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Thermosensitive Nanoparticle Formulations and Method of Making The Same

a technology of thermosensitive nanoparticles and formulations, which is applied in the field of thermosensitive liposome formulations, can solve the problems of limited techniques, long-term stability of drug products, and achieve the effects of long-term stability and significant impact on the storage temperatur

Inactive Publication Date: 2013-09-05
CELSION CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

The patent describes a new invention that has various benefits. These benefits are outlined in detail below.

Problems solved by technology

This technique is limited, however, to conditions where the phase transition temperature of the liposome is higher (greater than 37° C.) than the normal tissue temperature.
An additional important design issue discovered by the inventors with liposomal formulations of doxorubicin (e.g. disclosed in U.S. Pat. No. 7,901,709) is the stabilizing effect of doxorubicin complex (co-crystal or salt) formation on the stability of the finished drug product.
Successful control of degradation rates will result in significant impact on the storage temperature and long term stability of the drug product.

Method used

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  • Thermosensitive Nanoparticle Formulations and Method of Making The Same
  • Thermosensitive Nanoparticle Formulations and Method of Making The Same
  • Thermosensitive Nanoparticle Formulations and Method of Making The Same

Examples

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example 1

Preparation of Doxorubicin Loaded Temperature-Sensitive Liposomes by NH4+-Loading

[0092]Liposomes containing 1,2-dipalmitoyl-sn-glycero-3-phosphatidyl choline (DPPC), which comprises 86% (mole %) of the liposome membrane; 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-polyethylene glycol 2000 (DSPE-mPEG), at approximately 4% (mole %); and 1-stearoyl-2-hydroxy-sn-glycero phosphatidyl choline (MSPC) at approximately 10% (mole %) are prepared by the following technique: The appropriate lipid composition is first hydrated in 200 mM ammonium sulfate buffer, forming multi-lamellar liposomes. Small uni-lamellar liposomes are then formed by extrusion through 80 nm filters to form approximately 100 nm spheres in 200 mM ammonium sulfate buffer.

[0093]The liposomes prepared in the previous step were then subjected to a dialysis or diafiltration step exchanging the ammonium sulfate that is external to the liposome with a 10% sucrose solution, forming an ammonium concentration gradient across t...

example 2

Preparation of pH-Loaded Temperature Sensitive Doxorubicin Liposomes

[0094]Liposomes with doxorubicin loaded using a pH gradient are prepared according to the method described in WO 2007 / 024826, Liposomes containing 1,2-dipahnitoyl-sn-glycero-3-phosphatidyl choline (DPPC), which comprises 86% (mole %) of the liposome membrane; 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-polyethylene glycol 2000 (DSPE-mPEG), at approximately 4% (mole %); and 1-stearoyl-2-hydroxy-sn-glycero phosphatidyl choline (MSPC) at approximately 10% (mole %) are prepared by the following technique: The appropriate lipid composition is first hydrated in 300 mM citrate buffer (pH=4), forming multi-lamellar liposomes. Small uni-lamellar liposomes are then formed by extrusion through 80 nm filters to form approximately 100 nm spheres in 300 mM citrate buffer.

[0095]A 500 mM sodium carbonate solution is then added to the liposomes prepared in the previous step, increasing the external solution to a pH of ˜7.5. It...

example 3

Final Product Characterization Methods

[0097]The final product is characterized for total doxorubicin content, doxorubicin degradation products, pH, osmolality, particle size distribution, MSPC content, DPPC content, DSPE-mPEG content, % encapsulated doxorubicin, drug release at 37° C., and drug release at 41° C. to effectively complete assessment of the product. The target total doxorubicin content is between about 1.8 to about 2.2 mg / mL. The drug encapsulation was typically greater than 90%, and showed limited release, e.g. 80%, at 41.0° C. The volume averaged particle size of the liposomes as measured by dynamic light scattering is between about 50 to about 150 nm.

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Abstract

The present invention relates to a formulation of thermosensitive liposomes, and more specifically to a formulation of liposomes comprising phospholipids and a surface active agent, wherein the liposomes support long term storage at temperatures less than or equal to about 8° C., control degradate formation to maximize product potency and release their contents at mild hyperthermic temperatures. Methods of making formulations are also described.

Description

FIELD OF THE INVENTION[0001]The present invention relates to a formulation of thermosensitive liposomes, and more specifically to a formulation of liposomes comprising phospholipids and a surface active agent, wherein the liposomes support long term storage at temperatures less than or equal to about 8° C., control degradate formation to maximize product potency and release its contents at mild hyperthermic temperatures. Methods of making formulations are also described.BACKGROUND OF THE INVENTION[0002]Liposomes are composed of at least one lipid bilayer membrane enclosing an aqueous internal compartment. Liposomes may be characterized by membrane type and by size. Small unilamellar vesicles (SUVs) have a single membrane and typically range between 0.02 and 0.25 μm in diameter; large unilamellar vesicles (LUVs) are typically larger than 0.25 μm. Oligolamellar large vesicles and multilamellar large vesicles have multiple, usually concentric, membrane layers and are typically larger t...

Claims

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Application Information

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IPC IPC(8): A61K9/127A61K31/704
CPCA61K9/127A61K9/1278A61K9/1271A61K31/704A61P35/00
Inventor REED, ROBERT A.SU, DAISHUI
Owner CELSION CORP
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