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US5489610.Pdf |||||||| US00548961OA United States Patent 19 11 Patent Number: 5,489,610 Fung et al. 45) Date of Patent: 8 Feb. 6, 1996 54 SUSTAINED RELEASE ORGANIC NITRITE 58 Field of Search .................................... 514/506, 509, THERAPY 514/645, 740 75 Inventors: Ho-Leung Fung, Getzville; John A. 56) References Cited Bauer, Williamsville, both of N.Y. U.S. PATENT DOCUMENTS 73 Assignee: Research Foundation of the State 5,278,192 l/1994 Fung et al. .............................. 514f645 University of New York, Albany, N.Y. OTHER PUBLICATIONS * Notice: The portion of the term of this patent Derwent Abstracts 78–35053A, "Medicaments for Treating disclaimed.subsequent to Jan. 11, 2011, has been Cardiardiogenic Shock”, Fribolinis is et al. (1978). Patent Abstracts of Japan, vol. 12, No. 467, Dec. 7, 1988, 21 Appl. No.: 199,280 "Tape Preparation'. 22, PCT Filed: Jun. 30, 1993 Primary Examiner-Frederick Krass Attorney, Agent, or Firm-Kirschstein et al. 86 PCT No.: PCT/US93/06235 (57) ABSTRACT S371 Date: Mar. 1, 1994 A method of treating a patient suffering from a condition S 102(e) Date: Mar. 1, 1994 requiring vasodilator therapy, comprising long term, con 87 PCT Pub. No.: WO94/01103 tinuous adminstration of an organic nitrite to the patient in a dosage form capable of delivering a sufficient therapeutic PCT Pub. Date:Jan. 20, 1994 amount of nitrite to the bloodstream of the patient thereby providing effective vasodilator therapy for at least 24 hours Related U.S. Application Data without the development of tolerance in the patient. The a method of the invention is useful in treating conditions such 63 Continuation-in-part of Ser. No. 908,224, Jul. 2, 1992, Pat. as angina, particularly chronic, stable angina pectoris, No. 5,278,192. ischemic diseases and congestive heart failure, and for (51l int. Cl. ................................... A61K 31/13 controlling hypertension and/or impotence in male patients. 52 U.S. Cl. .......................... 514/506; 514/509; 514/645; 514f740 14 Claims, 4 Drawing Sheets U.S. Patent Feb. 6, 1996 Sheet 1 of 4 5,489,610 OO 80 5R.LVEDP% 60 . 40 20; 2 4 6 8 O' "22 HOURS OF INFUSION FG. OO 80 t LVEDP9, 60 OF INITIAL 40 20 O' 22 HOURS OF INFUSION FG.2 U.S. Patent Feb. 6, 1996 Sheet 2 of 4 5,489,610 20 OO 80 O LVEDP% sus 40 20 l O 2 4 6 8 O 22 HOURS OF INFUSION F. G. 3 OO 80 LVEDP, 60 % NITIAL 40 20 O O 5 O 5 20 25 HOURS OF INFUSION F. G. 4 U.S. Patent Feb. 6, 1996 Sheet 3 of 4 5,489,610 7 HEPTANE DINTRTE OO 8O LVEDP % NITIAL SO 40 20 O O 5 O 5 20 25 HOURS OF INFUSION F. G.5 CYCLOHEXYLMETHYL NITRITE LVEDP, % NITIAL O 5 O 5 20 25 HOURS OF INFUSION F. G. 6 U.S. Patent Feb. 6, 1996 Sheet 4 of 4 5,489,610 PHENYLETHY NITRITE OO 80 LVEDP, % NITAL 60 40 20 O 5 O 5 20 25 HOURS OF INFUSION F. G.7 3 CHLORO, 2.2 DIMETHYLPROPYL NITRITE OOH -- - - - - - - - - - - - 80 LVEDP % INITIAL 60 40 20 O 5 O 15 2O 25 HOURS OF INFUSION F. G. 8 5,489,610 1. 2 SUSTANED RELEASE ORGANIC NITRITE leaving the patient unprotected during the majority of the THERAPY "dose-off" period. Furthermore, a more frequent on/off dosing strategy (4 or 8 hour on/off cycles) was not successful CROSS-REFERENCE TO RELATED in avoiding tolerance development. At present no dosage APPLICATION regimen with nitrovasodilators has been developed that can achieve the dual objectives of avoidance of hemodynamic This application is a continuation-in-part of Application tolerance while continuously maintaining their beneficial Ser. No. 07/908,224, filed Jul. 2, 1992, now U.S. Pat. No. effects. 5,278,192. Additionally, headaches typically accompany treatment O with organic nitrates such as nitroglycerin. Headaches may FIELD OF THE INVENTION be recurring with each daily dose, especially at higher doses. The present invention relates generally to drug therapy Aside from headaches, which may be severe and persistent, and, more particularly, to a method of vasodilator therapy for other adverse central nervous system (CNS) reactions treating ischemic diseases, angina pectoris, hypertension include apprehension, restlessness, weakness, vertigo, diz and/or congestive heart failure. 15 Ziness and faintness. BACKGROUND OF THE INVENTION SUMMARY OF THE INVENTION Congestive heart failure is a complex and heterogeneous The primary object of the present invention is to provide disease state associated with decreased cardiac performance 20 a new and improved method of vasodilator therapy, for and increased pulmonary and peripheral oedema. Conges example, in treating ischemic diseases, angina pectoris, tive heart failure results when the left, right or both ven congestive heart failure, impotence, and/or controlling tricles fail to pump sufficient blood to meet the body's needs. hypertension, substantially without development of hemo An estimated 4 million people currently in the United States dynamic tolerance in the patient. have congestive heart failure. While no single drug or drug 25 We have now discovered