# US 11,110,175 B2 · Compositions with permeation enhancers for drug delivery

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- Number: US 11,110,175 B2
- Document ID: US11110175B2
- Status: Granted
- Kind: B2
- Application number: 15/749,951
- Filed: 2016-08-05
- Published: 2018-08-16
- Granted: 2021-09-07
- Earliest claimed: 2015-08-05
- Assignees: Children's Medical Center Corporation; Massachusetts Institute of Technology
- Applicants: Children's Medical Center Corporation; Massachusetts Institute of Technology
- Inventors: Daniel S. Kohane; Rong Yang; Lily Yun Lin
- Web page: https://patentgrep.com/patent/US11110175B2

## CPC

- A61K 47/34: Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers (A61K47/10 takes precedence)
- A61K 9/0046: {Ear}
- A61K 9/06: Ointments; Bases therefor; {Other semi-solid forms, e.g. creams, sticks, gels (composition of ointments, creams or gels A61K47/00)}
- A61K 31/407: condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
- A61K 31/424: condensed with heterocyclic ring systems, e.g. clavulanic acid
- A61K 31/431: containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
- A61K 31/445: Non condensed piperidines, e.g. piperocaine
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/5383: ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/573: substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
- A61K 38/12: Cyclic peptides {, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C (A61K38/043 - A61K38/046 take precedence)}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/06: Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61K 47/12: Carboxylic acids; Salts or anhydrides thereof
- A61K 47/20: containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
- A61K 47/22: Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
- A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
- A61P 27/16: Otologicals
- A61P 31/04: Antibacterial agents
- C08G 65/3355: {having phosphorus bound to carbon and oxygen}
- C08G 79/04: Phosphorus linked to oxygen or to oxygen and carbon
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C08G: MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS

## 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.

## Claims

### Claim 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 —R1 or -L2R2;
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 L2 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 R2 is independently optionally substituted acyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —ORb, —N(Rb)2, or an oxygen protecting group;
each occurrence of R3 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteryaryl, optionally substituted acyl, —ORb, or —N(R)2;
each occurrence of Rb 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 Rb taken together with the nitrogen to which they are attached form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring;
each of G1A and G2A 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.

### Claim 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 —R1 or -L2R2;
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 L2 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 R2 is independently optionally substituted acyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —ORb, —N(Rb)2, or an oxygen protecting group;
each occurrence of R3 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteryaryl, optionally substituted acyl, —ORb, or —N(R)2;
each occurrence of Rb 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 Rb taken together with the nitrogen to which they are attached form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring;
each of G1A and G2A 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.

### Claim 3

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 of Formula (I′):
wherein:
each occurrence of Y is independently —R1 or -L2R2;
each occurrence of R1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, or optionally substituted heteroaryl;
each occurrence of L2 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 R2 is independently optionally substituted acyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —ORb, —N(Rb)2, or an oxygen protecting group;
each occurrence of R3 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteryaryl, optionally substituted acyl, —ORb, or —N(R)2;
each occurrence of Rb 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 Rb taken together with the nitrogen to which they are attached form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring;
each of G1A and G2A 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.

### Claim 4 (depends on 3)

The polymer of claim 3, wherein the matrix forming agent or combination of matrix forming agents comprises a polymer of Formula:
wherein:
each occurrence of Z is independently —R4;
each occurrence of R4 is independently optionally substituted alkyl;
each of G1A and G2A is independently hydrogen, 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, wherein the sum of p and t is at least 1, and the sum of q, r, and s is at least 1;
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.

### Claim 5 (depends on 3)

The polymer of claim 3, wherein the polymer is of the formula:

### Claim 6 (depends on 3)

The polymer of claim 3, wherein the polymer is of the formula:

### Claim 7 (depends on 3)

The polymer of claim 3, further comprising an antibiotic that is a β-lactamase inhibitor or has a molecular weight of about 290 g/mol to about 749 g/mol.

### Claim 8 (depends on 3)

The composition of claim 3, wherein the polymer further comprises blocks selected from the group consisting polyethylene oxide, polypropylene oxide, poloxamers, poloxamer 407, poloxamer 188, poloxamines, methylcellulose, hydroxypropyl methylcellulose, ethyl(hydroxyethyl) cellulose, xyloglucan, acetates, phthalates, latex, poly(acrylic acid), N-isopropylacrylamides, cellulose, chitosan, dextran, and hyaluronic acid, and derivatives thereof.

### Claim 9 (depends on 3)

The composition of claim 3, wherein the polymer comprises phosphoester monomers of Formula (M):
wherein for each monomer Y is independently —R1 or -L2R2, wherein:
each occurrence of R1 is independently optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
each occurrence of L2 is independently optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, or optionally substituted heteroalkynylene;
each occurrence of R2 is independently optionally substituted acyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —ORb, —N(Rb)2; and
each occurrence of Rb 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 Rb taken together with the nitrogen to which they are attached form an optionally substituted heterocyclic or optionally substituted heteroaryl ring.

### Claim 10 (depends on 1)

The composition of claim 1, wherein the polymer is of formula:
wherein:
each occurrence of R1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
each occurrence of R3 is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteryaryl, optionally substituted acyl, —ORb, or —N(Rb)2; and
each of G1A and G2A is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted phosphate, or an oxygen protecting group.

### Claim 11 (depends on 10)

The composition of claim 10, wherein each R1 is unsubstituted C1-20 alkyl.

### Claim 12 (depends on 1)

The composition of claim 1, wherein each L2 is a bond or unsubstituted C1-6 alkylene.

### Claim 13 (depends on 12)

The composition of claim 12, wherein each L2 is a bond.

### Claim 14 (depends on 12)

The composition of claim 12, wherein each L2 is unsubstituted C1-6 alkylene.

### Claim 15 (depends on 1)

A kit for treating an ear disease comprising a container, a composition of claim 1, and instructions for administering the composition to a subject in need thereof.

### Claim 16 (depends on 1)

The composition of claim 1, wherein each instance of Y is R1.

### Claim 17 (depends on 16)

The composition of claim 16, wherein R1 is optionally substituted alkyl.

### Claim 18 (depends on 17)

The composition of claim 17, wherein R1 is optionally substituted C1-6 alkyl.

### Claim 19 (depends on 1)

The composition of claim 1, wherein each of p and t is an integer between 1 and 100, inclusive.

### Claim 20 (depends on 17)

The composition of claim 17, wherein each of p and t is an integer between 1 and 10, inclusive.

### Claim 21 (depends on 19)

The composition of claim 19, wherein r is an integer between 10 and 100, inclusive.

### Claim 22 (depends on 3)

The polymer of claim 3, wherein the polymer is of the formula:

### Claim 23 (depends on 1)

The composition of claim 1, wherein the polymer is of the formula:

### Claim 24 (depends on 1)

The composition of claim 1, wherein the polymer is of the formula:

### Claim 25 (depends on 2)

The composition of claim 2, wherein the polymer is of the formula:

### Claim 26 (depends on 2)

The composition of claim 2, wherein the polymer is of the formula: