WO2021038601A1 - Compositions pharmaceutiques liquides de mélatonine pour administration orale et parentérale - Google Patents

Compositions pharmaceutiques liquides de mélatonine pour administration orale et parentérale Download PDF

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WO2021038601A1
WO2021038601A1 PCT/IN2020/050759 IN2020050759W WO2021038601A1 WO 2021038601 A1 WO2021038601 A1 WO 2021038601A1 IN 2020050759 W IN2020050759 W IN 2020050759W WO 2021038601 A1 WO2021038601 A1 WO 2021038601A1
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melatonin
solution
composition
accordance
aqueous composition
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PCT/IN2020/050759
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English (en)
Inventor
Vijayendrakumar Virendrakumarji Redasani
Ritesh Anil Chavan
Poonam Sanjay BHATJIRE
Shweta V REDASANI
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Vijayendrakumar Virendrakumarji Redasani
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Priority to EP20859314.5A priority Critical patent/EP4021411A4/fr
Priority to AU2020339867A priority patent/AU2020339867A1/en
Publication of WO2021038601A1 publication Critical patent/WO2021038601A1/fr

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    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to a liquid compositions for the oral and parenteral administration of melatonin in the form of aqueous solutions comprising melatonin and at least one or two ingredients for enhancing properties of the composition wherein the ingredient(s) belong to the group consisting of solubilizers, polymeric solubilizers, crystal inhibitors, stabilizers, anti-oxidants, chelating agent and complexing agent and combinations thereof and the properties enhanced are at least solubility and stability.
  • the compositions are pharmaceutical compositions.
  • the compositions are nutraceutical compositions.
  • Melatonin is a hormone that regulates the sleep-wake cycle. It is primarily released by the pineal gland. Its chemical name is N-acetyl-5-methoxytriptamine. As a supplement, it is often used for the short-term treatment of trouble sleeping such as from jet lag or shiftwork.
  • the pharmaceutical forms proposed for these applications were those traditional forms already used for oral administration, such as capsules and tablets, wherein melatonin was administered alone or in association with several other pharmaceutically active ingredients and with the typical excipients of these pharmaceutical forms. Many other therapeutic applications of melatonin have been proposed, for instance in the treatment of Parkinson's disease, depression, osteoporosis, migraine, and even in the treatment of tumour forms.
  • Melatonin is characterised by low solubility in water (Shida C, Journal of Pineal Research, 16:198-201, 1994) and, when administered orally to humans, it exhibits a low bioavailability (about 30%) and high variability (10 to 56%) in the same subject, due both to liver metabolism reactions and absorption variability dependent on the different administration conditions and characteristics of the subject treated (Wei-Li D., New England Journal of Medicine, 336: 1028-1029, 1997).
  • melatonin The oral bioavailability of melatonin is low and very variable. Furthermore, melatonin is poorly soluble in water and degrades quickly.
  • the concentration of melatonin which circulates bound to albumin, varies in the range 10-300 pg/ml. Its half-life is short (30-60 minutes), due to the 90% clearance following its first passage through the liver. Approximately 75% of the melatonin metabolised by the liver cells is converted into 6-hydroxymelatonin, then conjugated with sulphate (70%) and, to a lesser extent, with glucuronic acid (6%). Bioavailability is low and equal to approximately 15%. Melatonin appears to be rapidly absorbed if administered as oral solutions, and the peak blood concentration is the highest of those reported for similar doses in healthy individuals. After oral administration, its peak blood concentration (Cmax) is influenced by the solubility of the melatonin in the formulation, bioavailability alterations and clearance.
  • WO 2012/156565 describes the various uses of melatonin such as regulation of the 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, the 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
  • US20180028498 describes pharmaceutical composition for the parenteral administration of melatonin in the form of an aqueous solution, comprising melatonin and physiological saline solution, said pharmaceutical composition having a melatonin concentration of between 0.2 and 0.4 mg/ml and being completely free of any excipients, co-solvents and/or diluents different from said physiological saline solution.
  • This pharmaceutical composition is used in the treatment of hypoxic-ischemic encephalopathy in neonatal patients.
  • WO2012156565 describes injectable composition
  • injectable composition comprising water, propylene glycol and melatonin, a derivative, a salt, a pro-drug or a solvate of same, which contains no other solvent, co-solvent or dispersing agent.
  • propylene glycol significantly enhances solubilization of as high as 50 mg/ml melatonin.
  • WO2013068565 describes preparation for injection in the form of a solution obtained by dissolving a powder to be reconstituted comprising melatonin, at least one soluble excipient and at least one surfactant, wherein the powder is prepared by spray drying wherein said powder has 90 % particles below 100 m.
  • US10342779 describes a concentrated melatonin solution, wherein melatonin is present in a quantity of 10% or higher in a substantially water-free carrier mixture of ethanol and a polyethoxylated derivative.
  • This patent also highlights the stability problems (such as crystallization of the solution) associated with the formulations of WO 2012156565 and WO2013068565.
  • US20170112810 describes a pharmaceutically acceptable composition comprising propylene glycol, polyethylene glycol and melatonin or a derivative, salt, prodrug, or solvate thereof.
  • US10307398 describes a resuscitation composition
  • a resuscitation composition comprising about 40 mM to 45 mM melatonin, about 3.8 M to about 4.2 M beta-hydroxybutyrate (BHB) or a pharmaceutically acceptable salt thereof in a solution of about 8% to about 12% hydroxypropyl-beta-cyclodextrin (HPbCD), about 4% to about 6% polyvinylpyrrolidone (PVP) and about 4% to about 6% polyethylene glycol (PEG).
  • BHB beta-hydroxybutyrate
  • HPbCD hydroxypropyl-beta-cyclodextrin
  • PVP polyvinylpyrrolidone
  • PEG polyethylene glycol
  • WO2018167162 describes a pharmaceutical formulation for use by parenteral administration for the treatment of brain injuries caused by birth asphyxia in a neonate comprising 2.5 or 5.0 mg/ml melatonin, 25 or 50 mg/ml sulfobutylether- cyclodextrin, 0.2 mg/ml phosphate buffer, optionally 4.5 mg/ml sodium chloride, and water for injection.
  • US9468626 describes pharmaceutical formulations comprising nanoparticles of melatonin are useful for the treatment of neonatal brain injury.
