EP0969831A1 - Composition permettant l'administration nasale de melatonine - Google Patents

Composition permettant l'administration nasale de melatonine

Info

Publication number
EP0969831A1
EP0969831A1 EP98920488A EP98920488A EP0969831A1 EP 0969831 A1 EP0969831 A1 EP 0969831A1 EP 98920488 A EP98920488 A EP 98920488A EP 98920488 A EP98920488 A EP 98920488A EP 0969831 A1 EP0969831 A1 EP 0969831A1
Authority
EP
European Patent Office
Prior art keywords
melatonin
pharmaceutical composition
dose
pharmaceutical
administration
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP98920488A
Other languages
German (de)
English (en)
Inventor
Franciscus Wilhelmus Henricus Maria Merkus
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Priority to EP98920488A priority Critical patent/EP0969831A1/fr
Publication of EP0969831A1 publication Critical patent/EP0969831A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose

Definitions

  • This invention relates to a pharmaceutical composition for intranasal administration of melatonin.
  • the invention further relates to doses or dosage units for intranasal administration, and the use of the same for the preparation of an intranasal dosage form.
  • Melatonin N-acetyl-5-methoxytryptamine
  • melatonin induces sleep when administered to a patient.
  • the sleep-inducing effects of melatonin have advantages over conventional hypnotics, since not being a hypnotic drug itself, it only induces a state of sleepiness without having the adverse side-effects of conventional hypnotics.
  • Melatonin is usually administered orally but, as with most oral preparations, it takes over an hour after administration for the blood plasma concentration of the active agent (melatonin) to reach its peak.
  • Other routes of administration, in particular nasal administration have been considered.
  • melatonin compositions suitable for nasal administration have yet to be prepared.
  • a pharmaceutically acceptable melatonin composition capable of providing a fast onset time, has yet to be developed.
  • a pharmaceutical composition for intranasal administration comprising melatonin and a pharmaceutically acceptable excipient, characterised by being effective to cause the blood plasma melatonin concentration in a human adult, receiving an amount of melatonin in the range of 50-1000 ⁇ g and in a single or simultaneous intranasal administration of said composition, to reach at least X pg/ml within 30 minutes of said administration, wherein X is equal to 5 times the amount of melatonin, expressed in ⁇ g, in said single or simultaneous administration.
  • X is preferably equal to 10, 15, 20 or 25 times the quantity of melatonin, expressed in ⁇ g, in said single or simultaneous administration and the amount of melatonin in said administration can be in the range of 100-800 or 200-400 mg.
  • a composition in accordance with the invention is effective to cause the blood plasma melatonin concentration in a human adult, receiving 200 ⁇ g of melatonin in a single or simultaneous intranasal administration of said composition, to reach at least lOOOpg/ml and, preferably, at least 2000, 3000, 4000, or 5000pg/ml, within 30 minutes of administration.
  • compositions in accordance with this aspect of the invention can also comprise a saccharide, a polysaccharide or a triol.
  • compositions in accordance with the present invention when intranasally administered, are effective to cause a peak blood plasma melatonin concentration, or t m consult, within 30 minutes of administration and, preferably, within 15 or 10 minutes of administration.
  • compositions in accordance with this aspect of the invention comprise less than 5-1% by volume of ethanol and less than 20-5% by weight of propylene glycol.
  • blood plasma melatonin concentration can be a mean value measured in a study of the type described in Example 4 below. Such studies or trials are well known to those skilled in the art.
  • single or simultaneous intranasal administration encompasses both the administration of a single dose or dose form, such as a single insufflation of a powder, or a single application of a spray, and the contemporaneous administration of a plurality of such doses or dose forms, (for example, the administration of two squirts of a spray or powder insufflations, one in each nostril).
  • glycerol and cyclodextrin when employed in nasal compositions containing melatonin, do not exhibit the unwanted toxic and adverse effects previously noted with the use of (poly)alcohols. It has further been found that cyclodextrin accelerates the absorption of melatonin in the nasal mucosa.
  • the present invention provides a pharmaceutical composition for intranasal administration, comprising melatonin and an additive, wherein the additive comprises cyclodextrin or glycerol.
  • a pharmaceutical composition for intranasal administration comprising melatonin and an additive, wherein the additive comprises cyclodextrin or glycerol.
  • Such pharmaceutical compositions can be in accordance with the first aspect of the invention and can be in the form of an aqueous or a powdered composition.
  • the additive can be a cyclodextrin, optionally in admixture with glycerol.
  • the additive is preferably a cyclodextrin.
  • the preferred cyclodextrin is ⁇ -cyclodextrin.
  • Such compositions are pharmaceutically acceptable because they do not cause the serious local irritation, pain and toxic side effects caused by the (poly)alcohols used in previously proposed compositions.
  • Nasal compositions in accordance with the invention can be administered as a nasal spray, drop, solution, suspension, gel, ointment, cream, or powder.
