+

WO2003018023A1 - Compositions et methodes permettant de cibler la circulation cerebrale et de traiter une cephalee - Google Patents

Compositions et methodes permettant de cibler la circulation cerebrale et de traiter une cephalee Download PDF

Info

Publication number
WO2003018023A1
WO2003018023A1 PCT/US2001/026459 US0126459W WO03018023A1 WO 2003018023 A1 WO2003018023 A1 WO 2003018023A1 US 0126459 W US0126459 W US 0126459W WO 03018023 A1 WO03018023 A1 WO 03018023A1
Authority
WO
WIPO (PCT)
Prior art keywords
headache
active substance
composition
person
ketoprofen
Prior art date
Application number
PCT/US2001/026459
Other languages
English (en)
Inventor
Bruce Frome
Original Assignee
Bruce Frome
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 Bruce Frome filed Critical Bruce Frome
Priority to US10/480,162 priority Critical patent/US20040138239A1/en
Priority to PCT/US2001/026459 priority patent/WO2003018023A1/fr
Priority to EP02753504A priority patent/EP1418918A4/fr
Priority to AU2002313785A priority patent/AU2002313785A1/en
Priority to US10/483,509 priority patent/US7981901B2/en
Priority to PCT/US2002/026613 priority patent/WO2003017932A2/fr
Publication of WO2003018023A1 publication Critical patent/WO2003018023A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • 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
    • A61K9/0085—Brain, e.g. brain implants; Spinal cord
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters

