Compositions of a polyorthoester and an aprotic solvent
Inventors
Ottoboni, Thomas B. • Schillinger, Lee Ann Lynn
Assignees
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Publication Number
US-9913909-B2
Publication Date
2018-03-13
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 disclosure relates to biodegradable polyorthoester-based delivery systems and compositions that include a polyorthoester of Formula III and an aprotic solvent miscible with the polymer so that the delivery system is formed as a single phase. The delivery system further contains a local amide- or anilide-type anesthetic dispersed or solubilized in the single phase. The aprotic solvent is selected from dimethyl sulfoxide, dimethyl acetamide, and N-methyl pyrrolidone.
The delivery system is defined by specified solvent selection and polymer composition parameters, including the amount of the aprotic solvent and the amount of the polyorthoester. The polyorthoester structure is described using Formula III, with A as R1 or R3, R* as C1-4 alkyl, n from 5 to 1000, and the fraction of A units that are of formula R1 between 10-25 mole percent. The disclosure states that the polymer structure and composition are linked to bioerodibility via hydrolysis at physiological pH.
The disclosure describes that the aprotic solvent and/or drug diffusion-controlled early release and polymer erosion-controlled later release can provide biphasic release kinetics. Release behavior is described using in vitro and in vivo-type release/plasma profiles, and the polyorthoester-based delivery system is associated with therapeutically active agents including granisetron and anesthetics such as ropivacaine and bupivacaine.
Claims Coverage
The provided claim set includes two independent claims and related claim language. Across these claims, the inventive content is centered on a delivery system defined by a polyorthoester of Formula III, a miscible aprotic solvent forming a single phase, and a local amide- or anilide-type anesthetic dispersed or solubilized in that single phase, with explicit compositional constraints and a pain-treatment method.
Single-phase polyorthoester delivery system with Formula III
A delivery system comprises a polyorthoester of Formula III with defined structural variables, including A as R1 or R3, R* as C1-4 alkyl, n from 5 to 1000, and the fraction of A units that are of formula R1 between 10-25 mole percent.
Miscible aprotic solvent forming a single phase
An aprotic solvent is miscible with the polyorthoester to form a single phase, where the aprotic solvent is selected from dimethyl sulfoxide, dimethyl acetamide, and N-methyl pyrrolidone.
Local amide- or anilide-type anesthetic dispersed or solubilized in the single phase
The delivery system includes a local amide- or anilide-type anesthetic dispersed or solubilized in the single phase.
Specified solvent and polyorthoester weight percentages
The aprotic solvent is present in amounts ranging from about 10-25% by weight of the delivery system and the polyorthoester of Formula III is present in amounts ranging from about 45-80% by weight of the delivery system.
Therapeutically effective administration to treat pain
Dispensing and administering to a subject a therapeutically effective amount of a composition comprised of the delivery system for treating pain.
Dimethyl sulfoxide as the aprotic solvent
The method is characterized wherein the aprotic solvent is dimethyl sulfoxide.
The independent claims are directed to administering a therapeutically effective amount using a delivery system with a Formula III polyorthoester and an aprotic solvent selected from dimethyl sulfoxide, dimethyl acetamide, or N-methyl pyrrolidone that is miscible with the polymer to form a single phase, together with a local amide- or anilide-type anesthetic dispersed or solubilized in that single phase. Where specified, the delivery system further includes particular weight percentage ranges for the aprotic solvent and the Formula III polyorthoester, and one claim specifies dimethyl sulfoxide and a pain-treatment purpose.
Stated Advantages
Prolonged detectable plasma levels over days.
Extended analgesic activity.
The aprotic solvent and/or drug diffusion-controlled early release and polymer erosion-controlled later release can provide biphasic release kinetics.
Increasing mole % of α-hydroxy acid–containing subunits provides increased bioerodibility via hydrolysis/catalysis by released hydroxyacids.
Documented Applications
Pain treatment, including post-surgical incisional pain (porcine model), using formulations containing polyorthoester III with aprotic solvents such as DMSO, NMP, and DMAc and local anesthetics such as ropivacaine and bupivacaine.
Method of administering a therapeutically active agent to a subject in need thereof using the delivery system.
Method of treating pain in a subject in need thereof using a therapeutically effective amount of the composition comprising the delivery system.
Associated with therapeutically active agents including granisetron and anesthetics such as ropivacaine and bupivacaine.
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