Description:RELATED APPLICATION
This patent application is a divisional application of patent application number IN202321052671 filed on 4th August 2023.

FIELD OF THE INVENTION

This invention relates to a room temperature stable solution for injection comprising Abaloparatide and stabilizer selected from L – methionine, disodium EDTA, D-?-tocopheryl polyethylene glycol succinate, hydroxypropyl betadex, mannitol, S- methyl-L- cysteine or a mixture thereof. Further, the present invention provides a process for the preparation of the said solution. The invention provides an injectable solution that is stable at room temperature which overcomes the limitations of the currently marketed formulation.

BACKGROUND OF THE INVENTION

Abaloparatide is an analog of human parathyroid hormone related peptide, PTHrP(1-34). It has 41% homology to hPTH (1-34) (human parathyroid hormone 1-34) and 76% homology to hPTHrP (1-34) (human parathyroid hormone-related peptide 1-34). Abaloparatide has a molecular formula of C174H300N56O49 and a molecular weight of 3961 daltons with the amino acid sequence as follows Ala-Val-Ser-Glu-His-Gln-Leu-Leu-His-Asp-Lys-Gly-Lys-Ser-Ile-Gln-Asp-Leu-Arg-Arg-Arg-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Aib-Lys-Leu-His-Thr-Ala-NH2.

Abaloparatide as a product was first disclosed in the US5969095.

The commercially available injection composition TYMLOS in the USA must be stored under refrigeration between 2°C to 8°C and after first use, needs to be stored for up to 30 days at 20°C to 25°C. Accordingly, the commercial injectable composition is not stable at room temperature for the entire shelf-life.

The assessment report by EMA for Eladynos which is a brand name of Abaloparatide injection in the EU states that stability data from 6 production scale batches of finished product stored for up to 36 months under long term conditions (5ºC / ambient RH), up to 24 months under accelerated conditions (25ºC / 60% RH) and from 3 batches up to 6 months under stressed conditions (40ºC / 75 % RH) were provided. Based on the data it was concluded that there were significant changes, out of specification results for the specified degradant impurity, occur between 3 and 6 months’ testing in accelerated and stressed conditions. Therefore, the proposed shelf-life of Eladynos is based on real time data at long-term conditions (5ºC / ambient RH) and Eladynos is not stable at room temperature.

US8148333 discloses a composition comprising Abaloparatide and an effective amount of a pH buffer to maintain the pH in a range of about 4.5 to about 5.6 wherein said composition does not contain a chemical stabilizer. Further, the solution composition discloses in the US8148333 is not stable at room temperature and only around 75% of the peptide was present after 12 months of stability study at 25 °C temperature and 60 % relative humidity.

US10996208 discloses a composition comprising =5% w/w beta-Asp10 of the total peptide content, and an aqueous buffer having a pH from 4.5-5.5. The formulations provided in the US10996208 are aqueous formulated drug products stored for 0-23 months or 0-35 months, at 2-8 °C and about 0-1 month at 20-25 °C or about 25±2 °C.

US7803770 discloses a method of treating osteoporosis comprising daily subcutaneous administration of a composition comprising 80 µg of Abaloparatide wherein the composition comprises a buffer to maintain the pH between 2 and 7. Further, the solution composition discloses in the US7803770 is not stable at room temperature and only around 75% of the peptide was present after 12 months of stability study at 25 °C temperature and 60 % relative humidity.

US8748382 discloses a method of stimulating bone growth in a subject in need thereof comprising administering to said subject a storage stable composition comprising Abaloparatide and buffer to maintain the pH in a range of about 4.5 to about 5.6. Further, the solution composition discloses in the US8748382 is not stable at room temperature and only around 75% of the peptide was present after 12 months of stability study at 25 °C temperature and 60 % relative humidity.

WO2009137093 discloses a composition comprising Abaloparatide and buffer for use in the treatment of osteoporosis, wherein the treatment of osteoporosis is by single daily subcutaneous injection of an amount of said composition containing 80 µg of Abaloparatide, wherein the buffer is present in an effective amount to maintain the pH in a range of about 4.5 to about 5.6. Further, the solution composition discloses in the WO2009137093 is not stable at room temperature and only around 75% of the peptide was present after 12 months of stability study at 25 °C temperature and 60 % relative humidity.

Accordingly, it can be concluded that the compositions disclosed in the prior arts are not stable at room temperature and therefore the compositions of the prior arts and the commercially available compositions are stored at 2 – 8 °C.

The storage of any pharmaceutical product below room temperature requires special arrangements during the transport of the goods, at a godown or warehouse, at a hospital, and at the pharmacy shelf. Accordingly, it will involve more cost, time, and effort, and as a result, it will increase the financial burden on the entire healthcare system.

Therefore, there is a need to have a room temperature stable solution for injection comprising Abaloparatide which overcomes the limitations of the currently marketed formulation.

OBJECT OF THE INVENTION

The principal object of this invention is to provide a room temperature stable solution for injection comprising Abaloparatide and stabilizer, wherein the solution is stable for at least 6 months when stored at 25 °C temperature and 60 % relative humidity.

