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WO2019038586A1 - Composition pharmaceutique de mélatonine - Google Patents

Composition pharmaceutique de mélatonine Download PDF

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Publication number
WO2019038586A1
WO2019038586A1 PCT/IB2018/000906 IB2018000906W WO2019038586A1 WO 2019038586 A1 WO2019038586 A1 WO 2019038586A1 IB 2018000906 W IB2018000906 W IB 2018000906W WO 2019038586 A1 WO2019038586 A1 WO 2019038586A1
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WO
WIPO (PCT)
Prior art keywords
melatonin
pharmaceutical composition
group
composition according
sodium
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.)
Ceased
Application number
PCT/IB2018/000906
Other languages
English (en)
Inventor
Vijay Patel
Sandip Mehta
Manish Kumar UMRETHIA
Jayanta Mandal
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.)
Liqmeds Ltd
FTF Pharma Pvt Ltd
Original Assignee
Liqmeds Ltd
FTF Pharma Pvt Ltd
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 Liqmeds Ltd, FTF Pharma Pvt Ltd filed Critical Liqmeds Ltd
Publication of WO2019038586A1 publication Critical patent/WO2019038586A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K9/08—Solutions
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof

Definitions

  • the present invention relates, in general, to the pharmaceutical field, and more precisely it relates to a pharmaceutical composition for the oral administration of Melatonin and to the process for the preparation thereof.
  • the present invention relates to the oral liquid composition comprising Melatonin.
  • Melatonin is a natural substance produced in humans by a gland, named pineal gland or epiphysis, placed at the base of the brain. This substance acts on the hypothalamus, a structure of the central nervous system that among other functions, also controls the sleep function and, just by means of substances like Melatonin, regulates the sleep-wake cycle.
  • the pharmaceutical forms proposed for these applications were those traditional forms already used for oral
  • US 20080254121 describes a solid orally administrable dosage form comprising: a first-layer comprising melatonin; a second-layer comprising melatonin, wherein the second- layer is disposed immediately adjacent the first-layer; and an inner-core comprising melatonin, wherein the inner-core is disposed immediately adjacent at least one of the group consisting of the first-layer and the second-layer.
  • US 20130122092 describes a three-phase melatonin-releasing tablet and a process for the preparation thereof.
  • US 20170165232 claims a process for the preparation of a tablet having an internal core and an external coating, both comprising melatonin at equal or different dosages.
  • EP 2949322 describes a pharmaceutical composition in the form of a bilayer tablet comprising melatonin.
  • EP 3127536 describes a method for the manufacturing of a solid formulation comprising melatonin as active pharmaceutical ingredient, said method comprises a melatonin dispersion step in one or more intra-granular excipients to form a melatonin blend, followed by a wet granulation step.
  • CN 1488346 describes double release tablets of melatonin and process for the preparation thereof.
  • CN 1628702 describes melatonin milk tablets preparation.
  • CN 101143135 describes an orally disintegrating tablet of melatonin.
  • CN 104248630 and CN 104306349 describes a melatonin containing osmotic pump tablets.
  • WO 2008/122104 describes a sleep aid composition comprising; a capsule containing a liquid and a plurality of beadlets suspended therein; said liquid comprising at least a first dosage of melatonin; and said plurality of beadlets comprising at least a second dosage of melatonin.
  • CN 101697968 describes melatonin soft capsule comprising melatonin, salad oil and water.
  • CN 101966167 describes a melatonin soft capsule and process for preparing thereof.
  • US 5498423 describes a pharmaceutical controlled-release formulation in dosage form which consists essentially of melatonin in combination with at least one pharmaceutical carrier, diluent or polymeric coating.
  • US 7858656 describes a controlled release tablet formulation of Melatonin.
  • EP 1272177 describes use of melatonin in the manufacture of a controlled release medicament, for the prevention or treatment of symptoms of hypertension.
  • WO 1995/003043 and WO 2008/148015 describes a sustained release melatonin formulation.
  • WO 2012/10341 1 describes a controlled release tablet formulation comprising Melatonin.
  • CN 104546777 describes a process for producing melatonin sustained release composition.
  • CN 1 195525 describes a melatonin sustained-release preparation of melatonin.
  • CN 101874783 describes a sustained release pellet containing melatonin.
  • CN 102018681 describes an extended release tablet composition of melatonin.
