Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-01-30
1997-09-09
Cintins, Marianne M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514475, 514533, 514548, 549464, A61K 3134, C07D49300
Patent
active
056657668
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/IE93/00040, filed Jul. 26, 1993.
The invention relates to pharmaceutical products.
The term "organic nitrates" as used in this specification refers to pharmacologically active organic nitrate compounds which relieve, or act as prophylactic against, angina pectoris.
Organic nitrates are dilators of arterial and venous smooth muscle. The dilation action on the venous system increases the venous capacity allowing pooling of venous blood. This in turn reduces the volume of blood returning to the heart thereby lessening the strains on the heart muscle by reducing the pressure in the heart chambers (ventricles). This, in turn, reduces the oxygen requirements of the heart muscle. The dilation action on the arterial system is achieved by increasing the volume of the arterial system with consequent lower resistance to blood flow. This, in turn, reduces the work that the heart is required to do. In the coronary arteries (heart) a transient widening of the arteries (vasodilation) increases blood circulation to the heart muscle thereby increasing oxygen availability to the heart muscle.
Patients with coronary artery narrowing may suffer from angina pectoris which is usually brought on by exercise, emotion or eating. The organic nitrates by virtue of their action described above relieve the symptoms of angina pectoris.
In more detail, organic nitrates act in two ways--indirectly and directly.
Indirectly: they are smooth muscle relaxants and thus dilate both arterial and venous blood vessels. At lower doses their action is mainly on the venous system resulting in a decreased right and left ventricular filling pressure. At lower doses, however, they have little effect on the systemic (arterial) filling pressure. At higher doses, the arterial effects are more marked and decreased systemic resistance is accompanied by a reduction in blood pressure (Flaherty et al 1976). The renodilating and arterial effects of nitrates relieve ischaemia (the cause of angina, pain) by reducing determinates of myocardial oxygen demand.
Directly: they relieve ischaemia by direct action on the coronary vasculature thereby increasing intercoronary collateral flow and reversal of coronary artery spasm.
One widely used organic nitrate is isosorbide mononitrate (ISMN) which is an active metabolite of Isosorbide dinitrate (ISDN). ISMN has a high bioavailability and has a comparatively long half life (4-5 hours). Thus it is very suitable for prophylactic angina therapy. This is particularly so when it is presented as a sustained release formulation.
According to the invention there is provided a pharmaceutical product comprising a salicylate of an esterifiable organic nitrate.
The term "salicylate" refers to a salicylate or derivative or complex thereof having anti-platelet activity.
Preferably, the organic nitrate is directly esterifiable. In other words, the organic nitrate has an hydroxy group which is available for esterification.
The organic nitrate may be an isosorbide nitrate such as isosorbide 2-mononitrate or, most preferably isosorbide 5-mononitrate.
Alternatively, the organic nitrate is a glyceryl nitrate such as glyceryl trinitrate (also known as 1,2,3-Propanetriol trinitrate and Nitroglycerin).
Alternatively, the organic nitrate is a pentaerythritol nitrate such as pentaerythritol trinitrate (also known as Pentrinitrol).
Alteratively, the organic nitrate may be indirectly esterifiable by removal of a nitrate from the nitrate compound and replacement by an hydroxy group prior to esterification.
In this case, the organic nitrate may be selected from the group consisting of Erythritol Anhydride, Mannitol Hexanitrate, Trolnitrate Phosphate, Pentaerythritol Tetranitrate, Propatyl Nitrate, Clonitrate, and Isosorbide Dinitrate.
In a particularly preferred embodiment of the invention the product is formed by esterification of an esterifiable organic nitrate with acetylsalicylic acid.
The product may be adapted for oral administration or percutaneous administration.
The invention also provides a tablet or capsule
REFERENCES:
patent: 4318921 (1982-03-01), Smith
patent: 4695465 (1987-09-01), Kagasawa et al.
patent: 4769379 (1988-09-01), Leitold et al.
patent: 4891373 (1990-01-01), Stoss et al.
European Heart Journal, vol. 12, Sup.A. 1991, pp. 2-4 "Why Use a Nitrate in 1990".
European Heart Journal, vol. 9, Supp.A 1988, pp. 45-49 "Mechanisms For The In Vivo Antiplatelet Effects of Isosorbide Dinitrate".
Eur. J. Clin. Pharmacology, vol. 25, 1983, pp. 779-782 "Pharmacological Internaction Between Nitroglycerin and Asprin After Acute and Chronic Aspirin Treatment of Healthy Subjects".
J. Cardiovascular Pharmacology, vol. 5, No. 5, 1983, pp. 874-877 "Influence of Aspirin on the Hemodynamic Effects of Sublingual Nitroglycerin".
AN 100 : 12587 Kim et al, "Phamaceutical Studies on the Estimation of Chloramphinzol with Antipyretics", Yahihak Hoech, 27(3), 207-13. Abstract Only 1983.
Byrne William
Rynne Andrew
Cal International Limited
Cintins Marianne M.
MacMillan Keith
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