WO2013019974A1 - Compositions comprenant un rétinoïde et un antibiotique lincosamide, destinées à être utilisées dans le traitement de la rosacée - Google Patents

Compositions comprenant un rétinoïde et un antibiotique lincosamide, destinées à être utilisées dans le traitement de la rosacée Download PDF

Info

Publication number
WO2013019974A1
WO2013019974A1 PCT/US2012/049374 US2012049374W WO2013019974A1 WO 2013019974 A1 WO2013019974 A1 WO 2013019974A1 US 2012049374 W US2012049374 W US 2012049374W WO 2013019974 A1 WO2013019974 A1 WO 2013019974A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
weight percent
acid
clindamycin
rosacea
Prior art date
Application number
PCT/US2012/049374
Other languages
English (en)
Inventor
Alexandra B. Kimball
Anne Lynn S. CHANG
Original Assignee
Medicis Pharmaceutical Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Medicis Pharmaceutical Corporation filed Critical Medicis Pharmaceutical Corporation
Publication of WO2013019974A1 publication Critical patent/WO2013019974A1/fr

Links

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
    • A61K31/185—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
    • A61K31/203—Retinoic acids ; Salts thereof
    • 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
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • 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
    • 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

Definitions

  • the invention relates to compositions containing a retinoid and a lincosamide antibiotic for the treatment or amelioration of rosacea.
  • the invention also relates to methods for treating or ameliorating rosacea using compositions containing a retinoid and a lincosamide antibiotic.
  • Rosacea is a common chronic skin disease affecting up to 10% of fair-skinned individuals (Wolff et /., FITZPATRICK'S COLOR ATLAS AND SYNOPSES OF CLINICAL DERMATOLOGY 8 (2005)).
  • the disease is characterized by inflammation and vascular abnormalities of the cheeks, nose, chin, forehead, or eyelids, and ca encompass various combinations of cutaneous signs including flushing, erythema, telangiectasia (dilation of superficial blood vessels on the face), papules, pustules, edema, ocular lesions, and rhinophyma (a red lobu!ated nose).
  • the erythematotelangiectatic subtype of rosacea is primarily characterized by flushing and persistent central facial erythema (redness of the skin).
  • the appearance of telangiectases small dilated blood vessels near the surface of the skin or mucous membranes that measure between about 0.5 to 1 mm in diameter
  • Patients may also experience central facial edema (abnormal accumulation of fluid beneath the skin), stinging, and burning sensations, as well as roughness or scaling.
  • a history of flushing alone is common among patients with this subtype of rosacea.
  • the papuiopustular subtype of rosacea is characterized by persistent central facial erythema with transient papules or pustules or both, the latter of which may or may not have a central facial distribution.
  • This subtype of rosacea is often associated with the erythematotelangiectatic subtype.
  • the phymatous subtype of rosacea is characterized by thickening skin, irregular surface nodularities, and enlargement of the nose. This subtype of rosacea is often seen in combination with the erythematotelangiectatic and papuiopustular subtypes, with the presence of persistent erythema and telangiectases.
  • the ocular subtype of rosacea is characterized by interpalpebral hyperemia and conjunctival, burning, stinging, light sensitivity, dryness, telangiectases of the
  • oral and topical antibiotics such as tetracyclines, macroiides, and metronidazole
  • topical tretinoin promotes remodeling of the collagen in the papillary and reticular dermis and decreases dermal inflammation
  • Retinoids also produce inhibitory effects on vascular endothelial growth factor production by cultured human skin keratinocytes ( Diaz et al., 2000, J. Biol. Chem.
  • the invention provides a method for treating or ameliorating the topical symptoms associated with rosacea comprising topically administering to a patient in need thereof a therapeutically effective amount of a composition comprising a retinoid and a lincosamide antibiotic.
  • the invention also provides the use of a composition comprising a retinoid and a lincosamide antibiotic for the manufacture of a medicament for treating or ameliorating rosacea.
  • the invention further provides a composition comprising a retinoid and a lincosamide antibiotic for the treatment or amelioration of rosacea.
  • the present disclosure provides a method for treating or ameliorating the topical symptoms associated with rosacea comprising topically administering to a patient in need thereof a therapeutically effective amount of a composition comprising a retinoid and a lincosamide antibiotic.
  • the lincosamide antibiotic is selected from the group consisting of clindamycin, clindamycin phosphate, and pharmaceutically acceptable salts thereof.
  • the lincosamide antibiotic is clindamycin phosphate.
  • the retinoid is tretinoin or a pharmaceutically acceptable salt thereof.
  • the composition comprises about 0.02 to about 0.03 weight percent of retinoid and about 1 ,0 to about 1.5 weight percent of lincosamide antibiotic. In particular embodiments, the composition comprises about 0.025 weight percent tretinoin and about 1.2 weight percent clindamycin or clindamycin phosphate.
  • the composition further comprises a topically acceptable pharmaceutical carrier.
