Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q7/00—Preparations for affecting hair growth
• • 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
  • A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
• • 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
  • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof

Definitions

• the invention relates to a cosmetic composition for topical application to mammalian skin or hair for increasing or at least maintaining hair growth, especially terminal hair growth on the human scalp.
• the hair growth cycle can be divided into three main stages, namely: i) an active stage known as anagen, during which the hair follicle penetrates deep into the dermis with the cells of the bulb dividing rapidly and differentiating to form the hair,
• a regressive stage known as catagen which is heralded by the cessation of mitosis, and during which the follicle regresses upwards through the dermis and hair growth ceases, and
• telogen a resting stage known as telogen, in which the regressed follicle contains a small secondary germ with an underlying ball of tightly packed dermal papilla cells.
• citrulline which condenses with aspartate to form argininosuccinate, may also regulate the steps of arginine/urea synthesis by its availability, which would depend on oxaloacetate and in turn TCA cycle intermediates.
• arginine may also be important for the availability of arginine.
• RNA and protein biosynthesis due to its being an essential amino acid.
• the significance of ornithine may be due to its role in the generation of arginine in the follicle rather than to urea.
• fumarate is produced which can feed into the TCA cycle and contribute to anaplerotic reactions.
• ithout ornithine and arginine the ammonia which results from a surplus of nitrogen caused by glutaminolysis may rise to toxic levels and prove fatal to cell function due its inhibition of transaminase reactions and hyperglutaminaemia.
• the invention is accordingly concerned with the use of these intermediates in hair follicle metabolism, so as to increase or maintain hair growth.
• the invention provides a composition which is suitable for topical application to mammalian skin or hair for increasing, enhancing or maintaining hair growth, which composition comprises: i) an effective amount of a metabolic intermediate of the urea cycle chosen from arginine, ornithine, citrulline, argininosuccinate, their salts, hydrosalts and precursors thereof, and mixtures thereof; and ii) a cosmetically acceptable vehicle for the intermediate.
• a metabolic intermediate of the urea cycle chosen from arginine, ornithine, citrulline, argininosuccinate, their salts, hydrosalts and precursors thereof, and mixtures thereof.
• the invention provides a method of increasing, enhancing or maintaining hair growth by use of such a composition. Use is by topical application especially to the bald or balding human scalp.
• the invention is concerned with the utilisation of a metabolic intermediate which is part of the urea cycle, or a derivative of such a metabolic intermediate, and its topical application for the purposes of increasing or maintaining hair growth, particularly on the human scalp.
• a metabolic intermediate which is part of the urea cycle, or a derivative of such a metabolic intermediate, and its topical application for the purposes of increasing or maintaining hair growth, particularly on the human scalp.
• SUBSTITUTE SHEET (TCA) cycle is shown in Figure 1. From this, four metabolic intermediates of the urea cycle, namely arginine, ornithine, citrulline and argininosuccinate have been selected as possessing the ability to promote linear hair growth to an extent which is significantly greater than glutamine itself.
• Each of these four metabolic intermediates can therefore incorporated into a composition for topical application to skin or hair, in particular the scalp, for promoting or at least maintaining hair growth.
• a particularly preferred example of a salt is the sodium salt, and a preferred example of a hydro salt is a hydrohalide especially the hyrochloride derivatives of these intermediates.
• R 1 is chosen from:
• amino acid residues or substituted amino acid residues as herein defined, being derived from one or more of the following amino acids:
• DOPA L-3,4-dihydroxyphenylalanine
• alkali metal cations chosen from Na + and K + , (i ⁇ ) NH 4 + or alkanolam onium ions, and
• x is a integer of from 1 to 22, and y is an integer of from 3 to 45;
• hydrohalide derivatives of urea cycle intermediates are:
• alkali metal salt derivatives of urea cycle intermediates are:
• dipeptide derivatives of urea cycle intermediates are:
• composition can comprise two or more urea cycle intermediates or derivatives thereof, as herein defined.
• the chosen urea cycle intermediate is citrulline, or a derivative thereof
• it is preferably to include aspartate in the composition according to the invention, in view of the combination of citrulline and aspartate to from arginosuccinate, as is evident from Figure 1.