  • WO20 10062153 describes a pharmaceutical composition and the method of manufacture thereof, wherein said composition serves to treat internal tissue and organ burns caused by corrosive substances, comprising pharmaceutically acceptable melatonin, polyethylene glycol, vehicles and excipients in the preparations.
  • W09947175 discloses pharmaceutical compositions containing inclusion complexes of melatonin in a polymeric material, in particular in b-cyclodextrin. Complex techniques such as spray-drying are required to prepare inclusion complexes.
  • WO2013068565 provides a powder composition of melatonin for reconstitution before use for preparations for injection containing melatonin.
  • the solubility and stability issues of melatonin are discussed in the prior arts. There is a continuous need to find out newer compositions of melatonin which are both stable and soluble.
  • the present invention provides liquid pharmaceutical compositions for the oral and parenteral administration of melatonin in the form of aqueous solutions wherein solubility and stability of melatonin are greatly enhanced.
  • the first object of the invention is to provide compositions of melatonin for the oral or parenteral administration in the form of liquids and solutions wherein melatonin can be in the form of melatonin or in a form of a derivative, a salt, a solvate, a prodrug or an inclusion complex also collectively termed as melatonin in any acceptable form and at least one or two ingredients enhancing properties of the composition and belonging to a group consisting of solubilizers, polymeric solubilizers, crystal inhibitors, stabilizers, anti-oxidant, solubilizer which is also an anti-oxidant, chelating agent and complexing agent and combinations thereof.
  • the compositions are pharmaceutical or nutraceutical compositions.
  • the second object of the invention is to provide compositions of melatonin for the oral or parenteral administration in the form of liquids and solutions wherein melatonin can be in the form of melatonin or in a form of a derivative, a salt, a solvate, a prodrug or an inclusion complex also collectively termed as melatonin in any acceptable form and at least one ingredient enhancing properties of the composition and belonging to a group consisting of solubilizers, polymeric solubilizers, crystal inhibitors, stabilizers, anti-oxidants, solubilizer which is also an anti-oxidant, chelating agent and complexing agent and combinations thereof wherein melatonin and the said ingredient are in a ratio of 10:1 to 1:10 and both melatonin and the said ingredient are present in amounts of 0.01 to 10 % and preferably 0.01 to 5 % and more preferably 0.05 to 5 % and most preferably 0.05 to 2 % of the composition when % is expressed as g/100m
  • compositions are pharmaceutical or nutraceutical compositions.
  • the third object of the invention is to provide process of preparing compositions of melatonin for the oral or parenteral administration in the form of liquids and solutions wherein melatonin can be in the form of melatonin or in a form of a derivative, a salt, a solvate, a prodrug or an inclusion complex also collectively termed as melatonin in any acceptable form and at least one but preferably two ingredients belonging to a group consisting of solubilizers, polymeric solubilizers, crystal inhibitors, stabilizers, anti-oxidants, solubilizer which is also an anti-oxidant and combinations thereof.
  • the compositions are pharmaceutical or nutraceutical compositions.
  • the compositions are free of cosolvent and free of preservative.
  • compositions are free of conventional surfactants.
  • the fourth object of the invention is to provide use of the pharmaceutical composition of melatonin in the manufacture of a medicament for various treatments wherein the composition is for an oral or a parenteral application in the form of liquid or solutions comprising A) at least two ingredients for enhancing properties of the pharmaceutical composition and belonging to a group consisting of solubilizers, polymeric solubilizers, crystal inhibitors, stabilizers, anti-oxidants, solubilizer which is also an anti-oxidant chelating agent and complexing agent and combinations thereof; or B) at least one ingredient wherein melatonin and the said ingredient are in a ratio of 10:1 to 1:10 and both melatonin and the said ingredient are present in amounts of 0.01 to 10 % and preferably 0.01 to 5 % and more preferably 0.05 to 5 % and most preferably 0.05 to 2 % of the composition when % is expressed as g/100ml.
  • the compositions are pharmaceutical or nutraceutical compositions..
  • the invention provides a pharmaceutical composition of melatonin for the oral or parenteral administration in the form of liquids and solutions wherein melatonin can be in the form of melatonin or in a form of a derivative, a salt, a solvate, a prodrug or an inclusion complex and at least one but preferably two ingredients enhancing properties of the composition and belonging to a group consisting of solubilizers, polymeric solubilizers, crystal inhibitors, stabilizers, anti-oxidants, solubilizer which is also an anti-oxidant chelating agent and complexing agent and combinations thereof.
  • the second aspect provides a pharmaceutical composition of melatonin for the oral or parenteral administration in the form of liquids and solutions wherein melatonin can be in the form of melatonin or in a form of a derivative, a salt, a solvate, a prodrug or an inclusion complex (melatonin in any acceptable form) and at least one ingredient enhancing properties of the composition and belonging to a group consisting of solubilizers, polymeric solubilizers, crystal inhibitors, stabilizers, anti oxidants, solubilizer which is also an anti-oxidant, chelating agent and complexing agent and combinations thereof wherein melatonin and the said ingredient are in a ratio of 10:1 to 1:10 and both melatonin and the said ingredient are present in amounts of 0.01 to 10 % and preferably 0.01 to 5 % and more preferably 0.05 to 5 % and most preferably 0.05 to 2 % of the composition when % is expressed as g/100ml..
  • the compositions are pharmaceutical or nutraceutical compositions.
  • the invention provides process of preparing a pharmaceutical composition of melatonin for the oral or parenteral administration in the form of liquids and solutions wherein melatonin can be in the form of melatonin or in a form of a derivative, a salt, a solvate, a prodrug or an inclusion complex and at least one but preferably two ingredients belonging to a group consisting of solubilizers, polymeric solubilizers, crystal inhibitors, stabilizers, anti oxidants, solubilizer which is also an anti-oxidant, chelating agents and combinations thereof and also process of preparing a pharmaceutical composition of melatonin for the oral or parenteral administration in the form of liquids and solutions wherein melatonin can be in the form of melatonin or in a form of a derivative, a salt, a solvate, a prodrug or an inclusion complex and at least one ingredient enhancing properties of the
  • the invention provides use of the pharmaceutical composition of melatonin in the manufacture of a medicament for various treatments wherein the composition comprises
  • compositions are pharmaceutical or nutraceutical compositions.
  • Figure 1 presents Effect on Locomotor activity after administering single dose.
