DESC:
FIELD OF THE INVENTION

The present invention relates to a stable pharmaceutical composition comprising etelcalcetide or pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION

Etelcalcetide (formerly known as AMG 416 or velcalcetide) is a synthetic, eight amino-acid selective peptide agonist of the calcium sensing receptor. Etelcalcetide hydrochloride is a white to off-white powder with a molecular weight of 1047.5 g/mol (monoisotopic; free base). It is soluble in water. The hydrochloride salt of etelcalcetide is described chemically as N-acetyl-D-cysteinyl-S-(L-cysteine disulfide)-D-alanyl-D-arginyl-D-arginyl-D-arginyl-D-alanyl-D-argininamide hydrochloride.

Etelcalcetide is effective in decreasing parathyroid hormone levels in vivo, and is useful, for example, in treating hypercalcemia or hyperparathyroidism. It is available under the trade name of Parsabiv® Solution; Intravenous (IV) for Infusion with pH of 3.3 and supplied as 2.5mg/0.5ml, 5mg/ml and 10mg/2ml.

US Pat. No. 8,999,932 and its family discloses etelcalcetide. It also discloses a method of treating secondary hyperparathyroidism (SHPT) using etelcalcetide.

US Pat. No. 1,0344,765 discloses a pharmaceutical formulation comprising etelcalcetide hydrochloride in aqueous solution, wherein the formulation has a pH of 2.0 to 5.0.

CN. Pub. No. 106137979 A1 discloses a lyophilized injectable powder of etelcalcetide and a preparation method thereof which can effectively solve the problem of broken bottle phenomenon in freeze-drying process by pre-freezing, evacuation and dry step.
Therapeutic peptides pose a number of challenges with respect to their formulation, one such challenge is the stability of these peptides.

In view of the above, it is therefore desirable to provide a stable pharmaceutical composition of etelcalcetide which has a pH between 5.1 to 9.0, wherein etelcalcetide is more stable.

SUMMARY OF THE INVENTION

The present invention relates to a stable lyophilized pharmaceutical composition comprising etelcalcetide or a pharmaceutically-acceptable salt thereof.

The present invention relates to a stable lyophilized pharmaceutical composition comprising etelcalcetide or a pharmaceutically-acceptable salt thereof, prepared from a bulk solution.

The present invention further relates to a stable lyophilized pharmaceutical composition comprising etelcalcetide or a pharmaceutically-acceptable salt thereof, and one or more pharmaceutically acceptable excipients, prepared from a bulk solution, wherein the bulk solution has a pH greater than 5.

The present invention further relates to a stable lyophilized pharmaceutical composition comprising etelcalcetide or a pharmaceutically-acceptable salt thereof, and one or more pharmaceutically acceptable excipients, prepared from a bulk solution, wherein the bulk solution has a pH between 5.1 to 9.0.

The present invention relates to a stable lyophilized pharmaceutical composition comprising etelcalcetide or a pharmaceutically-acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein the pH of the composition after reconstitution is greater than 5.

The present invention relates to a stable lyophilized pharmaceutical composition comprising etelcalcetide or a pharmaceutically-acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein the pH of the composition after reconstitution is between 5.1 to 9.0.

The present invention further relates to a stable lyophilized pharmaceutical composition comprising etelcalcetide or a pharmaceutically-acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein the composition is reconstituted using diluents.

The present invention further relates to a stable lyophilized pharmaceutical composition comprising etelcalcetide or a pharmaceutically-acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein the composition is reconstituted using sterile aqueous diluents.

The present invention further relates to a stable lyophilized pharmaceutical composition comprising etelcalcetide or a pharmaceutically-acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein the lyophilized composition has a total impurity of less than 5%, preferably less than 3% and more preferably less than 2% when stored at 2-8 °C for 6 months.

The present invention further relates to a stable lyophilized pharmaceutical composition comprising etelcalcetide or a pharmaceutically-acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein the lyophilized composition has a total impurity of less than 10%, preferably less than 5% and more preferably less than 3% when stored at 20-25 °C for 6 months.

The present invention further relates to a stable lyophilized pharmaceutical composition comprising etelcalcetide or a pharmaceutically-acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein the one or more pharmaceutically acceptable excipients are selected form the group comprising buffers, tonicity agents, pH adjusting agents, preservatives, vehicles, bulking agents, antioxidant, surfactants, chelating agent, lyoprotectants and/or other formulation agents and a combinations thereof.

