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WO1999047175A1 - Compositions pharmaceutiques contenant des complexes d'inclusion de melatonine - Google Patents

Compositions pharmaceutiques contenant des complexes d'inclusion de melatonine Download PDF

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Publication number
WO1999047175A1
WO1999047175A1 PCT/EP1999/001539 EP9901539W WO9947175A1 WO 1999047175 A1 WO1999047175 A1 WO 1999047175A1 EP 9901539 W EP9901539 W EP 9901539W WO 9947175 A1 WO9947175 A1 WO 9947175A1
Authority
WO
WIPO (PCT)
Prior art keywords
melatonin
composition according
fact
reticulated
inclusion complex
Prior art date
Application number
PCT/EP1999/001539
Other languages
English (en)
Inventor
Giancarlo Santus
Roberto Golzi
Giampiero Besana
Original Assignee
Recordati S.A. Chemical And Pharmaceutical Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Recordati S.A. Chemical And Pharmaceutical Company filed Critical Recordati S.A. Chemical And Pharmaceutical Company
Priority to AU34100/99A priority Critical patent/AU3410099A/en
Publication of WO1999047175A1 publication Critical patent/WO1999047175A1/fr

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds

Definitions

  • the present invention relates to pharmaceutical compositions containing inclusion complexes of melatonin in a polymeric material. These compositions are particularly useful for dissolving melatonin in aqueous solvents.
  • Melatonin N-acetyl-5-methoxytryptamine
  • melatonin is considered to be responsible.
  • An important role of melatonin seems to be that of controlling growth hormone secretion with a possible synergic action in antitumour treatments which use a combination of various drugs.
  • melatonin is known as a potent antioxidant and it has been suggested that it may protect the DNA and cell reproduction processes against errors which cause changes in the reproduction system, such as interaction with free radicals and mutagenic agents.
  • Melatonin is characterised by low solubility in water (5.10-3 M) (Shida C, Journal of Pineal Research, 16:198-201, 1994) and, administered orally to humans, it exhibits a low bioavailability (about 30%) which is also characterised by 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,
  • inclusion complexes of melatonin with an appropriate polymer (e.g. ⁇ -cyclodextrine) it is possible to improve the solubility and the bioavailability of melatonin, in particular when melatonin is to be delivered into an aqueous environment, like in the case of oral administration.
  • 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.
  • inclusion complexes can be found in Kirk Orthmer, Ed. 3, 6:179, 1979, where the different methods available for their preparation, such as, for example, co-grinding, lyophilisation, spray-drying and granulation, are also described.
  • the term inclusion complexes also includes those preparations where the active ingredient is supported by a polymeric material which carries it and helps its dissolution. Detailed description of the invention
  • the inclusion complexes which are part of the invention may include various polymeric materials such as water-soluble complexing agents, hydrophilic linear polymers or swelling reticulated polymers insoluble or slightly soluble in water.
  • the complexes can be prepared using known preparation methods by mixing the polymer with the active ingredient in varying ratios depending on the final characteristics desired.
  • the materials for active-ingredient inclusion or support complexes which can be used to implement the present invention include: - water-soluble complexing agents such as, for example, ⁇ -, ⁇ -, g-cyclodextrines and their derivatives such as, for example, hydroxypropyl- ⁇ -cyclodextrine.
  • ⁇ -Cyclodextrine is the preferred agent for melatonin inclusion.
  • - hydrophilic linear polymers such as polyvinylpyrrolidone (PVP), cellulose and their derivatives.
  • PVP polyvinylpyrrolidone
  • reticulated polyvinylpyrrolidone PVP XL
  • reticulated cyclodextrines reticulated carboxymethylamide
  • dextrans reticulated reticulated carboxymethylamide
  • PVP XL reticulated polyvinylpyrrolidone
  • reticulated cyclodextrines reticulated carboxymethylamide
  • dextrans dextrans
  • the preferred inclusion agent in this class is PVP XL.
  • Cyclodextrines are cyclic oligosaccharides where the glucopyranoside units are bound by glucoside bonds.
  • the cyclodextrine molecules are characterised by a hydrophilic outer surface and an apolar central inner cavity. This allows slightly polar molecules to penetrate into the cyclodextrine lipophilic cavity forming an inclusion complex.
  • melatonin and the vehicle are present in a 1 :1 molar ratio.
  • this ratio can be lower or higher depending on the peculiar characteristics of the polymer chosen and dissolution profile which melatonin should appropriately possess during administration.
  • molar ratios ranging from 1 :0.5 to 1 :20, preferably from 1 :1 to 1 :4, are used.
  • the methods of preparation which can be used to prepare the inclusion complexes as defined in this invention can be of different types and are anyhow part of the known art. Examples of these methods include:
