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(19) United States (12) Patent Application Publication (10) Pub US 20030035776A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0035776 A1 Hodges et al. (43) Pub. Date: Feb. 20, 2003 (54) DELIVERY OF AEROSOLS CONTAINING (60) Provisional application No. 60/296,225, ?led on Jun. SMALL PARTICLES THROUGH AN 5, 2001. INHALATION ROUTE (76) Inventors: Craig C. Hodges, Walnut Creek, CA Publication Classi?cation (US); Peter M. Lloyd, Walnut Creek, CA (US); Daniel Mufson, Napa, CA (51) Int. Cl? ............................. .. A61L 91/04; A61K 9/14 (US); Daniel D. Rogers, Oakland, CA (52) Us. 01. .............................................................. .. 424/46 (US); Martin J. Wensley, San Francisco, CA (US) (57) ABSTRACT Correspondence Address: Richard R. Eckman Morrison & Foerster LLP The present invention relates to the inhalation delivery of 755 Page Mill Road aerosols containing small particles. Speci?cally, it relates to Palo Alto, CA 94304-1018 (US) the delivery of drug containing aerosols having particles With a mass median aerodynamic diameter less than 1;! for (21) Appl. No.: 10/146,515 inhalation therapy. In a composition aspect of the present invention the drug containing aerosol comprises particles (22) Filed: May 13, 2002 having a mass median aerodynamic diameter betWeen 10 nm and 1p. Preferably, the particles have a mass median aero Related US. Application Data dynamic diameter betWeen 10 nm and 900 nm. More pref erably, the particles have a mass median aerodynamic diam (63) Continuation-in-part of application No. 10/057,198, eter betWeen 10 nm and 800 nm, 10 nm and 700 nm, 10 nm ?led on Oct. 26, 2001. Continuation-in-part of appli and 600 nm, 10 nm and 500 nm, 10 nm and 400 nm, 10 nm cation No. 10/057,197, ?led on Oct. 26, 2001. and 300 nm, 10 nm and 200 nm, or 10 nm and 100 nm. Patent Application Publication Feb. 20, 2003 Sheet 1 0f 14 US 2003/0035776 A1 10 42 130 J I ‘__.__.__ .6?” l 54 K In?‘ 1- e l i 58 g 1 l \\124 Pressure Patent Application Publication Feb. 20, 2003 Sheet 2 0f 14 US 2003/0035776 A1 ow mm 27/ AHV\\ mo 3€E:i 3:El /_7: Q§§§.\\\ 1\MJ/J/JJJdw Patent Application Publication Feb. 20, 2003 Sheet 3 0f 14 US 2003/0035776 A1 60 70 64 m2 108 90 100 Pg. 5 O 160 —__\3? f 10 60 164166 —\_;AW — ,./64 L89 168 ' L : I ‘ _ 'nn "mam _\ Patent Application Publication Feb. 20, 2003 Sheet 4 0f 14 US 2003/0035776 A1 Pulse 210 Clock Generator 190 Fig.8 Patent Application Publication Feb. 20, 2003 Sheet 5 0f 14 US 2003/0035776 A1 Fig. 9 Patent Application Publication Feb. 20, 2003 Sheet 6 0f 14 US 2003/0035776 A1 , 10 g- 302 l l z/d'd 314 ' i/ I I 310 I l _ ‘F 330 300 Patent Application Publication Feb. 20, 2003 Sheet 8 0f 14 US 2003/0035776 A1 530 60 540 550 \ 602/ / 608/ 160 Fig. 18 Patent Application Publication Feb. 20, 2003 Sheet 9 0f 14 US 2003/0035776 A1 Fig. 19 60 160’ 810 Fig. 20 Patent Application Publication Feb. 20, 2003 Sheet 10 0f 14 US 2003/0035776 A1 940 / 902 910 900 '-1 1+ m V 930 922 / @9 2 al 920 Fig. 22 Patent Application Publication Feb. 20, 2003 Sheet 11 of 14 US 2003/0035776 A1 Fig. 23 Number Concentration vs Time for Number Concentration to Halve 1.00E+14 1.00E+13 1.00E+12 1.00E+ll 1.00E+10 1.00E+09 NumberConcentration(#lcc) 1.00E+08 1.00E+07 1.00E+06 1.00E+05 1.00E+04 1.00E+03 0.00001 0.001 0.1 10 1000 100000 10000000 Time (seconds) Fig. 24 Coagulation Coefficient vs. Particle Size CoagulationCoefficient 10‘'6meters3/sccond)(Ix oN4>m00 l 10 100 1000 10000 Particle Size (nm) Patent Application Publication Feb. 20, 2003 Sheet 12 0f 14 US 2003/0035776 A1 Fig. 25 Vapor Pressure vs Temperature OI. II . ll) l a .525»9:233;32-55 ll”,-/ I: mumeemm m rm 21007654 /.W/ // HCGNDCwe.w.m xrmoh mmymm ccle?. _ WWWwMOWWO 110 210 310 410 Temperature (Centigrade) Fig. 26 Blood Levels vs Time; IV and Inhaled Fentanyl 100000 l 1 ao.n nI- !l .52:E3:5“... E DDDDDD000000 gggggg ###### ?$®$22993300 VVSSfm/mU wwwmwm j 100 0.2 0.4 0.6 0.8 Time (hours) Patent Application Publication Feb. 20, 2003 Sheet 13 of 14 US 2003/0035776 A1 Fig. 27 Actual vs Calculated Particle Diameter (MMD) for Number Concentration of 1x1 09/cc I0 1m.1mma mmwnm mC5 c = _. G_G 110 210 310 Compound Mass (ug) Fig. 28 Actual vs Calculated Particle Diameter (MMD) for Number Concentration of 0.5x109/cc ?ll!’ p : y , ’ ., /§l I I I __._. /. r I‘. r 158M9750000n_00 _ WGGSS 1__1,__1 .mmzmmmmmm Mmdd 30 90 110 Compound Mass (ug) Patent Application Publication Feb. 20, 2003 Sheet 14 of 14 US 2003/0035776 A1 Fig. 29 Ratio of vaporized Compound to Volume of Mixing Gas vs. Particle Diameter 1.00E-02 /' 1.00E+04 1.001-3-03 1.00E+03 AU 1.00E-04 1.00E+02 : a 1.00E-05 / 1.00E+01 E4: ‘; 1.00E-06 / 1.00E+00 : ‘5 10015-07 / 1.00E-01 ‘g '2 LOOE-OS / 1.00E-02 =4 1.00E-09 _ 1.00E-03 1005-10 .1.. 