United States Patent (19) 11) Patent Number: 4,704,119 Shaw et al. 45 Date of Patent: Nov. 3, 1987 54 METHOD COMPRISING TRANSDERMAL 4,060,084 1 1/1977 Chandrasekaran et al......... 128/260 AND BUCCAL TREATMENT OF ANGINA 4,262,003 4/1981 Urquhart et al. ................... 128/260 4,286,692 9/1981 Chandrasekaran ..... ... 128/260 75 Inventors: Jane Shaw, Atherton; Robert M. 4,329,333 5/1982 Barr....................................... 424/19 Gale, Mountain View, both of Calif. 4,350,785 9/1982 Habib .................................... 524/55 73) Assignee: ALZA Corporation, Palo Alto, Calif. FOREIGN PATENT DOCUMENTS 21 Appl. No.: 932,440 0013606 4/1980 European Pat. Off. 22 Filed: Nov. 19, 1986 OTHER PUBLICATIONS Boehm, ANGEWANDTE CHEMIE vol. 5, pp. 533, Related U.S. Application Data 538-541, 1966. 63 Continuation of Ser. No. 463,593, Feb. 3, 1983, Pat. Cabot, Advertisements, pp. 4, 9, 12 and 18, 1979. No. 4,650,484, which is a continuation of Ser. No. Parkyns, Cata. Proc. Int. Congr. 5th, vol. 12, pp. 255 & 285,862, Jul 22, 1981, abandoned. 261, 1973. 51) Int. Cl." ........................... A61K9/00; A61J 3/00; Goodman, The Pharmacological Basis of Therapeutics, AON 25/26 4th Ed., p. 752, 1970. I52) U.S.C. ..................................... 604/897; 604/304 Burch, Am. Heart J., p. 842, 1966. 58) Field of Search ................................ 604/304-307, Csaky, Handbook of Pharmacology, 6th Ed., pp. 604/896, 897; 128/156 241-243, 1979. 56) References Cited Banes, J. Pharm. Sci., vol. 57, pp. 893-894, 1968. Merck, The Merck Index, p. 965, 1968. U.S. PATENT DOCUMENTS Pauling, The Nature of The Chemical Bond, p. 495, 1960. 2,896,819 7/1975 Zaffaroni ............................ 128/130 3,028,307 4/1962 Ninger ... ... 67/82 Primary Examiner-Stephen C. Pellegrino 3,063,900 1 1/1962 Winsor ... 167/65 Assistant Examiner-Jerome R. Smith, Jr. 3,096,242 7/1963 Young ... ... 167/65 Attorney, Agent, or Firm-Paul L. Sabatine; Edward L. 3,428,723 2/1969 Lowey ... ... 424/14 Mandell; Steven F. Stone A. 3,742,951 7/1973 Zaffaroni .... 28/268 3,789,119 1/1974 Fusari et al. .......................... 424/78 57 ABSTRACT 3,797,494 3/1974 Zaffaroni ... ... 128/268 A method is disclosed for treating an ischemic condi 3,921,636 11/1975 Zaffaroni ... ... 28/260 3,948,262 4/1976 Zaffaroni .... ... 128A260 tion. The method comprises coadministering topically 3,980,084 9/1976 Kross ......... ... 128/263 and internally a vasodilator to a patient having the con 3,996,634 12/1976 Zaffaroni ... 28A268 dition for treating said condition. 4,014,335 3/1977 Arnold ................................ 28/260 4,031,894 6/1977 Urquhart et al. ................... 128/268 3 Claims, 3 Drawing Figures U.S. Patent Nov. 3, 1987 4,704,119 FG, 12 N 3 4 1121212121212124 29 3. 30 SSGN / N sS Ess3 4,704,119 1. 2 flicted with same by administering a vasodilator drug or METHOD COMPRISING TRANSIDERMAL AND different vasodilator drugs topically and simultaneously BUCCAL TREATMENT OF ANGINA internally for obtaining clinical and therapeutic efficacy in treating angina pectoris. CROSS-REFERENCE TO RELATED 5 Yet another object of this invention is to provide a APPLICATIONS method for lessening the incidence of anginal attacks by This a continuation of U.S. patent application Ser. administering at least one vasodilator drug in a thera No. 06/463,593 filed on Feb. 3, 1983 now U.S. Pat. No. peutically effective amount topically and internally for 4,650,484, which application Ser. No. 06/463,593 is a producing the intended result. continuation of U.S. patent application Ser. No. 10 Other objects features and advantages of this inven 06/285,862 filed on July 22, 1981 now abandoned. tion will be more apparent to those skilled in the art These applications are incorporated herein by reference from the detailed description of the invention, and the and benefit is claimed of their filing dates. These appli accompanying claims. cations are assigned to ALZA Corporation of Palo 15 DETAILED DESCRIPTION OF THE Alto, California. INVENTION FIELD OF THE INVENTION In accordance with the practice of the invention, This invention pertains to a method for the manage there is provided a method comprising administering a ment of ischemic conditions including angina pectoris vasodilator drug in a therapeutically effective and bene by administering topically and internally a vasodilator ficial amount both topically and internally to a human drug to a symptomatic patient. patient over time. The method comprises coadminister ing the vasodilator simultaneously topically and inter BACKGROUND OF THE INVENTION nally, topically then internally, internally then topically, Vasodilator drugs are the mainstay in the symptom multiple administrations topically and internally, multi atic treatment of ischemic conditions including angina 25 ple administrations internally and topically, and the like. pectoris. Patients afflicted with these conditions, espe The term topically as used herein, denotes adminis cially angina pectoris, may require almost immediate tering to the skin of a patient in need of a vasodilator therapeutic response