Compositions of a polyorthoester and an organic acid excipient
Inventors
Ottoboni, Thomas B. • Girotti, Lee Ann Lynn
Assignees
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Publication Number
US-11844837-B2
Publication Date
2023-12-19
Expiration Date
Abstract
Delivery systems and compositions comprised of a biodegradable polyorthoester polymer, an organic acid excipient, and a basic drug are described, along with related methods.
Core Innovation
The invention relates to biodegradable polyorthoester-based delivery systems in which a composition comprising a polyorthoester, maleic acid, an aprotic solvent selected from N-methyl-2-pyrrolidone (NMP) and dimethyl sulfoxide (DMSO), and a therapeutically active agent is administered to a subject or patient in need. The therapeutically active agent is selected from bupivacaine, levobupivacaine, dibucaine, mepivacaine, procaine, lidocaine, tetracaine, and ropivacaine, and is dispersed or solubilized in the composition.
Maleic acid is present in less than an equimolar amount when compared to the therapeutically active agent, such that the therapeutically active agent is present as a mixed salt-base and the composition is substantially free of crystals of the therapeutically active agent. The document states that adding an organic acid excipient to free-base local anesthetics in semi-solid polyorthoester formulations inhibits drug crystallization.
The polyorthoester is described as semi-solid and bioerodible, and the compositions use maleic acid as an excipient in an amount that is less than an equimolar amount when compared to the therapeutically active agent. The disclosed systems are described for local anesthesia and for acute and chronic pain management.
Claims Coverage
The independent claims cover four pain uses with the same core composition: pain management, prophylactic treatment of pain, managing or treating post-operative pain, and reducing or preventing post-operative pain. Across the independent claims, there are three main inventive features: the specific composition definition, the mixed salt-base and crystal-free constraint, and the pain-use application.
Polyorthoester composition with maleic acid and aprotic solvent
A composition comprising a polyorthoester, maleic acid, an aprotic solvent selected from N-methyl-2-pyrrolidone (NMP) and dimethyl sulfoxide (DMSO), and a therapeutically active agent dispersed or solubilized in the composition.
Selected amino-amide anesthetic dispersed or solubilized in the composition
The therapeutically active agent is selected from bupivacaine, levobupivacaine, dibucaine, mepivacaine, procaine, lidocaine, tetracaine, and ropivacaine.
Sub-equimolar maleic acid to form a mixed salt-base and avoid crystals
Maleic acid is present in less than an equimolar amount when compared to the therapeutically active agent, such that the therapeutically active agent is present as a mixed salt-base and the composition is substantially free of crystals of the therapeutically active agent.
Pain management, prophylactic treatment of pain, and post-operative pain uses
The composition is used for pain management, prophylactic treatment of pain, managing or treating post-operative pain, and reducing or preventing post-operative pain.
The shared inventive thrust is the administration of a polyorthoester, maleic acid, and aprotic solvent composition containing a selected amino-amide local anesthetic dispersed or solubilized such that maleic acid is present in less than an equimolar amount, producing a mixed salt-base and maintaining the composition substantially free of crystals of the therapeutically active agent.
Stated Advantages
Stabilization against crystallization.
Inhibits drug crystallization.
Therapeutically active agent is present as a mixed salt-base.
Composition is substantially free of crystals of the therapeutically active agent.
Accelerated early drug release.
The disclosed compositions control drug release and degradation, including accelerated release in early days and an enhanced release period followed by slower release.
Performance data indicate that addition of organic acid, especially maleic acid, markedly increases initial release and plasma levels.
Documented Applications
Pain management by administering the composition to a subject in need.
Prophylactic treatment of pain by locally administering the composition to a patient in need.
Managing or treating post-operative pain by administering the composition to a subject in need.
Reducing or preventing post-operative pain by administering the composition to a subject in need.
Local anesthesia and pain management, including acute and chronic pain management.
Local delivery contexts including instilling into a surgical site and dispensing from a needle at local delivery sites.
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