CA2116036A1 - Device for the transdermal administration of melatonin - Google Patents

Abstract

The present invention is directed to the transdermal administration of melatonin together with a suitable permeation enhancer. The invention includes a transdermal drug delivery device (10) comprising a matrix (12) adapted to be placed in melatonin- and permeation enhancer-transmitting relation with the skin site (18). The matrix (12) contains sufficient amounts of a permeation enhancer and of melatonin, in combination, to continuously administer to the skin (18) for a predetermined period of time the melatonin to provide an effective therapeutic result. The invention is also directed to a method for the transdermal administration of a therapeutically effective amount of melatonin together with a skin permeation-enhancing amount of a suitable permeation enhancer. The invention further includes methods for time- and rate-patterned transdermal delivery of melatonin to simulate the natural circadian rhythmic profile of melatonin in mammals.

Description

21~36 ` ~
WC '07870 PCIJUS92~08919 ~"

UEYICE FOR THE TRANS~ER~IAL ~MINISTRATION ~F MEUTONIN

FIELD OF THE INVENTION
This invention relates the efficacious and safe, controlled 5 transdermal administration of melatonin and related compounds ~or systemic hypnotic and soporific effects in the treatment of insomnias of several kinds.

BACKGROUND OF THE INVEN~ION
I0 Melatonin (N-acetyl-5-methoxytryptamine) is a hormone synthesized and secreted by the pineal gland. The exact function of ~-~ the hormone in adult human beings has not been determined. In healthy young adults, melatonin is secreted as a broad pulse during nighttime sleep in the total amount of approximately 25-30 ~9 per 5 night, producing peak plasma concentrations of approximately 7Q pgjml, occurring at approximately 0200 h. Melatonin is secreted into the blood stream and possibly also into cerebrospinal fluid (CSF) simultaneously. The CSF/plasma concentration ratio is 1.0 or less. The terminal plasma elimination half-life is approximately 20 45 minutes; volume of distribution is approximately 40 liters; and the metabolic clearance of melatonin is approximately I liter per minute. The melatonin circadian (-24 hr) rhythm is thought to be -~
driven by the same central nervous system oscillator that drives the ;
daily rhythms of cortisol, urine volume, and core temperature 2s (Shanahan and Czeisler, 1991). The relationship o~ the melatonin cycle to the activity~rest (sleep) cycle is not clear, but melatonin may organize the normal sleep pattern. ~-Melatonin has been administered to human beings orally and intranasally. It is readily absorbed through the gastrointestinal 30 tract. The liver inact~vates as much as 99YO of the absorbed melatonin on the first-pass. Thus, the oral route of administration ~`
~s ~nefficient and erratic. ~-Oral melatonin has been given to human beings to ~reat the ~ ;
phenomenon of "jet lag~ following airplane tr1ps associated with a 3s change in time zones (Arendt et al. (1987) Ergonomics 30:1379-1393);
:

WO 93~078'70 PC~US92~891g 211~036 ~ -.

U.S. Pats. 4,600,723 and 4,665,086). It has been given to patients with Parkinson's disease (Anton-Tay et al. (1971) Life Sciences : :
10:841-B50), epilepsy (Anton-Tay et al., ibid.~, or seasonal affective disorders (Wirz~ustice et al. (1990) J. Psychiat. Res.
24(2):129-137). It has been tried as a sleep-wake organizer in ;
desynchronized blind persons (Arendt et al. (1988) Lancet pp 772-773; -:
Folkard et al. (1990) Neu~oscience Lett. 113:193-198; Sack et al., (1987) in, ~Temporal Disorder in Human Oscillatory Systems", Eds. L.
Rensing et al., Springer-Yer7ag, Heidelberg, pp 219-224; Sack and Lewy (1988) Am. Psychiatric Assoc~ 141 Ann. Meeting, Montreal, Quebec). Improved timing of sleep cycles resulted. Oral melatonin as been given to insomniacs (Waldhousér et al. (1990) Psychopharm~co70gy 100:222-226; Arendt et al. (1991) Lancet 337:1121 1124). Melatonin red~ced the time awake be~ore sleep onset and ~
15 diminished sleep latency and number of awakenings. Overall sleep ~ `
efficiency was increased, and mood, drive, alertness, and reaction time were improved the next day. Most of the published studies are consistent with the assumption that melatonin has mild sedative and hypnotic properties and may be a natural, sleep-inducing and 20 sleep-organ king signal in humans. In addition, melatonin has been reported to lower intraocular pressure in glaucoma, to inhibit breast cancer (U.S. Pat. 4,855,305; Barch et al. (1991) Cancer 67:1681-1684), to be use~ul in the treatment of premenstrual depression (U.S.
Pat. 4,945,103; Parry et al. (1990) Arch. ~en. Psychiatry 47:1139-25 1146; Yen ~t al. (1990) Arch. Gen. Psych. 47:1139-1146), for effecting contraception in humans (PCT Appln. WO 90/14084), and to prevent sudden infant death syndrome (Wurtman et al. (1990) Forensic ~:
Science Interntl. 45:171-180). Melatonin appears to be useful in lanimal husbandry by, for example, regulating the reproductive-30 behavior of animal seasonal breeders (Reiter (1981) Endocr. Rev.
1:109-131; Nittman et al. ~1983) Endocrino70gy 113:2276-2283; Arendt (1986) Oxford Reviews of Reproductive Bio~ogy 8:266-320) and regulating f~r coat development in animals with seasonal variation.
Numerous analogs, homologs, agonists, antagonists and other 35 compounds related to melatonin are known in the art, representatives ~ ~~. .

