(12) Patent Application Publication (10) Pub. No.: US 2003/0005927 A1 Van Oort Et Al
Total Page：16
File Type：pdf, Size：1020Kb
US 20030005927A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0005927 A1 Van Oort et al. 43) Pub. Date: Jan. 9,9 2003 (54) PROCESS AND DEVICE FOR INHALATION (30) Foreign Application Priority Data OF PARTICULATE MEDCAMENTS Mar. 29, 1996 (GB)......................................... 96.06677.4 (76) Inventors: Michiel Mary Van Oort, Durham, NC (US); Mark Joseph Sacchetti, Raleigh, NC (US) Publication Classification Correspondence Address: (51) Int. Cl. ................................................ A61M 11/00 DAVIDJ LEVY, CORPORATE N.SYSPERTY (52) U.S. Cl. ................................. 128/200.23; 128/200.14 FIVE MOORE DR., PO BOX 13398 RESEARCH TRIANGLE PARK, NC 27709-3398 (US) (57) ABSTRACT (21)21) Appl. NoNo.: 10/226,665/226, A preSSurized metered dose inhaler comprising a canister, (22) Filed: Aug. 23, 2002 Said canister containing a liquid formulation comprising a O O preSSurized liquid propellant and Spherical hollow medica Related U.S. Application Data ment particles of respirable size Suspended therein. In pre (62) Division of application No. 09/155,388, filed on Sep. ferred embodiments, the density of the particles is equiva 28, 1998, filed as 371 of international application No. lent to that of the liquid propellant, Such that uniform PCT/EP97/01560, filed on Mar. 25, 1997. Suspension formulation is formed. Patent Application Publication Jan. 9, 2003 Sheet 1 of 7 US 2003/0005927 A1 Patent Application Publication Jan. 9, 2003 Sheet 2 of 7 US 2003/0005927 A1 Patent Application Publication Jan. 9, 2003 Sheet 3 of 7 US 2003/0005927 A1 : Patent Application Publication Jan. 9, 2003 Sheet 4 of 7 US 2003/0005927 A1 | i Patent Application Publication Jan. 9, 2003 Sheet 5 of 7 US 2003/0005927 A1 Patent Application Publication Jan. 9, 2003 Sheet 6 of 7 US 2003/0005927 A1 Patent Application Publication Jan. 9, 2003 Sheet 7 of 7 US 2003/0005927 A1 US 2003/0005927 A1 Jan. 9, 2003 PROCESS AND DEVICE FOR INHALATION OF 0006 Also, interest in dry powder inhalation systems has PARTICULATE MEDCAMENTS increased. Various dry powder inhalator devices for dosing of particulate powdered medicaments to a patient's respira 0001. This application is a divisional application of U.S. tory tract employ capsules, blisters, Velvet fibers, Screens, Ser. No. 09/155,388 filed Sep. 28, 1998, as a U.S. National and the like, as a carrier loaded with powdered medicament. Stage filing under 35 USC 371 of PCT application PCT/ For loading the powder in the carrier for the dosing of the EP97/01560 filed Mar. 25, 1997, claiming priority to GB powder via an inhalator, typically a Selected amount of the 96.06677.4 filed Mar. 29, 1996. powder (Such as 50 lug) is admixed with a Suspending agent (Such as perfluoro-pentane), and the resultant Suspension is Field of the Invention then dispensed from a metering device to the carrier, after 0002 The present invention relates, in general, to par which the Suspending agent evaporates and leaves micron ticulate medicaments and dosing of the medicaments for ized dry powder particles on the carrier. inhalation by a patient. More specifically, the present inven 0007 During use of the inhalator, an air stream (either tion relates to a particulate medicament and a method for generated by the patient or by an assist device, as is well dosing of the medicament, wherein the medicament is in the known in the art) lifts the powder from the carrier to entrain form of Spherical hollow particulates. the powder within the air stream which is then inhaled by the patient. The dose of a powder type of medicament employed Background of the Invention with Such dry powder inhalator devices is, in most instances, Significantly less than 50 mg, typically less than 5 mg, and 0.003 Asthma and other respiratory diseases are typically usually about 50 to about 500 lug. The powdered particles treated by the inhalation of an appropriate medicament for contained in the inhalator are micronized, Solid particles, deposition into the lungs of a human to ease patient breath typically having an average particle diameter (colloquially ing and increase air capacity. Two treatments for respiratory diseases have been widely used. One is inhalation of a referred to as particle size) of <10 um, more particularly <6 medicament from a drug Solution or Suspension, typically in tim, even more particularly <5 um, which is an appropriate an aerosol container (i.e., a pressurized container Such as a Size So that the particles can be drawn into the lungs. metered dose inhalator) that has a spray valve and uses a gas 0008 Representative dry powder inhalator devices hav propellant. The Second is inhalation of a powdered drug ing medicament carriers therein and Suitable for dispersing (generally admixed with an excipient) from a dry powder of respirable medicaments to patients are disclosed in U.S. inhalator. Pat. Nos. 3,906,950, 4,013,075, 3,807,400, and 3,991,761, each to Cocozza; U.S. Pat. No. 4,161,516 to Bell; U.S. Pat. 0004. Manufacture of pressurized aerosol containers No. 