Novel Levothyroxine formulations for oral use
Background of the Invention
Thyroxine active drugs are known for both therapeutic arid prophylactic treatment of thyroid disorders. The thyroid accomplishes its regulation functions by producing the hormones L-triiodothyronine (liothyrjonine; T3) and L-thyroxine (levothyroxine; T4). The physiological actions of thyroid hormones are produced predominantly by T3, the majority of which (approximately 80%) is derived from T4 by deiodination in peripheral tissues.
Administration of levothyroxine sodium provides T4 to a patient. Once absorbed in the body, the administered T4 behaves identically to T4 that otherwise would be secreted by the thyroid gland of the patient. It binds to the same serum proteins, providing a supply of circulating T4-thyroglobulin in the patient. The administered T4 may be deiodinated in vivo to T3. As a result, a patient receiving appropriate doses of levothyroxine sodium will exhibit normal blood levels of T3, even when the patient's thyroid gland has been removed or is not functioning.
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Levothyroxine sodium is prescribed for thyroid hormone replacement therapy in cases of reduced or absent thyroid function in e.g., ailments such as myxedema, cretinism and obesity. Levothyroxine sodium is quite unstable, hygroscopic and degrades rapidly when subjected to high humidity, light or high temperature. Because of the physicochemical properties of the drug, formulations of levothyroxine sodium have extremely short shelf life.
Levothyroxine sodium is available in the form of capsules, tablets and Injection. Levothyroxine sodium for injection is available as sterile lyophilized product for parenteral administration containing 100 and 500 mcg/vial.

U.S. Pat. Nos. 2,889,363 and 2,889,364, to Ginger, et al, disclose processes for producing thyroxine sodium.
U.S. Pat. Nos. 5,955,105 and 6,056,975 to Amit et al., disclose solid pharmaceutical preparation of thyroxine drug.
U.S Pat. No. 9,006,289, to Jiang, et al., discloses lyophilized composition comprising of levothyroxine sodium, phosphate buffer and mannitol.
U.S. application 20140073695 to Yannis et al., discloses a method for the preparation of an oral levothyroxine composition.
The oral formulations cannot deliver the drug into the blood at a rapid rate whereas the injection formulations are associated with painful administration to the patient. The present inventors have developed stable oral spray formulations of Levothyroxine that help in overcoming the disadvantages associated with the prior art formulations. These formulations may provide substantial benefits compared to oral and other modes of drug administration, such as faster appearance of the pharmaceutically active ingredient in the blood, improved dosage reliability, improved safety profile, increased bioavailability and improved patient compliance.
Summary of the Invention
One object of the invention provides stable oral spray formulations of Levothyroxine and methods of preparing such formulations.
Another aspect of the invention is to provide stable oral spray formulations comprising Levothyroxine sodium, buffering agents or pH adjusting agents, one or more solvents and other pharmaceutically acceptable adjuvants thereof.

Detailed description of the Invention
The present invention relates to a stable oral spray formulation of Levothyroxine. More particularly the invention relates to a stabilized Levothyroxine spray formulation comprising buffering agents, solvents, and other pharmaceutically acceptable adjuvants thereof.
In the context of this invention "Levothyroxine" refers to the pharmaceutically acceptable salts, solvates, hydrates and anhydrous forms thereof. The formulations of the present invention preferably comprise Levothyroxine sodium.
As used herein, "oral spray formulation of Levothyroxine" refers to formulation that contains Levothyroxine in dissolved or solubilized form and is intended for oral administration. The Levothyroxine oral spray formulation may be a clear solution designed to be sprayed directly into the mouth, over or under the tongue.
Levothyroxine sodium is quite unstable, hygroscopic and degrades rapidly when subjected to high humidity, light or high temperature. Degradation is further enhanced by the presence of water. The inventors of the present invention have successfully developed a stable oral liquid spray formulation of Levothyroxine despite its rapid degrading nature.
One embodiment of the invention relates to an oral spray formulation of Levothyroxine comprising Levothyroxine sodium and pharmaceutically acceptable excipients.
Another embodiment of the invention relates to oral spray formulation of Levothyroxine comprising:
i. Levothyroxine,
ii. Buffering agents or pH adjusting agents
iii. One or more solvents, and other pharmaceutically acceptable adjuvants.

