WO1997046241A1 - Formulation and method for treating congestive heart failure - Google Patents

Formulation and method for treating congestive heart failure Download PDF

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Publication number
WO1997046241A1
WO1997046241A1 PCT/US1997/009914 US9709914W WO9746241A1 WO 1997046241 A1 WO1997046241 A1 WO 1997046241A1 US 9709914 W US9709914 W US 9709914W WO 9746241 A1 WO9746241 A1 WO 9746241A1
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WIPO (PCT)
Prior art keywords
formulation
moxonidine
dosage form
pharmaceutically acceptable
acceptable salt
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PCT/US1997/009914
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English (en)
French (fr)
Inventor
John L. Mcnay
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Eli Lilly And Company
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Publication date
Application filed by Eli Lilly And Company filed Critical Eli Lilly And Company
Priority to HU0003885A priority Critical patent/HUP0003885A2/hu
Priority to PL97330637A priority patent/PL330637A1/xx
Priority to JP10500901A priority patent/JP2000511906A/ja
Priority to EP97928011A priority patent/EP0914128A1/en
Priority to BR9709546A priority patent/BR9709546A/pt
Priority to AU32331/97A priority patent/AU3233197A/en
Priority to IL12696697A priority patent/IL126966A0/xx
Publication of WO1997046241A1 publication Critical patent/WO1997046241A1/en
Priority to NO985695A priority patent/NO985695L/no
Priority to EA199900006A priority patent/EA199900006A1/ru

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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

  • the present invention is in the fields of pharmacology and pharmaceutical chemistry and provides formulations and a method for using 4 -chloro-5- (imidazoline- 2-ylamino)-6-methoxy-2-methylpyrimidine for the treatment of congestive heart failure.
  • CHF Congestive heart failure
  • the term describes a complicated symptom complex which may include dyspnea, fatigue, pulmonary congestion, an enlarged heart and peripheral edema.
  • CHF is the end result of long-term or severe cardiac or circulatory deficits. It is often caused by long-standing hypertension, acute myocardial infarction, valvular disease, idiopathic cardiomyopathy and a wide variety of secondary insults. CHF incidence is increasing and is the most frequent cause of hospitalization in patients over 65 years of age.
  • both cardiac and peripheral regulatory mechanisms come into play to help counteract the primary failure of the pump.
  • the heart rate increases, left ventricular volume and pressure may rise and the heart may dilate and/or undergo hypertrophy (currently termed a remodeling process).
  • hypertrophy currently termed a remodeling process.
  • blood volume is increased, sodium and water are retained and a reflex inqrease in the activity of the sympathetic nervous system enhances arterial and venous tone and increases contractility of the heart.
  • a panoply of neurohormones are elevated in the plasma
  • norepinephrine renin
  • renin neuropeptide Y
  • NPY neuropeptide Y
  • angiotensin II aldosterone
  • vasopressin atrial pressure
  • natriuretic factor natriuretic factor.
  • These compensatory changes act together to maintain perfusion of vital beds such as the brain and heart.
  • these potent mechanisms may have evolved originally to protect against acute loss of blood volume (e.g. hemorrhage), in the state of chronic CHF, continued activation of compensatory mechanisms (especially the sympathetic system) may act to impede efficient cardiac function by making it more difficult for the heart to eject blood.
  • the inappropriate elevation of peripheral neurohormones contributes to the exacerbation of many of the symptoms of CHF such as pulmonary and peripheral edema, dilutional hyponatremia and hypokalemia.
  • increased sympathetic tone may lead directly to an increase in cardiac rate, myocyte necrosis and hypertrophy leading to increased myocardial remodeling, increased wall tension and diastolic dysfunction resulting in increased heart failure.
  • Increased activity of the sympathetic nervous system also stimulates epinephrine, norepinephrine and renin release which in turn increase further the impedance to ventricular ejection and decreases blood flow to the kidneys. The latter acts as a further stimulus for activation of the renin-angiotensin system, and the cycle is perpetuated.
  • ACE inhibitors have been useful adjuncts to therapy and are now recommended for almost all patients with this disorder.
  • ⁇ -blockers are especially interesting since it was long thought that directly interfering with the compensatory function of the sympathetic nervous system to stimulate contractility and maintain blood pressure might worsen CHF. In fact, judicious use of such agents has proven beneficial especially in cardiomyopathy as opposed to ischemic heart disease.
