WO2002083136A1 - Compositions therapeutiques contenant des acides amino sulfoniques et leurs utilisations - Google Patents

Compositions therapeutiques contenant des acides amino sulfoniques et leurs utilisations Download PDF

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WO2002083136A1
WO2002083136A1 PCT/GB2002/001781 GB0201781W WO02083136A1 WO 2002083136 A1 WO2002083136 A1 WO 2002083136A1 GB 0201781 W GB0201781 W GB 0201781W WO 02083136 A1 WO02083136 A1 WO 02083136A1
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acid
pka
metal salts
free acid
bis
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PCT/GB2002/001781
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WO2002083136A8 (fr
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Peter Herbert North
Andrew Marc Salomon
Anthony Atkinson
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Process & Industrial Design Consultants Ltd
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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/133—Amines having hydroxy groups, e.g. sphingosine
    • 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
    • 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
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • 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
    • A61K8/46—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur
    • A61K8/466—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur containing sulfonic acid derivatives; Salts
    • 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
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
    • 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
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/70—Biological properties of the composition as a whole
    • 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
    • A61Q19/007—Preparations for dry skin

Definitions

  • This invention relates to the use of zwitterionic amino sulfonic acids and their derivatives and chemically related molecules in the treatment of skin disorders, non-dermatological inflammatory and other disease conditions.
  • Dermatological disorders and non-dermatological inflammatory disorders affect significant numbers of the population for a large proportion of their lives. At present, most treatments in the field of dermatology are aimed at providing symptomatic relief only, and this is often at the cost of side effects of varying severity.
  • the current situation can be summarised as follows:
  • Ichthyosis is a group of often inherited diseases which may be characterised by scaly, dry and often itchy skin. Treatments for genetically and non-genetically linked ichthyoses are different. The principal known treatments which have been used to greater or lesser success are: hydration of the skin with an emollient, which is common to all ichthyoses; in addition, use of a descaling topical salicylic acid product may be indicated in ichthyosis vulgaris, lamellar ichthyosis and sex-linked ichthyosis, all of which are genetically linked; oral retinoids, and in particular isotretinoin may be used as effective treatments for the scaling associated with most ichthyoses, although they may cause dryness of the skin themselves.
  • Dermatitis is a general term to denote a group of conditions which may be characterised by superficial skin inflammation presenting with redness, oedema, oozing, crusting scaling and usually itching. Conditions within the grouping include but are not limited to contact dermatitis (caused by a delayed hypersensitivity reaction or direct contact with a skin irritant), atopic dermatitis (also known as atopic eczema, an immune response disease often co-existing with hay fever and/or asthma), seborrheic dermatitis (known as "cradle cap” in infants), chronic dermatitis of hands and feet (in response to mechanical or chemical trauma), and generalised exfoliative dermatitis (a condition for which often no specific cause is found).
  • contact dermatitis caused by a delayed hypersensitivity reaction or direct contact with a skin irritant
  • atopic dermatitis also known as atopic eczema, an immune response disease often co-existing with hay fever and/or asthma
  • Drugs that have been recorded to cause iatrogenic skin and mucous membrane dryness include, but are not limited to, oral and topical retinoids, omeprazole, buserelin, calcipotriol, fluoxetine, famotidine, ganciclovir, losartan and topical metronidazole.
  • symptomatic treatment with an emollient may be used to counter the skin dryness, although in some cases, cessation of drug treatment is needed.
  • urea at low concentrations in topical products for the skin can provide an enhanced moisturising or hydrating effect over that provided by the emollient, occlusive or moisturising topical base itself.
  • This moisturising effect of urea is clearly applicable to most skin conditions where dryness is a feature. This effect is due to the ability of urea to take up and subsequently release water of hydration.
  • Urea suffers from the drawback, however, that it is potentially toxic to the cells of the skin given that it is readily converted, via biuret, to ammonia (Merck Index, 11th Edn). This production of ammonia is due, at least in part, to skin microorganisms. The liberation of ammonia on the skin also makes urea - containing products particularly unpleasant from the point of view of their smell.
  • Exposure of the skin to UNA in sunlight can lead to an increase in the levels of free radicals in the skin which produce tissue damage in a variety of ways. These may include crosslinking of proteins such as collagen, release of degradative enzymes such as proteases, including elastase, and inhibition of oxidative enzymes in fibroblasts and keratinocytes. At a microscopic level, non-photo associated components of skin ageing may lead to a decrease in the life of fibroblasts, thickening of fibrillar dermal elements, a decrease in hyaluronan concentration with consequent decrease in water levels in the tissues, and a change in the structure and composition of elastins.
  • skin ageing resulting from both photo and non-photo causes may be characterised by dryness of the skin, loss of elasticity of the skin, an increase in wrinkles, an increase in susceptibility to topical infections and infestations, and a general deterioration in the quality of the skin.
  • Psoriasis is a chronic recurrent disease characterised by dry well circumscribed, silvery scaling papules and plaques of various sizes and skin dryness in affected areas.
  • the severity of the disease can vary from small scaly patches on the elbows and knees to large plaques and papules covering 40 - 50% of the body. Whilst the exact aetiology of the disease has not yet been fully elucidated, it is believed to involve a large genetic component. It is known that on a cellular level, the plaques are caused by hyperproliferation of undifferentiated keratinocytes.
  • tissue infiltration by neutrophils and a range of T-cells may be a prominent feature of the disease.
  • psoriasis is generally recognised as being an auto-immune disease involving excess production of or presence in the affected tissues of oxygen free radicals, interleukin 1 (IL-1), leukotriene B (LTB 4 ), and tumour necrosis factor (TNF).
