WO2001017484A2 - Topical urea composition - Google Patents
Topical urea composition Download PDFInfo
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- WO2001017484A2 WO2001017484A2 PCT/CA2000/001031 CA0001031W WO0117484A2 WO 2001017484 A2 WO2001017484 A2 WO 2001017484A2 CA 0001031 W CA0001031 W CA 0001031W WO 0117484 A2 WO0117484 A2 WO 0117484A2
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- oxidants
- composition
- mammal
- delivery
- viable epidermis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/08—Anti-ageing preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
- A61K8/42—Amides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/67—Vitamins
- A61K8/671—Vitamin A; Derivatives thereof, e.g. ester of vitamin A acid, ester of retinol, retinol, retinal
-
- 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
- A61K8/67—Vitamins
- A61K8/676—Ascorbic acid, i.e. vitamin C
-
- 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
- A61K8/67—Vitamins
- A61K8/678—Tocopherol, i.e. vitamin E
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- 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
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/73—Polysaccharides
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- 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
- A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
- A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
- A61K8/9706—Algae
- A61K8/9711—Phaeophycota or Phaeophyta [brown algae], e.g. Fucus
-
- 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
- A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
- A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
- A61K8/9771—Ginkgophyta, e.g. Ginkgoaceae [Ginkgo family]
-
- 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
- A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
- A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
- A61K8/9783—Angiosperms [Magnoliophyta]
- A61K8/9789—Magnoliopsida [dicotyledons]
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- 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
- A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
- A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
- A61K8/9783—Angiosperms [Magnoliophyta]
- A61K8/9794—Liliopsida [monocotyledons]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
- A61K2800/52—Stabilizers
- A61K2800/522—Antioxidants; Radical scavengers
Definitions
- This invention relates to a topical skin composition containing an active ingredient and urea for enhancing delivery of the ingredient.
- the active ingredient can be, alone, or in combination with another active ingredient, one or more of an antioxidant, vitamin, a ⁇ -glucan, or other active ingredient.
- Particularly useful is a composition containing vitamin E and urea, or a composition containing urea, vitamins A, C and E, and green tea extract.
- Topical compositions are widely used in the cosmetics and pharmaceutical industries. It is well known to include an active agent in a topical composition for the purpose of treating the skin. Such agents contribute to valuable effects, such as controlling ageing or pigmentation of the skin, promoting repair of damaged skin and contributing to skin cell renewal.
- antioxidants those relating to this invention include antioxidants, vitamins and ⁇ -glucans, and others listed below in connection with detailed embodiments.
- vitamins some have antioxidant properties, and others are useful primarily for other beneficial effects.
- a particularly useful ingredient in the context of this invention is vitamin E.
- Vitamin C topically administered in a moisturizing cream base, has been found to enhance the production of collagen 10 11 which is involved in stimulation of fibroblasts necessary for the regeneration of older and damaged skin. Vitamin C administration has also been found to improve the lipid profile so as to enhance the barrier function of skin. 12 Topically applied vitamin C has also been found to have anti-inflammatory properties. 13 There are many studies supporting the topical utility of certain vitamins.
- Topically applied vitamin E is known to behave as an antioxidant 14 15 16 17 and can serve to decrease healing time 18 with reduction of the severity and frequency of pathological damage to cells.
- Vitamin E has been shown to enhance the ability of skin to retain moisture.
- a topically applied mixture of vitamin E and vitamin C was shown to protect against sun damage to the skin.
- 21 There is evidence vitamins E and C can protect the skin against oxidative damage caused by free radicals.
- 22 Vitamin A has also been found to offer protection of the skin from chemical insult, 23 but it should be transported through the skin to effectively promote the metabolism of skin cells.
- Topically applied vitamin A palmitate has been found to improve skin elasticity.
- Vitamin A also contributes to repair of photo- damaged skin by stimulating growth of the collagenous matrix. 26
- Vitamins A, C and E are utilized by the body in defence against skin damage 27 and it has been suggested that the three vitamins are most effective together. 28 There are studies which suggest that vitamins C and E need to be present before sun damage occurs in order to be an effective defence thereagainst. 29 ' 30 ' 31 ' 32,33 ' 34 Studies have shown, however, that oral administration of vitamin C and vitamin E does not lead to appreciably increased amounts of the vitamin in the skin. 35,36 The salutary effects of green tea are coming to be known.
