US20140249096A1 - Combination of compounds for treating or preventing skin diseases - Google Patents
Combination of compounds for treating or preventing skin diseases Download PDFInfo
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- US20140249096A1 US20140249096A1 US14/161,199 US201414161199A US2014249096A1 US 20140249096 A1 US20140249096 A1 US 20140249096A1 US 201414161199 A US201414161199 A US 201414161199A US 2014249096 A1 US2014249096 A1 US 2014249096A1
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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
- A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
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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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- 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
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- 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
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- 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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- 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
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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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
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the invention relates to a combination of compounds for treating skin diseases in humans, particularly rosacea and ocular rosacea.
- Rosacea is a common chronic and progressive inflammatory dermatosis related to vascular relaxation. It mainly affects the central part of the face and is characterized by a reddening of the face or hot flushes, facial erythema, papules, pustules, telangiectasia and sometimes ocular lesions called ocular rosacea. In serious cases, particularly in men, the soft tissue of the nose can swell and produce a bulbous swelling called rhinophyma.
- Rosacea generally occurs between the ages of 25 and 70, and it is much more common in people with a fair complexion. It affects more particularly women, although this disease is generally more severe in men. Rosacea is chronic and persists for years with periods of exacerbation and remission.
- rosacea The pathogenesis of rosacea is poorly understood. Many factors may be involved without necessarily inducing this disease. They are, for example, psychological factors, gastrointestinal disorders, environmental factors (exposure to the sun, temperature, humidity), emotional factors (stress), food-related factors (alcohol, spices), hormonal factors, vascular factors, or even an infection with Helicobacter pilori.
- rosacea is treated orally or topically with antibiotics such as tetracyclines, erythromycin or clindamycin, but also with vitamin A, salicylic acid, antifungal agents, steroids, metronidazole (an antibacterial agent) or with isotretinoin in severe forms or else with anti-infectives such as benzoyl peroxide or else with azelaic acid.
- antibiotics such as tetracyclines, erythromycin or clindamycin
- vitamin A salicylic acid
- antifungal agents such as erythromycin or clindamycin
- steroids metronidazole (an antibacterial agent) or with isotretinoin in severe forms or else with anti-infectives such as benzoyl peroxide or else with azelaic acid.
- metronidazole an antibacterial agent
- isotretinoin in severe forms or else with anti-infectives
- benzoyl peroxide or else with azelaic acid is also known (
- a combination of a compound of the avermectin family or of the milbemycin family with a compound of the alpha-1 or alpha-2 adrenergic receptor agonist family allows a more effective treatment of rosacea, with fewer side effects irrespective of the duration of application of this combination.
- such a combination makes it possible to substantially reduce the duration of treatment and to obtain a greater reduction in the symptoms of rosacea.
- This combination may also make it possible to eliminate the rebound effect normally observed at the end of treatment with alpha-1 or alpha-2 adrenergic receptor agonists.
- a subject of the invention is a combination of a compound of the avermectin family or of the milbemycin family with a compound of the alpha-1 or alpha-2 adrenergic receptor agonist family, for application thereof as a medicament for treating and/or preventing skin diseases and particularly rosacea and ocular rosacea.
- a subject of the invention is also the use of a combination of a compound of the avermectin family or of the milbemycin family with a compound of the alpha-1 or alpha-2 adrenergic receptor agonist family for the production of a medicament intended for treating and/or preventing skin diseases and particularly rosacea and ocular rosacea.
- a subject of the present invention is also a pharmaceutical, in particular dermatological, composition
- a pharmaceutical, in particular dermatological, composition comprising, in a physiologically acceptable medium, at least one compound of the avermectin family or of the milbemycin family and at least one compound of the alpha-1 or alpha-2 adrenergic receptor agonist family, intended for treating and/or preventing skin diseases and particularly rosacea and ocular rosacea.
- FIG. 1 is a graph of the average measurement of ear edema thickness in the evaluation of the anti-inflammatory activity of ivermectin and brimonidine after a single topical application in the arachidonic acid-induced mouse ear edema test.
- FIG. 2 is a graph of the average measurement of ear edema thickness in the evaluation of the anti-inflammatory activity of ivermectin and brimonidine after a single topical application in the TPA-induced mouse ear edema test.
- the term “dermatological composition” is intended to mean a pharmaceutical composition applied to the skin.
- physiologically acceptable medium is intended to mean a medium that is compatible with the skin, the mucous membranes and/or the skin appendages.
- skin diseases is intended to mean cutaneous and ocular disorders.
- the skin infection is more particularly rosacea or ocular rosacea.
- a subject of the invention is also the use of such a composition for the production of a medicament intended for preventing and/or treating skin diseases and particularly rosacea and ocular rosacea.
- a subject of the invention is also a product in the form of a kit compressing:
- first and second compositions can be applied simultaneously, separately or with a time delay
- a subject of the invention is also the use of a product in the form of a kit containing:
- first and second compositions can be applied simultaneously, separately or with a time delay.
- the compound of the avermectin family is advantageously chosen from ivermectin, invermectin, avermectin, abamectin, doramectin, eprinomectin and seiamectin, aversectin B, AB or C, emamectin B1a, emamectin B1b and their derivatives, or latidectin.
- the compound of the avermectin family is preferably ivermectin.
