Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
  • A61K8/42—Amides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
  • A61K8/41—Amines
• • 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
  • A61P17/16—Emollients or protectives, e.g. against radiation
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
  • A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
  • A61Q19/08—Anti-ageing preparations

Definitions

• This application relates to compositions and methods for alleviating the dermatological signs of aging, including changes or damage to skin associated with intrinsic aging, as well as changes or damage caused by extrinsic factors such as sunlight, radiation, air pollution, wind, cold, heat, dampness, chemicals and cigarette smoking.
• Human skin is a structurally complex, relatively thick membrane comprised of two principal components, the outer epidermis and the underlying dermis, which is situated above the subcutaneous adipose or fat tissues.
• the epidermis consists of four distinct layers: stratum corneum, stratum granulosum, stratum spinosum and stratum basale; in the skin of palms and soles only, there is normally one additional zone called the stratum lucidum between the stratum corneum and the stratum granulosum.
• the dermis is comprised mainly of collagen, elastic fibers, glycosaminoglycans and proteoglycans including hyaluronic acid, dermatan sulfate and chondroitin sulfate formerly known as mucopolysaccharides.
• Fibroblasts the predominant cells of the dermis, synthesize collagen, elastic fibers, proteoglycans and glycosaminoglycans.
• Collagen makes up approximately 77%, elastic fibers account for about 2%, and glycosaminoglycans constitute around 0.2% of the dry weight of the dermis.
• Collagen provides the tensile strength of and elastic fibers give resilience to the dermis.
• the glycosaminoglycans bind water to form a gelatinous mass between collagen and elastic fibers, which acts as a lubricant and shock absorber for the dermis during movement of the skin.
• Cutaneous aging while having epidermal concomitants, primarily involves dermal and subcutaneous changes, and is caused by (a) internal factors alone, as in intrinsic aging and (b) external factors, as in extrinsic aging.
• Intrinsic aging is also known as natural or chronologic aging, and extrinsic aging is often called photoaging.
• Photodamage implies skin damage caused by chronic sun exposure.
• Intrinsic aging of skin, in sun-protected skin of the upper arm and abdomen, is an inherent degenerative process due to declining physiologic functions and capacities. Such aging process may include qualitative and quantitative skin changes and includes diminished or defective synthesis of collagen and elastic fibers, and proteoglycans and glycosaminoglycans in the dermis. Signs of intrinsic aging include progressive thinning of skin, deepening of skin lines and fine wrinkles, lusterless skin surface, and loss of skin elasticity and recoilability. Although intrinsic aging of living creatures is neither reversible nor preventable, modification and improvement of skin signs associated with such aging process can be achieved through topical management.
• Extrinsic aging of skin is a distinctive process caused by external factors, which include sunlight, radiation, air pollution, wind, cold, dampness, heat and chemicals.
• Photoaging of skin may be defined as destructive cutaneous changes caused by chronic exposure to sunlight. Signs of photoaging on the face and back of hands include coarse and deepened wrinkles due to changes and degeneration of collagen and elastic fibers; marked loss of elasticity and recoilability; leathery skin surface and skin lesions with abnormal pigmentation and increased numbers of age spots, pigmented spots, blotches and nodules. Histologically, the qualities and quantities of elastin and collagen tissues are changed. Normal elastin in tissues is replaced by abnormal elastin characterized as solar elastosis, and the normal collagen fibers are decreased.
• Photodamage of skin also called solar damage, may be defined as cutaneous damage caused by chronic exposure to solar radiation and is associated with development of neoplastic lesions.
• Skin disorders caused by photodamage include pre-malignant lesions, basal cell carcinomas, squamous cell carcinomas and malignant melanomas.
• the intact skin of humans is an effective barrier to many natural and synthetic substances.
• Many cosmetic and pharmaceutical agents which are pharmacologically effective on oral or systemic administration, may be much less effective or even totally ineffective, when applied topically to the skin. Therefore, there is an ongoing need in the art for new and effective regimens for treating aging-related skin conditions.
• the present invention addresses these and other needs in the art by providing novel methods and topical formulations for treating a variety of aging-related skin conditions, including wrinkles, age spots, sun damage (particularly UV radiation-induced oxidative stress), blemishes, hyperpigmented skin, age spots, increased skin thickness, loss of skin elasticity and collagen content, dry skin, lentigines and melasmas.
• Treatment is effected by topical application of a cosmeceutically active base, a surprisingly effective yet simple means for treating aging-related skin conditions.
• a cosmeceutically active base as disclosed herein has not been suggested in the art and represents a significant and unexpected advance in the art.
• the cosmeceutically acceptable base is a hydroxide-releasing agent, such as an inorganic hydroxide (ammonium hydroxide, sodium hydroxide, potassium hydroxide, etc.), an inorganic oxide (magnesium oxide, calcium oxide, etc.), or a metal salt of a weak acid (sodium acetate, potassium bicarbonate, ammonium phosphate, etc.).
• a hydroxide-releasing agent such as an inorganic hydroxide (ammonium hydroxide, sodium hydroxide, potassium hydroxide, etc.), an inorganic oxide (magnesium oxide, calcium oxide, etc.), or a metal salt of a weak acid (sodium acetate, potassium bicarbonate, ammonium phosphate, etc.).
• the cosmeceutically acceptable base is an organic base, particularly a nitrogenous base.
• a topical formulation for carrying out the aforementioned methods, the formulation containing a cosmeceutically active agent consisting essentially of a cosmeceutically acceptable base at a concentration sufficient to provide a formulation pH in the range of approximately 7.5 to 13.0, preferably about 8.0 to 11.5, most preferably about 8.5 to about 11.0.
