WO2021165926A1

WO2021165926A1 - A stable ready to use pharmaceutical composition of levothyroxine

Info

Publication number: WO2021165926A1
Application number: PCT/IB2021/051455
Authority: WO
Inventors: Alex K. GEORGE; Mukesh Bothra; Vikas Kumar Srivastava
Original assignee: Intas Pharmaceuticals Ltd.
Priority date: 2020-02-21
Filing date: 2021-02-20
Publication date: 2021-08-26

Abstract

The present invention relates to a stable, ready to use, injectable pharmaceutical composition comprising Levothyroxine or a pharmaceutically acceptable salt thereof, a buffer selected from a group of leucine or glycine and other pharmaceutically acceptable excipients. Further, the present invention discloses process for the preparation of the said composition.

Description

A stable ready to use pharmaceutical composition of Levothyroxine

RELATED APPLICATIONS This application is related to Indian Provisional Application IN202021007525 filed 21^st February, 2020 and is incorporated herein in its entirety.

FILED OF THE INVENTION The present invention relates to a stable, ready to use, injectable pharmaceutical composition comprising Levothyroxine or a pharmaceutically acceptable salt thereof, a buffer selected from a group of leucine or glycine and other pharmaceutically acceptable excipients. Further, the present invention discloses process for the preparation of the said composition.

BACKGROUND OF THE INVENTION

Levothyroxine sodium is levothyroxine (T4) in sodium salt form. Levothyroxine sodium has an empirical formula of CisHioLNNaO^ a molecular weight of 798.85 g/mol (anhydrous), and the following structural formula:

(Levothyroxine sodium) Levothyroxine sodium is marketed as oral dosage forms (e.g. tablet, soft gelatin capsule, oral liquids) and injectable dosage forms. The injectable dosage forms are available as lyophilized powder for injection and liquid ready to use injection. Historically, due to stability issue of Levothyroxine, the first marketed injectable dosage form was in form of lyophilized powder. Currently, marketed lyophilized powder of Levothyroxine sodium contains levothyroxine sodium as active pharmaceutical ingredient, dibasic sodium phosphate, mannitol and sodium hydroxide as pharmaceutically acceptable excipients. The lyophilized powder of Levothyroxine sodium injection is available at three dosage strengths i.e. 100 meg per vial, 200 meg per vial and 500 meg per vial. The lyophilized powder requires reconstitution of the powder prior to administration to the patient in need thereof.

Recently, Fresenius Kabi has launched liquid, ready to use injectable composition which does not require reconstitution prior to administration to the patient in need thereof. The marketed liquid, ready to use injectable composition contains Levothyroxine sodium as active pharmaceutical ingredient, tromethamine, sodium iodide, sodium chloride, water for injection, sodium hydroxide, and/or hydrochloric acid as pharmaceutically acceptable excipients.

US9782376 discloses a liquid composition for parenteral administration comprising Levothyroxine, tromethamine, sodium iodide, and water. The US9782376 discloses use of tromethamine as stabilizer.

US10398669 discloses a liquid composition for parenteral administration comprising active pharmaceutical ingredient Levothyroxine and a stabilizing agent comprising tromethamine; not more than 2% liothyronine (T3); and water. The US 10398669 focuses on use of tromethamine as stabilizer.

US20180214374 discloses a liquid composition for parenteral administration comprising Levothyroxine, buffering agents, one or more solvents and one or more pharmaceutically acceptable excipients thereof. The US20180214374 focuses on use of arginine as buffering agent and cyclodextrin as stabilizing agents. WO2019023791 discloses aqueous parenteral formulation comprising Levothyroxine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. The WO2019023791 focuses on use of different pharmaceutically acceptable excipients like benzyl alcohol, sodium phosphate dibasic heptahydrate, monothioglycerol, sodium sulphite, edetate sodium, propylene glycol or glycerine.

From the prior-art literatures, it can be concluded that Levothyroxine has stability issue when manufactured in form of liquid injectable composition. Further, there are several pharmaceutically excipients known to produce stable liquid injectable composition. However, stability of liquid injectable composition of Levothyroxine depends of use of different stabilizers, solubilizers and buffers; however, all known stabilizers, solubilizers, and buffers do not provide desired stable liquid injectable composition of Levothyroxine.

