MX2013004472A - Topical gel composition. - Google Patents
Topical gel composition.Info
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- MX2013004472A MX2013004472A MX2013004472A MX2013004472A MX2013004472A MX 2013004472 A MX2013004472 A MX 2013004472A MX 2013004472 A MX2013004472 A MX 2013004472A MX 2013004472 A MX2013004472 A MX 2013004472A MX 2013004472 A MX2013004472 A MX 2013004472A
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- gel composition
- topical gel
- skin
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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
- 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
-
- 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
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- 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
- A61P17/06—Antipsoriatics
Abstract
Improved topical gel compositions, such as those containing brimonidine for the treatment of skin disorders are described. The gel compositions contain carbomer and paraben, and are substantially free of paraben crystalline particles after an extended period of storage.
Description
TOPICAL GEL COMPOSITION
CROSS REFERENCE WITH RELATED REQUESTS
This request has the right of priority according to 35 U.S.C. § 1 19 (e) of the provisional patent application of EE. UU No. 61 / 405,382, filed on October 21, 2010, which is hereby incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION
Parabens are esters of para-hydroxybenzoic acid. They are used mainly for their bactericidal and fungicidal properties. Examples of parabens include methyl paraben, ethyl paraben, propyl paraben, butyl paraben, isobutyl paraben, isopropyl paraben, benzyl paraben and their salts. Due to its low costs, long history of safe use and the ineffectiveness of natural alternatives, parabens are widely used as preservatives in the cosmetic and pharmaceutical industries. See Darbre et al., 24 J. Appl. Toxicol 5-13 (2004), and references therein.
Carbomer is a generic name for Carbopol®, a registered trademark of Lubrizol. The terms carbomer and Carbopol® are used reciprocally in the present application, referring to a synthetic polymer of acrylic acid entangled with polyalkenyl ethers or
divinyl glycol. It can be a homopolymer of acrylic acid, entangled with an allyl ether of pentaerythritol, allyl ether of sucrose or allyl ether of propylene. Carbomers have been used as vehicles for drug delivery. They have a long history of safe and effective use in topical gels, creams, lotions and ointments, as supported by extensive toxicology studies. They have been shown to have extremely low irritation properties and do not produce sensitivity with repeated use. The carbomers or copolymers of carbomers have been used in topical formulations, for example, for thickening, emulsification or suspension.
Brimonidine is a selective alpha-2-adrenergic agonist. It has been used as monotherapy or as an adjunctive therapy to decrease intraocular pressure (IOP) in the treatment of glaucoma and ocular hypertension (OHT) since its approval in 1996. It has also been found that brimonidine is useful in the treatment of various disorders of the skin, such as rosacea, the erythema caused by rosacea; see, for example, references: U.S. Serial No. 10 / 853,585 to DeJovin et al .; U.S. Serial No. 10 / 626,037 to Scherer; U.S. Serial No. 12 / 193,098 to Theobald et al .; and telangiectasias; see, for example, the US patent application. UU Publication No. 2006/0264515. Topical gel compositions comprising brimonidine, carbomer and paraben (s) have been described for the treatment of skin disorders; see, for example, U.S. Serial No. 10 / 853,585 of DeJovin et al .; and U.S. Serial No. 12 / 193,098 of Theobald et al., Etc.
In the present invention, they have unexpectedly been observed
crystalline particles of methylparaben in some topical formulations of brimonidine gel and placebo formulations containing carbomer and methylparaben.
There is a need for a topical gel composition containing carbomer and methyl paraben which is substantially free of crystalline particles of paraben and satisfies the antimicrobial requirement during an extended storage period. Said compositions and related methods and products are described in the present application.
BRIEF DESCRIPTION OF THE INVENTION
In a general aspect, the embodiments of the present invention relate to a topical gel composition, comprising:
0. 05 to 0.20% (w / w) of paraben;
one or more conservative seconds;
0. 80 to 1.50% (w / w) carbomer;
8 to 15% (w / w) of one or more organic constituents;
wherein the topical gel composition has a pH of 4.5 to 7.5, and where when the concentration of paraben is greater than 0.15% (in w / w), the carbomer concentration is less than 1.25% (in w / w) .
In another general aspect, the embodiments of the present invention relate to a topical gel composition, comprising:
0. 05 to 5% (w / w) of brimonidine;
0. 05 to 0.20% (w / w) of paraben;
0. 3% (in p / p) or more than one or more conservative seconds; 0.80 to 1.50% (in w / w) of carbomer;
8 to 15% (w / w) of one or more organic constituents, where the topical gel composition has a pH of 4.5 to 7.5, and where when the concentration of paraben is greater than 0.15% (in w / w) ), the carbomer concentration is less than 1.25% (in w / w).
Another general aspect of the present invention relates to a topical gel composition, comprising:
0. 1 to 0.6% (w / w) of brimonidine tartrate;
0. 05 to 0. 5% (w / w) of methylparaben;
one or more conservative seconds selected from the group consisting of sodium benzoate, phenoxyethanol, benzyl alcohol, imidazolidinyl urea and diazolidinyl urea;
0. 80 to 1.50% (w / w) carbomer;
4. 5 to 6.5% (w / w) of propylene glycol
Y
purified water,
wherein the pH of the topical gel composition is adjusted to a pH of 5.0 to 6.5 by a suitable amount of aqueous sodium hydroxide solution.