• carbamoyl phosphate when the chosen urea cycle intermediate is ornithine, or a derivative thereof, it is advantageous to include carbamoyl phosphate in the composition accordingly to the invention, as carbamoyl phosphate promotes the formulation of citrulline from ornithine, as can also be seen from Figure 1.
• the total amount of the urea cycle intermediate or derivative thereof present in the composition according to the invention is an amount which is sufficient to induce maintain or increase hair growth. This amount will depend on the effectiveness of the intermediate, some being more effective than others, but in general an amount of from 0.001 to 99%, usually from 0.01 to 30% by weight of the composition will provide an adequate concentration for application to the skin, particularly the scalp, which can then be repeated as necessary to promote hair growth.
• composition according to the invention also comprises a solid, semi-solid or liquid cosmetically and/or physiologically acceptable vehicle, to enable the urea cycle intermediate, or derivative thereof, to be conveyed to the skin at an appropriate dilution.
• vehicle will depend upon the method chosen for topical administration of the composition.
• the vehicle can itself be inert or it can possess physiological or pharmaceutical benefits of its own.
• a vehicle for this purpose presents a wide range of possibilities depending on the required product form of the composition. Suitable vehicles can be classified as described hereinafter.
• vehicles are substances which can act as diluents, dispersants, or solvents for the urea cycle intermediate, or derivative thereof, which therefore ensure that they can be applied to and distributed evenly over the hair and/or scalp at an appropriate concentration.
• the vehicle is preferably one which can aid penetration of the esters into the skin to reach the immediate environment of the hair follicle, compositions according to the invention can include water as a vehicle, and/or at least one cosmetically acceptable vehicle other than water.
• Vehicles other than water can include liquid or solid emollients, solvents, humectants, thickeners and powders. Examples of each of these types of vehicle, which can be used singly or as mixtures of one or more vehicles, are as follows:
• Emollients such as stearyl alcohol, glyceryl monoricinoleate, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, eicosanyl alcohol, behenyl alcohol, cetyl palmitate, silicone oils such as dimethylpolysiloxane, di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, cocoa butter, corn oil, cotton seed oil, olive oil, palm kernel oil, rapeseed oil, safflower seed oil, evening primrose oil, soybean oil,
• Propellants such as propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide;
• Solvents such as ethyl alcohol., methylene chloride, isopropanol, acetone, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulphoxid ⁇ , dimethyl formamide, tetrahydrofuran;
• Powders such as chalk, talc, fullers earth, kaolin, starch, gums, colloidal silica sodium polyacrylate, tetra alkyl and/or trialkyl aryl ammonium smectites, chemically modified magnesium aluminium silicate, organically modified montmorillonite clay, hydrated aluminium silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, ethylene glycol monostearate, ethylene glycol distearate;
• the cosmetically acceptable vehicle will usually form from 10 to 99.999%, preferably from 10 to 99% and most preferably from 50 to 99% by weight of the emulsion, and can, in the absence of other cosmetic adjuncts, form the balance of the composition.
• composition according to the invention can also optionally comprise an activity enhancer.
• the activity enhancer can be chosen from a wide variety of molecules which can function in different ways to enhance the hair growth effects of the urea cycle intermediate.
• Particular classes of activity enhancers include (a) other hair growth stimulants, (b) penetration enhancers and (c) cationic polymers, whose presence can further improve the delivery of the ester through the stratum corneum to its site of action in the immediate environment of the hair follicle.
• Some activity enhancers can also function as vehicles for the ester. .a. Other Hair Growth Stimulants
• Glycosaminoglycanase inhibitors as described by Unilever in EP 0 277 428, such as D-Glucaro-1,4- lactone.
• Glycosaminoglycanase inhibitors as described by Unilever in EP 0 277 428, such as N- acetylglucosamine.
• x. Glycosa inoglycan chain cellular uptake inhibitors as described by Unilever in EP 0 277 428, such as hexuronic acid and esters thereof.
• Glycosaminoglycanase inhibitors as described by Unilever in EP 0 348 184, chosen from acylated monosaccharides , such as 2-propionamido-2- deoxyglucose.
• esters of pyroglutamic acid as described by Lever Brothers Company in US 4 774 255, such as pyroglutamic acid ,n-hexyl ester and pyroglutamic acid n-octyl ester.
• a penetration enhancer can potentiate the benefit of the urea cycle intermediate or derivative thereof by improving its delivery through the stratum corneum to its site of action in the hair follicle.