Considering the prior efforts as disclosed in the background, a need exists which would address the issue of stability of liquid injectable composition of Levothyroxine and provide an alternative stable liquid injectable composition of Levothyroxine.

OBJECT OF THE INVENTION

It is therefore object of present invention is to provide a stable, ready to use, injectable pharmaceutical composition comprising Levothyroxine or a pharmaceutically acceptable salt thereof.

Another object of present invention is to provide a stable, ready to use, injectable pharmaceutical composition comprising Levothyroxine or a pharmaceutically acceptable salt thereof and leucine. Another object of present invention is to provide a stable, ready to use, injectable pharmaceutical composition comprising Levothyroxine sodium and leucine as buffering agent. Another object of present invention is to provide a stable, ready to use, injectable pharmaceutical composition comprising Levothyroxine sodium, leucine as buffering agent and other pharmaceutically acceptable excipients.

Another object of present invention is to provide a process for preparation of a stable, ready to use, injectable pharmaceutical composition comprising Levothyroxine sodium, leucine as buffering agent and other pharmaceutically acceptable excipients.

Another object of present invention is to provide a stable, ready to use, injectable pharmaceutical composition comprising Levothyroxine or a pharmaceutically acceptable salt thereof and glycine.

Another object of present invention is to provide a stable, ready to use, injectable pharmaceutical composition comprising Levothyroxine sodium and glycine as buffering agent.

Another object of present invention is to provide a stable, ready to use, injectable pharmaceutical composition comprising Levothyroxine sodium, glycine as buffering agent and other pharmaceutically acceptable excipients.

Another object of present invention is to provide process for preparation of a stable, ready to use, injectable pharmaceutical composition comprising Levothyroxine sodium, glycine as buffering agent and other pharmaceutically acceptable excipients. SUMMARY OF THE INVENTION

The present invention provides a stable, ready to use, injectable pharmaceutical composition comprising Levothyroxine or a pharmaceutically acceptable salt thereof, leucine or glycine as buffering agent and other pharmaceutically acceptable excipients, wherein leucine or glycine is present at a concentration of about 1 mg/ml to 10 mg/ml. Further, the present invention provides process for the preparation of said compositions.

DETAILED DESCRIPTION OF THE INVENTION

All terms as used herein in this application, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. Other more specific definitions for certain terms as used in the present application are as set forth below and are intended to apply uniformly throughout the specification and claims unless an otherwise expressly set out definition provides a broader definition.

For the purposes of the present invention, any ranges given include both the lower and the upper end points of the range. Ranges given should be considered approximate, unless specifically stated.

The term “ready to use” refers to a formulation is a sterile and stable injectable formulation that is not reconstituted from a solid by a healthcare provider prior to use. Further, a ready to use formulation is supplied by a pharmaceutical manufacturer in a suitable container (e.g., vial, syringe, bag, and container) in liquid form.

The term "buffering agent" refers to a compound used to resist change in pH upon dilution or addition of acid or alkali.

The term “about” refers to within plus or minus 10 % of a stated value. The present invention provides a stable, ready to use, injectable pharmaceutical composition comprising Levothyroxine or a pharmaceutically acceptable salt thereof and process for preparation of said composition.

In another embodiment the present invention provides a stable, ready to use, injectable pharmaceutical composition comprising Levothyroxine or a pharmaceutically acceptable salt thereof and leucine.

In another embodiment the present invention provides a stable, ready to use, injectable pharmaceutical composition comprising Levothyroxine sodium and leucine as buffering agent.

In another embodiment the present invention provides a stable, ready to use, injectable pharmaceutical composition comprising Levothyroxine or a pharmaceutically acceptable salt thereof, leucine as buffering agent and other pharmaceutically acceptable excipients; wherein, (a) leucine is present at a concentration of about 1 mg/ml to 10 mg/ml and (b) the said composition has pH 9.5 to 11.

According to present invention, a stable, ready to use, injectable pharmaceutical composition comprises (a) Levothyroxine sodium at a concentration of about 10 pg/ml to 200 pg/ml, (b) leucine as buffering agent at a concentration of about 1 mg/ml to 10 mg/ml and (c) other pharmaceutically acceptable excipients; wherein the said composition has pH 9.5 to 11.

