Composition and method for preparing stable unilamellar liposomal suspension

Patent metadata

Field	Value
Publication number	US-9445975-B2
Application number	US-24552808-A
Country	US
Kind code	B2
Filing date	Oct 3, 2008
Priority date	Oct 3, 2008
Publication date	Sep 20, 2016
Grant date	Sep 20, 2016

Abstract

Compositions and methods for producing and using stable transparent to translucent unilamellar liposomal suspensions are described. The suspensions include a liposome preparation having a uniform plurality of unilamellar liposomal particles with a mean particle size between about 50 nm to about 290 nm. The particles are suspended in an external phase composition that has a density between about 0.95 g/cc and about 1.25 g/cc, and that is present in an amount between about 30% to about 75% of the weight of the liposomal suspension. The liposome preparation is formed from an aqueous liposomal solution that includes an oil-soluble composition and a water-soluble composition. The oil-soluble composition is present at a concentration between about 5% to about 33% by weight of the liposomal solution and the water-soluble composition is present at a concentration between about 67% to about 95% by weight of the liposomal solution.

First claim

The invention claimed is:

1. A method for preparing a stable translucent to transparent unilamellar liposomal suspension comprising:
a. preparing an oil-soluble composition comprising
i. at least one phospholipid,
ii. a rigidity enhancer in an amount from about 0.02% to about 1% of the liposomal suspension and being selected from the group consisting of a sphingolipid, a ceramide, a phytosterol, a sterol and a combination thereof,
iii. an antioxidant selected from the group consisting of tocopherol, derivatives of tocopherol, alpha tocopherol, tocopheryl acetate, tocopherol succinate, ascorbic acid, derivatives of ascorbic acid, tetrahexyldecyl ascorbate, butylated hydroxyl toluene, butylated hydroxyanisole, and mixtures thereof, and
iv. a coupling agent for solubilizing immiscible phases of differing polarity and having a dielectric constant of about 10.5 or greater at 23° C., wherein the coupling agent is selected from the group consisting of butylene glycol, propylene glycol, hexylene glycol, and polyethylene glycol, and mixtures thereof;

b. preparing a water-soluble composition;
c. combining with agitation the water-soluble composition and the oil-soluble composition to form a multilamellar and multivesicular liposome preparation, wherein the water soluble composition is present in an amount from about 67% to about 95% by weight of the liposome preparation and the oil soluble composition is present in an amount from about 5% to about 33% by weight of the liposome preparation;
d. converting the multilamellar and multivesicular liposome preparation to a unilamellar liposome preparation by one of high pressure microfluidization, extrusion, high speed shearing, milling, sonication, selective microchannel filtration or homogenization, wherein the unilamellar liposome preparation comprises a plurality of unilamellar liposomal particles having a unimodal size distribution with a mean particle size between about 50 to about 290 nm; and
e. adding the unilamellar liposome preparation to an external phase composition that includes a viscosity promoting agent selected from thickening agents to provide the unilamellar liposomal suspension, wherein the external phase composition has a density within a range of about 1.05 g/cc to about 1.25 g/cc and a viscosity between about 2.5 cP and about 40,000 cP at a shear rate of 10 sec −1 at 21° C.; and,
wherein the liposomal suspension is translucent to transparent, has a refractive index between 1.30 and 1.45 and retains its stability in neat form at temperatures between about 4° C. to about 50° C. for a period of at least 30 days, or at 21° C. for a period of at least 180 days.

2. The method of claim 1 , wherein the coupling agent is butylene glycol.

3. The method of claim 1 , wherein the at least one phospholipid comprises a glycerophospholipid with varying fatty acyl moieties or a sphingolipid.

4. The method of claim 1 , wherein the at least one phospholipid comprises a phospholipid preparation comprising phosphatidylcholine at a concentration of between about 80% to about 95% by weight of the phospholipid preparation.

5. The method of claim 1 , comprising at least two rigidity enhancers, including at least one phytosterol and at least one member selected from the group consisting of ceramide, sphingosine, and phytosphingosine.

6. The method of claim 1 , wherein the weight ratio of the liposome preparation to the external phase composition is from about 0.002 to about 0.54.

