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Assignees
Plumb Pharmaceuticals, Inc.Plumb Pharmaceuticals is a Madison, Wisconsin-based pharmaceutical company developing extended-release formulations of FDA-approved drugs. Its liposome-based drug delivery approach uses loading-base exchange to load compounds and is intended to support drug release over periods measured in months. Its initial product focus is an injectable naltrexone formulation for opioid and alcohol use disorder.
Plumb Pharmaceuticals is a Madison, Wisconsin-based pharmaceutical company developing extended-release formulations of FDA-approved drugs. Its liposome-based drug delivery approach uses loading-base exchange to load compounds and is intended to support drug release over periods measured in months. Its initial product focus is an injectable naltrexone formulation for opioid and alcohol use disorder.
Publication Number
US-11000478-B2
Publication Date
2021-05-11
Expiration Date
Abstract
Provided herein is technology relating to incorporation of drugs into liposomes and particularly, but not exclusively, to methods for incorporating drugs into liposomes using a weak base and related compositions.
Core Innovation
The invention provides a liposome composition comprising liposomes, a bioactive agent, and a loading base selected from a group consisting of a pyridine, a pyridine derivative, an adenine, an adenine derivative, an aniline, and an aniline derivative. The liposomes include an intraliposomal space and the liposome composition includes an extraliposomal space. The intraliposomal space includes the loading base in a charged and protonated form, and the loading base is a weaker base than the bioactive agent, with the bioactive agent different from the loading base.
In the extraliposomal space, the composition includes a loading medium having a pH greater than the pKa of the charged and protonated form of the loading base. The described framework relies on selecting a weaker-base loading base and selecting an external loading medium pH that is greater than the loading base pKa, while maintaining different intra- and extraliposomal conditions.
The described formulation principles further include using loading base pKa values lower than the bioactive agent pKa and, in some cases, using intra- and extraliposomal concentration gradients. The document associates these principles with substantially high drug loading efficiency across multiple bioactive agents and with controlled release profiles showing reduced early leakage and controlled long-term release.
Claims Coverage
The document identifies one independent claim directed to a specific liposome composition structure and chemistry, with dependent claims further defining additional formulation constraints. Across the independent claim, the inventive features center on the selection of the loading base class, the intra-/extra-liposomal placement of the loading base in charged/protonated form, and the relative strength and pH relationship to pKa in the loading medium.
Weak-base loading base in charged and protonated intraliposomal space
The intraliposomal space comprises the loading base in its charged and protonated form, wherein the loading base is a weaker base than the bioactive agent, and wherein the bioactive agent is different from the loading base.
Loading medium pH greater than loading-base pKa in extraliposomal space
An extraliposomal space comprising a loading medium having a pH that is greater than the pKa of the charged and protonated form of the loading base.
Loading base selected from pyridine, adenine, and aniline derivatives group
A loading base selected from the group consisting of a pyridine, a pyridine derivative, an adenine, an adenine derivative, an aniline, and an aniline derivative.
Liposome composition structured with intraliposomal and extraliposomal spaces
The liposomes have an intraliposomal space and the liposome composition has an extraliposomal space.
Overall claim coverage is anchored on a liposome composition where a selected weaker loading base is present in charged and protonated form inside the liposome, while the external loading medium has a pH greater than the loading base pKa. Dependent claims further add constraints such as buffer inclusion, intra-/extra concentration relationships, optional pKa thresholds, and specific selection of phosphatidylcholine and specific named loading base embodiments.
Stated Advantages
Achieves high drug loading efficiency while reducing early-phase leakage compared with ammonium sulfate gradient loading.
Provides substantially low early leakage and controlled long-term release.
In vivo rat data for buprenorphine indicate sustained therapeutic serum levels and controlled kinetics when loaded using specific weak base salts.
Documented Applications
Drug delivery using liposome compositions for bioactive agents including buprenorphine.
Loading and delivery of multiple bioactive agents including chloroquine, hydromorphone, naltrexone, buprenorphine, and doxycycline, with described loading efficiency and release behavior.
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