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WO2025056929A1 - Récipient unidose scellé de solution aqueuse de lévothyroxine appropriée pour une administration orale - Google Patents

Récipient unidose scellé de solution aqueuse de lévothyroxine appropriée pour une administration orale Download PDF

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Publication number
WO2025056929A1
WO2025056929A1 PCT/GR2024/000027 GR2024000027W WO2025056929A1 WO 2025056929 A1 WO2025056929 A1 WO 2025056929A1 GR 2024000027 W GR2024000027 W GR 2024000027W WO 2025056929 A1 WO2025056929 A1 WO 2025056929A1
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WO
WIPO (PCT)
Prior art keywords
dose container
sealed single
container according
levothyroxine
composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/GR2024/000027
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English (en)
Inventor
Ioulia Tseti
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Individual
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Individual
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Publication of WO2025056929A1 publication Critical patent/WO2025056929A1/fr
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/14—Details; Accessories therefor
    • A61J1/1468—Containers characterised by specific material properties
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K47/26—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
    • 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
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to blow-fill-seal (BFS) sealed single-dose containers comprising a pharmaceutical composition of an aqueous solution for use in oral administration, which composition comprises levothyroxine or liothyronine or a pharmaceutically acceptable salt thereof, preferably levothyroxine sodium, water and one or more co-solvents and is alcohol-free, exhibits a pH from 8,1 to 8,7, an average density from 1,18 to 1,23 grams per milliliter (g/mL), and viscosity from 20 to 60 cps.
  • BFS blow-fill-seal
  • the thyroid gland is one of the most important endocrine glands of the human body as it regulates various metabolic functions.
  • the thyroid gland secretes the hormones liothyronine (T3) and levothyroxine (T4), which are vital for the metabolism and normal physical and mental development of humans under the control of the pituitary hormone thyrotropin (TSH).
  • TSH pituitary hormone thyrotropin
  • thyroid hormones Especially in the fetus and the newborn, thyroid hormones have a decisive role in the normal development of the central nervous system. Underactive thyroid is referred as hypothyroidism. In hypothyroidism there is a deficiency of T3 and T4 and an increase in TSH levels.
  • congenital hypothyroidism The incidence of congenital hypothyroidism, called congenital hypothyroidism, is up to 1:4000 newborns, with a higher incidence in girls, where it occurs in a 2:1 ratio compared to boys. Untimely detection of congenital hypothyroidism can lead to irreversible damage to the newborn's nervous system and permanent mental retardation. In childhood, the effects of hypofunction of the thyroid gland (e.g. due to undertreatment of the patient) can lead to disorders of psychomotor development, disorders of the child's growth and performance, anemia, etc.
  • hypothyroidism includes the oral administration of synthetic levothyroxine, usually its sodium salt, in tablet form.
  • the effective dose is determined after conducting regular clinical examinations and is equivalent to about 1,7 pg/kg per day, which for an average person corresponds to about 80-150 pg per day.
  • the tablet dissolves in the acidic pH of the gastric environment and levothyroxine is transported to the intestine, where it is absorbed by the intestinal epithelium in the first three hours after administration, at a rate of approximately 70%, either in the upper part of the jejunum or in the lower part of the small intestine, in the ileum [Hays MT. Localization of human thyroxine absorption. Thyroid 1991, 1, 241-248].
  • Intestinal absorption disorders in malabsorption syndromes e.g. celiac disease
  • Document W02013072304 relates to single-dose compositions of thyroid hormones in alcoholic-aqueous solutions. These compositions are stored in low density polyethylene containers, which are then secondarily sealed in a laminated envelope consisting of polyethylene, aluminum and polyethylene terephthalate or alternatively in laminated containers. The specific containers prevent the evaporation of the ethanol and, by extension, the alteration of the composition of the solution. However, these formulations are not indicated for pediatric patients due to the presence of ethanol.
  • Document W02018073209 relates to single-dose compositions of thyroid hormones in glycerol-water solutions, which are stored in low density polyethylene containers which are then secondarily sealed in a laminate envelope consisting of polyethylene, aluminum and polyethylene terephthalate to ensure its stability solution.
  • Document GR20100100508 refers to solutions of levothyroxine in the combination of ethanol, propylene glycol and water. These solutions can be formed into drops and remain stable for three months under normal storage conditions, i.e. at a temperature of 25°C and a humidity of 60%. These compositions also comprise 15- 30% ethanol and are contraindicated for use in pediatric and geriatric patients.
  • Document WO2016137969 refers to solutions of levothyroxine in glycerol and water, wherein the percentage of glycerol is at least 70%.
  • these solutions comprise, as an antioxidant agent, ethylenediaminetetraacetic acid (EDTA) at a rate of up to 1,5% in order to achieve the required stability of the solution.
  • EDTA ethylenediaminetetraacetic acid
  • Document EP2683361 refers to a preparation method of levothyroxine solutions in glycerol and water which have a final pH between 5-6 and which owe their stability to the presence of preservatives including the sodium salt of methyl p- hydroxy benzoate.