In another general aspect, the embodiments of the present invention relate to a method of treating or preventing a disorder
of the skin on a subject. The method comprises topically administering to a subject skin area a topical gel composition in accordance with an embodiment of the present invention, wherein the skin area is affected, or is prone to be affected, by the disorder of the skin.
Other aspects, features and advantages of the invention will be apparent from the following description, including the detailed description of the invention and its preferred embodiments and the appended claims.
DETAILED DESCRIPTION OF THE INVENTION
Several publications, articles and patents are cited or described in the background and throughout the specification; each of these references is incorporated herein by reference in its entirety. The discussion of documents, records, materials, devices, articles or the like that have been included in the present specification, is for the purpose of providing context for the present invention. Said discussion is not an admission that any or all of these matters form part of the prior art with respect to any invention described or claimed.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention pertains. Otherwise, certain terms used in the present have the
meanings as stated in the specification. All patents, published patent applications and publications cited herein, are incorporated by reference as if fully set forth herein. It should be noted that as used herein and in the appended claims, the singular forms "a", "an" and "the" include plural references, unless the context clearly dictates otherwise.
As used herein, the term "erythema or a symptom associated therewith" is intended to encompass any type or classification of skin redness caused by hyperemia or congestion of the capillaries in the lower layers of the skin, and any symptom associated with it. The term "erythema or a symptom associated with it" encompasses redness or rash of the skin that results from any cause. For example, it can be caused by skin lesion, surgery and other procedures on the skin, infection, inflammation, emotion, exercise, heat (erythema calorie), cold, photosensitivity, radiotherapy, allergy, hot flashes, medications, etc. Examples of the term "erythema or a symptom associated therewith" include, without limitation, photosensitivity, erythema multiforme, and erythema nodosum, and their associated symptoms. Photosensitivity is caused by a reaction to sunlight, which often occurs when some factors, such as infection or medication, increase sensitivity to ultraviolet radiation. However, photosensitivity can also occur without any increased sensitivity to ultraviolet radiation. Erythema multiforme
characterized by spots or other injuries produced on the skin, which are usually caused by a reaction to medications, infections or disease. Most erythema multiforme is associated with herpes simplex infections or mycoplasmas. Erythema nodosum is a form of erythema that is accompanied by delicate swellings, usually on the legs below the knees, and may be caused by certain medications or diseases.
In a particular embodiment of the present invention, the term "erythema or a symptom associated therewith" includes erythema of rosacea, i.e., erythema or a symptom associated therewith in a patient with rosacea. Rosacea is an inflammatory disorder of the skin that usually affects the cheeks, nose, chin and forehead of a patient. The main symptom of rosacea is erythema, that is, the abnormal redness of the skin.
The term "erythema or a symptom associated with it" encompasses different degrees or levels of erythema or a symptom associated with it, from mild to severe.
In view of the present disclosure, an area of skin that is affected by erythema or that is prone to be affected by erythema may be identified using any diagnostic means or means known in the art, and may be treated by the methods of in accordance with the embodiments of the present invention.
As used herein, the term "telangiectasia or a symptom associated therewith" refers to an abnormal dilation
permanent visible of blood vessels, such as arterioles and venules. A visible blood vessel is a visually discernible blood vessel as a line for an observer without the aid of a magnifying device (unlike the glasses normally worn by the observer). In various aspects, a telangiectatic blood vessel may have a diameter of at least about 0.5 mm. Telangiectasias can be associated with numerous conditions, syndromes, diseases and disorders. For example, a facial telangiectasia may be associated with age, sun exposure and alcohol use. Other diseases, disorders, conditions and syndromes associated with telangiectasias include, in a non-limiting example, scleroderma, hereditary hemorrhagic telangiectasia (Olser-Rendu syndrome), ataxia-telangiectasia, arachnoid angioma, marble skin, congenital telangiectasia, Bloom's syndrome, Klippel-Trenaunay-Weber syndrome, Sturge-Weber disease, xeroderma pigmentosum, nevus in flame, essential generalized telangiectasias (GET), serpiginous angioma, arachnoid nevus, CREST syndrome, basal cell carcinoma and unilateral nevoid telangiectasia.
In a particular embodiment of the present invention, the term "telangiectasia or a symptom associated therewith" includes telangiectasia associated with rosacea, i.e., telangiectasia or a symptom associated therewith in a patient with rosacea.
In another particular embodiment of the present invention, the term "telangiectasia or a symptom associated therewith" includes telangiectasia of
damage by light / induced by the sun.
The term "telangiectasia or a symptom associated with it"
covers different degrees or levels of telangiectasia or symptoms associated with
the same, from mild to severe.
In view of the present description, an area of the skin that is
affected by telangiectasia or that is prone to be affected by telangiectasia, can be identified using any sign or means of diagnosis known in the art, and can be treated by the methods of
in accordance with the embodiments of the present invention.
As used herein, the term "brimonidine" refers to the compound (5-bromo-quinoxalin-6-yl) - (4,5-dihydro-1 H-imidazol-2-yl) -amine
which has the structure of formula (I):
Formula (I)
and any salt of the pharmaceutically acceptable compound, such as brimonidine tartrate.
