US007585493B2
(12) United States Patent (10) Patent No.: US 7,585,493 B2 Hale et al. (45) Date of Patent: *Sep. 8, 2009
(54) THIN-FILM DRUG DELIVERY ARTICLE AND tion No. 60/336,218, filed on Oct. 30, 2001, provi METHOD OF USE sional application No. 60/335,049, filed on Oct. 30, 2001, provisional application No. 60/345,882, filed on (75) Inventors: Ron L. Hale, Woodside, CA (US); Amy Nov. 9, 2001, provisional application No. 60/345,145, Lu, Los Altos, CA (US); Daniel J. filed on Nov. 9, 2001, provisional application No. Myers, Mountain View, CA (US); 60/345,876, filed on Nov. 9, 2001, provisional appli Joshua D. Rabinowitz, Mountain View, cation No. 60/332,280, filed on Nov. 21, 2001, provi CA (US); Martin J. Wensley, San sional application No. 60/332.279, filed on Nov. 21, Francisco, CA (US) 2001, provisional application No. 60/332,165, filed on Nov. 21, 2001, provisional application No. 60/342, (73) Assignee: Alexza Pharmaceuticals, Inc., 066, filed on Dec. 18, 2001, provisional application Mountain View, CA (US) No. 60/371,457, filed on Apr. 9, 2002, provisional - application No. 60/412,068, filed on Sep. 18, 2002. (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 (51) Int. Cl. U.S.C. 154(b) by 995 days. A6IR 9/12 (2006.01) A6IR 9/14 (2006.01) This patent is Subject to a terminal dis- A6M I5/00 (2006.01) claimer. (52) U.S. Cl...... 424/45; 424/46; 424/434; 424/489: 424/499; 514/958: 128/200.14: (21) Appl. No.: 10/633,877 128/200.15; 128/200.24 (22) Filed: Aug. 4, 2003 (58) Field of Classification Search ...... 424/45, 424/46, 489, 499, 434; 514/958: 128/200.14, (65) Prior Publication Data 128/200.24, 203.15 See application file for complete search history. US 2007/OO31340 A1 Feb. 8, 2007 (56) References Cited Related U.S. Application Data U.S. PATENT DOCUMENTS (63) Continuation-in-part of application No. 10/322.227, filed on Dec. 17, 2002, now abandoned, application 1,239,634 A 9, 1917 Stuart No. 10/633,877, which is a continuation-in-part of Continued application No. 10/280,315, filed on Oct. 25, 2002, (Continued) now abandoned, application No. 10/633,877, which is FOREIGN PATENT DOCUMENTS a continuation-in-part of application No. 10/302.614, filed on Nov. 21, 2002, application No. 10/633,877, CA 2152684 1, 1996 which is a continuation-in-part of application No. 10/302,010, filed on Nov. 21, 2002, now Pat. No. (Continued) 7,078,016, application No. 10/633,877, which is a con- OTHER PUBLICATIONS tinuation-in-part of application No. 10/154,594, filed on May 23, 2002, now Pat. No. 6,740,309, application U.S. Appl. No. 10/633,876, filed Aug. 4, 2003, Hale et al. No. 10/633,877, which is a continuation-in-part of (Continued) application No. 10/154,765, filed on May 23, 2002, now Pat. No. 6,814,955, application No. 10/633,877, Primary Examiner Mina Haghighatian which is a continuation-in-part of application No. (74) Attorney, Agent, or Firm—Swanson & Bratschun, 10/155,097, filed on May 23, 2002, now Pat. No. L.L.C. 6,716,417, application No. 10/633,877, which is a con tinuation-in-part of application No. 10/155,373, filed (57) ABSTRACT on May 22, 2002, now Pat. No. 6,737,043, application No. 10/633,877, which is a continuation-in-part of An article for use in an aerosol device, for producing an application No. 10/155,621, filed on May 22, 2002, aerosol of a drug composition is disclosed. The article now Pat. No. 6,759,029, application No. 10/633,877, includes a heat-conductive Substrate having a Surface with a which is a continuation-in-part of application No. selected Surface area, and a drug composition film on the 10/155,703, filed on May 22, 2002, now Pat. No. substrate surface having a selected film thickness of between 6,803,031, application No. 10/633,877, which is a con- 0.05 and 20 um. The film thickness is such that an aerosol tinuation-in-part of application No. 10/155,705, filed formed by vaporizing the drug composition by heating the on May 22, 2002, now Pat. No. 6,805,854, application Substrate and condensing the vaporized compound contains No. 10/633,877, which is a continuation-in-part of 10% or less drug-degradation product and at least 50% of the total amount of drug composition contained in the film. The (Continued) selected substrate surface area is such as to yield an effective (60) Provisional application No. 60/294.203, filed on May human therapeutic dose of the drug aerosol. Also disclosed 24, 2001, provisional application No. 60/296,225, are methods of making and using the article. filed on Jun. 5, 2001, provisional application No. 60/317,479, filed on Sep. 5, 2001, provisional applica 12 Claims, 18 Drawing Sheets US 7,585,493 B2 Page 2
Related U.S. Application Data 2,309,846 2, 1943 Einar 2.469,656 5, 1949 Lienert application No. 10/153,839, filed on May 21, 2002, 2,714,649 8, 1955 Critzer now Pat. No. 6,776,978, application No. 10/633,877, 2,741,812 4, 1956 Andre which is a continuation-in-part of application No. 2,761,055 8, 1956 Ike 10/153.311, filed on May 21, 2002, now Pat. No. 2,887, 106 5, 1959 Robinson 6,884,408, application No. 10/633,877, which is a con 2,898,649 8, 1959 Murray tinuation-in-part of application No. 10/153,831, filed 2.902,484 9, 1959 Horclois 3,043,977 T. 1962 Morowitz on May 21, 2002, now Pat. 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Streitwieser, A. and Heathcock, C. H. eds., (1981). Introduction to Office Action mailed Feb. 27, 2004 with respect to U.S. Appl. No. Organic Chemistry. Second edition, Macmillan Publishing Co., Inc., 10/146,080. New York, pp. ix-xvi. (Table of Contents). Office Action mailed Mar. 20, 2007 with respect to U.S. Appl. No. Tsantilis, S. etal. (2001). "Sintering Time for Silica Particle Growth.” 10/146,080. Aerosol Science and Technology 34:237-246. Office Action mailed Jun. 5, 2006 with respect to U.S. Appl. No. Vapotronics, Inc. (1998) located at
10 14 18 -1. 16 Fig. 1A
U.S. Patent Sep. 8, 2009 Sheet 2 of 18 US 7,585,493 B2
t = 0 ms
t E 50 ms
it E 100 ms
t = 200 ms
t = 500 ms
U.S. Patent Sep. 8, 2009 Sheet 3 of 18 US 7,585,493 B2
Time(sec) Fig. 4A U.S. Patent Sep. 8, 2009 Sheet 4 of 18 US 7,585,493 B2
450 4 OO s 250 - 2OO - 150 - 1 OO
-0.2 O O.2 0.4 O.6 O.8 1 Time(sec) Fig. 4B U.S. Patent Sep. 8, 2009 Sheet 5 of 18 US 7,585,493 B2
450 400 350 300 250 200 150 100 5O
Time(sec) Fig. 5A U.S. Patent Sep. 8, 2009 Sheet 6 of 18 US 7,585,493 B2
-0.2 O 0.2 0.4 O.6 0.8 1 Time(sec) Fig. 5B U.S. Patent Sep. 8, 2009 Sheet 7 of 18 US 7,585,493 B2
atropine 100
9 8 A.
96
94 A
92
90 2 4. 6 8 10 film thickness (micrometers) Fig. 6
donepezil 100 99 98 97 96 - 95
94 0.5 1 15 2 2.5 3 3.5 film thickness (micrometers) Fig. 7 U.S. Patent Sep. 8, 2009 Sheet 8 of 18 US 7,585,493 B2
hydromorphone
100 Š 99.5 2 is 99 c S CD 98.5
98 O.5 1 15 2 2.5 3 film thickness (micrometers) Fig. 8
buprenorphine 100
s 99 2. 3. 98 o 3 A. 97 A. A. CS A 96 0.5 1 15 film thickness (micrometers) Fig. 9 U.S. Patent Sep. 8, 2009 Sheet 9 of 18 US 7,585,493 B2
clomipramine 100 sas 99 A > 'S 98 A. Ol : 97 A. (t 96 A.
95 O.5 1 1.5 2 2.5 3 3.5 4 film thickness (micrometers) Fig. 10
ciclesonide
1 OO 99 SS 98 is 97 S is 96 c 95 O O.5 1 15 2 2.5 film thickness (micrometers) Fig. 11 U.S. Patent Sep. 8, 2009 Sheet 10 of 18 US 7,585,493 B2
midazolam 100 99.9 & 99.8 5 99.7 O 3 99.6 c 99.5 99.4 1 2 3 4. 5 6 film thickness (micrometers) Fig. 12
nalbuphine
1OO S 99 2 3. 98 9 8 97
9 6 O.5 1 15 2 2.5 film thickness (micrometers) Fig. 13 U.S. Patent Sep. 8, 2009 Sheet 11 of 18 US 7,585,493 B2
naratriptan 100 s 99 N A E 98 A O Ol 97 9 & 96 A 95 0.5 1 1.5 2 2.5 film thickness (micrometers) Fig. 14
olanzapine 100 - a
A an A A SS d 99.5 S A Cl A A 9 99 Cld c A.
98.5 1 2 3 4 5 6 7 8 film thickness (micrometers) Fig. 15 U.S. Patent Sep. 8, 2009 Sheet 12 of 18 US 7,585,493 B2
duetiapine
9 9. 5
9 9
98.5 A
9 8 97.57. , , , , , , a film thickness (micrometers) Fig. 16
tadalafil
1OO 99 98 97 96 95 94 93. 0.5 1 1.5 2 2.5 3 film thickness (micrometers) Fig. 17 U.S. Patent Sep. 8, 2009 Sheet 13 of 18 US 7,585,493 B2
prochlorperazine 100
9 8
2 4 6 8 10 film thickness (micrometers) Fig. 18
100
99
98
97
96
95 1 2 3 4. 5 film thickness (micrometers) Fig. 19 U.S. Patent Sep. 8, 2009 Sheet 14 of 18 US 7,585,493 B2
1 OO
s 99 e 98 o 9 97
96 film thickness (micrometers) Fig. 20
100 A A A A A. A
an A SS 99 A e a 98 C (f) 9 97
96. 1 2 film thickness (micrometers) Fig. 21 U.S. Patent Sep. 8, 2009 Sheet 15 of 18 US 7,585,493 B2
sildenafil
100 99 s 98 2 97 5. 96 i 95 94 93 92 O 1 2 film thickness (micrometers) Fig. 22
albuterol
100
- 98 SS a 96 D C. 94 S. CD 92
90 2 3 4 5 6 7 film thickness (micrometers) Fig. 23 U.S. Patent Sep. 8, 2009 Sheet 16 of 18 US 7,585,493 B2
Fig. 24A t0 mSec
Fig. 24B t50 mSec
Fig. 24C t100 mSeC
Fig. 24D t200 mSec U.S. Patent Sep. 8, 2009 Sheet 17 of 18 US 7,585,493 B2
t=0 mSec
t50 mSec
t=100 mSec
t=200 mSec U.S. Patent Sep. 8, 2009 Sheet 18 of 18 US 7,585,493 B2
t=0 mSec
t50 mSeC
t100 mSeC
t=200 mSeC
Fig. 26E t300 mSec US 7,585,493 B2 1. 2 THIN-FILM DRUG DELIVERY ARTICLE AND cation No. 60/294.203, filed May 24, 2001, and of Provisional METHOD OF USE Application No. 60/317,479, filed Sep. 5, 2001. This application is also a continuation-in-part of applica The present application is a continuation-in-part of appli tion Ser. No. 10/151,596, filed May 16, 2002, now U.S. Pat. cation Ser. No. 10/057,197, filed Oct. 26, 2001, which claims No. 6,855,310, which claims the benefit of Provisional Appli benefit of Provisional Application No. 60/296,225, filed Jun. cation. No. 60/294,203, filed May 24, 2001, and of Provi 5, 2001. sional Application No. 60/317,479, filed Sep. 5, 2001. This application is also a continuation-in-part of applica This application is also a continuation-in-part of applica tion Ser. No. 10/057,198, filed Oct. 26, 2001, which claims tion Ser. No. 10/151,626, filed May 16, 2002, now U.S. Pat. benefit of Provisional Application No. 60/296,225, filed Jun. 10 No. 6,783,753, which claims the benefit of Provisional Appli 5, 2001. cation No. 60/294.203, filed May 24, 2001, and of Provisional This application is also a continuation-in-part of applica Application No. 60/317,479, filed Sep. 5, 2001. tion Ser. No. 10/146,080, filed May 13, 2002, which is a This application is also a continuation-in-part of applica continuation-in-part of application Ser. No. 10/057,198, filed tion Ser. No. 10/152,639, filed May 20, 2002, now U.S. Pat. Oct. 26, 2001, which claims the benefit of Provisional Appli 15 No. 6,716,416, which claims the benefit of Provisional Appli cation No. 60/296,225, filed Jun. 5, 2001. This Application is cation No. 60/294.203, filed May 24, 2001, and of Provisional also a continuation-in-part of application Ser. No. 10/057. Application No. 60/317,479, filed Sep. 5, 2001. 197, filed Oct. 26, 2001, which claims the benefit of Provi This application is also a continuation-in-part of applica sional Application No. 60/296,225, filed Jun. 5, 2001. tion Ser. No. 10/152,640, filed May 20, 2002, now U.S. Pat. This application is also a continuation-in-part of applica No. 6,743,415, which claims the benefit of Provisional Appli tion Ser. No. 10/146,086, filed May 13, 2002. cation No. 60/294.203, filed May 24, 2001, and prProvisional This application is also a continuation-in-part of applica Application No. 60/317,479, filed Sep. 5, 2001. tion Ser. No. 10/146,088, filed May 13, 2002, which is a This application is also a continuation-in-part of applica continuation-in-part of patent application Ser. No. 10/057. tion Ser. No. 10/152,652, filed May 20, 2002, now U.S. Pat. 198, filed Oct. 26, 2001, which claims the benefit of Provi 25 No. 6,740.307, which claims the benefit of Provisional Appli sional Application No. 60/296,225, filed Jun. 5, 2001. This cation No. 60/294.203, filed May 24, 2001, and of Provisional application is also a continuation-in-part of patent application Application No. 60/317,479, filed Sep. 5, 2001. Ser. No. 10/057,197, filed Oct. 26, 2001, which claims the This application is also a continuation-in-part of applica benefit of Provisional Application No. 60/296,225, filed Jun. tion Ser. No. 10/153,139, filed May 20, 2002, now U.S. Pat. 5, 2001. 30 No. 6,814,954, which claims the benefit of Provisional Appli This application is also a continuation-in-part of applica cation No. 60/294.203, filed May 24, 2001, and of Provisional tion Ser. No. 10/146,515, filed May 13, 2002, now U.S. Pat. Application No. 60/317,479, filed Sep. 5, 2001. No. 6,682.716, which is a continuation-in-part of patent This application is also a continuation-in-part of applica application Ser. No. 10/057,198, filed Oct. 26, 2001, which tion Ser. No. 10/153.311, filed May 21, 2002, now U.S. Pat. claims the benefit of Provisional Application No. 60/296,225, 35 No. 6,884,408, which claims the benefit of Provisional Appli filed Jun. 5, 2001. This application is also a continuation-in cation No. 60/294.203, filed May 24, 2001, and of Provisional part of patent application Ser. No. 10/057,197, filed Oct. 26, Application No. 60/317,479, filed Sep. 5, 2001. 2001, which claims the benefit of Provisional Application No. This application is also a continuation-in-part of applica 60/296,225, filed Jun. 5, 2001. tion Ser. No. 10/153.313, filed May 20, 2002, now abandoned This application is also a continuation-in-part of applica 40 which claims the benefit of Provisional Application No. tion Ser. No. 10/146,516, filed May 13, 2002, now U.S. Pat. 60/294.203, filed May 24, 2001, and of Provisional Applica No. 6,737,042, which claims the benefit of Provisional Appli tion No. 60/317,479, filed Sep. 5, 2001, and of Provisional cation No. 60/294.203, filed May 24, 2001, and also claims Application No. 60/345,145, filed Nov. 9, 2001. the benefit of Provisional Application No. 60/317,479, file This application is also a continuation-in-part of applica Sep. 5, 2001. 45 This application is also a continuation-in-part of applica tion Ser. No. 10/153,831, filed May 21, 2002, now U.S. Pat. tion Ser. No. 10/150,056, filed May 15, 2002, now U.S. Pat. No. 6,740,308, which claims the benefit of Provisional Appli No. 6,805,853, which claims the benefit of Provisional Appli cation No. 60/294.203, filed May 24, 2001, and of Provisional cation No. 60/345,882, filed Nov. 9, 2001. Application No. 60/317,479, filed Sep. 5, 2001. This application is also a continuation-in-part of applica 50 This application is also a continuation-in-part of applica tion Ser. No. 10/150,267, filed May 15, 2002, now U.S. Pat. tion Ser. No. 10/153,839, filed May 21, 2002, now U.S. Pat. No. 6,797.259, which claims the benefit of Provisional Appli No. 6,776,978, which claims the benefit of Provisional Appli cation No. 60/294.203, filed May 24, 2001, and of Provisional cation No. 60/294.203, filed May 24, 2001, and of Provisional Application No. 60/317,479, filed Sep. 5, 2001. Application No. 60/317,479, filed Sep. 5, 2001. This application is also a continuation-in-part of applica 55 This application is also a continuation-in-part of applica tion Ser. No. 10/150,268, filed May 15, 2002, now U.S. Pat. tion Ser. No. 10/154,594, filed May 23, 2002, now U.S. Pat. No. 6,780,399, which claims the benefit of Provisional Appli No. 6,740,309, which claims the benefit of Provisional Appli cation No. 60/294.203, filed May 24, 2001, and of Provisional cation No. 60/294.203, filed May 24, 2001, and of Provisional Application No. 60/317,479, filed Sep. 5, 2001. Application No. 60/317,479, filed Sep. 5, 2001. This application is also a continuation-in-part of applica 60 This application is also a continuation-in-part of applica tion Ser. No. 10/150,591, filed May 17, 2002, now U.S. Pat. tion Ser. No. 10/154,765, filed May 23, 2002, now U.S. Pat. No. 6,780.400, which claims the benefit of Provisional Appli No. 6,814,955, which claims the benefit of Provisional Appli cation No. 60/294.203, filed May 24, 2001, and of Provisional cation No. 60/294.203, filed May 24, 2001, and of Provisional Application No. 60/317,479, filed Sep. 5, 2001. Application No. 60/317,479, filed Sep. 5, 2001. This application is also a continuation-in-part of applica 65 This application is also a continuation-in-part of applica tion Ser. No. 10/150,857, filed May 17, 2002, now U.S. Pat. tion Ser. No. 10/155,097, filed May 23, 2002, now U.S. Pat. No. 6,716,415, which claims the benefit of Provisional Appli No. 6,716,417, which claims the benefit of Provisional Appli US 7,585,493 B2 3 4 cation No. 60/294.203, filed May 24, 2001, and of Provisional sought. Pulmonary delivery is one such alternative adminis Application No. 60/317,479, filed Sep. 5, 2001. tration route which can offer several advantages over the more This application is also a continuation-in-part of applica traditional routes. These advantages include rapid onset, the tion Ser. No. 10/155,373, filed May 22, 2002, now U.S. Pat. convenience of patient self-administration, the potential for No. 6,737,043, which claims the benefit of Provisional Appli reduced drug side-effects, ease of delivery by inhalation, the cation No. 60/294.203, filed May 24, 2001, and of Provisional elimination of needles, and the like. Many preclinical and Application No. 60/317,479, filed Sep. 5, 2001, and of Pro clinical studies with inhaled compounds have demonstrated visional Application No. 60/345,876, filed Nov. 9, 2001. that efficacy can be achieved both within the lungs and sys This application is also a continuation-in-part of applica temically. tion Ser. No. 10/155,621, filed May 22, 2002, now U.S. Pat. 10 However, despite such results, the role of inhalation No. 6,759,029, which claims the benefit of Provisional Appli therapy in the health care field has remained limited mainly to cation No. 60/294.203, filed May 24, 2001, and of Provisional treatment of asthma, in part due to a set of problems unique to Application No. 60/317,479, filed Sep. 5, 2001, and of Pro the development of inhalable drug formulations, especially visional Application No. 60/332,280, filed Nov. 21, 2001, and formulations for systemic delivery by inhalation. Dry powder of Provisional Application No. 60/336,218, filed Oct. 30, 15 formulations, while offering advantages over cumbersome 2001. liquid dosage forms and propellant-driven formulations, are This application is also a continuation-in-part of applica prone to aggregation and low flowability phenomena which tion Ser. No. 10/155,703, filed May 22, 2002, now U.S. Pat. considerably diminish the efficiency of dry powder-based No. 6,803,031, which claims the benefit of Provisional Appli inhalation therapies. cation No. 60/294.203, filed May 24, 2001, and of Provisional Thus, there remains a need in the art for devices capable of Application No. 60/317,479, filed Sep. 5, 2001. producing a drug aerosol for delivery by, for example, inha This application is also a continuation-in-part of applica lation or topical application. tion Ser. No. 10/155,705, filed May 22, 2002, now U.S. Pat. No. 6,805,854, which claims the benefit of Provisional Appli SUMMARY OF THE INVENTION cation No. 60/294.203, filed May 24, 2001, and of Provisional 25 Application No. 60/317,479, filed Sep. 5, 2001. In one aspect, the invention includes an article for use in an This application is also a continuation-in-part of applica aerosol device, for producing an aerosol of a compound, tion Ser. No. 10/280,315, filed Oct. 25, 2002, now abandoned comprising (a) aheat-conductive Substrate having an exterior which claims the benefit of Provisional Application No. Surface expanse with a selected Surface area, and (b) formed 60/335,049, filed Oct. 30, 2001, and of Provisional Applica 30 over the Surface expanse, a film containing the compound and tion No. 60/371,457, filed Apr. 9, 2002. having a selected film thickness of between 0.05um and 20 This application is also a continuation-in-part of applica um. The film thickness is such that an aerosol formed by tion Ser. No. 10/302,010, filed Nov. 21, 2002, now U.S. Pat. vaporizing the compound by heating the Substrate and con No. 7,078,016, which claims the benefit of Provisional Appli densing the vaporized compound contains 10% by weight or cation No. 60/332,279, filed Nov. 21, 2001. 35 less drug-degradation product and at least 50% of the total This application is also a continuation-in-part of applica amount of compound contained in the film. The selected area tion Ser. No. 10/302,614, filed Nov. 21, 2002, which claims of the substrate surface expanse is such as to yield an effective the benefit of Provisional Application No. 60/332,165, filed human therapeutic dose of the drug aerosol. Nov. 21, 2001. The film thickness may be selected such that the compound This application is also a continuation-in-part of applica 40 can be volatilized from the substrate with less than about 5% tion Ser. No. 10/322,227, filed Dec. 17, 2002, now abandoned by weight compound degradation. which claims the benefit of Provisional Application No. In a preferred embodiment, the selected substrate surface 60/342,066, filed Dec. 18, 2001, and of Provisional Applica area is between about 0.05-100 cm. The substrate may have tion No. 60/412,068, filed Sep. 18, 2002. an impermeable surface expanse on which film of the com All of the applications cited above are incorporated by 45 pound is formed. Exemplary Substrates are formed of metals, reference in their entirety. This invention was made with Such as stainless steel or aluminum, polymers, ceramics, and/ Government support under Grant No. R44 NS044800, or glass. Alternatively, or in addition, the Substrate Surface awarded by the National Institutes of Health. The Govern expanse is characterized by a contiguous Surface area of ment has certain rights in the invention. greater than 1 mm, preferably 10 mm, more preferable 50 50 mm and still more preferably 100 mm, and a material den FIELD OF THE INVENTION sity of greater than 0.5 g/cc. The compound may be one that, when vaporized from a The present invention relates generally to the field of compound film formed on an impermeable Surface expanse of devices and methods for administration of pharmaceutically a heat conductive Substrate and condensed to form aerosol active drugs. More specifically, the invention relates to a 55 particles, under selected vaporization conditions that lead to drug-supply device for use in production of drug-aerosol at least 50% recovery of compound in the aerosol particles, particles. exhibits (i) less than about 5% degradation product in aerosol particles when the compound is vaporized from a film having BACKGROUND OF THE INVENTION a selected film thickness between 0.05 and 20 microns, and 60 (ii) increasing levels of compound degradation in the aerosol Traditionally, inhalation therapy has played a relatively particles, with increasing film thickness above the selected minor role in the administration of therapeutic agents when film thickness. compared to more traditional drug administration routes of Exemplary compounds for use in the invention, and corre oral delivery and delivery via injection. Due to drawbacks sponding film thickness ranges are: associated with traditional routes of administration, including 65 alprazolam, film thickness between 0.1 and 10 um; slow onset, poor patient compliance, inconvenience, and/or amoxapine, film thickness between 2 and 20 um; discomfort, alternative administration routes have been atropine, film thickness between 0.1 and 10 um; US 7,585,493 B2 5 6 bumetanide film thickness between 0.1 and 5um; requires that the drug be delivered in a single inhalation buprenorphine, film thickness between 0.05 and 10 um; breath and preferably at the earliest stages of the breath, butorphanol, film thickness between 0.1 and 10 um; particularly as the time period for a breath can vary from clomipramine, film thickness between 1 and 8 um; individual to individual. The use of thin films allows a more donepezil, film thickness between 1 and 10 um; rapid rate of vaporization. Thus, rapid heating and generation hydromorphone, film thickness between 0.05 and 10 um; of the aerosol provides a means to deliver a consistent dose to loxapine, film thickness between 1 and 20 Lum; the deep lung in a single breath. Other embodiments of the midazolam, film thickness between 0.05 and 20 um; method are as described above. morphine, film thickness between 0.2 and 10 um; In still another aspect of the invention, a method of forming malbuphine, film thickness between 0.2 and 5um; 10 an article for use in an aerosol device, for producing aerosol naratriptan, film thickness between 0.2 and 5um; particles of a drug composition, is provided. The method olanzapine, film thickness between 1 and 20 um; includes (a) preparing on a heat-conductive impermeable paroxetine, film thickness between 1 and 20 um; Substrate a film containing a drug composition and having a prochlorperazine, film thickness between 0.1 and 20 um; first film thickness; (b) heating said Substrate to vaporize said quetiapine, film thickness between 1 and 20 Lum; 15 film, thereby producing aerosol particles containing said drug sertraline, film thickness between 1 and 20 um; composition; (c) determining (i) the drug purity of said aero sibutramine, film thickness between 0.5 and 2 um; sol particles and (ii) the fraction of film vaporized, and (d) sildenafil, film thickness between 0.2 and 3 um; repeating steps (a)-(c) one or more times but at a film thick Sumatriptan, film thickness between 0.2 and 6 um; ness different from the first film thickness to achieve anaero tadalafil, film thickness between 0.2 and 5um; sol particle purity of at least about 90% and a fraction of drug Vardenafil, film thickness between 0.1 and 2 um; film vaporized of at least about 50%. venlafaxine, film thickness between 2 and 20 um; In one embodiment of this method, the step of determining Zolpidem, film thickness between 0.1 and 10 um; further comprises selecting drug compositions having an apomorphine HCl, film thickness between 0.1 and 5um; aerosol particle purity of equal to or greater than 60% but less celecoxib, film thickness between 2 and 20 um; 25 than 90% and a fraction offilm vaporized of greater than 30% ciclesonide, film thickness between 0.05 and 5um; for the step of repeating (step (d)). eletriptan, film thickness between 0.2 and 20 um; In another embodiment, the step of preparing includes parecoxib, film thickness between 0.5 and 2 um; preparing a film of the therapeutic drug composition on a Valdecoxib, film thickness between 0.5 and 10 um; and selected surface area of the substrate sufficient to provide a fentanyl, film thickness between 0.05 and 5um. 30 therapeutic dose of drug composition in the form of aerosol The article may be formed, in accordance with another particles. aspect of the invention, by first determining, for a selected In one embodiment, the step of repeating includes heating compound, a film thickness between 0.05nd 20 microns such the Substrate in an inert atmosphere. Such as an argon or that an aerosol formed by (i) vaporizing the compound by nitrogen atmosphere. heating a heat-conductive Substrate having an exterior Surface 35 In another embodiment, the step of preparing comprises expanse and a film of the compound formed on the Surface preparing a film having a first film thickness of between about expanse to vaporize the compound and (ii) condensing the 1-20 um. The step of repeating comprises preparing a film vaporized compound contains 10% by weight or less drug having a different film thickness of between about 0.05-10 degradation product and at least 50% of the total amount of lm. drug composition contained in the film. There is then deter 40 These and other objects and features of the invention will mined an area of Surface expanse, when a film of the drug be more fully appreciated when the following detailed composition of the determined thickness is applied to the description of the invention is read in conjunction with the area, accommodating an effective human therapeutic inhala accompanying drawings. tion dose of the drug. A film of the selected drug of the identified thickness is then formed over the determined sub 45 BRIEF DESCRIPTION OF THE DRAWINGS strate area. Certain embodiments of the method are as described above. FIGS. 1A-1B are cross-sectional views of general embodi In a related aspect, the invention includes a method of ments of a drug-supply article in accordance with the inven forming an effective human therapeutic inhalation dose of a tion; drug composition in aerosol form having 10% or less drug 50 FIG. 2A is a perspective view of a drug-delivery device that degradation products and a selected aerosol particle mass incorporates a drug-supply article; median aerodynamic diameter (MMAD) between about 0.01 FIG. 2B shows another drug-delivery device that incorpo and 3 um. The method involves the steps of heating the rates a drug-supply article, where the device components are substrate in the article of claim 1 to a temperature between shown in unassembled form; 300° C. and 500° C., thereby to vaporize the film of drug 55 FIGS. 3A-3E are high speed photographs showing the composition formed on the Substrate, and during this heating, generation of aerosol particles from a drug-supply unit; flowing a gas across the Substrate at a gas flow rate effective FIGS. 4A-4B are plots of substrate temperature increase, to produce the desired size aerosol particles by condensation measured in still air with a thin thermocouple (Omega, Model of the vaporized drug composition. CO2-K), as a function of time. The substrate in FIG. 4A was The heating step may be effective to vaporize the film of 60 heated resistively by connection to a capacitor charged to 13.5 drug composition on the Substrate within a time period of 2 Volts (lower line), 15 Volts (middle line), and 16 Volts (upper seconds or less, e.g., 0.5 sec. The flowing step may be carried line); the substrate in FIG. 4B was heated resistively by dis out at a gas flow rate of between about 4 and 50 L/minutes. charge of a capacitor at 16 Volts; Rapid heating in combination with the air flow helps reduce FIGS. 5A-5B are plots of substrate temperature, in C., as the amount of decomposition. Rapid generation of the aerosol 65 a function of time, in seconds, for a hollow stainless steel is also necessary to ensure consistent delivery of an amount of cylindrical substrate heated resistively by connection to a drug to the deep lung. To deliver a drug in a single bolus capacitor charged to 21 Volts, where FIG. 5A shows the US 7,585,493 B2 7 8 temperature profile over a 4 second time period and FIG. 5B 25A) and during substrate heating at times of 50 milliseconds is a detail showing the temperature profile over the first sec (FIG. 25B), 100 milliseconds (FIG. 25C), and 200 millisec ond of heating: onds (FIG. 25D); and FIG. 6 is plot showing purity of thermal vapor as a function FIGS. 26A-26E are high speed photographs showing the of drug film thickness, in micrometers, for the drug atropine 5 generation of a thermal vapor of buprenorphine from a film of free base; drug coated on a Substrate drug-supply unit, where the pho FIG. 7 is plot showing purity of thermal vapor as a function tographs are taken at prior to Substrate heating (t=0 ms, FIG. of drug film thickness, in micrometers, for donepezil free 26A) and during substrate heating at times of 50 milliseconds base; (FIG. 26B), 100 milliseconds (FIG. 26C), 200 milliseconds FIG. 8 is plot showing purity of thermal vapor as a function 10 (FIG. 26D), and 300 milliseconds (FIG. 26E). of drug film thickness, in micrometers, for hydromorphone free base; DETAILED DESCRIPTION OF THE INVENTION FIG.9 is plot showing purity of thermal vapor as a function of drug film thickness, in micrometers, for buprenorphine I. Definitions free base; 15 The term "drug” as used herein means any Substance that is FIG. 10 is plot showing purity of thermal vapor as a func used in the prevention, diagnosis, alleviation, treatment or tion of drug film thickness, in micrometers, for clomipramine cure of a condition. The drug is preferably in a form suitable free base; for thermal vapor delivery, such as an ester, free acid, or free FIG. 11 is plot showing purity of thermal vapor as a func base form. The drugs are preferably other than recreational tion of drug film thickness, in micrometers, for ciclesonide; drugs. More specifically, the drugs are preferably other than FIG. 12 is plot showing purity of thermal vapor as a func recreational drugs used for non-medicinal recreational pur tion of drug film thickness, in micrometers, for midazolam poses, e.g., habitual use to Solely alter one’s mood, affect, free base; state of consciousness, or to affect a body function unneces FIG. 13 is plot showing purity of thermal vapor as a func sarily, for recreational purposes. The terms “drug”, “com tion of drug film thickness, in micrometers, for nalbuphine 25 free base; pound, and “medication' are herein used interchangeably. FIG. 14 is plot showing purity of thermal vapor as a func The drugs of use in the invention typically have a molecular tion of drug film thickness, in micrometers, for naratriptan weight in the range of about 150-700, preferably in the range free base; of about 200-650, more preferably in the range of 250-600, FIG. 15 is plot showing purity of thermal vapor as a func 30 still more preferably in the range of about 250-500, and most tion of drug film thickness, in micrometers, for olanzapine preferably in the range of about 300-450. free base; Specific drugs that can be used include, for example but not FIG. 16 is plot showing purity of thermal vapor as a func limitation, drugs of one of the following classes: anesthetics, tion of drug film thickness, in micrometers, for quetiapine anticonvulsants, antidepressants, antidiabetic agents, anti free base; 35 dotes, antiemetics, antihistamines, anti-infective agents, anti FIG. 17 is plot showing purity of thermal vapor as a func neoplastics, antiparkisonian drugs, antirheumatic agents, tion of drug film thickness, in micrometers, for tadalafil free antipsychotics, anxiolytics, appetite stimulants and Suppres base; sants, blood modifiers, cardiovascular agents, central nervous FIG. 18 is plot showing purity of thermal vapor as a func system stimulants, drugs for Alzheimer's disease manage tion of drug film thickness, in micrometers, for prochlorpera 40 ment, drugs for cystic fibrosis management, diagnostics, Zine free base; dietary Supplements, drugs for erectile dysfunction, gas FIG. 19 is plot showing purity of thermal vapor as a func trointestinal agents, hormones, drugs for the treatment of tion of drug film thickness, in micrometers, for Zolpidem free alcoholism, drugs for the treatment of addiction, immunosup base; pressives, mast cell stabilizers, migraine preparations, motion FIG. 20 is plot showing purity of thermal vapor as a func 45 sickness products, drugs for multiple Sclerosis management, tion of drug film thickness, in micrometers, for fentanyl free muscle relaxants, nonsteroidal anti-inflammatories, opioids, base; other analgesics and stimulants, opthalmic preparations, FIG. 21 is plot showing purity of thermal vapor as a func osteoporosis preparations, prostaglandins, respiratory tion of drug film thickness, in micrometers, for alprazolam agents, sedatives and hypnotics, skin and mucous membrane free base; 50 agents, Smoking cessation aids, Tourette's syndrome agents, FIG. 22 is plot showing purity of thermal vapor as a func urinary tract agents, and Vertigo agents. tion of drug film thickness, in micrometers, for sildenafil free Typically, where the drug is an anesthetic, it is selected base; from one of the following compounds: ketamine and FIG. 23 is plot showing purity of thermal vapor as a func lidocaine. tion of drug film thickness, in micrometers, for albuterol free 55 Typically, where the drug is an anticonvulsant, it is selected base; from one of the following classes: GABA analogs, tiagabine, FIGS. 24A-24D are high speed photographs showing the vigabatrin; barbiturates such as pentobarbital; benzodiaz generation ofathermal vapor of phenytoin from a film of drug epines such as clonazepam; hydantoins such as phenytoin: coated on a Substrate drug-supply unit, where the photo phenyltriazines such as lamotrigine; miscellaneous anticon graphs are taken prior to substrate heating (t=0 ms, FIG.24A) 60 Vulsants such as carbamazepine, topiramate, valproic acid, and during substrate heating at times of 50 milliseconds (FIG. and Zonisamide. 24B), 100 milliseconds (FIG. 24C), and 200 milliseconds Typically, where the drug is an antidepressant, it is selected (FIG.24D); from one of the following compounds: amitriptyline, amox FIGS. 25A-25D are high speed photographs showing the apine, benmoxine, butriptyline, clomipramine, desipramine, generation of a thermal vapor of disopyramide from a film of 65 doSulepin, doxepin, imipramine, kitanserin, lofepramine, drug coated on a Substrate drug-supply unit, where the pho medifoxamine, mianserin, maprotoline, mirtazapine, nortrip tographs are taken at prior to Substrate heating (t=0 ms, FIG. tyline, protriptyline, trimipramine, Venlafaxine, Viloxazine, US 7,585,493 B2 10 citalopram, cotinine, dulloxetine, fluoxetine, fluvoxamine, golide, piribedil, pramipexole, propentofylline, rasagiline, milnacipran, nisoxetine, paroxetine, reboxetine, Sertraline, remacemide, ropinerole, selegiline, spheramine, terguride, tianeptine, acetaphenazine, binedaline, brofaromine, cer entacapone, and tolcapone. iclamine, clovoxamine, iproniazid, isocarboxazid, moclobe Typically, where the drug is an antirheumatic agent, it is mide, phenyhydrazine, phenelzine, Selegiline, Sibutramine, selected from one of the following compounds: diclofenac, tranylcypromine, ademetionine, adrafinil, ameSergide, hydroxychloroquine and methotrexate. amisulpride, amperozide, benactyzine, bupropion, caroX Typically, where the drug is an antipsychotic, it is selected aZone, gepirone, idazoxan, metralindole, milnacipran, from one of the following compounds: acetophenazine, aliza minaprine, nefazodone, nomifensine, ritanserin, roXindole, pride, amisulpride, amoxapine, amperozide, aripiprazole, S-adenosylmethionine, tofenacin, traZodone, tryptophan, and 10 benperidol, benzquinamide, bromperidol, buramate, Zalospirone. butaclamol, butaperazine, carphenazine, carpipramine, chlo Typically, where the drug is an antidiabetic agent, it is rpromazine, chlorprothixene, clocapramine, clomacran, clo selected from one of the following compounds: pioglitaZone, penthixol, clospirazine, clothiapine, clozapine, cyame rosiglitaZone, and troglitaZone. mazine, droperidol, flupenthixol, fluiphenazine, fluspirilene, Typically, where the drug is an antidote, it is selected from 15 haloperidol, loxapine, melperone, mesoridazine, one of the following compounds: edrophonium chloride, flu metofenazate, molindrone, olanzapine, penfluridol, peri mazenil, deferoxamine, nalmefene, naloxone, and naltrex cyazine, perphenazine, pimozide, pipamerone, piperac OC. etazine, pipotiazine, prochlorperazine, promazine, quetiap Typically, where the drug is an antiemetic, it is selected ine, remoxipride, risperidone, sertindole, spiperone, from one of the following compounds: alizapride, azasetron, Sulpiride, thioridazine, thiothixene, trifluperidol, triflupro benzquinamide, bromopride, buclizine, chlorpromazine, cin mazine, trifluoperazine, Ziprasidone, Zotepine, and Zuclo narizine, clebopride, cyclizine, diphenhydramine, dipheni penthixol. dol, dolasetron, droperidol, granisetron, hyoscine, Typically, where the drug is an anxiolytic, it is selected lorazepam, dronabinol, metoclopramide, metopimazine, from one of the following compounds: alprazolam, bro ondansetron, perphenazine, promethazine, prochlorperazine, 25 mazepam, oxazepam, buspirone, hydroxy Zine, mecloqua Scopolamine, triethylperazine, trifluoperazine, triflupro lone, medetomidine, metomidate, adinazolam, chlordiazep mazine, trimethobenzamide, tropisetron, domperidone, and oxide, clobenzepam, flurazepam, lorazepam, loprazolam, palonosetron. midazolam, alpidem, alseroxlon, amphenidone, azacyclonol, Typically, where the drug is an antihistamine, it is selected bromisovalum, captodiamine, capuride, carbcloral, carbro from one of the following compounds: astemizole, azatadine, 30 mal, chloral betaine, enciprazine, flesinoxan, ipsapiraone, brompheniramine, carbinoxamine, cetrizine, chlorphe lesopitron, loxapine, methaqualone, methprylon, propanolol. niramine, cinnarizine, clemastine, cyproheptadine, dexme tandospirone, trazadone, Zopiclone, and Zolpidem. detomidine, diphenhydramine, doxylamine, fexofenadine, Typically, where the drug is an appetite stimulant, it is hydroxy Zine, loratidine, promethazine, pyrilamine and ter dronabinol. fenidine. 35 Typically, where the drug is an appetite Suppressant, it is Typically, where the drug is an anti-infective agent, it is selected from one of the following compounds: fenfluramine, selected from one of the following classes: antivirals such as phentermine and Sibutramine. efavirenz, AIDS adjunct agents such as dapsone; aminogly Typically, where the drug is a blood modifier, it is selected cosides Such as tobramycin; antifungals such as fluconazole; 40 from one of the following compounds: ciloStazol and dipy antimalarial agents such as quinine; antituberculosis agents ridamol. Such as ethambutol; B-lactams such as cefinetazole, cefazo Typically, where the drug is a cardiovascular agent, it is lin, cephalexin, cefoperaZone, cefoxitin, cephacetrile, cepha selected from one of the following compounds: benazepril, loglycin, cephaloridine; cephalosporins, such as cepha captopril, enalapril, quinapril, ramipril, doxazosin, praZosin, losporin C, cephalothin; cephamycins such as cephamycin A, clonidine, labetolol, candesartan, irbesartan, losartan, telmis cephamycin B, and cephamycin C, cephapirin, cephradine; 45 artan, Valsartan, disopyramide, flecanide, mexiletine, leprostatics such as clofazimine; penicillins such as amplicil procainamide, propafenone, quinidine, tocainide, amio lin, amoxicillin, hetacillin, carfecillin, carindacillin, carbeni darone, dolfetilide, ibutilide, adenosine, gemfibrozil, lovasta cillin, amylpenicillin, azidocillin, benzylpenicillin, clometo tin, acebutalol, atenolol, bisoprolol, esmolol, metoprolol. cillin, cloxacillin, cyclacillin, methicillin, nafcillin, nadolol, pindolol, propranolol, Sotalol, diltiazem, nifedipine, 2-pentenylpenicillin, penicillin N, penicillin O, penicillin S. 50 Verapamil, spironolactone, burnetanide, ethacrynic acid, penicillin V. dicloxacillin; diphenicillin; heptylpenicillin; and furosemide, torsemide, amiloride, triamterene, and metola metampicillin, quinolones such as ciprofloxacin, clinafloxa ZO. cin, difloxacin, grepafloxacin, norfloxacin, ofloxacine, tema Typically, where the drug is a central nervous system floxacin, tetracyclines Such as doxycycline and oxytetracy 55 stimulant, it is selected from one of the following compounds: cline; miscellaneous anti-infectives such as lineZolide, amphetamine, brucine, caffeine, dexfenfluramine, dextroam trimethoprim and Sulfamethoxazole. phetamine, ephedrine, fenfluramine, mazindol, methypheni Typically, where the drug is an anti-neoplastic agent, it is date, pemoline, phentermine, Sibutramine, and modafinil. selected from one of the following compounds: droloxifene, Typically, where the drug is a drug for Alzheimer's disease tamoxifen, and toremifene. 