US20080139488A1 - Compositions comprising avermectin/azelaic acid compounds useful for treating, e.g., rosacea - Google Patents
Compositions comprising avermectin/azelaic acid compounds useful for treating, e.g., rosacea Download PDFInfo
- Publication number
- US20080139488A1 US20080139488A1 US11/898,911 US89891107A US2008139488A1 US 20080139488 A1 US20080139488 A1 US 20080139488A1 US 89891107 A US89891107 A US 89891107A US 2008139488 A1 US2008139488 A1 US 2008139488A1
- Authority
- US
- United States
- Prior art keywords
- pharmaceutical
- agents
- dermatological composition
- azelaic acid
- avermectin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 63
- 239000005660 Abamectin Substances 0.000 title claims abstract description 27
- 201000004700 rosacea Diseases 0.000 title claims abstract description 25
- 241001303601 Rosacea Species 0.000 title claims abstract description 21
- RRZXIRBKKLTSOM-XPNPUAGNSA-N avermectin B1a Chemical compound C1=C[C@H](C)[C@@H]([C@@H](C)CC)O[C@]11O[C@H](C\C=C(C)\[C@@H](O[C@@H]2O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C2)[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 RRZXIRBKKLTSOM-XPNPUAGNSA-N 0.000 title claims description 16
- 150000001535 azelaic acid derivatives Chemical class 0.000 title 1
- BDJRBEYXGGNYIS-UHFFFAOYSA-N Nonanedioid acid Natural products OC(=O)CCCCCCCC(O)=O BDJRBEYXGGNYIS-UHFFFAOYSA-N 0.000 claims abstract description 44
- -1 avermectin compound Chemical class 0.000 claims abstract description 23
- SPBDXSGPUHCETR-JFUDTMANSA-N 8883yp2r6d Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](OC)C[C@H](O[C@@H]2C(=C/C[C@@H]3C[C@@H](C[C@@]4(O[C@@H]([C@@H](C)CC4)C(C)C)O3)OC(=O)[C@@H]3C=C(C)[C@@H](O)[C@H]4OC\C([C@@]34O)=C/C=C/[C@@H]2C)/C)O[C@H]1C.C1C[C@H](C)[C@@H]([C@@H](C)CC)O[C@@]21O[C@H](C\C=C(C)\[C@@H](O[C@@H]1O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C1)[C@@H](C)\C=C\C=C/1[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\1)O)C[C@H]4C2 SPBDXSGPUHCETR-JFUDTMANSA-N 0.000 claims abstract description 16
- AZSNMRSAGSSBNP-UHFFFAOYSA-N 22,23-dihydroavermectin B1a Natural products C1CC(C)C(C(C)CC)OC21OC(CC=C(C)C(OC1OC(C)C(OC3OC(C)C(O)C(OC)C3)C(OC)C1)C(C)C=CC=C1C3(C(C(=O)O4)C=C(C)C(O)C3OC1)O)CC4C2 AZSNMRSAGSSBNP-UHFFFAOYSA-N 0.000 claims abstract description 15
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- 229960003276 erythromycin Drugs 0.000 description 1
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- KUVMKLCGXIYSNH-UHFFFAOYSA-N isopentadecane Natural products CCCCCCCCCCCCC(C)C KUVMKLCGXIYSNH-UHFFFAOYSA-N 0.000 description 1
- 229960005280 isotretinoin Drugs 0.000 description 1
- 230000000366 juvenile effect Effects 0.000 description 1
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- FJQXCDYVZAHXNS-UHFFFAOYSA-N methadone hydrochloride Chemical compound Cl.C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 FJQXCDYVZAHXNS-UHFFFAOYSA-N 0.000 description 1
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- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
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- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
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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
- A61K31/70—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
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
-
- 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
-
- 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
- A61P17/00—Drugs for dermatological disorders
- A61P17/08—Antiseborrheics
-
- 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
- A61P17/10—Anti-acne agents
Definitions
- the present invention relates to pharmaceutical compositions, and especially dermatological compositions, for treating skin conditions, and especially for treating rosacea (formerly known as acne rosacea).
- this invention relates to pharmaceutical compositions, especially dermatological compositions, comprising, formulated into a physiologically acceptable medium, at least one compound of the avermectin family and azelaic acid.
- the present invention also relates to pharmaceutical compositions, especially dermatological compositions, comprising, formulated into a physiologically acceptable medium, at least ivermectin and azelaic acid.
- the invention also relates to the administration of such compositions as medicaments for treating skin conditions, disorders or afflictions, in particular rosacea.
- Rosacea is a chronic inflammatory dermatitis that mainly affects the median part of the face and the eyelids of certain adults. It is characterized by telangiectatic erythema, dryness of the skin, papules and pustules.
