WO2012156565A1 - Préparation injectable de mélatonine - Google Patents

Préparation injectable de mélatonine Download PDF

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Publication number
WO2012156565A1
WO2012156565A1 PCT/ES2012/070349 ES2012070349W WO2012156565A1 WO 2012156565 A1 WO2012156565 A1 WO 2012156565A1 ES 2012070349 W ES2012070349 W ES 2012070349W WO 2012156565 A1 WO2012156565 A1 WO 2012156565A1
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Prior art keywords
treatment
melatonin
composition
composition according
propylene glycol
Prior art date
Application number
PCT/ES2012/070349
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English (en)
Spanish (es)
Inventor
Pablo BUENO LARAÑO
Alfonso MANSILLA ROSELLÓ
José Antonio FERRÓN ORIHUELA
José Jorge HERNÁNDEZ MAGADALENA
Miguel Ángel CALLEJA HERNÁNDEZ
Desirée GONZÁLEZ CALLEJAS
Ana Comino Pardo
Carmen OLMEDO MARTÍN
Darío ACUÑA CASTROVIEJO
Germaine Escames Rosa
Original Assignee
Universidad De Granada
Servicio Andaluz De Salud
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.)
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Application filed by Universidad De Granada, Servicio Andaluz De Salud filed Critical Universidad De Granada
Publication of WO2012156565A1 publication Critical patent/WO2012156565A1/fr

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    • 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
    • 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