Definitions

  • the field of the invention is compositions and methods for targeting cerebral circulation, and particularly relates to treatment of headache.
  • vascular headaches and particularly migraine are at least in part caused by swelling of blood vessels in the scalp, in the meninges (i.e., pia mater, dura mater, and arachnoid membrane), and/or in the brain itself. Both scalp and meninges are innervated by pain fibers, onto which the swollen vessels are thought to press.
  • the swelling of the blood vessels can be triggered by a variety of factors, including intrinsic factors (e.g., stress), and/or extrinsic factors.
  • caffeine acts as a vasoconstrictive agent in the brain, and consequently many people experience headaches upon caffeine withdrawal.
  • pharmacologically active agents are systemically administered to target receptors that are functionally involved in vasoconstriction of blood vessels in the cerebral circulation, thereby relieving the pressure perceived as a blood vessels in the cerebral circulation, thereby relieving the pressure perceived as a headache.
  • pharmacologically active agents include triptans (e.g., Sumatriptan and Rizatriptan), and various ergots that target the 5HT receptors, which stimulate cerebral vasoconstriction [Hargreaves in Cephalalgia (2000) 20 Suppl 1:2-9].
  • caffeine and other methylxanthines (although vasodilat- ing in the periphery) stimulate vasoconstriction in the cerebral circulation.
  • Such methylxanthines are probably effective by stimulation of the release of endogenous epinephrine and norepinephrine, both of which are potent cerebral vasoconstrictors [Muller- Schweinitzer and Fanchamps in Adv. Neurol.(1982) 33:343-356].
  • Caffeine is a component of several over-the-counter migraine and headache medications. However, in known formulations caffeine needs to be orally ingested in substantial quantities to reduce a headache, which often produces undesirable side effects (e.g. , excessive central nervous stimulation).
  • contemplated methods and compositions are provided which are employed to target cerebral circulation and to treat headache. More particularly, contemplated methods and compositions include formulations comprising a pharmacologically active substance in a transdermal formulation, which is topically applied to an area of skin superficial to a carotid artery, a temporal artery, a vertebral artery, or to a tender spot associated with a headache.
  • contemplated transdermal formulations comprise a skin penetration enhancer (e.g., an azone derivative, a synthetic terpene, oleic acid, N-methyl-2-pyrrolidone, an epsilon-aminocaproic acid ester, a lecithin organ- ogel, a pluronic-lecithin-organogel, or an aromatic S,S-dimethyliminosulfurane).
  • a skin penetration enhancer e.g., an azone derivative, a synthetic terpene, oleic acid, N-methyl-2-pyrrolidone, an epsilon-aminocaproic acid ester, a lecithin organ- ogel, a pluronic-lecithin-organogel, or an aromatic S,S-dimethyliminosulfurane.
  • Particularly preferred pharmacologically active substances include xanthine derivatives (e.g., caffeine, theophylline, or
  • a method of treating a person having a headache includes a step in which a tender spot associated with the headache on a body surface (particularly neck, face, and scalp) of the person is identified.
  • contemplated compositions are topically applied to the tender spot in an amount effective to reduce the headache.
  • a method of marketing a pro- duct includes one step in which contemplated compositions are included in the product.
  • a person is instructed to identify a tender spot associated with a headache on a body surface, and in a still further step, the person is instructed to topically apply the product to the tender spot in an amount effective to reduce the headache.
  • a method of marketing a product includes one step in which contemplated compositions (including skin penetration enhancer and pharmacological active substance) are included in the product, and in which a person is instructed to identify an area of skin superficial to a carotid artery, a temporal artery, or a vertebral artery. In a further step, the person is instructed to topically apply the product to the area in an amount effective to direct the pharmacological active substance to a cerebral circulation.
  • contemplated compositions including skin penetration enhancer and pharmacological active substance
  • Fig. 1 is a schematic view of head and neck of a person depicting exemplary areas of application of contemplated compositions and formulations. Detailed Description
  • cerebral circulation can be targeted with various compositions comprising a pharmacologically active substance in a transdermal formula- tion, and that contemplated compounds (i.e., pharmacologically active substances), compositions, and formulations can advantageously be employed for treatment of various diseases or symptoms, particularly headache.
  • contemplated compounds i.e., pharmacologically active substances
  • compositions, and formulations can advantageously be employed for treatment of various diseases or symptoms, particularly headache.
  • contemplated compositions include a pharmacologically active substance that preferably has a vaso-active effect.
  • vaso-active effect includes vaso-constrictive (effecting at least 5% luminal constriction, more typically at least 10% luminal constriction) and vaso-dilatory effects (effecting at least 5% luminal dilation, more typically at least 10% luminal dilation), wherein the effect particularly refers to arteries, arteriolae, and arterial capillaries.
  • particularly preferred pharmacologically active substances include xan- thine derivatives according to structure 1, and especially include caffeine, theophylline, and dimeric forms such as aminophylline (ethyl ene diamine complex with theophylline).
  • R,-R 3 are independently hydrogen, methyl, branched or unbranched lower alkyl, all of which may or may not further comprise functional groups (e.g., nucleophilic, elec- trophilic, polar, non-polar, etc.), and which may include one or more conjugated or non- conjugated ⁇ -bonds.
  • one or more nitrogen atoms may be replaced with another heteroatom (e.g., O, S, Se, etc.), or be replaced with a carbon atom.
