ORAL PHARMACEUTICAL COMPOSITIONS CONTAINING MELATONIN

Abstract: Oral pharmaceutical compositions containing melatonin as the active principle in form of micro-emulsions are described.

Description: ORAL PHARMACEOTICAL COMPOSITIONS CONTAINING MELATONIN The present invention refers to oral pharmaceutical compositions containing melatonin. Melatonin is an hormone synthesized in the epiphysis, in the retina and, presumably in the chromaffinic cells of the intestinal tract. Its biosynthesis is subjected to a typical circadian rhythm, reaching a peak during the night. Its effects are numerous and particular attention has been recently focused on the immunostimulant and immunomodulatory effect of melatonin. A problem which considerably limits the therapeutic potentials of this hormone is however provided by its poor oral bioavailability. It has now been found that melatonin may be effectively administered by the oral route when formulated in form of micro-emulsions. Micro-emulsions are well-known and may be prepared according to conventional methods: a review of their properties and preparative methods has been recently published on Chemistry in Britain Vol. 26 (4) April 1990, 342-344 and cited references. As a pharmaceutically acceptable emulsifier, lecithins or purified components thereof such as L-CX-- phosphatidylσholine, L-O^phosphatidylethanolamine or L- (X-phosphatidylserine, both extractive and synthetic, are preferred. L-C^-phosphatidylcholine is preferably used in a weight ratio to melatonin of about 1:1 in a solution consisting of ethanol, propylene glycol and water. The active principle and a thickening agent such as gelatine, natural gums, cellulose derivatives an the like are then added to the above solution obtaine by usual methods. The following example further illustrate the invention. EXAMPLE Formulations in micro-emulsions 1.2 g of L-C^phosphatidylcholine are dispersed under vigorous agitations in 4.8 ml of a solution 10 consisting of [ethanol(2)/ propylene glycol (1)]/H 2 0 = 55/45 pp. After emulsifying, 1.5 g of melatonin are added, under stirring and then, after complete dissolution, 1 g of gelatine. 15 The so obtained micro-emulsion, hereinafter referred to as MR-111, has been subjected to pharmacokinetics studies, evaluating the serum levels of melatonin in healthy volunteers, according to the following method. 20 Experimental part Two healthy volunteers were treated at the zero (0) time with a dose of 2.5 mg, respectively of melatonin (subject 1) and of MR-111 (subject 2). 5 ml of venous blood were sampled at the times, 25. expressed in minutes, 0, 30, 90, 150, 210, 270 and 330. After separation, serum was frozen till the melatonin extraction. The extraction and the determination of melatonin were carried out according to the methods of Maestroni et al. , J. Neuroimmunol. 0 13, 19-30, 1986. Results Serum levels of melatonin expressed in pg/ml, Time (minutes) 0 30 90 150 210 270 330 390 405 The administration of 2.5 mg of melatonin (subject 1) confirms the kinetics observed in other studies (Wright J. et al. , Clin. Endocrinol. , 24, 375-382 (1989); Lieberman H.R. J. Neural. Trans., 21, 233-241 (Suppl.) (1986) with an high peak after 90 minutes and a fast decrease of the plasma concentration. The product MR-111 induces a wider peak, more similar to the physiological peak of melatonin, surprisingly showing an higher bioavailability.

Claims: CLAIMS 1. Oral pharmaceutical compositions containing melatonin as the active principle in form of icro- emulsions. 2. Compositions according to claim 1, characterized in that the micro-emulsion is obtained by using L-~ - phosphatidylcholine as emulsifier and a mixture consisting of ethanol, propylene glycol and water as solvent. 3. Compositions according to claim 1 or 2, also containing thickening agents. 4. Compositions according to claim 3, wherein the thickening agent is gelatine. 5. Compositions according to any one of the previous claims, wherein the weight ratio of - ~ - phosphatidylcholine to melatonin is about 1:1.

Inventors: BRUNO GRAZIELLA, BRUNO, GRAZIELLA
Applicants: MEDEA RES SRL, MEDEA RESEARCH S.R.L.
Application year: 1991
Main classification: A61K31
IPC codes: A61K9, A61K31