• the penetration enhancer can accordingly function in a variety of ways. It can for example, improve the distribution of the urea cycle intermediate on the skin surface or, it can increase its partition into the skin from the composition when applied topically, so aiding its passage to its site of action. Other mechanisms enhancing the benefit of the hair growth promoter may also be involved.
• penetration enhancers examples include:
• a cationic polymer can potentiate the benefit of the urea cycle intermediate or derivative thereof by improving its delivery to the hair and scalp.
• preferred cationic polymers include:
• Quaternised poly dimethylaminoethylmethacrylate
• the amount of activity enhancer when employed in accordance with the invention, will normally be from 0.1 to 50%, preferably from 0.5 to 25% and most preferably from 0.5 to 10% by weight of the composition.
• composition according to the invention is an emulsion, in which case an oil or oily material will normally be present, together with an emulsifier to provide either a water-in-oil emulsion or an oil-in-water emulsion, depending largely on the average hydrophilic-lyophilic balance (HLB) of the emulsifier employed.
• HLB hydrophilic-lyophilic balance
• composition according to the invention can optionally comprise one or more oils or other materials having the properties of an oil.
• oils examples include mineral oil and vegetable oils, and oil materials, such as those already proposed herein as emollients.
• oils or oily materials include silicone oils, both volatile and non- volatile, such as polydimethyl siloxanes.
• the oil or oily material when present for . the purposes for forming an emulsion, will normally form up to 90%, preferably from 10 to 80% by volume of the composition.
• composition according to the invention can also optionally comprise one or more emulsifiers the choice of which will normally determine whether a water-in-oil or and oil-in-water emulsion is formed.
• the chosen emulsifier or emulsifiers should normally have an average HLB value of from 1 to 6.
• a chosen emulsifier or emulsifiers should have an average HLB value of >6.
• Suitable emulsifiers are set below in Table 1 in which the chemical name of the emulsifiers is given together with an example of a trade name as commercially available, and the average HLB value.
• Sorbitan trioleate Sorbitan tristearate Glycerol monooleate Glycerol monostearate Glycerol monolaurate Sorbitan sesquioleate Sorbitan monooleate Sorbitan monostearate Poloxyethylene (2) stearyl ether Poloxyethylene sorbitol beeswax derivative PEG 200 dilaurate Sorbitan monopalraitate Polyoxyethylene (3.5) nonyl phenol PEG 200 monostearate
• the amount of emulsifier or mixtures thereof, to be incorporated in the composition of the invention, when appropriate is from 1 to 50%, preferably from 2 to 20% and most preferably from 2 to 10% by weight of the composition.
• composition of the invention can also comprise water, usually up to 90%, preferably from 5 to 80% by volume. Water can function as the cosmetically acceptable vehicle.
• composition of the invention can also optionally comprise a high molecular weight silicone surfactant which can also act as an emulsifier, in place of or in addition to the optional emulsifier(s) already mentioned.
• a high molecular weight silicone surfactant which can also act as an emulsifier, in place of or in addition to the optional emulsifier(s) already mentioned.
• the silicone surfactant is a high molecular weight polymer of dimethyl polysiloxane with polyoxyethylene and/or polyoxypropylene side chains having a molecular weight from 10,000 to 50,000.
• the dimethyl polysiloxane polymer is conveniently provided as a dispersion in a volatile siloxane, the dispersion comprising, for example, from 1 to 20% by volume of the polymer and from 80 to 99% by volume of the volatile siloxane.
• the dispersion consists of a 10% by volume of the polymer dispersed in the volatile siloxane.
• Examples of the volatile siloxanes in which the polysiloxane polymer can be dispersed include polydimethyl siloxane (pentamer and/or hexamer) .
• a particularly preferred silicone surfactant is cyclomethicone and dimethicone copolyol, such as DC 3225C
• Formulation Aid available from DOW CORNING. Another is laurylmethicone copolyol, such as DC Q2-5200, also available from Dow Corning.
• the amount of silicone surfactant, when present in the composition will normally be up to 25%, preferably from 0.5 to 15% by weight of the emulsion.
• composition for use in the method according to the invention can be formulated as a shampoo and will then accordingly comprise one or more surfactants which are cosmetically acceptable and suitable for topical application to the hair.
