Pharmaceutical preparation of carbohydrates for therapeutic use

• US 10,449,149 B2
• Filed: 10/19/2017
• Issued: 10/22/2019
• Est. Priority Date: 09/16/2013
• Status: Active Grant

• Current Assignee: Glycomine, Inc.
• Original Assignee: Glycomine, Inc.
• Inventors: Rafalko, Agnes, Chernenko, Tatyana
• Primary Examiner(s): Maewall, Snigdha
• Application Number:
  US15/788,591
• Publication Number:
  US 20180036239A1
• Time in Patent Office: 733 Days
• CPC Class Codes: A61K 31/7028 Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
• 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

Abstract

The disclosure provides methods for preparation of carbohydrate replacement therapies (CRT) that include nanocarriers of carbohydrates and glycolipids for pharmaceutical delivery to cell interior, endoplasmic reticulum, and Golgi for treating CDG type I and CDG type II diseases as well as other metabolic disorders.

Claims

1. A composition comprising:

(i) a lipid particle, wherein the lipid particle comprises phospholipids and polyethylene glycol (PEG),

wherein at least two of the phospholipids are phosphatidylethanolamine (PE) and phosphatidylcholine (PC), and

wherein the PEG is conjugated to at least one phospholipid; and

(ii) an endogenous carbohydrate selected from the group consisting of a phosphorylated mannose, a phosphorylated mannofuranose, and a phosphorylated mannopyranos, and

wherein the endogenous carbohydrate is encapsulated in the lipid particle.

2. The composition of claim 1, wherein the PE is present at a concentration of up to 50 molar percent.

3. The composition of claim 1, wherein the PC is present at a concentration of up to 50 molar percent.

4. The composition of claim 1, wherein the at least one phospholipid conjugated to PEG is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE).

5. The composition of claim 4, wherein the DSPE is present at a concentration of about 3 molar percent.

6. The composition of claim 4, wherein

the PE is present at a concentration of about 50 molar percent;

the PC is present at a concentration of about 50 molar percent; and

the DSPE conjugated to PEG is present at a concentration of about 3 molar percent.

7. The composition of claim 1, wherein the endogenous carbohydrate is mannose-1-phosphate.

8. The composition of claim 1, wherein the lipid particle comprises

phosphatidylethanolamine (PE) present at a concentration of about 50 molar percent;

phosphatidylcholine (PC) present at a concentration of about 50 molar percent; and

1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) attached to PEG, wherein the

DSPE conjugated to PEG is present at a concentration of about 3 molar percent; and

wherein the endogenous carbohydrate is mannose-1-phosphate.

9. The composition of claim 1, wherein the composition, when administered to a subject in need thereof, induces at least a 0.05-fold to at least a 3-fold increase in cellular production of higher-order lipid-linked oligosaccharides in the subject, as compared to cellular production of higher-order lipid-linked oligosaccharides in the subject in the absence of administering the composition to the subject.

10. A pharmaceutical composition comprising the composition of claim 1, and a pharmaceutically acceptable carrier.

11. The composition of claim 1, wherein the PE is present at a concentration of up to 80 molar percent.

12. The composition of claim 1, wherein the PC is present at a concentration of up to 70 molar percent.

13. The composition of claim 4, wherein the DSPE is present at a concentration of about 5 molar percent.

14. The composition of claim 4, wherein

the PE is present at a concentration of about 30 molar percent;

the PC is present at a concentration of about 70 molar percent; and

the DSPE conjugated to PEG is present at a concentration of about 3 molar percent.

15. The composition of claim 14, wherein the endogenous carbohydrate is mannose-1-phosphate.

16. The composition of claim 1, wherein the endogenous carbohydrate is a phosphorylated mannose.

17. The composition of claim 1, wherein the lipid particle is a liposome.

18. The composition of claim 17, wherein the endogenous carbohydrate is mannose-1-phosphate.

19. A method for delivering a carbohydrate to the interior of a cell, comprising administering to the cell the composition of claim 1, wherein the administered composition traverses the cell plasma membrane to deliver the carbohydrate to the interior of the cell.

20. A method for delivering a carbohydrate to a subject in need thereof, comprising administering to the subject the composition of claim 1.

21. A method for treating a congenital disorder of glycosylation (CDG) in a subject in need thereof, comprising administering to the subject the composition of claim 1.

22. The method of claim 21, wherein the congenital disorder of glycosylation (CDG) is a CDG-Ia disorder.

23. The method of claim 19, wherein administration of the composition induces at least a 0.05-fold to at least a 3-fold increase in cellular production of higher-order lipid-linked oligosaccharides in the interior of the cell, as compared to cellular production of higher-order lipid-linked oligosaccharides in the interior of the cell in the absence of administering the composition to the cell.