Compositions of a polyorthoester and an aprotic solvent
Inventors
Ottoboni, Thomas B. • Girotti, Lee Ann Lynn
Assignees
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Publication Number
US-11253504-B2
Publication Date
2022-02-22
Expiration Date
Abstract
Delivery systems and compositions comprised of a biodegradable polyorthoester polymer, an aprotic solvent, and a drug are described. The solvent is selected to modulate release of drug from the composition, where, in some embodiments, the solvent is rapidly released after administration and provides a corresponding rapid rate of drug release. Alternatively, in other embodiments, the solvent is slowly released from the composition after its administration, and provides a correspondingly slow rate of drug release.
Core Innovation
The invention provides biodegradable polyorthoester delivery systems and compositions for treating or preventing pain in a subject in need thereof. The delivery system comprises a polyorthoester and dimethyl sulfoxide in which the polyorthoester is miscible to form a single phase, and bupivacaine is dispersed or solubilized in the single phase. The polyorthoester is a polyorthoester of Formula III, and the composition includes representative active agents such as granisetron, local anesthetic anesthetics including bupivacaine and ropivacaine, and buprenorphine.
The disclosed system further defines Formula III by structural parameters including A being R1 or R3, R* being C1-4 alkyl, n ranging from 5 to 1000, p and q being integers varying between about 1 to 20 with an average number of p or an average of the sum of p and q between 1 and 7, R3 and R6 each independently defined with x as an integer of 0-10, and R5 being H or methyl. The fraction of A units that are of formula R1 is between 0 and 25 mole percent.
The identity and amount of the aprotic solvent modulate solvent release and drug release kinetics, and the release behavior exhibits biphasic diffusion/biodegradation behavior. The description links polymer parameters, including molecular weight, monomer/repeat variables, and fractions of α-hydroxy-acid-containing units, to biodegradability and hydrolysis behavior, including hydrolysis at physiological pH.
Claims Coverage
The independent claims center on a pain-treatment method using a miscible single-phase dimethyl sulfoxide/polyorthoester delivery system with bupivacaine and a Formula III polyorthoester. Across the merged independent-claim features, the claims recite at least five inventive aspects: the single-phase delivery system, bupivacaine dispersed or solubilized in the single phase, Formula III structural constraints, and defined limitations on A-unit composition and polymer parameters.
Single-phase dimethyl sulfoxide-polyorthoester delivery system for pain
A delivery system comprising a polyorthoester and dimethyl sulfoxide in which the polyorthoester is miscible to form a single phase.
Bupivacaine dispersed or solubilized in the single phase
Bupivacaine is dispersed or solubilized in the single phase of the delivery system for treating or preventing pain.
Formula III polyorthoester structural parameter set
The polyorthoester is a polyorthoester of Formula III with A being R1 or R3, R* being C1-4 alkyl, n ranging from 5 to 1000, p and q being integers varying between about 1 to 20 with an average number of p or an average of the sum of p and q between 1 and 7, R3 and R6 each independently defined with x as an integer of 0-10, and R5 being H or methyl.
Fraction of A units of formula R1 limited by mole percent
The fraction of A units that are of formula R1 is between 0 and 25 mole percent.
Quantitative composition and use refinements
Dependent refinements add limits on viscosity, component weight percentages, and administration modalities including intrathecal, epidural, nerve, surgical wound, nerve block, and sensory block administration.
Overall, the claim coverage requires a miscible single-phase dimethyl sulfoxide/polyorthoester system containing bupivacaine and a Formula III polyorthoester with specified structural constraints, including the A, R*, n, p, q, R3, R6, R5, and mole-percent limitations. The additional refinements concern viscosity, component weight percentages, and local administration modalities.
Stated Advantages
The identity and amount of the aprotic solvent modulate solvent release and drug release kinetics.
The release behavior exhibits biphasic diffusion/biodegradation behavior, with drug release extending from about 1 day to about 8 weeks.
The solvent release is correlated with solvent content.
The compositions are biodegradable.
The compositions are described as hydrolyzing at physiological pH.
Prolonged release and exposure over days, as supported by in vitro release and pharmacokinetics/pharmacodynamics outcomes described in the examples.
Documented Applications
Treating or preventing pain in a subject in need thereof.
Intrathecal administration.
Epidural administration.
Surgical wound administration.
Administration at a nerve.
Nerve block.
Sensory block.
Local anesthetic formulations evaluated using pharmacokinetics in canines and pharmacodynamics in pigs, with outcomes described in the examples.
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