- rosacea develops in adults from the ages of 30 to 50; it more frequently affects women, although the condition is generally more severe in men.
- acne rosacea is not a condition of the pilosebaceous follicles like juvenile acne, but a primitively vascular condition whose inflammatory stage lacks the cysts and comedones characteristic of common acne.
- rosacea The aetiology of rosacea is still poorly understood, although many theories have been advanced. The most common hypothesis is based on the characteristic presence of the parasite Demodex folliculorum in the case of patients suffering from rosacea. This organism is absent in common acne. Other factors have been described as possibly contributing towards the development of rosacea, such as hormonal factors and especially endocrine factors, climatic and immunological factors, and bacterial factors via the presence of Helicobacter pylori , a bacterium associated with gastrointestinal disorders.
- Rosacea develops in four stages over several years, in spasms aggravated by variations in temperature, alcohol, spices, exposure to sunlight and emotions.
- the various stages of the disease are the following:
- Stage 1 stage of erythema episodes.
- the patients have erythrosis spasms due to the sudden dilation of the arterioles of the face, which then take on a congestive, red appearance. These spasms are caused by the emotions, meals and temperature changes.
- Stage 2 stage of couperosis, i.e., of permanent erythema with telangiectasia. Certain patients also have oedema on the cheeks and the forehead.
- Stage 3 inflammatory stage with appearance of inflammatory papules and pustules, but without affecting the sebaceous follicles and thus with absence of cysts and comedones.
- Stage 4 rhinophyma stage. This late phase essentially affects men. The patients exhibit a bumpy, voluminous red nose with sebaceous hyperplasia and fibrous reordering of the connective tissue.
- rosacea is treated orally or topically with antibiotics such as tetracyclines, erythromycin, clindamycin or metronidazole, but also with vitamin A, salicylic acid, anti-fungal agents, steroids, anti-infectious agents such as benzoyl peroxide, with isotretinoin or with azelaic acid.
- antibiotics such as tetracyclines, erythromycin, clindamycin or metronidazole
- vitamin A vitamin A
- salicylic acid anti-fungal agents
- steroids anti-infectious agents
- benzoyl peroxide with isotretinoin or with azelaic acid.
- Azelaic acid (or 1,7-heptanedicarboxylic acid) is known in the prior art for its anti-acne and keratolytic properties.
- Azelaic acid shows anti-bacterial activity on P. acnes and S. epidermidis . It inhibits keratinocyte proliferation, reduces the level of free fatty acid in sebaceous secretions and also has anti-inflammatory activity.
- WO 2004/022 046 describes a method for treating rosacea via topical application of a composition based on azelaic acid and metronidazole.
- U.S. Pat. No. 5,952,372 also describes a method for treating rosacea using ivermectin orally or topically in order to reduce and eliminate the parasite Demodex folliculorum present on the skin of patients.
- Ivermectin belongs to the avermectin family, a group of macrocyclic lactones produced by the bacterium Streptomyces avermitilis (Reynolds JEF (Ed) (1993) Martindale. The Extra Pharmacopoeia. 29th Edition. Pharmaceutical Press, London).
- the avermectins especially include ivermectin, invermectin, avermectin, abamectin, doramectin, eprinomectin and selamectin.
- Ivermectin is known in the prior art for its anti-parasitic and anthelmintic properties.
- the anti-parasitic activity is thought to be due to the opening of a chlorine channel in the membrane of the neurons of the parasite under the effect of an increased release of the neuromediator GABA (gamma-aminobutyric acid), inducing neuromuscular paralysis that may lead to the death of certain parasites.
- Ivermectin also interacts with other chlorine channels, especially those dependent on the neuromediator GABA (gamma-aminobutyric acid).
- U.S. Pat. No. 6,133,310 describes the administration of ivermectin in the treatment of rosacea in order to reduce and eliminate the parasite Demodex folliculorum present on the skin of patients.
- compositions comprising a combination of at least one compound of the avermectin family and azelaic acid, which are useful for treating rosacea.
- compositions especially dermatological compositions, comprising, formulated into a physiologically acceptable medium, at least one compound of the avermectin family and azelaic acid.
- physiologically acceptable medium means any medium that is compatible with the skin, mucous membranes and/or the integuments.
- the azelaic acid according to the invention may be formulated in unmodified form, or, alternatively, in the form of a salt with a pharmaceutically acceptable base, or else in the form of a derivative.
- derivatives means compounds that differ from azelaic acid by substitution, addition or removal of one or more chemical groups and that have substantially the same activity.
- compositions especially dermatological compositions, comprising, formulated into a physiologically acceptable medium, at least one compound of the avermectin family, and at least one compound selected from among azelaic acid and salts and derivatives thereof.
