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Pharmaceutical formulation

A preparation and liquid preparation technology, applied in the field of pharmaceutical preparations, can solve problems such as reduced antibody activity, blockage, and hindrance to the proper administration of pharmaceutical preparations

Pending Publication Date: 2018-11-23
UCB PHARMA SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Firstly, aggregate formation can lead to reduced or no longer active antibody activity; aggregates can elicit an unwanted and unexpected immune response after administration, and finally aggregates can prevent proper administration of a pharmaceutical formulation, for example, by clogging a syringe or Pump

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0127] Example 1: Hydroxypropyl-γ-cyclodextrin (HPGCD) Screening

[0128] Stability and the propensity to precipitate in the formulation are greatly influenced by the concentration (steric crowding) and excipients used in the formulation, which control the interactions observed due to steric crowding.

[0129] To determine whether HPGCD has an effect on precipitation characteristics at physiological pH, a base formulation of romosumumab at a concentration of 120 mg / ml (pi 6.9) with and without HPGCD was run through the pH shift model.

[0130] A pH shift model was designed to replicate the pH shift that occurs when a drug-containing formulation is administered by subcutaneous injection (Elena García-Fruitós, Insoluble Proteins: Methods and Protocols, Methods in Molecular Biology, Vol. 1258, Chapter 18: 321-330, Springer Science+Business Media New York (2015)). Biotherapeutic proteins, especially antibodies, are typically formulated at physiological pH (~pH 7.0). If the pi ...

Embodiment 2

[0141] Example 2: Methionine Screening

[0142] Once the effect of HPGCD on the precipitation characteristics of the basic romoxomab formulation of Example 1 was assessed, the effect of methionine was investigated.

[0143] To determine whether methionine has an effect on precipitation characteristics at physiological pH, the pH shift model was run with (55 mM and 200 mM) and without methionine at a concentration of 90 mg / ml (control only ), 120 mg / mL or 180 mg / ml romoxomab base formulation (pI 6.9).

[0144] Romoxomab in 50 mM sodium acetate, 14 mM calcium acetate, 6% sucrose, 0.006% polysorbate 20 (pH 5.2) (drug solution, DS) was concentrated to 125 mg / ml using a 30 kDa Sartorius Viva Spin centrifugal spin filter. ml or to 190mg / ml. Spin tubes were centrifuged at 3000 rpm, 5°C for < 60 minutes; samples were mixed between spin cycles using positive displacement pipettes.

[0145] The required amount of methionine (0.018 g and 0.0066 g, respectively) to produce 2.2 mL of sa...

Embodiment 3

[0158] Example 3: Combination of HPGCD and Methionine Screening

[0159] Once the effect of HPGCD alone or methionine alone on the precipitation characteristics of the basic romoxomab formulation of Example 1 was assessed, the combined effect of HPGCD and methionine was investigated.

[0160] Romoxomab was concentrated to 125 mg in 50 mM sodium acetate, 14 mM calcium acetate, 6% sucrose, 0.006% polysorbate 20 (pH 5.2) (drug solution, DS) using a 30 kDa Sartorius Viva Spin centrifugal spin filter / ml or to 190mg / ml. Spin tubes were centrifuged at 3000 rpm, 5°C for < 60 minutes; samples were mixed between spin cycles using positive displacement pipettes.

[0161] The amount of methionine (0.018 g and 0.066 g, respectively) required to produce 2.2 mL of sample with the desired concentration (55 and 200 mM) was weighed using an analytical balance. Dissolve methionine in 2.2 mL of the appropriate protein solution (125 mg / ml or 190 mg / ml). The required amount (0.053 g) of HPGCD...

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Abstract

The invention relates to a liquid pharmaceutical formulation comprising an antibody or antigen- binding fragment thereof, cyclodextrin and methionine. In addition, it relates to a method for reducingprecipitation of an antibody or an antigen-binding fragment thereof in a liquid pharmaceutical formulation through addition of methionine and cyclodextrin. In particular, the liquid pharmaceutical formulations comprises an anti-sclerostin antibody, hydroxypropyl-gamma cyclodextrin and methionine and may be used in the treatment of a bone disorder associated with at least one of low bone formation,low bone mineral density, low bone mineral content, low bone mass, low bone quality and low bone strength, and especially for treating osteoporosis. Furthermore, the invention relates to a method ofreducing inflammation at injection site in a mammalian subject comprising administering a therapeutically effective amount of a liquid pharmaceutical formulation comprising an antibody or antigen-binding fragment thereof, cyclodextrin and methionine.

Description

field of invention [0001] The invention belongs to the field of pharmaceutical preparations. More specifically, it relates to pharmaceutical formulations comprising antibodies, cyclodextrins and methionine. Background of the invention [0002] Antibodies are large, complex molecules and inherently exhibit chemical and physical instability when stored at high concentrations for a period of time. Typical chemical instability can result in deamidation, hydrolysis, oxidation, β-elimination or disulfide bond exchange. Physical instability can lead to denaturation, aggregation or precipitation. [0003] Antibodies can be formulated in lyophilized, ie, lyophilized form, for reconstitution in solvent shortly before administration. Freeze-dried antibody formulations tend to be more stable than liquid water-based formulations, since water is or facilitates the transfer of reactants and is therefore critical to chemical degradation and protein instability. Although less stable, liq...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395A61K9/00C07K16/22A61K47/18A61K9/08A61K47/40
CPCA61K39/39591A61K9/08A61K9/0019A61K47/40A61K47/20A61P19/10A61P19/08A61P29/00C07K16/22A61K2039/54C07K2317/565C07K2317/56C07K2317/24A61P43/00A61K47/183
Inventor A·J·耶茨J·G·克利普斯通
Owner UCB PHARMA SA
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