Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-11-15
2002-11-05
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S321000
Reexamination Certificate
active
06476058
ABSTRACT:
BACKGROUND OF THE INVENTION
Pharmacological therapy utilizing pure formulations of S(−) amlodipine results in effective theraputic results while avoiding toxicities and adverse effects of racemic amlodipine. The methods and compositions described include the enriched deuterated forms of amlodipine as well as the nonenriched form. Amlodipine and deuteroamlodipine have a chiral center at C4 in the dihydropyridine ring, and thus can exist as optical isomers. The isomers may be separated by various methods, for example selective crystallization and column chromatography. See for example T. Shibanuma, et al., Chem.
Pharm. Bull
., 28, 2809-2812 (1980). Alternatively, S(−) amlodipine may be prepared using optically active reactants, or by a combination of separation and chiral synthesis. Optical isomers of compounds are specified (+) or (−), indicating the direction the chiral center rotates a plane of polarized light.
Optically active amlodipine, amlodipine derivatives and salts and deuterated amlodipine or deuterated amlodipine derivatives and salts are designated herein using the IUPAC R-S convention, sometimes called the “sequence rule.” A description of the R-S convention may be found, for example, in “Introduction to Organic Chemistry” by A. Streitwieser, Jr. and C. Heathcock, (Macmillan Pub. Co., New York, 1976), pages 110-114.
Optical purity is important since certain isomers may actually be deleterious rather than simply inert. For example, it has been suggested that the D-enantiomer of thalidomide was a safe and effective sedative when prescribed for the control of morning sickness during pregnancy, while the corresponding L-enantiomer has been thought to be a potent teratogen.
The active compound of the present invention is the S(−) isomer of the compound amlodipine and the s(−) isomer of deuterated amlodipine. Amlodipine is described in U.S. Pat. No. 4,572,909. Chemically, this compound is the S(−) isomer of amlodipine and is a long-acting calcium channel blocker.
Amlodipine is chemically described as (R.S.) 3-ethyl-5-1-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate. Its empirical formula is: C
2
0H
25
ClN
2
O
5
. Also encompassed within the present invention are compositions and methods of using deuterated compounds which are related to amlodipine. In the structures given below, R represents either hydrogen or deuterium. In a-preferred embodiment, R
1
represents either hydrogen or deuterium wherein one or more R
1
is deuterium. The symbol “*” denotes the chiral carbon.
The present commercial formulation of amlodipine contains the drug as the salt; amlodipine besylate. The term “amlodipine” herein refers to amlodipine and its pharmaceutically suitable salts and esters including amlodipine besylate and deuterated amlodipine and its pharmaceutically acceptable salts and esters including deuterated amlodipine besylate. This isomer will hereinafter be referred to as S(−) amlodipine. The terms “S(−) amlodipine” and “S(−) isomer of amlodipine” as used herein includes substantially optically pure S(−) amlodipine as well as optically pure S(−) amlodipine.
PHARMACOLOGICAL ACTION OF AMLODIPINE
Mechanism of Action
Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. The (−) isomer has been reported to be more active than the (+) isomer. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect.
Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.
The precise mechanisms by which amlodipine relieves angina have not been fully delineated, but are thought to include the following:
Exertional Angina: In patients with exertional angina, amlodipine reduces the total peripheral resistance (after-load) against which the heart works and reduces the rate pressure product, and thus myocardial oxygen demand, at any given level of exercise.
Vasospastic Angina: Amlodipine has been demonstrated to block constriction and restore blood flow in coronary arteries and arterioles in response to calcium, potassium epinephrine, serotonin, and thromboxane A2 analog in experimental animal models and in human coronary vessels in vitro. This inhibition of coronary spasm is responsible for the effectiveness of amlodipine in vasospastic (Prinzmetal's or variant) angina.
Pharmacokinetics and Metabolism
After oral administration of therapeutic doses of amlodipine, absorption produces peak plasma concentrations between 6 and 12 hours. Absolute bioavailability has been estimated to be between 64 and 90%. The bioavailability of amlodipine is not altered by the presence of food.
Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine. Ex vivo studies have shown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients. Elimination from the plasma is biphasic with a terminal elimination half-life of about 30-50 hours. Steady state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing.
The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial dose.
Elderly patients and patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40-60%, and a lower initial dose may be required.
Pharmacodynamics
Hemodynamics: Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. Although the acute intravenous administration of amlodipine decreases arterial blood pressure and increases heart rate in hemodynamic studies of patients with chronic stable angina, chronic administration of oral amlodipine in clinical trials did not lead to clinically significant changes in heart rate or blood pressures in normotensive patients with angina.
With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with amlodipine is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105-114 mmHg) had about a 50% greater response than patients with mild hypertension (diastolic pressure 90-104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressures (+1/−2 mmHg).
As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with
Criares Theodore J.
Isotechnika Inc.
Kim Jennifer
LandOfFree
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