Compositions for respiratory delivery of active agents and associated methods and systems

Abstract

Compositions, methods and systems are provided for pulmonary or nasal delivery of active agents via a metered dose inhaler. In one embodiment, the compositions include a suspension medium, active agent particles, and suspending particles, in which the active agent particles and suspending particles form a co-suspension within the suspension medium.

1 . A pharmaceutical composition deliverable from a metered dose inhaler, comprising:
 a suspension medium comprising a pharmaceutically acceptable propellant;   a first population of particles comprising active agent particles, wherein the active agent particles comprise respirable, micronized active agent; and   a second population of particles comprising respirable suspending particles, wherein the respirable suspending particles are substantially insoluble in the suspension medium, and comprise a phospholipid; and   wherein a weight ratio of total mass of respirable suspending particles to total mass of active agent particles ranges from 1:1 to about 200:1.   
     
     
         2 . The pharmaceutical composition according to  claim 1 , wherein at least 90% of the active agent particles by volume exhibits an optical diameter of 7 μm or less. 
     
     
         3 . The pharmaceutical composition according to  claim 1 , wherein at least 50% of the active agent particles by volume exhibits an optical diameter of 5 μm or less. 
     
     
         4 . The pharmaceutical composition according to  claim 1 , wherein the active agent particles comprise particles of active agent in crystalline form. 
     
     
         5 .- 7 . (canceled) 
     
     
         8 . The pharmaceutical composition according to  claim 1 , wherein the active agent particles comprise two or more species of respirable, micronized active agent particles. 
     
     
         9 . The pharmaceutical composition according to  claim 1 , wherein the active agent particles comprise one or more active agents selected from short-acting beta agonists, such as bitolterol, carbuterol, fenoterol, hexoprenaline, isoprenaline (isoproterenol), levosalbutamol, orciprenaline (metaproterenol), pirbuterol, procaterol, rimiterol, salbutamol (albuterol), terbutaline, tulobuterol, reproterol, and epinephrine; long-acting beta agonists, such as bambuterol, clenbuterol, formoterol, and salmeterol; ultra long-acting beta agonists, such as carmoterol, milveterol, indacaterol, and saligenin- or indole-containing and adamantyl-derived β 2  agonists; corticosteroids, such as beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methyl-prednisolone, mometasone, prednisone, and triamcinolone; anti-inflammatories, such as fluticasone propionate, beclomethasone dipropionate, flunisolide, budesonide, tripedane, cortisone, prednisone, prednisilone, dexamethasone, betamethasone, and triamcinolone acetonide; antitussives, such as noscapine; bronchodilators, such as ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, salbutamol, albuterol, salmeterol, and terbutaline; anticholinergics, such as glycopyrrolate, dexipirronium, scopolamine, tropicamide, pirenzepine, dimenhydrinate, tiotropium, darotropium, aclidinium, trospium, ipatropium, atropine, benzatropin, and oxitropium; including any pharmaceutically acceptable salts, esters, isomers, or solvates thereof. 
     
     
         10 . The pharmaceutical composition according to  claim 8 , wherein the two or more species of respirable, micronized active agent particles comprise two or more active agents selected from a combination of formoterol and budesonide; a combination of glycopyrrolate and formoterol; a combination of ciclesonide and formoterol; a combination of salmeterol and fluticasone; a combination of glycopyrrolate, formoterol, and budesonide; and a combination of glycopyrrolate, formoterol, and mometasone; including any pharmaceutically acceptable salts, esters, isomers, or solvates thereof. 
     
     
         11 . (canceled) 
     
     
         12 . The pharmaceutical composition according to  claim 1 , wherein the pharmaceutical composition is formulated to provide a delivered dose of active agent selected from between about 100 μg and about 100 mg per actuation of the metered dose inhaler, between about 100 μg and about 10 mg per actuation of the metered dose inhaler, between about 100 μg and 1 mg per actuation of the metered dose inhaler, between about 0.1 and about 2 μg per actuation of the metered dose inhaler, about 0.1 and about 1 μg per actuation of the metered dose inhaler, and about 0.1 and about 0.5 μg per actuation of the metered dose inhaler. 
     
