WO1997027862A1 - Apport complementaire de glucocorticoïdes - Google Patents

Apport complementaire de glucocorticoïdes Download PDF

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Publication number
WO1997027862A1
WO1997027862A1 PCT/AU1997/000048 AU9700048W WO9727862A1 WO 1997027862 A1 WO1997027862 A1 WO 1997027862A1 AU 9700048 W AU9700048 W AU 9700048W WO 9727862 A1 WO9727862 A1 WO 9727862A1
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WIPO (PCT)
Prior art keywords
zinc
formulation
acetate
glucocorticosteroid
valerate
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Application number
PCT/AU1997/000048
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English (en)
Inventor
Michael John Story
Desmond Berry Williams
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Bellara Medical Products Limited
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Publication date
Application filed by Bellara Medical Products Limited filed Critical Bellara Medical Products Limited
Priority to AU15365/97A priority Critical patent/AU1536597A/en
Publication of WO1997027862A1 publication Critical patent/WO1997027862A1/fr

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    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof

Definitions

  • This invention relates to pharmaceutical formulations which enhance the pharmacological effect of topical corticosteroids for the treatment of dermatological conditions.
  • the adrenal cortex synthesizes three classes of steroids: those with glucocorticoid actions, those with mineralocorticoid actions, and the sex corticoids which include mainly androgens.
  • This invention is concerned with the steroids having glucocorticoid actions.
  • glucocorticosteroids The pharmacological actions of the glucocorticosteroids are upon gluconeogenesis, glycogen deposition, and protein and calcium metabolism, together with inhibition of corticotrophin secretion, immunosuppression and anti-inflammatory activity.
  • the naturally occurring glucocorticosteroids principally hydrocortisone (endogenous hydrocortisone is often termed cortisol), are secreted by the adrenal cortex under the influence of the anterior pituitary corticotrophic hormone, corticotrophin, and they generally have both mineralocorticoid and glucocorticoid actions, the degree of these actions varying between the type of corticosteroid.
  • glucocorticosteroids have been produced with similar properties to the naturally occurring molecules.
  • the aim in developing these synthetic analogues has usually been to produce enhanced potency.
  • a second aim has been to synthesize compounds with increased glucocorticoid actions, but without a parallel increase in mineralocorticoid effect.
  • glucocorticoids refers to glucocorticosteroids. Esterification of glucocorticoids at the 17 or 21 positions with fatty acids generally increases the activity on the skin. Some glucocorticoids esterified at the 17 position are much more potent topically than systemically, eg, beclomethasone dipropionate and betamethasone valerate.
  • Glucocorticoids affect protein metabolism: they have an anabolic effect, or increase the rate of synthesis, of proteins and RNA in liver; whereas they have catabolic effects in muscle, lymphoid tissue, adipose tissue, skin, and bone.
  • Glucocorticoids act as immunosuppressants by suppressing protein synthesis, including synthesis of immunoglobulin. The also reduce populations of eosinophils, lymphocytes, and macrophages.
  • Glucocorticoids are known to promote atrophy of lymphoid tissue in the thymus, spleen, and lymph nodes. Glucocorticoids inhibit the production of both interleukin-1 and macrophages, and interleukin-2 by helper T cells, thus decreasing T cell responses. The diminished helper T cells cause a decrease in B cells and antibody production.
  • glucocorticoids decrease the number of circulating lymphocytes, monocytes/macrophages, and eosinophils with these cells being relocated from the vascular compartment to other sites including the bone marrow, lymphoid tissue and spleen.
  • Glucocorticoids inhibit the accumulation of leukocytes at the site of inflammation and inhibit the release from the leukocytes of substances involved in the inflammatory response (eg, kinins, plasminogen-activating factor, prostaglandins, and histamine).
  • Glucocorticoids inhibit fibroblast proliferation and function at the site of an inflammatory response. This inhibition accounts for the poor wound healing, skin atrophy and increased susceptibility to infection that are often seen with patients with a glucocorticoid excess.
  • Glucocorticoids have been found to cause symptomatic improvement in a wide range of disease conditions, but it has been recognized at the same time that the glucocorticoids are not a cure for these diseases. It is therefore apparent that although glucocorticoids have a role in alleviating the symptoms of many disease conditions, they cause deficiencies or side effects that can, to a variable extent, counteract their alleviating role. These deficiencies or side effects include immunosuppression and increased susceptibility to infection, poor wound healing, skin atrophy, and decreased inflammatory response. The various skin lesions caused by topical glucocorticoids differ from those observed after oral administration because the topically-applied drugs exert their actions in high concentrations at the application site.
