Bioerodible implant for long-term drug delivery and associated methods of manufacture and use
Inventors
BAILLIE, John H. • BAILLIE, Ruth • Blouin, George • Farahani, Newsha • MARX, Christopher
Assignees
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Publication Number
US-11833244-B2
Publication Date
2023-12-05
Expiration Date
Abstract
A drug delivery system is provided in the form of a controlled release, bioerodible pellet for subdermal implantation. The pellet is bioerodible, and provides for the sustained release of a pharmacologically active agent over an extended time period. As such, the drug delivery system finds significant utility in chronic drug administration. Bioerosion products are water soluble, bioresorbed, or both, obviating the need for surgical removal of the implant. Methods for manufacturing and using the drug delivery system are also provided.
Core Innovation
The invention relates to a method for administering an active agent to a subject in a controlled release manner by subdermally implanting a bioerodible pellet that provides controlled release of the active agent throughout an extended drug delivery time period. The pellet gradually bioerodes in situ and results in a serum level of the active agent sufficient to achieve therapeutic efficacy during the extended drug delivery time period. The method allows the pellet to remain in place throughout the extended drug delivery time period without requiring removal during that time.
The bioerodible pellet is an elongated dosage form with a non-polymeric inner core and a non-polymeric outer shell enclosing the inner core along its length but not the first end or the second end, such that the inner core has exposed surface area at the ends. The inner core and outer shell include a lipidic excipient composition having a first lipidic excipient and a second lipidic excipient with aqueous solubilities that differ by at least 10%. The active agent is distributed between the inner core and the outer shell according to specified wt.% relationships.
The active agent distribution requirement states that at least about 80 wt.% of the active agent is present in the core, at least about 80 wt.% is present in the shell, or the core and the shell each contain at least about 20 wt.% of the active agent. The extended drug delivery time period includes an effective drug delivery time period followed by a sub-effective drug delivery tail period, and the release can be substantially constant throughout the effective drug delivery time period for core-type pellets. The document also describes multiple pharmacologically active agents and relates pellet properties to pharmacokinetic profile changes.
Claims Coverage
The independent claim covers administering an active agent by subdermally implanting an elongated bioerodible pellet that gradually bioerodes to achieve therapeutic efficacy serum levels over an extended drug delivery time period, using a specific inner-core/outer-shell architecture and lipidic excipient solubility-difference distribution of the active agent. Dependent claims add further constraints to the extended-time structure, excipient selection, lipid ratio, release-rate behavior, and pharmacokinetic profile determination by pellet properties.
Subdermal implantation of bioerodible pellet for extended controlled release
Subdermally implanting into the subject a drug delivery system comprising a pellet that is bioerodible in situ and provides for controlled release of an active agent contained therein throughout an extended drug delivery time period; allowing the pellet to remain in place throughout the extended drug delivery time period, such that following subdermal implantation the pellet gradually bioerodes and results in a serum level of the active agent sufficient to achieve therapeutic efficacy during the extended drug delivery time period.
Elongated core-and-shell non-polymeric architecture with exposed core ends
Providing the pellet as an elongated dosage form with a first region comprising a non-polymeric inner core and a second region comprising a non-polymeric outer shell enclosing the surface of the inner core along its length but not the first end or the second end, such that the inner core has exposed surface area at the first and second ends.
Lipidic excipient composition with aqueous solubility difference of at least 10%
Comprising an inner core and outer shell comprised of a lipidic excipient composition including a first lipidic excipient and a second lipidic excipient having aqueous solubilities that differ by at least 10%.
Active agent distributed across core and shell by specified wt.% loading
Having active agent distribution such that at least about 80 wt.% of the active agent is present in the core, at least about 80 wt.% of the active agent is present in the shell, or the core and the shell each contain at least about 20 wt.% of the active agent.
Effective period followed by sub-effective tail period during extended time
Defining the extended drug delivery time period to include an effective drug delivery time period in which dosing provides therapeutic efficacy, followed by a sub-effective drug delivery tail period with continued release below that needed for therapeutic efficacy.
Substantially constant active-agent release during effective period
Releasing the active agent at a rate that is substantially constant throughout the effective drug delivery time period.
Lipidic excipient pair weight ratio constraint
Having a weight ratio of the first lipidic excipient to the second lipidic excipient in the range of about 3:1 to about 50:1.
Specific lipidic excipient selections for first and second lipidic excipients
Selecting the first lipidic excipient from cholesterol, 7-dehydrocholesterol, cholestatrienol, cholestanol, cholesteryl acetate, desmosterol, dehydroergosterol, thiocholesterol, 3-keto-delta-5-cholestene, 7-methyl-enecholesterol, epicholesterol, lathosterol, lanosterol, dihydrocholesterol, 25-hydroxycholesterol, cholestane, cholestane dial, cholest-4-en-3-one, zymosterol, and combinations thereof, and selecting the second lipidic excipient from phosphorylated diacyl glycerides.
Pharmacokinetic profile determined by pellet properties
Having a pharmacokinetic profile determined by at least one pellet property selected from width, length, diameter, surface area, size, composition, hardness, and degree of crystallinity.
Overall, the claim set centers on a subdermally implanted, bioerodible elongated pellet with a non-polymeric inner core and a non-polymeric outer shell that leaves core ends exposed, paired with a lipidic excipient composition where two excipients have aqueous solubility differences of at least 10% and the active agent is loaded across core and shell by specified wt.% thresholds. Dependent claims further refine the extended-time structure, optionally require substantially constant release during the effective period, constrain the lipidic excipient weight ratio and identify exemplary lipidic excipients, and tie pharmacokinetic profile behavior to pellet properties.
Stated Advantages
Gradually bioerodes in situ to result in a serum level of the active agent sufficient to achieve therapeutic efficacy during the extended drug delivery time period.
Provides controlled release of an active agent throughout an extended drug delivery time period while allowing the pellet to remain in place throughout that period.
Optionally provides a release rate that is substantially constant throughout the effective drug delivery time period.
Enables pharmacokinetic profiles to be determined by pellet properties selected from width, length, diameter, surface area, size, composition, hardness, and degree of crystallinity.
Documented Applications
Administering an active agent to a subject in a controlled release manner by subdermally implanting a bioerodible pellet for extended drug delivery to achieve therapeutic efficacy serum levels.
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