- the compound of the milbemycin family is advantageously chosen from lepimectin, milbemectin, milbemycin oxime, moxidectin, 6′-ethyliepimectin, 6′-methyllepimectin and its derivatives or nemadectin ⁇ , ⁇ , ⁇ or ⁇ .
- the compound of the alpha-1 adrenergic receptor agonist family is advantageously chosen from metaraminol bitartrate, midodrine, methoxamine, mephentermine, phenylephrine, oxymetazoline, tetrahydrozoline, naphazoline or xylometazoline, or their salts.
- the compound of the alpha-1 adrenergic receptor agonist family is in hydrochloride or bitartrate form.
- the compound of the alpha-2 adrenergic receptor agonist family is advantageously chosen from apraclonidine, brimonidine, clonidine, mirtazapine, dexmedetomidine, guanbenz acetate, lidamidine, lofexidine, methyldopa, rilmenidine, talipexole, tiamenidine, tizanidine, tolonidine or their salts.
- the compound of the alpha-2 adrenergic receptor agonist family is in tartrate form.
- the compound of the alpha-2 adrenergic receptor agonist family may be brimonidine or its tartaric salt.
- the combination according to the invention mare particularly contains a compound of the avermectin family and a compound of the alpha-2 adrenergic receptor agonist family.
- the combination according to the invention contains brimonidine and ivermectin.
- a combination of a compound of the avermectin family or of the milbemycin family with a compound of the alpha-1 or alpha-2 adrenergic receptor agonist family means that said combined compounds can be either present in the same composition, or present separately from one another in separate compositions, forming for example a product in the form of a kit.
- these compounds are intended to be administered to a patient in the context of the same treatment, i.e. over a common period of treatment, either at the same time, optionally being included in one and the same composition, or at different moments.
- they can be administered by identical or different administration methods and/or be included in identical or different compositions.
- compositions according to the invention are thus very well tolerated, precise in terms of amount of active compounds delivered, and practical to use. They also offer the patients comfort and hydration,
- a compound of the avermectin family or of the milbemycin family can first be applied to the skin of a patient, and then a compound of the alpha-1 or alpha-2 adrenergic receptor agonist family can be applied, or vice versa.
- the compound of the avermectin family or of the milbemycin family is present at a concentration of between 0.001 and 10% by weight, relative to the total weight of the composition comprising it, preferably between 0.01 and 5% by weight, and in particular 0.75%, 1%, 1.5% or 2%.
- concentration is included in the abovernentioned amounts.
- the compound of the alpha-1 or alpha-2 adrenergic receptor agonist family is present at a concentration of between 0.01 and 20% by weight, relative to the total weight of the composition, preferably between 0.02 and 10%, particularly preferably between 0.05 and 5% by weight, relative to the total weight of the composition.
- a composition comprises several of these compounds, their total concentration is included in the abovementioned amounts.
- the combination comprises a compound of the avermectin family or of the milbemycin family present at a concentration of between 0.01 and 5% by weight, relative to the total weight of the composition comprising K. and a compound of the alpha-1 or alpha-2 adrenergic receptor agonist family present at a concentration of between 0.01 and 5% by weight, relative to the total weight of the composition.
- composition according to the invention contains more particularly a compound of the avermectin family and a compound of the alpha-2 adrenergic receptor agonist family.
- composition according to the invention comprises brimonidine and ivermectin.
- compositions comprising the compounds of this combination are in particular intended for topical application to the skin and/or for ocular application to the eyes.
- compositions of the invention also comprise a pharmaceutically or cosmetically acceptable vehicle, i.e. a vehicle suitable for use in contact with human cells, without toxicity, irritation, undue allergic response and the like, and proportioned at a reasonable advantage/risk ratio.
- a pharmaceutically or cosmetically acceptable vehicle i.e. a vehicle suitable for use in contact with human cells, without toxicity, irritation, undue allergic response and the like, and proportioned at a reasonable advantage/risk ratio.
- compositions of the invention may also comprise at least one other therapeutic agent capable of increasing the efficacy of the treatment.
- compositions of the invention may also comprise any additive normally used in the pharmaceutical or dermatological field, which is compatible with the compound of the avermectin family or of the milbemycin family and/or the compound of the alpha-1 or alpha-2 adrenergic receptor agonist family that is/are present.
- these optional additional compound(s), and/or the amount thereof in such a way that the advantageous properties of the composition according to the invention are not, or not substantially, impaired.
- additives may be present in the composition in a proportion of from 0 to 20% by weight, relative to the total weight of the composition,
- the administration may be carried out topically, enterally or orally, parenterally or ocularly.
- the topical route and the ocular route are particularly preferred.
- compositions of the present invention may be in any of the galenical forms normally used for topical administration, in particular in the form of solutions, lotions, gels, emulsions of liquid or semi-liquid consistency of the milk type, obtained by dispersion of a fatty phase in an aqueous phase (O/W) or vice versa (W/O), or suspensions or emulsions of soft, semi-liquid or solid consistency, of the cream or ointment type, or else microemulsions, microcapsules, microparticles or vesicular dispersions of ionic and/or nonionic type.
- the composition comprises an ointment, a cream, a lotion or a gel.
- compositions according to the invention By way of illustration and without being in any way limiting in nature, various formulations of compositions according to the invention and also the results of a study of the anti-inflammatory activity of the combination of a compound of the avermectin family or of the milbemycin family with a compound of the alpha-1 or alpha-2 adrenergic receptor agonist family will now be given.
