Liposomal pharmaceutical preparation and method for manufacturing the same

Abstract

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 .- 20 . (canceled) 
     
     
         21 . A liposomal drug, wherein (1) the liposomal drug comprises a multivalent ionic drug as active ingredient, which has two or more dissociable groups with a dissociation constant pKa of 4.5-9.5; (2) the liposome of the liposomal drug has a size of 30-80 nm; (3) the bilayer of the liposome comprises a phospholipid with a phase transition temperature (Tm) higher than the body temperature, cholesterol, and a hydrophilic polymer-modified lipid; and (4) the intraliposomal phase of the liposome comprises a multivalent counter ion. 
     
     
         22 . The liposomal drug according to  claim 21 , wherein the size of the liposome is 35-75 nm. 
     
     
         23 . The liposomal drug according to  claim 21 , wherein the dissociation constant pKa of the active ingredient is 5.0-9.5. 
     
     
         24 . The liposomal drug according to  claim 21 , wherein the multivalent ionic drug is an anticancer drug selected from mitoxantrone, vincristine, vinorelbine, vinblastine, or any combination thereof. 
     
     
         25 . The liposomal drug according to  claim 21 , wherein the multivalent counter ion carries two or more charges opposite to the active drug ingredient, the multivalent counter ion being selected from a saturated or unsaturated organic acid anion, an inorganic acid anion or an ionic form of an amino acid, and wherein the organic acid is selected from citric acid, tartaric acid, fumaric acid, oxalic acid, malonic acid, succinic acid, malic acid and maleic acid; the inorganic acid is selected from sulfate anion and phosphate anion; the amino acid is selected from cystine. 
     
     
         26 . The liposomal drug according to  claim 25 , wherein the multivalent counter ion is sulfate anion. 
     
     
         27 . The liposomal drug according to  claim 21 , wherein the phospholipid with a phase transition temperature (Tm) higher than the body temperature in the phospholipid bilayer is selected from phosphatidylcholine, hydrogenated soybean phosphatidylcholine, hydrogenated egg yolk phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, or any combination thereof. 
     
     
         28 . The liposomal drug according to  claim 27 , wherein the phospholipid bilayer further comprises a phospholipid with a phase transition temperature Tm not higher than the body temperature. 
     
     
         29 . The liposomal drug according to  claim 28 , wherein the phospholipid with a phase transition temperature Tm higher than the body temperature is about 50-100 mol/mol % relative to the total content of the phospholipids in the phospholipid bilayer. 
     
     
         30 . The liposomal drug according to  claim 21 , wherein the cholesterol is about 2-60 mol/mol % relative to the total content of the ingredients in the phospholipid bilayer. 
     
     
         31 . The liposomal drug according to  claim 21 , wherein the hydrophilic polymer-modified lipid is selected from PEG-modified distearoyl phosphatidyl ethanolamine (DSPE-PEG), PEG-modified distearoyl phosphatidyl glycerol (DSPG-PEG), PEG-modified cholesterol (chol-PEG), polyvidone-modified distearoyl phosphatidyl ethanolamine (DSPE-PVP), polyvidone-modified distearoyl phosphatidyl glycerol (DSPG-PVP), or polyvidone-modified cholesterol (chol-PVP), or any combination thereof. 
     
     
         32 . The liposomal drug according to  claim 21 , wherein the hydrophilic polymer-modified lipid is in an amount of 0.1-20 mol/mol % relative to the total content of the phospholipids in the phospholipid bilayer. 
     
     
         33 . The liposomal drug according to  claim 21 , which comprises hydrogenated soybean phosphatidylcholine, cholesterol and PEG-modified distearoyl phosphatidyl ethanolamine in a weight ratio of 3:1:1, in which the PEG-modified distearoyl phosphatidyl ethanolamine is PEG2000-modified distearoyl phosphatidyl ethanolamine. 
     
     
         34 . The liposomal drug according to  claim 21 , wherein the phase transition temperature Tm of the liposome is higher than the body temperature. 
     
     
         35 . A method for preparing the liposomal drug according to  claim 21 , which comprises the following steps: (1) preparing a liposome with a size of 30-80 nm using a phospholipid with a Tm higher than the body temperature, cholesterol and a hydrophilic polymer-modified lipid; and (2) encapsulating a multivalent ionic drug in the liposome, wherein the multivalent ionic drug has two or more dissociable groups with a dissociation constant pKa of 4.5-9.5, and the intraliposomal phase of the liposome comprises a multivalent counter ion. 
     
     
         36 . A liposomal pharmaceutical preparation, which comprises the liposomal drug according to  claim 21 , and optionally a pharmaceutically acceptable carrier and/or an excipient. 
     
     
         37 . The liposomal pharmaceutical preparation according to claim  16 , which further comprises a salt for altering osmotic pressure, a buffering agent and/or an antioxidant. 
     
     
         38 . A method for the treatment of a tumor in a patient, which method comprises: administering a liposomal drug or a liposomal pharmaceutical preparation to a patient in need of the treatment;
 wherein (1) the liposomal drug comprises a multivalent ionic drug as active ingredient, which has two or more dissociable groups with a dissociation constant pKa of 4.5-9.5; (2) the liposome of the liposomal drug has a size of 30-80 nm; (3) the bilayer of the liposome comprises a phospholipid with a phase transition temperature (Tm) higher than the body temperature, cholesterol, and a hydrophilic polymer-modified lipid; and (4) the intraliposomal phase of the liposome comprises a multivalent counter ion; and   wherein the liposomal pharmaceutical preparation comprises the liposomal drug and optionally a pharmaceutically acceptable carrier and/or an excipient.   
     
     
         39 . The method according to  claim 38 , which further comprises treating the patient by thermotherapy.