60 management, it is selected from one of the following com Typically, where the drug is an antiparkisonian drug, it is pounds: donepezil, galanthamine and tacrin. selected from one of the following compounds: amantadine, Typically, where the drug is a drug for cystic fibrosis man baclofen, biperiden, benztropine, orphenadrine, procyclid agement, it is selected from one of the following compounds: ine, trihexyphenidyl, levodopa, carbidopa, andropinirole, tobramycin and cefadroXil. apomorphine, benserazide, bromocriptine, budipine, caber 65 Typically, where the drug is a diagnostic agent, it is goline, eliprodil, eptastigmine, ergoline, galanthamine, laza selected from one of the following compounds: adenosine bemide, lisuride, mazindol, memantine, mofegiline, per and aminohippuric acid. US 7,585,493 B2 11 12 Typically, where the drug is a dietary Supplement, it is pon, morphine, nalbuphine, nalorphine, oxycodone, papav selected from one of the following compounds: melatonin eretum, pethidine, pentazocine, phenazocine, remifentanil, and vitamin-E. Sufentanil, and tramadol. Typically, where the drug is a drug for erectile dysfunction, Typically, where the drug is an other analgesic it is selected it is selected from one of the following compounds: tadalafil. from one of the following compounds: apaZone, benzpipery sildenafil. Vardenafil, apomorphine, apomorphine diacetate, lon, benzydramine, caffeine, clonixin, ethoheptazine, flupir phentolamine, and yohimbine. tine, nefopam, orphenadrine, propacetamol, and pro Typically, where the drug is a gastrointestinal agent, it is poxyphene. selected from one of the following compounds: loperamide, Typically, where the drug is an opthalmic preparation, it is atropine, hyoscyamine, famotidine, lanSoprazole, omepra 10 selected from one of the following compounds: ketotifen and Zole, and rebeprazole. betaxolol. Typically, where the drug is a hormone, it is selected from Typically, where the drug is an osteoporosis preparation, it one of the following compounds: testosterone, estradiol, and is selected from one of the following compounds: alendr cortisone. onate, estradiol, estropitate, risedronate and raloxifene. Typically, where the drug is a drug for the treatment of 15 Typically, where the drug is a prostaglandin, it is selected alcoholism, it is selected from one of the following com from one of the following compounds: epoprostanol, dino pounds: naloxone, naltrexone, and disulfiram. prostone, misoprostol, and alprostadil. Typically, where the drug is a drug for the treatment of Typically, where the drug is a respiratory agent, it is addiction it is buprenorphine. selected from one of the following compounds: albuterol, Typically, where the drug is an immunosupressive, it is ephedrine, epinephrine, fomoterol, metaproterenol, terbuta selected from one of the following compounds: mycophe line, budesonide, ciclesonide, dexamethasone, flunisolide, nolic acid, cyclosporin, azathioprine, tacrolimus, and rapa fluticasone propionate, triamcinolone acetonide, ipratropium mycin. bromide, pseudoephedrine, theophylline, montelukast, and Typically, where the drug is a mast cell stabilizer, it is Zafirlukast. selected from one of the following compounds: cromolyn, 25 Typically, where the drug is a sedative and hypnotic, it is pemirolast, and nedocromil. selected from one of the following compounds: butalbital, Typically, where the drug is a drug for migraine headache, chlordiazepoxide, diazepam, estazolam, flunitrazepam, flu it is selected from one of the following compounds: almot razepam, lorazepam, midazolam, temazepam, triazolam, riptan, alperopride, codeine, dihydroergotamine, ergotamine, Zaleplon, Zolpidem, and Zopiclone. eletriptan, froVatriptan, isometheptene, lidocaine, lisuride, 30 Typically, where the drug is a skin and mucous membrane metoclopramide, naratriptan, oxycodone, propoxyphene, agent, it is selected from one of the following compounds: rizatriptan, Sumatriptan, tolfenamic acid, Zolmitriptan, ami isotretinoin, bergapten and methoxsalen. triptyline, atenolol, clonidine, cyproheptadine, diltiazem, Typically, where the drug is a Smoking cessation aid, it is doxepin, fluoxetine, lisinopril, methysergide, metoprolol. selected from one of the following compounds: nicotine and 35 Varenicline. nadolol, nortriptyline, paroxetine, pizotifen, pizotyline, pro Typically, where the drug is a Tourette's syndrome agent, it panolol, protriptyline, Sertraline, timolol, and Verapamil. is pimozide. Typically, where the drug is a motion sickness product, it is Typically, where the drug is a urinary tract agent, it is selected from one of the following compounds: diphenhy selected from one of the following compounds: tolteridine, dramine, promethazine, and Scopolamine. 40 darifenicin, propantheline bromide, and oxybutynin. Typically, where the drug is a drug for multiple Sclerosis Typically, where the drug is a vertigo agent, it is selected management, it is selected from one of the following com from one of the following compounds: betahistine and pounds: bencyclane, methylprednisolone, mitoxantrone, and meclizine. prednisolone. The term “drug composition” as used herein refers to a Typically, where the drug is a muscle relaxant, it is selected 45 composition that comprises only pure drug, two or more from one of the following compounds: baclofen, chlorZOX drugs in combination, or one or more drugs in combination aZone, cyclobenzaprine, methocarbamol, orphenadrine, qui with additional components. Additional components can nine, and tizanidine. include, for example, pharmaceutically acceptable excipi Typically, where the drug is a nonsteroidal anti-inflamma ents, carriers, and Surfactants. tory, it is selected from one of the following compounds: 50 The term “thermal vapor as used herein refers to a vapor aceclofenac, acetaminophen, alminoprofen, amfenac, amino phase, aerosol, or mixture of aerosol-vapor phases, formed propylon, amiXetrine, aspirin, benoxaprofen, bromfenac, preferably by heating. The thermal vapor may comprise a bufexamac, carprofen, celecoxib, choline, Salicylate, cin drug and optionally a carrier, and may be formed by heating chophen, cinmetacin, clopriac, clometacin, diclofenac, the drug and optionally a carrier. The term “vapor phase' diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, 55 refers to a gaseous phase. The term “aerosol phase' refers to indomethacin, indoprofen, ketoprofen, ketorolac, Solid and/or liquid particles Suspended in a gaseous phase. maZipredone, meclofenamate, nabumetone, naproxen, pare The term “drug degradation product as used herein refers coxib, piroXicam, pirprofen, rofecoxib, Sulindac, tolfe to a compound resulting from a chemical modification of the namate, tolmetin, and Valdecoxib. drug compound during the drug vaporization-condensation Typically, where the drug is an opioid, it is selected from 60 process. The modification, for example, can be the result of a one of the following compounds: alfentanil, allylprodine, thermally or photochemically induced reaction. Such reac alphaprodine, anilleridine, benzylmorphine, bezitramide, tions include, without limitation, oxidation and hydrolysis. buprenorphine, butorphanol, carbiphene, cipramadol, cloni The term “fraction drug degradation product as used taZene, codeine, dextromoramide, dextropropoxyphene, herein refers to the quantity of drug degradation products diamorphine, dihydrocodeine, diphenoxylate, dipipanone, 65 present in the aerosol particles divided by the quantity of drug fentanyl, hydromorphone, L-alpha acetyl methadol, lofenta plus drug degradation product present in the aerosol, i.e. (Sum nil, levorphanol, meperidine, methadone, meptazinol, meto of quantities of all drug degradation products present in the US 7,585,493 B2 13 14 aerosol)/((quantity of drug composition present in the aero ing the thermal vapor phase when heated (i.e., the dose pro Sol)+(sum of quantities of all drug degradation products duced by the starting drug or drugs), the bioavailability of the present in the aerosol)). The term "percent drug degradation thermal vapor phase drug or drugs, the Volume of patient product as used herein refers to the fraction drug degradation inhalation, and the potency of the thermal vapor drug or drugs product multiplied by 100%, whereas “purity” of the aerosol as a function of plasma drug concentration. refers to 100% minus the percent drug degradation products. Typically, the bioavailability of thermal vapors ranges To determine the percent or fraction drug degradation prod from 20-100% and is preferably in the range of 50-100% uct, typically, the aerosol is collected in a trap, Such as a filter, relative to the bioavailability of drugs infused intravenously. glass wool, an impinger, a solvent trap, or a cold trap, with The potency of the thermal vapor drug or drugs per unit collection in a filter particularly preferred. The trap is then 10 plasma drug concentration is preferably equal to or greater typically extracted with a solvent, e.g. acetonitrile, and the than that of the drug or drugs delivered by other routes of extract Subjected to analysis by any of a variety of analytical administration. It may substantially exceed that of oral, intra methods known in the art, with gas and liquid chromatogra muscular, or other routes of administration in cases where the phy preferred methods, and high performance liquid chroma clinical effect is related to the rate of rise in plasma drug tography particularly preferred. The gas or liquid chromatog 15 concentration more strongly than the absolute plasma drug raphy method includes a detector system, such as a mass concentration. In some instances, thermal vapor delivery spectrometry detector or ultraviolet absorption detector. Ide results in increased drug concentration in a target organ Such ally, the detector System allows determination of the quantity as the brain, relative to the plasma drug concentration (Lich of the components of the drug composition and drug degra tman et al., The Journal of Pharmacology and Experimental dation product by weight. This is achieved in practice by Therapeutics 279:69-76 (1996)). Thus, for medications cur measuring the signal obtained upon analysis of one or more rently given orally, the human dose or effective therapeutic known mass(es) of components of the drug composition or amount of that drug in thermal vapor form is generally less drug degradation product (standards) and comparing the sig than the standard oral dose. Preferably it will be less than nal obtained upon analysis of the aerosol to that obtained 80%, more preferably less than 40%, and most preferably less upon analysis of the standard(s), an approach well known in 25 than 20% of the standard oral dose. For medications currently the art. In many cases, the structure of a drug degradation given intravenously, the drug dose in a thermal vapor will product may not be known or a standard of the drug degra generally be similar to or less than the standard intravenous dation product may not be available. In Such cases, it is dose. Preferably it will be less than 200%, more preferably acceptable to calculate the weight fraction of the drug degra less than 100%, and most preferably less than 50% of the dation product by assuming that the drug degradation product 30 standard intravenous dose. has an identical response coefficient (e.g. for ultraviolet Determination of the appropriate dose of thermal vapor to absorption detection, identical extinction coefficient) to the be used to treat a particular condition can be performed via drug component or components in the drug composition. animal experiments and a dose-finding (Phase I/II) clinical When conducting Such analysis, for practicality drug degra trial. Preferred animal experiments involve measuring plasma dation products presentat less than avery Small fraction of the 35 drug concentrations after exposure of the test animal to the drug compound, e.g. less than 0.2% or 0.1% or 0.03% of the drug thermal vapor. These experiments may also be used to drug compound, are generally excluded from analysis. evaluate possible pulmonary toxicity of the thermal vapor. Because of the frequent necessity to assume an identical Because accurate extrapolation of these results to humans is response coefficient between drug and drug degradation facilitated if the test animal has a respiratory system similar to product in calculating a weight percentage of drug degrada 40 humans, mammals such as dogs or primates are a preferred tion product, it is preferred to use an analytical approach in group of test animals. Conducting such experiments in mam which Such an assumption has a high probability of validity. mals also allows for monitoring of behavioral or physiologi In this respect, high performance liquid chromatography with cal responses in mammals. Initial dose levels for testing in detection by absorption of ultraviolet light at 225 nm is a humans will generally be less than or equal to the least of the preferred approach. UV absorption at other than 225 nm, 45 following: current standard intravenous dose, current stan most commonly 250 nm, was used for detection of com dard oral dose, dose at which a physiological or behavioral pounds in limited cases where the compound absorbed Sub response was obtained in the mammal experiments, and dose stantially more strongly at 250 nm or for other reasons one in the mammal model which resulted in plasma drug levels skilled in the art would consider detection at 250 nm the most associated with a therapeutic effect of drug in humans. Dose appropriate means of estimating purity by weight using 50 escalation may then be performed in humans, until either an HPLC analysis. In certain cases where analysis of the drug by optimal therapeutic response is obtained or dose-limiting tox UV was not viable, other analytical tools such as GC/MS or icity is encountered. LC/MS were used to determine purity. The actual effective amount of drug for a particular patient The term “effective human therapeutic dose” means the can vary according to the specific drug or combination thereof amount required to achieve the desired effect or efficacy, e.g., 55 being utilized, the particular composition formulated, the abatement of symptoms or cessation of the episode, in a mode of administration and the age, weight, and condition of human. The dose of a drug delivered in the thermal vapor the patient and severity of the episode being treated. refers to a unit dose amount that is generated by heating of the drug under defined delivery conditions. A “unit dose amount II. Drug-Supply Article is the total amount of drug in a given Volume of inhaled 60 In one aspect, the invention provides a drug-supply article thermal vapor. The unit dose amount may be determined by for production of drug-aerosol particles. The article is par collecting the thermal vapor and analyzing its composition as ticularly suited for use in a device for inhalation therapy for described herein, and comparing the results of analysis of the delivery of a therapeutic agent to the lungs of a patient, for thermal vapor to those of a series of reference standards local or systemic treatment. The article is also Suited for use in containing known amounts of the drug. The amount of drug or 65 a device that generates an air stream, for application of drug drugs required in the starting composition for delivery as a aerosol particles to a target site. For example, a stream of air thermal vapor depends on the amount of drug or drugs enter carrying drug-aerosol particles can be applied to treat an US 7,585,493 B2 15 16 acute or chronic skin condition, can be applied during Surgery With continuing reference to FIG. 1A, deposited on all or a at the incision site, or can be applied to an open wound. In portion of the upper surface 14 of the substrate is a film 18 of Section A below, the drug-supply article and use of the drug drug. Preferably the film has a thickness of between about Supply article in an inhalation device are described. In Section 0.05um and 20 um. Film deposition is achieved by a variety B, the relationship between drug-film thickness, substrate 5 of methods, depending in part on the physical properties of area, and purity of drug-aerosol particles are discussed. the drug and on the desired drug film thickness. Exemplary The term “purity” as used herein, with respect to the aero methods include, but are not limited to, preparing a solution Sol purity, means the fraction of drug composition in the of drug in Solvent, applying the solution to the exterior Surface aerosol/the fraction of drug composition in the aerosol plus and removing the solvent to leave a film of drug. The drug drug degradation products. Thus purity is relative with regard 10 Solution can be applied by dipping the Substrate into the to the purity of the starting material. For example, when the Solution, spraying, brushing or otherwise applying the solu starting drug or drug composition used for Substrate coating tion to the substrate. Alternatively, a melt of the drug can be contained detectable impurities, the reported purity of the prepared and applied to the Substrate. For drugs that are aerosol does not include those impurities present in the start liquids at room temperature, thickening agents can be ing material that were also found in the aerosol, e.g., in certain 15 admixed with the drug to permit application of a solid drug cases if the starting material contained a 1% impurity and the film. Examples of drug film deposition on a variety of sub aerosol was found to contain the identical 1% impurity, the strates are given below. aerosol purity may nevertheless be reported as >99% pure, FIG. 1B is a perspective, cut-away view of an alternative reflecting the fact that the detectable 1% purity was not pro geometry of the drug-Supply article. Article 20 is comprised duced during the vaporization-condensation aerosol genera of a cylindrically-shaped substrate 22 formed from a heat tion process. conductive material. Substrate 22 has an exterior surface 24 that is preferably impermeable by virtue of material selection, A. Thin-Film Coated Substrate surface treatment, or the like. Deposited on the exterior sur A drug-supply article according to one embodiment of the face of the substrate is a film 26 of the drug composition. As invention is shown in cross-sectional view in FIG. 1A. Drug 25 will be described in more detail below, in use the substrate of supply article 10 is comprised of a heat-conductive substrate the drug-supply article is heated to vaporize all or a portion of 12. Heat-conductive materials for use informing the substrate the drug film. Control of air flow across the substrate surface are well known, and typically include metals, such as alumi during vaporization produces the desired size of drug-aerosol num, iron, copper, stainless steel, and the like, alloys, ceram particles. In FIG. 1B, the drug film and substrate surface is ics, and filled polymers. The substrate can be of virtually any 30 partially cut-away in the figure to expose aheating element 28 geometry, the square or rectangular configuration shown in disposed in the substrate. The substrate can be hollow with a FIG. 1A merely exemplary. Heat-conductive substrate 12 has heating element inserted into the hollow space or solid with a an upper Surface 14 and a lower Surface 16. heating element incorporated into the Substrate. The heating Preferred substrates are those substrates that have surfaces element in the embodiment shown takes the form of an elec with relatively few or substantially no surface irregularities so 35 trical resistive wire that produces heat when a current flows that a molecule of a compound vaporized from a film of the through the wire. Other heating elements are suitable, includ compound on the Surface is unlikely to acquire Sufficient ing but not limited to a solid chemical fuel, chemical compo energy through contact with either other hot vapor molecules, nents that undergo an exothermic reaction, inductive heat, etc. hot gases Surrounding the area, or the Substrate Surface to Heating of the Substrate by conductive heating is also Suit result in cleavage of chemical bonds and hence compound 40 able. One exemplary heating source is described in U.S. decomposition. To avoid Such decomposition, the vaporized patent application for SELF-CONTAINED HEATING UNIT compound should transition rapidly from the heated Surface AND DRUG-SUPPLY UNIT EMPLOYING SAME, U.S. or Surrounding heated gas to a cooler environment. While a Ser. No. 60/472,697 filed May 21, 2003 which is incorporated vaporized compound from a Surface may transition through herein by reference. Brownian motion or diffusion, the temporal duration of this 45 FIG. 2A is a perspective view of a drug-delivery device that transition may be impacted by the extent of the region of incorporates a drug-supply article similar to that shown in elevated temperature at the surface which is established by the FIG. 1B. Device 30 includes a housing 32 with a tapered end Velocity gradient of gases over the Surface and the physical 34 for insertion into the mouth of a user. On the end opposite shape of surface. A high Velocity gradient (a rapid increase in tapered end 34, the housing has one or more openings, such as Velocity gradient near the Surface) results in minimization of 50 slot 36, for air intake when a user places the device in the the hot gas region above the heated Surface and decreases the mouth and inhales a breath. Disposed within housing 32 is a time of transition of the vaporized compound to a cooler drug-supply article 38, visible in the cut-away portion of the environment. Likewise, a Smoother Surface facilitates this figure. Drug-supply article includes a Substrate 40 coated on transition, as the hot gases and compound vapor are not pre its external surface with a film 42 of a therapeutic drug to be cluded from rapid transition by being trapped in, for example, 55 delivered to the user. The drug-supply article can be rapidly depressions, pockets or pores. Although a variety of Sub heated to a temperature Sufficient to vaporize all or a portion strates can be used, specifically preferred Substrates are those of the film of drug to form a drug vapor that becomes that have impermeable Surfaces or have an impermeable Sur entrained in the stream of air during inhalation, thus forming face coating, such as, for example, metal foils, Smooth metal the drug-aerosol particles. Heating of the drug-supply article Surfaces, non-porous ceramics, etc. For the reasons stated 60 is accomplished by, for example, an electrically-resistive wire above, non-preferred Substrates for producing a therapeutic embedded or inserted into the substrate and connected to a amount of a compound with less than 10% compound degra battery disposed in the housing. Substrate heating can be dation via vaporization are those that have a Substrate density actuated by a user-activated button on the housing or via of less than 0.5 g/cc, such as, for example, yarn, felts and breath actuation, as is known in the art. foams, or those that have a surface area of less than 1 mm/ 65 FIG. 2B shows another drug-delivery device that incorpo particle Such as, for example Small alumina particles, and rates a drug-supply article, where the device components are other inorganic particles. shown in unassembled form. Inhalation device 50 is com US 7,585,493 B2 17 18 prised of an upper external housing member 52 and a lower the chamber may be altered by modifying the gas-flow con external housing member 54 that fit together. The down trol valve to increase or decrease the volumetric airflow rate. stream end of each housing member is gently tapered for For example, to produce condensation particles in the size insertion into a user's mouth, best seen on upper housing range 1-3.5 um MMAD, the chamber may have substantially member 52 at downstream end 56. The upstream end of the Smooth-Surfaced walls, and the selected gas-flow rate may be upper and lowerhousing members are slotted, as seen best in in the range of 4-50 L/minute. the figure in the upper housing member at 58, to provide for Additionally, as will be appreciated by one of skill in the air intake when a user inhales. The upper and lower housing art, particle size may be also altered by modifying the cross members when fitted together define a chamber 60. Posi section of the chamber condensation region to increase or tioned within chamber 60 is a drug-supply unit 62, shown in 10 decrease linear gas Velocity for a given Volumetric flow rate, a partial cut-away view. The drug Supply unit has a tapered, and/or the presence or absence of structures that produce substantially cylindrical substrate 64 coated with a film 66 of turbulence within the chamber. Thus, for example to produce drug on its external, smooth, impermeable surface 68. Visible condensation particles in the size range 20-100 nm MMAD, in the cut-away portion of the drug-Supply unit is an interior the chamber may provide gas-flow barriers for creating air region 70 of the substrate containing a substance suitable to 15 turbulence within the condensation chamber. These barriers generate heat. The Substance can be a solid chemical fuel, are typically placed within a few thousands of an inch from chemical reagents that mix exothermically, electrically resis the substrate surface. tive wire, etc. A power Supply source, if needed for heating, The heat source in one general embodiment is effective to and any necessary Valving for the inhalation device are con Supply heat to the Substrate at a rate that achieves a Substrate tained in end piece 72. temperature of at least 200°C., preferably at least 250° C., or In a typical embodiment, the device includes a gas-flow more preferably at least 300° C. or 350° C., and produces control valve disposed upstream of the drug-supply unit for Substantially complete volatilization of the drug composition limiting gas-flow rate through the condensation region to the from the substrate within a period of 2 seconds, preferably, selected gas-flow rate, for example, for limiting air flow within 1 second, or more preferably within 0.5 seconds. Suit through the chamber as air is drawn by the user's mouth into 25 able heat sources include resistive heating devices which are and through the chamber. In a specific embodiment, the gas Supplied current at a rate Sufficient to achieve rapid heating, flow valve includes an inlet port communicating with the e.g., to a substrate temperature of at least 200° C., 250°C., chamber, and a deformable flap adapted to divertorrestrict air 300° C., or 350° C. preferably within 50-500 ms, more pref flow away from the port increasingly, with increasing pres erably in the range of 50-200 ms. Heat sources or devices that Sure drop across the valve. In another embodiment, the gas 30 contain a chemically reactive material which undergoes an flow valve includes the actuation switch, with valve move exothermic reaction upon actuation, e.g., by a spark or heat ment in response to an air pressure differential across the element, such as flashbulb type heaters of the type described valve acting to close the switch. In still another embodiment, in several examples, and the heating source described in the the gas-flow valve includes an orifice designed to limit airflow above-cited U.S. patent application for SELF-CONTAINED rate into the chamber. 35 HEATING UNIT AND DRUG-SUPPLY UNITEMPLOY The device may also include a bypass valve communicat ING SAME, are also suitable. In particular, heat sources that ing with the chamber downstream of the unit for offsetting the generate heat by exothermic reaction, where the chemical decrease in airflow produced by the gas-flow control valve, as “load of the source is consumed in a period of between the user draws air into the chamber. The bypass valve coop 50-500 msec or less are generally Suitable, assuming good erates with the gas-control valve to control the flow through 40 thermal coupling between the heat Source and Substrate. the condensation region of the chamber as well as the total FIGS. 3A-3E are high speed photographs showing the amount of air being drawn through the device. Thus the total generation of aerosol particles from a drug-supply unit. FIG. volumetric airflow through the device, is the sum of the volu 3A shows a heat-conductive substrate about 2 cm in length metric airflow rate through the gas-control valve, and the coated with a film of drug. The drug-coated Substrate was volumetric airflow rate through the bypass valve. The gas 45 placed in a chamber through which a stream of air was flow control valve acts to limit air drawn into the device to a ing in an upstream-to-downstream direction (indicated by the preselected level, e.g., 15 L/minute, corresponding to the arrow in FIG.3A) at rate of about 15 L/min. The substrate was selected air-flow rate for producing aerosol particles of a electrically heated and the progression of drug vaporization selected size. Once this selected airflow level is reached, monitored by real-time photography. FIGS. 3B-3E show the additional air drawn into the device creates a pressure drop 50 sequence of drug vaporization and aerosol generation at time across the bypass valve which then accommodates airflow intervals of 50 milliseconds (msec), 100 msec, 200 msec, and through the bypass valve into the downstream end of the 500 msec, respectively. The white cloud of drug-aerosol par device adjacent the user's mouth. Thus, the user senses a full ticles formed from the drug vapor entrained in the flowing air breath being drawn in, with the two valves distributing the is visible in the photographs. Complete vaporization of the total airflow between desired airflow rate and bypass airflow 55 drug film was achieved by 500 m.sec. rate. The drug-supply unit generates a drug vapor that can These valves may be used to control the gas velocity readily be mixed with gas to produce anaerosol for inhalation through the condensation region of the chamber and hence to or for delivery, typically by a spray nozzle, to a topical site for control the particle size of the aerosol particles produced by a variety of treatment regimens, including acute or chronic vapor condensation. More rapid airflow dilutes the vapor such 60 treatment of a skin condition, administration of a drug to an that it condenses into Smaller particles. In other words, the incision site during Surgery or to an open wound. Rapid particle size distribution of the aerosol is determined by the vaporization of the drug film occurs with minimal thermal concentration of the compound vapor during condensation. decomposition of the drug, as will be further demonstrated in This vapor concentration is, in turn, determined by the extent Section B. to which airflow over the surface of the heating substrate 65 B. Selection of Drug Film Thickness and Substrate Area dilutes the evolved vapor. Thus, to achieve smaller or larger As discussed above, the drug Supply article includes a film particles, the gas Velocity through the condensation region of of drug formed on a substrate. In a preferred embodiment, the US 7,585,493 B2 19 20 drug composition consists of two or more drugs. In a more For each Substrate type, a drug film was formed by apply preferred embodiment, the drug composition comprises pure ing a solution containing the drug onto the Substrate. As drug. The drug film in one general embodiment of the inven described in Method A, a solution of the drug in a solvent was tion has a thickness of between about 0.05-20 lum, and pref prepared. A variety of Solvents can be used and selection is erably between 0.1-15 um, more preferably between 0.2-10 5 based, in part, on the solubility properties of the drug and the um and still more preferably 0.5-10 um, and most preferably desired solution concentration. Common solvent choices 1-10 um. The film thickness for a given drug composition is included methanol, chloroform, acetone, dichloromethane, Such that drug-aerosol particles, formed by vaporizing the other Volatile organic solvents, dimethylformamide, water, drug composition by heating the Substrate and entraining the and solvent mixtures. The drug solution was applied to the vapor in a gas stream, have (i) 10% by weight or less drug 10 Substrate by dip coating, yet other methods such as spray degradation product, more preferably 5% by weight or less, coating are contemplated as well. Alternatively, a melt of the most preferably 2.5% by weight or less and (ii) at least 50% of drug can be applied to the Substrate. the total amount of drug composition contained in the film. In Examples 1-236 below, a Substrate containing a drug The area of the substrate on which the drug composition film film of a certain thickness was prepared. To determine the is formed is selected to achieve an effective human therapeu 15 thickness of the drug film, one method that can be used is to tic dose of the drug aerosol. Each of these features of the drug determine the area of the substrate and calculate drug film article is described below. thickness using the following relationship: 1. Aerosol Particle Purity and Yield In studies conducted in Support of the invention, a variety film thickness (cm)=drug mass (g), drug density of drugs were deposited on a heat-conductive, impermeable (g/cm)xsubstrate area (cm) Substrate and the Substrate was heated to a temperature Suf The drug mass can be determined by weighing the Substrate ficient to generate a thermal vapor. Purity of drug-aerosol before and after formation of the drug film or by extracting the particles in the thermal vapor was determined by a suitable drug and measuring the amount analytically. Drug density analytical method. Three different substrate materials were can be experimentally determined by a variety of techniques, used in the studies: stainless steel foil, aluminum foil, and a 25 known by those of skill in the art or found in the literature or stainless steel cylinder. Methods B-G below detail the proce in reference texts, such as in the CRC. An assumption of unit dures for forming a drug film on each Substrate and the density is acceptable if an actual drug density is not known. method of heating each Substrate. The stainless steel foil substrate employed for drugs tested In the studies reported in the Examples, the substrate hav according to Method B was resistively heated by placing the 30 ing a drug film of known thickness was heated to a tempera Substrate between a pair of electrodes connected to a capaci ture Sufficient to generate a thermal vapor. All or a portion of tor. The capacitor was charged to between 14-17 Volts to the thermal vapor was recovered and analyzed for presence of resistively heat the substrate. FIG. 4A is a plot of substrate drug-degradation products, to determine purity of the aerosol temperature increase, measured in still air with a thin ther particles in the thermal vapor. Several drugs are discussed mocouple (Omega, Model CO2-K), as a function of time, in 35 here as merely exemplary of the studies reported in Examples seconds, for a stainless steel foil substrate resistively heated 1-236. Example 10 describes preparation of a drug-supply by charging the capacitor to 13.5 V (lower line), 15 V (middle article containing atropine, a muscarinic antagonist. Sub line), and 16 V (upper line). When charged with 13.5 V, the strates containing films of atropine ranging in thickness from substrate temperature increase was about 250° C. within between about 1.7 um to about 9.0 um were prepared. The about 200-300 milliseconds. As the capacitor voltage 40 stainless steel substrates were heated and the purity of the increased, the peak temperature of the Substrate also drug-aerosol particles in the thermal vapor generated from increased. Charging the capacitor to 16V heated the foil sub each substrate was determined. FIG. 6 shows the results, strate temperature about 375°C. in 200-300 milliseconds (to where drug aerosol purity as a function of drug film thickness a maximum temperature of about 400° C.). is plotted. There is a clear relationship between film thickness FIG. 4B shows the time-temperature relationship for a 45 and aerosol particle purity, where as the film thickness stainless steel foil substrate having a thickness of 0.005 decreases, the purity increases. An atropine film having a inches. The foil Substrate was heated by charging a capacitor, thickness of 9.0 Lim produced a thermal vapor having a purity connected to the substrate through electrodes, to 16 V. The of 91%; an atropine film having a thickness of 1.7 um pro substrate reached its peak temperature of 400°C. in about 200 duced a thermal vapor having a purity of 98%. milliseconds, and maintained that temperature for the 1 sec 50 Hydromorphone, an analgesic, was also tested, as describe ond testing period. in Example 66. Substrates having a drug film thickness of In Methods D and E, a hollow, stainless steel tube was used between about 0.7 um to about 2.7 um were prepared and as the drug-film substrate. The cylindrical tube in Method D heated to generate a thermal vapor. Purity of the aerosol had a diameter of 13 mm and a length of 34 mm. The cylin particles improved as the thickness of the drug film on the drical tube in Method E had a diameter of 7.6 mm and a length 55 Substrate decreased. of 51 mm. In Method D, the substrate was connected to two 1 FIG. 7 shows the relationship between drug film thickness Farad capacitors wired in parallel, whereas in Method E, the and aerosol-purity for donepezil. As described in Example Substrate was connected to two capacitors (a 1 Farad and a 0.5 44, donepezil was coated onto foil substrates to film thick Farad) wired in parallel. FIGS. 5A-5B show substrate tem nesses ranging from about 0.5 um to about 3.2 Lum. Purity of perature as a function of time, for the cylindrical substrate of 60 the aerosol particles from each of the films on the substrates Method D. FIG. SB shows a detail of the first 1 second of was analyzed. At drug film thicknesses of 1.5 um to 3.2 um, heating. purity of the aerosol particles improved as thickness of the Aluminum foil was used as a substrate for testing other drug film on the substrate decreased, similar to the trend compounds, as described in Methods C, F, and G. The drug found for atropine and hydromorphone. In contrast, at less coated Substrate was heated either by wrapping it around a 65 than 1.5 um thickness, purity of the aerosol particles wors halogen tube and applying 60 V or 90 V alternating current ened as thickness of the drug film on the Substrate decreased. through the bulb or by placing the substrate in a furnace. A similar pattern was also observed for albuterol, as described US 7,585,493 B2 21 22 in Example 3, with aerosol particles purity peaking for films ficient to vaporize the film. In the studies described herein, the of approximately 3 um, and decreasing for both thinner and percentage of drug film vaporized was determined by quan thicker films as shown in FIG. 23. tifying (primarily by HPLC or weight) the mass of drug FIGS. 9-23 present data for aerosol purity as a function of composition collected upon vaporization or alternatively by film thickness for the following compounds: buprenorphine 5 the amount of Substrate mass decrease. The mass of drug (Example 16), clomipramine (Example 28), ciclesonide (Ex composition collected after vaporization and condensation ample 26), midazolam (Example 100), nalbuphine (Example was compared with the starting mass of the drug composition 103), naratriptan (Example 106), olanzapine (Example 109), film that was determined prior to vaporization to determine a quetiapine (Example 127), tadalafil (Example 140), prochlo percent yield, also referred to hereinas a percent emitted. This rperazine (Example 122), Zolpidem (Example 163), fentanyl 10 value is indicated in many of the Examples set forth below. (Example 57), alprazolam (Example 4), sildenafil (Example For example, in Example 1 a film having a thickness of 1.1 um 134), and albuterol (Example 3). was formed from the drug acebutolol, a beta adrenergic In FIGS. 6-23, the general relationship between increasing blocking agent. The mass coated on the Substrate was 0.89 mg aerosol purity with decreasing film thickness is apparent; and the mass of drug collected in the thermal vapor was 0.53 however the extent to which aerosol purity varies with a 15 mg, to give a 59.6 percent yield. After vaporization, the Sub change in film thickness varies for each drug composition. strate and the testing chamber were washed to recover any For example, aerosol purity of sildenafil (FIG.22) exhibited remaining drug. The total drug recovered from the test appa a strong dependence on film thickness, where films about 0.5 ratus, including the emitted thermal vapor, was 0.8 mg. to give um in thickness had a purity of greater than 99% and films of a 91% total recovery. In another example, midazolam was about 1.6 um in thickness had a purity of between 94-95%. In coated onto a impermeable Substrate, as described in contrast, for midazolam (FIG. 12), increasing the film thick Example 100. A drug film having a thickness of 9 um was ness from approximately 1.2 um to approximately 5.8 um formed. Heating of the Substrate generated a thermal vapor resulted in a decrease in aerosol particle purity from greater containing drug aerosol particles having a purity of 99.5%. than 99.9% to approximately 99.5%, a smaller change in The fraction of drug film collected on the filter, i.e., the particle purity despite a larger increase in film thickness com 25 percent yield, was 57.9%. After vaporization, the substrate pared with the sildenafil example. Moreover, as was dis and the testing chamber were washed to recover any remain cussed above, the inverse relationship between film thickness ing drug. The total drug recovered from the test apparatus and and purity of aerosolized drug observed for many compounds the filter was 5.06 mg. to give a 94.2% total recovery. in the thickness rangeless than about 20 um does not neces 2. Substrate Area sarily apply at the thinnest film thicknesses that were tested. 30 Some compounds, such as illustrated by donepezil (FIG. 7) Another feature of the drug-supply article is that the show a rather pronounced decrease in purity at film thick selected substrate surface area is sufficient to yield a thera nesses both below and above an optimal film thickness, in this peutic dose of the drug aerosol when used by a subject. The case, above and below about 2 um film thicknesses. amount of drug to provide a therapeutic dose is generally One way to express the dependence of aerosol purity on 35 known in the art or can be determined as discussed above. The film thickness is by the slope of the line from a plot of aerosol required dosage and selected film thickness, discussed above, purity against film thickness. For compounds such as done dictate the minimum required Substrate area in accord with pezil (FIG. 7), the slope of the line is taken from the maximum the following relationship: point in the curve towards the higher film thickness. Table 1, film thickness (cm)xdrug density (g/cm)xSubstrate discussed below, shows the slope of the line for the curves 40 area (cm)-dose (g) shown in FIGS. 6-23. Particularly preferred compounds for delivery by the various embodiments of the present invention As noted above, drug density can be determined experimen are compounds with a substantial (i.e., highly negative) slope tally or from the literature, or if unknown, can be assumed to of the line on the aerosol purity versus thickness plot, e.g., a be 1 g/cc. To prepare a drug Supply article comprised of a drug slope more negative than -0.1% purity per micron and more 45 film on a heat-conductive Substrate that is capable of admin preferably -0.5% purity per micron. istering an effective human therapeutic dose, the minimum In addition to selection of a drug film thickness that pro Substrate surface area is determined using the relationships vides aerosol particles containing 10% or less drug-degrada described above to determine a substrate area for a selected tion product (i.e., an aerosol particle purity of 90% or more), film thickness that will yield a therapeutic dose of drug aero the film thickness is selected such that at least about 50% of 50 sol. Table 1 shows a calculated substrate surface area for a the total amount of drug composition contained in the film is variety of drugs on which an aerosol purity—film thickness vaporized when the substrate is heated to a temperature suf profile was constructed.