Definitions

  • the present invention is within the field of medicine and pharmacy, and refers to an injectable melatonin composition that exhibits greater stability.
  • the present invention also relates to the use of said composition as a medicament and its use in the treatment of various conditions, such as for example sepsis in adults.
  • Melatonin N-acetyl-5-methoxy-triptamine
  • pineal gland ⁇ cerebri epiphysis an endogenous neurohormone produced by the pineal gland ⁇ cerebri epiphysis physiologically. Its secretion rhythm follows a circardian rhythm related to the light-dark cycle, and plays a fundamental role in the induction of sleep.
  • melatonin plays a fundamental role in the regulation of the inflammatory response, since it acts as a powerful scavenge or scavenger of free oxygen radicals generated, for example, during Systemic Inflammatory Response Syndrome (SIRS) , myocardial infarction, mitochondrial damage, surgery, pulmonary edema, and in renal or hepatic failure.It is believed to activate antioxidant enzyme chains (superoxide dismutase, glutathione peroxidase, glutathionereductase), decrease the total number of circulating polymorphonuclear leukocytes and serum levels of manoldialdehyde (Gitto et al., 2004.
  • SIRS Systemic Inflammatory Response Syndrome
  • the vehicle used for the administration of melatonin is a mixture of water, propylene glycol (PPG) and 1-methyl-2-pyrrolidone (NMP) - 2: 1: 1.
  • PPG propylene glycol
  • NMP 1-methyl-2-pyrrolidone
  • NMP a widely used solvent, seems in this case essential to solubilize water-insoluble melatonin.
  • the use of NMP as a pharmaceutical vehicle is now posing problems due to its reproductive toxicity.
  • aqueous melatonin composition that possesses surprising stability and allows high concentrations of this water insoluble active ingredient.
  • the properties of this composition make it useful as an injection, for example, for intravenous administration.
  • a first aspect of the invention relates to a pharmaceutically acceptable injectable composition (composition of the invention) comprising water, propylene glycol and melatonin, a derivative, a salt, a prodrug, or a solvate thereof, characterized in that it does not It contains no other solvent, co-solvent or dispersing agent.
  • a second aspect of the invention relates to the use of the composition of the invention in the manufacture of a medicament.
  • a third aspect of the invention relates to the composition of the invention for use as a medicament.
  • a fourth aspect of the invention relates to the use of the composition of the invention in the preparation of a medicament for the regulation of circardial rhythm, the regulation of the inflammatory response, the treatment of systemic inflammatory response syndrome (SIRS), the treatment of multiple organ dysfunction syndrome (MODS), treatment of sepsis in neonates, treatment of sepsis in adults, treatment of myocardial infarctions, treatment of mitochondrial damage, treatment of pulmonary edema, treatment of a failure renal or hepatic, or the treatment of the 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 the regulation of the circadian rhythm, the regulation of the inflammatory response, the treatment of systemic inflammatory response syndrome (SIRS), the treatment of multiple organic dysfunction syndrome (MODS), the treatment of sepsis in neonates, treatment of myocardial infarctions, treatment of mitochondrial damage, treatment of pulmonary edema, treatment of renal or hepatic failure, or treatment of oxidative stress caused by surgery, a method that it comprises administering to a patient in need of said treatment or regulation a therapeutically effective amount of the composition of the invention.
  • SIRS systemic inflammatory response syndrome
  • MODS multiple organic dysfunction syndrome
  • the present invention relates to the composition of the invention for use in the regulation of circardial rhythm, the regulation of the inflammatory response, the treatment of systemic inflammatory response syndrome (SIRS), the treatment of multiple organic dysfunction syndrome (MODS), the treatment of sepsis in neonates, the treatment of myocardial infarctions, the treatment of mitochondrial damage, the treatment of pulmonary edema, the treatment of a renal or hepatic failure, or the treatment of oxidative stress caused by surgery.
  • SIRS systemic inflammatory response syndrome
  • MODS multiple organic dysfunction syndrome
  • compositions of the invention are prepared using standard methods such as those described or referred to in the Spanish and US Pharmacopoeias and similar reference texts.
  • a fifth aspect is directed to the preparation of the composition of the invention, which comprises mixing water, propylene glycol and melatonin, or a derivative, a salt, a prodrug, or a solvate thereof.
  • a sixth aspect of the invention is the use of melatonin, its salts, prodrugs, derivatives or solvates in the preparation of a medicament for the treatment of sepsis in adults, for the treatment of systemic inflammatory response syndrome (SIRS) in adults or for the treatment of multiple organ dysfunction syndrome (MODS) in adults.