According to present invention, a stable, ready to use, injectable pharmaceutical composition comprises Levothyroxine sodium at a concentration of about 10 pg/ml to 200 pg/ml, leucine as buffering agent and other pharmaceutically acceptable excipients, wherein leucine is present at a concentration of about 1 mg/ml to 10 mg/ml, more specifically leucine is present at a concentration of about 1 mg/ml, 1.25 mg/ml, 1.5 mg/ml, 1.75 mg/ml, 2 mg/ml, 2.25 mg/ml, 2.5 mg/ml, 2.75 mg/ml, 3 mg/ml, 3.25 mg/ml, 3.5 mg/ml, 3.75 mg/ml, 4 mg/ml, 4.25 mg/ml, 4.5 mg/ml, 4.75 mg/ml, 5 mg/ml, 5.25 mg/ml, 5.5 mg/ml, 5.75 mg/ml, 6 mg/ml, 7 mg/ml, 8 mg/ml, 9 mg/ml or 10 mg/ml.

More specifically, according to present invention leucine is L-leucine.

According to present invention, a stable, ready to use, injectable pharmaceutical composition comprises (a) Levothyroxine sodium at a concentration of 20 pg/ml, 40 pg/ml, 100 pg/ml, 150 pg/ml or 200 pg/ml, (b) leucine as buffering agent at a concentration of 1 mg/ml, 1.5 mg/ml, 2 mg/ml, 2.5 mg/ml, 3 mg/ml, 3.5 mg/ml, 4 mg/ml, 4.5 mg/ml or 5 mg/ml and (c) other pharmaceutically acceptable excipients; wherein the said composition has pH 9.5 to 11.

According to present invention, a stable, ready to use, injectable pharmaceutical composition comprises Levothyroxine sodium at a concentration of about 10 pg/ml to 200 pg/ml, more specifically at a concentration of about 10 pg/ml, 20 pg/ml, 30 pg/ml, 40 pg/ml, 50 pg/ml, 60 pg/ml, 70 pg/ml, 80 pg/ml, 90 pg/ml, 100 pg/ml, 110 pg/ml, 120 pg/ml, 130 pg/ml, 140 pg/ml, 150 pg/ml, 160 pg/ml, 170 pg/ml, 180 pg/ml, 190 pg/ml or 200 pg/ml.

In another embodiment the present invention provides a stable, ready to use, injectable pharmaceutical composition comprising Levothyroxine or a pharmaceutically acceptable salt thereof and glycine.

In another embodiment the present invention provides a stable, ready to use, injectable pharmaceutical composition comprising Levothyroxine sodium and glycine as buffering agent.

In another embodiment the present invention provides a stable, ready to use, injectable pharmaceutical composition comprising Levothyroxine or a pharmaceutically acceptable salt thereof, glycine as buffering agent and other pharmaceutically acceptable excipients; wherein, (a) glycine is present at a concentration of about 1 mg/ml to 10 mg/ml and (b) the composition has pH 9.5 to 11.

According to present invention, a stable, ready to use, injectable pharmaceutical composition comprises (a) Levothyroxine sodium at a concentration of about 10 pg/ml to 200 pg/ml (b) glycine as buffering agent at a concentration of about 1 mg/ml to 10 mg/ml and (c) other pharmaceutically acceptable excipients; wherein the composition has pH 9.5 to 11.

According to present invention, a stable, ready to use, injectable pharmaceutical composition comprises Levothyroxine sodium at a concentration of about 10 pg/ml to 200 pg/ml, glycine as buffering agent and other pharmaceutically acceptable excipients, wherein glycine is present at a concentration of about 1 mg/ml to 10 mg/ml, more specifically glycine is present at a concentration of about 1 mg/ml, 1.25 mg/ml, 1.5 mg/ml, 1.75 mg/ml, 2 mg/ml, 2.25 mg/ml, 2.5 mg/ml, 2.75 mg/ml, 3 mg/ml, 3.25 mg/ml, 3.5 mg/ml, 3.75 mg/ml, 4 mg/ml, 4.25 mg/ml, 4.5 mg/ml, 4.75 mg/ml, 5 mg/ml, 5.25 mg/ml, 5.5 mg/ml, 5.75 mg/ml, 6 mg/ml, 7 mg/ml, 8 mg/ml, 9 mg/ml or 10 mg/ml.

