Inhalable pharmaceutical compositions

Abstract

Inhalable pharmaceutical compositions can include an aqueous dispersion of particles including a hydrophobic bioactive agent (e.g., CoQ10) suitable for continuous aerosolization. Due to their chemical composition and methods of manufacture, the pharmaceutical compositions exhibit distinctive physicochemical properties that provide advantageous aerosol transmission and output.

1 . An inhalable pharmaceutical composition comprising a dispersion of liposomal particles suitable for continuous aerosolization, the composition comprising:
 a dispersion of liposomal particles having an average diameter between about 30 and 500 nm, each liposomal particle comprising a hydrophobic bioactive agent, a phospholipid, and an aqueous dispersion vehicle,   wherein the ratio of hydrophobic bioactive agent:phospholipid is between about 5:1 and about 1:5, the hydrophobic bioactive agent is between about 0.1 and 30% w/w of the composition, the phospholipid is between about 0.1 and 30% w/w of the composition, and the liposomal particles are dispersed within the aqueous dispersion vehicle, and   
       wherein, upon administration to a subject, the composition is characterized by continuous aerosolization sufficient to provide a therapeutic dose of the hydrophobic bioactive agent to the subject. 
     
     
         2 . The inhalable pharmaceutical composition of  claim 1 , wherein the aqueous dispersion vehicle comprises water or an aqueous salt solution. 
     
     
         3 . The inhalable pharmaceutical composition of  claim 1 , wherein the dispersion of liposomal particles is in the form of a continuous respirable aerosol comprising a plurality of aqueous droplets containing a dispersion of liposomal particles and having amass median aerodynamic diameter (MMAD) between about 1 and 5 μm. 
     
     
         4 . The inhalable pharmaceutical composition of  claim 1 , wherein:
 the composition is characterized by an average percent transmission (APT) between about 50 and 100% over at least 15 minutes of continuous aerosolization;   the plurality of droplets has a MMAD between about 1 and 5 μm over at least 15 minutes of continuous aerosolization;   the composition is characterized by an APT between about 50 and 100% after at least seven days of storage;   the composition has a flow index (n) of about 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, or 1.3;   the composition has a viscosity (η) of about 0.1, 0.15, 0.2, 1, 100, or 110 cP;   the composition has a zeta potential of about 2.5, 1.5, −2.5, −10, −50, −55, or −60 mV;   the composition has a surface tension of about 25, 30, 35, 40, 45, or 50 mN/m; or   the composition has a yield stress (α) of about 11, 12, 13, 14, 15, 16, 17, or 18 mPa.   
     
     
         5 . (canceled) 
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . The inhalable pharmaceutical composition of  claim 1 , wherein the liposomal particles have an average diameter between about 30 and 500 nm after at least seven days of storage. 
     
     
         9 .- 14 . (canceled) 
     
     
         15 . The inhalable pharmaceutical composition of  claim 1 , wherein the dispersion of liposomal particles have an average diameter between about 30 and 100 nm, 50 and 150 nm, 30 and 300 nm, 100 and 400 nm, or 200 and 300 nm. 
     
     
         16 . (canceled) 
     
     
         17 . The inhalable pharmaceutical composition of  claim 1 , wherein the composition does not comprise an opsonization reducer. 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . The inhalable pharmaceutical composition of  claim 1 , wherein the hydrophobic bioactive agent comprises CoQ10. 
     
     
         22 . The inhalable pharmaceutical composition of  claim 1 , wherein the hydrophobic bioactive agent is about 4% w/w or less of the composition. 
     
     
         23 . (canceled) 
     
     
         24 . The inhalable pharmaceutical composition of  claim 1 , wherein the phospholipid comprises DPPC, DSPC, DMPC, or a combination thereof. 
     
     
         25 . The inhalable pharmaceutical composition of  claim 1 , wherein the phospholipid is about 3% w/w or less of the composition. 
     
     
         26 . The inhalable pharmaceutical composition of  claim 1 , wherein the ratio of hydrophobic bioactive agent:phospholipid is about 1:1, 4:3, or 4:2.5. 
     
     
         27 . The inhalable pharmaceutical composition of  claim 1 , further comprising sodium chloride in an amount less than about 1.0% w/v of the composition. 
     
     
         28 . (canceled) 
     
     
         29 . The inhalable pharmaceutical composition of  claim 1 , wherein the dispersion is suspension, nano-suspension, emulsion, or microemulsion. 
     