W0'`7/07870 2 ~lS?~31~ pC~/us92/l~89l9 of which are disclosed in, for example, U.S. Pat. 4,880,826, W0 87/00432, W0 89/01472, W0 89/04659, W0 90/14084, and EP 420 064, and by Frohn et al. (Life Sciences, Vol. 27~ pp 2043-2046, Pergamon Press) and Clemens et al. (J. Neura1 Transm., (1986) (supp.) ~:451- :
s 4~9).
The transdermal route of administration for drugs and other biologically active asents ("agents~) has been proposed for a wide var~ety of systemically acting and locally acting agents on either a rate-controlled-or non rate-controlled basis and is described in o numerous technical publications and patents, such as U.S. Patents ~`
3,598,122; 3,~98,123; 3,731,683; 3,797,4g4; 4,031,894; 4,201,211;
~-4,286,592; 4,314,557; 4,379,454; 4,435,180; 4,5a8,5~0; 4,645,502;
4,704,282; 4,788,062; 4,816,258; 4,908,027; 4,943,435; and 5,004,610. The disclosures of the above patents are incorporated S herein by reference. -~
When first investigated in depth in the late 1960's, the transdermal route of administration of active agents appeared to offer many advantages, particularly with re~?ect to agents that had short half-lives and a high degree of first-pass metabolism by the 20 liver when orally administered. Pres~ntation of the agent through ~
the skin directly into the blood stream would eliminate ~first-pass" ;
metabolism of orally administered agents, which excludes the oral portal for some agents or requires extremely large oral doses for others.
2s In spite of inte~sive research and development activities by most of the major pharmaceutical companies on the potential candidates for transdermal administration, only six drugs are presently commercially available in the United States in the form of Itransdermal drug delivery devices: nitroglycerin, scopolamine, 30 clonidine, estradiol, nicotine and fentanyl. This set is small because of difficulties inherent in the barrier properties of skin lsee ~Transdermal Drug Delivery: Problems and PossibilitiesN, V. M. ~;
Knepp et al.? CRC Critica1 Re~iHws and Therapeutic Drug Carrier S~ste~sj Vol. 4, Issue 1, ~1987)].

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The skin is a complex structure that performs its barrier ~-~function in several ways:
1. As a physical barrier having a relatively low permeability for most substanc~s;
2. As a sensory organ;

3. As a metabolizing organ capable of converting some topically applied substances into metabolites.
Thus, the transdermal route of administration, rather than being useful forevery short half-life agent of h~gh potency, has o been found to be applicable only to a few agents possessing certain characteristics. ~hé most significant of these considerations are:
1. Skin permeability. The permeability of the agent through the skin must be sufficiently high so that it can be administered at therapeutically ef~ective rates through an area of skin no greater than approximately 100 cm2 and preferably no greater than 50 cm2.
The person-to-person variation in skin permeability at similar sites should also be relatively small.
2. Skin binding. The skin beneath a transdermal delivery device has the potential capability of binding or diss~lving a ~;
20 certain amount of agent. The amount of agent so bound ~ust be `;
supplied to the skin before the agent can be deliv~ed into the blood :
stream at therapeutically effective rates. If large amounts of the agent are bound in the skin, significant delays in the onset of ~r therapeutic effect (Nlag timen) wilt be observed, as well as ~`~
2s corresponding delays in termination of effect upon removal of the device. Skin binding is not related to skin permeabitity. Agents that are highly permeable may also be h~ghly bound, causing a lag time sufficiently long as to render them unsuitable for their ~ntended use.
3. Irritation. The skin reacts to many topically applied substances, particularly those maintained under occlusîon, by -bl~stering or reddening accompanied by unpleasant burning, itching, and stînging sensations. There is a wide intsr-subject variation in susceptibility to irritation. An agent must be minimally irritating ;~
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WO "~ '078 70 PCI'/US92/08919 in a large percentage of the potential patient population in order to be suitable for safe and effective transdermal administration.

4. Sensitization. Sensitization is an allergic reaction that is induced when an agent is first applied to the skin and is 5 eticited upon continued exposure, which may occur in~nediately or after a long period of seemingly harmless exposure. The :
sensitization may be local, elicited by topical exposure, which manifests itself as contact dermatitis accompanied by blistering, itching, reddening, and burning at the site of application. More o seriously, the sensitization may be systemic, elicited by topical application but manifesting itself by more general allergic reactions at sites other than the site of application. Most seriously, the systemic sensitization may be elicited by oral or intravenous administration of ~he drug. If the latter occurs, the patient will 15 be unable to take the drug by any route of administration.
There is a wide variation in allergic response among indiv~duals as well as between sexes, races, and skin types. It is `i obvious that a useful transdermal agent must be minimally sensitizing in a large percentage of the potential patient population.
5. Pharmacokinetic properties. The elimination half-life of an agent is the time after administration that half of the amount administered has been eliminated from the body. Blood concentrations of agents continuously administered at constant rates will continue to increase for approximately five half-lives before steady-state, 25 constant blood concentrations are achie~ed. It is usually desirable that an agent have a relativety short half-life to be suitable for controlled, transdermal administration. When half-lives of agents determined from intravenous administration are compared with Ihalf-lives determined from transdermal administration, the 30 transdermal half-lives are generally longer, but there can be wide variation in half-life among individuals based upon such factors as age, sex, health, and body type. The transdermal half~ es of most agents have not been determ~ned.

6. Pharmacodynamic properties. Constant blood levels may 35 not produce the optimal therapeutic effects. For example, a W0 93/07870 . PCI/US92/08919 2 1 1 ~ 6 6 therapeutic effect may only be observed at the peak blood concentration obtained from bolus dosing, but the peak concentration cannot be maintained because of side effects associated therewith.
Also, continuous administration of many agents produces tolerance. `
5 Other cases may require either some agent-free interval or continually varying doses of the agent.