- compositions especially dermatological compositions, comprising, formulated into a physiologically acceptable medium, at least ivermectin and azelaic acid.
- This invention also features the administration of such compositions, whether a regime or regimen, as medicaments for preventing and/or treating a skin condition, disorder or affliction.
- the compounds of the avermectin family that may be formulated according to the present invention especially include invermectin, ivermectin, avermectin, abamectin, doramectin, eprinomectin and selamectin.
- the compound of the avermectin family is preferentially ivermectin.
- the said compound of the avermectin family is present in concentrations of from 0.001% to 10% by weight and preferably from 0.01% to 5% by weight relative to the total weight of the composition.
- the azelaic acid and the salts and/or derivatives thereof are present in concentrations of from 0.01% to 40% by weight and preferably from 1% to 20% by weight relative to the total weight of the composition.
- compositions of the invention comprise, besides at least one compound of the avermectin family and azelaic acid, at least one other therapeutic active agent suitable for increasing the efficacy of the treatment.
- agents include antibiotics, anti-bacterial agents (for instance metronidazole), anti-viral agents, anti-parasitic agents, anti-fungal agents, anaesthetics, analgesics, anti-allergic agents, retinoids, free-radical scavengers, anti-pruritic agents, keratolytic agents, anti-seborrhoeic agents, anti-histamines, sulfides, and immunosuppressant or anti-proliferative products, or a mixture thereof.
- compositions according to the invention may also comprise any adjuvant usually employed in dermatology that is compatible with the said compound of the avermectin family and azelaic acid.
- chelating agents antioxidants, sunscreens, preservatives, fillers, electrolytes, humectants, dyes, common mineral or organic acids or bases, fragrances, essential oils, cosmetic active agents, moisturizers, vitamins, essential fatty acids, sphingolipids, self-tanning compounds, calmatives and skin-protecting agents, pro-penetrating agents and gelling agents, or a mixture thereof.
- additives, and the concentrations thereof should be such that they do not adversely affect the advantageous properties of the mixtures according to the invention.
- These additives may be present in the composition in a proportion of from 0% to 20% by weight and preferably from 1% to 10% by weight relative to the total weight of the composition.
- preservatives examples include benzalkonium chloride, phenoxyethanol, benzyl alcohol, diazolidinylurea and parabens, or mixtures thereof.
- Humectants that are exemplary, in particular, include glycerol and sorbitol.
- chelating agents include ethylenediaminetetraacetic acid (EDTA) and also derivatives or salts thereof, dihydroxyethylglycine, citric acid and tartaric acid, or mixtures thereof.
- EDTA ethylenediaminetetraacetic acid
- Pro-penetrating agents that are exemplary, in particular, include propylene glycol, dipropylene glycol, propylene glycol dipelargonate, lauryl glycol and ethoxydiglycol.
- compositions according to the invention are useful for treating and/or preventing rosacea.
- the administration of the composition is as a medicament for treating and/or preventing a skin condition and preferably for treating and/or preventing rosacea, common acne and/or seborrhoeic dermatitis and particularly preferably for treating rosacea.
- the present invention also features the use of at least one compound of the avermectin family for the formulation of pharmaceutical compositions, especially dermatological compositions, for preventing and/or treating a skin condition, the compound of the avermectin family being combined in the said composition with azelaic acid.
- the composition is as defined above.
- compositions according to the invention are preferably for topical application.
- compositions according to the invention are pharmaceutical compositions, and especially dermatological compositions, which may be in any galenical form conventionally used for topical application and especially in the form of aqueous gels, and aqueous or aqueous-alcoholic solutions.
- a fatty or oily phase same may also be in the form of dispersions of the lotion or serum type, emulsions of liquid or semi-liquid consistency of the milk type obtained by dispersing a fatty phase in an aqueous phase (O/W) or conversely (W/O), or suspensions or emulsions of soft, semi-liquid or solid consistency of the cream, gel or ointment type, or, alternatively, multiple emulsions (W/O/W or O/W/O), microemulsions, microcapsules, microparticles or vesicular dispersions of ionic and/or nonionic type, or wax/aqueous phase dispersions.
- These compositions are prepared according to the usual methods.
- the proportion of the oily phase of the emulsion may range, for example, from 5% to 80% by weight and preferably from 5% to 50% by weight relative to the total weight of the composition.
- the oils, emulsifiers and co-emulsifiers used in the composition in emulsion form are selected from among those conventionally used in dermatology.
- the emulsifier and the co-emulsifier are generally present in the composition in a proportion ranging from 0.3% to 30% by weight and preferably from 0.5% to 20% by weight relative to the total weight of the composition.
- the emulsion may also contain lipid vesicles.