• a cosmeceutically active base refers not only to a single such base but also to a mixture of two or more cosmeceutically active bases
• reference to “a vehicle” or “a carrier” includes a single vehicle or a single carrier as well as mixtures of two or more vehicles or carriers, and the like.
• treating and “treatment” as used herein refer to reduction in severity and/or elimination of skin related conditions resulting from intrinsic and/or extrinsic aging processes of the skin.
• the present method of “treating” a skin condition related to aging refers to the prevention of aging-related skin conditions as well as the treatment of aging-related skin conditions in affected individuals.
• aging-related skin condition relates to any skin condition or disorder associated with, caused by, or affected by, intrinsic aging and/or extrinsic aging.
• Aging-related skin conditions that may be treated using the present methods and formulations include, but are not limited to, wrinkles, age spots, sun damage (particularly UV radiation-induced oxidative stress), blemishes, hyperpigmented skin, age spots, increased skin thickness, loss of skin elasticity and collagen content, dry skin, lentigines and melasmas.
• cosmetically effective is meant a nontoxic agent that has medicinal or drug-like properties which, when applied to the surface of skin, beneficially affects the biological functioning of that skin.
• compositions of matter which, when topically administered to a human patient, is effective to treat one or more aging-related skin conditions as defined above. Also included are derivatives and analogs of those compounds or classes of compounds specifically mentioned that also induce the desired effect, i.e., treatment of an aging-related skin condition.
• cosmeceutically acceptable such as in the recitation of a “cosmeceutically acceptable carrier,” or a “cosmeceutically acceptable derivative,” is meant a compound that is not biologically or otherwise undesirable, i.e., the compound may be incorporated into a cosmeceutical formulation of the invention and topically administered to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the cosmeceutical formulation in which it is contained.
• hydroxide-releasing agent as used herein is intended to mean an agent that releases free hydroxide ions in an aqueous environment.
• the agent may contain hydroxide ions and thus release the ions directly (e.g., an alkali metal hydroxide), or the agent may be one that is acted upon chemically in an aqueous environment to generate hydroxide ions (e.g., a metal carbonate).
• drug and “pharmacologically active agent” are used interchangeably herein to refer to a chemical material or compound that induces a desired pharmacological effect when administered topically, and include agents that are therapeutically effective, prophylactically effective, or cosmeceutically effective. Also included are derivatives and analogs of those compounds or classes of compounds specifically mentioned that also induce the desired pharmacological effect. Topical pharmacologically active agents are optionally incorporated into the present cosmeceutical formulations. By “therapeutically effective” amount is meant a nontoxic but sufficient amount of a pharmacologically active agent to provide the desired therapeutic effect.
• topical administration is used in its conventional sense to mean topical application of a formulation to the skin.
• Carriers or “vehicles” as used herein refer to carrier materials suitable for incorporation in a topically applied composition. Carriers and vehicles useful herein include any such materials known in the art, which are nontoxic and do not interact with other components of the formulation in which it is contained in a deleterious manner.
• aqueous refers to a formulation that contains water or that becomes water-containing following application to the skin or mucosal tissue.
• alkyl refers to a branched or unbranched saturated hydrocarbon group typically although not necessarily containing 1 to about 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl, and the like, as well as cycloalkyl groups such as cyclopentyl, cyclohexyl and the like. Generally, although again not necessarily, alkyl groups herein contain 1 to about 12 carbon atoms.
• lower alkyl intends an alkyl group of one to six carbon atoms, preferably one to four carbon atoms. “Substituted alkyl” refers to alkyl substituted with one or more substituent groups, and the terms “heteroatom-containing alkyl” and “heteroalkyl” refer to alkyl in which at least one carbon atom is replaced with a heteroatom. If not otherwise indicated, the terms “alkyl” and “lower alkyl” include linear, branched, cyclic, unsubstituted, substituted, and/or heteroatom-containing alkyl or lower alkyl.
• alkenyl refers to a branched or unbranched hydrocarbon group typically although not necessarily containing 2 to about 24 carbon atoms and at least one double bond, such as ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, octenyl, decenyl, and the like. Generally, although again not necessarily, alkenyl groups herein contain 2 to about 12 carbon atoms.
• the term “lower alkenyl” intends an alkenyl group of two to six carbon atoms, preferably two to four carbon atoms.
• Substituted alkenyl refers to alkenyl substituted with one or more substituent groups
• heteroatom-containing alkenyl and “heteroalkenyl” refer to alkenyl in which at least one carbon atom is replaced with a heteroatom.
• aryl refers to an aromatic substituent containing a single aromatic ring or multiple aromatic rings that are fused together, linked covalently, or linked to a common group such as a methylene or ethylene moiety.
• the common linking group may also be a carbonyl as in benzophenone, an oxygen atom as in diphenylether, or a nitrogen atom as in diphenylamine.
• aryl groups contain one aromatic ring and are referred to as “monocyclic aryl.” “Substituted aryl” refers to an aryl moiety substituted with one or more substituent groups, and the terms “heteroatom-containing aryl” and “heteroaryl” refer to aryl in which at least one carbon atom is replaced with a heteroatom.
• heteroatom-containing refers to a molecule or molecular fragment in which one or more carbon atoms is replaced with an atom other than carbon, e.g., nitrogen, oxygen, sulfur, phosphorus or silicon.
• heteroalkyl refers to an alkyl substituent that is heteroatom-containing
• heterocyclic refers to a cyclic substituent that is heteroatom-containing
• heteroaryl refers to an aryl substituent that is heteroatom-containing