- Green tea has been shown to counter the irritative effects of ⁇ -hydroxy acids and been found to be a potent antioxidant 37,38 , to contain free radical scavengers 39 , and to be a chemopreventive agent against skin tumors and solar radiation damage. 40 ' 41,42 It has been shown that green tea antioxidants can protect against general free radical damage and skin cancer in 5 animal models.
- ⁇ -glucans are high molecular weight phosphorylated polysaccharides, generally obtained from oats, which can be solubilized and used as moisturizers and also aid in the healing of wounds and infections. 44
- a topical composition which can potentially include an active agent such as green tea, vitamin C and/or vitamin A.
- an active agent such as green tea, vitamin C and/or vitamin A.
- the specification of this patent describes an emulsion composition containing a water-sensitive active agent.
- the activity of water in an aqueous phase of the emulsion is lowered to 0.85 or less by inclusion of a polyol so as to stabilize the water-sensitve agent against degradation.
- the active agent or agents can be used in the composition in an amount ranging from 0.001 to
- the water-sensitive agent is an enzyme sold under the tradename Subtilisine SP544 present in the amount of 0.1%.
- the specification states that other water-sensitive active agents include green tea, ascorbic acid, vitamin A and urea, but describes no specific embodiment involving any of these agents.
- Such organic penetrants include lower alkyl diols, C 10 to C 20 fatty acids and esters thereof, and C 4 to C 20 aliphatic alcohols.
- penetrants are propylene glycol, oleic acid, butyl alcohol and, preferably, benzyl alcohol.
- the amount of penetrant is suggested to vary between about 0.5 and about 10 weight percent.
- Particular enhancers that are said to be useful in the lotions include dimethyl sulfoxide, N,N-dimethyl acetamide, 2-pyrrolidone, l-methyl-2-pyrrolidone, Carbitol solvent (Union Carbide), propylene carbonate, 1 ,5-dimethyl-2-pyrrolidone, 2-pyrrolidone-5-carboxylic acid, and the like, 0 wherein the lotion includes a penetration enhancing agent in an amount of about 0.01 to 20 weight percent.
- the dermatological agent could also be an anti-psoriatic compound such as anthralin (dithranol), coal tar extract, and the like; a keratolytic agent such as salicylic acid, urea, and the like.
- anthralin dithranol
- coal tar extract coal tar extract
- a keratolytic agent such as salicylic acid, urea, and the like.
- compositions various combinations of a retinoid compound, a D vitamin, an anti-free radical agent, an ⁇ -hydroxy acid, an ion channel blocker, a moisturizing agent, a wetting agent, a depigmenting agent, an antiseborrhoeic or antiacne agent, an antibiotic, an antifungal agent, a hair regrowth promoter, a non- steroidal anti-inflammatory agent, or an anti-psoriatic agent, 5,8,11,14-eicosatetraynoic or 5,8,11-eicosatrynoic acid or ester or amide thereof.
- the present invention is a topical composition containing urea and one or more active ingredient(s), in which the urea is present in the composition in an amount sufficient to enhance penetration of the active ingredient(s) of the composition.
- the invention includes a method of treatment of living skin (the viable epidermis, below the stratum corneum, and dermis) enhancing delivery of active ingredient(s) thereto by topically applying to the skin surface a composition of the invention.
- a preferred active ingredient is vitamin E and a preferred combination of ingredients is vitamins A, C and E, and green tea.
- Other active ingredients are antioxidants such as retinyl palmitate, ⁇ - carotene, tocopherol acetate, ascorbic acid, green tea, black tea, quercetin (flavonoids), sea kelp, pycnogenols (proanthocyanidins), selenium and alkylgylcerol-AKG (shark liver oil), taken alone or in combination, and others described below in connection with the detailed embodiments.
- An amount of urea sufficient to enhance penetration of the antioxidant is determined for each ingredient or family of ingredients for inclusion in a single composition of the invention. This is generally in excess of 10% and up to about 50% urea by weight of the total composition.
- Other agents that are typically included in topical compositions can be included in compositions of the invention, and are described in connection with detailed embodiments.
- compositions of the invention are generally used in situations in which it would be found advantageous to have the active ingredient(s) delivered to living skin below the stratum corneum.
