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1 N\ * ~ ~ J GV/l Eur Pean Patent Office <*S Office europeen des brevets (11) EP B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) int. CI.6: A61 K 33/04 of the grant of the patent: // (A61 K33/04, 31 :355, 31 :1 95) Bulletin 1998/39 v ' (21) Application number: (22) Date of filing: (54) Pharmaceutical preparation to be used as adjuvant treatment of the seborrheic dermatitis even in HIV positive subjects Pharmazeutische Zusammensetzung, die als Hilfsmittelbehandlung von Seborrhoid-Dermatitis, auch bei HIV-Patienten, verwendbar ist Preparation pharmaceutique utilisable comme traitement adjuvant de la dermatite seborrhique, meme chez les sujets HIV (84) Designated Contracting States: AT BE CH DE DK ES FR GB GR LI LU MC NL PT SE (30) Priority: IT RM (43) Date of publication of application: Bulletin 1992/52 (73) Proprietor: ISTITUTI FISIOTERAPICI OSPITALIERI Rome (IT) (72) Inventors: Ippolito, Ferdinando Roma (IT) Passi, Siro Roma (IT) (74) Representative: Sarpi, Maurizio Studio FERRARIO Via Collina, Roma (IT) (56) References cited: WO-A-83/01196 FR-A WORLD REV. NUTR. DIET. vol. 55, 1988, BASEL pages ; BRENNER S. & HORWITZ C: 'possible nutrient mediators in psoriasis and seborrheic dermatitis' CO CO co <7> LO O Q_ LU Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). Printed by Xerox (UK) Business Services /3.4

2 Description The present invention relates to a pharmaceutical preparation which can be used in the dermatologic field and, more particularly, as adjuvant treatment of the seborrheic dermatitis even in HIV positive subjects. 5 Seborrheic dermatitis has been referred to as a marker of AIDS. Of course it should be appreciated that it has not the same function of marker doubtless performed with a greater specificity by ulcerative chronic herpes simplex, oral hairy leukoplakia and epidemic kaposi. However, its presence with a particular acuteness and diffusion is very significant of HIV infection even because the epidemiologic incidence is 30% on the average. Recent researches reported in the literature (F. Ippolito et al.: "Seborrheic-like dermatitis in subjects having 10 acquired immunodeficiency", Giorn. It. Ann. Ven., Vol. 124, 1989; F. Ippolito et al.: "Insufficient haematic levels of the polyunsaturated fatty acids of the phospholipids, vitamin E and glutathione peroxidase as likely risk factors in the onset and development of the acquired immunodeficiency syndrome", Giorn. It. Derm. Ven. Vol. 125, 1990), have pointed out that the haematic levels of vitamin E, polyunsaturated fatty acids of the phospholipids (PUFA-PL) and glutathione peroxidase (GSH-PX) are considerably reduced in subjects having seborrheic dermatitis as well as in HIV positive subjects 15 affected and non-affected by seborrheic dermatitis with respect to controlled healthy subjects being the same age. PUFA-PL play a vital role in the physiology of the cells including the epidermal cells as they keep the integrity and the fluidity of the cell membranes and contribute to the normal development of the cellular physiologic processes through the biosynthesis of the regulating eicosanoids (prostaglandins and leucotrienes) and in association with other messengers. 20 PUFA are heading for peroxidation with ease, and the two major protective agents in vivo against the damage from lipoperoxides are vitamin E and GSH-PX. Thus, as reported in a number of printed papers of the literature, the primary site of the pathologies due to deficiency of vitamin E is the cell membrane. GSH-PX is adapted to modulate the radicalic reactions with chains supported by hydroperoxides. Since selenium is the prosthetic group of the enzyme, this element is very important for the neutralization in vivo of the damages due 25 to lipoperoxidative processes. On the base of such clinical-epidemiological, biochemical remarks the inventors have noted that the therapeutic