Another object of this invention is to provide a room temperature stable solution for injection comprising Abaloparatide and stabilizer, wherein the stabilizer is selected from L – methionine, disodium EDTA, D-?-tocopheryl polyethylene glycol succinate, hydroxypropyl betadex, mannitol, S- methyl-L- cysteine or mixture thereof, wherein the solution is stable for at least 6 months when stored at 25 °C temperature and 60 % relative humidity.

A further object of this invention is to provide a room temperature stable solution for injection comprising Abaloparatide and stabilizer, wherein the total impurities of the solution are not more than 2 % after 6 months when stored at 25 °C temperature and 60 % relative humidity.

Another object of this invention is to provide a room temperature stable solution for injection comprising Abaloparatide and stabilizer, wherein the total impurities of the solution are not more than 2 % and the single maximum impurity is not more than 1 % after 6 months when stored at 25 °C temperature and 60 % relative humidity.

Another object of this invention is to provide a room temperature stable solution for injection comprising Abaloparatide and stabilizer, wherein the stabilizer is selected from L – methionine, disodium EDTA, D-?-tocopheryl polyethylene glycol succinate, hydroxypropyl betadex, mannitol, S- methyl -L- cysteine or a mixture thereof, and wherein the total impurities of the solution are not more than 2 % and the single maximum impurity is not more than 1 % after 6 months when stored at 25 °C temperature and 60 % relative humidity.

Another object of this invention is to provide a room temperature stable solution for injection comprising Abaloparatide and stabilizer, wherein the stabilizer is selected from L – methionine, disodium EDTA, D-?-tocopheryl polyethylene glycol succinate, hydroxypropyl betadex, mannitol, S- methyl -L- cysteine or a mixture thereof, and wherein the total impurities of the solution are not more than 2 % and the single maximum impurity is not more than 1 % after 6 months when stored at 25 °C temperature and 60 % relative humidity, wherein the solution is stable for at least 6 months when stored at 25 °C temperature and 60 % relative humidity.

Another object of this invention is to provide a process for the preparation of a room temperature stable solution for injection comprising Abaloparatide and stabilizer.

Another object of this invention is to provide a room temperature stable solution for injection comprising Abaloparatide and methionine.

Another object of this invention is to provide a process for the preparation of a room temperature stable solution for injection comprising Abaloparatide and methionine.

Another object of this invention is to provide a process for the preparation of a room temperature stable solution for injection comprising Abaloparatide and L – methionine.

Another object of this invention is to provide a room temperature stable solution for injection comprising Abaloparatide and L – methionine.

Another object of this invention is to provide a room temperature stable solution for injection comprising Abaloparatide and L – methionine, wherein pH of the solution is 4.5 to 5.6.
Another object of this invention is to provide a room temperature stable solution for injection comprising Abaloparatide and methionine in a concentration of 0.1 mg/ml to 10 mg/ml, wherein pH of the solution is 4.5 to 5.6.

Another object of this invention is to provide a room temperature stable solution for injection comprising Abaloparatide and L – methionine in a concentration of 0.1 mg/ml to 10 mg/ml, wherein pH of the solution is 4.5 to 5.6.

Another object of this invention is to provide a room temperature stable solution for injection comprising Abaloparatide and L – methionine, wherein the solution is stable for at least 6 months when stored at 25 °C temperature and 60 % relative humidity.

Another object of this invention is to provide a room temperature stable solution for injection comprising Abaloparatide and L – methionine in a concentration of 0.1 mg/ml to 10 mg/ml, wherein the total impurities of the solution are not more than 2 % after 6 months when stored at 40 °C temperature and 75 % relative humidity.

Another object of this invention is to provide a room temperature stable solution for injection comprising Abaloparatide and L – methionine in a concentration of 0.1 mg/ml to 10 mg/ml, wherein pH of the solution is 4.5 to 5.6 and wherein the total impurities of the solution are not more than 2 % after 6 months when stored at 40 °C temperature and 75 % relative humidity.

Another object of this invention is to provide a room temperature stable solution for injection comprising Abaloparatide and L – methionine, in a concentration of 0.1 mg/ml to 10 mg/ml, wherein the total impurities of the solution are not more than 2 % and a single maximum impurity is not more than 1 % after 6 months when stored at 40 °C temperature and 75 % relative humidity.

Another object of this invention is to provide a room temperature stable solution for injection comprising Abaloparatide and L – methionine, in a concentration of 0.1 mg/ml to 10 mg/ml, wherein pH of the solution is 4.5 to 5.6 and wherein the total impurities of the solution are not more than 2 % and a single maximum impurity is not more than 1 % after 6 months when stored at 40 °C temperature and 75 % relative humidity.

SUMMARY OF THE INVENTION

The present invention provides a room temperature stable solution for injection comprising Abaloparatide and stabilizer selected from L – methionine, disodium EDTA, D-?-tocopheryl polyethylene glycol succinate, hydroxypropyl betadex, mannitol, S- methyl-L- cysteine or a mixture thereof, wherein the solution is stable for at least 6 months when stored at 25 °C temperature and 60 % relative humidity. Further, the present invention provides a process for the preparation of the said solution. The invention provides an injectable solution that is stable at room temperature which overcomes the limitations of the currently marketed formulation.

