# US 2019/0167630 A1 · Efflux inhibitor compositions and methods of treatment using the same

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- Number: US 2019/0167630 A1
- Document ID: US20190167630A1
- Status: Published application
- Kind: A1
- Application number: 16/268,386
- Filed: 2019-02-05
- Published: 2019-06-06
- Earliest claimed: 2012-07-27
- Assignees: Izumi Technology, LLC
- Applicants: Izumi Technology, LLC
- Inventors: Antonius Martinus Gustave Bunt; Olaf Van Tellingen
- Web page: https://patentgrep.com/patent/US20190167630A1

## CPC

- A61K 31/337: having four-membered rings, e.g. taxol
- A61K 9/145: {with organic compounds}
- A61K 9/146: {with organic macromolecular compounds}
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/451: having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 31/4725: containing further heterocyclic rings
- A61K 31/473: ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/517: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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

## Abstract

The present invention relates to efflux inhibitor compositions and methods of using these agents for treating conditions where the activity of efflux transporter proteins (e.g., Breast Cancer Resistance Protein (BCRP) and P-Glycoprotein (P-GP)) inhibit effective delivery of a therapeutic agent to a target tissue (e.g., brain, spinal cord, nerves, cerebrospinal fluid, testis, eyeballs, retina, inner ear, placenta, mammary gland, liver, biliary tract, kidney, intestines, lung, adrenal cortex, endometrium, hematopoietic cells, and/or stem cells).

## Claims

### Claim 1

A composition comprising at least about 1% by weight crystalline elacridar nanoparticles having a mean diameter of about 10 nm to about 400 nm and (i) at least about 12% by weight_D-α-Tocopherol polyethylene glycol succinate (TPGS) or (ii) at least about 1% by weight poloxamer 407, wherein said composition achieves one or more of:
a. a Cmax of elacridar of at least about 500 ng/ml;
b. bioavailability of elacridar of at least about 0.2:
c. an AUC(0-48 h) of elacridar of at least about 900 μg/ml*min;
d. an AUC(0-∞) of elacridar of at least about 1100 μg/ml*min; and
e. an elimination half-life (T½) of elacridar of at least about 10 h;
when the composition is administered by oral gavage in an aqueous suspension at about 100 mg/kg to fasted, female Sprague-Dawley rats.

### Claim 2 (depends on 1)

The composition of claim 1, wherein the composition comprises at least about 16% TPGS by weight.

### Claim 3 (depends on 1)

The composition of claim 1 wherein the composition comprises at least about 5% poloxamer 407 by weight.

### Claim 4 (depends on 1)

The composition of claim 1, wherein the nanoparticles are diluted in a TPGS aqueous solution to a final concentration of at least 16% TPGS by weight.

### Claim 5 (depends on 4)

The composition of claim 4, comprising about 5% elacridar by weight and about 5% poloxamer 407 by weight.

### Claim 6 (depends on 5)

The composition of claim 5, wherein the nanoparticles are suspended in an aqueous solvent.

### Claim 7 (depends on 1)

The composition of claim 1, wherein the composition further comprises a therapeutic agent.

### Claim 8 (depends on 7)

The composition of claim 7, wherein the therapeutic agent is a modulator of a biological target.

### Claim 9 (depends on 8)

The composition of claim 8, wherein the biological target is selected from one or more members of the group consisting of enzymes, receptors, ion channels, nucleic acids, ribosomes, hormones, vitamins, cytokine, chemokines, substrates, metabolites, proteins, transport molecules, physiochemical mechanisms, and antigen-antibody interactions.

### Claim 10 (depends on 9)

The composition of claim 9, wherein the therapeutic agent is a kinase inhibitor.

### Claim 11 (depends on 10)

The composition of claim 10, wherein the kinase inhibitor is selected from the group consisting of ABT-869, afatinib (BIBW-2992), AMG-706, AMN-107, amuvatinib, AST-487, axitinib (AG-013736), AZD-152HQPA, AZD-2171, BIBF-1120, BIRB-796, BMS-540215, bosutinib, cabozantinib, canertinib (Cl-1033), CHIR-258/TKI-258, crizotinib, dasatinib, DMBI, dovitinib, erlotinib, everolimus, EXEL-2880/GSK-1363089, gefitinib, GW-786034, imatinib, JNJ-28312141, Ki-20227, Ki8751, lapatinib, masitinib (AB-1010), midostaurin (PKC-412), motesanib, neratinib (HKl-272), nilotinib, OSI-930, pazopanib, PD-173955, PLX-4720, ponatinib, PTK-787, quizartinib (AC220), R406, regorafenib, SKI-606, sorafenib, staurosporine, SU-14813, sunitinib, tandutinib (MLN-518), telatinib, temsirolimus, tivozanib, vandetanib, vatalanib, and vemurafenib.

### Claim 12 (depends on 10)

The composition of claim 10, wherein the kinase inhibitor is imatinib, lapatinib, or gefitinib.

### Claim 13 (depends on 1)

The composition of claim 1, comprising at least about 12% by weight TPGS.

### Claim 14 (depends on 1)

The composition of claim 1, comprising at least about 1% by weight poloxamer 407.

### Claim 15 (depends on 1)

The composition of claim 1, consisting of 1% crystalline elacridar nanoparticles by weight, about 16% TPGS by weight and water.

### Claim 16 (depends on 1)

The composition of claim 1, consisting of 1% crystalline elacridar nanoparticles by weight, about 1% poloxamer 407 by weight and water.

### Claim 17 (depends on 1)

A method for treating a condition in a subject wherein treatment with a therapeutic agent is inhibited by BCRP and/or P-GP activity, the method comprising administering to the subject a therapeutic amount of a composition of claim 1, and a therapeutic agent useful for treating the condition, wherein the composition increases the concentration of the therapeutic agent in the target tissue or cell relative to administration of the therapeutic agent alone.

### Claim 18 (depends on 17)

The method of claim 17 wherein the condition is a neurological condition.

### Claim 19 (depends on 18)

The method of claim 18, wherein the neurological condition wherein the neurological condition is selected from neurofibromatosis, neuro-cardio-facial-cutaneous syndromes, primary brain cancer, secondary brain metastasis, multiple sclerosis, and Alzheimer's disease.

### Claim 20 (depends on 19)

The method of claim 19, wherein the neurological condition is neurofibromatosis.