  • the composition may also be administered using a nasal tampon or a nasal sponge.
  • the composition is preferably administered in the form of an aqueous composition or a dry powder.
  • the aqueous composition is preferably an aqueous solution, but can be a suspension, or a gel.
  • suitable compositions When taken as an aqueous composition suitable compositions can be obtained with or without glycerol as an additive.
  • Glycerol allows aqueous compositions containing relatively high amounts of melatonin, does not exert toxicity towards the epithelial membrane, and does not lead to irritation of the nasal mucosa.
  • An additional advantage of the use of glycerol is the preservative properties thereof, leading to stable solutions.
  • the composition When taken as a powder, the composition preferably contains cyclodextrin and more preferably a melatonin-cyclodextrin complex to obtain optimum onset times.
  • cyclodextrin refers to cyclodextrins such as ⁇ -cyclodextrin, ⁇ - cyclodextrin, ⁇ -cyclodextrin, and derivatives thereof, such as methylated or alkylated cyclodextrins.
  • examples are methylated 3-cyclodextrin, hydroxypropyl- and hydroxyethyl-cyclodextrin, (di)glucosyl- or (di)maltosyl-cyclodextrins, carboxymethyl- or sulfoalkylether cyclodextrins, such as sulfobutylether-0-cyclodextrin.
  • the preferred cyclodextrin is methylated 0-cyclodextrin, or more preferred 0-cyclodextrin.
  • the ratio of glycerolxyclodextrin may vary between 1:5 and 500:1 by weight, and preferably between 1:1 and 50:1 by weight.
  • compositions in accordance with the present invention can be formulated to provide a single melatonin dose of between lO ⁇ g and lmg and, preferably, of between 0.8, 0.6, 0.5 or 0.4mg and 0.2, 0.15, 0.1 or 0.05mg.
  • compositions in accordance with the invention will still provide a sufficiently high peak melatonin blood plasma concentration (t ⁇ sufficiently soon after administration to be effective in the treatment of human disease, particularly insomnia, or in causing drowsiness or sleep in humans.
  • the present invention allows effective melatonin blood plasma concentrations to be achieved even when using extremely low melatonin doses.
  • compositions in accordance with the invention comprise aqueous compositions of 0.1 to 10 mg/ml of melatonin, and one or more of 1 to 250 mg/ml of cyclodextrin and 5 to 50% by volume of glycerol, or powdered compositions of 0.5 to 50% by weight of melatonin, and 2.5 to 90% by weight of a cyclodextrin.
  • a nasal powder can comprise daily doses or dosage units of 0.01 to 1 mg of melatonin, and preferably of about 0.1 to 0.8 mg of melatonin, for sleep induction in man.
  • the present invention provides a pharmaceutical dose or dose form comprising sufficient of a pharmaceutical composition in accordance with the first or second aspect of the invention to contain up to lmg, 0.8mg, 0.6mg, 0.5mg or 0.4mg of melatonin and, preferably, at least O.Olmg, 0.05mg, O.lmg, 0.15mg or 0.2mg of melatonin.
  • Said pharmaceutical dose can be in any of the aforementioned forms, including a measured quantity of a liquid for application as a spray or in drops, a spray or drop of liquid, or a powder.
  • a pharmaceutical dose or dose unit in accordance with the invention preferably contains an additive selected from glycerol, cyclodextrin, and mixtures thereof, and will give effective sleep-induction in man.
  • the present invention provides a pharmaceutical product, comprising apparatus for intranasally administering a pharmaceutical dose or dose form in accordance with the third aspect of the invention, and a pharmaceutical composition in accordance with the first or second aspect of the invention.
  • the apparatus can comprise a reservoir and means for expelling the pharmaceutical dose in the form of a spray, wherein a quantity of the pharmaceutical composition is contained within the reservoir.
  • the apparatus comprises a pump spray device in which the means for expelling a dose comprises a metering pump.
  • the apparatus comprises a pressurized spray device, in which the means for expelling a dose comprises a metering valve and the pharmaceutical composition further comprises a conventional propellant.
  • Suitable propellants include one or mixture of chlorofluorocarbons, such as dichlorodifluoromethane, and the more recent and preferred hydrofluorocarbons, such as 1,1,1,2-tetrafluoroethane (HFC- 134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFC-227).
  • Suitable pressurized spray devices are well known in the art and include those disclosed in, inter alia, WO92/11190, US-A-4819834, US-A-4407481 and WO97/09034, when adapted for producing a nasal spray, rather than an aerosol for inhalation, or a sublingual spray.
  • Suitable nasal pump spray devices include the VP50, VP70 and VP100 models available from Valois S.A. in Marly Le Roi, France and the 50, 70 and lOO ⁇ l nasal pump sprays available from Pfeiffer GmbH in Radolfzell, Germany, although other models and sizes can be employed.
  • a pharmaceutical dose or dose unit in accordance with the invention can be present within the metering chamber of the metering pump or valve.
  • compositions, doses or products in accordance with the present invention are useful in the treatment of human diseases known to be responsive to melatonin, including insomnia, and for inducing drowsiness or sleep in human subjects. They also provide a fast onset time and are suitable for intranasal use.
  • melatonin including insomnia
  • the capacity of compositions in accordance with the present invention for providing high blood plasma melatonin concentrations very rapidly after administration, on the basis of significantly reduced doses of melatonin leads to their enhanced efficacy and reduces the likelihood of any unwanted side-effects being caused.
