Drug delivery system for administration of poorly water soluble pharmaceutically active substances

Abstract

This invention relates to a drug delivery system for administration of poorly water soluble pharmaceutically active substance, a pharmaceutical composition comprising such a drug delivery system, and a method for the preparation of such a drug delivery system. The invention also relates to a method for controlling the particle size and/or particle shape and/or particle size distribution in such a drug delivery system, and to a method for increasing the drug loading capacity of the particles. Furthermore the invention also relates to the use of such a drug delivery system for the preparation of a medicament for the treatment of cancer.

The invention claimed is: 
     
       1. A method for the preparation of a drug delivery system comprising nanoparticles formed of a sodium salt of the methyl ester of N-all-trans-retinoyl cysteic acid, a sodium salt of the methyl ester of N-13-cis-retinoyl cysteic acid, or a combination thereof, and at least one pharmaceutically active substance having a solubility per se in water of less than about 100 μg/ml wherein said substance is provided in the form of essentially amorphous particles with an effective average particle size of less than about 50 nm;
 and the size of said nanoparticles is controlled to have an effective average particle size of less than about 50 nm by adjusting the weight-to-weight ratio of said sodium salt of the methyl ester of N-all-trans-retinoyl cysteic acid, sodium salt of the methyl ester of N-13-cis-retinoyl cysteic acid, or combination thereof, to said substance to be in the range from about 0.5:1 to about 20:1, which method comprises the steps of: 
 providing an aqueous solution of a sodium salt of the methyl ester of N-all-trans-retinoyl cysteic acid, a sodium salt of the methyl ester of N-13-cis-retinoyl cysteic acid, or a combination thereof; 
 adding an organic solution of the pharmaceutically active substance to said aqueous solution; 
 evaporating said organic solvent leaving an aqueous solution comprising the pharmaceutically active substance in the form of essentially amorphous form nanoparticles; 
 and wherein said essentially amorphous particles are submitted into and/or produced in an aqueous the aqueous solutioncontaining, wherein the aqueous solution contains at least one ionized salt, said aqueous solution having an ionic strength I, to form the nanoparticles; and the particle size of the nanoparticles is increased by increasing I or decreased by decreasing I. 
 
     
     
       2. The method according to  claim 1 , wherein the weight-to-weight ratio of said sodium salt of the methyl ester of N-all-trans-retinoyl cysteic acid, sodium salt of the methyl ester of N-13-cis-retinoyl cysteic acid, or a combination thereof, to said pharmaceutically active substance is in the range from about 1:1 to about 10:1. 
     
     
       3. The method according to  claim 1 , wherein the sodium salt of the methyl ester of N-all-trans-retinoyl cysteic acid, a sodium salt of the methyl ester of N-13-cis-retinoyl cysteic acid, or a combination thereof is present in an amount of about 0.01-3 molar equivalents based on the pharmaceutically active substance. 
     
     
       4. The method according to  claim 1 , wherein said pharmaceutically active substance is chosen from among paclitaxel, docetaxel, and derivatives thereof. 
     
     
       5. A drug delivery system obtainable by the method according to  claim 1  comprising nanoparticles formed of a combination of a sodium salt of the methyl ester of N-all-trans-retinoyl cysteic acid and a sodium salt of the methyl ester of N-13-cis-retinoyl cysteic acid, and paclitaxel in the form of essentially amorphous particles with an effective average particle size of less than about 50 nm;
 wherein the weight ratio of sodium salt of the methyl ester of N-all-trans-retinoyl cysteic acid to sodium salt of methyl ester of N-13-cis-retinoyl cysteic acid is about 1:1; 
 and the size of said nanoparticles is controlled to have an effective average particle size of less than about 50 nm by adjusting the weight-to-weight ratio of said sodium salt of the methyl ester of N-all-trans-retinoyl cysteic acid and sodium salt of the methyl ester of N-13-cis-retinoyl cysteic acid to paclitaxel to be in the range from 1:1 to 1.5:1, which method comprises the steps of: 
 providing an aqueous solution of a combination of a sodium salt of the methyl ester of N-all-trans-retinoyl cysteic acid, a sodium salt of the methyl ester of N-13-cis-retinoyl cysteic acid; 
 adding an organic solution of paclitaxel to said aqueous solution; evaporating said organic solvent leaving an aqueous solution comprising paclitaxel in the form of essentially amorphous nanoparticles; 
 and wherein said essentially amorphous particles are submitted into and/or produced in the aqueous solution, wherein the aqueous solution contains at least one ionized salt, said aqueous solution having an ionic strength I, to form the nanoparticles; and the particle size of the nanoparticles is increased by increasing I or decreased by decreasing I. 
 