DETAILED DESCRIPTION OF THE INVENTION

The detailed description and the examples provided herein are exemplary and any modification or variation within the scope of the invention will be apparent to a person skilled in the art. Further, unless otherwise defined, all the technical and scientific terms used herein shall bear the meaning as understood by a person who is ordinarily skilled in the art.

The present invention provides a room temperature stable solution for injection comprising Abaloparatide and stabilizer, wherein the solution is stable for at least 6 months when stored at 25 °C temperature and 60 % relative humidity.

According to the present invention, the term “stable solution” refers to a solution of the present invention that is physically and chemically stable at room temperature for at least 6 months. The room temperature has the same meaning as known to the person skilled in the art and as mentioned in the official compendium like USP or IP. The stable solution of the present invention does not require to be stored at 2 to 8 °C, unlike the currently marketed composition.

According to the present invention, the term “solution” refers to a clear liquid solution for injection.

According to the present invention, the term “room temperature stable solution” or “solution stable at room temperature” refers to a solution of the present invention that, when stored at room temperature (25 °C) and 60 % relative humidity, remains physically and chemically stable. The total impurities of the solution are not more than 2 % and the single maximum impurity is not more than 1 % after 6 months of storage at 25 °C temperature and 60 % relative humidity.

According to the present invention, the term “stabilizer” means the pharmaceutically acceptable excipients used to increase the chemical and physical stability of the active pharmaceutical ingredient Abaloparatide in the solutions.

In one of the embodiments, the present invention provides a room temperature stable solution for injection comprising Abaloparatide and stabilizer, wherein the stabilizer is selected from L – methionine, disodium EDTA, D-?-tocopheryl polyethylene glycol succinate, hydroxypropyl betadex, mannitol, S- methyl-L- cysteine or mixture thereof, wherein the solution is stable for at least 6 months when stored at 25 °C temperature and 60 % relative humidity.

According to the present invention, the amount of Abaloparatide in the room temperature stable solution for injection is 0.25 mg/ml to 5 mg/ml, 0.25 mg/ml to 4 mg/ml, 0.25 mg/ml to 3 mg/ml, 0.25 mg/ml to 2 mg/ml, 0.25 mg/ml, 0.50 mg/ml, 0.75 mg/ml, 1.00 mg/ml, 1.25 mg/ml, 1.50 mg/ml, 1.75 mg/ml, 2.00 mg/ml, 2.50 mg/ml, 3.00 mg/ml, 3.50 mg/ml, 4.00 mg/ml, 4.50 mg/ml or 5.00 mg/ml.

According to the present invention, the stabilizer is selected from the group comprising methionine, L – methionine, disodium EDTA, D-?-tocopheryl polyethylene glycol succinate, hydroxypropyl betadex, mannitol, S- methyl-L- cysteine or a mixture thereof.

According to the present invention, the amount of L – methionine in the room temperature stable solution for injection is 0.1 mg/ml to 10 mg/ml, 0.1 mg/ml to 7.5 mg/ml, 0.1 mg/ml to 6 mg/ml, 0.1 mg/ml to 5 mg/ml, 0.1 mg/ml to 4 mg/ml, 0.1 mg/ml to 3 mg/ml, 0.1 mg/ml to 2 mg/ml, 0.1 mg/ml to 1 mg/ml, 0.1 mg/ml, 0.2 mg/ml, 0.3 mg/ml, 0.4 mg/ml, 0.5 mg/ml, 0.6 mg/ml, 0.7 mg/ml, 0.8 mg/ml, 0.9 mg/ml, 1 mg/ml, 1.25 mg/ml, 1.5 mg/ml, 1.75 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.

According to the present invention, the amount of disodium EDTA in the room temperature stable solution for injection is 0.1 mg/ml to 4 mg/ml, 0.1 mg/ml to 3 mg/ml, 0.1 mg/ml to 2 mg/ml, 0.1 mg/ml to 1.5 mg/ml or 0.1 mg/ml to 1.5 mg/ml,

According to the present invention, the amount of D-?-tocopheryl polyethylene glycol succinate in the room temperature stable solution for injection is 5 mg/ml to 100 mg/ml, 5 mg/ml to 80 mg/ml, 5 mg/ml to 60 mg/ml, 5 mg/ml to 40 mg/ml, 5 mg/ml to 30 mg/ml, or 5 mg/ml to 25 mg/ml.

According to the present invention, the amount of hydroxypropyl betadex in the room temperature stable solution for injection is 50 mg/ml to 500 mg/ml, 50 mg/ml to 400 mg/ml, 50 mg/ml to 300 mg/ml, 100 mg/ml to 300 mg/ml, or 150 mg/ml to 250 mg/ml.

According to the present invention, the amount of mannitol in the room temperature stable solution for injection is 5 mg/ml to 100 mg/ml, 5 mg/ml to 80 mg/ml, 5 mg/ml to 60 mg/ml, 5 mg/ml to 40 mg/ml, 5 mg/ml to 30 mg/ml, or 5 mg/ml to 25 mg/ml.