A preferred embodiment of the invention relates to oral spray formulation of Levothyroxine comprising:
i. Levothyroxine Sodium,
ii. Buffering agents or pH adjusting agents
iii. One or more solvents such as water, polyethylene glycol, ethanol, propylene glycol, glycerol
iv. And other pharmaceutically acceptable adjuvants thereof.
In a most preferred embodiment, the oral spray formulation of the present invention comprises:
i. Levothyroxine Sodium 0.0025 - 5%
ii. Buffering agent or pH adjusting agents 0.0015 - 5%
iii. Solvents qs
iv. Optionally other pharmaceutically acceptable adjuvants such as sweetening agents, flavoring agents, preservatives, penetration enhancers, stabilizers and the like.
Suitable buffering agents include, but not limited to phosphate buffer, citrate buffer, aconitic, sodium carbonate, sodium bicarbonate, tartarate, benzoate, lactate, acetate, boric acid buffer, lactic acid, glutaric, malic, succinic and carbonic acid, alkali or alkaline earth salt of one of these acids, Tris, meglumine, amino acid buffers such as arginine, alanine, histidine, glycine, lysine and the like.
Suitable solvents/cosolvents include, but are not limited to dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-Methylpyrrolidone, Dimethylisosorbide, ethanol, propylene glycol, polyethylene alcohol, glycerol, propylene glycol esters, polyethylene glycols (PEG), water and the like. Preferred solvents are water and propylene glycol.
Suitable pH adjusting agents include the following, but are not limited to sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, ammonium

carbonate, hydrochloric acid, citric acid, lactic acid, phosphoric acid, sodium phosphate, sulfuric acid, and the like. Preferred pH adjusting agents are sodium hydroxide and hydrochloric acid.
The pharmaceutical compositions of the present invention may also contain one or more anti-oxidants, preservatives such as, but are not limited to butylatedhydroxyanisole, butylated hydroxyl toluene, citric acid, lactic acid, benzoic acid, tocopherol, monothioglycerol, ascorbic acid, L-cysteine, methyl paraben, propyl paraben, benzyl alcohol, propyl gallate, thioglycolic acid, citric acid, tartaric acid, phosphoric acid, gluconic acid, thiodipropionic acid, acetonicdicarboxylic acid, chelating agents and the like.
The formulation may additionally contain one or more of flavoring or taste-masking agents and sweetening agents .Examples of taste-masking or flavoring agents include, but are not limited to, synthetic or natural peppermint oil, spearmint oil, citrus oil, fruit flavors (e.g., citrus, orange, lemon, lime, strawberry, melon and mixtures thereof) and sweeteners (e.g., sugars, sorbitol, mannitol, dextrose, sucrose, fructose, levulose, aspartame, sodium cyclamate, saccharin, and sucralose).
The formulation may also contain absorption enhancers or penetration enhancers such as, but not limited to surfactants such as sodium lauryl sulfate, sodium dodecyl sulfate, dioctyl sodium sulfosuccinate, tweens, polysorbates, cetylpyridinium chloride, chitosan, trimethyl chitosan, poly-L-arginine, L-lysine and the like; fatty acids and derivatives; bile salts; chelating agents; sulfoxides such as dimethyl sulfoxide (DMSO), decylmethylsulfoxide; polyols such as propylene glycol, polyethylene glycol; alcohols such as ethanol, isopropanol; glycerol, propanediol and cyclodextrins and the like.
Optionally stabilizing agents, solubility enhancers, and viscosity modifying agents may also be added.

The oral spray formulation can be packed into any suitable containers. Preferred containers are pharmaceutical^ acceptable glass, polyethyleneterephthalate (PET), high density polyethylene (HDPE), crystal zenith (CZ), polyolefins like polypropylene (PP) or polyethylene (PE), cyclic olefins polymer (COP), cyclic olefin copolymer (COC) bottles, Pfeiffer pumps or within any type of pharmaceutically acceptable package, container, pump, or bottle. The spray formulations are preferably propellant free.
The following examples further describe certain specific aspects and embodiments of the present invention and demonstrate the practice and advantages thereof. It is to be understood that the examples are given by way of illustration only and are not intended to limit the scope of the invention in any manner.

