Alkoxylation methods
Inventors
Kozlowski, Antoni • McManus, Samuel P. • Tipnis, Sachin • Lavaty, Greg • Swallow, David • Handley, John R. • Schaefer, Anthony G.
Assignees
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Publication Number
US-11834553-B2
Publication Date
2023-12-05
Expiration Date
Abstract
Among other aspects, provided herein is a mixed-acid salt of a water-soluble polymer-drug conjugate, along with related methods of making and using the same. The mixed-salt acid salt is stably formed, and appears to be more resistant to hydrolytic degradation than the corresponding predominantly pure acid salt or free base forms of the polymer-drug conjugate. The mixed acid salt is reproducibly prepared and recovered, and provides surprising advantages over non-mixed acid salt forms of the water-soluble polymer drug conjugate.
Core Innovation
The invention relates to a method of preparing a highly pure reactive multi-armed polyethylene glycol reagent suitable for use in preparing a pharmaceutical conjugate. The method starts by providing a previously isolated alkoxylatable oligomer having a specified weight average molecular weight range and substantially the same value of each n. The alkoxylatable oligomer is then alkoxylated in an aprotic, substantially anhydrous organic solvent in the presence of a strong base, using sequential addition of oxirane (ethylene oxide) under anhydrous liquid phase conditions of less than 20 ppm water to form an alkoxylated polymeric product having a specified weight-average molecular weight range.
The recovered alkoxylated polymeric product has a purity of greater than 92 weight percent, and in some embodiments greater than 97 weight percent. The invention further includes transforming the recovered alkoxylated polymeric product to bear reactive groups suitable for conjugation with a biologically active agent, thereby forming a reactive water-soluble multi-armed polyethylene glycol reagent. Dependent content further refines the process parameters, solvent selection, purity threshold, and the reactive-group functionality for conjugation.
The described downstream use is pharmaceutical conjugate preparation using the reactive multi-armed PEG reagent, including formation of conjugates with biologically active agents. In particular embodiments described in the provided content, the conjugates include multi-armed structures and mixed acid salt species, where basic nitrogen atoms can be neutral or protonated, with corresponding inorganic strong acid conjugate base and organic strong acid conjugate base counterions.
Claims Coverage
The provided content includes one independent claim defining the overall method and its core constraints. Dependent claims refine the process parameters, solvent selection, purity threshold, and the reactive-group functionality for conjugation.
Highly pure reactive multi-armed PEG reagent preparation for pharmaceutical conjugates
A method of preparing a highly pure reactive water-soluble multi-armed polyethylene glycol reagent suitable for use in preparing a pharmaceutical conjugate by providing a previously isolated alkoxylatable oligomer with a specified weight average molecular weight range and substantially the same value of each n, alkoxylating in an aprotic, substantially anhydrous organic solvent with a strong base and sequential addition of oxirane (ethylene oxide) under anhydrous liquid phase conditions of less than 20 ppm water to form an alkoxylated polymeric product with a specified weight-average molecular weight range, recovering the alkoxylated polymeric product having purity greater than 92 weight percent, and transforming the recovered alkoxylated polymeric product to bear reactive groups suitable for conjugation with a biologically active agent.
Constrained isolated alkoxylatable oligomer molecular weight for the method
the method uses an isolated alkoxylatable oligomer with a weight-average molecular weight between 500 daltons and 3,000 daltons.
Alkoxylation temperature constraint
the alkoxylating step is performed at a temperature between 50°C and 200°C.
Selected aprotic substantially anhydrous organic solvent options
the aprotic, substantially anhydrous organic solvent is selected from toluene, xylene, mesitylene, tetrahydrofuran (THF), or mixtures thereof.
Higher product purity threshold for recovered alkoxylated polymeric product
the recovered alkoxylated polymeric product has a purity greater than 97 weight percent.
Reactive multi-armed PEG reagent with N-hydroxysuccinimidyl ester reactive groups
a reactive multi-armed polyethylene glycol reagent contains reactive N-hydroxysuccinimidyl ester groups.
Coverage centers on an alkoxylation-to-purity-controlled recovery route for producing a highly pure multi-armed PEG polymer reagent, followed by transformation to introduce conjugation-ready reactive groups for biologically active agents. Dependent refinements further constrain starting oligomer molecular weight, alkoxylation conditions, named aprotic substantially anhydrous solvents, tightened purity thresholds, and specific reactive-group types such as N-hydroxysuccinimidyl ester groups.
Stated Advantages
Improved stability to hydrolysis compared with free base or single-salt forms.
Consistent lot-to-lot salt ratios.
Preservation of stereochemistry at irinotecan C-20 upon conjugation.
Produces a recovered alkoxylated polymeric product with a purity greater than 92 weight percent.
Produces a highly pure reactive multi-armed polyethylene glycol reagent suitable for use in preparing a pharmaceutical conjugate.
Enables transformation to bear reactive groups suitable for conjugation with a biologically active agent.
Documented Applications
Pharmaceutical conjugate preparation using the reactive water-soluble multi-armed polyethylene glycol reagent.
Drug conjugates involving camptothecin and SN-38/irinotecan, with irinotecan C-20 stereochemistry preserved upon conjugation.
Forming multi-armed conjugate structures with biologically active agents, including embodiments described as mixed acid salt species with neutral/protonated basic nitrogen atoms and counterion types.
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