TABLE 1 Slope of Line on Calculated aerosol purity vs. Typical Dose Preferred Film Substrate Surface thickness plot (% Drug (mg) Thickness (Lm) Area (cm) purity/micron) Albuterol O.2 O. 1-10 O.2-20 -0.64 (FIG. 23) Alprazolam O.25 O. 1-10 O.25-25 -0.44 (FIG. 21) Amoxapine 25 2-20 12.S-12S Atropine 0.4 O. 1-10 0.4-40 –0.93 (FIG. 6) Bumetanide O.S O. 1-5 1-SO Buprenorphine O.3 O.OS-10 O3-60 -0.63 (FIG.9) Butorphanol 1 O. 1-10 1-100 Clomipramine 50 1-8 62-500 -1.0 (FIG. 10) US 7,585,493 B2 23 24
TABLE 1-continued Slope of Line on Calculated aerosol purity vs. Typical Dose Preferred Film Substrate Surface thickness plot (% Drug (mg) Thickness (Lm) Area (cm) purity/micron) Donepezil 5 1-10 5-50 –0.38 (FIG. 7) Hydromorphone 2 O.OS-10 2-400 -0.55 (FIG. 8) Loxapine 10 1-20 S-100 Midazolam 1 O.OS-20 O.S.-200 –0.083 (FIG. 12) Morphine 5 O.2-10 5-250 Nalbuphine 5 O.2-5 10-2SO -1.12 (FIG. 13) Naratriptan 1 O.2-5 2-SO -1.42 (FIG. 14) Olanzapine 10 1-20 S-100 –0.16 (FIG. 15) Paroxetine 2O 1-20 10-200 Prochlorperazine 5 O. 1-2O 2.5-500 –0.11 (FIG. 18) Quetiapine 50 1-20 2S-SOO –0.18 (FIG. 16) Rizatriptan 3 O.2-2O 1.5-1SO Sertraline 25 1-20 12.S-2SO Sibutramine 10 O.5-2 SO-200 Sildenafil 6 O.2-3 20-300 –3.76 (FIG. 22) Sumatriptan 3 O.2-6 S-1SO Tadalafil 3 O.2-5 6-150 -1.52 (FIG. 17) Testosterone 3 O.2-2O 1.5-1SO Vardenafil 3 0.1-2 15-300 Venlafaxine 50 2-20 25-2SO Zolpidem 5 O. 1-10 5-500 –0.88 (FIG. 19) Apomorphine 2 O. 1-5 4-200 HCI Celecoxib 50 2-20 25-2SO Ciclesonide O.2 O.OS-5 0.4-40 -1.70 (FIG. 11) Fentanyl O.OS O.OS-5 O.1-10 Eletriptan 3 O.2-2O 1.5-1SO Parecoxib 10 O.5-2 SO-200 Valdecoxib 10 O.5-10 10-200
The actual dose of drug delivered, i.e., the percent yield or initiation of substrate heating (FIG. 24C), with formation percent emitted, from the drug-Supply article will depend on, substantially completed by about 200 milliseconds after ini along with other factors, the percent of drug film that is 35 tiation of substrate heating (FIG.24D). vaporized upon heating the Substrate. Thus, for drug films that FIGS. 25A-25D are high speed photographs showing the yield upon heating 100% of the drug film and aerosol particles generation of a thermal vapor of disopyramide from a film of that have a 100% drug purity, the relationship between dose, drug coated on a Substrate, prepared as described in Example thickness, and area given above correlates directly to the dose 42. FIG. 25A shows the drug-coated substrate prior to heating provided to the user. As the percent yield and/or particle 40 (t=0 milliseconds (ms)). The photographs in FIGS. 25B-25D purity decrease, adjustments in the Substrate area can be made show formation of a thermal vapor as a function of time after as needed to provide the desired dose. Also, as one of skill in initiation of substrate heating. As seen, 50 milliseconds after the art will recognize, larger Substrate areas other than the initiation of substrate heating (FIG. 25B), a thermal vapor is minimum calculated area for a particular film thickness can present over the Substrate Surface. The Subsequent photo be used to deliver a therapeutically effective dose of the drug. 45 graphs show that the majority of the thermal vapor is formed Moreover as can be appreciated by one of skill in art, the film prior to 100 milliseconds after initiation of substrate heating need not coat the complete surface area if a selected Surface (FIG. 25C), with formation substantially completed by about area exceeds the minimum required for delivering atherapeu 200 milliseconds after initiation of substrate heating (FIG. tic dose from a selected film thickness. 50 25D). 3. Characteristics of the Drug-Supply Article Similar photographs are shown for buprenorphine in FIGS. The drug-supply article of the invention is heated to gen 26A-26E. Upon heating of a buprenorphine substrate, pre erate a thermal vapor containing drug aerosol particles for pared as described in Example 16, presence of a thermal therapeutic administration to a patient. In studies performed vapor is evident in the photograph taken 50 milliseconds after in Support of the invention, high speed photography was used 55 heating was initiated (FIG. 26B). At 100 milliseconds (FIG. to monitor visually production of the thermal vapor. FIGS. 26C) and 200 milliseconds (FIG. 26D) after initiation of 24A-24D are high speed photographs showing the generation substrate heating the thermal vapor was still observed in the of a thermal vapor of phenytoin from a film coated on a photographs. Generation of the thermal vapor was complete substrate, prepared as described in Example 116. FIG.24A is by 300 milliseconds (FIG. 26E). a photograph showing the drug-coated Substrate prior to heat 60 4. Modifications to Optimize Aerosol Purity and/or Yield ing (t=0 milliseconds (ms)). The photographs in FIGS. 24B As discussed above, purity of aerosol particles for many 24D show formation of a thermal vapor as a function of time drugs correlates directly with film thickness, where thinner after initiation of substrate heating. The photograph in FIG. films typically produce aerosol particles with greater purity. 24B, taken 50 milliseconds after initiation of substrate heat Thus, one method to optimize purity disclosed in this inven ing, shows formation of a thermal vapor over the Substrate 65 tion is the use of thinner films. Likewise, the aerosol yield Surface. The Subsequent photographs show that the majority may also be optimized in this manner: The invention, how of the thermal vapor is formed prior to 100 milliseconds after ever, further contemplates strategies in addition to, or in com US 7,585,493 B2 25 26 bination with, adjusting film thickness to increase either aero aripiprazole, aspirin, astemizole, atenolol, benazepril, benz Sol purity or yield or both. These strategies include modifying tropine, bromazepam, budesonide, buspirone, caffeine, cap the structure or form of the drug, and/or producing the ther topril, carbamazepine, cinnarizine, clemastine, clemastine mal vapor in an inert atmosphere. fumarate, clofazimine, desipramine, dipyridamole, dolas Thus, in one embodiment, the invention contemplates gen etron, doxylamine, droperidol, enlapril maleate, fluphena eration of and/or use of an altered form of the drug, Such as, Zine, flurazepam, flurbiprofen, fluvoxamine, froVatriptan, for example but not limitation, use of a pro-drug, or a free hydrozy Zine, ibutilide, indomethacine norcholine ester, base, free acid or salt form of the drug. As demonstrated in ketorolac, ketorolac norcholine ester, levodopa, melatonin, various Examples below, modifying the form of the drug can methotrexate, methysergide, metoclopramide, nabumetone, impact the purity and or yield of the aerosol obtained. 10 maltrexone, nalmefene, perphenazine, pimozide, piroxicam, Although not always the case, the free base or free acid form pregnanolone, prochlorperazine 2HCl, protriptyline HCl, of the drug as opposed to the salt, generally results in either a protriptyline, pyrilamine, pyrilamine maleate, quinine, rami higher purity or yield of the resultant aerosol. Thus, in a pril, risperidone, Scopolamine, Sotalol, Sulindac, terfenadine, preferred embodiment of the invention, the free base and free triamcinolone acetonide, trihexyphenidyl, thiothixene, telm acid forms of the drugs are used. 15 isartan, temazepam, triamterene, trimipramine, Ziprasidone, Another approach contemplates generation of drug-aero and Zonisamide. Sol particles having a desired level of drug composition purity Examples 234-235 correspond to studies conducted on by forming the thermal vapor under a controlled atmosphere combinations of drugs that when deposited as a thin film of of an inert gas, Such as argon, nitrogen, helium, and the like. produced a thermal vapor (aerosol) having a drug purity of Various Examples below show that a change in purity can be greater than 90% and a recovered yield of each drug in the observed upon changing the gas under which vaporization aerosol of greater than 50%. OCCU.S. Example 236 corresponds to studies conducted on drugs More generally, and in another aspect, the invention con that when deposited as a thin film on a Substrate produce a templates a method of forming an article for use in an aerosol thermal vapor having a drug purity of less than about 60%. device, for producing aerosol particles of a drug composition 25 It will be appreciated that to provide a therapeutic dose the that have the desired purity and a film that provides a desired Substrate Surface area is adjusted according to the film thick percent yield. In the method, a drug film with a known film ness that yields the desired particle purity and percent yield, thickness is prepared on a heat-conductive, impermeable Sub as discussed above. strate. The substrate is heated to vaporize the film, thereby producing aerosol particles containing the drug compound. 30 III. Utility: Thin-Film Article, Device, and Methods The drug composition purity of the aerosol particles in the As can be appreciated from the above examples showing thermal vapor is determined, as well as the percent yield, i.e., generation of a pure drug thermal vapor, from thin films (i.e. the fraction of drug composition film vaporized and delivered 0.02-20 um) of the drug, the invention finds use in the medical by the method. If the drug composition purity of the particles field in compositions and articles for delivery of a therapeutic is less than about 90%, but greater than about 60%, more 35 of a drug. Thus, the invention includes, in one aspect, a preferably greater than about 70%, or if the percent yield is drug-supply article for production of a thermal vapor that less than about 50%, the thickness of the drug film is adjusted contains drug-aerosol particles. The drug-Supply article to a thickness different from the initial film thickness for includes a Substrate coated with a film of a drug composition testing. That is, a Substrate having an adjusted film thickness to be delivered to a subject, preferably a human subject. The is heated and the percent purity and percent yield are deter 40 thickness of the drug composition film is selected Such that mined. The film thickness is continually adjusted until the upon vaporizing the film by heating the Substrate to a tem desired drug composition aerosol purity and yield are perature sufficient to vaporize at least 50% of the drug com achieved. For example, the initial film thickness can be position film, typically to a temperature of at least about 200° between about 1-20 lum. A second, different film thickness C., preferably at least about 250° C., more preferably at least would be between about 0.05-10 um. This method is particu 45 about 300° C. or 350° C., a thermal vapor is generated that has larly Suited for drug compositions that exhibit a percent yield 10% or less drug-degradation product. The area of the sub of greater than about 30% and a drug composition aerosol strate is selected to provide a therapeutic dose, and is readily purity of between about 60%-90%, more preferably between determined based on the equations discussed above. about 70%-90%. In another aspect the invention relates to a method of form Examples 166-233 correspond to studies conducted on 50 ing a drug-Supply article comprised of a Substrate and a film drugs that when deposited as a thin film on a Substrate pro of a drug composition. The method includes identifying a duced a thermal vapor having a drug purity of less than about thickness of drug composition film that yields after vaporiza 90% but greater than about 60% or where the percent yield tion of the film the drug composition in a substantially non was less than about 50%. Purity of the thermal vapor of many pyrolyzed form, as evidenced, for example, by the purity of of these drugs would be improved by using one or more of the 55 the vapor. This may be done by an iterative process where one approaches discussed above. More specifically, for some first prepares on a heat-conductive Substrate, a drug compo drugs a simple adjustment in film thickness, typically to a sition having a given film thickness, e.g., 1-10 microns. The thinner film, improves purity of the aerosol particles. For Substrate is then heated, e.g., to a selected temperature other drugs, heating the Substrate in an inert atmosphere. Such between 200° C.-600° C., preferably 250° C. to 550°C., more as an argon or nitrogen atmosphere, alone or in combination 60 preferably,300° C.-500° C., or 350° C. to 500° C., to produce with an adjustment in film thickness, achieves aerosol par an aerosol of particles containing the compound. As seen in ticles with the requisite purity of 90% or more and volatiliza the examples below, the aerosol may be collected in particle tion of a fraction of the drug film that is greater than about form or simply collected on the walls of a Surrounding con 50%. tainer. The purity of the drug composition is then determined, Based on the studies conducted, the following drugs are 65 e.g., expressed as a weight percent or analytical percent deg particularly Suited to the method and approaches to optimiz radation product. If the percent degradation product is above ing purity or yield: adenosine, amoxapine, apomorphine, a selected threshold, e.g., 1, 2.5, 5, or 10 percent, the steps US 7,585,493 B2 27 28 above are repeated with different compound thicknesses, increase or decrease the volumetric airflow rate. For example, typically with Successively lower thicknesses, until the aero to produce condensation particles in the size range 1-3.5 um Solized compound is within the desired limit of degradation, MMAD, the chamber may have substantially smooth-sur e.g., 1, 2.5, 5, or 10%. Similarly, if the initial volatilization faced walls, and the selected gas-flow rate may be in the range study shows very low levels of degradation, e.g., less than 0.1. of 4-50 L/minute. 1, 2, or 5%, it may be desirable in subsequent tests to increase Additionally, as will be appreciated by one of skill in the film thickness, to obtain a greatest film thickness at which an art, particle size may be also altered by modifying the cross acceptable level of drug degradation is observed. section of the chamber condensation region to increase or After identification of the film thickness that generates a decrease linear gas Velocity for a given Volumetric flow rate, highly pure thermal drug composition vapor (e.g., drug com 10 and/or the presence or absence of structures that produce position purity greater than about 90%), the area of substrate turbulence within the chamber. Thus, for example to produce required to accommodate atherapeutic dose, when inhaled by condensation particles in the size range 20-100 nm MMAD, a human, is determined. For example, the required oral dose the chamber may provide gas-flow barriers for creating air for atropine is 0.4 mg (Example 10). Using the data shown in turbulence within the condensation chamber. These barriers FIG. 6, a thermal vapor comprised of substantially non-pyro 15 are typically placed within a few thousands of an inch from lyzed drug, e.g., a vapor having greater than about 90% drug the substrate surface. purity, is produced from film thicknesses of less than about 10 Typically, the flow rate of gas over the Substrate ranges um. Assuming unit density for atropine, a Substrate area of from about 4-50 L/min, preferably from about 5-30 L/min. about 0.8 cm coated with a 5um thick drug film is required Prior to, simultaneous with, or Subsequent to passing a gas to accommodate the oral dose of 0.4 mg if a drug of 95% over the substrate, heat is applied to the substrate to vaporize purity is desired. Selection of an atropine film thickness of the drug composition film. It will be appreciated that the about 1.7 um generated a thermal vapor having drug-aerosol temperature to which the substrate is heated will vary accord particles with less than 2% pyrolysis (i.e., greater than 98% ing to the drugs vaporization properties, but is typically drug purity). Selection of a film having a thickness of 1.7 um heated to a temperature of at least about 200°C., preferably of requires a substrate area of at least about 2.4 cm to accom 25 at least about 250° C., more preferably at least about 300° C. modate a dose of 0.4 mg. or 350° C. Heating the substrate produces a drug composition The drug-delivery article comprised of a substrate coated vapor that in the presence of the flowing gas generates aerosol with a thin drug film is particularly Suited, in another aspect of particles in the desired size range. In one embodiment, the the invention, for forming a therapeutic inhalation dose of substrate is heated for a period of less than about 1 second, drug-aerosol particles. The inhalation route of drug adminis 30 and more preferably for less than about 500 milliseconds, still tration offers several advantages for many drugs, including more preferably for less than about 200 milliseconds. The rapid uptake into the bloodstream, and avoidance of the first drug-aerosol particles are inhaled by a subject for delivery to pass effect allowing for an inhalation dose of a drug that can the lung. be substantially less, e.g., one half, that required for oral dosing. Efficient aerosol delivery to the lungs requires that the 35 IV. Utility: Rapid-heating Device and Method particles have certain penetration and settling or diffusional In another general embodiment, there is provided a device characteristics. For larger particles, deposition in the deep for producing an aerosol of compound condensation par lungs occurs by gravitational settling and requires particles to ticles, e.g., for use in inhalation therapy. The device has the have an effective settling size, defined as mass median aero elements described above with respect to FIGS. 2A and 2B, dynamic diameter (MMAD), of between 1-3.5 um. For 40 where the heat source is designed to Supply heat to the Sub Smaller particles, deposition to the deep lung occurs by a strate in the device at a rate effective to produce a substrate diffusional process that requires having a particle size in the temperature greater than 200° C. or in other embodiments 10-100 nm, typically 20-100 nm range. Particle sizes that fall greater than 250° C., 300° C. or 350° C., and to substantially in the range between 100 nm and 1 um tend to have poor volatilize the drug composition film from the substrate in a deposition and those above 3.5um tend to have poor penetra 45 period of 2 seconds or less. The thickness of the film of drug tion. Therefore, an inhalation drug-delivery device for deep composition on the Substrate is such that the device produces lung delivery should produce an aerosol having particles in an aerosol containing less than 10% by weight drug degrada one of these two size ranges, preferably between about 1-3 tion and at least 50% of the drug composition on the film. um MMAD. The device includes a drug composition delivery assembly Accordingly, a drug-supply article comprised of a Sub 50 composed of the Substrate, a film of the selected drug com strate and having a drug composition film thickness selected position on the Substrate Surface, and a heat source for Sup to generate a thermal vapor having drug composition-aerosol plying heat to the substrate at a rate effective to heat the particles with less than about 10% drug degradation product substrate to a temperature greater than 200° C. or in other is provided, more preferably less than about 5% drug degra embodiments to a temperature greater than 250° C., 300° C. dation product, and most preferably less than about 2.5% 55 or 350° C., and to produce substantially complete volatiliza drug degradation product. A gas, air oran inert fluid, is passed tion of the drug composition within a period of 2 seconds or over the substrate at a flow rate effective to produce the less. particles having a desired MMAD. The more rapid the air The drug composition in the assembly and device may be flow, the more diluted the vapor and hence the smaller the one that, when vaporized from a film on an impermeable particles that are formed. In other words the particle size 60 surface of a heat conductive substrate, the aerosol exhibits an distribution of the aerosol is determined by the concentration increasing level of drug degradation products with increasing of the compound vapor during condensation. This vapor con film thicknesses, particularly at a thickness of greater than centration is, in turn, determined by the extent to which air 0.05-20 microns. For this general group of drug composi flow over the surface of the heating substrate dilutes the tions, the film thickness on the substrate will typically be evolved vapor. Thus, to achieve Smaller or largerparticles, the 65 between 0.05 and 20 microns, e.g., the maximum or near gas Velocity through the condensation region of the chamber maximum thickness within this range that allows formation may be altered by modifying the gas-flow control valve to of a particle aerosol with drug degradation less than 5%. US 7,585,493 B2 29 30 Alternatively, the drug may show less than 5-10% degra charged with a power supply, typically to between 14-17 dation even at film thicknesses greater than 20 microns. For Volts. The circuit was closed with a Switch, causing the drug these compounds, a film thickness greater than 20 microns, coated foil to resistively heat to temperatures of about 280 e.g., 20-50 microns, may be selected, particularly where a 430° C. (as measured with an infrared camera (FLIR Ther relatively large drug dose is desired. macam SC3000)), in about 200 milliseconds. (For The device is useful in a method for producing a conden comparison purposes, see FIG. 4A, thermocouple measure sation aerosol by the steps of heating the device Substrate at a ment in still air.) After the drug had vaporized, airflow was rate that heats the substrate to a temperature greater than 200° stopped and the Teflon R filter was extracted with acetonitrile. C., or in other embodiments to a temperature greater than Drug extracted from the filter was analyzed generally by 250° C., 300° C., or 350° C., and produces substantially 10 HPLC UV absorbance generally at 225 nm using a gradient complete volatilization of the compounds within a period of 2 method aimed at detection of impurities to determine percent seconds or less. purity. Also, the extracted drug was quantified to determine a percent yield, based on the mass of drug initially coated onto V. EXAMPLES the Substrate. A percent recovery was determined by quanti 15 fying any drug remaining on the Substrate and chamber walls, The following examples further illustrate the invention adding this to the quantity of drug recovered in the filter and described herein and are in no way intended to limit the scope comparing it to the mass of drug initially coated onto the of the invention. substrate. Materials C. Preparation of Drug-Coated Aluminum Foil Substrate Solvents were of reagent grade or better and purchased A substrate of aluminum foil (10 cmx5.5 cm; 0.0005 commercially. inches thick) was precleaned with acetone. A solution of drug Unless stated otherwise, the drug free base or free acid in a minimal amount of solvent was coated onto the foil form was used in the Examples. Substrate to cover an area of approximately 7-8 cmx2.5 cm. Methods 25 The solvent was allowed to evaporate. The coated foil was A. Preparation of Drug-Coating Solution wrapped around a 300 watt halogen tube (Feit Electric Com Drug was dissolved in an appropriate solvent. Common pany, Pico Rivera, Calif.), which was inserted into a glass tube Solvent choices included methanol, dichloromethane, methyl sealed at one end with a rubber stopper. Sixty volts of alter ethyl ketone, diethyl ether, 3:1 chloroform:methanol mixture, nating current (driven by line power controlled by a Variac) 1:1 dichloromethane:methyl ethyl ketone mixture, dimethyl 30 were run through the bulb for 5-15 seconds, or in some studies formamide, and deionized water. Sonication and/or heat were 90 V for 3.5-6 seconds, to generate athermal vapor (including used as necessary to dissolve the compound. The drug con aerosol) which was collected on the glass tube walls. In some centration was typically between 50-200 mg/mL. studies, the system was flushed through with argon prior to B. Preparation of Drug-Coated Stainless Steel Foil Sub volatilization. The material collected on the glass tube walls Strate 35 was recovered and the following determinations were made: Strips of clean 304 stainless steel foil (0.0125 cm thick, (1) the amount emitted, (2) the percent emitted, and (3) the Thin Metal Sales) having dimensions 1.3 cm by 7.0 cm were purity of the aerosol by reverse-phase HPLC analysis with dip-coated with a drug solution. The foil was then partially detection typically by absorption of 225 nm light. The initial dipped three times into solvent to rinse drug off of the last 2-3 drug mass was foundby weighing the aluminum foil substrate cm of the dipped end of the foil. Alternatively, the drug 40 prior to and after drug coating. The drug coating thickness coating from this area was carefully scraped off with a razor was calculated in the same manner as described in Method B. blade. The final coated area was between 2.0-2.5 cm by 1.3 D. Preparation of Drug-Coated Stainless Steel Cylindrical cm on both sides of the foil, for a total area of between 5.2-6.5 Substrate cm Foils were prepared as stated above and then some were A hollow stainless steel cylinder with thin walls, typically extracted with methanol or acetonitrile as standards. The 45 0.12 mm wall thickness, a diameter of 13 mm, and a length of amount of drug was determined from quantitative HPLC 34 mm was cleaned in dichloromethane, methanol, and analysis. Using the known drug-coated Surface area, the acetone, then dried, and fired at least once to remove any thickness was then obtained by: residual volatile material and to thermally passivate the stain film thickness (cm)=drug mass (g) drug density less steel surface. The substrate was then dip-coated with a (g/cm)xSubstrate area (cm). 50 drug coating Solution (prepared as disclosed in Method A). The dip-coating was done using a computerized dip-coating If the drug density is not known, a value of 1 g/cm is machine to produce a thin layer of drug on the outside of the assumed. The film thickness in microns is obtained by mul substrate surface. The substrate was lowered into the drug tiplying the film thickness in cm by 10,000. solution and then removed from the solvent at a rate of typi After drying, the drug-coated foil was placed into a Vola 55 cally 5-25 cm/sec. (To coat larger amounts of material on the tilization chamber constructed of a Delrin R) block (the air substrate, the substrate was removed more rapidly from the way) and brass bars, which served as electrodes. The dimen solvent or the solution used was more concentrated.) The sions of the airway were 1.3 cm high by 2.6 cm wide by 8.9 cm substrate was then allowed to dry for 30 minutes inside a fume long. The drug-coated foil was placed into the Volatilization hood. If either dimethylformamide (DMF) or a water mixture chamber Such that the drug-coated section was between the 60 was used as a dip-coating solvent, the Substrate was vacuum two sets of electrodes. After securing the top of the volatil dried inside a desiccator for a minimum of one hour. The ization chamber, the electrodes were connected to a 1 Farad drug-coated portion of the cylinder generally has a Surface capacitor (Phoenix Gold). The back of the volatilization area of 8 cm. By assuming a unit density for the drug, the chamber was connected to a two micron Teflon R filter initial drug coating thickness was calculated. The amount of (Savillex) and filter housing, which were in turn connected to 65 drug coated onto the Substrates was determined in the same the house vacuum. Sufficient airflow was initiated (typically manner as that described in Method B: the substrates were 30 L/min=1.5 m/sec), at which point the capacitor was coated, then extracted with methanol or acetonitrile and ana US 7,585,493 B2 31 32 lyzed with quantitative HPLC methods, to determine the opening was connected to a 1 liter, 3-neck glass flask. The mass of drug coated onto the Substrate. glass flask was further connected to a piston capable of draw The drug-coated Substrate was placed in a Surrounding ing 1.1 liters of air through the flask. Ninety volts of alternat glass tube connected at the exit end via Tygon R tubing to a ing current (driven by line power controlled by a Variac) was filter holder fitted with a Teflon R filter (Savillex). The junc run through the bulb for 6-7 seconds to generate a thermal tion of the tubing and the filter was sealed with paraffin film. vapor (including aerosol) which was drawn into the 1 liter The substrate was placed in a fitting for connection to two 1 flask. The aerosol was allowed to sediment onto the walls of Farad capacitors wired in parallel and controlled by a high the 1 liter flask for 30 minutes. The material collected on the current relay. The capacitors were charged by a separate flask walls was recovered and the following determinations power source to about 18-22 Volts and most of the power was 10 were made: (1) the amount emitted, (2) the percent emitted, channeled to the Substrate by closing a Switch and allowing and (3) the purity of the aerosol by reverse-phase HPLC the capacitors to discharge into the Substrate. The Substrate analysis with detection by typically by absorption of 225 nm. was heated to a temperature of between about 300-500° C. light. Additionally, any material remaining on the Substrate (see FIGS.5A & 5B) in about 100 milliseconds. The heating was collected and quantified. process was done under an airflow of 15 L/min, which swept 15 the vaporized drug aerosol into a 2 micron Teflon R filter. Example 1 After volatilization, the aerosol captured on the filter was recovered for quantification and analysis. The quantity of Acebutolol (MW 336, melting point 123°C., oral dose 400 material recovered in the filter was used to determine a per mg), a beta adrenergic blocker (cardiovascular agent), was cent yield, based on the mass of drug coated onto the Sub coated on a stainless steel cylinder (8 cm) according to strate. The material recovered in the filter was also analyzed Method D. 0.89 mg of drug was applied to the substrate, for a generally by HPLC UV absorbance at typically 225 nm using calculated drug film thickness of 1.1 um. The Substrate was a gradient method aimed at detection of impurities, to deter heated as described in Method D at 20.5V and purity of the mine purity of the thermal vapor. Any material deposited on drug-aerosol particles were determined to be 98.9%. 0.53 mg the glass sleeve or remaining on the Substrate was also recov 25 was recovered from the filter after vaporization, for a percent ered and quantified to determine a percent total recovery yield of 59.6%. A total mass of 0.81 mg was recovered from ((mass of drug in filter+mass of drug remaining on Substrate the test apparatus and substrate, for a total recovery of 91%. and glass sleeve)/mass of drug coated onto Substrate). For High speed photographs were taken as the drug-coated compounds without UV absorption GC/MS or LC/MS was substrate was heated to monitor visually formation of a ther used to determine purity and to quantify the recovery. Some 30 mal vapor. The photographs showed that a thermal vapor was samples were further analyzed by LC/MS to confirm the initially visible 30 milliseconds after heating was initiated, molecular weight of the drug and any degradants. with the majority of the thermal vapor formed by 130 milli E. Preparation of Drug-Coated Stainless Steel Cylindrical seconds. Generation of the thermal vapor was complete by Substrate 500 milliseconds. A hollow stainless steel cylinder like that described in 35 Example D was prepared, except the cylinder diameter was Example 2 7.6 mm and the length was 51 mm. A film of a selected drug was applied as described in Example D. Energy for Substrate heating and drug vaporization was Acetaminophen (MW 151, melting point 171° C., oral supplied by two capacitors (1 Farad and 0.5 Farad) connected 40 dose 650mg), an analgesic agent, was coated on an aluminum in parallel, charged to 20.5 Volts. The airway, airflow, and foil substrate (20 cm) according to Method C. 2.90 mg of other parts of the electrical set up were as described in drug was applied to the Substrate, for a calculated thickness of Example D. The substrate was heated to a temperature of the drug film of 1.5 Lum. The substrate was heated under argon about 420°C. in about 50 milliseconds. After drug film vapor as described in Method C at 60V for 6 seconds. The purity of ization, percent yield, percent recovery, and purity analysis 45 the drug-aerosol particles were determined to be >99.5%. 1.9 were done as described in Example D. mg was recovered from the glass tube walls after vaporiza F. Preparation of Drug-Coated Aluminum Foil Substrate tion, for a percent yield of 65.5%. A solution of drug was coated onto a Substrate of aluminum foil (5 cm-150 cm; 0.0005 inches thick). In some studies, Example 3 the drug was in a minimal amount of Solvent, which was 50 allowed to evaporate. The coated foil was inserted into a glass Albuterol (MW 239, melting point 158°C., oral dose 0.18 tube in a furnace (tube furnace). A glass wool plug was placed mg), a bronchodilator, was coated onto six stainless steel foil in the tube adjacent to the foil sheet and an airflow of 2 L/min substrates (5 cm) according to Method B. The calculated was applied. The furnace was heated to 200-550° C. for 30, thickness of the drug film on each Substrate ranged from about 60, or 120 seconds. The material collected on the glass wool 55 1.5 um to about 6.1 um. The substrates were heated as plug was recovered and analyzed by reverse-phase HPLC described in Method B by charging the capacitors to 15 V. analysis with detection typically by absorption of 225 nm. Purity of the drug-aerosol particles from each substrate was light or GC/MS to determine the purity of the aerosol. determined and the results are shown in FIG. 23. G. Preparation of Drug-Coated Aluminum Foil Substrate Albuterol was also coated on a stainless steel cylinder (8 A substrate of aluminum foil (3.5 cmx7cm; 0.0005 inches 60 cm) according to Method D. 1.20 mg of drug was applied to thick) was precleaned with acetone. A solution of drug in a the Substrate, for a calculated drug film thickness of 2.4 um. minimal amount of solvent was coated onto the foil substrate. The substrate was heated as described in Method D by charg The solvent was allowed to evaporate. The coated foil was ing the capacitors to 20.5 V. The purity of the drug-aerosol wrapped around a 300 watt halogen tube (Feit Electric Com particles was determined to be 94.4%. 0.69 mg was recovered pany, Pico Rivera, Calif.), which was inserted into a T-shaped 65 from the filter after vaporization, for a percent yield of 57.2%. glass tube sealed at two ends with parafilm. The parafilm was A total mass of 0.9 mg was recovered from the test apparatus punctured with ten to fifteen needles for air flow. The third and substrate, for a total recovery of 73.5%. US 7,585,493 B2 33 34 Example 4 lated thickness of the drug film was 1.1 um. The substrate was heated as described in Method C at 90 V for 3 seconds. The Alprazolam (MW 309, melting point 229°C., oral dose purity of the drug-aerosol particles was determined to be 0.25 mg), an anti-anxiety agent (Xanax(R), was coated onto 96.9%. 2 mg was recovered from the glass tube walls after 13 stainless steel cylinder substrates (8 cm) according to vaporization, for a percent yield of 90.9%. Method D. The calculated thickness of the drug film on each Substrate ranged from about 0.1 um to about 1.4 um. The Example 8 substrates were heated as described in Method D by charging the capacitors to 20.5 V. Purity of the drug-aerosol particles The hydrochloride salt form of apomorphine was also from each substrate was determined and the results are shown 10 tested. Apomorphine hydrochloride (MW 304) was coated on in FIG. 21. a stainless steel foil (6 cm) according to Method B. 0.68 mg Another substrate (stainless steel cylinder, 8 cm) was of drug was applied to the Substrate, for a calculated drug film coated with 0.92 mg of drug, for a calculated drug film thick thickness of 1.1 um. The substrate was heated as described in ness of 1.2 Lum. The substrate was heated as described in Method B by charging the capacitor to 15 V. The purity of the Method D by charging the capacitors to 22.5V. Purity of the 15 drug-aerosol particles was determined to be 98.1%. 0.6 mg drug-aerosol particles was 99.8%. 0.61 mg was recovered was recovered from the filter after vaporization, for a percent from the filter after vaporization, for a percent yield of 66.2%. yield of 88.2%. A total mass of 0.68 mg was recovered from A total mass of 0.92 mg was recovered from the test apparatus the test apparatus and substrate, for a total recovery of 100%. and substrate, for a total recovery of 100%. Alprazolam was also coated on an aluminum foil substrate Example 9 (28.8 cm) according to Method C. 2.6 mg of the drug was coated on the Substrate for a calculated thickness of the drug The hydrochloride diacetate salt of apomorphine was also film of 0.9 um. The substrate was heated substantially as tested (MW 388). Apomorphine hydrochloride diacetate was described in MethodCat 75 V for 6 seconds. The purity of the coated on a piece of aluminum foil (20 cm) according to drug-aerosol particles was determined to be 99.9%. 25 Method C. The calculated thickness of the drug film was 1.0 High speed photographs were taken as the drug-coated um. The substrate was heated as described in Method C at 90 substrate according to Method D was heated to monitor visu V for 3 second purity of the drug-aerosol particles was deter ally formation of a thermal vapor. The photographs showed mined to be 94.0%. 1.65 mg was recovered from the glass that a thermal vapor was initially visible -35 milliseconds tube walls after vaporization, for a percent yield of 86.8%. after heating was initiated, with the majority of the thermal 30 vapor formed by 100 milliseconds. Generation of the thermal vapor was complete by 400 milliseconds. Example 10 Example 5 Atropine (MW 289, melting point 116°C., oral dose 0.4 35 mg), an muscarinic antagonist, was coated on five stainless Amantadine (MW 151, melting point 192 C., oral dose steel cylinder substrates (8 cm) according to Method D. The 100 mg), a dopaminergic agent and an anti-infective agent, calculated thickness of the drug films ranged from about 1.7 was coated on an aluminum foil substrate (20 cm) according um to 9.0 um. The substrate was heated as described in to Method C. A mass of 1.6 mg was coated onto the substrate Method D by charging the capacitors to 19 or 22 V. Purity of and the calculated thickness of the drug film was 0.8 um. The 40 the drug-aerosol particles from each Substrate was deter substrate was heated as described in Method C at 90 V for 4 mined. The results are shown in FIG. 6. For the substrate seconds. The purity of the drug-aerosol particles was deter having a drug film thickness of 1.7 um, 1.43 mg of drug was mined to be 100%. 1.5 mg was recovered from the glass tube applied to the substrate. After volatilization of drug from this walls after vaporization, for a percent yield of 93.8%. substrate with a capacitor charged to 22 V. 0.95 mg was 45 recovered from the filter, for a percent yield of 66.6%. The Example 6 purity of the drug aerosol recovered from the filter was found to be 98.5%. A total mass of 1.4 mg was recovered from the Amitriptyline (MW 277, oral dose 50mg), a tricyclic anti test apparatus and substrate, for a total recovery of 98.2%. depressant, was coated on a piece of aluminum foil (20 cm) High speed photographs were taken as the drug-coated according to Method C. The calculated thickness of the drug 50 substrate was heated to monitor visually formation of a ther film was 5.2 Lum. The substrate was heated as described in mal vapor. The photographs showed that a thermal vapor was Method C at 90 V for 5 seconds. The purity of the drug initially visible 28 milliseconds after heating was initiated, aerosol particles was determined to be 98.4%. 5.3 mg was with the majority of the thermal vapor formed by 90 milli recovered from the glass tube walls after vaporization, for a seconds. Generation of the thermal vapor was complete by percent yield of 51.5%. 