Claims:CLAIMS

We claim,

1. A ready to use liquid solution of levothyroxine comprising levothyroxine sodium, 1 to 20% propylene glycol and 0.1 mg/ml to 2 mg/ml of stabilizer, and water for injection.

2. The ready to use liquid solution of levothyroxine according to claim 1, wherein levothyroxine sodium is present in the range from 10 mcg/ml to 500 mcg/ml.

3. The ready to use liquid solution of levothyroxine according to claim 1, wherein levothyroxine sodium is present in the range from 20 mcg/ml to 100 mcg/ml.

4. The ready to use liquid solution of levothyroxine according to claim 1, wherein propylene glycol is present in the concentration of less than 1 to 15% w/v.

5. The ready to use liquid solution of levothyroxine according to claim 1, wherein propylene glycol is present in the concentration of 10% w/v.

6. The ready to use liquid solution of levothyroxine according to claim 1, wherein stabilizer is triethanolamine and is present in the concentration of 0.75 mg/mL to 1.25 mg/mL.

7. The ready to use liquid solution of levothyroxine according to claim 1, wherein pH adjusting agent is selected from the group consisting of hydrochloric acid, citric acid, sulfuric acid, acetic acid, tartaric acid, lactic acid, sodium hydroxide, potassium hydroxide, sodium carbonate or combinations thereof.

8. The ready to use liquid solution of levothyroxine according to claim 1, wherein pH of the solution is in the range from 7 to 11.

9. The ready to use liquid solution of levothyroxine according to claim 1, wherein pH of the solution is in the range from 8.5 to 10.5

10. The ready to use liquid solution of levothyroxine according to claim 1, wherein the solution is for parenteral administration.

11. The process for preparing ready to use liquid solution of levothyroxine according to claim 1, comprises the steps of;
a) Taking required quantity of water for Injection,
b) Adding required quantity of solubilizer till complete mixing,
c) Adding required quantity of stabilizer till complete mixing,
d) Adding required quantity of Levothyroxine sodium in till get clear solution,
e) Making up the volume of bulk as per theoretical batch size with water for injection.

Dated this 10th Apr, 2021

, Description:
FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)

1.Title of the invention – READY TO USE LIQUID SOLUTION OF LEVOTHYROXINE
2. Applicant(s)
NAME: AUXILLA PHARMACEUTICALS AND RESEARCH LLP
NATIONALITY: Indian
ADDRESS: Plot no. 194, Medows 2, Gokuldham, Village Sanathal, TA: Sanathal, Ahmedabad-382110, Gujarat, INDIA

3. PREAMBLE TO THE DESCRIPTION

The following specification particularly describes the invention and the manner in which it is to be performed

READY TO USE LIQUID SOLUTION OF LEVOTHYROXINE

FIELD OF THE INVENTION
The present invention is related to a ready to use liquid solution of levothyroxine. The present invention is also related to a ready to use liquid solution of levothyroxine which is comprising levothyroxine, a solubilizer, a stabilizer, and water for injection. The present invention also relates to process of preparation of ready to use liquid solution of levothyroxine.

BACKGROUND OF THE INVENTION
The thyroid accomplishes its regulation functions by producing the hormones l-triiodothyronine (liothyronine; T3) and l-thyroxine (levothyroxine; T4).The healthy thyroid produces hormones that regulate multiple metabolic processes and that play important roles in growth and development, in maturation of the central nervous system and bone including augmentation of cellular respiration and thermogenesis, and in metabolism of proteins, carbohydrates and lipids.

This hormone nuclear receptor complex then activates gene transcription and synthesis of messenger RNA and cytoplasmic proteins. The physiological actions of thyroid hormones are believed to be produced predominantly by T3, approximately 80% of which is derived from T4 by deiodination in peripheral tissues. As per studies the thyroid hormones are believed to exert their physiologic actions through control of DNA transcription and protein synthesis. It is presently believed that the T3 and T4 hormones diffuse into the cell nucleus and bind to thyroid receptor proteins attached to DNA.