  • IL-1 interleukin 1
  • LTB 4 leukotriene B
  • TNF tumour necrosis factor
  • the most common kind of psoriasis is psoriasis vulgaris, however, a rarer kind known as pustular psoriasis in which sterile pustules occur on the palms and soles also occurs. Due to the immune system involvement in both of these kinds of psoriasis, psoriatic arthritis may develop in a low percentage of patients as a side effect of the disease.
  • Topical corticosteroids which may be used as treatments for acute disease flare ups. Corticosteroids enter the cytosol of keratinocytes and alter DNA synthesis and hence rate of maturation of the cell. Corticosteroids also possess anti-LTB4 and anti-oxygen free radical actions. Toxicity of corticosteroids increases with potency, and may include disease rebound or relapse upon withdrawal, cutaneous atrophy, epidermal stretching and pituitary-adrenal-axis suppression;
  • Topical preparations of coal tar which suppresses epidermal DNA synthesis, and hence plaque formation, may be used for day to day treatment of mild to moderate psoriasis.
  • Side effects of coal tar include skin irritation and acne like eruptions.
  • use is limited by the unpleasant smell of coal tar preparations and their ability to stain skin and clothing.
  • use of these products may be compromised due to the carcinogenic nature of coal tar;
  • Topical salicylic acid which may be used in psoriasis to enhance the rate of scale loss. The major side effect of such preparations, however, may be skin irritation itself;
  • Topical vitamin D analogs such as calcipotriol and tacalcitol, which interfere with keratinocyte proliferation and enhance proper keratinocyte differentiation. These topical products may be used for treating mild to moderate psoriasis. However, recorded side effects include skin dryness, local irritation, photosensitivity and hypercalcaemia;
  • Oral retinoids including etritinate and it's active metabolite acitretin, which counter the hyper-proliferation and lack of differentiation of keratinocytes in psoriasis. They also have anti-inflammatory effects in their own right. Due to their side effects, which may include dryness of mucous membranes, thinning of the skin, photosensitivity, skeletal hyperostosis, myalgia and arthralgia, these drugs have been reserved for severe extensive psoriasis resistant to other treatments;
  • Cyclosporin which has anti-T cell properties, may be used in severe or recalcitrant psoriasis. Its restriction to severe disease is due to its side effects which can include hypertension, gingival hypertrophy, hepatic and renal impairment and neuropathy;
  • Methotrexate a dihydrofolate reductase inhibitor and consequently an anti-metabolite may also be used in the treatment of severe psoriasis.
  • Side effects can include bone marrow suppression, hepatic and renal damage, skin reactions and teratogenesis;
  • Non-dermatological inflammatory diseases include, but are by no means limited to:
  • Inflammatory bowel disease a group of inflammatory bowel disorders with overlapping clinical, epidemiological and pathological findings, but without a definite aetiology and including both ulcerative colitis and Crohn's disease. Whilst both diseases can be characterised by chronic non-specific inflammation of the gastrointestinal tract, ulcerative colitis is limited to the colonic mucosa, whereas Crohn's disease can effect any part of the GI tract from the mouth to the anal and perianal regions. In addition, unlike Crohn's disease, ulcerative colitis is also characterised by ulceration and bleeding in the colon, consequently presenting with bloody diarrhoea. Both diseases present with abdominal discomfort, weight loss and diarrhoea.
  • 5-aminosalicylic acid containing drugs such as sulphasalazine, mesalazine and olsalazine may be used as the mainstays of long term treatment for both ulcerative colitis and Crohn's disease.
  • the mechanisms of 5-aminosalicylic acid containing drugs have not been fully elucidated, but are thought to include inhibitory or down-regulating effects on LTB4, oxygen radicals, 5-lipoxygenase (the enzyme that produces leukotrienes) PAF and IL-1. Side effects of this class of drugs may include nausea, vomiting, abdominal discomfort, headache and skin rashes.
  • Orally or rectally administered corticosteroids may be used as therapy in acute flare ups of disease. Due to their side effect profile as outlined previously, their long term use may be contra-indicated. Immunosuppressive treatment with azathioprine may be used quite commonly in both ulcerative colitis and Crohn's disease. Its side effect profile may include pancreatitis, bone marrow suppression and hepatitis. Unlike azathioprine, cyclosporin is only of clinical value in Crohn's disease, not in ulcerative colitis. Methotrexate may be considered as an alternative to azathioprine or cyclosporin in patients with intolerable side effects to these agents.
  • methotrexate itself has a large side effect profile, as outlined above.
  • Metronidazole treatment has been shown to be useful in some Crohn's disease patients with colitis resistant to standard therapy. In this setting, the mechanism of metronidazole has not yet been established.
  • Side effects may include nausea, vomiting, GI disturbances, skin rashes, angioedema and dizziness.
  • Rheumatoid arthritis and juvenile rheumatoid arthritis are chronic syndromes of the peripheral joints which may be characterised by non-specific, usually symmetrical inflammation of the joints, normally leading to progressive destruction and deformation of articular and peri-articular structures. Generalised systemic manifestations may also present. As with many other complex diseases, the exact aetiology is not yet fully understood, but is thought to have genetic, auto-immune and infectious components. Patients may initially present with inflammation of the joint with progressive loss of joint function, eventually leading to fusing of the joint and complete loss of joint function.
  • the disease is characterised by raised levels of LTB 4 , neutrophils, oxygen free radicals, IL-1, TNF, T-cells, hyperactivity of metalloproteinases, gelatinases and collegenases and the presence of Rheumatoid Factor (RF).
  • LTB 4 neutrophils
  • oxygen free radicals IL-1
  • TNF TNF
  • T-cells hyperactivity of metalloproteinases
  • RF Rheumatoid Factor
  • NSAIDs non-steroidal anti-inflammatory drugs
  • slow acting disease modifying drugs designed to affect the progression of the actual disease.