55 140 milliseconds. Amitriptyline was also coated on an identical Substrate to a thickness of 1.1 um. The substrate was heated as described in Example 11 Method C under an argon atmosphere at 90 V for 3.5 seconds. The purity of the drug-aerosol particles was determined to be AZatadine (MW 290, melting point 126°C., oral dose 1 99.3%. 1.4 mg was recovered from the glass tube walls after 60 mg), an antihistamine, was coated on an aluminum foil Sub vaporization, for a percent yield of 63.6%. strate (20 cm) according to Method C. 5.70 mg of drug was applied to the Substrate, for a calculated thickness of the drug Example 7 film of 2.9 um. The substrate was heated as described in Method C at 60 V for 6 seconds. The purity of the drug Apomorphine diacetate (MW 351), a dopaminergic agent 65 aerosol particles was determined to be 99.6%. 2.8 mg was used as an anti-Parkinsonian drug, was coated on a piece of recovered from the glass tube walls after vaporization, for a aluminum foil (20 cm) according to Method C. The calcu percent yield of 49.1%. US 7,585,493 B2 35 36 Another azatadine coated Substrate was prepared accord Example 15 ing to Method G. The substrate was heated as described in Method G at 60 V for 6 seconds under an argon atmosphere. Bumetanide (MW 364, melting point 231°C., oral dose 0.5 The purity of the drug-aerosol particles was determined to be mg), a cardiovascular agent and diuretic, was coated on a 99.6%. The percent yield of the aerosol was 62%. stainless steel cylinder (8 cm) according to Method D. 1.09 mg of drug was applied to the Substrate, for a calculated drug Example 12 film thickness of 1.3 um. The substrate was heated as described in Method D by charging the capacitors to 20.5 V. Bergapten (MW 216, melting point 188°C., oral dose 35 The purity of the drug-aerosol particles was determined to be mg), an anti-psoriatic agent, was coated on a stainless Steel 10 98.4%. 0.56 mg was recovered from the filter after vaporiza cylinder (8 cm) according to Method D. 1.06 mg of drug was tion, for a percent yield of 51.4%. A total mass of 0.9 mg was applied to the Substrate, for a calculated drug film thickness of recovered from the test apparatus and Substrate, for a total 1.3 Lum. The substrate was heated as described in Method D by recovery of 82.6%. charging the capacitors to 20.5 V. The purity of the drug High speed photographs were taken as the drug-coated aerosol particles was determined to be 97.8%. 0.72 mg was 15 substrate was heated to monitor visually formation of a ther recovered from the filter after vaporization, for a percent yield mal vapor. The photographs showed that a thermal vapor was of 67.9%. A total mass of 1.0 mg was recovered from the test initially visible 40 milliseconds after heating was initiated, apparatus and substrate, for a total recovery of 98.1%. with the majority of the thermal vapor formed by 300 milli High speed photographs were taken as the drug-coated seconds. Generation of the thermal vapor was complete by substrate was heated to monitor visually formation of a ther 1200 milliseconds. mal vapor. The photographs showed that a thermal vapor was initially visible 40 milliseconds after heating was initiated, Example 16 with the majority of the thermal vapor formed by 85 milli seconds. Generation of the thermal vapor was complete by Buprenorphine (MW 468, melting point 209°C., oral dose 25 0.3 mg), an analgesic narcotic, was coated on a piece of 140 milliseconds. aluminum foil (20 cm) according to Method C. The calcu Example 13 lated thickness of the drug film was 0.7 um. The substrate was heated as described in Method C at 60 V for 5 seconds. The Betahistine (MW 136, melting point <25°C., oral dose 8 purity of the drug-aerosol particles was determined to be mg), a vertigo agent, was coated on a metal Substrate accord 30 98%. 1.34 mg was recovered from the glass tube walls after ing to Method F and heated to 300° C. to form drug-aerosol vaporization, for a percent yield of 95.7%. particles. Purity of the drug-aerosol particles was determined Buprenorphine was also coated onto five stainless steel to be 99.3%. 17.54 mg was recovered from the glass wool cylinder substrates (8 cm) according to Method Dexcept that after vaporization, for a percent yield of 58.5%. a 1.5 Farad capacitor was used as opposed to a 2.0 Farad 35 capacitor. The calculated thickness of the drug film on each Example 14 substrate ranged from about 0.3 um to about 1.5 um. The substrates were heated as described in Method D (with the single exception that the circuit capacitance was 1.5 Farad, Brompheniramine (MW 319, melting point <25°C., oral not 2.0 Farad) and purity of the drug-aerosol particles deter dose 4 mg), an anti-histamine agent, was coated on an alumi 40 mined. The results are shown in FIG. 9. For the substrate num foil substrate (20 cm) according to Method C. 4.50 mg having a 1.5um drug film, 1.24 mg of drug was applied to the of drug was applied to the Substrate, for a calculated thickness substrate. After volatilization of drug from this substrate by of the drug film of 2.3 lum. The substrate was heated as charging the capacitors to 20.5 V, 0.865 mg was recovered described in Method Cat 60V for 8 seconds. The purity of the from the filter, for a percent yield of 69.5%. A total mass of 1.2 drug-aerosol particles was determined to be 99.8%. 3.12 mg 45 mg was recovered from the test apparatus and Substrate, for a was recovered from the glass tube walls after vaporization, total recovery of 92.9%. The purity of the drug aerosol recov for a percent yield of 69.3%. ered from the filter was determined to be 97.1%. An identical substrate with the same thickness of bromphe High speed photographs were taken as one of the drug niramine (4.5 mg drug applied to Substrate) was heated under coated Substrates was heated, to monitor visually formation an argon atmosphere at 60 V for 8 seconds. The purity of the 50 of a thermal vapor. The photographs, shown in FIGS. 26A drug-aerosol particles was determined to be 99.9%. 3.3 mg 26E, showed that a thermal vapor was initially visible 30 was recovered from the glass tube walls after vaporization, milliseconds after heating was initiated, with the majority of for a percent yield of 73.3%. the thermal vapor formed by 120 milliseconds. Generation of The maleate salt form of the drug was also tested. Bro the thermal vapor was complete by 300 milliseconds. mpheniramine maleate (MW 435, melting point 134°C., oral 55 The salt form of the drug, buprenorphine hydrochloride dose 2 mg) was coated onto an aluminum foil Substrate (20 (MW 504), was also tested. The drug was coated on a piece of cm) according to Method C. The calculated thickness of the aluminum foil (20 cm) according to Method C. 2.10 mg of drug film was 2.8 Lum. The substrate was heated as described drug was applied to the Substrate, for a calculated thickness of in Method C at 60 V for 7 seconds. The purity of the drug the drug film of 1.1 um. The substrate was heated as described aerosol particles was determined to be 99.6%. 3.4 mg was 60 in Method C at 60 V for 15 seconds. The purity of the drug recovered from the glass tube walls after vaporization, for a aerosol particles was determined to be 91.4%. 1.37 mg was percent yield of 60.7%. recovered from the glass tube walls after vaporization, for a An identical substrate with a 3.2 Lum brompheniramine percent yield of 65.2%. maleate film was heated under an argon atmosphere at 60 V Buprenorphine was further coated on an aluminum foil for 7 seconds. The purity of the drug-aerosol particles was 65 substrate (24.5 cm) according to Method G. 1.2 mg of the determined to be 100%. 3.2 mg was recovered from the glass drug was applied to the Substrate, for a calculated thickness of tube walls after vaporization, for a percent yield of 50%. the drug film of 0.49 um. The substrate was heated substan US 7,585,493 B2 37 38 tially as described in Method G at 90 V for 6 seconds, except film of 2.7 um. The substrate was heated as described in that two of the openings of the T-shaped tube were left open Method C at 60 V for 6 seconds. The purity of the drug and the third connected to the 1 L flask. The purity of the aerosol particles was determined to be 92.5%. 2.8 mg was drug-aerosol particles was determined to be >99%. 0.7 mg of recovered from the glass tube walls after vaporization, for a the drug was found to have aerosolized, for a percent yield of 5 percent yield of 52.8%. 58%. A second Substrate was coated with carbinoxamine (6.5 mg drug) to a thickness of 3.3 Lum. The Substrate was heated as Example 17 described in Method C at 90 V for 6 seconds under an argon atmosphere. The purity of the drug-aerosol particles deter Bupropion hydrochloride (MW 276, melting point 234 10 mined was to be 94.8%. 3.1 mg was recovered from the glass C., oral dose 100 mg), an antidepressant psychotherapeutic tube walls after vaporization, for a percent yield of 47.7%. agent, was coated on a piece of aluminum foil (20 cm) The maleate salt form of the drug was also tested. Carbi according to Method C. The calculated thickness of the drug noxamine maleate (MW407, melting point 119°C., oral dose film was 1.2 Lum. The substrate was heated as described in 4 mg) was coated on a piece of aluminum foil (20 cm) Method C at 90 V for 3.5 seconds. The purity of the drug 15 according to Method C. The calculated thickness of the drug aerosol particles was determined to be 98.5%. 2.1 mg was film was 3.9 Lum. The substrate was heated as described in recovered from the glass tube walls after vaporization, for a Method C at 90 V for 6 seconds. The purity of the drug percent yield of 91.3%. An identical substrate having the aerosol particles was determined to be 99%. 4.8 mg was same drug film thickness was heated under an argon atmo recovered from the glass tube walls after vaporization, for a sphere according to Method C at 90 V for 3.5 seconds. 1.8 mg percent yield of 62.3%. was recovered from the glass tube walls after vaporization, for a percent yield of 78.3%. The recovered vapor had a purity Example 21 of 99.1%. Celecoxib (MW 381, melting point 159°C., oral dose 100 Example 18 25 mg), an analgesic non-steroidal anti-inflammatory agent, was coated on a piece of stainless steel foil (5 cm) according to Butalbital (MW 224, melting point 139° C., oral dose 50 Method B. 4.6 mg of drug was applied to the substrate, for a mg), a sedative and hypnotic barbituate, was coated on a piece calculated drug film thickness of 8.7 um. The substrate was of aluminum foil (20 cm) according to Method C. 2.3 mg heated as described in Method B by charging the capacitors to were coated on the foil, for a calculated thickness of the drug 30 16 V. The purity of the drug-aerosol particles was determined film of 1.2 Lum. The substrate was heated as described in to be >99.5%. 4.5 mg was recovered from the filter after Method C at 90 V for 3.5 seconds. The purity of the drug vaporization, for a percent yield of 97.8%. A total mass of 4.6 aerosol particles was determined to be >99.5%. 1.69 mg were mg was recovered from the test apparatus and Substrate, for a collected for a percent yield of 73%. total recovery of 100%. 35 Celecoxib was also coated on a piece of aluminum foil (100 Example 19 cm) according to Method G. The calculated thickness of the drug film was 3.1 um. The substrate was heated as described Butorphanol (MW 327, melting point 217°C., oral dose 1 in Method G at 60 V for 15 seconds. The purity of the drug mg), an analgesic narcotic agent, was coated on a piece of aerosol particles was determined to be 99%. 24.5 mg was aluminum foil (20 cm) according to Method C. The calcu 40 recovered from the glass tube walls after vaporization, for a lated thickness of the drug film was 1.0Lum. The substrate was percent yield of 79%. heated as described in Method C at 90 V for 3.5 seconds. The purity of the drug-aerosol particles was determined to be Example 22 98.7%. Butorphanol was also coated on a stainless steel cylinder (6 45 Chlordiazepoxide (MW 300, melting point 237° C., oral cm) according to Method E. 1.24 mg of drug was applied to dose 5 mg), a sedative and hypnotic agent, was coated on a the Substrate, for a calculated drug film thickness of 2.1 um. piece of aluminum foil (20 cm) according to Method C. The The substrate was heated as described in Method E and purity calculated thickness of the drug film was 2.3 um. The sub of the drug-aerosol particles was determined to be 99.4%. strate was heated as described in Method C at 45 V for 15 0.802 mg was recovered from the filter after vaporization, for 50 seconds. The purity of the drug-aerosol particles was deter a percent yield of 64.7%. A total mass of 1.065 mg was mined to be 98.2%. 2.5 mg was recovered from the glass tube recovered from the test apparatus and Substrate, for a total walls after vaporization, for a percent yield of 54.3%. recovery of 85.9%. High speed photographs were taken as the drug-coated Example 23 substrate was heated to monitor visually formation of a ther 55 mal vapor. The photographs showed that a thermal vapor was Chlorpheniramine (MW 275, melting point <25°C., oral initially visible 35 milliseconds after heating was initiated, dose 4 mg), an antihistamine, was coated onto an aluminum with the majority of the thermal vapor formed by 60 milli foil substrate (20 cm) according to Method C. 5.90 mg of seconds. Generation of the thermal vapor was complete by 90 drug was applied to the Substrate, for a calculated thickness of milliseconds. 60 the drug film of 3 um. The substrate was heated as described in Method C at 60 V for 10 seconds. The purity of the drug Example 20 aerosol particles was determined to be 99.8%. 4.14 mg was recovered from the glass tube walls after vaporization, for a Carbinoxamine (MW 291, melting point <25°C., oral dose percent yield of 70.2%. 2 mg), an antihistamine, was coated on a piece of aluminum 65 The maleate salt form (MW 391, melting point 135° C., foil (20 cm) according to Method C. 5.30 mg of drug was oral dose 8 mg) was coated on an identical Substrate to a applied to the Substrate, for a calculated thickness of the drug thickness of 1.6 um. The substrate was heated as described in US 7,585,493 B2 39 40 Method C at 60 V for 7 seconds. The purity of the drug stainless steel cylindrical substrates according to Method E. aerosol particles was determined to be 99.6%. 2.1 mg was The calculated thickness of the drug film on each substrate recovered from the glass tube walls after vaporization, for a ranged from about 0.8 um to about 3.9 um. The substrates percent yield of 65.6%. were heated as described in Method E and purity of the drug-aerosol particles determined. The results are shown in Example 24 FIG. 10. For the substrate having a drug film thickness of 0.8 um, 0.46 mg of drug was applied to the Substrate. After Chlorpromazine (MW 319, melting point <25° C., oral volatilization of drug from this substrate, 0.33 mg was recov dose 300 mg), an antipsychotic, psychotherapeutic agent, ered from the filter, for a percent yield of 71.7%. Purity of the was coated on an aluminum foil substrate (20 cm) according 10 drug-aerosol particles was determined to be 99.4%. A total to Method C. 9.60 mg of drug was applied to the substrate, for mass of 0.406 mg was recovered from the test apparatus and a calculated thickness of the drug film of 4.8 um. The sub substrate, for a total recovery of 88.3%. strate was heated as described in Method C at 90 V for 5 High speed photographs were taken as the drug-coated seconds. The purity of the drug-aerosol particles was deter substrate was heated to monitor visually formation of a ther mined to be 96.5%. 8.6 mg was recovered from the glass tube 15 mal vapor. The photographs showed that a thermal vapor was walls after vaporization, for a percent yield of 89.6%. initially visible 40 milliseconds after heating was initiated, Example 25 with the majority of the thermal vapor formed by 75 milli seconds. Generation of the thermal vapor was complete by ChlorZoxazone (MW 170, melting point 192°C., oral dose 115 milliseconds. 250 mg), a muscle relaxant, was coated on a piece of alumi num foil (20 cm) according to Method C. The calculated Example 29 thickness of the drug film was 1.3 um. The substrate was heated as described in Method C at 90 V for 3.5 seconds. The Clonazepam (MW 316, melting point 239°C., oral dose 1 purity of the drug-aerosol particles was determined to be mg), an anticonvulsant, was coated on an aluminum foil Sub 99.7%. 1.55 mg was recovered from the glass tube walls after 25 strate (50 cm) and heated according to Method F to a tem vaporization, for a percent yield of 59.6%. perature of 350° C. to form drug-aerosol particles. 46.4 mg of the drug was applied to the Substrate, for a calculated thick Example 26 ness of the drug film of 9.3 um. Purity of the drug-aerosol particles was determined to be 14%. Ciclesonide free base (MW 541, melting point 206.5-207 30 Clonazepam was further coated on an aluminum foil Sub C., oral dose 0.2 mg) a glucocorticoid, was coated on stainless strate (24 cm) according to Method C. 5 mg of the drug was steel foil substrates (6 cm) according to Method B. Eight applied to the substrate, for a calculated thickness of the drug Substrates were prepared, with the drug film thickness rang film of 2.1 um. The substrate was heated substantially as ing from about 0.4 um to about 2.4 Lum. The Substrates were described in MethodCat 60V for 8 seconds. The purity of the heated as described in Method B, with the capacitors charged 35 drug-aerosol particles was determined to be 99.9%. with 15.0 or 15.5 V. Purity of the drug-aerosol particles from each Substrate was determined and the results are shown in Example 30 FIG. 11. The substrate having a thickness of 0.4 um was prepared by depositing 0.204 mg drug on the Substrate Sur Clonidine (MW 230, melting point 130° C., oral dose 0.1 face. After volatilization of drug from this substrate using 40 mg), a cardiovascular agent, was coated on an aluminum foil capacitors charged to 15.0 V, 0.201 mg was recovered from substrate (50 cm) and heated according to Method F at 300° the filter, for a percent yield of 98.5%. The purity of the drug C. to form drug-aerosol particles. Purity of the drug-aerosol aerosol particles was determined to be 99%. A total mass of particles was determined to be 94.9%. The yield of aerosol 0.204 mg was recovered from the test apparatus and Substrate, particles was 90.9%. for a total recovery of 100%. 45 Example 27 Example 31 Citalopram (MW 324, melting point <25°C., oral dose 20 Clozapine (MW 327, melting point 184°C., oral dose 150 mg), a psychotherapeutic agent, was coated onto an alumi mg), a psychotherapeutic agent, was coated on an aluminum num foil substrate (20 cm) according to Method C. 8.80 mg 50 foil substrate (20 cm) according to Method C. 14.30 mg of of drug was applied to the Substrate, for a calculated thickness drug was applied to the Substrate, for a calculated thickness of of the drug film of 4.4 lum. The substrate was heated as the drug film of 7.2 um. The substrate was heated as described described in Method Cat 90 V for 4 seconds. The purity of the in Method C at 90 V for 5 seconds. The purity of the drug drug-aerosol particles was determined to be 92.3%. 5.5 mg aerosol particles was determined to be 99.1%. 2.7 mg was was recovered from the glass tube walls after vaporization, 55 recovered from the glass tube walls after vaporization, for a for a percent yield of 62.5%. percent yield of 18.9%. Another Substrate containing citalopram coated (10.10 mg Another Substrate containing clozapine coated (2.50 mg drug) to a film thickness of 5 um was prepared by the same drug) to a film thickness of 1.3 um was prepared by the same method and heated under an argon atmosphere. The purity of method and heated under an argon atmosphere at 90 V for 3.5 the drug-aerosol particles was determined to be 98%. 7.2 mg 60 seconds. The purity of the drug-aerosol particles was deter was recovered from the glass tube walls after vaporization, mined to be 99.5%. 1.57 mg was recovered from the glass for a percent yield of 71.3%. tube walls after vaporization, for a percent yield of 62.8%. Example 28 Example 32 65 Clomipramine (MW 315, melting point <25°C., oral dose Codeine (MW 299, melting point 156° C., oral dose 15 150 mg), a psychotherapeutic agent, was coated onto eight mg), an analgesic, was coated on an aluminum foil substrate US 7,585,493 B2 41 42 (20 cm) according to Method C. 8.90mg of drug was applied cylinder (8 cm) according to Method D. 0.92 mg of drug was to the substrate, for a calculated thickness of the drug film of applied to the Substrate, for a calculated drug film thickness of 4.5um. The substrate was heated as described in Method Cat 1.1 Lum. The substrate was heated as described in Method D by 90 V for 5 seconds. The purity of the drug-aerosol particles charging the capacitors to 20.5 V. The purity of the drug was determined to be 98.1%. 3.46 mg was recovered from the 5 aerosol particles was determined to be >99.5%. 0.92 mg was glass tube walls after vaporization, for a percent yield of recovered from the filter after vaporization, for a percent yield 38.9%. of 100%. The total mass was recovered from the test appara Another Substrate containing codeine coated (2.0 mg drug) tus and substrate, for a total recovery of about 100%. to a film thickness of 1 um was prepared by the same method and heated under an argon atmosphere at 90 V for 3.5 sec 10 Example 37 onds. The purity of the drug-aerosol particles was determined to be >99.5%. 1 mg was recovered from the glass tube walls Diazepam (MW 285, melting point 126° C., oral dose 2 after vaporization, for a percent yield of 50%. mg), a sedative and hypnotic, was coated on an aluminum foil substrate (20 cm) according to Method C. 5.30 mg of drug Example 33 15 was applied to the substrate, for a calculated thickness of the drug film of 2.7 um. The substrate was heated as described in Colchicine (MW 399, melting point 157°C., oral dose 0.6 Method C at 40 V for 17 seconds. The purity of the drug mg), a gout preparation, was coated on a stainless Steel cyl aerosol particles were determined to be 99.9%. 4.2 mg was inder (8 cm) according to Method D. 1.12 mg of drug was recovered from the glass tube walls after vaporization, for a applied to the Substrate, for a calculated drug film thickness of percent yield of 79.2%. 1.3 Lum. The substrate was heated as described in Method D by Diazepam was also coated on a circular aluminum foil charging the capacitors to 20.5 V. The purity of the drug substrate (78.5 cm). 10.0 mg of drug was applied to the aerosol particles was determined to be 97.7%. 0.56 mg was substrate, for a calculated film thickness of the drug of 1.27 recovered from the filter after vaporization, for a percent yield um. The Substrate was secured to the open side of a petri dish of 50%. A total mass of 1.12 mg was recovered from the test 25 (100 mm diameterx50mm height) using parafilm. The glass apparatus and substrate, for a total recovery of 100%. bottom of the petri dish was cooled with dry ice, and the High speed photographs were taken as the drug-coated aluminum side of the apparatus was placed on a hot plate at substrate was heated to monitor visually formation of a ther 240° C. for 10 seconds. The material collected on the beaker mal vapor. The photographs showed that a thermal vapor was walls was recovered and analyzed by HPLC analysis with initially visible 30 milliseconds after heating was initiated, 30 detection by absorption of 225 nm light used to determine the with the majority of the thermal vapor formed by 140 milli purity of the aerosol. Purity of the drug-aerosol particles was seconds. Generation of the thermal vapor was complete by determined to be 99.9%. 700 milliseconds. Diazepam was also coated on an aluminum foil substrate Example 34 (36 cm) according to Method G.5.1 mg of drug was applied 35 to the substrate, for a calculated thickness of the drug film of Cyclobenzaprine (MW 275, melting point <25° C., oral 1.4 Lum. The substrate was heated substantially as described in dose 10 mg), a muscle relaxant, was coated on an aluminum Method G, except that 90 V for 6 seconds was used, and purity foil substrate (20 cm) according to MethodC.9.0 mg of drug of the drug-aerosol particles was determined to be 99%. 3.8 was applied to the substrate, for a calculated thickness of the mg was recovered from the glass tube walls after vaporiza drug film of 4.5 um. The substrate was heated as described in 40 tion, for a percent yield of 74.5%. Method C at 90 V for 5 seconds. The purity of the drug Example 38 aerosol particles was determined to be 99%. 6.33 mg was recovered from the glass tube walls after vaporization, for a percent yield of 70.3%. Diclofenac ethyl ester (MW 324, oral dose 50 mg), an 45 antirheumatic agent, was coated on a metal Substrate (50cm) Example 35 and heated according to Method F at 300° C. to form drug aerosol particles. 50 mg of drug was applied to the Substrate, Cyproheptadine (MW 287, melting point 113° C., oral for a calculated thickness of the drug film of 10 um. Purity of dose 4 mg), an antihistamine, was coated on an aluminum foil the drug-aerosol particles was determined to be 100% by GC substrate (20cm) according to Method C. 4.5 mg of drug was 50 analysis. The yield of aerosol particles was 80%. applied to the Substrate, for a calculated thickness of the drug film of 2.3 lum. The substrate was heated as described in Example 39 Method C at 60 V for 8 seconds. The purity of the drug aerosol particles was determined to be >99.5%. 3.7 mg was Diflunisal (MW 250, melting point 211° C., oral dose 250 recovered from the glass tube walls after vaporization, for a 55 mg), an analgesic, was coated on a piece of aluminum foil (20 percent yield of 82.2%. cm) according to Method C. The calculated thickness of the Cyproheptadine HCl salt (MW 324, melting point 21.6°C., drug film was 5.3 lum. The substrate was heated as described oral dose 4 mg) was coated on an identical Substrate to a in Method C at 60 V for 6 seconds. The purity of the drug thickness of 2.2 Lum. The substrate was heated at 60V for 8 aerosol particles was determined to be >99.5%. 5.47 mg was seconds. The purity of the drug-aerosol particles was deter 60 recovered from the glass tube walls after vaporization, for a mined to be 99.6%. 2.6 mg was recovered from the glass tube percent yield of 51.6%. walls after vaporization, for a percent yield of 60.5%. Example 40 Example 36 65 Diltiazem (MW 415, oral dose 30 mg), a calcium channel Dapsone (MW 248, melting point 176° C., oral dose 50 blocker used as a cardiovascular agent, was coated on a stain mg), an anti-infective agent, was coated on a stainless Steel less steel cylinder (8 cm) according to Method D. 0.8 mg of US 7,585,493 B2 43 44 drug was applied to the Substrate, for a calculated drug film thermal vapor formed by 100 milliseconds. Generation of the thickness of 1 Lum. The substrate was heated as described in thermal vapor was complete by 200 milliseconds. Method D by charging the capacitors to 20.5V. The purity of the drug-aerosol particles was determined to be 94.2%. 0.53 Example 43 mg was recovered from the filter after vaporization, for a 5 percent yield of 66.3%. A total mass of 0.8 mg was recovered Doxepin (MW 279, melting point <25° C. oral dose 75 from the test apparatus and Substrate, for a total recovery of mg), a psychotherapeutic agent, was coated on an aluminum 100%. foil substrate (20 cm) according to MethodC. 2.0 mg of drug The drug was also coated on a piece of aluminum foil (20 was applied to the substrate, for a calculated thickness of the cm) according to Method C. The calculated thickness of the 10 drug film of 1.0 Lum. The substrate was heated as described in drug film was 1.0 lum. The substrate was heated as described Method C at 90 V for 3.5 seconds. The purity of the drug in Method C at 90 V for 3.5 seconds. The purity of the aerosol particles was determined to be 99%. The total mass drug-aerosol particles was determined to be 85.5%. 1.91 mg recovered from the glass tube walls after vaporization was recovered from the glass tube walls after vaporization, -100%. for a percent yield of 95.5%. 15 Another Substrate containing doxepin was also prepared. Diltiazam was also coated on a piece of aluminum foil (20 On an aluminum foil substrate (20 cm) 8.6 mg of drug was cm) according to Method C. The calculated thickness of the applied to the Substrate, for a calculated thickness of the drug drug film was 1.1 um. The substrate was heated as described film of 4.5 um. The substrate was heated as described in in Method C at 90 V for 3.5 seconds under an argon atmo Method C at 90 V for 5 seconds. The purity of the drug sphere. The purity of the drug-aerosol particles was deter aerosol particles was determined to be 81.1%. 6.4 mg was mined to be 97.1%. 1.08 mg was recovered from the glass recovered from the glass tube walls after vaporization, for a tube walls after vaporization, for a percent yield of 49.1%. percent yield of 74.4%. Another Substrate containing doxepin was also prepared Example 41 for testing under argon. On an aluminum foil substrate (20 25 cm) 1.8 mg of drug was applied to the substrate, for a cal Diphenhydramine (MW 255, melting point <25°C., oral culated thickness of the drug film of 0.9 Lum. The substrate dose 25 mg), an antihistamine, was coated on an aluminum was heated as described in Method C at 90 V for 3.5 seconds. foil substrate (20 cm) according to Method C. 5.50 mg of The purity of the drug-aerosol particles was determined to be drug was applied to the Substrate, for a calculated thickness of 99.1%. The total mass recovered from the glass tube walls the drug film of 2.8 Lum. The substrate was heated as described 30 after vaporization ~100%. in Method C at 108 V for 2.25 seconds. The purity of the drug-aerosol particles was determined to be 93.8%. 3.97 mg Example 44 was recovered from the glass tube walls after vaporization, for a percent yield of 72.2%. Donepezil (MW 379, oral dose 5 mg), a drug used in The hydrochloride salt was also tested. 4.90 mg of drug 35 management of Alzheimer's, was coated on a stainless Steel was coated onto an aluminum Substrate, for a calculated cylinder (8 cm) according to Method D. 5.73 mg of drug was thickness of the drug film of 2.5um. The substrate was heated applied to the Substrate, for a calculated drug film thickness of under an argon atmosphere as described in Method C at 60 V 6.9 um. The substrate was heated as described in Method D by for 10 seconds. The purity of the drug-aerosol particles was charging the capacitors to 20.5 V. The purity of the drug determined to be 90.3%. 3.70 mg was recovered from the 40 aerosol particles was determined to be 96.9%. 3 mg was glass tube walls after vaporization, for a percent yield of recovered from the filter after vaporization, for a percent yield 75.5%. Another experiment with the hydrochloride salt was of 52.4%. A total mass of 3 mg was recovered from the test done under an argon atmosphere. 5.20 mg of drug was coated apparatus and substrate, for a total recovery of 52.4%. onto an aluminum Substrate, for a calculated thickness of the Donepezil was also tested according to Method B, by coat drug film of 2.6 Lum. The substrate was heated as described in 45 ing a solution of the drug onto a piece of stainless steel foil (5 Method C at 60 V for 10 seconds. The purity of the drug cm). Six substrates were prepared, with film thicknesses aerosol particles was determined to be 93.3%. 3.90 mg was ranging from about 0.5 um to about 3.2 Lum. The Substrates recovered from the glass tube walls after vaporization, for a were heated as described in Method B by charging the capaci percent yield of 75.0%. tors to 14.5 or 15.5V. Purity of the drug aerosol particles from 50 each substrate was determined. The results are shown in FIG. Example 42 7. Donepezil was also tested by coating a solution of the drug Disopyramide (MW 339, melting point 95°C., oral dose onto a piece of stainless steel foil (5 cm). The substrate 100 mg), a cardiovascular agent, was coated on a stainless having a drug film thickness of 2.8 um was prepared by steel cylinder (8 cm) according to Method D. 1.07 mg of 55 depositing 1.51 mg of drug. After Volatilization of drug from drug was applied to the Substrate, for a calculated drug film the substrate by charging the capacitors to 14.5V, 1.37 mg of thickness of 1.3 m. The substrate was heated as described in aerosol particles were recovered from the filter, for a percent Method D by charging the capacitors to 20.5V. The purity of yield of 90.9%. The purity of drug compound recovered from the drug-aerosol particles was determined to be 99%. 0.63 mg the filter was 96.5%. A total mass of 1.51 mg was recovered was recovered from the filter after vaporization, for a percent 60 from the test apparatus and Substrate, for a total recovery of yield of 58.9%. A total mass of 0.9 mg was recovered from the 100%. test apparatus and substrate, for a total recovery of 84.1%. High speed photographs were taken as the drug-coated Example 45 substrate was heated to monitor visually formation of a ther mal vapor. The photographs, shown in FIGS. 25A-25D, 65 Eletriptan (MW 383, oral dose 3 mg), a serotonin 5-HT showed that a thermal vapor was initially visible 50 millisec receptor agonist used as a migraine preparation, was coated onds after heating was initiated, with the majority of the on a piece of stainless steel foil (6 cm) according to Method US 7,585,493 B2 45 46 B. 1.38 mg of drug was applied to the Substrate, for a calcu foil (20 cm) according to Method C. The calculated thick lated drug film thickness of 2.2 Lum. The substrate was heated ness of the drug film was 4.9 um. The substrate was heated as as described in Method B by charging the capacitors to 16 V. described in MethodCat 90 V for 5 seconds. The purity of the The purity of the drug-aerosol particles was determined to be drug-aerosol particles was determined to be 95.8%. 6.4 mg 97.8%. 1.28 mg was recovered from the filter after vaporiza was recovered from the glass tube walls after vaporization, tion, for a percent yield of 93%. The total mass was recovered for a percent yield of 65.3%. from the test apparatus and Substrate, for a total recovery of Esmolol was coated on a stainless steel cylinder (8 cm) 100%. according to Method D. 0.83 mg of drug was applied to the Substrate, for a calculated drug film thickness of 1.4 um. The Example 46 10 substrate was heated as described in Method D by charging the capacitors to 20.5 V. The purity of the drug-aerosol par Estradiol (MW 272, melting point 179°C., oral dose 2 mg), ticles was determined to be 93%. 0.63 mg was recovered from a hormonal agent, was coated on a piece of aluminum foil (20 the filter after vaporization, for a percent yield of 75.9%. A cm) according to Method C. The calculated thickness of the total mass of 0.81 mg was recovered from the test apparatus drug film was 1.3 lum. The substrate was heated as described 15 and substrate, for a total recovery of 97.6%. in Method C at 60 V for 9 seconds. The purity of the drug High speed photographs were taken as the drug-coated aerosol particles was determined to be 98.5%. 1.13 mg was substrate was heated to monitor visually formation of a ther recovered from the glass tube walls after vaporization, for a mal vapor. The photographs showed that a thermal vapor was percent yield of 45.2%. initially visible 25 milliseconds after heating was initiated, Another Substrate containing estradiol was also prepared with the majority of the thermal vapor formed by 60 milli for testing under argon. On an aluminum foil substrate (20 seconds. Generation of the thermal vapor was complete by 75 cm) 2.6 mg of drug was applied to the substrate, for a cal milliseconds. culated thickness of the drug film of 1.3 Lum. The substrate was heated as described in Method C at 60 V for 9 seconds. Example 51 The purity of the drug-aerosol particles was determined to be 25 98.7%. 1.68 mg was recovered from the glass tube walls after Estazolam (MW 295, melting point 229°C., oral dose 2 vaporization, for a percent yield of 64.6%. mg), a sedative and hypnotic, was coated on an aluminum foil substrate (20cm) according to Method C.2.0 mg of drug was Example 47 applied to the Substrate, for a calculated thickness of the drug 30 film of 1.0 um. The substrate was heated basically as Estradiol-3,17-diacetate (MW 357, oral dose 2 mg), a hor described in Method C at 60 V for 3 seconds then 45 V for 11 monal prodrug, was coated on a piece of aluminum foil (20 seconds. The purity of the drug-aerosol particles was deter cm) according to Method C. The calculated thickness of the mined to be 99.9%. 1.4 mg was recovered from the glass tube drug film was 0.9 um. The substrate was heated as described walls after vaporization, for a percent yield of 70%. in Method C at 60 V for 7 seconds. The purity of the drug 35 aerosol particles was determined to be 96.9%. 1.07 mg was Example 52 recovered from the glass tube walls after vaporization, for a percent yield of 62.9%. Ethacrynic acid (MW303, melting point 122°C., oral dose Example 48 25.0 mg), a cardiovascular agent, was coated on a stainless 40 steel cylinder (8 cm) according to Method E. 1.10 mg of drug Efavirenz (MW 316, melting point 141° C., oral dose 600 was applied to the Substrate, for a calculated drug film thick mg), an anti-infective agent, was coated on a stainless Steel ness of 1.3 um. The substrate was heated as described in cylinder (8 cm) according to Method D. 0.82 mg of drug was Method E and purity of the drug-aerosol particles was deter applied to the Substrate, for a calculated drug film thickness of mined to be 99.8%. 0.85 mg was recovered from the filter 1 um. The substrate was heated as described in Method D by 45 after vaporization, for a percent yield of 77.3%. A total mass charging the capacitors to 20.5 V. The purity of the drug of 1.1 mg was recovered from the test apparatus and Substrate, aerosol particles was determined to be 97.9%. 0.52 mg was for a total recovery of 100%. recovered from the filter after vaporization, for a percent yield Example 53 of 63.4%. A total mass of 0.6 mg was recovered from the test 50 apparatus and substrate, for a total recovery of 73.2%. Ethambutol (MW204, melting point 89° C., oral dose 1000 Example 49 mg), a anti-infective agent, was coated on a stainless Steel cylinder (8 cm) according to Method D. 0.85 mg of drug was Ephedrine (MW 165, melting point 40°C., oral dose 10 applied to the Substrate, for a calculated drug film thickness of mg), a respiratory agent, was coated on an aluminum foil 55 1 um. The substrate was heated as described in Method D by substrate (20cm) according to Method C.8.0 mg of drug was charging the capacitors to 20.5 V. The purity of the drug applied to the Substrate, for a calculated thickness of the drug aerosol particles was determined to be 90%. 0.50 mg was film of 4.0 lum. The substrate was heated as described in recovered from the filter after vaporization, for a percent yield Method C at 90 V for 5 seconds. The purity of the drug of 58.8%. A total mass of 0.85 mg was recovered from the test aerosol particles was determined to be 99%. 7.26 mg was 60 apparatus and substrate, for a total recovery of 100%. recovered from the glass tube walls after vaporization, for a High speed photographs were taken as the drug-coated percent yield of 90.8%. substrate was heated to monitor visually formation of a ther mal vapor. The photographs showed that a thermal vapor was Example 50 initially visible 25 milliseconds after heating was initiated, 65 with the majority of the thermal vapor formed by 50 milli Esmolol (MW 295, melting point 50° C., oral dose 35 mg), seconds. Generation of the thermal vapor was complete by 90 a cardiovascular agent, was coated on a piece of aluminum milliseconds. US 7,585,493 B2 47 48 Example 54 ing to Method D. 0.80 mg of drug was applied to the substrate, for a calculated drug film thickness of 1 um. The substrate was Fluticasone propionate (MW 501, melting point 272°C., heated as described in Method D by charging the capacitors to oral dose 0.04 mg), a respiratory agent, was coated on a piece 20.5 V. The purity of the drug-aerosol particles was deter of stainless steel foil (5 cm) according to Method B. The 5 mined to be 99.6%. 