Administration of Iloprost as Aerosol Bolus

Abstract

The present invention relates to novel methods, compositions and kits useful for the treatment of pulmonary diseases such as pulmonary arterial hypertension. In particular, aerosolisable compositions of iloprost are provided which are for use in inhalation therapy. Their administration is by bolus inhalation, which is patient-friendly, effective, and well tolerated. Bolus inhalation may, for example, be achieved using an efficient nebuliser based on the vibrating mesh technology.

1 - 15 . (canceled) 
     
     
         16 . A pharmaceutical composition comprising an active ingredient selected from iloprost and salts thereof for use as an aerosol for pulmonary administration to a patient in need thereof, wherein an amount of the composition comprises an effective single dose of the active ingredient and is provided in aerosolised form for bolus inhalation within a period of 2 minutes or less. 
     
     
         17 . The composition of  claim 16 , wherein the effective single dose is from about 1.5 μg to about 5.0 μg. 
     
     
         18 . The composition of  claim 16 , wherein the amount of the composition has a strength of 10 μg/mL or more. 
     
     
         19 . The composition of  claim 16 , wherein the effective single dose is 2.5 μg and the amount of the composition has a strength of 10 μg/mL. 
     
     
         20 . The composition of  claim 16 , wherein the effective single dose is 5 μg and the amount of the composition has a strength of 20 μg/mL. 
     
     
         21 . The composition of  claim 16 , wherein the composition is formulated as an aqueous solution further comprising one or more of:
 (a) a cosolvent;   (b) an isotonising agent;   (c) a pH-adjusting agent; and   (d) a stabilising agent.   
     
     
         22 . A method of treating a patient suffering from pulmonary arterial hypertension, comprising:
 (a) providing a pharmaceutical composition comprising an active ingredient selected from iloprost and salts thereof;   (b) providing an inhaler adapted for delivering an amount of the composition comprising an effective single dose of the active ingredient in aerosolised form for bolus inhalation within a period of 2 minutes or less; and   (c) administering the composition as an aerosol bolus to the patient by using the inhaler.   
     
     
         23 . The method of  claim 22 , wherein administering the composition requires 12 or less breathing manoeuvres. 
     
     
         24 . The method of  claim 22 , wherein administering the composition requires 8 or less breathing manoeuvres. 
     
     
         25 . The method of  claim 22 , wherein the inhaler is adapted to emit the composition in aerosolised form at an output rate of 0.5 mL/min or more. 
     
     
         26 . The method of  claim 22 , wherein the inhaler is adapted to emit the composition in aerosolised form at a rate of 5 μg of iloprost per minute or more. 
     
     
         27 . The method of  claim 22 , wherein the inhaler is adapted to emit, per inhalation phase, a predetermined volume of aerosol-free air immediately following a predetermined volume of the aerosol. 
     
     
         28 . The method of  claim 27 , wherein the predetermined volume of aerosol-free air is emitted by the inhaler over a period of 0.2 to 2 seconds at the end of each inhalation phase. 
     
     
         29 . The method of  claim 27 , wherein the predetermined volume of the aerosol is emitted by the inhaler over a period of 3 to 6 seconds per inhalation phase. 
     
     
         30 . The method of  claim 22 , wherein the inhaler is selected from metered-dose inhalers, soft mist inhalers, and vibrating mesh nebulisers. 
     
     
         31 . The method of  claim 22 , wherein administering the composition requires not more than four breathing manoeuvres. 
     
     
         32 . The method of  claim 22 , wherein the composition is aerosolised by a soft mist inhaler or a vibrating mesh nebuliser and the composition is formulated as an aqueous solution further comprising one or more of:
 (a) a cosolvent;   (b) an isotonising agent;   (c) a pH-adjusting agent; and   (d) a stabilising agent.   
     
     
         33 . The method of  claim 22 , wherein per inhalation phase, a predetermined volume of aerosol-free air is emitted immediately following the aerosol, and wherein a ratio of the aerosol volume to the volume of aerosol-free air is not higher than about 75:25. 
     
     
         34 . The method of  claim 22 , wherein per inhalation phase, a predetermined volume of aerosol-free air is emitted immediately following the aerosol, and wherein a ratio of the aerosol volume to the volume of aerosol-free air is not higher than about 85:15. 
     
     
         35 . A pharmaceutical kit comprising:
 (a) a composition comprising an active ingredient selected from iloprost and salts thereof; and   (b) an inhaler adapted for providing an amount of the composition comprising an effective single dose of the active ingredient in aerosolised form for bolus inhalation within a period of 2 minutes or less.   
     
     
         36 . The pharmaceutical kit of  claim 35 , wherein the inhaler is adapted to emit the composition at an output rate of 0.5 mL/min or more. 
     
     
         37 . The pharmaceutical kit of  claim 35 , wherein the inhaler is adapted to emit the composition at a rate of 5 μg of iloprost per minute or more. 
     
     
         38 . The pharmaceutical kit of  claim 35 , wherein the inhaler is adapted to emit, per inhalation phase, a predetermined volume of aerosol-free air immediately following a predetermined volume of the aerosol. 
     
     
         39 . The pharmaceutical kit of  claim 35 , wherein the inhaler is selected from metered-dose inhalers, soft mist inhalers, and vibrating mesh nebulisers. 
     
     
         40 . The pharmaceutical kit of  claim 35 , wherein the composition is formulated as an aqueous solution further comprising one or more of:
 (a) a cosolvent;   (b) an isotonising agent;   (c) a pH-adjusting agent; and   (d) a stabilising agent.   
     
     
         41 . The pharmaceutical kit of  claim 35  further comprising
 (d) an electronic data storage means capable of controlling the operation of the inhaler so as to provide the amount of the composition comprising the effective single dose of the active ingredient in aerosolised form for bolus inhalation within the period of 2 minutes or less. 
 
     
     
         42 . A nebulised aerosol comprising at least about 0.5 μg of iloprost or an equivalent amount of a salt thereof per litre of aerosol volume. 
     
     
         43 . The nebulised aerosol of  claim 42 , being emitted from a nebuliser
 (a) at an inspiratory flow rate from about 10 L/min to about 20 L/min;   and/or   (b) at an output rate of at least 0.5 to 1.5 mL/min during active nebulisation;   and/or   (c) such as to deliver a dose of 2.5 μg or more during four or less breathing manoeuvres.