- Arachidonic acid is dissolved in a mixture of THF/methanol at 4%.
- Ivermectin is dissolved in the solution of arachidonic acid (AA) and tested at the concentration of 1%.
- the thickness of the ear is measured at T+1 h, T+2 h and T+4 h.
- FIG. 1 represents the average measurement of the thickness of the ear edema, i.e. the average measurement of the thickness of the ear after treatment, from which is subtracted the average measurement of the thickness of the ear obtained with the control (nontreated) group, this being after treatment with 4% arachidonic acid ( ), 1% ivermectin ( ), 0.2% brimonidine ( ), and the combination of ivermectin and brimonidine ( ).
- Indomethacin (positive control) at 5% inhibits the ear edema caused by arachidonic acid by 95% (*“),
- the edema is induced by means of a single application of 20 ⁇ l of TPA (phorbol 12-myristate 13-acetate) dissolved in ethanol at 0.01%.
- TPA phorbol 12-myristate 13-acetate
- test compounds are diluted in the TPA solution.
- ⁇ -methasone valerate (BMV) at 0.01% is also tested; it inhibits the mouse ear edema by 89%.
- Ivermectin is applied at a concentration of 0.1%, 0.3% and 1%.
- Brimonidine added at the concentration of 0.2%,
- the thickness of the mouse ear is measured at T+6 h.
- FIG. 2 represents the average measurement of the ear edema thickness as a function of the dose of test compound as %, i.e. the average measurement of the ear thickness after treatment, from which is subtracted the average measurement of the thickness of the ear obtained with the control (nontreated) group,
- ivermectin at respectively 0.1, 0.3 and 1% ( ),
- the combination of ivermectin (at 0.1, 0.3 and 1%) and brirnonidine (0.2%) has a dose-dependent anti-inflammatory effect, and reduces the TPA-inciuced ear edema by, respectively, 91% (***) (at 0.1%), 94% (“'”) (at 0.3%) and 100% (***) (at 1%).
Abstract
A combination of compounds for treating skin diseases and particularly rosacea and ocular rosacea is described. The combination of a compound of the avermectin family or of the mylbemycin family with a compound of the family of the alpha-1 or alpha-2 adrenergic receptor agonists is also described. In addition, a product in the form of a kit including: (a) a first composition containing a compound of the avermectin family or of the mylbemycin family, and (b) a second composition different from the first one and containing a compound of the family of the alpha-1 or alpha-2 adrenergic receptor agonists, as a combination product to be used as a drug for treating and/or preventing skin diseases and particularly rosacea and ocular rosacea, wherein said first and second compositions can be applied simultaneously, separately or with a time delay, is described.
Description
- The invention relates to a combination of compounds for treating skin diseases in humans, particularly rosacea and ocular rosacea.
- Rosacea is a common chronic and progressive inflammatory dermatosis related to vascular relaxation. It mainly affects the central part of the face and is characterized by a reddening of the face or hot flushes, facial erythema, papules, pustules, telangiectasia and sometimes ocular lesions called ocular rosacea. In serious cases, particularly in men, the soft tissue of the nose can swell and produce a bulbous swelling called rhinophyma.
- Rosacea generally occurs between the ages of 25 and 70, and it is much more common in people with a fair complexion. It affects more particularly women, although this disease is generally more severe in men. Rosacea is chronic and persists for years with periods of exacerbation and remission.
- The pathogenesis of rosacea is poorly understood. Many factors may be involved without necessarily inducing this disease. They are, for example, psychological factors, gastrointestinal disorders, environmental factors (exposure to the sun, temperature, humidity), emotional factors (stress), food-related factors (alcohol, spices), hormonal factors, vascular factors, or even an infection with Helicobacter pilori.
- Conventionally, rosacea is treated orally or topically with antibiotics such as tetracyclines, erythromycin or clindamycin, but also with vitamin A, salicylic acid, antifungal agents, steroids, metronidazole (an antibacterial agent) or with isotretinoin in severe forms or else with anti-infectives such as benzoyl peroxide or else with azelaic acid. The treatment of rosacea with ivermectin, which targets the Demodex folliculorum parasite present on the skin of patients, is also known (U.S. Pat. No. 5,952,372). The treatment of rosacea with alpha-1 or alpha-2 adrenergic receptor agonists is also known (US 2006/0171974A1, US 2005/0165079A1, US 2005/0020600A1).
- These treatments have side effects that are unpleasant for the patient, such as irritation or intolerance phenomena. In addition, none of the existing treatments make it possible to effectively treat and/or prevent all the symptoms associated with rosacea.
- Taking into account the aforementioned, there is therefore a need to produce a more effective treatment for rosacea, which does not have the side effects observed in the prior art There is in particular a need to produce a composition which confers a greater tolerance of the active ingredients, while at the same time reducing their side effects.
- Surprisingly, the applicant has observed that a combination of a compound of the avermectin family or of the milbemycin family with a compound of the alpha-1 or alpha-2 adrenergic receptor agonist family allows a more effective treatment of rosacea, with fewer side effects irrespective of the duration of application of this combination. In particular, such a combination makes it possible to substantially reduce the duration of treatment and to obtain a greater reduction in the symptoms of rosacea. This combination may also make it possible to eliminate the rebound effect normally observed at the end of treatment with alpha-1 or alpha-2 adrenergic receptor agonists.
