DELIVERY OF AGENTS USING METASTABLE LIPOSOMES

• US 20160263031A1
• Filed: 10/22/2014
• Published: 09/15/2016
• Est. Priority Date: 10/22/2013
• Status: Active Grant

• Current Assignee: Lipella Pharmaceuticals Inc
• Original Assignee: Lipella Pharmaceuticals Inc
• Inventors: Kaufmann, Jonathan H., Chancellor, Michael B.
• Granted Patent: US 10,639,278 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/436 the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
• CPC Class Codes: A61K 49/0084 liposome, i.e. bilayered vesicular structure
• CPC Class Codes: A61K 9/0034 Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
• CPC Class Codes: A61K 9/1272 with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids with cholesterol as the only non-phosphatidyl surfactant A61K9/127; lipids as modifying agent A61K47/543
• CPC Class Codes: A61P 13/10 of the bladder

Abstract

Metastable liposomal formulations for hydrophobic drug delivery to a tissue or tissue lumen such the bladder have been developed. These are at least one micron in diameter and formed of one or more lipids having entrapped in the lipid a hydrophobic therapeutic, prophylactic or diagnostic agent. The greater stability of these liposomes, as well as the enhanced transfer of entrapped agent into the adjacent tissue, provides for better delivery, especially of hydrophobic agents such as tacrolimus which does not penetrate tissue well. The metastable liposomal formulations can be administered locally, preferably by instillation, or topically, for example, by spraying or painting, to a tissue or tissue lumen such as the bladder in need of treatment.

Claims

1. A dosage formulation of metastable liposomes comprising

(a) liposomes having a mean diameter of between one and 100 microns, inclusive,

wherein the ratio of the volume enclosed by the liposomes at 25°

C. relative to the volume enclosed by the liposomes following heating to a temperature that surpasses the gel-fluid phase transition of one or more lipids forming the liposomes is greater than 1.0; and

(b) one or more hydrophobic therapeutic, prophylactic or diagnostic agent(s),

wherein the one or more hydrophobic agent(s) is entrapped within the lipid forming the liposomes.

2. The formulation of claim 1 further comprising one or more therapeutic, prophylactic or diagnostic agents encapsulated within the liposomes.

3. The formulation of claim 1 in the form of a dry powder in a dosage unit container for reconstitution to form a metastable liposomal hydrophobic agent having a mass concentration ranging from 0.05 mg/ml to 10 mg/mL, inclusive.

4. The formulation of claim 1 wherein the liposomes are suspended in a gel or solution suitable for direct administration to a tissue or tissue lumen.

5. The formulation of claim 1 wherein the hydrophobic agent is for treatment of a bladder disease or disorder.

6. The formulation of claim 5, wherein the hydrophobic agent is tacrolimus.

7. The formulation of claim 1 wherein the liposomes comprise sphingomyelin.

8. The formulation of claim 7 wherein the liposomes have a mean diameter greater than 24.8 microns at 25°

C.

9. A method for treating an individual in need thereof comprising administering to a tissue or tissue lumen a dosage formulation of metastable liposomes comprising

(a) liposomes having a mean diameter of between one and 100 microns, inclusive,

wherein the ratio of the volume enclosed by the liposomes at 25°

C. relative to the volume enclosed by the liposomes following heating to a temperature that surpasses the gel-fluid phase transition of one or more lipids forming the liposomes is greater than 1.0; and

(b) one or more hydrophobic therapeutic, prophylactic or diagnostic agent(s),

wherein the one or more hydrophobic agent(s) is entrapped within the lipid forming the liposomes.

10. The method of claim 9 wherein the liposomes further comprise one or more therapeutic, prophylactic or diagnostic agents encapsulated within the liposomes.

11. The method of claim 9 wherein the formulation is in the form of a dry powder in a dosage unit container for reconstitution to form a metastable liposomal hydrophobic agent mass concentration ranging from 0.05 mg/ml to 10 mg/mL, comprising reconstituting the formulation with a sterile aqueous solution.

12. The method of claim 9 further comprising suspending the liposomes in a gel or solution suitable for direct administration to a tissue or tissue lumen.

13. The method of claim 9, wherein the formulation is administered via a cystoscope comprising an applicator selected from the group consisting of a spray device, gauze, roller, and sponge.

14. The method of claim 9 wherein the liposomes comprise sphingomyelin.

15. The method of claim 14 wherein the liposomes have a mean diameter greater than 24.8 microns at 25°

C.

16. The method of claim 9 comprising administering the liposomes to a lumen selected from the group consisting of lumens of the respiratory tract, the gastrointestinal tract, the urino-genital tract, and the reproductive tract.

17. The method of claim 9, wherein the hydrophobic agent is tacrolimus or a toxin.

18. The method of claim 9 wherein the hydrophobic agent is for treatment of a bladder disease or disorder, comprising administering the liposomes in an effective amount to an individual with a bladder disease or disorder.

19. The method of claim 18, comprising administering the liposomes via intravesical instillation in to the bladder of an individual with a bladder disease or disorder.

20. The method of claim 19, wherein the disorder is selected from the group consisting of hemorrhagic cystitis, interstitial cystitis/painful bladder syndrome, and cancer.