7. Potency. Although a high pot~ncy is required for feasibility of transdermal administration of an agent, it is possible for an agent to be too potent. As potency increases, lower blood o concentrations are required and much smaller total quantities are administered. Becau~e of the norma~ inter-individual variations in ~skin permeability, it may not be possible to control precisely the ~`
dose a patient receives, and for potent agents with narrow ~;
~therapeutic windows," this uncertainty can be hazardous.
Fortunately, in the present case, melatonin is -elatively non-toxic. ;, 8. Metabolism. One of the perceived advantages of ~ ;
transdermal administration was that it avo-~ed the "first-pass"
metabolism of the agent by the liver which is associated with oral ;
administration. It has now been recognized, however, that the skin, 20 not the liver, is the largest metabolizing organ in the body. Thus, although first-pass metabolism which occurs after an orally adjusted agent enters the blood stream can be avoided, skin metabolism, which occurs before the agent enters the blood stream, must be dealt with.
Skin metabolism is capable of creating metabolites which are inert, 25 toxic or comparable in biological activity to that of the agent. An agent, to be suitable for transdermal administration, must have the metabolic properties that are consistent with its therapeutic use on continuous administration.
I The above summarizes the primary characteristics recognized to 30 date that affect suitability of an agent for transdermal administration. There are undoubtedly others, some of which have not yet been recognized. In order for an agent to be suitable for ~-transdermal adm~nistration it must possess the right combination of all of these ch`aracteristics, a combination which, as illustrated by 35 the very few drugs which are now known to be suitable for 2 ~ 1 r~ ~ 3 6 WO 9~/07870 PCI/US92/08919 administration from transdermal delivery devices, is quite rare and unpredictable.

SUMMARY OF THE lNVENTION
According to the present invention, it ~as been discovered that me~atonin may be safely and efficaciously administered transdermally and in a controlled manner. Methods for the transdermal delivery of melatonin and delivery devices for effecting the same, which are suitable for the administration of melatonin through mucosa and intact skin, are provided.
More particula~ly, the present invention is directed to the .transdermal administration of melatonin, to~ether with a suitable A~
permeation enhancer. The invention includes a transdermal drug delivery device containin~ sufficient amounts of permeation enhancer 5 and of melatonin, in combination, to provide systemic administration of melat~nin through the skin for a predetermined period of time for the melatonin to provide an effective therapeutic result. ;
The invention is also directed to a method for the transdermal administration of a therapeutically effective amount of melatonin 20 together with a skin permeation-enhancing amount of a suitable permeation enhancer. The invention further includes methods for time- and rate patterned transdermal delivery of melatonin to simulate the natural circadian rhythmic profile of melatonin in mammals.
2s ~hile the preferred active agent according to the present invention is melatonin itself, the invention also includes analogs~
homologs, agonists, antagonists and other compounds related to melatonin. The term ~melatonin~ is used herein to designate both the actual melatonin and the related compounds thereof. ~`
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BRIEF DESCRIPTION OF THE DRA~INGS
FIG. 1 is a cross-section through a schematic perspective ~iew of one embodiment of transdermal therapeutic dev kes according to ~ -this invention. ~

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FIG. 2 is a cross-sertion through another embodiment of a transdermal therapeutic device according to this invention.
FIG. 3 is a cross-section through yet another embodiment of a transdermal therapeutic device according to this invention.
s FIG. 4 is a cross-section through yet another embodiment of a transdermal therapeutic device according to this invention. ; ~;~
FIG. 5 shows the baseline melatonin plasma concentrations of a ; ~ `
young woman over.two separate da~s.
FI6. 6 shows the melatonin plasma concentration of the same -~
indiYidual as in FIG. 5 on a different day when she wore and then removed a transdermal device according to this invention.
. FIGS. 7 and 8 show the plasma melatonin concentrations in another individual (an older man) during baseline monitoring (FIG. 7) and on a day when he wore and then removed a transdermal device accord~ng to this invention (FIG. 8).

DET~ILED DESCRIPTION OF THE INVENTION
AND PREFERRED EMBODIMENTS
According to the present invention, it has been found that ~-20 melatonin may be administered to the human body in a therapeut kally ~-effective amount via the transdermal route when it is co-administered with a suitable permeation enhancer. Therapeutic blood levels from 20 pg/ml to 1,000 pg/ml c~n be obtained from administration rates in the range of 1 mg/hr to 100 ms/hr. RepresentatiYe skin fluxes of 25 melatonin through living human skin are in the range of 0.05 mg/cm2/hr to 10 mg/cm2/hr, depending on the permeation enhancer. ~ ;
The plasma terminal half-life of melatonin administered transdermally is tn the range of 1 to Z hours. Therapeutic blood levels can be achieved within approximately 2 hours, and peak blood concentrations 30 are ach~eved at about 4-6 hours when the system is worn for ~;~
4-6 hours. The range of desired and achievable system fluxes of melatonin, arriving through the skin from a limited area, is 0.025-1.0 mg over a period of 4-8 hours. The system application is easily ~`
adapted for shorter or longer duration treatments, but generally 35 6 hours is the nominal duration for treatment o~ most insomnias.
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Typical transdermal delivery devices are described in U.S.
patent numbers 3,598,122; 3,598,123; 4,286,592; 4,314,557; 4,379,454;
4,559,222; 4,573,995; and 4,849,226, for example. All of these are incorporated herein by reference. The co-administration of melatonin s and a permeation enhancer as disclosed herein can be accomplished by using transdermal devices-of these kinds.
Because of the wide variation in skin permeability from 1ndiv~dual and from site to site on the same body, it may be preferable that melatonin and the permeation enhancer be administered o from a rate-controlled transdermal delivery device. Rate control can be obtained either through a rate-controlling membrane or adhesive or ~- through the other means disclosed in the patents noted above.
A certaln amount of melatonin will bind to the skin, and it is accordingly preferred that the skin-contacting layer of the device include this amount of the agent as a loading dose.
Examples of suitable transdermal delivery devices are illustrated in FIGS. 1, 2, 3 and 4. In the drawings, the same reference numbers are used throughout the different ~igures to -~
designate the same or similar components. The figures are not drawn 20 to scale. ;
In FIG. 1, transdermal delivery device 10 comprises a reservoir 12 containing both melatonin and a suitable permeation enhancer.
Reservoir 12 is preferably in the form of a matrix containing the drug and enhancer dispersed therein. Reservoir 12 is sandwiched 25 between a backing la~er 14, which is impermeable to both the drug and the enhancer, and an in-line contact adhesive layer 16. The device 10 adheres to the surface of the skin 18 by means of the adhesive layer 16. The adhesive layer 16 may optionally contain enhancer I and/or drug. A strippable release liner (not shown in FIG.~1) is 30 normally provided along the exposed surface of adhesive layer 16 and is removed prior to application of device 10 to the skin 18.
Optionally, a rate-controlling membrane (not shown) may be present ~
between the reservoir 12 and the adhesive layer 16. ; -`
Alternatively, as shown in FIG. 2, transdermal therapeutic 35 device 20 may be attached to the skin or mucosa of a patient by means WO 93/078'70 PCI`/US92/08919 211~036 lO ` ~- ~

