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Hazard-free microencapsulation for structurally delicate agents, an application of stable aqueous-aqueous emulsion

a technology of structurally delicate agents and microencapsulation, applied in the direction of spray delivery, peptide/protein ingredients, aerosol delivery, etc., can solve the problems of protein denaturement during the formulation process, sustained release or non-invasive, etc., to reduce the portion of incomplete release, prevent burst effect, and rapid release of considerable amount of loading

Inactive Publication Date: 2006-06-08
BIOPHARM SOLUTIONS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present invention provides a method for preparing polymer microspheres for sustained release of protein therapeutics. The method involves loading proteins into a stable polymer aqueous-aqueous emulsion system, which is then converted to glassy particles for inhalation or nasal spray use. The method is simple, reproducible, and environmentally friendly. The glassy particles can be easily prepared and used for inhalation or nasal spray drug delivery, or can be further formulated with other degradable polymers for sustained release. The method also protects the structure and function of the proteins, and prevents burst effect and incomplete release. The AqueSpheres help to reduce local acidity and buffer the release process. Overall, this invention provides a solution for developing sustained release protein microspheres with improved efficacy and stability."

Problems solved by technology

A major difficulty that delayed development of sustained release or non-invasive protein formulations is that proteins are denatured during the formulation process.

Method used

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  • Hazard-free microencapsulation for structurally delicate agents, an application of stable aqueous-aqueous emulsion
  • Hazard-free microencapsulation for structurally delicate agents, an application of stable aqueous-aqueous emulsion
  • Hazard-free microencapsulation for structurally delicate agents, an application of stable aqueous-aqueous emulsion

Examples

Experimental program
Comparison scheme
Effect test

example 1

Stability of Polymer Aqueous-aqueous Emulsion

[0056] Stability of polymer aqueous-aqueous emulsion was examined by observation of the fusion (the size change) of the dispersed phase under a microscope and by observation of formation of block phases of the colored dispersed phase directly by eyes as a function of time. The dispersed phase was formed by a dextran solution. Three concentrations of the dextran solution, 5, 20 and 40 w / w %, were used in the experiments without significant difference in the results, i.e. for either of the concentration, stable aqueous-aqueous emulsion was formed. For the average molecular weight of dextran, W=10,000, 67,000 and 500,000 were tested without significant difference in results. The continuous phase contained PEG with concentration 5, 20, and 40 w / w % in different tests, for all of which, stable emulsion was formed. Average molecular weight of PEG used were 8000 and 22,000. As emulsion stabilizers, sodium alginate, carboxymethyl dextran, carbox...

example 2

Preparation of AqueSpheres

[0061] AqueSpheres were prepared simply by freeze-drying the stable emulsions of above. After freeze-drying, the dextran droplets converted to solid particles. However, the most of dextran particles were dispersed in a solid matrix formed by the continuous phase, PEG. The PEG can be removed by washing the lyophilized powder with methylene chloride or acetonitrile. These solvents did neither dissolve nor swell the dried dextran phase. FIGS. 2A and 2B showed the microscopic images of the dispersed phase at different preparation stages: after emulsification, after freeze-drying followed by rinsing with dichloromethane (to remove PEG), and after recovery from PLGA coating, respectively. After freeze-drying, the diameter of the dispersed phase remained uniform but dropped from 3-7 μm to 1-3 μm, a reasonable size reduction from loss of water (See FIG. 2B). These images indicated that no droplet fusion occurred during lyophilization. This size range of the dried ...

example 3

Microencapsulation of AqueSpheres into PLGA Microspheres

[0062] AqueSpheres can be further microencapsulated into the matrix of PLGA and other biodegradable polymer microspheres through a “solid-in-oil-in-water” emulsification process. In the present study, PLGA with lactic:glycolic ratio of 50:50 and 75:25 were used. AqueSpheres prepared as in Example 2 were first suspended in a PLGA / dichloromethane solution (10-20%) at the AqueSphere / PLGA ratio of 1:2 to 1:20, then added into a water solution containing 0.1-10% sodium chloride and 0.1-4% polyvinyl alcohol (PVA) or PEG or polyvinyl parralidone (PVP) under stirring. The volume ratio of the two solutions was 1:2 to 1:10. After an emulsion was formed, the organic solvent was extracted by pouring the system into large volume of cold water (10 times of the emulsion) under stirring. FIGS. 3A and 3B show the microscopic images of the PLGA droplets before solvent extraction and PLGA particles after solvent extraction, respectively. Before ...

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Abstract

This invention provides method for sustained release delivery of structurally delicate agents such as proteins and peptides. Using unique emulsion system (Stable polymer aqueous-aqueous emulsion), proteins and peptides can be microencapsulated in polysacchride glassy particles under a condition free of any chemical or physical hazard such as organic solvents, strong interfacial tension, strong shears, elevated temperature, large amount of surfactants, and cross-linking agents. Proteins loaded in these glassy particles showed strong resistance to organic solvents, prolonged activity in hydrated state, and an excellent sustained release profile with minimal burst and incomplete release when being further loaded in degradable polymer microspheres. This invention provides a simple yet effective approach to address all the technical challenges raised in sustained release delivery of proteins.

Description

CROSS REFERENCE OF RELATED APPLICATION [0001] This application claims priority of U.S. Ser. No. 60 / 384,971, filed Jun. 3, 2002, and U.S. Ser. No. 60 / 418,100, filed Oct. 11, 2002, the contents of which are incorporated by reference here into this application. [0002] Throughout this application, various references are referred to. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains.FIELD OF THE INVENTION [0003] The present invention demonstrates a novel method for preparing a novel particulate glassy system which effectively preserve structure / activity of proteins peptides, DNA, liposomes and live viruses during formulation process, storage, and application. BACKGROUND OF THE INVENTION [0004] Due to the impermeability and short half-life, most of protein therapeutics require frequent injection. To reduce injection frequency, development of sustained...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K9/16B29C39/10A61K9/107A61K9/113A61K9/50A61K38/00A61K38/21
CPCA61K9/0024A61K9/0043A61K9/0073A61K9/1075A61K9/113A61K9/1652A61K9/19A61K9/5031A61K9/5036A61K9/5073A61K38/00
Inventor JIN, TUOZHU, HUAZHU, JIAHAO
Owner BIOPHARM SOLUTIONS
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