Polymeric benzyl carbonate-derivatives
Inventors
Yang, Guohan • Hai, Ton That • Melnick, Bennett • Sanders, Paul • Jiang, Cong • Quinn, Catherine • Li, Jie • Ambroise, Arounaguiry • Brown, Larry R.
Assignees
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Publication Number
US-8962549-B2
Publication Date
2015-02-24
Expiration Date
Abstract
The present invention relates to polymeric derivatives, which can be conjugated to an amino-containing drug to improve its in vivo properties. The polymeric derivative can subsequently be released to yield the drug in its native form. Methods of preparing and using these polymeric derivatives and drug conjugates are described.
Core Innovation
The invention relates to a method for treating a blood clotting disease in a patient by administering a pharmaceutical formulation comprising a pharmaceutically acceptable excipient and a drug conjugate of Formula II. The conjugates are polymeric drug conjugates derived from benzyl carbonate, in which water-soluble, non-peptidic polymer conjugates form carbamate-linked conjugates of Formula I/II. In Formula II, X is selected from O, S and NR3, n is 1 or 2, and the DRUG is a plasma protein or blood coagulation factor, or a pharmaceutically acceptable salt, ester, or solvate thereof.
The disclosure defines POLYMER as a water soluble, non-peptidic polymer different from poly(alkylene glycol), or as a poly(alkylene) glycol, depending on the claim. The structure further includes variables R1, R2, R3, and an activating group Y that is releasable. The patent describes PEGylated and functionalized intermediates used to produce drug-conjugates, including carbonyloxy/activated PEG derivatives, and confirms them by NMR and mass-spectral characterization to verify expected polymer end-group changes.
A release mechanism is described in which the native amino-containing drug is released from the polymeric derivative. The release is characterized as a multi-step mechanism associated with the benzyl carbonate-derived structure and the releasable activating group Y, and the document also states a rate-tuning concept via ester hydrolysis rather than carbamate hydrolysis. The disclosure further describes hydrolysis cleavage at pH 7–8 with rapid elimination/decarboxylation, providing increased half-life/solubility, reduced proteolysis, and regained drug activity upon release [procedural detail omitted for safety].
Claims Coverage
The document includes two independent claims, each directed to administering a pharmaceutical formulation comprising a pharmaceutically acceptable excipient and a drug conjugate of Formula II for treating a blood clotting disease. The inventive features differ primarily in the POLYMER definition and the restrictions on R1, while both claims share the same Formula II variable set and DRUG selection constraints.
Treating a blood clotting disease with a Formula II drug conjugate
Administering to a patient a pharmaceutical formulation comprising a pharmaceutically acceptable excipient and a drug conjugate of Formula II, wherein X is selected from O, S and NR3; n is 1 or 2; POLYMER is a water soluble, non-peptidic polymer different from poly(alkylene glycol); R1 and R2 are independently selected from hydrogen, (C1-C6)-alkyl, (C1-C6)-alkylenearyl, and aryl with the proviso that at least one of R1 and R2 is different from hydrogen; R3 is selected from hydrogen, (C1-C6)-alkyl, (C1-C6)-alkylenearyl, and aryl; DRUG is plasma protein or blood coagulation factor, or a pharmaceutically acceptable salt, ester, or solvate thereof; and wherein the disease is a blood clotting disease.
Poly(alkylene) glycol variant of Formula II
Administering to a patient a pharmaceutical formulation comprising a pharmaceutically acceptable excipient and a drug conjugate of Formula II, wherein X is selected from O, S and NR3; n is 1 or 2; POLYMER is a poly(alkylene) glycol; R1 is hydrogen; R2 is selected from (C1-C6)-alkyl, (C1-C6)-alkylenearyl, and aryl; R3 is selected from hydrogen, (C1-C6)-alkyl, (C1-C6)-alkylenearyl, and aryl; DRUG is plasma protein or blood coagulation factor, or a pharmaceutically acceptable salt, ester, or solvate thereof; and wherein the disease is a blood clotting disease.
Across the independent claims, the core claim coverage is directed to treating a blood clotting disease via administration of a pharmaceutical formulation containing a drug conjugate of Formula II with defined choices for X, n, POLYMER, and substituents R1/R2/R3, together with DRUG selection limited to plasma proteins or blood coagulation factors (or their salts/esters/solvates). The main structural divergence between the independent claims is the definition of POLYMER and the restriction that R1 is hydrogen in the poly(alkylene) glycol variant.
Stated Advantages
Increased half-life/solubility of the conjugate/disclosed polymeric drug conjugates.
Reduced proteolysis.
Regained drug activity upon release.
Documented Applications
Use of the method to treat a blood clotting disease in a patient by administering a pharmaceutical formulation comprising a pharmaceutically acceptable excipient and a drug conjugate of Formula II.
Use with DRUG selected from erythropoietin, Factor H, Factor VIII, von Willebrand Factor, Factor VIIa, or Factor IX (blood clotting disease context).
Use where the formulation is encapsulated in a microparticle (as a further constraint of the method).
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