Modafinil pharmaceutical compositions

Abstract

Pharmaceutical compositions comprising modafinil in the form of particles of defined size. The particle size of modafinil can have a significant effect on the potency and safety profile of the drug.

What is claimed is:  
     
         1 . A pharmaceutical composition comprising two or more portions of solid modafinil particles from a bulk batch of modafinil, wherein each portion has a bounded particle size range and wherein one or more particle size ranges present in the bulk batch are not represented in the pharmaceutical composition.  
     
     
         2 . A pharmaceutical composition comprising two or more portions of solid modafinil particles, wherein each portion has a bounded particle size range and wherein there is a particle size range between the size ranges represented in the two or more portions that is not represented in the pharmaceutical composition.  
     
     
         3 . The pharmaceutical composition of  claim 1  wherein more than about 5% of the particles in the composition are larger than about 200 microns.  
     
     
         4 . The pharmaceutical composition of  claim 3  wherein the composition has substantially the same dissolution profile as a modafinil composition in which at least about 95% of the particles are smaller than about 200 microns.  
     
     
         5 . The pharmaceutical composition of  claim 3  wherein the composition has substantially the same dissolution profile as PROVIGIL® (modafinil).  
     
     
         6 . The pharmaceutical composition of  claim 3  wherein at least about 80% of the modafinil dissolves after about 45 minutes.  
     
     
         7 . The pharmaceutical composition of  claim 3  wherein the composition is bioequivalent (80-125%) to a modafinil composition in which at least about 95% of the particles are smaller than about 200 microns.  
     
     
         8 . The pharmaceutical composition of  claim 3  wherein the composition is bioequivalent (80-125%) to PROVIGIL® (modafinil).  
     
     
         9 . The pharmaceutical composition of  claim 4  in which fewer than about 85% of the particles are small particles, i.e., smaller than about 200 microns.  
     
     
         10 . The pharmaceutical composition of  claim 5  in which fewer than about 85% of the particles are small particles, i.e., smaller than about 200 microns.  
     
     
         11 . The pharmaceutical composition of  claim 6  in which fewer than about 85% of the particles are small particles, i.e., smaller than about 200 microns.  
     
     
         12 . The pharmaceutical composition of  claim 7  in which fewer than about 85% of the particles are small particles, i.e., smaller than about 200 microns.  
     
     
         13 . The pharmaceutical composition of  claim 8  in which fewer than about 85% of the particles are small particles, i.e., smaller than about 200 microns.  
     
     
         14 . The pharmaceutical composition of  claim 4  in which fewer than about 75% of the particles are small particles, i.e., smaller than about 200 microns.  
     
     
         15 . The pharmaceutical composition of  claim 5  in which fewer than about 75% of the particles are small particles, i.e., smaller than about 200 microns.  
     
     
         16 . The pharmaceutical composition of  claim 6  in which fewer than about 75% of the particles are small particles, i.e., smaller than about 200 microns.  
     
     
         17 . The pharmaceutical composition of  claim 7  in which fewer than about 75% of the particles are small particles, i.e., smaller than about 200 microns.  
     
     
         18 . The pharmaceutical composition of  claim 8  in which fewer than about 75% of the particles are small particles, i.e., smaller than about 200 microns.  
     
     
         19 . The pharmaceutical composition of  claim 4  in which fewer than about 65% of the particles are small particles, i.e., smaller than about 200 microns.  
     
     
         20 . The pharmaceutical composition of  claim 5  in which fewer than about 65% of the particles are small particles, i.e., smaller than about 200 microns.  
     
     
         21 . The pharmaceutical composition of  claim 6  in which fewer than about 65% of the particles are small particles, i.e., smaller than about 200 microns.  
     
     
         22 . The pharmaceutical composition of  claim 7  in which fewer than about 65% of the particles are small particles, i.e., smaller than about 200 microns.  
     
     
         23 . The pharmaceutical composition of  claim 8  in which fewer than about 65% of the particles are small particles, i.e., smaller than about 200 microns.  
     