     
         13 . The pharmaceutical composition according to  claim 1 , wherein the pharmaceutical composition is formulated to provide a delivered dose of active agent selected from up to about 80 μg per actuation of the metered dose inhaler, up to about 40 μg per actuation of the metered dose inhaler, up to about 20 μg per actuation of the metered dose inhaler, and between about 10 μg and about 100 μg per actuation of the metered dose inhaler. 
     
     
         14 . (canceled) 
     
     
         15 . The pharmaceutical composition according to  claim 1 , wherein the respirable suspending particles exhibit an MMAD selected from between about 10 μm and about 500 nm, between about 5 μm and about 750 nm, and 1 μm and about 3 μm. 
     
     
         16 . The pharmaceutical composition according to  claim 1 , wherein the respirable suspending particles exhibit a volume median optical diameter selected from between about 0.2 μm and about 50 μm, between about 0.5 μm and about 15 μm, between about 1.5 μm and about 10 μm, and between about 2 μm and about 5 μm. 
     
     
         17 . The pharmaceutical composition according to  claim 1 , wherein the respirable suspending particles are included in the suspension medium at a concentration selected from about 0.5 mg/mL and up to about 25 mg/mL. 
     
     
         18 . The pharmaceutical composition according to  claim 17 , wherein the respirable suspending particles are included in the suspension medium at a concentration selected from between about 1 mg/mL to about 15 mg/mL, about 3 mg/mL to about 10 mg/mL, and about 1.5 mg/mL to about 10 mg/mL. 
     
     
         19 . The pharmaceutical composition according to  claim 17 , wherein the active agent particles comprise glycopyrrolate, and the respirable suspending particles are included in the suspension medium at a concentration selected from about 6 mg/mL, between about 3 mg/mL and about 10 mg/mL, and between about 1 mg/mL and about 15 mg/mL. 
     
     
         20 . The pharmaceutical composition according to  claim 17 , wherein the active agent particles comprise formoterol, and the respirable suspending particles are included in the suspension medium at a concentration selected from about 6 mg/mL, about 3 mg/mL, between about 1.5 mg/mL and about 5 mg/mL, between about 0.5 mg/mL and about 7.5 mg/mL, between about 3 mg/mL and about 10 mg/mL, and between about 1 mg/mL and about 15 mg/mL. 
     
     
         21 .- 22 . (canceled) 
     
     
         23 . The pharmaceutical composition according to  claim 17 , wherein the active agent particles comprise budesonide, and the respirable suspending particles are included in the suspension medium at a concentration selected from about 8 mg/mL, between about 5 mg/mL and about 20 mg/mL, and between about 0.5 mg/mL and about 30 mg/mL. 
     
     
         24 . (canceled) 
     
     
         25 . The pharmaceutical composition according to  claim 1 , wherein the total mass of the suspending particles exceeds the total mass of the active agent particles. 
     
     
         26 . The pharmaceutical composition according to  claim 25 , wherein the ratio of the total mass of the respirable suspending particles to the total mass of the active agent particles is selected from above about 1.5:1, up to about 5:1, up to about 10:1, up to about 15:1, up to about 20:1, up to about 30:1, up to about 50:1, up to about 75:1, up to about 100:1, up to about 150:1, and up to about 200:1. 
     
     
         27 . The pharmaceutical composition according to  claim 25 , wherein at least one of the active agents included in the active agent particles is a highly potent active agent and the ratio of the total mass of the respirable suspending particles to the total mass of the active agent particles is selected from between about 5:1 and about 175:1, between about 10:1 and about 150:1, between about 15:1 and about 125:1, and between about 25:1 and about 75:1. 
     
     
         28 . The pharmaceutical composition according to  claim 25 , wherein the active agent particles include one or more of glycopyrrolate, fluticasone, mometasone, and budesonide, and the ratio of the total mass of the respirable suspending particles to the total mass of the active agent particles is selected from between about 1:1 and about 20:1, between about 5:1 and about 15:1, and about 10:1. 
     
     
         29 . The pharmaceutical composition according to  claim 25 , wherein the active agent particles include one or more of fluticasone, mometasone, and budesonide, and the ratio of the total mass of the respirable suspending particles to the total mass of the active agent particles is selected from between about 1:1 and about 15:1, between about 1.5:1 and about 10:1, and between about 2.5:1 and about 5:1. 
     
     
         30 . (canceled) 
     
     
         31 . The pharmaceutical composition according to  claim 25 , wherein the active agent particles include formoterol, and the ratio of the total mass of the respirable suspending particles to the total mass of the active agent particles is selected from between about 10:1 and about 200:1, between about 50:1 and about 125:1, and about 75:1. 
     
