WO2000048570A1 - Pharmaceutical composition for balanic transmucosal administration of alfuzosin - Google Patents
Pharmaceutical composition for balanic transmucosal administration of alfuzosin Download PDFInfo
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- WO2000048570A1 WO2000048570A1 PCT/FR2000/000358 FR0000358W WO0048570A1 WO 2000048570 A1 WO2000048570 A1 WO 2000048570A1 FR 0000358 W FR0000358 W FR 0000358W WO 0048570 A1 WO0048570 A1 WO 0048570A1
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- dioxolane
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
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- 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
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- 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
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
Definitions
- the subject of the present invention is a pharmaceutical composition for balanic transmucosal administration, comprising as active ingredient N- [3- [(4-amino-6,7-dimethoxy-2-quinazolinyl) methylamino] propyl] tetrahydro-2-furanecarboxamide ( or alfuzosin), in free form or in a salt, as well as the use of this pharmaceutical composition in therapy.
- alfuzosin means N- [3 - [(4-amino- 6,7-dimethoxy-2-quinazolinyl) methylamino] propyl] tetrahydro-2-furanecarboxamide, in free form or in form of a salt with a pharmaceutically acceptable acid.
- pharmaceutically acceptable acids which can form a salt with alfuzosin, mention may be made, for example, of hydrochloric, ascorbic, maleic, succinic, tartaric, citric and hydroxymaleic acids.
- Alfuzosin hydrochlorides are the preferred salts in the context of the present invention.
- Alfuzosin some of its salts, as well as their preparation processes, are described in patent FR2466462. Alfuzosin, and in particular its hydrochloride, are currently marketed in the form of tablets for the treatment of benign prostatic hyperplasia.
- the present invention relates to a balanic transmucosal pharmaceutical composition, intended for the treatment of erectile dysfunctions, formulated so as to allow the absorption of alfuzosin through the balanic mucosa.
- Another object of the present invention is to allow rapid absorption of alfuzosin at the application site with a level of alfuzosin sufficient to achieve the desired therapeutic effect.
- the invention consists of a pharmaceutical composition characterized in that it comprises an active principle consisting of alfuzosin, as well as at least one specific absorption promoter, said composition being formulated to allow balanic transmucosal administration.
- absorption promoter is understood to mean a pharmaceutically acceptable compound which makes it possible to improve the passage of the principle through a mucosa and more particularly the balanic mucosa.
- the absorption promoter can, in particular, modify the permeability or change the state of the surface of the mucosa in order to facilitate passage.
- absorption promoters particularly suitable for a pharmaceutical composition according to the invention, are compounds having an exclusively hydrophilic or partially hydrophilic character. More specifically, we can cite:
- dioxolane or dioxane derivatives more specifically derivatives 1, 3-dioxolanes (1, 3-dioxacyclopentanes) or 1, 3-dioxanes (1, 3-dioxacyclohexanes) such as 1, 3 dioxolane, methyl-1 , 3-dioxolane, 4-hydroxymethyl-1, 3-dioxolane, 4-methyl-dioxolane, 1, 3-dioxane, 2-methyl-1, 3-dioxane, 2,2-dimethyl-1, 3-dioxolane-4-methanol (solketal), as well as the derivatives described in patent EP0268460 such as 2-n-pentyl-1, 3-dioxolane, 2-n-heptyl-1, 3-dioxolane, 2 -n-undecyl-1, 3-dioxolane, 2 (2 ', 6'-dimethyl-2'-heptaenyl) -1, 3-dioxolane
- the derivatives 1, 3 dioxolane, methyl-1, 3-dioxolane, 4-hydroxymethyl-1, 3-dioxolane, 4-methyl-dioxolane, 1, 3-dioxane, 2-methyl-1, 3-dioxane and the 2, 2-dimethyl-1, 3-dioxolane-4-methanol, more hydrophilic in character, are particularly preferred and more specifically 2,2-dimethyl-1,3-dioxolane-4-methanol (solketal);
- - fatty acid monoglycerides such as, for example, capric / caprylic acid monoglyceride
- - fatty esters of glycerols and polyethylene glycol (PEG) by way of example, there may be mentioned glycerol and PEG-6 monooleate and glycerol and PEG-8 linoleate
- - fatty esters of propylene glycol such as laurate or caprylate / caprate of propylene glycol
- - terpenes such as t-anethole, carvacrol, carvone, 1-8 cineole, d-limonene, 1-menthol, menthone, terpinene and thymol or
- the dioxolane or dioxane derivatives as mentioned above and more particularly 2,2-dimethyl-1, 3-dioxolane-4-methanol (solketal) and 2-n-nonyl- 1, 3-dioxolane are particularly preferred.