- A subject of the invention is a combination of a compound of the avermectin family or of the milbemycin family with a compound of the alpha-1 or alpha-2 adrenergic receptor agonist family, for application thereof as a medicament for treating and/or preventing skin diseases and particularly rosacea and ocular rosacea.
- A subject of the invention is also the use of a combination of a compound of the avermectin family or of the milbemycin family with a compound of the alpha-1 or alpha-2 adrenergic receptor agonist family for the production of a medicament intended for treating and/or preventing skin diseases and particularly rosacea and ocular rosacea.
- A subject of the present invention is also a pharmaceutical, in particular dermatological, composition comprising, in a physiologically acceptable medium, at least one compound of the avermectin family or of the milbemycin family and at least one compound of the alpha-1 or alpha-2 adrenergic receptor agonist family, intended for treating and/or preventing skin diseases and particularly rosacea and ocular rosacea.
-
FIG. 1 is a graph of the average measurement of ear edema thickness in the evaluation of the anti-inflammatory activity of ivermectin and brimonidine after a single topical application in the arachidonic acid-induced mouse ear edema test. -
FIG. 2 is a graph of the average measurement of ear edema thickness in the evaluation of the anti-inflammatory activity of ivermectin and brimonidine after a single topical application in the TPA-induced mouse ear edema test. - The term “dermatological composition” is intended to mean a pharmaceutical composition applied to the skin.
- The term “physiologically acceptable medium” is intended to mean a medium that is compatible with the skin, the mucous membranes and/or the skin appendages.
- The term “skin diseases” is intended to mean cutaneous and ocular disorders. By way of nonlimiting example, mention may be made of acne, hyperseborrhea, rosacea, ocular rosacea, psoriasis and atopic dermatitis.
- The skin infection is more particularly rosacea or ocular rosacea.
- A subject of the invention is also the use of such a composition for the production of a medicament intended for preventing and/or treating skin diseases and particularly rosacea and ocular rosacea.
- A subject of the invention is also a product in the form of a kit compressing:
- (a) a first composition comprising a compound of the avermectin family or of the milbemycin family, and
- (b) a second composition different from the first one and comprising a compound of the alpha-1 or alpha-2 adrenergic receptor agonist family,
- as a combination product for application thereof as a medicament for treating and/or preventing skin diseases and particularly rosacea and ocular rosacea, wherein said first and second compositions can be applied simultaneously, separately or with a time delay,
- A subject of the invention is also the use of a product in the form of a kit containing:
- (a) a first composition comprising a compound of the avermectin family or of the milbemycin family, and
- (b) a second composition different from the first one and comprising a compound of the alpha-1 or alpha-2 adrenergic receptor agonist
- as a combination product for the production of a medicament intended for treating and/or preventing skin diseases and particularly rosacea and ocular rosacea, wherein said first and second compositions can be applied simultaneously, separately or with a time delay.
- According to the invention, the compound of the avermectin family is advantageously chosen from ivermectin, invermectin, avermectin, abamectin, doramectin, eprinomectin and seiamectin, aversectin B, AB or C, emamectin B1a, emamectin B1b and their derivatives, or latidectin. The compound of the avermectin family is preferably ivermectin.
- According to the invention, the compound of the milbemycin family is advantageously chosen from lepimectin, milbemectin, milbemycin oxime, moxidectin, 6′-ethyliepimectin, 6′-methyllepimectin and its derivatives or nemadectin α, β, γ or δ.
- According to the invention, the compound of the alpha-1 adrenergic receptor agonist family is advantageously chosen from metaraminol bitartrate, midodrine, methoxamine, mephentermine, phenylephrine, oxymetazoline, tetrahydrozoline, naphazoline or xylometazoline, or their salts.
- More particularly, the compound of the alpha-1 adrenergic receptor agonist family, as defined above, is in hydrochloride or bitartrate form.
- According to the invention, the compound of the alpha-2 adrenergic receptor agonist family is advantageously chosen from apraclonidine, brimonidine, clonidine, mirtazapine, dexmedetomidine, guanbenz acetate, lidamidine, lofexidine, methyldopa, rilmenidine, talipexole, tiamenidine, tizanidine, tolonidine or their salts.
- More particularly, the compound of the alpha-2 adrenergic receptor agonist family, as defined above, is in tartrate form.
- More particularly, the compound of the alpha-2 adrenergic receptor agonist family may be brimonidine or its tartaric salt.
- The combination according to the invention mare particularly contains a compound of the avermectin family and a compound of the alpha-2 adrenergic receptor agonist family.
- Preferentially, the combination according to the invention contains brimonidine and ivermectin.
- In the context of the present invention, a combination of a compound of the avermectin family or of the milbemycin family with a compound of the alpha-1 or alpha-2 adrenergic receptor agonist family means that said combined compounds can be either present in the same composition, or present separately from one another in separate compositions, forming for example a product in the form of a kit. In other words, these compounds are intended to be administered to a patient in the context of the same treatment, i.e. over a common period of treatment, either at the same time, optionally being included in one and the same composition, or at different moments. Furthermore, they can be administered by identical or different administration methods and/or be included in identical or different compositions.