• heteroatom-containing When the term “heteroatom-containing” appears prior to a list of possible heteroatom-containing groups, it is intended that the term apply to every member of that group. That is, the phrase “heteroatom-containing alkyl, alkenyl and alkynyl” is to be interpreted as “heteroatom-containing alkyl, heteroatom-containing alkenyl and heteroatom-containing alkynyl.”
• substituted as in “substituted alkyl,” “substituted alkenyl,” “substituted aryl,” and the like, as alluded to in some of the aforementioned definitions, is meant that in the alkyl, alkenyl, aryl, or other moiety, at least one hydrogen atom bound to a carbon atom is replaced with one or more substituents that are functional groups such as hydroxyl, alkoxy, thio, amino, halo, and the like.
• alkyl alkenyl
• aryl aryl
• Any cosmeceutically active base and carrier material may be used at a concentration sufficient to provide a formulation pH in the range of approximately 7.5 to 13.0, preferably about 8.0 to 11.5, most preferably about 8.5 to 11.0, to produce a cream, lotion, solution, spray, gel, ointment, paste or the like, and/or may be prepared so as to contain liposomes, micelles, and/or microspheres, for use in a method of treating an aging-related skin condition.
• the synthetic or naturally occurring suitable bases may be classified into two groups, namely (I) hydroxide-releasing agents and (II) nitrogenous organic bases.
• “Hydroxide-releasing agents” are a chemical compounds that release free hydroxide ions in the presence of an aqueous fluid.
• the aqueous fluid may be natural moisture at the skin surface, or the composition used may contain added water.
• any liquid or semisolid formulation that is used is preferably aqueous or used in conjunction with.
• the pharmacologically active base is a hydroxide-releasing agent, it is preferred although not essential that water be present.
• such a formulation may be aqueous, i.e., contain water, or may be nonaqueous and optionally used in combination with an occlusive overlayer so that moisture evaporating from the body surface is maintained within the formulation upon application to the body surface and thereafter.
• hydroxide-releasing agent may be used provided that the compound releases free hydroxide ions in the presence of an aqueous fluid.
• Hydroxide-releasing agents herein that are suitable cosmeceutically active bases for use in conjunction with the method and formulation of the invention include, but are not limited to, inorganic hydroxides, inorganic oxides, and alkali metal or alkaline earth metal salts of weak acids.
• Inorganic hydroxides include, for example, ammonium hydroxide, alkali metal hydroxide and alkaline earth metal hydroxides, such as sodium hydroxide, calcium hydroxide, potassium hydroxide, magnesium hydroxide, and the like.
• Inorganic oxides include, for example, magnesium oxide, calcium oxide, and the like.
• Metal salts of weak acids include, for example, sodium acetate, sodium borate, sodium metaborate, sodium carbonate, sodium bicarbonate, sodium phosphate (tribasic), sodium phosphate (dibasic), potassium carbonate, potassium bicarbonate, potassium citrate, potassium acetate, potassium phosphate (dibasic), potassium phosphate (tribasic), ammonium phosphate (dibasic), and the like.
• Preferred hydroxide-releasing agents are metal hydroxides such as sodium hydroxide and potassium hydroxide.
• the amount of hydroxide-releasing agent is effective to provide a pH at the body surface in contact with a formulation of the invention (i.e., the interface between the body surface and the formulation) in the range of approximately 7.5 to 13.0, preferably 8.0 to 11.5, most preferably about 8.5 to 11.0.
• a formulation of the invention i.e., the interface between the body surface and the formulation
• the pH of the cosmeceutical formulation per se will be in the range of approximately 7.5 to 13.0, preferably 8.0 to 11.5, most preferably about 8.5 to 11.0.
• the amount of a metal hydroxide in the formulation will be the total of (a) the amount required to neutralize any acidic species in the formulation plus (b) an amount equal to approximately 0.5 wt. % to 4.0 wt. %, preferably about 0.5 wt. % to 3.0 wt. %, more preferably about 0.75 wt. % to 2.0 wt. % and optimally about 1.0 wt. %, of the formulation.
• the amount of hydroxide-releasing agent in the formulation or patch may be substantially higher, as high as 20 wt. %, in some cases as high as 25 wt. % or higher, but will generally be in the range of approximately 2 wt. % to 20 wt. %.
• hydroxide-releasing agent may be used by controlling the rate and/or quantity of release of the hydroxide-releasing agent, preferably during the drug delivery period itself.
• the cosmeceutically active base is not necessarily one that releases hydroxide ions in the presence of water.
• Other bases can also be used.
• Organic bases, particularly nitrogenous bases, represent another class of cosmeceutically active bases useful in the method and formulation of the invention.
• bases are generally selected from primary amines, secondary amines, tertiary amines, amides, oximes, nitrogen-containing heterocycles, and urea.
• Suitable nitrogenous bases may contain any one or a combination of the following:
• R is hydrocarbyl, generally either alkyl or aryl, e.g., lower alkyl or phenyl, and may be substituted with one or more nonhydrocarbyl substituents, e.g., 1 to 3 halo, hydroxyl, thiol, or lower alkoxy groups
• —NHR groups include, for example, methylamino, ethylamino, isopropylamino, butylamino, cyclopropylamino, cyclohexylamino, n-hexylamino, phenylamino, benzylamino, chloroethylamino, hydroxyethylamino, etc.);
• di-substituted (tertiary) amino groups —NR a R b where R a and R b may be the same or different and are as defined above for R (suitable —NR a R b include, for example, dimethylamino, diethylamino, diisopropylamino, dibutylamino, methylpropylamino, methylhexylamino, methylcyclohexylamino, ethylcyclopropylamino, ethylchloroethylamino, methylbenzylamino, methylphenylamino, methyltoluylamino, methyl-p-chlorophenylamino, methylcyclohexylamino, etc.);
• amides —(CO)—NR c R d where R c and R d may be the same or different and are either hydrogen or R, wherein R is as defined above (including, for example, amides wherein one of R c and R d is H and the other is methyl, butyl, benzyl, etc.);
• aromatic nitrogen-containing heterocycles typically five- or six-membered monocyclic substituents, or bicyclic fused or linked five- or six-membered rings (such as pyrrolyl, pyrrolidinyl, pyridinyl, quinolinyl, indolyl, pyrimidinyl, imidazolyl, 1,2,4-triazolyl, tetrazolyl, etc.); and