  • the composition is topically applied to an area of the skin of the patient where the symptoms are manifested.
  • the composition is topically applied at least once a day for at least twelve weeks.
  • the rosacea is the eiythematotelangiectatic subtype.
  • the treatment results in a reduction in erythema. In some embodiments, the treatment results in a reduction in telangiectasias.
  • the composition is in the form of a gel, liquid suspension, emulsion cream, ointment, or powder.
  • composition suitable use for any of the methods described herein comprises:
  • composition has a pH of about 3 to about 9 and a viscosity of less than about 15,000 cP.
  • the present disclosure provides for the use of a
  • composition comprising a retinoid and a lincosamide antibiotic for the manufacture of a medicament for treating or ameliorating rosacea.
  • the lincosamide antibiotic is selected from the group consisting of clindamycin, clindamycin phosphate, and pharmaceutically acceptable salts thereof.
  • the lincosamide antibiotic is clindamycin phosphate.
  • the retinoid is tretinoin or a pharmaceutically acceptable salt thereof.
  • the composition comprises about 0.02 to about 0.03 weight percent of retinoid and about 1.0 to about 1 .5 weight percent of lincosamide antibiotic. In other embodiments, the composition comprises about 0.025 weight percent tretinoin and about 1.2 weight percent clindamycin or clindamycin phosphate.
  • the composition further comprises a topically acceptable pharmaceutical carrier.
  • the composition is topical ly appl ied to an area of the skin of the patient where the symptoms are manifested.
  • the composition is topically applied at least once a day for at least twelve weeks.
  • the rosacea is the eiythematotelangiectatic subtype.
  • the treatment results in a reduction in erythema.
  • the treatment results in a reduction in telangiectasias.
  • the composition is in the form of a gel, liquid suspension, emulsion cream, ointment, or powder.
  • the present disclosure provides a composition comprising a retinoid and a lincosamide antibiotic for the treatment or amelioration of the symptoms of rosacea.
  • the lincosamide antibiotic is selected from the group consisting of clindamycin, clindamycin phosphate, and therapeutically acceptable salts thereof.
  • the lincosamide antibiotic is clindamycin phosphate.
  • the retinoid is tretinoin or a pharmaceutically acceptable salt thereof.
  • the composition comprises about 0.02 to about 0.03 weight percent of retinoid and about 1.0 to about 1.5 weight percent of lincosamide antibiotic. In particular embodiments, composition comprises about 0.025 weight percent tretinoin and about 1.2 weight percent clindamycin or clindamycin phosphate.
  • composition further comprises a topically acceptable pharmaceutical carrier.
  • the composition is topically applied to an area of the skin of the patient where the symptoms are manifested.
  • the composition is topically applied at least once a day for at least twelve weeks.
  • the rosacea is the erythematoteiangiectatic subtype.
  • the treatment results in a reduction in erythema.
  • the treatment results in a reduction in telangiectasias.
  • the composition is in the form of a gel, liquid suspension, emulsion cream, ointment, or powder.
  • Figure 1 il lustrates a summary of a study designed to assess the efficacy and safety of a clindamycin and tretinoin gel (ZIANA®) for the treatment of papulopustular rosacea.
  • ZIANA® clindamycin and tretinoin gel
  • patient refers to a human subject.
  • a “disease” or “disorder” is any condition that would benefit from treatment using the methods or compositions of the invention.
  • Disease or “disorder” and “condition” are used interchangeably herein and include chronic and acute disorders or diseases.
  • compositions and methods of the invention can be used to treat or amel iorate the topical symptoms of rosacea, in a preferred method, use, or composition of the invention, the subtype of rosacea being treated or ameliorated is the
  • the treatment results in a reduction in erythema. In another method, use, or composition of the invention, the treatment results in a reduction in telangiectases.
  • treat refers to both therapeutic treatment and
  • treatment refers to the alleviation of symptoms of a disease. Those in need of treatment include those having the disorder as well as those prone to have the disorder or those in which the disorder is to be prevented.
  • composition refers to a compound or composition capable of inducing a desired therapeutic effect when properly administered to a patient.
  • terapéuticaally acceptable or “topically acceptable” as used herein refer to one or more formulation materials suitable for accomplishing or enhancing the delivery of a composition of the invention.
  • pharmaceutically acceptable salt refers to a salt of an active compound of the compositions of the invention that possesses essentially the same pharmacological activity as the active compound and which is neither biologically nor otherwise undesirable.
  • a pharmaceutical ly acceptable salt of a compound is one that, upon administration of a composition of the invention to a subject, is capable of providing the compound or an active metabolite or residue thereof.
  • salts of the compounds of the compositions of the invention may be derived from inorganic or organic acids and bases.