  • Glucocorticoids cause another problem through a lowering of zinc levels in the human or animal body.
  • zinc metabolism is significantly affected either by inflammation or by glucocorticoid administration (Fontaine J, Neve J, Peretz A, Capel P and Famaey JP, Agents and Actions 1991 , 33:247-253).
  • These drugs seem to induce synthesis of hepatic metallothionein, a powerful ligand for the element, causing accumulation of zinc in the liver with a resulting alteration in plasma levels.
  • Zinc is an essential trace element in all animals and plants, with vital roles in cellular structure and function, and as a component of over 300 enzymes. Zinc is essential for bone formation, tissue growth, cell-mediated immune function, host defence and wound repair. Homeostatic mechanisms control the level of zinc in the human or animal body, regulating the entry of zinc into, distribution in, and excretion from ceils and tissues. Zinc can be absorbed percutaneously from topical application of some zinc compounds.
  • Zinc is an essential cofactor of DNA and RNA polymerase and is essential for cell division and RNA and protein synthesis. For this reason, relative zinc deficiencies seem to most significantly affect rapidly dividing cells or cells involved in protein synthesis. Major manifestations of zinc deficiency include a reduction in cell division leading to retarded growth and development, reproductive abnormalities, suppressed immunity, impaired wound healing, dermatitis, and impairments in neuropsychological functions. Low zinc levels are found when the body suffers from acute infection, inflammation, wounding, or physical or mental stress.
  • Zinc has a significant role in proper functioning of the immune system, as zinc deficiency affects cell proliferation, protein synthesis, receptor activation, membrane activation, and cell migration, all of which influence the immune system. Zinc induces interferon- ⁇ production, which in turn suppresses IgE synthesis through suppression of interleukin-4 synthesis. Zinc plays a central role in the activation and differentiation of T cells and natural killer cells, which are essential components of the cell-mediated immune system.
  • Zinc has been shown to influence the inflammatory process through stabilisation of the lysosomal membrane, inhibition of macrophage and neutrophil migration and phagocytic activity, inhibition of histamine release from mast cells, inhibition of prostaglandin synthesis, modulation of serotonin release from platelets, and modulation of lymphocyte proliferation.
  • Zinc has been found to have antibacterial activity. All living systems need zinc
  • Zinc deficiency causes a depression of the rate of childhood growth, loss of hair, skin lesions, reproductive abnormalities, skeletal defects, impaired wound healing, and decreased immunocompetence.
  • glucocorticoids are very effective in reducing inflammation in a range of disease states, together with other symptoms of the diseases.
  • This localized zinc deficiency can cause a further reduction in immunocompetence and a further decrease in the healing rate of lesions. It would therefore be an advantage if the localized zinc deficiency caused by a glucocorticoid could be overcome by an agent which corrects immunocompetence, increases healing rates, acts as an anti-inflammatory agent, and which also has antibacterial activity.
  • the invention is said to reside in a method of treatment of dermatological conditions comprising the application of a formulation consisting of a glucocorticosteroid, a pharmaceutically acceptable zinc compound and a pharmaceutically acceptable carrier.
  • the formulation according to this invention provides substantial advantages over the use of glucocorticoids alone when glucocorticoids are applied topically to intact or broken skin.
  • zinc When provided through a suitable delivery vehicle, zinc has anti-inflammatory properties which enhance the effect of the glucocorticoid in this respect, and zinc can also provide an antibacterial effect.
  • the presence of zinc is especially important in counteracting the negative aspects of glucocorticoid therapy: suppression of immunocompetence, reduction of healing rates, and atrophy of skin.
  • zinc enhances the immune function and it enhances healing rates of lesions and wounds.
  • the invention is said to reside in a method of treatment of dermatological conditions comprising the application of a formulation consisting of a glucocorticosteroid, a zinc compound and a pharmaceutically acceptable carrier, where the formulation is presented topically to intact skin or broken skin.
