Sealed single dose container of an aqueous levethylenin

Abstract

The present invention relates to a blow-potting (BFS) sealed single dose container comprising a pharmaceutical composition of an aqueous solution for oral administration, said composition comprising levothyroxine or liothyronin or a pharmaceutically acceptable salt thereof, water and one or more co-solvents and being alcohol-free, exhibiting a pH of 8.1 to 8.7, an average density of 1.18 to 1.23 g / ml (g / mL) and a viscosity of 20 to 60 cps, preferably, the pharmaceutically acceptable salt is levothyroxine sodium.

Description

Technical Field

[0001] This invention relates to a blow-fill-seal (BFS) sealed single-dose container comprising a pharmaceutical composition for oral administration of an aqueous solution, said composition comprising levothyroxine or iodine or a pharmaceutically acceptable salt thereof, water and one or more cosolvents and being alcohol-free, exhibiting a pH of 8.1 to 8.7, an average density of 1.18 to 1.23 g / mL and a viscosity of 20 to 60 cps, wherein the pharmaceutically acceptable salt is preferably levothyroxine sodium. Background Technology

[0002] The thyroid gland is one of the most important endocrine glands in the human body because it regulates various metabolic functions. The thyroid gland secretes the hormones iotheronine (T3) and levothyroxine (T4), which, under the control of the pituitary hormone thyroid-stimulating hormone (TSH), are essential for human metabolism and normal physical and mental development. Especially in fetuses and newborns, thyroid hormones play a decisive role in the normal development of the central nervous system. An underactive thyroid gland is called hypothyroidism. In hypothyroidism, T3 and T4 are deficient, and TSH levels are increased. The incidence of congenital hypothyroidism (called congenital hypothyroidism) is as high as 1 in 4000 newborns, with a higher incidence in girls (2:1 ratio compared to boys). Failure to detect congenital hypothyroidism in a timely manner can lead to irreversible damage to the neonatal nervous system and permanent intellectual disability. In childhood, the effects of hypothyroidism (e.g., due to inadequate treatment of the patient) can lead to psychomotor developmental disorders, growth and performance disorders, anemia, and other conditions. However, even in adults, more and more people are experiencing thyroid dysfunction, which has direct consequences in daily life (fatigue, weakness, drowsiness, weight fluctuations, etc.) and in the long term, as it can lead to increased cardiovascular morbidity and mortality.

[0003] Modern treatment for hypothyroidism includes oral administration of synthetic levothyroxine in tablet form, usually its sodium salt. The effective dose is determined after regular clinical examinations and is equivalent to approximately 1.7 μg / kg / day, which for the average person is approximately 80–150 μg / day. The tablets dissolve in the acidic pH of the gastric environment and transport levothyroxine into the intestines, where it is absorbed by the intestinal epithelium at a rate of approximately 70% within the first three hours after administration, either in the upper jejunum or the lower small intestine (in the ileum) [Hays MT, Localization of human thyroxine absorption. Thyroid 1991, 1, 241–248]. Malabsorption syndromes (e.g., celiac disease), dietary high-fiber foods, and co-administration of other medications (e.g., iron, calcium) can reduce levothyroxine absorption, while fasting increases it. For these reasons, it is recommended to take levothyroxine on an empty stomach and at a different time than other medications.

[0004] Replacement therapy for congenital hypothyroidism in infants, toddlers, and young children is administered using levothyroxine tablets, dissolved in water and given via syringe (for infants) or swallowed with a spoon (for older children). However, current consensus guidelines for congenital hypothyroidism prohibit the preparation of reusable suspensions from tablets due to levothyroxine's sensitivity to water and light, and its tendency to break down into other compounds such as iothronine (T3), 2-(4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodophenyl)acetic acid (TETRAC), and (4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodobenzoic acid (TETRAFA).

[0005] Therefore, it is considered necessary to develop a stable liquid formulation of levothyroxine, the use of which will, on the one hand, solve the practical and technical problems caused by the daily need for dissolving tablets, and on the other hand, facilitate administration to newborns, infants, and children. Furthermore, it is necessary to ensure the accuracy of the dosage, and in early childhood, there is always concern that the tablet form may not dissolve sufficiently or isomerically in water, thus potentially preventing the administration of the appropriate dose.

[0006] Various solutions of levothyroxine have been reported in the prior art.

[0007] Reference WO2013072304 relates to single-dose compositions of thyroid hormones in an alcohol-water solution. These compositions are stored in low-density polyethylene containers, which are then resealed in a laminated sleeve composed of polyethylene, aluminum, and polyethylene terephthalate, or optionally sealed in a laminated container. The specific containers prevent ethanol evaporation, thereby preventing changes in the solution composition. However, due to the presence of ethanol, these formulations are not suitable for pediatric patients.