• suitable shampoo surfactants are given below.
• a composition is formulated to contain surfactant in a quantity of 4% by weight or more, it may prove desirable to use the metabolic intermediate in a concentration of more than 5% by weight, possibly more than 8% by weight. This may even prove desirable when surfactant is present in lower concentrations, such as 1% by weight or more.
• composition of the invention can comprise an anionic surfactant which is preferably chosen from alkyl sulphate, alkyl ether sulphate, alkyl sulphonate, alkyl aryl sulphonate, olefin sulphonate, acyl sarcosinate, acyl tauride, acyl isethionate, nonoalkyl sulphosuccinate, dialkylsulphosuccinate, acryl lactylate, acylated ⁇ -amino acid, alkyl carboxylate, monoalkyl phosphate and dialkyl phosphate.
• anionic surfactant which is preferably chosen from alkyl sulphate, alkyl ether sulphate, alkyl sulphonate, alkyl aryl sulphonate, olefin sulphonate, acyl sarcosinate, acyl tauride, acyl isethionate, nonoalkyl s
• anionic surfactants include: alkyl sulphates, such as sodium lauryl sulphate [eg. EMPICOL CX available from Albright & Wilson] , and triethanolamine lauryl sulphate [eg. EMPICOL TL40/T, available from Albright & Wilson] .
• alkylether sulphates such as sodium lauryl ether sulphate
• alkyl sulphonates such as sodium alkane (C 13 _ 18 ) sulphonate [eg. HOSTAPUR SAS 30, available from Hoechst] .
• alkylaryl sulphonates such as sodium alkyl benzene sulphonate [eg. TEEPOL CM44, available from Shell] .
• SUBSTITUTESHEET olefin sulphonates such as sodium olefin sulphonate (C 5 _ 18 ) [eg. HOSTAPUR OS, available from Hoechst] .
• R 3 is chosen from C 6 . 1 alkyl
• M is a counterion chosen from alkali metals, ammonium and substituted ammonium such as alkanolammonium.
• acyl sarcosinate having the structure (51) is sodium lauryl sarcosinate [eg. HAMPOSYL L-95, available from Grace].
• acyl taurides having the structure (52) :
• R is chosen from C 8 . 18 alkyl
• acyl tauride having the structure (52) is coconut methyl taurine [eg. FENOPEN TC 42, available from GAF] .
• R 5 is chosen from C 8 _ 18 alkyl.
• acyl isethionate having the structure (53) is sodium acyl isethionate [eg. JORDAPON Cl, available from Jordon] .
• R 6 is chosen from C 10 _ 20 alkyl.
• Examples of monoalkyl sulphosuccinates having the structure (54) include:
• sodium lauryl sulphosuccinate eg. EMPICOL SLL, available from Albright & Wilson
• magnesium alkyl sulphosuccinate eg. ELFANOL 616 Mg, available from AKZO.
• sodium lauryl ethoxysulphosuccmate eg. EMPICOL SDD, available from Albright & Wilson.
• coconut monoethanolamide ethoxysulphosuccmate eg. EMPICOL SGG
• disodium lauryl polyglvcolether sulphosuccinate eg. SURTAGENE S30, available from CHEM-Y] .
• polyethylene ⁇ lvcol sulphosuccinate eg. REWOPOL SBFA 30, available from REWO] .
• dialkyl sulphosuccinates having the structure (55) :
• R 7 and R 8 are the same or different, and are chosen from C 6 _ 1 alkyl.
• dialkyl sulphosuccinate having the structure (55) is sodium dilauryl sulphosuccinate [eg. EMCOL 4500, available from Witco] .
• R 9 is chosen from C 6 . 16 alkyl
• n is 1. or 2.
• acyl lactylate having the structure (6) is decanoyl lactylate [eg. PATIONIC 122a, available from Patterson, CJ] .
• ethyl carboxlates such as alkyl C 12 _ 14 0(EO) ⁇ OCH 2 C0 2 Na [eg. AKYPO RLM 38, available from Akzo].
• monoalkyl phosphates such as monolauryl phosphate, and dialkyl phosphates. such as dioctyl phosphate.
• the shampoo compositions of the invention also comprise amphoteric surfactant.