The administration of levothyroxine sodium provides T4 to a patient. Once absorbed by the organism, the administered T4 behaves identically to T4 that otherwise would be secreted by the thyroid gland of the patient, and 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.

Marketed levothyroxine sodium for injection is a sterile lyophilized product for parenteral administration of levothyroxine sodium for thyroid replacement therapy. Levothyroxine sodium for injection is particularly useful when thyroid replacement is needed on an urgent basis, for short term thyroid replacement, and/or when oral administration is not possible, such as for a patient in a state of myxedema coma.

The conventional formulations of levothyroxine sodium for injection are preservative-free lyophilized powders containing synthetic crystalline levothyroxine sodium and the excipients mannitol, tribasic sodium phosphate, and sodium hydroxide. These conventional formulations typically contain 10 milligrams (mg) of mannitol, 700 µg of tribasic sodium phosphate, and either 200 µg or 500 µg of levothyroxine sodium. Administration of the conventional formulation involves reconstitution of the lyophilized powder in 5 milliliters (mL) of 0.9% sodium chloride injection (USP), to provide injectable solutions having levothyroxine sodium concentrations of 40 micrograms per milliliter (µg/mL) or 100 µg/mL, respectively.

US9006289B2 describes a levothyroxine composition includes levothyroxine sodium, mannitol and phosphate buffer. The composition is a solid and in lyophilized form and which is to be reconstituted at the time of administration.

However, use of the conventional lyophilized formulations requires reconstitution or dilution by healthcare practitioners prior to use. Once reconstituted, the levothyroxine sodium solutions have a limited stability, and must be used within a few hours of reconstitution. In addition, contaminants may be introduced into the solutions during the reconstitution process, thereby compromising patient safety. There remains an enduring difficulty for patients, care takers and healthcare professionals (particularly those looking after children) with the administration of levothyroxine as currently there is no entirely suitable formulation available.

US9782376 and US10398669 discloses liquid formulation comprising levothyroxine or a pharmaceutically acceptable salt thereof. The disclosed formulation includes tromethamine, sodium iodide, sodium chloride and water and has a pH of about 9.0 to about 11.5.

However, still there is need to develop ready to use liquid solution of levothyroxine which is ready to use and easy to manufacture with less number of excipients to avoid compatibility issue and still offering satisfactory stability.

In summary there is still exist a need to have a ready to use liquid solution of levothyroxine which overcomes all problems as mentioned in prior art.

The inventors in the present invention have arrived to the liquid solution of levothyroxine with aims to ameliorate one or more of problems cited in above prior arts by preparing a liquid solution of levothyroxine as described herein.

OBJECTIVES OF THE INVENTION

First objective of the present invention is to design and develop a liquid solution of levothyroxine.

Yet another objective of the present invention is to provide stable ready to use liquid solution of levothyroxine.

Yet another objective of this invention is to provide liquid solution of levothyroxine which do not require reconstitution before administration.

Yet another objective of this invention is to provide a liquid solution of levothyroxine which is stable.

Yet another objective of this invention is to provide liquid solution of levothyroxine which is easy to manufacture at large scale.

SUMMARY OF THE INVENTION

The present invention is all about to provide a ready to use liquid solution of levothyroxine.

The main aspect of the present invention is to provide a ready to use liquid solution of levothyroxine comprising levothyroxine sodium, 1 to 20% propylene glycol and 0.1 mg/ml to 2 mg/ml of stabilizer, and water for injection.

In another aspect the present invention provides a process for the preparation of a ready to use liquid solution of levothyroxine comprising steps of
a) Taking required quantity of water for Injection,
b) Adding required quantity of solubilizer till complete mixing,
c) Adding required quantity of stabilizer till complete mixing,
d) Adding required quantity of Levothyroxine sodium in till get clear solution,
e) Making up the volume of bulk as per theoretical batch size with water for injection.