0.54 mg was recovered from the filter calculated thickness of the drug film was 0.6 um. The sub after vaporization, for a percent yield of 67.5%. A total mass strate was heated as described in Method B by charging the of0.7 mg was recovered from the test apparatus and Substrate, capacitors to 15.5 V. The purity of the drug-aerosol particles for a total recovery of 90%. was determined to be 91.6%. 0.211 mg was recovered from High speed photographs were taken as the drug-coated the filter after vaporization, for a percent yield of 70.1%. A 10 substrate was heated to monitor visually formation of a ther total mass of 0.215 mg was recovered from the test apparatus mal vapor. The photographs showed that a thermal vapor was and substrate, for a total recovery of 71.4%. initially visible 25 milliseconds after heating was initiated, with the majority of the thermal vapor formed by 65 milli Example 55 seconds. Generation of the thermal vapor was complete by 15 110 milliseconds. Fenfluramine (MW 231, melting point 112°C., oral dose 20 mg), an obesity management, was coated on a piece of Example 59 aluminum foil (20 cm) according to Method C. 9.2 mg were coated. The calculated thickness of the drug film was 4.6 um. Fluconazole (MW 306, melting point 140° C., oral dose The substrate was heated as described in Method Cat 90 V for 200 mg), an anti-infective agent, was coated on a piece of 5 seconds. The purity of the drug-aerosol particles was deter stainless steel foil (5 cm) according to Method B. 0.737 mg mined to be >99.5%. The total mass was recovered from the of drug was applied to the Substrate, for a calculated drug film glass tube walls after vaporization, for a percent yield of thickness of 1.4 um. The substrate was heated as described in -100%. Method B by charging the capacitors to 15.5V. The purity of 25 the drug-aerosol particles was determined to be 94.3%. 0.736 Example 56 mg was recovered from the filter after vaporization, for a percent yield of 99.9%. A total mass of 0.737 mg was recov Fenoprofen (MW 242, melting point <25°C., oral dose 200 ered from the test apparatus and Substrate, for a total recovery mg), an analgesic, was coated on a piece of aluminum foil (20 of 100%. cm) according to Method C. The calculated thickness of the 30 Example 60 drug film was 3.7 lum. The substrate was heated as described in Method C at 60 V for 5 seconds. The purity of the drug Flunisolide (MW 435, oral dose 0.25 mg), a respiratory aerosol particles was determined to be 98.7%. 4.98 mg was agent, was coated was coated on a stainless steel cylinder (8 recovered from the glass tube walls after vaporization, for a cm) according to Method E. 0.49 mg of drug was applied to percent yield of 67.3%. 35 the substrate, for a calculated drug film thickness of 0.6 um. The substrate was heated as described in Method E and purity Example 57 of the drug-aerosol particles was determined to be 97.6%. 0.3 mg was recovered from the filter after vaporization, for a Fentanyl (MW 336, melting point 84° C., oral dose 0.2 percent yield of 61.2%. A total mass of 0.49 mg was recov mg), an analgesic, was coated onto ten stainless steel foil 40 ered from the test apparatus and Substrate, for a total recovery substrates (5 cm) according to Method B. The calculated of 100%. thickness of the drug film on each Substrate ranged from about Another substrate (stainless steel foil, 5 cm) was prepared 0.2 um to about 3.3 um. The substrates were heated as by applying 0.302 mg drug to form a film having a thickness described in Method B by charging the capacitors to 14 V. of 0.6 um. The substrate was heated as described in Method B Purity of the drug-aerosol particles from each substrate was 45 by charging the capacitor to 15.0 V. The purity of the drug determined and the results are shown in FIG. 20. aerosol particles was determined to be 94.9%. 0.296 mg was Fentanyl was also coated on a stainless steel cylinder (8 recovered from the filter after vaporization, for a percent yield cm) according to Method D. 0.29 mg of drug was applied to of 98%. A total mass of 0.302 mg was recovered from the test the Substrate, for a calculated drug film thickness of 0.4 um. apparatus and substrate, for a total recovery of 100%. The substrate was heated as described in Method D by charg 50 ing the capacitors to 18 V. The purity of the drug-aerosol Example 61 particles was determined to be 97.9%. 0.19 mg was recovered from the filter after vaporization, for a percent yield of 64%. Flunitrazepam (MW 313, melting point 167°C., oral dose A total mass of 0.26 mg was recovered from the test apparatus 0.5 mg), a sedative and hypnotic, was coated on a piece of and substrate, for a total recovery of 89%. 55 aluminum foil (24.5 cm) according to Method G. The cal High speed photographs were taken as the drug-coated culated thickness of the drug film was 0.6 um. The substrate substrate was heated to monitor visually formation of a ther was heated as described in Method G at 90 V for 6 seconds. mal vapor. The photographs showed that a thermal vapor was The purity of the drug-aerosol particles was determined to be initially visible 30 milliseconds after heating was initiated, 99.8%. 0.73 mg was recovered from the glass tube walls after with the majority of the thermal vapor formed by 100 milli 60 vaporization, for a percent yield of 60.8%. seconds. Generation of the thermal vapor was complete by Flunitrazepam was further coated on an aluminum foil 250 milliseconds. substrate (24 cm) according to Method C. 5 mg of the drug was applied to the substrate, for a calculated thickness of the Example 58 drug film of 2.08 um. The substrate was heated substantially 65 as described in Method C at 60V for 7 seconds. The purity of Flecainide (MW 414, oral dose 50 mg), a cardiovascular the drug-aerosol particles was determined to be at least agent, was coated on a stainless steel cylinder (8 cm) accord 99.9%. US 7,585,493 B2 49 50 Example 62 was flushed with argon prior to volatilization, the purity of the drug-aerosol particles was determined to be 97%. The percent Fluoxetine (MW 309, oral dose 20 mg), a psychotherapeu yield of the aerosol was 29%. tic agent, was coated on an aluminum foil substrate (20 cm) according to Method C. 1.90 mg of drug was applied to the 5 Example 66 substrate, for a calculated thickness of the drug film of 1.0Lum. The substrate was heated as described in Method Cat 90 V for Hydromorphone (MW 285, melting point 267 C., oral 3.5 seconds. The purity of the drug-aerosol particles was dose 2 mg), an analgesic, was coated on a stainless steel determined to be 97.4%. 1.4 mg was recovered from the glass cylinder (9 cm) according to Method D. 5.62 mg of drug was tube walls after vaporization, for a percent yield of 73.7%. 10 applied to the Substrate, for a calculated drug film thickness of Another Substrate containing fluoxetine coated (2.0 mg 6.4Lum. The substrate was heated as described in Method D by drug) to a film thickness of 1.0 um was prepared by the same charging the capacitors to 19 V. The purity of the drug-aerosol method and heated under an argon atmosphere at 90 V for 3.5 particles was determined to be 99.4%. 2.34 mg was recovered seconds. The purity of the drug-aerosol particles was deter from the filter after vaporization, for a percent yield of 41.6%. mined to be 96.8%. 1.7 mg was recovered from the glass tube 15 A total mass of 5.186 mg was recovered from the test appa walls after vaporization, for a percent yield of 85.0%. ratus and substrate, for a total recovery of 92.3%. Hydromorphone was also coated on a piece of aluminum Example 63 foil (20 cm) according to Method C. The calculated thick ness of the drug film was 1.1 Lum. The Substrate was heated as Galanthamine (MW 287, oral dose 4 mg) was coated on a 20 described in Method C at 90 V for 3.5 seconds. The purity of stainless steel cylinder (8 cm) according to Method D. 1.4 the drug-aerosol particles was determined to be 98.3%. 0.85 mg of drug was applied to the Substrate, for a calculated drug mg was recovered from the glass tube walls after vaporiza film thickness of 1.7 um. The substrate was heated as tion, for a percent yield of 40.5%. described in Method D by charging the capacitors to 20.5V. Hydromorphone was also coated onto eight stainless steel The purity of the drug-aerosol particles was determined to be 25 cylinder substrates (8 cm) according to Method D. The cal >99.5%. 1.16 mg was recovered from the filter after vapor culated thickness of the drug film on each Substrate ranged ization, for a percent yield of 82.6%. A total mass of 1.39 mg from about 0.7 um to about 2.8 um. The substrates were was recovered from the test apparatus and Substrate, for a total heated as described in Method D by charging the capacitors to recovery of 99.1%. 20.5 V. The purity of the drug-aerosol particles determined. 30 The results are shown in FIG. 8. For the substrate having a Example 64 drug film thickness of 1.4 um, 1.22 mg of drug was applied to the substrate. After vaporization of this substrate, 0.77 mg Granisetron (MW 312, oral dose 1 mg), a gastrointestinal was recovered from the filter, for a percent yield of 63.21%. agent, was coated on an aluminum foil substrate (20 cm) The purity of the drug-aerosol particles was determined to be according to Method C. 1.50 mg of drug was applied to the 35 99.6%. A total mass of 1.05 mg was recovered from the test substrate, for a calculated thickness of the drug film of 0.8 um. apparatus and substrate, for a total recovery of 86.1%. The substrate was heated as described in Method Cat30 V for 45 seconds. The purity of the drug-aerosol particles was Example 67 determined to be 99%. 1.3 mg was recovered from the glass 40 Hydroxychloroquine (MW 336, melting point 91° C., oral tube walls after vaporization, for a percent yield of 86.7%. dose 400 mg), an antirheumatic agent, was coated on a stain mg of granisetron was also coated on an aluminum foil less steel cylinder (8 cm) according to Method D. 6.58 mg of substrate (24.5 cm) to a calculated drug film thickness of drug was applied to the Substrate, for a calculated drug film 0.45um. The substrate was heated substantially as described thickness of 11 lum. The substrate was heated as described in in Method G at 90 V for 6 seconds. The purity of the drug- as Method D by charging the capacitors to 20.5V. The purity of aerosol particles was determined to be 93%. 0.4 mg was the drug-aerosol particles was determined to be 98.9%. 3.48 recovered from the glass tube walls, for a percent yield of mg was recovered from the filter after vaporization, for a 36%. percent yield of 52.9%. A total mass of 5.1 mg was recovered from the test apparatus and Substrate, for a total recovery of Example 65 50 77.8%. Haloperidol (MW 376, melting point 149°C., oral dose 2 Example 68 mg), a psychotherapeutic agent, was coated on an aluminum foil substrate (20 cm) according to Method C. 2.20 mg of Hyoscyamine (MW 289, melting point 109°C., oral dose drug was applied to the Substrate, for a calculated thickness of 55 0.38 mg), a gastrointestinal agent, was coated on a piece of the drug film of 1.1 Lum. The substrate was heated as described aluminum foil (20 cm) according to Method C. The calcu in Method C at 108 V for 2.25 seconds. The purity of the lated thickness of the drug film was 0.9 um. The substrate was drug-aerosol particles was determined to be 99.8%. 0.6 mg heated as described in Method C at 60 V for 8 seconds. The was recovered from the glass tube walls after vaporization, purity of the drug-aerosol particles was determined to be for a percent yield of 27.3%. 60 95.9%. 0.86 mg was recovered from the glass tube walls after Haloperidol was further coated on an aluminum foil sub vaporization, for a percent yield of 50.6%. strate according to Method C. The substrate was heated as described in Method C. When 2.1 mg of the drug was heated Example 69 at 90 V for 3.5 seconds, the purity of the resultant drug aerosol particles was determined to be 96%. 1.69 mg of 65 Ibuprofen (MW 206, melting point 77° C., oral dose 200 aerosol particles were collected for a percent yield of the mg), an analgesic, was coated on an aluminum foil substrate aerosol of 60%. When 2.1 mg of drug was used and the system (20 cm) according to Method C. 10.20 mg of drug was US 7,585,493 B2 51 52 applied to the Substrate, for a calculated thickness of the drug aerosol particles was determined to be 99%. 1.14 mg was film of 5.1 um. The substrate was heated as described in recovered from the glass tube walls after vaporization, for a Method C at 60 V for 5 seconds. The purity of the drug percent yield of 27.1%. aerosol particles was determined to be 99.7%. 5.45 mg was Another Substrate containing indomethacin methyl ester recovered from the glass tube walls after vaporization, for a 5 coated to a film thickness of 1.2 Lum was prepared by the same percent yield of 53.4%. method and heated under an argon atmosphere at 60 V for 6 seconds. The purity of the drug-aerosol particles was deter Example 70 mined to be 99%. 1.44 mg was recovered from the glass tube walls after vaporization, for a percent yield of 60%. Imipramine (MW 280, melting point <25°C., oral dose 50 10 mg), a psycho therapeutic agent, was coated on a piece of Example 74 aluminum foil (20 cm) according to Method C. 1.8 mg was coated on the aluminum foil. The calculated thickness of the Isocarboxazid (MW 231, melting point 106°C., oral dose drug film was 0.9 um. The substrate was heated as described 10 mg), a psychotherapeutic agent, was coated on a stainless in Method C at 90 V for 3.5 seconds. The purity of the 15 steel cylinder (8 cm) according to Method D. 0.97 mg of drug-aerosol particles was determined to be 98.3%. The total drug was applied to the Substrate, for a calculated drug film mass recovered from the glass tube walls after vaporization thickness of 1.2 Lum. The substrate was heated as described in was -100%. Method D by charging the capacitors to 20.5V. The purity of Another Substrate containing imipramine coated to a film the drug-aerosol particles was determined to be 99.6%. 0.52 thickness of 0.9 um was prepared by the same method and 20 mg was recovered from the filter after vaporization, for a heated under an argon atmosphere at 90 V for 3.5 seconds. percent yield of 53%. A total mass of 0.85 mg was recovered The purity of the drug-aerosol particles was determined to be from the test apparatus and Substrate, for a total recovery of 99.1%. 1.5 mg was recovered from the glass tube walls after 87.7%. vaporization, for a percent yield of 83.3%. High speed photographs were taken as the drug-coated 25 substrate was heated to monitor visually formation of a ther Example 71 mal vapor. The photographs showed that a thermal vapor was initially visible 30 milliseconds after heating was initiated, Indomethacin (MW 358, melting point 155° C., oral dose with the majority of the thermal vapor formed by 70 milli 25 mg), an analgesic, was coated on a piece of aluminum foil seconds. Generation of the thermal vapor was complete by (20 cm) according to Method C. The calculated thickness of 200 milliseconds. the drug film was 1.2 Lum. The Substrate was heated as described in Method Cat 60V for 6 seconds. The purity of the Example 75 drug-aerosol particles was determined to be 96.8%. 1.39 mg was recovered from the glass tube walls after vaporization, Isotretinoin (MW 300, melting point 175°C., oral dose 35 35 mg), a skin and mucous membrane agent, was coated on a for a percent yield of 60.4%. stainless steel cylinder (8 cm) according to Method D. 1.11 Another Substrate containing indomethacin coated to a film mg of drug was applied to the Substrate, for a calculated drug thickness of 1.5 um was prepared by the same method and film thickness of 1.4 um. The substrate was heated as heated under an argon atmosphere at 60V for 6 seconds. The described in Method D by charging the capacitors to 20.5 V. purity of the drug-aerosol particles was determined to be The purity of the drug-aerosol particles was determined to be 99%. 0.61 mg was recovered from the glass tube walls after 96.6%. 0.66 mg was recovered from the filter after vaporiza vaporization, for a percent yield of 20.3%. tion, for a percent yield of 59.5%. A total mass of 0.86 mg was recovered from the test apparatus and Substrate, for a total Example 72 recovery of 77.5%. 45 High speed photographs were taken as the drug-coated Indomethacin ethyl ester (MW 386, oral dose 25 mg), an substrate was heated to monitor visually formation of a ther analgesic, was coated on a piece of aluminum foil (20 cm) mal vapor. The photographs showed that a thermal vapor was according to Method C. The calculated thickness of the drug initially visible 30 milliseconds after heating was initiated, film was 2.6 um. The substrate was heated as described in with the majority of the thermal vapor formed by 65 milli Method C at 60 V for 9 seconds. The purity of the drug 50 seconds. Generation of the thermal vapor was complete by aerosol particles was determined to be 99%. 2.23 mg was 110 milliseconds. recovered from the glass tube walls after vaporization, for a percent yield of 42.9%. Example 76 Another Substrate containing indomethacin ethyl ester coated to a film thickness of 2.6 um was prepared by the same ss Ketamine (MW 238, melting point 93° C., IV dose 100 method and heated under an argon atmosphere at 60 V for 9 mg), an anesthetic, was coated on a stainless steel cylinder (8 seconds. The purity of the drug-aerosol particles was deter cm) according to Method D. 0.836 mg of drug was applied to mined to be 99%. 3.09 mg was recovered from the glass tube the substrate, for a calculated drug film thickness of 1.0 um. walls after vaporization, for a percent yield of 59.4%. The substrate was heated as described in Method D by charg 60 ing the capacitors to 20.5 V. The purity of the drug-aerosol Example 73 particles was determined to be 99.9%. 0.457 mg was recov ered from the filter after vaporization, for a percent yield of Indomethacin methyl ester (MW 372, oral dose 25 mg), an 54.7%. A total mass of 0.712 mg was recovered from the test analgesic, was coated on a piece of aluminum foil (20 cm) apparatus and substrate, for a total recovery of 85.2%. according to Method C. The calculated thickness of the drug 65 High speed photographs were taken as the drug-coated film was 2.1 um. The substrate was heated as described in substrate was heated to monitor visually formation of a ther Method C at 60 V for 6 seconds. The purity of the drug mal vapor. The photographs showed that a thermal vapor was US 7,585,493 B2 53 54 initially visible 30 milliseconds after heating was initiated, was heated as described in Method C at 60 V for 6 seconds. with the majority of the thermal vapor formed by 75 milli The purity of the drug-aerosol particles was determined to be seconds. Generation of the thermal vapor was complete by 98.8%. 3.17 mg was recovered from the glass tube walls after 100 milliseconds. vaporization, for a percent yield of 66.0%. Example 77 Example 82 Ketoprofen (MW 254, melting point 94° C., oral dose 25 Ketotifen (MW309, melting point 152°C., used as 0.025% mg), an analgesic, was coated on an aluminum foil substrate Solution in the eye) was coated on a stainless steel cylinder (8 (20 cm) according to Method C. 10.20 mg of drug was 10 cm) according to Method D. 0.544 mg of drug was applied to applied to the Substrate, for a calculated thickness of the drug the substrate, for a calculated drug film thickness of 0.7 um. film of 5.1 um. The substrate was heated as described in The substrate was heated as described in Method D by charg Method C at 60 V for 16 seconds. The purity of the drug ing the capacitors to 20.5 V. The purity of the drug-aerosol aerosol particles was determined to be 98%. 7.24 mg was particles was determined to be 99.9%. 0.435 mg was recov recovered from the glass tube walls after vaporization, for a 15 ered from the filter after vaporization, for a percent yield of percent yield of 71%. 80%. A total mass of 0.544 mg was recovered from the test apparatus and substrate, for a total recovery of 100%. Example 78 Example 83 Ketoprofen ethyl ester (MW 282, oral dose 25 mg), an analgesic, was coated on a piece of aluminum foil (20 cm) Lamotrigine (MW 256, melting point 218°C., oral dose according to Method C. The calculated thickness of the drug 150 mg), an anticonvulsant, was coated on a stainless steel film was 2.0 Lum. The substrate was heated as described in cylinder (8 cm) according to Method D. 0.93 mg of drug was Method C at 60 V for 8 seconds. The purity of the drug applied to the Substrate, for a calculated drug film thickness of aerosol particles was determined to be 99%. 3.52 mg was 25 1.1 Lum. The substrate was heated as described in Method D by recovered from the glass tube walls after vaporization, for a charging the capacitors to 20.5 V. The purity of the drug percent yield of 88%. aerosol particles was determined to be 99.1%. 0.58 mg was Another Substrate containing ketroprofen ethyl ester recovered from the filter after vaporization, for a percent yield coated to a film thickness of 2.7 um was prepared by the same of 62.4%. A total mass of 0.93 mg was recovered from the test method and heated under an argon atmosphere at 60 V for 8 30 apparatus and substrate, for a total recovery of 100%. seconds. The purity of the drug-aerosol particles was deter Example 84 mined to be 99.6%. 4.1 mg was recovered from the glass tube walls after vaporization, for a percent yield of 77.4%. Lidocaine (MW 234, melting point 69° C., oral dose 30 mg), an anesthetic, was coated on an aluminum foil substrate Example 79 35 (20 cm) according to MethodC.9.50 mg of drug was applied to the substrate, for a calculated thickness of the drug film of Ketoprofen Methyl Ester (MW 268, oral dose 25 mg), an 4.8 m. The substrate was heated as described in Method Cat analgesic, was coated on a piece of aluminum foil (20 cm) 90 V for 5 seconds. The purity of the drug-aerosol particles according to Method C. The calculated thickness of the drug was determined to be 99.8%. 7.3 mg was recovered from the film was 2.0 Lum. The substrate was heated as described in 40 glass tube walls after vaporization, for a percent yield of Method C at 60 V for 8 seconds purity of the drug-aerosol 76.8%. particles was determined to be 99%. 2.25 mg was recovered Lidocaine was further coated on an aluminum foil Sub from the glass tube walls after vaporization, for a percent strate (24.5 cm) according to Method G. 10.4 mg of the drug yield of 56.3%. was applied to the substrate, for a calculated thickness of the Another substrate containing ketoprofen methyl ester 45 drug film of 4.24 um. The substrate was heated as described in coated to a film thickness of 3.0 um was prepared by the same Method G at 90 V for 6 seconds. The purity of the drug method and heated under an argon atmosphere at 60 V for 8 aerosol particles was determined to be >99%. 10.2 mg of the seconds. The purity of the drug-aerosol particles was deter drug was found to have aerosolized, for a percent yield of mined to be 99%. 4.4 mg was recovered from the glass tube 98%. walls after vaporization, for a percent yield of 73.3%. 50 Example 85 Example 80 Linezolid (MW 337, melting point 183° C., oral dose 600 Ketorolac ethyl ester (MW 283, oral dose 10 mg), an anal mg), an anti-infective agent, was coated on a stainless Steel gesic, was coated on an aluminum foil substrate (20 cm) 55 cylinder (8 cm) according to Method D. 1.09 mg of drug was according to Method C. 9.20 mg of drug was applied to the applied to the Substrate, for a calculated drug film thickness of Substrate, for a calculated thickness of the drug film of 4.6Lum. 1.3 Lum. The substrate was heated as described in Method D by The substrate was heated as described in Method Cat 60V for charging the capacitors to 20.5 V. The purity of the drug 12 seconds. The purity of the drug-aerosol particles was aerosol particles was determined to be 95%. 0.70 mg was determined to be 99%. 5.19 mg was recovered from the glass 60 recovered from the filter after vaporization, for a percent yield tube walls after vaporization, for a percent yield of 56.4%. of 64.2%. A total mass of 1.09 mg was recovered from the test apparatus and substrate, for a total recovery of 100%. Example 81 Example 86 Ketorolac methyl ester (MW 269, oral dose 10 mg) was 65 also coated on an aluminum foil substrate (20 cm) to a drug Loperamide (MW 477, oral dose 4 mg), a gastrointestinal film thickness of 2.4 um (4.8 mg drug applied). The Substrate agent, was coated on a stainless steel cylinder (9 cm) accord US 7,585,493 B2 55 56 ing to Method D. 1.57 mg of drug was applied to the substrate, Example 90 for a calculated drug film thickness of 1.8 um. The substrate was heated as described in Method D by charging the capaci tors to 20.5 V. The purity of the drug-aerosol particles was Loxapine (MW 328, melting point 110°C., oral dose 30 determined to be 99.4%. 0.871 mg was recovered from the 5 mg), a psychotherapeutic agent, was coated on a stainless filter after vaporization, for a percent yield of 55.5%. A total steel cylinder (8 cm) according to Method D. 7.69 mg of mass of 1.57 mg was recovered from the test apparatus and drug was applied to the Substrate, for a calculated drug film substrate, for a total recovery of 100%. thickness of 9.2 um. The substrate was heated as described in High speed photographs were taken as the drug-coated Method D by charging the capacitors to 20.5V. The purity of substrate was heated to monitor visually formation of a ther- 10 the drug-aerosol particles was determined to be 99.7%. 3.82 mal vapor. The photographs showed that a thermal vapor was mg was recovered from the filter after vaporization, for a initially visible 30 milliseconds after heating was initiated, percent yield of 50%. A total mass of 6.89 mg was recovered with the majority of the thermal vapor formed by 80 milli from the test apparatus and Substrate, for a total recovery of seconds. Generation of the thermal vapor was complete by 89.6%. 165 milliseconds. 15 Example 91 Example 87 Maprotiline (MW 277, melting point 94° C., oral dose 25 Loratadine (MW 383, melting point 136°C., oral dose 10 mg), a psychotherapeutic agent, was coated on an aluminum mg), an antihistamine, was coated on an aluminum foil Sub strate (20 cm) according to Method C. 5.80 mg of drug was foil substrate (20 cm) according to MethodC. 2.0 mg of drug applied to the Substrate, for a calculated thickness of the drug was applied to the substrate, for a calculated thickness of the film of 2.9 um. The substrate was heated as described in drug film of 1.0 Lum. The substrate was heated as described in Method C at 60 V for 9 seconds. The purity of the drug Method C at 90 V for 3.5 seconds. The purity of the drug aerosol particles was determined to be 99%. 3.5 mg was 25 aerosol particles was determined to be 99.7%. 1.3 mg was recovered from the glass tube walls after vaporization, for a recovered from the glass tube walls after vaporization, for a percent yield of 60.3%. percent yield of 65.0%. Another Substrate containing loratadine coated (6.60 mg Another substrate containing maprotiline coated to a film drug) to a film thickness of 3.3 um was prepared by the same thickness of 1.0 Lim was prepared by the same method and method and heated under an argon atmosphere at 60 V for 9 30 heated under an argon atmosphere at 90 V for 3.5 seconds. seconds. The purity of the drug-aerosol particles was deter The purity of the drug-aerosol particles was determined to be mined to be 99.6%. 4.5 mg was recovered from the glass tube 99.6%. 1.5 mg was recovered from the glass tube walls after walls after vaporization, for a percent yield of 68.2%. vaporization, for a percent yield of 75%. Loratadine was further coated on an aluminum foil Sub 35 strate (24.5 cm) according to Method G. 10.4 mg of the drug Example 92 was applied to the substrate, for a calculated thickness of the drug film of 4.24 um. The substrate was heated substantially as described in Method G at 90 V for 6 seconds, except that Meclizine (MW 391, melting point <25°C., oral dose 25 two of the openings of the T-shaped tube were left open and mg), a vertigo agent, was coated on an aluminum foil Sub the third connected to the 1 L flask. The purity of the drug 40 strate (20 cm) according to Method C. 5.20 mg of drug was aerosol particles was determined to be >99%. 3.8 mg of the applied to the Substrate, for a calculated thickness of the drug drug was found to have aerosolized, for a percent yield of film of 2.6 um. The substrate was heated as described in 36.5%. Method C at 60 V for 7 seconds. The purity of the drug aerosol particles was determined to be 90.1%. 3.1 mg was Example 88 45 recovered from the glass tube walls after vaporization, for a percent yield of 59.6%. Lovastatin (MW 405, melting point 175°C., oral dose 20 The same drug coated on an identical Substrate (aluminum mg), a cardiovascular agent, was coated on a stainless Steel foil (20 cm)) to a calculated drug film thickness of 12.5um cylinder (8 cm) according to Method D. 0.71 mg of drug was so was heated under an argon atmosphere as described in applied to the Substrate, for a calculated drug film thickness of Method C at 60 V for 10 seconds. The purity of the drug 0.9 um. The substrate was heated as described in Method D by aerosol particles was determined to be 97.3%. 4.81 mg was charging the capacitors to 20.5 V. The purity of the drug recovered from the glass tube walls after vaporization, for a aerosol particles was determined to be 94.1%. 0.43 mg was percent yield of 19.2%. recovered from the filter after vaporization, for a percent yield ss The dihydrochloride salt form of the drug was also tested. of 60.6%. A total mass of 0.63 mg was recovered from the test Meclizine dihydrochloride (MW 464, oral dose 25 mg) was apparatus and substrate, for a total recovery of 88.7%. coated on a piece of aluminum foil (20 cm) according to Example 89 Method C. 19.4 mg of drug was applied to the substrate, for a 60 calculated thickness of the drug film of 9.7 um. The substrate Lorazepam N.O-diacetyl (typical inhalation dose 0.5 mg), was heated as described in Method C at 60 V for 6 seconds. was coated on a piece of aluminum foil (20 cm) according to The purity of the drug-aerosol particles was determined to be Method C. The calculated thickness of the drug film was 0.5 75.3%. 0.5 mg was recovered from the glass tube walls after um. The substrate was heated as described in Method C at 60 vaporization, for a percent yield of 2.6%. V for 7 seconds. The purity of the drug-aerosol particles was 65 An identical Substrate having a calculated drug film thick determined to be 90%. 0.87 mg was recovered from the glass ness of 11.7 um was heated under an argon atmosphere at 60 tube walls after vaporization, for a percent yield of 87%. V for 6 seconds. Purity of the drug-aerosol particles was US 7,585,493 B2 57 58 determined to be 70.9%. 0.4 mg was recovered from the glass stainless steel cylinder (8 cm) according to Method D. 1.03 tube walls after vaporization, for a percent yield of 1.7%. mg of drug was applied to the Substrate, for a calculated drug film thickness of 1.2 Lum. The substrate was heated as Example 93 described in Method D by charging the capacitors to 20.5 V. The purity of the drug-aerosol particles was determined to be Memantine (MW 179, melting point <25°C., oral dose 20 99.6%. 0.77 mg was recovered from the filter after vaporiza mg), an antiparkinsonian agent, was coated on a stainless tion, for a percent yield of 74.8%. A total mass of 1.03 mg was steel cylinder (8 cm) according to Method D. The calculated recovered from the test apparatus and Substrate, for a total thickness of the drug film was 1.7 um. The substrate was recovery of 100%. heated as described in Method D by charging the capacitors to 10 High speed photographs were taken as the drug-coated 20.5V. The purity of the drug-aerosol particles determined by substrate was heated to monitor visually formation of a ther LC/MS was >99.5%. 0.008 mg was recovered from the glass mal vapor. The photographs showed that a thermal vapor was tube walls after vaporization, for a percent yield of 0.6%. The initially visible 35 milliseconds after heating was initiated, total mass recovered was 0.06 mg, for a total recovery yield of with the majority of the thermal vapor formed by 80 milli 4.5%. The amount of drug trapped on the filter was low, most 15 seconds. Generation of the thermal vapor was complete by of the aerosol particles escaped into the vacuum line. 135 milliseconds. Example 94 Example 98 Meperidine (MW 247, oral dose 50mg), an analgesic, was coated on an aluminum foil substrate (20 cm) according to Metoprolol (MW 267, oral dose 15 mg), a cardiovascular Method C. 1.8 mg of drug was applied to the substrate, for a agent, was coated on an aluminum foil substrate (20 cm) calculated thickness of the drug film of 0.9 um. The substrate according to Method C. 10.8 mg of drug was applied to the was heated as described in Method C at 90 V for 3.5 seconds. substrate, for a calculated thickness of the drug film of 5.4 um. The purity of the drug-aerosol particles was determined to be The substrate was heated as described in Method Cat 90 V for 98.8%. 0.95 mg was recovered from the glass tube walls after 25 5 seconds. The purity of the drug-aerosol particles was deter vaporization, for a percent yield of 52.8%. mined to be 99.2%. 6.7 mg was recovered from the glass tube Another Substrate containing meperidine coated to a film walls after vaporization, for a percent yield of 62.0%. thickness of 1.1 Lim was prepared by the same method and Metoprolol was further coated on an aluminum foil sub heated under an argon atmosphere at 90 V for 3.5 seconds. strate (24.5 cm) according to Method G. 12.7 mg of the drug The purity of the drug-aerosol particles was determined to be 30 was applied to the substrate, for a calculated thickness of the 99.9%. 1.02 mg was recovered from the glass tube walls after drug film of 5.18 um. The substrate was heated as described in vaporization, for a percent yield of 48.6%. Method G at 90 V for 6 seconds. The purity of the drug Example 95 aerosol particles was determined to be >99%. All of the drug 35 was found to have aerosolized, for a percent yield of 100%. Metaproterenol (MW 211, melting point 100° C., oral dose 1.3 mg), a respiratory agent, was coated on a stainless steel Example 99 cylinder (8 cm) according to Method D. 1.35 mg of drug was applied to the Substrate, for a calculated drug film thickness of Mexiletine HCl (MW 216, melting point 205°C., oral dose 1.6 Lum. The substrate was heated as described in Method D by 40 200 mg), a cardiovascular agent, was coated on a stainless charging the capacitors to 20.5 V. The purity of the drug steel cylinder (8 cm) according to Method D. 0.75 mg of aerosol particles was determined to be 99.1%. 0.81 mg was drug was applied to the Substrate, for a calculated drug film recovered from the filter after vaporization, for a percent yield thickness of 0.9 um. The substrate was heated as described in of 60%. A total mass of 1.2 mg was recovered from the test Method D by charging the capacitors to 20.5V. The purity of apparatus and substrate, for a total recovery of 88.9%. 45 the drug-aerosol particles was determined to be 99.4%. 0.44 High speed photographs were taken as the drug-coated mg was recovered from the filter after vaporization, for a substrate was heated to monitor visually formation of a ther percent yield of 58.7%. A total mass of 0.75 mg was recov mal vapor. The photographs showed that a thermal vapor was ered from the test apparatus and Substrate, for a total recovery initially visible 30 milliseconds after heating was initiated, of 100%. with the majority of the thermal vapor formed by 150 milli 50 High speed photographs were taken as the drug-coated seconds. Generation of the thermal vapor was complete by substrate was heated to monitor visually formation of a ther 300 milliseconds. mal vapor. The photographs showed that a thermal vapor was initially visible 25 milliseconds after heating was initiated, Example 96 with the majority of the thermal vapor formed by 75 milli 55 seconds. Generation of the thermal vapor was complete by Methadone (MW 309, melting point 78° C., oral dose 2.5 200 milliseconds. mg), an analgesic, was coated on an aluminum foil substrate (20 cm) according to Method C. 1.80mg of drug was applied Example 100 to the substrate, for a calculated thickness of the drug film of 0.9 m. The substrate was heated as described in Method Cat 90 V for 3.5 seconds. The purity of the drug-aerosol particles 60 Midazolam (MW 326, melting point 160°C., oral dose 2.5 was determined to be 92.3%. 1.53 mg was recovered from the mg), a sedative and hypnotic, was coated onto five stainless glass tube walls after vaporization, for a percent yield of 85%. steel cylindrical substrates according to Method E. The cal culated thickness of the drug film on each Substrate ranged Example 97 from about 1.1 um to about 5.8 um. The substrates were 65 heated as described in Method E and purity of the drug Methoxsalen (MW 216, melting point 148°C., oral dose 35 aerosol particles determined. The results are shown in FIG. mg), a skin and mucous membrane agent, was coated on a 12. US 7,585,493 B2 59 60 Another substrate (stainless steel cylindrical, 6 cm) was aerosol particles was determined to be 92.5%. 3.1 mg was prepared by depositing 5.37 mg drug to obtain a drug film recovered from the glass tube walls after vaporization, for a thickness of 9 um. After volatilization of drug from this sub percent yield of 32.3%. strate according to Method E, 3.11 mg was recovered from the filter, for a percent yield of 57.9%. A total mass of 5.06 mg Example 103 was recovered from the test apparatus and Substrate, for a total Nalbuphine (MW 357, melting point 231° C., oral dose 10 recovery of 94.2%. Purity of the drug aerosol particles was mg), an analgesic, was coated onto four stainless Steel cylin 99.5%. The yield of aerosol particles was 57.9%. der substrates (8 cm) according to Method D. The calculated High speed photographs were taken as the drug-coated 10 thickness of the drug film on each Substrate ranged from about substrate was heated to monitor visually formation of a ther 0.7 um to about 2.5 um. The substrates were heated as mal vapor. The photographs showed that a thermal vapor was described in Method D by charging the capacitors to 20.5 V. initially visible 35 milliseconds after heating was initiated, The purity of the drug-aerosol particles from each substrate with the majority of the thermal vapor formed by 130 milli was determined and the results are shown in FIG. 13. For the 15 substrate having a drug film thickness of 0.7 m, 0.715 mg of seconds. Generation of the thermal vapor was complete by drug was applied to the substrate. After volatilization of this 240 milliseconds. substrate, 0.455 mg was recovered from the filter, for a per Midazolam was also coated on an aluminum foil Substrate cent yield of 63.6%. A total mass of 0.715 mg was recovered (28.8 cm) according to Method C. 5.0 mg of the drug was from the test apparatus and Substrate, for a total recovery of applied to the Substrate, for a calculated thickness of the drug 100%. film of 1.74 um. The substrate was heated substantially as described in Method Cat 60V for 6 seconds. The purity of the Example 104 drug-aerosol particles was determined to be 99.9%. Another aluminum foil substrate (36 cm) was prepared Naloxone (MW 327, melting point 184°C., oral dose 0.4 25 mg), an antidote, was coated on an aluminum foil (20 cm) essentially according to Method G. 16.7 mg of midazolam according to Method C. 2.10 mg of drug was applied to the was applied to the substrate, for a calculated thickness of the Substrate, for a calculated thickness of the drug film of 1.1 um. drug film of 4.64 Lum. The substrate was heated substantially The substrate was heated as described in Method Cat 90 V for as described in Method G at 90 V for 6 seconds, except that 3.5 seconds. The purity of the drug-aerosol particles was one of the openings of the T-shaped tube was sealed with a 30 determined to be 78.4%. 1.02 mg was recovered from the rubber stopper, one was loosely covered with the end of the glass tube walls after vaporization, for a percent yield of halogen tube, and the third connected to the 1 L flask. The 48.6%. purity of the drug-aerosol particles was determined to be Another Substrate containing naloxone coated to a film >99%. All of the drug was found to have aerosolized, for a thickness of 1.0 Lim was prepared by the same method and percent yield of 100%. 