredient that facilitates the absorption of the skin for an application in drops via the urethra and thereby guaranteeing rapid action of the drugs and their effectiveness avoiding effects.
  • the present invention relates to compositions and their fast-acting dosage form for the treatment of sexual dysfunction in humans guaranteeing rapid action of the drugs and their effectiveness avoiding adverse effects.
  • this invention relates to the use of compositions comprising a DDAIP hydrochloride salt (DDAIP-HCI) for its improved transdermal absorption by application of drops via the urethra as a rapid and long-lasting pharmacological action for the application of assets for the treatment of male erectile dysfunction based on alprostadil, phentolamine, papaverine and atropine in their pharmaceutically acceptable salts.
  • DDAIP-HCI DDAIP hydrochloride salt
  • the object and purpose of the present invention comprises a pharmaceutical composition for erectile dysfunction which further includes an active DDAIP hydrochloride salt (DDAIP-HCI) in an aqueous pharmaceutical support comprising disodium EDTA.
  • DDAIP-HCI active DDAIP hydrochloride salt
  • Said DDAIP hydrochloride salt as it is a permeation enhancer that dynamically changes the lipid bilayer temporarily and It opens the tight junctions between the skin cells for drug molecules of the present invention so that it can be rapidly absorbed through the skin into the systemic circulation. It can also improve the solubility of the compounds that result in improved drug penetration. Particularly this corresponds to:
  • DDAIP-HCL hydrochloride salt corresponds to dodecyl-2- N, N-dimethylaminopropionate hydrochloride.
  • Dodecyl-2-N, N-dimetilaminopropionato DDAIP is prepared as indicated in US Patent N s 6.1 18.020 of Büyüktimkin, illustrated here for informational purposes.
  • the DDAIP corresponds to CAS 149196-89-4 N s, is not soluble in water, but is miscible with most organic solvents. It comprises a molecular weight 285.47; transparent colorless liquid form; whose freezing point is -17.5 ° C and a boiling point of 142 to 144 ° C / 0.1 mmHG; and, a viscosity 7.32 centiStokes at 23 ° C.
  • the composition comprises a DDAIP hydrochloride salt (DDAIP-HCI) and the effective amount should be 0.3 g per 100 g of the composition, via the urethral route.
  • DDAIP-HCI DDAIP hydrochloride salt
  • the advantages according to the present invention is that it allows to guarantee rapidity of action of the drugs and their effectiveness avoiding adverse effects.
  • composition of the present invention seeks a pharmaceutical form transdermal administration of drops application for the treatment of sexual dysfunction in humans through the urethra, so that its use is allowed in patients with some level of diabetes, heart problems and that by Your age or physical condition does not allow for a normal erection.
  • compositions containing the active useful in the treatment of male erectile dysfunction such as: Prostaglandin PG1 C 20 H 34 O 3
  • compositions are for transdermal use.
  • Papaverine is a potent and non-specific, muscle relaxant, and is a non-selective phosphodiesterase cAMP inhibitor of phosphodiesterase, causing vasodilation of the penis. It has a relatively short half-life (1-2 hours) and is metabolized in the liver.
  • phentolamine is a competitive inhibitor of a1 and a2-adrenergic receptors and is believed to act by inhibiting arterial constriction in the corpora cavernosa. Its main salt to be used is the Mesylate.
  • Atropine sulfate has been used as an intracavernous injection. In low doses (10 sup -8 m.), This anticholinergic agent decreases the inhibition of adrenergic and cholinergic excitation of the non-adrenergic, non-cholinergic neuroefector systems that control the neurogenic body relaxation of the smooth muscle. However, in high pharmacological doses (10 sup -3 m.) Atropine sulfate causes the release of endothelium-derived relaxing factor.
  • the present invention is providing immediate action compositions for local use of transdermal administration via the urethral, without cause pain in addition to irritation, as well as physicochemical stable compositions.
  • composition according to the present invention further comprises an aqueous pharmaceutical support comprising disodium EDTA and additionally, solubilization aids; a thickener; a stabilizer of the composition; one to several condoms; and, C.S.P sterile water as a vehicle.
  • aqueous pharmaceutical support comprising disodium EDTA and additionally, solubilization aids; a thickener; a stabilizer of the composition; one to several condoms; and, C.S.P sterile water as a vehicle.
  • EDTA and its derivatives have the valuable chemical property of combining with polyvalent metal ions in solution to form non-ionic, water soluble and virtually non-dissociable cyclic coordinated complexes. These complexes are known as chelates.
  • a preferred solubilization aid for the present invention can be chosen from various types of alcohols.
  • a naturally occurring hydrocolloid such as guar gum is possible.
  • the suitable guar gum is hydroxypropyl guar gum.
  • Hydroxypropyl guar gum is a non-ionic derivative of guar gum that is used as a thickening and stabilizing agent as a gelling agent. The need to give a certain viscosity to the composition in drops, helps in that it is slowly absorbed by the skin inside the urethra before drying in an unwanted way. Additionally, it is intended that each drop slide slowly through the urethra for proper transfer of the formulation.