  • certain ⁇ -blockers such as bucindolol and carvedilol may also decrease plasma renin and
  • Clonidine was examined in a clinical trial, but only 13 patients were enrolled and treatment duration was relatively short (12 weeks), Giles et al., Angiology, 38, 537-548, (1987).
  • moxonidine has been suggested as a potentially beneficial therapeutic agent, Mangiapane et al., FASEB , 9 , 265 (1995), Michel et al., J. Cardiovasc. Pharmacol., 20, Supp. 4, 524-530, (1992).
  • Elevated systolic and diastolic blood pressure are major risk factors for cardiovascular disorders such as myocardial infarction, coronary artery disease, and stroke. While it is well-recognized that hypertension is not due to cardiovascular disorders. While it is well-recognized that hypertension is not due to cardiovascular disorders. While it is well-recognized that hypertension is not due to cardiovascular disorders. While it is well-recognized that hypertension is
  • hypertension is also an important risk factor for coronary heart disease; equally important as elevated serum lipids.
  • Hypertension is generally defined as an elevation of systolic and/or diastolic blood pressures to above 140/90 mm Hg and is the most common cardiovascular disease. In the United States alone, about 20-40 million people require treatment for hypertension.
  • the currently available therapies include converting enzyme inhibitors, diuretics, vasodilators, beta blockers, central
  • Blood pressure is a function of vascular resistance, intravascular volume, cardiac output and the contractile state of the blood vessels.
  • Many physiological systems are involved in regulating the homeostasis of intravascular volume, mainly through renal salt and water excretion. Cardiac output is regulated both by intrinsic cardiac factors and by extrinsic factors and the sympathetic nervous systems.
  • contractile state of the blood vessels is determined by intrinsic vascular factors, the sympathetic nervous system, relaxing factors from endothelial cells, the renin
  • RAS angiotensin system
  • fluid balance The RAS is the principle means by which the body controls fluid
  • electrolyte balance and blood pressure. It is part of a complex homeostatis mechanism that involves a variety of hormones, enzymes, and autonomic signals.
  • the key physiologic end product of the RAS is the
  • Angiotensin II octapeptide Angiotensin II.
  • the physiological activation of the RAS may be viewed as a primitive yet highly developed system evolved to protect the organism against sudden loss of blood volume or more gradual loss of sodium.
  • Angiotensin II increases perfusion pressure of vital beds and promotes readsorption of sodium and water. The latter affects occur through the action of aldolsterone and
  • Overactivity of the local RAS may be responsible for end-organ abnormalities associated with chronic
  • Angiotensin II is known to be an important mediator of smooth muscle cell growth and differentiation. Thus, Angiotensin II may mediate the vascular proliferative response that accompanies injury to the vessel wall by mechanical means (i.e. angioplasty) or long-term elevated systemic pressure. As noted above, Angiotensin II is an important regulator of glomerular function, and overactivity of the RAS is undoubtedly an important factor in the development and progression of renal diseases such as diabetic nephropathy and the
  • renin and angiotensin converting enzyme are primarily responsible for the generation of Angiotensin II and are widely distributed throughout the body.
  • renin and prorenin are synthesized in the juxtaglomerular (JG) cells of the kidney and released into the circulation, more recent data suggests strongly a broader distribution.
  • JG juxtaglomerular
  • Renin and/or its mRNA are found in the brain, blood vessels, anterior pituitary, adrenal cortex, kidney, ovary, uterus, and heart. Renin is subject to feedback inhibition by Angiotensin II as well as by elevated glomerular pressures and an increase in the sodium load.
  • ACE is a dipeptidyl carboxypeptidase found mainly in association with the capillary lining of the lung. Like Renin, it is also widely distributed, being located in blood vessels, heart, kidney, intestinal tract, and liver. ACE mediates the removal of the terminal dipeptide from
  • Angiotensin I and also catalyzes the breakdown of
  • ACE angiotensin II synthesis
  • ACE is not a rate limiting factor. Furthermore, it lacks specificity, requiring only a tripeptide sequence with a free carboxy group (as long as the intermediate amino acid is not
  • proline a variety of endogenous peptides are substrates for the enzyme including enkephalins, substance P and Lys-bradykinin.