  • the principal known treatments which have been used with greater or lesser success include:
  • NSAIDs which may be used for treatment, are a chemically disparate group of drugs with a common mechanism of action. All members of the group may exert their analgesic and anti-inflammatory actions by inhibiting cyclo-oxygenase-2 (COX-2) thereby preventing the production of pro-inflammatory prostaglandins. Whilst inhibition of COX-2 is desirable, to date all NSAIDs also inhibit COX-1 to a greater or lesser degree, which may lead to loss of cytoprotective prostaglandin Ei and GI bleeding and potential ulceration as major side effects.
  • COX-2 cyclo-oxygenase-2
  • 5-aminosalicylic acid containing drugs such as sulphasalazine, olsalazine and mesalazine, as well as corticosteroids and methotrexate may all be used to slow or halt the progression of rheumatoid arthritis.
  • drugs such as sulphasalazine, olsalazine and mesalazine, as well as corticosteroids and methotrexate
  • gold salts such as sodium aurothiomalate and auranofin
  • auranofin which may be used to slow or halt the progression of the disease
  • Side effects can include dermatitis, inflammation of the mucous membranes, various blood dyscrasias and hepatitis.
  • D-penicillamine which may be used for treatment
  • free radical scavenging, anti-T cell and modification of collagen formation effects have been shown.
  • up to 75% of patients respond to penicillamine a high proportion (up to 40%) of those suffer side effects that necessitate cessation of treatment. These can include myasthenia gravis, thrombocytopaenia, rashes and aphthous ulcers.
  • Chloroquine and hydroxychloroquine which may be used for treatment, appear to have various mechanisms of action including inhibition of phospholipase A2 (therefore decreasing levels of leukotriene and PAF) interference with hydrolase activity, free radical scavenging, decrease of IL-1 production and inhibition of leukocyte chemotaxis.
  • Side effects of long term use of these drugs can include haemolytic anaemia, rashes, ototoxicity and rarely retinopathy.
  • Asthma a lung disease which may be characterised by reversible bronchoconstriction, inflammation of the pulmonary tissues and an increased airway responsiveness to a variety of stimuli, particularly allergens. The exact underlying cause of the disease is not fully understood. However, the disease presents with increased mast cell release of histamine granules, neutropliil and eosinophil infiltration of the tissues, raised levels of LTB and LTC D 4 and E 4 (known as the Slow Reacting Substance of Anaphylaxis (SRSA)) and a raised pulmonary immunogenic response. The importance of LTC 4 D 4 and E 4 in the disease has increasingly become recognised, as have the roles of certain phosphodiesterases.
  • the goal of asthma treatment is to prevent the onset of an acute bronchoconstrictive episode, and then treat the episode should it occur.
  • the principal known treatments which have been used include:
  • Inhaled corticosteroids particularly beclomethasone, fluticosone and budesonide, which may be used prophylactically to prevent tissue inflammation.
  • Oral corticosteroids, particularly prednisone and prednisolone may also be used to reduce inflammation in acute asthma attacks requiring hospitalisation. Whilst the side effect profile of inhaled steroids may be significantly lower than in other forms of administration, the use of high doses has raised concerns about adreno-cortical suppression and growth retardation in young children.
  • Xanthines which include theophylline and aminophylline are bronchodilating agents which may be used prophylactically to maintain bronchoconstriction at a minimum. Their mechanism of action is not clearly understood, although anti-LTB activity is thought to play a significant role. Side effects may include tachycardia, arrhythmias, palpitations and GI disturbances. The risk of side effects may also be enhanced as a result of the very narrow therapeutic window of the xanthines.
  • Nedocromil and sodium cromoglycate are mast cell stabilisers that prevent the release of bronchoconstrictive histamine from mast cells, and may be used for treatment. These agents, which are of no value in an acute attack, may be used prophylactically. Side effects of these drugs are normally minor and transient.
  • the anti-histamine ketotifen may be of some use prophylactically in paediatric asthma, although its clinical usefulness in adult asthma may be limited. Its main side effect may be sedation.
  • Beta- 2 adrenoceptor agonists such as salbutamol, terbutaline and salmeterol appear to reverse the bronchoconstriction during acute bronchoconstrictive episodes by direct stimulation of beta- 2 adrenoceptors in the lung tissue.
  • Their anti-asthmatic action may also in part be mediated by their free radical scavenging effects.
  • Side effects may include tachycardia, fine tremor of the hands and headache. Most of these side effects are often short- lived if the drug is inhaled.
  • Ipratropium bromide is an inhaled anti-muscarinic agent which may be used for treating bronchoconstriction in an acute asthma attack in patients whose disease is largely mediated by irritant stimuli. As there is no significant systemic absorption from an inhaled dose, there are few reported significant systemic anti-muscarinic side effects.
  • LTC D 4 E receptor antagonists such as zafirlukast and montelukast have recently been introduced as adjunct therapies for asthma. Side effects are generally minor but may include headache, skin rashes, abdominal pain, dizziness, insomnia and gastrointestinal disturbances.
  • D Chronic Obstructive Pulmonary Disease a broad term which may be used to describe both chronic bronchitis and emphysema either alone or when presenting concurrently in a patient.
  • chronic bronchitis there is a chronic narrowing of the bronchial tract
  • emphysema there is a loss of elasticity of the lung tissue. Due to the serious damage to the lung tissue, respiratory tract infections may be common in chronic obstructive pulmonary disease patients.
  • Xanthines which may be used to minimise bronchoconstriction
  • beta- 2 adrenoceptor agonists may be used for bronchodilation in severe acute cases of dyspnoea.
