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(12) United States Patent (10) Patent No.: US 6,250,300 B1 Andersson Et Al

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(12) United States Patent (10) Patent No.: US 6,250,300 B1 Andersson Et Al USOO6250300B1 (12) United States Patent (10) Patent No.: US 6,250,300 B1 Andersson et al. (45) Date of Patent: Jun. 26, 2001 (54) SYSTEM FOR DISPENSING FOREIGN PATENT DOCUMENTS PHARMACEUTICALLY ACTIVE 0 069 715 6/1982 (EP). COMPOUNDS O 237 507 2/1987 (EP). O530440 6/1992 (EP). (75) Inventors: Jan Andersson, Sodra Sandby; Hans WO 90/13328 11/1990 (WO). Jägfäldt; Eva Trofast, both of Lund; WO 92/04069 3/1992 (WO). Kjell Wetterlin, Sodra Sandby, all of WO 93/17728 9/1993 (WO). (SE) OTHER PUBLICATIONS (73) Assignee: AB Astra, Sodertalje (SE) Bogaard et al., Dose-effect Relationship of Terbutaline (*) Notice: Subject to any disclaimer, the term of this Using a Multi-dose Power Inhalation System patent is extended or adjusted under 35 (Turbuhaler) ... Powder Inhalation (Rotahaler) in Asth U.S.C. 154(b) by 0 days. matics, Pharmatherapeutica 5:400-406, 1989. Tukiainen and Terho, Comparison of Inhaled Salbutamol (21) Appl. No.: 09/418,342 Powder and Aerosol in Asthmatic Patients with Low Peak Expiratory Flow Level, Eur. J. Clin. Pharmacol. (22) Filed: Oct. 14, 1999 27:645-647, 1985. Related U.S. Application Data (List continued on next page.) (62) Division of application No. 09/309,039, filed on May 10, 1999, which is a continuation of application No. 08/866,749, Primary Examiner-Glenn K. Dawson filed on May 30, 1997, now Pat. No. 5,934,273, which is a ASSistant Examiner V. Srivastava continuation of application No. 08/654,006, filed on May 29, (74) Attorney, Agent, or Firm-Fish & Richardson P.C. 1996, now Pat. No. 5,642,728, which is a continuation of application No. 08/165,402, filed on Dec. 10, 1993, now (57) ABSTRACT abandoned. A System for dispensing a clinically effective dose of an (30) Foreign Application Priority Data inhalable, pharmaceutically active compound, which System Dec. 11, 1992 (SE) ................................................... 92O3743 includes a dry powder inhaler device containing a powder containing the pharmaceutically active compound, wherein (51) Int. Cl." ................................................ A61M 16/00 (a) of the powder particles dispensed by the inhaler device (the “metered DPI dose”), at least 40% are less than (52) U.S. Cl. ................................. 128/203.15; 128/203.12 about 10 microns in diameter at the point the particles exit the inhaler, (58) Field of Search ......................... 128/203.15, 203.12, (b) the metered DPI dose is sufficient to produce a 128/200.14, 203.21, 203.19; 604/58 clinically effective result in a patient; and (c) the amount of the compound in the metered DPI dose (56) References Cited is not more than 70% of the minimal amount of the U.S. PATENT DOCUMENTS compound which, when dispensed in a pressurized metered dose inhaler, produces an equivalent clinically 4,143,658 3/1979 Rambosek et al. ............. 128/203.15 effective result in the same patient. 4,524,769 6/1985 Wetterlin ........... ... 128/203.15 4,534,345 8/1985 Wetterlin ......................... 128/203.15 (List continued on next page.) 8 Claims, 2 Drawing Sheets US 6,250,300 B1 Page 2 U.S. PATENT DOCUMENTS PCT Search Report in the corresponding PCT Application 4,570,630 2/1986 Elliott et al. .................... 128/203.15 No. 9203743-1. 4,627,432 12/1986 Newell et al. ... 128/203.15 4,667,668 5/1987 Wetterlin .... ... 128/203.15 Murray, John F. et al., “Textbook of Respiratory Medicine,” 4,668.218 5/1987 Virtanen ................................. 604/58 vol. 1, 2d ed., pp. 362-3 (W.B. Saunders Co., Phila., 1988, 4,907.583 3/1990 Wetterlin et al. 128/203.15 1994). 4,973,582 11/1990 Yoshida et al. ........................ 514/78 5,161,524 11/1992 Evans .............................. 128/203.15 Earle B. Weiss et al., Brochial Asthma: mechanisms and 5,190,029 3/1993 Bryonet al. ... ... 128/200.14 therapueitcs, Little, Brown & Co. (Boston: 1985, 1993), pp. 5,204,113 4/1993 Hartley et al. ......................... 424/45 727-729. 5,327,883 7/1994 Williams et al. ... 128/203.12 5,341,800 8/1994 Clark et al. ..................... 128/203.15 Borgström, A Possible New Approach of Comparing Dif 5,349,947 9/1994 Newhouse et al. ............. 128/203.21 5,522,385 6/1996 Lloyd et al. ....... ... 128/203.26 ferent Inhalers and Inhaled Substaces, J. Aerosol. Med. 5,570,683 * 11/1996 Zapol ................ ... 128/200.14 5:298, 1992. 5,642,728 7/1997 Andersson et al. ........... ... 