- compositions of the present invention can find usefulness in application to skin of subjects suffering from diabetes, menopause, eczema, scleroderma, psoriasis, cancer, multiple sclerosis, allergy sensitivities, Down's syndrome, circulatory disorders, and so on.
- the invention is a topical composition that includes about 10 to about
- the anti-oxidant can be selected from the group consisting of vitamin E, vitamin C, vitamin D, retinyl palmitate, ⁇ -carotene, green tea, black tea, quercetin, sea kelp, pycnogenols (proanthocyanidins), selenium and alkylgylcerol-AKG, allopurinol, ⁇ -lipoic acid, astaxanthin, azulenic retinoid compounds, coenzyme Q-10, cysteine, zinc, copper, magnesium, potassium, selenium, BHA,
- the composition includes between about 10% and about 45% urea, about 15% and about 40% about urea, between about 20% and about 40% urea, between about 20% and about 35% urea, between about 20% and about 30% urea, or more preferably, about 25% urea.
- a preferred anti-oxidant is vitamin E, which can be in the form of tocopherol acetate.
- the composition can include up to about 10% by weight of vitamin E, but more preferably, about 5% and at least about 0.1% by weight of vitamin E.
- Other compositions include at least about 0.5%, or at least about 1% be weight of vitamin E, between about 1% and about 4%, between about 1% and 2% by weight of vitamin E, or about 1% by weight of vitamin E, or about 1.5%.
- a preferred family of anti-oxidants present in a composition is vitamin A, vitamin C, vitamin E and green tea extract, although these ingredients can be taken separately or in any combination.
- the entire family is present in the composition.
- Such a composition can include up to about 5% by weight of vitamin A, at least about 0.1%, between about 0.2% and 4%, between about 0.3% and 3%, or about 0.3% by weight of vitamin A.
- the composition can include up to about 10% by weight of vitamin C, or at least about 0.1%, between about 0.1% and 5%, between about 0.1% and about 3%, between about 0.1 and 2%, between about 0.1% and 1%, or about 0.1% or about 0.5% vitamin C.
- the composition can include up to about 10% by weight of green tea extract. 37.
- composition of any of claims 21 to 36 comprising at least about 0.1% by weight of green tea extract, between about 0.1% and 5%, between about 0.1% and 3%, between about 0.1% and 1%, or about 0.3%, or about 0.5% by weight of green tea extract.
- the invention is a method of enhancing delivery of an anti-oxidant to the viable epidermis, the method comprising the step of topically applying a composition of the invention to a skin surface of a mammal.
- the invention is the use of a composition of the invention in the preparation of a topical medicament for use in delivery of one or more anti-oxidants to the viable epidermis of a mammal.
- the invention includes topical use of a composition of the invention in the delivery of one or more anti-oxidants to the viable epidermis of a mammal.
- the invention also includes a method of manufacturing a topical preparation comprising a composition of the invention, the method comprising combining the one or more anti-oxidants and urea so as to form a homogeneous topical skin preparation.
- the skin preparation is a cosmetic preparation.
- the method can include incorporating water into the preparation, wherein the final amount of water is between about 15% and 80% by weight, between about 30% and 80%, or between about 50% and 70%.
- the method can further include incorporating glycerin into the preparation, wherein the final amount of glycerin is up to about 20% by weight, but more preferably the amount of glycerin is between about 55 and 15%.
- Figures 1(a) to 1(e) graphically illustrates the effects of a composition containing 15% urea and vitamins A, C, and E, and green tea extract (plot above the most lightly shaded area), and a similar composition without any of vitamins A, C, and E, and green tea extract (plot above the most darkly shaded area) on the condition of skin as measured using a Corneometer, as evaluated for five different subjects.
- the condition of an untreated area (the remaining plot) was also evaluated. Measurements were taken over a 10 1/2 day period as explained in detail below.
- the present invention is a topical composition that includes at least one active ingredient in combination with urea in which the urea is present in an amount sufficient to enhance penetration of the active ingredient(s).
- the active ingredient(s) is selected for its beneficial effects to the skin, which effect is to be enhanced by exposure of the viable epidermis and/or dermis, which underlies the stratum corneum, to the ingredient.
- urea in a concentration sufficient to enhance penetration of the agent through the stratum corneum in a topical composition, such effect is enhanced.
- the proportion of the composition which should be urea is at least 10 percent by weight.
- compositions containing less of a given active ingredient would be necessary to obtain the same or comparable effect due to the the ingredient's activity in the absence of a penetration enhancing amount of urea.
- the precise minimum amount of urea necessary to enhance penetration of a particular active ingredient agent(s) is determined according to the method given below. In general, the minimum amount of urea that is necessary to obtain penetration enhancement is at least about 10%, but it would generally be higher, and could be as high as 50%. Typical compositions have about 15%, or about 20%, or about 25%, or about 30%, or about 35%, or about 40% urea. In the context of this invention, percentages are given as "weight percent".
- a preferred active ingredient is selected from vitamins, antioxidants and ⁇ -glucans.
- Preferred vitamins are vitamin E (particularly, alpha tocopherol, as well as beta, delta, and gamma-tocopherols and alpha, beta, delta and gamma tocotrienols), vitamin C, and vitamin D.
- vitamin E particularly, alpha tocopherol, as well as beta, delta, and gamma-tocopherols and alpha, beta, delta and gamma tocotrienols
- vitamin C particularly, alpha tocopherol, as well as beta, delta, and gamma-tocopherols and alpha, beta, delta and gamma tocotrienols
- vitamin C particularly, alpha tocopherol, as well as beta, delta, and gamma-tocopherols and alpha, beta, delta and gamma tocotrienols
- vitamin C particularly, alpha tocopherol, as well as beta, delta, and gamma-
- Preferred antioxidants include retinyl palmitate, ⁇ -carotene, tocopherol acetate, ascorbic acid, green tea, black tea, quercetin (fiavonoids), sea kelp, pycnogenols (proanthocyanidins), selenium and alkylgylcerol-AKG (shark liver oil). It is generally considered that if ⁇ -carotene is included, vitamin E should also be included as discolorization of the skin by vitamin A can be reduced in the presence of vitamin E. 45
- vitamins E and C can protect the skin against oxidative damage caused by free radicals. 46
- Green tea is known to contain polyphenols and their use in antioxidant formulations has been suggested. See, for example, United States Patent No. 5,648,377, which issued to Bombardelli et al. on July 15, 1997.
- antioxidants include: Allopurinol; ⁇ -lipoic acid; astaxanthin; azulenic retinoid compounds; vitamin A related compounds such as ⁇ -carotene, carotenoid, lycopene, xanthophylls and lycopene; coenzyme Q-10; cysteine; metals such as zinc, copper, magnesium, potassium selenium; BHA; BHT; maharishi amrit kalash (MAK); melatonin; N-acetylcysteine (NAC); olive oil; phenolics; pyrimidines; activin (from seeds of red grapes); superoxide dismutase (SOD); prozyme (Polbax); black tea in addition to green tea (camelia sinensis); proanthocynidins (OPC); pycnogenol grape seed); curcumin from tumeric; silymarin, the flavonoid complex of milk thistle (Silybum maria
- Urea is a well known component of topical compositions. In the bulk of products in which is it used, it is included as a moisturizing agent. This is true, for example, where it is suggested for use in compositions described in United States Patent No. 5,935,585. When used as a moisturizing agent in a composition, the amount of urea included is usually limited to small amounts. Urea is also known to improve the elasticity of the stratum corneum. 47
- Lotion A contained 2% by weight lactic acid and 0.2% by weight malic acid in an oil-in-water emulsion.
- Lotion B was the same as lotion A with urea added to make up 10% by weight of the total composition.
- Lotion C was the same as lotion B with 0.2% allantoin, 0.3% vitamin E, 0.25% vitamin A, 0.10% vitamin C, and 0.3% green tea extract, all percentages being weight percent.
- the three areas of the subject were equally exposed to natural sunlight over a one week period.
- Results were evaluated by measuring skin impedance using a Surface Characterizing Impedance Monitor (SCIM) developed by Ollmar, which measures bioelectrical impedance of the skin at multiple frequencies. 52,53,54,55,56,57
- SCIM Surface Characterizing Impedance Monitor
- the instrument is basically an AC-bridge fabricated from standard laboratory instruments: a function generator, a digital oscilloscope, impedance references, and a driver for the probe. The results obtained are given in Table I.
- the baseline is given as the "before" measurement in Table I.
- the depths of skin measured varied from the most superficial stratum corneum (1) to the live epidermis (5).