  • Corticosteroids are of no value in treating clironic obstructive pulmonary disease with a predominantly emphysemic character, however, they may be of some use in chronic bronchitic chronic obstructive pulmonary disease or chronic obstructive pulmonary disease with co-existing asthma.
  • Gastroduodenal inflammation and ulceration may be caused by many different factors including the use of NSAIDs and the presence of GI Helicobacter pylori infection. Whilst the exact mechanism of GI inflammation and ulceration is not completely understood, it is believed that NSAID associated gastric ulceration is a neutrophil dependent process, possibly mediated by LTB4 (Wallace JL et al, Am. J. Physiol. 259 (3 pt 1) : G462-467, 1990 Sept.). It is also believed that the presence of free radicals is involved in GI tissue inflammation and ulceration in all forms of gastroduodenal inflammation and ulcerations.
  • Antacids such as magnesium tricilicate and aluminium hydroxide, which may be used to counter excess acid levels.
  • Side effects may include constipation (aluminium products) and diarrhoea (magnesium products).
  • H2 receptor antagonists such as ranitidine.
  • famotidine and cimetidine which may be used to decrease gastric acid production. Whilst significant side effects are rare, inhibition of cytochrome P450 enzyme particularly by cimetidine may be highly problematic when co-administered with drugs metabolised by that enzyme system.
  • Proton pump inhibitors such as omeprazole, lansoprazole and pantoprazole, which are used to decrease gastric acid production by the parietal cell.
  • Side effects may include dry skin and membranous membranes, diarrhoea and dizziness.
  • Combinations of antibiotics such as metronidazole, amoxicillin, clarithromycin and tetracycline, used to eradicate Helicobacter pylori infections.
  • Side effects vary according to the antibiotics used and may include diarrhoea, rashes, urticaria, dizziness and darkening of the urine.
  • Bismuth chelates such as tripotassium dicitratobismuth, which help eradicate Helicobacter pylori.
  • bismuth chelates are thought to have stimulating effects on the production of cytoprotective mucosal PGEi. Side effects may include darkening of the tongue and blackening of the faeces.
  • Sucralfate believed to form a protective coating over the area of mucosal damage protecting it from gastric acid attack and therefore used to allow recovery of damaged gastric mucosa.
  • Side effects may include constipation, diarrhoea, dry mouth, rash and back pain.
  • PGEi analogs such as misoprostol, which may be used to counter the decrease in cytoprotective PGEi caused by the inhibition of COX-1 by most currently used NSAIDs.
  • Side effects may include diarrhoea, abnormal vaginal bleeding, rashes and dizziness.
  • Zwitterionic amino sulfonic acids have been suggested to have therapeutic potential in certain diseases.
  • WO97/29745 (Theodore)
  • such compounds are described as biological response modifiers, and it is suggested that they may possess beneficial properties in the treatment of cancer and associated pain, and rheumatoid arthritis.
  • the amino sulfonic acids were administered parenterally in combination with other components selected from vitamins, amino acids and cell culture supernatants.
  • EP0228239A describes the use of topical formulations of selected amino sulfonic acids for the treatment of arthritis and rheumatism.
  • compositions for treatment of inflammatory conditions are described, the compositions containing fatty acid esters of amino sulfonic acids having a pKa of 6.0 to 8.3 and intended for use on the skin.
  • WO96/23490 discloses compositions for inhibiting skin irritation, the compositions containing multiply-protonated organic polyamines.
  • HEPES is used as an example of a heterocyclic polyamine.
  • EP 1090630 A skin conditioners suitable for treatment of atropic dermatitis and for skin moisture retention are presented.
  • Preferred active ingredients are L-arginine and ethanolamine.
  • compositions for the moisturisation and protection of human skin are shown, the compositions containing, as an essential moisturising ingredient, urea.
  • N-substituted amino sulfonic acids are added solely in an attempt to slow the degradation of the urea.
  • one aspect of the present invention provides the use of at least one zwitterionic amino sulfonic acid, having at least one pKa at 25-38°C in the range of 7.3 ⁇ 0.5, in the preparation of a medicament for enhancement of superoxide dismutase activity.
  • the invention provides a method of enhancing the activity of superoxide dismutase in a patient, the method comprising administering to a patient in need of such treatment an effective superoxide dismutase activity enhancing amount of a composition comprising at least one zwitterionic amino sulfonic acid having at least one pKa at 25-38°C in the range of 7.3 ⁇ 0.5.
  • a further aspect of the invention provides a moisturiser comprising at least one zwitterionic amino sulfonic acid having at least one pKa in the range 7.3 ⁇ 0.5 at 25-38°C, the moisturiser not containing urea.
  • the moisturiser of this invention may also include one or more other active ingredients known to be efficacious in the treatment or prevention of photo and non-photoageing of the skin, iatrogenic skin dryness, mucosal membrane dryness (iatrogenic or non-iatrogenic), skin dryness associated with all forms of psoriasis, skin dryness associated with both photo and non-photo ageing of skin, skin dryness in all forms of dermatitis, skin dryness in all forms of eczema, and skin dryness in all forms of ichthyosis.
  • active ingredients known to be efficacious in the treatment or prevention of photo and non-photoageing of the skin, iatrogenic skin dryness, mucosal membrane dryness (iatrogenic or non-iatrogenic), skin dryness associated with all forms of psoriasis, skin dryness associated with both photo and non-photo ageing of skin, skin dryness in all forms of dermatitis, skin dryness in all forms of ecze
  • compositions in accordance with the invention are particularly useful for treating or preventing photo and non-photoageing of the skin, iatrogenic skin dryness, mucosal membrane dryness (iatrogenic or non-iatrogenic), skin dryness associated with all forms of psoriasis, skin dryness associated with both photo and non-photo ageing of skin, skin dryness in all forms of dermatitis, skin dryness in all forms of eczema, and skin dryness in all forms of ichthyosis.