- The combination of the abovementioned compounds present separately in separate compositions, and in particular in the case of a product in the form of a kit, makes it possible to limit the interactions of the compound(s) of the avermectin family, in particular ivermectin, or of the milbemycin family, with the compound(s) of the alpha-1 or alpha-2 adrenergic receptor agonist family. This also makes it possible to limit as much as possible the interactions of the compound(s) of the avermectin family, in particular ivermectin, or of the milbemycin family, with the numerous excipients normally contained in a single composition, and in particular the excipients contained in the composition comprising the compounds of the alpha-1 or alpha-2 adrenergic receptor agonist family. The compositions according to the invention, applied simultaneously or successively, are thus very well tolerated, precise in terms of amount of active compounds delivered, and practical to use. They also offer the patients comfort and hydration,
- In the case of a combination of the abovementioned compounds present separately in separate compositions, and in particular in the case of a product in the form of a kit, a compound of the avermectin family or of the milbemycin family can first be applied to the skin of a patient, and then a compound of the alpha-1 or alpha-2 adrenergic receptor agonist family can be applied, or vice versa.
- In the compositions according to the invention, the compound of the avermectin family or of the milbemycin family is present at a concentration of between 0.001 and 10% by weight, relative to the total weight of the composition comprising it, preferably between 0.01 and 5% by weight, and in particular 0.75%, 1%, 1.5% or 2%. When a composition comprises several of these compounds, their total concentration is included in the abovernentioned amounts.
- In the compositions according to the invention, the compound of the alpha-1 or alpha-2 adrenergic receptor agonist family is present at a concentration of between 0.01 and 20% by weight, relative to the total weight of the composition, preferably between 0.02 and 10%, particularly preferably between 0.05 and 5% by weight, relative to the total weight of the composition. When a composition comprises several of these compounds, their total concentration is included in the abovementioned amounts.
- Particularly preferably, the combination comprises a compound of the avermectin family or of the milbemycin family present at a concentration of between 0.01 and 5% by weight, relative to the total weight of the composition comprising K. and a compound of the alpha-1 or alpha-2 adrenergic receptor agonist family present at a concentration of between 0.01 and 5% by weight, relative to the total weight of the composition.
- Said composition according to the invention contains more particularly a compound of the avermectin family and a compound of the alpha-2 adrenergic receptor agonist family.
- Preferentially, the composition according to the invention comprises brimonidine and ivermectin.
- The combination according to the invention and the compositions comprising the compounds of this combination are in particular intended for topical application to the skin and/or for ocular application to the eyes.
- The compositions of the invention also comprise a pharmaceutically or cosmetically acceptable vehicle, i.e. a vehicle suitable for use in contact with human cells, without toxicity, irritation, undue allergic response and the like, and proportioned at a reasonable advantage/risk ratio.
- The compositions of the invention may also comprise at least one other therapeutic agent capable of increasing the efficacy of the treatment.
- The compositions of the invention may also comprise any additive normally used in the pharmaceutical or dermatological field, which is compatible with the compound of the avermectin family or of the milbemycin family and/or the compound of the alpha-1 or alpha-2 adrenergic receptor agonist family that is/are present.
- Mention may in particular be made of sequestering agents, antioxidants, sunscreens, preservatives, for example DL-alpha-tocopherol, fillers, electrolytes, humectants, colorants, of customary inorganic or organic bases or acids, fragrances, essential oils, cosmetic active agents, moisturizers, vitamins, essential fatty acids, sphingolipids, artificial tanning compounds such as DHA, agents for soothing and protecting the skin, such as allantoin, propenetrating agents, gelling agents, or a mixture thereof. Of course, those skilled in the art will take care to select this or these optional additional compound(s), and/or the amount thereof, in such a way that the advantageous properties of the composition according to the invention are not, or not substantially, impaired.
- These additives may be present in the composition in a proportion of from 0 to 20% by weight, relative to the total weight of the composition,
- The administration may be carried out topically, enterally or orally, parenterally or ocularly.
- Among these routes of administration, the topical route and the ocular route are particularly preferred.
- The compositions of the present invention may be in any of the galenical forms normally used for topical administration, in particular in the form of solutions, lotions, gels, emulsions of liquid or semi-liquid consistency of the milk type, obtained by dispersion of a fatty phase in an aqueous phase (O/W) or vice versa (W/O), or suspensions or emulsions of soft, semi-liquid or solid consistency, of the cream or ointment type, or else microemulsions, microcapsules, microparticles or vesicular dispersions of ionic and/or nonionic type.
- Advantageously, the composition comprises an ointment, a cream, a lotion or a gel.
- By way of illustration and without being in any way limiting in nature, various formulations of compositions according to the invention and also the results of a study of the anti-inflammatory activity of the combination of a compound of the avermectin family or of the milbemycin family with a compound of the alpha-1 or alpha-2 adrenergic receptor agonist family will now be given.