of an adhesive overlay 22. Devi~e 20 is comprised of a melatonin~
and permeation enhancer-containing reservoir 12 which is preferably :
in the form of a matrix containing the drug and the enhancer dispersed therein. An impermeable backing layer 14 is provided 5 adjacent one surface of reservoir 12. Adhesive overlay 22 maintains the device on the skin and may be fabricated together with, or provided separately from, the remaining elements of the device. With certain formulations, the adhesive overlay 22 may be preferable to ~;
the in-line contact adhesive 16 as shown in FIG. 1. This is true, 10 for example, where the drug/enhancer reser~oir contains a material ;~
(such as, for example, an oily surfactant permeation enhancer) which ~-adversely affects the adhesive properties of the in-line contact adhesive layer 16. Impermeable backing layer 14 is preFerably slightly larger than reservoir 12, and in this manner prevents the 15 materials in reservoir 12 from adversely interacting with the ;
adhesive in overlay 22. Optionally, a rate-controlling membrane (not shown in FI6. 2) may be provided on the skin-proximal side of -reservoir 12. A strippable release liner 24 is also provided with ~; ;
device 20 and is removed just prior to application of device 20 tQ
20 the skin.
In FIG. 3, transdermal delivery device 30 comprises a melatonin- and permeation enhancer-containing reservoir ("drug reservoir~) 12 substantially as described with respect to FI6. 1.
Permeation enhancer reservoir (~enhancer reservoirn) 26 comprises 25 permeation enhancer dispersed throughout and is substantially free of any undissolved melatonin. Enhancer reservoir 26 is preferably made from substantially the same matrix as is used to form drug reservoir 12. A rate-controlling membrane 28 for controlling the release rate of the permeation enhancer from enhancer reservoir 26 to drug ~ ~-30 reservoir 12 is placed between the two reservoirs. A rate~
controlling membrane (not shown in FIG. 3) for controlling the ~;
release rate of the enhancer from drug reservoir 12 to the skin may also opt~onally be utilized and would be present between adhesive ~-~
layer 16 ànd reservoir 12. - ;

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The rate-controlling membrane may be fabricated from permeable, semipermeable or microporous materials which are known in the art to control the rate of agents into and out of delivery devices and having a permeabil~ty to the permeation enhancer lower than that of 5 drug reservoir 12. Suitable materials include, but are not limited to, polyethylene, polyvinyl acetate and ethylene vinyl acetate copolymers.
Superimposed over the permeation enhancer reservoir 26 of device 30 is an impermeable backing 14. On the skin-proximal side of o reservoir 12 are an adhesive layer 16 and a strippable liner 24 which `~
would be removed prior to application of the device 30 to the skin.
~- In the embodiments of FIGS. 1, 2 and 3, the carrier or matrix material of the reservoirs has sufficient viscosity to maintain its shape without oozing or flowing. If, however, the matrix or carrier 5 is a low-viscosity flowable material such as a liquid or a gel, the composition can be fully enclosed in a pouch or pocket, as known to the art from U.S. Pat. No. 4,379,454 (noted above), for example, and as illustrated in FI6. 4. Device 40 shown in FIG. 4 comprises a backing member 14 which serves as a protective cover for the device, 20 imparts structural support, and substantially keeps components in device 40 from escaping the device. Device 40 also includes reservoir 12 which~contains the melatonin and permeation enhancer and ;
bears on its surface distant from backing member 14 a rate-controlling membrane 28 for controlling the release of melatonin 25 and/or perm~ation enhancer from device 40. The outer edges of backing member 14 overlay the edges of reservoir 12 and are joined ~;;
along the peri Nter with the outer edges of the rate-controlling membrane 28 jD a fluid-tight arrangement. This sealed reservoir may ~- ~
be ef*cted by pressure, fusion, adhesion, an adhesive appliled to the ~ 1 30 edges, or other methods known in the art. In this~manner, reservoir ~ `-12 is contained~wholly between backing member 14 and rate-controlling , ~embrane 28. On the skin-proximal side of rate-controlling membrane 28 are an adhesive layer 16 and a strippable liner 24 which would be ;~
removed prior to application of the device 40 to the skin.
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In an alternative embodiment of device 40 of FIG. 4, reservoir ~-12 contains the permeation enhancer only and is substantially free of melatonin. The melatonin and an additional amount of permeation enhancer are present in adhesive layer 16 which acts as a separate 5 reservoir.
~ he melatonin and the permeation enhancer can be co-extensively administered to human skin or mucosa by direct application to the skin or mucosa in the form of an ointment~ gel, cream or lotion, for -~
exampl~, but are preferably administered from a skin patch or other known transdermal delivery device which contains a saturated or unsaturated formulation of the drug and the enhancer. The formulation may be aqueous or non-aqueous based. The formulation should be designed to deliver the melatonin and the permeation ~;~
enhancer at the necessary ~luxes; Aqueous formulations typioally 15 comprise water or water/ethanol and about 1-2 wtX of a gelling agent, an example being a hydrophilic polymer such as ri3rdroxyethylcellulose ~;
or hydroxypropylcellulose. Typical non-aqueous gels are comprised of silicone fluid or mineral oil. Mineral oil-based gels also typically ~-~
contain 1-2 wt% of a gelling agent such as colloidal silicon 20 dioxide. The suitability of a particular gel depends upon the compatibility of its constituents with both the melatonin and the permeation enhancer and any other components in the formulation.
The reservoir matrix should be compatible with the drug, the permeation enhancer and any carrier therefor. The term ~matrix" as 25 used herein refers to a well-mixed composite of ingredients fixed into shape. When using an aqueous-based formulation, the reservoir matrix is preferably a hydrophilic polymer, e.g., a hydrogel. When using a non-aqueous-based formulation, the reservoir matrix is preferably composed of a hydrophobic polymer. Suitable polymeric ~o matrices are well known in the transdermal drug deliYery art, and examples are listed in the above-named patents previously incorporated herein by reference.
A typical laminated system would comprise a polymeric membrane -and/or matrix such as ethylene vinyl acetate (EVA) copolymers, such as those described in U.S. Pat. No. 4,144,31~, preferably having a ' .