- compositions containing vitamins A, C, E and green tea extract are contemplated as follows:
- Composition A A:
- Composition A was obtained according to the following procedure:
- phase I In a s.s. kettle the ingredients of phase I are combined and heated to 70° - 75°C and maintained at that temperature. In a separate s.s. kettle the ingredients of phase II are combined and heated to 75° - 80°C and maintained at that temperature. Phase II is added at 75° - 80°C to phase I at 70° - 75°C with mixing to homogenous solution and the solution is permitted to cool. At 60 - 65°C, phase III is added and cooling and mixing is continued. At 50° - 55°C, phase IV is added and cooling and mixing is continued. At 35° - 40°C, the ingredients of phase V are added with mixing. Cooling and mixing until a temperature of 30° 35°C is reached and mixing is stopped.
- Composition B is a composition of Composition B:
- Composition B was obtained according to the following procedure:
- Imidazolidinyl urea 0.30 Methyl paraben 0.20 Allantoin 0.20 Malic acid 0.20 Ascorbic acid 0.10 Trisodium EDTA 0.10
- phase I In a s.s. kettle the ingredients of phase I are combined and heated to 70° - 75°C and the temperature maintained. In a second s.s. kettle the ingredients of phase II are combined and heated to 75° - 80°C and the temperature maintained. Phase II, at 75° - 80°C is added to phase I at 70° - 75°C with mixing. A homogeneous solution is obtained and the mixture is permitted to cool with mixing. At 60° - 65°C, phase III is added to the solution and cooling and mixing is continued. At 50° - 55°C, phase IV is added and mixing and cooling is continued.
- ingredients of phase V are added in the order indicated with mixing and mixing is continued until the solution reaches a temperture of 35° - 35°C.
- Composition C is a composition having Composition C:
- Composition C was obtained according to the following procedure:
- phase I In a s.s. kettle the ingredients of phase I are added the order indicated and mixed until the carbomer is completely dispersed and hydrated. The solution is headed to 70° - 75° C and the temperature maintained. In a separate s.s. kettle the ingredients of phase II are combined and heated to 75° - 80°C with mixing and the temperature maintained. The phase II mixture at 75° - 80° C is added to the phase I solution at 10 70° - 75°C with mixing. The batch is mixted to obtain a homogeneous solution and the solution is permitted to cool. At 60° - 65°C, phase III is added with mixing and cooling is continued. At 50° - 55°C, phase IV is added with mixting and cooling continued. At 35° - 40°C, the ingredients of phase V are added with mixing in the order indicated. Mixing is stopped when a temperature of 30° - 35°C is reached.
- Composition D is a composition of Composition D:
- Composition D was obtained according to the following procedure:
- phase I In a s.s. kettle, the ingredients of phase I are combined in the order indicated and mixed until carbomer is completely dispersed and hydrated. The mixturue is heated to 70° - 75°C and the temperature maintained. In a separate s.s. kettle the ingredients of phase II are combined and heated to 75° - 80°C with mixing and the temperature maintained. The phase II mixture is added at 75° - 80°C to phase I at 70° -75°C with mixing. The mixture is mixed to obtain a homogeneous solution and permitted to cool with mixing. At 60° - 65°C, phase III is added to the batch and mixing and cooling are continued. At 50° - 55°C, phase IV is added to the batch and mixing and cooling are continued.
- phase V is added to the batch and mixing and cooling is continued.
- the ingredients of phase VI are added to the batch in the order indicated and mixing is continued until a temperature of 30° - 35°C is reached. It is preferable to have homogeneous formulations.
- In vitro skin penetration studies can be used to evaluate a suitable amount of urea to be used in connection with a particular ingredient.
- the penetration of vitamins through human skin can be measured using various formulations with and without urea.
- Transepidermal water loss can be measured by evaporimetery using a Servo-Med evaporimeter or similar device, for example.
- Test compositions including an ingredient to be evaulated are prepared along with control compositions, which are the same except that the urea is omitted.
- Each composition is applied to the skin surface at 2 mg/square cm for between about 0.5 to 6 hours. After the specified period oftune the site is washed thoroughly with mild detergent and water. The site is dried. The site is then tape stripped using D-Squame adhesive disks. Five strips are taken and combined and then five more and five more for a total of 25. The tapes are then extracted and analyzed for the active ingredient, say vitamin E, using HPLC.
- composition E containing 25 % urea and vitamin E was tested.