Manufacturing process
Ultrapure water was taken in a compounding vessel and arginine was added and stirred. Propylene glycol was added to the solution and stirred. pH of the solution was adjusted to 11 ± 0.5 by the addition of sodium hydroxide solution. Then the bulk solution was cooled to 2°C to 8°C. Levothyroxine sodium was added and stirred till a clear solution was obtained, while maintaining the temperature at 5±3°C. The solution was filtered, followed by filling into suitable containers.

Example 2
S.No Ingredients Quantity
1 Levothyroxine Sodium 0.01-1 mg
~~2 Alanine 0.006 - 4 mg
3 Propylene glycol 0.01-1 ml
4 Sodium hydroxide Qs
5 Ultrapure water qs to 0.1 - 2ml
Example 2
S.No Ingredients Quantity
1 Levothyroxine Sodium 0.01-1 mg
~~2 Alanine 0.006 - 4 mg
3 Propylene glycol 0.01-1 ml
4 Sodium hydroxide Qs
5 Ultrapure water qs to 0.1 - 2ml
Manufacturing process
Ultrapure water was taken in a compounding vessel and alanine was added and stirred. Propylene glycol was added to the solution and stirred. pH of the solution was adjusted to 11 ± 0.5 by the addition of sodium hydroxide solution. Then the bulk solution was cooled to 2°C to 8°C. Levothyroxine sodium was added and stirred till a clear solution was obtained, while maintaining the temperature at 5±3°C. The solution was filtered, followed by filling into suitable containers.
Example 3:
~~7T~| ~ i Quantities in mg
S.No Ingredients — 1 — 1 — 1 —
B Fl F2 F3 F4
1 Levothyroxine sodium 0.5 0.5 0.5 0.5
2 Mannitol 3 - - -
3 Dibasic sodium phosphate heptahydrate
4 Arginine - 15
5 Alanine - - 6 -
6 Glycine - - - 15
7 Sodium hydroxide q.s to adjust the pH 11.0±1.0
8 Ultrapure water qstolml
Example 3:
~~7T~| ~ i Quantities in mg
S.No Ingredients — 1 — 1 — 1 —
B Fl F2 F3 F4
1 Levothyroxine sodium 0.5 0.5 0.5 0.5
2 Mannitol 3 - - -
3 Dibasic sodium phosphate heptahydrate
4 Arginine - 15
5 Alanine - - 6 -
6 Glycine - - - 15
7 Sodium hydroxide q.s to adjust the pH 11.0±1.0
8 Ultrapure water qstolml
Manufacturing process
Ultrapure water was taken in a compounding vessel and buffering agent (as mentioned in example 3) was added and stirred. Mannitol was added if necessary (Fl). pH of the solution

was adjusted to 11 ± 1.0 by the addition of sodium hydroxide solution. Then the bulk solution was cooled to 2°C to 8°C. Levothyroxine sodium was added and stirred till a clear solution was obtained, while maintaining the temperature at 5±3°C. The solution was filtered, followed by filling into suitable containers.
Levothyroxine formulations prepared according to example 3, were tested for stability at 25±2°C/60±5%RH (1 week); 40±2°C/75±5%RH (1 week) and 60±2°C (3 days). The data is summarized in table 1.

Manufacturing process
Ultrapure water was taken in a compounding vessel and L-Arginine was added and stirred. Propylene glycol was added to the solution and stirred. Methyl paraben was added. pH of

the solution was adjusted to 11 ± 0.5 by the addition of sodium hydroxide solution. The solution was cooled to 2°C to 8°C. Levothyroxine sodium was added and stirred till a clear solution was obtained. The solution was filtered, followed by filling into suitable containers.

Manufacturing process
Ultrapure water was taken in a compounding vessel and L-Arginine was added and stirred. Propylene glycol was added to the solution and stirred. Propylparaben was added. Sorbitol was added to the solution and stirred. pH of the solution was adjusted to 11 ± 0.5 by the addition of sodium hydroxide solution. The solution was cooled to 2°C to 8°C. Levothyroxine sodium was added and stirred till a clear solution was obtained. The solution was filtered, followed by filling into suitable containers.