According to present invention, a stable, ready to use, injectable pharmaceutical composition comprises (a) Levothyroxine sodium at a concentration of 20 pg/ml, 40 pg/ml, 100 pg/ml, 150 pg/ml or 200 pg/ml, (b) glycine as buffering agent at a concentration of 1 mg/ml, 1.5 mg/ml, 2 mg/ml, 2.5 mg/ml, 3 mg/ml, 3.5 mg/ml, 4 mg/ml, 4.5 mg/ml or 5 mg/ml and (c) other pharmaceutically acceptable excipients; wherein the composition has pH 9.5 to 11.

In another embodiment the present invention provides a stable, ready to use, injectable pharmaceutical composition comprising Levothyroxine sodium and leucine or glycine as buffering agent and other pharmaceutically acceptable excipients.

The other pharmaceutically acceptable excipients are selected from solvent, stabilizing agent, solubilizing agent, isotonicity adjuster, antioxidant, chelating agent and pH adjusting agent.

The solvent for the present invention is water.

The stabilizing agent at a concentration of 0.01 - 0.5 mg/ml is a salt of iodine, such as sodium iodide or potassium iodide and the likes thereof.

The solubilizing agent can be selected from cyclodextrin for example, alpha- cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, hydroxypropyl beta- cyclodextrins, sulfobutylether-beta-cyclodextrin and the likes thereof. The total amount of the solubilizing agent can be from 0 - 20% w/v of the total composition.

The isotonicity adjuster at a concentration of 3 - 15 mg/ml can be selected from sodium chloride, potassium chloride, dextrose and mannitol and the likes thereof.

The antioxidant can be selected from alpha-tocopherol, monothioglycerol, ascorbic acid, sodium ascorbate, butylated hydroxyanisole, butylated hydroxytoluene, gentisic acid, gentisic ethanolamide, glutathione, methionine, sodium formaldehyde sulfoxylate and the likes thereof. The total amount of the antioxidant can be from 0 - 20% w/v of the total composition.

The chelating agent can be selected from ethylenediamine tetraacetic acid (EDTA), edetate sodium, edetate calcium disodium, edetic acid, citric acid and the likes thereof. The total amount of the chelating agent can be from 0 - 20% w/v of the total composition. The pH adjusting agent can be selected from sodium hydroxide, hydrochloric acid, calcium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, acetic acid, acetic anhydride acid and the likes thereof.

In another embodiment the present invention provides a stable, ready to use, injectable pharmaceutical composition comprising Levothyroxine sodium, leucine or glycine as buffering agent and other pharmaceutically acceptable excipients, wherein the composition is prepared by process comprising following steps;

(a) leucine or glycine are added in water.

(b) Sodium iodide and sodium chloride are added in solution obtained in step (a).

(c) Levothyroxine sodium is added into solution of step (b) to prepare bulk solution.

(d) pH of the bulk solution is adjusted to 9.5 - 11.0 with sodium hydroxide and / or hydrochloride acid.

According to the present invention, a stable ready to use pharmaceutical composition refers to a stable, ready to use, injectable pharmaceutical composition comprising Levothyroxine sodium, leucine or glycine as buffering agent and other pharmaceutically acceptable excipients; wherein single maximum impurity in the composition is not more than (NMT) 0.83 % w/w when stored at 40 °C temperature and 75 % relative humidity for at least 2 months. The said composition according to the present invention shall be stored at room temperature.