DETAILED DESCRIPTION OF THE INVENTION

The invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

As used herein all percentages are by weight/volume (w/v) of the total composition unless otherwise specified.
The following terms are used interchangeably herein:
"active", "drug", and "active ingredient" are interchangeable;

The term “levothyroxine” as used herein is in the form of sodium salt and can be used interchangeably with levothyroxine. In the whole specification, wherever levothyroxine is mentioned is to be considered as levothyroxine sodium only.

A “therapeutically effective amount” or “effective amount” is that amount of a pharmaceutical agent to achieve a pharmacological effect. The term “therapeutically effective amount” includes, for example, a prophylactically effective amount.

The terms “a” and “an” do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item.

The term “about” is used synonymously with the term “approximately.” As one of ordinary skill in the art would understand, the exact boundary of “about” will depend on the component of the composition. Illustratively, the use of the term “about” indicates that values slightly outside the cited values, i.e., plus or minus 0.1% to 10%, which are also effective and safe. Thus compositions slightly outside the cited ranges are also encompassed by the scope of the present claims.

The terms “comprising,” “including,” and “containing” are non-limiting. Other non-recited elements may be present in embodiments claimed by these transitional phrases. Where “comprising,” “containing,” or “including” are used as transitional phrases other elements may be included and still form an embodiment within the scope of the claim. The open-ended transitional phrase “comprising” encompasses the intermediate transitional phrase “consisting essentially of” and the close-ended phrase “consisting of.”

By the term "pH", as used herein, is meant "apparent pH" wherein the pH measurement is carried out on the levothyroxine containing composition in final form, for example, by measuring the pH of the solution.

The main embodiment of the present invention is about a ready to use liquid solution of levothyroxine comprising levothyroxine sodium, 1 to 20 % propylene glycol and 0.1 mg/ml to 2 mg/ml of stabilizer, and water for injection.

The ready to use liquid solution of levothyroxine is offering advantage of avoiding reconstitution process before administration which can avoid medical error.

As per one embodiment, levothyroxine sodium is present in the range from about 10 mcg/ml to about 500 mcg/ml, preferably about 10 mcg/ml to about 450 mcg/ml, preferably about 10 mcg/ml to about 400 mcg/ml, preferably about 10 mcg/ml to about 350 mcg/ml, preferably about 10 mcg/ml to about 300 mcg/ml, preferably about 10 mcg/ml to about 250 mcg/ml, preferably about 10 mcg/ml to about 200 mcg/ml, preferably about 10 mcg/ml to about 150 mcg/ml, preferably about 10 mcg/ml to about 100 mcg/ml, preferably about 15 mcg/ml to about 100 mcg/ml, most preferably about 20 mcg/ml to about 100 mcg/ml.

As per one embodiment, the present invention contains solubilizer. As per one embodiment, solubilizer can be selected from group consisting of glycol ethers, polyethylene glycol, polyethylene glycol derivatives, propylene glycol derivatives, fatty alcohols, aromatic alcohols, propylene glycol, glycerols, oils, surfactants, glucosides, and mixtures thereof.

As per preferred embodiment, the solubilizer is propylene glycol. As per preferred embodiment, the propylene glycol is present in the concentration of less than 40% w/v, preferably less than 35% w/v, preferably less than 30% w/v, preferably less than 25% w/v, more preferably less than 20% w/v and most preferably less than 20% w/v.

As per most preferred embodiment, the solubilizer is propylene glycol and is present in the range from 1 to 10%.

Stabilizer as per present invention is playing a critical role in establishing the stability of the liquid solution of levothyroxine sodium.

As per present invention, the stabilizer can be selected from group consisting of triethanolamine, arginine, histidine, Polyvinylpyrrolidone, triaryl phosphate, alkyldiaryl phosphate.