  • - co-grinding which is based on intimate mixing of the active ingredient and selected inclusion vehicle by grinding. Dry co-grinding can use various types of mills (with rotating or vibrating spheres, rotor or high-energy mills) or any other apparatus for grinding/micronising capable of making crystalline melatonin partially or totally amorphous.
  • a variant of this method which uses high-energy mills to prepare the co-ground material is particularly suitable for the formulations of the present invention as it allows a melatonin complex with a very small particle size, typically smaller than 10 ⁇ m and preferably smaller than 5 ⁇ m, to be obtained. Obtaining these particles allows further optimisation of the solubility characteristics of the complex and active ingredient included.
  • melatonin is dissolved in water at 50°C and mixed with the polymer in which it is to be included. After mixing, the water is removed by drying at 45°C.
  • melatonin and the polymer are both distributed in an appropriate solvent.
  • the suspension is sprayed in a hot-air current so that the solvent can evaporate leaving the inclusion complex as a residue.
  • compositions of various types for administration e.g. by the oral, parenteral, rectal, nasal, ocular, vaginal or buccal route.
  • compositions can be formulated into conventional pharmaceutical forms such as hard-gelatine and soft-gelatine capsules; various types of tablets including rapid-dissolution, coated, sugar-coated, slow-release, enteric-coated and lyophilised tablets; granulates; suppositories; solutions for various uses: nasal spray, drops, syrups and the like.
  • compositions according to the invention are generally suitable to provide a daily-dosage of the melatonin inclusion complex in a range from 0.1 to 100 mg, preferably from 1 to 10 mg.
  • the compositions according to the present invention can be used in all those therapeutic areas where melatonin has been found to have a biological activity, such as in tumour prevention and treatment, AIDS treatment, treatment of panic conditions; it can further be used as a medicament having antispastic effects, mild hypnotic effects, myelotropic actions, antimitotic actions, modulating action of NK-cell activity, maintaining an effective immune response and controlling the circadian rhythms.
  • a solution obtained by mild heating of a 1 :4 molar mixture made up of 232 mg of melatonin and 5.13 g of ⁇ -cyclodextrine was filled into 10-cm-diameter plates and lyophilised in a Brizio-Basi freeze-drier using a cycle with the following experimental conditions: cooling -35°C for 4 hours, vacuum 0.1-0.2 mBar, lyophilisation time 24 hours. 5.2 g of complex were obtained.
  • a solution of melatonin and ⁇ -cyclodextrine in a 1 :2 molar ratio was prepared in 1 litre of water, heated to 50°C for 1 hour, then allowed to cool with stirring and slowly evaporated under vacuum to obtain the desired complex.
  • DSC Differential thermal analysis
  • FIG. 1 shows the chromatograms of: a) pure melatonin b) pure ⁇ -cyclodextrine c) a physical mixture of melatonin + ⁇ -cyclodextrine (1 :1 molar ratio) d) a melatonin/ ⁇ -cyclodextrine inclusion complex in a 1 :1 molar ratio for the most significant temperature range (40 to 200°C).
  • a comparison of the chromatograms shows the disappearance in plot d) of the melatonin melting peak at about 118°C due to formation of the inclusion complex.
  • Figure 2 shows: a) a pure melatonin spectrum b) a pure ⁇ -cyclodextrine spectrum c) overlapping of the spectrum of the melatonin/ ⁇ -cyclodextrine inclusion complex in a 1 :1 ratio (d ) and spectrum of the melatonin + ⁇ -cyclodextrine physical mixture (c2).
  • melatonin/ ⁇ -cyclodextrine inclusion compound in a 1 :4 ratio prepared according to the description in Example 1 (method B) was mixed in a V mixer with avicel, lactose, carboxymethylamide and magnesium stearate. 5 kg of this mixture was compressed using the direct-compression method to a weight of 200 mg/tablet in a RONCHI tabletting machine equipped with round 8-mm dies to obtain tablets having the following composition: melatonin/ ⁇ -cyclodextrine 69 mg (equivalent to 3 mg of melatonin), lactose 69 mg, avicel 50 mg, carboxymethylamide 10 mg, magnesium stearate 2 mg. 9
  • the melatonin/ ⁇ -cyclodextrine inclusion complex in a 1 :4 ratio prepared according to the description in Example 1 (method B) was diluted with sorbitol, and lemon flavour and aspartame were then added.
  • the mixture so obtained contained 260 mg of the melatonin/ ⁇ -cyclodextrine complex equivalent to 10 mg of melatonin, and was filled into 3-gram packages each having the following composition: melatonin/ ⁇ -cyclodextrine 260 mg, sorbitol 2695 mg, lemon flavour 30 mg, aspartame 15 mg.
  • Dissolution of tablets containing the inclusion complex The dissolution property of the tablets prepared according to the description in Example 5 was compared with that of tablets prepared using the same excipients but containing melatonin without ⁇ -cyclodextrine ( ⁇ -CDX). Dissolution was conducted in 250 ml of 0.1 N HCI at 37°C stirring at 50 revolutions/minute, using apparatus 2 from the United States Pharmacopoeia (USP, Ed. 23, page 1791, 1995). The samples collected at the times shown in Table 2 below were analysed with a UV spectrophotometer at a wavelength of 276 nm to determine the melatonin percentage released.

