USOO5719123A United States Patent 19 11 Patent Number: 5,719,123 Morley et al. 45) Date of Patent: Feb. 17, 1998

54 CICLOSPORINFORM FOR PULMONARY 56) References Cited ADMINISTRATION FOREIGN PATENT DOCUMENTS 75 Inventors: John Morley, Muttenz, Switzerland; 221 1848 12/1989 United Kingdom...... COTK 7/64 Andreas Rummelt, Lörrach, Germany; Martin List, Basel, Switzerland OTHER PUBLICATIONS 73) Assignee: Sandoz Ltd., Basel, Switzerland Dowling et al., Surgery, vol. 108, No. 2 (1990) PP 198-205. Primary Examiner-Howard E. Schain 21 Appl. No.: 254,094 Attorney, Agent, or Firm-Robert S. Honor; Melvyn M. 22 Filled: Jun. 6, 1994 Kassenoff; Thomas O. McGovern 57 ABSTRACT Related U.S. Application Data Pulmonary administration of Ciclosporin in orthorhombic 63 Continuation of Ser. No. 128,444, Sep. 28, 1993, abandoned, crystal form (designated "CY-AX-III"), e.g. for the treat which is a continuation of Ser. No. 852,597, Mar. 17, 1992, ment of obstructive or inflammatory airways disease, e.g. abandoned. asthma, as well as crystalline Ciclosporin, e.g. CY-A/X-III, 30 Foreign Application Priority Data in spheroidal particulate form, processes for its preparation and its pharmaceutical use, e.g. for pulmonary administra Mar 18, 1991 GB United Kingdom ...... 9105705 tion. Pharmaceutical compositions comprising CYA/X-III (51 nt C. m. A61K 38/13 and crystalline Ciclosporin, e.g. CY-AX-III, in spheroidal 52 U.S. Cl...... 514/11: 514/15; 530/328; particulate form as well as Ciclosporin in solution in aerosol 53O?333 propellants are also provided. 58) Field of Search ...... 514/15, 11; 530/328, 530/333 13 Claims, No Drawings 5,719,123 1. 2 CCLOSPORN FORM FOR PULMONARY ents of organ transplants and for the treatment of a wide variety of autoimmune diseases. Further areas of investiga ADMNSTRATION tion have included potential applicability as an anti-parasitic agent as well as use in reversing tumor resistance to This is a continuation of application Ser. No. 08/128,444, chemotherapeutic, e.g. cytostatic, drug therapy and in pro filed Sep. 28, 1993, now abandoned, which in turn is a moting hair growth. continuation of application Ser. No. 07/852,597, filed Mar. More recently Ciclosporin has further been found to be 17, 1992, now abandoned. effective in the treatment of obstructive or inflammatory The present invention relates to novel pharmaceutical airways disease, notably asthma. Controlled clinical trials uses of and novel pharmaceutical compositions comprising involving oral administration of Ciclosporin to asthmatics, Ciclosporin in non-solvate orthorhombic crystal form as 10 e.g. asthmatics resistant to or dependent on steroid asthma well as to a novel form of crystalline Ciclosporin and further therapy, have been proposed and now reported in the litera novel pharmaceutical compositions comprising Ciclosporin. ture: see e.g. Czczecklik et al., Allergy, 46 Art. 072, (1991) Ciclosporin, also known as cyclosporin A, is the drug and Alexander et al., Lancet 339 (Feb. 8, 1992) p. 324 and substance of formula further references cited therein.

MeBmt-oAbu-Sar-MeLeu-Val-MeLeu-Ala-(D)Ala-Meeu-MeLeu-MeVal

2O Ciclosporin is known and commercially available under Reports have also appeared in the literature describing the Registered Trade Mark SANDIMMUNE) or SANDIM administration of Ciclosporin, in particular in animal lung MUNECE). transplantation models, by the pulmonary route: see e.g. In the solid state, Ciclosporin exists in both amorphous Dowling et al., Surgery (St.Louis) 108, (2), 198-205 (1990); and crystalline form. In the crystalline state various modi 25 Zenati et al., J. Heart Transplant 9, (1), 64 (1990); Mugger fications exist. In a first aspect the present invention relates burg et al., Am. Rev. Resp. Dis., 139 (4/Pt 2), A267 (1989); to Ciclosporin in the crystal form designated "CY-AX-III" and Burckart et al., J. Clin. Pharmacol., 29, (9), 860 (1989). . By "CY-AX-III" as used herein and throughout the accom Suppression of eosinophil infiltration of the airways follow pany