According to the present invention, the amount of S- methyl-L- cysteine in the room temperature stable solution for injection is 0.1 mg/ml to 5 mg/ml, 0.1 mg/ml to 4 mg/ml, 0.1 mg/ml to 3 mg/ml, 0.1 mg/ml to 2 mg/ml, 0.1 mg/ml to 1 mg/ml, 0.1 mg/ml, 0.2 mg/ml, 0.3 mg/ml, 0.4 mg/ml, 0.5 mg/ml, 0.6 mg/ml, 0.7 mg/ml, 0.8 mg/ml, 0.9 mg/ml, 1 mg/ml, 1.25 mg/ml, 1.5 mg/ml, 1.75 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.

According to the present invention, a room temperature stable solution for the injection of Abaloparatide has a pH in the range of 4.5-5.6. Preferably the pH is 5.1.

In another embodiment, the present invention provides a room temperature stable solution for injection comprising Abaloparatide and stabilizer, wherein the total impurities of the solution are not more than 2 % after 6 months when stored at 25 °C temperature and 60 % relative humidity.

In another embodiment, the present invention provides a room temperature stable solution for injection comprising Abaloparatide and stabilizer, wherein the total impurities of the solution are not more than 2 % and the single maximum impurity is not more than 1 % after 6 months when stored at 25 °C temperature and 60 % relative humidity.

In another embodiment, the present invention provides a room temperature stable solution for injection comprising Abaloparatide and stabilizer, wherein the stabilizer is selected from L – methionine, disodium EDTA, D-?-tocopheryl polyethylene glycol succinate, hydroxypropyl betadex, mannitol, S- methyl -L- cysteine or a mixture thereof, and wherein the total impurities of the solution are not more than 2 % and the single maximum impurity is not more than 1 % after 6 months when stored at 25 °C temperature and 60 % relative humidity.

In another embodiment, the present invention provides a room temperature stable solution for injection comprising Abaloparatide and stabilizer, wherein the stabilizer is selected from L – methionine, disodium EDTA, D-?-tocopheryl polyethylene glycol succinate, hydroxypropyl betadex, mannitol, S- methyl -L- cysteine or a mixture thereof, and wherein the total impurities of the solution are not more than 2 % and the single maximum impurity is not more than 1 % after 6 months when stored at 25 °C temperature and 60 % relative humidity, wherein the solution is stable for at least 6 months when stored at 25 °C temperature and 60 % relative humidity.

In another embodiment, the present invention provides a process for the preparation of a room temperature stable solution for injection comprising Abaloparatide and stabilizer.

In another embodiment, the present invention provides a room temperature stable solution for injection comprising Abaloparatide and methionine.

In another embodiment, the present invention provides a process for the preparation of a room temperature stable solution for injection comprising Abaloparatide and methionine.

In another embodiment, the present invention provides a process for the preparation of a room temperature stable solution for injection comprising Abaloparatide and L – methionine.

In another embodiment, the present invention provides a room temperature stable solution for injection comprising Abaloparatide and L – methionine.

In another embodiment, the present invention provides a room temperature stable solution for injection comprising Abaloparatide and L – methionine, wherein pH of the solution is 4.5 to 5.6.

In another embodiment, the present invention provides a room temperature stable solution for injection comprising Abaloparatide and methionine in a concentration of 0.1 mg/ml to 10 mg/ml, wherein pH of the solution is 4.5 to 5.6.

In another embodiment, the present invention provides a room temperature stable solution for injection comprising Abaloparatide and L – methionine in a concentration of 0.1 mg/ml to 10 mg/ml, wherein pH of the solution is 4.5 to 5.6.

In another embodiment, the present invention provides a room temperature stable solution for injection comprising Abaloparatide and L – methionine, wherein the solution is stable for at least 6 months when stored at 25 °C temperature and 60 % relative humidity.

In another embodiment, the present invention provides a room temperature stable solution for injection comprising Abaloparatide and L – methionine, wherein the solution is stable for at least 12 months when stored at 25 °C temperature and 60 % relative humidity.

In another embodiment, the present invention provides a room temperature stable solution for injection comprising Abaloparatide and L – methionine, wherein the solution is stable for at least 12 months, wherein the total impurities of the solution are not more than 2 % and a single maximum impurity is not more than 1 % after 12 months of stability study when stored at 40 °C temperature and 75 % relative humidity.

In another embodiment, the present invention provides a room temperature stable solution for injection comprising Abaloparatide and L – methionine in a concentration of 0.1 mg/ml to 10 mg/ml, wherein the total impurities of the solution are not more than 2 % after 6 months when stored at 40 °C temperature and 75 % relative humidity.

In another embodiment, the present invention provides a room temperature stable solution for injection comprising Abaloparatide and L – methionine in a concentration of 0.1 mg/ml to 10 mg/ml, wherein pH of the solution is 4.5 to 5.6 and wherein the total impurities of the solution are not more than 2 % after 6 months when stored at 40 °C temperature and 75 % relative humidity.

In another embodiment, the present invention provides a room temperature stable solution for injection comprising Abaloparatide and L – methionine, in a concentration of 0.1 mg/ml to 10 mg/ml, wherein the total impurities of the solution are not more than 2 % and a single maximum impurity is not more than 1 % after 6 months when stored at 40 °C temperature and 75 % relative humidity.