[0008] Document WO2018073209 relates to a single-dose composition of thyroid hormone in an aqueous glycerol solution, which is stored in a low-density polyethylene container and then resealed in a laminated enclosure composed of polyethylene, aluminum and polyethylene terephthalate to ensure its stability.

[0009] Reference GR20100100508 describes levothyroxine solutions in a combination of ethanol, propylene glycol, and water. These solutions can form droplets and remain stable for three months under normal storage conditions (i.e., at 25°C and 60% humidity). These compositions also contain 15-30% ethanol and are contraindicated in pediatric and elderly patients.

[0010] Reference WO2016137969 relates to a levothyroxine solution in glycerol and water, wherein the percentage of glycerol is at least 70%. Furthermore, these solutions contain up to 1.5% ethylenediaminetetraacetic acid (EDTA) as an antioxidant to achieve the required stability of the solution.

[0011] Document EP2683361 describes a method for preparing a levothyroxine solution in glycerol and water, with a final pH of 5-6, and its stability is attributed to the presence of preservatives (including the sodium salt of methylparaben).

[0012] All of the above-described levothyroxine solutions either use solvents unsuitable for pediatric and elderly populations (e.g., high concentrations of ethanol), or contain preservatives (e.g., methylparaben) and antioxidants (e.g., EDTA), are not single-dose, or do not have a pH of 8.1 to 8.7, an average density of 1.18 to 1.23 g / mL, and a viscosity of 20 to 60 cps to achieve their long-term maintenance.

[0013] Despite the achievements already mentioned in the existing technology, there is still a need to further improve the stability and dosage accuracy of levothyroxine aqueous solutions due to increasing requirements for quality and safety.

[0014] However, there are no reports in the prior art of blow-fill-seal (BFS) sealed single-dose containers containing a pharmaceutical composition of an aqueous solution for oral administration, the composition comprising levothyroxine or iothronine or a pharmaceutically acceptable salt thereof, water and one or more cosolvents and being alcohol-free, exhibiting a pH of 8.1 to 8.7, an average density of 1.18 to 1.23 g / mL and a viscosity of 20 to 60 cps, wherein the pharmaceutically acceptable salt is preferably levothyroxine sodium. Summary of the Invention

[0015] The novel combination of container and composition with these specific features proposed in this invention exhibits all the advantages of the prior art, and even has a surprisingly improved stability over time.

[0016] More specifically, the present invention is defined as follows:

[0017] Definition 1. A blow-fill-seal (BFS) sealed single-dose container containing a pharmaceutical composition for oral administration of an aqueous solution, the composition comprising levothyroxine or iodine or a pharmaceutically acceptable salt thereof, water and one or more cosolvents and being alcohol-free, exhibiting a pH of 8.1 to 8.7, an average density of 1.18 to 1.23 g / mL and a viscosity of 20 to 60 cps, wherein the pharmaceutically acceptable salt is preferably levothyroxine sodium.

[0018] Definition 2. A sealed single-dose container according to Definition 1, wherein the concentration of levothyroxine or iodothronine or a salt thereof is 0.0005% to 0.2% by weight (w / v).

[0019] Definition 3. A sealed single-dose container according to any one of Definitions 1 to 2, which is made of low-density polyethylene and placed in an aluminum pouch.

[0020] Definition 4. A sealed single-dose container according to any one of Definitions 1 to 3, wherein the cosolvent is preferably selected from polyols, such as alkyltriols, alkyldiols and polyethylene glycol; acetone; benzyl benzoate; phthalates, such as dibutyl phthalate, diethyl phthalate, dimethyl phthalate; dimethyl sulfoxide; dimethyl acetamide; tetraethylene glycol, isopropyl myristate, isopropyl palmitate, propylene carbonate, pyrrolidine, triacetyl triacetate, triethyl citrate, triolein or combinations of two or more thereof, preferably the cosolvent contains glycerol, more preferably the cosolvent is only glycerol.

[0021] Definition 5. A sealed single-dose container according to any one of Definitions 1 to 4, wherein the percentage of glycerol in the composition is 85% to 95% by weight / volume (w / v) of the total solution volume.

[0022] Definition 6. A sealed single-dose container according to any one of Definitions 1 to 5, wherein the composition is free of preservatives, such as methylparaben and / or propylparaben, and / or antioxidants, such as ethylenediaminetetraacetic acid.

