Drug delivery system for administration of a water soluble, cationic and amphiphilic pharmaceutically active substance

1. A drug delivery system for administration of a pharmaceutically active substance that is a cationic amphiphile by itself and has a solubility per se in water of at least 4 mg/ml, wherein the drug delivery system comprises nanoparticles smaller than about 50 nm having a solubility in water below 0.1 mg/ml, said nanoparticles being formed by said substance in association with a sodium salt of the methyl ester of N-all-trans-retinoyl cysteic acid, a sodium salt of methyl ester of N-13-cis-retinoyl cysteic acid, or a combination thereof.

2. A drug delivery system according to claim 1 , wherein said nanoparticles have a solubility in water below 0.01 mg/ml.

3. A drug delivery system according to claim 1 , wherein said substance is non-covalently associated with a sodium salt of the methyl ester of N-all-trans-retinoyl cysteic acid, a sodium salt of methyl ester of N-13-cis-retinoyl cysteic acid, or a combination thereof.

4. A drug delivery system according to claim 1 , wherein said substance is a cytotoxic or a cytostatic compound.

5. A drug delivery system according to claim 1 , wherein said substance is a cytotoxic or cytostatic compound chosen among a protonated form of doxorubicin, mitoxantrone, epirubicin, daunorubicin, idarubicin, topotecan, irinotecan, vinblastine, vincristine, vinorelbine, amsacrine, procarbazine, mechlorethamine, or a combination thereof.

6. A drug delivery system according to claim 4 for use in treatment of cancer.

7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the drug delivery system according to claim 1 .

8. A pharmaceutical composition according to claim 7 in the form of an aqueous solution, a gel, a cream, an ointment, a tablet, a capsule, or a softgel.

9. A method for the preparation of a drug delivery system for administration of at least one pharmaceutically active substance that is a cationic amphiphile by itself and has a solubility per se in water of at least 4 mg/ml, wherein said substance is combined with a sodium salt of the methyl ester of N-all-trans-retinoyl cysteic acid, a sodium salt of methyl ester of N-13-cis-retinoyl cysteic acid, or a combination thereof to form nanoparticles smaller than about 50 nm having a solubility in water below 0.1 mg/ml.

10. A method according to claim 9 , wherein a sodium salt of the methyl ester of N-all-trans-retinoyl cysteic acid, a sodium salt of methyl ester of N-13-cis-retinoyl cysteic acid, or a combination thereof is non-covalently bound to said substance.

11. A method according to claim 9 , wherein said nanoparticles have a solubility in water below 0.01 mg/ml.

12. A method for the preparation of pharmaceutical composition comprising a pharmaceutically acceptable carrier and a drug delivery system according to claim 1 , wherein said drug delivery system is combined with an amount of about 0.2-10 equivalents, based on the cationic charge of the amphiphile comprised in the drug delivery system, of the methyl ester of N-all-trans-retinoyl cysteic acid, a sodium salt of methyl ester of N-13-cis-retinoyl cysteic acid, or a combination thereof.

13. A method for enhancing the drug efficiency of at least one pharmaceutically active substance that is a cationic amphiphile by itself and has a solubility per se in water of at least 4 mg/ml, wherein said substance is combined with a sodium salt of the methyl ester of N-all-trans-retinoyl cysteic acid, a sodium salt of methyl ester of N-13-cis-retinoyl cysteic acid, or a combination thereof to form nanoparticles having a solubility in water below 0.1 mg/ml.

14. A method according to claim 13 , wherein 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 is non-covalently bound to said substance.

15. A method according to claim 13 , wherein said substance is combined with an excess of about 0.2-10 equivalents of said sodium salt of the methyl ester of N-all-trans-retinoyl cysteic acid, sodium salt of methyl ester of N-13-cis-retinoyl cysteic acid, or combination thereof.

16. A method according to claim 13 , wherein said nanoparticles have a solubility in water below 0.01 mg/ml.

17. A method for increasing the bioavailability of at least one pharmaceutically active substance that is a cationic amphiphile by itself and has a solubility per se in water of at least 4 mg/ml,

wherein said substance is combined with 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 to form nanoparticles having a solubility in water below 0.1 mg/ml.

18. A method according to claim 17 , wherein 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 is non-covalently bound to said substance.

19. A method according to claim 17 , wherein said substance is combined with an excess of about 0.2-10 equivalents of said sodium salt of the methyl ester of N-all-trans-retinoyl cysteic acid, sodium salt of methyl ester of N-13-cis-retinoyl cysteic acid, or combination thereof.

20. A method according to claim 17 , wherein said nanoparticles have a solubility in water below 0.01 mg/ml.

21. A method for the treatment of cancer, wherein a drug delivery system according to claim 1 is administered in a therapeutically effective amount to a patient in need of such treatment.

22. A method for the treatment of cancer, wherein a pharmaceutical composition according to claim 7 in the form of an aqueous solution, a gel, a cream, an ointment, a tablet, a capsule, or a softgel, is administered in a therapeutically effective amount to a patient in need of such treatment.