  • the carbonyl oxygen may be replaced with atoms other than oxygen, or substituted with a functional group (e.g., carboxylic acid, hydroxyl, nitrile, ethynyl, amino, imino, etc.).
  • suitable pharmacologically active compounds also include various vaso-active substances other than xanthine derivatives, and particularly include vitamin B6, digitalis, diuretics, or angiotensin-converting enzyme inhibitors.
  • nitrate-generating compounds e.g., nitro- glycerin, isosorbide-5-mononitrate, etc.
  • vasodilators may be included to improve cerebral blood flow.
  • contemplated compositions include a muscular-active compound
  • muscle relaxants are contemplated suitable for use herein.
  • the term "muscular-active compound” as used herein refers to all compounds that modulate the tonus of a muscle. Particularly contemplated muscular-active compounds reduce the tonus of smooth muscles and/or voluntarily con- trolled muscles.
  • appropriate muscle relaxants include carisoprodol, cyclo- benzaprine, chlorzoxazone, metaxolone, or methocarbamol.
  • an especially preferred muscular-active compounds is ketoprofen (infra).
  • suitable compounds include all compounds that have a desired pharmacological activity in the cerebral circu- lation and/or the brain.
  • alternative drugs include drugs that interact with the hypothalamus, the hypophysis, receptors in the brain, or particular cells (e.g., neuronal cells, glial cells, astrocytes, etc.), which may or may not be diseased. Consequently, suitable compounds include fever reductants, anti-inflammatory drugs, anti-depressants, anti-coagulants, stimulants, cytokines, and so forth.
  • contemplated compounds With respect to the amount of contemplated compounds, it should be appreciated that a particular amount of a particular pharmacologically active compound will typically depend on the desired strength of the formulation, the type of pharmacologically active compound, and the particular application of the formulation. Consequently, contemplated compounds may be in the range of less than 0.1 % w/w to 90% w/w, and even more. More typically, contemplated compounds may be in the range of about 1 % w/w to 20% w/w.
  • the pharmacologically active substance is a xanthine derivative according to Structure 1
  • appropriate amounts will typically be within a range of 1% w/w to about 70% w/w, more preferably within the range of at least 2% w/w to about 50% w/w, and most preferably in the range of at least 4% w/w to about 15% w/w.
  • Muscular-active compounds e.g., Ketoprofen
  • suitable formulations in a range of about at least 0.5% w/w to about 50% w/w, preferably at least 2% w/w to about 25% w/w, and more preferably between about at least 4% w/w to about 15% w/w.
  • contemplated compositions include a transdermal formulation (i.e., contemplated compounds are formulated in a transdermal formulation).
  • transdermal formulation refers to any formulation that facilitates passage of a pharmacologically active substance across the epidermal layer into at least the papillary, and more preferably the reticular layer of the human dermis.
  • transdermal formulations There are numerous transdermal formulations known in the art, and all of the known transdermal formulations are considered suitable for use in conjunction with the teachings presented herein.
  • transdermal formulations include ionic compounds (e.g., ascorbate, calcium thioglycolate, cetyl trimethyl ammonium bromide, ionic surfactants, 5-methoxysalicylate, etc.), dimethyl sulfoxide and related compounds (e.g., cyclic sulfoxides, decylmethyl sulfoxide, etc.), azone and related compounds (e.g., 1-dodecyl azacycloheptan-2-one, N-Dodecyl-2-pyrrolidone, azacycloalkane derivatives, l-geranylazacycloheptan-2-one, etc.).
  • ionic compounds e.g., ascorbate, calcium thioglycolate, cetyl trimethyl ammonium bromide, ionic surfactants, 5-methoxysalicylate, etc.
  • dimethyl sulfoxide and related compounds e.g., cyclic sul
  • skin penetration enhancer include solvents (e.g., alkanols, esp. ethanol, dimethyl formamide, polyoxyethylene sorbitan monoesters, propylene glycol, etc.), or fatty alcohols, fatty acids, and related structures (e.g., aliphatic and lauryl alcohols, dodecyl N,N-dimethylamino acetate, ethyl acetate, alkanoic acids and oleic acids, isopropyl myristate, etc.).
  • solvents e.g., alkanols, esp. ethanol, dimethyl formamide, polyoxyethylene sorbitan monoesters, propylene glycol, etc.
  • fatty alcohols e.g., aliphatic and lauryl alcohols, dodecyl N,N-dimethylamino acetate, ethyl acetate, alkanoic acids and oleic acids, isopropyl myristate, etc.
  • formulations include enzymes (e.g., papain), amines and amides (e.g., N,N- Diethyl-m-toluamide), complexing agents (e.g., Brij, Pluronic, etc), and N-methyl pyrrolidone and related compounds (e.g., l,3-Dimethyl-2-imidazolikinone or 2- Pyrrolidone).
  • enzymes e.g., papain
  • amines and amides e.g., N,N- Diethyl-m-toluamide
  • complexing agents e.g., Brij, Pluronic, etc
  • N-methyl pyrrolidone and related compounds e.g., l,3-Dimethyl-2-imidazolikinone or 2- Pyrrolidone
  • Particularly suitable skin penetration enhancers include azone derivatives, natural and synthetic terpenoid compounds and their alcohols, oleic acid, N-methyl-2- pyrrolidone, epsilon-aminocaproic acid esters, lecithin organogels, pluronic-lecithin- organogels, aromatic S,S-dimethyliminosulfurane, Padimate O, oil-water emulsions with sub-micron droplets, capsaicin, and various esters of organic acids.
  • Contemplated compositions and formulations can be prepared using various protocols, and a particular composition will typically determine (at least in part) a particular protocol.
  • contemplated compositions and formulations are typically preparations for topical application, and particularly include preparations in form of a cream, gel, lotion, ointment, salve, or a paste.
  • contemplated compositions and formu- lations may also include preparations in liquid form (e.g., a syrup, tincture, spray, drops, etc.), all of which may or may not be applied with a patch.
  • compositions include a xanthine derivative in a concentration of about 4%(wt) to 70%(wt) and ketoprofen in a concentration of about 0.5% (wt) to 50%) (wt).
  • a xanthine derivative in a concentration of about 4%(wt) to 70%(wt) and ketoprofen in a concentration of about 0.5% (wt) to 50%) (wt).