• Suitable amphoteric surfactants are derivatives of aliphatic quaternary ammonium, phosphonium and sulphonium ⁇ ompunds, wherein the aliphatic radicals contain from 8 to 18 carbon atoms, and may be straight chain or branched, and further contain an anionic water-solubilising group, such as carboxyl, sulphonate, sulphate, phosphate or phosphonate.
• Preferred amphoteric surfactants include:
• Alkyl betaines having the structure (57) :
• R 10 is C ⁇ alkyl
• alkyl betaine having the structure (57) is lauryldimethyl betaine [eg. EMPIGEN BB, available from Albright & Wilson] .
• Alkylamidopropyl betines having the structure (58) :
• alkylamidopropyl betaine having the structure (58) is cocamidcpropyl betaine [eg. TEGOBETAIN L7, available from Goldsch idt) .
• Alkylamphoqlvcinates or Alkylamphopropionates having the structure (59) :
• R 11 is chosen from H, CH 2 COO " and (CH 2 ) 2 COO "
• R 12 is chosen from CH 2 COO " and (CH 2 ) 2 COO ⁇
• Suitable examples of compounds (59) are cocoamphoglycinate (available from GAF) , and cocoamphopropionate.
• R 13 is chosen from C 12 _ 16 alkyl alkylamido groups.
• An example of a sultaine having the structure (60) is cocamidopropylhydroxysultaine [eg. CYCLOTERIC BET-CS, available from Alcolac) .
• amphoteric surfactant are lauryl dimethyl betaine and cocamidopropyl betaine.
• amphoteric surfactants can contribute to the foaming of the shampoo of the invention, while ameliorating the harshness of the anionic surfactant.
• the shampoo composition of the invention can also comprise alkoxylated or glycosidic nonionic surfactant having an HLB of 8 or more. Above this value nonionics generally form clear isotropic solutions in combination with the other surfactants in the ranges defined above.
• Preferred nonionic surfactants are polyoxyethylene alkyl esters and polyoxyethylene alkyl ethers and alkyl p ⁇ lyglycosides.
• a suitable example of a polyoxyethylene alkyl ester is that having the CTFA designation Polysorbate 80 which is a mixture of oleate esters of sorbitol and sorbitol anhydrides, condensed with approximately 20 moles of ethylene oxide. Also suitable is Polysorbate 20 which is a mixture of laurate esters or sorbitol and sorbitol anhydrides condensed with approximately 20 moles of ethylene oxide.
• Polysorbate 80 and Polysorbate 20 are available commercially as TWEEN 80 and TWEEN 20 respectively, from ICI Americas.
• compositions of the invention are also suitable for use in the compositions of the invention.
• polyethylene glycol ether of Cg.- ⁇ alcohol with an average of 8 ethoxy units which is available commercially as NONIDET LE-8T or as SYNPERONIC 91-8T
• polyethylene glycol ether of C 12 _ 13 alcohol with an average of 9 ethoxy units which is available commercially as DOBANOL 25-9.
• alkyl polyglycosides include the glycosides of glucose or glucose oligomers where the alkyl chain can be C 8 . 16 and the average number of glucose units is 1 to 2.
• a suitable example is ORAMIX NS 10 which is the glucoside of C 10 . 12 fatty alcohol with an average of about 1.5 glucose units.
• the amount of surfactant that can be present in the composition accordingly to the invention is up to 30%, preferably from l to 20% by weight of the composition.
• adjuncts examples include antioxidants, such butyl hydroxy toluene; sunscreens, such as octyl methoxycinnamate and butylmethoxy di-benzoyl methane; film forming agents, such as perfluoropolymethylisopropyl ether humectants, such as glycerol, sorbitol, 2-pyrrolidone-5-carboxylate, dibutylphthalate, gelatin, polyethylene glycol, such as PEG 200-600; buffers, such as lactic acid together with a base such as triethanolamine or sodium hydroxide; waxes, such as beeswax, ozokerite wax, paraffin wax: plant extracts, such as Aloe vera, cornflower, witch hazel, elderflower, cucumber; thickeners; activity enhancers; colourants; and perfumes. Cosmetic adjuncts can form the balance of the composition.
• Cosmetic adjuncts can form the balance of the composition.
• composition according to the invention is preferably preserved in such a manner that it will enjoy an extended shelf life following manufacture and prior to sale and use. Ideally the composition will have an indefinite shelf life.
