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Patent Application Publication ( 10 ) Pub . No . : US 2019 / 0231688 A1

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Patent Application Publication ( 10 ) Pub . No . : US 2019 / 0231688 A1 US 20190231688A1 ( 19) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2019 /0231688 A1 Ottoboni et al. (43 ) Pub. Date : Aug. 1 , 2019 ( 54 ) METHOD OF ADMINISTERING EMULSION A61K 9 / 00 ( 2006 .01 ) FORMULATIONS OF AN NK - 1 RECEPTOR A61K 47 / 24 (2006 .01 ) ANTAGONIST A61K 31/ 573 (2006 . 01 ) A61K 47 /44 ( 2006 .01 ) (71 ) Applicant: Heron Therapeutics , Inc . , San Diego , A61K 47/ 10 ( 2006 .01 ) CA (US ) A61K 47 / 12 ( 2006 . 01 ) A61K 47 / 26 ( 2006 . 01 ) ( 72 ) Inventors : Thomas B . Ottoboni, Belmont, CA A61K 31/ 496 ( 2006 .01 ) ( US ) ; Barry D . Quart, Las Vegas, NV (52 ) U . S . CI. (US ) CPC .. .. .. A61K 9 / 107 ( 2013 . 01 ) ; A61K 31/ 5377 ( 2013 .01 ) ; A61K 9 /0019 ( 2013 . 01 ) ; A61K ( 21 ) Appl. No .: 16 / 261, 459 47 / 24 ( 2013 .01 ) ; A61K 31 /496 ( 2013 .01 ) ; A61K 47/ 44 ( 2013 .01 ) ; A61K 47 /10 (2013 .01 ) ; (22 ) Filed : Jan . 29 , 2019 A61K 47 /12 ( 2013 .01 ) ; A61K 47 /26 ( 2013 .01 ) ; Related U . S . Application Data A61K 31/ 573 (2013 .01 ) ( 60 ) Provisional application No . 62/ 624 , 050 , filed on Jan . 30 , 2018 . (57 ) ABSTRACT Publication Classification ( 51 ) Int. Ci. Disclosed herein are methods of administering pharmaceu A61K 9 / 107 ( 2006 .01 ) tical formulations of a neurokinin - 1 (NK - 1 ) receptor antago A61K 31/ 5377 ( 2006 . 01 ) nist to a subject in need of treatment of emesis . Patent Application Publication Aug. 1 , 2019 Sheet 1 of 4 US 2019/ 0231688 A1 Ayyyyy . * L-9.21um SSS * 44 FIG.1B FIG.1D . S MXXS .91umL-2 FIG.1A FIG.1C * : * :: : : 00 28 PO20. 2020 Patent Application Publication Aug . 1 , 2019 Sheet 2 of 4 US 2019 / 0231688 A1 14 ? ?12 *AprepitantEmuslion ? -Fosaprepitant ?10 ? & ? FIG.2 ? Hours oe 8000 UTTTTTT ) mL/ ng ( Aprepitant Plasma Patent Application Publication Aug . 1 , 2019 Sheet 3 of 4 US 2019 / 0231688 A1 Aprepitant/Dexamethasone 20 Emuslion #Fosaprepitant - 12 Hours FIG.3 w 15007 )mL / ng ( Aprepitant Plasma Patent Application Publication Aug . 1 , 2019 Sheet 4 of 4 US 2019 / 0231688 A1 DexamethasonePhosphate -*AprepDexEmulsion Hours FIG.4 150- )mL / ng( Dexamethasone Plasma US 2019 /0231688 A1 Aug. 1 , 2019 METHOD OF ADMINISTERING EMULSION administered concentrated . IV infusion , however, may have FORMULATIONS OF AN NK - 1 RECEPTOR drawbacks such as time - consuming and risk of infection and ANTAGONIST complications due to the potential for blood clots and air bubble formation . IV push , also known as bolus , rapidly CROSS -REFERENCE TO RELATED delivers a single dose of medicine directly into the blood APPLICATIONS stream and takes very little time (such as not greater than about 15 minutes ) . Because of the short duration taken to [0001 ] This application is a Non - Provisional patent appli deliver a single dose , IV push can avoid the drawbacks cation which claims the benefit of priority to Provisional which may occur in IV infusion . Thus, IV push can be Patent Application No . 62 /624 , 050 , filed Jan . 