Modafinil oral lyophilizate

Abstract

The invention concerns an oral lyophilizate comprising modafinil particles having a median diameter of about 10 to about 1000 μm in association with an appropriate amount of at least one excipient selected from the group consisting of fatty acid esters of glycerol, cyclic oligosaccharides, sweeteners or mixtures thereof.

1 . Oral lyophilizate comprising modafinil particles having a median diameter of about 10 to about 1000 μm in association with an appropriate amount of at least one excipient selected from the group consisting of fatty acid esters of glycerol, cyclic oligosaccharides, sweeteners or mixtures thereof.  
   
   
       2 . Oral lyophilizate according to  claim 1 , comprising a cyclic oligosaccharide and a fatty acid glycerol ester.  
   
   
       3 . Oral lyophilizate according to  claim 1 , wherein the fatty acid esters of glycerol are selected from the group consisting of fatty acid mono-, di- and/or triglycerides and mixtures thereof.  
   
   
       4 . Oral lyophilizate according to  claim 1 , wherein the fatty acid esters of glycerol are esters of saturated or unsaturated fatty acids containing 6 to 48 carbon atoms.  
   
   
       5 . Oral lyophilizate according to  claim 4 , wherein the fatty acids are selected from the group consisting of dibehenic acid, palmitostearic acid, stearic acid, oleic acid, linoleic acid, caprylic acid, capric acid or mixtures thereof.  
   
   
       6 . Oral lyophilizate according to  claim 5 , wherein the fatty acid is palmitostearic acid.  
   
   
       7 . Oral lyophilizate according to  claim 1 , wherein the fatty acid esters of glycerol are a mixture of mono-, di- and triglycerides of palmitostearic acid.  
   
   
       8 . Oral lyophilizate according to  claim 7 , wherein the diglyceride of palmitostearic acid represents the main fraction by weight of the total weight of the mixture of mono-, di- and triglycerides of palmitostearic acid.  
   
   
       9 . Oral lyophilizate according to  claim 1  comprising modafinil particles coated with fatty acid esters of glycerol.  
   
   
       10 . Oral lyophilizate according to  claim 1 , wherein the fatty acid esters of glycerol are present in an amount of up to about 50% by weight with respect to the weight of modafinil.  
   
   
       11 . Oral lyophilizate according to  claim 10 , wherein the fatty acid esters of glycerol are present in an amount of less than about 10% by weight with respect to the weight of modafinil.  
   
   
       12 . Oral lyophilizate according to  claim 1 , wherein the cyclic oligosaccharides are selected from natural cyclodextrins or derivatives thereof.  
   
   
       13 . Oral lyophilizate according to  claim 12 , wherein the cyclic oligosaccharides are selected from the group consisting of α-cyclodextrins, β-cyclodextrins, γ-cyclodextrins and ether derivatives thereof.  
   
   
       14 . Oral lyophilizate according to  claim 12 , wherein the ether derivatives of cyclodextrins are selected from the group consisting of methyl-, dimethyl-, trimethyl-, ethyl-, hydroxypropyl-, hydroxyethyl-, sulfobutyl-, glucosyl-and maltosyl ether derivatives of cyclodextrins.  
   
   
       15 . Oral lyophilizate according to  claim 13 , wherein the cyclodextrin is β-cyclodextrin.  
   
   
       16 . Oral lyophilizate according to  claim 1 , wherein the cyclic oligosaccharides are present in an amount up to 70% by weight with respect to the weight of modafinil.  
   
   
       17 . Oral lyophilizate according to  claim 1 , wherein the modafinil particles have a monodisperse particle size distribution.  
   
   
       18 . Oral lyophilizate according to  claim 1 , comprising discrete particle size lots of modafinil particles.  
   
   
       19 . Oral lyophilizate according to  claim 1 , wherein the modafinil particles have a median diameter between 10 μm and 315 μm.  
   
   
       20 . Oral lyophilizate according to  claim 19 , wherein the modafinil particles have a median diameter between 20 μm and 40 μm.  
   
   
       21 . Oral lyophilizate according to  claim 20 , comprising about 1% to about 5% by weight of a fatty acid glycerol ester with respect to the weight of modafinil.  
   
   
       22 . Oral lyophilizate according to  claim 1 , wherein the excipient is a sweetener.  
   
   
       23 . Oral lyophilizate according to  claim 22 , wherein the modafinil particle size has a median diameter between 100 μm and 500 μm.  
   
   
       24 . Oral lyophilizate according to claims  22 , wherein the sweetener is selected from the group consisting of aspartam, saccharine, sodium saccharinate, potassium acesulfam, maltitol, isomaltidex, sodium cyclamate, sucralose and mixtures thereof.  
   
   
       25 . Oral lyophilizate according to  claim 22 , wherein the modafinil particles have a median diameter of 10 to 100 μm.  
   
   
       26 . Oral lyophilizate according to  claim 25 , wherein the sweetener is selected from the group consisting of natural or synthetic sweeteners more than 100 times sweeter than saccharose.  
   
   
       27 . Oral lyophilizate according to  claim 26 , wherein the sweetener is selected from the group consisting of saccharine, sodium saccharinate, aspartam, sodium acesulfam, sucralose and alitame.  
   
   
       28 . Oral lyophilizate according to  claim 1 , wherein the modafinil particles have a median diameter of between 200 and about 1000 μm.  
   