• the urea cycle intermediate is likely to be prone to attack by bacteria, moulds and fungi and other microbial influences, particularly at pH values near that of the skin that characterise the preferred composition.
• the shelf-life of the composition can therefore be unacceptably short due to the biodegradation of the precursor unless steps are taken to preserve the composition.
• the composition should preferably be free, or substantially free, from viable microbial contaminants that are capable of resulting in microbial spoilage of the composition, and/or biodegradation of the precursor prior to topical application of the composition to mammalian skin or hair. It is to be understood, however, that the invention is also concerned with compositions, as herein defined, which may contain viable but dormant microorganisms, such as bacterial spores, provided that the conditions of preservation do not result in substantial proliferation of the microorganisms prior to use of the composition.
• composition according to the invention can be preserved by sterilisation to remove or kill substantially all viable microbial contaminants. This can be achieved for example by irradiation using a lethal dose of gamma rays, by heat sterilisation or by ultrafiltration using techniques that are well established in the pharmaceutical industry.
• composition according to the invention can also be preserved by including in it a chemical preservative which functions to prevent the growth of or kill bacteria, fungi or other microorganisms.
• Examples of chemical preservatives include ethanol, benzoic acid, sodium benzoate, sorbic acid, potassium sorbate, sodium propionate and the methyl, ethyl, propyl and butyl esters of p-hydroxybenzoic acid.
• the amount of chemical preservative that can be incorporated in the composition according to the invention will generally be from 0.05 to 5%, preferably from 0.1 to 2% by weight, the amount chosen being sufficient to arrest microbial proliferation.
• composition according to the invention can also be preserved by the inclusion of a water activity depressant such as glycerol, propylene glycol, sorbitol, sugars and salts, for examples alkali metal halides sulphates and carboxylates.
• a water activity depressant such as glycerol, propylene glycol, sorbitol, sugars and salts, for examples alkali metal halides sulphates and carboxylates.
• a water activity depressant sufficient should be incorporated in the composition according to the invention to reduce the water activity (c_ w ) from 1 to ⁇ 0.9, preferably to ⁇ 0.85 and most preferably ⁇ 0.8, the lowest of these values being that at which yeasts, moulds and fungi will not proliferate.
• the topical skin and/or hair treatment composition of the invention can be formulated shampoo or hair conditioner, or as a liquid or gel, or as a lotion having a viscosity of from 4,000 to 10,000 mPas, a fluid cream having a viscosity of from 10,000 to 20,000 mPas or a cream having a viscosity of from 20,000 to 100,000 mPas, or above.
• the composition can be packaged in a container to suit its viscosity and intended use by the consumer.
• a shampoo, conditioner, liquid, gel, lotion or fluid cream can be packaged in a bottle or a sachet or a propellant-driven aerosol device or a container fitted with a pump suitable for finger operation.
• the composition can simply be stored in a non-deformable bottle or squeeze container, such as a tube or a lidded jar.
• the invention accordingly also provides a closed container containing a cosmetically acceptable composition as herein defined.
• the invention also provides a process for preparing a hair growth composition which comprises the steps of mixing an effective amount of a urea cycle intermediate, as herein defined, together with a cosmetically acceptable carrier for the intermediate.
• a process for preparing a hair growth composition which comprises the steps of mixing an effective amount of a urea cycle intermediate, as herein defined, together with a cosmetically acceptable carrier for the intermediate.
• the invention accordingly also provides for the use of a urea cycle intermediate, as herein defined, for topical application to mammalian skin or hair for increasing or maintaining hair growth.
• compositions according to the invention are primarily intended for topical application to the scalp of the human subject, particularly where the head is already bald or balding, in order to convert vellus hair to growth as terminal hair, or to increase the rate of growth of terminal hair.
• the compositions can also be applied prophylactically to the hair and hence the scalp to reduce or prevent the onset of baldness, by maintaining the hair in a healthy, growing state, with less that usual hair loss.
• the amount of the composition and the frequency of application to the hair and/or scalp can vary widely, depending on personal needs, but it is suggested as an example that topical application of from 0.1 to 5g daily containing from 0.00001 to lg of a selected urea cycle intermediate over the period of at least six months will in most cases result in an improvement in hair growth.