35 heated under an argon atmosphere at 90 V for 3.5 seconds. The purity of the drug-aerosol particles was determined to be Example 101 99.2%. 1.07 mg was recovered from the glass tube walls after vaporization, for a percent yield of 53.5%. Mirtazapine (MW 265, melting point 116°C., oral dose 10 mg), a psychotherapeutic agent used as an antidepressant, 40 Example 105 was coated on an aluminum foil substrate (24.5 cm) accord ing to Method G. 20.7 mg of drug was applied to the substrate, Naproxen (MW 230, melting point 154°C., oral dose 200 for a calculated thickness of the drug film of 8.4 um. The mg), an analgesic, was coated on a piece of aluminum foil (20 substrate was heated as described in Method G at 90 V for 6 cm) according to Method C. 8.7 mg were coated on the foil 45 for a calculated thickness of the drug film of 4.4 um. The seconds. The purity of the drug-aerosol particles was deter substrate was heated as described in Method C at 60 V for 7 mined to be 99%. 10.65 mg was recovered from the glass tube seconds. The purity of the drug-aerosol particles was deter walls after vaporization, for a percent yield of 51.4%. mined to be >99.5%. 4.4 mg was recovered from the glass tube walls after vaporization, for a percent yield of 50.5%. Example 102 50 Example 106 Morphine (MW 285, melting point 197°C., oral dose 15 mg), an analgesic, was coated on a stainless steel cylinder (8 Naratriptan (MW 335, melting point 171°C., oral dose 1 cm) according to Method D. 2.33 mg of drug was applied to mg), a migraine preparation, was coated onto seven stainless the Substrate, for a calculated drug film thickness of 2.8 Lum. 55 steel cylinder substrates (8 cm) according to Method D. The The substrate was heated as described in Method D by charg calculated thickness of the drug film on each Substrate ranged ing the capacitors to 20.5 V. The purity of the drug-aerosol from about 0.5 um to about 2.5 lum. The substrates were particles was determined to be 99.1%. 1.44 mg was recovered heated as described in Method D by charging the capacitors to from the filter after vaporization, for a percent yield of 61.8%. 20.5 V. Purity of the drug-aerosol particles from each sub 60 strate was determined and the results are shown in FIG. 14. A total mass of 2.2 mg was recovered from the test apparatus For the substrate having a drug film thickness of 0.6 um, 0.464 and substrate, for a total recovery of 94.2%. mg of drug was applied to the Substrate. After vaporization of Morphine (MW 285, melting point 197°C., oral dose 15 this substrate by charging the capacitors to 20.5 V. 0.268 mg mg), an analgesic, was coated on a piece of aluminum foil (20 was recovered from the filter, for a percent yield of 57.8%. cm) according to Method C. The calculated thickness of the 65 The purity was determined to be 98.7%. A total mass of 0.464 drug film was 4.8 um. The substrate was heated as described mg was recovered from the test apparatus and Substrate, for a in Method C at 90 V for 5 seconds. The purity of the drug total recovery of 100%. US 7,585,493 B2 61 62 High speed photographs were taken as the drug-coated Olanzapine was also coated on an aluminum foil substrate substrate was heated to monitor visually formation of a ther (24.5 cm) according to Method G. 11.3 mg of drug was mal vapor. The photographs showed that a thermal vapor was applied to the Substrate, for a calculated thickness of the drug initially visible 35 milliseconds after heating was initiated, film of 4.61 um. The substrate was heated as described in with the majority of the thermal vapor formed by 100 milli Method G at 90 V for 6 seconds. The purity of the drug seconds. Generation of the thermal vapor was complete by aerosol particles was determined to be >99%. 7.1 mg was 250 milliseconds. collected for a percent yield of 62.8%. Example 107 Example 110 10 Nefazodone (MW 470, melting point 84°C., oral dose 75 Orphenadrine (MW 269, melting point <25°C., oral dose mg), a psychotherapeutic agent, was coated on a piece of 60mg), a muscle relaxant, was coated on a piece of aluminum aluminum foil (20 cm) according to Method C. The calcu foil (20 cm) according to Method C. The calculated thick lated thickness of the drug film was 4.6 um. The substrate was ness of the drug film was 1.0 m. The substrate was heated as heated as described in Method C at 60 V for 15 seconds. The 15 described in Method C at 90 V for 3.5 seconds. The purity of purity of the drug-aerosol particles was determined to be the drug-aerosol particles was determined to be >99.5%. 1.35 91%. 4.4 mg was recovered from the glass tube walls after mg was recovered from the glass tube walls after vaporiza vaporization, for a percent yield of 47.8%. tion, for a percent yield of 71.1%. Another Substrate containing nefazodone coated to a film thickness of 3.2 Lum was prepared by the same method and Example 111 heated under an argon atmosphere at 60V for 15 seconds. The purity of the drug-aerosol particles was determined to be Oxycodone (MW 315, melting point 220°C., oral dose 5 97.5%. 4.3 mg was recovered from the glass tube walls after mg), an analgesic, was coated on an aluminum foil substrate vaporization, for a percent yield of 68.3%. (20 cm) according to Method C. 2.4 mg of drug was applied Example 108 25 to the substrate, for a calculated thickness of the drug film of 1.2 Lum. The substrate was heated as described in Method Cat Nortriptyline (MW 263, oral dose 15 mg), a psychothera 90 V for 3.5 seconds. The purity of the drug-aerosol particles peutic agent, was coated on an aluminum foil Substrate (20 was determined to be 99.9%. 1.27 mg was recovered from the cm) according to Method C. The calculated thickness of the glass tube walls after vaporization, for a percent yield of drug film was 1.0 lum. The substrate was heated as described 30 52.9%. in Method C at 90 V for 3.5 seconds. The purity of the drug-aerosol particles was determined to be 99.1%. 1.4 mg Example 112 was recovered from the glass tube walls after vaporization, for a percent yield of 70.0%. Oxybutynin (MW 358, oral dose 5 mg), a urinary tract Another Substrate containing nortriptyline was prepared 35 agent, was coated on a piece of aluminum foil (20 cm) for testing under an argon atmosphere. 1.90 mg of drug was according to Method C. The calculated thickness of the drug applied to the Substrate, for a calculated thickness of the drug film was 2.8 Lum. The substrate was heated as described in film of 1.0 lum. The substrate was heated as described in Method C at 60 V for 6 seconds. The purity of the drug Method C at 90 V for 3.5 seconds. The purity of the drug aerosol particles was determined to be 90.6%. 3.01 mg was aerosol particles was determined to be 97.8%. 1.6 mg was 40 recovered from the glass tube walls after vaporization, for a recovered from the glass tube walls after vaporization, for a percent yield of 54.7%. percent yield of 84.2%. Example 113 Example 109 45 Parecoxib (MW 370, oral dose 10 mg), a non-steroidal Olanzapine (MW 312, melting point 195°C., oral dose 10 anti-inflammatory analgesic, was coated on a piece of stain mg), a psychotherapeutic agent, was coated onto eight stain less steel foil (5 cm) according to Method B. The calculated less steel cylinder substrates (8-9 cm) according to Method thickness of the drug film was 6.0 m. The substrate was D. The calculated thickness of the drug film on each substrate heated as described in Method B by charging the capacitors to ranged from about 1.2 Lum to about 7.1 um. The Substrates 50 15.5 V. The purity of the drug-aerosol particles was deter were heated as described in Method D by charging the capaci mined to be 80%. 1.264 mg was recovered from the filter after tors to 20.5 V. Purity of the drug-aerosol particles from each vaporization, for a percent yield of 39.5%. substrate was determined and the results are shown in FIG. Another substrate (stainless steel foil, 5 cm) was prepared 15. The substrate having a thickness of 3.4 um was prepared by applying 0.399 mg drug to form a film having a thickness by depositing 2.9 mg of drug. After Volatilization of drug 55 of 0.8 um. The substrate was heated as described in Method B from this substrate by charging the capacitors to 20.5V, 1.633 by charging the capacitors to 15 V. The purity of the drug mg was recovered from the filter, for a percent yield of 54.6%. aerosol particles was determined to be 97.2%. 0.323 mg was The purity of the drug aerosol recovered from the filter was recovered from the filter after vaporization, for a percent yield found to be 99.8%. The total mass was recovered from the test of 81.0%. A total mass of 0.324 mg was recovered from the apparatus and substrate, for a total recovery of ~100%. 60 test apparatus and substrate, for a total recovery of 81.3%. High speed photographs were taken as the drug-coated substrate was heated to monitor visually formation of a ther Example 114 mal vapor. The photographs showed that a thermal vapor was initially visible 30 milliseconds after heating was initiated, Paroxetine (MW 329, oral dose 20 mg), a psychotherapeu with the majority of the thermal vapor formed by 80 milli 65 tic agent, was coated on a stainless steel cylinder (8 cm) seconds. Generation of the thermal vapor was complete by according to Method D. 2.02 mg of drug was applied to the 130 milliseconds. Substrate, for a calculated drug film thickness of 2.4 um. The US 7,585,493 B2 63 64 substrate was heated as described in Method D (with the mal vapor. The photographs, shown in FIGS. 24A-24D, single exception that the circuit capacitance was 1.5 Farad, showed that a thermal vapor was initially visible 25 millisec not 2.0 Farad), and purity of the drug-aerosol particles was onds after heating was initiated, with the majority of the determined to be 99.5%. 1.18 mg was recovered from the thermal vapor formed by 90 milliseconds. Generation of the filter after vaporization, for a percent yield of 58.4%. A total thermal vapor was complete by 225 milliseconds. mass of 1.872 mg was recovered from the test apparatus and substrate, for a total recovery of 92.7%. Example 117 Paroxetine was also coated on an aluminum foil substrate (24.5 cm) as described in Method G. 19.6 mg of drug was Pindolol (MW 248, melting point 173°C., oral dose 5 mg). applied to the substrate, for a calculated drug film thickness of 10 a cardiovascular agent, was coated on an aluminum foil Sub 8 um. The substrate was heated as described in Method Gat strate (20 cm) according to Method C. 4.7 mg of drug was 90 V for 6 seconds purity of the drug-aerosol particles was applied to the substrate, for a calculated thickness of the drug determined to be 88%. 7.4 mg were lost from the substrate film of 2.4 um. The substrate was heated as described in after vaporization, for a percent yield of 37.8%. Method C at 60 V for 7 seconds. The purity of the drug 15 aerosol particles was determined to be >99.5%. 2.77 mg was Example 115 recovered from the glass tube walls after vaporization, for a percent yield of 58.9%. Pergolide (MW 314, melting point 209° C., oral dose 1 Another substrate containing pindolol coated to a film mg), an antiparkinsonian agent, was coated on a stainless thickness of 3.3 um was prepared by the same method and steel cylinder (8 cm) according to Method D. 1.43 mg of heated under an argon atmosphere at 60 V for 7 seconds. The drug was applied to the substrate, for a calculated drug film purity of the drug-aerosol particles was determined to be thickness of 1.9 um. The substrate was heated as described in >99.5%. 3.35 mg was recovered from the glass tube walls Method D by charging the capacitors to 20.5V. The purity of after vaporization, for a percent yield of 50.8%. the drug-aerosol particles was determined to be 99.7%. 1.18 mg was recovered from the filter after vaporization, for a 25 Example 118 percent yield of 82.5%. A total mass of 1.428 mg was recov ered from the test apparatus and substrate, for a total recovery Pioglitazone (MW 356, melting point 184°C., oral dose 15 of 99.9%. mg), an antidiabetic agent, was coated on a stainless steel Pergolide was also coated on a piece of aluminum foil (20 cylinder (8 cm) according to Method D. 0.48 mg of drug was cm) according to Method C. The calculated thickness of the 30 applied to the substrate, for a calculated drug film thickness of drug film was 1.2 m. The substrate was heated as described 0.6 pum. The substrate was heated as described in Method Dby in Method C at 90 V for 3.5 seconds. The purity of the charging the capacitors to 20.5 V. The purity of the drug drug-aerosol particles was determined to be 98%. 0.52 mg aerosol particles was determined to be 95.6%. 0.30 mg was was recovered from the glass tube walls after vaporization, recovered from the filter after vaporization, for a percent yield for a percent yield of 22.6%. 35 of 62.5%. A total mass of 0.37 mg was recovered from the test High speed photographs were taken as the drug-coated apparatus and substrate, for a total recovery of 77.1%. substrate according to Method D was heated to monitor visu High speed photographs were taken as the drug-coated ally formation of a thermal vapor. The photographs showed substrate was heated to monitor visually formation of a ther that athermal vapor was initially visible 30 milliseconds after mal vapor. The photographs showed that a thermal vapor was heating was initiated, with the majority of the thermal vapor 40 initially visible 35 milliseconds after heating was initiated, formed by 225 milliseconds. Generation of the thermal vapor with the majority of the thermal vapor formed by 100 milli was complete by 800 milliseconds. seconds. Generation of the thermal vapor was complete by Pergolide was further coated on an aluminum foil substrate 125 milliseconds. (24.5 cm) according to Method G. 1.0 mg of the drug was applied to the substrate, for a calculated thickness of the drug 45 Example 119 film of 0.4 um. The substrate was heated substantially as described in Method G at 90 V for 6 seconds, except that two Piribedil (MW 298, melting point 98°C., IV dose 3 mg), an of the openings of the T-shaped tube were left open and the antiparkinsonian agent, was coated on a stainless steel cylin third connected to the 1 L flask. The purity of the drug-aerosol der (8 cm) according to Method D. 1.1 mg of drug was particles was determined to be >99%. All of the drug was 50 applied to the substrate, for a calculated drug film thickness of found to have aerosolized via weight loss from the substrate, 1.5um. The substrate was heated as described in Method D by for a percent yield of 100%. charging the capacitors to 20.5 V. The purity of the drug aerosol particles was determined to be 99.7%. 1.01 mg was Example 116 recovered from the filter after vaporization, for a percent yield 55 of 91.8%. A total mass of 1.1 mg was recovered from the test Phenytoin (MW 252, melting point 298°C., oral dose 300 apparatus and substrate, for a total recovery of 100%. mg), an anti-convulsant, was coated on a stainless steel cyl inder (8 cm) according to Method D. 0.9 mg of drug was Example 120 applied to the substrate, for a calculated drug film thickness of 1.1 um. The substrate was heated as described in Method D by 60 Pramipexole (MW 211, oral dose 0.5 mg), an antiparkin charging the capacitors to 20.5 V. The purity of the drug sonian agent, was coated on a stainless steel cylinder (8 cm) aerosol particles was determined to be >99.5%. 0.6 mg was according to Method D. 1.05 mg of drug was applied to the recovered from the filter after vaporization, for a percent yield substrate, for a calculated drug film thickness of 1.4 Lum. The of 66.7%. A total mass of 0.84 mg was recovered from the test substrate was heated as described in Method D by charging apparatus and substrate, for a total recovery of 93.3%. 65 the capacitors to 20.5 V. The purity of the drug-aerosol par High speed photographs were taken as the drug-coated ticles was determined to be 99.3%. 0.949 mg was recovered substrate was heated to monitor visually formation of a ther from the filter after vaporization, for a percent yield of 90.4%. US 7,585,493 B2 65 66 A total mass of 1.05 mg was recovered from the test apparatus heated as described in Method C at 90 V for 5 seconds. The and substrate, for a total recovery of 100%. purity of the drug-aerosol particles was determined to be Pramipexole was also coated on a piece of stainless steel 94%. 10.45 mg was recovered from the glass tube walls after foil (5 cm) according to Method B. 0.42 mg of drug was vaporization, for a percent yield of 99.5%. applied to the Substrate, for a calculated drug film thickness of 5 0.9 um. The substrate was heated as described in Method B by Example 124 charging the capacitors to 14V. The purity of the drug-aerosol particles was determined to be 98.9%. 0.419 mg was recov Promethazine (MW 284, melting point 60° C., oral dose ered from the filter after vaporization, for a percent yield of 12.5 mg), a gastrointestinal agent, was coated on an alumi 99.8%. A total mass of 0.42 mg was recovered from the test 10 num foil substrate (20 cm) according to Method C. 5.10 mg apparatus and substrate, for a total recovery of 100%. of drug was applied to the Substrate, for a calculated thickness High speed photographs were taken as the drug-coated of the drug film of 2.6 um. The substrate was heated as substrate was heated to monitor visually formation of a ther described in Method C at 60 V for 10 seconds. The purity of mal vapor. The photographs showed that a thermal vapor was the drug-aerosol particles was determined to be 94.5%. 4.7 initially visible 25 milliseconds after heating was initiated, 15 mg was recovered from the glass tube walls after vaporiza with the majority of the thermal vapor formed by 80 milli tion, for a percent yield of 92.2%. seconds. Generation of the thermal vapor was complete by 140 milliseconds. Example 125 Example 121 Propafenone (MW 341, oral dose 150 mg), a cardiovascu lar agent, was coated on a stainless steel cylinder (8 cm) Procainamide (MW 236, oral dose 125 mg), a cardiovas according to Method D. 0.77 mg of drug was applied to the cular agent, was coated on a stainless steel cylinder (8 cm) substrate, for a calculated drug film thickness of 0.9 um. The according to Method D. 0.95 mg of drug was applied to the substrate was heated as described in Method D by charging substrate, for a calculated drug film thickness of 1.1 um. The 25 the capacitors to 20.5 V. The purity of the drug-aerosol par substrate was heated as described in Method D by charging ticles was determined to be >99.5%. 0.51 mg was recovered the capacitors to 20.5 V. The purity of the drug-aerosol par from the filter after vaporization, for a percent yield of 66.2%. ticles was determined to be >99.5%. 0.56 mg was recovered A total mass of 0.77 mg was recovered from the test apparatus from the filter after vaporization, for a percent yield of 58.9%. and substrate, for a total recovery of 100%. A total mass of 0.77 mg was recovered from the test apparatus 30 and substrate, for a total recovery of 81.1%. High speed photographs were taken as the drug-coated High speed photographs were taken as the drug-coated substrate was heated to monitor visually formation of a ther substrate was heated to monitor visually formation of a ther mal vapor. The photographs showed that a thermal vapor was mal vapor. The photographs showed that a thermal vapor was initially visible 20 milliseconds after heating was initiated, initially visible 25 milliseconds after heating was initiated, 35 with the majority of the thermal vapor formed by 60 milli with the majority of the thermal vapor formed by 90 milli seconds. Generation of the thermal vapor was complete by seconds. Generation of the thermal vapor was complete by 110 milliseconds. 250 milliseconds. Example 126 Example 122 40 Propranolol (MW 259, melting point 96° C., oral dose 40 Prochlorperazine free base (MW 374, melting point 60°C., mg), a cardiovascular agent, was coated on an aluminum foil oral dose 5 mg), a psychotherapeutic agent, was coated onto substrate (20 cm) according to Method C. 10.30 mg of drug four stainless steel foil substrates (5 cm) according to was applied to the substrate, for a calculated thickness of the Method B. The calculated thickness of the drug film on each 45 drug film of 5.2 Lum. The substrate was heated as described in substrate ranged from about 2.3 um to about 10.1 um The Method C at 90 V for 5 seconds. The purity of the drug substrates were heated as described in Method B by charging aerosol particles was determined to be 99.6%. 8.93 mg was the capacitors to 15 V. Purity of the drug-aerosol particles recovered from the glass tube walls after vaporization, for a from each substrate was determined and the results are shown percent yield of 86.7%. in FIG. 18. 50 Prochlorperazine, a psychotherapeutic agent, was also Example 127 coated on a stainless steel cylinder (8 cm) according to Method D. 1.031 mg of drug was applied to the substrate, for Quetiapine (MW 384, oral dose 75 mg), a psychotherapeu a calculated drug film thickness of 1.0 Lum. The substrate was tic agent, was coated onto eight stainless steel cylinder Sub heated as described in Method D by charging the capacitors to 55 strates (8 cm) according to Method D. The calculated thick 19 V. The purity of the drug-aerosol particles was determined ness of the drug film on each substrate ranged from about 0.1 to be 98.7%. 0.592 mg was recovered from the filter after um to about 7.1 um. The substrates were heated as described vaporization, for a percent yield of 57.4%. A total mass of in Method D by charging the capacitors to 20.5V. Purity of the 1.031 mg was recovered from the test apparatus and Substrate, drug-aerosol particles from each Substrate was determined for a total recovery of 100%. 60 and the results are shown in FIG. 16. The substrate having a drug film thickness of 1.8Lum was prepared by depositing 1.46 Example 123 mg drug. After Volatilization of drug this substrate by charg ing the capacitors to 20.5V. 0.81 mg was recovered from the Promazine (MW 284, melting point <25°C., oral dose 25 filter, for a percent yield of 55.5%. The purity of the drug mg), a psychotherapeutic agent, was coated on a piece of 65 aerosol recovered from the filter was found to be 99.1%. A aluminum foil (20 cm) according to Method C. The calcu total mass of 1.24 mg was recovered from the test apparatus lated thickness of the drug film was 5.3 um. The substrate was and substrate, for a total recovery of 84.9%. US 7,585,493 B2 67 68 Example 128 Example 132 Quinidine (MW 324, melting point 175°C., oral dose 100 Sertraline (MW 306, oral dose 25 mg), a psychotherapeutic mg), a cardiovascular agent, was coated on a stainless Steel agent used as an antidepressant (Zoloft(R), was coated on a cylinder (8 cm) according to Method D. 1.51 mg of drug was 5 stainless steel cylinder (6 cm) according to Method E. 3.85 applied to the Substrate, for a calculated drug film thickness of mg of drug was applied to the Substrate, for a calculated drug 1.8Lum. The substrate was heated as described in Method D by film thickness of 6.4 um. The substrate was heated as charging the capacitors to 20.5 V. The purity of the drug described in Method E and purity of the drug-aerosol par aerosol particles was determined to be >99.5%. 0.88 mg was ticles was determined to be 99.5%. 2.74 mg was recovered recovered from the filter after vaporization, for a percent yield 10 from the filter after vaporization, for a percent yield of 71.2%. of 58.3%. A total mass of 1.24 mg was recovered from the test Sertraline was also coated on a piece of aluminum foil (20 apparatus and substrate, for a total recovery of 82.1%. cm) according to Method C. The calculated thickness of the drug film was 3.3 lum. The substrate was heated as described Example 129 in Method C at 60 V for 10 seconds. The purity of the drug 15 aerosol particles was determined to be 98.0%. 5.35 mg was Rizatriptan (MW 269, melting point 121°C., oral dose 5 recovered from the glass tube walls after vaporization, for a mg), a migraine preparation, was coated on a stainless Steel percent yield of 81.1%. cylinder (6 cm) according to Method E. 2.1 mg of drug was Another sertraline coated substrate (aluminum foil, 20 applied to the Substrate, for a calculated drug film thickness of cm) having a drug film thickness of 0.9 um was heated as 3.5um. The substrate was heated as described in Method E described in Method C under a pure argon atmosphere at 90 V and purity of the drug-aerosol particles was determined to be for 3.5 seconds. The purity of the drug-aerosol particles was 99.2%. 1.66 mg was recovered from the filter after vaporiza determined to be 98.7%. 1.29 mg was recovered from the tion, for a percent yield of 79%. A total mass of 2.1 mg was glass tube walls after vaporization, for a percent yield of recovered from the test apparatus and Substrate, for a total 75.9%. recovery of 100%. 25 High speed photographs were taken as the drug-coated Rizatriptan was further coated on an aluminum foil sub substrate from Method D was heated to monitor visually strate (150 cm) according to Method F. 10.4 mg of the drug formation of a thermal vapor. The photographs showed that a was applied to the substrate, for a calculated thickness of the thermal vapor was initially visible 30 milliseconds after heat drug film of 0.7 Lum. The substrate was heated as described in ing was initiated, with the majority of the thermal vapor Method F at 250° C. and the purity of the drug-aerosol par 30 formed by 135 milliseconds. Generation of the thermal vapor ticles was determined to be 99%. 1.9 mg was collected in was complete by 250 milliseconds. glass wool for a percent yield of 18.3%. Another aluminum foil substrate (36 cm) was prepared Example 133 according to Method G. 11.6 mg of rizatriptan was applied to the substrate, for a calculated thickness of the drug film of 3.2 35 Selegiline (MW 187, melting point <25° C., oral dose 5 um. The substrate was heated substantially as described in mg), an antiparkinsonian agent, was coated on an aluminum Method G at 90 V for 7 seconds, except that one of the foil substrate (20 cm) according to Method C. 3.7 mg of drug openings of the T-shaped tube was sealed with a rubber stop was applied to the substrate, for a calculated thickness of the per, one was loosely covered with the end of the halogen tube, drug film of 1.9 um. The substrate was heated as described in and the third connected to the 1 L flask. The purity of the 40 Method C at 60 V for 8 seconds. The purity of the drug drug-aerosol particles was determined to be >99%. All of the aerosol particles was determined to be 99.2%. 2.41 mg was drug was found to have aerosolized, for a percent yield of recovered from the glass tube walls after vaporization, for a 100%. percent yield of 65.1%.
Example 130 45 Example 134 Rofecoxib (MW 314, oral dose 50 mg), an analgesic, was Sildenafil (MW 475, melting point 189° C., oral dose 25 coated on an aluminum foil substrate (20 cm) according to mg), an agent used for erectile dysfunction (ViagraR), was Method C. 6.5 mg of drug was applied to the substrate, for a coated onto six stainless steel foil substrates (5 cm) accord calculated thickness of the drug film of 3.3 um. The substrate 50 ing to Method B. The calculated thickness of the drug film on was heated as described in Method C at 60 V for 17 seconds. each substrate ranged from about 0.5um to about 1.6 um. The The purity of the drug-aerosol particles was determined to be substrates were heated as described in Method B by charging 97.5%. 4.1 mg was recovered from the glass tube walls after the capacitors to 16 V. Purity of the drug-aerosol particles vaporization, for a percent yield of 63.1%. from each substrate was determined and the results are shown 55 in FIG. 22. Example 131 Sildenafil was also coated on a stainless steel cylinder (6 cm) according to Method E. 1.9 mg of drug was applied to Ropinirole (MW 260, oral dose 0.25 mg), an antiparkinso the Substrate, for a calculated drug film thickness of 3.2 Lum. nian agent, was coated on a stainless steel cylinder (8 cm) The substrate was heated as described in Method E and purity according to Method D. 0.754 mg of drug was applied to the 60 of the drug-aerosol particles was determined to be 81%. 1.22 substrate, for a calculated drug film thickness of 1.0 Lum. The mg was recovered from the filter after vaporization, for a substrate was heated as described in Method D by charging percent yield of 64.2%. A total mass of 1.5 mg was recovered the capacitors to 20.5 V. The purity of the drug-aerosol par from the test apparatus and Substrate, for a total recovery of ticles was determined to be 99%. 0.654 mg was recovered 78.6%. from the filter after vaporization, for a percent yield of 86.7%. 65 Sildenafil was also coated on a piece of aluminum foil (20 A total mass of 0.728 mg was recovered from the test appa cm) according to Method C. The calculated thickness of the ratus and substrate, for a total recovery of 96.6%. drug film was 2.5um. The substrate was heated as described US 7,585,493 B2 69 70 in Method C at 90 V for 4 seconds. The purity of the drug with the majority of the thermal vapor formed by 175 milli aerosol particles was determined to be 66.3%. 1.05 mg was seconds. Generation of the thermal vapor was complete by recovered from the glass tube walls after vaporization, for a 600 milliseconds. percent yield of 21%. Sildenafil was also coated on a piece of stainless steel foil Example 137 (6 cm) according to MethodB.0.227 mg of drug was applied to the Substrate, for a calculated drug film thickness of 0.4 um. Sibutramine (MW 280, oral dose 10 mg), an obesity man The substrate was heated as described in Method B by charg agement appetite Suppressant, was coated on a stainless steel ing the capacitors to 16 V. The purity of the drug-aerosol cylinder (8 cm) according to Method D. 1.667 mg of drug particles was determined to be 99.3%. 0.224 mg was recov 10 was applied to the Substrate, for a calculated drug film thick ered from the filter after vaporization, for a percent yield of ness of 2 um. The substrate was heated as described in 98.7%. A total mass of 0.227 mg was recovered from the test Method D (with the single exception that the circuit capaci apparatus and substrate, for a total recovery of 100%. tance was 1.5 Farad, not 2.0 Farad), and purity of the drug High speed photographs were taken as the drug-coated aerosol particles was determined to be 94%. 0.861 mg was substrate was heated to monitor visually formation of a ther 15 recovered from the filter after vaporization, for a percent yield mal vapor. The photographs showed that a thermal vapor was of 51.6%. A total mass of 1.35 mg was recovered from the test initially visible 45 milliseconds after heating was initiated, apparatus and substrate, for a total recovery of 81%. with the majority of the thermal vapor formed by 250 milli High speed photographs were taken as the drug-coated seconds. Generation of the thermal vapor was complete by substrate was heated to monitor visually formation of a ther 400 milliseconds. mal vapor. The photographs showed that a thermal vapor was Sildenafil was also coated on a piece of aluminum foil at a initially visible 25 milliseconds after heating was initiated, calculated film thickness of 3.4 um, 3.3 um, 1.6 um, 0.8 um, with the majority of the thermal vapor formed by 55 milli 0.78 um, 0.36 um, 0.34um, 0.29 um, and 0.1 um. The coated seconds. Generation of the thermal vapor was complete by Substrate was placed on an aluminum block that was pre 150 milliseconds. heated to 275° C. using a hot plate. A PyrexC) beaker was 25 synchronously placed over the foil and the substrate was Example 138 heated for 1 minute. The material collected on the beaker walls was recovered and analyzed by reverse-phase HPLC Tamoxifen (MW 372, melting point 98°C., oral dose 10 analysis with detection by absorption of 250 nm light to mg), an antineoplastic, was coated on a stainless steel cylin determine the purity of the aerosol. The purity of the drug 30 der (8 cm) according to Method D. 0.46 mg of drug was aerosol particles was determined to be 84.8% purity at 3.4 um applied to the Substrate, for a calculated drug film thickness of thickness; 80.1% purity at 3.3 um thickness: 89.8% purity at 0.6 um. The substrate was heated as described in Method D by 1.6 um thickness; 93.8% purity at 0.8 um thickness; 91.6% charging the capacitors to 20.5 V. The purity of the drug purity at 0.78 um thickness: 98.0% purity at 0.36 um thick aerosol particles was determined to be 91.4%. 0.27 mg was ness: 98.6% purity at 0.34 um thickness: 97.6% purity at 0.29 35 recovered from the filter after vaporization, for a percent yield um thickness; and 100% purity at 0.1 um thickness. of 58.7%. A total mass of 0.39 mg was recovered from the test apparatus and substrate, for a total recovery of 84.8%. Example 135 High speed photographs were taken as the drug-coated substrate was heated to monitor visually formation of a ther Spironolactone (MW 417, melting point 135°C., oral dose 40 mal vapor. The photographs showed that a thermal vapor was 25 mg), a cardiovascular agent, was coated on a stainless steel initially visible 30 milliseconds after heating was initiated, cylinder (8 cm) according to Method D. 0.71 mg of drug was with the majority of the thermal vapor formed by 70 milli applied to the Substrate, for a calculated drug film thickness of seconds. Generation of the thermal vapor was complete by 0.9 um. The substrate was heated as described in Method D by 250 milliseconds. charging the capacitors to 20.5 V. The purity of the drug 45 aerosol particles was determined to be >99.5%. 0.41 mg was Example 139 recovered from the filter after vaporization, for a percent yield of 57.7%. A total mass of 0.7 mg was recovered from the test Tacrine (MW 198, melting point 184°C.), an Alzheimer's apparatus and substrate, for a total recovery of 98.6%. 50 disease manager, was coated on a stainless Steel cylinder (8 cm) according to Method D. 0.978 mg of drug was applied to Example 136 the Substrate, for a calculated drug film thickness of 1.2 Lum. The substrate was heated as described in Method D by charg Sumatriptan (MW 295, melting point 171°C., oral dose 6 ing the capacitors to 20.5 V. The purity of the drug-aerosol mg), a migraine preparation, was coated on a stainless Steel 55 particles was determined to be 99.8%. 0.502 mg was recov cylinder (8 cm) according to Method E. 1.22 mg of drug was ered from the filter after vaporization, for a percent yield of applied to the Substrate, for a calculated drug film thickness of 51.3%. A total mass of 0.841 mg was recovered from the test 1.5 lum. The substrate was heated as described in Method E apparatus and substrate, for a total recovery of 86%. and purity of the drug-aerosol particles was determined to be 97.9%. 0.613 mg was recovered from the filter after vapor 60 Example 140 ization, for a percent yield of 50.2%. A total mass of 1.03 mg was recovered from the test apparatus and Substrate, for a total Tadalafil (MW 389, oral dose 5 mg), an erectile dysfunc recovery of 84.4%. tion therapeutic agent, was coated onto eight stainless Steel High speed photographs were taken as the drug-coated foil substrates (5 cm) according to MethodB. The calculated substrate was heated to monitor visually formation of a ther 65 thickness of the drug film on each Substrate ranged from about mal vapor. The photographs showed that a thermal vapor was 0.5 um to about 2.9 um. The substrates were heated as initially visible 35 milliseconds after heating was initiated, described in Method B by charging the capacitors to 16 V. US 7,585,493 B2 71 72 Purity of the drug-aerosol particles from each substrate was thickness of 0.7 um. The substrate was heated as described in determined and the results are shown in FIG. 17. Method D by charging the capacitors to 20.5V. The purity of Tadalafil was also coated on a stainless steel cylinder (8 the drug-aerosol particles was determined to be >99.5%. 0.43 cm). The calculated thickness of the drug film was 4.5um. mg was recovered from the filter after vaporization, for a The substrate was heated as described by the flashbulb and the percent yield of 75.4%. A total mass of 0.54 mg was recov purity of the drug-aerosol particles was determined to be ered from the test apparatus and Substrate, for a total recovery 94.9%. 0.67 mg was recovered from the filter after vaporiza of 94.7%. tion, for a percent yield of 18.1%. A total mass of 1.38 mg was recovered from the test apparatus and Substrate, for a total Example 144 recovery of 37.3%. 10 Tadalafil was also coated on a piece of aluminum foil (20 Theophylline (MW 180, melting point 274°C., oral dose cm) according to Method C. The calculated thickness of the 200 mg), a respiratory agent, was coated on a stainless steel drug film was 0.5um. The substrate was heated as described cylinder (8 cm) according to Method D. 0.859 mg of drug in Method C at 60 V for 13 seconds. The purity of the drug was applied to the Substrate, for a calculated drug film thick aerosol particles was determined to be 91.2%. 0.45 mg was 15 ness of 1.0 Lum. The substrate was heated as described in recovered from the glass tube walls after vaporization, for a Method D by charging the capacitors to 20.5V. The purity of percent yield of 45%. the drug-aerosol particles was determined to be 100.0%. Tadalafil was also coated on a piece of stainless steel foil (5 0.528 mg was recovered from the filter after vaporization, for cm) according to Method B. 1.559 mg of drug was applied to a percent yield of 61.5%. A total mass of 0.859 mg was the substrate, for a calculated drug film thickness of 2.9 um. recovered from the test apparatus and Substrate, for a total The substrate was heated as described in Method B by charg recovery of 100%. ing the capacitors to 16 V. The purity of the drug-aerosol High speed photographs were taken as the drug-coated particles was determined to be 95.8%. 1.42 mg, was recov substrate was heated to monitor visually formation of a ther ered from the filter after vaporization, for a percent yield of mal vapor. The photographs showed that a thermal vapor was 91.1%. A total mass of 1.559 mg was recovered from the test 25 initially visible 40 milliseconds after heating was initiated, apparatus and substrate, for a total recovery of 100%. with the majority of the thermal vapor formed by 160 milli The drug was also coated (1.653 mg) to a thickness of 3.1 seconds. Generation of the thermal vapor was complete by um on a piece of stainless steel foil (5 cm) according to 350 milliseconds. Method B. The substrate was heated under an N atmosphere by charging the capacitors to 16 V. The purity of the drug 30 Example 145 aerosol particles was determined to be 99.2%. 1.473 mg was recovered from the filter after vaporization, for a percent yield Tocainide (MW 192, melting point 247°C., oral dose 400 of 89.1%. A total mass of 1.653 mg was recovered from the mg), a cardiovascular agent, was coated on a stainless Steel test apparatus and substrate, for a total recovery of 100%. cylinder (8 cm) according to Method D. 0.86 mg of drug was 35 applied to the Substrate, for a calculated drug film thickness of Example 141 1 um. The substrate was heated as described in Method D by charging the capacitors to 20.5 V. The purity of the drug Terbutaline (MW 225, melting point 122°C., oral dose 0.2 aerosol particles was determined to be 99.7%. 0.65 mg was mg), a respiratory agent, was coated on a stainless Steel cyl recovered from the filter after vaporization, for a percent yield inder (9 cm) according to Method D. 2.32 mg of drug was 40 of 75.6%. A total mass of 0.86 mg was recovered from the test applied to the Substrate, for a calculated drug film thickness of apparatus and substrate, for a total recovery of 100%. 2.7m. The substrate was heated as described in Method D by High speed photographs were taken as the drug-coated charging the capacitors to 20.5 V. The purity of the drug substrate was heated to monitor visually formation of a ther aerosol particles was determined to be 99.3%. 1.54 mg was mal vapor. The photographs showed that a thermal vapor was recovered from the filter after vaporization, for a percent yield 45 initially visible. 