• non-aromatic nitrogen-containing heterocycles typically four- to six-membered rings, including lactams and imides, e.g., pyrrolidino, morpholino, piperazino, piperidino, N-phenyl- ⁇ -propiolactam, ⁇ -butyrolactam, ⁇ -caprolactam, acetimide, phthalimide, succinimide, etc.
• lactams and imides e.g., pyrrolidino, morpholino, piperazino, piperidino, N-phenyl- ⁇ -propiolactam, ⁇ -butyrolactam, ⁇ -caprolactam, acetimide, phthalimide, succinimide, etc.
• Primary amines, secondary amines, and tertiary amines may be generically grouped as encompassed by the molecular structure NR 1 R 2 R 3 wherein R 1 , R 2 and R 3 are selected from H, alkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, hydroxyalkenyl, alkoxyalkenyl, cycloalkyl, cycloalkyl-substituted alkyl, monocyclic aryl, and monocyclic aryl-substituted alkyl, with the proviso that at least one of R 1 , R 2 and R 3 is other than H.
• amines include, without limitation, diethanolamine, triethanolamine, isopropanolamine, triisopropanolamine, dibutanol amine, tributanol amine, N-dodecylethanolamine, N-(2-methoxyethyl) dodecylamine, N-(2,2-dimethoxyethyl)dodecylamine, N-ethyl-N-(dodecyl)ethanolamine, N-ethyl-N-(2-methoxyethyl)dodecylamine, N-ethyl-N-(2,2-dimethoxyethyl) dodecylamine, dimethyldodecylamine-N-oxide, monolauroyl lysine, dipalmitoyl lysine, dodecylamine, stearylamine, phenylethylamine, triethylamine, PEG-2 oleamine, PEG-2
• R 4 —(CO)—NR 5 R 6 where R 4 , R 5 and R 6 are generally selected from H, alkyl, cycloalkyl, cycloalkyl-substituted alkyl, monocyclic aryl, and monocyclic aryl-substituted alkyl.
• Suitable amides herein include, without limitation, hexamethyleneacetamide, hexamethyleneoctamide, hexamethylene lauramide, hexamethylene palmitamide, N,N-dimethyl formamide, N,N-dimethyl acetamide, N,N-dimethyloctamide, N,N-dimethyldecamide, toluamide, dimethyl-m-toluamide, diethyl-m-toluamide, and combinations thereof.
• Nitrogen-containing heterocycles suitable as the pharmacologically active base herein include, by way of example, 2-pyrrolidone, 1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone, 1,5-dimethyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone, 1-propyl-3-dodecylpyrrolidine, 1-dodecyclazacycloheptan-2-one, ethylene thiourea, hydantoin, oxalylurea, imidazolidilyl urea, N-octadecyl morpholine, dodecylpyridinium, N-dodecylpyrrolidine, N-dodecylpiperidine, N-dodecylhomopiperidine, and combinations thereof.
• the optimum amount of any particular base will depend on the strength or weakness of the base, the molecular weight of the base, and other factors.
• One skilled in the art may readily determine the optimum amount of any particular base by ensuring that a formulation is effective to provide a pH at the skin surface, upon application of the formulation, in the range of about 7.5 to about 13.0, preferably about 8.0 to about 11.5, preferably in the range of about 8.5 to about 11.0. This in turn ensures that the degree of treatment is maximized while the possibility of damage to the body surface is eliminated or at least substantially minimized.
• topical formulations may take any of a wide variety of forms, and include, for example, creams, lotions, solutions, sprays, gels, ointments, pastes or the like, and/or may be prepared so as to contain liposomes, micelles, and/or micro spheres.
• Creams are viscous liquids or semisolid emulsions, either oil-in-water or water-in-oil.
• Cream bases are water-washable, and contain an oil phase, an emulsifier and an aqueous phase.
• the oil phase also called the “internal” phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol.
• the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant.
• the emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant.
• Lotions which are preferred for delivery of cosmetic agents, are preparations to be applied to the skin surface without friction, and are typically liquid or semiliquid preparations in which solid particles, including the active agent, are present in a water or alcohol base.
• Lotions are usually suspensions of solids, and preferably, for the present purpose, comprise a liquid oily emulsion of the oil-in-water type.
• Lotions are preferred formulations herein for treating large body areas, because of the ease of applying a more fluid composition. It is generally necessary that the insoluble matter in a lotion be finely divided.
• Lotions will typically contain suspending agents to produce better dispersions as well as compounds useful for localizing and holding the active agent in contact with the skin, e.g., methylcellulose, sodium carboxymethylcellulose, or the like.
• Solutions are homogeneous mixtures prepared by dissolving one or more chemical substances (solutes) in a liquid such that the molecules of the dissolved substance are dispersed among those of the solvent.
• the solution may contain other pharmaceutically acceptable chemicals to buffer, stabilize or preserve the solute.
• solvents used in preparing solutions are ethanol, water, propylene glycol or any other pharmaceutically acceptable vehicles.
• gels are semisolid, suspension-type systems.
• Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the carrier liquid, which is typically aqueous, but also, preferably, contain an alcohol and, optionally, an oil.
• organic macromolecules i.e., gelling agents, are crosslinked acrylic acid polymers such as the “carbomer” family of polymers, e.g., carboxypolyalkylenes that may be obtained commercially under the Carbopol® trademark.
• hydrophilic polymers such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers and polyvinylalcohol
• cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methyl cellulose
• gums such as tragacanth and xanthan gum
• sodium alginate and gelatin.
• dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing or stirring, or combinations thereof.
• Ointments are semisolid preparations that are typically based on petrolatum or other petroleum derivatives.
• the specific ointment base to be used is one that will provide for optimum drug delivery, and, preferably, will provide for other desired characteristics as well, e.g., emolliency or the like.
• an ointment base should be inert, stable, nonirritating and nonsensitizing. As explained in Remington: The Science and Practice of Pharmacy, 19th Ed.
• ointment bases may be grouped in four classes: oleaginous bases; emulsifiable bases; emulsion bases; and water-soluble bases.
• Oleaginous ointment bases include, for example, vegetable oils, fats obtained from animals, and semisolid hydrocarbons obtained from petroleum.