• This test includes the important step of isolating hair follicles having an undamaged hair bulb from human skin, for example, facelift skin, by microdissection.
• the method employed is described by Philpott et al; in J Cell
• the critical step of separating the hair follicle with intact undamaged hair bulb from the subcutaneous fatty tissue in which it is situated accordingly involves severing the hair shaft of the follicle at a point below the epidermis of skin surface, so as to leave the hair bulb intact and undamaged while still bearing a portion of the hair shaft.
• the hair shaft of the follicle is severed at the dermal-subcutaneous fat interface.
• Any suitable cutting instrument can be employed to sever the hair shaft in this manner, but a keratotome or a scalpel are preferred.
• the hair bulb with a hair shaft stump attached is then isolated from the skin by mechanically separating the hair from loosely adhering subcutaneous fat which normally surrounds the hair bulb. This is achieved after the dermis or upper layer of the skin has been separated and removed, to avoid damaging the hair bulb as it is pulled away.
• the hair bulb together with hair shaft stump attached is then transferred in an otherwise undamaged and fully functioning, viable state to a nutrient medium.
• the hair follicles isolated by the technique described herein are transferred to a suitable culture' medium for subsequent testing of substances that can then influence their future development.
• isolated hair follicles obtained from facelift skin are maintained in 1 ml of Williams E medium, supplemented with L-glutamine (2mM) , insulin (10 ⁇ g/ml) , hydrocortisone (lOng/ml) and antibiotics, either with or without a test hair growth substance (urea cycle intermediate) .
• the medium was incubated at 37°C in an atmosphere of 5% C0 2 + 95% air in individual wells of a 24 multiwell dish (Corning) , which permits detailed measurements to be made of the length of individual hair follicles.
• Williams E medium is available from FLOW Laboratory under Catalogue No. 12-502. The formula of Williams E medium is described by Williams GM, et al., in Experimental Cell Research &9 (1971) on page 106.
• the response of an isolated hair follicle to a test substance can accordingly be assessed by measuring the increase in length, if any, in the presence of a test substance against a control.
• the in vitro method described herein was used to assess the effect of three urea cycle intermediate, namely arginine hydrochloride, ornithine hydrochloride and citrulline, when used in the presence of- glutamine, compared with glutamine alone, to demonstrate the superiority of the urea cycle intermediates over glutamine alone.
• a test procedure for total protein synthesis utilised a similar culture of isolated follicles.
• the follicles were cultured in arginine-deficient Williams E medium supplemented so as to contain 0.287mM, 0.574mM or 1.435mM arginine, for two days. Incubation was then continued for a further three hours in the presence of 14 C labelled leucine as well as the same concentration of arginine as before.
• the follicles were removed from the radioactive media, and washed with 3 x 1ml of PBS supplemented with lOmM unlabelled leucine, to displace non-covalently bound 1 C-leucine. They were then homogenised in 1ml of ice-cold 0.1M K 2 EDTA, pH 12.3, in a hand-held glass/glass homogeniser. The homogenate was left at 4°C for 30 min. to release and dissolve the protein. Cell debris was removed by centrifugation, and HO ⁇ l samples of the supernatant removed for total protein determination by the Bio-Rad assay [based on Bradford, Anal.Biochem. , 72, 248 (1976)] .
• the invention is illustrated by the following examples, each of which provides a composition comprising one or more specific metabolic intermediates of the urea cycle or derivatives thereof in in accordance with the invention. Selected metabolic intermediates are indicated by the s gagture numbers l is ted earlier in this specif ication .
• This Example illustrates a lotion according to the invention which is suitable for topical application to the skin in order to enhance hair growth.
• the lotion has the following formulation:
• This Example illustrates a hair tonic which is suitable for application to hair or scalp.
• the hair tonic has the following formulation:
• This Example also illustrates a lotion which is suitable for topical application to the scalp.
• the lotion has the following formulation:
• This Example also illustrates a hair tonic which is suitable for application to hair or scalp.
• the hair tonic has the following formulation:
• the following formulations represent lotions which can be used topically in the treatment of bald or balding male or female heads.
• the following formulations represent creams which can b used in the treatment of baldness.
• This Example illustrates a water-in-oil high internal phas emulsion containing an amine according to the invention.
• the emulsion consisted of 10% by volume oily phase and 90 by weight aqueous phase.