  • SIRS systemic inflammatory response syndrome
  • MODS multiple organ dysfunction syndrome
  • the The present invention also relates to a method for the treatment of sepsis in adults, for the treatment of systemic inflammatory response syndrome (SIRS) in adults or for the treatment of multiple organic dysfunction syndrome (MODS) in adults which comprises administering to a adult patient who needs such treatment a therapeutically effective amount of melatonin, that is, melatonin, its salts, prodrugs, derivatives or solvates, for use in the treatment of sepsis in adults, for the treatment of systemic inflammatory response syndrome ( SIRS) in adults or for the treatment of multiple organic dysfunction syndrome (MODS) in adults.
  • SIRS systemic inflammatory response syndrome
  • MODS multiple organic dysfunction syndrome
  • the composition comprises between 50% and 95% v / v of water, and between 5% and 50% v / v of propylene glycol, measured in relation to the total volume of the solution.
  • the proportion of PPG is between 10% and 30% v / v, more particularly between 20% and 30% v / v, more particularly between 23% and 28%, more particularly between 24% and 26%, more particularly around 25% v / v, where volumes are measured in relation to the total volume of the composition.
  • one embodiment of the invention relates to a composition
  • a composition comprising between 20% and 30% v / v of PPG, between 70% and 80% v / v of water and between 5 and 50 mg of melatonin per ml of composition, or between 7 and 20 mg / ml of composition, more particularly between 8 and 12 mg / ml of composition, more particularly about 10 mg / ml of composition.
  • the composition may also comprise other pharmaceutically acceptable excipients.
  • excipients that can be used in the injectable composition of the composition include antimicrobial preservatives, such as methylparaben, propylparaben; antioxidants, such as sodium metabisulfite, propyl gallate; stabilizing and suspending agents, such as soluble or swellable modified celluloses, for example sodium carboxymethyl cellulose (Aquasorb, Blanose, Nymcel); tonicity agents, such as sodium chloride; or solubilizers, such as propylene glycol or polyethylene glycols.
  • antimicrobial preservatives such as methylparaben, propylparaben
  • antioxidants such as sodium metabisulfite, propyl gallate
  • stabilizing and suspending agents such as soluble or swellable modified celluloses, for example sodium carboxymethyl cellulose (Aquasorb, Blanose, Nymcel); tonicity agents, such as sodium chloride; or solubilizers, such as propylene glyco
  • excipients must be within the limits of the definition of the invention and therefore do not include solvents, co-solvents or dispersing agents other than water and PPG.
  • solvents, co-solvents or dispersing agents can consult in reference books such as the "Handbook of Pharmaceutical Excipients", sixth eddition, Rowe, R. C; Sheskey, PJ; Quinn, ME, Ed. PhP; or "Remington: The Science and Practice of Pharmacy", 21 st Ed .; Lippincott Williams & Wilkins.
  • Typical solvents and cosolvents in injectable formulations are, for example NMP, alcohols with one to eighteen carbon atoms, such as ethanol or ter-butanol, aryl alcohols, such as benzyl alcohol, pyridinium salts, glycerin and stearates. thereof, such as glycerin monostearate, polymers such as hypromellose, polyoxyalkyl ethers (for example, polyoxyethylene, polyoxypropylene or poloxamer), pyrrolidone.
  • a "pharmaceutically acceptable" composition or component thereof indicates that they are physiologically tolerable and whose administration carries 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 being.
  • the term "pharmaceutically acceptable” means that it has been approved by a state or federal government regulatory agency or is listed in the US Pharmacopoeia or other pharmacopoeia generally recognized for use in animals. and more particularly in humans. Therefore, the composition of the invention is pyrogen free.
  • composition of the invention includes melatonin, as well as a derivative, a salt, a prodrug or a solvate thereof.
  • pharmaceutically acceptable salts are synthesized from melatonin by conventional chemical methods, generally by reacting it with an appropriate acid in water or in an organic solvent or in a mixture of both.
  • non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
  • acid addition salts include mineral acid addition salts such as, for example, hydrochloride, hydrobromide, iohydrate, sulfate, nitrate, phosphate, and organic acid addition salts such as, for example, acetate, maleate. , fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate.
  • mineral acid addition salts such as, for example, hydrochloride, hydrobromide, iohydrate, sulfate, nitrate, phosphate
  • organic acid addition salts such as, for example, acetate, maleate. , fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate.
