Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/06—Antiarrhythmics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/08—Vasodilators for multiple indications
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives

Definitions

• compositions of matter containing optically pure S(-) felodipine possess potent activity in treating both systolic and diastolic hypertension while avoiding adverse effects including but not limited to edema of the extremities, headache and dizziness, which are associated with administration of the racemic mixture of felodipine.
• compositions of matter containing optically pure S(-) felodipine are useful in treating angina and such other conditions as may be related to the activity of S(-) felodipine as a calcium channel antagonist, including but not limited to cerebral ischemia, cerebral disorders, arrhythmias, cardiac hypertrophy, coronary vasospasm, myocardial infarction, renal impairment and acute renal failure, while avoiding the adverse effects associated with administration of the racemic mixture of felodipine. Also disclosed are methods for treating the above-described conditions in a human while avoiding the adverse effects that are associated with the racemic mixture of felodipine, by administering the S(-) isomer of felodipine to said huma .
• Stereoche ical purity is of importance in the field of pharmaceuticals, where 12 of the 20 most prescribed drugs exhibit chirality.
• a case in point is provided by the L-form of the jS-adrenergic blocking agent, propranolol, which is known to be 100 times more potent than the D-enantiomer.
• optical purity is important since certain isomers may actually be deleterious rather than simply inert.
• 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 this composition and method is an optical isomer of the compound felodipine, which is described in Berntsson et al. r United States Patent No. 4,264,611. Chemically, this S(-) isomer is ethyl methyl 4-(2,3-dichlorophenyl)-1, -4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate. This isomer will hereinafter be referred to as S(-) felodipine.
• S(-) Felodipine includes the optically pure and the substantially optically pure S(-) felodipine isomer. Felodipine, which is the subject of the present invention, is available commercially only as the 1:1 racemic mixture. That is, it is available only as the 1:1 mixture of optical isomers, called enantiomers.
• the pharmacologic class of calcium antagonists consists of three main chemical types; phenylalkylamines (e.g.. verapamil) , benzothiazepines (e.g. diltiazem) , and 1,4-dihydropyridines (e.g. nifedipine) . Given the structural heterogeneity of the class it is likely that the pharmacological action involves more than one site or mechanism of action.
• Nifedipine the first commercially available 1,4-dihydropyridine, is achiral and therefore cannot exist in optically active forms.
• Several second- generation 1,4-dihydropyridines have been produced that are chiral, existing as R or S enantiomers (or alternatively, (+) or (-)) . These include amlodipine, nicardipene, nimodipine, nitrendipine, isradipine, felodipine, nisoldipine and nilvadipine.
• the enantiomers of each of these compounds have been shown to have very different biological activities both in vitro and in vivo . Despite the fact that each enantiomer is pharmacologically distinct, all of the commercially available preparations of these compounds are racemic mixtures.
• the enantiomers of felodipine have different pharmacokinetic and pharmacodynamic properties.
• a racemic mixture of felodipine was given orally to healthy human subjects.
• the R(+) isomer of felodipine was found to have a 2.4-fold higher clearance than the S(-) isomer, with the S(-) isomer exhibiting a 2.1-fold higher maximum plasma concentration; the terminal half-lives of the two enantiomers were comparable (Soons, P.A. , et al.. J. Chromat. , 528: 343-356, 1990). This difference indicates stereoselective oxidation of the 1,4- dihydropyridine to its corresponding pyridine metabolite.
• S(-) Felodipine was determined to be 13 times more potent than R(+) felodipine in this in vitro assay.
• the competitive binding of the enantiomers to guinea pig skeletal muscles was also examined. Each isomer competed for binding sites with radiolabelled isradipine, another 1,4-dihydropyridine.
• S(-) Felodipine was found to compete 12 times more effectively than R(+) felodipine for these binding sites.
• An in vivo study with spontaneously hypertensive rats showed that S(-) felodipine was 13 times more potent in lowering blood pressure (Eltze, M. et aL, Chirality 2: 233-240, 1990).
• the racemic mixture of felodipine is presently used primarily as an antihypertensive agent and is generally taken orally. As stated above, the racemic mixture of felodipine produces peripheral vasodilation, resulting in decreases in both systolic and diastolic blood pressure when used as an antihypertensive agent. This antihypertensive effect occurs in the relative absence of significant or sustained effects on cardiac rate.