The phrase "pharmaceutically acceptable salts", as used herein, means those salts of a compound of interest that are safe and effective for topical use in mammals and that possess the desired biological activity. Pharmaceutically acceptable salts include salts of
acidic or basic groups present in the specified compounds. Pharmaceutically acceptable acid addition salts include, but are not limited to, the salts of hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1, 1 '-methylene-bs- (2 -hydroxy-3-naphthoate)). Certain compounds used in the present invention can form pharmaceutically acceptable salts with various amino acids. Suitable basic salts include, but are not limited to, the aluminum, calcium, lithium, magnesium, potassium, sodium, zinc and diethanolamine salts. For a review on pharmaceutically acceptable salts, see BERGE ET AL., 66 J. PHARM. SCI. 1-19 (1977), citation incorporated herein by reference.
As used herein, the term "hydrate" means a compound of interest, or a pharmaceutically acceptable salt thereof, that further includes a stoichiometric or non-stoichiometric amount of water bound thereto by non-covalent intermolecular forces.
The term "topical gel composition" or "topical gel formulation", as used herein, means any formulation or gel composition that is pharmaceutically and / or cosmetically acceptable for the topical delivery of the specified compounds in accordance with embodiments of the invention.
As used herein, the term "composition" is intended to encompass a product comprising the specified ingredient in the specified amount, as well as any product that results, directly or indirectly, from combinations of the specified ingredient in the specified amount.
As used herein, the term "subject" means any animal, preferably a mammal, more preferably a human, to whom the topical compounds or formulations will be administered or administered in accordance with the embodiments of the invention. The term "mammal", as used herein, encompasses any mammal. Examples of mammals include, without limitation, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., most preferably a human. Preferably, a subject is in need of, or has been the subject of observation or experiment of, treating or preventing a skin disorder, such as rosacea, erythema of rosacea, telangiectasia, psoriasis, purpura, acne erythema , eczema, inflammation of the skin not related to rosacea, embarrassment, sinking, folding and / or wrinkling of the skin, or a symptom associated with them.
In one embodiment, the term "treatment" or "treating" refers to an improvement, prophylaxis or reversal of a disease or disorder, or of at least one distinguishable symptom thereof. In another modality, the term "treatment" or "treat" refers to an improvement, prophylaxis or investment of
less a measurable physical parameter related to the disease or disorder being treated, not necessarily discernible in or by the mammal. In another embodiment, the term "treatment" or "treating" refers to inhibiting or slowing the progression of a disease or disorder, either physically, for example, by stabilizing a discernible symptom, physiologically, for example, by stabilizing a physical parameter, or both. In another embodiment, the term "treatment" or "treating" refers to delaying the onset of a disease or disorder.
In certain modalities, compounds of interest are administered as a preventive measure. As used herein, the term "prevention" or "prevent" refers to a reduction in the risk of acquiring a given disease or disorder. In a preferred mode of the embodiment, the specified compounds are administered as a preventive measure to a subject having a predisposition to a disease or disorder, even when the symptoms of the disease or disorder are absent, or are minimal.
In one embodiment of the present invention, crystalline particles of methyl paraben have been observed in topical formulations of bromonidine gel containing 0.2% (w / w) or more methylparaben, in particular in lot size from 300 g to 250 kg. See example 1 below. This observation is surprising in view of the solubility of methylparaben. In accordance with a Material Safety Data Sheet (MSDS) for methylparaben, the solubility of methylparaben in water is
approximately 0.25% (in w / w) at 20 ° C or approximately 0.30% (in w / w) at 25 ° C. The solubility of methylparaben in propylene glycol is 1 in 5 at 25 ° C, and the solubility of methylparaben in hot glycerol is about 1.4%; see, MSDS, Chemicals & Laboratory Equipment, Science Lab.com, World Wide Web: sciencelab.com/msds. php? msdsld = 9926083. In addition, in accordance with the citation Handbook of Pharmaceutical Excipient (cited above), the solubility of methylparaben in propylene glycol is 1 in 5 at 25 ° C.
In view of the solubility of the paraben in organic constituents and water, it would have been reasonably expected that 0.30% (w / w) or less of methylparaben would remain completely soluble in a topical gel composition comprising about 4.5 to 6.5% (on p / p) of an organic constituent in which the paraben is substantially soluble, such as about 4.5 to 6.5% (w / w) of propylene glycol, and about 90% (w / w) or less of water. The detection of crystalline particles of methyl paraben in the composition is completely unexpected. While not wishing to be bound by theory, the crystalline particles of methyl paraben observed in the placebo compositions and topical brimonidine gel compositions may have been caused by one or more reasons, such as recrystallization of methyl paraben during the manufacturing process, or the recrystallization of methylparaben during storage resulting from the excipient-excipient interaction. Without the surprising observation made in the present invention, there would be
reasonably expected the existence of methylparaben crystals in the topical gel compositions, still less to develop a topical gel formulation improved free of the crystals.
The embodiments of the present invention relate to an improved gel topical composition that is substantially free of crystalline particles and has microbiological quality during an extended storage period. The improved gel topical composition according to one embodiment of the present invention comprises:
0. 05 to 0.20% (w / w) of paraben;
one or more conservative seconds;
0. 80 to 1.50% (w / w) carbomer;
8 to 15% (w / w) of one or more organic constituents, where the topical gel composition has a pH of 4.5 to 7.5, and where when the concentration of paraben is greater than 0.15% (in w / w) ), the carbomer concentration is less than 1.25% (in w / w).
In a particular embodiment, the topical gel composition comprises 0.05 to 0.20% (w / w) of methyl paraben.
In accordance with the embodiments of the present invention, the amount of paraben in the composition is approximately 0.05%, 0.075%, 0.10%, 0.125%, 0.15% or 0.20% (in w / w).