  • Renin release from the juxtaglomerular (JG) cells in the kidney is inhibited by a direct action of Angiotensin II on the JG cells.
  • Angiotensin II also stimulates
  • aldosterone secretion which increases sodium retention and increases potassium excretion in the kidney. With increased sodium retention, intravascular volume increases and thus inhibits renin secretion.
  • These feedback loops are divided into long (volume), short (circulating angiotensin II), and ultra-short (intra-JG cell angiotensin II).
  • pharmacological interventions are activators or inactivators of renin secretion. Specifically, many drugs used in high blood pressure treatment directly or indirectly alter renin secretion. This effect may counteract or enhance the effect of the medicine used to treat high blood pressure.
  • Renin and angiotensinogen are also located in the vessel walls and in the brain. This has been termed as the extra renal renin-angiotensin-system (RAS).
  • RAS extra renal renin-angiotensin-system
  • the low renin levels and the non-responsiveness of renin secretion to physiological stimuli in hypertensives may be masked by the presence of a very active extravascular renin system.
  • Agents which interfere with the renin angiotensin system have been used for over 15 years to treat
  • ACE Angiotensin converting enzyme
  • alpha 2 -adrenoceptor- agonists such as clonidine
  • side effects such as sedation, dry mouth, and other non-specific effects.
  • Plasma half life (t 1/2 ) is between 2 and 3 hours.
  • moxonidine is 1 - 3 ng/ml.
  • the maximum plasma level occurs in 30 - 180 minutes.
  • the duration of the antihypertensive effect (up to 24 hours), in contrast to the plasma half life, may be due to moxonidine's slower clearance from its central sites of action (deep compartment).
  • Moxonidine has low plasma protein binding of 7% and is over 60% eliminated unchanged by the renal route. In patients with impaired renal function, peak plasma concentration (C max ), plasma half life and area under plasma concentration curve from 0 - 24 hours (AUC 0-24 ) are increased, but no accumulation occurs.
  • Moxonidine has turned out to be a very well tolerated antihypertensive drug. As a typical side effect, dry mouth occurred in 2 - 15% of patients but usually improved with ongoing treatment. Other side effects like tiredness, headache and dizziness appeared in just a few patients. After acute administration moxonidine lowered plasma levels of norepinephrine and epinephrine, and plasma renin activity was decreased. Moxonidine has no influence on the circadian rhythm of blood pressure. No rebound phenomenon was seen after cessation of treatment.
  • Moxonidine is a well tolerated antihypertensive agent alone and in combination with other antihypertensive drugs, such as diuretics, calcium-antagonists and ACE-inhibitors.
  • moxonidine is a suitable medication for hypertensive drivers. It is neutral in respect to metabolic parameters and causes no respiratory depression, which is important in treatment of
  • moxonidine has been an effective daily dose range, with reductions in blood pressure between 10 and 20%.
  • the antihypertensive efficacy of moxonidine was confirmed in open studies of up to 2 years duration as well as in comparative studies of up to 6 months duration.
  • moxonidine was an efficacious and safe antihypertensive agent which improves quality of life. Following a 12 week treatment period, blood pressure decreased and heart rate was slightly reduced by 3 beats/minute. Clinical laboratory parameters remained unchanged except for slight reductions in uric acid, glucose, triglyceride and cholesterol. In 6.9% of patients side effects were reported.
  • an antihypertensive drug should induce regression of myocardial hypertrophy, which often proceeds heart failure.
  • therapeutic regimens which lead to a decrease in growth-factors, i.e. norepinephrine and angiotensin II, induce regression of left ventricular hypertrophy.
  • the antihypertensive effect and regression of left ventricular hypertrophy were evaluated in 20 hypertensive patients.
  • Drugs, especially ACE-inhibitors, used in the treatment of hypertension are increasingly important in the treatment of congestive heart failure. These drugs
  • the self-regulating cardiovascular-system counteracts drug-induced changes with compensatory reflex mechanisms.
