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Spherical Protein Particles and Methods of Making and Using Them

a protein particle and spherical technology, applied in the field of spherical protein particles, can solve the problems of poor bioavailability, high cost and time consumption of medical care for patients who require parenteral administration of protein drugs, and difficult patient compliance, and achieve simple, efficient and high yield

Inactive Publication Date: 2012-11-08
ALTHEA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a simple, efficient, and high yield method for making spherical nanocrystalline composite particles and crystalline SPPs. The method involves adding reagents slowly to a protein solution to allow them to equilibrate and precipitate the protein of interest. This process can be carried out using dialysis or direct addition. The resulting particles are stable and soluble in dilute buffer systems. The invention also includes a method for purifying specific proteins from complex mixtures and removing aggregated proteins from solutions. The invention also includes crosslinked and / or encapsulated SPPs, spherical nanocrystalline composite particles, and crystalline SPPs of biologically active proteins.

Problems solved by technology

Protein drugs are generally formulated for parenteral administration, i.e., injection or infusion, because of their extremely poor bioavailability.
As a result, medical care for patients who require parenteral administration of protein drugs is often expensive and time-consuming.
Furthermore, patient compliance is often problematic, especially for those patients who require long-term treatment.
These methods are problematic because they typically denature proteins by heat and mechanical stress.
The method disclosed in the '910 patent requires suspending the protein of interest in 90% organic solvent, which is not suitable for a number of proteins.
Furthermore, the method disclosed in Morita requires the addition of organic solvents, e.g., methylene chloride, to remove the PEG used in a previous step, which, as stated above, is not suitable for a number of proteins.
Also, the method disclosed in Morita requires the use of PEG, which may or may not stabilize the protein being used.
Another limitation of the Morita method is that the disclosed technique involves rapid cooling of the material and can be applied only to freeze stable products.
Ice formation is usually destructive to the protein crystal lattice, which destabilizes the protein molecule, and sometimes leads to the formation of amorphous precipitate.

Method used

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  • Spherical Protein Particles and Methods of Making and Using Them

Examples

Experimental program
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Effect test

example 1

Preparation of Spherical Protein Particles of Infliximab

[0237]Infliximab is a chimeric murine / human monoclonal antibody commercially available as Remicade™ (Centocor, Leiden, the Netherlands). This monoclonal antibody has been widely used to treat rheumatoid arthritis and Crohn's disease. Infliximab is a chimeric IgG1 kappa immunoglobulin that binds to the TNFα antigen. It is composed of murine light- and heavy-chain variable region sequences and a human constant region sequence. The Infliximab antibody has an approximate molecular weight (MWt) of 149 kD.

Infliximab SPP Preparation

[0238]Materials:

[0239]Infliximab antibody (each vial contains 100 mg Infliximab, 500 mg sucrose, 0.5 mg polysorbate 80, 2.2 mg monobasic sodium phosphate and 6.1 mg dibasic sodium phosphate) reconstituted in 10 ml water, pH approximately 7.2 (concentration equal to 10 mg / ml).

[0240]Procedure:

[0241]Infliximab SPPs were formed using a Slide-A-Lyzer (Pierce Chemicals, Catalog #69570), which was used as follows:...

example 2

Preparation of Spherical Protein Particles of Rituximab

[0253]Rituximab is a chimeric murine / human monoclonal antibody commercially available as Rituxan™ (Genentech, Inc., South San Francisco, Calif.). This monoclonal antibody has been widely used to treat non-Hodgkins lymphoma. Rituximab is a chimeric IgG1 kappa immunoglobulin that binds to the CD20 antigen on the surface of normal and malignant B-lymphocytes. It is composed of murine light- and heavy-chain variable region sequences and a human constant region sequence. The Rituximab antibody has an approximate molecular weight (MWt) of 145 kD.

Rituximab SPP Preparation

[0254]Materials:

[0255]Rituximab antibody (stored until use at 4° C., at 10 mg / ml in 9.0 mg / ml sodium chloride, 7.35 mg / ml sodium citrate anhydrate, 0.7 mg / ml Polysorbate 80 and sterile water, pH 6.5)

[0256]Procedure:

[0257]Rituximab SPPs were formed using a 10,000 MW cut-off Slide-A-Lyzer, according to the method described above for Infliximab (Example 1).

