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Highly Concentrated Pharmaceutical Formulations

Inactive Publication Date: 2011-03-31
GENENTECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0015]The present invention provides a highly concentrated, stable pharmaceutical formulation of a pharmaceuti

Problems solved by technology

Unfortunately the amount of antibody that can be administered via the intravenous route is limited by the physico-chemical properties of the antibody, in particularly by its solubility and stability in a suitable liquid formulation and by the volume of the infusion fluid.
No highly concentrated, stable pharmaceutical anti-CD20 antibody formulation suitable for subcutaneous administration is currently available on the market.
The preparation of high concentration protein formulations is very challenging and there is a need to adapt each formulation to the particular proteins used because each protein has a different aggregation behavior.
Immunogenic reaction against protein or antibody aggregates may lead to neutralizing antibodies which may render the therapeutic protein or antibody ineffective.
It appears that the immunogenicity of protein aggregates is most problematic in connection with subcutaneous injections, whereby repeated administration increases the risk of an immune response.

Method used

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  • Highly Concentrated Pharmaceutical Formulations
  • Highly Concentrated Pharmaceutical Formulations

Examples

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example 1

Preparation of Highly Concentrated Liquid Formulations

[0206]Rituximab is manufactured by techniques generally known from the production of recombinant proteins. A genetically engineered Chinese hamster ovary cell line (CHO) prepared as described in U.S. Pat. No. 7,381,560 is expanded in cell culture from a master cell bank. The Rituximab monoclonal antibody is harvested from the cell culture fluid and purified using immobilized Protein A affinity chromatography, cation exchange chromatography, a filtration step to remove viral contaminations, followed by anion exchange chromatography and an ultrafiltration / diafiltration step.

[0207]rHuPH20 is manufactured by techniques generally known from the production of recombinant proteins. The process begins with thawing of cells from the working cell bank (WCB) or master cell bank (MCB) and expansion through cell culture in a series of spinner flasks. The cell culture up to 6 liters is used to provide a continuous source of cells maintained un...

example 2

Preparation of Humanized 2H7 Anti-CD20 Liquid Formulations

[0226]For the preparation of the liquid formulations, recombinant humanized 2H7 anti-CD20 antibody (2H7.v16 as disclosed in WO 2006 / 084264) was buffer exchanged against a diafiltration buffer containing the anticipated buffer composition and where required, concentrated to an antibody concentration of approx. 60 and 120 mg / ml. After achieving the target concentration, the excipients (e.g. trehalose, rHuPH20, polysorbate 20) were then added as stock solutions to the antibody solution. Finally the protein concentration was adjusted with the final formulation buffer to a humanized 2H7 concentration of approx. 30, 50, and 100 mg / ml.

[0227]All formulations were sterile-filtered through 0.22 μm low protein binding filters and aseptically filled into sterile 3 ml glass vials stoppered with fluoro-resin laminated butyl rubber stoppers and capped with aluminum / plastic flip-off seals. The fill volume was approx. 1.2 ml. These formulatio...

example 3

Treatment of Patients with the Formulation

[0239]Rituximab-containing regimens have become the standard of care for patients suffering from various CD20-positive B-cell malignancies. Currently, rituximab is administered as an intravenous (IV) infusion over several hours. These long infusion times and the side effects related to the infusion were cited by some patients as uncomfortable consequences of the current therapeutic treatment. Furthermore, the required procedure to establish intravenous access is considered invasive and can be painful, particularly in patients with malignant diseases who are treated repeatedly. Subcutaneous (SC) administration could significantly simplify treatment, shortening administration to less than 10 minutes and improving patient experience. Recombinant human hyaluronidase (rHuPH20) has been developed and approved to improve dispersion and absorption of co-administered drugs. It has been combined with rituximab to allow injection volumes larger than 10...

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Abstract

The present invention relates to a highly concentrated, stable pharmaceutical formulation of a pharmaceutically active anti-CD20 antibody, such as e.g. Rituximab, Ocrelizumab, or HuMab<CD20>, or a mixture of such antibody molecules for subcutaneous injection. In particular, the present invention relates to formulations comprising, in addition to a suitable amount of the anti-CD20 antibody, an effective amount of at least one hyaluronidase enzyme as a combined formulation or for use in form of a co-formulation. The said formulations comprise additionally at least one buffering agent, such as e.g. a histidine buffer, a stabilizer or a mixture of two or more stabilizers (e.g. a saccharide, such as e.g. α,α-trehalose dihydrate or sucrose, and optionally methionine as a second stabilizer), a nonionic surfactant and an effective amount of at least one hyaluronidase enzyme. Methods for preparing such formulations and their uses thereof are also provided.

Description

[0001]The present invention relates to highly concentrated, stable pharmaceutical formulations of a pharmaceutically active anti-CD20 antibody or a mixture of such antibody molecules for subcutaneous injection. Such formulations comprise, in addition to the high amounts of anti-CD20 antibody or mixture thereof, a buffering agent, a stabilizer or a mixture of two ore more stabilizing agents, a nonionic surfactant and an effective amount of at least one hyaluronidase enzyme. The invention also relates to a process for the preparation of the formulation and to the uses of such formulation.BACKGROUND OF THE INVENTION[0002]The pharmaceutical use of antibodies has increased over the past years. In many instances such antibodies are either injected or infused via the intravenous (IV) route. Unfortunately the amount of antibody that can be administered via the intravenous route is limited by the physico-chemical properties of the antibody, in particularly by its solubility and stability in ...

Claims

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Application Information

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IPC IPC(8): A61K39/395A61P35/00
CPCA61K9/0019A61K47/22A61K47/10A61K47/183A61K47/26C07K2317/24C07K2317/21C07K16/2887A61K2039/505C07K2317/94A61K47/20A61K45/06A61K39/3955A61K38/47A61K9/19A61K47/42C07K16/3061C07K2317/734A61P35/00A61P37/02A61P43/00A61K39/39591A61K9/0021A61K47/12A61K2039/54A61K2300/00
Inventor ADLER, MICHAELMAHLER, HANNS-CHRISTIANSTAUCH, OLIVER BORIS
Owner GENENTECH INC
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