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Publication Number
US-10016411-B2
Publication Date
2018-07-10
Expiration Date
Abstract
Conjugates of SN-38 that provide optimal drug release rates and minimize the formation of the corresponding glucuronate are described. The conjugates release SN-38 from a polyethylene glycol through a β-elimination mechanism.
Core Innovation
The invention relates to slow-release SN-38 conjugates linked to PEG by a non-enzymatic β-elimination mechanism. The disclosed aim is to optimize drug release rates while minimizing SN-38 glucuronide (SN-38G) formation, and the disclosure provides conjugate structural formula parameters and release targets directed to a long release half-life profile.
The conjugates are described with broad formula parameters for PEG molecular weight and structural indices, including PEG MW 20,000–60,000 Da with m=1–6 and n=200–250, together with substituent definitions for R1 and an electron-withdrawing substituent Y, such as CONEt2. The description includes in vitro and in vivo kinetics and pharmacokinetic modeling intended to support the slow-release behavior and low SN-38G exposure.
The disclosure further states that improved solubility is achieved via an amide linkage to PEG compared to earlier cycloaddition/amide-less connections, and that stability is maintained across pH 4–8. Release half-life targets are described, including ranges around ~100–1000 h with preferred values such as ~300–500 h and ~400–500 h, and the document reports low SN-38G levels at Cmax, including SN-38G/SN-38 ≤0.1.
Claims Coverage
The independent claim defines a conjugate by its structural formula with two key parameter ranges, with additional dependent claims that narrow parameters and constrain downstream use as a pharmaceutical formulation.
Conjugate formula with m and n ranges
A conjugate having the formula wherein m = 1-6 and n is 200-250.
Fixed m parameter for the conjugate
The conjugate wherein m is set to 1.
Pharmaceutical formulation with excipient
A pharmaceutical formulation comprising a conjugate of the preceding claim together with a pharmaceutically acceptable excipient.
Formulation pH range 4.0 to 6.0
The formulation wherein the pH of the formulation is between 4.0 and 6.0.
Overall, the claim set is centered on a PEG-linked SN-38 conjugate defined by a structural formula with m = 1–6 and n = 200–250, narrowed by setting m = 1 in a dependent claim, and then scoped further to pharmaceutical formulations containing pharmaceutically acceptable excipients under a pH range of 4.0–6.0.
Stated Advantages
Optimize drug release rates.
Minimize SN-38G (SN-38 glucuronide) formation.
Improved solubility via an amide linkage to PEG compared to earlier cycloaddition/amide-less connections.
Low SN-38G levels at Cmax (SN-38G/SN-38 ≤0.1).
Stability across pH 4–8.
Documented Applications
Formulation of the conjugate as a pharmaceutical formulation together with a pharmaceutically acceptable excipient, with a pH between 4.0 and 6.0.
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