Targeted nano-liposome co-entrapping anti-cancer drugs

• US 9,855,216 B2
• Filed: 04/15/2016
• Issued: 01/02/2018
• 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, Rezayat, Seyed Mahdi, Akbarzadeh, Azim, Ebrahimi, Bahman
• Primary Examiner(s): Shomer, Isaac
• Application Number:
  US15/130,144
• Publication Number:
  US 20160228362A1
• Time in Patent Office: 627 Days
• Field of Search: None
• 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 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, and

one of the at least two herbal drugs is silibinin and another of the at least two herbal drugs is glycyrrhizic acid,

the mass ratio of silibinin to glycyrrhizic acid is approximately 1;

3, and the liposome comprises poly(ethylene glycol)-phospholipid conjugate (PEG-lipid).

2. The liposome composition of claim 1, wherein the at least one phospholipid compound comprises dipalmitoyl phosphatidyl choline (DPPC).

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 rang of about 7;

3;

5;

0.3 to about 7;

4;

0.4.

5. The liposome composition of claim 1, wherein the weight ratio of silibinin:

glycyrrhizic acid;

lipid phase is in the range of about 1;

3;

7 to 1;

3;

11.

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

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

18. A method of preparing the liposome composition of claim 1, the method comprising:

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

evaporating the solvent from a result of mixing the lipid mixture with the 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 multilamellar vesicles to form a co-encapsulated nano-liposome composition that simultaneously includes the at least two herbal drugs co-encapsulated.

19. The method of claim 18, wherein hydrating the lipid film with the aqueous solvent is performed in a buffer.

20. The method of claim 19, wherein the at least one phospholipid compound comprises dipalmitoyl phosphatidyl choline (DPPC).

21. The method of claim 20, wherein the PEG-lipid is distearoyl-phosphatidylethanolamine-N-[methoxy(polyethene glycol)-2000] (DSPE-mPEG2000).

22. The method of claim 21, 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.

23. The method of claim 18, 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.

24. The method of claim 18, further comprising:

drying of the liposome composition.

30. The method of claim 18, wherein the method provides a loading efficacy in a range of about 25% to about 70% for the at least two herbal drugs.

31. The method of claim 18, wherein the liposome composition has an average diameter of less than about 90 nanometers.

32. A method of treating cancer in an individual in need of liver cancer treatment comprising administering the liposome composition of claim 1 to said individual.

8. A targeted liposome composition for the treatment of cancer comprising:

at least one phospholipid compound;

a poly(ethylene glycol)-phospholipid conjugate (PEG-lipid);

cholesterol;

at least one monoclonal antibody; and

at least two herbal drugs co-encapsulated in the liposome composition, wherein;

one of the at least two herbal drugs is silibinin,

another one of the at least two herbal drugs is glycyrrhizic acid, and

glycyrrhizic acid is present at approximately three times the mass of silibinin.

9. The targeted liposome composition of claim 8, wherein the at least two herbal drugs co-encapsulated in the liposome composition include a third member selected from the group consisting of isosilibinin, silichristin, silidanin, glycyrrhetinic acid and combinations thereof.

10. The targeted liposome composition of claim 8, wherein the targeted liposome composition has an average diameter of less than about 90 nanometers.

11. The targeted liposome composition of claim 8, wherein the monoclonal antibody is selected from the group consisting of anti-CD147, HAb18, anti-CD166, anti-CD20, anti-HER2, anti-VEGF-A, anti-EGFR and rituximab.

12. The targeted liposome composition of claim 8, wherein said monoclonal antibody is Hab18 monoclonal antibody.

13. The targeted liposome composition of claim 12, wherein the number of Hab18 monoclonal antibodies on the surface of the liposome is at least 6.

14. The targeted liposome composition of claim 8, wherein the at least one phospholipid comprises dipalmitoyl phosphatidyl choline (DPPC).

15. The targeted liposome composition of claim 8, wherein the PEG-lipid is distearoyl-phosphatidylethanolamine-N-[methoxy(polyethene glycol)-2000 (DSPE-mPEG2000).

16. The targeted liposome composition of claim 8, wherein the phospholipid component comprises dipalmitoyl phosphatidyl choline (DPPC), wherein the PEG-lipid is distearoyl-phosphatidylethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG), and 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.

17. The targeted liposome composition of claim 16, wherein the targeted liposome composition has a negative zeta potential.

25. A method for preparing the liposome composition of claim 10, the method comprising:

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

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

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

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

adding the monoclonal antibody to the prepared liposome composition to form the targeted liposome composition.

26. The method of claim 25, wherein the monoclonal antibody is selected from the group consisting of anti:

HER2, anti-VEGF-A, and anti-EGFR.

27. The method of claim 25, wherein the monoclonal antibody is Hab18 monoclonal antibody.

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

29. The method of claim 25, wherein the liposome composition has an average diameter of less than about 90 nanometers.

33. A method of treating liver cancer in an individual in need of liver cancer treatment comprising administering the liposome composition of claim 8 to said individual.