Metolazone emulsion formulation
The present invention relates to pharmaceutical formulations comprising metolazone, a lipid, and an emulsifier that provide a lipid formulation of metolazone that can be administered intravenously to patients, thereby enhancing the therapeutic delivery and improving patient care for acute heart failure and resistant edmitious states.
1. An intravenous metolazone oil-in-water emulsion formulation, comprising:
a) 0.1-10 mg/mL of metolazone or a pharmaceutically acceptable salt thereof;
b) 2-30% v/v of a lipid selected from the group consisting of soybean oil, safflower seed oil, olive oil, cottonseed oil, sunflower oil, sesame oil, peanut oil, corn oil, medium chain triglycerides, triacetin, propylene glycol diesters, monoglycerides, and a mixture of two or more thereof;
c) 0.1-2% w/v of an emulsifier selected from the group consisting of egg yolk phospholipids, soybean phospholipids, synthetic phosphatidyl cholines, purified phosphatidyl cholines and hydrogenated phosphatidyl choline, and mixtures of two or more thereof;
d) water;
e) 1-4% w/v of a tonicity modifier selected from the group consisting of sodium chloride, sodium acetate, potassium chloride, mannitol, sucrose, lactose, fructose, maltose, dextrose, dextrose anhydrous, and glycerin; and,
f) 0.05-5% v/v of a co-emulsifier selected from the group consisting of poloxamers, polyoxyethylene stearates, sorbitan fatty acid esters, polysorbates, tocopherol PEG succinate, cholic acid, deoxycholic acid, oleic acid, and pharmaceutically acceptable salts thereof;
wherein the formulation is suitable for intravenous administration; and
wherein benzyl alcohol is excluded.
2. The formulation of claim 1 , further comprising:
g) 0.001-1% w/v of an antimicrobial agent.
3. The formulation of claim 2 , wherein the antimicrobial agent is selected from the group consisting of EDTA, sodium ascorbate, citric acid, and mixtures and salts thereof.
4. The formulation of claim 2 , wherein the antimicrobial agent is EDTA.
5. The formulation of claim 1 , wherein the formulation has a pH of 6.0-8.8.
6. The formulation of claim 1 , wherein the lipid is soybean oil.
7. The formulation of claim 1 , wherein the emulsifier is L-α-Lecithin.
8. The formulation of claim 1 , wherein the co-emulsifier is polysorbate 80.
9. The formulation of claim 1 , wherein the co-emulsifier is poloxamer 188.
10. The formulation of claim 1 , wherein the tonicity agent is glycerin.
11. The formulation of claim 1 , further comprising:
h) an antioxidant, present at about 0.01 to about 1.0% w/v.
12. The formulation of claim 11 , wherein the antioxidant is selected from the group consisting of sodium ascorbate, sodium citrate, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate, tocopherol, and a pharmaceutically acceptable salt thereof.
13. The formulation of claim 11 , wherein the antioxidant is sodium ascorbate.
14. The formulation of claim 1 , wherein the formulation is contained in a sterile pre-filled syringe.
15. The formulation of claim 1 , wherein the formulation, comprises:
a) 0.1-10 mg/mL of metolazone or a pharmaceutically acceptable salt thereof;
b) 2-30% v/v of soybean oil;
c) 0.1-2% w/v of L-α-Lecithin;
d) water;
e) 1-4% w/v of glycerin;
0.05-5% v/v of a co-emulsifier selected from the group consisting of poloxamer 188 and polysorbate 80;
wherein the formulation is suitable for intravenous administration.
16. The formulation of claim 15 , wherein the co-emulsifier is poloxamer 188.
17. The formulation of claim 15 , wherein the co-emulsifier is polysorbate 80.
18. The formulation of claim 1 , further comprising:
g) 0.001-1% w/v of an antimicrobial agent.
19. The formulation of claim 18 , wherein the antimicrobial agent is selected from the group consisting of EDTA, sodium ascorbate, citric acid, and mixtures and salts thereof.