     
         32 . The pharmaceutical composition according to  claim 1 , wherein the respirable suspending particles co-locate with the active agent particles even when subjected to buoyancy forces amplified by centrifugation at an acceleration selected from accelerations of at least 1 g, at least 10 g, at least 50 g, and at least 100 g. 
     
     
         33 .- 35 . (canceled) 
     
     
         36 . The pharmaceutical composition according to  claim 1 , wherein the suspension medium comprises propellant substantially free of additional constituents. 
     
     
         37 . The pharmaceutical composition according to  claim 36 , wherein the propellant comprises a propellant selected from an HFA propellant, a PFC propellant, and combinations thereof. 
     
     
         38 . (canceled) 
     
     
         39 . The pharmaceutical composition according to  claim 1 , wherein the active agent particles are prepared by a micronization process selected from milling, grinding, crystallization, recrystallization, and supercritical or near-supercritical precipitation processes, and the respirable suspending particles are prepared using a spray drying process. 
     
     
         40 . A metered dose inhaler comprising a canister with an outlet valve including an actuator for dispensing a metered volume of a pharmaceutical composition as defined in  claim 1 , wherein the metered dose inhaler exhibits a delivered dose uniformity (“DDU”) for the active agent selected from a DDU of ±30%, or better, a DDU of ±25%, or better, and a DDU of ±20%, or better, throughout emptying of the canister. 
     
     
         41 . The metered dose inhaler according to  claim 40 , wherein the metered dose inhaler dispenses the pharmaceutical composition at an initial fine particle fraction and the initial fine particle fraction dispensed from the metered dose inhaler is substantially maintained, such that, throughout emptying of the canister, the fine particle fraction delivered from the metered dose inhaler is maintained within 80% of the initial fine particle fraction. 
     
     
         42 . The metered dose inhaler according to  claim 41 , wherein the fine particle fraction delivered from the metered dose inhaler is maintained within 90% of the initial fine particle fraction. 
     
     
         43 . The metered dose inhaler according to  claim 41 , wherein the fine particle fraction delivered from the metered dose inhaler is maintained within 95% of the initial fine particle fraction. 
     
     
         44 . The metered dose inhaler according to  claim 40 , wherein the pharmaceutical composition contained within the canister of the metered dose inhaler is storage stable for at least six months. 
     
     
         45 . The metered dose inhaler according to  claim 40 , wherein the metered dose inhaler exhibits a delivered dose uniformity (“DDU”) for the active agent selected from a DDU of ±30%, or better, a DDU of ±25%, or better, and a DDU of ±20%, or better, throughout emptying of the canister, after said canister is subjected to temperature cycling, wherein the temperature cycling is carried out for duration of three (3) weeks and comprises alternately cycling the pharmaceutical composition between −5° C., where it is held for six (6) hours, and 40° C. where it is held for six (6) hours. 
     
     
         46 . The metered dose inhaler according to  claim 41 , wherein the fine particle fraction is substantially maintained throughout emptying of the canister, after said canister is subjected to temperature cycling, wherein the temperature cycling is carried out for duration of three (3) weeks and comprises alternately cycling the pharmaceutical composition between −5° C. where it is held for six (6) hours, and 40° C., where it is held for six (6) hours. 
     
     
         47 .- 51 . (canceled) 
     
     
         52 . A method for treating a patient suffering from an inflammatory or obstructive pulmonary disease or condition, the method comprising administering to the patient via an MDI a therapeutically effective amount of a pharmaceutical composition as defined in  claim 1 . 
     
     
         53 . The method of  claim 52 , wherein the disease or condition is selected from asthma, COPD, exacerbation of airways hyper reactivity consequent to other drug therapy, allergic rhinitis, sinusitis, pulmonary vasoconstriction, inflammation, allergies, impeded respiration, respiratory distress syndrome, pulmonary hypertension, and pulmonary inflammation and obstruction associated with cystic fibrosis. 
     
     
         54 . (canceled) 
     
     
         55 . The pharmaceutical composition according to  claim 9 , wherein the active agent particles comprise salbutamol (albuterol). 
     
     
         56 . The pharmaceutical composition according to  claim 9 , wherein the active agent particles comprise budesonide.