  • compositions of levothyroxine solutions either use solvents incompatible for use in pediatric and geriatric populations (e.g., high concentrations of ethanol), or use preservatives (e.g. methyl p-hydroxybenzoate) and antioxidants (e.g. ethylenediaminetetraacetic acid) substances, either not singledose, or not having a pH from 8,1 to 8,7, an average density from 1,18 to 1,23 grams per milliliter (g/mL), and viscosity from 20 to 60 cps, so as to achieve their long-term maintenance.
  • preservatives e.g. methyl p-hydroxybenzoate
  • antioxidants e.g. ethylenediaminetetraacetic acid
  • blow-fill-seal (BFS) sealed single-dose containers comprising a pharmaceutical composition of an aqueous solution for use in oral administration, which composition comprises levothyroxine or liothyronine or a pharmaceutically acceptable salt thereof, preferably levothyroxine sodium, water and one or more cosolvents and is alcohol-free, exhibits a pH from 8,1 to 8,7, an average density from 1,18 to 1,23 grams per milliliter (g/mL), and viscosity from 20 to 60 cps have not been reported in the prior art yet.
  • BFS blow-fill-seal
  • the present invention is defined by the following:
  • BFS Blow-fill-seal sealed single-dose container
  • a pharmaceutical composition of an aqueous solution for use in oral administration which composition comprises levothyroxine or liothyronine or a pharmaceutically acceptable salt thereof, preferably levothyroxine sodium, water and one or more cosolvents and is alcohol-free, exhibits a pH from 8,1 to 8,7, an average density from 1,18 to 1,23 grams per milliliter (g/mL), and viscosity from 20 to 60 cps.
  • Definition 2 Sealed single-dose container according to definition 1, wherein the concentration of levothyroxine or liothyronine or salts thereof ranges from 0,0005% to 0,2% weight by volume (w/v) of the final solution.
  • the co-solvents are preferably selected from polyols, such as alkanetriols, alkanediols and polyethylene glycol, acetone, benzyl benzoate, phthalates, such as dibutyl phthalate, diethyl phthalate, dimethyl phthalate, dimethyl sulfoxide, dimethylacetamide, glycofurol, isopropyl myristate, isopropyl palmitate, propylene carbonate, pyrrolidine, glycerin triacetate, triethyl citrate, trilein, or a combination of two or more thereof, preferably the co-solvent comprises glycerin and more preferably the co-solvent is only glycerin.
  • polyols such as alkanetriols, alkanediols and polyethylene glycol, acetone, benzyl benzoate, phthalates, such as dibutyl phthalate, diethyl phthalate, dimethyl phthal
  • Definition 7 Sealed single-dose container according to any of the definitions 1 to 6, wherein the composition comprises pH buffers, which pH buffers are preferably selected from metal hydroxides and/or citric acid and/or salts thereof.
  • Definition 8 Sealed single-dose container according to any of the definitions 1 to 7, wherein the composition comprises a pharmaceutically acceptable flavoring agent preferably selected from strawberry, banana, apricot, cherry, orange, lemon, caramel and/or coffee.
  • a pharmaceutically acceptable flavoring agent preferably selected from strawberry, banana, apricot, cherry, orange, lemon, caramel and/or coffee.
  • Definition 9 Sealed single-dose container according to any of the definitions 1 to 8, for use in the management, treatment or prevention of hypothyroidism in neonatal, pediatric, adult and geriatric patients, of goitre, of nodular thyroid disease, of thyroid cancer, of subclinical hypothyroidism and of myxoedematous coma.
  • blow-fill-seal (BFS) sealed single-dose containers comprising a pharmaceutical composition of an aqueous solution for use in oral administration, which composition comprises levothyroxine or liothyronine or a pharmaceutically acceptable salt thereof, preferably levothyroxine sodium, water and one or more co-solvents and is alcohol-free, exhibits increased stability over time, especially when it exhibits a pH from 8,1 to 8,7, an average density from 1,18 to 1,23 grams per milliliter (g/mL), and viscosity from 20 to 60 cps and more specifically at least one year longer shelf life than aqueous solutions of levothyroxine in other types of containers e.g. multi-dose.
  • BFS blow-fill-seal
  • this solution does not comprise alcohol, improves patient tolerance, as it does not cause the slightest irritation or toxicity even in pediatric patients.
  • compositions of the present invention can be prepared by methods already known in the state of art.
  • composition of the present invention comprises the following per ml_
  • the above composition exhibits an average density from 1,18 to 1,23 grams per milliliter (g/ml_) and a viscosity from 20 to 60 cps.
  • composition of the present examples 1 exhibits all the advantages of the present invention mentioned above.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des récipients à dose unique scellés par formage-remplissage-scellage (BFS) comprenant une composition pharmaceutique d'une solution aqueuse destinée à être utilisée en administration orale, laquelle composition comprend de la lévothyroxine ou de la liothyronine ou un sel pharmaceutiquement acceptable de celles-ci, de préférence de la lévothyroxine sodique, de l'eau et un ou plusieurs co-solvants et est exempte d'alcool, présente un pH de 8,1 à 8,7, une densité moyenne de 1,18 à 1,23 gramme par millilitre (g/ml) et une viscosité de 20 à 60 cps.
PCT/GR2024/000027 2023-09-15 2024-09-13 Récipient unidose scellé de solution aqueuse de lévothyroxine appropriée pour une administration orale Pending WO2025056929A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GR20230100740 2023-09-15
GR20230100740A GR1010807B (el) 2023-09-15 2023-09-15 Σφραγισμενος μονοδοσικος περιεκτης υδατικου διαλυματος λεβοθυροξινης καταλληλος για απο του στοματος χορηγηση