  • the invention is said to reside in a formulation for topical use consisting of a glucocorticosteroid, a pharmaceutically acceptable zinc compound and a pharmaceutically acceptable carrier, wherein the zinc compound is in a concentration of from 1 to 50%, and the glucocorticosteroid is at a concentration of 0.01 to 1%.
  • Topical glucocorticoids Topical glucocorticoids
  • Topical glucocorticoids are the treatment of choice in a number of dermatological conditions, including contact dermatitis, atopic dermatitis, nummular eczema, stasis eczema, lichen planus, lichen simplex chronicus, some burns and sunburns, and keloids. Topical glucocorticoids are useful as alternative or adjuvant treatments in psoriasis, seborrhoeic dermatitis, diaper dermatitis (nappy rash), and a number of other miscellaneous dermatological disorders.
  • Clinical potencies of topical glucocorticoids are classed as mild (class I), moderately potent (class II), potent (class III), and very potent (class IV).
  • Mild topical glucocorticoids include: aclomethasone dipropionate 0.05%, dexamethasone 0.01%, dexamethasone acetate 0.1%, hydrocortisone (alcohol or acetate) 0.1 to 1%, methylprednisolone acetate 0.25%, and prednisolone 0.5%.
  • Moderately potent topical glucocorticoids include betamethasone valerate 0.02%, clobetasone butyrate 0.05%, flumethasone pivalate 0.02%, fluocinolone acetonide 0.01%, fluocortin butylester 0.75%, fluocortolone hexanoate 0.1%, fluocortolone pivalate 0.1 - 0.2%, fludroxycortide (flurandrenolone) 0.0125 to 0.025%, hydrocortisone 1% with urea, and triamcinolone acetonide 0.02%.
  • Potent topical glucocorticoids include beclomethasone dipropionate 0.025%, betamethasone benzoate 0.025%, betamethasone dipropionate 0.05%, betamethasone valerate 0.05 to
  • Very potent topical glucocorticoids include amcinonide 0.1%, beclomethasone dipropionate 0.5%, betamethasone dipropionate 0.5%, clobetasol propionate 0.05%, dexamethasone dipropionate 0.1%, diflorasone diacetate 0.05%, diflucortolone valerate 0.3%, difluprednate 0.05%, fluocinolone acetonide 0.2%, halcinonide 0.1%, hydrocortisone butyrate propionate 0.1%, ulobetasol (halobetasol) 0.05%, mometasone furoate 0.1%, and prednicarbate.
  • Zinc is widely available for oral administration to humans in the form of sulphate, acetate, acexamate, L-carnosine, gluconate and orotate salts, and a host of chelated complexes.
  • efficacy of oral zinc supplementation for a range of disease conditions has been found to be positive, negative, or inconclusive. It is believed that this lack of consistency, where the occurrence of spasmodic positive results indicates a positive effect of zinc, has been due to the limited delivery of zinc to the circulating plasma, as the absorption of zinc is dependent on the capacity of plasma to take up more zinc.
  • rate of absorption and the amount absorbed, will not only depend on the amount of the dose dissolved in the stomach contents, but it will also depend on the concentration of zinc in the blood stream at the time of dosing.
  • Zinc supplementation with the intention of increasing the transfer of zinc to specific tissue sites in the body, can therefore require special delivery systems or vehicles to distribute zinc to these tissues through pathways other than through the gastrointestinal tract.
  • the zinc compound for use in the present invention may be selected from any physiologically acceptable zinc compound. This may include zinc acetate, zinc acexamate, zinc bacitracin, zinc caprylate, zinc carbonate, zinc L- carnosine, zinc chloride, zinc citrate, zinc lactate, zinc oleate, zinc orotate, zinc oxalate, zinc oxide, zinc permanganate, zinc p-phenolsulphate, zinc phosphate, zinc propionate, zinc salicylate, zinc stearate, zinc sulphate, zinc tartrate, and zinc valerate.
  • This may include zinc acetate, zinc acexamate, zinc bacitracin, zinc caprylate, zinc carbonate, zinc L- carnosine, zinc chloride, zinc citrate, zinc lactate, zinc oleate, zinc orotate, zinc oxalate, zinc oxide, zinc permanganate, zinc p-phenolsulphate, zinc phosphate, zinc propionate, zinc salicylate, zinc stearate, zinc
  • the invention is said to reside in a method of treatment of dermatological conditions comprising the application of a formulation consisting of a glucocorticosteroid selected from the group of compounds listed above and a zinc compound selected from the group of compounds listed above.
  • zinc monoglycerolate ZMG or Glyzinc
  • ZMG zinc monoglycerolate
  • This relatively new form of zinc has been found to have advantageous physiological effects and is produced by mixing zinc oxide or a zinc oxide forming compound together with glycerol at temperatures sufficient for the reaction to proceed quantitatively to form zinc monoglycerolate which has the formula (C3H6 ⁇ 3Zn) ⁇ , with structure described by:
  • Zinc monoglycerolate is a white lubricious powder, the latter property being imparted by its polymeric two-dimensional structure.
  • the compound is highly insoluble in water, but it is slowly soluble in a variety of biological fluids which imparts controlled release properties to the zinc (Fairlie, Whitehouse and Taylor, Agents Actions 1992; 36:152-158).
