DESC:FIELD OF THE INVENTION

The present invention is related to a stable lyophilized pharmaceutical composition of daptomycin comprising daptomycin or its pharmaceutically acceptable salt thereof, meglumine, buffer and one or more pharmaceutical acceptable excipient, wherein the said lyophilized composition is stable for at least 6 months when stored at 2°-8°C or 25°C.

BACKGROUND OF THE INVENTION

Daptomycin is a cyclic lipopeptide antibacterial agent and is chemically described as N-decanoyl-L-tryptophyl-Dasparaginyl-L-aspartyl-L-threonylglycyl -L-ornithyl-L-aspartyl-D-alanyl-L-aspartylglycyl-D-seryl-threo-3-methyl-L-glutamyl-3-anthraniloyl-L-alanine ?1-lactone. The chemical structure is:

Formula I

Daptomycin is indicated for the treatment of complicated skin and skin structure infections and bacteremia in adult patients and pediatric patients

Daptomycin is currently commercially available in the form of lyophilized powder for intravenous infusion (Cubicin® and Cubicin RF®). Cubicin® contains only sodium hydroxide as pH adjustment and Cubicin® should be kept at refrigerated temperatures from to 2°C to 8°C and avoid exposure to excessive heat. Cubicin RF® is supplied as lyophilized powder containing 500 mg of daptomycin and contains 713 mg of sucrose and sodium hydroxide is used to adjust the pH. The pH of the solution upon reconstitution is 6.8. Cubicin RF® is kept at 20°C to 25°C with excursions of temperature permitted to 15°C to 30°C.

US4482487 patent discloses daptomycin as a compound.

US9138456 patent discloses a solid pharmaceutical daptomycin composition wherein said composition is prepared by lyophilizing an aqueous daptomycin solution comprising daptomycin and sucrose.

US9662397 patent discloses a solid lyophilized pharmaceutical daptomycin composition comprising daptomycin and non-reducing sugar trehalose.

US20170348382 patent application discloses a lyophilized injectable composition comprising daptomycin or pharmaceutically acceptable salts or solvates thereof and a preservative.

EP0386951 patent application discloses a parenteral formulation comprising daptomycin with sufficient amount of a parentally acceptable buffer selected from dibasic sodium phosphate and tris(hydroxymethyl)aminomethane, to maintain the pH between about 6.0 and about 8.0 and one or more pharmaceutically acceptable diluents or excipients.

WO2014045296 patent application discloses a stable, lyophilized formulation comprising daptomycin and tocopheryl phosphate hydrolysate mixture, wherein said lyophilized formulation is directly reconstitutable within 5 minutes for parental administration.

IN201841009343 patent application discloses a lyophilized powder composition comprising daptomycin and at least one excipient selected from arginine, meglumine, mannitol, lactose, sucralose, isomaltose, fructose, galactose, maltose, dextrose glycine, succinic acid, fumaric acid and sodium chloride.

WO2021131314 patent application discloses a stable lyophilized preparation containing daptomycin and one or more stabilizers selected from L-arginine, inositol, dextran, meglumine, macrogol and L-histidine.

WO2014041425 patent application discloses a lyophilized daptomycin formulations comprising an additive, which can be a pharmaceutically acceptable antioxidant, a pharmaceutically acceptable organic acid, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable glucose derivative or a pharmaceutically acceptable salt thereof, or a combination thereof.

WO2019043008 patent application discloses a pharmaceutical composition comprising daptomycin and at least one amino acid or its pharmaceutically acceptable salt or derivative thereof.

Accord Healthcare markets daptomycin 350 mg and 500 mg powder for solution for injection/infusion; however, the said product needs to be stored at 2°C - 8°C. Hence, there still exists a need for the room temperature stable pharmaceutical composition comprising Daptomycin. The present invention provides a stable pharmaceutical composition of daptomycin comprising daptomycin or its pharmaceutically acceptable salt thereof, meglumine, buffer and one or more pharmaceutical acceptable excipient, wherein the said lyophilized composition is stable after being stored even at room temperature.

OBJECT OF THE INVENTION

The primary object of the present invention is to provide a stable lyophilized pharmaceutical composition of daptomycin comprising daptomycin or its pharmaceutically acceptable salt thereof, meglumine, buffer and one or more pharmaceutical acceptable excipient.