30 , 2018 , desired , especially in situations when there is an acute which is hereby incorporated by reference in its entirety. shortage of small - volume parenteral solutions used to dilute TECHNICAL FIELD the dosage forms for infusion . [0002 ] The disclosure relates generally to a method of BRIEF SUMMARY administering emulsion formulations of an NK - 1 receptor [0007 ] The following aspects and embodiments thereof antagonist for treatment of emesis and /or for prevention of described and illustrated below are meant to be exemplary acute and delayed nausea and vomiting . The emulsion and illustrative , not limiting in scope. formulations are stable for prolonged periods of time. [0008 ] In one aspect, a method for treating a subject in need thereof is provided . The method comprises intrave BACKGROUND nously administering a single dose of a stable emulsion to [ 0003 ] Emesis is a critical problem experienced as a result the subject at an average rate of about 6 . 5 to 70 mg /minute of anticancer cytotoxic therapy. Up to 80 % of patients will of an NK - 1 receptor antagonist comprised in the stable experience chemotherapy -induced nausea and vomiting emulsion , wherein the stable emulsion comprises an oil ( CINV ) without prophylactic therapy ( Vieira dos Santos et phase, wherein the oil phase comprises the neurokinin 1 al ., 2012 , J Natl Cancer Inst , 104 : 1280 - 1292 ) . Navari et al. (NK - 1 ) receptor antagonist , a surfactant and a co - surfactant ; ( 1999 , N Engl J Med , 340 : 190 - 195 ) showed that neuroki and an aqueous phase , wherein the aqueous phase comprises nin - 1 (NK - 1 ) receptor antagonists improve CINV when used water, a tonicity agent, and a pH modifier . in combination with cisplatin -based chemotherapy . NK - 1 [0009 ]. In one aspect , a method for treating a subject in receptor antagonists block binding of substance P to the need thereof is provided . The method comprises intrave receptor , thereby preventing or limiting induction of vom nously administering a single dose of a stable emulsion to iting pathways mediated by the NK - 1 receptor ( Aziz , 2012 , the subject at an average rate of about 6 . 5 to 260 mg/ minute Ann Palliat Med , 1 : 130 - 136 ) . of an NK - 1 receptor antagonist comprised in the stable [ 0004 ] NK - 1 receptor antagonists in oral dosage forms can emulsion , wherein the stable emulsion comprises an oil create a problem for patients suffering from emesis , specifi phase , wherein the oil phase comprises the neurokinin 1 cally , for example , on days two and three of chemotherapy . (NK - 1 ) receptor antagonist , a surfactant and a co -surfactant ; Accordingly , it is desirable to have injectable formulations and an aqueous phase , wherein the aqueous phase comprises to simplify treatment for these patients . Emulsions formu water , a tonicity agent, and a pH modifier . lated for administering an NK - 1 receptor antagonist to a [0010 ] In some embodiments , the method comprises intra patient by injection have been described in U . S . application venously administering over about 30 seconds to 15 minutes Ser. No. 14 /859 , 013 (the '013 application ) and Ser . No. ( such as about 2 to 15 minutes ) a single dose of a stable 15 /012 ,532 ( the '532 application ), each of which is incor emulsion to the subject , wherein the stable emulsion com porated by reference in its entirety . These emulsions are prises an oil phase , wherein the oil phase comprises a formulated to contain neurokinin - 1 receptor antagonists neurokinin 1 (NK - 1 ) receptor antagonist , a surfactant and a which may be poorly soluble in aqueous solvents or unstable co - surfactant; and an aqueous phase , wherein the aqueous in aqueous- based liquid formulations. They are both physi phase comprises water , a tonicity agent, and