Liposome compositions comprising weak acid drugs and uses thereof
The present invention relates to a pharmaceutical composition comprising a weak acid drug, with the use of a bicarbonate salt to achieve a high incorporation of the drug into the liposome and a better therapeutic efficacy. Also disclosed is a method for treating a respiratory disease using the pharmaceutical composition disclosed herein.
1. A pharmaceutical composition, comprising liposomes, said liposomes comprising:
(a) a lipid bilayer formed of a first phospholipid, a second phospholipid, and cholesterol, wherein the first phospholipid is hydrogenated soy phosphatidylcholine (HSPC), dipalmitoyl phosphatidylcholine (DPPC), distearyloyl phosphatidylcholine (DSPC), diarachidoyl phosphatidylcholine, dimyristoyl phosphatidylcholine (DMPC) or any combination thereof and the second phospholipid is distearyloylphosphatidylglycerol (DSPG), or PEG-DSPE; and
(b) an internal aqueous medium inside the lipid bilayer, the internal aqueous medium comprising a bicarbonate salt with a concentration about 50 mM to about 800 mM and a weak acid drug, said weak acid drug is Iloprost, treprostinil, Piroxicam, Meloxicam, and Warfarin sodium,
wherein the liposomes are suspended in an external medium, the pH of the external medium is above the pK a of the weak acid drug and less than about 7, and
wherein the external medium is substantially free of bicarbonate salt such that there is from less than 2% to 0% bicarbonate salt and the encapsulation efficiency of the weak acid drug is at least 80%.
2. The pharmaceutical composition of claim 1 , wherein the molar ratio of the weak acid drug to the bicarbonate salt is from about 0.1:1 to about 1:1.
3. The pharmaceutical composition of claim 1 , wherein the concentration of the bicarbonate salt is about 250 mM to about 800 mM.
4. The pharmaceutical composition of claim 1 , wherein the bicarbonate salt is potassium bicarbonate, sodium bicarbonate, magnesium bicarbonate, cesium bicarbonate, lithium bicarbonate, nickel bicarbonate, ferrous iron bicarbonate or any combination thereof.
5. A pharmaceutical composition, comprising liposomes, said liposomes comprising:
a. a lipid bilayer formed of a first phospholipid, a second phospholipid, and cholesterol, wherein the first phospholipid is hydrogenated soy phosphatidylcholine (HSPC), dipalmitoyl phosphatidylcholine (DPPC), distearyloyl phosphatidylcholine (DSPC), diarachidoyl phosphatidylcholine, dimyristoyl phosphatidylcholine (DMPC) or any combination thereof and the second phospholipid is distearyloylphosphatidylglycerol (DSPG)or PEG-DSPE; and
b. an internal aqueous medium inside the lipid bilayer, the internal aqueous medium comprising a bicarbonate salt with a concentration about 200 mM to about 400 mM and prostacyclin, selected from treprostinil and iloprost,
wherein the pH of the external medium is above the pK a of prostacyclin and less than about 7, and
wherein the external medium is substantially free of bicarbonate salt such that there is from less than 2% to 0% bicarbonate salt.
6. The pharmaceutical composition of claim 5 , wherein the mole percent of the first phospholipid:cholesterol:the second phospholipid is 50-70:20-45:0.1-10.
7. The pharmaceutical composition of claim 5 , wherein the bicarbonate salt is potassium bicarbonate, sodium bicarbonate, magnesium bicarbonate, cesium bicarbonate, lithium bicarbonate, nickel bicarbonate, ferrous iron bicarbonate or any combination thereof.
8. The pharmaceutical composition of claim 1 , wherein the mole percent of the first phospholipid:cholesterol:the second phospholipid is 50-70:20-45:0.1-10.
9. The pharmaceutical composition of claim 1 , wherein the concentration of the bicarbonate salt is about 200 mM to about 400 mM.
10. The pharmaceutical composition of claim 9 , wherein the weak acid drug is treprostinil.
11. The pharmaceutical composition of claim 1 , wherein the liposomes comprise:
(a) a lipid bilayer formed of a first phospholipid, a second phospholipid, and cholesterol, wherein the first phospholipid is hydrogenated soy phosphatidylcholine (HSPC), and the second phospholipid is distearyloylphosphatidylglycerol (DSPG); and
(b) an internal aqueous medium inside the lipid bilayer, the internal aqueous medium comprising a bicarbonate salt with a concentration about 50 mM to about 800 mM and a weak acid drug, said weak acid drug is Piroxicam or Meloxicam,
wherein the liposomes are suspended in an external medium, the pH of the external medium is above the pK a of the weak acid drug and less than about 7,
wherein the external medium is substantially free of bicarbonate salt such that there is from less than 2% to 0% bicarbonate salt and the encapsulation efficiency of the weak acid drug is at least 80%,
wherein the molar ratio of the weak acid drug to the bicarbonate salt is from about 0.1:1 to about 0.4:1.
12. A pharmaceutical composition, comprising liposomes, said liposomes comprising:
a lipid bilayer formed of a first phospholipid and a second phospholipid, wherein the first phospholipid is hydrogenated soy phosphatidylcholine (HSPC) and the second phospholipid is PEG-DSPE; and
an internal aqueous medium inside the lipid bilayer, the internal aqueous medium comprising a bicarbonate salt with a concentration about 50 mM to about 800 mM and a weak acid drug, said weak acid drug is Iloprost or treprostinil,
wherein the liposomes are suspended in an external medium, the pH of the external medium is above the pKa of the weak acid drug and less than about 7,
wherein the external medium is substantially free of bicarbonate salt such that there is less than 2% or without bicarbonate salt and the encapsulation efficiency of the weak acid drug is at least 80%, and
wherein the molar ratio of the weak acid drug to the bicarbonate salt is from about 0.1:1 to about 0.8:1.
13. The pharmaceutical composition of claim 9 , wherein the weak acid drug is iloprost.