Slow and controlled released liposomal gel composition comprising hypoglycemic active ingredient and method of preparing thereof

Patent metadata

Field	Value
Publication number	US-9980906-B2
Application number	US-201414783433-A
Country	US
Kind code	B2
Filing date	Oct 20, 2014
Priority date	Feb 19, 2014
Publication date	May 29, 2018
Grant date	May 29, 2018

Abstract

The present invention provides a slow and controlled released liposomal gel composition for subcutaneous administration comprises insulin or exenatide as active ingredient for reduction of blood sugar level and method of preparation thereof. Said controlled released composition has high bioavailability and is demonstrated to be able to sustain release therapeutically effective concentration of drug over a period of time and without rapid release of drug after initial administration. Method of preparing the controlled released composition of the present invention comprises the following steps: mixing insulin or exenatide, lipid and aqueous dispersion medium together; then mixing with poloxamer (e.g. F127 or P123) and/or gelatin and hyaluronic acid (HA) or the like gel solution so as to form a protective layer on surface of every lipid micro vesicles or nano-vesicles for use in intramuscular, abdominal and subcutaneous administration. A single administration of the present composition lasts 2 to 7 days to reduce side-effects, such as pain and irritation.

First claim

The invention claimed is:

1. A subcutaneous slow and controlled release liposome gel composition comprising:
therapeutically effective amount of hypoglycemic active ingredient;
a lipid;
a thermoreversible gel, wherein said thermoreversible gel is a gel composition comprising a poloxamer hydrogel or a thiol-terminated poloxamer, and optionally gelatin, hyaluronic acid, hyaluronic acid-dopamine conjugate or a combination thereof and said lipid is soybean phosphatidylcholine (SPC); and
an aqueous dispersion medium.

2. The composition of claim 1 , wherein said thermoreversible gel composition comprises poloxamer hydrogel and does not contain gelatin, hyalunronic acid, hyaluronic acid-dopamine conjugate or a combination thereof.

3. The composition of claim 1 , wherein said thermoreversible gel composition comprises poloxamer hydrogel in combination with gelatin, hyaluronic acid, and hyaluronic acid-dopamine conjugate.

4. The composition of claim 1 , wherein the liposome gel composition comprises 0.05-50%, 0.5-35%, 1-20%, 5-15% or 10-12% by weight of thermoreversible gel.

5. The composition of claim 3 , wherein the liposome gel composition comprises 10-30% and 0.05-2%, 15-25% and 0.08-1%, 18-20% and 0.1-0.5% or 20% and 0.1% by weight of poloxamer hydrogel and gelatin, hyaluronic acid, hyaluronic acid-dopamine conjugate or a combination thereof, respectively.

6. The composition of claim 1 , wherein the liposome gel composition comprises 0.05-50%, 0.7-30%, 1-20%, 1-10% or 2-5% by weight of lipid.

7. The composition of claim 1 , wherein said hypoglycemic active ingredient is insulin, Exenatide, Liraglutide, Pramlintide or a combination thereof.

8. The composition of claim 1 , wherein said poloxmaer hydrogel is poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) having an average molecular weight of 12,600 Daltons or poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) having an average molecular weight of 5,800 Daltons.

9. The composition of claim 1 , wherein said aqueous dispersion medium is selected from purified water suitable for administration, amino acid buffer, polypeptide buffer and pH buffer.

10. The composition of claim 1 , wherein the liposome gel composition comprises 0.01-2.5% by weight of hypoglycemic active ingredient.

11. The composition of claim 7 , wherein said insulin is selected from insulin analogue, human insulin, animal insulin or a combination thereof.

12. The composition of claim 7 , wherein said Exenatide is selected from Exendin-3, Exendin-4, C-terminal amide substituted Exenatide derivative, non-substituted Exenatide derivative and pharmaceutically acceptable salts thereof.

13. The composition of claim 7 , wherein the lipid comprises liposomes having a particle size of 50nm-20 μm, in a lipid suspension, W/O/W type emulsion or homogeneous mixture; said hypoglycemic active ingredient is loaded or dispersed in said liposome and said hypoglycemic active ingredient loaded or dispersed in said liposome is loaded in said thermoreversible gel.

14. The composition of claim 1 , wherein said liposome gel composition is capable of releasing the hypoglycemic active ingredient for 2-7 days or longer in vivo.

15. A method of preparing a hypoglycemic active ingredient-containing, slow and controlled release liposome gel composition, said method comprises:
mixing a therapeutically effective amount of a hypoglycemic active ingredient, a lipid and an aqueous dispersion medium to form vesicular lipid gel, lipid suspension, W/O/W type emulsion or homogeneous mixture having hypoglycemic active ingredient loaded or dispersed therein; and
adding said vesicular lipid gel, lipid suspension, W/O/W type emulsion or homogeneous mixture to a thermoreversible gel for emulsification to folio a liposome gel,
wherein said thermoreversible gel is a gel composition comprising a poloxamer hydrogel or a thiol-terminated poloxamer, and optionally gelatin, hyaluronic acid, hyaluronic acid-dopamine conjugate or a combination thereof and said lipid is soybean phosphatidylcholine (SPC).

16. The method of claim 15 , wherein said thermoreversible gel composition comprises a poloxamer hydrogel and does not contain gelatin, hyaluronic acid, hyaluronic acid-dopamine conjugate or a combination thereof.

17. The method of claim 15 , wherein said thermoreversible gel composition comprises poloxamer hydrogel in combination with gelatin, hyaluronic acid, and hyaluronic acid-dopamine conjugate.

18. The method of claim 15 further comprises drying the liposome gel to obtain hypoglycemic active ingredient-containing liposome gel powder.

19. A hypoglycemic active ingredient-containing liposome gel or liposome gel powder prepared according to method of claim 15 .

Assignees

• Univ Hong Kong Baptist Univ

Inventors

• Yang Zhijun
• Lu Aiping
• Bian Zhaoxiang
• Chen Xiaoyu
• Wong Blenda Chi Kwan

Classifications

• A61K47/36

  Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin · CPC title

• A61K38/28

  Insulins · CPC title

• A61K47/10

  Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers · CPC title

• A61K47/42

  Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein (oligopeptides having up to five amino acids {A61K47/183}; polyamino acids A61K47/34) · CPC title

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title