  • acids include, but are not limited to, 4-acetamidobenzoic acid, acetic acid, adipic acid, alginic acid, L-ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, butyric acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, carbonic acid, cimiamic acid, citric acid, cyclamic acid, cvclopentanepropionic acid, decanoic acid, 2,2-diehioroacetic acid, dodecylsulfuric acid, ethane- 1 ,2-disulfonic acid, ethanesuifonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, genlisic acid, D-glucoheptonic acid, D-gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid, 2-oxo
  • methanesuifonic acid naphthalme-1 ,5-disulfonic acid, naphthalene-2-sulfonic acid, 1- hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, octanoic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, pantothenic acid, pectinic acid, pectic acid, perchloric acid, phenylpropionic acid, phosphoric acid, picric acid, pivaiic acid, propionic acid, (-)-L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, (H-)-L-tartaric acid, thiocyanic acid, toluenesulfonic acid, p-to!uenesu!fonic acid
  • bases include, but are not limited to, alkali metals (e.g., sodium) hydroxides, alkaline earth metals (e.g., magnesium), hydroxides, ammonia, and compounds of formula NW 4 + , wherein W is C 1- alkyl, and the like.
  • alkali metals e.g., sodium
  • alkaline earth metals e.g., magnesium
  • hydroxides e.g., ammonia
  • compounds of formula NW 4 + wherein W is C 1- alkyl, and the like.
  • salts of a compound of the compositions of the invention are contemplated as being pharmaceutically acceptable.
  • salts of acids and bases that are non-pharmaceutically acceptable may also be used, for example, in the preparation or purification of a pharmaceutically acceptable compound.
  • Examples of pharma ceutically acceptable acids suitable for the preparation of pharmaceutically acceptable salts of an active compound include, but are not limited to, acetic acid, adipic acid, L-aspartic acid, beiizenesulfonic acid, benzoic acid, citric acid, (+)-camphoric acid, (r)-camphor-lO-sulfonic acid, dodecylsulfuric acid, D-gluconic acid, D-glucuronic acid, ethanesuifonic acid, fumaric acid, D-glucoheptonic acid,
  • glycerophosphoric acid hexanoic acid, hydrobromic acid, hydrochloric acid, 2- hydroxyethanesuifonic acid, isobutyric acid, DL-lactic acid, maleic acid, methanesuifonic acid, naphthalene-1 ,5-disulfonic acid, naphthalene-2-sulfonic acid, 1 -hydroxys- naphthoic acid, nicotinic acid, oxalic acid, palmitic acid, propionic acid, succinic acid, sulfuric acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and the like.
  • suitable cation such as Na + , N3 ⁇ 4 "r , and NWV (wherein W is a CM alkyl group), and the like.
  • a therapeutically effective amount when used in reference to a composition of the invention refers to an amount or dosage sufficient to produce a desired therapeutic result. More specifically, a therapeutically effective amount is an amount of the composition sufficient to inhibit, for some period of time, one or more of the clinically defined pathological processes associated with the condition being treated. The effective amount may vary depending on the specific composition that is being used, and also depends on a variety of factors and conditions related to the patient being treated and the severity of the disorder. The determination of an effecti ve amount or therapeutically effective amount of a given composition is well within the ability of those skilled in the art.
  • retinoid refers to a class of compounds that are chemically related to vitamin A (retinol), and which includes, but is not limited to, retinal (retinal dehyde or vitamin A aldehyde), tretinoin (retinoie acid or vitamin A acid), isotretinoin, tazarotene, adapalene, bexarotene, alitretinoin, retinyl acetate, and retinyl palmitate (vitamin A palmitate or retinol palmitate).
  • retinal retinal
  • tretinoin retinoie acid or vitamin A acid
  • isotretinoin tazarotene
  • adapalene bexarotene
  • retinyl palmitate vitamin A palmitate or retinol palmitate
  • the retinoid is tretinoin or a pharmaceutically acceptable salt thereof, in other embodiments of the invention, the retinoid is tazarotene or adapalene. In another embodiment of the in vention, the retinoid is any known retinoid with the exception of adapalene.
  • lincosamide antibiotic refers to a class of antibiotics that includes, but is not limited to, lincomycin. clindamycin, clindamycin phosphate, and pirhmycin as well as pharmaceutically acceptable salts thereof. Without wishing to be bound by any particular theory, it is believed that lincosamide antibiotics kill bacteria by binding to bacterial ribosomes and causing prem a ture dissociation of peptidyl-tRNA from the ribosome. In one method, use, or composition of the invention, the lincosamide antibiotic is clindamycin or a pharmace tically acceptable salt thereof. In another method, use, or composition of the invention, the lincosamide antibiotic is clindamycin hydrochloride. In yet another method, use, or composition of the invention, the lincosamide antibiotic is clindamycin phosphate.
  • Topical or therapeutic compositions comprising a retinoid (such as tretinoin) and a lincosamide antibiotic (such as clindamycin or clindamycin phosphate) are within the scope of the invention.
  • Such topical or therapeutic compositions can comprise a therapeutically effective amount of a retinoid (such as tretinoin) and a lincosamide antibiotic (such as clindamycin or clindamycin phosphate), in admixture with one or more therapeutically or physiologically acceptable formulation agents selected for suitability with the mode of administration.
