Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1997-02-07
2003-11-04
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
Reexamination Certificate
active
06641839
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to isosorbide mononitrates (ISMN) and the use thereof in the preparation of ISMN-containing pharmaceutical formulations which allow one to achieve a controlled absorption of ISMN in vivo. The invention relates, in particular, to an ISMN formulation suitable for once-daily administration, which circumvents the tolerance and attenuation problems commonly observed in nitrate therapy.
Isosorbide mononitrates are vasodilators and arterial dilators, and by these actions in patients with angina pectoris reduce myocardial oxygen demands while maintaining or increasing coronary artery flow. The organic nitrate vasodilator, isosorbide dinitrate (ISDN) which is used in the treatment of angina pectoris has two major mononitrate metabolites, isosorbide-5-mononitrate (IS-5-MN) and isosorbide-2-mononitrate (IS-2-MN). It is now widely accepted that these metabolites are themselves pharmacologically active and IS-5-MN is now used in the treatment of angina pectoris in several countries. It is also thought that both metabolites contribute to the time course and character of response to ISDN. While ISDN has been used successfully for many years in the prophylaxis of angina pectoris and as adjunctive therapy in congestive heart failure, the discovery that it functions to a significant extent as a prodrug has led to an increase in the direct administration of ISMN for the same therapeutic indications. Unlike the parent substance (ISDN), ISMN does not undergo first-pass metabolism in the liver, thus providing for an overall greater systemic bioavailability of the mononitrate dose. ISMN is also completely absorbed from the gastrointestinal tract after oral administration and has a much longer half-life than ISDN. It has also been discovered by the Applicants that ISMN is absorbed through the skin, thus enabling one to achieve the desired plasma levels by administering ISMN transdermally.
These factors make ISMN a more attractive form of nitrate therapy for the management of angina and also for the development of long-acting oral nitrate formulations which serve to increase patient compliance, concomitantly indirectly increasing the therapeutic efficacy of nitrates in the population at large. Once-daily administration of ISMN offers many advantages over conventional more frequently administered forms. One of the main advantages is the increased patient compliance which is gained as a result of less frequent administration. It has been demonstrated that with once-a-day administration of a drug, patient compliance can be as high as 80%, while with twice-a-day and three times-a-day dosing, compliance levels can fall to 60% and 40% respectively. Thus, it is obvious that any reduction of dosage frequency can only serve to provide a therapeutic benefit to the patient. Another advantage offered by once-a-day dosing is the potential to reduce the incidence of side effects caused by the high-peak/low-trough plasma profile observed with more frequently administered drugs.
While this ambition has been realised with the recent introduction of ISMN formulations for once-daily administration in several countries, a remaining problem in nitrate therapy has not yet been addressed, this problem being nitrate tolerance and attenuation.
The issue of once-daily nitrate therapy was first addressed with the advent of transdermal nitroglycerin administration. Sustained release transdermal preparations of ISDN have since followed. However, it has been found that tolerance can develop extremely quickly to such transdermal systems and patients have been shown to achieve only minimal increases in exercise tolerance after 24 hours of transdermal nitrate administration. (AM J. Cardiol 1985;56:281-311). (The ability to increase a patient's capacity for exercise without onset of anginal symptomology is a major clinical criterion for determining the efficacy of anti-anginal agents).
Nitrate tolerance may be defined as that condition where the haemodynamic responsiveness of the target tissue is lost. Whilst the direct cause of nitrate tolerance is still a matter of some speculation, it is suspected that it may be due to changes in pharmacokinetics or to alterations in the property of target tissues such as the arterial and venal smooth muscle, making them less sensitive or refractory to the nitrate effect.
Nitrate therapy is the oldest treatment modality for angina pectoris and the phenomenon of nitrate tolerance has been observed in humans with all commonly used nitrates, regardless of the method or route of administration. This problem is as much a part of ISMN administration as with any other nitrate, and so to maximise the undoubted beneficial effects and recognised advantages of ISMN, it is necessary to design a formulation which overcomes the tolerance effect. ISMN, both in conventional (administered 10-40 mg two to three times daily) and sustained release (20-60 mg one to two times daily) forms achieves initial beneficial effects, but during the course of continued therapy, there is a marked attenuation of the effect in both magnitude and duration whereby the maximum therapeutic benefit can only be maintained by gradually increasing the dosage. The occurrence of this nitrate attenuation in patients suffering from such serious conditions as chronic angina pectoris is clearly undesirable, and requires constant monitoring and re-titration to safely manage the patient.
The ideal concept or model for an efficacious once-daily drug is one which provides constant blood levels in the therapeutic range over 24 hours. However, in the case of chronic nitrate therapy, maintenance of such constant levels over 24 hours, regardless of the route or frequency of administration, have been directly linked to the development of tolerance. Therefore, the ideal model does not hold true in the case of nitrates. Haemodynamic studies conducted to date suggest that short periods of nitrate withdrawal restore the haemodynamic and therapeutic effect of the nitrates. In this manner, the concept arose of allowing a washout period for a portion of the day, where the nitrate plasma concentration is allowed to fall below certain critical levels. With the conventional orally administered nitrates, it appears desirable to administer on a two or three times-a-day basis, omitting the final dose in the evening to allow a washout period or in the case of a transdermal device, to remove it after 12 or more hours following application: However, with the currently available once- and twice-a-day ISMN products, the simple withdrawal of one of the doses becomes impossible or in the case of the twice-a-day product, potentially dangerous as the patient would have sub-therapeutic levels for at least 12 hours. With ISMN and nitrates in general, the most effective duration for the washout period is suggested as being somewhat less than 12 hours. A washout phase occurs during which the concentrations fall precipitously (preferably with a peak-to-trough ratio of 6:1 or greater) and below critical minimum levels (100 ng/ml approx. for IS-5-MN and 20 ng/ml approx. for IS-2-MN).
SUMMARY OF THE INVENTION
Therefore, it is an object of the present invention to provide a formulation of a drug such as ISMN for once-daily administration, which is characterised by a high degree of absorption, which achieves significant and therapeutic plasma levels of the drug which are maintained for an extended period after administration, and which exhibits a controlled reduction in plasma levels sufficient to prevent or reverse drug tolerance.
In nitrate therapy, it is now widely believed that there is a critical minimum plasma level, above which one gets beneficial clinical effect, and below which one prevents nitrate tolerance. The minimum critical plasma concentration for therapeutic effect is, as indicated above, approximately 100 ng/ml for IS-5-MN and approximately 20 ng/ml for IS-2-MN, which is pharmacologically more active than the IS-5-MN metabolite. It is desirable to fall below these levels for a certain period of the day, preferabl
Foynes Mary Margaret
Geoghegan Edward James
Mulligan Seamus
Athpharma Limited
Travers Russell
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