that tolerance associated with class has proven to be ideal in treating this disease, vasodi conventional vasodilator therapy (i.e., nitrovasodilators) can lator therapy constitutes a major approach in its clinical be avoided while providing effective long term, continuous management. treatment. More particularly, the present invention provides Organic nitrate esters, such as nitroglycerin, isosorbide a method for treating a patient suffering from a condition dinitrate, isosorbide-5-mononitrate, etc. are organic chemi 30 requiring vasodilator therapy, comprising the long term, cals that contain the ONO group. Nitrates are part of a continuous administration of an organic nitrite to the patient family of vasodilators called nitrovasodilators and have in a dosage form capable of delivering a sufficient amount of enjoyed extensive use in cardiovascular therapy; but other the nitrite to the bloodstream to provide effective vasodilator members of this class, e.g., nitroprusside, molsidomine and therapy for at least 24 hours without development of toler organic nitrites are not organic nitrates. Nitrovasodilators 35 ance in the patient. The method of the invention is useful in such as isosorbide dinitrate and glyceryl trinitrate are useful treating conditions such as, for example, angina, particularly in treating congestive heart failure because they cause a chronic, stable angina pectoris, ischemic diseases and con prompt reduction in preload and/or afterload, and relieve the gestive heart failure, and for controlling hypertension and/or venous congestion often associated with this disease. impotence in male patients. Nitroglycerin, also referred to as trinitroglycerin or glyc 40 In connection with the method of the invention, any erin trinitrate, has also been used to treat angina pectoris for conventional drug delivery system for the dosage form can over 100 years. Nitroglycerin and other nitrovasodilators be employed. It is understood that the drug delivery system have been available for the treatment of angina pectoris and can take virtually as many different forms as there are congestive heart failure in a number of different dosage dosage forms available for delivery of nitrite to patients. For forms for some time. These include sublingual, oral and 45 example, drug delivery systems within the scope of the buccal tablets as well as capsules, topical creams and invention include sublingual, oral and buccal tablets as well ointments, patches, tapes, lingual sprays and intravenous as capsules, caplets, tablets, topical creams and ointments, Solutions. patches, tapes, lingual sprays and intravenous solutions. Transdermal nitroglycerin patches were introduced in 50 recent years in an effort to overcome some of the disadvan BRIEF DESCRIPTION OF THE DRAWINGS tages and inconveniences of other dosage forms. In particu FIG. 1 is a graph illustrating the effects of continuous lar, transdermal patches were formulated to provide intravenous infusion (10-15 g/min) of nitroglycerin to increased systemic bioavailability as well as constant deliv congestive heart failure rats. The pharmacologic effect mea ery of the drug over a 24 hour period or longer. Typically, the 55 patches are applied once daily, either in the morning or sured was the left ventricular end-diastolic pressure evening, and changed daily at approximately the same time, (LVEDP). and have become popular in the treatment of chronic, stable FIG. 2 is a graph illustrating the effects of continuous angina and congestive heart failure. intravenous infusion (3.13 or 5.0 l/hr) of isobutyl nitrite to However, the positive effects of these patches are often 60 congestive heart failure rats. The pharmacologic effect mea short lived. For example, it has been shown that nitroglyc Sured was the LVEDP. erin produces rapid hemodynamic tolerance (within several FIG. 3 is a graph illustrating the effects of continuous hours) in congestive heart failure after continuous adminis intravenous infusion (3.13 pul/hr) of isoamyl nitrite to con tration either by intravenous or transdermal routes. Inter gestive heart failure rats. The pharmacologic effect mea mittent dosing with a regimen of 12 hours on/12 hours off 65 Sured was the LVEDP. can avoid development of tolerance but the effect of the FIG. 4 is a graph illustrating the effects of continuous previous dose is lost within 2 hours of drug withdrawal, intravenous infusion (1.0 ul/hr) of 1,3-propane dinitrite to 5,489,610 3 4 congestive heart failure rats. The pharmacologic effect mea use of an intermittent dosing schedule with a nitrate free Sured was the LVEDP. interval of 10-12 hours (e.g., removal of a transdermal nitroglycerin system in the early evening and application of FIG. 5 is a graph illustrating the effects of continuous a new system the next morning, or other dosing regimens intravenous infusion (1.0 ul/hr) of 1,7-heptane dinitrite to that allow for a nitrate-free period).
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