  • Acceptable formulation materials preferably are nontoxic to recipients at the dosages and concentrations employed.
  • Topical or therapeutic compositions can contain formulation materials for modifying, maintaining, or preserving, for example, the H, osmolality, viscosity, clarity, color, isotonicity, odor, sterility, stability, adsorption, or penetration of the composition.
  • Suitable formulation materials include, but are not limited to, amino acids (such as glycine, glutamine, asparagine, arginine, or lysine), antimicrobials, antioxidants (such as ascorbic acid, sodium sulfite, or sodium hydrogen-sulfite), buffers (such as borate, bicarbonate, Tris-HCl, citrates, phosphates, or other organic acids), bulking agents (such as mannitol or glycine), chelating agents (such as ethylenediamine tetraacetic acid (EDTA)), compiexing agents (such as caffeine, polyvinylpyrrolidone, beta-cyclodextrin, or hydroxypropyi-beta-cyciodextrin), fillers, monosaccharides, disaccharides, and other carbohydrates (such as glucose, mannose, or dextrins), proteins (such as serum albumin, gelatin, or immunoglobulins), coloring and diluting agents, e
  • propylparaben chlorhexidine, sorbic acid, or hydrogen peroxide
  • solvents such as glycerin, propylene glycol, or polyethylene glycol
  • sugar alcohols such as mannitol or sorbitol
  • suspending agents such as piuronics; PEG;
  • sorbitan esters such as polysorbate 20 or poiysorbate 80; triton;
  • the composition comprises a topically acceptable pharmaceutical carrier.
  • compositions can influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of a retinoid (such as tretinoin) and a imcosamide antibiotic (such as clindamycin or clindamycin phosphate).
  • a retinoid such as tretinoin
  • a imcosamide antibiotic such as clindamycin or clindamycin phosphate.
  • the composition is in the form of a gel, liquid suspension, emulsion cream, ointment, or powder.
  • the composition is in the form of a gel.
  • a gel comprising a lincosamide antibiotic (such as clindamycin or clindamycin phosphate) and a retinoid (such as tretinoin) can be formulated using components described in U.S. Patent No, 6,387,383, the entirety of which is incorporated herein by reference.
  • Such components include a hydrophilic pharmaceutically acceptable lightly cross-linked polyacrylic acid polymer compatible with the lincosamide antibiotic and retinoid, an optional water miscible solvent, an optional preservative, and an optional oil phase and surfactant.
  • the composition has a pH of about 3.0 to about 9.0 and a viscosity of less than about 15,000 centipoise (cP).
  • the lincosamide antibiotic and retinoid are formulated with a hydrophilic lightly cross-linked polyacrylic acid polymeric material that is present in an amount sufficient to bring the viscosity of the composition to a level of not more than about 15,000 cP, preferably between about 100 and about 12,000 cP, and more preferably between about 300 and about 10,000 cP.
  • the polymers that are particularly useful in the composition of the invention are lightly cross-linked polyacrylic acid polymers that are marketed under the tradename CARBOPOL®. Such polymers are generically referred to as carbomers.
  • the CARBOPOL® polymers are hydrophilic poiyniers based on a polyacrylic acid structure.
  • the hydrophilic lightly cross-linked polyacrylic acid polymers include CARBOPOL ⁇ 910, 941 , 971, and 981, and CARBOPOL® ETD 2050.
  • the hydrophilic lightly cross-linked polyacrylic acid polymer is present in the composition in an amount of about 0.05 to about 3 weight percent, and preferably about 0.05 to about 1 weight percent based on the total weight of the composition. In a more preferred embodiment of the invention, the hydrophilic lightly cross-linked polyacrylic acid polymer is present in the composition in an amount of about 0.1 to about 0,5 weight percent.
  • the composition optionally includes a water miscible solvent and a preservative.
  • the water miscible solvent i.e., a cosolvent
  • the cosolvent may be a single component or a mixture. Examples include those that are miscible with water such as ethanol, propylene glycol, glycerin, polyethylene glycol 400, and the like.
  • Certain water miscible solvents, such as glycerin or propylene glycol also add beneficial humectant properties to the composition. Drug delivery and penetration into the skin can be modified by the water miscible cosolvent composition.
  • the water miscible solvent is present in the composition in an amount of 0 to about 70 weight percent, and preferably 0 to about 40 weight percent based on the total weight of the composition. In a more preferred embodiment of the invention, the water miscible solvent is present in the composition in an amount of 0 to about 25 weight percent.
  • the preservative may be useful for ensuring a stable composition and preventing growth of bacteria.
  • a preservative may be one or more of an antioxidant, a chelator, an antibacterial, or the like.
  • Suitable preservatives include methylparaben, butylparaben, propylparaben, benzyl alcohol, sorbic acid, imidurea, thimerisal, propyl gallate, BHA, BHT, citric acid, di sodium edetate, and the like,
  • the preservative is present in the composition in an amount of 0 to about 3 weight percent, and preferably about 0.01 to about 1 weight percent based on the total weight of the composition. In a more preferred embodiment of the invention, the preservative is present in the composition in an amount of about 0,05 to about 0.25 weight percent.