  • ketoprofen in a concentration of about 0.5% (wt) to 50%) (wt).
  • Ketoprofen is the only NSAID effective in treatment of a headache when used in protocols according to the inventive subject matter (see also examples). While not wishing to be bound by a particular hypothesis or theory, the inventors contemplate that the effect of Ketoprofen may be at least in part mediated by a muscle-relaxant effect rather than via a suppressive effect in inflammation.
  • contemplated compounds i.e., pharmacologically active substances
  • expressly exclude complex herbal extracts i.e., herbal extracts prepared from more than one, more typically ore than five plants or plant parts
  • such as Tiger Balm, plant oils and essences such as Tiger Balm, plant oils and essences.
  • compositions and formulations according to the inventive subject matter are topically applied onto the surface of a body of an animal, preferably a mammal, and most preferably a human.
  • surface of a body refers to any surface on a body of a person that is directly and manually accessible by the same or other person, and particularly includes the scalp, neck, temples, and areas of skin superficial to a carotid artery, a temporal artery, and a vertebral artery.
  • the term “superficial” as used herein means in a proximity of no more than 1cm, preferably no more than 7mm, and more preferably no more than 4mm. It is further contemplated that such application will direct contemplated compounds to the cerebral circulation. While it is generally contemplated that all methods of topical application are considered suitable for use herein, particularly preferred methods include manual application (e.g., rubbing in or massaging in), application using a transdermal patch, and needle-less injection.
  • Cerebral circulation refers to all blood vessels and compartments that supply blood and/or other physiological substances to and remove them from the cranial vault, and especially encompass the arterial systems of the head and neck, the venous system collecting and returning blood from the head to the trunk, the lymphatic systems draining the head and the cerebro-spinal fluid system bathing the brain, brain stem and spinal cord.
  • Particularly contemplated blood vessels supply blood and physiological substances to the hypothalamus and are generally located above the trunk (i.e., areas including the neck and head).
  • contemplated compositions e.g., 3.2% w/w theophylline and 2% w/w ketoprofen in a transdermal formulation in cream form
  • the application is performed upon onset of the headache.
  • the area of application need not be limited to an area superficial to a temporal artery (here: the temple), and numerous alternative areas are also considered suitable for application of contemplated compositions and formulations.
  • particularly preferred alternative areas include a skin area superficial to a carotid artery and a skin area superficial to a vertebral artery as depicted in Figure 1 (shaded areas).
  • contemplated compositions or formulations may be applied to any area of the body, so long as the application will result in directing contemplated compounds to the cerebral circulation.
  • composition of contemplated compositions and formulations may vary significantly.
  • the pharmacological agent is an anti-depressant
  • application may be performed to improve the mood of the patient.
  • the pharmacologi- cal agent includes a fever reductant
  • application may be performed to normalize the body temperature of the patient.
  • the pharmacological agent includes an anticoagulant or vaso-dilator
  • application may be performed to reduce deleterious effects of impaired blood circulation (e.g., due to a stroke).
  • contem- plated compositions and formulations are employed to treat a headache, wherein a tender spot associated with the headache is identified on a body surface of a person. Contemplated compositions and formulations are then applied to the tender spot in an amount effective to lessen the headache.
  • tender spot refers to a defined area on the body surface of a person that is (a) tender to the touch and (b) perceptible as tender only when the person suffers from a headache.
  • a tender spot can be found by palpitation, and tender spots are often found on the parietal area (above the ears, forwards and behind), around the temples, or above the forehead. Tender spots are less frequently found on the top and rear of the skull.
  • contemplated compositions and formulations may be used for prophylactic, temporary, permanent, and acute treatment of the condition that is to be treated by administration of contemplated compositions and formulations.
  • a method of directing a compound to a cerebral circulation comprises a step in which a composition having a pharmacologically active substance is provided, wherein the composition is formulated in a transdermal formulation.
  • the transdermal formulation is topically applied to an area of skin superficial to a carotid artery, a temporal artery, and/or a vertebral artery.
  • Further contemplated methods include a method of treating a person having a headache, in which a composition having a pharmacologically active substance is provided.
  • a tender spot associated with the headache on a body surface of the person is identified, and in a still further step, the composition is topically applied to the tender spot in an amount effective to reduce the headache.
  • a method of marketing a product may include a step in which a skin penetration enhancer is included as a component of the product.
  • a person is instructed to identify a tender spot associated with a headache on a body surface of the person, and in a still further step, the person is instructed to topically apply the product to the tender spot in an amount effective to reduce the headache.
  • a method of marketing a product may include a step in which a skin penetration enhancer and a pharmacological active substance are included as a component of the product.
  • the person is instructed to identify an area of skin superficial to at least one of a carotid artery, a temporal artery, and a vertebral artery, and in yet another step, the person is instructed to apply the product topically to the area in an amount effective to direct the pharmacological active substance to a cerebral circulation.
