Sustained-release lipid pre-concentrate of pharmacologically active substance and pharmaceutical composition comprising the same

Patent metadata

Field	Value
Publication number	US-9526787-B2
Application number	US-201214241696-A
Country	US
Kind code	B2
Filing date	Aug 28, 2012
Priority date	Aug 30, 2011
Publication date	Dec 27, 2016
Grant date	Dec 27, 2016

Abstract

Disclosed is a sustained release lipid pre-concentrate, comprising: a) a sorbitan unsaturated fatty acid ester having a polar head with at least two or more —OH (hydroxyl) groups; b) a phospholipid; and c) a liquid crystal hardener, free of an ionizable group, having a hydrophobic moiety of 15 to 40 carbon atoms with a triacyl group or a carbon ring structure. The lipid pre-concentrate exists as a liquid phase in the absence of aqueous fluid and forms into a liquid crystal in the presence of aqueous fluid. Also, a pharmaceutical composition further comprising a pharmacologically active ingredient plus the pre-concentrate is provided.

First claim

The invention claimed is:

1. A sustained release lipid pre-concentrate, comprising:
a) a sorbitan unsaturated fatty acid ester having two or more —OH (hydroxyl) groups on a polar head and having the structure of Formula 1:

wherein:
R 1 is OH;
R 2 is OH or an alkylester of 4 to 30 carbon atoms with one or more unsaturated bonds; and
R 3 is an alkylester of 4 to 30 carbon atoms with one or more unsaturated bonds;

b) a phospholipid; and
a liquid crystal hardener selected from the group consisting of triglyceride having a hydrophobic moeity of 15 to 40 carbon atoms, tocopheryl acetate, cholesterol, benzyl benzoate and a mixture thereof
wherein the lipid pre-concentrate exists in a liquid state in the absence of an aqueous fluid and transforms from the liquid state into a liquid crystal gel state in the presence of an aqueous fluid.

2. The sustained release lipid pre-concentrate of claim 1 , wherein the sorbitan unsaturated fatty acid ester is selected from the group consisting of sorbitan monooleate, sorbitan monolinoleate, sorbitan monopalmitoleate, sorbitan monomyristoleate, sorbitan sesquioleate, sorbitan sesquilinoleate, sorbitan sesquipalmitoleate, sorbitan sesquimyristoleate, sorbitan dioleate, sorbitan dilinoleate, sorbitan dipalmitoleate, sorbitan dimyristoleate and a mixture thereof.

3. The sustained release lipid pre-concentrate of claim 1 , wherein the sorbitan unsaturated fatty acid ester is selected from the group consisting of sorbitan monooleate, sorbitan monolinoleate, sorbitan monopalmitoleate, sorbitan monomyristoleate and a mixture thereof.

4. The sustained release lipid pre-concentrate of claim 1 , wherein the phospholipid contains a saturated or unsaturated alkyl ester group of 4 to 30 carbon atoms and is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerine, phosphatidylinositol, phosphatidic acid, sphingomyelin and a mixture thereof.

5. The sustained release lipid pre-concentrate of claim 1 , wherein the liquid crystal hardener is tocopheryl acetate.

6. The sustained release lipid pre-concentrate of claim 1 , wherein the weight ratio of component of a) to component b) is 10:1 to 1:10.

7. The sustained release lipid pre-concentrate of claim 1 , wherein the weight ratio of a sum of the components of a) and b) to the component of c) is 100:1 to 1:1.

8. A pharmaceutical composition, comprising:
the sustained release lipid pre-concentrate of claim 1 ; and
a pharmacologically active ingredient selected from among a protein, a peptide, a vaccine, a gene, a non-peptidic hormone, a synthetic chemical drug, and a combination thereof.

9. The pharmaceutical composition of claim 8 , wherein the weight ratio of the component of a) to the component of b) is 10:1 to 1:10.

10. The pharmaceutical composition of claim 8 , wherein the weight ratio of a sum of the components of a) and b) to the component of c) is 100:1 to 1:1.

11. The pharmaceutical composition of claim 8 , which is in a formulation selected from among an injection, an ointment, a gel, a lotion, a capsule, a tablet, a liquid, a suspension, a spray, an inhaler, an eye drop, an adhesive, and a patch.

12. A method for sustained release of a pharmacologically active ingredient, comprising administering the pharmaceutical composition of claim 8 to a mammal, whereby the composition transforms from a liquid state into a liquid crystal gel state in the presence of an aqueous fluid.

13. The method of claim 12 , wherein the pharmaceutical composition is administered by a method selected from among injecting, coating, dropping, padding, oral administering, and spraying.

14. The method of claim 12 , wherein the pharmaceutical composition is administered by subcutaneous or intramuscular injection.

15. The method of claim 12 , wherein the liquid crystals have a non-lamellar phase structure.

16. A pharmaceutical composition, comprising:
the sustained release lipid pre-concentrate of claim 2 ; and
a pharmacologically active ingredient selected from among a protein, a peptide, a vaccine, a gene, a non-peptidic hormone, a synthetic chemical drug, and a combination thereof.

17. A method for sustained release of a pharmacologically active ingredient, comprising administering the pharmaceutical composition of claim 16 to a mammal, whereby the composition transforms from a liquid state into a liquid crystal gel state in the presence of an aqueous fluid.

Assignees

• Ko Jin Young
• Kim Ji Yeon
• Park So Hyun
• An Sung Won
• Ki Min Hyo
• Chong Kun Dang Pharmaceutical Corp

Inventors

• Ko Jin Young
• Kim Ji Yeon
• Park So Hyun
• An Sung Won
• Ki Min Hyo

Classifications

• A61K48/0016

  wherein the nucleic acid is delivered as a 'naked' nucleic acid, i.e. not combined with an entity such as a cationic lipid · CPC title

• A61K9/0024

  Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue (compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L) · CPC title

• A61K9/0019 Primary

  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

• A61K31/58

  containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin (digitoxin {A61K31/7048}) · CPC title

• A61K38/26

  Glucagons · CPC title