     
         24 . The pharmaceutical composition of  claim 4  in which fewer than about 50% of the particles are small particles, i.e., smaller than about 200 microns.  
     
     
         25 . The pharmaceutical composition of  claim 5  in which fewer than about 50% of the particles are small particles, i.e., smaller than about 200 microns.  
     
     
         26 . The pharmaceutical composition of  claim 6  in which fewer than about 50% of the particles are small particles, i.e., smaller than about 200 microns.  
     
     
         27 . The pharmaceutical composition of  claim 7  in which fewer than about 50% of the particles are small particles, i.e., smaller than about 200 microns.  
     
     
         28 . The pharmaceutical composition of  claim 8  in which fewer than about 50% of the particles are small particles, i.e., smaller than about 200 microns.  
     
     
         29 . The pharmaceutical composition of  claim 7  in which the small particles are smaller than about 175 microns.  
     
     
         30 . The pharmaceutical composition of claims  7  in which the small particles are smaller than about 150 microns.  
     
     
         31 . The pharmaceutical composition of  claim 7  in which the small particles are smaller than about 125 microns.  
     
     
         32 . The pharmaceutical composition of  claim 7  in which the small particles are smaller than about 100 microns.  
     
     
         33 . The pharmaceutical composition of  claim 7  in which the small particles are smaller than about 75 microns.  
     
     
         34 . The pharmaceutical composition of  claim 7  in which the small particles are smaller than about 50 microns.  
     
     
         35 . The pharmaceutical composition of  claim 7  in which the small particles are smaller than about 25 microns.  
     
     
         36 . The pharmaceutical composition of  claim 7  in which the small particles are smaller than about 10 microns.  
     
     
         37 . A pharmaceutical composition comprising modafinil prepared by the process of blending a first and a second portion of solid modafinil particles wherein said first portion has a pre-determined particle size range and said second portion has a pre-determined particle size range that is different from that of the first portion.  
     
     
         38 . A pharmaceutical composition comprising at least a first and a second portion of modafinil wherein: 
 a) the first portion of modafinil being in the form of solid modafinil particles is from a bulk batch and has a bounded particle size distribution; and    b) the second portion of modafinil being in the form of solid modafinil particles from a the same or another bulk batch and has a bounded particle size distribution;    wherein the combination of the first portion and the second portion yields a bounded particle size distribution that is different than the particle size distribution of the bulk batch and the other bulk batch if the other bulk batch is different from the first bulk batch.    
     
     
         39 . The pharmaceutical composition of  claim 38 , wherein 95% of the cumulative total of particles in the composition are smaller than or equal to about 200 microns in diameter.  
     
     
         40 . The pharmaceutical composition of  claim 38 , wherein at least one portion comprises small particles.  
     
     
         41 . The pharmaceutical composition of  claim 38 , wherein at least one other portion comprises large particles.  
     
     
         42 . The pharmaceutical composition of  claim 40 , wherein at least one other portion comprises very large particles.  
     
     
         43 . The pharmaceutical composition of  claim 40 , wherein the first portion comprises an effective amount of modafinil.  
     
     
         44 . The pharmaceutical composition of  claim 40 , wherein the first and second portion together comprise an effective amount of modafinil.  
     
     
         45 . The pharmaceutical composition of  claim 38 , wherein the first and second portion comprise at least 15 milligrams of modafinil having particle diameters of between about 10 microns and 80 microns.  
     
     
         46 . The pharmaceutical composition of  claim 38 , wherein the composition releases at least 80% of the modafinil in 45 minutes in a 0.1 N HCl solution.  
     
     
         47 . A method of formulating a composition of modafinil comprising the steps of: 
 a) providing a batch of modafinil, wherein the particles in the batch have a distribution of particle diameters;    b) separating the particles in the batch of modafinil into at least two discrete lots of modafinil particles, wherein each discrete lot contains modafinil of a defined particle diameter, thereby forming at least a first discrete lot and a second discrete lot;    c) blending a portion of the first lot with a portion of the second lot; and    d) forming a composition of modafinil from the blend of the first lot and the second lot.    
     