• hypertension appears to be the product of an inherited predisposition — coupled with dietary, emotional, and environmental factors, which results in a structural adaptation of the cardiac muscle and the large blood vessels. Most patients display heightened vascular and cardiac reactions to sympathetic nervous stimulation, but the precise relationship of sympathetic nervous stimulation to the etiology of the disease has yet to be determined. Nevertheless, hypertension results in chronic readjustment of cardiovascular hemodynamics, alteration of blood vessel walls, cardiovascular resistance and regional transmural pressures.
• Pharmacologic management of hypertension is generally directed to the normalization of altered he odynamic parameters, and many drugs and drug classes, either as monotherapy or in combination treatment, can reduce and control elevated blood pressure.
• treatment of hypertension does not always correspondingly benefit the morbidity and mortality of the condition, either because chronic hypertension has produced other significant and irreversible cardiovascular changes, or because present drugs have an adverse effect on some other risk factor for cardiovascular disease. Rather, current drug therapy simply provides sustained arterial pressure reduction.
• the racemic mixture of felodipine is useful in treating other disorders such as angina pectoris.
• Angina pectoris is a highly variable, rather poorly understood clinical syndrome reflecting a myocardial ischemia.
• cardiac work or myocardial oxygen demand exceeds the ability of the coronary arterial vascular system to supply oxygen, the resulting ischemia stimulates the sensory nerves of the heart, producing the sensation of angina characterized by episodes of precordial pressure, discomfort, or a severe, intense crushing pain which may radiate to several sites including the left shoulder and left arm.
• Physical activity or exertion characteristically initiates the condition, and rest or drug therapy relieves the condition.
• the signs and symptoms of an episode persist for a few minutes, but can be induced or exaggerated by a meal or exposure to cold air.
• Treatment is directed to the underlying disease, usually atherosclerosis, or to drugs which either reduce myocardial oxygen demand or improve oxygen supply.
• Calcium antagonists such as felodipine have been particularly useful in treating vasospastic angina, the angina of effort, and the unstable angina, due to the effect of the calcium channel antagonist on cardiac and vascular smooth muscle.
• Racemic felodipine may be useful in the treatment of cerebral ischemia. Cerebral ischemia, often the result of atherosclerotic disease or hypertension, results from insufficient cerebral circulation. Under normal circumstances, an extensive collateral circulation ensures adequate blood flow. However, cerebral ischemia may result from either an intra- or extracranial interruption of arterial blood flow. If interruption is transient, the cerebral tissues recover, and neurologic symptoms disappear. If the ischemia lasts for a somewhat more extended period, infarction results and the resulting neurologic damage is permanent. In the case of extended ischemia resulting in infarction, treatment is directed to the underlying vascular disease, to blood platelet aggregation inhibitors, and anticoagulant therapy.
• racemic felodipine may also be useful in treating cardiac arrhythmias.
• Cardiac arrhythmias represent a broad, complex group of electrophysiologic disorders that affect the mechanical properties of the heart and vasculature, altering normal cardiac rhythm, function and output. Normal cardiac rhythm originates with the sinoatrial node, which possesses high intrinsic automaticity. Adequate automaticity and conduction lead to activation of atria1 and ventricular fibers, producing in sequence the elements of normal functional heart beat.
• Calcium antagonists may be of value in conditions where calcium-related changes in membrane potential and conduction alter normal rhythm. In the absence of treatment, symptoms vary with individual arrhythmias, but are often the consequence of inadequate cardiac filling and output and often include fatigue, decreased exercise tolerance, syncope, shortness of breath, nausea, lightheadedness and the like.
• Racemic felodipine may be useful to treat cardiac hypertrophy.
• Cardiac hypertrophy can result from excessive workload either due to an obstruction to outflow, termed systolic overload, or to excessive volumes presented to the heart in diastole, termed diastolic overload.
• Systolic overload results in concentric ventricular hypertrophy, in which there is an increased thickness in the walls of the heart not associated with increased volume.
• Diastolic overload causes dilation and hypertrophy with an increased blood volume.
• An inadequate cardiac output results from the heart's failure in systolic or diastolic overload, leading to fatigue, shortness of breath, pulmonary congestion, edema and the like.
• Calcium channel antagonists effect workload and, as such, may be useful in treating cardiac hypertrophy due to the effect of the calcium antagonist on cardiac and vascular smooth muscle in reducing blood pressure.