• Emulsifiable ointment bases also known as absorbent ointment bases, contain little or no water and include, for example, hydroxystearin sulfate, anhydrous lanolin and hydrophilic petrolatum.
• Emulsion ointment bases are either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, and include, for example, cetyl alcohol, glyceryl monostearate, lanolin and stearic acid.
• W/O water-in-oil
• O/W oil-in-water
• Preferred water-soluble ointment bases are prepared from polyethylene glycols of varying molecular weight; again, see Remington: The Science and Practice of Pharmacy for further information.
• Pastes are semisolid dosage forms in which the active agent is suspended in a suitable base. Depending on the nature of the base, pastes are divided between fatty pastes or those made from single-phase aqueous gels.
• the base in a fatty paste is generally petrolatum or hydrophilic petrolatum or the like.
• the pastes made from single-phase aqueous gels generally incorporate carboxymethylcellulose or the like as a base.
• Formulations may also be prepared with liposomes, micelles, and microspheres.
• Liposomes are microscopic vesicles having a lipid wall comprising a lipid bilayer, and can be used as drug delivery systems herein as well. Generally, liposome formulations are preferred for poorly soluble or insoluble pharmaceutical agents. Liposomal preparations for use in the instant invention include cationic (positively charged), anionic (negatively charged) and neutral preparations. Cationic liposomes are readily available.
• N[1-2,3-dioleyloxy)propyl]-N,N,N-triethylammonium (DOTMA) liposomes are available under the tradename Lipofectin® (GIBCO BRL, Grand Island, N.Y.).
• DOTMA N[1-2,3-dioleyloxy)propyl]-N,N,N-triethylammonium
• anionic and neutral liposomes are readily available as well, e.g., from Avanti Polar Lipids (Birmingham, Ala.), or can be easily prepared using readily available materials.
• Such materials include phosphatidyl choline, cholesterol, phosphatidyl ethanolamine, dioleoylphosphatidyl choline (DOPC), dioleoylphosphatidyl glycerol (DOPG), dioleoylphoshatidyl ethanolamine (DOPE), among others. These materials can also be mixed with DOTMA in appropriate ratios. Methods for making liposomes using these materials are well known in the art.
• Micelles are known in the art as comprised of surfactant molecules arranged so that their polar headgroups form an outer spherical shell, while the hydrophobic, hydrocarbon chains are oriented towards the center of the sphere, forming a core. Micelles form in an aqueous solution containing surfactant at a high enough concentration so that micelles naturally result.
• Surfactants useful for forming micelles include, but are not limited to, potassium laurate, sodium octane sulfonate, sodium decane sulfonate, sodium dodecane sulfonate, sodium lauryl sulfate, docusate sodium, decyltrimethylammonium bromide, dodecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide, tetradecyltrimethyl-ammonium chloride, dodecylammonium chloride, polyoxyl-8 dodecyl ether, polyoxyl-12 dodecyl ether, nonoxynol 10 and nonoxynol 30.
• Micelle formulations can be used in conjunction with the present invention either by incorporation into the reservoir of a topical or transdermal delivery system, or into a formulation to be applied to the body surface.
• Microspheres similarly, may be incorporated into the present formulations and drug delivery systems. Like liposomes and micelles, microspheres essentially encapsulate a drug or drug-containing formulation. They are generally although not necessarily formed from lipids, preferably charged lipids such as phospholipids. Preparation of lipidic microspheres is well known in the art and described in the pertinent texts and literature.
• Suitable enhancers include, but are not limited to, ethers such as diethylene glycol monoethyl ether (available commercially as Transcutol®) and diethylene glycol monomethyl ether; surfactants such as sodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide, benzalkonium chloride, Poloxamer® (231, 182, 184), Tween® (20, 40, 60, 80) and lecithin (U.S. Pat. No.
• ethers such as diethylene glycol monoethyl ether (available commercially as Transcutol®) and diethylene glycol monomethyl ether
• surfactants such as sodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide, benzalkonium chloride, Poloxamer® (231, 182, 184), Tween® (20, 40, 60, 80) and lecithin (U.S. Pat. No.
• alcohols such as ethanol, propanol, octanol, benzyl alcohol, and the like; polyethylene glycol and esters thereof such as polyethylene glycol monolaurate (PEGML; see, e.g., U.S. Pat. No. 4,568,343); amides and other nitrogenous compounds such as urea, dimethylacetamide (DMA), dimethylformamide (DMF), 2-pyrrolidone, 1-methyl-2-pyrrolidone, ethanolamine, diethanolamine and triethanolamine; terpenes; alkanones; and organic acids, particularly citric acid and succinic acid.
• Azone® and sulfoxides such as DMSO and C 10 MSO may also be used, but are less preferred.
• enhancers are those lipophilic co-enhancers typically referred to as “plasticizing” enhancers, i.e., enhancers that have a molecular weight in the range of about 150 to 1000, an aqueous solubility of less than about 1 wt. %, preferably less than about 0.5 wt. %, and most preferably less than about 0.2 wt. %.
• the Hildebrand solubility parameter ⁇ of plasticizing enhancers is in the range of about 2.5 to about 10, preferably in the range of about 5 to about 10.
• Preferred lipophilic enhancers are fatty esters, fatty alcohols, and fatty ethers.
• fatty acid esters examples include methyl laurate, ethyl oleate, propylene glycol monolaurate, propylene glycerol dilaurate, glycerol monolaurate, glycerol monooleate, isopropyl n-decanoate, and octyldodecyl myristate.
• Fatty alcohols include, for example, stearyl alcohol and oleyl alcohol
• fatty ethers include compounds wherein a diol or triol, preferably a C 2 -C 4 alkane diol or triol, are substituted with one or two fatty ether substituents.
• compositions of the present invention may be included in addition to those identified above. These include, but are not limited to, antioxidants, astringents, perfumes, preservatives, emollients, pigments, dyes, humectants, propellants, and sunscreen agents, as well as other classes of materials whose presence may be cosmetically, medicinally or otherwise desirable.