  • US 5362745 describes an oral pharmaceutical composition consisting of melatonin as the active principle in form of a micro-emulsion, L-a-phosphatidylcholine as an emulsifier and a solvent mixture consisting of ethanol, propylene glycol and water.
  • WO 2010/062153 describes an oral solution to treat burns to internal tissues and organs caused by corrosive substances characterized in that it comprises Melatonin, Tween 80, Polyethylene Glycol (400), Acesulfame potassium, Sucrose, Chocolate flavour essence, the essence mint flavour, Sodium benzoate and Purified water.
  • US 20160166543 describes a stable liquid formulation composition for oral administration comprising a therapeutic dose of first component diphenhydramine hydrochloride; a therapeutic dose of second component melatonin; and pharmaceutically acceptable excipients; wherein one of the excipients is hydroxypropylbetacyclodextrin.
  • US 201701 12810 describes a pharmaceutically acceptable composition comprising propylene glycol, polyethylene glycol and melatonin or a derivative, salt, pro-drug or solvate thereof.
  • WO 2012/156565 describes a stable and sterile pharmaceutical composition for the parenteral administration of melatonin in the form of an aqueous solution.
  • 2015/135997 describes a parenteral formulation comprising Melatonin, one or more phospholipids selected from the group consisting of a phosphatidylcholine and a lecithin, and, optionally, one or more stabilization agents selected from the group consisting of a tocopherol, deoxycholic acid, a pharmaceutically acceptable salt of deoxycholic acid, and a C12 to C20 saturated or unsaturated fatty acid and mixture of mannitol and trehalose.
  • WO 2016/058985 describes substantially water free composition consisting of liquid preparation of melatonin.
  • WO 2016/139635 describes a stable and sterile pharmaceutical composition for the parenteral administration of melatonin in the form of an aqueous solution, comprising melatonin and physiological saline solution and it is completely free of any excipients, co- solvents and/or diluents different from said physiological saline solution.
  • WO 2008/127609 describes a Melatonin tablet formulation for sublingual or buccal administration and process for the preparation thereof.
  • JP 2014237700 describes a solid dosage form for sublingual or buccal administration of melatonin.
  • US 20100256215 describes a thin film for the delivery of melatonin to a person's bloodstream via a mucosal membrane.
  • US 5939084 describes a stable, recrystallization-resistant dermatological/cosmetic composition which comprises a substantially ethanol-free aqueous phase, said aqueous phase comprising an active amount of solubilized melatonin or analog thereof and an amount of at least one glycol effective to dissolve said melatonin or analog thereof.
  • US 20080131496 describes a pharmaceutical composition enabling delivery to the skin after topical application of a therapeutically effective amount of melatonin.
  • EP 0820766 describes topical composition comprising melatonin or analogues thereof and a cosmetically or pharmaceutically acceptable support.
  • WO 2016/131784 describes a topical liquid composition comprising melatonin or an analog thereof or a pharmaceutically acceptable salt or solvate thereof; a buffer system and a first amino acid comprising at least one sulphur atom.
  • J P 10067648 describes topical composition containing melatonin or its analogue.
  • JP 2001058960 describes a transdermally applied melatonin characterized by blending an oleyl alcohol derivative.
  • US 6007834 describes a pharmaceutical composition for intranasal
  • melatonin and an additive selected from the group consisting of a cyclodextrin, glycerol, and admixtures thereof.
  • EP 0867181 describes a pharmaceutical composition for nasal administration comprising melatonin and an additive selected from glycerol, cyclodextrin, and mixtures thereof.
  • US 20040002536 describes an anesthetic composition comprising a pharmaceutically acceptable anesthetic carrier, and an anesthetic inducing effective amount of N-acetyl-5-methoxytryptamine (Melatonin), or a biologically active analogue thereof.
  • Melatonin N-acetyl-5-methoxytryptamine
  • WO 1999/047175 describes a pharmaceutical composition for the administration of melatonin comprising an inclusion complex of melatonin with polymeric materials.
  • US 20140308357 describes a powder for use as a medicament, wherein it comprises melatonin, at least one water soluble excipient and at least one water soluble surfactant.
  • WO 2014/044896 describes an orodispersible solid pharmaceutical composition comprising melatonin.
  • CN 1348758 describes a composition comprising melatonin and ⁇ -glucan.
  • Liquid preparations of Melatonin are available either in the form of topical administration or in the form of parenteral administration.