Suitable conservative seconds that can be used in the embodiments of the present invention, include any preservative that is suitable for topical application. Examples of the seconds
preservatives include, without limitation, sodium benzoate, phenoxyethanol, benzyl alcohol, imidazolidinyl urea or diazolidinyl urea. Other examples of the second preservatives may include quaternary ammonium compounds, such as benzalkonium chloride, benzethonium chloride, cetrimide, decquinium chloride, and cetylpyridinium chloride; alcoholic agents, such as chlorobutanol; antibacterial asters, such as esters of parahydroxybenzoic acid; and other antimicrobial agents, such as chlorhexidine, chlorocresol, benzoic acid, polymyxin, mupirocin, erythromycin, clindamycin, gentamicin, polymyxin, bacitracin, silver sulfadiazine, etc.
Preferably, the second conservator is effective in inactivating the challenge doses of Gram-negative and Gram-positive microorganisms, such as yeasts.
In accordance with the embodiments of the present invention, the amount of conservative seconds in the composition is greater than 0.3%, 0.35%, 0.4%, 0.45% or 0.5% (in w / w).
In accordance with the embodiments of the present invention, the carbomer is a synthetic polymer of acrylic acid crosslinked with polyalkenyl or divinyl glycol ethers. It can be a homopolymer of acrylic acid, entangled with an allyl ether of pentaerythritol, allyl ether of sucrose or allyl ether of propylene. Examples of carbomers that can be used in the present invention include, without limitation, carbomer 910, 934P, 940, 941, 1342, Carbopol® 974P (carbomer 974P) and Carbopol® 980 (carbomer 980).
Preferably, the carbomer is carbomer 934P, carbomer 974P or carbomer 980.
In accordance with the embodiments of the present invention, the amount of the carbomer in the composition is about 0.8%, 0.85%, 0.95%, 0.05%, 1.15%, 1.25%, 1.35%, 1.45% or 1.5% (in p / p).
The polyols in the gel formulations can fulfill one or more functions, such as solubilizing agents, moisturizing emulsions, emollients, skin moisturizer, skin penetrating agents, etc. Suitable polyols that can be used in the embodiments of the present invention include, without limitation, glycerin, propylene glycol, dipropylene glycol, hexylene glycol, butylene glycol, and liquid polyethylene glycols such as polyethylene glycol 200 to 600, and glycerol.
In one embodiment of the present invention, the paraben used in the topical gel composition is substantially soluble in at least one of the polyols used in the composition. Preferably, the polyol is propylene glycol.
It will be readily appreciated by those skilled in the art that an organic constituent other than a polyol can also be used in the topical formulation in accordance with the embodiments of the present invention.
In accordance with the embodiments of the present invention, the amount of the organic constituent such as polyol in the composition is about 4.5%, 5.0%, 5.5%, 6.0% or 6.5% (w / w).
In a preferred embodiment, a topical gel composition according to embodiments of the invention further comprises a water dispersible form of titanium dioxide (??? 2), preferably in an amount that is sufficient to mask the color of the brimonidine or other colored ingredient in the formulation, but would not cause skin irritation. The Ti02 can cause mild irritation and redness of the eyes, and in this way contact of the eyes with the topically administrable composition containing Ti02 should be avoided. The titanium dioxide imparts a whiteness to the topically administrable composition, and helps increase the opacity and reduce the transparency of the composition. Titanium dioxide absorbs, reflects or scatters light (including ultraviolet radiation in light), which can help protect products from deterioration. Titanium dioxide can also be used as a sunscreen that protects the user from the harmful effects of ultraviolet radiation that is part of sunlight.
In accordance with the embodiments of the present invention, the amount of dispersible water of the titanium dioxide in the composition is about 0.04%, 0.0425%, 0.0525%, 0.0625%, 0.0725% or 0.08% (w / w).
In another general aspect, a topical gel formulation according to an embodiment of the present invention further comprises an active pharmaceutical ingredient, such as an alpha-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof, which is effective in preventing or treating a skin disorder
Alpha-adrenergic receptor agonists are well known in the art. In a preferred embodiment, the alpha-adrenergic receptor agonist can be an alpha-1 or alpha-2 adrenergic receptor agonist. The alpha-adrenergic receptor agonists included in the invention may or may not show selectivity for any of the alpha-1 or alpha-2 adrenergic receptors. For example, some may be considered to be alpha-1 or alpha-2 adrenergic receptor agonists. More preferably, the alpha-adrenergic receptor agonist can be a selective alpha-1 adrenergic receptor agonist or a selective alpha-2 adrenergic receptor agonist.
Examples of selective alpha-1-adrenergic receptor agonists include oxymetazoline, phenylephrine and methoxyamine. Examples of selective alpha-2 adrenergic receptor agonists include brimonidine, tetrahydrozaline, naphazoline, xylometazoline, epinephrine and norepinephrine.
In one embodiment of the present invention, the active pharmaceutical ingredient comprises 0.05 to 5% (w / w) of brimonidine. The active pharmaceutical ingredient may optionally include one or more pharmaceutically active ingredients in addition to brimonidine, including, but not limited to, medications used to treat the skin disorder or the underlying disease causing the skin disorder, antihistamines to control itching. , antibiotics, corticosteroids, intravenous immunoglobulins, acetaminophen, etc.
In a preferred embodiment, brimonidine is tartrate of
brimonidine.
