US 20140323451A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0323451 A1 SHREWSBURY et al. (43) Pub. Date: Oct. 30, 2014 (54) METHODS FOR ADMINISTERING Publication Classification CORTICOSTEROD FORMULATIONS (51) Int. Cl. (71) Applicant: MAP Pharmaceuticals, Inc., Irvine, CA A619/00 (2006.01) (US) A613 L/58 (2006.01) (72) Inventors: STEPHEN B. SHREWSBURY, (52) U.S. Cl. Cupertino, CA (US); PAUL S. USTER, CPC ................. A61K9/007 (2013.01); test Pleasanton, CA (US); ANDREW P. USPC S1.47174 BOSCO, San Francisco, CA (US); ' '. “ THOMASA. ARMER, Los Altos, CA (US) (57) ABSTRACT (21) Appl. No.: 14/326, 197 (22) Filed: Jul. 8, 2014 Described here are methods for the treatment of respiratory conditions using nebulized corticosteroids. The methods Related U.S. Application Data administer a dose of corticosteroid twice a day or more with (63) Continuation of application No. 12/268.394, filed on nebulization times of 5 minutes or less. The faster nebuliza Nov. 10, 2008 s-- is tion times improve patient compliance. The methods also • ws employ a lower corticosteroid dose while achieving therapeu (60) Provisional application No. 61/069,498, filed on Mar. tic efficacy similar to commercially available formulations. 14, 2008, provisional application No. 61/002,645, This results in improved patient safety by reducing the sys filed on Nov. 9, 2007. temic exposure of the corticosteroid. Patent Application Publication Oct. 30, 2014 Sheet 1 of 4 US 2014/0323451 A1 i t R O O w S S s (uffduoeueouod eused epuoseph Patent Application Publication Oct. 30, 2014 Sheet 2 of 4 US 2014/0323451 A1 Z Xeuu0GC1mjo6uugz'0 OIHZ* Patent Application Publication Oct. 30, 2014 Sheet 3 of 4 US 2014/0323451 A1 9."OIH ufid) uoleueguo eLused epuoSepng Patent Application Publication Oct. 30, 2014 Sheet 4 of 4 US 2014/0323451 A1 E US 2014/0323451 A1 Oct. 30, 2014 METHODS FOR ADMINISTERING ties due to the added energy required to from droplets con CORTICOSTEROID FORMULATIONS taining Suspended particulates. Children and adults who become impatient because of lengthy nebulization times CROSS-REFERENCE TO RELATED often stop treatment prematurely. Drug delivery is often not APPLICATIONS linear overtime, with the bulk of the drug being delivered near the end of the recommended nebulization time. Thus, early 0001. This application claims priority to U.S. Provisional termination of treatment can result in a disproportionally Patent Application Ser. No. 61/002,645, filed Nov. 9, 2007, decreased delivery of drug. This can lead to further non and U.S. Provisional Patent Application Ser. No. 61/069,498, compliance since the inadequate dose will likely fail to pro filed Mar. 14, 2008, which are hereby incorporated by refer vide adequate therapy, and thus discourage further use of the ence in their entirety. nebulizer treatment regimen. 0006 Another issue with nebulizing drugs relates to the FIELD amount of drug actually delivered to the lungs. For example, 0002. The methods described here are in the field of res when nebulizing budesonide using a conventional jet nebu piratory medicine. Specifically, methods that administer cor lizer, the doses of budesonide are those added to the nebuliz ticosteroid formulations by nebulization are described. More ing device. However, only approximately 40% to 60% of the specifically, methods for the treatment of asthma that admin drug typically leaves the nebulizer, so only approximately ister lower doses of corticosteroid, and which are associated 40% to 60% of the nominal dose is delivered to the patient. with improved patient compliance and safety are described. This is because the drug is delivered constantly, and when the patient is exhaling, the drug leaving the nebulizer will not be BACKGROUND delivered to the patient; instead, it will be lost to the environ 0003 Asthma is a pulmonary condition characterized by ment. Of the amount delivered to the patient, only a fraction airway inflammation, airway hyperresponsiveness, and is in droplets having diameters in the respirable range (less reversible airway obstruction. During asthmatic episodes, than approximately 5 microns) which leaves approximately afflicted individuals often experience labored breathing, 10% to 20% of the nominal dose delivered to the lungs. To wheezing, and coughing. These symptoms may be treated increase the amount of budesonide delivered to the lungs, with medications such as corticosteroids, which are adminis either the budesonide dose volume or concentration can be tered via pressurized metered-dose inhalers (pMDIs) or dry increased. In turn, this may lead to higher maximum plasma powder inhalers (DPIs). However, certain patient popula concentrations, which are associated with a greater risk of tions, e.g., pediatric, neurologically impaired, or elderly asth systemic side-effects such as cortisol Suppression. matics, may lack the breath coordination needed for pMDIs 0007 Consequently, new methods for administering or lack the lung capacity needed to use DPIs. Thus, these nebulized drugs would be useful