  • Figure 2 presents Decrease or depression in locomotor activity after multiple dosing of melatonin solutions intraperitoneally
  • Melatonin compositions are used for regulating the 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, the 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 provides various novel compositions of melatonin for oral or parenteral administration in the form of liquids and solutions.
  • the compositions are pharmaceutical or nutraceutical compositions.
  • the melatonin used for preparing the compositions of the invention may be for instance synthetic melatonin in powder of injectable pharmaceutical grade, or wherein melatonin can be in the form of a derivative, a salt, a solvate, a prodrug or an inclusion complex also collectively termed as melatonin in any acceptable form.
  • composition of the invention includes melatonin or its derivative, a salt, a solvate or a prodrug of melatonin or an inclusion complex of melatonin.
  • pharmaceutically acceptable salts are synthesized from melatonin by conventional chemical methods, generally, by reacting with an appropriate acid in water or in an organic solvent or a mixture of the two.
  • nonaqueous media like ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
  • salts of acid addition salts include mineral acid addition such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, and salts of organic acid addition such as, for example, acetate, maleate fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p- toluenesulfonate.
  • the melatonin derivative is defined according to formula (I), as
  • Ri and R3 are independently selected from the group consisting of linear or branched alkyl C1-C4;
  • R 2 is selected from the group consisting of hydrogen, linear or branched C 1 -C 4 alkyl,
  • Ra is a linear or branched C1-C4 alkyl group
  • n is an integer selected from the group consisting of 1, 2, 3 and 4.
  • prodrug as used in this application is defined herein to mean a chemical compound which has undergone a chemical derivation such as a substitution or addition of a further chemical group to change (for pharmaceutical use) any of physicochemical, such as solubility or bioavailability of, for example ester derivatives, ether or amide of an active compound provide the active compound itself upon administration to a subject properties.
  • Inclusion complexes are defined as formations made up of a polymeric material and an active ingredient, where the active ingredient is included in the polymer.
  • the polymer helps carrying the drug in the aqueous medium changing some of the physical properties typical of the active ingredient so that, after the complex has formed, the solubility of the active ingredient in aqueous solvents increases to a particularly significant extent.
  • the materials for active-ingredient inclusion complexes which can be used to implement the present invention include water-soluble complexing agents such as, for example, a- cyclodextrin, b-cyclodextrin, g-cyclodextrin and their derivatives such as, for example, hydroxypropyl-P-cyclodextrin.
  • solvate is understood as meaning any form of melatonin according to the invention having another molecule (most likely a polar solvent) attached via a noncovalent bond.
  • examples of such solvates include hydrates and alcoholates, for example methanolates.
  • the preparation of salts, solvates and prodrugs can be carried out by methods known in the art. It will be appreciated that salts, solvates or prodrugs not pharmaceutically acceptable are also within the scope of the invention since those may be useful in the preparation of salts, prodrugs or pharmaceutically acceptable solvates.
  • Solubility and stability issues of melatonin are discussed in the prior arts. Solubility of melatonin is reported in literature as 1 mg / ml or even 2 mg/ml. The present inventors carried out an extensive study on solubility of melatonin. Part of the study relevant to the present invention is as reported in table 18. The inventors have noted that the actual melatonin solubility is not even 1 mg / ml. Heating may temporarily enhance solubility but upon cooling the insoluble particles become visible. Even if particles are not visible, turbid solution is sometimes resulted. This is probably one of the reasons why there are no liquid compositions of melatonin in market.
  • compositions wherein solubility of melatonin is greatly enhanced.
  • the solubility is enhanced two times, four times, five times and even greater.
  • the present invention does not employ any co-solvent to dissolve melatonin.
  • the compositions are entirely aqueous without employing any solvent other than water.
  • the aqueous compositions can be prepared even without employing conventional surfactant.
  • compositions do not require adding preservatives. Stability studies conducted on several compositions indicate that single maximum impurity and total impurities after 6 months stability comply with the drug regulation.
  • compositions of the present invention have been prepared by a process of preparation comprising dissolving the melatonin and at least one but preferably two ingredients from the group of solubilizers, polymeric solubilizers, crystal inhibitors, stabilizers, anti -oxidants, solubilizer which is also an anti-oxidant, chelating agent and complexing agent and combinations thereof in Water for Inj ection.
  • the solution obtained can be deaerated with an inert gas, preferably with filtered nitrogen.
  • a pharmaceutical composition of the present invention has been prepared by a process of preparation comprising dissolving the melatonin, crystal inhibitor and Solubilizer in Water for Injection.
  • The, solution obtained can be deaerated with an inert gas, preferably with filtered nitrogen.
  • the content of oxygen dissolved in solution is constantly monitored at the aim of maintaining it at values lower than 2 ppm. Also the processing of the solution subject of the invention after the solution's preparation, including the bottling, or anyway the packaging in containers of the desired dosage, are carried out under inert gas, preferably under filtered nitrogen, controlling again the content of oxygen dissolved in the solution.
  • the present pharmaceutical compositions of melatonin are packed in containers made of Type I glass, i.e. of glass of amber colour, suitable for the preparations of products sensitive to ultraviolet rays.
  • Containers of Type I glass suitable for packing and storing the present compositions are for instance vials, in particular 2 ml, 5 ml and 10 ml vials. Obviously these containers have to guarantee maintenance of the desired conditions of deaeration, wherein the content of oxygen is always lower than 2 ppm; so, for instance, the vials, once they are filled up under inert gas atmosphere, are closed by torch welding of the molten glass and checked with an apparatus of the type Leaker Test to test the seal of the vial.
  • the oral compositions are filled in vials in polypropylene vials or suitable vials with actuator to apply as an oral spray.
  • the present pharmaceutical compositions are sterilisable, in particular they are autoclavable, for example by treatment in a super-heated water autoclave.
  • a sterilisation cycle commonly used for injectable products in glass vials may be used, at 121°C and 15 lb Pressure.
  • compositions according to the present invention are suitable for the oral or parenteral administration in the form of liquids and solutions of melatonin by any one of the known oral or parenteral administration in the form of liquids and solutions routes, such as the injection or infusion route, that may be intramuscular, intravenous, intradermal, subcutaneous, intra-arterial, or intrathecal.
  • the liquids and solutions of melatonin can be administered orally as oral spray or oral liquid or can be administered parenterally as shots.
  • the compositions comprise of at least one ingredient is specific amounts or at least one but preferably two ingredients enhancing properties of the composition.