In accordance with the embodiments of the present invention, the amount of brimonidine in the topical gel composition is about 0.05% at 0.1%, 0.1% at 0.4%, 0.4% at 0.7%, 0.7% at 1%, 1% at 2 %, 2% to 3%, 3% to 4% or 4% to 5% (in w / w). Preferably, the amount of brimonidine tartrate in the composition is about 0.1 to 0.6% (w / w).
In a preferred embodiment of the present invention, a topical gel composition comprises:
0. 1 to 0.6% (w / w) of brimonidine tartrate;
0. 05 to 0.15% (w / w) of methylparaben;
one or more conservative seconds selected from the group consisting of sodium benzoate, phenoxyethanol, benzyl alcohol, imidazolidinyl urea and diazolidinyl urea;
0. 80 to 1.50% (w / w) carbomer;
4. 5 to 6.5% (w / w) of propylene glycol;
Y
purified water,
wherein the pH of the topical gel composition is adjusted to 5.0 to 6.5 by a suitable amount of aqueous sodium hydroxide solution.
In one embodiment of the present invention, the composition further comprises 4.5% to 6.5% (w / w) of a second polyol, such as glycerol.
In another embodiment of the present invention, the second
Conservatives comprise more than 0.3% (w / w) of phenoxyethanol, when 0.15% (w / w) or less of methylparaben is used in the formulation.
A topical gel composition according to the embodiments of the present invention may comprise additional pharmaceutically acceptable excipients, such as those listed in Remington: The Science and Practice of Pharmacy, 866-885 (Alfonso R. Gennaro ed., Nineteenth edition, 1995 ); Ghosh, T. K. et al., Transdermal and Topical Drug Delivery Systems (1997), citations incorporated herein by reference. Examples of additional excipients include, without limitation, protectants, adsorbents, antioxidants, local anesthetics, buffering agents, surfactants, flavorings, fragrances, dyes, etc.
Suitable protective agents and / or cosmetic agents and adsorbents may include, without limitation, dustable powders, zinc stearate, collodion, dimethicone, silicones, zinc carbonate, Aloe vera gel and other Aloe products, vitamin E oil, allantoin, petrolatum, titanium dioxide and zinc oxide.
Suitable antioxidants may include, without limitation, ascorbic acid and its esters, sodium bisulfite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherols, and chelating agents such as EDTA and citric acid.
Suitable damping agents may include, without limitation, acetate buffers, citrate buffers,
phosphate buffers, lactic acid buffers, sodium buffers and borate buffers.
A topical gel composition according to the embodiments of the present invention may also include local anesthetics and analgesics, such as camphor, menthol, lidocaine, dibucaine and pramoxine; antifungals, such as ciclopirox, chloroxylenol, triacetin, sulconazole, nystatin, undecylenic acid, tolnaftate, miconazole, clotrimazole, oxiconazole, griseofulvin, econazole, ketoconazole and amphotericin B.
A topical gel composition according to the embodiments of the present invention may further include one or more antiseptics, such as iodine, iodopovidone, benzalkonium chloride, benzoic acid, nitrofurazine, benzoyl peroxide, hydrogen peroxide, hexachlorophene, phenol, resorcinol and cetylpyridinium chloride.
The topical gel composition according to the embodiments of the present invention can be prepared by mixing the ingredients of the composition according to methods known in the art, for example, the methods provided by standard reference texts, such as REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 1577-1591, 1672-1673, 866-885 (Alfonso R. Gennaro ed., Nineteenth edition, 1995); Ghosh, T. K .; et al. TRANSDERMAL AND TOPICAL DRUG DELIVERY SYSTEMS (1997), citations that are incorporated herein by reference.
The pH of the topical gel formulations of the invention is of
preferably within a physiologically acceptable pH, for example, within the range of about 4.5 to about 7.5, preferably from about 5.0 to about 6.5, such as pH 5.1, 5.3, 5.5, 5.7, 5.9, 6.1, 6.3 or 6.5. To stabilize the pH, preferably, an effective amount of a buffer is included. Acids or bases can be used to adjust the pH, as necessary.
In a general aspect, the embodiments of the present invention relate to a method of treating or preventing a skin disorder, such as rosacea, erythema of rosacea, telangiectasia, psoriasis, purpura, acne erythema, eczema, inflammation of skin not related to rosacea, embarrassment, subsidence, folding and / or wrinkling of the skin, or a symptom associated therewith, in a subject, by topically administering to a subject's skin area a topical gel composition of compliance with an embodiment of the present invention, wherein the skin area is affected, or is prone to be affected, by the skin disorder. Relevant descriptions, for example, on the use of brimonidine to treat skin disorders, in U.S. Serial No. 10 / 853,585 of DeJovin et al .; U.S. Serial No. 10 / 626,037 from Scherer; U.S. Serial No. 10 / 607,439 of Gil et al .; U.S. Serial No. 10 / 763,807 to Shanler et al .; U.S. Serial No. 12 / 193,098 of Theobald et al .; the US patent application UU Publication No. 2006/0264515 of DeJovin et al .; U.S. Serial No. 12/621, 942 of DeJovin et al .; the US patent application UU publication No. 2005/0020600 of Scherer; and the US patent application. UU Publication No. 2009/0130027
of Shanler et al., are incorporated herein by reference, as if fully set forth herein.
In one embodiment of the present invention, the topically administrable composition comprises from about 0.1% to 0.6% (w / w), such as about 0.1%, 0.15%, 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55% or about 0.6%, by weight of brimonidine tartrate.