- the formulations of compositions used in the studies are as follows: Ingredients (w/w%)
- Vitamin E tocopheryl acetate
- An especially preferred composition of the present invention thus is one that contains between 10 and 50 % urea, more preferably between 15 and 50 % urea, more preferably between 20 and 45% urea, and more preferably still between 25 and 40%, and most preferrably about 25%.
- Composition F had the same composition as that set out above for Composition C. In these studies, five subjects were tested over a period of 10 Vi days. For each subject, three different areas of skin were tested. The first area was not treated. The second area was treated with a control containing urea but no vitamin E, here called Composition F'. The third area was treated with Composition F.
- Composition F' a control containing urea but no vitamin E
- compositions F and F' were applied to the two treatment areas.
- the compositions were similarly applied and measurements taken 12 hours later and at 12 hour intervals thereafter.
- Treatment with Compositions F and F' were stopped after the eighth day (i.e., after the 16th treatment) but measurements were continued, for a total of twenty-two measurements.
- Results are plotted in Figures 1(a) to 1(e), one plot for each of the five subjects.
- the plot above the most lightly shaded area in each figure is that obtained by taking measurement using the Corneometer of the area treated with Composition F.
- the initial measurement taken of a particular area was substracted from each measurement before plotting of the results.
- the plot above the most darkly shaded area in each figure is that obtained from measurements taken of the area treated with Composition F'.
- the remaining plot shows measurements obtained from the untreated area.
- the x-coordinate of each plot shows the number of the measurement taken, at 12-hour intervals.
- the y-coordinate is the reading taken from the Corneometer having the initial reading for the area subtracted. The higher the reading the greater the moisture content of the skin.
- Raab also suggests that urea increases the bioavailablity, or topical activity, of other drugs.
- glucocorticoids e.g., 1% hydrocortisone with 10% urea
- Raab describes improvement in the antisporiatic action of anthralin in a composition containing 17% urea.
- Raab also describes treatment of certain severe ichthyoses with a combination of 0.03% tretinoin (all-fraws-retinoic acid) and 10% urea, and the treatment of hyperkeratoses with a combination of 10% urea and 10% salicylate.
- WO 86/00014 (Weiner), published January 3, 1986, describes topical cream compositions that includes 15% urea, possibly up to 40% urea, in combination with UV absorbing sun screen agents, for the purposes of prevention and/or reduction of skin damage caused by reactive chemical substances generated in the skin by ultraviolet radiation.
- the amount of vitamin A to be included in a composition would be from about 0.1 to about 5%, vitamm E would be from about 0.1 to about 10%.
- ln vivo efficacy can be evaluated against dry skin in the case of active ingredients that would be thought to be helpful to such condition.
- Subjects with dry itchy skin use a product containing urea in combination with the test ingredient in a controlled clinical test. The skin is graded, subjective assessments are obtained and a number of different instruments are used to determine effects on skin. Again systematic studies using various concentrations of urea, various concentrations of the test ingredient, test times and controls (compositions lacking the test ingredient and/or urea, for example) are carried out to determine optimal composition makeup.
- In vivo barrier repair can be tested for ingredients thought to play a role in wound repair. Tape stripping, for example, is used to damage skin and the damage is then judged by measuring trans- epidermal water loss and erythema. Test compositions can be applied to the damage area and effects on the rate of healing determined. Again, various concentrations of the test ingredient, in combination with various concentrations of urea, and appropriate controls, etc., would be used. Additionally, of course, different application methods might also be tested.
- Vitamins E and C especially in combination with each other, have been shown to protect against sunburn even though they do not absorb significant amounts of UV light. This is because they reduce damage caused by free radicals that result from UV exposure.
- urea In terms of the minimum amount of urea that is to be included in a composition in combination with a particular active ingredient, it may be found that there is a particular minimum associated with a group of ingredients that are chemically related to the one tested. For example, if it is found that at least 20% urea is suitable for two or more compounds of a family of compounds that a person skilled in the art would understand to share hydrophilic properties, have similar molecular weights, etc., then it would be reasonably expected that 20% urea would be a suitable amount of urea to be used in combination with other compounds of that family. Of course, the greater the number of compounds within a family that are actually tested and found to behave similarly, the greater the certainty that other compounds of the family that are not tested will behave similarly to those that have been tested.
- compositions of the present invention are described below.