In another embodiment, the present invention provides a room temperature stable solution for injection comprising Abaloparatide and L – methionine, in a concentration of 0.1 mg/ml to 10 mg/ml, wherein pH of the solution is 4.5 to 5.6 and wherein the total impurities of the solution are not more than 2 % and a single maximum impurity is not more than 1 % after 6 months when stored at 40 °C temperature and 75 % relative humidity.

In another embodiment, the present invention provides a room temperature stable solution for injection comprising 0.1 mg/ml - 5 mg/ml Abaloparatide and 0.1 mg/ml – 10 mg/ml L-Methionine. In another embodiment, the present invention provides a room temperature stable solution for injection comprising 2 mg/ml Abaloparatide and 0.1 mg/ml – 10 mg/ml L-Methionine. In another embodiment, the present invention provides a room temperature stable solution for injection comprising 0.1 mg/ml - 5 mg/ml Abaloparatide and 0.1 mg/ml – 5 mg/ml L-Methionine. In another embodiment, the present invention provides a room temperature stable solution for injection comprising 0.1 mg/ml – 2.5 mg/ml Abaloparatide and 0.1 mg/ml – 2.5 mg/ml L-Methionine. In another embodiment, the present invention provides a room temperature stable solution for injection comprising 2 mg/ml Abaloparatide and 1 mg/ml L-Methionine, wherein pH of the solution is 4.5 to 5.6. In another embodiment, the present invention provides a room temperature stable solution for injection comprising 0.1 mg/ml - 5 mg/ml Abaloparatide and 0.1 mg/ml – 10 mg/ml L-Methionine, wherein pH of the solution is 4.5 to 5.6.

In another embodiment, the present invention provides a room temperature stable solution for injection comprising 0.1 mg/ml - 5 mg/ml Abaloparatide and 0.1 mg/ml – 10 mg/ml L-Methionine, wherein pH of the solution is 4.5 to 5.6 and wherein the total impurities of the solution are not more than 2 % after 6 months when stored at 40 °C temperature and 75 % relative humidity.

In another embodiment, the present invention provides a room temperature stable solution for injection comprising 0.1 mg/ml - 5 mg/ml Abaloparatide and 0.1 mg/ml – 10 mg/ml L-Methionine, wherein pH of the solution is 4.5 to 5.6 and wherein the total impurities of the solution are not more than 2 % and a single maximum impurity is not more than 1 % after 6 months when stored at 40 °C temperature and 75 % relative humidity.

In another embodiment, the present invention provides a room temperature stable solution for injection comprising Abaloparatide and stabilizer, wherein the stabilizer is disodium EDTA, and wherein the solution is stable for at least 6 months when stored at 25 °C temperature and 60 % relative humidity.

In another embodiment, the present invention provides a room temperature stable solution for injection comprising Abaloparatide and stabilizer, wherein the stabilizer is disodium EDTA, and wherein pH of the solution is 4.5 to 5.6.

In another embodiment, the present invention provides a room temperature stable solution for injection comprising Abaloparatide and stabilizer, wherein the stabilizer is disodium EDTA in a concentration of 0.1 mg/ml to 4 mg/ml, and wherein pH of the solution is 4.5 to 5.6.

In another embodiment, the present invention provides a room temperature stable solution for injection comprising Abaloparatide and stabilizer, wherein the stabilizer is disodium EDTA in a concentration of 0.1 mg/ml to 4 mg/ml, wherein pH of the solution is 4.5 to 5.6, and wherein the total impurities of the solution are not more than 2 % and the single maximum impurity is not more than 1 % after 6 months when stored at 25 °C temperature and 60 % relative humidity.

In another embodiment, the present invention provides a room temperature stable solution for injection comprising Abaloparatide and stabilizer, wherein the stabilizer is D-?-tocopheryl polyethylene glycol succinate, and wherein the solution is stable for at least 6 months when stored at 25 °C temperature and 60 % relative humidity.

In another embodiment, the present invention provides a room temperature stable solution for injection comprising Abaloparatide and stabilizer, wherein the stabilizer is D-?-tocopheryl polyethylene glycol succinate, and wherein pH of the solution is 4.5 to 5.6.

In another embodiment, the present invention provides a room temperature stable solution for injection comprising Abaloparatide and stabilizer, wherein the stabilizer is D-?-tocopheryl polyethylene glycol succinate in a concentration of 5 mg/ml to 100 mg/ml, and wherein pH of the solution is 4.5 to 5.6.

In another embodiment, the present invention provides a room temperature stable solution for injection comprising Abaloparatide and stabilizer, wherein the stabilizer is D-?-tocopheryl polyethylene glycol succinate in a concentration of 5 mg/ml to 100 mg/ml, wherein pH of the solution is 4.5 to 5.6, and wherein the total impurities of the solution are not more than 2 % and the single maximum impurity is not more than 1 % after 6 months when stored at 25 °C temperature and 60 % relative humidity.

In another embodiment, the present invention provides a room temperature stable solution for injection comprising Abaloparatide and stabilizer, wherein the stabilizer is hydroxypropyl betadex, and wherein the solution is stable for at least 6 months when stored at 25 °C temperature and 60 % relative humidity.