• Typical examples of optional additives for inclusion in the formulations of the invention are as follows: preservatives such as sorbate; solvents such as isopropanol and propylene glycol; astringents such as menthol and ethanol; emollients such as polyalkylene methyl glucosides; humectants such as glycerine; emulsifiers such as glycerol stearate, PEG-100 stearate, polyglyceryl-3 hydroxylauryl ether and polysorbate 60; sorbitol and other polyhydroxyalcohols such as polyethylene glycol; sunscreen agents such as octyl methoxyl cinnamate (available commercially as Parsol MCX) and butyl methoxy benzoylmethane (available under the tradename Parsol 1789); antioxidants such as ascorbic acid (vitamin C), ⁇ -tocopherol (Vitamin E), ⁇ -tocopherol, ⁇ -
• conditioners and moisturizing agents include, by way of example, pyrrolidine carboxylic acid and amino acids; organic antimicrobial agents such as 2,4,4′-trichloro-2-hydroxy diphenyl ether (triclosan) and benzoic acid; anti-inflammatory agents such as acetylsalicylic acid and glycyrrhetinic acid; anti-seborrhoeic agents such as retinoic acid; vasodilators such as nicotinic acid; inhibitors of melanogenesis such as kojic acid; and mixtures thereof.
• Other embodiments may include a variety of non-carcinogenic, non-irritating healing materials that facilitate treatment with the formulations of the invention.
• healing materials may include nutrients, minerals, vitamins, electrolytes, enzymes, herbs, plant extracts, glandular or animal extracts, or safe therapeutic agents that may be added to the formulation to facilitate the healing of dermal disorders.
• the amounts of these various additives are those conventionally used in the cosmetics field, and range, for example, from about 0.01% to about 20% of the total weight of the topical formulation.
• the formulations of the invention may also include conventional additives such as opacifiers, fragrance, colorant, gelling agents, thickening agents, stabilizers, surfactants and the like.
• Other agents may also be added, such as antimicrobial agents, to prevent spoilage upon storage, i.e., to inhibit growth of microbes such as yeasts and molds.
• Suitable antimicrobial agents are typically selected from the group consisting of the methyl and propyl esters of p-hydroxybenzoic acid (i.e., methyl and propyl paraben), sodium benzoate, sorbic acid, imidurea, and combinations thereof.
• the formulations may also contain irritation-mitigating additives to minimize or eliminate the possibility of skin irritation or skin damage resulting from the chemical entity to be administered, or other components of the composition.
• Suitable irritation-mitigating additives include, for example: a-tocopherol; monoamine oxidase inhibitors, particularly phenyl alcohols such as 2-phenyl-1-ethanol; glycerin; salicylates; ascorbates; ionophores such as monensin; amphiphilic amines; ammonium chloride; N-acetylcysteine; capsaicin; and chloroquine.
• the irritation-mitigating additive if present, may be incorporated into the present enhancer compositions at a concentration effective to mitigate irritation or skin damage, typically representing not more than about 20 wt. %, more typically not more than about 5 wt. %, of the formulation.
• the formulations of the invention may also contain a therapeutically effective amount of a pharmacologically active agent suitable for topical administration.
• a pharmacologically active agent suitable for topical administration.
• agents include an asymmetrical lamellar aggregate consisting of phospholipids and oxygen-loaded fluorocarbon or a fluorocarbon compound mixture, which are capable of improving oxygen supply in skin tissue, as described, for example, in International Patent Publication Nos. WO 94/00098 and WO 94/00109.
• Suitable pharmacologically active agents that may be incorporated into the present formulations and thus topically applied along with the cosmeceutically active base include, but are not limited to, the following: agents that improve or eradicate pigmented or non-pigmented age spots, keratoses and wrinkles; antimicrobial agents; antibacterial agents; antipruritic and antixerotic agents; antiinflammatory agents; local anesthetics and analgesics; corticosteroids; retinoids; vitamins; hormones; and antimetabolites.
• topical pharmacologically active agents include acyclovir, amphotericins, chlorhexidine, clotrimazole, ketoconazole, econazole, miconazole, metronidazole, minocycline, nystatin, neomycin, kanamycin, phenytoin, para-amino benzoic acid esters, octyl methoxycinnamate, octyl salicylate, oxybenzone, dioxybenzone, tocopherol, tocopheryl acetate, selenium sulfide, zinc pyrithione, diphenhydramine, pramoxine, lidocaine, procaine, erythromycin, tetracycline, clindamycin, crotamiton, hydroquinone and its monomethyl and benzyl ethers, naproxen, ibuprofen, cromolyn, retinol, retin
• a pharmacological acceptable carrier may also be incorporated in the cosmeceutical formulation of the present invention and may be any carrier conventionally used in the art. Examples thereof include water, lower alcohols, higher alcohols, polyhydric alcohols, monosaccharides, disaccharides, polysaccharides, hydrocarbon oils, fats and oils, waxes, fatty acids, silicone oils, nonionic surfactants, ionic surfactants, silicone surfactants, and water-based mixtures and emulsion-based mixtures of such carriers.
• the method of delivery of the active agent may vary, but necessarily involves application of a formulation of the invention to an area of body surface prone to or affected by an aging-related skin condition, e.g., any skin condition or disorder associated with, caused by, or affected by, intrinsic aging and/or extrinsic aging.
• the aging-related skin condition may, for example, involve wrinkles, age spots, sun damage (particularly UV radiation-induced oxidative stress), blemishes, hyperpigmented skin, age spots, increased skin thickness, loss of skin elasticity and collagen content, dry skin, lentigines and melasmas.
• a cream, lotion, gel, ointment, paste or the like may be spread on the affected surface and gently rubbed in.
• a solution may be applied in the same way, but more typically will be applied with a dropper, swab, or the like, and carefully applied to the affected areas.
• the application regimen will depend on a number of factors that may readily be determined, such as the severity of the condition and its responsiveness to initial treatment, but will normally involve one or more applications per day on an ongoing basis.
• One of ordinary skill may readily determine the optimum amount of the formulation to be administered, administration methodologies and repetition rates. In general, it is contemplated that the formulations of the invention will be applied in the range of once or twice weekly up to once or twice daily.