  • the instruction comprises providing a printed information, and especially contemplated printed information includes written instructions, a pictogram, a graph, and/or a photographic image.
  • numerous known alternative instruction methods e.g., video class, internet class, person-to-person are also considered suitable.
  • the pressure sensed by swelling of these vessels is thought to be transmitted through the trigeminal ganglion to the thalamus, and then to the cortex where the pain is experienced subjectively [Hargreaves in Cephalalgia (2000) 20 Suppl 1:2-9].
  • migraine symptoms typically follow a uniform pattern, which are thought to originate in the hypothalmus upon integration of a variety of triggers by the cortex [Bruyn in Adv. Neurol. (1982) 33:151- 169].
  • the concept of basilar arterial migraine first presented by Bicker staff [Lancet (1961) 1:15-17] unifies the vascular perfusion deficiency with the multitude of symptoms by proposing that the lower cerebral circulation at the level of the mid brain is the primary source of pathology.
  • the thalamus and hypothalamus are the location of several regulatory nuclei of the sympathetic and parasympathetic regulatory centers, among them central regulation of blood pressure, sleep, water balance and body temperature.
  • a pharmacologically active agent for the treatment of headache must be delivered through the cerebral circulation to the area of the brain stem (e.g., hypothalamus or post ganglionic visceromotor and viscerosensory system of the pericarotid plexus) in order to act effectively.
  • this is accomplished by oral delivery, injection, inhalation, or absorption through the rectal mucosa in a quantity sufficient to achieve an effective concentration in the blood plasma.
  • the entire body (especially the plasma) of a patient must be saturated with the agent in a conventional approach to achieve a therapeutic effect (and concentration of the pharmacologically active agent) in the brain. This process of saturating the plasma takes considerable time, except in the case of injection into a vein or inhalation, both of which are less preferable than oral administration.
  • the inventors have observed an unexpected result, in that topical application of a pharmacologically active agent to the skin superficial to the arteries of the extracranial circulation will direct (i.e., deliver) the agent to the cerebral circulation of the hypothalamus and midbrain, and that such a delivery requires significantly less agent to achieve a therapeutically effective concentration.
  • a pharmacologically active agent applied to the anterior triangle of the neck will penetrate the carotid sheath and enter the carotid blood supply of the brain and skull, or when applied below the ear behind the jawbone, the agent can enter the external carotid artery and its branches, or when applied to the temples, the agent will enter the superficial temporal artery and lacrimal arteries, as well as the maxillary and deep temporal arteries (Branching from the external carotid between the temple and below the ear, the middle meningeal and anterior tympanic arteries enter the posterior fossa, the chamber which contains the midbrain, through the jugular foramen and the condylar canal).
  • the parie- tal branch of the superficial temporal artery curves upwards and backwards on the side of the head and anastomoses with the opposite artery, as well as the posterior auricular and occipital arteries.
  • These latter arteries penetrate passages at the rear and base of the skull, where they supply the tympanic chamber, glands, and probably anastomose with the meningeal artery. Therefore, the inventors contemplate that a substance entering the arteries below the temples can be distributed widely through the face and scalp, and through anastomoses enter the cerebral circulation of the skull.
  • the inventors do not wish to be limited to the theory as outlined above.
  • the pharmacologically active agent reaches the hypothalamus through the diploic channel, after having been distributed somewhat by the arterial circulation.
  • the venous drainage of the cerebral circulation passes through large sinuses before being gathered into the jugular vein and returned to the heart.
  • the agent may diffuse out of the venous blood and enter the midbrain directly.
  • the agent may be entering the cerebrospinal fluid from the venous or arterial flow and reach the areas of action in this manner.
  • Example 1 Example 1 (Exemplary formulation with aminophylline " )
  • lecithin with suitable purity e.g., Spectrum brand (LE 102)
  • 600 ml octyl palmitate e.g., Waring 1 liter stainless steel
  • a blender e.g., Waring 1 liter stainless steel
  • the mixture is subsequently transferred to 500 ml beakers (350 ml ⁇ 30 ml per beaker).
  • a magnetic stirrer bar is added to each beaker and the mixtures are stirred for at least 12 hours.
  • the resulting stirred solution has a dark amber color, and is translucent with a syrupy consistency.
  • the pharmacologically active substance (here: aminophylline) is dissolved in, or added to purified water, preferably in half the anticipated amount of purified water (here: in 50 ml) for the entire preparation.
  • the aqueous solution comprising the pharmacologically active substance is slowly added to the lecithin syrup (e.g., by hand-stirring or small hand blender).
  • the lecithin syrup will start to gel as soon as the aqueous solution is added.
  • the exemplary formulation (4% w/w with respect to pharmacologically active substance) comprises 1,000 gram lecithin, 510 gram octyl palmitate, 100 gram water, and 64.4 gram of aminophylline.
  • Example 2 (Exemplary formulation with penetration enhancer)
  • the oil phase of this composition comprises lOOg (here: 10%, typically between
  • the water phase comprises 200g (here:20%) Polyoxamer F127 (Dow Corning) (Plu- ronic), lOOmg sorbic acid, and 600ml (here:60%) purified water.
  • the active ingredient here: e.g., 3.2% (w/w) theophylline
  • the appropriate phase i.e., water soluble active ingredients in the water phase, and lipid soluble active ingredients in the lipid phase.
  • the final formulation is then prepared by adding the water phase to the oil phase, and blending the two phases to completion.