     
         48 . The method of  claim 47 , further comprising the step of adjusting the proportions of the first lot and the second lot in the composition to make a composition which releases at least 80% of the modafinil in 45 minutes in a 0.1 N HCl solution.  
     
     
         49 . A pharmaceutical dosage unit comprising an effective amount of modafinil wherein at least about 10% of the total cumulative modafinil particles are smaller than about 25 microns in diameter and more than about 5% of the total cumulative particles are more than about 200 microns in diameter.  
     
     
         50 . The pharmaceutical dosage unit of  claim 49  wherein at least about 15% of the total cumulative modafinil particles are smaller than or equal to about 25 microns in diameter and more than about 5% of the total cumulative particles are more than about 200 microns.  
     
     
         51 . The pharmaceutical dosage unit of  claim 49  wherein at least about 20% of the total cumulative modafinil particles are smaller than or equal to about 25 microns in diameter and more than about 5% of the total cumulative particles are more than about 200 microns.  
     
     
         52 . The pharmaceutical dosage unit of  claim 49  wherein at least about 25% of the total cumulative modafinil particles are smaller than or equal to about 25 microns in diameter and more than about 5% of the total cumulative particles are more than about 200 microns.  
     
     
         53 . The pharmaceutical dosage unit of  claim 48  wherein at least about 95% of the total cumulative modafinil particles are smaller than 400 microns in diameter.  
     
     
         54 . The pharmaceutical dosage unit of  claim 49  wherein at least about 95% of the total cumulative modafinil particles are smaller than 400 microns in diameter.  
     
     
         55 . The pharmaceutical dosage unit of  claim 50  wherein at least about 95% of the total cumulative modafinil particles are smaller than 400 microns in diameter.  
     
     
         56 . The pharmaceutical dosage unit of  claim 51  wherein at least about 95% of the total cumulative modafinil particles are smaller than 400 microns in diameter.  
     
     
         57 . The pharmaceutical dosage unit of  claim 52  wherein at least about 95% of the total cumulative modafinil particles are smaller than 400 microns in diameter.  
     
     
         58 . The pharmaceutical dosage unit of any one of claims  48 - 52  wherein the amount of modafinil is about 100 mg.  
     
     
         59 . The pharmaceutical dosage unit of any one of claims  48 - 52  wherein the amount of modafinil is about 200 mg.  
     
     
         60 . The pharmaceutical dosage unit of  claim 53  wherein more than about 10% of the total cumulative particles are more than about 200 microns.  
     
     
         61 . The pharmaceutical dosage unit of  claim 54  wherein more than about 10% of the total cumulative particles are more than about 200 microns.  
     
     
         62 . The pharmaceutical dosage unit of  claim 55  wherein more than about 10% of the total cumulative particles are more than about 200 microns.  
     
     
         63 . The pharmaceutical dosage unit of  claim 56  wherein more than about 10% of the total cumulative particles are more than about 200 microns.  
     
     
         64 . The pharmaceutical dosage unit of  claim 57  wherein more than about 10% of the total cumulative particles are more than about 200 microns.  
     
     
         65 . The pharmaceutical dosage unit of  claim 53  wherein more than about 15% of the total cumulative particles are more than about 200 microns.  
     
     
         66 . The pharmaceutical dosage unit of  claim 54  wherein more than about 15% of the total cumulative particles are more than about 200 microns.  
     
     
         67 . The pharmaceutical dosage unit of  claim 55  wherein more than about 15% of the total cumulative particles are more than about 200 microns.  
     
     
         68 . The pharmaceutical dosage unit of  claim 56  wherein more than about 15% of the total cumulative particles are more than about 200 microns.  
     
     
         69 . The pharmaceutical dosage unit of  claim 57  wherein more than about 15% of the total cumulative particles are more than about 200 microns.  
     
