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Publication Number
US-10342792-B2
Publication Date
2019-07-09
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 provides PEG-based SN-38 slow-release conjugates and pharmaceutical formulations thereof for sustained low-dose exposure to a patient in need of such exposure. The disclosure focuses on conjugates of formula II defined by parameters m=1-6 and n=200-250, and includes PEG structures such as PEG molecular weight ranges of 20,000-60,000 Da and multi-armed PEG including 4-arm PEG.
A key aspect is the release of SN-38 via a non-enzymatic β-elimination mechanism from a PEG linker. The linker and substituent choices support the desired slow release behavior, and the slow release is associated with reduced formation of SN-38 glucuronide (SN-38G).
The disclosure states that very slow release yields extremely low SN-38G levels, including a reported SN-38G/SN-38 ratio of ≤0.1 at Cmax, and that release half-life targets in vivo are in the range of about 100-1000 h, with preferred ranges and examples extending to approximately 300-350 h and about 400-450 h. Formulation strategies are also described to solubilize the conjugates, with examples including PEG and DMSO, and the overall approach is presented as enabling continuous low-dose SN-38 exposure while limiting SN-38G.
Claims Coverage
The partial content identifies two independent methods. Across these independent methods, the main inventive features are administering a conjugate of formula II, with m=1-6 and n=200-250, and achieving defined exposure or control outcomes using that conjugate and pharmaceutical formulations thereof.
Continuous, low-dose SN-38 exposure by formula II conjugate administration
Administering to a patient in need of continuous, low-dose exposure a conjugate of formula II or a pharmaceutical formulation thereof, wherein m=1-6 and n is 200-250.
Control of SN-38G level using formula II conjugate with SN-38G/SN-38 limitation
Administering to a patient requiring SN-38 treatment a conjugate of formula II or a pharmaceutical formulation thereof, wherein m=1-6 and n is 200-250, wherein the resulting SN-38G/SN-38 ratio is less than 0.2.
Overall, the independent claims define methods that rely on administering a PEG-based SN-38 conjugate of formula II with defined m and n parameters, and they distinguish the therapeutic objectives: one method targets continuous, low-dose SN-38 exposure, while the other targets reducing SN-38G in plasma by imposing an SN-38G/SN-38 ratio threshold (<0.2).
Stated Advantages
Provides continuous, low-dose exposure to SN-38 to a patient in need of such exposure.
Reduces the level of SN-38 glucuronide (SN-38G) in plasma, as reflected by controlling the SN-38G/SN-38 ratio to be less than 0.2.
Documented Applications
Treatment of a patient requiring continuous, low-dose exposure to SN-38.
Treatment of a patient requiring SN-38 therapy with control of SN-38 glucuronide (SN-38G) levels in plasma.
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