  • melatonin for the preparation of a pharmaceutical composition, dose or product in accordance with any previously described aspect of the invention, for treating insomnia, or inducing sleep or drowsiness.
  • Use of a pharmaceutical composition, dose or product in accordance with any previous aspect of the invention, for the preparation of a medicament for treating insomnia, or inducing sleep or drowsiness, is also encompassed by the present invention.
  • the invention also comprises methods for treating disease, including insomnia, and for inducing sleep in humans by intranasally administering a pharmaceutical composition in accordance with the first or second aspect of the invention or a pharmaceutical dose in accordance with the third aspect of the invention.
  • the preferred unit dose is 0.01 to 1 mg of melatonin, and more preferably is 0.1 to 0.8 mg of melatonin.
  • auxiliaries and liquids such as those described in the standard reference, Gennaro et al., Remington's Pharmaceutical
  • compositions of the present invention can be included in compositions of the present invention.
  • Such compositions can be processed into vials or containers, for instance, to provide a spray as aforesaid.
  • any pharmaceutically acceptable additives or excipients which do not interfere with the function of the active compound can be used.
  • nasal abso ⁇ tion enhancers which are known in the art, may be added.
  • viscosity enhancers may be added, for example natural gums, cellulose derivatives such as hydroxypropylmethyl cellulose or methyl cellulose, acrylic polymers (carbopol), and vinyl polymers (polyvinylpyrrolidone).
  • Other conventional pharmaceutically acceptable excipients may also be added, such as preservatives, surfactants, colorants, co-solvents, adhesives, anti-oxidants, buffers, and agents to adjust the pH and osmolarity.
  • Nasal powder compositions can be made by mixing the active ingredients and the excipients, both possessing the desired particle size.
  • Other methods to make a suitable powder formulation are the preparation of a solution of active ingredients and excipients, followed by precipitation, filtration, and pulverization, or followed by removal of the solvent by freeze-drying, followed by pulverization of the powder to the desired particle size.
  • the final step can be sieving to obtain particles with a size of less than 100 ⁇ m in diameter, preferably between 50 and 100 ⁇ m in diameter.
  • Powders can be administered using a nasal insufflator, a jet-spray, or any other conventional device known in the art.
  • a solution was prepared from the following ingredients: melatonin 50 mg
  • the solution was filtered, stored at 5°C for 24 h, and filtered again.
  • the solution was then packaged into vials or pump spray devices, each containing 10 ml of the solution and arranged to provide 100 doses of 0.2 mg of melatonin.
  • a solution was prepared containing 200 mg of melatonin, 1.2 g of a complex of 200 mg of melatonin and 1 g of ⁇ -cyclodextrin, 5 g of sorbitol, 5 10 ml of glycerol, and 10 mg of benzalkonium chloride in sufficient water to make the total volume up to 100 ml.
  • the solution was filtered, stored at 5°C for 24 h, and filtered again.
  • This solution can be packaged into vials or containers as discussed in Example 1 and, for instance, a container filled with 10 ml of the solution will contain 100 doses of 0.4 mg of melatonin.
  • Example 1 administered intranasally to one nostril
  • Example 1 each administered intranasally to a separate nostril
  • compositions in accordance with the present invention are su ⁇ risingly effective and useful in treating insomnia, or causing drowsiness or sleep, when compared to previously known oral compositions.
  • the high peak levels provide an enhanced effect and the rapid onset means that compositions in accordance with the present invention can be taken immediately before their effect is required, rather than 1-2 hours beforehand.
  • the total dose required to provide a useful effect is much lower than previously required. Accordingly, compositions in accordance with the present invention are not only more effective than previously proposed oral compositions, but they can achieve their effect at lower dose levels than those previously proposed.
  • Plasma melatonin concentrations (mean + SD).
  • N number of volunteers in the survey.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nanotechnology (AREA)
  • Biophysics (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Medical Informatics (AREA)
  • Molecular Biology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Otolaryngology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition pharmaceutique destinée à être administrée de manière intranasale. Ladite composition contient de la mélatonine et un excipient pharmaceutiquement acceptable. Elle peut entraîner l'augmentation de la concentration de la mélatonine dans le plasma sanguin du corps d'un adulte recevant, au cours d'une administration intranasale unique ou simultanée de ladite composition, une quantité de mélatonine située entre 50 et 1000 νg. Cette augmentation peut atteindre au moins X pg/ml et ce, dans les trente minutes suivant ladite administration, X étant cinq fois supérieur à la teneur en mélatonine, exprimée en νg, de ladite administration unique ou simultanée.
EP98920488A 1997-03-26 1998-03-24 Composition permettant l'administration nasale de melatonine Withdrawn EP0969831A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP98920488A EP0969831A1 (fr) 1997-03-26 1998-03-24 Composition permettant l'administration nasale de melatonine