  • Other available Melatonin preparations include intranasal, buccal or sublingual. All these preparations have their own disadvantages and limitations, for example they are not suitable for all types of patient populations (e.g. pediatric patients). Therefore, there is an existing need for oral liquid pharmaceutical composition comprising Melatonin having improved stability and palatability. Further, the oral liquid preparations are more patient compliant as compared to oral solid dosage forms. Oral solid dosage forms may not be convenient for all types of patient populations (e.g. pediatric patients) to take because of swallowing problems. Therefore it is preferable to administer active ingredient in pharmaceutical liquid dosage form.
  • the principal object of the present invention is to provide oral liquid pharmaceutical preparation of Melatonin.
  • Another object of the present invention is to provide oral liquid pharmaceutical preparation of Melatonin without risk of over dosage of the drug.
  • a further object of the present invention is to provide oral liquid pharmaceutical preparation of Melatonin with sweetening agent and flavoring agent to mask the bitter taste of Melatonin and to provide pleasant taste.
  • a further object of the present invention is to provide process for the preparation of the oral liquid pharmaceutical preparation of Melatonin of the present invention.
  • a further object of the present invention is to provide use of the composition of the invention in the manufacture of a medicament.
  • a further object of the present invention is to provide composition of the invention for use as a medicament.
  • a further object of the present invention is to provide composition for use in the manufacture of a medicament for regulating circadian rhythm, regulation of the inflammatory response, treatment of systemic inflammatory response syndrome (SIRS), treatment the multiple organ dysfunction syndrome (MODS), the treatment of sepsis in neonates, treatment of sepsis in adults, the treatment of myocardial infarction, the treatment of mitochondrial damage, treatment of pulmonary edema, treatment failure kidney or liver, or treating oxidative stress situation generated during surgery, and particularly during abdominal surgery.
  • SIRS systemic inflammatory response syndrome
  • MODS multiple organ dysfunction syndrome
  • the present invention relates to a method for regulating the circadian rhythm, regulation of the inflammatory response, treatment of systemic inflammatory response syndrome (SIRS), the treatment of multiple organ dysfunction syndrome (MODS), the treatment of sepsis in neonates, treatment of myocardial infarction, the treatment of mitochondrial damage, treatment of pulmonary edema, treatment of kidney or liver failure, or treatment of the situation of oxidative stress caused by surgery.
  • SIRS systemic inflammatory response syndrome
  • MODS multiple organ dysfunction syndrome
  • the treatment of sepsis in neonates treatment of myocardial infarction
  • the treatment of mitochondrial damage treatment of mitochondrial damage
  • treatment of pulmonary edema treatment of kidney or liver failure
  • treatment of the situation of oxidative stress caused by surgery or treatment of the situation of oxidative stress caused by surgery.
  • the present invention provides a liquid pharmaceutical composition
  • a liquid pharmaceutical composition comprising Melatonin and one or more pharmaceutically acceptable excipients selected from the group comprising of vehicles, preservatives, buffering agents, sweetening agents, flavoring agents or combinations thereof with improved stability and palatability.
  • Melatonin chemically known as N-acetyl-5-methoxytryptamine having an empirical formula C 13H16N2O2 and a molecular weight of 232.3 gm/mol has a following structural formula:
  • Melatonin is a natural substance produced in humans by a gland, named pineal gland or epiphysis, placed at the base of the brain. This substance acts on the hypothalamus, a structure of the central nervous system that among other functions, also controls the sleep function and, just by means of substances like Melatonin, regulates the sleep-wake cycle.
  • the pharmaceutical forms proposed for these applications were those traditional forms already used for oral
  • Oral dosage forms include solid preparations (e.g. tablets, capsules, and powders etc.) and liquid preparations (e.g. solutions, suspensions etc.).
  • Solid dosage forms include sustained release, prolonged release and extended release dosage forms.
  • Oral liquid preparations are more patient compliant as compared to oral solid dosage forms.
  • Oral solid dosage forms may not be convenient for all types of patient populations (e.g. pediatric patients) to take because of swallowing problems. Therefore it is preferable to administer active ingredient in pharmaceutical liquid dosage form.
  • pharmaceutical agents are known to have strong bitterness which results into a bitter taste and a feeling of numbness in the mouth. Therefore oral solid dosage forms are not preferred for some types of patient population especially pediatric patient population.