  • Zinc monoglycerolate has been shown to have special properties when applied topically as a powder or in a vehicle as it is readily absorbed into the skin, but it is not so effective when taken orally (Whitehouse, Rainsford, Taylor and Vernon-Roberts, Agents Actions 1990; 31 :47-58). Poor oral absorption of zinc from zinc monoglycerolate can be attributed to a pH-dependent rate of hydrolysis of the compound by gastric acid, causing irregular and variable quantities of zinc ions to be available for absorption.
  • zinc monoglycerolate is an effective delivery system for zinc in the reduction of inflammation caused by adjuvant arthritis (Whitehouse, Rainsford, Taylor and Vernon-Roberts, Agents Actions 1990; 31 :47-58).
  • the animal studies indicated that zinc complexes given parenterally (dermally, intramuscularly, subcutaneously) are able to suppress chronic inflammation, while the same complexes given orally were virtually ineffective.
  • Zinc monoglycerolate is as effective as 1% hydrocortisone ointment in treating this disease.
  • Zinc monoglycerolate has also been shown to be effective in the treatment of diaper dermatitis (nappy rash).
  • Other studies have shown that zinc monoglycerolate is effective in enhancing healing of leg ulcers, pressure sores and bums.
  • Zinc monoglycerolate therefore provides a useful delivery system for zinc in topical applications, both to intact skin and to open wounds.
  • the compound zinc monoglycerolate is preferred to other zinc compounds due to its structure which includes a three-carbon backbone providing a weak lipophilic property to the compound which assists in absorption of the zinc compound into tissues.
  • Zinc monoglycerolate is innocuous from the aspect of toxicity as the products of hydrolysis are divalent zinc ions and glycerol.
  • Zinc monoglycerolate also provides a slow release of zinc which is a distinct advantage when compared with soluble salts such as zinc sulphate or chloride which could be toxic to tissues in broken skin.
  • the invention is said to reside in a method of treatment of dermatological conditions comprising the application of a formulation consisting of a glucocorticosteroid selected from the group of compounds listed above and zinc monoglycerolate.
  • the mode of administration of the formulations may be similar to those currently used for the various disease states being treated.
  • treatment of dermatological conditions would be by an ointment when formulating zinc monoglycerolate with a glucocorticoid, as zinc monoglycerolate hydrolyzes in an aqueous environment.
  • a cream could be used with a zinc compound that did not have this property of hydrolysis in aqueous media.
  • Other forms of administration may include powder, liquid, suspension, gel, paste, wax or lotion.
  • the zinc compound may be included at a concentration of from 1 to 50%, and preferably 5 to 25%, the glucocorticoid being at a concentration in line with its potency, for example, 0.01 to 1%.
  • Figure 1 shows a graph of Percentage Improvement in Mean Area
  • Figure 2 shows a graph of Percentage Improvement in Mean Skin Condition Scores plotted against weeks of treatment
  • Figure 3 shows a graph of Percentage Improvement in Mean Total Scores plotted against weeks of treatment, where Total Scores is the sum of the Area Affected Scores and Skin Condition Scores.
  • Figure 1 for the Mean Area Affected Scores zinc monoglycerolate and 1% hydrocortisone ointment were equally effective over the two study periods.
  • Figure 2 for Mean Skin Condition Scores shows that the two preparations were equally effective over the first period, with hydrocortisone showing a non-significant improvement over zinc monoglycerolate in the second period. This difference in the second period may well have been due to a carry-over effect, where the prior treatment with zinc monoglycerolate provided an improved basis for continued treatment with hydrocortisone, in contrast to the other treatment schedule where hydrocortisone preceded zinc monoglycerolate.
  • Fig 3 shows the improvement in Mean Total Scores over the two treatment periods, where Total Scores is the sum of the Area Affected Scores and Skin Condition Scores.
  • the improvement was equivalent for both zinc monoglycerolate and hydrocortisone for the first treatment period, with hydrocortisone showing a non-significant improvement over zinc monoglycerolate in the second period.
  • a further example is currently being created.
  • a study is to be conducted where 10% zinc monoglycerolate ointment is compared with 1% hydrocortisone ointment, and compared with 1% hydrocortisone ointment plus 10% zinc monoglycerolate ointment.
  • This example will show the synergy of adding zinc monoglycerolate to hydrocortisone ointment, providing an increased effectiveness over hydrocortisone alone in treating atopic dermatitis.
  • the study period will include 16 weeks of continuous treatment for each of the three formulations.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
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Abstract