• a cream composition containing 30% dodecylamine is formulated as follows. Dodecylamine (30 grams) is dissolved in propylene glycol (15 ml). The solution thus prepared is mixed with hydrophilic ointment (55 grams) until a consistent cream is obtained.
• a cream composition containing 25% N,N-dimethyloctamide is formulated as follows. N,N-Dimethyloctamide (25 grams) is dissolved in propylene glycol (15 ml). The solution thus prepared is mixed with hydrophilic ointment (55 grams) until a consistent cream is obtained.
• a solution composition containing 5% stearylamine, in oil-in-water emulsion is prepared as follows. Stearylamine, (5 grams) is dissolved in propylene glycol (10 ml). The solution is then mixed with hydrophilic ointment, USP grade (85 grams) and the mixing continued until a uniform consistency is obtained.
• a cream composition containing 10% isopropanolamine in oil-in-water emulsion is prepared as follows. Isopropanolamine (10 grams) are dissolved in propylene glycol (20 ml). The solution is then mixed with hydrophilic ointment, USP grade (70 grams) and the mixing continued until a uniform consistency is obtained.
• a cream composition containing 25% 1-ethyl-2-pyrrolidone is formulated as follows. 1-Ethyl-2-pyrrolidone (25 grams) is dissolved in propylene glycol (5 ml). The solution thus prepared is mixed with hydrophilic ointment (70 grams) until a consistent cream is obtained.
• a therapeutic composition containing 5% hydroquinone and 8% N-ethyl-N(dodecyl)ethanolamine in solution form for age spots, melasmas, lentigines and other pigmented skin spots may be formulated as follows. N-Ethyl-N-(dodecyl)ethanolamine (8 grams), hydroquinone (5 grams) and sodium metabisulfite (0.5 grams) are dissolved in a mixture of ethanol (70 ml), water (15 ml) and propylene glycol (7 ml) with stirring until a clear solution is obtained.
• a therapeutic composition containing 0.5% hydrocortisone and 10% N-ethyl-N-(dodecyl)ethanolamine in solution form for use as an anti-inflammatory agent may be formulated as follows. N-Ethyl-N-(dodecyl)ethanolamine (10 grams), hydrocortisone (0.5 grams) are dissolved in a mixture of ethanol (70 ml), water (10 ml) and propylene glycol (10 ml) with stirring until a clear solution is obtained.
• a therapeutic composition containing 5% hydroquinone and 8% N,N-dimethyldecamide in solution form for age spots, keratoses, melasmas, lentigines and other pigmented skin spots may be formulated as follows. N,N-Dimethyldecamide (8 grams), hydroquinone (5 grams) and sodium metabisulfite (0.5 grams) are dissolved in a mixture of ethanol (75 ml), water (10 ml) and propylene glycol (7 ml) with stirring until a clear solution is obtained.
• a therapeutic composition containing 1% hydrocortisone and 8% N,N-dimethyloctamide in solution form for use as an anti-inflammatory agent may be formulated as follows. N,N-Dimethyloctamide (8 grams) and hydrocortisone (1 gram) are dissolved in a mixture of ethanol (70 ml), water (15 ml) and propylene glycol (7 ml) with stirring until a clear solution is obtained.
• a therapeutic composition containing 2% kojic acid and 10% N-ethyl-N-(dodecyl)ethanolamine in solution form for age spots, keratoses, melasmas, lentigines and other pigmented skin spots may be formulated as follows. N-Ethyl-N-(dodecyl)ethanolamine (10 grams), kojic acid (2 grams) are dissolved in a mixture of ethanol (70 ml), water (10 ml) and propylene glycol (10 ml) with stirring until a clear solution is obtained.
• a sunscreen composition containing 5% octyl dimethyl para-amino benzoate, 3% dioxybenzone and 2% hexamethyleneoctamide may be formulated as follows. Octyl dimethyl para-aminobenzoate (5 grams), dioxybenzone (3 grams) and hexamethyleneoctamide (2 grams) are dissolved in a mixture of ethanol (75 ml), water (10 ml) and propylene glycol (15 ml) with stirring until a clear solution is obtained.
• a therapeutic composition containing 5% monolauroyl lysine to alleviate dry or flay skin may be formulated as follows. Monolauroyl lysine (5 grams) is dissolved in ethanol (20 ml), and the solution thus obtained is mixed with hydrophilic ointment USP (75 grams) with stirring until a uniform consistency is obtained.
• a therapeutic composition containing 0.5% hydrocortisone and 2% potassium phosphate (dibasic) in solution form for use as an anti-inflammatory agent may be formulated as follows. Potassium phosphate (dibasic) (2 grams) and hydrocortisone (0.5 grams) are dissolved in a mixture of ethanol (80 ml), water (15 ml) and propylene glycol (5 ml) with stirring until a clear solution is obtained.
• a therapeutic composition containing 0.5% hydrocortisone and 2% sodium phosphate (tribasic) in solution form for use as an anti-inflammatory agent may be formulated as follows. Sodium phosphate (dibasic) (2 grams) and hydrocortisone (0.5 grams) are dissolved in a mixture of ethanol (80 ml), water (15 ml) and propylene glycol (5 ml) with stirring until a clear solution is obtained.
• a therapeutic composition containing 3% hydroquinone and 5% potassium citrate in solution form for age spots, keratoses, melasmas, lentigines and other pigmented skin spots may be formulated as follows. Potassium citrate (5 grams), hydroquinone (3 grams) are dissolved in a mixture of ethanol (80 ml), water (10 ml) and propylene glycol (10 ml) with stirring until a clear solution is obtained.
• a therapeutic composition containing 5% hydroquinone and 8% ammonium phosphate (dibasic) in solution form may be formulated as follows. Ammonium phosphate (dibasic) (8 grams), hydroquinone (5 grams) are dissolved in a mixture of ethanol (80 ml), water (10 ml) and propylene glycol (10 ml) with stirring until a clear solution is obtained.
• a cream composition containing 10% isopropanolamine and 1% hydrocortisone in oil-in-water emulsion is prepared as follows. Isopropanolamine (10 grams) and hydrocortisone (1 gram) are dissolved in propylene glycol (20 ml). The solution is then mixed with hydrophilic ointment, USP grade (70 grams) and the mixing continued until a uniform consistency is obtained.
• a cream composition containing 15% N,N-dimethyloctamide and 2% hydroquinone is formulated as follows. N,N-Dimethyloctamide (15 grams) and hydroquinone (2 grams) are dissolved in propylene glycol (5 m)l. The solution thus prepared is mixed with hydrophilic ointment (80 grams) until a consistent cream is obtained.
• a solution composition containing 10% hexamethylene palmitide, in oil-in-water emulsion is prepared as follows. Hexamethylene palmitide, (10 grams) is dissolved in propylene glycol (10 ml). The solution is then mixed with hydrophilic ointment, USP grade (80 grams) and the mixing continued until a uniform consistency is obtained.