25 milliseconds after heating was initiated, of 66.4%. A total mass of 1.938 mg was recovered from the with the majority of the thermal vapor formed by 75 milli test apparatus and substrate, for a total recovery of 83.5%. seconds. Generation of the thermal vapor was complete by 130 milliseconds. Example 142 50 Example 146 Testosterone (MW 288, melting point 155° C., oral dose 3 mg), a hormone, was coated on a stainless Steel cylinder (8 Tolfenamic Acid (MW 262, melting point 208 C., oral cm) according to Method D. 0.96 mg of drug was applied to dose 200 mg), an analgesic, was coated on a piece of alumi the Substrate, for a calculated drug film thickness of 1.2 Lum. num foil (20 cm) according to Method C. The calculated The substrate was heated as described in Method D by charg 55 thickness of the drug film was 5.0 m. The substrate was ing the capacitors to 20.5 V. The purity of the drug-aerosol heated as described in Method C at 60 V for 6 seconds. The particles was determined to be 99.6%. 0.62 mg was recovered purity of the drug-aerosol particles was determined to be from the filter after vaporization, for a percent yield of 64.6%. 94.2%. 6.49 mg was recovered from the glass tube walls after A total mass of 0.96 mg was recovered from the test apparatus vaporization, for a percent yield of 65.6%. and substrate, for a total recovery of 100%. 60 Example 147 Example 143 Tolterodine (MW 325, oral dose 2 mg), an urinary tract Thalidomide (MW 258, melting point 271°C., oral dose agent, was coated on a stainless steel cylinder (8 cm) accord 100 mg), an immunomodulator, was coated on a stainless 65 ing to Method D. 1.39 mg of drug was applied to the substrate, steel cylinder (8 cm) according to Method D. 0.57 mg of for a calculated drug film thickness of 1.7 um. The substrate drug was applied to the Substrate, for a calculated drug film was heated as described in Method D by charging the capaci US 7,585,493 B2 73 74 tors to 20.5 V. The purity of the drug-aerosol particles was Example 150 determined to be 96.9%. 1.03 mg was recovered from the filter after vaporization, for a percent yield of 74.1%. A total Tranylcypromine (MW 133, melting point <25°C., oral mass of 1.39 mg was recovered from the test apparatus and dose 30 mg), a psychotherapeutic agent, was coated on a substrate, for a total recovery of 100%. piece of aluminum foil (20 cm) according to Method C. The High speed photographs were taken as the drug-coated calculated thickness of the drug film was 5.4 um. The sub substrate was heated to monitor visually formation of a ther strate was heated as described in Method C at 90 V for 5 mal vapor. The photographs showed that a thermal vapor was seconds. The purity of the drug-aerosol particles was deter initially visible 30 milliseconds after heating was initiated, mined to be 93.7%. 7.4 mg was recovered from the glass tube with the majority of the thermal vapor formed by 80 milli 10 walls after vaporization, for a percent yield of 68.5%. seconds. Generation of the thermal vapor was complete by Another Substrate containing tranylcypromine coated to a 100 milliseconds. film thickness of 2.7 um was prepared by the same method and heated under an argon atmosphere at 90 V for 3.5 sec Example 148 onds. The purity of the drug-aerosol particles was determined 15 to be 95.9%. 3 mg was recovered from the glass tube walls Toremifene (MW406, melting point 110° C., oral dose 60 after vaporization, for a percent yield of 56.6%. mg), an antineoplastic, was coated on a stainless steel cylin Tranylcypromine HCl (MW 169, melting point 166° C., der (8 cm). 1.20 mg of drug was applied to the substrate, for oral dose 30 mg), a psychotherapeutic agent, was coated on a a calculated thickness of the drug film of 1.4 um, and heated piece of aluminum foil (20 cm) according to Method C. The to form drug-aerosol particles according to Method D by calculated thickness of the drug film was 1.2 Lum. The sub charging the capacitors to 20.5 V. The purity of the drug strate was heated as described in Method C at 90 V for 3.5 aerosol particles was determined to be 98.7%. The yield of seconds. The purity of the drug-aerosol particles was deter aerosol particles was 50%. 1.09 mg of total mass was recov mined to be 97.5%. 1.3 mg was recovered from the glass tube ered for a total recovery yield of 90.8%. walls after vaporization, for a percent yield of 56.5%. 25 Example 149 Example 151 Tramadol (MW 263, oral dose 50 mg), an analgesic, was Trazodone (MW 372, melting point 87°C., oral dose 400 coated on an aluminum foil substrate (20 cm) according to mg), a psychotherapeutic agent, was coated on an aluminum Method C. 4.90 mg of drug was applied to the substrate, for a 30 foil substrate (20 cm) according to Method C. 10.0 mg of calculated thickness of the drug film of 2.5um. The substrate drug was applied to the Substrate, for a calculated thickness of was heated as described in Method C at 108 V for 2.25 the drug film of 5.0Lum. The substrate was heated as described seconds. The purity of the drug-aerosol particles was deter in Method C at 60 V for 15 seconds. The purity of the drug mined to be 96.9%. 3.39 mg was recovered from the glass aerosol particles was determined to be 98.9%. 8.5 mg was 35 recovered from the glass tube walls after vaporization, for a tube walls after vaporization, for a percent yield of 69.2%. percent yield of 85%. Tramadol (2.6 mg) was also coated on a piece of aluminum Trazodone was further coated on an aluminum foil sub foil (20 cm) according to Method C to a film thickness strate according to Method G. The substrate was heated as (calculated) of 1.3 lum. The substrate was heated as described described in Method Gat 90 V for 3.5 seconds. The purity of in Method C under an argon atmosphere at 90 V for 3.5 40 the drug-aerosol particles was determined to be 97.9%. The seconds. The purity of the drug-aerosol particles was deter percent yield of the aerosol was 29.1%. The purity of the mined to be 96.1%. 1.79 mg was recovered from the glass drug-aerosol particles was determined to be 98.5% when the tube walls after vaporization, for a percent yield of 68.8%. system was flushed through with argon prior to volatilization. Tramadol (2.1 mg) was also coated on a piece of aluminum The percent yield of the aerosol was 25.5%. foil (20 cm) according to Method C to a film thickness 45 (calculated) of 1.1 Lum. The substrate was heated as described Example 152 in Method C under air at 90 V for 3.5 seconds. The purity of the drug-aerosol particles was determined to be 96.6%. 1.33 Triazolam (MW 343, melting point 235°C., oral dose 0.13 mg was recovered from the glass tube walls after vaporiza mg), a sedative and hypnotic, was coated on an aluminum foil tion, for a percent yield of 63.8%. 50 substrate (20cm) according to Method C. 1.7 mg of drug was The hydrochloride salt form was also tested. 2.6 mg of drug applied to the Substrate, for a calculated thickness of the drug was coated onto an aluminum foil substrate (20 cm) accord film of 0.9 um. The substrate was heated as described in ing to Method C to a film thickness (calculated) of 1.3 um. Method C at 45 V for 18 seconds. The purity of the drug The substrate was heated as described in Method C and purity aerosol particles was determined to be 99.2%. 1.6 mg was of the drug-aerosol particles was determined to be 97.6%. 55 recovered from the glass tube walls after vaporization, for a 1.67 mg was recovered from the glass tube walls after vapor percent yield of 94.1%. ization, for a percent yield of 64.2%. An identical substrate Another aluminum foil substrate (28.8 Cm) was prepared having an identical drug film thickness was tested under an according to Method C. 1.7 mg of triazolam was applied to argon atmosphere at 90 V for 3.5 seconds. The purity of the the substrate, for a calculated thickness of the drug film of drug-aerosol particles was determined to be 89%. 1.58 mg 60 0.69 Lum. The substrate was heated substantially as described was recovered from the glass tube walls after vaporization, in Method C at 75 V for 2 seconds and then at 45 V for 8 for a percent yield of 60.8% seconds. The purity of the drug-aerosol particles was deter Tramadol (17.5 mg) was also coated on a piece of alumi mined to be 99.3%. 1.7 mg of aerosol particles were collected num foil (40 cm) according to Method F to a film thickness for a percent yield of 100% (calculated) of 4.38 um. The substrate was heated as 65 Triazolam was also applied to an aluminum foil substrate described in Method F and purity of the drug-aerosol particles (36 cm) according to Method G. 0.6 mg of the drug was was determined to be 97.3%. applied to the Substrate, for a calculated thickness of the drug US 7,585,493 B2 75 76 film of 0.17 lum. The substrate was heated substantially as of 3.758 mg was recovered from the test apparatus and sub described in Method G at 90 V for 6 seconds, except that one strate, for a total recovery of 87.9%. of the openings of the T-shaped tube was sealed with a rubber Valdecoxib was also coated on a piece of stainless steel foil stopper, one was loosely covered with the end of the halogen (6 cm) according to MethodB. 0.716 mg of drug was applied tube, and the third connected to the 1 L flask. The purity of the 5 to the Substrate, for a calculated drug film thickness of 1.3 um. drug-aerosol particles was determined to be >99%. All of the The substrate was heated as described in Method B by charg drug was found to have aerosolized, for a percent yield of ing the capacitors to 15 V. The purity of the drug-aerosol 100%. particles was determined to be 98.6%. 0.466 mg was recov ered from the filter after vaporization, for a percent yield of Example 153 10 65.1%. A total mass of 0.49 mg was recovered from the test apparatus and substrate, for a total recovery of 68.4%. Trifluoperazine (MW407, melting point <25°C., oral dose 7.5 mg), a psychotherapeutic agent, was coated on a stainless Example 156 steel cylinder (9 cm) according to Method D. 1.034 mg of drug was applied to the Substrate, for a calculated drug film 15 Valproic Acid (MW 144, melting point <25°C., oral dose thickness of 1.1 um. The substrate was heated as described in 60 mg), an anticonvulsant, was coated on a metal Substrate Method D by charging the capacitors to 19 V. The purity of the (50 cm) according to Method F. 82.4 mg of drug was applied drug-aerosol particles was determined to be 99.8%. 0.669 mg to the substrate, for a calculated drug film thickness of 16.5 was recovered from the filter after vaporization, for a percent um. The substrate was heated according to Method F at 300° yield of 64.7%. A total mass of 1.034 mg was recovered from C. to form drug-aerosol particles. Purity of the drug-aerosol the test apparatus and substrate, for a total recovery of 100%. particles was determined to be 99.7% by GC analysis. 60 mg Trifluoperazine2HCl salt (MW480, melting point 243°C., of the drug were collected for a percent yield of 72.8%. oral dose 7.5 mg) was coated on an identical Substrate. Spe cifically, 0.967 mg of drug was applied to the substrate, for a Example 157 calculated drug film thickness of 1.1 um. The Substrate was 25 heated as described in Method D by charging the capacitors to Vardenafil (MW 489, oral dose 5 mg), an erectile dysfunc 20.5 V. The purity of the drug-aerosol particles was deter tion therapy agent, was coated on a stainless steel cylinder (6 mined to be 87.5%. 0.519 mg was recovered from the filter cm) according to Method E. The calculated thickness of the after vaporization, for a percent yield of 53.7%. A total mass drug film was 2.7 um. The substrate was heated as described of 0.935 mg was recovered from the test apparatus and sub 30 in Method E and purity of the drug-aerosol particles was strate, for a total recovery of 96.7%. determined to be 79%. 0.723 mg was recovered from the filter High speed photographs of trifluoperazine 2HCl were after vaporization, for a percent yield of 44.4%. taken as the drug-coated Substrate was heated to monitor Another substrate (stainless steel cylinder (6 cm)) was visually formation of a thermal vapor. The photographs prepared by applying 0.18 mg drug to form a film 0.3 um in 35 thickness. The substrate was heated as described in Method E showed that a thermal vapor was initially visible 25 millisec and purity of the drug-aerosol particles was determined to be onds after heating was initiated, with the majority of the 96.8%. 0.11 mg was recovered from the filter after vaporiza thermal vapor formed by 120 milliseconds. Generation of the tion, for a percent yield of 63.1%. A total mass of 0.14 mg was thermal vapor was complete by 250 milliseconds. recovered from the test apparatus and Substrate, for a total 40 recovery of 81.8%. Example 154 High speed photographs were taken as the drug-coated substrate was heated to monitor visually formation of a ther Trimipramine maleate (MW 411, melting point 142°C., mal vapor. The photographs showed that a thermal vapor was oral dose 50mg), a psychotherapeutic agent, was coated on a initially visible 30 milliseconds after heating was initiated, piece of aluminum foil (20 cm) according to Method C. The 45 with the majority of the thermal vapor formed by 90 milli calculated thickness of the drug film was 1.2 Lum. The sub seconds. Generation of the thermal vapor was complete by strate was heated as described in Method C at 90 V for 3.5 110 milliseconds. seconds. The purity of the drug-aerosol particles was deter mined to be 95.9%. 1.6 mg was recovered from the glass tube Example 158 walls after vaporization, for a percent yield of 66.7%. 50 Another Substrate containing trimipramine maleate coated Venlafaxine (MW 277, oral dose 50 mg), a psychothera to a film thickness of 1.1 um was prepared by the same peutic agent, was coated on a stainless steel cylinder (6 cm) method and heated under an argon atmosphere at 90 V for 3.5 according to Method E. 5.85 mg of drug was applied to the seconds. The purity of the drug-aerosol particles was deter substrate, for a calculated drug film thickness of 9.8 um. The mined to be 97.4%. 2.1 mg was recovered from the glass tube 55 substrate was heated as described in Method E and purity of walls after vaporization, for a percent yield of 95.5%. the drug-aerosol particles was determined to be 99.4%. 3.402 mg was recovered from the filter after vaporization, for a Example 155 percent yield of 58.1%. A total mass of 5.85 mg was recov ered from the test apparatus and Substrate, for a total recovery Valdecoxib (MW 314, melting point 155° C., oral dose 10 60 of 100%. mg), an anti-rheumatic agent, was coated on a piece of stain High speed photographs were taken as the drug-coated less steel foil (5 cm) according to Method B. The calculated substrate was heated to monitor visually formation of a ther thickness of the drug film was 8.0 um. The substrate was mal vapor. The photographs showed that a thermal vapor was heated as described in Method B by charging the capacitors to initially visible 30 milliseconds after heating was initiated, 15.5 V. The purity of the drug-aerosol particles was deter 65 with the majority of the thermal vapor formed by 100 milli mined to be 96.9%. 1.235 mg was recovered from the filter seconds. Generation of the thermal vapor was complete by after vaporization, for a percent yield of 28.9%. A total mass 400 milliseconds. US 7,585,493 B2 77 78 Example 159 Zolmitriptan was further coated on an aluminum foil sub strate (24.5 cm) according to Method G. 2.6 mg of the drug Verapamil (MW 455, melting point <25°C., oral dose 40 was applied to the substrate, for a calculated thickness of the mg), a cardiovascular agent, was coated on a piece of alumi drug film of 1.1 um. The substrate was heated as described in num foil (20 cm) according to Method C. The calculated Method G at 90 V for 6 seconds. The purity of the drug thickness of the drug film was 1.1 um. The substrate was aerosol particles was determined to be >96%. 1.5 mg of the heated under an argon atmosphere at 90 V for 3.5 seconds. drug was found to have aerosolized, for a percent yield of The purity of the drug-aerosol particles was determined to be 57.7%. 96.2%. 1.41 mg was recovered from the glass tube walls after vaporization, for a percent yield of 64.1%. 10 Example 163 Verapamil was also coated on a stainless steel cylinder (8 cm) according to Method D. 0.75 mg of drug was applied to Zolpidem (MW 307, melting point 196° C., oral dose 5 the substrate, for a calculated drug film thickness of 0.9 um. mg), a sedative and hypnotic, was coated onto six stainless The substrate was heated as described in Method D by charg steel cylindrical substrates according to Method E. The cal ing the capacitors to 20.5 V. The purity of the drug-aerosol 15 culated thickness of the drug film on each Substrate ranged particles was determined to be 89.6%. 0.32 mg was recovered from about 0.1 um to about 4.2 Lum. The substrates were from the filter after vaporization, for a percent yield of 42.7%. heated as described in Method E and purity of the drug A total mass of 0.6 mg was recovered from the test apparatus aerosol particles generated from each Substrate determined. and substrate, for a total recovery of 80%. The results are shown in FIG. 19. Zolpidem was also coated on a stainless steel cylinder (6 Example 160 cm) according to Method E. 4.13 mg of drug was applied to the substrate, for a calculated drug film thickness of 6.9 um. Vitamin E (MW 430, melting point 4°C.), a dietary supple The substrate was heated as described in Method E and purity ment, was coated on a stainless steel cylinder (8 cm) accord of the drug-aerosol particles was determined to be 96.6%. 2.6 ing to Method D. 0.78 mg of drug was applied to the substrate, 25 mg was recovered from the filter after vaporization, for a for a calculated drug film thickness of 0.9 um. The substrate percent yield of 63%. A total mass of 3.18 mg was recovered was heated as described in Method D by charging the capaci from the test apparatus and Substrate, for a total recovery of tors to 20.5 V. The purity of the drug-aerosol particles was 770%. determined to be 99.3%. 0.48 mg was recovered from the High speed photographs were taken as the drug-coated filter after vaporization, for a percent yield of 61.8%. A total 30 substrate was heated to monitor visually formation of a ther mass of 0.6 mg was recovered from the test apparatus and mal vapor. The photographs showed that a thermal vapor was substrate, for a total recovery of 81.4%. initially visible 35 milliseconds after heating was initiated, with the majority of the thermal vapor formed by 120 milli Example 161 seconds. Generation of the thermal vapor was complete by 35 225 milliseconds. Zaleplon (MW 305, melting point 159°C., oral dose 5 mg), Zolpidem was also coated on an aluminum Substrate (24.5 a sedative and hypnotic, was coated on a piece of aluminum cm) according to Method G. 8.3 mg of drug was applied to foil (20 cm) according to Method C. The calculated thick the Substrate, for a calculated drug film thickness of 3.4 um. ness of the drug film was 2.3 Lum. The Substrate was heated as The substrate was heated as described in Method Gat 90 V for described in Method C at 60 V for 12 seconds. The purity of 40 6 seconds. The purity of the drug-aerosol particles was deter the drug-aerosol particles was determined to be 99.5%. 4.07 mined to be >97%. 7.4 mg of the drug was found to have mg was recovered from the glass tube walls after vaporiza aerosolized by weight loss from Substrate mass, for a percent tion, for a percent yield of 90.4%. yield of 89.2%.
Example 162 45 Example 164 Zolmitriptan (MW 287, melting point 141° C., oral dose Zopiclone (MW 388, melting point 178°C., oral dose 7.50 1.25 mg), a migraine preparation, was coated on a piece of mg), a sedative and hypnotic, was coated on an aluminum foil aluminum foil (20 cm) according to Method C. The calcu substrate (20cm) according to Method C.3.7 mg of drug was lated thickness of the drug film was 1.6 um. The substrate was 50 applied to the Substrate, for a calculated thickness of the drug heated as described in Method C at 60 V for 11 seconds. The film of 1.9 um. The substrate was heated as described in purity of the drug-aerosol particles was determined to be Method C at 60 V for 9 seconds. The purity of the drug 93%. 1.1 mg was recovered from the glass tube walls after aerosol particles was determined to be 97.9%. 2.5 mg was vaporization, for a percent yield of 35.5%. recovered from the glass tube walls after vaporization, for a Another Substrate containing Zolmitriptan coated to a film 55 percent yield of 67.6%. thickness of 2.0 Lim was prepared by the same method and Zopiclone was further coated on an aluminum foil Sub heated under an argon atmosphere at 90 V for 4 seconds. The strate (24 cm) according to Method C. 3.5 mg of drug was purity of the drug-aerosol particles was determined to be applied to the Substrate, for a calculated thickness of the drug 98.4%. 0.6 mg was recovered from the glass tube walls after film of 1.5 m. The substrate was heated substantially as vaporization, for a percent yield of 15%. 60 described in MethodCat 60V for 6 seconds. The purity of the Another substrate (36 cm) containing Zolmitriptan was drug-aerosol particles was determined to be >99%. prepared according to Method C. 9.8 mg of the drug was applied to the Substrate, for a calculated thickness of the drug Example 165 film of 2.7 um. The substrate was heated substantially as described in Method C at 60 V for 15 seconds. The purity of 65 Zotepine (MW 332, melting point 91°C., oral dose 25 mg), the drug-aerosol particles was determined to be 98%. The a psychotherapeutic agent, was coated on a stainless steel aerosol percent yield was 38%. cylinder (8 cm) according to Method D. 0.82 mg of drug was US 7,585,493 B2 79 80 applied to the Substrate, for a calculated drug film thickness of ness of 1.4 Lum. The substrate was heated as described in 1 um. The substrate was heated as described in Method D by Method D by charging the capacitors to 20.5V. The purity of charging the capacitors to 20.5 V. The purity of the drug the drug-aerosol particles was determined to be 91.1%. 0.251 aerosol particles was determined to be 98.3%. 0.72 mg was mg was recovered from the filter after vaporization, for a recovered from the filter after vaporization, for a percent yield percent yield of 22%. A total mass of 1.12 mg was recovered of 87.8%. A total mass of 0.82 mg was recovered from the test from the test apparatus and Substrate, for a total recovery of apparatus and substrate, for a total recovery of 100%. 98%. High speed photographs were taken as the drug-coated High speed photographs were taken as the drug-coated substrate was heated to monitor visually formation of a ther substrate was heated to monitor visually formation of a ther mal vapor. The photographs showed that a thermal vapor was 10 mal vapor. The photographs showed that a thermal vapor was initially visible 30 milliseconds after heating was initiated, initially visible 55 milliseconds after heating was initiated, with the majority of the thermal vapor formed by 60 milli with the majority of the thermal vapor formed by 300 milli seconds. Generation of the thermal vapor was complete by seconds. Generation of the thermal vapor was complete by 110 milliseconds. 1250 milliseconds. 15 A second Substrate coated with arirpirazole was prepared Example 166 for testing. 1.139 mg was coated on a stainless steel cylinder (8 cm) according to Method D, for a calculated drug film Adenosine (MW 267, melting point 235° C., oral dose 6 thickness of 1.4 um. The substrate was heated as described in mg), an anti-arrhythmic cardiovascular agent, was coated on Method D by charging the capacitors to 20.5V. The purity of a stainless steel cylinder (8 cm) according to Method D. 1.23 the drug-aerosol particles was determined to be 86.9%. 0.635 mg of drug was applied to the Substrate, for a calculated drug mg was recovered from the filter after vaporization, for a film thickness of 1.5 um. The substrate was heated as percent yield of 55.8%. A total mass of 1.092 mg was recov described in Method D by charging the capacitors to 20.5V. ered from the test apparatus and Substrate, for a total recovery The purity of the drug-aerosol particles was determined to be of 95.8%. 70.6%. 0.34 mg was recovered from the filter after vaporiza 25 High speed photographs were taken as the drug-coated tion, for a percent yield of 27.6%. A total mass of 0.68 mg was substrate was heated to monitor visually formation of a ther recovered from the test apparatus and Substrate, for a total mal vapor. The photographs showed that a thermal vapor was recovery of 55.3%. initially visible 30 milliseconds after heating was initiated, High speed photographs were taken as the drug-coated with the majority of the thermal vapor formed by 200 milli substrate was heated to monitor visually formation of a ther 30 seconds. Generation of the thermal vapor was complete by mal vapor. The photographs showed that a thermal vapor was 425 milliseconds. initially visible 40 milliseconds after heating was initiated, with the majority of the thermal vapor formed by 250 milli Example 170 seconds. Generation of the thermal vapor was complete by 535 milliseconds. 35 Aspirin (MW 180, melting point 135° C., oral dose 325 mg), an analgesic agent, was coated on a piece of aluminum Example 167 foil (20 cm) according to Method C. The calculated thick ness of the drug film was 1.2 Lum. The Substrate was heated as Amoxapine (MW 314, melting point 176°C., oral dose 25 described in MethodCat 60V for 5 seconds. The purity of the mg), an anti-psychotic agent, was coated on a stainless Steel 40 drug-aerosol particles was determined to be 82.1%. 1.23 mg cylinder (8 cm) according to Method D. 6.61 mg of drug was was recovered from the glass tube walls after vaporization, applied to the Substrate, for a calculated drug film thickness of for a percent yield of 53.5%. 7.9 um. The substrate was heated as described in Method D by charging the capacitors to 20.5 V. The purity of the drug Example 171 aerosol particles was determined to be 99.7%. 3.13 mg was 45 recovered from the filter after vaporization, for a percent yield Astemizole (MW459, melting point 173° C., oral dose 10 of 47.4%. A total mass of 6.61 mg was recovered from the test mg), an antihistamine, was coated on an aluminum foil Sub apparatus and substrate, for a total recovery of 100%. strate (20 cm) according to Method C. 5.0 mg of drug was applied to the Substrate, for a calculated thickness of the drug Example 168 50 film of 2.5 lum. The substrate was heated as described in Method C at 60 V for 11 seconds. The purity of the drug Apomorphine 10, 11 cyclocarbonate (MW 293, typical aerosol particles was determined to be 88%. 1.6 mg was aerosol dose 1 mg), a dopaminergic agent used in Parkinson's recovered from the glass tube walls after vaporization, for a patients, was coated on a piece of aluminum foil (20 cm) percent yield of 32.0%. according to Method C. The calculated thickness of the drug 55 A similarly prepared Substrate having the same film thick film was 1.2 Lum. The substrate was heated as described in ness was heated at 60 V for 11 seconds under a pure argon Method C at 90 V for 3 seconds. The purity of the drug atmosphere. The purity of the drug-aerosol particles was aerosol particles was determined to be 78.4%. 1.46 mg was determined to be 93.9%. 1.7 mg was recovered from the glass recovered from the glass tube walls after vaporization, for a tube walls after vaporization, for a percent yield of 34.0%. percent yield of 60.8%. 60 Example 172 Example 169 Atenolol (MW 266, melting point 152°C., oral dose 25 Aripiprazole (MW 448, melting point 140°C., oral dose 5 mg), a beta adrenergic blocking agent, was coated on a piece mg), an anti-psychotic agent, was coated on a stainless Steel 65 of aluminum foil (20 cm) according to Method C. 22.6 mg cylinder (8 cm) according to Method D. 1.139 mg of drug was applied to the substrate, for a calculated thickness of the was applied to the Substrate, for a calculated drug film thick drug film of 11.3 um. The substrate was heated as described in US 7,585,493 B2 81 82 Method C at 60 V for 11 seconds. The purity of the drug heated as described in Method D by charging the capacitors to aerosol particles was determined to be 94%. 1.0 mg was 20.5 V. The purity of the drug-aerosol particles was deter recovered from the glass tube walls after vaporization, for a mined to be 70.5%. 0.37 mg was recovered from the filter percent yield of 4.4%. after vaporization, for a percent yield of 25.3%. A total mass Another atenolol-coated substrate was prepared by the of 0.602 mg was recovered from the test apparatus and sub same method, with 17.9 mg of drug applied to the substrate, strate, for a total recovery of 41.2%. for a calculated film thickness of 9.0 Lum. The substrate was heated under an argon atmosphere according to Method Cat Example 177 60V for 3.5 seconds. The purity of the drug-aerosol particles Buspirone (MW 386, oral dose 15 mg), a psychotherapeu was determined to be >99.5%. 2.0 mg was recovered from the 10 tic agent, was coated on an aluminum foil substrate (20 cm) glass tube walls after vaporization, for a percent yield of 11%. according to Method C. 7.60 mg of drug was applied to the Atenolol was further coated on an aluminum foil substrate substrate, for a calculated thickness of the drug film of 3.8Lum. according to Method G. The substrate was heated as The substrate was heated as described in Method Cat 60V for described in Method G, and the purity of the drug-aerosol 7 seconds. The purity of the drug-aerosol particles was deter particles was determined to be 100%. The percent yield of the 15 mined to be 96.5%. 1.75 mg was recovered from the glass aerosol was 10%. tube walls after vaporization, for a percent yield of 23%. Example 173 Another Substrate containing buspirone coated to a film thickness of 4.6 um was prepared by the same method and heated under an argon atmosphere at 60V for 7 seconds. The Benazepril (MW 424, melting point 149°C., oral dose 10 purity of the drug-aerosol particles was determined to be mg), an ACE inhibitor, cardiovascular agent, was coated on a 96.1%. 2.7 mg was recovered from the glass tube walls after stainless steel cylinder (8 cm) according to Method D. The vaporization, for a percent yield of 29.7%. calculated thickness of the drug film was 0.9 um. The sub The hydrochloride salt (MW 422) was also tested. Bus strate was heated as described in Method D by charging the pirone hydrochloride was coated on a piece of aluminum foil capacitors to 20.5 V. The purity of the drug-aerosol particles 25 was determined to be 90%. 0.34 mg was recovered from the (20 cm) according to Method C. 8.30 mg of drug was applied filter after vaporization, for a percent yield of 45.3%. A total to the substrate, for a calculated thickness of the drug film of mass of 0.6 mg was recovered from the test apparatus and 4.2 Lum. The substrate was heated as described in Method Cat substrate, for a total recovery of 77.3%. 90 V for 5 seconds. The purity of the drug-aerosol particles 30 was determined to be 97.8%. 2.42 mg was recovered from the Example 174 glass tube walls after vaporization, for a percent yield of 29.2%. Benztropine (MW 307, melting point 143°C., oral dose 1 Example 178 mg), an anti-cholinergic, antiparkinsonian agent, was coated onto an aluminum foil substrate (20 cm) according to 35 Caffeine (MW 194, melting point 238°C., oral dose 100 Method C. 2.10 mg of drug was applied to the substrate, for a mg), a central nervous system stimulant, was coated on a calculated thickness of the drug film of 1.1 um. The substrate metal substrate (50 cm). 100 mg of drug was applied to the was heated as described in Method C at 90 V for 3.5 seconds. Substrate, for a calculated drug film thickness of 14 um The purity of the drug-aerosol particles was determined to be and heated to 300° C. according to Method F to form 98.3%. 0.83 mg was recovered from the glass tube walls after 40 drug-aerosol particles. Purity of the drug-aerosol particles vaporization, for a percent yield of 39.5%. was determined to be >99.5%. 40 mg was recovered from the Another benztropine-coated substrate was prepared by the glass wool after vaporization, for a percent yield of 40%. same method, with 2.0 mg of drug was applied to the Sub Example 179 strate, for a calculated film thickness of 1.0Lum. The substrate was heated under an argon atmosphere at 90 V for 3.5 sec 45 Captopril (MW 217, melting point 104°C., oral dose 25 onds. The purity of the drug-aerosol particles was determined mg), an ACE inhibitor, cardiovascular agent, was coated on a to be 99.5%. 0.96 mg was recovered from the glass tube walls stainless steel cylinder (8 cm) according to Method D. 0.88 after vaporization, for a percent yield of 48%. mg of drug was applied to the Substrate, for a calculated drug film thickness of 1.1 um. The substrate was heated as Example 175 50 described in Method D by charging the capacitors to 20.5 V. The purity of the drug-aerosol particles was determined to be Bromazepam (MW 316, melting point 239°C., oral dose 2 87.5%. 0.54 mg was recovered from the filter after vaporiza mg), a psychotherapeutic agent used as an anti-anxiety drug, tion, for a percent yield of 61.4%. A total mass of 0.8 mg was was coated on a piece of aluminum foil (20 cm) according to recovered from the test apparatus and Substrate, for a total Method C. The calculated thickness of the drug film was 5.2 55 um. The substrate was heated as described in Method C at 30 recovery of 90.9%. V for 45 seconds. The purity of the drug-aerosol particles was High speed photographs were taken as the drug-coated determined to be 96.9%. 2.2 mg was recovered from the glass substrate was heated to monitor visually formation of a ther tube walls after vaporization, for a percent yield of 21.2%. mal vapor. The photographs showed that a thermal vapor was 60 initially visible 20 milliseconds after heating was initiated, Example 176 with the majority of the thermal vapor formed by 100 milli seconds. Generation of the thermal vapor was complete by Budesonide (MW 431, melting point 232°C., oral dose 0.2 170 milliseconds. mg), an anti-inflammatory steroid used as a respiratory agent, Example 180 was coated on a stainless steel cylinder (9 cm) according to 65 Method D. 1.46 mg of drug was applied to the substrate, for a Carbamazepine (MW 236, melting point 193°C., oral dose calculated drug film thickness of 1.7 um. The substrate was 200 mg), an anticonvulsant agent, was coated on a stainless US 7,585,493 B2 83 84 steel cylinder (8 cm) according to Method D. 0.73 mg of aluminum foil (20 cm) according to Method C. The calcu drug was applied to the Substrate, for a calculated drug film lated thickness of the drug film was 5.2 Lum. The substrate was thickness of 0.9 m. The substrate was heated as described in heated as described in Method C at 90 V for 5 seconds. The Method D by charging the capacitors to 20.5V. The purity of purity of the drug-aerosol particles was determined to be the drug-aerosol particles was determined to be 88.9%. 0.43 5 82.2%. 7.2 mg was recovered from the glass tube walls after mg was recovered from the filter after vaporization, for a vaporization, for a percent yield of 69.9%. percent yield of 58.9%. A total mass of 0.6 mg was recovered from the test apparatus and Substrate, for a total recovery of Example 185 78.1%. Dipyridamole (MW 505, melting point 163°C., oral dose Example 181 10 75 mg), a blood modifier, was coated on a stainless steel cylinder (6 cm) according to Method D. 1.15 mg of drug was Cinnarizine (MW 369, oral dose 15 mg), an antihistamine, applied to the Substrate, for a calculated drug film thickness of was coated on an aluminum foil substrate (20 cm) according 1.9 Lum. The substrate was heated as described in Method D by to Method C. 18.0 mg of drug was applied to the substrate, for charging the capacitors to 20.5 V. The purity of the drug a calculated thickness of the drug film of 9 Lum. The substrate 15 aerosol particles was determined to be 95.3%. 0.22 mg was was heated as described in Method C at 60 V for 8 seconds. recovered from the filter after vaporization, for a percent yield The purity of the drug-aerosol particles was determined to be of 19.1%. A total mass of 1.1 mg was recovered from the test 96.7%. 3.15 mg was recovered from the glass tube walls after apparatus and substrate, for a total recovery of 94.8%. vaporization, for a percent yield of 17.5%. Another Substrate containing cinnarizine coated (5.20 mg Example 186 drug) to a film thickness of 2.6 um was prepared by the same method and heated under an argon atmosphere at 60 V for 8 Dolasetron (MW 324, oral dose 100 mg), a gastrointestinal seconds. The purity of the drug-aerosol particles was deter agent, was coated on a piece of aluminum foil (20 cm) mined to be 91.8%. 2.3 mg was recovered from the glass tube according to Method C. The calculated thickness of the drug walls after vaporization, for a percent yield of 44.2%. 25 film was 5 lum. The substrate was heated as described in Method C at 30 V for 45 seconds. The purity of the drug Example 182 aerosol particles was determined to be 83%. 6 mg was recov ered from the glass tube walls after vaporization, for a percent Clemastine (MW 344, melting point <25°C., oral dose 1 yield of 60%. mg), a antihistamine, was coated on a piece of aluminum foil 30 Dolasetron was further coated on an aluminum foil sub (20 cm) according to Method C. The calculated thickness of strate according to Method C. The substrate was heated sub the drug film was 3.2 Lum. The substrate was heated as stantially as described in Method C, and the purity of the described in MethodCat 60 V for 7 seconds. The purity of the drug-aerosol particles was determined to be 99%. drug-aerosol particles was determined to be 94.3%.3 mg was recovered from the glass tube walls after vaporization, for a 35 Example 187 percent yield of 46.9%. Clemastine fumarate (MW 460, melting point 178°C., oral Doxylamine (MW 270, melting point <25°C., oral dose dose 1.34 mg) was coated on an identical Substrate to a 12.5 mg), an antihistamine, was coated on a stainless steel thickness of 2.9 m. The substrate was heated at 60 V for 8 cylinder (8 cm) according to Method D. The calculated seconds. The purity of the drug-aerosol particles was deter 40 thickness of the drug film was 7.8 m. The substrate was mined to be 76.6%. 1.8 mg was recovered from the glass tube heated as described in Method D by charging the capacitors to walls after vaporization, for a percent yield of 31.6%. 20.5 V. The purity of the drug-aerosol particles was deter mined to be 99.8%. 2.96 mg was recovered from the filter Example 183 after vaporization, for a percent yield of 45.6%. A total mass 45 of 6.49 mg was recovered from the test apparatus and Sub Clofazimine (MW 473, melting point 212°C., oral dose strate, for a total recovery of 100%. 100 mg), an anti-infective agent, was coated on a stainless steel cylinder (6 cm) according to Method D. 0.48 mg of Example 188 drug was applied to the Substrate, for a calculated drug film thickness of 0.8 um. The substrate was heated as described in Droperidol (MW 379, melting point 147°C., oral dose 1 Method D by charging the capacitors to 20.5V. The purity of 50 mg), a psychotherapeutic agent, was coated on a piece of the drug-aerosol particles was determined to be 84.4%. 0.06 aluminum foil (20 cm) according to Method C. The calcu mg was recovered from the filter after vaporization, for a lated thickness of the drug film was 1.1 um. The substrate was percent yield of 12.5%. A total mass of 0.48 mg was recov heated as described in Method C at 90 V for 3.5 seconds. The ered from the test apparatus and Substrate, for a total recovery purity of the drug-aerosol particles was determined to be of 100%. 55 51%. 0.27 mg was recovered from the glass tube walls after High speed photographs were taken as the drug-coated vaporization, for a percent yield of 12.9%. substrate was heated to monitor visually formation of a ther Another Substrate containing droperidol coated to a film mal vapor. The photographs showed that a thermal vapor was thickness of 1.0 Lim was prepared by the same method and initially visible 45 milliseconds after heating was initiated, heated under an argon atmosphere at 90 V for 3.5 seconds. with the majority of the thermal vapor formed by 300 milli 60 The purity of the drug-aerosol particles was determined to be seconds. Generation of the thermal vapor was complete by 65%. 