128/203.15 Thorsson et al., Lung Deposition of Budesonide from Tur OTHER PUBLICATIONS buhaler is Twice that from a Pressurized Metered Dose Zainudin et al., Comparison of Bronchodilator Responses Inhaler (MDI), Poster presented at the British Thoracic and Deposition Patterns of Salbutamol Inhaled from a Society Winter Meeting, London, UK, Dec. 9-11, 1992. Pressurised . Dose Inhaler, as a Dry Powder, and as a Nebulised Solution, Thorax 45:469-473, 1990. * cited by examiner U.S. Patent Jun. 26, 2001 Sheet 1 of 2 US 6,250,300 B1 O TURBUHALER 60 72 pm.0l 50 %(W/w) 40 DELVERED DOSE 30 20 10 'throat' >13 um 7-13 um 4-7 um 1-4 um FIG. 1 QUZ () U.S. Patent Jun. 26, 2001 Sheet 2 of 2 US 6,250,300 B1 2.1 2.0 1.9 MEAN VALUES OF FEV1 1.8 1.7 1.6 15 e SALBUTAMOL TBH g-SALBUTAMOL MDl 1.4 too 400 800 1600 CUMULATIVE DOSE (ug) FIG.2 46 42 38 MEAN VALUES OF FEV1 IN% OF 34 MEAN BASELINE 30 26 22 18 e SALBUTAMOL TBH 14 g-SALBUTAMOL MD 102 CUMULATIVE DOSE (ug) 103 FIG. 3 US 6,250,300 B1 1 2 SYSTEM FOR DISPENSING lungs is lost mainly in the apparatus itself, and in the PHARMACEUTICALLY ACTIVE gastrointestinal tract. This is disadvantageous, Since loSS of COMPOUNDS active Substance in the apparatus is costly and may reduce efficiency further, by for example clogging the mouthpiece This application is a divisional of U.S. application Ser. 5 or inhalation channel. More significantly for the patient, loSS No. 09/309,039, filed May 10, 1999, which is a continuation in the gastrointestinal tract can trigger or accentuate side of U.S. application Ser. No. 08/866,749, filed May 30, 1997, effects associated with the use of any effective pharmaceu U.S. Pat. No. 5,934,273, which is a continuation of U.S. tical. In the case of bronchodilators, for example, possible application Ser. No. 08/654,006, filed May 29, 1996, U.S. Side effects commonly include tremor and increased heart Pat. No. 5,642,728 which is a continuation of U.S. applica rate, and irritation of the hyperreactive airways of many tion Ser. No. 08/165,402, filed Dec. 10, 1993 now aban Sufferers of airway disease. doned. It is known that optimal deposition of powder particles in This invention relates to a dry powder inhaler system for the lung occurs when the particle diameter is under 10 dispensing a clinically effective dose of a pharmaceutically microns, Since particles having a diameter above this range active compound. 15 are preferentially deposited in the mouth and throat. However, such fine powder will typically tend either to cling BACKGROUND OF THE INVENTION to the sides of its container, or to clump, So that a high Inhalable drugs are commonly used in the treatment of proportion of the powder takes the form of large, loosely diseases of the airways, Such as rhinitis, asthma, and chronic Structured agglomerates of a size much larger than 10 bronchitis. Examples of Such drugs include microns, and only a Small percentage of the powder particles B2-adrenoreceptor agonists Such as Salbutamol, terbutaline, remain within the primary particle diameter range. Certain rimiterol, fenoterol, reproterol, adrenaline, pirbuterol, new types of dry powder inhalers, including those described isoprenaline, orciprenaline, bitolterol, Salmeterol, in European Patent Nos. 0237 507 and 69 715 (e.g., the formoterol, clenbuterol, procaterol, broXaterol, picumeterol, TURBUHALER(R), are able to facilitate the delivery of a TA-2005, mabuterol and the like, and their pharmacologi 25 pharmaceutical powder in which a high proportion of the cally acceptable esters and Salts, anticholinergic bronchodi dispensed particles are of diameter in the desired range. This latorS Such as ipratropium bromide and the like, glucocorSti is accomplished by means of a mechanism or Structural costeroids Such as betamethasone, fluticaSone, budeSonide, feature which causes the particle agglomerates to disinte tipredane, dexamethasone, betamethasone, flucinolone, grate during inhalation, yielding a significantly higher pro triamcinolone, mometasone, D-5519 and the like, and their portion of the powder in particles of the primary particle pharmacologically acceptable esters and Salts, anti-allergy diameter range below 10 microns. It has generally been drugs. Such as Sodium cromoglycate and nedocromil Sodium; thought (See, for example, Bogaard et al. in expectorants; antibiotics; mucolytics; antihistamines; “Pharmatherapeutica”, Vol.5, No.6, 1989) that the efficiency cyclooxygenase inhibitors, leukotriene Synthesis inhibitors, of this new type of inhaler in delivering a clinically effective leukotriene antagonists, PLA2 inhibitors, PAF antagonists 35 dose to the patient is comparable to the efficiency of previ and prophylactics of asthma. In addition to these, Some ous dry powder inhalers (and therefore also to an MDI). Systemically active drugs might be deliverable via inhala Dosage levels recommended for a given pharmaceutical in tion. the new type of inhaler have therefore been of the same Inhalable drugs are commonly administered using either order as those recommended for the same pharmaceutical in a metered dose inhaler (MDI) or a dry powder inhaler (DPI). 40 an MDI. The MDI, in which the drug is dissolved or suspended in a SUMMARY OF THE INVENTION liquid propellant mixture (Sometimes including Small amounts of a volatile organic or inorganic Solvent) stored in It has been found that administration of a pharmaceuti a pressurized container, is currently the more widely used cally active compound by means of a dry powder inhaler 45 device which delivers a large proportion of the powder in the device.
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