Landscapes

• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Birds (AREA)
• Epidemiology (AREA)
• Dermatology (AREA)
• Chemical & Material Sciences (AREA)
• Inorganic Chemistry (AREA)
• Gerontology & Geriatric Medicine (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Pharmacology & Pharmacy (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Toxicology (AREA)
• Medicinal Preparation (AREA)
• Cosmetics (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Priority Applications (7)

Applications Claiming Priority (1)

Related Child Applications (1)

Publications (1)

Family

ID=25506145

Family Applications (2)

Family Applications After (1)

Country Status (5)

Cited By (11)

Families Citing this family (29)

Family Cites Families (34)

• 2001
  • 2001-09-24 US US09/962,622 patent/US20030059450A1/en not_active Abandoned
• 2002
  • 2002-09-23 US US10/252,784 patent/US7205003B2/en not_active Expired - Fee Related
  • 2002-09-23 JP JP2003530315A patent/JP2005528323A/ja active Pending
  • 2002-09-23 WO PCT/US2002/030162 patent/WO2003026680A2/en active Application Filing
  • 2002-09-23 EP EP02766342A patent/EP1429791A4/en not_active Withdrawn
  • 2002-09-23 CA CA002464436A patent/CA2464436A1/en not_active Abandoned

Also Published As

Similar Documents

Legal Events