  • the invention provides the use of at least one zwitterionic amino sulfonic acid, having at least one pKa at 25-38°C in the range 7.3 ⁇ 0.5, in the preparation of a medicament for moisturisation of the skin and/or mucosal membranes, provided that the medicament does not contain urea.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one zwitterionic amino sulfonic acid having at least one pKa at 25-38°C in the range 7.3 ⁇ 0.5, in combination with one or more agents of known efficacy in the prevention or treatment of the abnormal dermatological disorders and/or non-dermatological inflammatory conditions described in this document, for use in therapy by co-administration or by sequential administration, the composition not containing urea.
  • the invention also provides, in yet another aspect, the use of at least one zwitterionic amino sulfonic acid, having at least one pKa at 25-38°C in the range 7.3 ⁇ 0.5, and at least one other compound known to be efficacious in the treatment or prevention of dermatological disorders and/or non-dermatological inflammatory conditions in the preparation of a medicament for the treatment of dermatological disorders and/or non-dermatological inflammatory conditions by co-administration or by sequential administration, provided that the medicament does not contain urea.
  • the invention provides the use of at least one zwitterionic amino sulfonic acid, having at least one pKa at 25-38°C in the range 7.3 ⁇ 0.5, in the preparation of a medicament for the treatment or prevention of photo and non-photoageing of the skin, iatrogenic skin dryness, mucosal membrane dryness (iatrogenic or non-iatrogenic), skin dryness associated with all forms of psoriasis, skin dryness associated with both photo and non-photo ageing of skin, skin dryness in all forms of dermatitis, skin dryness in all forms of eczema, and skin dryness in all forms of ichthyosis, provided that the medicament does not contain urea.
  • the selected pKa range for the amino sulfonic acids helps to ensure minimal adverse effects on the surface to be treated or in any other body system by maintaining a pH as close as possible to that of the non-diseased surface or non-diseased body system.
  • the medicament may include, or may be administered in addition to as part of a treatment regimen, other active compounds known to be of use in the conditions.
  • the invention provides a method of cosmetically improving the appearance of the skin, the method comprising the application to the skin of a composition comprising, as an active ingredient, at least one zwitterionic amino sulfonic acid having at least one pKa at 25-38°C in the range 7.3 ⁇ 0.5 provided that the composition does not contain urea.
  • the cosmetic composition may also include one or more agents known to be efficacious in the treatment or prevention of photo and non-photoageing of the skin, any form of ichthyosis, any form of dermatitis, any form of psoriasis, iatrogenic skin dryness, mucosal membrane dryness (iatrogenic or non-iatrogenic), skin dryness associated with all forms of psoriasis, skin dryness associated with both photo and non-photo ageing of skin, skin dryness in all forms of dermatitis, skin dryness in all forms of eczema, and skin dryness in all forms of ichthyosis.
  • agents known to be efficacious in the treatment or prevention of photo and non-photoageing of the skin any form of ichthyosis, any form of dermatitis, any form of psoriasis, iatrogenic skin dryness, mucosal membrane dryness (iatrogenic or non-iatrogenic), skin dryness associated
  • Another aspect of the invention provides a hydroperoxyl radical and/or hydrogen peroxide scavenging composition comprising at least one zwitterionic amino sulfonic acid having at least one pKa at 25-38°C in the range 7.3 ⁇ 0.5.
  • the invention also provides the use of at least one zwitterionic amino sulfonic acid having at least one pKa at 25-38°C in the range 7.3 ⁇ 0.5 in the preparation of a medicament for scavenging hydroperoxyl radicals and/or hydrogen peroxide.
  • the hydroperoxyl radicals and/or hydrogen peroxide may be extracellular.
  • the invention also provides, in yet another aspect, a method of scavenging hydroperoxyl radicals and/or hydrogen peroxide, the method comprising administering to a patient in need of such treatment an effective scavenging amount of a composition comprising at least one zwitterionic amino sulfonic acid having at least one pKa at 25-38°C in the range 7.3 ⁇ 0.5.
  • Yet a further aspect of the present invention provides the use of at least one zwitterionic amino sulfonic acid having at least one pKa at 25-38°C in the range 7.3 ⁇ 0.5 in the preparation of a medicament for improving epidermal cell integrity and normalising dermal survival, growth, maturation and replication.
  • the invention also provides, in yet another aspect, a dermal and epidermal cell survival enhancing composition comprising at least one zwitterionic amino sulfonic acid having at least one pKa at 25-38°C in the range 7.3 ⁇ 0.5.
  • the invention provides the use of at least one zwitterionic amino sulfonic acid having at least one pKa at 25-38°C in the range 7.3 ⁇ 0.5 in the preparation of a medicament for improving epidermal cell integrity and normalising dermal survival, growth, maturation and replication.
  • Another aspect of the invention provides a method of improving epidermal cell integrity and normalising dermal survival, growth, maturation and replication, the method comprising administering to a patient in need of such improvement and normalisation an effective normalising amount of a composition comprising at least one zwitterionic amino sulfonic acid having at least one pKa at 25-38°C in the range 7.3 ⁇ 0.5.
  • the invention provides a method of treatment or prevention of photo and non-photoageing of the skin, skin dryness associated with photo and non-photo ageing of skin, skin dryness associated with all forms of psoriasis, iatrogenic skin dryness, mucosal membrane dryness (iatrogenic or non-iatrogenic), skin dryness in all forms of dermatitis, skin dryness in all forms of eczema and skin dryness in all forms of ichthoyosis, the method comprising the administration of a therapeutically effective amount of at least one zwitterionic amino sulfonic acid having at least one pKa at 25-38°C in the range 7.3 ⁇ 0.5 to a patient in need of such treatment, provided that the treatment does not also include the administration of urea.