  • Centrally acting drugs avoid compensatory counter-regulations, particularly the increase of
  • Moxonidine reduces systemic vascular resistance while increasing cardiac output in hypertensive patients. These hemodynamic changes may have beneficial effects in patients suffering from symptomatic congestive heart
  • Moxonidine was administered as a single oral dose of 0.4 mg. Hemodynamic and neurohumoral parameters at rest and during exercise were investigated before as well as 1, 2 and 3 hours after drug intake. Pulmonary pressure indices and cardiac output were determined both at rest and during ergometric exercise by means of Swan-Ganz catheterisation.
  • the presently claimed invention provides a method of treating congestive heart failure comprising
  • the invention also provides pharmaceutical
  • formulations comprising an effective dose of moxonidine, or a pharmaceutically acceptable salt thereof, in association with one or more carriers, diluents or excipients to afford nonimmediate release of said moxonidine.
  • the present invention further provides a method and formulations to afford a mean plasma elimination half- life of from 6 to 16 hours.
  • the present invention provides a method and formulations to afford a mean time to maximum plasma concentration of from 2.5 to 5 hours.
  • 4-chloro-5-(imidazoline-2-ylamino)-6-methoxy- 2-methylpyrimidine is prepared as follows.
  • N-acetelimidazoline-2-one is prepared by reacting acetic anhydride with 2-imidazolidone at room temperature. The reaction mixture is heated to between 80 °C and 100 °C for 90 minutes and then cooled to from about 10 °C to about -10 °C to afford N-acetelimidazoline-2-one.
  • the first intermediate, 4,6-dihydroxy-2- methylpyrimidinamine is synthesized by preparing sodium ethoxide in situ from sodium and anhydrous ethanol under a nitrogen blanket. Acetamidine hydrochloride and diethyl malonate are added and the reaction mixture heated to boiling for 2 to 5 hours to afford 4,6-dihydroxy-2- methylpyrimidine.
  • the second intermediate, 4,6-dihydroxy-2-methyl-5- nitropyrimidine is then synthesized by slowly adding 4 , 6 - dihydroxy- 2 -methylpyrimidine to a reaction mixture of fuming nitric acid in acetic acid. Once addition of 4, 6- dihydroxy-2-methylpyrimidine is complete, the reaction mixture is stirred for one-half to 2 hours to afford 4,6- dihydroxy-2-methyl-5-nitropyrimidine.
  • the fifth intermediate, N-(1-acetylimidazolin-2- ylidene)-4,6-dichloro-5-pyrimidinamine, is then prepared by combining phosphorous oxychloride, N-acetylimidazolin-2-one and 5-amino-4,6-dichloro-2-methylpyrimidine, and heating to boiling during from 2 to 4 hours, and then cooling, with stirring to room temperature.
  • the final product 4-chloro-N-(imidazolin-2- ylidene)-6-methoxy-2-methyl-5-pyrimidinamine is synthesized by first preparing sodium methoxide in situ from anhydrous methanol and sodium.
  • the compound of the present invention may be isolated per se or may be converted to an acid addition salt using conventional methods.
  • the invention includes pharmaceutically acceptable salts of moxonidine.
  • Moxonidine can react with any of a number of nontoxic inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluene-sulfonic, methanesulfonic acid, oxalic acid, p-bromophenyl-sulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • examples of such pharmaceutically acceptable salts thus are the sulfate pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,
  • dihydrogenphosphate metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate,
  • compositions are those formed with mineral acids such as hydrochloric acid,
  • treating includes therapeutic and prophylaxis of the symptoms and named condition and amelioration or elimination of the condition once it has been established.
  • “Plasma elimination half-life” refers to the time required after administration of a single dose to reduce the amount of moxonidine in the plasma by 50 percent. At times, plasma elimination half- life will be referred to herein as t 1/2 .
  • Time to maximum plasma concentration refers to the time required after administration of a single dose for moxonidine to reach the maximum concentration in the plasma. Unless otherwise stated, “mean” when associated with plasma elimination half- life and time to maximum plasma concentration refers to the geometric average of stated values.
  • the compound of the present invention is an I 1 - imidazoline ligand demonstrating substantial selectivity for I 1 receptors over ⁇ 2 adrenergic receptors.
  • moxonidine In saturation binding experiments in bovine rostral ventrolateral medulla (bovine RVLM), moxonidine demonstrates a selectivity value (K i at ⁇ 2 sites in uM/Ki at I 1 sites in uM) of greater than 20 and preferably greater than 30 X, where K i is the
  • selectivity value in bovine RVLM is less than 4.
