Liposomal pharmaceutical preparation and method for manufacturing the same
The present invention relates to a liposomal pharmaceutical preparation containing a multivalent ionic drug, a process for the preparation of the liposomal pharmaceutical preparation, and a use thereof in the treatment of diseases, in which the liposome has a size of about 30-80 nm, and the phospholipid bilayer has a phospholipid with a Tm higher than body temperature, so that the phase transition temperature of the liposome is higher than the body temperature.
1. A method for treating sarcoma, comprising administering to a patient in need thereof liposomes, wherein
the liposomes encapsulate mitoxantrone, and have a mean size of 35-75 nm,
the bilayer of the liposomes comprises (a) a phospholipid that is hydrogenated soybean phosphatidylcholine (HSPC), (b) cholesterol, and (c) PEG-modified distearoyl phosphatidyl ethaolamine (DSPE), and the intraliposomal phase of the liposomes comprises a multivalent counter ion,
the phospholipid of (a) amounts to 55-95 mol/mol % relative to the total content of phospholipids of the liposomes,
the cholesterol of (b) amounts to 2-60 mol/mol % relative to the mole number of the total amount of ingredients of the liposomes, and
the PEG-modified DSPE of (c) amounts to 0.1-20 mol/mol % relative to the mole number of the total content of phospholipids of the liposomes.
2. The method of claim 1 , wherein the phospholipid bilayer of the liposomes comprises additional phospholipid having a phase transition temperature (Tm) not higher than body temperature.
3. The method of claim 2 , wherein the additional phospholipid comprises dimyristoyl phosphatidylcholine (DMPC).
4. The method of claim 1 , wherein the PEG-modified DSPE amounts to 1-10 mol/mol % relative to the mole number of the phospholipid.
5. The method of claim 1 , wherein the PEG-modified DSPE amounts to 2.5-7 mol/mol % relative to the mole umber of the phospholipid.
6. The method of claim 1 , wherein the liposomes have a mean size of 40-75 nm.
7. The method of claim 1 , wherein the liposomes have a mean size of 40-70 nm.
8. The method of claim 1 , wherein the liposomes have a mean size of 40-60 nm.
9. The method of claim 1 , wherein the liposomes comprise HSPC, cholesterol and PEG-modified distearoyl phosphatidyl ethanolamine in a weight ratio of 3:1:1.
10. The method of claim 9 , wherein the PEG-modified distearoyl phosphatidyl ethanolamine is a PEG2000-modified distearolyl phosphatidyl ethanolamine.
11. The method of claim 1 , wherein the liposomes comprise one or more additional active pharmaceutical ingredients, and/or pharmaceutically acceptable carriers and/or excipients.
12. The method of claim 1 , wherein the multivalent counter ion is an organic acid anion, an inorganic acid anion, or an ionic from of amino acid.
13. The method of claim 12 , wherein the organic acid anion is an acid anion of citric acid, tartaric acid, fumaric acid, oxalic acid, malonic acid, succinic acid, malic acid, or maleic acid; the inorganic acid anion is sulfate anion or phosphate anion; and an ionic form of amino acid is cysteine.