To treat or prevent a skin disorder, in view of the present disclosure, the topical gel compositions of the invention can be applied topically directly to the affected area in any conventional manner known in the art, for example, by dropper, applicator bar or cotton swab, as a vapor by means of an aerosol applicator, by means of an intradermal or transdermal patch, or simply by spreading a formulation of the invention on the affected area with the fingers, a sponge, a pad or cloths. In general, the amount of a topical formulation of the invention applied to the affected areas of the skin ranges from about 0.0001 g / cm2 of skin surface area to about 0.05 g / cm2, preferably 0.002 g / cm2 to about 0.005 g / cm2 of surface area of the skin. Typically, one to four applications per day are recommended during the term of treatment.
The methods of the present invention can be used in
combined with one or more other treatments and medications for the skin disorder, such as medications used to treat the underlying disease causing the skin disorder, antihistamines to control itching, antibiotics, corticosteroids, intravenous immunoglobulins, acetaminophen, etc.
The other drug or treatment can be administered to the subject simultaneously with, or in a sequence and within a time interval of, the administration of brimonidine, so that the active ingredients or agents can act together to treat or prevent the disorder of the skin. For example, the other drug or treatment and brimonidine can be administered in the same formulation or in separate formulations at the same time or at different times.
Any suitable route of administration can be used to deliver the additional treatment or medication and includes, but is not limited to, oral, intraoral, rectal, parenteral, topical, epicutaneous, transdermal, subcutaneous, intramuscular, intranasal, sublingual, buccal routes of administration , intradural, intraocular, intra-respiratory, or nasal inhalation.
This invention will be better understood by reference to the non-limiting examples that follow, but t skilled in the art will readily appreciate that the examples are illustrative only of the invention as more fully described in the claims below.
EXAMPLE 1
Observation of crystalline particles of methylparaben in the
topical gel compositions
Crystalline particles were first observed visually in a sample of 7 tubes from a batch of topical brimonidine gel composition. These particles were isolated. The identity of the particles was analyzed by several analytical methods, such as the HPLC test for the identification by comparison of the retention time against standards, differential scanning calorimetry (DSC) for the determination of the melting point, NMR for structural identification (for H and 13C), mass / mass with UV detector and QTOF to separate and identify the different masses, etc. Based on these analyzes, it has been concluded that the crystals observed are methylparaben crystals (abbreviated hereinafter as "POBM" or "MPOB"), which is a preservative used in the composition. In accordance with the procedure used to manufacture the batch, methylparaben was first dissolved in propylene glycol at 50 ° C in the preservative phase.
Microscopic observations were made on additional representative batches of topical brimonidine gel compositions and placebo gel compositions containing 1.25% (w / w) carbomer, POBM and other ingredients. The observations were made in a tube of each batch, with the microscope Axiolab DRBKT Zeiss no. 023733.01 with a Zeiss ICC camera or the Olympus BX60 microscope. The
Microscopic observations were made at 5 ° C and at room temperature.
As shown in Table 1, crystalline particles of methyl paraben were unpredictably observed in the brimonidine and placebo gel compositions containing 0.2% or 0.3% by weight of methyl paraben (POBM).
TABLE 1
Results of microscopic observations of representative batches of the gel composition
Date of Observation No. of tubes Date of the
Composition Lot size
microscopic manufacturing observed observation
Placebo, 0.3% of
April 2008 Crystals 130 kg Dec. 2008
POBM
Placebo, 0.3% Absence of
April 2008 130 kg 5 Dec. 2008
POBM crystals
Placebo, 0.3% of
July 1, 2009 Crystals 300g-2kg 1 Oct. 2009
POBM
Placebo, 0.3% of
August 25 from POBM 300g-2kg
Crystals Oct. 2009 2009 0.03% from 200 - 250 kg
brimonidine
0. 3% of
September 2, POBM Absence of
200 - . 200 - 250 kg Feb. 2010 2010 0.06% crystals
brimonidine
0. 3% of
September 7 of POBM
Crystals 200 - 250 kg Feb. 2010 2010 0.07%
brimonidine
0. 3% of
POBM
July 6, 2009 Crystals 300g - 2kg Féb. of 2010
0. 18 of
brimonidine
TABLE 1 (CONTINUED)
Date of Observation No. of tubes Date of the
Composition Lot size
microscopic manufacturing observed observation
September 15 of 0.3% of POBM
Crystals 200 - 250 kg Oct. 2009
2009 0.5% brimonidine
July 16, 2009 0.3% of POBM Cristales Feb. 2010
1% brimonidine
September 0.3%
18 of POBM Absence of 200 - 250 kg Feb. 2010 of 2009 crystals
27th brimonidine
0. 3% of POBM
September 29 Absence of
0. 06% of 300g - 2kg Feb. 2010 of 2009 crystals
brimonidine
September 10 0.3% of POBM
Crystals 300g - 2kg Oct. 2009 of 2009 1% brimonidine
September 17 Absence of
0. 3% of POBM Oct. 2009 of 2009 crystals
January 12 Placebo, 0.2% of
Crystals 300 g 4 of Feb. 2010 2010. POBM
0. 18% of 800g 10 Feb. 2010 brimonidine
December 22 Absence of
0. 2% of POBM
2009 crystals
Tests were performed to estimate the concentration of methylparaben solubilized in a batch that originally contained 0.3% (w / w) of methylparaben, in which crystalline particles were observed. Centrifugation was done in the batch to collect the crystals at the bottom of the centrifuge tube, thus removing them from the supernatant. The concentration of methyl paraben in the supernatant was measured and found to be about 0.2% (w / w), which was about 66% of 0.3% (w / w) in the original formulation. Reducing the concentration of soluble methylparaben in the composition generates problems of nonconformity, and can result in poor microbiological quality of the composition during an extended storage period.