- oils and especially mineral oils liquid petroleum jelly
- oils of plant origin oils of plant origin
- oils of animal origin lanolin
- synthetic oils perhydrosqualene
- silicone oils cyclomethicone
- fluoro oils perfluoropolyethers
- Fatty alcohols such as cetyl alcohol, fatty acids, waxes and gums, in particular silicone gums, may also be used as fatty substances.
- examples thereof include fatty acid esters of polyethylene glycol such as PEG-100 stearate, PEG-50 stearate and PEG-40 stearate; fatty acid esters of polyols such as glyceryl stearate, sorbitan tristearate and the oxyethylenated sorbitan stearates available under the trademark Tween 20 or Tween 60, for example; and mixtures thereof.
- polyethylene glycol such as PEG-100 stearate, PEG-50 stearate and PEG-40 stearate
- fatty acid esters of polyols such as glyceryl stearate, sorbitan tristearate and the oxyethylenated sorbitan stearates available under the trademark Tween 20 or Tween 60, for example
- Tween 20 or Tween 60 for example
- Non-limiting examples of gelling agents include the polyacrylamide family such as the sodium acryloyldimethyltaurate copolymer/isohexadecane/polysorbate 80 mixture marketed under the trademark SimulgelTM 600 by SEPPIC, the polyacrylamide/C13-14 isoparaffin/Laureth-7 mixture, for instance the product marketed under the trademark Sepigel 305TM by SEPPIC, the family of acrylic polymers coupled to hydrophobic chains, such as the PEG-150/decyl/SMDI copolymer marketed under the trademark Aculyn 44TM (polycondensate comprising at least, as components, a polyethylene glycol containing 150 or 180 mol of ethylene oxide, decyl alcohol and methylenebis(4-cyclohexyl isocyanate) (SMDI), at 35% by weight in a mixture of propylene glycol (39%) and water (26%)), and the family of modified starches such as the modified potato starch marketed under the trademark Structure Solan
- the preferred gelling agents are derived from the polyacrylamide family, such as Simulgel 600TM or Sepigel 305TM, or mixtures thereof.
- the gelling agent as described above may be used in a concentration ranging from 0.1% to 15% to preferably from 0.5% to 5%.
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- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- Dermatology (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
Description
- This application claims priority under 35 U.S.C. § 119 of FR 05/02645, filed Mar. 17, 2006, and is a continuation of PCT/FR 2006/000570, filed Mar. 15, 2006 and designating the United States (published in the French language on Sep. 21, 2006 as WO 2006/097628 A1; the title and abstract were also published in English), each hereby expressly incorporated by reference in its entirety and each assigned to the assignee hereof.
- 1. Technical Field of the Invention
- The present invention relates to pharmaceutical compositions, and especially dermatological compositions, for treating skin conditions, and especially for treating rosacea (formerly known as acne rosacea). In particular, this invention relates to pharmaceutical compositions, especially dermatological compositions, comprising, formulated into a physiologically acceptable medium, at least one compound of the avermectin family and azelaic acid.
- The present invention also relates to pharmaceutical compositions, especially dermatological compositions, comprising, formulated into a physiologically acceptable medium, at least ivermectin and azelaic acid. The invention also relates to the administration of such compositions as medicaments for treating skin conditions, disorders or afflictions, in particular rosacea.
- 2. Description of Background and/or Related and/or Prior Art
- Rosacea is a chronic inflammatory dermatitis that mainly affects the median part of the face and the eyelids of certain adults. It is characterized by telangiectatic erythema, dryness of the skin, papules and pustules.
- Conventionally, rosacea develops in adults from the ages of 30 to 50; it more frequently affects women, although the condition is generally more severe in men.
- Despite its former name, acne rosacea is not a condition of the pilosebaceous follicles like juvenile acne, but a primitively vascular condition whose inflammatory stage lacks the cysts and comedones characteristic of common acne.
- The aetiology of rosacea is still poorly understood, although many theories have been advanced. The most common hypothesis is based on the characteristic presence of the parasite Demodex folliculorum in the case of patients suffering from rosacea. This organism is absent in common acne. Other factors have been described as possibly contributing towards the development of rosacea, such as hormonal factors and especially endocrine factors, climatic and immunological factors, and bacterial factors via the presence of Helicobacter pylori, a bacterium associated with gastrointestinal disorders.
- Rosacea develops in four stages over several years, in spasms aggravated by variations in temperature, alcohol, spices, exposure to sunlight and emotions. The various stages of the disease are the following:
- Stage 1: stage of erythema episodes. The patients have erythrosis spasms due to the sudden dilation of the arterioles of the face, which then take on a congestive, red appearance. These spasms are caused by the emotions, meals and temperature changes.
- Stage 2: stage of couperosis, i.e., of permanent erythema with telangiectasia. Certain patients also have oedema on the cheeks and the forehead.