- Allopurinol is not, strictly speaking, an antioxidant. This ingredient is though to suppress the body's production of an oxidation catalyst, xanthine oxidase.
- Alpha lipoic acid is a water soluble and lipid soluble antioxidant. Apparently, ALA promtes the regeneration of the redox reaction between vitamin C, E, and glutathione. 58
- Astaxanthin is a carotenoid produced by a microalgae called Haematocococcus pluvialis.
- Azulenic retinoid compounds are compounds related to Vitamin A and retinoic acid.
- a new type of azulene-containing retinoid has been synthesised and is similar in size and shape to Vitamin A, but its electronic properties are different.
- Vitamin A ⁇ -carotene, carotenoid, lycopene, xanthophylls and lycopene
- carotenoids ⁇ -carotenoids, carotenoid, lycopene, xanthophylls and lycopene
- Vitamin C ascorbic acid
- This anti oxidant is thought to slow down loss of glutathione to neutralise some destructive cell oxidants.
- Vitamin E occurs in nature in several forms - alpha, beta, delta, and gamma-tocopherols and alpha, beta, delta and gamma tocotrienols. Most vitamin E supplements contain alpha tocopherol form which is thought to have significant biological activity. 59
- Melatonin has been found to rescue DA neurons from cell death in several experimental paradigms associated with oxidative stress. 60 The combined findings suggest that melatonin counteracts the in vitro destructive effects of NMD A or hypoxia/reperfusion by preventing accumulation of excessive free radicals. 61 Melatonin protects primary cultures of rat cortical neurones from NMDA excitotoxicity and hypoxia reoxygenation. 62
- silica hydride This silica mineral is 5 nanometers in total area - the smallest nutritional particle ever discovered. When combined, this molecule is a million times smaller than the next smallest antioxidant.
- NAC N-Acetylcysteine
- Phenolics are naturally occurring anti oxidants found in the skins of many fruits, vegetables and herbs.
- Pyrimidines are a group of antioxidant compounds, the pyrrolopyrimidines, discovered recently. They appear to quench lipid peroxidation reactions by electron-donating and/or radical-trapping mechanisms. 64
- Activin (TM) can be obtained from the seeds of the red grape.
- SOD Superoxide Dimutase
- Black and green teas (camelia sinensis) have anti oxidant properties. Black tea is though to have similar anti oxidant properties to those of green tea.
- Coenzyme Q-10 (ubiquinone) is an essential cofactor of the electron transport chain as well as a potent free radical scavenger in lipid and mitochondrial membranes. 67 Coenzyme Q10 administration is though to increase brain mitochondrial concentrations and to exert neuroprotective effects. 68
- silymarin the flavonoid complex of milk thistle (Silybum marianum) and Ginkgo biloba extract is thought to be an antioxidant.
- Curcumin can be obtained from tumeric. Curcurnin is the yellow pigment of turmeric
- Curcuma longa an ingredient of curry powder and prepared mustard. Curcumin is though to be an antioxidant.
- the amount of active ingredient to be included in a composition is a topically effective amount, and can be determined by a person skilled in the art according to the purposes for which the ingredient is being applied.
- the amount of vitamin E measured at the skin level just above the viable epidermis is between two and three times that found when no urea was used (control).
- the amount of vitamin E to be included in a composition containing 25% urea can be 1/3 to 1/2 the amount that would be included in a composition lacking urea.
- a person skilled in the art, provided with this specification would be readily capable of deriving other formulations within the scope of the invention described herein.