The presence of crystalline particles of methyl paraben in topical gel formulations is surprising in view of the solubility of methyl paraben. To find a solution to avoid the problem of crystallization, several hypotheses have been postulated and evaluated to discover the potential cause and possible solution of the problem.
EXAMPLE 2
Improved gel topical compositions free of crystalline particles of methyl paraben
Several changes have been made to the formulation and manufacturing process of the formulation, to obtain topical gel formulations
that are free of the observed paraben crystals and have acceptable microbiological quality. For example, methylparaben, also called methyl parahydroxybenzoate (POBM), was replaced with sodium (Na) POBM more soluble in water, but crystalline particles of sodium POBM at 0.3% (w / w) were still observed. Sodium POBM The addition of 0.1% EDTA in the formulation resulted in the immediate recrystallization of the POBM at 0.3% (w / w) in the formulation, suggesting that the concentration of 0.3% (w / w) of POBM may be too high.
Many formulations were prepared with different ingredients and varying concentrations of the ingredients, and the presence of the paraben crystals was analyzed by microscopic observations. The microbiological quality of the formulations was also analyzed using the test acceptance criteria of the conservative efficacy analysis (PET) of the United States Pharmacopeia (USP) and the European Pharmacopoeia (EP).
Based on the microscopic observations and analyzes of
PET, improved topical gel compositions containing 0.05% to 0.20% (w / w) of methylparaben; one or more conservative seconds, such as 0.3% (w / w) or more phenoxyethanol; 0.80 to 1.50% (w / w) of carbomer, such as Carbopol®974P NF; 9.0% to 13.0% (w / w) of total polyol, such as 4.5 to 6.5% (w / w) of a first polyol, for example, propylene glycol, 4.5 to 6.5% (w / w) of a second polyol, for example, glycerol; and one or more other ingredients, such as purified water, titanium dioxide, optionally an effective amount of brimonidine tartrate, with a
pH from 5.0 to 6.5 adjusted for an adequate amount of sodium hydroxide, were free of methylparaben crystals after an extended storage period and passed the criteria of the EP and USP. See table 2, in which the carbomer concentration in each of the formulations was 1.25% (w / w).
TABLE 2
Results of microscopic observations and PET of the
topical gel formulations
It was further discovered that when the amount of methylparaben was more than 0.15% (w / w), the decrease in the amount of carbomer reduced the formation of methylparaben crystals. See, for example, table 3.
TABLE 3
Results of the microscopic observation of the compositions of qel
Those skilled in the art will appreciate that changes could be made to the modalities described above, without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not limited to the particular embodiments described, but is intended to encompass the modifications within the spirit and scope of the present invention as defined by the appended claims.
Claims (24)
1. - A topical gel composition, comprising: 0.05 to 0.20% (w / w) paraben; one or more conservative seconds; 0.80 to 1.50% (w / w) carbomer; 8 to 15% (w / w) of one or more organic constituents; wherein the topical gel composition has a pH of 4.5 to 7.5; and when the paraben concentration is greater than 0.15% (w / w), the carbomer concentration is less than 1.25% (w / w).
2. - The topical gel composition according to claim 1, further characterized in that the organic constituents comprise a first polyol.
3. - The topical gel composition according to claim 2, further characterized in that the organic constituents further comprise a second polyol.
4. - The topical gel composition according to claim 1, further characterized in that it comprises an alpha-adrenergic receptor agonist.
5. The topical gel composition according to claim 4, further characterized in that the alpha-adrenergic receptor agonist is an alpha-1 or alpha-2 adrenergic receptor agonist.
6. - The topical gel composition in accordance with the claim 5, further characterized in that the alpha-adrenergic receptor agonist is selected from the group consisting of oxymetazoline, phenylephrine, methoxyamine, brimonidine, tetrahydrozaline, naphazoline, xylometazoline, epinephrine and norepinephrine.
7. - The topical gel composition according to claim 1, further characterized in that the paraben is methylparaben.
8. - A topical gel composition, comprising: 0.05 to 5% (w / w) brimonidine; 0.05 to 0.20% (w / w) of paraben; one or more conservative seconds; 0.80 to 1.50% (w / w) carbomer; 8 to 15% (w / w) of one or more organic constituents, wherein the topical gel composition has a pH of 4.5 to 7.5; and when the paraben concentration is greater than 0.15% (w / w), the carbomer concentration is less than 1.25% (w / w).
9. - The topical gel composition according to claim 8, further characterized in that the organic constituents comprise a first polyol.
10. - The topical gel composition according to claim 9, further characterized in that the organic constituents further comprise a second polyol.
11. The topical gel composition according to claim 8, further characterized in that it additionally comprises 0.04 to 0.08% (w / w) in a water dispersible form of titanium dioxide.
12. - The topical gel composition in accordance with the claim 8, further characterized in that the carbomer is selected from the group consisting of carbomer 934P, Carbopol® 974P and Carbopol® 980.
13. The topical gel composition according to claim 8, further characterized in that brimonidine is brimonidine tartrate.
14. The topical gel composition according to claim 8, further characterized in that the second preservatives are selected from the group consisting of sodium benzoate, phenoxyethanol, benzyl alcohol, imidazolidinyl urea and diazolidinyl urea.