association of vitamin E, selenium and methionine administered in suitable proportion and posology is able to improve the general and cutaneous cell homeostasis. Firstly methionine is the precursor of the reduced glutathione, the main non-lipidic membrane antioxidant which is 30 the essential component of the glutathione peroxidase, of which selenium is the prosthetic group, and the choline indispensable in the biosynthesis of the lecithin or phosphatidylcholine which is the major component of the phospholipids. The integration of vitamin E, the main lipidic antioxidant directly present in the membranes, and selenium by compensating the respective hematochemical deficiencies completes the action of the methionine on the hepatic functional capacity, thus making it possible to provide a valid protective response to the damage due to lipoperoxidation and as a 35 consequence to restore the cutaneous homeostasis with the regression of the symptomatology of the seborrheic dermatitis. The administration of vitamin E and selenium cannot make up for the reduction of the polyunsaturated acids of the phospholipid fraction but there is needed the direct contribution of a diet rich in PUFA-PL present in the red meat, the cell membranes of which are generally characterized by high levels of eicosanoic acid, precursor of prostaglandins and 40 leucotrienes playing an important role in the cell homeostasis. Considering the above cited data the pharmaceutical preparation according to the present invention is proposed with the following formulation for a capsule: Active principles: - L-methionine 150 mg - d,l-a-tocopherol equivalent to basic vitamin E 75 mg - selenium-d-l-methionine 0,65 mg equivalent to selenium mg - capric-caprilic triglyceride mg - glyceryl palmitostearate mg - soybean lecithin mg 2

3 Researches have emphasized that the advisable posology ranges between a minimum of 4 and a maximum of 8 capsules a day. 5 Claims 1. Use of methionine in association with vitamin E and selenium as active principles for the preparation of a medicament for adjuvant treatment of the seborrheic dermatitis even in HIV positive subjects. 2. Use of methionine in association with vitamin E and selenium according to claim 1, characterized in that said active 10 principles contribute directly or indirectly to develop a protective action against the damage due to lipoperoxidase. 3. Use of methionine in association with vitamin E and selenium according to the preceding claims, characterized in that selenium is present in an amount ranging between and 0.025% by weight of methionine Use of methionine in association with vitamin E and selenium according to the preceding claims, characterized in that selenium is used in the form of selenium-d-l-methionine Use of methionine in association with vitamin E and selenium according to the preceding claims, characterized in that vitamin E is used in the form of d,l-tocopherol. 6. Use of methionine in association with vitamin E and selenium according to the preceding claims, characterized in that the following formulation is provided for a capsule of pharmaceutical preparation: 25 Active principles: - L-methionine 150 mg - d,l-a-tocopherol equivalent to basic vitamin E 75 mg - selenium-d-l-methionine 0,65 mg equivalent to selenium mg - capric-caprilic triglyceride mg - glyceryl palmitostearate mg - soybean lecithin mg 7. Use of methionine in association with vitamin E and selenium according to the preceding claims, characterized in 40 that the medicament is adapted to a daily administration of said active principles in ranges between 600 and 1200 mg of L-methionine, mg of vitamin E and mg of selenium corresponding to the administration of 4-8 capsules pro die. 45 so Patentanspruche 1. Verwendung von Methionin in Verbindung mit Vitamin E und Selen als Wirkstoffe zur Herstellung eines Medikament zur unterstiitzenden Behandlung bei Seborrhoid-Dermatitis, auch bei HIV-positiven Patienten. 