TARGETTED NANO-LIPOSOME CO-ENTRAPPING ANTI-CANCER DRUGS

• US 20160228362A1
• Filed: 04/15/2016
• Published: 08/11/2016
• Est. Priority Date: 05/27/2015
• Status: Active Grant

• Current Assignee: Ghasem Amoabediny, Mohammad Mahdi Ochi, University Of TEHRAN
• Original Assignee: Ghasem Amoabediny, Mohammad Mahdi Ochi, University Of TEHRAN
• Inventors: Amoabediny, Ghasem, Ochi, Mohammad Mahdi, Akbarzadeh, Azim, Ebrahimi, Bahman, Rezayat, Seyed Mahdi
• Granted Patent: US 9,855,216 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/353 3,4-Dihydrobenzopyrans, e.g. chroman, catechin
• CPC Class Codes: A61K 31/357 having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61K 47/6913 the liposome being modified on its surface by an antibody
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61K 9/1271 Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers liposome as conjugate A61K47/6911
• CPC Class Codes: A61K 9/1277 Processes for preparing; Proliposomes
• CPC Class Codes: A61K 9/5123 Organic compounds, e.g. fats, sugars
• CPC Class Codes: C07K 16/2803 against the immunoglobulin superfamily
• CPC Class Codes: Y10S 977/773 Nanoparticle, i.e. structure having three dimensions of 100 nm or less
• CPC Class Codes: Y10S 977/906 Drug delivery
• CPC Class Codes: Y10S 977/907 Liposome

Abstract

A liposomal composition includes at least two anti-tumor herbal drugs that are simultaneously co-encapsulated. Optionally, the liposomal composition is targeted by adding a monoclonal antibody is added to the liposomes.

Claims

1. A liposome composition for use in the treatment of cancer, comprising:

at least a phospholipid compound;

cholesterol; and

at least two herbal drugs, wherein said at least two herbal drugs are co-encapsulated in the liposome composition.

2. The liposome composition of claim 1, wherein the at least one phospholipid compound comprises dipalmitoyl phosphatidyl choline (DPPC), and a poly (ethylene glycol)-phospholipid conjugate (PEG-lipid).

3. The liposome composition of claim 2, wherein the PEG-lipid is distearoyl-phosphatidylethanolamine-N-[methoxy(polyethene glycol)-2000]. (DSPE-mPEG2000).

4. The liposome composition of claim 3, wherein the molar ratio of (DPPC):

cholesterol;

DSPE-mPEG2000 in the liposome is in the range of about 7;

3.5;

0.3 to about 7;

4;

0.4.

5. The liposome composition of claim 1, wherein the at least two herbal drugs include at least two mutually different members selected from the group consisting of silibinin, isosilibinin, silichristin, silidanin, glycyrrhizic acid, and glycyrrhetinic acid.

6. The liposome composition of claim 1, wherein one of the at least two herbal drugs is silibinin and another of the at least two herbal drugs is glycyrrhizic acid.

7. The liposome composition of claim 6, wherein the molar ratio of the silibinin to glycyrrhizic acid is in a range of about 1.5:

1 to about 2;

1.

8. The liposome composition of claim 1, wherein the liposome composition has a negative zeta potential.

9. The liposome composition of claim 1, wherein said liposome composition has an average diameter of less than 50 nanometers.

10. A targeted liposome composition for use in the treatment of cancer comprising:

At least one phospholipid compound;

cholesterol;

at least one monoclonal antibody; and

at least two herbal drugs co-encapsulated in the liposome composition.

11. The targeted liposome composition of claim 10, wherein the targeted liposome composition has an average diameter of less than about 90 nanometers.

12. The targeted liposome composition of claim 10, wherein the at least two herbal drugs co-encapsulated in the liposome composition include at least two members selected from the group consisting of silibinin, isosilibinin, silichristin, silidanin, glycyrrhizic acid, glycyrrhetinic acid and combinations thereof.

13. The targeted liposome composition of claim 10, wherein one of the at least two herbal drugs co-encapsulated in the liposome composition is silibinin, and another one of the at least two herbal drugs is glycyrrhizic acid.

14. The targeted liposome composition of claim 13, wherein the molar ratio of the silibinin to the glycyrrhizic acid is in the range of about 1.5:

1 to about 2;

1.

15. The targeted liposome composition of claim 10, wherein the monoclonal antibody is selected from the group consisting of anti-CD147 (HAb18), anti-CD166, anti-CD20, anti-HER2, anti-VEGF-A, and anti-EGFR, rituximab.