- Some absorption promoters can, to be correctly formulated, be at least partially dissolved by one or more organic solvents, if necessary, in mixture with water. These organic solvents can also, in combination with absorption promoters, facilitate the transmucosal passage of the active principle.
- organic solvents which can be used to dissolve the absorption promoters, mention may be made of ethanol, propanol, isopropanol, diethylene glycol monoethyl ether (transcutol®), glycofurol, glycerol, propylene glycol and polyethylene glycols. liquid state.
- the composition can contain a natural or synthetic prostaglandin.
- a prostaglandin is for example PGE1 or PGE2.
- Prostaglandin is preferably added in an amount of 10 ⁇ g to 25 mg / ml in the composition, preferably 50 ⁇ g to 10 mg / ml.
- the pharmaceutical composition in the form of a hydrophilic pharmaceutical composition.
- a hydrophilic pharmaceutical composition consists, for example, of a hydrophilic cream, a gel, an emulsion or microemulsion or a lotion.
- the pharmaceutical composition is in the form of a gel.
- gel is intended to mean a semi-solid aqueous preparation comprising in particular gelling agents.
- the gelling agents according to the invention are:
- HEC hydoxyethylcellulose
- HPMC hydroxypropylmethylcellulose
- Methocel® E4M, F4M or 4KM in proportions of 5 to 20% or hydroxypropylcellulose (HPC) (for example Klucel®) in proportions of 1 to 10%,
- polyacrylic derivatives such as those sold under the Carbopol® brand or polyacrilamides such as Sepigel® 305, in proportions of 2 to 5%,
- poloxamers block copolymers of polyoxyethylene and polyoxypropylene
- poloxamer 407 in proportions of 15 to 50%
- - natural gums such as xanthan gum, guar gum, locust bean gum in proportions of 1 to 10%.
- the preparation can also include mineral thickening agents such as aluminum hydroxide gel or colloidal silica in proportions of 1 to 10%.
- a pharmaceutical composition according to the invention can comprise from 1 to 50 mg / ml of active principle, preferably 5 to 25 mg / ml.
- the content of absorption promoter in the composition of the invention can vary within wide limits, in particular as a function of the concentration of active principle and of the very nature of the absorption promoter used. It is thus possible to use an absorption promoter content of between 0.5 and 50% by weight of the composition. However, the promoter content is generally between 0.5 to 5% in the case of terpenes 2 to 50% in the case of other promoters.
- the solvent content can vary depending, in particular, on the nature of the absorption promoter and on the fact that the solvent itself can facilitate the absorption of the active product.
- the solvent in addition to its role as solubilizing agent for the absorption promoter, the solvent can also be useful as a solubilizing agent for the active principle and / or as an excipient constituting said pharmaceutical composition. Based on these different parameters, the skilled person can determine the solvent content required.
- a pharmaceutical composition according to the invention can comprise conventional excipients such as perfumes, essential oils, preservatives, soothing moisturizers, or colorings.
- compositions can be prepared according to conventional methods for a person skilled in the art.
- the methods are an integral part of the invention.
- the active principle can be mixed in solution in water and / or in a solvent necessary for the dissolution of the absorption promoter, as defined above, with this absorption promoter.
- Conventional excipients as defined above, can be added to this solution.
- the gelling agent is preferably added last.
- the pharmaceutical compositions of the invention can be applied to the scrotum and the penis, but more particularly the application site concerns the balanic mucosa, either the glans or the balano-prepucial sulcus, preferably the glans. At the application site, the pharmaceutical composition is applied in an amount of 0.1 to 1 ml.
- compositions according to the invention can be contained in a device for topical application.
- Another object of the present invention is such a device comprising a pharmaceutical composition as described above.
- This device may in particular consist of a metering dispenser consisting of a reservoir provided with a system capable of releasing the pharmaceutical composition in a predetermined dose, such as a piston system. This dose can then be spread over the skin.
- the gel can then be packaged in a rigid and opaque polypropylene tube, equipped with a dosing pump.
- absorption is monitored in Franz diffusion cells through the hairiess rat skin (normal or delaminated) and / or through a mucosa (great equine or possibly human).
- a dose of 5 to 10 mg / cm 2 of the pharmaceutical composition can be applied to a defined surface which can range from 1 to 2 cm 2 depending on the nature of the anatomical part.