  • the pH was adjusted to less than 7.0, most typically to about 5.3-5.6 using acid or base.
  • Example 3 Example 3 (Exemplary formulation with Ketoprofen)
  • Example 2 Same as in Example 2, comprising 3.2% (w/w) theophylline and 2% (w/w) Ketoprofen as active ingredients.
  • Example 4 (Exemplary formulation with penetration enhancer and acet- aminophen)
  • Example 2 Same as in Example 2, comprising 5% (w/w) acetaminophen as active ingredient.
  • Example 5 Delivery of acetaminophen to the thalamic and hypothalamic region
  • Acetaminophen is usually indicated for fever reduction and is thought to modu- late the body temperature through interaction with thermoregulatory nuclei in the hypothalamus. Acetaminophen is typically given as drops in children running a high fever at a dosage of about 160mg for a child of 2-3 years in age. Using oral delivery, acetaminophen will enter the blood stream through the stomach, and will require approximately at least 20 minutes to achieve sufficient concentration in the plasma to lower the fever.
  • a skin-penetrating formulation of acetaminophen as described in Example 4 was applied in a single dosage of 25 mg acetaminophen (corresponding to 500 mg of the formulation) to the temples of a group of patients with a fever of between about 38.5°C to about 39.5°C. In this group, the fever was reduced within three minutes in all of the twenty children and adults within the group. If transdermal delivery would have occurred systemically, insufficient quantities of acetaminophen would have been administered for significant fever reduction since the total dosage applied to the skin was less than 25 mg (and the amount penetrating the skin likely to be less than 15mg).
  • acetaminophen entered the cerebral circulation and reached the temperature-regulating center in the hypothalamus via the temporal artery by topically applying a transdermal formulation containing acetaminophen. Consequently, the inventors contemplate that an essential aspect of directing a pharmacologically active agent to the cerebral circulation includes formulation of the agent in a skin penetration-enhancing vehicle (transdermal formulation). In formulations without penetration enhancers, only a fraction of a pharmacologically active agent applied to the skin will penetrate percutaneously.
  • transdermal formulation skin penetration-enhancing vehicle
  • the amount that penetrates is typically limited by the amount applied, the way the material is spread out on the skin, and the speed with which the vehicle dries. Once the vehicle is dry, the agent will precipitate and no further material can enter the skin through the outer layer, the stratum corneum.
  • Conventional vehicles can deliver no more than micrograms of agent through the stratum corneum under normal circumstances [Flynn; “Topical and transdermal delivery - provinces of realism.” in Dermal and Transdermal Drug Delivery edition, CRC Press, Inc., Boca Raton, FL, 1993, ISBN: 3804712231].
  • Alternative particularly suitable skin penetration enhancers include azone derivatives, synthetic and natural terpenes, oleic acid, N-methyl-2-pyrrolidone, epsilon- aminocaproic acid esters, lecithin organogels, pluromc-lecithin-organogels, aromatic S,S- dimethyliminosulfuranes, Padimate O, oil-water emulsions with sub-micron droplets, and capsaicin.
  • alternative xanthine derivatives include caffeine, theophylline, and aminophylline, in concentrations preferably of at least 2%wt, more preferably at least 4%wt.
  • suitable formulations may further include muscle-active substances, and particularly Ketoprofen (preferably in a concentration of at least 0.5%>wt to at least 10%) wt).
  • muscle-active substances and particularly Ketoprofen (preferably in a concentration of at least 0.5%>wt to at least 10%) wt).
  • Example 1 The formulation of Example 1 was tested in a prospective clinical trial at the Pain Centers of America (415 North Crescent Drive Beverly Hills 90210, CA). 155 patients were screened for headache history and other eligibility criteria, and 106 patients gave informed consent and entered the trial.
  • the temples were prepared by cleaning using witch hazel and alcohol astringent. One milliliter of the formulation was applied to each temple and rubbed into the skin until it was absorbed completely. Headache relief was rapid, within 5 minutes of application for 81 patients. Evaluation was determined by achieving a score of 7 out of 10 on a NAS pain relief scale. Eleven of these patients had a return of their pain by 15 minutes. These patients reapplied the gel and eight out of the eleven had relief persisting at least one hour from the second application. Consequently, the formulation was effective for 78 out of 106 patients (74%). Interestingly, non-responders to the gel were heavy users of analgesics, especially opioids. Consequently, it is contemplated that success rates among the general population may well be higher than 74% of patients in this trial.
  • Example 6A Treatment of postdural puncture headache
  • Example 2 The formulation of Example 2 was tested in a prospective clinical trial at the Pain Centers of America (415 North Crescent Drive Beverly Hills 90210, CA). 24 patients were screened for headache history and other eligibility criteria, and 21 patients gave informed consent and entered the trial.
  • the temples were prepared by cleaning using witch hazel and alcohol astringent. One milliliter of the formulation was applied to each temple and rubbed into the skin until it was absorbed completely. Headache relief was rapid, within about 10 minutes of application for 18 patients. Evaluation was determined by achieving a score of 7 out of 10 on a VAS pain relief scale. Where pain symptoms reappeared (three patients), the patients reapplied the gel and two of the three had relief persisting at least one hour from the second application.
  • Example 7 Prophylactic treatment of headache
  • formulation and application similar to the protocol as described in Example 6 was used.
  • Patients with a history of recurring headaches were sent home with a supply to test prophylactic efficacy and safety.
  • the patients applied the gel to the temples before meals (3x daily). 62% did not experience a severe headache in the 30-day test period.