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Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU69756/00A AU6975600A (en) | 1999-09-07 | 2000-09-07 | Topical urea composition |
CA002382833A CA2382833A1 (en) | 1999-09-07 | 2000-09-07 | Topical urea composition |
EP00958066A EP1214049A2 (en) | 1999-09-07 | 2000-09-07 | Topical urea composition |
US10/087,850 US20030104080A1 (en) | 1999-09-07 | 2002-03-05 | Topical urea composition |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US15263799P | 1999-09-07 | 1999-09-07 | |
US60/152,637 | 1999-09-07 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/087,850 Continuation-In-Part US20030104080A1 (en) | 1999-09-07 | 2002-03-05 | Topical urea composition |
Publications (3)
Publication Number | Publication Date |
---|---|
WO2001017484A2 true WO2001017484A2 (en) | 2001-03-15 |
WO2001017484A3 WO2001017484A3 (en) | 2001-09-27 |
WO2001017484A9 WO2001017484A9 (en) | 2002-08-29 |
Family
ID=22543746
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CA2000/001031 WO2001017484A2 (en) | 1999-09-07 | 2000-09-07 | Topical urea composition |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP1214049A2 (en) |
AU (1) | AU6975600A (en) |
CA (1) | CA2382833A1 (en) |
WO (1) | WO2001017484A2 (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004022027A1 (en) * | 2002-09-04 | 2004-03-18 | Omega Pharma Nv | Anti-wrinkles cosmetic compositions |
FR2844716A1 (en) * | 2002-09-23 | 2004-03-26 | Marcel Jacques Chicouri | Synergistic composition for hygiene and prophylactic treatment of feet of diabetics, comprising anti-dehydration agent, microcirculation modulator and antiseptic |
US7435725B2 (en) | 2001-11-06 | 2008-10-14 | The Quigly Corporation | Oral compositions and methods for prevention, reduction and treatment of radiation injury |
WO2010048686A1 (en) * | 2008-10-30 | 2010-05-06 | Natura Cosméticos S.A. | Antioxidant complex, cosmetic and pharmaceutical compositions containing said complex, and use thereof |
WO2014041528A3 (en) * | 2012-09-14 | 2014-12-18 | Martin Roslain Margaret | A composition for the treatment of cutaneous signs of ageing |
WO2017034384A1 (en) * | 2015-08-24 | 2017-03-02 | Rīgas Stradiņa Universitāte | Epidermal lipid barrier restoring cream for facial skin, neck and decollete area for metabolic syndrome patients |
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SU439288A1 (en) * | 1971-07-29 | 1974-08-15 | Республиканский Ожоговый Центр При Грьковском Научно-Исследовательском Институте Травматологии И Ортопедии | Means for dissolving necrotic tissue |
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2000
- 2000-09-07 AU AU69756/00A patent/AU6975600A/en not_active Abandoned
- 2000-09-07 EP EP00958066A patent/EP1214049A2/en not_active Withdrawn
- 2000-09-07 CA CA002382833A patent/CA2382833A1/en not_active Abandoned
- 2000-09-07 WO PCT/CA2000/001031 patent/WO2001017484A2/en not_active Application Discontinuation
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Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7435725B2 (en) | 2001-11-06 | 2008-10-14 | The Quigly Corporation | Oral compositions and methods for prevention, reduction and treatment of radiation injury |
WO2004022027A1 (en) * | 2002-09-04 | 2004-03-18 | Omega Pharma Nv | Anti-wrinkles cosmetic compositions |
FR2844716A1 (en) * | 2002-09-23 | 2004-03-26 | Marcel Jacques Chicouri | Synergistic composition for hygiene and prophylactic treatment of feet of diabetics, comprising anti-dehydration agent, microcirculation modulator and antiseptic |
WO2010048686A1 (en) * | 2008-10-30 | 2010-05-06 | Natura Cosméticos S.A. | Antioxidant complex, cosmetic and pharmaceutical compositions containing said complex, and use thereof |
FR2937866A1 (en) * | 2008-10-30 | 2010-05-07 | Natura Cosmeticos Sa | ANTIOXIDANT COMPLEX, COSMETIC AND PHARMACEUTICAL COMPOSITIONS COMPRISING SAID COMPLEX AND THE USE OF SAID COMPLEX |
US8383168B2 (en) | 2008-10-30 | 2013-02-26 | Natura Cosmeticos S.A. | Antioxidant complex, cosmetic and pharmaceutical compositions containing said complex and use of said complex |
WO2014041528A3 (en) * | 2012-09-14 | 2014-12-18 | Martin Roslain Margaret | A composition for the treatment of cutaneous signs of ageing |
WO2017034384A1 (en) * | 2015-08-24 | 2017-03-02 | Rīgas Stradiņa Universitāte | Epidermal lipid barrier restoring cream for facial skin, neck and decollete area for metabolic syndrome patients |
Also Published As
Publication number | Publication date |
---|---|
CA2382833A1 (en) | 2001-03-15 |
WO2001017484A3 (en) | 2001-09-27 |
AU6975600A (en) | 2001-04-10 |
EP1214049A2 (en) | 2002-06-19 |
WO2001017484A9 (en) | 2002-08-29 |
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