  • the composition for oral use may additionally have sweeteners, flavours etc.
  • the sweeteners is selected from the group consisting of sucrose, fructose, dextrose, high fructose corn syrup, xylitol, maltitol, sorbitol, mannitol, erythritol, sucralose, stevia, aspartame, advantame, acesulfame potassium, saccharin, sodium saccharin, neotame and any combinations thereof and any other suitable sweetener.
  • compositions of melatonin comprise of ingredients which enhance properties of the composition.
  • the properties enhanced are solubility and stability.
  • the invention provides a pharmaceutical composition of melatonin for the oral or parenteral administration in the form of liquids and solutions wherein melatonin can be in the form of melatonin or in a form of a derivative, a salt, a solvate, a prodrug or an inclusion complex and at least one but preferably two ingredients enhancing properties of the composition and belonging to a group consisting of solubilizers, polymeric solubilizers, crystal inhibitors, stabilizers, anti-oxidants, solubilizer which is also an anti-oxidant, chelating agent and complexing agent and combinations thereof.
  • the preferred ingredients used in combination to enhance properties of pharmaceutical composition of melatonin for oral or parenteral administration in the form of liquids and solutions are as follows: a) solubilizer + polymeric solubilizer; b) solubilizer + crystal inhibitor; c) crystal inhibitor + polymeric solubilizer; d) solubilizer + antioxidant; e) polymeric solubilizer + antioxidant; f) solubilizer + crystal inhibitor + antioxidant; g) solubilizer alone; h) solubilizer which is also anti-oxidant alone.
  • Preferred crystal inhibitor according to the invention includes polyvinylpyrrolidone (PVP).
  • meglumine is preferred as a solubilizer and PVP K-30 as crystal inhibitor.
  • PVP K-30 is preferred as crystal inhibitor and Soluplus® is preferred as polymeric solubilizer.
  • Soluplus® is preferred as polymeric solubilizer and Vitamin E Acetate (Tocopheryl acetate) is preferred as an anti-oxidant.
  • Soluplus® is available commercially from BASF Corporation.
  • Soluplus® is a graft copolymer comprised of polyethylene glycol, polyvinylcaprolactam and polyvinylacetate.
  • the second aspect provides a pharmaceutical composition of melatonin for the oral or parenteral administration in the form of liquids and solutions wherein melatonin can be in the form of melatonin or in a form of a derivative, a salt, a solvate, a prodrug or an inclusion complex and at least one ingredient enhancing properties of the composition and belonging to a group consisting of solubilizers, polymeric solubilizers, crystal inhibitors, stabilizers, anti-oxidants, chelating agent and complexing agent and combinations thereof wherein melatonin and the said ingredient are in a ratio of 10: 1 to 1:10 and both melatonin and the said ingredient are present in amounts of 0.01 to 10 % and preferably 0.01 to 5 % and more preferably 0.05 to 5 % and most preferably 0.05 to 2 % of the composition.
  • a preferred solubilizer is meglumine.
  • meglumine is used in an amount of 0.1 % of the total composition. In another embodiment, meglumine is used in an amount of 0.2 % of the total composition.
  • ratio of melatonin to meglumine is from 1:0.5 - 1:1. In another embodiment the ratio is 1 :2. In yet another embodiment the ratio is 1:5.
  • crystal inhibitor is present to enhance properties of the solution wherein ratio of melatonin to a crystal inhibitor is from 1:2 to 2:1 and the amount of the crystal inhibitor in the composition is from 0.01% to 10% w/v, measured relative to the total volume of the solution.
  • the additional ingredient when used for enhancing properties of the pharmaceutical composition of melatonin, the additional ingredient also belongs to a group consisting of solubilizers, polymeric solubilizers, crystal inhibitors, stabilizers, anti-oxidants, chelating agent and complexing agent and combinations thereof wherein ratio of melatonin (in any form): first ingredient and the additional ingredient are as follows: 10:1:1 to 1:10:10.
  • the ratio employed between melatonin, first ingredient and second ingredient is 1:2:1.
  • the ratio is 1:1:1. In one more embodiment, the ratio is 2:1:1. In yet another embodiment, the ratio is 1 :2:2. In one more embodiment, the ratio is 1:1:2.
  • a pharmaceutical composition of melatonin for the oral or parenteral administration in the form of liquids and solutions comprising melatonin, or its derivative, a salt, a solvate or a prodrug of melatonin or an inclusion complex of melatonin, a solubilizer and Water for Injection and optionally, an antioxidant. Whether there is a single ingredient or two ingredients enhancing properties of the pharmaceutical composition of the melatonin, Polyvinylpyrrolidone (PVP) is one of the or the only preferred crystal inhibitor.
  • PVP Polyvinylpyrrolidone
  • Polyvinylpyrrolidone is made from the monomer, N-vinylpyrrolidone, and is soluble in water. PVP binds to polar molecules exceptionally well, owing to its polarity. PVP is approved by the FDA for many uses and is generally considered safe. For example, and without limitation, PVP K12, PVP K17 or PVP K30 can be used in a composition.
  • the invention provides process of preparing a pharmaceutical composition of melatonin for the oral or parenteral administration in the form of liquids and solutions wherein melatonin can be in the form of melatonin or in a form of a derivative, a salt, a solvate, a prodrug or an inclusion complex and at least one but preferably two ingredients belonging to a group consisting of solubilizers, polymeric solubilizers, crystal inhibitors, stabilizers, anti oxidants, chelating agents and combinations thereof and also process of preparing a pharmaceutical composition of melatonin for the oral or parenteral administration in the form of liquids and solutions wherein melatonin can be in the form of melatonin or in a form of a derivative, a salt, a solvate, a prodrug or an inclusion complex and at least one ingredient enhancing properties of the composition and belonging to a group consisting of solubilizers, polymeric solubilizers, crystal inhibitors, stabilizer
  • the process comprises 1) dissolving two ingredients for enhancing properties of the pharmaceutical composition of melatonin in water for injection to prepare first solution;
  • the process comprises:
  • ratio of melatonin to the first ingredient is from 10:1 to 1:10 and the amount of both first ingredient and melatonin are from 0.01 to 10 % of the final melatonin solution.
  • the fourth aspect of the invention relates to the use of the composition of the invention in the manufacture of a medicament.