• racemic felodipine could be used to treat coronary arterial spasm.
• Coronary arterial spasm can occur in the absence of significant coronary atherosclerosis and is thought to be an initiating event in variant angina and in myocardial infarction. Coronary spasm may occur without the patient feeling any significant discomfort.
• diverse neural impulses to the heart may provoke coronary vascular spasm. This may result in enhanced myocardial ischemia and arrhythmia, which in turn may culminate in ventricular fibrillation and sudden cardiac death.
• the calcium channel antagonists may be of particular usefulness due to their effect on cardiac and vascular smooth muscle.
• racemic felodipine may be useful in the treatment of myocardial infarction, ische ic myocardial necrosis, and ischemia reperfusion injury.
• Myocardial infarction or ischemic myocardial necrosis generally results from the abrupt reduction of coronary blood flow to a portion of the myocardium. The condition likely originates from atherosclerosis of the coronary arteries. Either coronary artery vasospasm or acute coronary thrombosis precipitates the condition, although the etiology is the subject of continuing research.
• Myocardial infarction is predominantly a disease of the left ventricle. Precordial pain and left ventricular dysfunction characterize the disease.
• the pain which can be severe aching or pressure, leads to apprehension.
• Symptoms include left ventricular heart failure, pulmonary edema, shock or significant cardiac arrhythmia.
• Calcium channel antagonists may find utility in the management of myocardial infarction patients due to their effects on coronary artery vasospasm, blood pressure or other effects on cardiac function or vascular smooth muscle.
• Racemic felodipine may be used to treat congestive heart failure.
• Congestive heart failure can be caused by hypertension, cardiomyopathy , coronary artery disease or valvular heart disease. Congestive failure results in poor cardiac output and elevated left-ventricular diastolic pressure, leading to dyspnea, fatigue, peripheral edema, and coughing.
• the ability of some calcium antagonists to lower afterload by dilating peripheral arteries without having a significant inotropic effect may increase their use in treating congestive heart failure.
• Racemic felodipine may also be of use in treating migraine.
• Classic migraine typically begins with visual auras followed by severe headaches, often accompanied by nausea and vomiting. Common migraine has similar symptoms without the preceding visual aura. The causes of migraine have been studied intensely, and are still a matter of debate. The most generally accepted cause is hypoxia due to reduced cerebral blood flow.
• Calcium channel antagonists have been used for migraine prophylaxis since they can increase cerebral blood flow.
• racemic felodipine may be useful for treating Raynaud's phenomenon, which is characterized by vascular spasm of the extremities. These vasospasms can be caused by cold or stress. A pallor or cyanosis is usually present due to severe constriction of the digital arteries. The phenomenon is often seen as a secondary disorder with arterial diseases or connective tissue diseases such as scleroder a, arthritis or lupus erythematosus. Calcium channel antagonists have been shown to be effective in treating Raynaud's phenomenon.
• Racemic felodipine may be useful in the treatment of asthma and bronchospas .
• Symptoms of asthma - coughing, wheezing, and dyspnea - are caused by constriction of tracheobronchial smooth muscle.
• Asthma attacks can be triggered by antigenic stimuli (pollen, dust) or non-antigenic stimuli (exercise, pollution, infection) .
• antigenic stimuli polylen, dust
• non-antigenic stimuli exercise, pollution, infection
• the response to these stimuli lead to secretions of chemical mediators that cause smooth muscle contraction.
• Calcium channel antagonists can be used to control bronchoconstriction and relieve asthma attacks.
• the racemic mixture of felodipine may be useful to treat renal impairment and acute renal failure.
• Renal impairment and acute renal failure are clinical conditions of diverse etiology, which are associated with an increasing azotemia or urea nitrogen in the blood, and often an oliguria or a diminished volume of urine in relation to fluid intake.
• the pathophysiology may originate prerenally, manifest as inadequate renal perfusion, due to extracellular fluid volume depletion or cardiac failure.
• the most common cause of intrinsic renal failure is prolonged renal ischemia.
• Postrenal azotemia may be associated with obstruction or renal glomerular and tubular dysfunction.
• Laboratory findings disclose progressive azotemia, acidosis, hyperkalemia, and hyponatremia.
