Cyclodextrin and antibody-drug conjugate formulations

Patent metadata

Field	Value
Publication number	US-9987374-B2
Application number	US-201715454953-A
Country	US
Kind code	B2
Filing date	Mar 9, 2017
Priority date	Mar 13, 2013
Publication date	Jun 5, 2018
Grant date	Jun 5, 2018

Abstract

Disclosed are formulations, including both liquid and lyophilized formulations, comprising a benzodiazepine antibody-drug conjugate (ADC) and a cyclodextrin. Also disclosed are methods of purifying mixtures comprising benzodiazepine antibody-drug conjugates and process drug-related impurities.

First claim

What is claimed is:

1. A liquid pharmaceutical formulation, wherein the formulation is an aqueous solution comprising:
a benzodiazepine ADC at a concentration of from about 1 mg/mL to about 3 mg/mL;
a cyclodextrin, wherein the cyclodextrin is hydroxypropyl beta cyclodextrin or sulfobutylether beta cyclodextrin at a concentration of from about 6% w/v to about 10% w/v;
a lyoprotectant, wherein the lyoprotectant is a sugar at a concentration of about 4% to about 8%;
a buffer, wherein the buffer is TRIS at a concentration of about 50 mM; and
wherein the pH of the aqueous solution is from about 7 to about 7.5.

2. The liquid pharmaceutical formulation of claim 1 , wherein the concentration of the benzodiazepine ADC within the aqueous solution is about 1 mg/mL.

3. The liquid pharmaceutical formulation of claim 1 , wherein the lyoprotectant is sucrose, wherein the concentration of sucrose within the aquesous solution is about 6% w/v.

4. The liquid pharmaceutical formulation of claim 1 , wherein, wherein the cyclodextrin is hydroxypropyl beta cyclodextrin, wherein the concentration of hydroxypropyl beta cyclodextrin within the aqueous solution is about 6% w/v.

5. The liquid pharmaceutical formulation of claim 1 wherein the aqueous solution has no more than 0.1 μM benzodiazepine drug-related impurites.

6. The liquid pharmaceutical formulation of claim 1 , wherein the aqueous solution comprises:
benzodiazepine ADC at a concentration of about 1 mg/mL or about 3 mg/mL;
hydroxypropyl beta cyclodextrin at a concentration of about 6% w/v;
sucrose as the lyoprotectant at a concentration of about 6% w/v; and
TRIS buffer at a concentration of about 50 mM;
wherein the pH of the aqueous solution is about 7.3; and
wherein the aqueous solution has no more than 0.1 μM benzodiazepine drug-related impurites.

7. The liquid pharmaceutical formulation of claim 6 wherein the benzodiazepine ADC is a monoclonal antibody conjugated to a pyrrolobenzodiazepine dimer, an indolinobenzodiazepine dimer or an oxazolidinobenzodiazepine.

8. The liquid pharmaceutical formulation of claim 7 wherein the benzodiazepine ADC is a monoclonal antibody conjugated to a pyrrolobenzodiazepine dimer and the benzodiazepine ADC is as follows:

or a pharmaceutically acceptable salt thereof; wherein Ab is the monoclonal antibody and p represents the average number of drug-linker molecules in parentheses per antibody in the formulation and is about 2.

9. The liquid pharmaceutical formulation of claim 8 wherein the monoclonal antibody component of the benzodiazepine ADC is a monoclonal antibody that is capable of specifically binding to an extracellular domain of a cancer cell antigen that is expressed on the surface of a cancer cell.

10. A lyophilized pharmaceutical formulation wherein the lyophilized pharmaceutical formulation is from lyophilization of the aqueous solution of claim 6 .

11. A method of preparing a pharmaceutical formulation comprising the steps of:
diafiltration of an aqueous solution comprising benzodizepine ADCs and benzodiazepine drug-related impurities,
wherein diafiltration is through eluting of the aqueous solution through an ultrafiltration membrane of suitable pore size in a tagentail flow filtration device,
wherein the aqueous solution is further comprised of:
from about 1 mg/mL to about 3 mg/mL benzodiazepine ADC;
about 1 μM benzodiazepine drug-related impurities;
from about 6% w/v to about 10% w/v hydroxypropyl beta cyclodextrin;
about 6% w/v of a lyoprotectant; and
from about 20 mM to about 50 mM TRIS buffer,

wherein the aqueous solution is buffered at pH from about 7 to about 7.5,
wherein benzodizepine drug-related impurities are reduced to a level of no more than 0.1 μM.

12. The method of claim 11 wherein the benzodiazepine drug-related impurities have a hydrophobic SlogP value of no more than 7.50 or no more than 6.5.

13. The method of preparing a pharmaceutical formulation of claim 11 further comprising the step of lyophilization of the aqueous formulation obtained subsequent to diafiltration, wherein the formulation so prepared is a pharmaceutical lyophilized formulation.

14. The method of preparing a pharmaceutical formulation of claim 13 further comprising the step of contacting the pharmaceutical lyophilized formulation with a pharmaceutically acceptable diluent so as to reconstitute an aqueous formulation having a benzodiazepine ADC concentration from about 0.6 mg/mL to about 3 mg/mL.

Assignees

• Seattle Genetics Inc

Inventors

• Li Hui
• Jiang Shan
• Wallace Mary
• Meyer Damon

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61K47/6951

  using cyclodextrin (cyclodextrins used as simple excipients A61K47/40) · CPC title

• A61K47/40

  Cyclodextrins; Derivatives thereof · CPC title

• B01D2315/10

  Cross-flow filtration · CPC title