Another object of the present invention is to provide a stable lyophilized pharmaceutical composition of daptomycin comprising daptomycin or its pharmaceutically acceptable salt thereof, meglumine, buffer and one or more pharmaceutical acceptable excipient, wherein the said lyophilized composition is stable for at least 6 months when stored at 2°-8°C or 25°C.

Another object of the present invention is to provide a stable lyophilized pharmaceutical composition of daptomycin comprising daptomycin or its pharmaceutically acceptable salt thereof, meglumine, buffer and one or more pharmaceutical acceptable excipient, wherein the weight ratio of daptomycin to meglumine is in a range of about 1:0.01 to about 1:0.5.

Another object of the present invention is to provide a process for the preparation of a stable lyophilized pharmaceutical composition of daptomycin comprising daptomycin or its pharmaceutically acceptable salt thereof, meglumine, buffer and one or more pharmaceutical acceptable excipient.

Another object of the present invention is to provide a stable lyophilized pharmaceutical composition of daptomycin comprising daptomycin or its pharmaceutically acceptable salt thereof, meglumine, buffer and one or more pharmaceutical acceptable excipient, wherein the said lyophilized composition is stable for at least 6 months when stored at 2°-8°C or 25°C, wherein the said lyophilized composition is having a reconstitution time of less than 5 minutes.

Another object of the present invention is to provide a stable lyophilized pharmaceutical composition of daptomycin comprising daptomycin or its pharmaceutically acceptable salt thereof, meglumine, buffer and one or more pharmaceutical acceptable excipient, wherein the said lyophilized composition have not more than 1.5% (w/w) of anhydro-dapto impurity of daptomycin, after being stored at specific storage conditions.

Another object of the present invention is to provide a stable lyophilized pharmaceutical composition of daptomycin comprising daptomycin or its pharmaceutically acceptable salt thereof, meglumine, buffer and one or more pharmaceutical acceptable excipient, wherein the said lyophilized composition have not more than 3.0% (w/w) of total impurity of daptomycin, after being stored at specific storage conditions.

SUMMARY OF THE INVENTION

The present invention is related to a stable lyophilized pharmaceutical composition of daptomycin comprising daptomycin or its pharmaceutically acceptable salt thereof, meglumine, buffer and one or more pharmaceutical acceptable excipient, wherein the said lyophilized composition is stable for at least 6 months when stored at 2°-8°C or 25°C.

DETAILED DESCRIPTION

Unless otherwise indicated, terms in this specification are intended to have their ordinary meaning in the relevant art.

The present invention is related to a stable lyophilized pharmaceutical composition of daptomycin comprising daptomycin or its pharmaceutically acceptable salt thereof, meglumine, buffer and one or more pharmaceutical acceptable excipient.

In one of the embodiments, the present invention is to provide a stable lyophilized pharmaceutical composition of daptomycin comprising daptomycin or its pharmaceutically acceptable salt thereof, meglumine, buffer and one or more pharmaceutical acceptable excipient, wherein the said lyophilized composition is stable for at least 6 months when stored at 2°-8°C or 25°C.

The term “Daptomycin” used throughout the specification refers to not only their base per se, but also their other pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof.

The term “pharmaceutically acceptable” means salt, carriers, excipients, and other formulation ingredients that are compatible with all other pharmaceutical ingredients of a composition and are not deleterious to an individual treated with the said composition.

The term “stable” as used throughout the specification, refers to a pharmaceutical composition in which the active pharmaceutical ingredient daptomycin is present in an amount of at least 90% of the original label specified amount for each such ingredient during specific storage conditions.

The term “specific storage conditions” as used throughout the specification, refers to the pharmaceutical composition of present invention stored for at least 6 months at 25°C/60% RH and at least 6 months at 2°-8°C.

In accordance with the present invention, the term “about” shall mean a variation up to 10% (plus or minus 10%) of the particular term.

In accordance with the present invention, an assay value of daptomycin in pharmaceutical composition of daptomycin is within the limits of 90% to 110% after stability study according to ICH guidelines which is comparable when compared with reference product Cubicin® and Cubicin RF®.

In one of the embodiments, the present invention is to provide a stable lyophilized pharmaceutical composition of daptomycin comprising daptomycin or its pharmaceutically acceptable salt thereof, meglumine, buffer and one or more pharmaceutical acceptable excipient, wherein the weight ratio of daptomycin to meglumine from ranging about 1:0.01 to about 1:0.5.