  • the invention relates to the use of the pharmaceutical composition of melatonin in the manufacture of a medicament for regulating the 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, the 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, the treatment of pulmonary edema, treatment of kidney or liver failure, or treatment of the situation of oxidative stress caused by surgery, method comprising administering to a patient in need of such treatment a therapeutically effective amount of the composition of the invention wherein the pharmaceutical composition comprises either
  • the present invention also relates to the composition of the invention for use in the regulation of circadian rhythms, 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, the treatment of pulmonary edema, treatment of kidney or liver failure, or treatment of oxidative stress caused by surgery.
  • SIRS systemic inflammatory response syndrome
  • MODS multiple organ dysfunction syndrome
  • the melatonin may find a therapeutic application in the treatment of hypoxic- ischemic encephalopathy in infants, and therefore the present pharmaceutical compositions are particularly useful in the treatment of this serious disease.
  • the melatonin concentration is between 0.1 and 50 mg/ml of composition.
  • the composition of the invention also allows high loads of melatonin while are stable.
  • the melatonin concentration is greater than 5 mg/ml of composition.
  • the melatonin concentration is between 5 and 50 mg/ml of composition.
  • the composition of the invention is injectable intravenously.
  • a particular aspect includes the presence of a second drug in the composition of the invention.
  • Said second drug may be part of the composition or may be provided as a separate administration simultaneously or at different times composition.
  • a composition or a component thereof "pharmaceutically acceptable" it indicates that are physiologically tolerable and whose administration has a low risk of allergies, side effects, adverse events or other similar reactions, such as gastric disorders, dizziness and the like, when administered to a human.
  • the term "pharmaceutically acceptable” means that has been approved by a generally recognized for use in animals government regulatory agency state or federal or which is listed in the US Pharmacopoeia or other pharmacopoeia and more particularly in humans. Therefore, the composition of the invention is pyrogen free.
  • a "therapeutically effective amount" of the composition of the invention depends on various factors such as the severity of the condition being treated, the sex, age, or weight of the patient, among others.
  • the composition of the invention may be administered once or more times a day for example 1, 2, 3 or 4 times daily, with typical total daily doses in the range of from 0.01 to 1000 mg / kg / day, preferably, 0.01 to 100 mg/kg/day and more preferably, 0.01 - 10 mg/kg/day.
  • the administration is by infusion.
  • melatonin, its salts, prodrugs, derivatives or solvates administered 1, 2, 3, 4, 5 or 6 times a day up to the total daily dose indicated in the previous paragraph.
  • the administration is 1, 2 or 3 times daily, preferably once a day.
  • the treatment period can vary according to the evolution of the patient and lasts normally between 1 and 30 days.
  • an adult is a patient with an age of 18 years or more.
  • a neonate is a patient aged between 0 and 27 days, a baby between 28 days and 23 months a child of 24 months to 11 years and a teenager from 12 to 17 years.
  • the correlation is not always linear and must be identified for each patient group.
  • treatment refers to the administration of a compound or formulation according to the invention to prevent, ameliorate or eliminate the disease or one or more symptoms associated with such disease.
  • Treatment also encompasses preventing, ameliorating or eliminating the physiological sequelae of the disease.
  • the invention provides melatonin aqueous compositions which are free of co solvent and free of preservative and stable.
  • compositions exhibited enhanced solubility of melatonin which is enhanced two times, four times, five times and even greater.
  • the aqueous compositions can be prepared even without employing conventional surfactant.
  • the aqueous composition of the present invention can be used in treatment of one or more of regulation of circadian rhythms, regulation of the inflammatory response, systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), sepsis in neonates, myocardial infarction, mitochondrial damage, pulmonary edema, kidney or liver failure, or oxidative stress caused by surgery.
  • SIRS systemic inflammatory response syndrome
  • MODS multiple organ dysfunction syndrome
  • sepsis in neonates myocardial infarction
  • mitochondrial damage pulmonary edema
  • kidney or liver failure or oxidative stress caused by surgery.
  • the invention relates to method of treating one or more of regulation of circadian rhythms, regulation of the inflammatory response, systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), sepsis in neonates, myocardial infarction, mitochondrial damage, pulmonary edema, kidney or liver failure, or oxidative stress caused by surgery comprising administering the aqueous composition of any of the preceding claim.
  • SIRS systemic inflammatory response syndrome
  • MODS multiple organ dysfunction syndrome
  • Example 1 Pharmaceutical composition of melatonin for the parenteral administration in the form of liquids and solutions Table 1: pH of Solution 6.5 - 7.5 (to be adjusted with 0.1 N HC1 or 0.1 N NaOH, as required)
  • PVP K 30 100 mg
  • Meglumine 200 mg
  • Melatonin 100 mg
  • the pH of the solution was adjusted in between 6.5 to 7.5, using 0.1 N HC1 or 0.1 N NaOH, as required.
  • the volume was adjusted up to 100 ml with Water for Injection.
  • the solution was filtered through 0.45 micron filter and followed by 0.2 micron filter.
  • the vials were filled with 2 ml and 5 ml volume in USP type I glass Vials. The vials were subjected to Autoclave at 121°C at 15 lb Pressure.
  • composition of melatonin for the oral or parenteral administration in the form of liquids and solutions Table 2 pH of Solution 6.5 - 7.5 (to be adjusted with 0.1 N HC1 or 0.1 N NaOH, as required) Procedure: (Batch size: 100 ml)
  • PVP K 30 100 mg
  • Meglumine 200 mg
  • Melatonin 200 mg
  • the pH of the solution was adjusted in between 6.5 to 7.5, using 0.1 N HC1 or 0.1 N NaOH, as required.
  • the volume was adjusted up to 100 ml with Water for Injection.
  • the solution was filtered through 0.45 micron filter and followed by 0.2 micron filter.
  • the vials were filled with 2 ml and 5 ml volume in USP type I glass Vials. The vials were subjected to Autoclave at 121°C at 15 lb Pressure.
  • composition of melatonin for the parenteral administration in the form of liquids and solutions Table 3 pH of Solution 6.5 - 7.5 (to be adjusted with 0.1 N HC1 or 0.1 N NaOH, as required) Procedure: (Batch size: 100 ml)
  • PVP K 30 100 mg
  • Soluplus® 200 mg
  • Melatonin 100 mg
  • the pH of the solution was adjusted in between 6.5 to 7.5, using 0.1 N HC1 or 0.1 N NaOH, as required.