4,395,421 to Taylor et al.; European Published Pat. filled with medicament and useful as inhalators for respira Application No. 0455 463 A1 to Velasquez et al.; European tory drug delivery is well known, and a representative Published Pat. Application No. 0211 595 A2 to Newell et discussion of Such manufacture can be found in Byron, P., al.; European Published Pat. Application No. 04670 172 A1 Respiratory Drug Delivery, CRC Press, Inc. 185 et seq., to Cocozza et al., PCT International Publication No. WO (1990). In connection with the manufacture of aerosol 92/00115, published Jan. 9, 1992, to Gupte et al.; and PCT inhalators, it is noted that in View of recent evidence of the International Publication No. WO94/20164, published Sep. link between chlorofluorocarbon gas emissions and the 15, 1994, to Mulhauser et al. Also, the commercially avail deterioration of the earth's protective oZone layer, use of able TURBUHALER(R) inhalator is disclosed in U.S. Pat. drugs in pressurized aerosol inhalators employing a chlo Nos. 4,667,668 and 4,805,811, each to Wetterlin, and U.S. rofluorocarbon (i.e., materials that are totally halogenated Pat. No. 4,668,218 to Virtanen. The disclosures of all of with both chlorine and fluorine and thus have no hydrogen these are incorporated herein by reference. on the carbon, for instance, trichloromonofluoromethane, sold by DuPont under the registered trademark FREON 11 0009. Additionally, it is noted that U.S. Pat. No. 5,503, and colloquially known as CFC-11, or dichlorodifluo 869, issued Apr. 2, 1996, and U.S. pat. application Ser. No. romethane, sold by DuPont under the registered trademark 08/328,578, filed on Oct. 21, 1994, both to Van Oort, the FREON 12 and colloquially known as CFC-12) as the gas disclosures of which are incorporated herein by reference, propellant has declined. Each of FREON 11 and FREON 12 describe a medicament carrier which is adapted for use in a has an ozone depletion potential (hereinafter, ODP) of 1, and dry powder inhalator device and includes at least one carrier the Environmental Protection Agency of the U.S. Govern Screen having carrier Surfaces that define a plurality of ment has imposed regulations to phase out use of Such interstices in the Screen. At least one dose of a powdered propellants having an ODP=1. medicament is loaded onto the carrier Screen Surfaces whereby the interstices of the Screen are at least partially 0005 Instead, environmentally safe propellants having open and free of the powdered medicament. Spray drying for an ODPe0 and <0.5 are of increasing interest for use in preparation of particles, including for Selected medicinal preSSurized aerosol inhalators. Examples of Such environ uses, is well known. Additionally, the concept is well known mentally Safe propellants include, but are not limited to, the that, under certain conditions during spray drying from following: monochlorodifluoromethane (a hydrochlorofluo Solution, the resultant particles are not Solid, but rather are rocarbon which has an ODP=0.05 and is sold by DuPont hollow structures. Selected uses of Such hollow structures under the registered trademark DYMEL 22); perfluoroet involve certain medical applications. hane; 1,1,1,2-tetrafluoroethane (which has an ODP=0 and is sold by ICI under the trade name HFC-134a); and 1,1,– 0010 For instance, U.S. Pat. No. 4,590,206 to Forrester difluoroethane (which has an ODP=0 and is sold by various et al. ShowS spray dried respirable medicament particulates, companies under the trade name HFC-152a). Such as Sodium cromoglycate, in the shape of doughnut US 2003/0005927 A1 Jan. 9, 2003 rings, where the hollowness is the hole in the middle of the preSSurized aerosol inhalator, the Spherical hollow medica ring and the ring is Solid. Since Spray dried hollow spheres ment particulates should have a mass median aerodynamic have a low particle density, they are considered by Forrester diameter Suitable for deposition in a human being's lungs. et al. to be too fragile and are consequently to be avoided. 0016. It is therefore an object of the present invention to 0011. Also, U.S. Pat. No. 4,127,622 to Watanabe et al. provide a medicament for use in an inhalator which provides shows hollow particulates for gastric medicines Suspendable for administration of a dosage of medicament particles in gastric juice and which may remain in the Stomach for a wherein the particles that leave the inhalator and are inhaled long time. They are prepared by dissolving S-PI (Substance into the patient's lungs are formed as Spherical hollow for pepsin inhibition as the active ingredient) and ethylcel particulates having a desirable aerodynamic particle size and lulose (as the excipient) in a lower chlorinated hydrocarbon thus are of respirable particles size (i.e., they should have a (as the Solvent), So that the concentration of ethylcellulose is mass median aerodynamic diameter Suitable for deposition 0.5 to 4% by weight on the basis of the total weight of the in a human being's lungs) for maximum beneficial effi Solution, and then Spray drying the Solution at a temperature ciency, providing maximum efficacy to the patient.