  • the method may also include the administration of one or more agents (either together with the amino sulfonic acid in a single pharmaceutical or cosmetic form, or sequentially in individual pharmaceutical or cosmetic forms)
  • a further aspect of the invention provides a method of moisturisation of the skin or mucosal membranes, the method comprising administering to a patient in need of such moisturisation an effective moisturising amount of a composition comprising at least one zwitterionic amino sulfonic acid having at least one pKa at 25-38°C in the range 7.3 ⁇ 0.5, provided that the composition does not contain urea.
  • Preferred zwitterionic amino sulfonic acids for the purposes of the present invention are:
  • one of the zwitterionic amino sulfonic acids used in the compositions or methods according to the present invention is HEPES.
  • compositions according to the present invention preferably include one or more excipients appropriate to the type of formulation, as would be obvious to those skilled in the art.
  • Different routes of administration for such formulations include, but are not limited to, topical, oral, buccal, rectal, parenteral or pulmonary routes.
  • compositions are preferably administered topically.
  • compositions of the present invention which do not contain urea
  • the presence of urea or its derivatives is at or below a level which does not lead to any physiological effects, such that the invention is intended to extend to compositions containing merely a colourable amount of urea or a derivative thereof, such as might result from an impurity or from the addition of an incidental or ineffectual amount.
  • a cream for topical administration is made up from the following recipe:
  • the ingredients in the oily phase are melted together and brought to 75 °C.
  • the ingredients of the aqueous phase are mixed together until the HEPES is dissolved in the water and brought to 75 °C.
  • the oily phase is added to the heated aqueous phase and the two phases thoroughly mixed.
  • the emulsified mixture is allowed to cool to about 40 °C (whilst continually stirring the mixture) at which point the mixture is packed in a suitable container so as to prevent water loss.
  • a composition for a capsule for oral administration is made up from the following recipe: Material Weight per capsule (mg)
  • the components are thoroughly mixed using appropriate equipment e.g. a Y-blender and then filled into hard gelatine capsules using a capsule filler.
  • the capsules are then coated with a pH control enteric coat e.g. Eudragit to ensure release of the active at the required place and time in the gastrointestinal tract.
  • a pH control enteric coat e.g. Eudragit to ensure release of the active at the required place and time in the gastrointestinal tract.
  • a suitable amount of the agent of known efficacy is incorporated into the capsule powder mixture and the starch content is reduced accordingly.
  • separate dosage forms containing the agent of known efficacy are prepared and presented alongside the HEPES capsules, together with instructions as to dosage and use.
  • Loss of water from skin tissue is caused by a variety of different mechanisms, such as those at work in photo and non-photo ageing of skin, psoriasis and iatrogenic skin dryness, which are understood, whilst others such as in ichthyosis or atopic dermatitis are less well understood. However, the resulting symptom of dry and often itchy skin is the same irrespective of the underlying mechanism.
  • urea as humectants for the rehydration of skin in dry skin conditions such as psoriasis.
  • the zwitterionic amino sulfonic acids described above are heavily hydrated and able to give up their water of hydration at or around physiological pH.
  • HEPES has a solubility of around 3.47M (free acid) and 3.33M (sodium salt) at 33°C. This compares favourably with urea which has a solubility of around 5M.
  • the zwitterionic amino sulfonic acids can therefore act as water carriage and delivery molecules.
  • the zwitterionic amino sulfonic acids of this invention are therapeutically and cosmetically efficacious in rehydration of skin and mucosal surfaces. Unlike urea, however, they do not liberate toxic ammonia or biuret on the skin or mucosal surface. This feature makes the compositions of the invention safer and more pleasant to use, as well as being less prone to degradation on storage.
  • a range of inflammatory diseases including psoriasis, ulcerative colitis, Crohn's disease and rheumatoid arthritis are characterised by, amongst other things, infiltration into the inflamed tissues of neutrophils, with a consequent increase in the local levels of reactive oxygen species, degradative enzymes and LTB , all of which are produced by the neutrophils.
  • Reactive oxygen species and degradative enzymes all contribute to tissue damage in the inflammatory tissues.
  • LTB (a derivative of cell membrane associated arachidonic acid), which is the most potent chemotactic agent known in the body, powerfully attracts more neutrophils to the site of inflammation and activates them to produce more reactive oxygen species and LTB 4 and to release more degradative enzymes.
  • LTB 4 is not as important in the pathogenesis of the disease as the cysteinyl leukotrienes LTC 4 D E 4 (SRSA). These molecules are also derived from cell membrane associated arachadonic acid.
  • Drugs whose mechanism in inflammatory diseases are thought to be at least partly mediated by anti-leukotriene mechanisms include corticosteroids, such as hydrocortisone, betamethasone and prednisolone, beta- 2 adrenoceptor agonists, such as salbutamol, terbutaline and salmeterol, xanthines, such as theophylline and aminophylline, and nedocromil sodium.
  • compositions and uses of the zwitterionic amino sulfonic acids described herein maintain the correct pH environment for the supply of ample substrate to neutrophil myeloperoxidase and eosinophil peroxidase.
  • These enzymes form the central part of the myeloperoxidase-hydrogen peroxide-halide and peroxidase-hydrogen peroxide-halide systems which produce hypochlorous acid (HOCl) using hydrogen peroxide and chlorine as substrates.
  • the zwitterionic sulfonic acids described herein crucially maintain the correct pH environment to optimise the activity of superoxide dismutase (SOD) to create H 2 O 2 as a substrate for the myeloperoxidase-hydrogen peroxide-halide and peroxidase-hydrogen peroxide-halide systems.
  • SOD superoxide dismutase
  • SOD is demonstrated not to be active at acidic pHs, that is, pH below 6.0 to 6.5 (for further details of the SOD assay, see Example 5).