   
       29 . Oral lyophilizate according to  claim 28 , which further comprises cyclic oligosaccharides.  
   
   
       30 . Oral lyophilizate according to  claim 1 , which further comprises one or more excipients selected from the group consisting of sweeteners, flavors, bitter blockers, taste enhancers, diluents, binders and surfactants.  
   
   
       31 . Oral lyophilizate according to  claim 30 , wherein the sweeteners are selected from the group consisting of aspartam, saccharine, sodium saccharinate, potassium acesulfam, maltitol, isomaltidex, sodium cyclamate sucralose and mixtures thereof.  
   
   
       32 . Oral lyophilizate according to  claim 30 , wherein the sweetener is present in an amount of about 0.5 to about 15% by weight with respect to the unit dose weight.  
   
   
       33 . Oral lyophilizate according to  claim 30 , wherein the binder is selected from the group consisting in dextran, polyvinylpyrrolidone, methylcellulose and hydroxymethylcellulose and mixtures thereof.  
   
   
       34 . Oral lyophilizate according to  claim 30 , wherein the binder is present in an amount up to about 15% by weight with respect to the unit dose weight.  
   
   
       35 . Oral lyophilizate according to  claim 30 , wherein the diluent is selected from the group consisting in lactose, mannitol and isomaltidex and mixtures thereof.  
   
   
       36 . Oral lyophilizate according to  claim 30 , wherein the diluent is present in an amount of up to about 25% by weight with respect to the unit dose weight.  
   
   
       37 . Oral lyophilizate according to  claim 30 , wherein the flavor is selected from the group consisting in peppermint, tutti frutti, pineapple, cherry, strawberry, banana, bubble gum, grape, raspberry and blackcurrant aromatic oils and mixtures thereof.  
   
   
       38 . Oral lyophilizate according to  claim 30 , wherein the flavor is present in an amount of about 1% to about 10% by weight with respect to the unit dose weight.  
   
   
       39 . Oral lyophilizate according to  claim 30 , wherein the surfactant is selected from the group consisting in sucroesters, polysorbates, poloxamers, PEF and sorbitan stearate and mixtures thereof.  
   
   
       40 . Oral lyophilizate according to  claim 30 , wherein the surfactant is present in amount of about 0.1% to about 5% by weight with respect to the unit dose weight.  
   
   
       41 . Oral lyophilizate according to  claim 30 , wherein the bitter blocker is present in an amount of up to about 15% in weight with respect to the unit dose weight.  
   
   
       42 . Oral lyophilizate according to  claim 1 , comprising about 50 mg to about 850 mg of modafinil.  
   
   
       43 . Oral lyophilizate according to  claim 1 , wherein more than 75% by weight of the active substance are dissolved within 30 minutes in 0.1 M HCl at 37° C.  
   
   
       44 . Oral lyophilizate according to  claim 1 , wherein less than 75% by weight of the active substance are dissolved within 30 minutes in 0.1 M HCl at 37° C.  
   
   
       45 . Oral lyophilizate according to  claim 1 , wherein the modafinil compound is racemic modafinil.  
   
   
       46 . Oral lyophilizate of  claim 1 , wherein the modafinil compound is the levorotatory isomer of modafinil.  
   
   
       47 . Oral lyophilizate of  claim 1 , wherein the modafinil compound is the dextrorotatory isomer of modafinil.  
   
   
       48 . Oral lyophilizate of  claim 1 , presenting a disintegration time of 2 to 60 seconds.  
   
   
       49 . Method for the manufacture of an oral lyophilizate according to  claim 1 , comprising the steps of: 
 (i) preparing a water suspension comprising modafinil particles having a median diameter of about 10 to about 1000 μm and at least one excipient selected from the group consisting of cyclic oligosaccharides, fatty acid esters of glycerol, sweeteners or a mixture thereof, and optionally one or more excipients; and    (ii) submitting the obtained suspension to lyophilization to obtain the oral lyophilizate.    
   
   
       50 . Method according to  claim 49 , wherein step (i) comprises: 
 a) preparing a mixture from modafinil particles having a median diameter of about 10 to about 1000 μm, at least one excipient selected from the group consisting of cyclic oligosaccharides, fatty acid esters of glycerol, sweeteners or a mixture thereof, and optionally one or more excipients;    b) granulating the resulting mixture; and    c) suspending the obtained granules in water.    
   
   
       51 . Method according to  claim 50 , wherein step a) comprises: 
 a1) heating the modafinil particles at a temperature between 300 to 500 C;    a2) mixing the modafinil particles with a melted fatty acid ester of glycerol;    a3) mixing the obtained coated modafinil particles with at least one excipient selected from the group consisting of cyclic oligosaccharides, fatty acid esters of glycerol, sweeteners or a mixture thereof, and optionally one or more excipients.    
   
   
       52 . A method of treating a disease or disorder in a subject in need thereof comprising administering to a subject a therapeutically effective amount of an oral lyophilizate according to  claim 1 .  
   
   
       53 . The method of  claim 52 , wherein the composition is administered for the treatment of sleepiness, promotion of wakefulness, treatment of Parkinson's disease, cerebral ischemia, stroke, sleep apneas, eating disorders, stimulation of appetite and weight gain, treatment of attention deficit hyperactivity disorder and fatigue, shift work, sleep disorders, depression and improvement of cognitive dysfunction.