Formulation pour et procédé de traitement d'états dermatologiques consistant en l'application d'une formulation composée d'un glucocorticostéroïde et d'un composé de zinc acceptable sur le plan pharmaceutique. Le composé de zinc peut être du monoglycérolate de zinc.
PCT/AU1997/000048 1996-02-02 1997-01-30 Apport complementaire de glucocorticoïdes WO1997027862A1 (fr)

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AU15365/97A AU1536597A (en) 1996-02-02 1997-01-30 Supplementation of glucocorticoids

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AUPN7847A AUPN784796A0 (en) 1996-02-02 1996-02-02 Supplementation of glucocorticoids
AUPN7847 1996-02-02

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0914826A1 (fr) * 1996-07-17 1999-05-12 Zeria Pharmaceutical Co., Ltd. Accelerateurs de cicatrisation
EP0938900A1 (fr) * 1996-07-03 1999-09-01 Zeria Pharmaceutical Co., Ltd. Medicaments pour la prevention/le traitement de la stomatite
US6479058B1 (en) 1999-09-02 2002-11-12 Mccadden Michael E. Composition for the topical treatment of poison ivy and other forms of contact dermatitis
US6656928B1 (en) * 1999-09-02 2003-12-02 Mccadden Michael E. Composition for the topical treatment of rashes, dermatoses and lesions
WO2004005300A1 (fr) * 2002-07-09 2004-01-15 Pure Pharmaceuticals, Inc. Complexes de zinc-glycerol microfins
WO2006061260A1 (fr) * 2004-12-08 2006-06-15 Galderma S.A. Shampooings au clobetasol propionate pour le traitement de dermatite seborrheique du cuir chevelu
WO2009070431A1 (fr) * 2007-11-27 2009-06-04 Harry Dugger Préparations à base d'antihistamine/corticosteroïde pour le traitement de la dermatite atopique