  • the zwitterionic amino sulfonic acids used according to this invention have therapeutic efficacy either alone or in combination with other agents (either administered together in a single pharmaceutical or cosmetic form, or sequentially in individual pharmaceutical or cosmetic forms) such as, but not limited to, those used conventionally in the treatment of the dermatological conditions described herein.
  • drugs whose mechanism of action in inflammatory diseases is now thought to be partly or largely mediated by anti-oxidant or free radical scavenging actions include sulphasalazine, 5 -amino salicylic acid, methotrexate, gold salts, corticosteroids, some non-steroidal anti-inflammatory drugs, chloroquine, D-penicillamine, beta- 2 adrenoceptor agonists such as salbutamol and iptratropium.
  • HEPES is known to have antioxidant activity. All other amino sulfonic acids suitable for the present invention contain a piperazine or other moiety susceptible to attack by certain free radicals. It has been found that these compounds are themselves free radical scavengers. As such, they are of use in the treatment of the conditions described, either alone or in combination with other free radical scavenging agents (either administered together in a single pharmaceutical or cosmetic form, or sequentially in individual pharmaceutical or cosmetic forms). Compositions comprising these compounds also have cosmetic efficacy in helping to prevent free radical tissue damage in photo and non-photoageing of skin.
  • SOD superoxide dismutase
  • superoxide dismutase the enzyme primarily responsible for conversion of superoxide radicals to hydrogen peroxide
  • SOD superoxide dismutase
  • Skin pH is generally accepted as being around 1-2 units lower than normal physiological pH (7.3 to 7.4) (Rieger, M (1989). Cosmetics and Toiletries 104, 53) and in inflammatory conditions this deviation may be more pronounced.
  • HO 2 hydroperoxyl radicals
  • compositions according to the present invention By the use of a composition according to the present invention, the pH of the affected area is raised to a value close to the pKa of the amino sulfonic acids and thus close to normal physiological pH. This effect, as mentioned above, optimises SOD activity and thus increases HOCl production. In addition, however, the compositions and uses according to the present invention also have a more direct effect on free radicals.
  • HEPES or the other zwitterionic amino sulfonic acids listed above to the SOD activity assay has no effect on the rate of reaction. This suggests that these compounds do not scavenge superoxide radicals, on which the stated assay is dependent.
  • HEPES causes a reduction in free radical activity in chemiluminescence-based assays of activated neutrophils, and thus it is proposed that the amino sulfonic acids listed above scavenge free radicals other than superoxide.
  • NDA Nitroso dimethylamine
  • HEPES and the other zwitterionic amino sulfonic acids can also scavenge hydrogen peroxide under suitable conditions.
  • the presence of the zwitterionic amino sulfonic acids optimises the activity of SOD with respect to pH, thus resulting in greater production of H 2 O 2 as a substrate for myeloperoxidase to produce HOCl.
  • the zwitterionic amino sulfonic acids inhibit conversion of superoxide to hydroperoxyl, both by a pH raising effect and by scavenging of hydroperoxyl radicals, thus providing increased superoxide substrate for SOD. The result is a dramatic increase in the production of antiinflammatory HOCl by means of SOD enhancement.
  • compositions, methods and uses of the present invention cause synergistic effects in the abnormal conditions described.
  • the conditions benefit from the normalisation of the environment in which vital enzymes are present and from the enhanced removal of reactive oxygen species from the vicinity of biomolecules.
  • the hydration effect as described above in Example 3 is also an important contributory factor, as is the pH buffering effect, since the decreased need for cells in the affected areas to pump protons from their intracellular compartments will reduce cellular energy expenditure and improve cell integrity, growth, maturation and replication.
  • most "skin-care" compositions on the market today are specifically formulated to have a pH of around 5.5.
  • the compositions and uses of the present invention aim to bring the pH of the body surface to which they are applied up to around pH 7.3. In this way, antiinflammatory enzyme activity can be enhanced and cellular energy needs and cellular stress can be reduced.
  • a mucosal swab was taken from the inner cheek of the human mouth. Cells were incubated at 35°C in Ringer's solution adjusted to pH 5.5 and at pH 7.3 both with and without HEPES at a concentration of 20mM after pH adjustment.
  • HEPES had little effect at pH5.5 but at pH 7.3 cells in the solution containing HEPES appeared healthier than at pH7.3 without HEPES.
  • the zwitterionic amino sulfonic acids used according to this invention are all general buffers with buffering capacity close to physiological pH. Such use of these zwitterionic amino sulfonic acids, in combination (either in separate formulations, or as a combined formulation) with existing topical products will significantly increase the pH compatibility of the latter with the skin, and thereby decrease the incidence of local irritation reactions.
  • the topical products with which the zwitterionic amino sulfonic acids can be combined include all those in general use in dermatology, particularly those described above.
  • the zwitterionic amino sulfonic acids can also be included in cosmetic compositions to improve the biocompatibility of the latter.
  • the hydrating effect of the zwitterionic amino sulfonic acids may also enhance the penetration and efficacy of other agents.
  • the zwitterionic amino sulfonic acids for use according to this invention, and in particular HEPES and HEPES sodium therefore provide either a single or a combination of mechanisms by which they are able to correct the underlying aetiology of the abnormal dermatological conditions.
  • these compounds are apparently non-toxic, as demonstrated by industry-standard skin studies in guinea-pigs and rabbits which showed HEPES to be free from hypersensitivity and irritant effects, respectively.