  • a preferred composition particularly for the treatment of rosacea, will exhibit a pH of about 3 to 9, preferably about 4 to so 7, and most preferably at about 5 to 6.
  • the composition may also include a pH-adj listing agent as needed at a level to adjust the pH to the desired range.
  • Such agents include many pharmaceutically acceptable organic or inorganic bases, e.g., sodium hydroxide and tromethamine.
  • the pH chosen for a composition of the invention will depend in part on the pH tolerance of the lincosamide antibiotic and retinoid chosen for the composition.
  • Another aspect of this invention is an emollient embodiment, i.e., a fluid emulsion or l otion.
  • This aspect of the invention is a composition having an internal oil phase dispersed with the aid of at least one surfactant, e.g., an emulsifier, in water.
  • Suitable surfactants are well known in the art and include those referred to as anionic and nonionic agents.
  • Representative surfactants include polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, sorbitan laurate, sorbitan oleate, sorbitan stearate, polyoxyethylene stearate, sodium laureth sulfate, and laureth- 10.
  • Oil phase components include those that are commonly used in the art such as mineral oil, petrolatum, stearyi alcohol, cetyl alcohol, isopropyl myristate, diisopropyl adipate, stearic acid, white wax, and the like.
  • the surfactant is present in the composition in an amount of 0 to about 8 weight percent, and preferably 0 to about 5 weight percent based on the total weight of the composition, In a more preferred embodiment of the invention, the surfactant is present in the composition in an amount of 0 to about 3.5 weight percent.
  • the oil phase component is present in the composition in an amount of 0 to about 50 weight percent, and preferably 0 to about 25 weight percent based on the total weight of the composition. In a more preferred embodiment of the invention, the oil phase component is present in the composition in an amount of 0 to about 15 weight percent,
  • compositions of the invention are described in U.S. Patent No, RE41,134, the entirety of which is hereby incorporated by reference.
  • a retinoid (such as tretinoin) is present in the composition in an amount of about 0.01 to about 0.5 weight percent, preferably about 0.01 to about 0.25 weight percent, and more preferably about 0.01 to about 0.1 weight percent based on the total weight of the composition.
  • the retinoid is present in the composition in an amount of about 0.025, about 0.05, or about 0,1 weight percent.
  • the retinoid is present in the composition in an amount of about 0.025 weight percent.
  • the composition comprises about 0.025 weight percent of the retinoid tretinoin.
  • a lincosamide antibiotic (such as clindamycin or clindamycin phosphate) is present in the composition in an amount of about 0.1 to about 5 weight percent, and preferably about 0.5 to about 2 weight percent based on the total weight of the composition.
  • the lincosamide antibiotic is present in the composition in an amount of about 1.2 weight percent.
  • the composition comprises about 1.2 w eight percent of the lincosamide antibiotic clindamycin or clindamycin phosphate.
  • the composition comprises about 0.02 to about 0.03 weight percent of retinoid and about 1 ,0 to about 1.5 weight percent of lincosamide antibiotic.
  • the retinoid is tretinoin and the lincosamide antibiotic is clindamycin or clindamycin phosphate
  • the composition comprises about 0,025 weight percent of tretinoin and about 1.2 weight percent of clindamycin or clindamycin phosphate.
  • Topical compositions for use in the invention will typically be applied directly to the sites of rosacea lesions, including areas of redness and pustules, as well as
  • compositions of the invention are generally topically applied to the affected skin once or twice daily.
  • compositions of the invention are typically used under a physician's care, the precise treatment regimen in each case will be determined by the physician based upon the exact diagnosis, severity of the condition, concurrent use of other therapeutic agents, responsiveness to treatment, tolerance of treatment, and other related medical considerations.
  • the composition is topically applied at least once a day for at least twelve weeks to an area of the skin of the patient where the symptoms are manifested.
  • Topical appl ication of the compositions of the invention can be accomplished by using a earner, particularly one in which the composition's ingredients are soluble or are effectively solubilized (e.g., as an emulsion or mieroemulsion),
  • the carrier is inert in that it does not bring about a deactivation or oxidation of the active ingredients, and does not cause any adverse effect on the skin areas to which the composition is applied
  • the active ingredients are applied in admixture with a topically acceptable carrier or vehicle (e.g., as a lotion, cream, or ointment) so as to laciliiate topical application and, in some cases, provide additional therapeutic effects, such as moisturizing the affected skin areas.
  • the carrier for dermatological compositions can consist of a relatively simple solvent or dispersant such as water
  • the carrier comprise a composition more conducive to topical application, and particularly one that will form a film or layer on the skin to which the composition is applied so as to localize the application and provide some resistance to washing off by immersion in water or by perspiration and aid in the percutaneous delivery of the active ingredients.
