An inhalable formulation of fluticasone propionate and albuterol sulfate

Abstract

This invention relates to a fixed-dose dry powder inhalation formulation comprising fluticasone propionate and albuterol sulfate, together with an α-lactose monohydrate carrier. In the formulation, the albuterol sulfate stabilises fluticasone propionate.

1 . A dry powder inhalable formulation comprising fluticasone propionate, albuterol sulfate and a-lactose monohydrate, wherein the particle size distribution of the inhaled fluticasone propionate is d10=0.4-1.0 pm, d50=1.0-3.0 pm, d90=2.5-7.5 pm and NLT99%<10 pm. 
     
     
         2 . A dry powder inhalable formulation as claimed in  claim 1 , wherein the weight ratio of albuterol sulfate to fluticasone propionate is from 1.0-10.0 to 1.0, preferably from 2.0-5.0 to 1.0. 
     
     
         3 . A dry powder inhalable formulation as claimed in  claim 1 , wherein the formulation does not include a ternary excipient. 
     
     
         4 . A dry powder inhalable formulation as claimed in  claim 1 , wherein the formulation consists of fluticasone propionate, albuterol sulfate and a-lactose monohydrate. 
     
     
         5 . A method of treating asthma or COPD comprising administering to a subject in need thereof the dry powder inhalable formulation as claimed in  claim 1 . 
     
     
         6 . A method for the long-term treatment of asthma and/or COPD and the treatment of acute exacerbations of asthma and/or COPD, the method comprising administering the dry powder inhalable formulation as claimed in  claim 1  as a maintenance dose for the long-term treatment of asthma and pro re nata (p.r.n.) as a rescue medication for the treatment of acute exacerbations of asthma. 
     
     
         7 . The method of  claim 5 , wherein the total administered daily dose of fluticasone propionate does not exceed 1,000 pg, and wherein the total administered daily dose of albuterol sulfate does not exceed 800 pg. 
     
     
         8 . A process for preparing the dry powder inhalable formulation as claimed in  claim 1 , comprising mixing fluticasone propionate, albuterol sulfate and a-lactose monohydrate to form the formulation. 
     
     
         9 . A process as claimed in  claim 8 , comprising the steps of:
 (i) preparing a mixture of fluticasone propionate and a-lactose monohydrate to form a first blend;   (II) preparing a mixture of albuterol sulfate and a-lactose monohydrate to form a second blend; and   (Hi) mixing the first blend and the second blend to form the formulation.   
     
     
         10 . The process as claimed in  claim 9 , further comprising step (iv), wherein step (iv) includes conditioning the formulation. 
     
     
         11 . The process as claimed in  claim 10 , wherein step (iv) includes exposure of the formulation to 65% RH/30° C. for a duration of 21 to 36 days, or wherein step (iv) includes exposure of the formulation to 65% RH/30° C.for a duration of 28 to 35 days, or wherein step (iv) includes exposure of the formulation to 65% RH/30° C. for a duration of 28 days. 
     
     
         12 . The process as claimed in  claim 10 , wherein the formulation is loaded into a formulation reservoir of a dry powder inhaler, and the dry powder inhaler is placed on a tray prior to the performance of step (iv). 
     
     
         13 . The process as claimed in  claim 10 , wherein the formulation is loaded into a formulation reservoir of a dry powder inhaler, and the dry powder inhaler is placed on a tray and the inhaler and tray are wrapped with a polyethylene wrap prior to the performance of step (iv). 
     
     
         14 . A product obtainable by the process as claimed in  claim 8 . 
     
     
         15 . A process for preparing a dry powder inhalable formulation, comprising the steps of:
 (I) preparing a mixture of fluticasone propionate, albuterol sulfate and a-lactose monohydrate; and   (ii) conditioning the mixture.   
     
     
         16 . The process as claimed in  claim 15 , wherein step (ii) includes exposure of the formulation to 65% RH/30° C. for a duration of 21 to 36 days, or wherein step (ii) includes exposure of the formulation to 65% RH/30° C. for a duration of 28 to 35 days, or wherein step (ii) includes exposure of the formulation to 65% RH/30° C. for a duration of 28 days. 
     
     
         17 . The process as claimed in  claim 15  wherein the formulation is loaded into a formulation reservoir of a dry powder inhaler, and the dry powder inhaler is placed on a tray prior to the performance of step (ii). 
     
     
         18 . The process as claimed in  claim 15 , wherein the formulation is loaded into a formulation reservoir of a dry powder inhaler, and the dry powder inhaler is placed on a tray and the inhaler and tray are wrapped with a polyethylene wrap prior to the performance of step (ii). 
     
     
         19 . A product obtainable by the process as claimed in  claim 15 . 
     
     
         20 . A dry powder inhaler or a dry powder inhaler comprising a cyclone deagglomerator for breaking up agglomerates of the dry powder, wherein the dry powder inhaler further comprises the dry powder inhalable formulation as claimed in  claim 1 . 
     
     
         21 . The inhaler as claimed in  claim 20 , wherein the deagglomerator comprises:
 an inner wall defining a swirl chamber extending along an axis from a first end to a second end; a dry powder supply port in the first end of the swirl chamber for providing fluid communication between a dry powder delivery passageway of the inhaler and the first end of the swirl chamber; at least one inlet port in the inner wall of the swirl chamber adjacent to the first end of the swirl chamber providing fluid communication between a region exterior to the deagglomerator and the first end of the swirl chamber;   an outlet port providing fluid communication between the second end of the swirl chamber and a region exterior to the deagglomerator; and   vanes at the first end of the swirl chamber extending at least in part radially outwardly from the axis of the chamber, each of the vanes having an oblique surface facing at least in part in a direction transverse to the axis, whereby a breath induced low pressure at the outlet port causes air flows into the swirl chamber through the dry powder supply port and the inlet port.   
     
     
         22 . The inhaler as claimed in  claim 21 , comprising:
 a sealed reservoir including a dispensing port;   a channel communicating with the dispensing port and including a pressure relief port;   a conduit providing fluid communication between an interior of the sealed reservoir and the pressure relief port of the channel; and a cup assembly movably received in the channel and including, a recess adapted to receive formulation when aligned with the dispensing port, a first sealing surface adapted to seal the dispensing port when the recess is unaligned with the dispensing port, and a second sealing surface adapted to sealing the pressure relief port when the recess is aligned with the dispensing port and unseal the pressure relief port when the recess is unaligned with the dispensing port.   
     
     
         23 . (canceled) 
     
     
         24 . A dry powder inhalable formulation as claimed in  claim 1 , wherein the particle size distribution of the inhaled albuterol sulfate is d10=0.4-1.0 pm, d50=1.0-3.0 pm, d90=2.5-9.0 pm and NLT99%<10 pm. 
     
     
         25 . A dry powder inhalable formulation as claimed in  claim 1 , wherein the particle size distribution of the inhaled α-lactose monohydrate is d10=10-25 pm, d50=85-105 pm, d90=140-180 pm, NLT99%<300 pm and 1.5-8.5%<10 pm, or d10=19-43 pm, d50=50-65 pm, d90=75-106 pm, NLT99%<300 pm and 1.5-2-5%<10 pm.