-
-
% by weight relative to the total weight of the Ingredients composition Ivermectin 1.00 Brimonidine tartrate 0.20 EDTA 0.1 Polysorbate 80 8.0 Propylene glycol 20.00 Benzyl alcohol 3 Water qs 100 -
-
% by weight relative to the total weight of the Ingredients composition Emamectin 0.5 Brimonidine tartrate 0.3 Codex petroleum jelly 56.00 Liquid petroleum jelly 43.00 -
-
% by weight relative to the total weight of the Ingredients composition Ivermectin 1.40 Oxymetazoline hydrochloride 0.20 Glycerol 4.0 Steareth-2 1.0 Steareth-21 2.0 Aluminum magnesium 1.0 silicate/titanium dioxide/silica Methyl para-hydroxybenzoate 0.2 Propyl para-hydroxybenzoate 0.1 Disodium EDTA 0.05 Citric acid monohydrate 0.05 Isopropyl palmitate 4.0 Glyceryl/PEG 100 stearate 2.0 Self-emulsifiable wax 1.0 Palmitostearic acid 2.00 Dimethicone 200-350 cS 0.5 Propylene glycol 4.0 Glyceryl triacetate 1.00 Phenoxyethanol 0.5 10% sodium hydroxide qs pH Water qs 100 -
-
% by weight relative to the total Ingredients weight of the composition Ivermectin 0.03 Brimonidine 0.15 Polysorbate 80 2.00 Benzalkonium chloride 0.05 EDTA 0.05 Water qs 100 Buffer system pH 6.3 - Arachidonic acid is dissolved in a mixture of THF/methanol at 4%.
- Treatment:
- Ivermectin is dissolved in the solution of arachidonic acid (AA) and tested at the concentration of 1%.
- 20 μl of the solution are applied to the internal surface of the right ear.
- The thickness of the ear is measured at T+1 h, T+2 h and T+4 h.
- Results:
-
FIG. 1 represents the average measurement of the thickness of the ear edema, i.e. the average measurement of the thickness of the ear after treatment, from which is subtracted the average measurement of the thickness of the ear obtained with the control (nontreated) group, this being after treatment with 4% arachidonic acid (), 1% ivermectin (), 0.2% brimonidine (), and the combination of ivermectin and brimonidine (). - Indomethacin (positive control) at 5% inhibits the ear edema caused by arachidonic acid by 95% (*“),
- Ivermectin alone (1%) reduces the ear edema by 56% (**).
- The combination of ivermectin (1%) with brimonidine (0.2%) inhibits the ear edema caused by arachidonic add by 84% (***), it therefore shows a strong anti-inflammatory effect in the arachidonic acid-induced mouse ear edema model
- Treatment:
- The edema is induced by means of a single application of 20 μl of TPA (phorbol 12-myristate 13-acetate) dissolved in ethanol at 0.01%.
- The test compounds are diluted in the TPA solution.
- A positive control, β-methasone valerate (BMV) at 0.01% is also tested; it inhibits the mouse ear edema by 89%.
- Ivermectin is applied at a concentration of 0.1%, 0.3% and 1%. Brimonidine added at the concentration of 0.2%,
- The thickness of the mouse ear is measured at T+6 h.
- Resuits:
- The results are presented in
FIG. 2 . -
FIG. 2 represents the average measurement of the ear edema thickness as a function of the dose of test compound as %, i.e. the average measurement of the ear thickness after treatment, from which is subtracted the average measurement of the thickness of the ear obtained with the control (nontreated) group, -
-
-
-
- After a single topical application of ivermectin at 0.3% and 1% diluted in the TPA solution, a reduction in the ear edema of respectively 57% (**) and 90% (***) is observed.
- The application of brimonidine alone at 0.2% reduces the mouse ear edema by 50%.
- The combination of ivermectin (at 0.1, 0.3 and 1%) and brirnonidine (0.2%) has a dose-dependent anti-inflammatory effect, and reduces the TPA-inciuced ear edema by, respectively, 91% (***) (at 0.1%), 94% (“'”) (at 0.3%) and 100% (***) (at 1%).
Claims (5)
1-32. (canceled)
33. A method for treating rosacea, the method comprising topically administering to a subject in need of such treatment, a first pharmaceutical composition comprising, in a physiologically acceptable medium, ivermectin in an amount of 0.01% to 5% by weight of the composition, and a second pharmaceutical composition comprising, in a physiologically acceptable medium, brimonidine or a salt thereof in an amount of from 0.01% to 5% by weight of the composition, the first composition being administered first and the second composition being administered thereafter, or the second composition being administered first and the first composition being administered thereafter, or both compositions being administered simultaneously.
34. The method as claimed in claim 33 , wherein the second pharmaceutical composition comprises, in a physiologically acceptable medium, brimonidine or brimonidine tartrate in an amount of from 0.01% to 5% by weight of the composition.
35. The method as claimed in claim 34 , wherein the ivermectin is present in an amount of 0.1%, 0.3% or 1% by weight of the composition.
36. The method as claimed in claim 33 , wherein the first pharmaceutical composition comprises, in a physiologically acceptable medium, ivermectin in an amount of 0.1%, 0.3% or 1% by weight of the composition, and the second pharmaceutical composition comprises, in a physiologically acceptable medium, brimonidine in an amount of 0.2% by weight of the composition.