• the oily phase and the aqueous phase had the followin constitution: % w/w
• the emulsion was prepared by taking 10 parts by volume of the oily phase and to it adding slowly with stirring 90 parts by volume of the aqueous phase.
• the high internal phase water-in-oil emulsion so formed can be applied topically to the scalp, to improve hair growth and regrowth.
• examples 14 and 15 illustrate shampoos for use in washing the hair and scalp, and for promoting hair growth on the scalp.
• This Example also illustrates a lotion which is suitable fo topical application to the scalp.
• the lotion has the following formulation:
• This example illustrates a powder composition according t the invention which can be applied topically to the scalp.
• the following example illustrates a lotion according to th invention which can be applied topically to the scalp to preven hair loss and stimulate hair regrowth.
• the hair tonics had the following formulation:
• This example illustrates a shampoo which is suitable for topical application to hair in order to cleanse it, at the same time delivering a metabolic intermediate to the scalp to enhance hair growth or regrowth.
• the shampoo had the following formulation:
• This example illustrates a shampoo in accordance with the invention.
• the shampoo had the following formulation:
• This example illustrates a shampoo in accordance with this invention.
• the shampoo had the following formulation:
• This example illustrates a shampoo in accordance with this invention.
• the shampoo had the following formulation:
• Example 25 illustrate shampoos for use in washing the hair and scalp, and for promoting hair growth on the scalp.
• Example 25 illustrate shampoos for use in washing the hair and scalp, and for promoting hair growth on the scalp.
• Lauryl dimethylamino acetic acid betaine [30% AD] Coconut fatty acid diethanolamine Oleyl triethoxy phosphate (BRIPHOS 03D) Polyglycol-polyamine condensation resin (POLYQUART H) [50% active] Preservative, colouring matter, salt Intermediate (33) Perfume Water
• This Example also illustrates a lotion which is suitable for topical application to the scalp.
• the lotion has the following formulation: w/w
• This example illustrates a powder composition according t the invention which can be applied topically to the scalp.
• the following example illustrates a lotion according to th invention which can be applied topically to the scalp to preven hair loss and stimulate hair regrowth.
• This example illustrates a shampoo which is suitable for topical application to hair in order to cleanse it, at the same time delivering a metabolic intermediate to the scalp to enhance hair growth or regrowth.
• the shampoo had the following formulation:
• This example illustrates a shampoo in accordance with th invention.
• a pre-emulsion of polyisobutylene was made by mixing at room temperature the following ingredients in a Winkworth twin-Z-blade mixer (model MZ150) .
• the pre-emulsion was then mixed, with stirring, with the additional ingredients of . the shampoo. to give a final composition as follows:
• the shampoo is prepared using a simple hot process whereby all the ingredients except perfume are mixed at 70°C using a paddle stirrer. The mixture is then cooled slowly, and perfume added below 40°C.
• Silicone emulsion comprises 50% by weight silicone oil (60,000 cs) , 4% by weight cetostearyl alcohol and 25% by weight SLES 2E0.
• ammonium lauryl sulphate/ammonium lauryl ether sulphate and the BHT were heated in the main vessel to 75°C to melt the BHT, with constant stirring.
• CARBOPOL 1342 was dispersed with stirring in 50% of the water, and the resulting dispersion added to the main vessel.

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• 1992
  • 1992-10-30 GB GB929222772A patent/GB9222772D0/en active Pending
• 1993
  • 1993-10-27 JP JP6510821A patent/JPH08502509A/ja active Pending
  • 1993-10-27 CA CA002146348A patent/CA2146348A1/en not_active Abandoned
  • 1993-10-27 AU AU53426/94A patent/AU5342694A/en not_active Abandoned
  • 1993-10-27 EP EP93923626A patent/EP0666729A1/de not_active Withdrawn
  • 1993-10-27 WO PCT/GB1993/002210 patent/WO1994009750A1/en not_active Application Discontinuation
  • 1993-10-27 ZA ZA938000A patent/ZA938000B/xx unknown
  • 1993-10-29 CN CN93119716A patent/CN1091952A/zh active Pending
• 1994
  • 1994-01-12 TW TW083100214A patent/TW262384B/zh active
• 1995
  • 1995-04-29 KR KR1019950701705A patent/KR950703926A/ko not_active Application Discontinuation

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