  • the appropriate viscosity should not exceed 600 cps at room temperature.
  • the viscosity of the composition is between 500 and 600 cps at room temperature.
  • it comprises potassium dehydrogenate and as preservatives it can comprise methylparaben and / or propylparaben in addition to sterile CSP water as a vehicle to complete the formulation.
  • the present invention comprises a pharmaceutical composition for erectile dysfunction of transdermal administration via the urethra comprising total weight, alprostadil or protaglandin E1 in an amount 0.2% and 0.4%, preferably 0.3%; Papaverine is present for the same formulation in an amount of 0.009% to 0.02%, preferably 0.01%; phentolamine in an amount of 0.09% to 0.2%, preferably 0.13%; and, atropine in an amount of 0.009% to 0.2%, preferably 0.015%.
  • Preferred salts are for each of the active ingredients; Papaverine hydrochloride, Phentolamine hydrochloride or mesylate and Atropine Sulfate hydrated or non-hydrated.
  • the present invention thus further comprises a DDAIP-HCL hydrochloride salt of dodecyl-2-N, N-dimethylaminopropionate hydrochloride in an amount of 0.2% and 0.4%, preferably 0.3 %.
  • compositions further comprise disodium EDTA in an amount of 0.01% to 0.09%, preferably 0.02%.
  • the composition further comprises other pharmaceutically acceptable ingredients such as preservatives and solubilizers, among others.
  • preservative the composition comprises sodium methylparaben in an amount of 0.09% to 0.2%, preferably 0.1% and sodium propylparaben in an amount of 0.009% to 0.02%, preferably 0.01%.
  • stabilizer of the composition it then comprises potassium dehydrogenation in an amount of 0.1% to 0.5%, preferably 0.3%; and, hydroxypropyl guar gum in an amount of 2% to 7%, depending on the necessary viscosity, a pharmaceutical composition comprising 5% being preferable.
  • the pharmaceutical composition as defined above comprises CSP sterile water in a proportion to form an aqueous pharmaceutical form of transdermal absorption and urethral application by drops.
  • the methods of treatment include administration by the transdermal route through the urethra, at the concentrations previously contemplated for administration at time intervals: every 6, 8, 12, 24 or 48 hours.
  • composition and sterile C.S.P water as a vehicle it comprises:
  • the preferable composition according to the present invention comprises a pharmaceutical drop composition for erectile dysfunction comprising total weight, alprostadil or protaglandin E1 in an amount 0.2% and 0.4%, preferably 0, 3%;
  • Papaverine is present for the same formulation in an amount of 0.009% to 0.02%, preferably 0.01%; phentolamine in an amount of 0.09% to 0.2%, preferably 0.13%; and, atropine in an amount of 0.009% to 0.2%, preferably 0.015%; wherein said assets are in an aqueous pharmaceutical support comprising a DDAIP-HCL hydrochloride salt of dodecyl-2-N, N-dimethylaminopropionate hydrochloride in an amount of 0.2% and 0.4%, preferably 0.3% in combination with disodium EDTA in an amount of 0.01% to 0.09%, preferably 0.02%; as a preservative, sodium methylparaben in an amount of 0.09% to 0.2%, preferably 0.1% and sodium prop
  • the pharmaceutical composition as defined above comprises sterile CSP water in a proportion to form an aqueous pharmaceutical form of transdermal absorption in drops via the urethra.
  • composition according to the present invention comprises a pH between 3 and 8, preferably 5.5. According to the present, 0.1 N sodium hydroxide and / or 0.1 N phosphoric acid is used to adjust the pH.
  • a low density polyethylene plastic container in a dropper with a round tip and a lid.
  • compositions and their dosage form for the treatment of sexual dysfunction in humans can be chosen from a plurality of alternatives without departing from the spirit of the invention according to the following claims.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne des compositions et leur administration transdermique pour le traitement de la dysfonction sexuelle chez les êtres humains par voie urétrale. La présente invention comprend notamment une composition pharmaceutique aqueuse d'absorption percutanée et d'application urétrale en gouttes. Plus particulièrement, cette invention concerne l'utilisation de compositions qui comprennent les principes actifs d'alprostadil, de phentolamine, de papavérine et d'atropine dans ses sels pharmaceutiquement acceptables sur un support pharmaceutique basé sur un sel de chlorhydrate de DDAIP (DDAIP-HCI) pour son administration transdermique par voie urétrale. L'objet et la finalité de la présente invention comprend une composition pharmaceutique pour le traitement de la dysfonction érectile qui contient en outre un principe actif qui augmente sa pénétration à travers la peau par application par voie urétrale ce qui garantit une rapidité d'action des médicaments et leur efficacité tout en évitant des effets secondaires.
PCT/IB2018/050324 2018-01-18 2018-01-18 Composition pharmaceutique d'administration transdermique par voie urétrale en gouttes pour le traitement de la dysfonction érectile WO2019142015A1 (fr)