  • prodrug as used in this application is defined herein as meaning a chemical compound that has undergone a chemical derivation such as a substitution or addition of an additional chemical group to change (for pharmaceutical use) any of its physicochemical properties, such as solubility or bioavailability, for example ester, ether or amide derivatives of an active compound that provide the active compound itself upon administration to a subject.
  • a chemical derivation such as a substitution or addition of an additional chemical group to change (for pharmaceutical use) any of its physicochemical properties, such as solubility or bioavailability, for example ester, ether or amide derivatives of an active compound that provide the active compound itself upon administration to a subject.
  • solubility or bioavailability for example ester, ether or amide derivatives of an active compound that provide the active compound itself upon administration to a subject.
  • Particularly favored prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (for example, allowing a compound administered orally to be more easily absorbed into the blood) or that improve the supply of the compound. original to a biological compartment (for example, the brain or lymphatic system) with respect to the original species.
  • solvate is to be understood as meaning any form of melatonin according to the invention that has another molecule (most likely a polar solvent) attached by means of a non-covalent 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 non-pharmaceutically acceptable salts, solvates or prodrugs are also within the scope of the invention since they may be useful in the preparation of pharmaceutically acceptable salts, solvates or prodrugs.
  • melatonin derivatives are known in the state of the art, which are also included in the present invention. According to a particular embodiment, the melatonin derivative is defined according to formula (I), a s
  • n is an integer that is selected from the group consisting of 1, 2, 3 and 4;
  • Ri and R3 are independently selected from the group consisting of CC 4 alkyl, linear or branched; Y
  • the composition of the invention is intravenously injectable.
  • a particular aspect includes the presence of a second medicament in the composition of the invention. Said second medicament may be part of the composition or may be provided as a separate composition for administration at the same time or at different times.
  • composition of the invention and therefore of melatonin, will depend on various factors such as the severity of the disorder being treated, sex, age, or the weight of the patient, among many others.
  • the composition of the invention can be administered one or more times per day for example 1, 2, 3 or 4 times a day, with typical total daily dosages in the range of from 0.1 to 1000 mg / kg / day.
  • the present invention is directed to the use of melatonin, its salts, prodrugs, derivatives or solvates in the preparation of a medicament for the treatment of sepsis in adults, for the treatment of systemic inflammatory response syndrome (SIRS) in adults or for treatment of multiple organic dysfunction syndrome (MODS) in adults.
  • SIRS systemic inflammatory response syndrome
  • MODS multiple organic dysfunction syndrome
  • said use involves the administration of between 5 and 100 mg of melatonin every 24 hours.
  • the amount of melatonin administered to a patient is between 30 and 90 mg every 4 hours, preferably between 40 and 70.
  • between 55 and 75 mg of melatonin is administered every 24 hours. .
  • administration is performed by infusion.
  • melatonin, its salts, prodrugs, derivatives or solvates is administered 1, 2, 3, 4, 5 or 6 times a day until reaching the total daily dose indicated in the previous paragraph.
  • the administration is performed 1, 2 or 3 times a day, preferably once a day.
  • the treatment period may vary according to the evolution of the patient, and normally lasts between 1 and 30 days, preferably between 3 and 10 days.
  • said sepsis in adults is severe sepsis.
  • SIRS is a generalized inflammatory response of a variety of clinical insults severe According to the definition agreed by the "American College of Chest Physicians / Society of Critical Care Medicine", this syndrome is clinically recognized by the presence of 2 or more of the following symptoms (i) to (iv): (i) Temperature> 38 ° C or ⁇ 36 ° C.
  • hypoperfusion may be included but not limited to lactic acidosis (lactic acid> 3 mmol / l), oliguria (diuresis ⁇ 30 ml / h for 3 hours or 700 ml in 24 hours), coagulopathy (prolonged prothrombin time or plaquetopenia less than 100,000 / ml), or acute alteration in mental state (agitation, obnubilation).
  • lactic acidosis lactic acid> 3 mmol / l
  • oliguria diuresis ⁇ 30 ml / h for 3 hours or 700 ml in 24 hours
  • coagulopathy prolonged prothrombin time or plaquetopenia less than 100,000 / ml
  • acute alteration in mental state agitation, obnubilation
  • situations of oxidative stress can be determined by measuring hydrogen peroxide levels, or the response in the body of antioxidant enzyme activity (for example, by measuring antioxidant enzyme activities such as superoxide dismutase / catalase, glutathione peroxidase and glutathione reductase) or malondialdehyde levels.