- the survival liquid phosphate buffer
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Abstract
Description
COMPOSITION PHARMACEUTIQUE POUR ADMINISTRATION TRANSMUCOSALE BALANIQUE D'ALFUZOSINE PHARMACEUTICAL COMPOSITION FOR BALANIC TRANSMUCOSAL ADMINISTRATION OF ALFUZOSINE
La présente invention a pour objet une composition pharmaceutique pour administration transmucosale balanique, comprenant comme principe actif le N-[3- [(4-amino-6,7-diméthoxy-2-quinazolinyl)méthylamino]propyl]tétrahydro-2- furanecarboxamide (ou alfuzosine), sous forme libre ou d'un sel, ainsi que l'utilisation de cette composition pharmaceutique en thérapeutique.The subject of the present invention is a pharmaceutical composition for balanic transmucosal administration, comprising as active ingredient N- [3- [(4-amino-6,7-dimethoxy-2-quinazolinyl) methylamino] propyl] tetrahydro-2-furanecarboxamide ( or alfuzosin), in free form or in a salt, as well as the use of this pharmaceutical composition in therapy.
Au titre de la présente invention, on entend par «alfuzosine» le N-[3-[(4-amino- 6,7-diméthoxy-2-quinazolinyl)méthylamino]propyl]tétrahydro-2- furanecarboxamide, sous forme libre ou sous forme d'un sel avec un acide pharmaceutiquement acceptable. Parmi les acides pharmaceutiquement acceptables, pouvant former un sel avec l'alfuzosine, on peut citer, à titre d'exemple, les acides chlorhydrique, ascorbique, maléique, succinique, tartrique, citrique et hydroxymaléique. Les chlorhydrates de l'alfuzosine sont les sels préférés dans le cadre de la présente invention.For the purposes of the present invention, the term "alfuzosin" means N- [3 - [(4-amino- 6,7-dimethoxy-2-quinazolinyl) methylamino] propyl] tetrahydro-2-furanecarboxamide, in free form or in form of a salt with a pharmaceutically acceptable acid. Among the pharmaceutically acceptable acids which can form a salt with alfuzosin, mention may be made, for example, of hydrochloric, ascorbic, maleic, succinic, tartaric, citric and hydroxymaleic acids. Alfuzosin hydrochlorides are the preferred salts in the context of the present invention.
L'alfuzosine, certains de ses sels, ainsi que leurs procédés de préparation, sont décrits dans le brevet FR2466462. L'alfuzosine, et notamment son chlorhydrate, sont actuellement commercialisés sous forme de comprimés dans le traitement de l'hypertrophie bénigne de la prostate.Alfuzosin, some of its salts, as well as their preparation processes, are described in patent FR2466462. Alfuzosin, and in particular its hydrochloride, are currently marketed in the form of tablets for the treatment of benign prostatic hyperplasia.
La présente invention a trait à une composition pharmaceutique transmucosale balanique, destinée au traitement des dysfonctionnements érectiles, formulée de façon à permettre l'absorption de l'alfuzosine au travers de la muqueuse balanique.The present invention relates to a balanic transmucosal pharmaceutical composition, intended for the treatment of erectile dysfunctions, formulated so as to allow the absorption of alfuzosin through the balanic mucosa.
Un autre but de la présente invention est de permettre une absorption rapide de l'alfuzosine au site d'application avec un taux d'alfuzosine suffisant pour atteindre l'effet thérapeutique recherché.Another object of the present invention is to allow rapid absorption of alfuzosin at the application site with a level of alfuzosin sufficient to achieve the desired therapeutic effect.
Dans le cadre de la présente invention, les quantités, sauf indication contraire, sont exprimées en % en poids de la composition totale.In the context of the present invention, the quantities, unless otherwise indicated, are expressed in% by weight of the total composition.
Plus spécifiquement, l'invention consiste en une composition pharmaceutique caractérisée en ce qu'elle comprend un principe actif consistant en l'alfuzosine, ainsi qu'au moins un promoteur d'absorption spécifique, ladite composition étant formulée pour permettre une administration transmucosale balanique. On entend par le terme promoteur d'absorption, un composé pharmaceutiquement acceptable, qui permet d'améliorer le passage du principe à travers une muqueuse et plus particulièrement la muqueuse balanique. A cette fin, le promoteur d'absorption peut, notamment, modifier la perméabilité ou changer l'état de la surface de la muqueuse afin de faciliter le passage.More specifically, the invention consists of a pharmaceutical composition characterized in that it comprises an active principle consisting of alfuzosin, as well as at least one specific absorption promoter, said composition being formulated to allow balanic transmucosal administration. The term absorption promoter is understood to mean a pharmaceutically acceptable compound which makes it possible to improve the passage of the principle through a mucosa and more particularly the balanic mucosa. To this end, the absorption promoter can, in particular, modify the permeability or change the state of the surface of the mucosa in order to facilitate passage.