15. - The topical gel composition according to claim 8, further characterized in that the paraben is methylparaben.
16. - A topical gel composition, comprising: 0.1 to 0.6% (w / w) of brimonidine tartrate; 0.05 to 0.15% (w / w) of methylparaben; one or more conservative seconds selected from the group consisting of sodium benzoate, phenoxyethanol, benzyl alcohol, imidazolidinyl urea and diazolidinyl urea; 0.80 to 1.50% (w / w) carbomer; 4.5 to 6.5% (w / w) of propylene glycol and purified water, wherein the pH of the topical gel composition is adjusted to a pH of 5.0 to 6.5 by a suitable amount of aqueous sodium hydroxide solution.
17. - The topical gel composition according to claim 16, further characterized in that it comprises more than 0.3% (w / w) of phenoxyethanol as the second preservative, and comprises additionally 4.5% to 6.5% (w / w) glycerol.
18. The topical gel composition according to claim 17, further characterized in that it additionally comprises 0.04 to 0.08% (w / w) in a water dispersible form of titanium dioxide.
19. - The use of the topical gel composition according to claim 8, for preparing a medicament for treating or preventing a skin disorder in a subject, wherein the area of the skin is affected, or is prone to be affected, for the skin disorder.
20. - The use as claimed in claim 19, wherein the skin disorder is rosacea, erythema of rosacea, telangiectasias, psoriasis, purpura, acne erythema, eczema, skin inflammation unrelated to rosacea , embarrassment, sinking, folding and / or wrinkling of the skin, or a symptom associated with them.
21. - The use of the topical gel composition according to claim 16, for preparing a medicament for treating or preventing a skin disorder in a subject, wherein the area of the skin is affected, or is prone to be affected, for the skin disorder.
22. - The use as claimed in claim 21, wherein the skin disorder is rosacea, erythema of rosacea, telangiectasias, psoriasis, purpura, acne erythema, eczema, skin inflammation unrelated to rosacea , embarrassment, sinking, folding and / or wrinkling of the skin, or a symptom associated with them.
23. - The use of the topical gel composition according to the claim 1, for preparing a medicament for treating or preventing a skin disorder in a subject, wherein the gel composition additionally comprises an alpha-adrenergic receptor agonist selected from the group consisting of oxymetazoline, phenylephrine, methoxyamine, brimonidine, tetrahydrozaline , naphazoline, xylometazoline, epinephrine and norepinephrine, and where the skin area is affected, or is prone to be affected, by the skin disorder.
24. - The use as claimed in claim 23, wherein the skin disorder is rosacea, erythema of rosacea, telangiectasia, psoriasis, purpura, acne erythema, eczema, skin inflammation unrelated to rosacea , embarrassment, sinking, folding and / or wrinkling of the skin, or a symptom associated with them.
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US40538210P | 2010-10-21 | 2010-10-21 | |
FR1058611A FR2966365B1 (en) | 2010-10-21 | 2010-10-21 | TOPICAL GEL COMPOSITION |
PCT/EP2011/068261 WO2012052478A2 (en) | 2010-10-21 | 2011-10-19 | Topical gel composition |
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CA2841632A1 (en) * | 2011-07-14 | 2013-01-17 | Allergan, Inc. | Gel compositions of oxymetazoline and methods of use |
CN104666239A (en) * | 2013-11-27 | 2015-06-03 | 杭州赛利药物研究所有限公司 | Brimonidine tartrate gel and preparation method thereof |
CN103919717A (en) * | 2014-04-15 | 2014-07-16 | 天津中医药大学 | Brimonidine d-tartrate ophthalmic gel preparation as well as preparation method and application thereof |
WO2018000067A1 (en) * | 2016-06-28 | 2018-01-04 | Doris Maria Hexsel | Use of an active substance in the treatment of telangiectatic melasma |
KR20220002950A (en) | 2019-05-01 | 2022-01-07 | 클렉시오 바이오사이언시스 리미티드 | How to treat pruritus |
CN110882211A (en) * | 2019-12-31 | 2020-03-17 | 深圳市瀚德标检生物工程有限公司 | Hydroxyphenyl ester gel and preparation method thereof |
CN116159018A (en) * | 2023-03-01 | 2023-05-26 | 中国药科大学 | Novel external brimonidine gel |
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US7439241B2 (en) * | 2003-05-27 | 2008-10-21 | Galderma Laboratories, Inc. | Compounds, formulations, and methods for treating or preventing rosacea |
US20050020600A1 (en) | 2003-07-23 | 2005-01-27 | Scherer Warren J. | Methods of treating cutaneous flushing using selective alpha-2-adrenergic receptor agonists |
ES2424644T3 (en) * | 2004-05-25 | 2013-10-07 | Galderma Pharma S.A. | Compounds, formulations and methods to treat or prevent inflammatory skin disorders |
US20090061020A1 (en) * | 2007-08-31 | 2009-03-05 | Theobald Klaus P | Brimonidine Compositions for Treating Erythema |
EP2207424B1 (en) | 2007-11-16 | 2014-06-04 | Allergan, Inc. | Compositions and methods for treating purpura |
CA2709199A1 (en) * | 2007-12-21 | 2009-07-02 | Galderma Laboratories, Inc. | Pre-surgical treatment |
JP5052558B2 (en) * | 2009-04-03 | 2012-10-17 | ロート製薬株式会社 | Gel ointment |
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