Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-02-26
2001-06-12
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S026000, C514S423000, C514S223500
Reexamination Certificate
active
06245787
ABSTRACT:
This invention relates to compositions comprising (1) amlodipine, a pharmaceutically acceptable amlodipine acid addition salt, or felodipine and (2) an angiotensin converting enzyme (ACE) inhibitor. The invention further relates to methods for reducing mortality and/or morbidity in patients with congestive heart failure, comprising co-administering a congestive heart failure treating amount of a combination comprising amlodipine, a pharmaceutically acceptable amlodipine salt, or felodipine and an ACE inhibitor.
BACKGROUND OF THE INVENTION
Congestive heart failure, regardless of its etiology, is characterized by a weakness of the myocardial tissue of the left and/or right ventricle of the heart to pump and circulate blood into systemic and/or pulmonary circulations. It is accompanied by circulatory and neurohumoral changes which result in failure to deliver sufficient blood and oxygen supply to peripheral tissues and vital organs. If left untreated, the health of a patient with congestive heart failure could progress to the point where the disease would be fatal.
Amlodipine, 3-ethyl-5-methyl-2-(2-aminoethoxymethyl)4-(2-chlorophenyl)-1,4-dihydro-6-methylpyridine-3,5-dicarboxylate, and its pharmaceutically acceptable acid addition salts are calcium channel blockers known for their effectiveness in the treatment, inter alia, of congestive heart failure, see U.S. Pat. No. 5,155,120 to Lazar et al. Amlodipine is currently marketed as the besylate salt.
Felodipine, ±ethyl methyl-4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate, is also a calcium channel blocker. It is disclosed in U.S. Pat. No. 4,264,611 to Berntsson et al. and is currently marketed as the free base.
ACE inhibitors are well known in the art for their activity in inhibiting angiotensin converting enzyme, thereby blocking conversion of the decapeptide angiotensin I to angiotensin II. The principal pharmacological and clinical effects of ACE inhibitors arise from suppression of synthesis of angiotensin II. Angiotensin II is a potent pressor substance and, therefore, blood pressure lowering can result from inhibition of its biosynthesis, especially in animals and humans whose hypertension is angiotensin II related. ACE inhibitors are effective antihypertensive agents in a variety of animal models and are clinically useful for the treatment of hypertension in humans.
ACE inhibitors are also employed for the treatment of heart conditions such as angina. It is known that at least some ACE inhibitors can improve (i.e., decrease) morbidity and mortality in patient populations with heart conditions.
International application PCT/US92/03873, published as WO 92/20342, discloses pharmaceutical compositions containing a combination of an angiotensin II antagonist and a calcium channel blocker for use in the treatment of hypertension and congestive heart failure. The publication states that the particular compositions can further contain antihypertensives and/or diuretics and/or angiotensin converting enzyme inhibitors.
SUMMARY OF THE INVENTION
This invention provides compositions comprising
a compound selected from amlodipine, pharmaceutically acceptable salts of amlodipine, and felodipine; and
an ACE inhibitor.
The invention further provides methods for reducing morbidity and/or mortality in patients with congestive heart failure, comprising co-administering to a mammal, especially a human, in need of such treatment a congestive heart failure treating amount of a combination comprising:
a compound selected from amlodipine, pharmaceutically acceptable salts of amlodipine, and felodipine; and
an ACE inhibitor.
The phrase “with congestive heart failure” includes patients who are at risk of suffering from this condition relative to the general population, even though they may not have suffered from it yet, by virtue of exhibiting risk factors. For example, a patient with untreated hypertension may not have suffered from congestive heart failure, but is at risk because of his or her hypertensive condition.
Amlodipine besylate is preferred as the calcium channel blocker. “Co-administration” of a combination of amlodipine (or its salts, or felodipine) and an ACE inhibitor means that these components can be administered together as a composition or as part of the same, unitary dosage form. “Co-administration” also includes administering amlodipine and an ACE inhibitor separately but as part of the same therapeutic treatment program or regimen. The two components need not necessarily be administered at essentially the same time, although they can if so desired. Thus “co-administration” includes, for example, administering amlodipine plus an ACE inhibitor as separate dosages or dosage forms, but at the same time. “Co-administration” also includes separate administration at different times and in any order. For example, a patient may take one component of the treatment in the morning and the other component at night.
The method referred to above for reducing morbidity and/or mortality generally refers to benefits and/or survival in the long term. Clinical benefits may be observable within a few weeks, for example 2-3 weeks. It is preferred, however that co-administration be effected long term; that is for longer than 16 weeks, and prefereably longer than 6 months. It is noted that a variety of short term (less than 16 weeks) exercise and hemodynamic trials have demonstrated that the addition of amlodipine to ACE inhibitors for the treatment of heart failure is safe. Recent studies in heart failure with a variety of pharmacologic compounds have demonstrated that short-term gain may not be predictive of long-term benefit, however.
Other components may also be optionally included as part of the compositions or methods of this invention. When included, such optional components will generally include digoxin and/or a diuretic. As known in the art, digoxin is a glycoside obtained from the leaves of digitalis. Other forms of digitalis exist, although digoxin is the form employed completely, or nearly so, throughout the medical profession.
The invention is surprising because, as demonstrated by the clinical studies disclosed below, the combination of amlodipine and an ACE inhibitor decreases the morbidity and/or mortality of a patient population with congestive heart failure over and above that which can be attributed to an ACE inhibitor alone. This result is surprising because, although ACE inhibitors are known to be capable of improving morbidity and/or mortality in patients with congestive heart failure, calcium channel blockers are not known to produce such a desirable effect.
REFERENCES:
patent: 4572909 (1986-02-01), Campbell et al.
patent: 4879303 (1989-11-01), Davison et al.
patent: 5098910 (1992-03-01), Becker et al.
patent: 5155120 (1992-10-01), Lazar et al.
patent: 5500434 (1996-03-01), Becker et al.
patent: 5948799 (1999-09-01), Cropp
patent: 0265685 (1988-04-01), None
patent: 9220342 (1992-11-01), None
Ramo et al., Amlodipine, a long acting calcium antagonist drug . . . , Am. J. Cardiol., vol. 64/17, pp. 781-831 (1989).*
Pieper, John., Evolving role of calcium channel . . . , vol. 16/2, pp. 43s-49s, (1965).*
Cohn, J., ACE-inhibitors in nonischemic heart failure . . . , European Heart Journal, vol. 16, pp. 133-136, (1995).*
Eur. J. Clin. Pharmacol., 1994, 285-9, Sun, J.X. et al: “Pharmacokinetic interaction study between benazepril and amlodipine in healthy subjects”.
J. Am. Coll. Cardiol., 1993, 22/4 Suppl. A (139A-144A), USA, Elkayam U. et al: “Calcium channel blockers in heart failure”.
American College of Cardiology 40th Annual Scientific Session, Atlanta, Georgia, USA Mar. 3-7, 1991. J AM Coll Cardiol, 17 (2 Suppl. A). 1991. 274A, ZP000578571 Packer M et al: “Randomized Multicenter Double-blind Placebo-Controlled Evaluation of Amlodipine in Patients with Mild-to-Moderate heart Failure”.
Drugs, 1994, 47/Suppl. 4 (47-58), Cohn J. N.: “Vasodilators in heart failure. Conclusions from V-HeFT II and rationale for Y-HeFT III”.
Prakash C. Deedwania, Arch Intern Med, vol. 150, Sep. 1990, pp. 1798-1805.
Cropp Anne B.
Kraska Allen R.
Benson Gregg C.
Jarvis William R. A.
Jones James T.
Kim Vickie
Pfizer Inc.
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