  • the present invention provides a pharmaceutical composition comprising Melatonin and one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition comprises Melatonin and one or more pharmaceutically acceptable excipients selected from the group comprising of vehicles, preservatives, buffering agents, sweetening agents and flavouring agents or combination thereof. [00030] In one of the further embodiments, the pharmaceutical composition comprises Melatonin and one or more vehicles, one or more preservatives, one or more buffering agents, one or more sweetening agents and one or more flavouring agents or combination thereof.
  • the pharmaceutical composition comprises Melatonin, a vehicle, a preservative, a buffering agent, a sweetening agent and a flavouring agent or combination thereof.
  • the pharmaceutical composition is a liquid pharmaceutical composition.
  • the liquid pharmaceutical composition is suitable for oral administration.
  • the liquid pharmaceutical composition has pH in between 3.0 and 7.0.
  • the pharmaceutical composition is useful for the manufacture of a medicament.
  • the pharmaceutical composition is useful as a medicament.
  • Some embodiments provide a pharmaceutical composition in liquid solution form comprising an aqueous solvent; melatonin; and a buffering agent in sufficient quantity such that the pH is less than 5.
  • the buffering agent is selected from Acetic acid, Adipic acid, Ammonium carbonate, Ammonium hydroxide, Ammonium phosphate, Boric acid, Citric acid, Diethanolamine, Fumaric acid, Hydrochloric acid, Malic acid, Nitric acid, Propionic acid, Potassium acetate, Potassium bicarbonate, Potassium chloride, Potassium citrate, Potassium metaphosphate, Potassium phosphate, Sodium acetate, Sodium bicarbonate, Sodium borate, Sodium carbonate, Sodium chloride, Sodium citrate, Sodium glycolate, Sodium hydroxide, Sodium lactate, Sodium phosphate, Sodium proprionate, Succinic acid, Sulfuric acid, Tartaric acid, Triethylamine, Triethanolamine, Tromethamine, Trolamine and any combination thereof.
  • the pH is 3-5.
  • the aqueous solvent is selected from water.
  • the pharmaceutical composition is useful for the manufacture of a medicament for regulating circadian rhythm, regulation of the inflammatory response, treatment of systemic inflammatory response syndrome (SIRS), treatment the multiple organ dysfunction syndrome (MODS), the treatment of sepsis in neonates, treatment of sepsis in adults, the treatment of myocardial infarction, the treatment of mitochondrial damage, treatment of pulmonary edema, treatment failure kidney or liver, or treating oxidative stress situation generated during surgery, and particularly during abdominal surgery.
  • SIRS systemic inflammatory response syndrome
  • MODS multiple organ dysfunction syndrome
  • the present invention relates to a method for regulating the circadian rhythm, regulation of the inflammatory response, treatment of systemic inflammatory response syndrome (SIRS), the treatment of multiple organ dysfunction syndrome (MODS), the treatment of sepsis in neonates, treatment of myocardial infarction, the treatment of mitochondrial damage, treatment of pulmonary edema, treatment of kidney or liver failure, or treatment of the situation of oxidative stress caused by surgery.
  • SIRS systemic inflammatory response syndrome
  • MODS multiple organ dysfunction syndrome
  • Vehicles referred in the present invention are the liquid bases which carry drug and other excipients in dissolved or dispersed state and can be selected from either aqueous vehicles or oily vehicles.
  • aqueous vehicles are but not limited to purified water, hydro-alcoholic, polyhydric alcohols and buffers, while suitable examples of oily vehicles are but not limited to vegetable oils, mineral oils, organic oily bases or emulsified bases.
  • the preferred vehicle is purified water.
  • Preservatives referred in the present invention are the compounds which are included in pharmaceutical dosage form to prevent the growth of microorganisms during the product's manufacture and shelf life.
  • suitable preservatives are but not limited to benzyl alcohol, chloro-butanol, chloro-cresol, alkyl esters of paraben, phenol, phenyl ethanol, benzoic acid, potassium sorbate, sodium benzoate, chlorobutanol etc. and antimicrobial solvents like propylene glycol, chloroform etc.
  • the preferred preservative is sodium benzoate.
  • Buffering agents referred in the present invention are the compounds which provide stability and pH control to the pharmaceutical formulations.
  • suitable buffering agents are but not limited to sodium acetate, sodium citrate, ammonium sulfate, sodium phosphate, disodium hydrogen phosphate, potassium citrate, citric acid monohydrate, trisodium citrate dihydrate.