2. Verwendung von Methionin in Verbindung mit Vitamin E und Selen nach Anspruch 1, dadurch gekennzeichnet, dab die Wirkstoffe direkt Oder indirekt zur Entwicklung einer Schutzwirkung gegen die durch Lipoperoxidase herbeigefuhrten Schadigungen beitragen. 3. Verwendung von Methionin in Verbindung mit Vitamin E und Selen nach den vorhergehenden Anspriichen, dadurch gekennzeichnet, dab Selen in einer Menge im Bereich zwischen 0,015 und 0,025 % Gew. %, bezogen auf 55 Methionin, vorhanden ist. 4. Verwendung von Methionin in Verbindung mit Vitamin E und Selen nach den vorhergehenden Anspriichen, dadurch gekennzeichnet, dab Selen in Form von Selen-D-L-Methionin eingesetzt wird. 3

4 Verwendung von Methionin in Verbindung mit Vitamin E und Selen nach den vorhergehenden Anspriichen, dadurch gekennzeichnet, dab Vitamin E in Form von d,l-tocopherol eingesetzt wird. Verwendung von Methionin in Verbindung mit Vitamin E und Seien nach den vorhergehenden Anspriichen, dadurch gekennzeichnet, dab fur eine Kapsel mit einer pharmazeutischen Zusammensetzung die folgende Formulierung vorgesehen ist: 10 Wirkstoffe: 1S - L-Methionin 150 mg - d,l-<x-tocopherol Aquivalent zum zugrundeliegenden Vitamin E 75 mg - Selen-D-L-Methionin, 0,65 mg Aquivalent zu Selen 0,030 mg Arzneimitteltrager: - Caprin-Capril-Triglyzerid 152,436 mg - Glyzeryl-Palmitostearat 5,000 mg 20 - Lecithin aus Sojabohnen 2,500 mg. 7. Verwendung von Methionin in Verbindung mit Vitamin E und Selen nach den vorhergehenden Anspriichen, dadurch gekennzeichnet, dab das Medikament auf eine tagliche Verabreichung der Wirkstoffe jeweils im Bereich 25 zwischen 600 und 1200 mg L-Methionin, zwischen 300 und 600 mg Vitamin E und zwischen 0,120 und 0,240 mg Selen entsprechend der Verabreichung von 4 bis 8 Kapseln pro Tag eingestellt ist. Revendications Utilisation de methionine en association avec de la vitamine E et du selenium comme principes actifs, pour la preparation d'un medicament pour le traitement adjuvant de la dermatite seborrheique, meme chez les sujets seropositifs au HIV. 2. Utilisation de methionine en association avec de la vitamine E et du selenium selon la revendication 1, caracterisee 35 en ce que lesdits principes actifs contribuent directement ou indirectement au developpement d'une action protectee contre les lesions dues a la lipoperoxydase. 3. Utilisation de methionine en association avec de la vitamine E et du selenium selon les revendications precedentes, caracterisee en ce que le selenium est present dans une proportion s'echelonnant entre 0,015 et 0,025%, par 40 rapport au poids de la methionine. 4. Utilisation de methionine en association avec de la vitamine E et du selenium selon les revendications precedentes, caracterisee en ce que le selenium est utilise sous forme de selenium-d-l-methionine Utilisation de methionine en association avec de la vitamine E et du selenium selon les revendications precedentes, caracterisee en ce que la vitamine E est utilisee sous forme de d,l-tocopherol Utilisation de methionine en association avec de la vitamine E et du selenium selon les revendications precedentes, caracterisee en ce que la formulations suivante est fournie pour une preparation pharmaceutique en capsule: 55 4

5 Principes actifs: -L-methionine 150 mg - d,l-a-tocopherol equivalent a une quantite de vitamine E basique 75 mg de - selenium-d-l-methionine 0,65 mg equivalent a selenium 0,030 mg - triglyceride caprique-caprilique 1 52,436 mg - palmitostearate de glyceryle 5,000 mg - lecithine de soja 2,500 mg Utilisation de methionine en association avec de la vitamine E et du selenium selon les revendications precedentes, caracterisee en ce que le medicament est congu pour une administration quotidienne desdits principes actifs dans les gammes entre 600 et mg de L-methionine, mg de vitamine E et 0,120-0,240 mg de selenium, correspondant a I'administration de 4 a 8 capsules par jour.