a pH modifier . cally and chemically stable . [0011 ] In some embodiments , the NK - 1 receptor antago [0005 ] NK - 1 receptor antagonists approved by the U . S . nist is selected from the group consisting of aprepitant , Food and Drug Administration (“ FDA ” ) via intravenous rolapitant, netupitant, fosnetupitant , lanepitant, vestipitant, injection for treating certain nausea and /or emesis include orvepitant maleate , casopitant, ezlopitant, serlopitant, aprepitant and rolapitant HCl. For example , EMEND® for befetupitant and maropitant, or a pharmaceutically accept Injection and VARUBI® contain as the active ingredient a able salt thereof. In other embodiments , the NK - 1 receptor prodrug of aprepitant and rolapitant HC1, respectively ; CIN antagonist is poorly soluble in water . VANTI® comprises aprepitant as the active ingredient. The [0012 ] In some embodiments , the NK - 1 receptor antago prescribed administration for each of EMENDR for Injec nist is selected from the group consisting of rolapitant, tion , VARUBI® , and CINVANTI® requires intravenous netupitant, fosnetupitant, casopitant, ezlopitant, vestipitant, ( IV ) infusion of a single dose over 30 minutes (prior to serlopitant, maropitant, and orvepitant . infusion , the single dose of EMEND® for Injection , which [0013 ] In some embodiments , the NK - 1 receptor antago is in a lyophilized powder form , is subject to reconstitution nist is aprepitant. In some embodiments , the NK - 1 receptor and dilution and a single dose of CINVANTI® containing antagonist is not aprepitant . 100 mg or 130 mg aprepitant is diluted . The single dose of [ 0014 ] In some embodiments , the composition is an oil VARUBI® contains 166 . 5 mg rolapitant in an emulsion of in -water emulsion comprising an oil wherein the oil is 92 . 5 mL , requiring no dilution ). selected from the group consisting of coconut oil, olive oil , 10006 ] IV infusion is preferred when either the formula soybean oil , safflower oil , triglycerides , octyl and decyl tions or drugs are irritating to veins or cause reactions when glycerate , ethyl oleate , glyceryl linoleate , ethyl linoleate , US 2019 /0231688 A1 Aug. 1, 2019 glyceryl oleate , cholesteryl oleate /linoleate or a mixture embodiments , the oleate is sodium oleate . In still another thereof. In other embodiments , the oil is hydrolyzed . In still embodiment, the oleate or sodium oleate is the pH modifier. other embodiments, the oil is structurally modified . [0024 ] In some embodiments , the composition comprises [0015 ] In some embodiments , the emulsifier comprises a about 20 wt/ wt % to 50 wt/ wt % , 30 wt/ wt % to 50 wt/ wt % , phospholipid . In another embodiment , the emulsifier is 35 wt/ wt % to 45 wt/ wt % , 30 wt/ wt % to 45 wt/ wt % , 37 selected from the group consisting of egg phospholipids , soy wt/ wt % to 42 wt/ wt % , 38 wt/ wt % to 40 wt/ wt % , 30 wt/ wt phospholipids, phosphatidylcholines, phosphatidylethano % , 31 wt/ wt % , 32 wt/wt % , 33 wt/ wt % , 34 wt/ wt % , 35 lamines , phosphatidylserines , phosphatidylglycerols , phos wt/ wt % , 36 wt/ wt % , 37 wt/ wt % , 38 wt/ wt % , 39 wt/ wt % , phatidylinositols , phosphatidic acids, mixed chain phospho 40 wt/wt % , 41 wt/ wt % , 42 wt/ wt % , 43 wt/wt % , 44 wt/wt lipids, lysophospholipids, hydrogenated phospholipids , % , 45 wt/ wt % , 46 wt/ wt % , 47 wt/ wt % , 48 wt/ wt % , 49 partially hydrogenated phospholipids, and mixtures thereof.
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