In another embodiment, the present invention provides a room temperature stable solution for injection comprising Abaloparatide and stabilizer, wherein the stabilizer is hydroxypropyl betadex, and wherein pH of the solution is 4.5 to 5.6.

In another embodiment, the present invention provides a room temperature stable solution for injection comprising Abaloparatide and stabilizer, wherein the stabilizer is hydroxypropyl betadex in a concentration of 50 mg/ml to 500 mg/ml, and wherein pH of the solution is 4.5 to 5.6.

In another embodiment, the present invention provides a room temperature stable solution for injection comprising Abaloparatide and stabilizer, wherein the stabilizer is Hydroxypropyl betadex in a concentration of 50 mg/ml to 500 mg/ml, wherein pH of the solution is 4.5 to 5.6, and wherein the total impurities of the solution are not more than 2 % and the single maximum impurity is not more than 1 % after 6 months when stored at 25 °C temperature and 60 % relative humidity.

In another embodiment, the present invention provides a room temperature stable solution for injection comprising Abaloparatide and stabilizer, wherein the stabilizer is S- methyl -L- cysteine, and wherein the solution is stable for at least 6 months when stored at 25 °C temperature and 60 % relative humidity.

In another embodiment, the present invention provides a room temperature stable solution for injection comprising Abaloparatide and stabilizer, wherein the stabilizer is S- methyl -L- cysteine, and wherein pH of the solution is 4.5 to 5.6.

In another embodiment, the present invention provides a room temperature stable solution for injection comprising Abaloparatide and stabilizer, wherein the stabilizer is S- methyl -L- cysteine in a concentration of 0.1 mg/ml to 10 mg/ml, and wherein pH of the solution is 4.5 to 5.6.

In another embodiment, the present invention provides a room temperature stable solution for injection comprising Abaloparatide and stabilizer, wherein the stabilizer is S- methyl -L- cysteine in a concentration of 0.1 mg/ml to 10 mg/ml, wherein pH of the solution is 4.5 to 5.6, and wherein the total impurities of the solution are not more than 2 % and the single maximum impurity is not more than 1 % after 6 months when stored at 25 °C temperature and 60 % relative humidity.

In another embodiment, the present invention provides a room temperature stable solution for injection comprising Abaloparatide and stabilizer, wherein the stabilizer is mannitol, and wherein the solution is stable for 6 months when stored at 25 °C temperature and 60 % relative humidity.

In another embodiment, the present invention provides a room temperature stable solution for injection comprising Abaloparatide and stabilizer, wherein the stabilizer is mannitol, and wherein pH of the solution is 4.5 to 5.6.

In another embodiment, the present invention provides a room temperature stable solution for injection comprising Abaloparatide and stabilizer, wherein the stabilizer is mannitol in a concentration of 5 mg/ml to 100 mg/ml, and wherein pH of the solution is 4.5 to 5.6.

In another embodiment, the present invention provides a room temperature stable solution for injection comprising Abaloparatide and stabilizer, wherein the stabilizer is mannitol in a concentration of 5 mg/ml to 100 mg/ml, wherein pH of the solution is 4.5 to 5.6, and wherein the total impurities of the solution are not more than 2 % and the single maximum impurity is not more than 1 % after 6 months when stored at 25 °C temperature and 60 % relative humidity.

EXAMPLES

The present invention has been described by way of example only, and it is to be recognized that modifications thereto filling 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.

Examples 1 – 10

Quantity in mg/ ml
Sr. No. Ingredients Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 5 Ex. 6 Ex. 7 Ex. 8 Ex. 9 Ex. 10
1 Abaloparatide 2 2 2 2 2 2 2 2 2 2
2 Phenol 5 5 5 5 - 5 5 5 5 5
3 Sodium acetate trihydrate 5.08 5.08 5.08 5.08 - 5.08 5.08 5.08 5.08 5.08
4 Glacial acetic acid 6.38 6.38 - - - - - - - -
5 2% w/v Glacial acetic acid - - Qs* Qs* Qs* Qs* Qs* Qs* Qs* Qs*
6 S- Methyl-L- cysteine - - 1 - - - - - - -
6 L-methionine - - - - - - - 1 1 1
7 Glycerine - - - - - 150 - - - 150
8 Disodium EDTA - - - - - - 0.5 0.5 0.5 1
9 Vit E TPGS - - - - - - 20 - - -
10 Hydroxypropyl betadex - - - - - - - - 200 200
11 Mannitol - - - - - - - - 20 -
12 Water for Injection QS to 1 ml QS to 1 ml QS to 1 ml QS to 1 ml QS to 1 ml QS to 1 ml QS to 1 ml QS to 1 ml QS to 1 ml QS to 1 ml
* - QS to adjust pH.

