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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-12059499-B2
Publication Date
2024-08-13
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 relates to preparing liposomes encapsulating a bioactive agent using a loading base located in an intraliposomal space. A composition comprising liposomes is provided in which the liposomes comprise a loading base in the intraliposomal space, and a bioactive agent is added to the composition. The charged and protonated form of the loading base has a pKa that is lower than the pKa of the bioactive agent, and the loading base is selected from pyridine or a pyridine derivative, a pyridinium, a 2-methoxy-pyridinium, or a pyridazinium.
The relationship between pKa values is used to control the encapsulation and retention behavior of the bioactive agent within the liposomes. Additional embodiments include a loading medium in the extraliposomal space having a pH greater than the pKa of the bioactive agent. Other embodiments select the loading base based on a comparative physicochemical criterion using (log P − pKa) values for the loading base relative to the bioactive agent.
The disclosed technology is reported to achieve high encapsulation/loading efficiency and to markedly reduce early-phase leakage compared with ammonium sulfate gradient loading. The document attributes the reduced early-phase leakage to weak bases acting as sacrificial leakage agents. The disclosure further describes pharmaceutical compositions and therapeutic use for pain reduction, and includes examples and comparisons involving different counterions and drug embodiments including buprenorphine.
Claims Coverage
The partial claims content includes one independent claim. Across the independent claim and its dependent refinements, the coverage centers on selecting a specific intraliposomal loading base class and enforcing pKa and related physicochemical relationships between the loading base and the bioactive agent.
Using an intraliposomal loading base with a lower pKa than the bioactive agent
A method comprising providing liposomes comprising a loading base in an intraliposomal space and adding a bioactive agent, where the charged and protonated form of the loading base has a pKa lower than the pKa of the bioactive agent.
Selecting the loading base from specified pyridine/pyridinium classes
The method where the loading base is selected from pyridine or pyridine derivative, a pyridinium, a 2-methoxy-pyridinium, or a pyridazinium.
Extraliposomal loading medium pH greater than bioactive agent pKa
Providing a loading medium in the extraliposomal space having a pH greater than the pKa of the bioactive agent.
Comparing (log P − pKa) of loading base to bioactive agent
Carrying out the method such that the (log P − pKa) of the loading base is greater than the (log P − pKa) of the bioactive agent.
The claim set covers liposome preparation for encapsulating a bioactive agent by combining an intraliposomal loading base chosen from specified pyridine/pyridinium types with a required pKa ordering relative to the bioactive agent, with optional constraints on extraliposomal pH and on comparative (log P − pKa) selection.
Stated Advantages
High encapsulation/loading efficiency.
Markedly reduced early-phase leakage.
Reduced peak concentrations in vivo for eprodisate-loaded systems with sustained serum concentration levels for buprenorphine.
Therapeutic use for pain reduction.
Documented Applications
Pain reduction using pharmaceutical compositions containing the described liposome-encapsulated bioactive agents, including buprenorphine.
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