- Stage 3: inflammatory stage with appearance of inflammatory papules and pustules, but without affecting the sebaceous follicles and thus with absence of cysts and comedones.
- Stage 4: rhinophyma stage. This late phase essentially affects men. The patients exhibit a bumpy, voluminous red nose with sebaceous hyperplasia and fibrous reordering of the connective tissue.
- Conventionally, rosacea is treated orally or topically with antibiotics such as tetracyclines, erythromycin, clindamycin or metronidazole, but also with vitamin A, salicylic acid, anti-fungal agents, steroids, anti-infectious agents such as benzoyl peroxide, with isotretinoin or with azelaic acid.
- Azelaic acid (or 1,7-heptanedicarboxylic acid) is known in the prior art for its anti-acne and keratolytic properties. Azelaic acid shows anti-bacterial activity on P. acnes and S. epidermidis. It inhibits keratinocyte proliferation, reduces the level of free fatty acid in sebaceous secretions and also has anti-inflammatory activity.
- WO 2004/022 046 describes a method for treating rosacea via topical application of a composition based on azelaic acid and metronidazole.
- U.S. Pat. No. 5,952,372 also describes a method for treating rosacea using ivermectin orally or topically in order to reduce and eliminate the parasite Demodex folliculorum present on the skin of patients.
- Ivermectin belongs to the avermectin family, a group of macrocyclic lactones produced by the bacterium Streptomyces avermitilis (Reynolds JEF (Ed) (1993) Martindale. The Extra Pharmacopoeia. 29th Edition. Pharmaceutical Press, London). The avermectins especially include ivermectin, invermectin, avermectin, abamectin, doramectin, eprinomectin and selamectin.
- Ivermectin is known in the prior art for its anti-parasitic and anthelmintic properties. The anti-parasitic activity is thought to be due to the opening of a chlorine channel in the membrane of the neurons of the parasite under the effect of an increased release of the neuromediator GABA (gamma-aminobutyric acid), inducing neuromuscular paralysis that may lead to the death of certain parasites. Ivermectin also interacts with other chlorine channels, especially those dependent on the neuromediator GABA (gamma-aminobutyric acid). It is already described in man in the treatment of onchocercosis caused by Onchocerca volvulus, gastrointestinal strongyloidosis (anguillulosis) (product Stromectol®), human scabies (Meinking T. L. et al., N. Engl. J. Med. 1995, Jul. 6; 333 (1): 26-30 The treatment of scabies with ivermectin) and also in the treatment of diagnosed or suspected microfilaraemia in the case of individuals suffering from lymphatic filariasis caused by Wuchereria bancrofti.
- U.S. Pat. No. 6,133,310 describes the administration of ivermectin in the treatment of rosacea in order to reduce and eliminate the parasite Demodex folliculorum present on the skin of patients.
- However, these treatments have drawbacks such as irritation and intolerance phenomena, especially when they are administered for a prolonged period. Furthermore, these treatments are only suppressive and not curative, acting especially on the pustulous spasms occurring during the inflammatory stage.
- Considering the chronic nature of rosacea, the ideal treatment requires prolonged use, in a safe and effective manner. Taking the foregoing into account, there is thus a need for a composition that shows improved efficacy in the treatment of rosacea and that does not exhibit the side effects described in the prior art. There is especially a need to formulate a composition that imparts greater tolerance to the active principles, while at the same time reducing their side effects.
- Accordingly, the present invention features compositions comprising a combination of at least one compound of the avermectin family and azelaic acid, which are useful for treating rosacea.
- This invention thus features pharmaceutical compositions, especially dermatological compositions, comprising, formulated into a physiologically acceptable medium, at least one compound of the avermectin family and azelaic acid.
- The term “physiologically acceptable medium” means any medium that is compatible with the skin, mucous membranes and/or the integuments.
- The azelaic acid according to the invention may be formulated in unmodified form, or, alternatively, in the form of a salt with a pharmaceutically acceptable base, or else in the form of a derivative. The term “derivatives” means compounds that differ from azelaic acid by substitution, addition or removal of one or more chemical groups and that have substantially the same activity.
- The present invention thus features pharmaceutical compositions, especially dermatological compositions, comprising, formulated into a physiologically acceptable medium, at least one compound of the avermectin family, and at least one compound selected from among azelaic acid and salts and derivatives thereof.
- This invention preferentially features pharmaceutical compositions, especially dermatological compositions, comprising, formulated into a physiologically acceptable medium, at least ivermectin and azelaic acid.
- This invention also features the administration of such compositions, whether a regime or regimen, as medicaments for preventing and/or treating a skin condition, disorder or affliction.
- The present invention and the advantages resulting therefrom will be understood more clearly from the description of the non-limiting embodiments that follow.
