Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1993-02-04
1994-11-08
Cintins, Marianne M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514419, A61K 3121, A61K 31275
Patent
active
053627458
DESCRIPTION:
BRIEF SUMMARY
The present invention refers to oral pharmaceutical compositions containing melatonin.
Melatonin 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 admininistered 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-.alpha.-phosphatidylcholine, L-.alpha.-phosphatidylethanolamine or L-.alpha.-phosphatidylserine, both extractive and synthetic, are preferred. L-.alpha.-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 thicken agent such as gelatine, natural gums, cellulose derivatives and the like are then added to the above solution obtained by usual methods.
The following example further illustrate the invention.
EXAMPLE
Formulations in micro-emulsions
1.2 g of L-.alpha.-phosphatidylcholine are dispersed under vigorous agitations in 4.8 ml of a solution consisting of [ethanol(2)/propylene glycol (1)]/H.sub.2 O=55/45 pp.
After emulsifying, 1.5 g of melatonin are added, under stirring and then, after complete dissolution, 1 g of gelatine.
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.
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, 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. 13 , 19-30, 1986.
______________________________________ Results
Serum levels of melatonin expressed in pg/ml.
Time (minutes) Melatonin MR-111
______________________________________
0 25 27
30 362 268
90 1788 719
150 240 984
210 680 844
270 66 439
330 0 295
390 0 199
405 0 93
______________________________________
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, 233-24 (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 a higher bioavailability.
1. An oral pharmaceutical composition consisting of melatonin as the active principle in form of a microemulsion, L-.alpha.-phosphatidylcholine as an emulsifier and a solvent mixture consisting of ethanol, propylene glycol and water and wherein the weight ratio of L-.alpha.-phosphatidylcholine to melatonin is about 1:1 and wherein the composition optionally contins a thicker agent.
2. The composition according to claim 1 which contains at least one thickening agent selected from the group consisting of gelatin, natural gums and cellulose derivatives.
3. The composition according to claim 3 wherein the thickening agent is gelatin.
4. A method of increasing the bioavailab
REFERENCES:
patent: 4388324 (1983-06-01), Horrobin
patent: 4746674 (1988-05-01), Pierpaoli et al.
patent: 4855305 (1989-08-01), Cohen
Merck Index, Eleventh Edition (1989) #5311.
Cintins Marianne M.
Criares T. J.
Medea Research S.r.l.
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