  • antioxidant enzyme activities such as superoxide dismutase / catalase, glutathione peroxidase and glutathione reductase
  • malondialdehyde levels for example, by measuring antioxidant enzyme activities such as superoxide dismutase / catalase, glutathione peroxidase and glutathione reductase
  • a decrease in these enzymes is indicative of the inadequate response to a situation of oxidative stress.
  • an adult is considered to be a patient with an age of 18 years or more.
  • a neonate is a patient between the ages of 0 and 27 days, a baby between 28 days and 23 months, a child from 24 months to 1 1 years, and a teenager from 12 to 12 17 years.
  • weight and dose this correlation is not always linear and must be identified for each group of patients.
  • 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 said disease.
  • Treatment also covers the prevention, improvement or elimination of the physiological sequelae of the disease.
  • compositions of the invention Melatonin for the solution for injection has been prepared at a concentration of 10 mg / ml in 25% propylene glycol, with pyrogen-free water in sufficient quantity (API).
  • the batch of injectables prepared was composed of 17 vials with Melatonin (10mg / ml) in Propylene Glycol (25%) API. Of the 17 vials, 9 of them were autoclaved (121 Q C for 20 min) and the remaining 8 were not. All vials were protected from light.
  • the stable solution for at least 7 days, both at room temperature and at 4 ° C.
  • Endotoxin limit 87.7 EU / ml. M.D.V: 1,754.
  • ⁇ cartridge 0.05-5 EU / ml. Lot cartridges: 3434160.
  • Cartridge calibration code 513337283560. Dilution: 1: 100
  • RESULT the analyzed sample has ⁇ 5UE / ml.
  • the calculated endotoxin limit is 87.7 EU / ml.
  • the remaining values obtained are in the percentage allowed.
  • A) Melatonin Group which receives 60mg / 24h intravenously in continuous infusion for 5 days.
  • C) Reference Group (n 20) composed of patients undergoing cholecystectomy, and whose data serve as a reference group.
  • Peripheral blood samples are taken on days 0, 1, 2, 3, 4 and 5 after surgery to proceed to assess the inflammatory, immunological and apoptosis response by determining by CBA technique ⁇ Cytometric Beads Arrays) that combines ELISA with flow cytometry of plasma cytokine levels (IL-2, IL-4, IL-6, IL-10, TNF- ⁇ and IFN- ⁇ ), adhesion molecules (ICAM-1, VCAM-1, ELAM -1), and apoptosis markers (caspase-3, Bcl-2), antioxidant enzyme levels (SOD, catalase, glutathione peroxidase and glutathione reductase) and lipid peroxidation index (malondialdehyde) are determined by spectrophotometry.
  • the levels of melatonin and 6-sulfatoxymelatonin are determined
  • INCLUSION CRITERIA Patients who are in a clinical condition of "severe sepsis" according to the diagnostic criteria of the "American College of Chest Physicians / Society of Critical Care Medicine” defined above, that is, patients with systemic inflammatory response syndrome of Infectious etiology associated with organic dysfunction, hypoperfusion or hypotension, and which will be surgically operated.
  • EXCLUSION CRITERIA Age under 18, pregnancy, medical or surgical terminal illness, chronic liver or kidney failure, psychiatric illness under treatment or refusal to participate in the study.
  • PROTOCOL The sample size has been calculated based on accepting an alpha risk of 0.05 and a beta risk of 0.20 in a unilateral contrast. 20 patients are required in each study group to detect a minimum difference of 10% between groups, assuming that there are 3 study groups and a standard deviation of 7%.
  • ASSESSMENT OF THE INFLAMMATORY AND IMMUNOLOGICAL RESPONSE Determination of plasma cytokine levels (IL-2, IL-4, IL-6, IL-10, TNF-a and IFN-g), slCAM-1 adhesion molecule, markers of apoptosis (sFas, FasL, sFasL), apoptosis proteins (caspase-3, Bcl-2, and PARP), antioxidant enzymes (superoxide dismutase, SOD), catalase glutathione peroxidase and glutathione reductase) as well as levels of lipid peroxidation (malondialdehyde) ) during days 0 (pre-surgical intervention and previous administration of melatonin or placebo) and 1, 2, 3, 4 and 5 after surgery and during the treatment of melatonin or placebo.
  • IL-2, IL-4, IL-6, IL-10, TNF-a and IFN-g slCAM-1 adhe
  • CLINICAL ASSESSMENT To assess the clinical evolution of the patients and the functional status of their organic systems in the days after the surgical intervention, the rating scale of the multiple organic dysfunction syndrome related to sepsis (SOFA) will be used every 24 hours during the study period.
  • SOFA multiple organic dysfunction syndrome related to sepsis
  • SAMPLE MANAGEMENT AND COLLECTION In the blood samples, the level of cytokines, adhesion molecules, markers and apoptosis proteins, antioxidant enzymes, malondialdehyde; the immediate marking and determination of cell apoptosis in leukocytes and lymphocytes after their isolation and separation in ficoll-hypaque and determinations are made biochemical parameters of organic functionality using an automatic Hitachi-912 analyzer (Roche). Melatonin plasma levels are also measured.