• Factors aggravating kidney impairment or failure must be specifically treated, including heart failure, obstruction and the like. Moderate or severe hypertension has a deleterious effect on renal function, and management of the hypertension with a variety of drugs including calcium channel antagonists may be useful therapy.
• the racemic mixture of felodipine could be useful in the treatment of cognitive disorders. Cognitive disorders include but are not limited to dementia and age-associated memory impairment. Dementia can occur at any age. It is a structurally caused permanent or progressive decline in several dimensions of intellectual function that interferes substantially with individual normal social or economic activity.
• Alzheimers-type dementia One particular type of dementia is Alzheimers-type dementia.
• Alzheimers-type of dementia is thought to be due to a degenerative process, with a large loss of cells from the cerebral cortex and other brain areas. Acetylcholine-transmitting neurons and their target nerve cells are particularly affected.
• the brain shows marked atrophy with wide sulci and dilated ventricles. Senile plaques and neurofibrillary tangles are present. Memory loss is the most prominent early symptom. Disturbances of arousal do not occur early in the course.
• Alzheimer's presenile and senile onset dementias are similar in both clinical and pathologic features, with the former commonly beginning in the 5th and 6th decades and the latter in the 7th and 8th decades. The dementia usually progresses steadily, becoming well advanced in 2 to 3 years. Some cases of dementia occurring in the presenile period are hard to classify and are sometimes labelled idiopathic or simple presenile dementia.
• AAMI age-associated memory impairment
• compositions of matter containing optically pure S(-) felodipine are useful in treating other conditions as may be related to the activity of S(-) felodipine as a calcium channel antagonist, including but not limited to cerebral ischemia, cerebral disorders, arrhythmias, cardiac hypertrophy, coronary vasospasm, myocardial infarction, renal impairment and acute renal failure while avoiding the adverse effects associated with the administration of the racemic mixture of felodipine.
• the present invention also includes methods for treating the above-described conditions in a human while avoiding the adverse effects that are associated with the racemic mixture of felodipine by administering the S(-) isomer of felodipine to said human.
• the present invention encompasses a method of treating hypertension in a human, while avoiding the concomitant liability of adverse effects associated with that administration of racemic felodipine, which comprises administering to said human in need of such antihypertensive therapy, an amount of S(-) felodipine or a pharmaceutically acceptable salt thereof, substantially free of its R(+) stereoisomer, said amount being sufficient to alleviate said hypertension, but insufficient to cause said adverse effects associated with administration of racemic felodipine.
• the present invention also encompasses an antihypertensive composition for the treatment of a human in need of antihypertensive therapy, which comprises an amount of S(-) felodipine or a pharmaceutically acceptable salt thereof, substantially free of its R(+) stereoisomer, said amount being sufficient to alleviate said hypertension but insufficient to cause adverse effects associated with the administration of racemic felodipine.
• the present invention further encompasses a method of treating angina in a human, while avoiding the concomitant liability of adverse effects, which comprises administering to said human in need of such anti-angina therapy, an amount of S(-) felodipine, or a pharmaceutically acceptable salt thereof, substantially free of its R(+) stereoisomer, said amount being sufficient to alleviate said angina but insufficient to cause said adverse effects associated with the administration of racemic felodipine.
• the present invention encompasses an antianginal composition for the treatment of a human having angina, which comprises an amount of S(-) felodipine or a pharmaceutically acceptable salt thereof, substantially free of its R(+) stereoisomer, said amount being sufficient to alleviate said angina but insufficient to cause adverse effects of racemic felodipine.
• a further aspect of the present invention includes a metho ⁇ of treating a condition caused by excessive calcium influx in cells in a human, while avoiding the concomitant liability of adverse effects, which comprises administering to said human in need of a reduction in excessive calcium influx an amount of S(-) felodipine, or a pharmaceutically acceptable salt thereof, substantially free of its R(+) stereoisomer, sufficient to alleviate said condition but insufficient to cause the adverse effects associated with the administration of racemic felodipine.
• Conditions caused by excessive calcium influx in cells in a human include but are not limited to cerebral ischemia, cerebral disorders such as cognitive disorders including but not limited to Alzheimer's dementia and memory impairment, arrhythmias, cardiac hypertrophy, congestive heart failure, coronary vasospasm, migraine, bronchospasm and asthma,
• the present invention includes a composition for treating a condition caused by excessive calcium influx in cells in a human, which comprises an amount of S(-) felodipine, or a pharmaceutically acceptable salt thereof, substantially free of its R(+) stereoisomer, said amount being sufficient to alleviate said condition but insufficient to cause the adverse effects associated with the administration of racemic felodipine.