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US14/161,199 US20140249096A1 (en) | 2009-02-16 | 2014-01-22 | Combination of compounds for treating or preventing skin diseases |
Applications Claiming Priority (5)
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FR0950981A FR2942138A1 (en) | 2009-02-16 | 2009-02-16 | ASSOCIATION OF COMPOUNDS FOR THE TREATMENT OR PREVENTION OF DERMATOLOGICAL DISEASES |
FR0950981 | 2009-02-16 | ||
PCT/FR2010/050259 WO2010092312A1 (en) | 2009-02-16 | 2010-02-16 | Combination of avermectins or mylbemycins with adrenergic receptors for treating or preventing skin diseases |
US201113201762A | 2011-10-10 | 2011-10-10 | |
US14/161,199 US20140249096A1 (en) | 2009-02-16 | 2014-01-22 | Combination of compounds for treating or preventing skin diseases |
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US13/201,762 Continuation US8669233B2 (en) | 2009-02-16 | 2010-02-16 | Combination of compounds for treating or preventing skin diseases |
PCT/FR2010/050259 Continuation WO2010092312A1 (en) | 2009-02-16 | 2010-02-16 | Combination of avermectins or mylbemycins with adrenergic receptors for treating or preventing skin diseases |
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EP (1) | EP2395998B1 (en) |
JP (1) | JP5538434B2 (en) |
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CN (1) | CN102395365B (en) |
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Cited By (1)
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---|---|---|---|---|
WO2017085226A1 (en) * | 2015-11-17 | 2017-05-26 | Galderma Sa | Use of ivermectin and brimonidine in the treatment and/or prevention of moderate to severe rosacea |
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US7812049B2 (en) | 2004-01-22 | 2010-10-12 | Vicept Therapeutics, Inc. | Method and therapeutic/cosmetic topical compositions for the treatment of rosacea and skin erythema using α1-adrenoceptor agonists |
US20120171348A1 (en) * | 2009-06-30 | 2012-07-05 | Segall Kevin I | Production of acid soluble soy protein isolates ("s800") |
US20120082625A1 (en) * | 2010-09-28 | 2012-04-05 | Michael Graeber | Combination treatment for rosacea |
WO2013016072A1 (en) | 2011-07-22 | 2013-01-31 | Allergan, Inc. | Pharmaceutical compositions comprising 4-bromo-n-(imidazolidin-2-ylidene)-1h-benzimidazol-5-amine for treating skin diseases |
UA109359C2 (en) | 2011-11-10 | 2015-08-10 | TREATMENT OF SKIN DISEASES AND STATES | |
US9283217B2 (en) | 2011-11-10 | 2016-03-15 | Allergan, Inc. | Pharmaceutical compositions comprising 7-(1 H-imidazol-4-ylmethyl)-5,6,7,8-tetrahydro-quinoline for treating skin diseases and conditions |
FR3000395A1 (en) * | 2012-12-31 | 2014-07-04 | Galderma Res & Dev | COMBINATION OF LAROPIPRANT AND OXYMETAZOLINE FOR THE TREATMENT OF ROSACEA |
US9233118B2 (en) | 2013-07-08 | 2016-01-12 | Galderma S.A. | Treatment of papulopustular rosacea with ivermectin |
US9782425B2 (en) | 2013-07-08 | 2017-10-10 | Galderma S.A. | Treatment of papulopustular rosacea with ivermectin |
RU2658463C2 (en) | 2013-10-07 | 2018-06-21 | ТЕЙКОКУ ФАРМА ЮЭсЭй, ИНК. | Attention deficit hyperactivity disorder, anxiety and insomnia treatment methods and compositions with application of the dexmedetomidine based transdermal compositions |
TWI645866B (en) | 2013-10-07 | 2019-01-01 | 美商帝國製藥美國股份有限公司 | Dexmedetomidine transdermal delivery device and method of using same |
CA2924236C (en) | 2013-10-07 | 2020-01-07 | Teikoku Pharma Usa, Inc. | Methods and compositions for transdermal delivery of a non-sedative amount of dexmedetomidine |
EP3074021B1 (en) * | 2013-11-29 | 2021-05-12 | Galderma SA | Compound of the avermectin family or of the milbemycin family for the treatment and/or prevention of atopic dermatitis |
WO2016096795A1 (en) * | 2014-12-15 | 2016-06-23 | Galderma Sa | Compound of the avermectin family for treating and/or preventing inflammatory dermatoses |
CN109789118B (en) * | 2016-08-04 | 2022-09-02 | 盖尔德玛控股有限公司 | Composition for treating or preventing rosacea and application thereof |
RU2645932C1 (en) * | 2017-02-15 | 2018-02-28 | Ольга Юрьевна Олисова | Method of complex extrinsic for patients with erithematous papular rosacea |
KR102039608B1 (en) * | 2017-11-03 | 2019-11-01 | 주식회사 셀버틱스 | Composition including midodrine and its uses |
BR112021006821A2 (en) * | 2018-10-12 | 2021-07-13 | Hovione Scientia Limited | method of treating inflammation and ophthalmic pathologies, solid dispersion, pharmaceutical formulation, method of killing mites and kit |
US20220160668A1 (en) | 2020-11-23 | 2022-05-26 | Sight Sciences, Inc. | Formulations and methods for treating conditions of the eye |
