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(12) Patent Application Publication (10) Pub. N0.: US 2014/0235631 A1 Bunt Et Al

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(12) Patent Application Publication (10) Pub. N0.: US 2014/0235631 A1 Bunt Et Al US 20140235631A1 (19) United States (12) Patent Application Publication (10) Pub. N0.: US 2014/0235631 A1 Bunt et al. (43) Pub. Date: Aug. 21, 2014 (54) EFFLUX INHIBITOR COMPOSITIONS AND A61K 45/06 (2006.01) METHODS OF TREATMENT USING THE A61K 31/451 (200601) SAME (52) us. Cl. (71) Applicants; Antonius Martinus Gustave Bunt, CPC ........... .. A61K 31/4 73 (2013.01); A61K 31/451 Lexington, MA (US); Olaf van (2013.01); A61K 31/337 (2013.01); A61K Tellingen, Zaandam (NL) 45/06 (201301) (72) Inventors: Antonius Martinus Gustave Bunt, USPC ...... .. 514/233.2; 514/297; 514/327; 514/449; Lexington, MA (Us); Olaf van 546/103; 546/217; 549/510; 514/266.24; Tellingen, Zaandam (NL) 514/253.07; 514/312; 514/252.18 (21) Appl. N0.: 13/952,476 (57) ABSTRACT (22) Filed: Jul. 26, 2013 The present invention relates to ef?ux inhibitor compositions R l t d U s A l_ t_ D t and methods of using these agents for treating conditions 6 a e ' ' PP lea Ion a a Where the activity of ef?ux transporter proteins (e.g., Breast (60) Prowslonal applicatlon No. 61/767,689, ?led on Feb. Cancer Resistance protein (BCRp) and p_G1yCOpr0tein 21’ 2013' (P-GP)) inhibit effective delivery of a therapeutic agent to a Publication Classi?cation target tissue (e.g., brain, spinal cord, nerves, cerebrospinal ?uid, testis, eyeballs, retina, inner ear, placenta, mammary (51) Int- Cl- gland, liver, biliary tract, kidney, intestines, lung, adrenal cortex, endometrium, hematopoietic cells, and/ or stem cells). Patent Application Publication Aug. 21, 2014 Sheet 1 0f3 US 2014/0235631 A1 2652:: 5.mt @35363Mxxémxu (1w/6u) [lemma] Patent Application Publication Aug. 21, 2014 Sheet 2 0f 3 US 2014/0235631 A1 0 L0 _C> LO 0 (I) E D E L o m _ E <I' L o L“ LIJ aU) 5A N I E -3 cu m E 2" >3 |— I. + _O (\l _O O 1000.0 100.0 0 0. Patent Application Publication Aug. 21, 2014 Sheet 3 0f 3 US 2014/0235631 A1 ENPVitTPGS—|]— —O—ENPPoloxamer —A—E-suspension 7} g 54 3'0 T|me(h) 3Fig. 20 Z a 6000 5000 400.0 3000 2000- 1000 0.0 US 2014/0235631A1 Aug. 21,2014 EFFLUX INHIBITOR COMPOSITIONS AND (e.g., elacridar) enhances the penetration of one or more METHODS OF TREATMENT USING THE therapeutic agents (e.g., imatinib and lapatinib) across the SAME blood-brain barrier and/or the blood-nerve barrier in mam mals (e.g., humans). Accordingly, the present invention pro RELATED APPLICATIONS vides compositions and methods for treating conditions (e. g., [0001] This application claims priority to and the bene?t of NFl and BCBM) Where the activity of e?qu transport pro US. Provisional Application No. 61/676,689, ?led Jul. 27, teins (e.g., BCRP and/or P-GP) inhibit effective delivery of a 2012, Which is hereby incorporated by reference in its therapeutic agent to a target tissue (e.g., brain, spinal cord, entirety. nerves, cerebrospinal ?uid, testis, eyeballs, retina, inner ear, placenta, mammary gland, liver, biliary tract, kidney, intes FIELD OF THE INVENTION tines, lung, adrenal cortex, endometrium, hematopoietic cells, and/or stem cells). [0002] The present invention relates to e?qu inhibitor [0007] In a ?rst aspect, the invention provides compositions compositions and methods of using these agents for treating comprising an e?qu inhibitor, Wherein the ef?ux inhibitor is conditions Where the activity of ef?ux transporter proteins formulated to achieve one or more of: 1) a Cmax of at least (e.g., Breast Cancer Resistance Protein (BCRP) and P-Gly 500 ng/ml (e.g., about 500, 550, 600, 650, 700, 750, 800, 850, coprotein (P-GP)) inhibit effective delivery of a therapeutic 900, 950, or 1000 ng/ml); 2) a bioavailability of at least 0.1 agent to a target tissue (e.g., brain, spinal cord, nerves, cere (e.g., about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0); 3) brospinal ?uid, testis, eyeballs, retina, inner ear, placenta, an AUC(0-48h) of at least 900 ug/ml*min (e.g., about 900, mammary gland, liver, biliary tract, kidney, intestines, lung, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, adrenal cortex, endometrium, hematopoietic cells, and/or 2000, 2500, 3000, 3500, 4000, 4500, or 5000 ug/ml*min); 4) stem cells). an AUC(0-OO) of at least 1100 ug/ml*min (e.g., about 1100, BACKGROUND 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900,2000, 2500, 3000, 3500, 4000, 4500, or 5000 ug/ml*min); and, 5) an [0003] Neuro?bromatosis (NF) is a genetic disorder of the elimination half-life (Tl/2) of at least 10 h (e.g., 10, 11, 12, nervous system, Which causes tumors to form on nerve tis 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 h), When the sues, such as the brain, spinal cord, and peripheral nerves. composition is administered by oral gavage at 100 mg/kg to Particularly, Type 1 neuro?bromatosis (NFl) occurs in one fasted, female Sprague-Dawley rats. out of every 3,000 children and affects approximately 100, [0008] In certain embodiments, the composition comprises 000 people in the United States. NFl can lead to blindness, a nanoparticle formulation of the e?qu inhibitor. In certain dis?gurement, malignancies, and learning disabilities in embodiments, the nanoparticles have a mean diameter of more than 50% of the affected children. Currently, there is no between about 1 and 200 nM (e.g., about 1, 10, 20, 30, 40, 50, proven drug treatment for NFl. 60, 70, 80, 90, 100, 110, 120, 0130, 140, 150, 160, 170, 180, [0004] In another example, the incidence of breast cancer 190, or 200, 300, 400, 500, 600, 700, 800, 900, 100, 1100, brain metastasis (BCBM) in patients is approximately 30% 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 and 20,000-34,000 patients develop BCBM each year. The nM). standard of care for these patients is palliative care and [0009] In certain embodiments, the e?qu inhibitor is includes steroids, anti-epilepsy drugs, pain medications, selected from one or more members of the group consisting of radiotherapy, and surgery. The life expectancy for these a Breast Cancer Resistance Protein (BCRP) inhibitor, and a patients is only twelve months. Effective treatment for P-Glycoprotein (P-GP) inhibitor. BCBM remains to be developed. [0010] In certain embodiments, the e?qu inhibitor is a [0005] A signi?cant challenge in the treatment of neuro BCRP inhibitor selected from the group consisting of chrysin, logical disorders/conditions such as NFl and BCBM is the ge?tinib, K0143, fumitremorgin C, diethylstilbestrol, e?icient delivery of therapeutic agents across the blood-brain cyclosporine-A, prazosin, saquinavir, ritonavir, [3-estradiol, and/ or the blood-nerve barriers to target lesions in the central verapamil, tamoxifen, Hoechst 33342, quercetin, omepra and peripheral nervous systems. Physiologically, the blood Zole, methotrexate, ergocristine, nicardipine, ethinylestra brain barrier and the blood-nerve barrier act to protect the diol, astemizole, felodipine, glibenclamide, ketoconazole, brain and the endoneurial microenvironment from, for chlorprotixene, nitrendipine, chlorpromaZine, progesterone, example, rapid ?uctuations in the composition of the blood or mifepristone, dipyridamole, lopinavir, amiodarone, simvas of the extra neural spaces. However, in the process of protect tatin, loperamide, terfenadine, clotrimazol, spironolactone, ing the nervous systems, the blood-brain and the blood-nerve maprotiline, digoxin, quinine, fexofenadine, diltiazem, eryth barriers also present obstacles for delivering potentially use romycin, etoposide, prednisone, trimethoprim, chlorzox ful therapeutic agents to the brain and the endoneurial azone, folic acid, lansoprazol, ranitidine, cimetidine, microenvironment. Accordingly, there remains a need for indomethacin, prednisolone, propranolol, timolol, neW methods of enhancing the distribution of therapeutic desipramine, pravastatin, hydrocortisone, sul?npyrazone, agents into diseased tissues or cells that are protected by the feno?brate, tipranavir, erlotinib, ?upentixol, celecoxib, thior blood-organ barrier and/ or the e?qu transporters P-GP and or idaZine, isradipine, fendiline, medroxyprogesterone, BCRP for the prevention and/or treatment of conditions pramoxine, piroxicam, terazosin, diazoxide, oxazepam, pro Where treatment With a therapeutic agent is inhibited by pafenone, tinidazole, mecliZine, tetracycline, budesonide, BCRP and/or P-GP activity, e.g., neurological conditions. desmethyldiazepam, nevirapine, diazepam, zanamivir, ?ur biprofen, neomycin sulfate, nitrofurantoin, valacyclovir, car SUMMARY OF THE INVENTION bamazepine, chenodeoxycholic acid, hydrochlorothiaZide, [0006] The present invention is based in part on the discov amantadine, amoxicillin, phenyloin, antipyrine, bendro?u ery that a composition comprising at least one ef?ux inhibitor methiaZide, ganciclovir, metoclopramide, pindolol, warfarin, US 2014/0235631A1 Aug. 21,2014 amiloride, bupivacaine, carisoprodol, nizatidine, 35, 40, 45, 50% W/W). In certain embodiments, the composi orphenadrine, procyclidine, acyclovir, atropine, captopril, tion or nanoparticle formulation comprises at least about 16% furosemide, hydralaZine, levothyroxine, salicylic acid, TPGS W/W. sotalol, valganciclovir, levodopa, methimazole, sulindac, [0015] In certain embodiments, the composition or nano metoprolol, Zidovudine, gliclaZide, mesalaZine, bupropion, particle formulation further comprises a solubility enhancer. and sulfasalaZine. Suitable solubility enhancers include, Without limitation, [0011] In certain embodiments, the ef?ux inhibitor is a TPGS, polyethylene glycol 300, polyethylene glycol 400, P-GP inhibitor selected from the group consisting of alfenta ethanol, propylene glycol, glycerin,
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