DESC:FIELD OF THE INVENTION
The present invention relates to parenteral compositions of daptomycin and process for preparation thereof.
BACKGROUND OF THE INVENTION
Daptomycin is a cyclic lipopeptide antibiotic indicated for the treatment of complicated skin and skin structure infections and bacteremia, including bacteremia with suspected or proven infective endocarditis.
Daptomycin is a cyclic lipopeptide antibacterial agent. The chemical name of Daptomycin is N-decanoyl-L-tryptophyl-Dasparaginyl-L-aspartyl-L-threonylglycyl-L-ornithyl-L-aspartyl-D-alanyl-L-aspartylglycyl-Dseryl-threo-3-methyl-L-glutamyl-3-anthraniloyl-L-alanine e1-lactone. The empirical formula is C72H101N17O26 and the molecular weight is 1620.67. The chemical structure is:

In United States, daptomycin powder for injection is marketed under the brand name of Cubicin®. Daptomycin for injection can be administered intravenously to treat infections caused by susceptible strains of multiple Gram-positive microorganisms including methicillin-resistant Staphylococcus aureus (MRSA). Daptomycin for injection (CUBICIN®) is supplied as a lyophilized powder that is reconstituted and compounded as a pharmaceutical composition for parenteral administration.
U.S. Patent No. 4,482,487 discloses daptomycin.
U.S. Patent No. 9,138,456 discloses solid pharmaceutical daptomycin composition, wherein said composition is prepared by lyophilizing an aqueous daptomycin solution comprising daptomycin and sucrose.
U.S. Patent No. 9,662,397 discloses solid lyophilized pharmaceutical daptomycin composition comprising daptomycin and non-reducing sugar, trehalose.
U.S. Patent Publication No. 2017/0348382 assigned to Dr. Reddy's Laboratories Limited discloses a lyophilized injectable composition comprising daptomycin or pharmaceutically acceptable salts or solvates thereof and a preservative.
European Patent Publication No. 0386951 A2 assigned to Eli Lilly Company discloses a parenteral formulation comprising daptomycin with a sufficient amount of a parenterally-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.
Still, there is a need to develop new parenteral compositions of daptomycin with improved properties.

SUMMARY OF THE INVENTION
One embodiment of the present invention relates to parenteral composition comprising daptomycin and at least one pharmaceutically acceptable excipient.

Another embodiment of the present invention relates to a parenteral composition comprising daptomycin and at least one pharmaceutically acceptable excipient selected from arginine, meglumine, mannitol, lactose, sucralose, isomaltose, fructose, galactose, maltose, dextrose, glycine, succinic acid, fumaric acid and sodium chloride.

Another embodiment of the present invention relates to a lyophilized powder composition comprising daptomycin and at least one pharmaceutically acceptable excipient selected from arginine, meglumine, mannitol, lactose, sucralose, isomaltose, fructose, galactose, maltose, dextrose, glycine, succinic acid, fumaric acid and sodium chloride.

Another embodiment of the present invention relates to a lyophilized powder composition comprising daptomycin as an active ingredient and at least one pharmaceutically acceptable excipient selected from arginine, meglumine, mannitol, lactose, sucralose, isomaltose, fructose, galactose, maltose, dextrose, glycine, succinic acid, fumaric acid and sodium chloride; wherein said lyophilized powder composition requires a reconstitution step before the administration.

Another embodiment of the present invention relates to process for preparation of daptomycin composition comprises:
(a) dissolving the daptomycin in water for injection under continuous stirring,
(b) dissolving the excipient in drug solution of step (a),
(c) adjusting the pH of solution of step (b) using a suitable pH adjusting agent and making up the remaining volume with water for injection,
(d) filling the solution of step (c) in to vials and loading in to the lyophilizer and finally,
(e) sealing the lyophilized vials of step (d) with aluminium seals.

The method of treating complicated skin and skin structure infections and staphylococcus aureus bloodstream infections comprising administering to the patient the composition of present invention.
DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to pharmaceutical composition comprising daptomycin as an active agent.
The term “active ingredient” used interchangeably, is defined to mean active drug (e.g. daptomycin), that induce a desired pharmacological or physiological effect.
The term “pharmaceutically acceptable” as used herein means that which is useful in preparing a pharmaceutical composition that is generally safe and non-toxic.
The term “excipient” as used herein means a component of a pharmaceutical product that is not an active ingredient such as, for example, fillers, diluents, carriers and the like. The excipients that are useful in preparing a pharmaceutical composition are generally safe and non-toxic.
As used in the specification and the appended claims, the singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise. Thus for example, reference to “a process” includes one or more processes, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure so forth.
One embodiment of the present invention relates to parenteral composition comprising daptomycin and at least one pharmaceutically acceptable excipient.

Another embodiment of the present invention relates to a parenteral composition comprising daptomycin and at least one pharmaceutically acceptable excipient selected from arginine, meglumine, mannitol, lactose, sucralose, isomaltose, fructose, galactose, maltose, dextrose, glycine, succinic acid, fumaric acid and sodium chloride.

Another embodiment of the present invention relates to a lyophilized powder composition comprising daptomycin and at least one pharmaceutically acceptable excipient selected from arginine, meglumine, mannitol, lactose, sucralose, isomaltose, fructose, galactose, maltose, dextrose, glycine, succinic acid, fumaric acid and sodium chloride.