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Abstract

L'invention concerne une composition injectable pharmaceutiquement acceptable qui comprend de l'eau, du propylenglycol et de la mélatonine, un dérivé, un sel, un promédicament, ou un solvate de cette dernière. Ladite composition ne contient aucun autre dissolvant, co-dissolvant ou agent dispersant.
PCT/ES2012/070349 2011-05-17 2012-05-17 Préparation injectable de mélatonine WO2012156565A1 (fr)

Applications Claiming Priority (2)

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ESP201130792 2011-05-17
ES201130792A ES2392903B1 (es) 2011-05-17 2011-05-17 Preparación inyectable de melatonina

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WO2012156565A1 true WO2012156565A1 (fr) 2012-11-22

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015144965A1 (fr) * 2014-03-27 2015-10-01 Servicio Andaluz De Salud Préparation durable sous forme de produit injectable de mélatonine stable à long terme
WO2016139635A1 (fr) * 2015-03-04 2016-09-09 Industria Farmaceutica Galenica Senese S.R.L. Composition pharmaceutique pour l"administration parentérale de mélatonine, et son procédé de préparation
WO2018167162A1 (fr) 2017-03-17 2018-09-20 Chiesi Farmaceutici S.P.A. Dosage et régime thérapeutiques pour la mélatonine
WO2019038586A1 (fr) 2017-08-19 2019-02-28 Ftf Pharma Private Limited Composition pharmaceutique de mélatonine
US10342779B2 (en) 2014-10-13 2019-07-09 Worphmed Srl Anhydrous liquid melatonin composition
WO2021038601A1 (fr) 2019-08-30 2021-03-04 Vijayendrakumar Virendrakumarji Redasani Compositions pharmaceutiques liquides de mélatonine pour administration orale et parentérale

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Publication number Priority date Publication date Assignee Title
GR1009541B (el) * 2018-02-26 2019-06-07 Λαμδα Φαρμακευτικα Εργαστηρια Εφαρμοσμενης Ερευνας & Αναπτυξης Α.Ε. Ποσιμα φαρμακευτικα διαλυματα που περιλαμβανουν μελατονινη

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CHEUNG RAYMOND TAK FAI ET AL.: "Preclinical evaluation of pharmacokinetics and safety of melatonin in propylene glycol for intravenous administration", JOURNAL OF PINEAL RESEARCH, vol. 41, no. 4, November 2006 (2006-11-01), pages 337 - 343 *
KESIK, VURAL ET AL.: "Melatonin and 1400W ameliorate both intestinal and remote organ injury following mesenteric ischemia/reperfusion", JOURNAL OF SURGICAL RESEARCH, vol. 157, 2009, pages E97 - E105 *
LIN XIAO-JING ET AL.: "Therapeutic effects of melatonin on heatstroke-induced multiple organ dysfunction syndrome in rats", JOURNAL OF PINEAL RESEARCH, vol. 50, 2011, pages 436 - 444 *
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015144965A1 (fr) * 2014-03-27 2015-10-01 Servicio Andaluz De Salud Préparation durable sous forme de produit injectable de mélatonine stable à long terme
CN106659711A (zh) * 2014-03-27 2017-05-10 安达卢西亚健康服务部 呈现长期稳定性的褪黑素注射剂的持久制剂
US11344531B2 (en) 2014-03-27 2022-05-31 Servicio Andaluz De Salud Durable preparation of an injectable of melatonin exhibiting long-term stability
US10342779B2 (en) 2014-10-13 2019-07-09 Worphmed Srl Anhydrous liquid melatonin composition
WO2016139635A1 (fr) * 2015-03-04 2016-09-09 Industria Farmaceutica Galenica Senese S.R.L. Composition pharmaceutique pour l"administration parentérale de mélatonine, et son procédé de préparation
WO2018167162A1 (fr) 2017-03-17 2018-09-20 Chiesi Farmaceutici S.P.A. Dosage et régime thérapeutiques pour la mélatonine
WO2019038586A1 (fr) 2017-08-19 2019-02-28 Ftf Pharma Private Limited Composition pharmaceutique de mélatonine
WO2021038601A1 (fr) 2019-08-30 2021-03-04 Vijayendrakumar Virendrakumarji Redasani Compositions pharmaceutiques liquides de mélatonine pour administration orale et parentérale
EP4021411A4 (fr) * 2019-08-30 2023-08-09 Vijayendrakumar Virendrakumarji Redasani Compositions pharmaceutiques liquides de mélatonine pour administration orale et parentérale

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