Particulate materials

Abstract

Embodiments of the invention relate to particles of active substances, methods for preparing the particles, formulations containing the particles, and metered dose inhalers containing such particles or formulations. In one embodiment, a composition of an aerosol formulation is provided and contains a particulate active substance of non-micronized, solid particles having a mass median aerodynamic diameter of less than 10 μm suspended in a hydrofluorocarbon fluid vehicle at a concentration within a range from about 0.2% w/v to about 5% w/v. The aerosol formulation exhibits a flocculation volume of about 85% or greater about 1 minute after mixing the particulate active substance and the hydrofluorocarbon fluid vehicle. The particulate active substance contains an alkaloid ergotamine, pharmaceutically acceptable salts thereof, analogues thereof, or derivatives thereof. In some examples, the alkaloid ergotamine contains dihydroergotamine, such as dihydroergotamine mesylate and the hydrofluorocarbon fluid vehicle contains HFA 134a, HFA 227ea, or mixtures thereof.

1 . An aerosol formulation containing a particulate active substance having a mass median aerodynamic diameter (MMAD) of less than 10 μm, suspended in a nonsolvent hydrofluorocarbon fluid vehicle at a concentration of 0.5% w/v or greater. 
     
     
         2 . An aerosol formulation according to  claim 1 , wherein the particulate active substance has a MMAD of less than 5 μm. 
     
     
         3 . An aerosol formulation according to  claim 1 , wherein the concentration of the active substance in the vehicle is from 0.5 to 1.5% w/v. 
     
     
         4 . An aerosol formulation according to  claim 1 , wherein the fluid vehicle is either 1,1,1,2-tetrafluoroethane (HFA 134a) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227ea) or a mixture thereof. 
     
     
         5 . An aerosol formulation according to  claim 4 , wherein the active substance is a pharmaceutically or nutraceutically active substance which is suitable for delivery by inhalation. 
     
     
         6 . An aerosol formulation according to  claim 4 , which contains no or substantially no dispersion enhancing or stabilizing additives or co-solvents or lubricity enhancing additives. 
     
     
         7 . An aerosol formulation of  claim 6 , which is suitable for use in a metered dose inhaler. 
     
     
         8 . An aerosol formulation of  claim 4 , which when delivered in a succession of equal volume doses using a metered dose inhaler, or when delivered in a succession of equal volume doses into a cascade impactor, gives one or more of the following results:
 a) the relative standard deviation RSD (ie, the standard deviation expressed as a percentage of the mean value) in the quantity of active substance delivered in each dose is no more than 15% over 100 successive doses;   b) the RSD in the fine particle content (the quantity of delivered active substance having a MMAD in the fine particle range, <3.5 μm) of the delivered doses is no more than 15% over 100 successive doses;   c) the RSD in the fine particle fraction contained in each dose (ie, the quantity of active substance having a MMAD in the fine particle range, expressed as a percentage of the total active substance content in the relevant dose) is no more than 17% over 100 successive doses;   d) the RSD in the MMAD of the active substance particles contained in each dose is no more than 9.5% over 100 successive doses;   e) the fine particle fraction contained in each dose is at least 25% over 100 successive doses;   f) the MMAD of the particles delivered in each dose is 4 μm or less over 100 successive doses.   
     
     
         9 . An aerosol formulation according to  claim 8 , which gives one or more of the results (a) to (f) after storage at 25° C. and 60% relative humidity for a period of at least 12 months. 
     
     
         10 . An aerosol formulation of  claim 1 , which when delivered to a live human or animal patient using a metered dose inhaler or an equivalent delivery device, leads to a more rapid release of the active substance into the patient's bloodstream than does a formulation containing, in the same fluid vehicle and at the same concentration, the same chemical entity having the same or a similar particle size but produced by micronisation. 
     
     
         11 . An aerosol formulation according to  claim 10 , which when delivered to a live human or animal patient using a metered dose inhaler or an equivalent delivery device, leads to the maximum concentration, C max , of the active substance in the patient's bloodstream being achieved within 30 minutes of delivery. 
     
     
         12 . An aerosol formulation according to  claim 11 , wherein C max  is achieved within 15 minutes of delivery. 
     
     
         13 . An aerosol formulation according to  claim 4 , which when delivered to a live human or animal patient using a metered dose inhaler or an equivalent delivery device, yields a higher total and/or maximum plasma concentration of the active substance in the patient, following dose delivery, than does a formulation containing, in the same fluid vehicle and at the same concentration, the same chemical entity having the same or a similar particle size but produced by micronisation. 
     
     
         14 . An aerosol formulation of  claim 4 , which exhibits a flocculation volume of 35% or greater 30 seconds after mixing of the active substance and vehicle. 
     
     
         15 . An aerosol formulation according to  claim 14 , which exhibits a flocculation volume in the relevant vehicle of 50% or greater 30 seconds after mixing. 
     
     
         16 . An aerosol formulation according to  claim 14 , wherein the defined flocculation volume is exhibited 5 minutes after mixing. 
     
     
         17 . An aerosol formulation according to  claim 16 , wherein the defined flocculation volume is exhibited 10 minutes after mixing. 
     
     
         18 . An aerosol formulation of  claim 4 , which exhibits a rate of change (decrease) in flocculation volume, during the first 60 seconds after thorough mixing of the active substance and vehicle, of 20% per minute or less. 
     
     
         19 . An aerosol formulation according to  claim 18 , which in the defined circumstances exhibits a rate of change (decrease) in flocculation volume, during the first 60 seconds after thorough mixing of the active substance and vehicle, of 10% per minute or less. 
     
     
         20 . An aerosol formulation according to  claim 18 , which in the defined circumstances exhibits a rate of change (decrease) in flocculation volume, during the first 120 seconds after thorough mixing of the active substance and vehicle, of 20% per minute or less. 
     
     
         21 . An aerosol formulation according to  claim 4 , which exhibits a flocculation volume, 5 minutes after mixing of the active substance and vehicle, which is at least 20% higher than that exhibited by a formulation, in the same vehicle and at the same concentration, containing the same chemical entity having the same or a similar particle size but prepared using a micronisation process. 
     
     
         22 . An aerosol formulation of  claim 4 , wherein the mass median aerodynamic diameter (MMAD) of the active substance particles is less than 3.5 μm. 
     
     
         23 . An aerosol formulation of  claim 4 , wherein the active substance is in the form of solid particles. 
     
     
         24 . An aerosol formulation of  claim 23 , wherein the active substance is in a crystalline form. 
     
     
         25 . An aerosol formulation according to  claim 24 , wherein the active substance has a crystalline form which is significantly longer in one dimension than in at least one other dimension. 
     
     
         26 . An aerosol formulation according to  claim 23 , wherein the active substance contains less than 200 ppm residual solvent. 
     
     
         27 . An aerosol formulation according to  claim 26 , wherein the active substance comprises a drug for use in the treatment of a condition selected from the group consisting of migraine, nausea, insomnia, allergic (including anaphylactic) reactions, neurological or psychiatric disorders, erectile dysfunction, diabetes and related disorders, cardiac disorders, convulsions, bronchial disorders, pain, inflammation and combinations thereof. 
     
     
         28 . An aerosol formulation according to  claim 4 , wherein the active substance has been prepared by contacting a solution or suspension of the active substance in a fluid carrier (the “target solution/suspension”) with a compressed fluid anti-solvent, under conditions which allow the anti-solvent simultaneously both to extract the fluid carrier from, and to disperse, the target solution/suspension so as to cause particles of the active substance to precipitate from it.