Methods for the preparation of a pharmaceutical-vesicle formulation and associated products and uses

Patent metadata

Field	Value
Publication number	US-11524080-B2
Application number	US-201917273059-A
Country	US
Kind code	B2
Filing date	Sep 13, 2019
Priority date	Sep 14, 2018
Publication date	Dec 13, 2022
Grant date	Dec 13, 2022

Abstract

The invention relates to methods for the preparation of a pharmaceutical-vesicle formulation comprising steps of: preparing and processing vesicle components and a pharmaceutical agent to entrap the pharmaceutical agent in the vesicle and form a pharmaceutical-vesicle formulation, wherein the pharmaceutical-vesicle formulation is reconstituted in a known quantity of the pharmaceutical agent dissolved in a pharmaceutically-acceptable carrier to provide a biphasic pharmaceutical-vesicle formulation. The invention also relates to the associated pharmaceutical-vesicle formulations, pharmaceutical kits and uses as a medicament, in particular for the prevention or treatment of infection by bacteria such as Burkholderia pseudomallei and Francisella tularensis , and viruses such as Venezuelan Equine Encephalitis Virus (VEEV).

First claim

The invention claimed is:

1. A method for the preparation of a pharmaceutical-vesicle formulation, the method comprising the steps of:
a) heating vesicle components comprising monopalmitoyl glycerol, cholesterol and dicetyl phosphate at a temperature in the range of 50° C. to 150° C.;
b) dissolving a pharmaceutical agent in a pharmaceutically-acceptable carrier and heating the resultant pharmaceutical agent-carrier mixture at a range of 30-99° C.;
adding the pharmaceutical agent-carrier mixture to the vesicle components to provide a formulation mixture; and,
d) processing the formulation mixture to form a pharmaceutical-vesicle formulation, whereby the pharmaceutical agent and carrier is entrapped within a plurality of vesicles
wherein the pharmaceutical agent is an orally-available antibiotic,
wherein the pharmaceutical-vesicle formulation is reconstituted in a known quantity of the pharmaceutical agent dissolved in a pharmaceutically-acceptable carrier to provide a biphasic pharmaceutical-vesicle formulation,
wherein the vesicles are modified with i) glucosamine and/or ii) transferrin,
wherein, for i), palmitic acid is covalently linked to the glucosamine to provide palmitoylated glucosamine, and
wherein, for ii), cholesterol is modified by replacing a portion of the cholesterol by, cholesterol-PEG-malemide, and the vesicle components further comprise thiolated transferrin, or any variant which is at least 70% identical to transferrin wild-type or base sequence, or any fragment which is any amino acid portion which retains the desired properties of transferrin wild-type or base sequence, such that a covalent bond forms between the thiolated transferrin, or variant or fragment, and the modified cholesterol.

2. The method according to claim 1 , wherein the monopalmitoyl glycerol, cholesterol and dicetyl phosphate are provided in a 5:4:1 molar ratio respectively.

3. The method according to claim 1 , wherein sodium deoxycholate is provided in the vesicle components and/or when dissolving a pharmaceutical agent in a pharmaceutically-acceptable carrier.

4. The method according to claim 1 , wherein the pharmaceutical agent-carrier mixture and vesicle components are provided in a respective ratio of 3:1.

5. The method according to claim 1 , wherein the pharmaceutical-vesicle formulation undergoes at least one freeze-drying and thawing cycle following processing.

6. The method according to claim 1 , wherein the antibacterial agent is selected from a group consisting of fluoroquinolones and tetracyclines.

7. The method according to claim 1 , wherein the antibacterial agent is selected from a group consisting of levofloxacin, ciprofloxacin and doxycycline.

8. The method according to claim 1 , wherein the antibacterial agent is at a concentration of 30 mg/ml.

9. A pharmaceutical-vesicle formulation prepared by the method of claim 1 .

10. The pharmaceutical-vesicle formulation according to claim 9 , wherein the monopalmitoyl glycerol, cholesterol and dicetyl phosphate are present in a 5:4:1 molar ratio respectively.

11. The pharmaceutical-vesicle formulation according to claim 9 , wherein the vesicle is of a size of 50-4000 nm.

12. The pharmaceutical-vesicle formulation according to claim 9 , wherein the antibacterial agent is selected from a group consisting of fluoroquinolones and tetracyclines.

13. The pharmaceutical-vesicle formulation according to claim 12 , wherein the antibacterial agent is selected from a group consisting of levofloxacin, ciprofloxacin and doxycycline.

14. The pharmaceutical-vesicle formulation according to claim 9 , wherein the antibacterial agent is present at concentration of 30 mg/ml.

15. A pharmaceutical kit comprising the pharmaceutical-vesicle formulation of claim 9 .

16. The method according to claim 1 , wherein, for ii), a ratio of cholesterol to cholesterol-PEG-malemide is 4:1.

17. The pharmaceutical-vesicle formulation according to claim 9 , wherein, for ii), a ratio of cholesterol to cholesterol-PEG-malemide is 4:1.

18. The pharmaceutical-vesicle formulation according to claim 9 , wherein sodium deoxycholate is provided in the vesicle components and/or when dissolving a pharmaceutical agent in a pharmaceutically-acceptable carrier.

19. The pharmaceutical-vesicle formulation according to claim 9 , wherein the pharmaceutical agent-carrier mixture and vesicle components are provided in a respective ratio of 3:1.

Assignees

• Secr Defence
• The Univ Of Strathclyde

Inventors

• Williamson Ethel Diane
• D'Elia Riccardo Vincenzo
• Roberts Craig William
• Woods Stuart

Classifications

• C07K16/116

  Togaviridae (F); Matonaviridae (F); Flaviviridae (F) · CPC title

• A61K9/0053 Primary

  Mouth and digestive tract, i.e. intraoral and peroral administration · CPC title

• A61K47/26

  Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin · CPC title

• A61K9/1272 Primary

  comprising non-phosphatidyl surfactants as bilayer-forming substances, e.g. cationic lipids or non-phosphatidyl liposomes coated or grafted with polymers (lipids as modifying agents {A61K47/543}) · CPC title

• A61K47/24

  containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids · CPC title