  • Mammalia class of higher vertebrates includes, but is not limited to, a human.
  • the dose of compound to be administered in general, is from about 0.001 to about 5.0 mg/day; as usual, the daily dose may be
  • a more preferred range of doses is from about 0.01 to about 2.0 mg/day; other dosage ranges which may be preferred in certain circumstances are from about 0.005 to about 2.0 mg/day; from about 0.1 to about 2.0 mg/day; from about 0.05 to about 0.8 mg/day; and a particularly preferred range is from about 0.05 to about 2.0 mg/day.
  • the dose for a given patient is always to be set by the judgment of the attending physician, and that the dose is subject to modification based on the size of the patient, the lean or fat nature of the patient, the characteristics of the particular compound (freebase or salt) chosen, the severity of the patient's symptoms and psychological factors which may affect the patient's physiological responses.
  • Pharmaceuticals are substantially always formulated into pharmaceutical dosage forms, in order to provide an easily controllable dosage of the drug, and to give the patient an elegant and easily handled product.
  • nonimmediate (sustained) release pharmaceutical formulation comprising one or more pharmaceutically acceptable carriers, diluents or excipients and the compound or a
  • Such formulations will contain, by weight, from about 0.01 percent to about 99 percent of the compound.
  • the active ingredient will usually be mixed with at least one carrier, or diluted by at least one carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container using conventional techniques and procedures for the preparing of
  • the carrier when the carrier serves as a diluent, it may be a solid, semi-solid or liquid material which acts as a vehicle, excipient or medium for the active ingredient.
  • the formulations can be in the form of tablets, granules, pills, powders, lozenges, sachets, cachets, elixirs, emulsions, solutions, syrups, suspensions, aerosols (as a solid or in a liquid medium) and soft and hard gelatin capsules.
  • Suitable carriers, diluents and excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate,
  • microcrystalline cellulose microcrystalline cellulose, polyvinylpyrrolidone, cellulose, tragcanth, gelatin, syrup, methylcellulose, methyl- and propyl-hydroxybenzoates, vegetable oils, such as olive oil, injectable organic esters such as ethyl oleate, talc, magnesium stearate, water and mineral oil.
  • the formulations may also include wetting agents, lubricating, emulsifying and suspending agents, preserving agents, sweetening agents, perfuming agents, stabilizing agents or flavoring agents.
  • the formulations of the invention are formulated so as to provide nonimmediate release of the active ingredient, by procedures well-known in the art.
  • the formulations of the present invention are formulated to provide nonimmediate release of the active ingredient for oral or implantable administration.
  • Nonimmediate release dosage forms release of the drug from its dosage form is the rate limiting step in the release-absorption-elimination kinetic scheme. This is distinguished from the immediate release dosage forms where absorption of drug across a biological membrane is a rate limiting step.
  • Nonimmediate release delivery systems have been divided into four categories: (1) delayed release; (2) sustained release; (3) site-specific release; and (4) receptor release.
  • delayed release systems are those that employ repetitive, intermediate dosing of a drug from one or more immediate release units incorporated into a single dosage form.
  • delayed release systems include repeat action tablets and capsules and enteric-coated tablets where timed release is achieved by a barrier
  • Sustained release delivery systems include both controlled release and prolonged release.
  • sustained release systems include any drug delivery system that achieves slow release of drug over an extended period of time. When the system maintains relatively constant drug levels in the blood or target tissue it is considered a controlled release system. Where the system extends the duration of action over that afforded by a conventional delivery system, it is considered a prolonged release system.
  • Site-specific and receptor release systems refer to targeting of a drug directly to a desired biological location.
  • a target is a particular organ or tissue.
  • the target is the particular receptor for a drug within a particular organ or tissue.
  • Typical oral nonimmediate release forms include diffusional systems and dissolution systems.
  • diffusional systems the release rate of drug is determined by its diffusion through a water-insoluble polymer.
  • diffusional devices There are generally two types of diffusional devices, reservoir devices in which a core of drug is surrounded by polymeric membrane; and matrix devices in which dissolved or dispersed drug is distributed substantially uniformly and throughout an inert polymeric matrix.