Il a été découvert que des promoteurs d'absorption spécifique, convenant particulièrement pour une composition pharmaceutique selon l'invention, sont des composés ayant un caractère exclusivement hydrophile ou partiellement hydrophile. Plus précisément, on peut citer :It has been discovered that specific absorption promoters, particularly suitable for a pharmaceutical composition according to the invention, are compounds having an exclusively hydrophilic or partially hydrophilic character. More specifically, we can cite:
- les dérivés de dioxolanes ou de dioxanes, plus spécifiquement les dérivés 1 ,3- dioxolanes (1 ,3-dioxacyclopentanes) ou 1 ,3-dioxanes (1 ,3-dioxacyclohexanes) tels que le 1 ,3 dioxolane, le méthyl-1 ,3-dioxolane, le 4-hydroxyméthyl-1 ,3- dioxolane, le 4-méthyl-dioxolane, le 1 ,3-dioxane, le 2-méthyl-1 ,3-dioxane, le 2,2- diméthyl-1 ,3-dioxolane-4-méthanol (solketal), ainsi que les dérivés décrits dans le brevet EP0268460 tels que le 2-n-pentyl-1 ,3-dioxolane, le 2-n-heptyl-1 ,3- dioxolane, le 2-n-undecyl-1 ,3-dioxolane, 2(2', 6'-diméthyl-2'-heptaenyl)-1 ,3- dioxane et le 2-n-nonyl-1 ,3-dioxolane. Les dérivés 1 ,3 dioxolane, méthyl-1 ,3- dioxolane, 4-hydroxyméthyl-1 ,3-dioxolane, 4-méthyl-dioxolane, 1 ,3-dioxane, 2- méthyl-1 ,3-dioxane et le 2,2-diméthyl-1 ,3-dioxolane-4-méthanol, à caractère plus hydrophile, sont particulièrement préférés et plus spécifiquement le 2,2-diméthyl- 1 ,3-dioxolane-4-méthanol (solketal);- dioxolane or dioxane derivatives, more specifically derivatives 1, 3-dioxolanes (1, 3-dioxacyclopentanes) or 1, 3-dioxanes (1, 3-dioxacyclohexanes) such as 1, 3 dioxolane, methyl-1 , 3-dioxolane, 4-hydroxymethyl-1, 3-dioxolane, 4-methyl-dioxolane, 1, 3-dioxane, 2-methyl-1, 3-dioxane, 2,2-dimethyl-1, 3-dioxolane-4-methanol (solketal), as well as the derivatives described in patent EP0268460 such as 2-n-pentyl-1, 3-dioxolane, 2-n-heptyl-1, 3-dioxolane, 2 -n-undecyl-1, 3-dioxolane, 2 (2 ', 6'-dimethyl-2'-heptaenyl) -1, 3-dioxane and 2-n-nonyl-1, 3-dioxolane. The derivatives 1, 3 dioxolane, methyl-1, 3-dioxolane, 4-hydroxymethyl-1, 3-dioxolane, 4-methyl-dioxolane, 1, 3-dioxane, 2-methyl-1, 3-dioxane and the 2, 2-dimethyl-1, 3-dioxolane-4-methanol, more hydrophilic in character, are particularly preferred and more specifically 2,2-dimethyl-1,3-dioxolane-4-methanol (solketal);
- les monogiycérides d'acide gras, tels que par exemple le monoglycéride de l'acide caprique/caprylique; - les esters gras de glycérols et de polyéthylène glycol (PEG), à titre d'exemple, on peut citer le monooléate de glycérol et de PEG-6 et le linoléate de glycérol et de PEG-8; - les esters gras de propylene glycol tels que le laurate ou le caprylate/caprate de propylene glycol- fatty acid monoglycerides, such as, for example, capric / caprylic acid monoglyceride; - fatty esters of glycerols and polyethylene glycol (PEG), by way of example, there may be mentioned glycerol and PEG-6 monooleate and glycerol and PEG-8 linoleate; - fatty esters of propylene glycol such as laurate or caprylate / caprate of propylene glycol
- les terpènes tels que t-anéthole, carvacrol, carvone, 1-8 cinéole, d-limonène, 1 -menthol, menthone, terpinène et thymol ou- terpenes such as t-anethole, carvacrol, carvone, 1-8 cineole, d-limonene, 1-menthol, menthone, terpinene and thymol or
- les constituants d'huiles essentielles tels que carvéol, nérolidol et linalool.- the constituents of essential oils such as carveol, nerolidol and linalool.
Au titre de la présente invention les dérivés de dioxolanes ou de dioxanes, tels que cités ci-dessus et plus particulièrement le 2,2-diméthyl-1 ,3-dioxolane-4- methanol (solketal) et le 2-n-nonyl-1 ,3-dioxolane sont particulièrement préférés.Under the present invention, the dioxolane or dioxane derivatives, as mentioned above and more particularly 2,2-dimethyl-1, 3-dioxolane-4-methanol (solketal) and 2-n-nonyl- 1, 3-dioxolane are particularly preferred.