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP97200920 1997-03-26
EP97200920A EP0867181A1 (fr) 1997-03-26 1997-03-26 Composition nasale de mélatonine
PCT/EP1998/001783 WO1998042333A1 (fr) 1997-03-26 1998-03-24 Composition permettant l'administration nasale de melatonine
EP98920488A EP0969831A1 (fr) 1997-03-26 1998-03-24 Composition permettant l'administration nasale de melatonine

Publications (1)

Publication Number Publication Date
EP0969831A1 true EP0969831A1 (fr) 2000-01-12

Family

ID=26070305

Family Applications (2)

Application Number Title Priority Date Filing Date
EP97200920A Withdrawn EP0867181A1 (fr) 1997-03-26 1997-03-26 Composition nasale de mélatonine
EP98920488A Withdrawn EP0969831A1 (fr) 1997-03-26 1998-03-24 Composition permettant l'administration nasale de melatonine

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP97200920A Withdrawn EP0867181A1 (fr) 1997-03-26 1997-03-26 Composition nasale de mélatonine

Country Status (2)

Country Link
EP (2) EP0867181A1 (fr)
WO (1) WO1998042333A1 (fr)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1298731B1 (it) * 1998-03-13 2000-02-02 Recordati Chem Pharm Composizioni farmaceutiche contenenti complessi di inclusione con melatonina
US6638966B2 (en) 2000-09-19 2003-10-28 University Of Iowa Research Foundation Use of melatonin analogues for induction of general anesthesia
US6552064B2 (en) * 2000-09-19 2003-04-22 University Of Iowa Research Foundation Use of melatonin for induction of general anesthesia
KR100849916B1 (ko) 2002-10-30 2008-08-04 아에스아테 아게 어플라이드 사이언스 앤드 테크놀로지 멜라토닌 일일 투여 유닛
EP2285365A1 (fr) * 2007-08-03 2011-02-23 Tullin, Søren Utilisation d'une composition contenant au moins un bêta-bloquant pour le traitement de troubles du sommeil
EP2570126B1 (fr) 2011-09-16 2014-03-26 Darius Rassoulian Utilisation de la mélatonine pour le traitment de l'intoxication ethylique aigue
WO2019038586A1 (fr) 2017-08-19 2019-02-28 Ftf Pharma Private Limited Composition pharmaceutique de mélatonine
CA3197420A1 (fr) * 2020-11-05 2022-05-12 Bo Martinsen Formulation topique comprenant des acides gras omega-3, de la melatonine et de la vitamine d
WO2023220273A1 (fr) * 2022-05-11 2023-11-16 Ambo Innovations Llc Formulation topique comprenant des acides gras oméga-3, de la mélatonine et de la vitamine d

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5557563A (en) * 1978-10-21 1980-04-28 Hoechst Ag Melatonine nasal application composition
US5449683A (en) * 1992-10-01 1995-09-12 Massachussetts Institute Of Technology Methods of inducing sleep using melatonin
US5688520A (en) * 1995-03-29 1997-11-18 Minnesota Mining And Manufacturing Company Transmucosal delivery of melatonin for prevention of migraine
US5891465A (en) * 1996-05-14 1999-04-06 Biozone Laboratories, Inc. Delivery of biologically active material in a liposomal formulation for administration into the mouth

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9842333A1 *

Also Published As

Publication number Publication date
EP0867181A1 (fr) 1998-09-30
WO1998042333A1 (fr) 1998-10-01

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