- The compounds of the avermectin family that may be formulated according to the present invention especially include invermectin, ivermectin, avermectin, abamectin, doramectin, eprinomectin and selamectin. The compound of the avermectin family is preferentially ivermectin.
- In the compositions according to the invention, the said compound of the avermectin family is present in concentrations of from 0.001% to 10% by weight and preferably from 0.01% to 5% by weight relative to the total weight of the composition.
- In the compositions according to the invention, the azelaic acid and the salts and/or derivatives thereof are present in concentrations of from 0.01% to 40% by weight and preferably from 1% to 20% by weight relative to the total weight of the composition.
- Throughout the present text, unless otherwise specified, it is understood that when concentration ranges are given, they include the upper and lower limits of the said range.
- Advantageously, the compositions of the invention comprise, besides at least one compound of the avermectin family and azelaic acid, at least one other therapeutic active agent suitable for increasing the efficacy of the treatment. Non-limiting examples of such agents include antibiotics, anti-bacterial agents (for instance metronidazole), anti-viral agents, anti-parasitic agents, anti-fungal agents, anaesthetics, analgesics, anti-allergic agents, retinoids, free-radical scavengers, anti-pruritic agents, keratolytic agents, anti-seborrhoeic agents, anti-histamines, sulfides, and immunosuppressant or anti-proliferative products, or a mixture thereof.
- The compositions according to the invention may also comprise any adjuvant usually employed in dermatology that is compatible with the said compound of the avermectin family and azelaic acid. Especially representative are chelating agents, antioxidants, sunscreens, preservatives, fillers, electrolytes, humectants, dyes, common mineral or organic acids or bases, fragrances, essential oils, cosmetic active agents, moisturizers, vitamins, essential fatty acids, sphingolipids, self-tanning compounds, calmatives and skin-protecting agents, pro-penetrating agents and gelling agents, or a mixture thereof. These additives, and the concentrations thereof, should be such that they do not adversely affect the advantageous properties of the mixtures according to the invention. These additives may be present in the composition in a proportion of from 0% to 20% by weight and preferably from 1% to 10% by weight relative to the total weight of the composition.
- Examples of preservatives include benzalkonium chloride, phenoxyethanol, benzyl alcohol, diazolidinylurea and parabens, or mixtures thereof.
- Humectants that are exemplary, in particular, include glycerol and sorbitol.
- Examples of chelating agents include ethylenediaminetetraacetic acid (EDTA) and also derivatives or salts thereof, dihydroxyethylglycine, citric acid and tartaric acid, or mixtures thereof.
- Pro-penetrating agents that are exemplary, in particular, include propylene glycol, dipropylene glycol, propylene glycol dipelargonate, lauryl glycol and ethoxydiglycol.
- The compositions according to the invention are useful for treating and/or preventing rosacea.
- According to a first embodiment of the invention, the administration of the composition is as a medicament for treating and/or preventing a skin condition and preferably for treating and/or preventing rosacea, common acne and/or seborrhoeic dermatitis and particularly preferably for treating rosacea.
- The present invention also features the use of at least one compound of the avermectin family for the formulation of pharmaceutical compositions, especially dermatological compositions, for preventing and/or treating a skin condition, the compound of the avermectin family being combined in the said composition with azelaic acid. In this embodiment, the composition is as defined above.
- The compositions according to the invention are preferably for topical application.
- The compositions according to the invention are pharmaceutical compositions, and especially dermatological compositions, which may be in any galenical form conventionally used for topical application and especially in the form of aqueous gels, and aqueous or aqueous-alcoholic solutions. By addition of a fatty or oily phase, same may also be in the form of dispersions of the lotion or serum type, emulsions of liquid or semi-liquid consistency of the milk type obtained by dispersing a fatty phase in an aqueous phase (O/W) or conversely (W/O), or suspensions or emulsions of soft, semi-liquid or solid consistency of the cream, gel or ointment type, or, alternatively, multiple emulsions (W/O/W or O/W/O), microemulsions, microcapsules, microparticles or vesicular dispersions of ionic and/or nonionic type, or wax/aqueous phase dispersions. These compositions are prepared according to the usual methods.
- When the composition is in emulsion form, the proportion of the oily phase of the emulsion may range, for example, from 5% to 80% by weight and preferably from 5% to 50% by weight relative to the total weight of the composition. The oils, emulsifiers and co-emulsifiers used in the composition in emulsion form are selected from among those conventionally used in dermatology. The emulsifier and the co-emulsifier are generally present in the composition in a proportion ranging from 0.3% to 30% by weight and preferably from 0.5% to 20% by weight relative to the total weight of the composition. The emulsion may also contain lipid vesicles.