Selon un autre aspect de la présente invention, on peut mettre également en oeuvre une association d'au moins deux des promoteurs d'absorption tels que décrits ci-dessus.According to another aspect of the present invention, it is also possible to use a combination of at least two of the absorption promoters such as described above.
Certains promoteurs d'absorption peuvent, pour être correctement formulés, être au moins partiellement solubilisés par un ou plusieurs solvants organiques, le cas échéant, en mélange avec de l'eau. Ces solvants organiques peuvent également, en association avec les promoteurs d'absorption, faciliter le passage transmucosale du principe actif. Parmi ces solvants pouvant être utilisés pour solubiliser les promoteurs d'absorption, on peut citer l'éthanol, le propanol, l'isopropanol, le diéthylèneglycol monoéthyléther (transcutol®), le glycofurol, le glycérol, le propylèneglycol et les polyéthylèneglycols à l'état liquide.Some absorption promoters can, to be correctly formulated, be at least partially dissolved by one or more organic solvents, if necessary, in mixture with water. These organic solvents can also, in combination with absorption promoters, facilitate the transmucosal passage of the active principle. Among these solvents which can be used to dissolve the absorption promoters, mention may be made of ethanol, propanol, isopropanol, diethylene glycol monoethyl ether (transcutol®), glycofurol, glycerol, propylene glycol and polyethylene glycols. liquid state.
Selon un autre aspect avantageux de l'invention, la composition peut contenir une prostaglandine naturelle ou synthétique. Une prostaglandine est par exemple la PGE1 ou la PGE2. La prostaglandine est ajoutée de préférence en une quantité de 10 μg à 25 mg/ml dans la composition, de préférence 50μg à 10 mg/ml.According to another advantageous aspect of the invention, the composition can contain a natural or synthetic prostaglandin. A prostaglandin is for example PGE1 or PGE2. Prostaglandin is preferably added in an amount of 10 μg to 25 mg / ml in the composition, preferably 50 μg to 10 mg / ml.
D'autre part, afin de faciliter l'absorption de l'alfuzosine au travers de la muqueuse balanique, la composition pharmaceutique se présente sous forme d'une composition pharmaceutique hydrophile. Une telle composition pharmaceutique hydrophile consiste par exemple en une crème hydrophile, un gel, une émuision ou micro-émulsion ou une lotion. Avantageusement, la composition pharmaceutique se trouve sous forme d'un gel.On the other hand, in order to facilitate the absorption of alfuzosin through the balanic mucosa, the pharmaceutical composition is in the form of a hydrophilic pharmaceutical composition. Such a hydrophilic pharmaceutical composition consists, for example, of a hydrophilic cream, a gel, an emulsion or microemulsion or a lotion. Advantageously, the pharmaceutical composition is in the form of a gel.
On entend par gel, une préparation aqueuse semi-solide comprenant notamment des agents gélifiants.The term “gel” is intended to mean a semi-solid aqueous preparation comprising in particular gelling agents.
Les agents gélifiants selon l'invention sont :The gelling agents according to the invention are:
- des dérivés cellulosiques dans des proportions de 1 à 20%, plus particulièrement la carboxyméthylcellulose sodique, l'hydoxyéthylcellulose (HEC) (par exemple le Natrosol®) dans des proportions de 1 à 5%, l'hydroxypropylméthylcellulose (HPMC) (par exemple la Métolose® de grade- cellulose derivatives in proportions of 1 to 20%, more particularly sodium carboxymethylcellulose, hydoxyethylcellulose (HEC) (for example Natrosol®) in proportions of 1 to 5%, hydroxypropylmethylcellulose (HPMC) (for example Metolose® grade
65SH-400 et 65SH-4000, ou Méthocel® E4M, F4M ou 4KM) dans des proportions de 5 à 20% ou l'hydroxypropylcellulose (HPC)(par exemple le Klucel®) dans des proportions de 1 à 10%,65SH-400 and 65SH-4000, or Methocel® E4M, F4M or 4KM) in proportions of 5 to 20% or hydroxypropylcellulose (HPC) (for example Klucel®) in proportions of 1 to 10%,
- des dérivés polyacryliques tels ceux commercialisés sous la marque Carbopol® ou des polyacrilamides tels que Sepigel® 305, en des proportions de 2 à 5%,polyacrylic derivatives such as those sold under the Carbopol® brand or polyacrilamides such as Sepigel® 305, in proportions of 2 to 5%,
- des poloxamères (copolymères séquences de polyoxyéthylène et polyoxypropylène), plus précisément le poloxamer 407 dans des proportions de 15 à 50%, et - des gommes naturelles comme la gomme de xanthane, la gomme de guar, la gomme de caroube dans des proportions de 1 à 10%.poloxamers (block copolymers of polyoxyethylene and polyoxypropylene), more specifically poloxamer 407 in proportions of 15 to 50%, and - natural gums such as xanthan gum, guar gum, locust bean gum in proportions of 1 to 10%.