7. The method of claim 1 , wherein the external phase comprises glycerin at a concentration between about 35% to about 75% of the liposomal suspension.

8. The method of claim 1 , wherein the unilamellar liposome preparation is lyophilized prior to suspension in the external phase composition.

9. A method for preparing a cosmetic formulation, comprising:
combining the liposomal suspension of claim 1 with a cosmetically suitable matrix to form a cosmetic formulation in the form of a cream, lotion, gel, serum, tonic, emulsion, paste, or spray.

10. A translucent unilamellar liposomal suspension comprising:
a liposome preparation suspended in an external phase composition, the liposome preparation comprising a plurality of unilamellar liposomal particles having a unimodal size distribution and a mean particle size between about 50 nm to about 290 nm, the liposome preparation formed from an aqueous liposomal solution comprised of an oil-soluble composition and a water-soluble composition, the oil-soluble composition at a concentration between about 5% to about 33% by weight of the liposomal solution, the water-soluble composition at a concentration between about 67% to about 95% by weight of the liposomal solution,
wherein the oil-soluble composition comprises a lecithin preparation, butylene glycol, ceramide IIIB, and β-sitosterol;
wherein the external phase composition comprises glycerin at a concentration between about 35% to about 75% by weight of the liposomal suspension; and
wherein the liposomal suspension is translucent and has a refractive index between about 1.30 and about 1.45.

11. A stable unilamellar liposomal suspension comprising:
a liposome preparation suspended in an external phase composition, the liposome preparation comprising a plurality of unilamellar liposomal particles having a unimodal size distribution and a mean particle size between about 50 nm to about 290 nm, the liposome preparation formed from an aqueous liposomal solution comprised of an oil-soluble composition and a water-soluble composition, the oil-soluble composition at a concentration between about 5% to about 33% by weight of the liposomal solution, the water-soluble composition at a concentration between about 67% to about 95% by weight of the liposomal solution,
wherein the oil-soluble composition comprises at least one phospholipid, at least one rigidity enhancer, and an antioxidant, and a coupling agent for solubilizing immiscible phases of differing polarity and having a dielectric constant of about 10.5 or greater at 23° C., wherein the antioxidant is selected from the group consisting of tocopherol, derivatives of tocopherol, alpha tocopherol, ascorbic acid, derivatives of ascorbic acid, butylated hydroxyl toluene, butylated hydroxyanisole, and mixtures thereof, wherein the at least one rigidity enhancer is selected from the group consisting of sphingolipid, phytosterol, cholesterol, and mixtures thereof and wherein the coupling agent is selected from the group consisting of butylene glycol, propylene glycol, hexylene glycol, and polyethylene glycol, and mixtures thereof;
wherein the external phase composition is at a concentration between about 30% to about 75% by weight of the liposomal suspension, the external phase composition comprising a viscosity promoting agent selected from thickening agents and having a density between about 0.95 g/cc and about 1.25 g/cc and a viscosity between about 2.5 cP and about 40,000 cP at a shear rate of 10 sec −1 at 21° C.; and
wherein the liposomal suspension is translucent to transparent, has a refractive index between about 1.30 and about 1.45, and retains its stability in neat form at a temperature of between about 4° C. to about 50° C. for a period of at least 30 days or at 21° C. for a period of at least 180 days.

12. The liposomal suspension of claim 11 , wherein the coupling agent is butylene glycol.

13. The liposomal suspension of claim 11 , wherein the at least one phospholipid comprises a glycerophospholipid with varying fatty acyl moieties or a sphingomyelin.

14. The liposomal suspension of claim 11 , wherein the at least one phospholipid comprises a phospholipid preparation compris

Assignees

• Anderson Penelope M
• Access Business Group Int Llc

Inventors

• Anderson Penelope M

Classifications

• A61K8/345

  containing more than one hydroxy group · CPC title

• A61K2800/262

  Transparent; Translucent · CPC title

• A61K9/06

  Ointments; Bases therefor; {Other semi-solid forms, e.g. creams, sticks, gels (composition of ointments, creams or gels A61K47/00)} · CPC title

• A61K9/1277

  Preparation processes; Proliposomes · CPC title

• A61K8/678

  Tocopherol, i.e. vitamin E · CPC title