• the commercially available racemic mixture of felodipine (e.g. , a 1:1 racemic mixture of the two enantiomers) causes antihypertensive and antianginal activity; however, this racemic mixture, while offering the expectation of efficacy, causes adverse effects.
• Utilizing the S(-) isomer of felodipine results in clearer dose-related definitions of efficacy, surprisingly diminished adverse effects, and accordingly, an improved therapeutic index. It is, therefore, more desirable to use the S(-) isomer of felodipine.
• cardiovascular effects includes, .but is not limited to, cardiovascular effects (including tachycardia and diminished contractility of the heart) , edema of the extremities, headache, dizziness, flushing, fatigue, vertigo, and muscle cramps.
• composition contains a greater proportion or percentage of the S(-) isomer of felodipine in relation to the R(+) isomer of felodipine, the percentages being based on the total amount of felodipine.
• the term “substantially free of its R(+) stereoisomer” as used herein means that the composition contains a greater proportion or percentage of the S(-) isomer of felodipine in relation to the R(+) isomer of felodipine, the percentages being based on the total amount of felodipine.
• the term “substantially free of its R(+) stereoisomer” means that the composition contains a greater proportion or percentage of the S(-) isomer of felodipine in relation to the R(+) isomer of felodipine, the percentages being based on the total amount of felodipine.
• substantially free of its R(+) stereoisomer means that the composition contains at least 90% by weight of S(-) felodipine, and 10% by weight or less of R(+) felodipine. In the most preferred embodiment the term "substantially free of the R(+) stereoisomer” means that the composition contains at least 99% by weight S(-) felodipine, and 1% or less of R(+) felodipine. In another preferred embodiment the term "substantially free of its R(+) stereoisomer" as used herein means that the composition contains 100% by weight of S(-) felodipine.
• substantially optically pure S(-) isomer of felodipine and “optically pure S(-) isomer of felodipine” are also encompassed by the above-described meanings.
• treating hypertension means providing a normalization to otherwise elevated systolic and/or diastolic blood pressure, and by so doing providing relief from any possible symptoms or other hemodynamic effects caused by the elevated pressure.
• a method of treating angina means relief from the symptoms of myocardial ischemia, which include, but are not limited to, episodes of precordial pressure, discomfort, or a severe intense, crushing pain which may radiate, and which may be accompanied by changes in respiration, pulse rate, and blood pressure.
• a condition caused by excessive calcium influx in cells in a human includes but is not limited to conditions involving calcium influx into a human cell that may be present in smooth muscle, cardiac, and other tissues including lung and brain. These conditions include, but are not limited to, cerebral ischemia, cerebral disorders such as cognitive disorders including Alzheimer's dementia and memory impairment, arrhythmias, cardiac hypertrophy, congestive heart failure, coronary vasospasm, migraine, bronchospasm and asthma, Raynaud's phenomenon, myocardial infarction, renal impairment and acute renal failure.
• the symptoms associated with these disorders include, but are not limited to, the symptoms of precordial discomfort or pain, headache, fatigue, decreased exercise tolerance, syncope, shortness of breath, nausea, lightheadedness, edema, pulmonary congestion, arrhythmia or palpitation, azotemia, and/or oliguria.
• optically pure S(-) felodipine can be accomplished by the methods disclosed in Lamm, B. , and Simonsson, R. , Tett . Letters, 30(46): 6423-6426 (1989) which is hereby incorporated by reference and Eltze, M. et. al. Chirality 2:233 (1990).
• the magnitude of a prophylactic or therapeutic dose of (-) felodipine in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
• the dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient.
• the total daily dose ranges, for the conditions described herein is from about 0.01 mg. to about 100.0 mg.
• a daily dose range should be between about 0.5 mg to about 20.0 mg. while most preferably, a daily dose range should be between about 0.5 mg to about 10 mg.
• the therapy should be initiated at a lower dose, perhaps about 0.025 mg to about 2.5 mg and increased up to about 20 mg or higher depending on the patient's global response.
