Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Patent
1995-09-12
2000-07-11
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
424468, 424473, 424472, 424451, A61R 914
Patent
active
060869194
DESCRIPTION:
BRIEF SUMMARY
This Application is a 371 of PCT/SE95/00792 filed Aug. 30, 1995.
FIELD OF THE INVENTION
The present invention being a new pharmaceutical composition is related to a novel pharmaceutical preparation for oral administration and the use of this pharmaceutical preparation in the therapy of hypertension and of diseases in the cardiovascular system and secondary effects thereof in mammals including man. It is also related to compositions and to methods of preparing said pharmaceutical preparations. The pharmaceutical preparation is a fixed unit dosage form of the long-acting angiotensin converting enzyme (ACE) inhibitor, ramipril, in instant release form and a calcium antagonist of the dihydropyridine type i.e. a calcium channel blocking agent (dihydropyridine compound) in an extended release formulation.
The present invention also relates to solid preparations which are fixed combinations of the long acting ACE inhibitor ramipril in instant release form and a dihydropyridine compound such as the vascular selective drug felodipine in extended release form having the characteristic of achieving an effect over 24 hours after once daily administration. The pharmaceutical preparations of the present invention retain a good therapeutic effect in the treatment of hypertension even when the active drugs are administered in low doses. The pharmaceutical preparations reduce the dose related adverse events which result from administering higher doses of each of the drugs separately. The pharmaceutical preparations of this invention simplify the regimen and improve patient compliance.
BACKGROUND OF THE INVENTION
ACE inhibitors are compounds which inhibit the conversion of angiotensine I into the active angiotensine II as well as the breakdown of the active vasodilator bradykinin. Both of these mechanisms lead to vasodilation. Such compounds have been described in, for example, EP 158927, EP 317878, U.S. Pat. No. 4,743,450, and U.S. Pat. No. 4,857,520. Ramipril (disclosed in EP 079022) is a long-acting ACE inhibitor. Its active metabolite is the free acid ramiprilat, which is obtained in vivo upon administration of ramipril. In hypertensive patients administration of ramipril is known to cause a reduction in peripheral arterial resistance and thus a reduction of the blood pressure without a compensatory rise in heart rate. It is being used in the treatment of hypertension and congestive heart failure. Furthermore, ramipril has been shown to reduce mortality in patients with clinical signs of congestive heart failure after surviving an acute myocardial infarction. Ramipril has been suggested to have an added advantage over many other ACE inhibitors due to its pronounced inhibition of ACE in tissues resulting in organ protective effects in e.g. the heart, lung, and kidney.
Ramipril substance is sensitive to high temperature, moisture or compression and therefore, upon formulation into pharmaceutical preparations needs special attention in order to retain its stability (U.S. Pat. No. 5,151,433).
Calcium antagonists are compounds which influence the inflow of calcium ions into cells, in particular into the cells of smooth muscles. Such compounds of the dihydropyridine type have been described in, for example, GB 1358951 (nitrendipine), U.S. Pat. No. 3,644,627 (nifedipine), EP 007293 (felodipine), and GB 2164336 (lacidipine).
The most common adverse events which are observed in clinical use of the ACE inhibitor and the calcium antagonists of this invention are headache, coughing, peripheral oedema, flush, dizziness, fatigue and nausea.
Some dihydropyridines, for example nifedipine and felodipine are decomposed when exposed to light, and therefore, upon handling and formulation into pharmaceutical preparations need special attention in order to retain their stability.
Combinations of ACE inhibitors and calcium antagonists of dihydropyridine type in the treatment of hypertension have been described in, for example EP 488059, EP 180785 and EP 265685.
Bainbridge, A.D. et al. (Br. J. Clin. Pharmac. 1993, 36: 323-330) have studi
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Br. J. Clin. Pharmac., vol. 36, (1993), pp. 323-330.
Bauer Brigitte
Karlsson Christer
Lundberg Per Johan
Nilsson Berit
Sandberg Anders
Astra Aktiebolag
Benston, Jr. William E.
Page Thurman K.
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