1 . 1 1,005.94 10 100 1000 10000 Particle Diameter [MMD] (um) US 2003/0035776 A1 Feb. 20, 2003 DELIVERY OF AEROSOLS CONTAINING SMALL Preferably, at least 75 percent by Weight of the aerosol is PARTICLES THROUGH AN INHALATION ROUTE amorphous in form. More preferably, at least 90 percent by Weight of the aerosol is amorphous in form. [0001] This application is a continuation-in-part of US. patent application Ser. No. 10/057,198 entitled “Method and [0009] Typically, the aerosol comprises less than 10 per Device for Delivering a Physiologically Active Compound,” cent by Weight of drug degradation products. Preferably, the ?led Oct. 26, 2001, Lloyd et al. and of US. patent applica particles contain less than 5 percent of drug degradation tion Ser. No. 10/057,197 entitled “Aerosol Generating products. More preferably, the particles contain less than Device and Method,” ?led Oct. 26, 2001, Wensley et al., 2.5, 1, 0.5, 0.1 or 0.03 percent by Weight of drug degradation both of Which are hereby incorporated by reference for all products. purposes. This application further claims priority to US. provisional application Ser. No. 60/296,225 entitled “Aero [0010] Typically, the mass of the aerosol is at least 0.05 sol Generating Device and Method,” ?led Jun. 5, 2001, mg. Preferably, the mass of the aerosol is at least 0.10 mg. Wensley et al., the entire disclosure of Which is hereby More preferably, the mass of the aerosol is at least 0.15 mg, incorporated by reference. 0.20 mg, or 0.25 mg. [0011] Typically, the geometric standard deviation around FIELD OF THE INVENTION the mass median aerodynamic diameter of the aerosol par ticles is less than 2. Preferably, the geometric standard [0002] The present invention relates to the inhalation deviation is less than 1.9. More preferably, the geometric delivery of aerosols containing small particles. Speci?cally, standard deviation is less than 1.8, 1.7, 1.6 or 1.5. it relates to the delivery of drug containing aerosols having particles With a mass median aerodynamic diameter less [0012] Typically, the drug has a decomposition indeX less than 1;! for inhalation therapy. than 0.15. Preferably, the drug has a decomposition indeX less than 0.10. More preferably, the drug has a decomposi BACKGROUND OF THE INVENTION tion indeX less than 0.05. [0003] Currently, there are a number of approved devices [0013] Typically, the drug of the aerosol is of one of the for the inhalation delivery of drugs, including dry poWder folloWing classes: antibiotics, anticonvulsants, antidepres inhalers, nebuliZers, and pressuriZed metered dose inhalers. sants, antiemetics, antihistamines, antiparkisonian drugs, A typical goal of these devices is to produce an aerosol antipsychotics, anXiolytics, drugs for erectile dysfunction, containing drug particles With a mass median aerodynamic drugs for migraine headaches, drugs for the treatment of diameter between 1” and 10 y. alcoholism, drugs for the treatment of addiction, muscle relaXants, nonsteroidal anti-in?ammatories, opioids, other [0004] It is desirable to provide aerosols having particles analgesics and stimulants. With a mass median aerodynamic diameter less than 1p. The provision of such aerosols is an object of the present [0014] Typically, Where the drug is an antibiotic, it is invention. selected from one of the folloWing compounds: ce?netaZole; cefaZolin; cephaleXin; cefoXitin; cephacetrile; cephalogly SUMMARY OF THE INVENTION cin; cephaloridine; cephalosporins, such as cephalosporin C; cephalotin; cephamycins, such as cephamycin A, cephamy [0005] The present invention relates to the inhalation cin B, and cephamycin C; cepharin; cephradine; ampicillin; delivery of aerosols containing small particles. Speci?cally, amoXicillin; hetacillin; carfecillin; carindacillin; carbenicil it relates to the delivery of drug containing aerosols having lin; amylpenicillin; aZidocillin; benZylpenicillin; clometo particles With a mass median aerodynamic diameter less cillin; cloXacillin; cyclacillin; methicillin; nafcillin; 2-pen than 1;! for inhalation therapy. tenylpenicillin; penicillins, such as penicillin N, penicillin [0006] In a composition aspect of the present invention the O, penicillin S, penicillin V; chlorobutin penicillin; dicloX drug containing aerosol contains particles having a mass acillin; diphenicillin; heptylpenicillin; and metampicillin. median aerodynamic diameter betWeen 10 nm and 1p. [0015] Typically, Where the drug is an anticonvulsant, it is Preferably the particles have a mass median aerodynamic selected from one of the folloWing compounds: gabapentin, diameter betWeen 10 nm and 900 nm.
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