• an amount sufficient to alleviate hypertension but insufficient to cause said adverse effects is angina; and “an amount sufficient to alleviate said condition but insufficient to cause said adverse effects” wherein said condition includes but is not limited to cerebral ischemia, cerebral disorders, arrhythmias, cardiac hypertrophy, coronary vasospasm, myocardial infarction, renal impairment and acute renal failure are encompassed by the above described dosage amounts and dose frequency schedule.
• any suitable route of administration may be employed for providing the patient with an effective dosage of S(-) felodipine.
• oral, rectal, parenteral, transdermal, subcutaneous, intramuscular, and the like may be employed.
• Dos g forms include tablets, troches, dispersions, suspensions, solutions, capsules, patches, and the like.
• the pharmaceutical compositions of the present invention comprise S(-) felodipine as active ingredient, or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier, and optionally, other therapeutic ingredients.
• pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic acids including inorganic acids and organic acids.
• salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids.
• acids include acetic, benzene-sulfonic (besylate) , benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pa oic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid, p-toluenesulfonic, and the like.
• Particularly preferred are besylate, hydrobromic, hydrochloric, phosphoric and sulfuric acids. (See Campbell, S.F. et al. , US 4,806,557.)
• compositions include compositions suitable for oral, rectal and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated.
• the most preferred route of the present invention is the oral route.
• the compositions may be conveniently presented in unit dosage form, and prepared by any of the methods well known in the art of pharmacy.
• a suitable dosage range for use is from about 0.01 mg. to about 100.0 mg. total daily dose, given as a once daily administration in divided doses such as twice daily, if required.
• S(-) felodipine is given by tablet twice daily or as a sustained-release formulation which allows once-a-day dosage schedule.
• a dose range of between about 0.5 mg to about 20.0 mg is given as a once daily administration or in divided doses if required, and most preferably a dose range of from between about 0.5 mg to about 10.0 mg is given as a once daily administration or in divided doses if required.
• Patients may be upward titrated from below to within this dose range to a satisfactory control of symptoms or blood pressure as appropriate.
• S(-) felodipine can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
• the carrier may take a wide variety of forms depending on the form of the preparation desired for administration, e.g., oral or parenteral (including intravenous injections or infusions) .
• oral or parenteral including intravenous injections or infusions
• any of the usual pharmaceutical media may be employed.
• Usual pharmaceutical media include, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as for example, suspensions, solutions, and elixirs) ; aerosols; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like, in the case of oral solid preparations (such as for example, powders, capsules, and tablets) with the oral solid preparations being preferred over the oral liquid preparations.
• oral liquid preparations such as for example, suspensions, solutions, and elixirs
• aerosols or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like
• oral solid preparations such as for example, powders, capsules, and tablets
• the most preferred oral solid preparation is tablets.
• tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. in addition to the common dosage forms set out above, the compounds of the present invention may also be administered by controlled release and sustained release means and/or delivery devices such as those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; EPA
• compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, or aerosols sprays, each containing a predetermined amount of the active ingredient, as a powder or granules, or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion.
• Such compositions may be prepared by any of the methods of pharmacy, but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients.
• the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
• a tablet may be prepared by compression or molding, optionally, with one or more accessory ingredients.
• Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, and/or surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
• each tablet contains from about 0.01 mg to about 50 mg of the active ingredient, and each cachet or capsule contains from about 0.5 mg to about 50 mg of the active ingredient, S(-) felodipine.
• the tablet, cachet or capsule contains either one of three dosages, 0.5 mg, 2.5 mg and 5.0 mg (as scored tablets, the preferable dose form) of the active ingredient.
• negative inotropic activity may be comparably assessed using isolated heart preparations of adult rats.
• the tissues are prepared and perfused in vitro with Krebs- Henseleit buffer solution, with the activity of the calcium channel antagonists evaluated as a function of their concentration.
• the compounds are tested for their ability to alter cardiac contraction. Relative potency is calculated from the ICy values of the compounds, i.e. , the concentration required to depress contraction by 25%.
• Hind limb skeletal muscles from rats or guinea pigs are minced and homogenized. After filtration and repeated centrifugation, the pellet is homogenized and diluted in a Tris buffer to a protein concentration of 1-3 mg/ml. Volumes of this suspension containing 3-10 ⁇ g protein are incubated in the presence of a fixed concentration of 0.2 to 0.5 nM (+)-[ 3 H]-isradipine or a similar radioactive ligand and increasing concentrations of racemic felodipine, S(-) felodipine or R(+) felodipine. After 1 hour incubation, the bound and free radioactivity is measured in a scintillation counter and the affinity of the test compounds to the receptors is calculated.
