Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
1995-12-05
2001-04-10
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S464000, C424S482000, C424S497000, C424S489000
Reexamination Certificate
active
06214377
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to a method of using melatonin for the production of peroral pulsatile forms of medication for safeguarding an effective blood level of the medical substance melatonin, which pulsatile forms realize a controlled delivery within a relatively short invasion phase in contrast to conventional forms of medication containing melatonin and which pulsatile forms exclude at the same time the known side effects.
2. Brief Description of the Background of the Invention Including Prior Art
The term “pulsatile forms of medication” is synonymous with the term “regulated or modulated delivery systems” and designates according to Peppas (N. A. Peppas, Preface in R. Gurny; H. E. Junginger; N. A. Peppas (Eds.) Pulsatile Drug Delivery, Current Applications and Future Trends, 1 Ed., page 5-5, Wiss. Verlagsges., Stuttgart 1993) a delivery system for medication which is capable of delivering the contained medical agent in prescribed intervals in response to the situation in the surrounding liquid or based on an external stimulus.
The preferred field of application of pulsatile forms of medication are illnesses such as ischaemia, asthma, arthritis, sleep disorders, Parkinson's Syndrome, incontinence, aids, and states of pain (H. E. Junginger, Oral Applications of Pulsatile Drug Delivery in R. Gurny; H. E. Junginger; N. A. Peppas (Eds.) Pulsatile Drug Delivery, Current Applications and Future Trends, Ed. 1, pages 113-134, Wiss. Verlagsges., Stuttgart 1993). These illnesses or states of pain are subjected to time variations such that they can be treated best with forms of medication, which are adapted with the intermittent (pulsatile) release of the medical agents to the occurrence of episodes of the illness or of attacks of the pain.
Typical pulsatile forms of medication deliver the contained medical agent in one step (one pulse system) or in two steps (bimodal, double pulse system).
In addition, however also more complicated systems and mixed systems have been described, which can possibly deliver the medical substance melatonin in several steps.
Junginger (H. E. Junginger, Oral Applications of Pulsatile Drug Delivery in R. Gurny; H. E. Junginger; N. A. Peppas (Eds.) Pulsatile Drug Delivery, Current Applications and Future Trends, Ed. 1., pages 1 13-134, Wiss. Verlagsges., Stuttgart 1993) gives examples for pulsatile forms of medication and recites in particular:
coated tablets, pellets or microballs,
osmotic systems,
special capsules,
time-controlled explosion systems,
special layer tablets.
The methods known up to now for the production of a pulsatile form of medication are thus all associated with the substantial disadvantage that special lines of production as well as expensive devices or a costly precision production are necessary.
Melatonin (N-acetyl-5-methoxy-triptamine) itself is a hormone of the pineal gland and is secreted predominantly during the night hours. Since melatonin interacts in many ways in the different regulating circles in the human body and exerts different physiological and pharmacological effects, various experiments and results are known from the professional and patent literature relating to the different directions of effectiveness of the melatonin.
For example,
FIG. 1
according to K. A. Stokkan et al.; J. Pineal Res. 16, 33-36, 1994, and B. L. Parry et al.: Arch. Gen. Psychiatry 47, 1139-1146, 1990, shows in its graphical representation of the blood level curve (concentration of the melatonin versus time) the physiological course of the circadian delivery of melatonin in a healthy person (I) and in an ill person (II).
It can be recognized that
a relatively steep rise of the surging on of the endogenous melatonin is recorded in a healthy human being, whereby a quick falling-asleep phase is characterized; then, there occurs a relatively flat drop of the endogenous melatonin level in the blood, which safeguards the sleep-through phase,
the maximum of the level of endogenous melatonin in the blood (C
max-e
) occurs belatedly in an ill person and there is associated therewith a delay of the falling-asleep phase; then, there occurs a steep drop of the level of endogenous melatonin in the blood, i.e. a wake-up phase occurs, and the sleep-through phase is not safeguarded.
Melatonin was applied up to now for example in an intranasal, intraocular, intravaginal, or rectal form of preparation. The circumvention of the liver passage was thereby in fact realized, however, the disadvantage of these solutions resides in that a follow-up administration is necessary at short-time intervals of from 1 to 2 hours. The cause for this according to L. Wetterberg et al.: A Simplified Radioimmunoassay for Melatonin and its Application to Biological Fluids, Preliminary Observations on the Half-Line of Plasma Melatonin in Man, Clinica Chimica Acta 86: 169-177, 1978; M. Aldhous et al.: Plasma Concentration of Melatonin in Man Following Oral Absorption of Different Preparations, Br. J. Clin. Pharmac. 19: 517, 521, 1985, and C. Mallo et al.: Eur. J. Clin. Pharmacol. 38: 297-301, 1990, is associated with the extremely short half-life period of melatonin in the human body which amounts to about 30 minutes.
Both the production as well as the application possibilities of adhesive carrier systems, i.e. transmucosal patches, are described in the Printed Patent document WO 91/06290. It is pointed out that these carrier systems are particularly well suited to produce and/or to maintain therapeutically an effective blood level. According to an embodiment, the use of the patches for the administration of melatonin is described. The transdermal application with various plasters does not bring satisfying results according to R. V. Short: Melatonin. Hormone of Darkness. Br. Med. J. 307: 952-953, 1993, since the melatonin rise in the serum is very flat and since no clear and abrupt drop can be proven after removal of the plaster.
Further known applications of melatonin are performed orally, in the form of tablets, of dragées, or of hard gelatin capsules.
According to investigations, after an oral administration of melatonin, there result extremely high interindividual differences with respect to the resorption of the melatonin from the gastro-intestinal tract as well as initially extremely overshooting melatonin levels in the blood as well as a poorly controllable kinetic of the active agent in case of a repeated application, compare F. Waldhauser et al.: Sleep Laboratory Investigations on Hypnotic Properties of Melatonin, Psychopharmacology 100: 222-226, 1990, and A. Vermeulen: The Male Climacterium, Ann. Med. 25: 531-534, 1993.
In the case of peroral administrations based on melatonin, the first-pass mechanism forces an administration which is overdone in an unphysiological overdose, compare E. A. Lane et al.: Pharmacokinetics of Melatonin in Man: First Pass Hepatic Metabolism. J. Clin. Endocrinol. Metab. 61: 1214-1216, 1985. Increased spasmogenic situations, confusion, and sleeplessness are thereby caused according to investigations, compare F. Waldhauser et al.: Sleep Laboratory Investigations on Hypnotic Properties of Melatonin, Psychopharmacology 100: 222-226, 1990, and A. Vermeulen: The Male Climacterium, Ann. Med. 25: 531-534, 1993.
An oral form of medication, containing among others a melatonin, is taught in the Printed Patent document WO 95/03043, which realizes the regulation of the physiological course of the circadian delivery of melatonin in older patients, in particular in patients suffering from Alzheimer's disease.
The disadvantage of this solution comprises that the application of the form of medication should occur
either 4 to 17 hours prior to the time of the endogenous delivery of melatonin
or 6 to 19 hours prior to the normal sleep phase.
This requires a very original and willful rhythm of ingestion, which is very hard to realize in particular in case of patients which are suffering from Alzheimer's disease. The above recited rhythm of ingestion allows to suspect a very low initial level of melatonin
Dittgen Michael
Fricke Sabine
Graser Thomas
Lippert Theodor Hermann
Oettel Michael
Jenapharm GmbH
Kasper Horst M.
Page Thurman K.
Pulliam A.
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