WO~/07870 ~ 1 1 6 ~13 ~ PCI~/us92/û8g1g 13 ; ~:

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vinyl acetate (VA) content in the range of from about gx up to about 60% and more preferably about 28X to 60X VA. Polyisobutylene/oil ~`
polymers containing from 4-25% high molecular weight polyisobutylene and 20-81Z low molecular weight polyisobutylene with the balance 5 being an oil such as mineral oil or polyisobutynes may also be used as the matrix material.
The aforementioned patents describe a wide variety of materials which can be used for fabricating the various layers or components of the transdermal melatonin delivery devices according to this invention. This invention therefore contemplates the use of materials other than those spec~fically disclosed herein, including ~- -~-those which may hereafter become known to the art to be capable of performing the necessary functions.
The amount of melatonin present in the therapeutic device and ;--~
15 required to achieve an effective therapeutic result depends on many ~`
factors, such as the minimum necessary dosage of the drug for the -~
particular indication being treated; the solubility and permeability of the matrixt of the adhesive layer and of the rate-controlling ~`
membrane, if present; and the period o. time for which the device 20 will be fixed to the skin. The minimum amount of melatonin is determined by the requirement that sufficient quantities of drug must be present in the device to maintain the desired rate of release over the given period of application. The maximum amount for safety purposes is determined by the re~uirement that the quantity of -25 melatonin present cannot exceed a rate of release that reaches tox k levels. Melatonin is retatively non-toxic. An LD50 has been ~
detenmined ~n mice at 1375 mg/kg by intraperitoneal administration ~-and 180 mg/kg by intravenous administration. These are `--lextraordinarily high levels. In the human being the natural twenty~
30 four hour secretion in 0.3 ~g/kg. During daylight hours, the secretion rate is essentially zero. ` .When a constant drug delivery rate is desired, the melatonin is normally present in the matrix or carrier at a concentration in -~-excess of saturation, the amount of excess being a function of the 35 desired length of the drug delivery period of the system. The ~;

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melatonin may, however, be present at a level below saturation without departing from this inYention as long as the drug is continuously administered to the skin or mucosa site in an amount and for a period of time sufficient to provide the desired therapeutic 5 rate and delivery profile of melatonin delivery.
The permeation enhancer is dispersed through the matrix or carrier, preferably at a concentration sufficient to provide ~;;
permeation-enhancing amounts of enhancer in the reservoir throughout the anticipated administration period. Where there is an additional, o separate permeation enhancer matrix layer as well, as in FIGS. 3 and 4, the permeat~on enhancer normally is present in the separate ;
~, reservoir in excess of saturation. -The permeation enhancer useful in the present invention is selected from those compounds which are compatible with melatonin and wh kh provide enhanced skin permeation to melatonin when it is administered togetr.er with the drug to the skin o~ a user. Such permeation enhancers can be selected from, but are not limited to, C24 alcoho;~ such as ethanol and isopropanol, polyethylene glycol monolaurate, polyethylene glycol-3-lauramide, dimethyl lauramide, 20 sorbitan trioleate, esters of fatty acids having from about 10 to about 20 carbon atoms, monoglycerides or mixtures of monoglycerides of fatty acids having a total monoesters content of at least ~1%
where the monoesters are those with from 10 to 20 carbon atoms, and mixtures of mono-, di- and tri-glycerides of fatty acids. Fatty 25 acids are, for example, lauric acid, myristic acid, stearic acid, oleic acid, linoleic acid and palmitic acid. Monoglyceride permeation enhancers include glycerol monooleate, glycerol monolaurate and glycerol monolinoleate, for example. In a preferred lembodiment, the permeation enhancer is glycerol monooleate or 30 glycerol monolinoleate, more preferably glycerol monooleate.
Combinations of two or more permeation enhancers or of permeation j~
enhancers with bile salts are also contemplated.
In addition to melatonin and a suitable permeation enhancer, which are essential to the invention, the matrix or oarrier may also 35 contain dyess pigments, inert fillers, excipients and other ~
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21~ ~ 0 3 6 WO ~/07870 PC~/VS92/08919 conventional components of pharmaceutical products or transdermal devices known to the art.
In the present invention, melatonin is delivered at a ~ :
therapeutically effective rate (that is, a rate that provides a 5 desired therapeutic effect) and the permeation enhaneer is delivered .::;
at a permeation-enhancing rate (that is, a rate that-provides :
increased permeability of the application site to the melatonin) for . ~:a predetermined time period and in the required delivery pattern.
A preferred embodiment of the present invention comprises a o method of treating any disorder in which it is therapeutic to mimic or inhibit melatonin function or influence circadian rhythms by administering a therapeutically effective amount of one or more of the compounds of the present invention to a patient suffering from .
such disorder.
Another preferred embodiment of the present invention comprises a method of treating chronobiological disorders, e.g., seasonal affective disorders (SAD), sleep disorders, and symptoms such as drowsiness and fatigue that are associated with disturbances in sleep/wake cycles (e.g., jet lag, workers on night shi-fts, etc.) by ..
20 admin~stering a therapeutically effective amount of one or more of ~
the compounds of the present invention to a patient suffering from ~:.
one or more of such chronobiological disorders. .~.. ;
Another preferred embodiment of the present invention comprises .. ;:
a method of treating various psychiatric disorders related to altered :.
25 melatonin.function or.influenced by melatonin and circadian rhythms, ~
e.g., affective disorders (mania and depression), alcoholism, and ;~`
stress by administering a therapeutically effective amount of one or ~.
more of the compounds of the present invention to a patient suffering from one orimore of such psychiatric disorders.
Another preferred embodiment of the present invention comprises .
a method of treating or inducing various endocrine-related conditions attributed to altered melatonin function or influenced by melatonin and biological rhythms, particularly relating to regulation of .``
reproductive maturation and function, e.g.7 idiopathic delayed 3s puberty, premature labor, and antifertility, by administering a ~.