[0023] Definition 7. A sealed single-dose container according to any one of Definitions 1 to 6, wherein the composition comprises a pH buffer, the pH buffer preferably being selected from metal hydroxides and / or citric acid and / or salts thereof.

[0024] Definition 8. A sealed, single-dose container according to any one of 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.

[0025] Definition 9. A sealed, single-dose container according to any one of Definitions 1 to 8, used for the control, treatment or prevention of hypothyroidism, goiter, nodular thyroid disease, thyroid cancer, subclinical hypothyroidism and myxedema coma in neonates, pediatrics, adults and elderly patients.

[0026] Surprisingly, blow-fill-seal (BFS) sealed single-dose containers containing pharmaceutical compositions of aqueous solutions for oral administration, the compositions comprising levothyroxine or iodine or a pharmaceutically acceptable salt thereof (preferably levothyroxine sodium), water and one or more cosolvents and being alcohol-free, exhibit increased stability over time, particularly when they exhibit a pH of 8.1 to 8.7, an average density of 1.18 to 1.23 g / mL, and a viscosity of 20 to 60 cps, and more specifically, a shelf life at least one year longer than that of aqueous levothyroxine solutions in other types of containers (e.g., multi-dose containers).

[0027] In addition to stability, it was surprisingly found that although the blow-fill-seal (BFS) sealed single-dose container is a single dose, it has the advantage of accurate dosage to be received by the patient.

[0028] Furthermore, it was surprisingly found that the fact that the solution does not contain alcohol improved patient tolerance, as it did not cause even the slightest irritation or toxicity in pediatric patients.

[0029] Furthermore, it has been surprisingly found that the more limited the scope of the claims, the stronger the effects and advantages of the invention.

[0030] The compositions of the present invention can be prepared by methods known in the prior art. Detailed Implementation

[0031] The present invention is further described by way of the following indicative but non-limiting embodiments.

[0032] Example 1: In a preferred embodiment, each mL of the composition of the present invention comprises the following substances:

[0033]

[0034] The above compositions exhibit an average density of 1.18 to 1.23 g / mL and a viscosity of 20 to 60 cps.

[0035] The composition of this Example 1 exhibits all the advantages of the present invention described above.

Claims

1. A blow-fill-seal (BFS) sealed single-dose container comprising a pharmaceutical composition of an aqueous solution for oral administration, said composition comprising levothyroxine or iothronine or a pharmaceutically acceptable salt thereof, water and one or more cosolvents and being alcohol-free, exhibiting a pH of 8.1 to 8.7, an average density of 1.18 to 1.23 g / mL and a viscosity of 20 to 60 cps, wherein said pharmaceutically acceptable salt is preferably levothyroxine sodium.

2. The sealed single-dose container according to claim 1, wherein, The concentration of the levothyroxine or iodine or its salt is 0.0005%-0.2% by weight (w / v) of the final solution.

3. The sealed single-dose container according to any one of claims 1 to 2, which is made of low-density polyethylene and placed in an aluminum pouch.

4. The sealed single-dose container according to any one of claims 1 to 3, wherein, The cosolvent is preferably selected from polyols, such as alkyltriols, alkyldiols, and polyethylene glycol; acetone; benzyl benzoate; phthalates, such as dibutyl phthalate, diethyl phthalate, and dimethyl phthalate; dimethyl sulfoxide; dimethyl acetamide; tetraethylene glycol; isopropyl myristate; isopropyl palmitate; propylene carbonate; pyrrolidine; glyceryl triacetate; triethyl citrate; glyceryl trioleate, or a combination of two or more thereof. Preferably, the cosolvent contains glycerol, and more preferably, the cosolvent is only glycerol.

5. The sealed single-dose container according to any one of claims 1 to 4, wherein, The percentage of glycerol in the composition is 85% to 95% by weight (w / v) of the total solution volume.

6. The sealed single-dose container according to any one of claims 1 to 5, wherein, The composition does not contain preservatives, such as methylparaben and / or propylparaben, and / or antioxidants, such as ethylenediaminetetraacetic acid.

7. The sealed single-dose container according to any one of claims 1 to 6, wherein, The composition contains a pH buffer, which is preferably selected from metal hydroxides and / or citric acid and / or their salts.

8. The sealed single-dose container according to any one of claims 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.

9. A sealed single-dose container according to any one of claims 1 to 8, for the control, treatment or prevention of hypothyroidism, goiter, nodular thyroid disease, thyroid cancer, subclinical hypothyroidism and myxedema coma in neonates, pediatrics, adults and elderly patients.

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