Meglumine is an amino sugar derived from glucose that contains an amino group modification.

The buffers can be selected from the group comprising of but not limited to sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate dihydrate, boric acid, citric acid monohydrate, carbonic acid, amino acids or mixture thereof, more preferably sodium dihydrogen phosphate monohydrate and disodium hydrogen phosphate dihydrate.

In one of the embodiments, the present invention is to provide a process for preparation of a stable lyophilized pharmaceutical composition of daptomycin comprising daptomycin or its pharmaceutically acceptable salt thereof, meglumine, buffer and one or more pharmaceutical acceptable excipient. Further, one of the process for preparation of a stable lyophilized pharmaceutical composition of daptomycin according to the present invention comprising following steps:
1. Take the required quantity of solvent into the manufacturing vessel and continue nitrogen sparging.
2. Add the required quantity of buffer to the solution of step 1. Stir well to obtain a clear solution.
3. Add the required quantity of Daptomycin to the solution obtained in step 2. Stir well to obtain a clear solution.
4. Add the required quantity of Meglumine to the solution obtained in step 3. Stir well to obtain a clear solution.
5. Make up the volume with WFI to obtain the bulk solution.
6. Filter the bulk solution and fill the filtrate into glass vials and half stopper the vials.
7. Load the vials into the lyophilizer and start the lyophilization process.
8. After completion of lyophilization, unload the vials.
9. Seal the vials.

The solvent used for the preparation of the bulk solution can be selected from the group of pharmaceutically acceptable solvents comprising of water, dichloromethane, alcohols or the mixture thereof.

The pH of the bulk solution is in the range of 4 to 7. Required quantities of buffer and / or pH adjusting agent are added attain the pH of the bulk solution in the range of 4 to 7.

After the lyophilization of the bulk solution, a lyophilized pharmaceutical composition of daptomycin is obtained. After the reconstitution of the lyophilized pharmaceutical composition of daptomycin, the pH of the reconstituted solution is in the range of 4 to 7.

In one of the embodiments, the present invention is to provide a stable lyophilized pharmaceutical composition of daptomycin comprising daptomycin or its pharmaceutically acceptable salt thereof, meglumine, buffer and one or more pharmaceutical acceptable excipient, wherein the said lyophilized composition is stable for at least 6 months when stored at 2°-8°C or 25°C, wherein the said lyophilized composition is having a reconstitution time of less than 5 minutes.

In one of the embodiments, the present invention is to provide a stable lyophilized pharmaceutical composition of daptomycin comprising daptomycin or its pharmaceutically acceptable salt thereof, meglumine, buffer and one or more pharmaceutical acceptable excipient, wherein the said lyophilized composition does not have more than 1.5% (w/w) of anhydro-dapto impurity of daptomycin, after being stored at specific storage conditions.

In one of the embodiments, the present invention is to provide a stable lyophilized pharmaceutical composition of daptomycin comprising daptomycin or its pharmaceutically acceptable salt thereof, meglumine, buffers and one or more pharmaceutical acceptable excipient, wherein the said lyophilized composition does not have more than 3.0% (w/w) of total impurity of daptomycin, after being stored at specific storage conditions.

The present invention has been described by way of example only. It is to be recognized that modifications falling within the scope and spirit of the claims, which would be obvious to a person skilled in the art based upon the disclosure herein, are also considered to be included within the scope of this invention. The scope of the invention is in no manner limited by the disclosed example.

Example 1:
Sr. No. Material Name Qty. (mg/mL)
1 Daptomycin 100.0
2 Buffer 0.01 - 45.0
3 Meglumine 0.01 - 20.0
4 Solvent q.s.

Manufacturing process:
1. Take the required quantity of solvent into the manufacturing vessel and continue nitrogen sparging.
2. Add the required quantity of buffer to the solution of step 1. Stir well to obtain a clear solution.
3. Add the required quantity of Daptomycin to the solution obtained in step 2. Stir well to obtain a clear solution.
4. Add the required quantity of Meglumine to the solution obtained in step 3. Stir well to obtain a clear solution.
5. Make up the volume with WFI to obtain the bulk solution.
6. Filter the bulk solution and fill the filtrate into glass vials and half stopper the vials.
7. Load the vials into the lyophilizer and start the lyophilization process.
8. After completion of lyophilization, unload the vials.
9. Seal the vials.