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

Abstract

L'invention concerne des compositions pharmaceutiques contenant des complexes d'inclusion de mélatonine dans une matière polymère, notamment dans la β-cyclodextrine. Ces compositions sont particulièrement utiles pour dissoudre la mélatonine dans des solvants aqueux et augmenter la biodisponibilité de la mélatonine.
PCT/EP1999/001539 1998-03-13 1999-03-10 Compositions pharmaceutiques contenant des complexes d'inclusion de melatonine WO1999047175A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU34100/99A AU3410099A (en) 1998-03-13 1999-03-10 Pharmaceutical compositions containing melatonin inclusion complexes

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI98A000510 1998-03-13
IT98MI000510A IT1298731B1 (it) 1998-03-13 1998-03-13 Composizioni farmaceutiche contenenti complessi di inclusione con melatonina

Publications (1)

Publication Number Publication Date
WO1999047175A1 true WO1999047175A1 (fr) 1999-09-23

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IT (1) IT1298731B1 (fr)
WO (1) WO1999047175A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008127609A1 (fr) * 2007-04-11 2008-10-23 Mccarty John A Comprimé de mélatonine et procédés de préparation et d'utilisation
JP2014533251A (ja) * 2011-11-10 2014-12-11 エラテック エス．アール．エル．Ｅｒａｔｅｃｈ Ｓ．Ｒ．Ｌ． メラトニンベースの溶液およびそれらの製造のための粉末
EP3127536A1 (fr) 2015-08-05 2017-02-08 Versailles B.V. Formulations de mélatonine et procédés de préparation et d'utilisation
ITUB20156299A1 (it) * 2015-12-03 2017-06-03 S B M S R L Prodotto comprendente collagene e almeno un farmaco amorfo micronizzato, procedimento per la sua preparazione e relativi usi in campo medico.
US10143654B2 (en) 2011-01-28 2018-12-04 Physician's Seal, LLC Controlled-release compositions of melatonin combined with sedative and/or analgesic ingredients
WO2019038586A1 (fr) 2017-08-19 2019-02-28 Ftf Pharma Private Limited Composition pharmaceutique de mélatonine
US10226447B2 (en) * 2011-01-28 2019-03-12 Physician's Seal, LLC Controlled-release melatonin compositions and related methods
EP3705117A1 (fr) 2019-03-05 2020-09-09 Tradichem Industrial Services, S.L. Mélatonine ayant une meilleure solubilité dans l'eau, sa préparation et ses utilisations
WO2021038601A1 (fr) 2019-08-30 2021-03-04 Vijayendrakumar Virendrakumarji Redasani Compositions pharmaceutiques liquides de mélatonine pour administration orale et parentérale
US20210267942A1 (en) * 2015-03-06 2021-09-02 Repoceuticals Aps Melatonin for preventing and treating radiation vaginitis and proctitis