  • the remaining subjects who had a headache despite the use of the gel were asked to try an additional dosage at bedtime during the second month of observation.
  • An additional 11% found this an effective prophylaxis, yielding total headache prevention for 73%> of patients.
  • non- responders to prophylactic treatments still found immediate relief at the beginning of the headache using the medication.
  • contemplated prophylactic treatments will also be effective to prevent onset and/or lessen the severity of morning sickness and fibro- myalgia, and especially preferred xanthine derivatives for these symptoms include aminophylline).
  • Example 1 The formulation of Example 1 was tested in a prospective study including 120 patients suffering from intermittent acute headaches.
  • a first group of patients was instructed to locate a tender spot on their scalp and to topically apply about 500mg of the formulation to the tender spot, while a second group was instructed to apply about 500mg of the formulation to the pulse points of their temples under a protocol similar as described in example 6.
  • Application to the pulse points lead to rapid relief of the headache within 2-5 minutes in about 75%> of the patients, while application to the tender spot lead to almost instantaneous relief in almost all of the patients.
  • the tender spot corresponds to the location where arteries branching from the external carotid artery enter the skull and anastomose with arteries of the cerebral circulation. Swelling of the scalp arteries (as a result of the headache) constricts the vessels at their passage through the skull bone, which is experienced as local pain, inflammation or tenderness.
  • Particularly contemplated alternative formulations include skin penetration enhancers such as azone derivatives, synthetic terpenes, oleic acid, N-methyl-2-pyrrol- idone, epsilon-aminocaproic acid esters, pluronic-lecithin-organogels, or aromatic S,S- dimethyliminosulfurane.
  • skin penetration enhancers such as azone derivatives, synthetic terpenes, oleic acid, N-methyl-2-pyrrol- idone, epsilon-aminocaproic acid esters, pluronic-lecithin-organogels, or aromatic S,S- dimethyliminosulfurane.
  • pharmacologically active substances comprise a vaso-active substance such as xanthine derivatives, and may further comprise a muscular-active substance (e.g., Ketoprofen).
  • a muscular-active substance e.g., Ketoprofen
  • Example 3 The formulation of Example 3 (comprising 3.2% (w/w) theophylline and 5%> ketoprofen as active ingredients) was tested in a group of 25 patients suffering from cervicogenic headache. The patients were instructed to rub approximately 1ml of the formulation onto the back of their neck, and to reapply the formulation when needed. Where treatment of headaches was performed using a protocol according to any one of examples 5-9, reduction in pain was observed in at least 60%, more typically in at least 70%), and most typically in at least 85% of all patient. The subjective pain relief was generally at least 4, more typically at least 5, and most typically at least 7 on a 10-point scale (VAS pain relief scale).
  • VAS pain relief scale The subjective pain relief was generally at least 4, more typically at least 5, and most typically at least 7 on a 10-point scale (VAS pain relief scale).
  • compositions and methods for targeting cerebral circulation and treatment of headache have been disclosed. It should be apparent, however, to those skilled in the art that many more modifications besides those already described are possible without departing from the inventive concepts herein. The inventive subject matter, therefore, is not to be restricted except in the spirit of the appended claims. Moreover, in interpreting both the specification and the claims, all terms should be interpreted in the broadest possible manner consistent with the context. In particular, the terms “comprises” and “comprising” should be interpreted as referring to elements, components, or steps in a non-exclusive manner, indicating that the referenced elements, components, or steps may be present, or utilized, or combined with other elements, components, or steps that are not expressly referenced.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • General Chemical & Material Sciences (AREA)
  • Neurosurgery (AREA)
  • Pain & Pain Management (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Dermatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Psychology (AREA)
  • Emergency Medicine (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des méthodes et des compositions permettant de cibler la circulation cérébrale et de traiter une céphalée. Ces compositions comprennent des préparations contenant une substance à activité pharmacologique dans une préparation transdermique, laquelle est appliquée de manière topique sur une zone de la peau à la surface d'une artère carotide, d'une artère temporale, d'une artère vertébrale, ou d'une zone douloureuse à la pression associée à une céphalée. Des préparations particulièrement préférées comprennent un dérivé de la xanthine (par exemple, la théophylline, la caféine, l'aminophylline), et également, le kétoprofène. En outre, cette invention concerne des méthodes favorisant l'utilisation des compositions susmentionnées.
PCT/US2001/026459 2001-08-23 2001-08-23 Compositions et methodes permettant de cibler la circulation cerebrale et de traiter une cephalee WO2003018023A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
US10/480,162 US20040138239A1 (en) 2001-08-23 2001-08-23 Compositions and methods for targeting cerebral circulation and treatment of headache
PCT/US2001/026459 WO2003018023A1 (fr) 2001-08-23 2001-08-23 Compositions et methodes permettant de cibler la circulation cerebrale et de traiter une cephalee
EP02753504A EP1418918A4 (fr) 2001-08-23 2002-08-20 Compositions et techniques de ciblage de la circulation cerebrale et de traitement de cephalee
AU2002313785A AU2002313785A1 (en) 2001-08-23 2002-08-20 Compositions and methods for targeting cerebral circulation and treatment of headache
US10/483,509 US7981901B2 (en) 2001-08-23 2002-08-20 Compositions and methods for targeting cerebral circulation and treatment of headache
PCT/US2002/026613 WO2003017932A2 (fr) 2001-08-23 2002-08-20 Compositions et techniques de ciblage de la circulation cerebrale et de traitement de cephalee