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US3255079A (en) * 1963-06-17 1966-06-07 American Cyanamid Co Therapeutic dental cement and a method for treating carious teeth
US4121940A (en) * 1977-02-24 1978-10-24 Michel George H Endodontic formula for treatment of root canal
AU1655388A (en) * 1988-05-25 1989-11-30 Biogal Gyogyszergyar Pharmaceutical composition comprising a compound containing sulfhydryl group(s) for the treatment of otitis
AU6966494A (en) * 1993-06-15 1995-01-03 Glyzinc Pharmaceuticals Limited Zinc monoglycerolate complex for anti-rejection treatment of the human or animal body

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US3255079A (en) * 1963-06-17 1966-06-07 American Cyanamid Co Therapeutic dental cement and a method for treating carious teeth
US4121940A (en) * 1977-02-24 1978-10-24 Michel George H Endodontic formula for treatment of root canal
AU1655388A (en) * 1988-05-25 1989-11-30 Biogal Gyogyszergyar Pharmaceutical composition comprising a compound containing sulfhydryl group(s) for the treatment of otitis
AU6966494A (en) * 1993-06-15 1995-01-03 Glyzinc Pharmaceuticals Limited Zinc monoglycerolate complex for anti-rejection treatment of the human or animal body

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DERMATOL. MON. SCHR., 175, (1989), MUELLER, VON R. et al., "Reaktion und Wirksamkeit von Prednisolon in Zinkoxidhaltigen Dermatika", pages 82-86. *
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FOLIA PHARMACOL. JAPON., Vol. 98, (1991), YOSHIDA A. et al., "Basal Studies on the Mode of Circular Excision Wounds Made on the Dorsal Skin of Rats Treated With Hydrocorticone", pages 369-377. *
JOURNAL OF INVESTIGATIVE DERMATOLOGY, Volume 89, No. 2, (1987), MULLIN C.H. et al., "Specific Induction of Metallothionein in Hairless Mouse Skin by Zinc and Dexamethasone", pages 164-166. *
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THE JOURNAL OF OSAKA UNIVERSITY DENTAL SOCIETY, Vol. 20, No. 2, (1975), NAKAMURA MASAYUKI, "Effects of Corticosteroids and Zinx on Wound Healing of Rat Skin", pages 105-119. *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0938900A1 (fr) * 1996-07-03 1999-09-01 Zeria Pharmaceutical Co., Ltd. Medicaments pour la prevention/le traitement de la stomatite
EP0938900A4 (fr) * 1996-07-03 2004-03-31 Zeria Pharm Co Ltd Medicaments pour la prevention/le traitement de la stomatite
EP0914826A1 (fr) * 1996-07-17 1999-05-12 Zeria Pharmaceutical Co., Ltd. Accelerateurs de cicatrisation
EP0914826A4 (fr) * 1996-07-17 2001-09-26 Zeria Pharm Co Ltd Accelerateurs de cicatrisation
US6479058B1 (en) 1999-09-02 2002-11-12 Mccadden Michael E. Composition for the topical treatment of poison ivy and other forms of contact dermatitis
US6656928B1 (en) * 1999-09-02 2003-12-02 Mccadden Michael E. Composition for the topical treatment of rashes, dermatoses and lesions
US6890544B2 (en) 1999-09-02 2005-05-10 Mccadden Michael E. Gel composition for the topical treatment of poison ivy and other forms of contact dermatitis
WO2004005300A1 (fr) * 2002-07-09 2004-01-15 Pure Pharmaceuticals, Inc. Complexes de zinc-glycerol microfins
WO2006061260A1 (fr) * 2004-12-08 2006-06-15 Galderma S.A. Shampooings au clobetasol propionate pour le traitement de dermatite seborrheique du cuir chevelu
JP2008523021A (ja) * 2004-12-08 2008-07-03 ガルデルマ・ソシエテ・アノニム 頭皮の脂漏性皮膚炎を治療するための、プロピオン酸クロベタゾールシャンプー
WO2009070431A1 (fr) * 2007-11-27 2009-06-04 Harry Dugger Préparations à base d'antihistamine/corticosteroïde pour le traitement de la dermatite atopique

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