• 450 g are killed by cervical dislocation.
• the hearts are removed and perfused with Krebs-Henseleit solution at c stant pressure (60 cm water) by means of retrograde cannulation of the aorta in a Langendorff apparatus.
• the Krebs-Henseleit solution consisting of 118.0 mM NaCl, 4.7 mM KC1, 5.5 M CaCl 2 , 1.2 mH MgS0 4 , 25.0 mM NaHC0 3 and 5.0 mM glucose, is prewarmed to 37° C and gassed with a mixture of 95% oxygen/5% carbon dioxide.
• a balloon catheter connected to a pressure transducer is placed in the left ventricle via the left atrium and is preloaded to a pressure of 40 mm Hg. Coronary perfusate flow is measured continuously, and changes in heart rate and left ventricular contractility are also monitored continuously.
• Each experiment consists of a 30 minute equilibrium period during which coronary flow is stabilized at 9-12 ml/min. Following this period, a vasoconstrictor is injected 3 times >.t 40 minute intervals into the cannulated aorta.
• This dose of U- 46619 (9,ll-methanoepoxy-PGH 2 ) evokes approximately a 75% decrease in coronary flow within 30-40 sec, and the effect is fully reversible after 20-25 min continuous perfusion.
• Racemic felodipine, S(-) felodipine or R(+) felodipine dissolved in dimethyl sulfoxide or the vehicle are injected in increasing concentrations prior to further U-46619 injections.
• the mean decrease in coronary flow obtained with three consecutive injections of U-46619 in the absence of the test substance is taken to be 100% and the percent inhibition of this effect in the presence of increasing concentrations of the test drugs is calculated.
• Complete individual dose-response curves for each test drug are generated in five hearts, enabling the calculation of the dose for the half- maximal antivasoconstrictor effect (ID 50 ) .
• Insulin is a hormone that activates various biochemical processes in the body, the most well known being facilitation of glucose transport over cell membranes and activation of cell growth.
• the development of insulin resistance is common both in diabetics and nondiabetics, but it is only the glucose transport system that develops resistance to insulin.
• To " pensate for the impaired glucose transport, the no . .1 body produces more insulin and the diabetic patient has to inject higher doses of insulin.
• insulin also is a growth hormone, the increased insulin concentration induces an accelerated growth of atherosclerotic lesions and increased risk for cardiovascular morbidity and mortality.
• the present studies are performed in old, spontaneously hypertensive rats (SHRs) , which are known to develop insulin resistance.
• SHRs spontaneously hypertensive rats
• Racemic felodipine, S(-) felodipine, and R(+) felodipine are studied for their effects on glucose transport, insulin plasma concentration and arterial blood pressure.
• systolic blood pressure measured via tail cuff occlusion
• fasting levels of plasma insulin and triglycerides are made: (1) systolic blood pressure (measured via tail cuff occlusion) ; (2) fasting levels of plasma insulin and triglycerides; and (3) glucose tolerance.
• the SHRs receive vehicle or test compound via oral gavage once or twice daily for two or four weeks. Measurements of blood pressure, circulating insulin and triglycerides, and glucose clearance are made following two (and four) weeks of drug administration. Any changes in insulin resistance resulting from the drug treatment are evident as changes in the ratio of plasma glucose/plasma insulin levels and from the glucose tolerance tests.
• the active ingredient, S(-) felodipine, lactose, and corn starch are blended until uniform; then the magnesium stearate is blended into the resulting powder.
• the resulting mixture is encapsulated into suitably sized two-piece hard gelatin capsules.
• Active ingredient S(-)felodipine 0 lactose BP starch BP
• the active ingredient, S(-) felodipine is sieved through a suitable sieve and blended with lactose, starch, and pregelatinized maize starch.
• Suitable volumes of purified water are added and the Q powders are granulated. After drying, the granules are screened and blended with the magnesium stearate.
• the granules are then compressed into tablets using 7 mm diamter of punches.
• Tablets of other strengths may be prepared _ by altering the ratio of active ingredient to lactose or the compression weight and using punches to suit.

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• 1992
  • 1992-12-01 JP JP5510392A patent/JPH07501551A/ja active Pending
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