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(12) United States Patent (10) Patent No.: US 6,641,839 B1 Geoghegan Et Al

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(12) United States Patent (10) Patent No.: US 6,641,839 B1 Geoghegan Et Al USOO6641839B1 (12) United States Patent (10) Patent No.: US 6,641,839 B1 Geoghegan et al. (45) Date of Patent: Nov. 4, 2003 (54) PHARMACEUTICAL FORMULATIONS FOR JP 59 84.820 5/1984 PREVENTING DRUG TOLERANCE JP 62126127 * 6/1987 (75) Inventors: Edward James Geoghegan, Athlone OTHER PUBLICATIONS (IE); Seamus Mulligan, Athlone (IE); “Isosorbide-5-Nitrate Sustained-release pellets-an Mary Margaret Foynes, Athlone (IE) example of computer Supported drug development', Zerbe et al., Pharmacuetical Resarch 1985, No. 1, Jan., pp. 30–36. (73) Assignee: Athpharma Limited, Roscommon (IE) “Glyceryl trinitrate (nitroglycerine) and the Organic nitrates choosing the method of administration”, J. Abrahms, Drugs (*) Notice: Subject to any disclaimer, the term of this 34; 391-403 (1987). patent is extended or adjusted under 35 “Dose Dependence of Tolerance during treatment with U.S.C. 154(b) by 407 days. mono-nitrates', M. Tauchert et al., Z. Cardiol. 72, Suppl. 3, 218–228 (1983). (21) Appl. No.: 08/797,318 “Tolerance Development during isosorbide dinitrate treat ment: Can it be circumvented?”, W. Rudolf et al., Z. Cardiol. (22) Filed: Feb. 7, 1997 72, Supple. 3, 195-198 (1983). Related U.S. Application Data “Anti-ischemic effects of 80mg tablet of isosorbide dinitrate in Sustained-release form before and after two weeks treat (63) Continuation of application No. 08/419,520, filed on Apr. ment with 80mg once daily or twice daily', S.Silver et al., 10, 1995, which is a continuation of application No. 08/320, Z.Cardiol. 72, Suppl. 3, 211-217 (1983). 599, filed on Oct. 11, 1994, which is a continuation of application No. 07/823,597, filed on Jan. 17, 1992, now “Hemodynamic measurements and excercise testing to abandoned, which is a continuation of application No. assess the development of tolerance against Slow-release 07/273,217, filed on Nov. 18, 1988, now abandoned. isosorbide dinitrate', H. Weidemann et al., Z. Cardiol.72, Suppl. 3, 229–232. (30) Foreign Application Priority Data “Tolerance to isosorbide dinitrate: rate of development and Nov. 20, 1987 (IE) ............................................... 3157/87 reversal', J. Parker et al., Circuation vol. 86, No. 5, 11/83. "Nitrate Tolerance', Leier, Amer. Heart Journ., 7/85, (51) Int. Cl. .................................................. A61K 9/24 224-232. (52) U.S. Cl. ....................................................... 424/473 “Effect of Intervals between doses on the development of (58) Field of Search .......................................... 424/473 tolerance to lisosorbide dinitrate', Parker et al., the New England Journal of Medicine, Jun. 4, 1987, pp. 1140–1444. (56) References Cited "Pharmacology of Nitroglycerine and long-acting nitrates', U.S. PATENT DOCUMENTS J. Abrahms, American Journ. of Card., vol. 56, 7/85, pp. 12a-18a. 4.291,015 A 9/1981 Keith et al. 4,336.243 A 6/1982 Sanvordeker et al. “New nitroglycerine formulations: Transdermal and Trans 4,369,172 A 1/1983 Schor .......................... 424/19 mucosal nitroglycerine', J. Abrahms, Z. Caridol, 74. Suppl. 4,615,699 A 10/1986 Gale et al. 4. 10–15 (1985). 4,655,766 A 4f1987 Theeuwes et al. Chem. Abstracts 101:78879s “Sustained-release transder 4,663,150 A 5/1987 Panoz et al. mal tapes” corresponding to Kokai Koho JP 59-85820, May 4,681.584 A 7/1987 Gale et al. 16, 1984. 4,698,062 A 10/1987 Gale et al. 4,721,619 A 1/1988 Panoz et al. ................ 424/459 * cited by examiner 4,767.808 A * 8/1988 Kydonieus et al. ........... 524/98 4,800,084 A 1/1989 Zerbe ......................... 424/458 Primary Examiner Russell Travers 4,863,742 A 9/1989 Panoz et al. ................ 424/473 (74) Attorney, Agent, or Firm-Finnegan, Henderson, 4,938,967 A * 7/1990 Newton et al. ... 424/458 Farabow, Garrett & Dunner, L.L.P. 5,071,656 A 12/1991 Lee et al. ...... ... 424/448 5,141,750 A 8/1992 Lee et al. ................... 424/448 (57) ABSTRACT FOREIGN PATENT DOCUMENTS ISOSorbide mononitrate formulations and methods of treat ment are disclosed. The formulations and treatments provide EP O159168 10/1985 EP O163000 12/1985 for Subtherapeutic levels of the mononitrate in a washout EP 2O7397 1/1987 .......... A61 K/31/44 period to prevent nitrate tolerance. EP O2SO267 12/1987 EP 29O262 11/1988 ............ A61 K/9/70 18 Claims, No Drawings US 6,641,839 B1 1 2 PHARMACEUTICAL FORMULATIONS FOR While this ambition has been realised with the recent PREVENTING DRUG TOLERANCE introduction of ISMN formulations for once-daily adminis tration in Several countries, a remaining problem in nitrate This disclosure is a continuation of patent application therapy has not yet been addressed, this problem being Ser. No. 08/419,520, filed Apr. 10, 1995, which is a con nitrate tolerance and attenuation. tinuation of patent application Ser. No. 08/320,599, filed The issue of once-daily nitrate therapy was first addressed Oct. 11, 1994, which is a continuation of patent application with the advent of transdermal nitroglycerin administration. Ser. No. 07/823,597, filed Jan. 17, 1992, now abandoned, Sustained release transdermal preparations of ISDN have since followed. However, it has been found that tolerance which is, itself, a continuation of patent application Ser. No. can develop extremely quickly to Such transdermal Systems 07/273,217, filed Nov. 18, 1988, now abandoned. and patients have been shown to achieve only minimal BACKGROUND OF THE INVENTION increases in exercise tolerance after 24 hours of transdermal nitrate administration. (AM J. Cardiol 1985:56:281-311). This invention relates to isosorbide mononitrates (ISMN) (The ability to increase a patients capacity for exercise and the use thereof in the preparation of ISMN-containing without onset of anginal Symptomology is a major clinical pharmaceutical formulations which allow one to achieve a 15 criterion for determining the efficacy of anti-anginal agents). controlled absorption of ISMN in vivo. The invention Nitrate tolerance may be defined as that condition where relates, in particular, to an ISMN formulation Suitable for the haemodynamic responsiveness of the target tissue is lost. once-daily administration, which circumvents the tolerance Whilst the direct cause of nitrate tolerance is still a matter of and attenuation problems commonly observed in nitrate Some speculation, it is Suspected that it may be due to therapy. changes in pharmacokinetics or to alterations in the property ISOSorbide mononitrates are vasodilators and arterial of target tissueS Such as the arterial and Venal Smooth dilators, and by these actions in patients with angina pectoris muscle, making them leSS Sensitive or refractory to the reduce myocardial oxygen demands while maintaining or nitrate effect. increasing coronary artery flow. The organic nitrate 25 Nitrate therapy is the oldest treatment modality for angina vasodilator, isosorbide dinitrate (ISDN) which is used in the pectoris and the phenomenon of nitrate tolerance has been treatment of angina pectoris has two major mononitrate observed in humans with all commonly used nitrates, metabolites, isosorbide-5-mononitrate (IS-5-MN) and regardless of the method or route of administration. This isosorbide-2-mononitrate (IS-2-MN). It is now widely problem is as much a part of ISMN administration as with accepted that these metabolites are themselves pharmaco any other nitrate, and So to maximise the undoubted ben logically active and IS-5-MN is now used in the treatment of eficial effects and recognised advantages of ISMN, it is angina pectoris in Several countries. It is also thought that necessary to design a formulation which overcomes the both metabolites contribute to the time course and character tolerance effect. ISMN, both in conventional (administered of response to ISDN. While ISDN has been used success 10–40 mg two to three times daily) and Sustained release fully for many years in the prophylaxis of angina pectoris 35 (20–60 mg one to two times daily) forms achieves initial and as adjunctive therapy in congestive heart failure, the beneficial effects, but during the course of continued discovery that it functions to a Significant extent as a prodrug therapy, there is a marked attenuation of the effect in both has led to an increase in the direct administration of ISMN magnitude and duration whereby the maximum therapeutic for the same therapeutic indications. Unlike the parent benefit can only be maintained by gradually increasing the substance (ISDN), ISMN does not undergo first-pass 40 dosage. The occurrence of this nitrate attenuation in patients metabolism in the liver, thus providing for an overall greater Suffering from Such Serious conditions as chronic angina systemic bioavailability of the mononitrate dose. ISMN is pectoris is clearly undesirable, and requires constant moni also completely absorbed from the gastrointestinal tract after toring and re-titration to safely manage the patient. oral administration and has a much longer half-life than The ideal concept or model for an efficacious once-daily ISDN. It has also been discovered by the Applicants that 45 drug is one which provides constant blood levels in the ISMN is absorbed through the skin, thus enabling one to therapeutic range over 24 hours. However, in the case of achieve the desired plasma levels by administering ISMN chronic nitrate therapy, maintenance of Such constant levels transdermally. over 24 hours, regardless of the route or frequency of These factors make ISMN a more attractive form of administration, have been directly linked to the development nitrate therapy for the management of angina and also for the 50 of tolerance. Therefore, the ideal model does not hold true development of long-acting oral nitrate formulations which in the case of nitrates. Haemodynamic Studies conducted to Serve to increase patient compliance, concomitantly indi date Suggest that short periods of nitrate withdrawal restore rectly increasing the therapeutic efficacy of nitrates in the the haemodynamic and therapeutic effect of the nitrates.
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