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WO1998008490A1 (fr) * 1996-09-01 1998-03-05 Pharmos Corporation Coprecipites solides augmentant la biodisponibilite de substances lipophiles
EP0867181A1 (fr) * 1997-03-26 1998-09-30 Franciscus Wilhelmus Henricus Maria Merkus Composition nasale de mélatonine
CN1195525A (zh) * 1998-04-13 1998-10-14 广州市美乐健生物技术有限公司 褪黑素缓释制剂及其生产工艺

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WO1998008490A1 (fr) * 1996-09-01 1998-03-05 Pharmos Corporation Coprecipites solides augmentant la biodisponibilite de substances lipophiles
EP0867181A1 (fr) * 1997-03-26 1998-09-30 Franciscus Wilhelmus Henricus Maria Merkus Composition nasale de mélatonine
CN1195525A (zh) * 1998-04-13 1998-10-14 广州市美乐健生物技术有限公司 褪黑素缓释制剂及其生产工艺

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KONSIL J, PARROTT KA, AYRES JW: "development of a transdermal delivery device for melatonin in vitro study", DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY, vol. 21, no. 12, 1995, pages 1377 - 87, XP002108639 *
LEE BJ, CHOI HG, KIM CK, PARROTT KA, AYRES JW, SACK RL: "Solubility and stability of melatonin in propylene glycol and 2-hydroxypropyl-beta-cyclodextrin vehicles", ARCHIVES OF PHARMACAL RESEARCH, vol. 20, no. 6, December 1997 (1997-12-01), pages 560 - 565, XP002108638 *

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101677994B (zh) * 2007-04-11 2015-07-22 药品生产公司 褪黑激素片剂及制备和使用的方法
EP3056220A1 (fr) 2007-04-11 2016-08-17 John A. Mccarty Comprimé d'une hormone et procédés de préparation et d'utilisation
WO2008127609A1 (fr) * 2007-04-11 2008-10-23 Mccarty John A Comprimé de mélatonine et procédés de préparation et d'utilisation
US10226447B2 (en) * 2011-01-28 2019-03-12 Physician's Seal, LLC Controlled-release melatonin compositions and related methods
US11389428B2 (en) 2011-01-28 2022-07-19 Société des Produits Nestlé S.A. Controlled-release melatonin compositions and related methods
US10143654B2 (en) 2011-01-28 2018-12-04 Physician's Seal, LLC Controlled-release compositions of melatonin combined with sedative and/or analgesic ingredients
JP2014533251A (ja) * 2011-11-10 2014-12-11 エラテック エス．アール．エル．Ｅｒａｔｅｃｈ Ｓ．Ｒ．Ｌ． メラトニンベースの溶液およびそれらの製造のための粉末
US20210267942A1 (en) * 2015-03-06 2021-09-02 Repoceuticals Aps Melatonin for preventing and treating radiation vaginitis and proctitis
EP3127536A1 (fr) 2015-08-05 2017-02-08 Versailles B.V. Formulations de mélatonine et procédés de préparation et d'utilisation
CN109069409A (zh) * 2015-12-03 2018-12-21 Sbm责任有限公司 包含水解胶原和至少一种无定形微粉化药物的产品，其制备方法及在医学领域的相关应用
WO2017094038A1 (fr) * 2015-12-03 2017-06-08 S.B.M. S.R.L. Produit comprenant du collagène hydrolysé et au moins un médicament micronisé amorphe, son procédé de préparation et ses utilisations dans le domaine médical
ITUB20156299A1 (it) * 2015-12-03 2017-06-03 S B M S R L Prodotto comprendente collagene e almeno un farmaco amorfo micronizzato, procedimento per la sua preparazione e relativi usi in campo medico.
WO2019038586A1 (fr) 2017-08-19 2019-02-28 Ftf Pharma Private Limited Composition pharmaceutique de mélatonine
EP3705117A1 (fr) 2019-03-05 2020-09-09 Tradichem Industrial Services, S.L. Mélatonine ayant une meilleure solubilité dans l'eau, sa préparation et ses utilisations
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

Also Published As

Publication number Publication date
ITMI980510A1 (it) 1999-09-13
AU3410099A (en) 1999-10-11
IT1298731B1 (it) 2000-02-02

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