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US7439241B2 (en) * | 2003-05-27 | 2008-10-21 | Galderma Laboratories, Inc. | Compounds, formulations, and methods for treating or preventing rosacea |
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US5952372A (en) | 1998-09-17 | 1999-09-14 | Mcdaniel; William Robert | Method for treating rosacea using oral or topical ivermectin |
US20050020600A1 (en) * | 2003-07-23 | 2005-01-27 | Scherer Warren J. | Methods of treating cutaneous flushing using selective alpha-2-adrenergic receptor agonists |
US7812049B2 (en) * | 2004-01-22 | 2010-10-12 | Vicept Therapeutics, Inc. | Method and therapeutic/cosmetic topical compositions for the treatment of rosacea and skin erythema using α1-adrenoceptor agonists |
FR2883181B1 (en) * | 2005-03-17 | 2007-05-18 | Galderma Sa | COMPOSITION BASED ON AVERMECTIN AND AZELAIC ACID, IN PARTICULAR FOR THE TREATMENT OF ROSACEA |
FR2886851B1 (en) * | 2005-06-10 | 2007-10-05 | Galderma Sa | COMPOSITION BASED ON AVERMECTIN AND METRONIDAZOLE, IN PARTICULAR FOR THE TREATMENT OF ROSACEA |
FR2886852B1 (en) | 2005-06-10 | 2007-11-23 | Galderma Sa | COMPOSITION BASED ON AVERMECTIN AND HYDROCORTISONE, IN PARTICULAR FOR THE TREATMENT OF ROSACEA |
FR2886850B1 (en) | 2005-06-10 | 2007-10-05 | Galderma Sa | COMPOSITION BASED ON AVERMECTIN AND BENZOYL PEROXIDE, IN PARTICULAR FOR THE TREATMENT OF ROSACEA |
WO2007054822A2 (en) * | 2005-09-30 | 2007-05-18 | Galderma S.A. | Use of at least one avermectin or milbemycin in the treatment of ophthalmic pathologies |
FR2891460B1 (en) * | 2005-09-30 | 2010-07-30 | Galderma Sa | USE OF AT LEAST ONE COMPOUND OF THE AVERMECTIN FAMILY FOR THE TREATMENT OF OPHTHALMIC DISEASES DUE TO DEMODEX FOLLICULORUM. |
KR20080065704A (en) * | 2005-11-09 | 2008-07-14 | 콤비네이토릭스, 인코포레이티드 | Methods, compositions, and kits for the treatment of medical conditions |
FR2901703B1 (en) * | 2006-05-31 | 2012-12-07 | Galderma Res & Dev | USE OF ZATOSETRON FOR THE TREATMENT OF ROSACEA, AND PHARMACEUTICAL COMPOSITIONS |
FR2906466B1 (en) * | 2006-09-28 | 2008-11-28 | Galderma Sa | USE OF COMPOUNDS FROM THE MILBEMYCIN FAMILY FOR THE TREATMENT OF DERMATOLOGICAL DISORDERS IN MAN |
FR2906470B1 (en) * | 2006-09-28 | 2012-09-21 | Galderma Sa | USE OF 6'-ETHYL-LEPIMECTIN, 6'-METHYL-LEPIMECTIN OR DERIVATIVES THEREOF FOR THE TREATMENT OF DERMATOLOGICAL DISORDERS IN MAN |
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2009
- 2009-02-16 FR FR0950981A patent/FR2942138A1/en not_active Withdrawn
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2010
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- 2010-02-16 KR KR1020117021522A patent/KR101365011B1/en not_active IP Right Cessation
- 2010-02-16 EP EP10709876.6A patent/EP2395998B1/en active Active
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- 2010-02-16 JP JP2011549648A patent/JP5538434B2/en not_active Expired - Fee Related
- 2010-02-16 MX MX2011008391A patent/MX2011008391A/en active IP Right Grant
- 2010-02-16 AU AU2010212634A patent/AU2010212634B2/en not_active Ceased
- 2010-02-16 ES ES10709876.6T patent/ES2545395T3/en active Active
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2014
- 2014-01-22 US US14/161,199 patent/US20140249096A1/en not_active Abandoned
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US7439241B2 (en) * | 2003-05-27 | 2008-10-21 | Galderma Laboratories, Inc. | Compounds, formulations, and methods for treating or preventing rosacea |
Cited By (2)
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WO2017085226A1 (en) * | 2015-11-17 | 2017-05-26 | Galderma Sa | Use of ivermectin and brimonidine in the treatment and/or prevention of moderate to severe rosacea |
US11213539B2 (en) | 2015-11-17 | 2022-01-04 | Galderma Holding SA | Use of ivermectin and brimonidine in the treatment and/or prevention of moderate to severe rosacea |
Also Published As
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JP5538434B2 (en) | 2014-07-02 |
FR2942138A1 (en) | 2010-08-20 |
KR20110116059A (en) | 2011-10-24 |
ES2545395T3 (en) | 2015-09-10 |
JP2012517989A (en) | 2012-08-09 |
CN102395365B (en) | 2014-06-25 |
EP2395998A1 (en) | 2011-12-21 |
RU2531087C2 (en) | 2014-10-20 |
CA2751543C (en) | 2015-06-16 |
EP2395998B1 (en) | 2015-07-08 |
HK1166604A1 (en) | 2012-11-02 |
AU2010212634A1 (en) | 2011-09-08 |
MX2011008391A (en) | 2011-09-01 |
BRPI1005931A2 (en) | 2017-05-30 |
BRPI1005931A8 (en) | 2017-12-26 |
KR101365011B1 (en) | 2014-02-19 |
AU2010212634B2 (en) | 2015-09-10 |
US8669233B2 (en) | 2014-03-11 |
US20120035123A1 (en) | 2012-02-09 |
RU2011138021A (en) | 2013-03-27 |
WO2010092312A1 (en) | 2010-08-19 |
CA2751543A1 (en) | 2010-08-19 |
CN102395365A (en) | 2012-03-28 |
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