  • the preferred buffering agent is citric acid monohydrate.
  • Further buffering agents include but are not limited to acetic acid, adipic acid, ammonium carbonate, ammonium hydroxide, ammonium phosphate, boric acid, citric acid, diethanolamine, fumaric acid, hydrochloric acid, malic acid, nitric acid, propionic acid, potassium acetate, potassium bicarbonate, potassium chloride, potassium citrate, potassium metaphosphate, potassium phosphate, sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate, sodium chloride, sodium citrate, sodium glycolate, sodium hydroxide, sodium lactate, sodium phosphate, sodium proprionate, succinic acid, sulfuric acid, tartaric acid, triethylamine, triethanolamine, tromethamine, trolamine and the like or any combinations thereof.
  • Sweetening agents referred in the present invention are the compounds that impart sweetness and improve patient compliance through taste masking.
  • suitable sweetening agents are but not limited to sucralose, sucrose, liquid glucose, glycerol, sorbitol, maltitol, saccharin sodium and aspartame.
  • the preferred sweetening agent is sucralose.
  • Flavouring agents referred in the present invention are the compounds which are added to increase patient acceptance of the drug by masking the specific taste sensations.
  • suitable flavouring agent are but not limited to essential oils including peppermint oil, orange oil, and lemon oil etc. or can be selected from fruit flavour, e.g.
  • peppermint flavour strawberry flavour
  • tutti fruit flavour etc.
  • the preferred flavouring agent is strawberry flavour.
  • composition of the oral liquid formulation according to the present invention can be described in following general formula.
  • the present invention provides process for the preparation of the pharmaceutical composition comprising Melatonin and one or more pharmaceutically acceptable excipients selected from the group comprising of vehicles, preservatives, buffering agents, sweetening agents and flavouring agents or combination thereof as described herein above.
  • a general process for the preparation of the pharmaceutical composition according to the present invention is described below.
  • Example-1 A liquid oral pharmaceutical composition comprising Melatonin Table-2: Melatonin liquid composition
  • a liquid oral pharmaceutical composition comprising Melatonin as active ingredient and Sodium benzoate, Citric acid monohydrate, Sucralose, Strawberry flavour and Purified water was prepared following below mentioned process comprising steps of:
  • step (b) Add required quantity of Melatonin into the mixture obtained in step (a) and mix till it dissolves;
  • Example 2 Stability studies of the pharmaceutical composition prepared in Example 1
  • the oral liquid pharmaceutical composition prepared according to Example 1 exhibits unexpected stability profile when tested after three (3) months under the conditions 40 ⁇ 2°C/25% RH and 25 ⁇ 2°C/60% RH.
  • the liquid composition according to the present invention possess very less amount of impurities and highest degree of purity. The results of the stability tests conducted are summarized in the table below.
  • Example 3 a 0.1% melatonin solution
  • a liquid oral pharmaceutical composition comprising Melatonin as active ingredient and Sodium benzoate, Citric acid monohydrate, Sucralose, Strawberry flavour and Purified water was prepared following below mentioned process comprising steps of: [00059] Add required quantity of Purified water and adjust desirable pH using required quantity of Citric acid monohydrate;
  • the solutions disclosed herein are useful to treat a variety of conditions, diseases, disorders, or other ailments.
  • the solutions are meant to mimic their solid form counterparts, providing the same effectiveness in the same dose.
  • the method of treating the condition, disease, disorder or other ailment comprises administering the suspension to a patient in need of such treatment to provide a desired or therapeutically acceptable dose of the active pharmaceutical ingredient.
  • the methods disclosed are for the treatment of a disease or a condition that can be treated by the active pharmaceutical ingredient in the solution.
  • the method comprises administering to a patient, such as human, an effective dosage amount of a liquid
  • composition comprising the active pharmaceutical ingredient and one or more pharmaceutically acceptable excipients or additives as disclosed and described herein.
  • Effective dosage amount as used herein with respect to, for example liquid pharmaceutical compositions of the present invention shall mean that dosage that provides the specific pharmacological response for which the active pharmaceutical ingredient
  • liquid pharmaceutical compositions of the present invention are proposed to have unexpectedly dramatic dissolution profiles. Rapid dissolution of an administered active agent is preferable, as faster dissolution generally leads to greater bioavailability and faster onset of action. To improve the dissolution profile and bioavailability of the active it would be useful to increase dissolution of the active used so that it could attain a level close to 100% dissolution of the drug substance.