WO 93/07870 PCI`IUS9~/08919 2 1 1 6 0 3 Ç~ 1 6 therapeutically effective amount of one or more of the compounds of the present invention to a patient suffering from or desiring to induce one or more of such endocrine-related conditions. In addition, it is thought that the compounds of the invention can be s used to treat or prevent glaucoma by lowering the intraocular pressure and to manip~late body weight by administering an effective amount of one or more o~ the compounds herein.
A further preferred embodiment of the present invention comprises a method for manipulating the breeding and fur-bearing o cycles in animals by administering to such animal an effective amount of one or more of the compounds of the present invention.
A further preferred embodiment of the present invention comprises a method for restoring the youthful natural pattern or profile of excretidn of specific cyclical hormones which are affected ~ ;
15 by the levels of melatonin in the body, such as growth hormone, calc~tonin, and in males, testosterone.
In a presently particularly preferred embodiment, melatonin is useful as a sleep-producing agent for use by elderly persons who have fragmented sleep.
To be useful as a hypnotic, melatonin should be present in plasma at levels above 20 pg/ml for about 5 or 6 hours during the normal sleep cycle of the user, and preferably at levels which approximate the natural bell-shaped curve distribution of melatonin ln the body. FIG. 5 presents the natural plasma levels of melatonin 25 1n a healthy, normal individual and illustrates the bell curve-shaped di tribution. To achieve this result, the melatonin is delivered at a therapeutic rate of at least about O.l ~9 per hour, but typically of at least 2 ~g/hr, and more typically at about lO ~g/hr to about 200 ~g/hr, for the treatment period, usuàlly about 4 to 6 hours, 30 after which melatonin delivery is discontinued. The delivery device containing the melatonin and a permeation enhancer is placed on a ~-user at a time prior to the bedtime of the user such that the device is delivering melatonin in a therapeutically effective amount to the ~-user when the user goes to bed.

W 0 ~ ~07870 2 1 1 S 0 3 6 PC~IUS92/08919 : .

To provide the proper effect, or in other words to provide the desired bell-shaped curve, it is necessary that, at the end of the period of melatonin delivery, the supply of melatonin from the therapeutic device is "shut off" or discontinued so that melatonin 5 will clear from the body. Thus, in a departure from previous uses of transdermal drug delivery, steady-state delivery of melatonin is not desired.
The melatonin supply from a device of the present invention may be discontinued in one of several ways. The first is to physically ;~
10 remove the device after about 4-5 hours. However, since this usually ;
will require that the user wakes up, it defeats the purpose of ;~
providing an uninterrupted period of sleep. An alternative, which is ~: .
a preferred embodiment of the invention, is to provide means in the -~
delivery device ~tself for shutting off the supply of drug after a predetermined period of time, usually after about 1-6 hours and preferably after about 4-5 hours, depending on the user's need and `~
variations in skin binding and systemic clearance of melatonin. ~ ;
This may be accomplished by limiting the amount of melatonin present in the delivery device to only that amount which will be 20 delivered at the therapeutic rate for the predetermined time period.
For example, where the drug is delivered from the system at a rate of ~
5 ~g/hr and the desired period of delivery is 5 hours, the total ;;
amount of melatonin present in the device will be about 25 ~9~ Thus after 5 hours, systemic delivery of melatonin will oease and the 25 amount of melatonin in the blood plasma will decrease as the melatonin is cleared from the body. In such cases where there is a limited amount o~ melatonin present in the device, it is usually desired that the permeation enhancer present in the device be in an iamount in excess of that which is necessary to provide increased 30 permeab~lity to the melatonin that is present. Where there is a limited amount of melatonin and an excess of permeation enhancer in the transdermal device, the device of FIG. 3 or FIG. 4 ~s preferred, having a separate permeation enhancer reservoir containing an excess of enhancer. In this way, the melatonin is concentrated near the 35 skin while an adequate permeation enhancer supply is maintained.

WO 93/07870 . PCI/US92/0891 2111i036 .

Alternatively, means for shutting off the supply of melaton;n that enters the body transdermally may be accomplished by l;miting the amount of permeation enhancer present in the deliYery device, rather than the amount of melatonin. Because melatonin alone has a 5 very low flux through skin, delivery of the drug in therapeutically effective amounts or rates will effectively cease once permeation enhancer is no longer present. In this situation it is not necessary .
~or the drug and permeation enhancer to be separated, so that a transdermal device such as illustrated in FIG. 1 may be used.
o In a third alternative, the amounts of both melatonin and permeation enhancer are limited in ~he delivery device so that after i predetermined period of time systemic melatonin delivery will cease and the amount of melatonin in the body will decline to an undetectable level. A device such as that in FIG. 1 may be used in 5 th~s embodiment.
The lengt~ of time of melatonin presence and the total amount of melatonin in the plasma can be changed following the teachings of this invention to provide different treatment regimens. Thus, they can be controlled by the amount of time during which exogenous 20 melatonin is delivered transdermally to an individual or animal.
The devices of this invention can be designed to effectively deliver melatonin for an extended time period of from several hours up to 7 days or longer. Seven days is generally the maximum time -llmit for application of a single device because the skin site is z5 adversely affected when occluded for a period greater than 7 days.
However, when the indication is to provide uninterrupted sleep, it is only necessary for the device to be applied to the skin during the no~mal sleep cycle of the user, after which it is removed and discarded.
The transdermal therapeutic devices of the present invention are prepared in a manner known in the art, such as by those ;~
procedures, for example, described in the transdermal de~ice patents ;~
listed previously herein.
Having thus generally described the inYention~ the following 3s specific examples describe preferred embodiments thereof.

w o ~0787~ 2 1 1 ~ ~ 3 6 pCT/US~2/089l9 19 , ~`
. .

