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(12) Patent Application Publication (10) Pub. No.: US 2004/0105818 A1 Every Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2004/0105818 A1 Every Et Al US 2004O105818A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0105818 A1 Every et al. (43) Pub. Date: Jun. 3, 2004 (54) DURETICAEROSOLS AND METHODS OF Publication Classification MAKING AND USING THEM (51) Int. Cl." ............................. A61L 9/04; A61K 31/58 (75) Inventors: Nathan R. Every, Seattle, WA (US); (52) U.S. Cl. .............................................. 424/45; 514/173 Ron L. Hale, Woodside, CA (US); Amy T. Lu, Los Altos, CA (US); (57) ABSTRACT Joshua D. Rabinowitz, Mountain View, Described herein are diuretic condensation aerosols and CA (US) methods of making and using them. Kits for delivering a condensation aerosol are also described. The diuretic aero Correspondence Address: Sols typically comprise diuretic condensation aerosol par ALEXZAMOLECULAR DELIVERY ticles that comprise a diuretic compound. In Some variations CORPORATION the diuretic compound is Selected from the group consisting 1001 EAST MEADOW CIRCLE of bumetanide, ethacrynic acid, furosemide, muZolimine, PALO ALTO, CA 94.303 (US) Spironolactone, torSemide, triamterene, tripamide, BG 9928, Assignee: Alexza Molecular Delivery Corpora and BG 9719. Methods of treating edema using the (73) described aerosols are also provided. In general, the methods tion, Palo Alto, CA (US) typically comprise the Step of administering a therapeuti (21) Appl. No.: 10/712,365 cally effective amount of diuretic condensation aerosol to a person with edema. The diuretic condensation aerosol may (22) Filed: Nov. 12, 2003 be administered in a Single inhalation, or may be adminis tered in more than one inhalation. Methods of forming a Related U.S. Application Data diuretic condensation aerosol are also described. The meth ods typically comprise the Steps of providing a diuretic (60) Provisional application No. 60/429,123, filed on Nov. composition, vaporizing the composition to form a vapor, 26, 2002. and then condensing the diuretic composition vapor. Patent Application Publication Jun. 3, 2004 Sheet 1 of 4 US 2004/0105818A1 - - s Patent Application Publication Jun. 3, 2004 Sheet 2 of 4 US 2004/0105818A1 air Patent Application Publication Jun. 3, 2004 Sheet 3 of 4 US 2004/0105818A1 - - 312 ''' E.g " '' . ". SE f i& Patent Application Publication Jun. 3, 2004 Sheet 4 of 4 US 2004/0105818A1 (%) Aunosoev US 2004/0105818 A1 Jun. 3, 2004 DURETICAEROSOLS AND METHODS OF 0006. In some variations, the aerosol comprises at least MAKING AND USING THEM 50% by weight of diuretic condensation particles. In other variations the aerosol comprises at least 75% or 95% by CROSS REFERENCE TO RELATED weight of the diuretic condensation particles. Similarly, in APPLICATIONS Some variations, the aerosol is Substantially free of thermal 0001. This application claims priority to U.S. Provisional degradation products, and in Some variations, the diuretic Application Serial No. 60/429,123 entitled, “Delivery of a condensation aerosol has a NMAD in the range of 1-3 lum. Diuretic through an Inhalation Route' filed on Nov. 26, 0007. The kit for delivering a diuretic condensation aero 2002, the entirety of which is hereby incorporated by Sol typically comprises a composition comprising a diuretic reference. compound, and a device for forming a diuretic aeroSol. The device for forming a diuretic aerosol typically comprises an BACKGROUND element configured to heat the composition to form a vapor, 0002 Edema is a localized or general Swelling caused by an element allowing the vapor to condense to form a the build-up of fluid within body tissues. It most commonly condensation aeroSol, and an element permitting a user to occurs in the feet and legs, where it also is referred to as inhale the condensation aeroSol. The composition may fur peripheral edema. However, exceSS fluid can occur any ther comprise a pharmaceutically acceptable excipient, and where in the Subcutaneous tissue or lungs. This exceSS fluid the device my further comprise features Such as breath may be the result of any number of causes. For example, it actuation or lock-out elements. may be the result of poor blood circulation, lymphatic 0008 Methods of treating edema using the aerosols System failure, disease of the heart or kidneys, reduction in described herein are also provided. In general, the method the amount of blood protein (e.g., which may occur as a comprises the Step of administering a therapeutically effec result of cirrhosis), chronic nephritis, malnutrition, or tox tive amount of a diuretic condensation aerosol to a perSon emia of pregnancy (preeclampsia). Some other causes of with edema. The edema may be caused or be associated with edema are use of birth control pills, premenstrual Syndrome, any number of