- As fatty substances according to the invention, it is possible to use oils and especially mineral oils (liquid petroleum jelly), oils of plant origin (avocado oil or soybean oil), oils of animal origin (lanolin), synthetic oils (perhydrosqualene), silicone oils (cyclomethicone) and fluoro oils (perfluoropolyethers). Fatty alcohols such as cetyl alcohol, fatty acids, waxes and gums, in particular silicone gums, may also be used as fatty substances.
- As emulsifiers and co-emulsifiers according to the invention, examples thereof include fatty acid esters of polyethylene glycol such as PEG-100 stearate, PEG-50 stearate and PEG-40 stearate; fatty acid esters of polyols such as glyceryl stearate, sorbitan tristearate and the oxyethylenated sorbitan stearates available under the trademark Tween 20 or Tween 60, for example; and mixtures thereof.
- Non-limiting examples of gelling agents include the polyacrylamide family such as the sodium acryloyldimethyltaurate copolymer/isohexadecane/polysorbate 80 mixture marketed under the trademark Simulgel™ 600 by SEPPIC, the polyacrylamide/C13-14 isoparaffin/Laureth-7 mixture, for instance the product marketed under the trademark Sepigel 305™ by SEPPIC, the family of acrylic polymers coupled to hydrophobic chains, such as the PEG-150/decyl/SMDI copolymer marketed under the trademark Aculyn 44™ (polycondensate comprising at least, as components, a polyethylene glycol containing 150 or 180 mol of ethylene oxide, decyl alcohol and methylenebis(4-cyclohexyl isocyanate) (SMDI), at 35% by weight in a mixture of propylene glycol (39%) and water (26%)), and the family of modified starches such as the modified potato starch marketed under the trademark Structure Solanace™, or mixtures thereof.
- The preferred gelling agents are derived from the polyacrylamide family, such as Simulgel 600™ or Sepigel 305™, or mixtures thereof.
- The gelling agent as described above may be used in a concentration ranging from 0.1% to 15% to preferably from 0.5% to 5%.
- Each patent, patent application, publication, text and literature article/report cited or indicated herein is hereby expressly incorporated by reference.
- While the invention has been described in terms of various specific and preferred embodiments, the skilled artisan will appreciate that various modifications, substitutions, omissions, and changes may be made without departing from the spirit thereof. Accordingly, it is intended that the scope of the present invention be limited solely by the scope of the following claims, including equivalents thereof.
Claims (16)
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12/830,576 US20110165100A1 (en) | 2005-03-17 | 2010-07-06 | Compositions comprising avermectin/azelaic acid compounds useful for treating, e.g., rosacea |
US13/410,234 US8563524B2 (en) | 2005-03-17 | 2012-03-01 | Compositions comprising avermectin/azelaic acid compounds useful for treating e.g., rosacea |
US14/040,402 US9125927B2 (en) | 2005-03-17 | 2013-09-27 | Compositions comprising avermectin/azelaic acid compounds useful for treating, e.g., rosacea |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR0502645 | 2005-03-17 | ||
FR0502645A FR2883181B1 (en) | 2005-03-17 | 2005-03-17 | COMPOSITION BASED ON AVERMECTIN AND AZELAIC ACID, IN PARTICULAR FOR THE TREATMENT OF ROSACEA |
PCT/FR2006/000570 WO2006097628A1 (en) | 2005-03-17 | 2006-03-15 | Composition based on an avermectin and azelaic acid in particular for treating rosacea |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/FR2006/000570 Continuation WO2006097628A1 (en) | 2005-03-17 | 2006-03-15 | Composition based on an avermectin and azelaic acid in particular for treating rosacea |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
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US12/830,576 Continuation US20110165100A1 (en) | 2005-03-17 | 2010-07-06 | Compositions comprising avermectin/azelaic acid compounds useful for treating, e.g., rosacea |
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US20080139488A1 true US20080139488A1 (en) | 2008-06-12 |
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Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
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US11/898,911 Abandoned US20080139488A1 (en) | 2005-03-17 | 2007-09-17 | Compositions comprising avermectin/azelaic acid compounds useful for treating, e.g., rosacea |
US12/830,576 Abandoned US20110165100A1 (en) | 2005-03-17 | 2010-07-06 | Compositions comprising avermectin/azelaic acid compounds useful for treating, e.g., rosacea |
US13/410,234 Active US8563524B2 (en) | 2005-03-17 | 2012-03-01 | Compositions comprising avermectin/azelaic acid compounds useful for treating e.g., rosacea |