The present invention further relates to a stable lyophilized pharmaceutical composition comprising etelcalcetide or a pharmaceutically-acceptable salt thereof, and one or more pharmaceutically acceptable excipients, which is useful for treating hypercalcemia or hyperparathyroidism.

The present invention relates to a stable liquid pharmaceutical composition comprising etelcalcetide or a pharmaceutically-acceptable salt thereof.

The present invention further relates to a stable liquid pharmaceutical composition comprising etelcalcetide or a pharmaceutically-acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein the pH of the composition is greater than 5.

The present invention further relates to a stable liquid pharmaceutical composition comprising etelcalcetide or a pharmaceutically-acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein the pH of the composition is between 5.1 to 9.0.

The present invention further relates to a stable aqueous pharmaceutical composition comprising etelcalcetide or a pharmaceutically-acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein the pH of the composition is greater than 5.

The present invention further relates to a stable aqueous pharmaceutical composition comprising etelcalcetide or a pharmaceutically-acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein the pH of the composition is between 5.1 to 9.0.

The present invention further relates to a stable liquid pharmaceutical composition comprising etelcalcetide or a pharmaceutically-acceptable salt thereof, and one or more pharmaceutically acceptable excipients, which is useful for treating hypercalcemia or hyperparathyroidism.

DESCRIPTION OF THE INVENTION

The present invention relates to a stable lyophilized pharmaceutical composition comprising etelcalcetide or a pharmaceutically-acceptable salt thereof, which can maintain stability during its storage.

Applicant has developed a stable lyophilized pharmaceutical composition comprising etelcalcetide or a pharmaceutically-acceptable salt thereof, which can encounter stress conditions like freeze/thaw cycles, agitation, long term storage, pumping, filtration, or unrefrigerated storage.

Applicant has developed stable lyophilized pharmaceutical composition comprising etelcalcetide or a pharmaceutically-acceptable salt thereof, which is prepared from a bulk solution having a pH between 5.1 to 9.0.

Applicant has developed a stable lyophilized pharmaceutical composition comprising etelcalcetide or a pharmaceutically-acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein the pH of the composition after reconstitution is between 5.1 to 9.0.

In another aspect of the present invention, there is provided a stable lyophilized pharmaceutical composition comprising etelcalcetide or a pharmaceutically-acceptable salt thereof and pharmaceutically acceptable excipients, wherein the pharmaceutical composition comprising from about 0.01 mg/mL to about 10 mg/mL of etelcalcetide or pharmaceutically acceptable salts thereof.

In another aspect of the present invention, there is provided a stable lyophilized pharmaceutical composition comprising etelcalcetide or a pharmaceutically-acceptable salt thereof and pharmaceutically acceptable excipients, wherein the composition can be reconstituted using diluent.

In another aspect of the present invention, there is provided a stable lyophilized pharmaceutical composition comprising etelcalcetide or a pharmaceutically-acceptable salt thereof and pharmaceutically acceptable excipients, wherein the composition can be reconstituted using a sterile aqueous diluent.

In another aspect of the present invention, there is provided a stable lyophilized pharmaceutical composition comprising etelcalcetide or a pharmaceutically-acceptable salt thereof and pharmaceutically acceptable excipients, wherein the composition can be reconstituted with one or more diluent such as sterile water for injection, Bacteriostatic Water for Injection, purified water, 0.9% sodium chloride injection, 5% dextrose injection, lactated ringer's injection or any other diluent.

In another aspect of the present invention, there is provided a stable lyophilized pharmaceutical composition comprising etelcalcetide or a pharmaceutically-acceptable salt thereof and pharmaceutically acceptable excipients, wherein the lyophilized composition has a total impurity of less than 2% when stored at 2-8 °C for 6 months.

In another aspect of the present invention, there is provided a stable lyophilized pharmaceutical composition comprising etelcalcetide or a pharmaceutically-acceptable salt thereof and pharmaceutically acceptable excipients, wherein the lyophilized the lyophilized composition has a total impurity of less than 3% when stored at 20-25 °C for 6 months.