Delivery devices according to the present inYention were ~
prepared as follows. ~;
EVA 40 (EVA with 40~ vinyl acetate~ (2.7 9), glycerol monooleate (1.5 9; Myverol~ 1899K, Eastman Chemical Produc~s, having a glycerol monooleate content of 61% and a total monoes~ers content of 93%; "M-GMOn) and ehloroform (27.0 9) were added together in a vial. The vial was capped (Teflon~-lined) and rotated for 4-6 hours, ;~
until the EVA 40 was dissolved. The resulting homogeneous solutio~
10 was then poured onto a glass plate lined with a siliconized polyester ~-release liner film (silieonized PET). The chloroform was evaporated -~
off until the film was dry. Melatonin (0.35 g; Sigma Chemicals) was then dry blended into 1.98 9 of the EVA 40/M-GM0 dry film in a rubber mill until homogeneous. The resulting material, having a composition ~-15 of lS wt% melatonin, 30 wtX M-GM0 and 55 wt% EVA 40~ was melt pressed (PHI press) to about 8 mil (0.2 mm) thickness between two sheets of siliconized PET release liner at 60^C and 10,000 lbs. pressure. The resulting film was heat-laminated to an impermeable backing (Medpar~ ~-or Scotchpak~, for example!~ The drug matrix/impermeable backing ~
20 laminate was then laminated, on the side opposite the impermeable -;
back~ng, to an acrylic contact adhesive (2 mil; MSX 1010P, 3M) to provide a monolith with an in-line adhesive. Discs of 19 cm2 size each were punched or die-cut from the laminate to give devices having 55.6 mg of melatonin per device or 2.92 mg of melatonin per cm2. ~ :

The in vitro transdermal melatonin fluxes through the epidermis of nine human skin donors from devices of Example 1 were determined.
For each device tested, the drug-releasing adhesive surface was -~
30 placed against the stratum corneum side of a disc of human epidermis ~-which had been blotted dry just prior to use. The excess epidermis was wrapped around the device so that none of the device edge was exposed to the receptor solution. The device covered with epidermis was attached to the flat side of the Teflon holder of a release rate 35 rod by wrapping around a square nylon mesh and tied with metal WO 93/078~0 PCI/US92/08919 211603~ ~

string. The rods were reciprocated in a fixed volume of receptor ~:
solution (3% ethanol in distilled water). The entire receptor solution was changed at each sampling t~me. The temperature of the receptor solution in the water bath was maintained at 35-C.
The in vitro transdermal flux of the devices ranged from 0.5 to 20 ~g/cm2~hr (Ns27).

. EXAMPLE 3 The in vivo blood plasma levels of melatonin in two individuals o treated with a device according to Example 1 were determined.
Blood samples were drawn from a 39 year old healthy female over ~-a 24-hour period at two different times two weeks apart, and the concentration of melatonin in the plasma of each sample was ~ -~
determined. These formed the baseline endogenous melatonin 15 concentrations (the control) of the individual, as shown in FIG. 5. -~
One day a~ter ~he second (last) baseline sampling, one transdermal device according to Example 1, of 19 cm2 size and containing 64 mg of melatonin, was placed by the individu- o~, the lateral abdomen in the morning (8:00 a.m.) and was worn for 4 hours, during which period the 20 endogenous melatonin levels were very low, as determined in the control phase. After 4 hours (noon), the device was removed. Blood samples were drawn before the device was applied and then at intervals over 24 hours a~ter the device was applied. The results are shown in FIG. 6.
In the same manner as above, blood samples were drawn from a 63 year old healthy male over a 24-hour period at two different times one week apart, and the concentration of melatonin in the plasma of each sample was determined. These formed the baseline endogenous melatonin concentrations (the control) of the individual, as shown in 30 FIG. 7. Two days after the second (last) baseline sampling, one transdermal device according to Example 1, of 19 cm2 size and containing 64 mg of melatonin, was placed by the individual on the lateral aW omen in the m~rning (8:00 a.m.) and was worn for 4 hours, during which period the endogenous melatonin levels were very low.
35 After 4 hours (noon), the device was removed. Blood samples were ':

won~Jo7870 2~ a 3~ Pcr/usg~/089l9 21 ~

drawn before the dev;ce was applied and then at intervals over 24 -;
hours a~ter the device was applied. The results are shown in FIG. 8.
~he results are shown in FIGS. 5-8, which present the plasma -~
concentration of melatonin as a result of the exogenous detivery o~
5 melatonin from the transdermal device (FIGS. 6 and 8), in comparison w~th the endogenous control baseline concentrations ~FIGS. 5 and 7).
FIGS. 6 and 8 illustrate the increasing melatonin concentration as a result of delivery of melatonin from the transdermal device, the concentration peaking at about the po~nt where the device is removed o and followed by a decrease to normal endogenous levels (nTTS" ~
transdermal therapeutic system or device). They additionally show a ~`-~-second curve peaking at about 10:00 p.m. (22:00), which is consonant with the natural endogenous production of melatonin by each of the -two individuals.
Having thus generalty described the present invention and described certain specifio embodiments thereof including the embodiments that the applicants consider the best mode of practicing their invention, it will be readily apparent that various 20 modifications to the invention may be made by workers skilled in the ~
art without departing from the scope of this invention which is i limited only by the following claims. `

. ` ;~ ~

Claims (33)

WHAT IS CLAIMED IS:

1. A device for the systemic delivery of melatonin, at a therapeutically effective rate, by transdermal administration, which device comprises:
(a) a reservoir comprising a therapeutically effective amount of melatonin and a skin permeation-enhancing amount of a permeation enhancer;
(b) a backing impermeable to the melatonin on the skin-distal surface of the reservoir; and (c) means for maintaining the reservoir in melatonin- and permeation enhancer-transmitting relation with the skin.