  • oils or alcohols and emollients include lotions containing oils or alcohols and emollients, vegetable oils, hydrocarbon oils and waxes, silicone oils, animal or marine fats or oils, glyceride derivatives, fatty acids or fatty acid esters or alcohols or alcohol ethers, lecithin, lanolin and derivatives, polyhydric alcohols or esters, wax esters, sterols, phospholipids and the like, and generally also emulsifiers (nonionic, cationic, or anionic), although some of the emollients inherently possess emulsifying properties.
  • These same general ingredients can be formulated into a cream rather than a lotion, or into gels, by utilization of different proportions of the ingredients and by inclusion of thickening agents such as gums or other forms of hydrophilic colloids.
  • Topical compositions of the invention can comprise additional ingredients commonly found in skin care compositions, such as tinting agents, emollients, skin conditioning agents, emulsifying agents, humectants, preservatives, antioxidants, perfumes, and chelating agents, provided that they are physically and chemically compatible with the active ingredients and other components of the composition.
  • additional ingredients commonly found in skin care compositions such as tinting agents, emollients, skin conditioning agents, emulsifying agents, humectants, preservatives, antioxidants, perfumes, and chelating agents, provided that they are physically and chemically compatible with the active ingredients and other components of the composition.
  • Buffering agents may also be employed in the compositions of the invention.
  • buffering agents are chemically and physically stable agents commonly found in skin care compositions, and can include compounds that are also adjunct ingredients such as citric acid, malic acid, and glycolic acid buffers. 3, Examples
  • Study subjects were selected based on the following inclusion criteria: were 18 years of age or older and had a clinical diagnosis of papulopustu!ar facial rosacea with a minimum of four but not more than 50 facial inflammatory lesions (papules plus pustules).
  • the fol lowing exclusion criteria were used:
  • a history or presence of regional enteritis or inflammatory bowel disease e.g., ulcerative colitis, pseudomembranous colitis, chronic diarrhea, or a history of antibiotic- associated colitis, bloody diarrhea) or similar symptoms;
  • study subjects participated in four study visits: baseline (day 1), interim assessments (at weeks 2 and 6), and final assessments (at week 12). Subjects that did not require a washout before treatment were enrolled and participated in their baseline visit assessments on the same day. Subjects who required a washout period (wherein the washout period depended on the agent being used by the subject) were asked to return for their baseline visit once the washout period had been observed.
  • Primary endpoints in the study included a statistically significant decrease in absolute papule and pustule count on a study subject's face at week 12 as compared with baseline, as well as a percent decrease in papule and pustule count on a study subject's face at week 12 as compared with baseline.
  • Secondary endpoints in the study included a statistically significant decrease in the clinical features of rosacea at week 12 as compared with baseline.
  • telangiectasia severity was significantly different at baseline between the CT and placebo groups.
  • Table 4 shows the results of subject self-assessment of rosacea severity.
  • this table indicates that the CT group showed more improvement at 12 weeks on almost all parameters as compared with the placebo group. However, none of the individual survey items reached statistical significance in the CT group as compared with the placebo group.
  • CT gel was well tolerated by subjects in the treatment group.
  • subjects who did not complete the study, but completed at least one baseline visit their last completed visit was carried over, if there was missing data within that visit, it was not carried over from the previous visit, but considered missing.
  • Tables 5-7 show that scaling, dryness, and erythema were not significantly increased in the treatment group as compared with the placebo group at week 12.
  • Table 8 shows adverse events that were observed more than once in the CT and placebo groups.
  • CT gel was well tolerated in the treatment group, especially considering that patients with rosacea typically have sensitivity to agents such as tretinoin, which may promote scaling, dryness and erythema.
  • erythematotelangiectatic subtype of rosacea observed in the current study is due to a reduction in telangiectasias. This possibility is supported by the finding that physician- assessed erythema symptoms in the CT group did not improve at 12 weeks.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Molecular Biology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des compositions contenant un rétinoïde et un antibiotique lincosamide pour le traitement ou l'amélioration de la rosacée. L'invention concerne également des procédés de traitement ou d'amélioration de la rosacée à l'aide de compositions contenant un rétinoïde et un antibiotique lincosamide.
PCT/US2012/049374 2011-08-02 2012-08-02 Compositions comprenant un rétinoïde et un antibiotique lincosamide, destinées à être utilisées dans le traitement de la rosacée WO2013019974A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201161514364P 2011-08-02 2011-08-02
US61/514,364 2011-08-02