that maximize compliance asthma patients require the administration of therapy via and therapeutic efficacy while minimizing safety issues or nebulizers. side effects. Specifically, administration methods having 0004 Formulations that undergo nebulization are dis faster nebulization times would be desirable to improve persed in air to form an aerosol of very fine liquid droplets patient compliance. Administration methods that result in suitable for inhalation into the lung. Nebulizers typically use improved lung deposition (marker of enhanced therapeutic compressed air, piezoelectric or servomechanically gener efficacy) without increasing systemic or oropharyngeal expo ated ultrasonic waves, or a vibrating mesh to create the mist of sure (which leads to side effects) would also be desirable. the droplets, and may also have a baffle to remove larger droplets from the mist by impaction. A variety of nebulizers SUMMARY are available for this purpose. Such as Soft mist nebulizers, 0008. Described here are methods for the treatment of vibrating mesh nebulizers, ultrasonic nebulizers, jet nebuliz respiratory conditions using nebulized corticosteroids. The ers, and breath-actuated nebulizers. In use, the nebulized methods may include administration of a dose of corticoster formulation is administered to the individual via a mouth oid at least once a day with nebulization times that are faster piece or mask. than commercially available formulations. This administra 0005 Low patient compliance is a generally known prob tion regimen improves patient convenience by minimizing lem with nebulized drugs. This is primarily due to the amount delivery times as evidenced by time to maximum plasma of time required for nebulizing the drug, which can last up to concentrations, and thus, may improve patient compliance. 30 minutes or longer, depending on Such factors as the Vol Further, because of the unexpected pharmacokinetics exhib ume of liquid formulation to be nebulized, the particular ited by the administered corticosteroid, as further detailed active agent being nebulized, the concentration and Surface below, a lower dose of the corticosteroid may be used in tension of the active agent in the formulation, and the result comparison to commercially available formulations while ing viscosity of the formulation. Other factors include the achieving similar lung dose and therefore therapeutic effi condition or symptom being treated, and whether the active cacy. For example, low doses of 0.25 mg or 0.125 mg or less agent is present as a solution or Suspension. Active agent of budesonide, a corticosteroid, may be administered. This formulations are generally supplied as nominal 2.0 ml Vol results in improved patient safety by reducing the systemic umes with solution or Suspension viscosities ranging from exposure of the corticosteroid. that of water, to 100 times the viscosity of water. These 0009. In one variation, the methods for treating respiratory typically require about four to about 20 minutes to nebulize, conditions include administering a dose of a corticosteroid with the nebulization time increasing as the Viscosity once a day by nebulization for at least one week (7 days), at increases from that of water. If the formulation is a suspen least two weeks (14 days), at least three weeks (21 days), at sion, an additional 15% to 30% longer time is required to least four weeks (28 days), at least five weeks (35 days), or at nebulize than solution formulations with comparable viscosi least six weeks (42 days) or more. For example, the corticos US 2014/0323451 A1 Oct. 30, 2014 teroid may be administered for at least two months or at least 0014. The methods described here may also reduce one or three months or more if required. The corticosteroid may also more systemic side-effects of corticosteroids. In one varia be administered more frequently, for example, two, three or tion, the methods include administering less than about 0.30 four times a day. mg dose of a corticosteroid twice a day for at least six weeks 0010. The methods also include nebulization times that in an aerosol, wherein the C is less than about 850 pg/ml. are faster than commercially available corticosteroid formu 00.15 Methods for reducing one or more systemic side lations. In one variation, the nebulization time is about 5.0 effects of corticosteroids comprising administering a dose of minutes or less. In another variation, the nebulization time is about 0.30 mg or less of a corticosteroid twice a day for at about 4.0 minutes of less. In yet another variation, the nebu least six weeks in anaerosol, wherein the AUCo. is less than lization time is about 3.0 minutes or less. In some instances, about 75,000 pg-min/ml are also described. the nebulization time may be less than about 2.0 minutes. 0016. The dose of corticosteroid that may be administered ranges from about 0.05 mg to about 1.0 mg. In some varia 0011. In one variation, the methods include administering tions, the dose of corticosteroid is less than about 0.30 mg.