     
     
       6. A drug delivery system comprising nanoparticles formed of a combination of a sodium salt of the methyl ester of N-all-trans-retinoyl cysteic acid and a sodium salt of the methyl ester of N-13-cis-retinoyl cysteic acid, and paclitaxel, wherein the nanoparticles are essentially amorphous and have an effective average particle size of about 8-30 nm;
 wherein the weight ratio of sodium salt of the methyl ester of N-all-trans-retinoyl cysteic acid to sodium salt of methyl ester of N-13-cis-retinoyl cysteic acid is about 1:1;   wherein a weight-to-weight ratio of said combination of sodium salt of the methyl ester of N-all-trans-retinoyl cysteic acid and sodium salt of the methyl ester of N-13-cis-retinoyl cysteic acid, to paclitaxel is in the range from 1:1 to 1.5:1,   wherein the nanoparticles are prepared by a method which comprises the steps of:   providing a solution of a combination of sodium salt of the methyl ester of N-all-trans-retinoyl cysteic acid and a sodium salt of the methyl ester of N-13-cis-retinoyl cysteic acid;   adding an organic solution of paclitaxel to said solution;   and evaporating the resulting solution, leaving the nanoparticles in essentially amorphous form.    
     
     
       7. The drug delivery system of claim 6, wherein the effective average particle size is a particle size determined in 9 mg/mL NaCl at 1 mg/ml concentration of paclitaxel.  
     
     
       8. The drug delivery system of claim 6, wherein the nanoparticles do not comprise a polyethoxylated castor oil.  
     
     
       9. The drug delivery system of claim 6, wherein the nanoparticles do not comprise human serum albumin (HSA).  
     
     
       10. The drug delivery system of claim 6, wherein when said essentially amorphous nanoparticles are submitted into an aqueous solution containing at least one ionized salt, the resulting solution comprises micelles.  
     
     
       11. The drug delivery system of claim 6, wherein paclitaxel is entrapped, encapsulated or enclosed in the nanoparticles.  
     
     
       12. The drug delivery system of claim 11, wherein paclitaxel is entrapped in the nanoparticles.  
     
     
       13. A drug delivery system comprising nanoparticles formed of a combination of a sodium salt of the methyl ester of N-all-trans-retinoyl cysteic acid and a sodium salt of the methyl ester of N-13-cis-retinoyl cysteic acid, and paclitaxel, wherein the nanoparticles are essentially amorphous and have an effective average particle size of about 8-30 nm when measured in an aqueous solution of 9 mg/mL NaCl at 1 mg/ml concentration of paclitaxel;
 wherein a weight-to-weight ratio of the combination of said sodium salt of the methyl ester of N-all-trans-retinoyl cysteic acid and sodium salt of the methyl ester of N-13-cis-retinoyl cysteic acid to paclitaxel is in the range from 1:1 to 1.5:1,   wherein the nanoparticles are prepared by a method which comprises the steps of:   mixing a sodium salt of the methyl ester of N-all-trans-retinoyl cysteic acid, a sodium salt of the methyl ester of N-13-cis-retinoyl cysteic acid, and an organic solution of paclitaxel; and   evaporating the resulting solution, wherein the weight ratio of sodium salt of the methyl ester of N-all-trans-retinoyl cysteic acid to sodium salt of methyl ester of N-13-cis-retinoyl cysteic acid is about 1:1,   leaving the nanoparticles in essentially amorphous form.    
     
     
       14. The drug delivery system of claim 6, wherein the effective average particle size is a particle size determined in a solution comprising sodium chloride, calcium chloride dihydrate, calcium chloride, calcium chloride hexahydrate, magnesium chloride, potassium chloride, or sodium lactate, or a combination of any one or more of the foregoing, at 0.5 mg/ml, 1 mg/ml, or 2 mg/ml concentration of paclitaxel.  
     
     
       15. The drug delivery system of claim 13, wherein when said essentially amorphous nanoparticles are submitted into an aqueous solution containing at least one ionized salt, the resulting solution comprises micelles.  
     
     
       16. The drug delivery system of claim 15, wherein said ionized salt is sodium chloride.  
     
     
       17. The drug delivery system of claim 13, wherein the nanoparticles do not comprise a polyethoxylated castor oil, or wherein the nanoparticles do not comprise HSA.  
     
     
       18. The drug delivery system of claim 13, wherein paclitaxel is entrapped, encapsulated or enclosed in the nanoparticles.  
     
     
       19. A method of treating a tumor disease, comprising administering by infusion to a patient in need of such treatment a therapeutically effective amount of the drug delivery system of claim 6, wherein the method does not comprise premedication with one or more of a steroid, an antiemetic or an antihistamine.  
     
     
       20. The method of claim 19, wherein the disease is ovarian cancer.  
     
     
       21. A method of treating a tumor disease, comprising administering by infusion to a patient in need of such treatment a therapeutically effective amount of the drug delivery system of claim 13, wherein the method does not comprise premedication with one or more of a steroid, an antiemetic or an antihistamine.  
     
     
       22. The method of claim 21, wherein the disease is ovarian cancer.  
     
     
       23. The drug delivery system of claim 10, wherein said ionized salt is sodium chloride.