US14/040,402 Expired - Fee Related US9125927B2 (en) | 2005-03-17 | 2013-09-27 | Compositions comprising avermectin/azelaic acid compounds useful for treating, e.g., rosacea |
Family Applications After (3)
Application Number | Title | Priority Date | Filing Date |
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US12/830,576 Abandoned US20110165100A1 (en) | 2005-03-17 | 2010-07-06 | Compositions comprising avermectin/azelaic acid compounds useful for treating, e.g., rosacea |
US13/410,234 Active US8563524B2 (en) | 2005-03-17 | 2012-03-01 | Compositions comprising avermectin/azelaic acid compounds useful for treating e.g., rosacea |
US14/040,402 Expired - Fee Related US9125927B2 (en) | 2005-03-17 | 2013-09-27 | Compositions comprising avermectin/azelaic acid compounds useful for treating, e.g., rosacea |
Country Status (7)
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US (4) | US20080139488A1 (en) |
EP (1) | EP1861083B1 (en) |
JP (1) | JP2008533112A (en) |
BR (1) | BRPI0607976A2 (en) |
CA (1) | CA2599663A1 (en) |
FR (1) | FR2883181B1 (en) |
WO (1) | WO2006097628A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8669233B2 (en) | 2009-02-16 | 2014-03-11 | Galderma Research & Development | Combination of compounds for treating or preventing skin diseases |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2886851B1 (en) * | 2005-06-10 | 2007-10-05 | Galderma Sa | COMPOSITION BASED ON AVERMECTIN AND METRONIDAZOLE, IN PARTICULAR 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 |
JP6232250B2 (en) * | 2013-10-18 | 2017-11-15 | ピアス株式会社 | Topical skin preparation |
RU2669942C1 (en) | 2013-11-29 | 2018-10-17 | Галдерма Са | Compound of avermectin family or of milbemycin family for treatment and/or prevention of atopic dermatitis |
WO2016096797A1 (en) * | 2014-12-15 | 2016-06-23 | Galderma Sa | Compound of the avermectin family in combination with an other active compound for treating and/or preventing inflammatory dermatoses |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5952372A (en) * | 1998-09-17 | 1999-09-14 | Mcdaniel; William Robert | Method for treating rosacea using oral or topical ivermectin |
US20060100165A1 (en) * | 2003-04-24 | 2006-05-11 | Galderma S.A. | Topical application of ivermectin for the treatment of dermatological conditions/afflictions |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
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US7060729B2 (en) * | 2002-09-05 | 2006-06-13 | Reza Babapour | Composition and method for treating skin |
FR2854074B1 (en) * | 2003-04-24 | 2007-11-23 | Galderma Res & Dev | USE OF IVERMECTIN FOR THE TREATMENT OF DERMATOLOGICAL DISORDERS |
-
2005
- 2005-03-17 FR FR0502645A patent/FR2883181B1/en not_active Expired - Fee Related
-
2006
- 2006-03-15 JP JP2008501369A patent/JP2008533112A/en not_active Withdrawn
- 2006-03-15 EP EP06726096.8A patent/EP1861083B1/en not_active Not-in-force
- 2006-03-15 CA CA 2599663 patent/CA2599663A1/en not_active Abandoned
- 2006-03-15 WO PCT/FR2006/000570 patent/WO2006097628A1/en not_active Application Discontinuation
- 2006-03-15 BR BRPI0607976-8A patent/BRPI0607976A2/en not_active Application Discontinuation
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2007
- 2007-09-17 US US11/898,911 patent/US20080139488A1/en not_active Abandoned
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2010
- 2010-07-06 US US12/830,576 patent/US20110165100A1/en not_active Abandoned
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2012
- 2012-03-01 US US13/410,234 patent/US8563524B2/en active Active
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2013
- 2013-09-27 US US14/040,402 patent/US9125927B2/en not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5952372A (en) * | 1998-09-17 | 1999-09-14 | Mcdaniel; William Robert | Method for treating rosacea using oral or topical ivermectin |
US20060100165A1 (en) * | 2003-04-24 | 2006-05-11 | Galderma S.A. | Topical application of ivermectin for the treatment of dermatological conditions/afflictions |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8669233B2 (en) | 2009-02-16 | 2014-03-11 | Galderma Research & Development | Combination of compounds for treating or preventing skin diseases |
Also Published As
Publication number | Publication date |
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US8563524B2 (en) | 2013-10-22 |
JP2008533112A (en) | 2008-08-21 |
EP1861083B1 (en) | 2018-01-31 |
US9125927B2 (en) | 2015-09-08 |
BRPI0607976A2 (en) | 2009-10-27 |
EP1861083A1 (en) | 2007-12-05 |
CA2599663A1 (en) | 2006-09-21 |
FR2883181B1 (en) | 2007-05-18 |
US20110165100A1 (en) | 2011-07-07 |
FR2883181A1 (en) | 2006-09-22 |
US20140161747A1 (en) | 2014-06-12 |
US20130064780A1 (en) | 2013-03-14 |
WO2006097628A1 (en) | 2006-09-21 |
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