As per preferred embodiment, the stabilizer for the present invention is triethanolamine. As per one embodiment the stabilizer or triethanolamine is present in the range from 0.1 mg/ml to 2 mg/ml, preferably 0.1 mg/ml to 1.75 mg/ml, preferably 0.1 mg/ml to 1.50 mg/ml, preferably 0.2 mg/ml to 1.50 mg/ml, more preferably 0.5 mg/ml to 1.50 mg/ml.

As per most preferred embodiment, the stabilizer for the present invention is triethanolamine present in the range from 0.75 mg/ml to 1.25 mg/ml, most preferably 1.00 mg/ml to 1.25 mg/ml.

As per present invention, the pH adjusting agents can be selected from the group consisting of hydrochloric acid, citric acid, sulfuric acid, acetic acid, tartaric acid, lactic acid, sodium hydroxide, potassium hydroxide, sodium carbonate or combinations thereof.

As per one embodiment, the pH of the ready to use liquid solution of levothyroxine of present invention is in the range from 7 to 11, more preferably in the range from 8.5 to 10.5.

The vehicle for the ready to use liquid solution of levothyroxine of present invention is selected from group consisting of sodium chloride, lactated ringers, dextrose, water for injection, sterile water for injection, bacteriostatic water for injection, glycerin, ethyl alcohol, water immiscible solvents like ethyl oleate, isopropyl myristate, benzyl benzoate, fixed oil, com oil, cottonseed oil, peanut oil, sesame oil or combinations thereof. The preferred vehicle for present invention is water for injection.

The ready to use liquid solution of levothyroxine of present invention may contain one or more inactive excipients which can be selected from the group consisting of chelating agents, antioxidants, buffers and preservatives.

The chelating agent can be selected from disodium edetate dihydrate, disodium edetate, edetic acid, ethylenediamine tetraacetic acid, calcium disodium ethylenediamine tertaacetic acid, diethylenetriamine pentaacetic acid, calcium versetamide sodium or combinations thereof.

The antioxidants can be selected from ascorbic acid, sodium metabisulfite, sodium bisulfite, sodium formaldehyde sulfoxylate, thiourea, butylated hydroxyl anisole, butylated hydroxytoluene, ascorbic acid esters, propyl gallate, vitamin E, alpha-tocopherol or combinations thereof

The buffers can be selected from sodium acetate trihydrate, phosphate, citrate, tris, succinate, histidine, glycine, arginine, malic, tartaric, acetic, benzoic, gluconic, glyceric, lactic, aconitic, adipic, ascorbic, carbonic, glutamic, ammonium chloride, triethanolamine or combinations thereof.

The preservative can be selected from parabens, benzalkonium chloride, benzethonium chloride, benzyl alcohol, chlorobutanol, m-cresol, myristyl gamma picolinium chloride, phenol, 2-phenoxyethanol, phenyl mercuric nitrate, phenyl ethyl alcohol, EDTA or combinations thereof.

As per one embodiment, the ready to use liquid solution of levothyroxine of present invention is to be filled in glass vial or container or alternatively can be also provided as pre-filled syringe.

The ready to use liquid solution of levothyroxine of present invention is stable and contain no more than 2.0 of the impurity as liothyronine (T3) when stored at 25°C/
60%RH and 40°C/75%RH.

In some embodiments, the liquid formulation contains not more than a specified amount of liothyronine as measured after storage of the formulation at a predetermined temperature for a predetermined time period. In certain embodiments, the liquid formulation contains not more than 2.0% liothyronine.

As per one embodiment, the route of administration for ready to use liquid solution of levothyroxine of present invention is parenteral, preferably intravenous route.

As per one embodiment, the ready to use liquid solution of levothyroxine of present invention can be used in replacement or supplemental therapy in congenital or acquired hypothyroidism of any etiology, except transient hypothyroidism during the recovery phase of subacute thyroiditis. Specific indications include: primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) hypothyroidism. Primary hypothyroidism may result from functional deficiency, primary atrophy, partial or total congenital absence of the thyroid gland, or from the effects of surgery, radiation, or drugs, with or without the presence of goiter.