[0258]100 μl of...

example 3

Preparation of Spherical Protein Particles of Trastuzumab

[0261]Trastuzumab is a monoclonal antibody commercially available as Herceptin™ (Genentech, Inc., South San Francisco, Calif.).

Trastuzumab SPP Preparation

[0262]Materials:

[0263]Trastuzumab antibody (available as a lyophilized powder containing 22 mg Trastuzumab, 1 mg L-histidine HCl, 0.64 mg L-Histidine, 40 mg trehalose dihydrate, 0.18 mg polysorbate 20), reconstituted in 1 ml water (22 mg / ml), pH 6.

[0264]Procedure:

[0265]Trastuzumab SPPs were formed using a 10,000 MW cut-off Slide-A-Lyzer, according to the method described above for Example 1.

[0266]100 μl of a Trastuzumab solution (at 22 mg / ml Trastuzumab) was dialyzed against 3.9 ml of a solution consisting of 2.1M ammonium sulfate, 0.1M sodium acetate pH 5.8, 1% propylene glycol. A 10,000 MW cut-off dialysis membrane was used. The mixture was dialyzed at room temperature for 28 hours. Then the protein solution was washed twice in 800 μl of a solution consisting of 2.42 M ammo...

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Abstract

This invention relates to SPPs, spherical nanocrystalline composite particles or crystalline SPPs of biologically active proteins or compositions, including formulations, comprising such SPPs, spherical nanocrystalline composite particles or crystalline SPPs. More particularly, methods are provided for the production of SPPs, spherical nanocrystalline composite particles or crystalline SPPs of high concentrations of biologically active proteins, and for the preparation of stabilized SPPs, spherical nanocrystalline composite particles or crystalline SPPs for use alone, or in dry or slurry compositions. This invention also relates to methods for stabilization, storage and delivery of biologically active proteins using SPPs, spherical nanocrystalline composite particles or crystalline SPPs. The present invention further relates to methods using SPPs, spherical nanocrystalline composite particles or crystalline SPPs, or compositions or formulations comprising such SPPs, spherical nanocrystalline composite particles or crystalline SPPs, for biomedical applications, including biological delivery to humans and animals.

Description

TECHNICAL FIELD OF THE INVENTION[0001]This invention relates to spherical protein particles (“SPPs”), spherical nanocrystalline composite particles and crystalline SPPs, methods for producing them and methods and compositions, including formulations, for using them.[0002]More particularly, the present invention further relates to methods using SPPs, spherical nanocrystalline composite particles and crystalline SPPs for biological delivery to humans and animals. More specifically, the SPPs, spherical nanocrystalline composite particles and crystalline SPPs of this invention can be used to provide alternative dosage / delivery forms, e.g., aerosol, needleless injection, for delivery of biologically active pharmaceutical proteins.[0003]The present invention further relates to methods using SPPs, spherical nanocrystalline composite particles or crystalline SPPs, or compositions, including formulations, containing them, for biomedical applications, including more particularly, highly conce...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/16A61P9/00B32B5/16A61P37/06A61P35/00A61K9/00A61P11/00G01N33/53A61K9/16A61K9/51A61K9/52A61K9/54A61K39/395A61K48/00A61K49/00A61M5/307A61P9/10A61P29/00C07K1/14C07K16/08C07K16/18C07K16/24C07K16/26C12P21/08G01N33/577
CPCA61K9/1688Y10S977/904A61K39/39591B82Y5/00C07K14/00C07K16/00C07K16/241C07K16/2887C07K16/32C07K2317/732C07K2317/734C30B7/06C30B29/58C30B29/60Y10T428/2982A61K9/5146A61P11/00A61P29/00A61P35/00A61P37/06A61P9/00A61P9/10Y02A50/30
Inventor YAKOVLEVSKY, KIRILLSHAMASHKIN, MICHAELKHALAF, NAZERGOVARDHAN, CHANDRIKA P.JUNG, CHU W.
Owner ALTHEA TECH
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