La préparation peut également comporter des agents épaississants minéraux comme le gel d'hydroxyde d'aluminium ou la silice colloïdale dans des proportions de 1 à 10%.The preparation can also include mineral thickening agents such as aluminum hydroxide gel or colloidal silica in proportions of 1 to 10%.
Une composition pharmaceutique selon l'invention peut comprendre de 1 à 50 mg/ml de principe actif, de préférence 5 à 25 mg/ml.A pharmaceutical composition according to the invention can comprise from 1 to 50 mg / ml of active principle, preferably 5 to 25 mg / ml.
La teneur en promoteur d'absorption dans la composition de l'invention peut varier dans de grandes proportions, notamment en fonction de la concentration en principe actif et de la nature même du promoteur d'absorption mis en œuvre. On peut ainsi utiliser une teneur en promoteur d'absorption comprise entre 0,5 et 50% en poids de la composition. Toutefois, la teneur en promoteur est généralement comprise entre 0,5 à 5% dans le cas des terpènes 2 à 50% dans le cas des autres promoteurs.The content of absorption promoter in the composition of the invention can vary within wide limits, in particular as a function of the concentration of active principle and of the very nature of the absorption promoter used. It is thus possible to use an absorption promoter content of between 0.5 and 50% by weight of the composition. However, the promoter content is generally between 0.5 to 5% in the case of terpenes 2 to 50% in the case of other promoters.
La teneur en solvant peut varier en fonction, notamment, de la nature du promoteur d'absorption et du fait que le solvant peut lui-même faciliter l'absorption du produit actif. En effet, outre son rôle d'agent solubilisant du promoteur d'absorption, le solvant peut également être utile comme agent solubilisant du principe actif et/ou en tant qu'excipient constitutif de ladite composition pharmaceutique. En fonction de ces différents paramètres, l'homme du métier pourra déterminer la teneur en solvant requise.The solvent content can vary depending, in particular, on the nature of the absorption promoter and on the fact that the solvent itself can facilitate the absorption of the active product. In fact, in addition to its role as solubilizing agent for the absorption promoter, the solvent can also be useful as a solubilizing agent for the active principle and / or as an excipient constituting said pharmaceutical composition. Based on these different parameters, the skilled person can determine the solvent content required.
En outre, une composition pharmaceutique selon l'invention peut comprendre des excipients classiques tels des parfums, des huiles essentielles, des conservateurs, des agents hydratants apaisants, ou des colorants.In addition, a pharmaceutical composition according to the invention can comprise conventional excipients such as perfumes, essential oils, preservatives, soothing moisturizers, or colorings.
Ces compositions peuvent être préparées selon des procédés conventionnels pour l'homme du métier. Les procédés font partie intégrante de l'invention.These compositions can be prepared according to conventional methods for a person skilled in the art. The methods are an integral part of the invention.
Par exemple, on peut mélanger le principe actif en solution dans l'eau et/ou dans un solvant nécessaire à la dissolution du promoteur d'absorption, tel que défini ci- dessus, avec ce promoteur d'absorption. Les excipients classiques, tels que définis auparavant, peuvent être ajoutés à cette solution. Dans le cas d'un gel, l'agent gélifiant est ajouté de préférence en dernier. Les compositions pharmaceutiques de l'invention peuvent être appliquées sur le scrotum et le pénis mais plus particulièrement le site d'application concerne la muqueuse balanique soit le gland ou le sillon balano-prépucial, de préférence le gland. Au niveau du site d'application, la composition pharmaceutique est appliquée en une quantité de 0,1 à 1 ml.For example, the active principle can be mixed in solution in water and / or in a solvent necessary for the dissolution of the absorption promoter, as defined above, with this absorption promoter. Conventional excipients, as defined above, can be added to this solution. In the case of a gel, the gelling agent is preferably added last. The pharmaceutical compositions of the invention can be applied to the scrotum and the penis, but more particularly the application site concerns the balanic mucosa, either the glans or the balano-prepucial sulcus, preferably the glans. At the application site, the pharmaceutical composition is applied in an amount of 0.1 to 1 ml.