As per one embodiment, the ready to use liquid solution of levothyroxine of present invention is to be prepared by process comprising the steps of
a) Taking required quantity of water for Injection,
b) Adding required quantity of solubilizer till complete mixing,
c) Adding required quantity of stabilizer till complete mixing,
d) Adding required quantity of Levothyroxine sodium in till get clear solution,
e) Making up the volume of bulk as per theoretical batch size with water for injection.
One embodiment of present invention is to provide a ready to use liquid solution of levothyroxine comprising 10 mcg/ml to 500 mcg/ml levothyroxine sodium, 1 to 15% w/v of propylene glycol and 0.1 mg/ml to 2 mg/ml of triethanolamine and water for injection.
One embodiment of present invention is to provide a ready to use liquid solution of levothyroxine comprising 10 mcg/ml to 100 mcg/ml levothyroxine sodium, 1 to 15% w/v of propylene glycol and 0.1 mg/ml to 1.5 mg/ml of triethanolamine and water for injection.
One preferred embodiment of present invention is to provide a ready to use liquid solution of levothyroxine comprising 20 mcg/ml to 100 mcg/ml levothyroxine sodium, 1 to 10% w/v of propylene glycol and 0.2 mg/ml to 1.25 mg/ml of triethanolamine and water for injection.
One preferred embodiment of present invention is to provide a ready to use liquid solution of levothyroxine comprising 20 mcg/ml to 100 mcg/ml levothyroxine sodium, 1 to 10% w/v of propylene glycol and 1 mg/ml of triethanolamine and water for injection.
One preferred embodiment of present invention is to provide a ready to use liquid solution of levothyroxine comprising 20 mcg/ml to 100 mcg/ml levothyroxine sodium, 1 to 10% w/v of propylene glycol and 1.25 mg/ml of triethanolamine and water for injection.

The present inventors have carried out various researches in order to develop stable ready to use liquid solution of levothyroxine for injection, having an improved stability.

The present inventors surprisingly found that, when headspace oxygen in the vials & ampoules filled with solution for injection was less substantially removed (i.e. approximately less than 5%) by e.g. bubbling of nitrogen gas into the solution & purging nitrogen gas over head space of vials/ ampoules after solution filling, a stable liquid solution of levothyroxine is obtained compared to head space of 10 to 15%.

EXAMPLES

Example 1:
Effect of solubilizer:
Table 1 : Formulation details with varying concentration of solubilizer
Ingredient Quantity (mg/mL)
Trial 1 Trial 2
Levothyroxine sodium 0.1 0.1
Propylene glycol 100 200
Triethanolamine 0.75 0.75
Water for injection q.s to 1 mL q.s to 1 mL
Sodium hydroxide/Hydrochloric acid q.s to adjust pH 8.5 to 10.5 q.s to adjust pH 8.5 to 10.5

Table 2 : Stability data of formulations prepared using varying concentration of solubilizer
Sr. No. Test Specification Trial 1 Trial 2
Solubilizer 10% Solubilizer 20%
60°C 60°C
7 days 7 days
1 Description Clear colorless solution Complies Complies
2 Related Substances (%)
Liothyronine NMT 2.0 1.9 1.4
T4-Hydroxyacetic acid NMT 1.0 0.37 0.33
T4-Benzoic acid NMT 1.0 0.35 0.25
Individual unspecified impurity NMT 1.0 0.5 (RRT 0.33) 2.1 (RRT0.33)
Total impurities NMT 3.0 3.8 4.5

Conclusion: 10% solubilizer concentration shows less degradation in formulation as compared to formulation with 20% solubilizer.

