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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-9931298-B2
Publication Date
2018-04-03
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 disclosed invention relates to producing liposomes by forming a lipid solution in a C3 or C4 alcohol solvent and then adding an aqueous solution containing an encapsulant to produce liposomes. The approach defines the use of lipids dissolved in a C3/C4 alcohol, followed by addition of an aqueous encapsulant solution to form the liposomal system with the encapsulant present in the intraliposomal space.
The disclosure emphasizes encapsulant selection and composition/system relationships to improve drug loading and reduce early leakage or release. It contrasts the weak-base/weak-base-salt loading approach with ammonium sulfate gradient loading and passive aqueous capture, associating differences in release behavior with counterion effects and with weak base exchange and sacrificial leakage agent concepts driven by pKa and logP relationships.
The partial content also describes documented liposome loading outcomes for multiple drugs, including chloroquine, hydromorphone, naltrexone, buprenorphine, and doxycycline. It includes discussion of reduced early release in serum for buprenorphine after single injection in rats and indicates that counterions such as sulfate/eprodisate are associated with low release while other counterions such as chloride/nitrate are associated with higher release, tied to controlled release and leakage/release rate behavior.
Claims Coverage
The partial content identifies one independent claim directed to a method of producing liposomes using a solvent-selected lipid dissolution step and an aqueous encapsulant addition step. Dependent claims further narrow the solvent, lipid processing conditions, mixing method, cooling relative to phase transition temperature, aqueous acidity/basicity, and encapsulant salt selection.
C3 or C4 alcohol lipid dissolution followed by aqueous encapsulant addition
A method of producing liposomes comprising dissolving lipids in a solvent selected from C3 and C4 alcohols to produce a lipid solution, and adding an aqueous solution comprising an encapsulant dissolved therein to produce liposomes.
Warming lipids and solvent for dissolving
The method further specifies dissolving by warming the lipids and solvent to 40 to 85°C.
Injecting aqueous encapsulant solution into a vessel containing dissolved lipids
A method where an aqueous solution containing an encapsulant is injected into a vessel containing the dissolved lipid composition.
Cooling liposomes below lipid phase transition temperature
The method further includes cooling the liposomes to a temperature below the phase transition temperature of the lipids.
Aqueous solution characterized as acidic or basic
The method of claim 1 is specified to use an aqueous solution that is either acidic or basic.
Weak base salt encapsulant selection including sulfate, eprodisate, and edisylate salts
The method is characterized by using a weak base salt selected from sulfate salt, eprodisate salt, and edisylate salt.
Across the independent claim and its dependent refinements shown in the partial content, the key claim coverage centers on producing liposomes by dissolving lipids in a selected C3/C4 alcohol solvent and forming liposomes by adding an encapsulant-containing aqueous solution, with further limitations on processing conditions, mixing by injection, post-cooling relative to phase transition temperature, aqueous acidity/basicity, and weak-base-salt encapsulant selection (including sulfate, eprodisate, and edisylate).
Stated Advantages
Achieves high drug encapsulation efficiency (including for chloroquine, hydromorphone, naltrexone, and buprenorphine, as described in the partial content).
Reduces early leakage/release compared with ammonium sulfate gradient loading and passive aqueous capture, as described for release behavior and serum profiles.
Provides controlled release behavior influenced by counterion selection, with sulfate/eprodisate associated with low release and chloride/nitrate associated with higher release, as described in the partial content.
Shows prolonged therapeutically significant concentrations in serum after single injection for buprenorphine in rats, with reduced peak/early release for certain counterions, as described in the partial content.
Documented Applications
Liposomal formulations used for drug loading and controlled release performance, with in vivo rat serum profiling described for buprenorphine after single injection.
Use of different weak base salts and counterions to modulate leakage/release rate in liposomal drug delivery, including examples involving chloroquine, hydromorphone, naltrexone, buprenorphine, and doxycycline as described in the partial content.
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