  • the volume was adjusted upto 100 ml with Water for Injection.
  • the solution was filtered through 0.45 micron filter and followed by 0.2 micron filter.
  • the vials were filled with 2 ml and 5 ml volume in USP type I glass Vials. The vials were subjected to Autoclave at 121°C at 15 lb Pressure.
  • composition of melatonin for the parenteral administration in the form of liquids and solutions Table 4
  • Vitamin E Acetate (Tocopheryl acetate) (100 mg) and Soluplus® (100 mg) were dissolved in 60 ml of Water for Injection. Then, Melatonin (100 mg) was added and stirred till it gets dissolved. The pH of the solution was adjusted in between 6.5 to 7.5, using 0.1 N HC1 or 0.1 N NaOH, as required. The volume was adjusted upto 100 ml with Water for Injection. The solution was filtered through 0.45 micron filter and followed by 0.2 micron filter. The vials were filled with 2 ml and 5 ml volume in USP type I glass Vials. The vials were subjected to Autoclave at 121°C at 15 lb Pressure.
  • composition of melatonin for the oral administration in the form of liquids and solutions Table 5 pH of Solution 6.5 - 7.5 (to be adjusted with 0.1 N HC1 or 0.1 N NaOH, as required) Procedure: (Batch size: 100 ml)
  • PVP K 30 100 mg
  • Meglumine 200 mg
  • Melatonin 200 mg
  • the pH of the solution was adjusted in between 6.5 to 7.5, using 0.1 N HC1 or 0.1 N NaOH, as required.
  • Acesulfame Potassium, as sweetener and make up the volume up to 100 ml with Purified water.
  • the solution was filtered through 0.45 micron filter.
  • the vials were filled with 2 ml and 5 ml volume in polypropylene vials or suitable vials with actuator.
  • composition of melatonin for the oral administration in the form of liquids and solutions Table 6 pH of Solution 6.5 - 7.5 (to be adjusted with 0.1 N HC1 or 0.1 N NaOH, as required) Procedure: (Batch size: 100 ml)
  • PVP K 25 (100 mg) were dissolved in 60 ml of Purified Water. Then, Melatonin (200 mg) was added under Nitrogen atmosphere and stirred till it gets dissolved. The pH of the solution was adjusted in between 6.5 to 7.5, using 0.1 N HC1 or 0.1 NNaOH, as required. The sucralose 20 mg was added, and the volume was adjusted up to 100 ml with Purified Water. The solution was filtered through 0.45 micron filter. The solution was filtered through 0.45micron filter. The vials were filled with 2 ml and 5 ml volume in polypropylene vials or suitable vials with actuator.
  • Example 7 Pharmaceutical composition of melatonin for the oral or parenteral administration in the form of liquids and solutions Table 7 pH of Solution 6.5 - 7.5 (to be adjusted with 0.1 N HC1 or 0.1 N NaOH, as required)
  • PVP K 30 50 mg / 100 mg / 150 mg
  • Meglumine 100 mg/ 200 mg/ 300 mg
  • Melatonin 50 mg / 100 mg/ 150 mg
  • the pH of the solution was adjusted to 7.4 (6.5 to 7.5), using 0.1 N HC1 or 0.1 N NaOH, as required.
  • the volume was adjusted up to 100 ml with Water for Injection.
  • the solution was filtered through 0.45-micron filter and followed by 0.2-micron filter.
  • the vials were filled with 2 ml and 5 ml volume in USP type I glass Vials and were subjected to Autoclave at 121 °C at 15 lb Pressure.
  • Example 8 Pharmaceutical composition of melatonin for the oral or parenteral administration in the form of liquids and solutions
  • PVP K 30 300 mg
  • Meglumine 600 mg
  • Melatonin 300 mg
  • the pH of the solution was adjusted to 7.4 (6.5 to 7.5), using 3.7% HC1 or 0.1 N NaOH, as required.
  • the volume was adjusted up to 200 ml with Water for Injection.
  • the solution was filtered through 0.45-micron filter and followed by 0.2- micron filter.
  • the vials were filled with 2 ml and 5 ml volume in USP type I glass Vials with chlorobutyl rubber closer and were subjected to Autoclave at 121°C at 15 lb Pressure.
  • Example 9 Pharmaceutical composition of melatonin for the oral or parenteral administration in the form of liquids and solutions
  • the Vitamin E TPGS (300 mg) was dissolved in hot water (50 ml) at 65°C ( ⁇ 5°C) under stirring and allowed to get clear solution.
  • the PVP K 30 (150 mg) was dissolved in same under stirring. Then, Melatonin (150 mg) was added under stirring till it gets dissolved.
  • the pH of the solution was adjusted to 7.4 (7.0 to 7.5), using 0.37%v/v HC1 or 0.01 N NaOH, as required.
  • the volume was adjusted up to 100 ml with Water for Injection.
  • the solution was filtered through 0.45-micron PVDF filter and followed by 0.2-micron PVDF filter.
  • the vials were filled with 2 ml and 5 ml volume in USP type I glass Vials with chlorobutyl rubber closer and were subjected to Autoclave at 121°C at 15 lb Pressure.
  • the Vitamin E TPGS (3.0 gm) was dissolved in hot water (100 ml) at 60°C ( ⁇ 5°C) under stirring for 10 min and allowed to get clear solution.
  • the PVP K 30 (3.0 gm) was dissolved in same under stirring.
  • Melatonin (3.0 gm) was added under stirring till it gets dissolved, if required warm the solution to NMT 65°C, under stirring.
  • the pH of the solution was adjusted to 7.4 (7.0 to 7.5), using 0.37%v/v HC1 or 0.01 N NaOH, as required.
  • the volume was adjusted up to 1000 ml with Water for Injection.
  • the solution was filtered through 0.45-micron PVDF filter and followed by 0.2-micron PVDF filter.
  • the vials were filled with 2 ml and 5 ml volume in USP type I glass Vials with chlorobutyl rubber closer and were subjected to Autoclave at 121°C at 15 lb Pressure. The batches were charged for the stability study and also to study any adverse effect of same on the animal models.
  • the Vitamin E TPGS (0.90 gm) was dissolved in hot water (150 ml) at 60°C ( ⁇ 5°C) under stirring for 30 min and allowed to get clear solution.
  • the PVP K 30 (0.45 gm) was dissolved in same under stirring.