Example 2:
Effect of stabilizer:
Table 3 : Formulation details with varying concentration of stabilizer
Ingredient Quantity (mg/mL)
Trial 3 Trial 4
Levothyroxine sodium 0.1 0.1
Propylene glycol 100 100
Triethanolamine 0.75 1.25
Water for Injection q.s to 1 mL q.s to 1 mL
Sodium hydroxide/Hydrochloric acid q.s to adjust pH 8.5 to 10.5 q.s to adjust pH 8.5 to 10.5

Table 4 : Stability data of formulations prepared using varying concentration of stabilizer
Sr. No. Test Specification Trial 3 Trial 4
Initial 40°C/75%RH Initial 40°C/75%RH
1 M 1 M
1 Description Clear colorless solution Complies Complies Complies Complies
2 % Assay 90.0 to 110.0 96.5 98.3 97.6 99.2
3 Related Substances (%)
Liothyronine NMT 2.0 BQL 0.2 BQL 0.14
Individual unspecified impurity NMT 1.0 BQL BQL BQL BQL
Total impurities NMT 3.0 BQL 0.2 BQL 0.14

Conclusion: stabilizer is controlling the degradation in formulation in all concentrations, i.e 0.75 mg/mL and 1.25 mg/mL

Example 3: Effect of Head space oxygen

Table 5 : Formulation details with varying head space oxygen content in filled vials
Ingredient Quantity (mg/mL)
Trial 4 Trial 5
Levothyroxine sodium 0.1 0.1
Propylene glycol 100 100
Triethanolamine 1.25 1.25
Water for Injection q.s to 1 mL q.s to 1 mL
Sodium hydroxide/Hydrochloric acid q.s to adjust pH 8.5 to 10.5 q.s to adjust pH 8.5 to 10.5
Head space oxygen content Below 5% Between 5% to 15%

Table 6 : Stability data of formulations prepared using varying headspace
Sr. No. Test Specification Trial 4 Trial 5
Initial 40°C/
75%RH Initial 40°C/
75%RH
1 M 1 M
1 Description Clear colorless solution Complies Complies Complies Complies
2 %HSO - 3.90 2.60 9.20 11.16
3 % Assay 90.0 to 110.0 97.6 99.2 95.6 97.2
4 Related Substances (%)
Liothyronine NMT 2.0 BQL 0.14 BQL 0.17
Individual unspecified impurity NMT 1.0 BQL BQL BQL 0.92 (RRT0.31)
Total impurities NMT 3.0 BQL 0.14 BQL 1.2

Conclusion: Formulation with lower head space (below 5%) helps to prevent degradation of formulation during stability as compared to formulation with higher head space (between 5-15%).

Example 4: Formulation of levothyroxine sodium

Table 7 : Formulation details of different strength
Ingredient Quantity (mg/mL)
Trial 6 Trial 7 Trial 8
Levothyroxine sodium 0.1 0.04 0.02
Propylene glycol 100 100 100
Triethanolamine 1.00 1.00 1.00
Water for Injection q.s to 1 mL q.s to 1 mL q.s to 1 mL
Sodium hydroxide/Hydrochloric acid q.s to adjust pH 8.5 to 10.5 q.s to adjust pH 8.5 to 10.5 q.s to
adjust pH 8.5 to 10.5

Table 8 : Stability data of different strength formulations
Test Specification Trial 6 Trial 7 Trial 8
Initial 40°C/
75%RH Initial 40°C/
75%RH Initial 40°C/
75%RH
1 M 1 M 1 M
Description Clear colorless solution Complies Complies Complies Complies Complies Complies
% Assay 90.0 to 110.0 107.4 109.0 108.5 106.5 109.5 109.2
Related Substances (%)
Liothyronine NMT 2.0 BQL 0.19 BQL 0.15 BQL 0.16
Individual unspecified impurity NMT 1.0 BQL 0.2 BQL 0.13 BQL 0.15
Total impurities NMT 3.0 BQL 0.39 0.12 0.27 BQL 0.32

Conclusion: All three strength of test product is having stability data well within acceptance criteria up to 1 M at 40°C & 25°C.