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Lyophilized formulations for small modular immunopharmaceuticals

A technology of immune drugs and small modules, applied in drug combination, drug delivery, freeze-drying delivery, etc., can solve the problems of protein complexity and infeasibility of liquid preparations

Inactive Publication Date: 2012-09-26
WYETH LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, for many proteins, liquid formulations are not feasible
The complexity of proteins leads to protein degradation due to the stresses encountered during preparation, packaging and shipping

Method used

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  • Lyophilized formulations for small modular immunopharmaceuticals
  • Lyophilized formulations for small modular immunopharmaceuticals
  • Lyophilized formulations for small modular immunopharmaceuticals

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0087] preparation of formulations

[0088] SMIP to be prepared TM Proteins can be produced using techniques well established in the art, including but not limited to recombinant techniques and peptide synthesis or a combination of these techniques. SMIP TM Proteins may be obtained from any in vivo or in vitro protein expression system, including but not limited to recombinant cells producing products, bacteria, fungal cells, insect cells, transgenic plants or plant cells, transgenic animals or animal cells or animal serum, ascites fluid, hybridomas or myeloma supernatant. Suitable bacterial cells include, but are not limited to, E. coli cells. Examples of suitable E. coli strains include: HB101, DH5[alpha], GM2929, JM 109, KW251, NM538, NM539 and any E. coli strain that cannot cleave foreign DNA. Suitable fungal host cells that may be used include, but are not limited to, Saccharomyces cerevisiae, Pichia pastoris, and Aspergillus cells. Suitable insect cells include, but...

Embodiment 1

[0129] Example 1: Acetate-Glycine-Sucrose ("AGS") Lyophilized Formulation Containing 25 mg / ml TRU-015

[0130] In this example, the AGS formulation was designed to lyophilize TRU-015 at a concentration of approximately 25 mg / ml. Specifically, the AGS formulation used in this example included 6.5% sucrose, 50 mM glycine, 20 mM sodium acetate, pH 6.0. Protein concentration is 25 mg / ml, 100 mg protein per vial. Sucrose is used as a stabilizer and bulking agent, and glycine is added as a stabilizer and isotonic agent. Sodium acetate is a buffer. The AGS formulation had a glass transition of -34.2°C as measured by a modulated differential scanning calorimeter ("DSC"). The collapse temperature of the AGS formulation was found to be -31.4°C as measured by Freeze Drying Microscopy ("FDM"). The total lyophilization process in the laboratory scale lyophilizer lasted about 120 hours. An optional renaturation step at -10°C resulted in a shortened cycle time of 90 hours at laboratory ...

Embodiment 2

[0137] Example 2: Acetate-Mannitol-Sucrose ("AMS") or Histidine-Mannitol-Sucrose ("HMS") Formulations

[0138] In this example, two formulations were developed, AMS and HMS formulations. The acetate-mannitol-sucrose (AMS) based formulation contained 20 mM sodium acetate as a buffer, 4% mannitol as a bulking agent and 1% sucrose as a stabilizer. In the histidine-mannitol-sucrose (HMS) formulation, 20 mM histidine was used instead of sodium acetate buffer. The remaining components are the same (eg 4% mannitol, 1% sucrose). The solution pH was 6.0 for both formulations. The isotonicity of both formulations was 270 mOsm / kg. The fill volume for both formulations is 4 ml in 10-ml vials, with 100 mg protein per vial. A refolding step at -15°C was used during lyophilization. Without wishing to be bound by any theory, it is expected that this refolding step promotes crystallization of mannitol. For AMS and HMS formulations, once mannitol crystallizes, the glass transition tempera...

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Abstract

The present invention provides, among other things, stable formulations for small modular immunopharmaceutical (SMIPTM) proteins. In some embodiments, the present invention provides a formulation containing a lyophilized mixture of a small modular immunopharmaceutical protein, wherein less than 7% of the lyophilized small modular immunopharmaceutical protein exists in aggregated form. Formulations according to the invention may contain buffering agents, stabilizers, bulking agents, surfactants and / or other excipients. The present invention also provides formulations for lyophilization, reconstitution and methods of use thereof.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Patent Application Serial Nos. 61 / 218,388 and 61 / 218,386, both filed June 18, 2009, each of which is incorporated herein by reference in its entirety. Background of the invention [0003] During the past decade, developments in biotechnology have enabled the production of various proteins for pharmaceutical applications. Because proteins are larger and more complex (ie, possess multiple functional groups in addition to their complex three-dimensional structure) than conventional organic and inorganic pharmaceuticals, the formulation, packaging, and storage of such proteins present special problems. Liquid formulations are often desirable for clinical convenience, patient convenience, and ease of manufacture. However, for many proteins, liquid formulations are not feasible. The complexity of proteins leads to degradation of proteins due to the stresses encountered durin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/19
CPCA61K9/19C07K2317/622C07K2319/00A61K9/0014C07K2317/52A61K47/26A61K39/39591A61K47/183C07K16/2887C07K2317/56C07K2317/24A61K47/20A61P37/00A61K9/14A61K9/16
Inventor S·切莎洛夫A·坎特李力N·卢克沙N·沃恩
Owner WYETH LLC
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