Afin de simplifier l'application de la dose requise, les compositions pharmaceutiques selon l'invention, peuvent être contenues dans un dispositif pour application topique.In order to simplify the application of the required dose, the pharmaceutical compositions according to the invention can be contained in a device for topical application.
Un tel dispositif comprenant une composition pharmaceutique telle que décrite plus haut, constitue un autre objet de la présente invention. Ce dispositif peut notamment consister en distributeur doseur constitué d'un réservoir muni d'un système apte à libérer la composition pharmaceutique en une dose prédéterminée, tel un système à piston. Cette dose peut alors être étalée sur la peau.Another object of the present invention is such a device comprising a pharmaceutical composition as described above. This device may in particular consist of a metering dispenser consisting of a reservoir provided with a system capable of releasing the pharmaceutical composition in a predetermined dose, such as a piston system. This dose can then be spread over the skin.
L'utilisation d'une composition pharmaceutique selon la présente invention pour la préparation d'un médicament destiné à traité les dysfonctionnements érectiles est un autre objet de l'invention.The use of a pharmaceutical composition according to the present invention for the preparation of a medicament intended for treating erectile dysfunctions is another object of the invention.
Les exemples qui suivent ont pour but d'illustrer la présente invention.The following examples are intended to illustrate the present invention.
EXEMPLE 1 Gel pour application locale (en % en poids): Chlorhydrate d'alfuzosine 4%EXAMPLE 1 Gel for local application (in% by weight): Alfuzosin hydrochloride 4%
Solketal 10%Solketal 10%
Miglyol 15%Miglyol 15%
Poloxamer 407 15%Poloxamer 407 15%
Isopropanol 5% Eau qsIsopropanol 5% Water qs
Préparation : le principe actif est dissout dans l'eau, puis les excipients sont ajoutés, l'agent gélifiant étant introduit en dernier. EXEMPLE 2 Emulsion/gel pour application locale (en % en poids):Preparation: the active principle is dissolved in water, then the excipients are added, the gelling agent being introduced last. EXAMPLE 2 Emulsion / gel for local application (in% by weight):
Chlorhydrate d'alfuzosine 1 ,5%Alfuzosin hydrochloride 1.5%
Propylene glycol 24% Monoglycéride de l'acide caprique/caprylique 24%Propylene glycol 24% Capric / caprylic acid monoglyceride 24%
Carbopol 974 1 %Carbopol 974 1%
Triéthanolamine q.s. pHTriethanolamine q.s. pH
Tween 80 2%Tween 80 2%
Eau q.sWater q.s
La préparation est identique à celle de l'exemple 1.The preparation is identical to that of Example 1.
EXEMPLE 3 Gel pour application locale (en % en poids):EXAMPLE 3 Gel for local application (in% by weight):
Chlorhydrate d'alfuzosine 1 ,5% Propylene glycol 19 %Alfuzosin hydrochloride 1.5% Propylene glycol 19%
Limonène 1 %Limonene 1%
Ethanol 10%Ethanol 10%
Carbopol 974 4,5%Carbopol 974 4.5%
Triéthanolamine q.s. pH Eau q.sTriethanolamine q.s. pH water q.s
La préparation est identique à celle de l'exemple 1.The preparation is identical to that of Example 1.
EXEMPLE 4 Gel pour application locale (en % en poids Chlorhydrate d'alfuzosine 4%EXAMPLE 4 Gel for local application (in% by weight Alfuzosin hydrochloride 4%
2-n-nonyl-1 ,3 dioxolane 10%2-n-nonyl-1, 3 dioxolane 10%
Miglyol 15%Miglyol 15%
Poloxamer 407 15%Poloxamer 407 15%
Isopropanol 5% Eau qs EXEMPLE 5 Gel pour application locale (en % en poids):Isopropanol 5% Water qs EXAMPLE 5 Gel for local application (in% by weight):
Chlorhydrate d'alfuzosine 4%Alfuzosin hydrochloride 4%
Solketal 10%Solketal 10%
Miglyol 15%Miglyol 15%
Poloxamer 407 15%Poloxamer 407 15%
Isopropanol 5%Isopropanol 5%
PGE1 2%PGE1 2%
Eau qsWater qs
La préparation est identique à celle de l'exemple 1. The preparation is identical to that of Example 1.
Le gel peut ensuite être conditionné en tube de polypropylène rigide et opaque, équipé d'une pompe doseuse.The gel can then be packaged in a rigid and opaque polypropylene tube, equipped with a dosing pump.
Mesure du flux transmucosalTransmucosal flow measurement
Cette détermination a été effectuée sur un modèle «ex-vivo» décrit par T.J. Franz (Current Problems in Dermatology, 7, 58-68, 1978) et par B. Neau et coll. (Skin Pharmacol., 7, 121-129, 1994).This determination was carried out on an “ex-vivo” model described by T.J. Franz (Current Problems in Dermatology, 7, 58-68, 1978) and by B. Neau et al. (Skin Pharmacol., 7, 121-129, 1994).