Process for preparation for example 1 – 10:

1. Water for injection was taken and maintained at 2 to 8°C temperature with nitrogen purging.
2. Phenol was added under stirring into the water of step 1.
3. Stabilizer selected from L – methionine, disodium EDTA, D-?-tocopheryl polyethylene glycol succinate, hydroxypropyl betadex, mannitol, S- methyl-L- cysteine or a mixture thereof was added under stirring, the stirring was continued until complete dissolution of the stabilizer into the solution of step 2.
4. Sodium acetate trihydrate was added into the solution of step 3 under stirring, and the stirring was continued until complete dissolution of Sodium acetate trihydrate.
5. The pH of the solution of step 4 was adjusted between 4.6 to 5.6 with the help of 2 % w/v Glacial acetic acid solution.
6. Abaloparatide was added into the solution of step 5 under stirring and the stirring was continued until complete dissolution of the Abaloparatide.
7. The pH of the solution of step 6 was adjusted between 4.6 to 5.6 with the help of 2 % w/v Glacial acetic acid solution.
8. The volume of the solution of step 7 was adjusted to 100% with water for injection.
9. The solution of step 8 was filtered through 0.2 µ nylon/PES capsule filter.
10. The filtered solution for step 9 was filled into USP Type I clear glass cartridge of 1.50 ml capacity.

Example 11:

S. No. Ingredients Quantity in
mg/ ml
1 Abaloparatide 2
2 Phenol 5
3 L-Methionine 1
4 Sodium acetate trihydrate 5.08
5 2% w/v Glacial acetic acid solution Qs to adjust pH
6 Water for Injection QS to 1 ml

Process for preparation for example 11:

1. Water for injection was taken and maintained at 2 to 8°C temperature with nitrogen purging.
2. Phenol was added under stirring into the water of step 1.
3. L – methionine was added under stirring, the stirring was continued until the complete dissolution of the stabilizer into the solution of step 2.
4. Sodium acetate trihydrate was added into the solution of step 3 under stirring, and the stirring was continued until complete dissolution of Sodium acetate trihydrate.
5. The pH of the solution of step 4 was adjusted between 4.6 to 5.6 with the help of 2 % w/v Glacial acetic acid solution.
6. Abaloparatide was added into the solution of step 5 under stirring and the stirring was continued until complete dissolution of the Abaloparatide.
7. The pH of the solution of step 6 was adjusted between 4.6 to 5.6 with the help of 2 % w/v Glacial acetic acid solution.
8. The volume of the solution of step 7 was adjusted to 100% with water for injection.
9. The solution of step 8 was filtered through 0.2 µ nylon/PES capsule filter.
10. The filtered solution for step 9 was filled into USP Type I clear glass cartridge of 1.50 ml capacity.

The room temperature stable injection solution of Examples 1 -11 were evaluated for their physical and chemical characteristics. Following are the study results:

Stability study result of examples 1-4 and 6-11 (Initial):

Sr. No. Test Parameters Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 6 Ex. 7 Ex. 8 Ex. 9 Ex. 10 Ex. 11
1 Description CCS* CCS* CCS* CCS* CCS* CCS* CCS* CCS* CCS* CCS*
2 pH 4.3 4.1 5.15 5.1 5.1 5.1 5.1 5.1 5.1 5.1
3 Assay 100 97.5 101 100 98 100 100 100 98 100
4 Phenol content % 100 103 100 101 97 101 98 99 97 100
5 Related Substances
Single maximum impurity % 0.22 0.23 0.35 0.35 0.26 0.24 0.27 0.22 0.302 0.379
Total impurities % 0.8 0.81 0.61 0.85 0.87 0.86 0.81 0.86 0.88 0.612
CCS* - Clear colourless solution

Further, the room temperature stable injection solutions of Examples 1 -11 were subject to stability study at 25°C temperature 60% relative humidity for 6 months.

Stability study result of examples 1-4 and 6-11 (25°C/60% RH – 3 and 6 months):

3 Months (25°C/60% RH)
Sr. No. Test Parameter Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 6 Ex. 7 Ex. 8 Ex. 9 Ex. 10 Ex. 11
1 Description CCS* CCS* CCS* CCS* CCS* CCS* CCS* CCS* CCS* CCS*
2 pH 4.3 4.1 5 5 5.1 5.1 5.1 5.1 5.1 5.1
3 Assay 98 97 100 100 97 99 98 99 97 100
4 Phenol content % 96 98 99.9 100 96 100 100 98 96 100
5 Related Substances
Single maximum impurity % 0.62 0.628 0.446 0.646 0.658 0.637 0.672 0.624 0.602 0.479
Total impurities % 1.2 1.211 0.806 1.2 1.2 1.261 1.209 1.255 1.28 0.88
6 Months (25°C/60% RH)
Sr. No. Ingredients Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 6 Ex. 7 Ex. 8 Ex. 9 Ex. 10 Ex. 11
1 Description CCS* CCS* CCS* CCS* CCS* CCS* CCS* CCS* CCS* CCS*
2 pH 4.3 4.1 5 5 5.1 5.1 5.1 5.1 5.1 5.1
3 Assay 97 96 99 99 96 98 97 98 96 99
4 Phenol content % 96 98 98.9 99 95 99 99 97 96 99
5 Related Substances
Single maximum impurity % 0.72 0.728 0.546 0.746 0.758 0.737 0.772 0.724 0.702 0.579
Total impurities % 1.4 1.411 1.1 1.4 1.4 1.461 1.409 1.455 1.48 1.1
CCS* - Clear colourless solution

Stability study result of examples 11 (25°C/60% RH – 9 and 12 months):

Ex. 11 (25°C/60% RH)
S. No. Test Parameter 9M 12 M
1 Description Clear colourless solution Clear colourless solution
2 pH 5.10 5.10
3 Assay 98.0 97.0
4 Phenol content % 98.0 97.0
5 Related Substances
Single maximum impurity % 0.69 0.80
Total impurities % 1.20 1.60

From the above stability studies, it can be concluded that the room temperature stable solutions for injection of the present invention comprising Abaloparatide and stabilizer selected from L – methionine, disodium EDTA, D-?-tocopheryl polyethylene glycol succinate, hydroxypropyl betadex, mannitol, S- methyl-L- cysteine or a mixture thereof are stable at room temperature.