EXAMPLES

The present invention has been described by way of example only, and it is to be recognized that modifications thereto falling within the scope and spirit of appended claims, and which would be obvious to a person skilled in the art based upon the disclosure herein, are also considered to be within the scope of this invention. Example 1: Ready to use, injectable composition with leucine

Meg = Microgram (i.e. gg) Example 2: Ready to use, injectable composition with glycine

Meg = Microgram (i.e. gg)

Example 3: Ready to use, injectable composition with leucine

Meg = Microgram (i.e. gg) Example 4: Ready to use, injectable composition with glycine

Meg = microgram (i.e. gg)

5 Example 5 to 8: Comparative compositions (not according to present invention)

Meg = Microgram (i.e. gg)

Example 9: Ready to use, injectable composition with glycine

0 Meg = microgram (i.e. gg) Example 10: Ready to use, injectable composition with glycine

Meg = microgram (i.e. gg) Process for preparation of composition of example 1 to example 10:

1. Water was transferred into stainless steel vessel.

2. Leucine / glycine / disodium hydrogen phosphate heptahydrate / meglumine / L-histidine was added in water of step 1.

3. Sodium iodide and sodium chloride were added in solution of step 2.

4. Levothyroxine sodium was added into solution of step 3 to prepare bulk solution.

5. pH of the bulk solution was adjusted to 9.5 - 11.0 with sodium hydroxide and / or hydrochloride acid and final volume were adjusted with water.

6. The solution was filtered with 0.2 micron filtered and filled in vials.

Stability study of the composition of example 3 - 10:

For the stability study, the composition obtained in example 3 - 10 were stored at (1) 40 °C temperature and 75% relative humidity and (2) 25 °C temperature and 60 % relative humidity. The stability study results are tabulated below: Table 1:

NMT - Not more than, M - Month, Single max. impurity - Single maximum impurity, Total RS - Total related substances, ND

- Not Detected Table 2:

NMT - Not more than, M - Month, Single max. impurity - Single maximum impurity, Total RS - Total related substances, ND -

Not Detected Table 3:

Not Detected

From the above stability study results, it can be concluded that leucine or glycine can be used in preparation of a stable, ready to use, injectable pharmaceutical composition comprising Levothyroxine sodium.

Claims

We Claim:

1. A stable, ready to use, injectable pharmaceutical composition comprising,

(a) Levothyroxine sodium at a concentration of about 10 pg/ml to 200 pg/ml;

(b) Buffering agent selected from leucine or glycine having concentration in between 1 - 10 mg/ml; and

(c) Other pharmaceutically acceptable excipients,

Wherein, single maximum impurity in the composition is not more than (NMT) 0.83 % w/w when stored at 40 °C temperature and 75 % relative humidity for at least 2 months.

2. The stable, ready to use, injectable pharmaceutical composition according to claim 1, wherein the Levothyroxine sodium at a concentration of 20 pg/ml, 40 pg/ml and 100 pg/ml.

3. The stable, ready to use, injectable pharmaceutical composition according to claim 1, wherein the other pharmaceutically acceptable excipients comprises solvent, stabilizing agent, isotonicity adjuster, and pH adjusting agent.

4. The stable, ready to use, injectable pharmaceutical composition according to claim 3, wherein the solvent is water.

5. The stable, ready to use, injectable pharmaceutical composition according to claim 3, wherein the stabilizing agent is selected from sodium iodide or potassium iodide.

6. The stable, ready to use, injectable pharmaceutical composition according to claim 3, wherein the isotonicity adjuster is selected from sodium chloride or potassium chloride.

7. The stable, ready to use, injectable pharmaceutical composition according to claim 3, wherein the pH adjusting agent(s) is sodium hydroxide and /or hydrochloric acid.

8. The stable, ready to use, injectable pharmaceutical composition according to claim 1, wherein the composition has pH in between 9.5 - 11.

9. A process for preparation of a stable, ready to use, injectable pharmaceutical composition comprising,

(a) Levothyroxine sodium at a concentration of about 10 pg/ml to 200 pg/ml; (b) Buffering agent selected from leucine or glycine having concentration in between 1 - 10 mg/ml; and (c) Other pharmaceutically acceptable excipients, comprising step of:

(a) Leucine or glycine is added in water,

(b) Sodium iodide and sodium chloride are added in solution obtained in step (a),

(c) Levothyroxine sodium is added into solution of step (b) to prepare bulk solution,

(d) pH of the bulk solution is adjusted in between 9.5 - 11.0 with sodium hydroxide and / or hydrochloride acid.