Another embodiment of the present invention relates to a lyophilized powder composition comprising daptomycin as an active ingredient and at least one pharmaceutically acceptable excipient selected from arginine, meglumine, mannitol, lactose, sucralose, isomaltose, fructose, galactose, maltose, dextrose, glycine, succinic acid, fumaric acid and sodium chloride; wherein said lyophilized powder composition requires a reconstitution step before the administration.

Another embodiment of the present invention relates to process for preparation of daptomycin composition comprises:
(a) dissolving the daptomycin in water for injection under continuous stirring,
(b) dissolving the excipient in drug solution of step (a),
(c) adjusting the pH of solution of step (b) using a suitable pH adjusting agent and making up the remaining volume with water for injection,
(d) filling the solution of step (c) in to vials and loading in to the lyophilizer and finally,
(e) sealing the lyophilized vials of step (d) with aluminium seals.

In one embodiment of the present invention, pH of the composition is from 5.0 to 8.0, preferably, from 6.5 to 7.5.

The present invention relates to pharmaceutical composition comprising daptomycin as an active agent, an aqueous solvent and one or more pharmaceutically acceptable excipients selected from a diluent, a pH adjusting agent, a preservative, a buffer and the like and combination thereof.

Diluents according to the present invention include but are not limited to arginine, meglumine, mannitol, lactose, sucralose, isomaltose, fructose, galactose, maltose, dextrose, glycine and the like and combinations thereof.
pH adjusting agents according to the present invention include but are not limited to sodium hydroxide, hydrochloric acid, citric acid, potassium bicarbonate, sodium citrate, potassium citrate, potassium hydroxide, sodium bicarbonate and the like and combinations thereof.
Preservatives according to the present invention include but are not limited to benzyl alcohol, chlorobutanol, m-cresol, methylparaben, phenol, phenoxyethanol, propylparaben, thimerosal, phenylmercuric acetate, phenylmercuric nitrate, benzalkonium chloride, chlorocresol, phenylmercuric salts and the like and combinations thereof.

Buffers according to the present invention include but are not limited to sodium or potassium salts of phosphoric acid, boric acid, citric acid, carbonic acid, hydroxide and the like; tris(hydroxymethyl)aminomethane; amino acids and the like and combinations thereof.

The method of treating complicated skin and skin structure infections and staphylococcus aureus bloodstream infections comprising administering to the patient the composition of present invention.

EXAMPLES

Following examples further illustrate the invention and do not limit the scope of the invention.

S. No Ingredients Qty (mg/ Vial)
1 Daptomycin 500
2 Diluent* q.s
3 Sodium hydroxide q.s. to adjust pH 7.0
(6.5 to 7.5)
4 Water for injection q.s. (to 5 mL)
*Diluent: arginine, meglumine, mannitol, lactose, sucralose, isomaltose, fructose, galactose, maltose, dextrose , glycine, succinic acid, fumaric acid and sodium chloride.

Brief manufacturing process:

1. Collect water for injection equal to 110% of total batch quantity in a SS manufacturing vessel.
2. Keep approximately 80% of total batch quantity of water for injection in the manufacturing vessel and allow the water for injection to cool down to the temperature approximately 2 to 8°C.
3. Purge the water for injection with nitrogen to get the dissolved oxygen content less than 2ppm.
4. Add diluent under stirring and dissolve it completely, adjust the pH if required.
5. Add Daptomycin under stirring and dissolve it completely.
6. Check initial pH and adjust the pH of the solution between 6.8 and 7.0 (Limit: 6.5 to 7.5) with Sodium Hydroxide. Stir the final solution for 10min.
7. Make up the volume to 100% with water for injection.
8. Filter the resulting solution through a sterile 0.2 µm filter into a sterile container.
9. Fill the solution into vials with targeted fill volume, half stopper the vials with lyostopper and load into lyophilizer. Do the lyophilization.
10. After lyophilization process gets completed, do the stoppering, unload the vials and seal with aluminum seals

Stability of Daptomycin:

Table 1, shows chemical stability of daptomycin by measuring content of anhydro daptomycin impurity.

Table 1:
Impurity name Limits Mannitol Sucralose L-Arginine Lactose Anhydrate
Anhydro Daptomycin NMT 3.0 % 1.59 0.57 0.6 0.59

,CLAIMS:We Claim:

1. 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.

2. The lyophilized powder composition composition according to claim 1, requires reconstitution prior to administration.

3. The lyophilized powder composition according to claim 1, further comprises pH adjusting agent.

4. The lyophilized powder composition according to claim 3, wherein the pH adjusting agent is sodium hydroxide, hydrochloric acid, citric acid, potassium bicarbonate, sodium citrate, potassium citrate, potassium hydroxide, sodium bicarbonate and the like and combinations thereof.

5. The lyophilized powder composition according to claim 1, wherein the pH of the composition is 6.5 to 7.5.

6. The lyophilized powder composition according to claim 1, wherein the composition contain one or more impurities in acceptable levels.

7. A process for preparation of a lyophilized powder composition comprising daptomycin, the process comprising the steps of: dissolving daptomycin, atleast one pharmaceutically acceptable excipient and optional buffer in a solvent; filtering to eliminate any bacteria or other contaminants; subpackaging into sterile containers; lyophilizing; and drying.

8. The lyophilized powder composition according to claim 7, wherein the buffer is sodium or potassium salts of phosphoric acid, boric acid, citric acid, carbonic acid, hydroxide and the like; tris(hydroxymethyl)aminomethane; amino acids and the like and combinations thereof.

9. The process according to claim 7, wherein the solvent comprises water for injection.

10. The method of treating complicated skin and skin structure infections and staphylococcus aureus bloodstream infections comprising administering to the patient the composition of claim 1.