Publications (1)

Publication Number Publication Date
WO2025056929A1 true WO2025056929A1 (fr) 2025-03-20

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Country Status (2)

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GR (1) GR1010807B (fr)
WO (1) WO2025056929A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GR20100100508A (el) 2010-09-10 2012-04-30 Alapis Α.Β.Ε.Ε., Ποσιμα φαρμακευτικα διαλυματα για τη θεραπεια του υποθυρεοειδισμου
WO2013072304A1 (fr) 2011-11-14 2013-05-23 Altergon S.A. Préparation pharmaceutique monodose d'hormones thyroïdiennes t3 et/ou t4
EP2683361A1 (fr) 2011-03-10 2014-01-15 EMP Pharma GmbH Procédé de préparation d'une solution de lévothyroxine
WO2016137969A2 (fr) 2015-02-27 2016-09-01 Parikh Nilesh Formulations liquides de lévothyroxine
WO2018073209A1 (fr) 2016-10-18 2018-04-26 Altergon Sa Solutions conditionnées à stabilité élevée d'hormone thyroïdienne t4
US20190060217A1 (en) * 2015-11-04 2019-02-28 Leiutis Pharmaceuticals Pvt. Ltd. Novel levothyroxine formulations for oral use

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11241382B2 (en) * 2019-03-01 2022-02-08 Altergon Sa Administration regimen of compositions of T4 thyroid hormone with high oral absorption
GR1009815B (el) * 2019-07-25 2020-09-15 Ιουλια Κλεωνος Τσετη Μη αλκοολουχο ελευθερο απο συντηρητικα και καταλληλο για απο του στοματος χορηγηση πολυδοσικο διαλυμα λεβοθυροξινης για την αντιμετωπιση του υποθυρεοειδισμου

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GR20100100508A (el) 2010-09-10 2012-04-30 Alapis Α.Β.Ε.Ε., Ποσιμα φαρμακευτικα διαλυματα για τη θεραπεια του υποθυρεοειδισμου
EP2683361A1 (fr) 2011-03-10 2014-01-15 EMP Pharma GmbH Procédé de préparation d'une solution de lévothyroxine
US20140073695A1 (en) * 2011-03-10 2014-03-13 Emp Pharma Gmbh Method for the preparation of a levothyroxine solution
WO2013072304A1 (fr) 2011-11-14 2013-05-23 Altergon S.A. Préparation pharmaceutique monodose d'hormones thyroïdiennes t3 et/ou t4
WO2016137969A2 (fr) 2015-02-27 2016-09-01 Parikh Nilesh Formulations liquides de lévothyroxine
US20190060217A1 (en) * 2015-11-04 2019-02-28 Leiutis Pharmaceuticals Pvt. Ltd. Novel levothyroxine formulations for oral use
WO2018073209A1 (fr) 2016-10-18 2018-04-26 Altergon Sa Solutions conditionnées à stabilité élevée d'hormone thyroïdienne t4

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