  • Melatonin (0.90 gm) was added under stirring till it gets dissolved.
  • the solution was mixed for 20 min.
  • the pH of the solution was adjusted to 7.4 (7.0 to 7.5), using 0.37%v/v HC1 or 0.01 N NaOH, as required.
  • the volume was adjusted up to 225 ml with Water for Injection.
  • the solution was filtered through 0.45-micron PVDF filter and followed by 0.2-micron PVDF filter.
  • the vials were filled with 2 ml (8 mg / vial) and 5 ml (20 mg / vial) volume in USP type I glass Vials with chlorobutyl rubber closer and were subjected to Autoclave at 121°C at 15 lb Pressure. The batches were charged for the stability study and also to study the locomotor activity on the animal models. Table 12
  • Example 10 Pharmaceutical composition of melatonin for the oral administration in the form of solutions
  • the Vitamin E TPGS (0.600 gm) was dissolved in hot water (100 ml) at 60°C ( ⁇ 5°C) under stirring for 10 min and allowed to get clear solution.
  • the PVP K 30 (0.300 gm) was dissolved in same under stirring.
  • Melatonin (0.600 gm) was added under stirring till it gets dissolved, if required warm the solution to NMT 65°C, under stirring.
  • the Vitamin E TPGS (5.0 gm) was dissolved in hot water (100 ml) at 60°C ( ⁇ 5°C) under stirring for 10 min and allowed to get clear solution.
  • the PVP K 30 (3.0 gm) was dissolved in same under stirring.
  • Melatonin (5.0 gm) was added under stirring till it gets dissolved, if required warm the solution to NMT 65°C, under stirring.
  • Example 11 Pharmaceutical composition of melatonin for the oral or parenteral administration (slow IV infusion) in the form of liquids and solutions Table 14 required)
  • Procedure for BB001014A (Batch size: 1000 ml)
  • the Vitamin E TPGS (0.100 gm) was dissolved in hot water (500 ml) at 60°C ( ⁇ 5°C) under stirring for 30 min and allowed to get clear solution.
  • the PVP K 30 (0.05 gm) was dissolved in same under stirring.
  • Melatonin (0.100 gm) was added under stirring till it gets dissolved.
  • Add Sodium Chloride (0.90 gm) to the solution and was mixed for 20 min.
  • the pH of the solution was adjusted to 7.4 (7.0 to 7.5), using 0.37%v/v HC1 or 0.01 N NaOH, as required.
  • the volume was adjusted up to 1000 ml with Water for Injection.
  • the solution was filtered through 0.45-micron PVDF filter and followed by 0.2-micron PVDF filter.
  • the solution can be given as slow IV infusion.
  • the Vitamin E TPGS (1.00 gm) was dissolved in hot water (40 ml) at 60°C ( ⁇ 5°C) under stirring for 30 min and allowed to get clear solution.
  • the PVP K 30 (0.50 gm) was dissolved in same under stirring.
  • the pH of the solution was adjusted to 7.4 (6.0 to 8.0), using 0.37%v/v HC1 or 0.01 N NaOH, as required.
  • the volume was adjusted up to 100 ml with Water for Injection.
  • the solution was filtered through 0.45-micron PVDF filter and followed by 0.2-micron PVDF filter.
  • the solution can be given as slow IV infusion or can be diluted to normal saline solution or dextrose solution prior to use.
  • the Vitamin E TPGS (2.000 gm) was dissolved in hot water (100 ml) at 60°C ( ⁇ 5°C) under stirring for 30 min and allowed to get clear solution.
  • the PVP K 30 (1.200 gm) was dissolved in same under stirring.
  • Melatonin (1.200 gm) was added under stirring till it gets dissolved.
  • the solution was mixed for 20 min.
  • the pH of the solution was adjusted to 7.4 (7.0 to 7.5), using 0.37%v/v HC1 or 0.01 N NaOH, as required.
  • the volume was adjusted up to 200 ml with Water for Injection.
  • the solution was filtered through 0.45-micron PVDF filter and followed by 0.2-micron PVDF filter.
  • the vials were filled with 2 ml (8 mg / vial) and 5 ml (20 mg / vial) volume in USP type I glass Vials with chlorobutyl rubber closer and were subjected to Autoclave at 121 °C at 15 lb Pressure.
  • mice were selected as an animal for investigational purpose.
  • the Animals were divided into group of three each and were grouped as Test 1 (Placebo Treatment), Test 2 (Receiving 1.5 mg / ml dose), Test 3 (Receiving 3.0 mg / ml dose), Test 4 (Receiving 4.0 mg / ml dose) and Test 5 (Receiving 10 mg / ml dose).
  • Test 1 Prolacebo Treatment
  • Test 2 Receiving 1.5 mg / ml dose
  • Test 3 Receiving 3.0 mg / ml dose
  • Test 4 Receiving 4.0 mg / ml dose
  • Test 5 Receiving 10 mg / ml dose.
  • Initial locomotor activity of every animal from each group is recorded. This activity is the activity before administration of dose to that animal.
  • the dose was administered by two major routes that include the IP (Intra Peritoneal) and iv (Intravenous). On the first day, one dose is administered intraperitoneally
  • the dose is continued for a total of seven days including the first day and change in the locomotor activity is recorded. This is termed as multiple dose.
  • the onset of action for each animal was monitored post dose along with the duration of action and Locomotor activity. Beside the activity the major objective was to understand side effects, if any that including but not limited to seizures, long hypnotism or even death. Finally based on the groups studied, the recovery rate of animal was calculated. Table 15: Effect on Locomotor activity after administering single dose.
  • Table 16 Onset and duration of action of Melatonin and recovery rate.
  • Table 17 Decrease or depression in locomotor activity after multiple dosing of melatonin solutions intraperitoneally
  • Example 13 Solubility testing of melatonin in water alone and in the solution of crystal inhibitors, solubilizers, anti-oxidant is done as provided in table 18.
  • Example 14 Pharmaceutical composition of melatonin for the oral or parenteral administration in the form of liquids and solutions Table 18: Melatonin along with two solubilizers pH of Solution 6.0 - 9.0 (to be adjusted with 0.37%v/v HC1 or 0.01 N NaOH, as required)
  • the Vitamin E TPGS (0.750 gm) was dissolved in hot water (50 ml) at 60°C ( ⁇ 5°C) under stirring for 30 min and allowed to get clear solution.