16. The targeted liposome composition of claim 10, wherein said monoclonal antibody is Hab18 monoclonal antibody.

17. The targeted liposome composition of claim 16, wherein the effective number of Hab18 monoclonal antibody on the surface of the liposome is at least 6.

18. The targeted liposome composition of claim 10, wherein the at least one phospholipid comprises dipalmitoyl phosphatidyl choline (DPPC), and a poly (ethylene glycol)-phospholipid conjugate (PEG-lipid).

19. The targeted liposome composition of claim 18, wherein the PEG-lipid is distearoyl-phosphatidylethanolamine-N-[methoxy(polyethene glycol)-2000] (DSPE-mPEG2000).

20. The targeted liposome composition of claim 10, wherein the molar ratio of (DPPC):

cholesterol;

DSPE-mPEG2000 in the liposome composition is in the range of about 7;

3.5;

0.3 to about 7;

4;

0.4.

21. The targeted liposome composition of claim 20, wherein the targeted liposome composition has a negative zeta potential.

22. A method for preparing a liposome composition, the method comprising:

mixing a lipid mixture with at least two herbal drugs, in a solvent;

evaporating the solvent from a result of mixing the lipid mixture with at least two herbal drugs to form a lipid film;

hydrating the lipid film with an aqueous solvent to form multilamellar vesicles; and

sonicating the multilameral vesicles to form a co-encapsulated nano-liposome composition that simultaneously includes the at least two herbal drugs co-encapsulated.

23. The method of claim 22, wherein hydrating the lipid film with the aqueous solvent is performed in a buffer.

24. The method of claim 22, wherein the lipid mixture includes cholesterol and at least one phospholipid compound.

25. The method of claim 24, wherein the at least one phospholipid compound comprises dipalmitoyl phosphatidyl choline (DPPC) and a poly (ethylene glycol)-phospholipid conjugate (PEG-lipid).

26. The method of claim 25, wherein the PEG-lipid is distearoyl-phosphatidylethanolamine-N-[methoxy(polyethene glycol)-2000] (DSPE-mPEG2000).

27. The method of claim 25, wherein the specific molar ratio of DPPC:

cholesterol;

DSPE-mPEG2000 is in the range of about 7;

3.5;

0.3 to about 7;

4;

0.4.

28. The method of claim 22, wherein hydrating the lipid film with the aqueous solvent is performed in a buffer, and wherein the specific weight ratio of the at least two herbal drugs:

the lipid mixture;

the aqueous solvent in the buffer is in the range of about 1;

2;

7 to about 1;

3;

11.

29. The method of claim 22, further comprising:

drying of the liposome composition.

30. The method of claim 22, further comprising targeting the liposome composition, wherein targeting the liposome composition comprises:

forming of micelles;

coupling a monoclonal antibody to the micelles; and

transferring of the monoclonal antibody coupled to the micelles to the prepared liposome composition to form a targeted liposome composition.

31. The method of claim 30, wherein the monoclonal antibody is selected from the group consisting of anti HER2, VEGF-A, and EGFR, and derivations thereof.

32. The method of claim 30, wherein the monoclonal antibody is Hab18 monoclonal antibody.

33. The method of claim 30, wherein the at least two herbal drugs are selected from the group consisting of silibinin, isosilibinin, silichristin, silidanin, glycyrrhizic acid, and glycyrrhetinic acid and combinations thereof.

34. The method of claim 30, wherein one of the at least two herbal drugs is silibinin and another one of the at least two herbal drugs is glycyrrhizic acid.

35. The method of claim 30, wherein the In vitro controlled release rate of the at least two herbal drugs from the liposome composition is sensitive in the pH range of about 5 to about 7 and more preferably in a range of about 5 to about 6.

36. The method of claim 30, wherein method provides a loading efficacy in a range of about 25% to about 70% for the at least two herbal drugs.

37. The method of claim 30, wherein the liposome composition has an average diameter of less than about 90 nanometers.

38. The method of claim 22, wherein the at least two herbal drugs are selected from the group consisting of silibinin, isosilibinin, silichristin, silidanin, glycyrrhizic acid, and glycyrrhetinic acid and combinations thereof.

39. The method of claim 22, wherein one of the at least two herbal drugs is silibinin and another one of the at least two herbal drugs is glycyrrhizic acid.

40. The method of claim 22, wherein the In vitro controlled release rate of the at least two herbal drugs from the liposome composition is sensitive in the pH range of about 5 to about 7 and more preferably in a range of about 5 to about 6.

41. The method of claim 22, wherein method provides a loading efficacy in a range of about 25% to about 70% for the at least two herbal drugs.

42. The method of claim 22, wherein the liposome composition has an average diameter of less than about 90 nanometers.