     
         70 . The pharmaceutical dosage unit of  claim 53  wherein more than about 20% of the total cumulative particles are more than about 200 microns.  
     
     
         71 . The pharmaceutical dosage unit of  claim 54  wherein more than about 20% of the total cumulative particles are more than about 200 microns.  
     
     
         72 . The pharmaceutical dosage unit of  claim 55  wherein more than about 20% of the total cumulative particles are more than about 200 microns.  
     
     
         73 . The pharmaceutical dosage unit of  claim 56  wherein more than about 20% of the total cumulative particles are more than about 200 microns.  
     
     
         74 . The pharmaceutical dosage unit of  claim 57  wherein more than about 20% of the total cumulative particles are more than about 200 microns.  
     
     
         75 . The pharmaceutical dosage unit of  claim 53  wherein more than about 25% of the total cumulative particles are more than about 200 microns.  
     
     
         76 . The pharmaceutical dosage unit of  claim 54  wherein more than about 25% of the total cumulative particles are more than about 200 microns.  
     
     
         77 . The pharmaceutical dosage unit of  claim 55  wherein more than about 25% of the total cumulative particles are more than about 200 microns.  
     
     
         78 . The pharmaceutical dosage unit of  claim 56  wherein more than about 25% of the total cumulative particles are more than about 200 microns.  
     
     
         79 . The pharmaceutical dosage unit of  claim 57  wherein more than about 25% of the total cumulative particles are more than about 200 microns.  
     
     
         80 . The pharmaceutical dosage unit of  claim 53  wherein more than about 30% of the total cumulative particles are more than about 200 microns.  
     
     
         81 . The pharmaceutical dosage unit of  claim 54  wherein more than about 30% of the total cumulative particles are more than about 200 microns.  
     
     
         82 . The pharmaceutical dosage unit of  claim 55  wherein more than about 30% of the total cumulative particles are more than about 200 microns.  
     
     
         83 . The pharmaceutical dosage unit of  claim 56  wherein more than about 30% of the total cumulative particles are more than about 200 microns.  
     
     
         84 . The pharmaceutical dosage unit of  claim 57  wherein more than about 30% of the total cumulative particles are more than about 200 microns.  
     
     
         85 . The pharmaceutical dosage unit of any one of claims  60 - 84  wherein the amount of modafinil is about 100 mg.  
     
     
         86 . The pharmaceutical dosage unit of any of claims  60 - 84  wherein the amount of modafinil is about 200 mg.  
     
     
         87 . A method of formulating a composition of modafinil comprising the steps of: 
 a) providing a first batch and a second batch of modafinil, wherein the particles in each batch have distribution of particle diameters;    b) separating the particles of the first batch of modafinil into at least two discrete lots of modafinil particles, wherein each discrete lot contains modafinil of a defined particle diameter, thereby forming at least a first discrete lot and a second discrete lot;    c) recombining at least one of the discrete lots with the second batch; and    d) altering the distribution of particle diameters of the particles in the second batch.    
     
     
         88 . A pharmaceutical composition comprising at least a first and second portion of modafinil wherein: 
 a) the first portion of modafinil being in the form of solid modafinil particles is from a bulk batch and has a bounded particle size distribution; and    b) a second portion of modafinil being in the form of solid modafinil particles from the same or another bulk batch and has a bounded particle size distribution;    wherein the combination of the first portion and the second portion yields a bounded particle size distribution that is different than the particle size distribution of the bulk batch and the other bulk batch if the other bulk batch is different from the first bulk batch, and    wherein the particle size distribution of the first batch is at least one particle size distribution selected from the group consisting of 0.01≦P≦200, 0.01≦P≦40, 40≦P≦80, 80≦P≦120, 120≦P≦160, 160≦P≦200, 0.01≦P≦10, 10≦P≦20, 20≦P≦30, 30≦P≦40, 40≦P≦50, 50≦P≦60, 60≦P≦70, 70≦P≦80, 80≦P≦90, 90≦P≦100, 100 ≦P≦110, 110≦P≦120, 120≦P≦130, 130≦P≦140, 140≦P≦150, 150≦P≦160, 160≦P≦170, 170≦P≦180, 180≦P≦190, and 190≦P≦200.    
     