Publications (1)

Publication Number Publication Date
WO2013019974A1 true WO2013019974A1 (fr) 2013-02-07

Family

ID=46651623

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2012/049374 WO2013019974A1 (fr) 2011-08-02 2012-08-02 Compositions comprenant un rétinoïde et un antibiotique lincosamide, destinées à être utilisées dans le traitement de la rosacée

Country Status (1)

Country Link
WO (1) WO2013019974A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016012523A1 (fr) * 2014-07-23 2016-01-28 Skintech Life Science Limited Agent pharmaceutique

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002011683A1 (fr) * 2000-08-03 2002-02-14 Dow Pharmaceutical Sciences Systeme de distribution d'un gel topique
WO2009116086A2 (fr) * 2008-03-17 2009-09-24 Glenmark Pharmaceuticals Limited Formulation topique stable sous forme de doses fixes
USRE41134E1 (en) 1989-06-07 2010-02-16 Alyzan, Inc. Slow release vehicles for minimizing skin irritancy of topical compositions
WO2012053014A2 (fr) * 2010-10-21 2012-04-26 Cadila Healthcare Limited Procédé de traitement de l'acné à l'aide de compositions pharmaceutiques de clindamycine et d'adapalène

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE41134E1 (en) 1989-06-07 2010-02-16 Alyzan, Inc. Slow release vehicles for minimizing skin irritancy of topical compositions
WO2002011683A1 (fr) * 2000-08-03 2002-02-14 Dow Pharmaceutical Sciences Systeme de distribution d'un gel topique
US6387383B1 (en) 2000-08-03 2002-05-14 Dow Pharmaceutical Sciences Topical low-viscosity gel composition
WO2009116086A2 (fr) * 2008-03-17 2009-09-24 Glenmark Pharmaceuticals Limited Formulation topique stable sous forme de doses fixes
WO2012053014A2 (fr) * 2010-10-21 2012-04-26 Cadila Healthcare Limited Procédé de traitement de l'acné à l'aide de compositions pharmaceutiques de clindamycine et d'adapalène