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2001/026459 WO2003018023A1 (fr) 2001-08-23 2001-08-23 Compositions et methodes permettant de cibler la circulation cerebrale et de traiter une cephalee

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US10483509 Continuation-In-Part 2002-08-20

Publications (1)

Publication Number Publication Date
WO2003018023A1 true WO2003018023A1 (fr) 2003-03-06

Family

ID=21742800

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/US2001/026459 WO2003018023A1 (fr) 2001-08-23 2001-08-23 Compositions et methodes permettant de cibler la circulation cerebrale et de traiter une cephalee
PCT/US2002/026613 WO2003017932A2 (fr) 2001-08-23 2002-08-20 Compositions et techniques de ciblage de la circulation cerebrale et de traitement de cephalee

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/US2002/026613 WO2003017932A2 (fr) 2001-08-23 2002-08-20 Compositions et techniques de ciblage de la circulation cerebrale et de traitement de cephalee

Country Status (3)

Country Link
EP (1) EP1418918A4 (fr)
AU (1) AU2002313785A1 (fr)
WO (2) WO2003018023A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5250529A (en) * 1990-02-08 1993-10-05 Kos Pharmaceuticals, Inc. Method alleviating migraine headache with mast cell degranulation blocking agents
US5552406A (en) * 1994-06-17 1996-09-03 The Mclean Hospital Corporation Method for treating pain and brain perfusion abnormalities using mixed opioid agonist-antagonists
US5885597A (en) * 1997-10-01 1999-03-23 Medical Research Industries,Inc. Topical composition for the relief of pain

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4777174A (en) * 1982-07-22 1988-10-11 Analgesic Associates Analgesic and anti-inflammatory compositions comprising caffeine and methods of using same
US4532244A (en) * 1984-09-06 1985-07-30 Innes Margaret N Method of treating migraine headaches
US4777147A (en) 1987-01-28 1988-10-11 Texas Instruments Incorporated Forming a split-level CMOS device
HRP921157A2 (en) * 1991-12-20 1994-10-31 Lohmann Therapie Syst Lts Transdermal system of applying acetilsalicilyc acid in antithrombosys therapy
AUPN814496A0 (en) * 1996-02-19 1996-03-14 Monash University Dermal penetration enhancer
DE10025644A1 (de) * 2000-05-24 2001-12-06 Lohmann Therapie Syst Lts Schmales bandförmiges transdermales therapeutisches System zur Applikation von Wirkstoffen direkt über dem arteriellen oder venösen Gefäßsystem

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5250529A (en) * 1990-02-08 1993-10-05 Kos Pharmaceuticals, Inc. Method alleviating migraine headache with mast cell degranulation blocking agents
US5552406A (en) * 1994-06-17 1996-09-03 The Mclean Hospital Corporation Method for treating pain and brain perfusion abnormalities using mixed opioid agonist-antagonists
US5885597A (en) * 1997-10-01 1999-03-23 Medical Research Industries,Inc. Topical composition for the relief of pain

Also Published As

Publication number Publication date
EP1418918A2 (fr) 2004-05-19
WO2003017932A3 (fr) 2003-07-10
AU2002313785A1 (en) 2003-03-10
WO2003017932A2 (fr) 2003-03-06
WO2003017932B1 (fr) 2003-09-12
EP1418918A4 (fr) 2006-11-29

Similar Documents

Publication Publication Date Title
JP3211027B2 (ja) カプサイシン含有外用剤
JP4352114B2 (ja) 有益な効果を奏するアルギニンの投薬
JP3511074B2 (ja) ニコチン依存症治療のための薬学的処方
JPH11514999A (ja) ビタミンｄおよびその誘導体による掻痒症治療
JP2991642B2 (ja) エスクロシドを含む調製物および薬剤および美容分野におけるそれらの使用
JP2001504463A (ja) ククイノキナッツ油を含有する医薬組成物
KR950015056B1 (ko) 통증을 수반하는 염증성 또는 알레르기성 질환치료에 사용되는 의약조성물
US20110135627A1 (en) Pain relief composition, system and method
US7871647B1 (en) Topical treatment of neuropathy
RU2005128993A (ru) Средство для коррекции стресс-индуцируемых нейромедиаторных, нейроэндокринных и метаболических нарушений, а также способ профилактики и лечения сопутствующих им паталогических состояний
US20080102089A1 (en) Topical and transdermal treatments using urea formulations
US20040138239A1 (en) Compositions and methods for targeting cerebral circulation and treatment of headache
US5736126A (en) Liquid transdermal analgesic
US10195180B2 (en) Methods and compositions for treating foot or hand pain
US7981901B2 (en) Compositions and methods for targeting cerebral circulation and treatment of headache
JP2905210B2 (ja) 経皮、経粘膜吸収促進剤および経皮、経粘膜製剤
EP0234143A1 (fr) Formes galéniques à base de plantes fraîches et leurs procédés de préparation
WO2003018023A1 (fr) Compositions et methodes permettant de cibler la circulation cerebrale et de traiter une cephalee
WO2016028811A1 (fr) Système pour soulager la douleur
JP3113705B2 (ja) 外用剤
US20190365735A1 (en) Compositions and methods for treating varicose veins
RU2308962C1 (ru) Средство для лечения и профилактики заболеваний опорно-двигательного аппарата
KR960015725B1 (ko) 모발처리용 조성물
JPH0639380B2 (ja) 消炎鎮痛剤組成物
FR2581875A1 (fr) Composition cosmetique a base d'agents emollients et adoucissants utilisable en application externe pour l'assouplissement du corps

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EE FI GD GE GH GM HR HU ID IL IN IS JP KG KP KR KZ LC LK LR LS LT LU MA MD MG MK MN MW MX MZ NO PH PL PT RO RU SD SE SG SI SK SL TJ TM TT TZ UA UG US UZ VN YU ZA

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ CZ DE DE DK DK DM DZ EC EE EE ES FI FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PH PL PT RO RU SD SE SG SI SK SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ UG ZW AM AZ BY KG KZ MD TJ TM AT BE CH CY DE DK ES FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 10480162

Country of ref document: US

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

DPE2 Request for preliminary examination filed before expiration of 19th month from priority date (pct application filed from 20040101)
点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载