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Abstract

L'invention concerne l'utilisation d'au moins un acide amino sulfonique zwitterionique, ayant au moins un pKa de 25-38 °C de l'ordre de 7.3 ± 0.5, dans la préparation d'un médicament destiné au traitement ou à la prévention de vieillissement cutané photo-induit et non-photoinduit, de la sécheresse cutanée iatrogène, de la sécheresse des membranes muqueuses (iatrogènes ou non-iatrogènes), de la sécheresse cutanée associée à toutes les formes de psoriasis, de la sécheresse cutanée associée à la fois au vieillissement cutané photo-induit et non-photoinduit, de la sécheresse cutanée dans toutes les formes de dermites, de la sécheresse cutanée dans toutes les formes d'eczéma et de la sécheresse cutanée dans toutes les formes d'ichthyose, sachant que le médicament ne contient pas d'urée. L'invention concerne également un hydratant et des compositions phagocytant les radicaux libres et protégeant les cellules dermiques et épidermiques.
PCT/GB2002/001781 2001-04-17 2002-04-17 Compositions therapeutiques contenant des acides amino sulfoniques et leurs utilisations WO2002083136A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007082908A2 (fr) * 2006-01-20 2007-07-26 L'oréal Utilisation de derives de biuret pour hydrater la peau
FR2896408A1 (fr) * 2006-01-20 2007-07-27 Oreal Utilisation de derives du biuret pour hydrater la peau
WO2007100006A1 (fr) * 2006-03-03 2007-09-07 Shiseido Company, Ltd. Anti-rides préventif/traitant
US8329208B2 (en) 2009-07-28 2012-12-11 Methylation Sciences International Srl Pharmacokinetics of S-adenosylmethionine formulations
TWI381855B (zh) * 2003-11-27 2013-01-11 Shiseido Co Ltd Not keratosis inhibitors and skin topical compositions
US20220071860A1 (en) * 2018-12-21 2022-03-10 Pierre Fabre Medicament Emollient composition in emulsion form

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0228239A2 (fr) * 1985-12-18 1987-07-08 O'Sullivan, Donncha Préparation d'un médicament pour l'arthrite et le rheumatisme
WO1988009657A1 (fr) * 1987-06-04 1988-12-15 William Patrick Millrine Composition anti-leucotriene et ses emplois
EP0469813A2 (fr) * 1990-07-30 1992-02-05 Bloomfield D.A. Utilisation des composés zwitterioniques et leurs dérivés N-halo
EP0761203A1 (fr) * 1995-09-07 1997-03-12 L'oreal Utilisation de l'acide cystéique ou homocystéique pour favoriser la desquamation de la peau ou stimuler le renouvellement épidermique
EP0993825A2 (fr) * 1998-09-09 2000-04-19 L'oreal Composition contenant de l'urée et ses utilisations dans le domaine cosmétique et/ou dermatologique
EP1090630A1 (fr) * 1998-03-11 2001-04-11 Kabushiki Kaisha Soken Agents de normalisation pour la peau
WO2002039975A1 (fr) * 2000-11-17 2002-05-23 L'oreal Utilisation d'au moins un derive amino sulfonique dans une composition destinee a favoriser la desquamation de la peau

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0228239A2 (fr) * 1985-12-18 1987-07-08 O'Sullivan, Donncha Préparation d'un médicament pour l'arthrite et le rheumatisme
WO1988009657A1 (fr) * 1987-06-04 1988-12-15 William Patrick Millrine Composition anti-leucotriene et ses emplois
EP0469813A2 (fr) * 1990-07-30 1992-02-05 Bloomfield D.A. Utilisation des composés zwitterioniques et leurs dérivés N-halo
EP0761203A1 (fr) * 1995-09-07 1997-03-12 L'oreal Utilisation de l'acide cystéique ou homocystéique pour favoriser la desquamation de la peau ou stimuler le renouvellement épidermique
EP1090630A1 (fr) * 1998-03-11 2001-04-11 Kabushiki Kaisha Soken Agents de normalisation pour la peau
EP0993825A2 (fr) * 1998-09-09 2000-04-19 L'oreal Composition contenant de l'urée et ses utilisations dans le domaine cosmétique et/ou dermatologique
WO2002039975A1 (fr) * 2000-11-17 2002-05-23 L'oreal Utilisation d'au moins un derive amino sulfonique dans une composition destinee a favoriser la desquamation de la peau

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI381855B (zh) * 2003-11-27 2013-01-11 Shiseido Co Ltd Not keratosis inhibitors and skin topical compositions
US8586638B2 (en) 2003-11-27 2013-11-19 Shiseido Company, Ltd Parakeratosis inhibitor and skin preparation for external use
WO2007082908A2 (fr) * 2006-01-20 2007-07-26 L'oréal Utilisation de derives de biuret pour hydrater la peau
FR2896408A1 (fr) * 2006-01-20 2007-07-27 Oreal Utilisation de derives du biuret pour hydrater la peau
WO2007082908A3 (fr) * 2006-01-20 2007-11-01 Oreal Utilisation de derives de biuret pour hydrater la peau
WO2007100006A1 (fr) * 2006-03-03 2007-09-07 Shiseido Company, Ltd. Anti-rides préventif/traitant
US8329208B2 (en) 2009-07-28 2012-12-11 Methylation Sciences International Srl Pharmacokinetics of S-adenosylmethionine formulations
US8580296B2 (en) 2009-07-28 2013-11-12 Methylation Sciences International Srl Pharmacokinetics of S-adenosylmethionine formulations
US8865203B2 (en) 2009-07-28 2014-10-21 Methylation Sciences International Srl Pharmacokinetics of S-adenosylmethionine formulations
US9931356B2 (en) 2009-07-28 2018-04-03 Methylation Sciences International Srl Pharmacokinetics of S-adenosylmethionine formulations
US20220071860A1 (en) * 2018-12-21 2022-03-10 Pierre Fabre Medicament Emollient composition in emulsion form

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