Example 2:
Sr. No. Material Name 350 mg/vial strength 500 mg/vial strength
1 Daptomycin 350 500
2 Sodium dihydrogen phosphate monohydrate 99.96 142.8
3 Disodium hydrogen phosphate dihydrate 45.78 65.4
4 Meglumine 62.44 89.2
5 Water for Injection q.s. q.s.

Manufacturing process:
1. Take the required quantity of water for injection into the manufacturing vessel. Cool down the temperature of Water for Injection to 2 ºC to 8ºC and continue nitrogen sparging.
2. Add the required quantity of Disodium hydrogen phosphate dihydrate in the solution obtained in step 1. Stir well to obtain a clear solution.
3. Add the required quantity of Sodium dihydrogen phosphate monohydrate in the solution obtained in step 2. Stir well to obtain a clear solution.
4. Add the required quantity of Daptomycin to the solution obtained in step 3. Stir well to dissolve completely to obtain a clear solution.
5. Add the required quantity of Meglumine the solution obtained in step 4. Stir well to obtain a clear solution.
6. Make up the volume with WFI with continuous stirring.
7. Filter the bulk solution through 0.2 µ filter and fill into glass vials and half stopper the vials.
8. Load the vials into the lyophilizer and start the lyophilization process.
9. After completion of lyophilization, unload the vials.
10. Seal the vials.

STABILITY STUDY
Table 1:
Stability data of daptomycin under 6 months-time interval at condition of 25 °C/60% RH and 2°- 8°C.

Condition Water Content (%w/w) Recons. Time
(Seconds) pH
(Recon. Solution) Related Substances (%w/w) Assay
(%w/w)
Anhydro Daptomycin Total Impurities
Initial 1.73 185 4.48 0.848 1.391 98.7
6M
25°C/60% 1.20 210 4.81 1.453 2.701 97.5
6M
2°-8°C 1.52 117 4.50 1.143 2.009 98.3

The above data shows the obtained lyophilized pharmaceutical composition of daptomycin according to the present invention is stable. The total impurity of the said composition is not more than 3.0 % w/w, the reconstitution time is less than 5 minutes and the assay value within the range of ICH guideline indicative of stability of daptomycin in the drug product. ,CLAIMS:We claims:

1. A stable lyophilized pharmaceutical composition of daptomycin comprising daptomycin or its pharmaceutically acceptable salt thereof, meglumine, buffer and one or more pharmaceutical acceptable excipient, wherein the weight ratio of daptomycin to meglumine is in the range of about 1:0.01 to about 1:0.5.

2. The stable lyophilized pharmaceutical composition of daptomycin as claimed in claim 1, wherein the said buffers is selected from the group comprising of sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate dihydrate, boric acid, citric acid monohydrate, carbonic acid, amino acids or mixture thereof.

3. The stable lyophilized pharmaceutical composition of daptomycin as claimed in claim 1, wherein the said lyophilized composition having a reconstitution time is less than 5 minutes.

4. The process for preparation of a pharmaceutical composition of daptomycin as claimed in claim 1, comprising the steps of:
a. Take the required quantity of solvent into the manufacturing vessel and continue nitrogen sparging.
b. Add the required quantity of buffer to the solution of step 1. Stir well to obtain a clear solution.
c. Add the required quantity of Daptomycin to the solution obtained in step 2. Stir well to obtain a clear solution.
d. Add the required quantity of Meglumine to the solution obtained in step 3. Stir well to obtain a clear solution.
e. Make up the volume with WFI to obtain the bulk solution.
f. Filter the bulk solution and fill the filtrate into glass vials and half stopper the vials.
g. Load the vials into the lyophilizer and start the lyophilization process.
h. After completion of lyophilization, unload the vials.
i. Seal the vials.

5. The stable lyophilized pharmaceutical composition of daptomycin as claimed in claim 1, wherein the said lyophilized composition have not more than 1.5% (w/w) of anhydro-dapto impurity of daptomycin, after being stored at least 6 months when stored at 2°-8°C or 25°C.

6. The stable lyophilized pharmaceutical composition of daptomycin as claimed in claim 1, wherein the said lyophilized composition does not have more than 3.0% (w/w) of total impurity of daptomycin, after being stored at least 6 months when stored at 2°-8°C or 25°C.