In another aspect of the present invention, there is provided a stable lyophilized pharmaceutical composition comprising etelcalcetide or a pharmaceutically-acceptable salt thereof and pharmaceutically acceptable excipients, wherein the composition can be reconstituted using diluent just prior to use, it is preferred that the reconstituted solution be used within 4-6 hours after reconstitution.

In another aspect of the present invention, the stable lyophilized pharmaceutical composition comprising etelcalcetide or a pharmaceutically-acceptable salt thereof may be in the form of a unit dose formulation or multi dose formulation.

In another aspect of the present invention, the stable lyophilized pharmaceutical composition comprising etelcalcetide or a pharmaceutically-acceptable salt thereof wherein the composition is free of preservative.

In another aspect of the present invention, the stable lyophilized pharmaceutical composition comprising etelcalcetide or a pharmaceutically-acceptable salt thereof wherein the composition contains preservative.

In another aspect of the present invention, the stable lyophilized pharmaceutical composition comprising etelcalcetide or a pharmaceutically-acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the one or more pharmaceutically acceptable excipients comprising buffers, tonicity agents, pH adjusting agents, preservatives, vehicles, bulking agents, antioxidant, surfactants, chelating agent, lyoprotectants and/or other formulation agents and combinations thereof.

Another aspect of the present invention relates to a stable liquid pharmaceutical composition comprising etelcalcetide or a pharmaceutically-acceptable salt thereof.

In another aspect of the present invention the stable liquid pharmaceutical composition comprising etelcalcetide or a pharmaceutically-acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein the pH of the composition is greater than 5.

In another aspect of the present invention the stable liquid pharmaceutical composition comprising etelcalcetide or a pharmaceutically-acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein the pH of the composition is between 5.1 to 9.0.

Another aspect of the present invention relates to a stable aqueous pharmaceutical composition comprising etelcalcetide or a pharmaceutically-acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein the pH of the composition is greater than 5.

In another aspect of the present invention the stable aqueous pharmaceutical composition comprising etelcalcetide or a pharmaceutically-acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein the pH of the composition is between 5.1 to 9.0.

Those skilled in the art would readily recognize a variety of buffers that could be used in the compositions, and dosage forms used in the invention. Typical buffers include, but are not limited to pharmaceutically acceptable weak acids, weak bases, salts of weak acid or weak bases or mixtures thereof. Exemplary buffer components include phosphoric acid, tartaric acids, lactic acid, boric acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, or salts thereof. Suitable buffers may include one or more of buffers such as, for example, citrate, phosphate, succinate, acetate, gluconate, Tromethamine, HCl or other organic acid buffers and amino acids such as glycine, aspartate, histidine, cysteine, tyrosine, phenylalanine, proline, arginine, threonine, serine, valine, isoleucine, lysine, and glutamine or mixtures thereof.

In another aspect, the suitable pH adjusting agent include, but are not limited to sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium succinate, potassium hydroxide, ammonium carbonate, hydrochloric acid, citric acid, lactic acid, phosphoric acid, sodium phosphate, sulfuric acid, succinic acid, acetic acid or mixtures thereof and the like can also be used.

In another aspect, the solvent used to prepare the bulk solution prior to lyophilisation include but is not limited to purified water, sterile water for injection, ethanol, physiological saline solution, citrate buffered saline, or combination thereof or any other materials common in compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles.

In another aspect, suitable tonicity agents include, but is not limited to but are not limited to, alkaline and alkaline earth metal salts, dextrose, glycerol, propylene glycol, sodium chloride, potassium chloride, glycerine, mannitol and / or mixtures thereof.

In another aspect, suitable preservative is selected from, but is not limited to quaternary ammonium compounds, benzyl alcohol, parabens (methyl, propyl, butyl), benzalkonium chloride, phenylmercuric nitrate, thiomersal, stabilized oxychloro complex, benzethonium chloride, phenol, cresol, phenethyl alcohol, dehydroacetic acid, sorbic acid and chlorobutanol and / or mixtures thereof.

In another aspect, suitable lyoprotectants include, but are not limited to amino acids such as monosodium glutamate or histidine; a methylamine such as betaine; a lyotropic salt such as magnesium sulfate; a polyol such as sucrose, trehalose, glycine, lysine, glycerin, dextran, erythritol, glycerol, arabitol, xylitol, sorbitol, and mannitol; propylene glycol; polyethylene glycol; Pluronics®; and combinations thereof. Additional examples of lyoprotectants include, but are not limited to, glycerin and gelatin, lactose, sugars, saccharides and / or mixtures thereof.