maladies. For example, the edema may be the Sunburn, and an imbalance of Sodium and potassium. Local result of congestive heart failure, cirrhosis of the liver, poor ized edema may also result from injury or infection. blood circulation, lymphatic System failure, chronic nephri 0.003 Diuretics are most typically used to treate edema. tis, malnutrition, toxemia of pregnancy (preeclampsia), use Some diuretics are used to treat Meniere's disease and other of birth control pills, premenstrual Syndrome, Sunburn, types of Vertigo where excessive fluid pressure builds up hypertension, overdosage of certain drugs, Meniere's dis within the inner ear. Some diuretics are used to treat glau ease, glaucoma, cystic fibrosis, and an imbalance of Sodium coma, where excessive fluid pressure builds up within the and potassium. Localized edema may also result from injury eyeball. Similarly, Some diuretics are used to treat pulmo or infection. nary edema, where fluid accumulates in the lung tissue. 0009. In some variations, the method for treating edema Diuretics may also be used to treat high blood pressure (i.e., comprising the Step of administering a therapeutically effec hypertension), overdosage of certain drugs, and cystic fibro tive amount of a diuretic aerosol to a person with edema, SS. wherein the diuretic aeroSol comprises a diuretic compound 0004. There are a number of compositions commercially and has a MMAD in the range of about 1-3 lum, and wherein available as diuretics. These include ethacrynic acid, bumet a peak plasma level of at least 30 ng/mL of the diuretic anide, furosemide, muZolimine, Spironolactone, torSemide, compound is achieved within 10 minutes of administration. triamterene, and tripamide. These diuretics are most com In Some variations, the method comprises the Steps of monly delivered as an oral dosage form (e.g. as a pill, obtaining a weight measurement of the person with edema capsule, or tablet), or delivered intravenously. Disadvan prior to the Step of administering a therapeutically effective tages of oral dosage forms include a delay in the onset of amount of a diuretic aeroSol, and using that weight mea activity and loSS of drug therapeutic effect due to hepatic Surement to assess whether to administer a therapeutically first-pass metabolism. Intravenous delivery, while typically effective amount of a diuretic aeroSol. more effective than oral delivery (particularly for loop diuretics), is often painful and inconvenient. Currently, 0010. In some variations, the described condensation intravenous delivery is the only option available for exac aerosol has a MMAD in the range of about 1-3 lum. In some erbations of congestive heart failure. It would be desirable to variations, the condensation aerosol comprises a diuretic provide other dosage forms and routes of administration Selected from the group consisting of bumetanide, with improved properties. ethacrynic acid, furosemide, muzolimine, Spironolactone, torsemide, triamterene, tripamide, BG 9928, and BG 9719. SUMMARY In Some variations the diuretic compound is bumetanide. In 0005. Described herein are diuretic condensation aero other variations, the diuretic achieves a C within a certain Sols and methods of making and using them. Kits for time period after the aerosol is administered. For example, delivering a condensation aerosol are also described. The in Some variations, the diuretic achieves a C in 10 diuretic aerosols described herein typically comprise minutes or less after the aeroSol is administered. The diuretic diuretic condensation aeroSol particles, where the particles condensation aerosol may be administered in a Single inha comprises a diuretic Selected from the group consisting of lation, or may be administered in more than one inhalation. bumetanide, ethacrynic acid, furosemide, muZolimine, 0011 Methods of treating congestive heart failure using Spironolactorie, torisemide, triamterene, tripamide, BG the aerosols described herein are also provided. In general, 9928, and BG 9719. In some variations the diuretic com the method comprises the Step of administering a therapeu pound is bumetanide. tically effective amount of a loop diuretic condensation US 2004/0105818 A1 Jun. 3, 2004 aeroSol to a person with congestive heart failure. This 0022 “Mass median aerodynamic diameter” or method may be particularly useful in treating those Symp “MMAD” of an aerosol refers to the aerodynamic diameter toms associated with congestive heart failure exacerbations. for which half the particulate mass of the aerosol is con 0012. In some variations, the method for treating con tributed by particles with an aerodynamic diameter larger gestive heart failure exacerbation comprising the Step of than the MMAD and half by particles with an aerodynamic administering a therapeutically effective amount of a loop diameter
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