High-concentration monoclonal antibody formulations

Abstract

The present application discloses high-concentration monoclonal antibody formulations suitable for subcutaneous administration, e.g. via a pre-filled syringe. In particular, it discloses a formulation comprising a spray dried monoclonal antibody at a concentration of about 200 mg / mL or more suspended in a non-aqueous suspension vehicle where the viscocity of the suspension vehicle is less than about 20 centipoise. Also disclosed are: a subcutaneous administration device with the formulation therein, a method of making the formulation, a method of making an article of manufacture comprising the suspension formulation, use of the formulation in the preparation of a medicament, and a method of treating a patient with the formulation.

Description

[0001]This non-provisional application filed under 37 CFR §1.53(b), claims the benefit under 35 USC §119(e) of U.S. Provisional Application Ser. No. 61 / 649,146, filed on May 18, 2012, which is incorporated by reference in entirety.FIELD OF THE INVENTION[0002]The present invention concerns high-concentration monoclonal antibody formulations suitable for subcutaneous administration, e.g. via a pre-filled syringe. In particular, the invention concerns a formulation comprising a spray dried monoclonal antibody at a concentration of about 200mg / mL or more suspended in a non-aqueous suspension vehicle, wherein the viscocity of the suspension vehicle is less than about 20 centipoise. The invention also concerns a subcutaneous administration device with the formulation therein, a method of making the suspension formulation, a method of making an article of manufacture comprising the suspension formulation, use of the suspension formulation in the preparation of a medicament, and a method of...

AI Technical Summary

Benefits of technology

[0009]The objectives of the present study were to: (1) identify process parameters that dictate suspension performance; (2) assess the feasibility of establishing monoclonal antibody powder suspensions (i.e. >250 mg monoclonal antibody / mL) with acceptable injectability (i.e. injection force ≦20 N through 27-guage thin-walled (TW) needle) and physical suspension stability; and / or (3) understand the mechanism of suspension performance. To prepare monoclonal antibody powders, spray drying was used. Spray drying is a mature, scalable, and efficient manufacturing process. The short-term effect of spray drying on monoclonal antibody was studied at accelerated temperature. An important criterion for suspension vehicle selection was that the viscosity of the suspension vehicle be below 10 centipoise (cP). The three model suspension vehicles, propylene glycol dicaprylate / dicaprate, benzyl benzoate, and ethyl lactate, tested in this study have low viscosity and met this requirement.

Problems solved by technology

The subcutaneous route of administration that requires injections using syringes, auto-injectors, or other devices generally restricts product formulation with regards to injection volume and solution viscosity, and device functionalities in terms of injection force and time.

A potential challenge in the development of high protein concentration formulations is concentration-dependent solution viscosity.

Unfortunately, formulation scientists are constantly challenged against a conflicting reality with high monoclonal antibody concentration and high solution viscosity (Shire et al., J Pharm Sci 93:1390-1402 (2004); Kanai et al., J Pharm Sci 97:4219-4227 (2005)).

Another challenge with liquid formulations at high monoclonal antibody concentration is protein physical stability.

However, the effectiveness of these approaches may be limited at monoclonal antibody concentration beyond 100 mg / mL or due to specific characteristics of certain monoclonal antibodies.

This approach can certainly improve the protein stability in the solid state during the entire shelf life, however the high viscosity issue still remains because the spray dried monoclonal antibody powder needs to be reconstituted at high monoclonal antibody concentration prior to injection.

However, no viscosity or injection force data were presented in these references and this concept remained speculative.

Furthermore, monoclonal antibody crystallization is not yet a mature process platform applicable to a wide range of monoclonal antibodies although some successful examples have been presented (Trilisky et al., “Crystallization and liquid-liquid phase separation of monoclonal antibodies and Fc-fusion proteins: Screening results,” AICHE online publication DOI 10, 1002 / btrp.621 (published by Wiley Online Library) (2011)).

Tn addition, the oil vehicles used by Pena et al. were too viscous to be considered for use in pre-filled syringe administration.

In addition, Pena et al. determined the suspension performance of spray dried powder was inferior to lyophilized counterpart.

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