In another aspect, suitable bulking agents include, but are not limited to hydroxyethyl starch, saccharides, preferably monosaccharides or oligosaccharides, sugar alcohols, and mixtures thereof. Suitable bulking agents include the following, but are not limited to mannitol, sodium chloride, glucose, sucrose, lactose, trehalose, dextrose, maltose, sorbitol, dextran, raffinose, PVP, histidine, amino acids such as glycine, arginine, aspartic acid and / or mixtures thereof.

Other Pharmaceutically acceptable excipients may comprise, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, polyvinylpyrrolidone (PVP), cholesterol, cholesterol esters, sodium caseinate, soy lecithin, taurocholic acid, phosphotidylcholine, sodium chloride, tricalcium phosphate, dipotassium phosphate, cellulose and cellulose conjugates, sugars sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, and the like. Suitable antifoaming agents include dimethicone, myristic acid, palmitic acid, simethicone and / or mixtures thereof.

The pharmaceutical composition is suitable for parenteral administration to a patient. The pharmaceutical compositions can be in a form suitable for parenteral injection such as a sterile suspension, solution, or emulsion in oily or aqueous vehicles.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and don't limit the scope of the invention. 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.

Examples:
Table 1: Pharmaceutical composition of Etelcalcetide

Ingredient Composition
1 Composition
2 Composition
3 Composition
4 Composition
5
% % % % %
Etelcalcetide 0.5 0.5 0.5 0.5 0.5
Mannitol 1-2000 1-2000 1-2000 1-2000 1-2000
Sodium Chloride 1-180 - - - -
Sodium Phosphate
Dibasic - 1-139.2 - - 1-139.2
Sodium Phosphate
Monobasic - 1-18.81 - - 1-18.81
Tromethamine base - - 0.1-2.4 - -
Succinic acid - - - 0.1-15.3 -
Methyl Paraben - - - - 0.1-15
Propyl Paraben - - - - 0.1-0.8
Hydrochloric Acid* qs
pH 5.1 – 9.0 qs
pH 5.1 – 9.0 qs
pH 5.1 – 9.0 qs
pH 5.1 – 9.0 qs
pH 5.1 – 9.0
Sodium Hydroxide* qs
pH 5.1 – 9.0 qs
pH 5.1 – 9.0 qs
pH 5.1 – 9.0 qs to
pH 5.1 – 9.0 qs
pH 5.1 – 9.0
Water for injection qs qs qs qs qs
.
Table 2: Pharmaceutical composition of Etelcalcetide
Ingredient Composition
6 Composition
7 Composition
8 Composition
9 Composition
10
% % % % %
Etelcalcetide 1-10 1-10 1-10 1-10 1-10
Lactose 1-750 1-750 1-750 1-750 1-750
Sodium Chloride 1-180 - - - -
Sodium Phosphate Dibasic - 1-139.2 - - 1-139.2
Sodium Phosphate Monobasic - 1-18.81 - - 1-18.81
Tromethamine base - - 0.1-2.4 - -
Succinic acid - - - 0.1-15.3 -
Methyl Paraben - - - - 0.1-15
Propyl Paraben - - - - 0.1-0.8
Hydrochloric Acid qs
pH 5.1 – 9.0 qs
pH 5.1 – 9.0 qs
pH 5.1 – 9.0 qs
pH 5.1 – 9.0 qs
pH 5.1 – 9.0
Sodium Hydroxide qs
pH 5.1 – 9.0 qs
pH 5.1 – 9.0 qs
pH 5.1 – 9.0 qs
pH 5.1 – 9.0 qs
pH 5.1 – 9.0
Water for injection qs qs qs qs qs