Par exemple l'absorption est suivie en cellules de diffusion de Franz à travers la peau de rat hairiess (normal ou délaminée) et/ou à travers une muqueuse (grand équin ou éventuellement humain). Une dose de 5 à 10 mg/cm2 de la composition pharmaceutique peut être appliquée sur une surface délimitée pouvant aller de 1 à 2 cm2 selon la nature de la pièce anatomique. Le liquide de survie (tampon phosphate) est prélevé totalement et analysé à des temps déterminés. For example, absorption is monitored in Franz diffusion cells through the hairiess rat skin (normal or delaminated) and / or through a mucosa (great equine or possibly human). A dose of 5 to 10 mg / cm 2 of the pharmaceutical composition can be applied to a defined surface which can range from 1 to 2 cm 2 depending on the nature of the anatomical part. The survival liquid (phosphate buffer) is completely removed and analyzed at specified times.
Claims
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU26766/00A AU2676600A (en) | 1999-02-16 | 2000-02-14 | Pharmaceutical composition for balanic transmucosal administration of alfuzosin |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9901803A FR2789586A1 (en) | 1999-02-16 | 1999-02-16 | Compositions containing alfuzosin for treatment of erectile dysfunction, applied by balanic transmucosal administration |
| FR99/01803 | 1999-02-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2000048570A1 true WO2000048570A1 (en) | 2000-08-24 |
Family
ID=9542029
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/FR2000/000358 Ceased WO2000048570A1 (en) | 1999-02-16 | 2000-02-14 | Pharmaceutical composition for balanic transmucosal administration of alfuzosin |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU2676600A (en) |
| FR (1) | FR2789586A1 (en) |
| WO (1) | WO2000048570A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2869232B1 (en) * | 2004-04-21 | 2007-09-21 | Gattefosse Sas Soc Par Actions | NOVEL PHARMACEUTICAL OR COSMETIC EXCIPIENTS BASED ON CYCLIC ACETALS |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4801587A (en) * | 1987-03-02 | 1989-01-31 | Gene Voss | Impotence ointment |
| EP0582502A1 (en) * | 1992-08-05 | 1994-02-09 | Synthelabo | Transdermal composition containing alfuzosin |
| DE4309830C1 (en) * | 1993-03-26 | 1994-05-05 | Lohmann Therapie Syst Lts | Transdermal patches for oestradiol admin. - contg. isopropylidene mono- or di-glycerol as penetration enhancer |
| WO1996028142A1 (en) * | 1995-03-14 | 1996-09-19 | Vivus, Incorporated | Method and kit for preventing erectile dysfunction |
| JPH1045597A (en) * | 1996-07-31 | 1998-02-17 | Toko Yakuhin Kogyo Kk | External preparation for treating hypertension and urinary disturbance |
| US5942545A (en) * | 1998-06-15 | 1999-08-24 | Macrochem Corporation | Composition and method for treating penile erectile dysfunction |
-
1999
- 1999-02-16 FR FR9901803A patent/FR2789586A1/en not_active Withdrawn
-
2000
- 2000-02-14 WO PCT/FR2000/000358 patent/WO2000048570A1/en not_active Ceased
- 2000-02-14 AU AU26766/00A patent/AU2676600A/en not_active Abandoned
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4801587A (en) * | 1987-03-02 | 1989-01-31 | Gene Voss | Impotence ointment |
| EP0582502A1 (en) * | 1992-08-05 | 1994-02-09 | Synthelabo | Transdermal composition containing alfuzosin |
| DE4309830C1 (en) * | 1993-03-26 | 1994-05-05 | Lohmann Therapie Syst Lts | Transdermal patches for oestradiol admin. - contg. isopropylidene mono- or di-glycerol as penetration enhancer |
| WO1996028142A1 (en) * | 1995-03-14 | 1996-09-19 | Vivus, Incorporated | Method and kit for preventing erectile dysfunction |
| JPH1045597A (en) * | 1996-07-31 | 1998-02-17 | Toko Yakuhin Kogyo Kk | External preparation for treating hypertension and urinary disturbance |
| US5942545A (en) * | 1998-06-15 | 1999-08-24 | Macrochem Corporation | Composition and method for treating penile erectile dysfunction |
Non-Patent Citations (1)
| Title |
|---|
| DATABASE WPI Week 9817, Derwent World Patents Index; AN 1998-189172, XP002120649 * |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2789586A1 (en) | 2000-08-18 |
| AU2676600A (en) | 2000-09-04 |
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