to a vasodilator drug for relief drug, the drug for percutaneous passage of the vasodi from pain, and in some instances fright, or patients with angina pectoris may require a continuous therapeutic 30 lator into the systemic circulation of the patient. The response to a vasodilator drug to decrease the fre skin sites include anatomic regions for transdermally quency and severity of attacks. Consequently, vasodi administering the drug as represented by the forearm, lator drugs frequently are administered sublingually abdomen, chest, back, buttock, mastoidal area and the because this method provides a rapid onset of therapeu like. The vasodilator is administered to the skin by plac tic effect and accompanying immediate relief of symp 35 ing on the skin a bandage that administers the vasodi toms; also vasodilator drugs are frequently administered lator, and which bandage is designed, shaped, sized, and orally because this method provides a longer duration adapted for easy placement and comfortable retention of action for alleviating clinical symptoms and can pro on the skin. vide prophylactic benefit. The term internally as used herein, denotes adminis While the above methods of administration provide 40 tering the vasodilator orally into the gastrointestinal needed benefits, there are disadvantages associated tract, administering the vasodilator into the mouth such therewith. For example, sublingually administered vas as buccally to the inner surface of the cheeks, and sub odilator drugs have a brief duration of action making it lingually beneath the tongue. The vasodilator can be necessary for some patients to take many doses, and administered internally in pharmaceutical formulations orally administered vasodilator drugs often are used in 45 expressed as tablet, sustained release, pellet, capsule, high doses, they are erratically absorbed into the sys solution, suspension, and the like. temic circulation, and do not provide continuous ther The phrase vasodilator drug, and the term vasodi apy. lator as used herein denotes vasodilators including ni trites, nitrates and their esters, such as their esters of OBJECTS OF THE INVENTION 50 sugars and polyols. The vasodilators generically possess Accordingly, it is an immediate object of this inven a member selected from the group consisting of ONO, tion to provide both a novel and useful method for and ONO2. The vasodilators include amyl nitrite, ethyl treating ischemic conditions including angina pectoris, nitrite, glyceryl trinitrate, also known as nitroglycerin, which method overcomes the disadvantages known to nitroglycerin absorbed on lactose such as 1 to 30% the prior art. 55 nitroglycerin on 99 to 70% lactose, preferrably 10% Another object of the invention is to provide a nitroglycerin and 90% beta-lactose, or optionally on method for treating ischemic conditions including an alpha-lactose, octyl nitrite, sodium nitrite, clonitrate, gina pectoris, which method comprises a combination erythrityl tetranitrate, isosorbide dinitrate, mannitol of administering a vasodilator drug topically and inter hexanitrate, pentaerythritol tetranitrate, penetrinitol, nally to a patient in need of such treatment. 60 triethanolamine trinitrate, trolnitrate phosphate (trieth Another object of the invention is to provide a anolamine trinitrate diphosphate), propatylnitrate, and method for treating ischemic conditions including in the like. tractable angina pectoris which method comprises ad The expression ischemic conditions as used herein ministering a vasodilator drug topically and concomi generically denotes coriditions that respond to vasodi tantly internally to produce clinically satisfactory re 65 lator therapy through hemodynamic response and the sults. like. The condition includes vasodilators used to relieve Yet still another object of this invention is to provide pain in the treatment of its most common clinical ex a method for treating angina pectoris in a human af. pression angina pectoris, as a prophylactic for the pre 4,704,119 3 4 vention of angina pectoris and in hypertension, for the Reservoir 22 is formed of a gelled fluid 26 having a low relaxation of the involuntary muscles of the blood ves to high viscosity. Reservoir 22 is preferrably made as a sels mainly the arteries and arterioles, for increasing continuous phase and it contains rheology agent 27 with oxygenation from vasodilation, mainly for increasing vasodilator dispersed throughout the reservoir. In ban the supply of oxygen to the heart, for improving exer 5 dage 20, outer edges 28 of backing member 21 can over cise performance, in the pharmaco-prevention of coro lay edges 19 of reservoir 22 and in this manufacture they nary disease, for increasing the circulation in the vascu will join edges 29 of membrane 24 in fluid tight arrange lar bed for warming cold fingers and toes and for treat ment. The sealed reservoir is made by pressure sealing, ing frostbite. The vasodilators and their uses are known fusion, adhesion, or through an adhesive applied to the in Cutting's Handbook of Pharmacology, Sixth Edition, O edges of contacting members.