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
"REMINGTON'S PHARMACEUTICAL SCIENCES", 1990, MACK PUBLISHING COMPANY
DIAZ ET AL., J. BIOL. CHEM., vol. 27, no. 1, 2000, pages 642 - 50
KLIGMAN ET AL., ARCH. DERMATOL. RES., vol. 288, no. 10, 1996, pages 615 - 20
NICHOLSON ET AL., J. AM. ACAD. DERMATOL., vol. 57, no. 2, 2007, pages 213 - 21
PELLE ET AL., J. AM. ACAD. DERMATOL., vol. 51, no. 4, 2004, pages 499 - 512
TAN ET AL., J. CUTAN. MED. SURG., vol. 6, no. 6, 2002, pages 529 - 34
VAN AUUREN ET AL., COCHRANE DATABASE SV.ST..REV., vol. 20, no. 3, 2005, pages CD003262
VOORHEES ET AL., J INT. MED. RES., vol. 18, no. 3, 1990, pages 26C - 28C
WILKIN ET AL., AM. ACAD. DERMATOL., vol. 50, no. 6, January 2004 (2004-01-01), pages 907 - 12
WILKIN ET AL., J. AM. ACAD. DERMATOL., vol. 46, no. 4, 2002, pages 584 - 87
WOLFF ET AL., FITZPATRICK'S COLOR ATLAS AND SYNOPSIS OF CLINICAL DERMATOLOGY, 2005, pages 8

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016012523A1 (fr) * 2014-07-23 2016-01-28 Skintech Life Science Limited Agent pharmaceutique
GB2543709A (en) * 2014-07-23 2017-04-26 Skintech Life Science Ltd Pharmaceutical agent
CN106714788A (zh) * 2014-07-23 2017-05-24 皮肤科技生命科学有限公司 药物制剂

Similar Documents

Publication Publication Date Title
US20200276094A1 (en) Compositions for skin expoliation and use thereof
EP2863886B1 (fr) Compositions et procédés permettant une administration topique de prostaglandines à la graisse sous-cutanée
CA2526642A1 (fr) Compositions sous forme de spray comprenant un actif pharmaceutique, au moins un silicone volatile et une phase huileuse non volatile
US20220125817A1 (en) Pharmaceutical compositions for demodex related blepharitis and eyelid crusting
KR20010034857A (ko) 피부질환 예방 및 치료제
US11116714B2 (en) Systems and methods for treating and/or preventing acne
JP2013538853A (ja) 酒瘡の併用による治療
CA3150975A1 (fr) Traitement topique du vitiligo par un inhibiteur de jak
JP2024016022A (ja) 皮膚炎および炎症性皮膚状態のためのカンナビノイド投薬レジメン
US7655255B2 (en) Topical composition for transdermal administration
Adamski et al. Acne–therapeutic challenges to the cooperation between a dermatologist and a cosmetologist
KR20130140100A (ko) 피부 장애 치료용 국소 사용을 위한 조성물
JP6359456B2 (ja) ７−（１ｈ−イミダゾール−４−イルメチル）−５，６，７，８−テトラヒドロキノリンを含む肌の疾患および状態を治療するための医薬組成物
WO2013019974A1 (fr) Compositions comprenant un rétinoïde et un antibiotique lincosamide, destinées à être utilisées dans le traitement de la rosacée
CN113038920A (zh) 用于治疗美学皮肤病症的铁螯合化合物
US9642877B1 (en) Method of administration of chromium and magnesium sulfate for treatment of acne
KR20050103906A (ko) 포유동물의 피부병학적 병변들의 치료 및/또는 예방을 위한비타민 케이1 산화물 또는 그의 유도체를 포함하는조성물의 용도
JP2007016025A (ja) 皮膚の局部組成物及び方法
US20200330429A1 (en) Method of treating truncal acne with trifarotene
JP2024516316A (ja) 萎縮性瘢痕を治療するためのキヌレニンおよびその誘導体
WO1997018804A1 (fr) Rajeunissement de la peau a l'aide d'une combinaison de vitamine a et d'acides alphahydroxy
US6169110B1 (en) Rejuvenating the skin using a combination of vitamin A and alphahydroxy acids
EP3738588A1 (fr) Formulations topiques et orales comprenant de la taurine et du magnésium pour l'utilisation pour le traitement de la rosacée
CA3195357A1 (fr) Traitement topique du vitiligo
CN117915904A (zh) 包含过氧化苯甲酰和壬二酸的局部制剂及其用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12746447

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12746447

Country of ref document: EP

Kind code of ref document: A1