Table 3: Pharmaceutical composition of Etelcalcetide
Ingredient Composition
11 Composition
12 Composition
13 Composition
14
% % % %
Etelcalcetide 1-10 1-10 1-10 1-10
Sodium Chloride 1-180 1-180 1-180 1-180
Sodium Phosphate Dibasic 1-139.2 - - 1-139.2
Sodium Phosphate Monobasic 1-18.81 - - 1-18.81
Tromethamine base - 0.1-2.4 - -
Succinic acid - - 0.1-15.3 -
Methyl Paraben - - - 0.1-15
Propyl Paraben - - - 0.1-0.8
Hydrochloric Acid qs
pH 5.1 – 9.0 qs
pH 5.1 – 9.0 qs
pH 5.1 – 9.0 qs
pH 5.1 – 9.0
Sodium Hydroxide qs
pH 5.1 – 9.0 qs
pH 5.1 – 9.0 qs
pH 5.1 – 9.0 qs
pH 5.1 – 9.0
Water for injection qs qs qs qs
Process:
1. 80% of water for injection is collected and cooled to room temperature (20-25°C).
2. Bulking agent (mannitol or lactose, and/or sodium chloride) is added in above collected water and stirred till clear solution is formed.
3. Optionally buffers (Sodium Phosphate Dibasic and Sodium Phosphate monobasic or Tromethamine and Succinic acid) are added to the solution of step 3 and stirred till clear solution is formed.
4. pH if required is adjusted with hydrochloric acid or sodium hydroxide in the range of 5.1-9.0.
5. Etelcalcetide is added to the solution of step 4 and stirred till clear solution is formed.
6. pH if required is adjusted with hydrochloric acid or sodium hydroxide in the range of 5.1-9.0.
7. Final volume is made to 100% batch size.
8. The solution of step 7 is filtered through using 0.2micron sterile grade PVDF capsule filter and the filtered solution is filled in a glass vials.
To obtain a lyophilised composition the glass vials filled with the solution as prepared above were subjected to lyophilisation cycle including pre-freezing, evacuation, and drying to get a stable lyophilized composition.
Compositions 2, 3, 5, 7, 8, 11 and 13 were subjected to stability studies at 20-25 °C for 6 months and at 2-8 °C for 6 months.
Formulation Total impurity
20-25 °C for 6 months Total impurity
2-8 °C for 6 months.
Composition 2 1.43% 0.94%
Composition 4 1.6% 0.98%
Composition 5 0.98% 0.46%
Composition 7 1.73% 1.27%
Composition 8 2.01% 1.74%
Composition 11 1.22% 0.98%
Composition 13 2.98% 2.11%

CLAIMS:

WE CLAIM:

1. A stable pharmaceutical composition comprising Etelcalcetide or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein pH of the composition is between 5.1 to 9.0.

2. The stable pharmaceutical composition as claimed in claim 1, wherein the one or more pharmaceutically acceptable excipients are selected form the group comprising buffers, tonicity agents, pH adjusting agents, preservatives, vehicles, bulking agents, antioxidants, surfactants, chelating agents, lyoprotectants, other formulation agents, or a combination thereof.

3. The stable pharmaceutical composition as claimed in claim 1, wherein the composition is in the form of a liquid, an aqueous solution or is lyophilized.

4. The stable pharmaceutical composition as claimed in claim 3, wherein the composition comprises bulking selected from mannitol, lactose, or sodium chloride or a combination thereof, buffering agent selected citrate, phosphate, acetate, borate, gluconate, or tromethamine, succinic acid, optionally a preservative, sodium hydroxide and/or hydrochloric acid to adjust the pH, and water for injection.

5. The stable pharmaceutical composition as claimed in claim 4, wherein the composition comprises a preservative selected from methyl paraben, propyl paraben, or a combination thereof.

6. The stable pharmaceutical composition as claimed in claim 3, wherein the composition has a total impurity of less than 3% when stored at 20-25 °C for 6 months and less than 2% when stored at 2-8 °C for 6 months.

7. The pharmaceutical composition as claimed in claim 3, wherein the composition is free of preservative.

8. The stable pharmaceutical composition as claimed in claim 3, wherein the composition has a pH of greater than 5 after reconstitution with one or more diluents.

9. The stable pharmaceutical composition as claimed in claim 8, wherein the one or more diluent is selected from sterile water for injection, Bacteriostatic Water for Injection, purified water, 0.9% sodium chloride injection, 5% dextrose injection, lactated ringer's solution or any other pharmaceutically acceptable diluent.

10. The pharmaceutical composition as claimed in claim 3, wherein the composition is lyophilized and particle size of etelcalcetide or a pharmaceutically acceptable salt thereof is characterised by having D90 less than 150 µm.

Dated 13th Day of April 2021 For Mankind Pharma Ltd.
Dr. Anil Kumar
Chief Scientific Officer