0.24 mg was recovered from the glass tube walls after 1200 milliseconds. vaporization, for a percent yield of 12.6%. Example 184 Example 189 65 Desipramine (MW 266, melting point <25°C., oral dose 25 Enalapril maleate (MW 493, melting point 145° C., oral mg), a psychotherapeutic agent, was coated on a piece of dose 5 mg), a cardiovascular agent, was coated on a stainless US 7,585,493 B2 85 86 steel cylinder (8 cm) according to Method D. The calculated drug-aerosol particles was determined to be 99.6%. The per thickness of the drug film was 1.1 um. The substrate was cent yield of the aerosol was 36%. heated as described in Method D by charging the capacitors to 20.5 V. The purity of the drug-aerosol particles was deter Example 194 mined to be 61%. 0.29 mg was recovered from the filter after 5 vaporization, for a percent yield of 34.1%. A total mass of Flurbiprofen (MW244, melting point 111° C., oral dose 50 0.71 mg was recovered from the test apparatus and Substrate, mg), an analgesic, was coated on a piece of aluminum foil (20 for a total recovery of 83.5%. cm) according to Method C. The calculated thickness of the drug film was 4.7 um. The substrate was heated as described Example 190 10 in Method C at 60 V for 5 seconds. The purity of the drug aerosol particles was determined to be >99.5%. 4.1 mg was Estradiol-17-acetate (MW 314, oral dose 2 mg), a hor recovered from the glass tube walls after vaporization, for a monal pro-drug, was coated on a piece of aluminum foil (20 percent yield of 43.6%. cm) according to Method C. The calculated thickness of the drug film was 0.9 um. The substrate was heated as described 15 Example 195 in Method C at 60 V for 6 seconds. The purity of the drug aerosol particles was determined to be 98.6%. 0.59 mg was Fluvoxamine (MW 318, oral dose 50 mg), a psychothera recovered from the glass tube walls after vaporization, for a peutic agent, was coated on a piece of aluminum foil (20 cm) percent yield of 34.7%. according to Method C. The calculated thickness of the drug film was 4.4 Lum. The substrate was heated as described in Example 191 Method C at 90 V for 5 seconds. The purity of the drug aerosol particles was determined to be 65%. 6.5 mg was Estradiol 17-heptanoate (MW 384 melting point 94° C. recovered from the glass tube walls after vaporization, for a oral dose 1 mg), a hormone, was coated on a metal Substrate percent yield of 77.8%. (50 cm). 42 mg was applied to the substrate, for a calculated 25 Another substrate containing fluvoxamine coated to a film drug film thickness of 8.4 um and heated according to Method thickness of 4.4 um was prepared by the same method and F at 300° C. to form drug-aerosol particles. Purity of the heated under an argon atmosphere at 60V for 8 seconds. The drug-aerosol particles was determined to be 90% by GC purity of the drug-aerosol particles was determined to be analysis. The total mass recovered was 11.9%. 88%. 6.9 mg was recovered from the glass tube walls after 30 vaporization, for a percent yield of 78.4%. Example 192 Example 196 Fluphenazine (MW 438, melting point <25°C., oral dose 1 mg), a psychotherapeutic agent, was coated on a piece of Frovatriptan (MW 379, melting point 102°C., oral dose 2.5 aluminum foil (20 cm) according to Method C. The calcu 35 mg), a migraine preparation, was coated on a piece of alumi lated thickness of the drug film was 1.1 um. The substrate was num foil (20 cm) according to Method C. The calculated heated as described in Method C at 90 V for 3.5 seconds. The thickness of the drug film was 3.3 m. The substrate was purity of the drug-aerosol particles was determined to be heated as described in Method C at 60 V for 12 seconds. The 93%. 0.7 mg was recovered from the glass tube walls after purity of the drug-aerosol particles was determined to be vaporization, for a percent yield of 33.3%. 40 73%. 1.4 mg was recovered from the glass tube walls after The fluphenazine 2HCl salt form of the drug (MW 510, vaporization, for a percent yield of 21.2%. melting point 237°C.) was also tested. The drug was coated Frovatriptan was further coated on an aluminum foil sub on a metal substrate (10 cm) according to Method D. The strate (24.5 cm) according to Method G. 5.0 mg of the drug calculated thickness of the drug film was 0.8 um. The sub 45 was applied to the substrate, for a calculated thickness of the strate was heated as described in Method D by charging the drug film of 2.0 um. The substrate was heated substantially as capacitors to 20.5 V. The purity of the drug-aerosol particles described in Method G at 90 V for 6 seconds, except that two was determined to be 80.7%. 0.333 mg was recovered from of the openings of the T-shaped tube were left open and the the filter after vaporization, for a percent yield of 42.6%. A third connected to the 1 L flask. The purity of the drug-aerosol total mass of 0.521 mg was recovered from the test apparatus 50 particles was determined to be >91%. 2.8 mg of the drug was and substrate, for a total recovery of 66.7%. found to have aerosolized by mass lost from substrate, for a percent yield of 56%. Example 193 Example 197 Flurazepam (MW 388, melting point 82°C., oral dose 15 55 mg), sedative and hypnotic, was coated on a piece of alumi Hydroxyzine (MW 375, oral dose 50 mg), an antihista num foil (20 cm) according to Method C. The calculated mine, was coated on a piece of aluminum foil (20 cm) thickness of the drug film was 2.5 lum. The substrate was according to Method C. The calculated thickness of the drug heated as described in Method C at 60 V for 6 seconds. The film was 14 lum. The substrate was heated as described in purity of the drug-aerosol particles was determined to be 60 Method C at 60 V for 9 seconds. The purity of the drug 99.2%. 1.8 mg was recovered from the glass tube walls after aerosol particles was determined to be 93%. 5.54 mg was vaporization, for a percent yield of 36%. recovered from the glass tube walls after vaporization, for a Flurazepam was further coated on an aluminum foil Sub percent yield of 19.9%. strate (24 cm) according to Method C. 5 mg of the drug was The same drug coated on an identical Substrate (aluminum applied to the Substrate, for a calculated thickness of the drug 65 foil, 20 cm) to a calculated drug film thickness of 7.6 um was film of 2.08 um. The substrate was heated substantially as heated under an argon atmosphere as described in Method C described in Method Cat 60V for 5 seconds. The purity of the at 60V for 9 seconds. Purity of the drug-aerosol particles was US 7,585,493 B2 87 88 determined to be 98.6%. 4.31 mg was recovered from the strate was heated as described in Method C at 60 V for 5 glass tube walls after vaporization, for a percent yield of seconds. The purity of the drug-aerosol particles was deter 28.5%. mined to be 98.5%. 1.1 mg was recovered from the glass tube The dihydrochloride salt form of the drug was also tested. walls after vaporization, for a percent yield of 40.7%. Hydroxyzine dihydrochloride (MW 448, melting point 193° 5 C., oral dose 50mg) was coated on a piece of aluminum foil Example 202 (20 cm) according to Method C. The calculated thickness of Levodopa (MW 197, melting point 278° C., oral dose 500 the drug film was 13.7 lum. The substrate was heated as mg), an antiparkinsonian agent, was coated on a piece of described in MethodCat 60 V for 7 seconds. The purity of the aluminum foil (20 cm) according to Method C. The calcu drug-aerosol particles was determined to be 41.2%. 0.25 mg 10 lated thickness of the drug film was 3.7 um. The substrate was was recovered from the glass tube walls after vaporization, heated as described in Method C at 45 V for 15 seconds, then for a percent yield of 0.9%. at 30 V for 10 seconds. The purity of the drug-aerosol par The salt form of the drug coated on an identical substrate ticles was determined to be 60.6%. The percent yield of the (aluminum foil, 20 cm) to a calculated drug film thickness of aerosol was 7.2%. 12.8 Lum was heated under an argon atmosphere as described 15 in Method C at 60 V for 7 seconds. Purity of the drug-aerosol Example 203 particles was determined to be 70.8%. 1.4 mg was recovered from the glass tube walls after vaporization, for a percent Melatonin (MW 232, melting point 118°C., oral dose 3 yield of 5.5%. mg), a dietary Supplement, was coated on an aluminum foil substrate (20cm) according to Method C.2.0 mg of drug was Example 198 applied to the Substrate, for a calculated thickness of the drug film of 1.0 lum. The substrate was heated as described in Ibutilide was coated on a stainless steel cylinder (8 cm) Method C at 90 V for 3.5 seconds. The purity of the drug according to Method D. 1.436 mg of drug was applied to the aerosol particles was determined to be >99.5%. 0.43 mg was substrate, for a calculated drug film thickness of 1.7 um. The 25 recovered from the glass tube walls after vaporization, for a substrate was heated as described in Method D by charging percent yield of 21.5%. the capacitors to 20.5 V. The purity of the drug-aerosol par Another Substrate containing melatonin coated to a film ticles was determined to be 98.4%. 0.555 mg was recovered thickness of 1.1 Lim was prepared by the same method and from the filter after vaporization, for a percent yield of 38.6%. heated under an argon atmosphere at 90 V for 3.5 seconds. A total mass of 1.374 mg was recovered from the test appa 30 The purity of the drug-aerosol particles was determined to be ratus and substrate, for a total recovery of 95.7%. >99.5%. 1.02 mg was recovered from the glass tube walls High speed photographs were taken as the drug-coated after vaporization, for a percent yield of 46.4%. substrate was heated to monitor visually formation of a ther mal vapor. The photographs showed that a thermal vapor was Example 204 initially visible 25 milliseconds after heating was initiated, 35 Methotrexate (oral dose 2.5 mg) was coated on a stainless with the majority of the thermal vapor formed by 300 milli steel cylinder (8 cm) according to Method D. The calculated seconds. Generation of the thermal vapor was complete by thickness of the drug film was 1.3 m. The substrate was 1200 milliseconds. heated as described in Method D by charging the capacitors to 20.5 V. The purity of the drug-aerosol particles was deter Example 199 40 mined to be 66.3%. The percent yield of the aerosol was 2.4%. Indomethacin norcholine ester (MW 429, oral dose 25 Example 205 mg), an analgesic, was coated on a piece of aluminum foil (20 cm) according to Method C. The calculated thickness of the Methysergide (MW 353, melting point 196°C., oral dose 2 drug film was 5.1 um. The substrate was heated as described 45 mg), a migraine preparation, was coated on a piece of alumi in Method C at 60 V for 7 seconds. The purity of the drug num foil (20 cm) according to Method C. The calculated aerosol particles was determined to be >99.5%. 2.94 mg was thickness of the drug film was 1.0 m. The substrate was recovered from the glass tube walls after vaporization, for a heated as described in Method C at 90 V for 3.5 seconds. The percent yield of 29.1%. purity of the drug-aerosol particles was determined to be 50 67.5%. 0.21 mg was recovered from the glass tube walls after Example 200 vaporization, for a percent yield of 10.5%. Ketorolac (MW 254, melting point 161° C., oral dose 10 Example 206 mg), an analgesic, was coated on a piece of aluminum foil (20 Metoclopramide (MW 300, melting point 148° C., oral cm) according to Method C. The calculated thickness of the 55 dose 10 mg), a gastrointestinal agent, was coated on an alu drug film was 1.1 um. The substrate was heated as described minum foil substrate (20 cm) according to Method C.2.0 mg in Method C at 60 V for 6 seconds. The purity of the drug of drug was applied to the Substrate, for a calculated thickness aerosol particles was determined to be 65.7%. 0.73 mg was of the drug film of 1.0 um. The substrate was heated as under recovered from the glass tube walls after vaporization, for a an argon atmosphere at 90 V for 3.5 seconds. The purity of the percent yield of 33.2%. 60 drug-aerosol particles was determined to be 99.1%. 0.43 mg was recovered from the glass tube walls after vaporization, Example 201 for a percent yield of 21.7%. Ketorolac norcholine ester (MW 326, oral dose 10 mg), Example 207 was coated on an aluminum foil substrate (20 cm) according 65 to Method C. 2.70 mg of drug was applied to the substrate, for Nabumetone (MW 228, melting point 80° C., oral dose a calculated thickness of the drug film of 1.4 um. The sub 1000 mg), an analgesic, was coated on a piece of aluminum US 7,585,493 B2 89 90 foil (20 cm) according to Method C. The calculated thick drug-aerosol particles was determined to be 87.7%. 2.74 mg ness of the drug film was 4.9 um. The substrate was heated as was recovered from the glass tube walls after vaporization, described in Method Cat 60V for 6 seconds. The purity of the for a percent yield of 27.7%. drug-aerosol particles was determined to be >99.5%. 4.8 mg was recovered from the glass tube walls after vaporization, 5 Example 213 for a percent yield of 49%. Pregnanolone (MW 318, melting point 150° C., typical Example 208 inhalation dose 2 mg), an anesthetic, was coated on a metal substrate (50 cm). 20.75 mg was coated on the substrate, for Naltrexone (MW 341, melting point 170° C., oral dose 25 10 a calculated film thickness of 4.2 um, and heated according to mg), an antidote, was coated on an aluminum foil substrate Method F at 300° C. to form drug-aerosol particles. Purity of (20 cm) according to Method C. 10.3 mg of drug was applied the drug-aerosol particles was determined to be 87%. 9.96 mg to the substrate, for a calculated thickness of the drug film of of aerosol particles were collected for a percent yield of 48%). 5.2 m. The substrate was heated as described in Method Cat 90 V for 5 seconds. The purity of the drug-aerosol particles 15 Example 214 was determined to be 96%. 3.3 mg was recovered from the glass tube walls after vaporization, for a percent yield of 32%. Prochlorperazine 2HCl (MW 446, oral dose 5 mg), a psy Naltrexone was coated on an aluminum foil substrate (20 chotherapeutic agent, was coated on a stainless steel cylinder cm) according to Method C. 1.8 mg of drug was applied to (8 cm) according to Method D. 0.653 mg of drug was applied the substrate, for a calculated thickness of the drug film of 0.9 to the substrate, for a calculated drug film thickness of 0.8 um. um. The substrate was heated as described in Method C at 90 The substrate was heated as described in Method D by charg V for 3.5 seconds under an argon atmosphere. The purity of ing the capacitors to 20.5 V. The purity of the drug-aerosol the drug-aerosol particles was determined to be 97.4%. 1.0 particles was determined to be 72.4%. 0.24 mg was recovered mg was recovered from the glass tube walls after vaporiza from the filter after vaporization, for a percent yield of 36.8%. tion, for a percent yield of 55.6%. 25 A total mass of 0.457 mg was recovered from the test appa ratus and substrate, for a total recovery of 70%. Example 209 Example 215 Nalmefene (MW 339, melting point 190° C., IV dose 0.5 mg), an antidote, was coated on a metal substrate (50 cm). 30 Protriptyline HCl (MW 299, melting point 171° C., oral 7.90 mg of drug was coated on the substrate, to form a cal dose 15 mg), a psychotherapeutic agent, was coated on an culated film thickness of 1.6 um, and heated according to aluminum foil substrate (20 cm) according to Method C. Method F to form drug-aerosol particles. Purity of the drug 2.20 mg of drug was applied to the Substrate, for a calculated aerosol particles was determined to be 80%. 2.7 mg was thickness of the drug film of 1.1 um. The substrate was heated recovered from the glass wool after vaporization, for a per 35 as described in Method C at 90 V for 3.5 seconds. The purity cent yield of 34%. of the drug-aerosol particles was determined to be 99.7%. 0.99 mg was recovered from the glass tube walls after vapor Example 210 ization, for a percent yield of 45.0%. Perphenazine (MW404, melting point 100°C., oral dose 2 40 Example 216 mg), a psychotherapeutic agent, was coated on an aluminum foil substrate (20 cm) according to Method C.2.1 mg of drug Protriptyline (MW 263, oral dose 15 mg) was coated on an was applied to the substrate, for a calculated thickness of the aluminum foil substrate (20 cm) according to Method C. 5.6 drug film of 1.1 Lum. The substrate was heated as described in 45 mg of drug was applied to the Substrate, for a calculated Method C at 90 V for 3.5 seconds. The purity of the drug thickness of the drug film of 2.8 Lim. The substrate was heated aerosol particles was determined to be 99.1%. 0.37 mg was as described in Method C at 90 V for 3.5 seconds. The purity recovered from the glass tube walls after vaporization, for a of the drug-aerosol particles was determined to be 89.8%. 1.4 percent yield of 17.6%. mg was recovered from the glass tube walls after vaporiza 50 tion, for a percent yield of 25%. Example 211 Another substrate containing protriptyline coated to a film thickness of 2.7 Lim was prepared by the same method and Pimozide (MW 462, melting point 218°C., oral dose 10 heated under an argon atmosphere at 90 V for 3.5 seconds. mg), a psychotherapeutic agent, was coated on a piece of The purity of the drug-aerosol particles was determined to be aluminum foil (20 cm) according to Method C. The calcu 55 90.8%. 1.4 mg was recovered from the glass tube walls after lated thickness of the drug film was 4.9 um. The substrate was vaporization, for a percent yield of 26.4%. heated as described in Method C at 90 V for 5 seconds. The purity of the drug-aerosol particles was determined to be Example 217 79%. The percent yield of the aerosol was 6.5%. 60 Pyrilamine (MW 285, melting point <25°C., oral dose 25 Example 212 mg), an antihistamine, was coated on a piece of aluminum foil (20 cm) according to Method C. The calculated thickness of Piroxicam (MW 248, melting point 200° C., oral dose 20 the drug film was 5.2 Lum. The substrate was heated as mg), a CNS-active steroid was coated on a piece of aluminum described in MethodCat 60V for 6 seconds. The purity of the foil (20 cm) according to Method C. The calculated thick 65 drug-aerosol particles was determined to be 98.4%. 4.3 mg ness of the drug film was 5.0 um. The substrate was heated as was recovered from the glass tube walls after vaporization, described in MethodCat 60 V for 7 seconds. The purity of the for a percent yield of 41.7%. US 7,585,493 B2 91 92 Pyrilamine maleate (MW 401, melting point 101° C., oral heated as described in Method D by charging the capacitors to dose 25 mg), an antihistamine, was coated on a piece of 20.5 V. The purity of the drug-aerosol particles was deter aluminum foil (20 cm) according to Method C. The calcu mined to be 96.9%. 0.66 mg was recovered from the filter lated thickness of the drug film was 10.8 um. The substrate after vaporization, for a percent yield of 36.7%. A total mass was heated as described in Method C at 60 V for 7 seconds. of 1.06 mg was recovered from the test apparatus and Sub The purity of the drug-aerosol particles was determined to be strate, for a total recovery of 58.9%. 93.7%. 10.5 mg was recovered from the glass tube walls after High speed photographs were taken as the drug-coated vaporization, for a percent yield of 48.8%. substrate was heated to monitor visually formation of a ther mal vapor. The photographs showed that a thermal vapor was Example 218 10 initially visible 30 milliseconds after heating was initiated, with the majority of the thermal vapor formed by 90 milli Quinine (MW 324, melting point 177° C., oral dose 260 seconds. Generation of the thermal vapor was complete by mg), an anti-infective agent, was coated on a piece of alumi 500 milliseconds. num foil (20 cm) according to Method C. The calculated Example 223 thickness of the drug film was 1.1 um. The substrate was 15 heated as described in Method C at 60 V for 6 seconds. The purity of the drug-aerosol particles was determined to be Sulindac (MW 356, melting point 185°C., oral dose 150 >99.5%. 0.9 mg was recovered from the glass tube walls after mg), an analgesic, was coated on a piece of aluminum foil (20 vaporization, for a percent yield of 40.9%. cm) according to Method C. The calculated thickness of the drug film was 4.3 um. The substrate was heated as described Example 219 in Method C at 60 V for 8 seconds. The purity of the drug aerosol particles was determined to be 80.4%. 1.19 mg was Ramipril (MW 417, melting point 109° C., oral dose 1.25 recovered from the glass tube walls after vaporization, for a mg), a cardiovascular agent, was coated on a stainless Steel percent yield of 14%. cylinder (8 cm) and heated to form drug-aerosol particles 25 Example 224 according to Method D by charging the capacitors to 20.5V. The purity of the drug-aerosol particles was determined to be Terfenadine (MW472, melting point 149°C., oral dose 60 61.5%. 0.27 mg was recovered from the filter after vaporiza mg), an antihistamine, was coated on a piece of aluminum foil tion, for a percent yield of 30%. A total mass of 0.56 mg was (20 cm) according to Method C. The calculated thickness of recovered from the test apparatus and Substrate, for a total 30 the drug film was 2.5 lum. The substrate was heated as recovery of 62.2%. described in MethodCat 60V for 8 seconds. The purity of the drug-aerosol particles was determined to be 75.4%. 0.178 mg Example 220 was recovered from the glass tube walls after vaporization, for a percent yield of 3.6%. Risperidone (MW 410, melting point 170° C., oral dose 2 35 An identical substrate coated with terfenadine (2.8 um mg), a psychotherapeutic agent, was coated on a piece of thick) was heated under an argon atmosphere at 60 V for 8 aluminum foil (20 cm) according to Method C. The calcu seconds. The purity of the drug-aerosol particles was deter lated thickness of the drug film was 1.4 um. The substrate was mined to be 74.7%. 0.56 mg was recovered from the glass heated as described in Method C at 90 V for 3.5 seconds. The tube walls after vaporization, for a percent yield of 10.2%. purity of the drug-aerosol particles was determined to be 40 79%. The percent yield of the aerosol was 7.9%. Example 225 Risperidone was also coated on a stainless steel cylinder (8 cm). 0.75 mg of drug was manually applied to the substrate, Triamcinolone acetonide (MW 434, melting point 294°C., for a calculated drug film thickness of 0.9 um. The substrate oral dose 0.2 mg), a respiratory agent, was coated on a stain was heated as described in Method D by charging the capaci 45 less steel cylinder (6 cm) according to Method D. 0.2 mg of tors to 20.5 V. The purity of the drug-aerosol particles was drug was applied to the Substrate, for a calculated drug film determined to be 87.3%. The percent yield of aerosol particles thickness of 0.3 um. The substrate was heated as described in was 36.7%. A total mass of 0.44 mg was recovered from the Method D by charging the capacitors to 20.5V. The purity of test apparatus and substrate, for a total recovery of 59.5%. the drug-aerosol particles was determined to be 92%. 0.02 mg 50 was recovered from the filter after vaporization, for a percent Example 221 yield of 10%. A total mass of 0.09 mg was recovered from the test apparatus and substrate, for a total recovery of 45%. Scopolamine (MW 303, melting point <25°C., oral dose Example 226 1.5 mg), a gastrointestinal agent, was coated on a metal Sub strate (50 cm) according to Method Fat 200° C. 37.5 mg of 55 Trihexyphenidyl (MW 302, melting point 115° C., oral drug was applied to the Substrate, for a calculated drug film dose 2 mg), an antiparkinsonian agent, was coated on a piece thickness of 7.5um. The substrate was heated according to of aluminum foil (20 cm) according to Method C. The cal Method F to form drug-aerosol particles. Purity of the drug culated thickness of the drug film was 1.4 lum. The substrate aerosol particles was determined to be 90% by GC analysis. was heated as described in Method C at 90 V for 3.5 seconds. 1.2 mg were recovered for a percent yield of 3.2%. 60 The purity of the drug-aerosol particles was determined to be 77%. 1.91 mg was recovered from the glass tube walls after Example 222 vaporization, for a percent yield of 68.2%. Sotalol (MW 272, oral dose 80mg), a cardiovascular agent, Example 227 was coated on a stainless steel cylinder (8 cm) according to 65 Method D. 1.8 mg of drug was applied to the substrate, for a Thiothixene (MW 444, melting point 149°C., oral dose 10 calculated drug film thickness of 2.3 lum. The substrate was mg), a psychotherapeutic agent used as an anti-psychotic, US 7,585,493 B2 93 94 was coated on a piece of aluminum foil (20 cm) according to ing to Method D. 0.74 mg of drug was applied to the substrate, Method C. The calculated thickness of the drug film was 1.3 for a calculated drug film thickness of 0.9 um. The substrate um. The substrate was heated as described in Method C at 90 was heated as described in Method D by charging the capaci V for 3.5 seconds. The purity of the drug-aerosol particles tors to 20.5 V. The purity of the drug-aerosol particles was was determined to be 74.0%. 1.25 mg was recovered from the 5 determined to be 87.3%. 0.28 mg was recovered from the glass tube walls after vaporization, for a percent yield of filter after vaporization, for a percent yield of 37.8%. A total 48.1%. mass of 0.44 mg was recovered from the test apparatus and substrate, for a total recovery of 59.5%. Example 228 10 Example 233 Telmisartan (MW 515, melting point 263°C., oral dose 40 mg), a cardiovascular agent, was coated on a stainless steel Zonisamide (MW 212, melting point 163°C., oral dose 75 cylinder (8 cm) according to Method D. 2.73 mg of drug was mg), an anticonvulsant, was coated on a metal substrate and applied to the substrate, for a calculated drug film thickness of heated to form drug-aerosol particles. The substrate was 3.3 Lum. The substrate was heated as described in Method Dby 15 heated as described in Method C and the purity of the drug charging the capacitors to 20.5 V. The purity of the drug aerosol particles was determined to be 99.7%. The percent aerosol particles was determined to be 96%. 0.64 mg was yield of the aerosol was 38.3%. recovered from the filter after vaporization, for a percent yield of 23.4%. A total mass of 2.73 mg was recovered from the test Example 234 apparatus and substrate, for a total recovery of 100%. High speed photographs were taken as the drug-coated A. Preparation of Drug-Coated Stainless Steel Foil Sub Substrate was heated to monitor visually formation of a ther Strate mal vapor. The photographs showed that a thermal vapor was Strips of clean 302/304 stainless-steel foil (0.0025 cm initially visible 50 milliseconds after heating was initiated, thick. Thin Metal Sales) having dimensions 1.5 cm by 7.0 cm with the majority of the thermal vapor formed by 400 milli 25 were dip-coated with a drug solution. The final coated area seconds. Generation of the thermal vapor was complete by was 5.1 cm by 1.5 cm on both sides of the foil, for a total area 1100 milliseconds. of 15 cm. Foils were prepared as stated above and then extracted with acetonitrile. The amount of drug was deter Example 229 mined from quantitative HPLC analysis. Using the known 30 drug-coated surface area, the thickness was then obtained by: Temazepam (MW301, melting point 121°C., oral dose 7.5 film thickness (cm)=drug mass (g) drug density mg), a sedative and hypnotic, was coated on an aluminum foil (g/cm)xsubstrate area (cm) Substrate (20 cm) according to Method C. 4.50 mg of drug was applied to the substrate, for a calculated thickness of the If the drug density is not known, a value of 1 g/cm is drug film of 2.3 um. The substrate was heated as described in 35 assumed. The film thickness in microns is obtained by mul Method C at 60 V for 7 seconds. The purity of the drug tiplying the film thickness in cm by 10,000. aerosol particles was determined to be 97.1%. 1.9 mg was After drying, the drug-coated foil was placed into a vola recovered from the glass tube walls after vaporization, for a tilization chamber constructed of a Delrin(R) block (the air percent yield of 42.2%. way) and brass bars, which served as electrodes. The dimen 40 sions of the airway were 1.0 high by 5.1 wide by 15.2 cm long. Example 230 The drug-coated foil was placed into the volatilization cham ber such that the drug-coated section was between the two Triamterene (MW 253, melting point 316° C., oral dose sets of electrodes. After securing the top of the volatilization 100 mg), a cardiovascular agent, was coated on a stainless chamber, the electrodes were connected to three 12V batter steel cylinder (8 cm) according to Method D. 0.733 mg of 45 ies wired in series with a switch controlled by circuit. The drug was applied to the substrate, for a calculated drug film circuit was designed to close the switch in pulses so as to thickness of was 0.9 um. The substrate was heated as resistively heat the foil to a temperature within 50 millisec described in Method D by charging the capacitors to 20.5 V. onds (typically between 320° and 470° C.) and maintain that The purity of the drug-aerosol particles was determined to be temperature for up to 3 seconds. The back of the volatilization >99.5%. 0.233 mg was recovered from the filter after vapor 50 chamber was connected to a two micron Teflon(R) filter ization, for a percent yield of 31.8%. (Savillex) and filter housing, which were in turn connected to the house vacuum. Sufficient airflow was initiated (typically Example 231 30.5 L/min-1.0 m/sec). After the drug had vaporized, airflow was stopped and the Teflon R filter was extracted with aceto Trimipramine (MW 294, melting point 45° C., oral dose 50 55 nitrile. Drug extracted from the filter was analyzed by HPLC mg), a psychotherapeutic agent, was coated on a piece of UV absorbance at 225 nm using a gradient method aimed at aluminum foil (20 cm) according to Method C. The calcu detection of impurities to determine percent purity. Also, the lated thickness of the drug film was 2.8 um. The substrate was extracted drug was quantified to determine a percent yield, heated as described in Method C at 90 V for 3.5 seconds. The based on the mass of drug initially coated onto the substrate. purity of the drug-aerosol particles was determined to be 60 A percent recovery was determined by quantifying any drug 99.2%. 2.6 mg was recovered from the glass tube walls after remaining on the substrate, adding this to the quantity of drug vaporization, for a percent yield of 46.4%. recovered in the filter and comparing it to the mass of drug initially coated onto the substrate. Example 232 Celecoxib and rizatriptan were tested together according to 65 the method above, by coating a solution of the drug onto a Ziprasidone (MW 413, oral dose 20 mg), an anti-psychotic piece of stainless steel foil (15 cm). Twelve substrates were agent, was coated on a stainless steel cylinder (8 cm) accord prepared, with film thicknesses ranging from about 4.4 um to US 7,585,493 B2 95 96 about 11.4 Lum. The substrates were heated as described in the ciclesonide, film thickness between 0.05 and 5um; method above to 350° C. Purity of the drug aerosol particles clomipramine, film thickness between 1 and 8 um; from each substrate was determined. The substrate having a diazepam, film thickness between 0.05 and 20 Lum; thickness of 4.4 um was prepared by depositing 0.98 mg of diphenhydramine, film thickness between 0.05 and 20 um; rizatriptan and 5.82 mg of celecoxib. After volatilization of 5 donepezil, film thickness between 1 and 10 um; drug this substrate, 0.59 mg of rizatriptan and 4.40 mg of eletriptan, film thickness between 0.2 and 20 um; celecoxib were recovered from the filter, for a percent yield of fentanyl, film thickness between 0.05 and 5um; 73.6%. The purity of the aerosol particles was 96.5%. granisetron, film thickness between 0.05 and 20 Lum; hydromorphone, film thickness between 0.05 and 10 um; Example 235 10 lorazepam, film thickness between 0.05 and 20 um; loxapine, film thickness between 1 and 20 um; Using a solution of 50 mg sildenafil +10 mg caffeine per midazolam, film thickness between 0.05 and 20 Lum; mL of solvent (2:1 chloroform:methanol), 0.0025 cm thick morphine, film thickness between 0.2 and 10 um; stainless steel foils (dimensions of 5.0x6.9 cm) were coated malbuphine, film thickness between 0.2 and 5 um; with 4.1 mg of sildenafil and 0.5 mg of caffeine on 45 cm of 15 naratriptan, film thickness between 0.2 and 5um; surface area. After drying, a variation of Method B was used. olanzapine, film thickness between 1 and 20 Lum; However, instead of a capacitive discharge, a feedback cir parecoxib, film thickness between 0.5 and 2 um; cuit, powered by three 12 V sealed lead acid batteries in paroxetine, film thickness between 1 and 20 um; series, was used to heat the foil to 425° C. and maintain the prochlorperazine, film thickness between 0.1 and 20 um; temperature for 500 milliseconds. Also, the 1.3x2.6x8.9 cm quetiapine, film thickness between 1 and 20 um; airway/vaporization chamber of Method B was replaced with ropinirole, film thickness between 0.05 and 20 um; a 5.1 by 1.0 by 15.3 cm airway to accommodate the larger sertraline, film thickness between 1 and 20 um; foils. The airflow rate was set at 30.5 L/m (1.0 m/s). The sibutramine, film thickness between 0.5 and 2 um; generated aerosol was captured in a single Teflon filter, which sildenafil, film thickness between 0.2 and 3 um; was extracted with acetonitrile and analyzed on HPLC for 25 Sumatriptan, film thickness between 0.2 and 6 um; purity and mass recovery. The purity of the aerosol was 91.9% tadalafil, film thickness between 0.2 and 5 um; by peak area under the curve at 225 nm. The mass recovery in Valdecoxib, film thickness between 0.5 and 10 um; and the extracted filter was 2.9 mg sildenafil and 0.5 mg caffeine. Vardenafil, film thickness between 0.1 and 2 um; venlafaxine, film thickness between 2 and 20 um; Example 236 30 Zaleplon, film thickness between 0.05 and 20 um; and Zolpidem, film thickness between 0.1 and 10 um; A number of other drugs were tested according to one of wherein an aerosol formed by vaporizing the drug compo the above methods (A-G) or a similar method, but exhibited sition by heating the Substrate and condensing the vapor purity less than about 60%. These drugs were not further ized drug composition contains 10% by weight or less tested for optimization: amiloride, amiodarone, amoxicillin, 35 drug degradation products and at least 50% of the total beclomethasone, bromocriptine, bufeXamac, candesartan, amount of drug composition in the film, and wherein the candesartan cilexetil, cetirizine, cortisone, cromolyn, Substrate surface area is such as to yield an effective cyclosporin A, dexamethasone, diclofenac, dihydroergota human therapeutic dose of the drug aerosol. mine, disulfiram, dofetilide, edrophonium chloride, famoti 2. The article of claim 1, wherein said substrate surface dine, fexofenadine, formoterol, furosemide, heparin, ipratro 40 area is between about 0.05-100 cm. pium bromide, irbesartan, labetalol, lanSoprazole, lisuride, 3. The article of claim 1, wherein said substrate surface is lorazepam, losartan, methocarbamol, metolaZone, modafinil, impermeable. montelukast, myricetin, nadolol, omeprazole, ondansetron, 4. The article of claim 1, wherein said substrate comprises oxazepam, pheneizine, phentermine, propantheline bromide, a material selected from the group consisting of metals, poly quinapril hydrochloride, rabeprazole, raloxifene, rosiglita 45 mers, ceramics, and glass. Zone, tolmetin, torsemide, Valsartan, and Zafirlukast. 5. The article of claim 4, wherein said material is a metal Although the invention has been described with respect to selected from the group consisting of stainless steel and alu particular embodiments, it will be apparent to those skilled in minum. the art that various changes and modifications can be made 6. The article of claim 1, wherein said substrate has a without departing from the invention. 50 contiguous surface area of greater than 1 mm and a material It is claimed: density of greater than 0.5 g/cc. 1. An article for use in an aerosol device, for producing an 7. The article of claim 1, wherein said aerosol has 5% by aerosol, comprising a heat conductive Substrate having a Sur weight or less drug degradation products. face with a Surface area, and a film comprising a drug com 8. A method of forming an effective human therapeutic position on the Surface, the film having a film thickness, 55 inhalation dose of a drug composition aerosol having 10% or wherein the drug composition and film thickness are selected less drug degradation products and an aerosol particle mass from the group consisting of the following combinations: median aerodynamic diameter (MMAD) between 0.01 and 3 alprazolam, film thickness between 0.1 and 10 um; um, comprising amoxapine, thickness between 2 and 20 um; (a) providing a heat conductive Substrate having a Surface apomorphine HCl, film thickness between 0.1 and 5um; 60 with a Surface area, and a film comprising a drug com atropine, film thickness between 0.1 and 10 um; position on the Surface, the film having a film thickness, budesonide, film thickness between 0.05 and 20 um; wherein the drug composition and film thickness are bumetanide film thickness between 0.1 and 5um; Selected from the group consisting of the following com buprenorphine, film thickness between 0.05 and 10 um; binations: butorphanol, film thickness between 0.1 and 10 um; 65 alprazolam, film thickness between 0.1 and 10 um; celecoxib, film thickness between 2 and 20 um; amoxapine, thickness between 2 and 20 Lum; chlorpheniramine, film thickness between 0.05 and 20 um; apomorphine HCl, film thickness between 0.1 and 5um; US 7,585,493 B2 97 98 atropine, film thickness between 0.1 and 10 um; quetiapine, film thickness between 1 and 20 um; budesonide, film thickness between 0.05 and 20 Lum; ropinirole, film thickness between 0.05 and 20 um; bumetanide film thickness between 0.1 and 5um; sertraline, film thickness between 1 and 20 um; buprenorphine, film thickness between 0.05 and 10 um; sibutramine, film thickness between 0.5 and 2 um; butorphanol, film thickness between 0.1 and 10 um; 5 sildenafil, film thickness between 0.2 and 3 um; celecoxib, film thickness between 2 and 20 Lum; Sumatriptan, film thickness between 0.2 and 6 um; chlorpheniramine, film thickness between 0.05 and 20 tadalafil, film thickness between 0.2 and 5um; lm, Valdecoxib, film thickness between 0.5 and 10 um; and ciclesonide, film thickness between 0.05 and 5um; Vardenafil, film thickness between 0.1 and 2 um; clomipramine, film thickness between 1 and 8 um; 10 venlafaxine, film thickness between 2 and 20 Lum; diazepam, film thickness between 0.05 and 20 um; Zaleplon, film thickness between 0.05 and 20 Lum; and diphenhydramine, film thickness between 0.05 and 20 Zolpidem, film thickness between 0.1 and 10 um; lm, (b) heating the substrate to a temperature between 300° C. donepezil, film thickness between 1 and 10 um; and 500°C., thereby vaporizinga at least a portion of the eletriptan, film thickness between 0.2 and 20 um; 15 drug composition film, and fentanyl, film thickness between 0.05 and 5um; (c) flowing a gas during said heating across the Substrate at granisetron, film thickness between 0.05 and 20 um; a gas flow rate effective to produce a desired size of hydromorphone, film thickness between 0.05 and 10 aerosol particles by condensation. lm, 9. The method according to claim 8, wherein said heating lorazepam, film thickness between 0.05 and 20 um; 20 vaporizes the drug composition film on the Substrate within a loxapine, film thickness between 1 and 20 um; time period of 2 seconds. 10. The method according to claim 9, wherein said heating midazolam, film thickness between 0.05 and 20 um; vaporizes the drug composition film on the Substrate within a morphine, film thickness between 0.2 and 10 um; time period of 0.5 seconds. malbuphine, film thickness between 0.2 and 5um; 11. The method of claim 8, wherein said flowing is at a gas naratriptan, film thickness between 0.2 and 5um; flow rate of between 4 and 50 L/minute. olanzapine, film thickness between 1 and 20 um; 12. The method of claim 8, wherein the aerosol contains parecoxib, film thickness between 0.5 and 2 um; 5% by weight or less drug degradation products. paroxetine, film thickness between 1 and 20 um; prochlorperazine, film thickness between 0.1 and 20 um; k k k k k