     
         30 . (canceled) 
     
     
         31 . An inhalable pharmaceutical composition comprising a dispersion of liposomal particles suitable for continuous aerosolization, the composition comprising:
 a dispersion of liposomal particles having an average diameter between about 30 and 300 nm, each liposomal particle comprising CoQ10, DPPC, and an aqueous dispersion vehicle,   wherein the ratio of CoQ10:DPPC is between about 5:1 and about 1:5, the CoQ10 is between about 0.1 and 6% w/w of the composition, and the liposomal particles are dispersed within the aqueous dispersion vehicle, and   
       wherein, upon administration to a subject, the composition is characterized by continuous aerosolization sufficient to provide a therapeutic dose of the hydrophobic bioactive agent to the subject. 
     
     
         32 . An inhalable pharmaceutical composition comprising a dispersion of liposomal particles suitable for continuous aerosolization, the composition comprising:
 a dispersion of liposomal particles having an average diameter between about 30 and 300 nm, each liposomal particle comprising CoQ10, DSPC, and an aqueous dispersion vehicle,   wherein the ratio of CoQ10:DSPC is between about 5:1 and about 1:5, the CoQ10 is between about 0.1 and 6% w/w of the composition, and the liposomal particles are dispersed within the aqueous dispersion vehicle, and   
       wherein, upon administration to a subject, the composition is characterized by continuous aerosolization sufficient to provide a therapeutic dose of the hydrophobic bioactive agent to the subject. 
     
     
         33 . An inhalable pharmaceutical composition comprising a dispersion of liposomal particles suitable for continuous aerosolization, the composition comprising:
 a dispersion of liposomal particles having an average diameter between about 30 and 300 nm, each liposomal particle comprising CoQ10, DMPC, and an aqueous dispersion vehicle,   wherein the ratio of CoQ10:DMPC is between about 5:1 and about 1:5, the CoQ10 is between about 0.1 and 6% w/w of the composition, and the liposomal particles are dispersed within the aqueous dispersion vehicle, and   
       wherein, upon administration to a subject, the composition is characterized by continuous aerosolization sufficient to provide a therapeutic dose of the hydrophobic bioactive agent to the subject. 
     
     
         34 . (canceled) 
     
     
         35 . A method for preparing an inhalable pharmaceutical composition comprising the steps of: hydrating a phospholipid, thereby forming a hydrated phospholipid;
 mixing the hydrated phospholipid, a hydrophobic bioactive agent, and an aqueous dispersion vehicle, thereby producing a mixture; and   homogenizing the mixture, thereby producing a dispersion of liposomal particles comprising the phospholipid and hydrophobic bioactive agent dispersed within the aqueous dispersion vehicle and having an average diameter between about 30 and 500,
 wherein the ratio of hydrophobic bioactive agent:phospholipid is between about 5:1 and about 1:5, the hydrophobic bioactive agent is between about 0.1 and 30% w/w of the composition, and the phospholipid is between about 0.1 and 30% w/w of the composition, and 
   wherein, upon administration to a subject, the composition is characterized by continuous aerosolization sufficient to provide a therapeutic dose of the hydrophobic bioactive agent to the subject.   
     
     
         36 . The method of  claim 35 , further comprising:
 aerosolizing the dispersion of liposomal particles, thereby forming a respirable aerosol comprising a plurality of droplets, each droplet comprising a dispersion of liposomal particles and having a mass median aerodynamic diameter (MMAD) between about 1 and 5 μm.   
     
     
         37 . The method of  claim 35 , wherein:
 mixing comprises high shear mixing for up to about 5 minutes at about 10,000 to 20,000 rpm and at about 50 to 65° C.;   homogenizing comprises microfluidization;   homogenizing comprises high pressure homogenization for about 1-50 passes at about 30,000 psi and at about 50 to 65° C.;   homogenizing comprises ultrasonic homogenization; or   aerosolization comprises vibrating mesh nebulization.   
     
     
         38 .- 55 . (canceled) 
     
     
         56 . An inhalable pharmaceutical composition prepared by a process comprising the steps of hydrating a phospholipid, thereby forming a hydrated phospholipid;
 mixing the hydrated phospholipid, a hydrophobic bioactive agent, and an aqueous dispersion vehicle, thereby producing a mixture; and   homogenizing the mixture, thereby producing a dispersion of liposomal particles comprising the phospholipid and hydrophobic bioactive agent dispersed within the aqueous dispersion vehicle and having an average diameter between about 30 and 500,
 wherein the ratio of hydrophobic bioactive agent:phospholipid is between about 5:1 and about 1:5, the hydrophobic bioactive agent is between about 0.1 and 30% w/w of the composition, and the phospholipid is between about 0.1 and 30% w/w of the composition, and 
   wherein, upon administration to a subject, the composition is characterized by continuous aerosolization sufficient to provide a therapeutic dose of the hydrophobic bioactive agent to the subject.   
     
     
         57 .- 60 . (canceled)