Injectable neurosteroid formulations containing nanoparticles

Abstract

The disclosure provides an injectable neurosteroid nanoparticle formulation comprising nanoparticles having a D50 of less than 2000 nm the nanoparticles comprising a neurosteroid of Formula I,where the variables R1-R9 and X are defined herein and at least one surface stabilizer. The surface stabilizer can be a polymeric surface stabilizer such as hydroxyethyl starch, dextran, or povidone. The injectable neurosteroid nanoparticle formulation can be an intravenous formulation. The disclosure also provides a lyophilized powder of the injectable neurosteroid nanoparticle formulation that can be reconstituted in an aqueous solution prior to administration. The disclosure provides injectable neurosteroid nanoparticle formulations and dry powders of such formulations that have been sterilized by ebeam irradiation. The disclosure provides a method of treating a patient having a seizure disorder, stroke, or traumatic brain injury, comprising administering an effective amount of the injectable neurosteroid nanoparticle formulation. The disclosure also provides combination methods in which the injectable neurosteroid nanoparticle formulation is a first active agent that is administered in combination with at least one additional active agent.

What is claimed is: 
     
         1 . An injectable neurosteroid formulation comprising nanoparticles having a D50 of less than 2000 nm, the nanoparticles comprising
 a) a neurosteroid of the Formula I:   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         X is O, S, or NR 10 ; 
         R 1  is hydrogen, hydroxyl, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted aryl, or optionally substituted arylalkyl; 
         R 4  is hydrogen, hydroxyl, oxo, optionally substituted alkyl, or optionally substituted heteroalkyl, 
         R 2 , R 3 , R 5 , R 6 , and R 7  are each independently hydrogen, hydroxyl, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl; 
         R 8  is hydrogen or alkyl and R 9  is hydroxyl; or 
         R 8  and R 9  are taken together to form an oxo group; 
         R 10  is hydrogen, hydroxyl, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted aryl, or optionally substituted arylalkyl where 
         each alkyl is a C 1 -C 10 alkyl, C 3 -C 6 cycloalkyl, (C 3 -C 6 cycloalkyl)C 1 -C 4 alkyl, and optionally contains a single bond replaced by a double or triple bond; 
         each heteroalkyl group is an alkyl group in which one or more methyl group is replaced by an independently chosen —O—, —S—, —N(R 10 )—, —S(═O)— or —S(═O) 2 —, where R 10  is hydrogen, alkyl, or alkyl in which one or more methylene group is replaced by —O—, —S—, —NH, or —N— alkyl; and 
         b) at least one surface stabilizer. 
       
     
     
         2 . The injectable neurosteroid formulation of  claim 1 ,
 comprising nanoparticles having a D50 of less than 500 nm;   wherein the formulation is an intravenous formulation; and   the neurosteroid is ganaxolone.   
     
     
         3 . The injectable neurosteroid formulation of  claim 1  or  2 , wherein the at least one surface stabilizer is a polymeric surface stabilizer and the polymeric surface stabilizer is hydroxyethyl starch, dextran, povidone, or a mixture of any the foregoing. 
     
     
         4 . The injectable neurosteroid formulation of any one of  claims 1  to  3 , wherein the formulation comprises
 an additional surface stabilizer and the additional surface stabilizer is an ionic or nonionic surfactant; and 
 an antifoaming agent. 
 
     
     
         5 . The injectable neurosteroid formulation of  claim 4 , wherein
 the polymeric surface stabilizer is hydroxyethyl starch;   the surfactant is sodium cholate, sodium deoxycholate, sodium cholesterol sulfate, or a mixture of any of the foregoing; and   the antifoaming agent is simethicone.   
     
     
         6 . The injectable neurosteroid formulation of any one of  claims 1  to  5  additionally comprising a cryoprotectant, wherein the cryoprotectant is sucrose, dextrose, lactose, D-sorbitol, or a mixture of any of the foregoing. 
     
     
         7 . The injectable neurosteroid formulation of any one of  claims 1  to  6  additionally comprising one or more of the following
 (a) 0.5% to 1.5% sodium chloride (weight percent); 
 (b) a buffer; 
 (c) a preservative, wherein the preservative is benzyl alcohol, chlorbutanol, 2-ethoxyethanol, parabens (including methyl, ethyl, propyl, butyl, and combinations), benzoic acid, sorbic acid, chlorhexidene, phenol, 3-cresol, thimerosal, a phenylmercurate salt, or a mixture of any of the foregoing. 
 
     
     
         8 . The injectable neurosteroid formulation of  claim 1 , wherein
 the neurosteroid is ganaxolone or allopregnanolone;   the at least one surface stabilizer is a polymeric surface stabilizer selected from hydroxyethyl starch, dextran, povidone, and a mixture of any of the foregoing, wherein the (wt:wt) ratio of the neurosteroid to the polymeric surface stabilizer is about 4:1 to about 0.5:1; and   the formulation comprises an additional surface stabilizer and the additional surface stabilizer is a surfactant, selected from sodium deoxycholate, sodium cholesterol sulfate, and a mixture of any of the foregoing; wherein the ratio of neurosteroid to surfactant (w:w) is about 10:1.5 to about 10:0.1.   
     
     
         9 . The formulation of any one of  claims 1  to  8 , wherein the formulation is in the form of a lyophilized powder. 
     
     
         10 . The formulation any one of  claims 1  to  9 , wherein the formulation is an aqueous suspension and the neurosteroid concentration is about 0.1 mg/mL to about 300 mg/mL. 
     