Further, the room temperature stable injection solutions of Examples 1 -11 were further subject to stability study at 40°C temperature 75% relative humidity for 6 months. Following are the study results:

Stability study result of examples 1-4 and 6-11 (40°C/75% RH – 3 and 6 months):

3 Months (40°C/75% RH)
Sr. No. Test Parameter Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 6 Ex. 7 Ex. 8 Ex. 9 Ex. 10 Ex. 11
1 Description CCS* CCS* CCS* CCS* CCS* CCS* CCS* CCS* CCS* CCS*
2 pH 4.3 4.1 5.1 5 5.1 5.1 5.1 5.1 5.1 5.1
3 Assay 97 96 100 99 96 99 97 98 96 100
4 Phenol content % 95 97 99.9 100 95 100 98 97 95 100
5 Related Substances
Single maximum impurity % 1.35 1.178 0.42 0.5 2.2 0.5 0.65 0.5 2.01 0.56
Total impurities % 2.23 2 1.6 1.7 3.43 1.3 1.84 2.36 4.1 0.8
6 Months (40°C/75% RH)
S. No. Test Parameter Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 6 Ex. 7 Ex. 8 Ex. 9 Ex. 10 Ex. 11
1 Description CCS* CCS* CCS* CCS* CCS* CCS* CCS* CCS* CCS* CCS*
2 pH 4.3 4.1 5 5 5.1 5.1 5.1 5.1 5.1 5.1
3 Assay 95 94 98 97 95 97 96 96 95 99
4 Phenol content % 93 95 98.9 98 94 98 97 95 94 98
5 Related Substances
Single maximum impurity % 2.35 2.178 0.8 1.02 3.2 0.88 0.85 0.85 3.01 0.8
Total impurities % 3.23 3 1.8 2.7 4.43 2.2 2.84 2.436 5.1 1.6
CCS* - Clear colourless solution

From the above stability studies, it can be concluded that the room temperature stable solutions for injection of the present invention comprising Abaloparatide and L – methionine are stable for 6 months at 40°C temperature 75% relative humidity.

From the above examples and study results, it can be concluded the present invention provides a room temperature stable solution for injection comprising Abaloparatide and stabilizer selected from L – methionine, disodium EDTA, D-?-tocopheryl polyethylene glycol succinate, hydroxypropyl betadex, mannitol, S- methyl-L- cysteine or a mixture thereof, wherein the solution is stable for at least 6 months when stored at 25 °C temperature and 60 % relative humidity. Further, the present invention provides a process for the preparation of the said solution. The invention provides an injectable solution that is stable at room temperature which overcomes the limitations of the currently marketed formulation.

, Claims:I / We claim,

1. A room temperature stable injectable solution comprising 0.25 mg/ml to 5 mg/ml Abaloparatide and stabilizer selected from m 0.1 mg/ml to 10 mg/ml L-methionine, 0.1 mg/ml to 4 mg/ml disodium EDTA, 5 mg/ml to 100 mg/ml D-?-tocopheryl polyethylene glycol succinate, 50 mg/ml to 500 mg/ml hydroxypropyl betadex, 5 mg/ml to 100 mg/ml mannitol, 0.1 mg/ml to 10 mg/ml S- methyl-L- cysteine or mixture thereof, wherein the solution is stable for at least 6 months when stored at 25 °C temperature and 60 % relative humidity, wherein the total impurities of the solution are not more than 2 % and the single maximum impurity is not more than 1 % after 6 months when stored at 25 °C temperature and 60 % relative humidity.

2. A room temperature stable injectable solution as claimed in claim 1, wherein pH of the solution is 4.5 to 5.6.

3. A room temperature stable injectable solution as claimed in claim 1, wherein the stabilizer is 0.1 mg/ml to 10 mg/ml S- methyl-L- cysteine.

4. A room temperature stable injectable solution as claimed in claim 3, wherein pH of the solution is 4.5 to 5.6.

5. A room temperature stable injectable solution comprising 0.25 mg/ml to 5 mg/ml Abaloparatide and 0.1 mg/ml to 10 mg/ml S- methyl-L- cysteine.

6. A room temperature stable injectable solution as claimed in claim 5, wherein pH of the solution is 4.5 to 5.6.

7. A room temperature stable injectable solution comprising;
(a) 0.1 mg/ml - 5 mg/ml Abaloparatide
(b) 0.1 mg/ml – 10 mg/ml S- methyl-L- cysteine
wherein pH of the solution is 4.5 to 5.6 and;
wherein the total impurities of the solution are not more than 2 % after 6 months when stored at 25 °C temperature and 60 % relative humidity.