     
         89 . The pharmaceutical composition of  claim 88 , wherein the particle size distribution of the second batch is at least one particle size distribution selected from the group consisting of 220<P≦400, 220<P≦310, 310≦P≦400, 220<P≦230, 230≦P≦240, and 240≦P≦250, 250≦P≦260, 260≦P≦270, 270≦P≦280, 280≦P≦290, 290≦P≦300, 300≦P≦310, 310≦P≦320, 330≦P≦340, 340≦P≦350, 350≦P≦360, 360≦P≦370, 370≦P≦380, 380≦P≦390, and 390≦P≦400.  
     
     
         90 . A pharmaceutical composition manufactured by the steps comprising: 
 a) preparing a bulk batch; and    b) removing at least one discrete lot of particles having a bounded particle size range from the bulk batch.    
     
     
         91 . A pharmaceutical composition obtained from a bulk batch of modafinil, wherein the pharmaceutical composition has a particle size distribution that is different from the particle size distribution of the bulk batch.  
     
     
         92 . The pharmaceutical composition of  claim 88 , further comprising a surfactant.  
     
     
         93 . The pharmaceutical composition of  claim 92 , wherein the surfactant is selected from the group consisting of non-ionic, ionic, and bile salt surfactants.  
     
     
         94 . The pharmaceutical composition of  claim 92 , wherein the surfactant is the ionic surfactant sodium dodecyl sulfate.  
     
     
         95 . The pharmaceutical composition of  claim 92 , wherein the surfactant is a non-ionic surfactant selected from the group consisting of polyoxethylene stearates and block copolymers of etheylene oxide and propylene oxide.  
     
     
         96 . The pharmaceutical composition of  claim 92 , wherein the surfactant is a bile salt surfactant selected from the group consisting of sodium cholate, sodium taurocholate and sodium deoxycholate.  
     
     
         97 . A method of altering the somnolent state of a mammal, said method comprising administering an effective amount of the composition of  claim 1  to said mammal.  
     
     
         98 . A method for enhancing alertness or increasing regularity of sleep rhythms in a mammal said method comprising administering an effective amount of the composition of  claim 1  to said mammal.  
     
     
         99 . A method of treating a mammal diagnosed with a modafinil-responsive disease or condition selected from the group consisting of narcolepsy, sleepiness, excessive sleepiness, excessive daytime sleepiness associated with narcolepsy, Parkinson's disease, urinary incontinence, multiple sclerosis fatigue, ADHD, Alzheimer's disorder, sleep apnea, obstructive sleep apnea, depression, and ischemia, said method comprising administering an amount of modafinil, as one or more oral unit doses, to said mammal, said oral unit doses comprising an effective amount of the composition of  claim 1 .  
     
     
         100 . A composition comprising two or more portions of solid modafinil particles from a bulk batch of modafinil, wherein each portion has a bounded particle size range and wherein one or more particle size ranges present in the bulk batch are not represented in the pharmaceutical composition.  
     
     
         101 . A composition comprising two or more portions of solid modafinil particles, wherein each portion has a bounded particle size range and wherein there is a particle size range between the size ranges represented in the two or more portions that is not represented in the pharmaceutical composition.  
     
     
         102 . The composition of  claim 100  wherein more than about 5% of the particles in the composition are larger than about 200 microns.  
     
     
         103 . The composition of  claim 102  wherein the composition has substantially the same dissolution profile as a modafinil composition in which at least about 95% of the particles are smaller than about 200 microns.  
     
     
         104 . The composition of  claim 102  wherein the composition has substantially the same dissolution profile as PROVIGIL® (modafinil).