  • the liquid pharmaceutical compositions of the present invention comprising the active pharmaceutical ingredient or salt thereof or derivative thereof, exhibit improved or comparable pharmacokinetic profiles as compared to marketed or known compositions of the same active pharmaceutical ingredient or salt or derivative thereof.
  • the Cmax and/or AUC of the liquid pharmaceutical compositions of disclosed herein can be greater than or substantially equal to the Cmax and/or AUC for known or marketed compositions, e.g. solid formulations, administered at the same dose.
  • the Tmax of the liquid compositions of the present invention can be lower than or substantially equal to that obtained for a known or marketed compositions, administered at the same dose.
  • liquid compositions of the invention may result in m.l different absorption levels when administered under fed as compared to fasting conditions.
  • the liquid compositions exhibit in comparative pharmacokinetic testing with marketed or known formulations, administered at the same dose, a Tmax not greater than about 90%, not greater than about 80%, not greater than about 70%, not greater than about 60%, not greater than about 50%, not greater than about 30%, not greater than about 25%, not greater than about 20%, not greater than about 15%, not greater than about 10%, or not greater than about 5% of the Tmax exhibited by the marketed or known formulation.
  • the liquid compositions exhibit in comparative
  • a Cmax which is at least about 50%, at least about 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, at least about 1000%, at least about 1 100%, at least about 1200%, at least about 1300%, at least about 1400%, at least about 1500%, at least about 1600%, at least about 1700%, at least about 1800%, or at least about 1900% greater than the Cmax exhibited by the marketed or known formulation.
  • the liquid compositions of the present invention exhibit in comparative pharmacokinetic testing with marketed or known formulation, administered at the same dose, an AUC which is at least about 25%, at least about 50%, at least about 75%, at least about 100%, at least about 125%, at least about 150%, at least about 175%, at least about 200%, at least about 225%, at least about 250%, at least about 275%, at least about 300%, at least about 350%, at least about 400%, at least about 450%, at least about 500%, at least about 550%, at least about 600%, at least about 750%, at least about 700%, at least about 750%, at least about 800%, at least about 850%, at least about 900%, at least about 950%, at least about 1000%, at least about 1050%), at least about 1 100%, at least about 1150%, or at least about 1200% greater than the AUC exhibited by the marketed or known formulation.
  • the Tmax of the active pharmaceutical ingredient or salt thereof used for the preparation of the liquid composition according to the present invention when assayed in the plasma of the mammalian subject, is less than about 6 to about 8 hours. In other aspects of the invention, the Tmax of the active or salt thereof is less than about 6 hours, less than about 5 hours, less than about 4 hours, less than about 3 hours, less than about 2 hours, less than about 1 hour, or less than about 30 minutes after administration.
  • the liquid compositions exhibit improved or comparable bioavailability as compared to known or marketed compositions.
  • liquid pharmaceutical compositions of the present invention are suitable for use in the industry.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne la composition pharmaceutique comprenant de la mélatonine et un ou plusieurs excipients pharmaceutiquement acceptables. La présente invention concerne également le procédé pour la préparation de la composition pharmaceutique comprenant de la mélatonine.
PCT/IB2018/000906 2017-08-19 2018-08-18 Composition pharmaceutique de mélatonine Ceased WO2019038586A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020039262A1 (fr) * 2018-08-18 2020-02-27 Ftf Pharma Private Limited Solution d'agents pharmaceutiques pour forme posologique orale
ES2837877A1 (es) * 2019-12-31 2021-07-01 Laboratorios Vinas S A Composicion galenica, para uso oral, liquida, que comprende melatonina y una sal de zinc y metodo y uso correspondientes
CN114681425A (zh) * 2022-04-14 2022-07-01 江苏天美健大自然生物工程有限公司 一种褪黑素软胶囊及其制备方法
EP4186504A1 (fr) * 2021-11-25 2023-05-31 Alissa Healthcare Research Limited Solutions aqueuses pharmaceutiques orales comprenant de la mélatonine et leur utilisation
US12539300B2 (en) 2018-08-18 2026-02-03 Liqmeds Worldwide Limited Method of treating seizures and epilepsy using liquid pharmaceutical composition for oral dosage of vigabatrin

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