     
         11 . The injectable neurosteroid formulation of  claim 1 , wherein the formulation is an aqueous formulation comprising
 (a) nanoparticles having a D50 of less than 500 nm, the nanoparticles comprising ganaxolone, wherein the weight percent of the ganaxolone is 1 to 10%;   (b) a polymeric surface stabilizer selected from hydroxy ethyl starch, dextran, and povidone, wherein the weight percent of the polymeric surface stabilizer is 2 to 20%;   (c) an additional surface stabilizer wherein the additional surface stabilizer is an ionic or nonionic surfactant selected from sodium cholate, sodium deoxycholate, and sodium cholesterol sulfate, wherein the weight percent of surfactant is 0.1% to 2.0%; and   (d) an antifoaming agent.   
     
     
         12 . The injectable neurosteroid formulation of  claim 1  wherein the formulation is an aqueous formulation comprising
 (a) nanoparticles having a D50 of less than 500 nm, the nanoparticles comprising ganaxolone, wherein the weight percent of the ganaxolone is about 5%; 
 (b) a polymeric surface stabilizer selected from hydroxy ethyl starch 130/0.4 and plasdone C-12, wherein the weight percent of the polymeric surface stabilizer is about 5% to about 10%; 
 (c) an additional surface stabilizer wherein the additional surface stabilizer is sodium deoxycholate, wherein the weight percent of sodium deoxycholate is about 0.75%; and 
 (d) simethicone, wherein the weight percent of simethicone is 0.009%. 
 
     
     
         13 . A method for sterilizing the injectable neurosteroid nanoparticle formulation of any one of  claims 1  to  12 , comprising subjecting the formulation to ebeam radiation, wherein the method produces a sterilized neurosteroid nanoparticle formulation containing a degradant concentration of not more than 0.2% w/w of neurosteroid. 
     
     
         14 . The injectable neurosteroid formulation of any one of  claims 1  to  12 , wherein the formulation has been sterilized by ebeam irradiation and wherein the formulation contains a degradant concentration of not more than 0.2% w/w of the neurosteroid. 
     
     
         15 . The injectable neurosteroid formulation of  claim 14 , wherein the ebeam irradiation is a cumulative dose of about 25 kGray. 
     
     
         16 . An injectable ganaxolone nanoparticulate formulation comprising:
 (a) ganaxolone nanoparticles having a D50 of 2000 nm or less and (b) at least one surface stabilizer;   wherein in comparative pharmacokinetic testing with an injectable non-particulate ganaxolone formulation of the same dosage strength the nanoparticulate formulation exhibits a greater Cmax than the non-particulate ganaxolone formulation.   
     
     
         17 . An injectable ganaxolone nanoparticulate formulation comprising:
 (a) ganaxolone nanoparticles having a D50 of 2000 nm or less and (b) at least one surface stabilizer;   wherein in comparative pharmacokinetic testing with an injectable non-particulate ganaxolone formulation of the same dosage strength the nanparticulate formulation exhibits a greater brain concentration at any time from 15 to 100 minutes after administration than the non-particulate ganaxolone formulation exhibits at the same time after administration.   
     
     
         18 . A method of treating a patient having a seizure disorder, stroke, or traumatic brain injury, the method comprising administering intravenously a therapeutically effective amount of the injectable neurosteroid formulation of any one of  claims 1  to  17 , wherein the neurosteroid is ganaxolone. 
     
     
         19 . The method of  claim 18 , wherein the seizure disorder is status epilepticus, refractory status epilepticus, super refractory status epilepticus, or PCDH19 female pediatric epilepsy. 
     
     
         20 . The method of  claim 18  wherein the dosage of ganaxolone administered is from about 1 mg/kg to about 200 mg/kg. 
     
     
         21 . The method of  claim 18  or  19  comprising administering a single bolus dose of the formulation to the patient; wherein the single bolus dose provides a sufficient amount of ganaxolone to provide a plasma C max  of ganaxolone of at least 1000 ng/mL in the patient. 
     
     
         22 . The method of  claim 18  or  19  comprising administering multiple bolus doses of the ganaxolone formulation to the patient, wherein the multiple bolus doses are given over 1 to 10 days at intervals of 1 to 24 hours, wherein each bolus dose provides a sufficient amount of ganaxolone to produce a plasma C max  of ganaxolone of at least 1000 ng/mL in the patient. 
     
     
         23 . The method of  claim 18  or  19  comprising administering an intravenous infusion of the ganaxolone formulation to the patient, with or without an initial bolus dose, for 1 to 10 consecutive days at a rate of 1 to 10 mg/kg/hr without an initial bolus dose. 
     
     
         24 . The method of  claim 23  comprising
 administering an initial bolus dose of from about 1 mg/kg to about 20 mg/kg ganaxolone, followed within 24 hours by administration of an intravenous infusion of the ganaxolone formulation for 1 to 10 consecutive days at a rate of 1 to 10 mg/kg/hr; sufficient amount of ganaxolone to provide an initial plasma C max  of ganaxolone of at least 1000 ng/mL in the patient and the concentration of ganaxolone in the patient's plasma does not fall below 25% of the initial C max  until after the infusion is concluded. 
 
     
     
         25 . The method any one of  claims 18  to  24  wherein
 the injectable ganaxolone formulation is a first active agent and is administered concurrently or sequentially with at least one additional active agent; and 
 the at least one additional active agent is an anticonvulsant or anesthetic/sedative.