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PCT/IB2018/050324 WO2019142015A1 (fr) 2018-01-18 2018-01-18 Composition pharmaceutique d'administration transdermique par voie urétrale en gouttes pour le traitement de la dysfonction érectile

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PCT/IB2018/050324 WO2019142015A1 (fr) 2018-01-18 2018-01-18 Composition pharmaceutique d'administration transdermique par voie urétrale en gouttes pour le traitement de la dysfonction érectile

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4232002A4 (fr) * 2020-10-22 2024-10-23 Madera Pharmaceuticals Inc Traitement transdermique pour le dysfonctionnement érectile

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030134903A1 (en) * 2000-01-10 2003-07-17 Nexmed (Holdings), Inc. Prostaglandin compositions and methods of treatment for male erectile dysfunction
US20040131664A1 (en) * 2003-01-03 2004-07-08 Mo Y. Joseph Topical stabilized prostaglandin E compound dosage forms
CO7240095A1 (es) * 2013-10-07 2015-04-17 Hmc Internat Medical Ct Sas Producto magistral para la impotencia masculina

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030134903A1 (en) * 2000-01-10 2003-07-17 Nexmed (Holdings), Inc. Prostaglandin compositions and methods of treatment for male erectile dysfunction
US20040131664A1 (en) * 2003-01-03 2004-07-08 Mo Y. Joseph Topical stabilized prostaglandin E compound dosage forms
CO7240095A1 (es) * 2013-10-07 2015-04-17 Hmc Internat Medical Ct Sas Producto magistral para la impotencia masculina

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ISRAILOV S ET AL.: "Intracavernous injections for erectile dysfunction in patients with cardiovascular diseases and failure or contraindications for sildenafil citrate", INTERNATIONAL JOURNAL OF IMPOTENCE RESEA, vol. 14, no. 1, 1 February 2002 (2002-02-01), stockton, basingstoke, GB, pages 38 - 43, XP008044473, ISSN: 0955-9930 *
SALAMA S. ET AL.: "Nouvelle alternative locale dans le traitement de la dysfonction érectile: l'offre thérapeutique s'étoffe", SEXOLOGIES, vol. 25, no. 4, marseille, Fr., pages 153 - 159, XP029815720, ISSN: 1158-1360 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4232002A4 (fr) * 2020-10-22 2024-10-23 Madera Pharmaceuticals Inc Traitement transdermique pour le dysfonctionnement érectile

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