Compositions with permeation enhancers for drug delivery

Patent metadata

Field	Value
Publication number	US-11110175-B2
Application number	US-201615749951-A
Country	US
Kind code	B2
Filing date	Aug 5, 2016
Priority date	Aug 5, 2015
Publication date	Sep 7, 2021
Grant date	Sep 7, 2021

Abstract

The present invention provides compositions and methods for delivery of therapeutic agents across an barrier. The compositions include a therapeutic agent (e.g., antimicrobial agent, antibiotic, or anesthetic agent), a permeation enhancer which increases the flux of the therapeutic agent across the barrier, and a matrix forming agent. The matrix forming agent forms a gel at a suitable gelation temperature and rheological properties for use in drug delivery, and in some cases, the gelation temperature and rheological properties are not significantly changed from those of the composition without the permeation enhancer. The invention also provides a matrix forming agent and compositions thereof. Such compositions are particularly useful in the treatment of otitis media. Methods of treatment, methods of delivery, and kits for the compositions described herein are also provided.

First claim

What is claimed is:

1. A composition comprising:
(a) an antibiotic or a combination of antibiotics, wherein each antibiotic is a β-lactamase inhibitor or has a molecular weight of about 290 g/mol to about 749 g/mol;
(b) a permeation enhancer or a combination of permeation enhancers selected from the group consisting of limonene, cymene, pinene, camphor, menthol, comphone, phellandrine, sabinene, terpinene, borneol, cineole, geraniol, linalol, pipertone, terpineol, eugenol, eugenol acetate, safrole, benzyl benzoate, humulene, beta-caryophylene, eucakytol, hexanoic acid, octanoic acid, decanoic acid, undecanoic acid, dodecanoic acid, tridecanoic acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, cholic acid; ethyl undecanoate, methyl laurate, methyl myristate, isopropyl myristate, isopropyl palmitate, palmityl palmitate, diethyl sebaccate, glyceryl monolaurate, glyceryl monooleate, and ethylpiperazine carboxylate; and a permeation enhancer with a molecular weight of about 232 g/mol to about 1310 g/mol; wherein the permeation enhancer or combination of permeation enhancers increases the flux of the therapeutic agent or combination of therapeutic agents across a barrier; and
(c) a matrix forming agent or a combination of matrix forming agents, wherein the matrix forming agent or combination of matrix forming agents comprises a polymer;

wherein:
the composition forms a gel at temperatures above a phase transition temperature; and
the phase transition temperature is less than about 37° C.;

and at least one of conditions (i), (ii), and (iii) are met:
(i) the phase transition temperature of the composition is less than the phase transition temperature of a reference composition plus about 5° C.;
(ii) the storage modulus of the composition is greater than about 15% of the storage modulus of the reference composition or greater than about 500 Pa, whichever is smaller, at a temperature of about 37° C.; and
(iii) the loss modulus of the composition is between about 15% and about 150% of the loss modulus of the reference composition at a temperature of about 37° C.;

wherein the reference composition is the composition in the absence of the permeation enhancer or combination of permeation enhancers;
wherein the polymer comprises a polymer of Formula (I′):

wherein:
each occurrence of Y is independently —R 1 or -L 2 R 2 ;
each occurrence of R is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, or optionally substituted heteroaryl;
each occurrence of L 2 is independently a bond, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, or optionally substituted heteroalkynylene;
each occurrence of R 2 is independently optionally substituted acyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR b , —N(R b ) 2 , or an oxygen protecting group;
each occurrence of R 3 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteryaryl, optionally substituted acyl, —OR b , or —N(R) 2 ;
each occurrence of R b is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, an oxygen protecting group, or a nitrogen protecting group, or two R b taken together with the nitrogen to which they are attached form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring;
each of G 1A and G 2A is independently hydrogen, halogen, optionally substituted amine, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl, optionally substituted acyl, optionally substituted phosphate, or an oxygen protecting group; and
each of p, q, r, s, and t is independently an integer between 1 and 200, inclusive, wherein the sum of p and t is at least 1, and the sum of q, r, and s is at least 1.

2. A composition comprising:
(a) an antibiotic or a combination of antibiotics, wherein each antibiotic is a β-lactamase inhibitor or has a molecular weight of about 290 g/mol to about 749 g/mol;
(b) a permeation enhancer or a combination of permeation enhancers selected from the group consisting of limonene, cymene, pinene, camphor, menthol, comphone, phellandrine, sabinene, terpinene, borneol, cineole, geraniol, linalol, pipertone, terpineol, eugenol, eugenol acetate, safrole, benzyl benzoate, humulene, beta-caryophylene, eucakytol, hexanoic acid, octanoic acid, decanoic acid, undecanoic acid, dodecanoic acid, tridecanoic acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, cholic acid; ethyl undecanoate, methyl laurate, methyl myristate, isopropyl myristate, isopropyl palmitate, palmityl palmitate, diethyl sebaccate, glyceryl monolaurate, glyceryl monooleate, and ethylpiperazine carboxylate; and a permeation enhancer with a molecular weight of about 232 g/mol to about 1310 g/mol; and
(c) a matrix forming agent or a combination of matrix forming agents, wherein the matrix forming agent or combination of matrix forming agents comprises a polymer;

wherein:
the composition forms a gel at temperatures above a phase transition temperature; and
the phase transition temperature is less than about 37° C.;

and at least one of conditions (i), (ii), and (iii) are met:
(i) the phase transition temperature of the composition is less than the phase transition temperature of a reference composition plus about 5° C.;
(ii) the storage modulus of the composition is greater than about 15% of the storage modulus of the reference composition at a temperature of about 37° C.; and
(iii) the loss modulus of the composition is between about 80% and about 120% of the loss modulus of the reference composition at a temperature of about 37° C.;

wherein the reference composition is the composition in the absence of the permeation enhancer or combination of permeation enhancers;
wherein the polymer comprises a polymer of Formula (I′):

wherein:
each occurrence of Y is independently —R 1 or -L 2 R 2 ;
each occurrence of R is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, or optionally substituted heteroaryl;
each occurrence of L 2 is independently a bond, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, or optionally substituted heteroalkynylene;
each occurrence of R 2 is independently optionally substituted acyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR b , —N(R b ) 2 , or an oxygen protecting group;
each occurrence of R 3 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteryaryl, optionally substituted acyl, —OR b , or —N(R) 2 ;
each occurrence of R b is independently optionally substituted alkyl, optionally substi

Assignees

• Childrens Medical Center
• Massachusetts Inst Technology

Inventors

• Kohane Daniel S
• Yang Rong
• Lin Lily Yun

Classifications

• A61K31/431

  containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin · CPC title

• A61K31/424

  condensed with heterocyclic ring systems, e.g. clavulanic acid · CPC title

• C08G79/04

  Phosphorus linked to oxygen or to oxygen and carbon · CPC title

• C08G65/3355

  having phosphorus bound to carbon and oxygen · CPC title

• A61K31/407

  condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine · CPC title