2. A device according to claim 1 wherein the permeation enhancer is a monoglyceride or mixture of monoglycerides of fatty acids with a total monoesters content of at least 51%.

3. A device according to claim 2 wherein the permeation enhancer is glycerol monooleate or glycerol monolinoleate.

4. A device according to claim 1 wherein the melatonin is administered through the skin at a rate of at least 0.1 µg/hour for a predetermined period of time.

5. A device according to claim 4 wherein the predetermined period of time is about 1 to 6 hours.

6. A device according to claim 1 wherein the permeation enhancer is glycerol monooleate and the matrix comprises ethylene vinyl acetate copolymer having from about 9% to 60% vinyl acetate.

7. A device according to claim 6 wherein the means for maintaining the reservoir in relation with the skin comprises an in-line adhesive layer on the skin-proximal surface of the reservoir.

8. A device for the systemic delivery of melatonin, at a therapeutically effective rate, by transdermal administration, which device comprises:
(a) a first reservoir comprising a therapeutically effective amount of melatonin and a skin permeation-enhancing amount of a permeation enhancer;
(b) a second reservoir comprising an excess of the permeation enhancer and being substantially free of melatonin;
(c) a rate-controlling membrane between the first reservoir and the second reservoir;
(d) a backing impermeable to melatonin on the skin-distal surface of the second reservoir; and (e) means for maintaining the first and second reservoirs in melatonin- and permeation enhancer-transmitting relation with the skin.

9. A device according to claim 8 wherein the melatonin is administered through the skin at a rate of at least 0.1 µg/hour for a predetermined period of time.

10. A device according to claim 9 wherein the predetermined period of time is about 1 to 6 hours.

11. A device according to claim 8 wherein the means for maintaining the reservoirs in relation with the skin comprises an in-line adhesive layer on the skin-proximal surface of the first reservoir.

12. A device according to claim 8 wherein the first reservoir also is an adhesive layer which functions as the means for maintaining the reservoirs in relation with the skin.

13. A device according to claim 8 wherein the permeation enhancer is a monoglyceride or mixture of monoglycerides of fatty acids with a total monoesters content of at least 51%.

14. A device according to claim 13 wherein the permeation enhancer is glycerol monooleate or glycerol monolinoleate.

15. A method for the systemic delivery of melatonin by transdermal administration, which method comprises:
(a) administering melatonin at a therapeutically effective rate to an area of skin; and (b) simultaneously administering a permeation enhancer to the area of skin at a rate which is sufficient to substantially increase the permeability of the area to the melatonin.

16. A method according to claim 15 wherein the permeation enhancer is a monoglyceride or mixture of monoglycerides of fatty acids with a total monoesters content of at least 51%.

17. A method according to claim 16 wherein the permeation enhancer is glycerol monooleate or glycerol monolinoleate.

18. A method according to claim 15 wherein the melatonin is administered through the skin at a rate of at least 0.1 µg/hour for a predetermined period of time.

19. A method according to claim 18 wherein the predetermined period of time is about 1 to 6 hours.

20. A method for providing uninterrupted sleep to a person having fragmented sleep, the method comprising the step of placing a melatonin transdermal delivery device onto the skin of a person prior to the bedtime of the person, the melatonin transdermal delivery device comprising:
(a) a reservoir comprising melatonin in an amount sufficient to provide an hypnotic effect for a predetermined period of time and a permeation enhancer in a skin permeation-enhancing amount;

(b) an impermeable backing on the skin-distal surface of the reservoir; and (c) means for maintaining the reservoir in melatonin- and permeation enhancer-transmitting relation with the skin.

21. A method according to claim 20 wherein the permeation enhancer is a monoglyceride or mixture of monoglycerides of fatty acids with a total monoesters content of at least 51%.

22. A method according to claim 21 wherein the permeation enhancer is glycerol monooleate or glycerol monolinoleate.

23. A method according to claim 20 wherein the melatonin is administered through the skin at a rate of at least 0.1 µg/hour for the predetermined period of time.

24. A method according to claim 23 wherein the predetermined period of time is about 1 to 6 hours.

25. A method according to claim 20 wherein the permeation enhancer is glycerol monooleate and the matrix comprises ethylene vinyl acetate copolymer having from about 9% to 60% vinyl acetate.

26. A method according to claim 25 wherein the means for maintaining the reservoir in relation with the skin comprises an in-line adhesive layer on the skin-proximal surface of the reservoir.

27. A method for providing uninterrupted sleep to a person having fragmented sleep, the method comprising the step of placing a melatonin transdermal delivery device onto the skin of a person prior to the bedtime of the person, the melatonin transdermal delivery device comprising:
(a) a first reservoir comprising melatonin in an amount sufficient to provide an hypnotic effect for a predetermined period of time and a permeation enhancer in a skin permeation-enhancing amount;
(b) a second reservoir comprising an excess of the permeation enhancer and substantially free of melatonin;
(c) a rate-controlling membrane between the first reservoir and the second reservoir;
(d) an impermeable backing on the skin-distal surface of the second reservoir; and (c) means for maintaining the first and second reservoirs in melatonin- and permeation enhancer-transmitting relation with the skin.

28. A method according to claim 27 wherein the melatonin is administered through the skin at a rate of at least 0.1 µg/hour for a predetermined period of time.

29. A method according to claim 28 wherein the predetermined period of time is about 1 to 6 hours.

30. A method according to claim 27 wherein the means for maintaining the reservoirs in relation with the skin comprises an in-line adhesive layer on the skin-proximal surface of the first reservoir.

31. A method according to claim 27 wherein the first reservoir also is an adhesive layer which functions as the means for maintaining the reservoirs in relation with the skin.

32. A method according to claim 27 wherein the permeation enhancer is a monoglyceride or mixture of monoglycerides of fatty acids with a total monoesters content of at least 51%.

33. A device according to claim 32 wherein the permeation enhancer is glycerol monooleate or glycerol monolinoleate.