  • the Meglumine (1.125 gm) was dissolved in same under stirring.
  • Melatonin (0.750 gm) was added under stirring till it gets dissolved.
  • the solution was mixed for 45 min.
  • the pH of the solution was adjusted to 8.5 (6.0 to 9.0), using 0.37 %v/v HC1 or 0.01 NNaOH, as required.
  • the volume was adjusted up to 100 ml with Water for Injection.
  • the solution was filtered through 0.45-micron PVDF filter and followed by 0.2-micron PVDF filter.
  • the vials were filled with 2 ml (15 mg / vial) volume in USP type I glass vials with rubber closer and were subjected to Autoclave at 121 °C at 15 lb Pressure.
  • Example 15 Pharmaceutical composition of melatonin for the oral or parenteral administration in the form of liquids and solutions Table 19: Melatonin along with meglumine alone pH of Solution 7.0 - 9.0 (to be adjusted with 0.37%v/v HC1 or 0.01 N NaOH, as required)
  • the Meglumine (3.60 gm) was dissolved in hot water (50 ml) at 60°C ( ⁇ 5°C) under stirring for 10 min and allowed to get clear solution.
  • the pH of the solution was adjusted to 8.0 (7.0 to 9.0), using 0.37%v/v HC1 or 0.01 NNaOH, as required. 5.
  • the volume was adjusted up to 200 ml with Water for Injection.
  • the solution was filtered through 0.45-micron PVDF filter and followed by 0.2-micron PVDF filter.
  • the vials were filled with 1 ml (6 mg / vial) , 2 ml (12 mg / vial) and 5 ml (30 mg / vial) volume in USP type I glass Vials with chlorobutyl rubber closer and were subjected to Autoclave at 121°C at 15 lb Pressure.
  • the solution can be used as IV infusion or Iv bolus administration, by diluting with the dextrose solution or saline solution.
  • Example 16 Pharmaceutical composition of melatonin for the oral or parenteral administration in the form of liquids and solutions Table 20: Melatonin along with Vitamin TPGS alone pH of Solution 7.0 - 7.5 (to be adjusted with 0.37%v/v HC1 or 0.01 N NaOH, as required)
  • step 2 dispersion, under stirring, to step 1 solution and mix till it gets dissolved.
  • the pH of the solution was adjusted to 7.4 (7.0 to 7.5), using 0.37%v/v HC1 or 0.01 NNaOH, as required.
  • the volume was adjusted up to 200 ml with Water for Injection. 7.
  • the solution was filtered through 0.45-micron PVDF filter and followed by 0.2- micron PVDF filter.
  • the vials were filled with 2 ml (10 mg / vial) and 4 ml (20 mg / vial) volume in USP type I glass Vials with chlorobutyl rubber closer and were subjected to Autoclave at 121 °C at 15 lb Pressure.
  • the solution can be used as IV infusion or Iv bolus administration, by diluting with the dextrose solution or saline solution.
  • Example 16 Pharmaceutical composition of melatonin for the oral or parenteral administration in the form of liquids and solutions
  • Table 20 Melatonin with combination of solubilizer, anti-oxidant and crystal inhibitor.
  • melatonin solution is prepared using a combination of solubilizer, solubilizer which is also an anti-oxidant and crystal inhibitor.
  • This solution is converted into granules which are further processed to prepare other compositions such as dispersible tablets, orally disintegrating tablets, granules for oral solution, granules for filling into capsules etc.
  • the aqueous melatonin solution can be sprayed on to another ingredient such as diluent for example, xylitol, mannitol, sugar alcohol, polyol, saccharide, cellulose to produce granules which are processed further into capsules or compressed into tablets etc.
  • the Vitamin E TPGS (6.00 gm) was dissolved in hot water (300 ml) at 60°C ( ⁇ 5°C) under stirring for 30 min and allowed to get clear solution.
  • the Meglumine (16.00 gm) was dissolved in same under stirring.
  • Melatonin (8.00 gm) was added under stirring till it gets dissolved.
  • the solution was homogenized for 45 min.
  • Polyvinyl Pyrrolidone (PVP K 12) was added with 300 ml of Purified water. The pH of the solution was adjusted to 7.5 (6.0 to 9.0), using 0.37%v/v HC1 or 0.01 N
  • the solution was used as granulating fluid to adsorb on to the Mannitol 25 C using Top spray granulation.
  • the dried granules (LOD NMT - 2.0% w/w) were passed through 40 mesh. Mix the granules with Sodium Stearyl Fumarate (1.00 gm) and compress the tablets using 5.00 mm round punch.

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Abstract

La présente invention concerne des compositions liquides pour l'administration orale et parentérale de mélatonine sous la forme de solutions aqueuses comprenant de la mélatonine et au moins un mais de préférence deux ingrédients pour améliorer les propriétés de la composition, dans laquelle le ou les ingrédients appartiennent au groupe consistant en des solubilisants, des solubilisants polymères, des inhibiteurs de cristaux, des stabilisants, des antioxydants, un agent chélatant et un agent complexant et des combinaisons de ceux-ci et les propriétés améliorées sont au moins la solubilité et la stabilité. De préférence, les compositions sont des compositions pharmaceutiques. De préférence, les compositions sont des compositions neutraceutiques.
PCT/IN2020/050759 2019-08-30 2020-08-31 Compositions pharmaceutiques liquides de mélatonine pour administration orale et parentérale WO2021038601A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP20859314.5A EP4021411A4 (fr) 2019-08-30 2020-08-31 Compositions pharmaceutiques liquides de mélatonine pour administration orale et parentérale
AU2020339867A AU2020339867A1 (en) 2019-08-30 2020-08-31 Liquid pharmaceutical compositions of melatonin for oral and parenteral administration

Applications Claiming Priority (2)

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EP4186504A1 (fr) 2021-11-25 2023-05-31 Alissa Healthcare Research Limited Solutions aqueuses pharmaceutiques orales comprenant de la mélatonine et leur utilisation

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CN113072479A (zh) * 2021-03-26 2021-07-06 罗田县新普生药业有限公司 一种从褪黑素结晶母液中提取褪黑素的方法
EP4186504A1 (fr) 2021-11-25 2023-05-31 Alissa Healthcare Research Limited Solutions aqueuses pharmaceutiques orales comprenant de la mélatonine et leur utilisation

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