  • matrix devices in which dissolved or dispersed drug is distributed substantially uniformly and throughout an inert polymeric matrix.
  • many systems that utilize diffusion may also rely to some extent on dissolution to determine the release rate.
  • microencapsulation of drug particles and press-coating of whole tablets or particles.
  • particles coated by microencapsulation form a system where the drug is contained in the coating film as well as in the core of the microcapsule.
  • Drug release typically includes a combination of dissolution and diffusion with dissolution being the process that controls the release rate.
  • Common material used as the membrane barrier coat, alone or in combination, are hardened gelatine, methyl and
  • hydroxypropylcellulose polyvinylacetate, and various waxes.
  • Plastic matrices which have been employed include methyl acrylate-methyl methacrylate, polyvinyl chloride and polyethylene.
  • Hydrophilic polymers include methyl cellulose, hydroxypropylcellulose and
  • Fatty compounds include various waxes such as carnauba wax, and glyceryl
  • tristearate Preparation of these matrix systems are by methods well known to those skilled in the art. These methods of preparation generally comprise mixing the drug with the matrix material and compressing the mixture into tablets. With wax matrixes, the drug is generally dispersed in molten wax, which is then congealed, granulated and compressed into cores. As with other nonimmediate systems, it is common for a portion of the drug to be available immediately as a priming dose and the remainder to be released in a sustained fashion. This is generally
  • a priming dose in a coat on the tablet.
  • the coat can be applied by press coating or by conventional pan or air suspension coating.
  • Dissolution systems generally are products that have a decreased dissolution rate where the drug is highly soluble.
  • Several approaches to achieving a slow dissolution rate include preparing an appropriate salt or derivative of the active agent, by coating the drug with a slowly
  • Encapsulated dissolution systems are prepared either by coating particles or granules of drug with varying thickness' of slowly soluble polymers or by microencapsulation.
  • the most common method of microencapsulation is coacervation, which involves addition of a hydrophilic substance to a coloidal
  • the hydrophilic substance which operates as the coating material, is selected from a wide variety of natural and synthetic polymers including shellacs, waxes, starches, cellulose acetate, phthalate or butyrate,
  • microencapsule is immediately available for dissolution and absorption.
  • Drug release therefore, can be controlled by adjusting the thickness and dissolution rate of the coat.
  • the thickness can be varied from less than one ⁇ m to 200 ⁇ m by changing the amount of coating material from about 3 to about 30 percent by weight of the total weight.
  • different thickness' typically three of four, the active agent will be released at different,
  • Coated particles can, of course, be directly compressed into tablets or placed into capsules.
  • a slowly dissolving polymer carrier into a tablet.
  • aqueous dispersion methods there are two methods for preparing drug-polymer particles, congealing and aqueous dispersion methods.
  • congealing method the drug is mixed with a polymer or wax material and either cooled or cooled and screened or spray-congealed.
  • aqueous dispersion method the drug-polymer mixture is simply sprayed or placed in water and the resulting particles are collected.
  • Osmotic systems are also available where osmotic pressure is employed as the driving force to afford release of a drug.
  • Such systems generally consist of a core of drug surrounded by a semipermeable membrane containing one or more orifices.
  • the membrane allows diffusion of water into the core, but does not allow release of the drug except through the orifices.
  • materials used as the semipermeable membrane include polyvinyl alcohol,
  • a further system comprises ion-exchange resins.
  • These resins are water-insoluble cross-linked polymers containing salt forming groups in repeating positions on the polymer chain.
  • the active agent is bound to the resin by repeated exposure of the resin to the drug in a
  • Drug release from the drug- resin complex depends on the ionic environment; that is pH and electrolyte concentration within the gastrointestinal tract, as well as the specific properties of the resin.
  • the rate of diffusion is controlled by the area of diffusion, diffusional path link, and extent of crosslinking in the resin.
  • a further modification of the release rate can be afforded by coating the drug-resin complex.
  • dosage forms used for parenteral nonimmediate release drug therapy are intramuscular injections, implants for subcutaneous tissues and various body cavities, and transdermal devices.
  • intramuscular injections involve a formation of a dissociable complex of a drug with another molecule.
  • the drug-molecule complex serves as a reservoir at the site of injection for drug release to the surrounding tissues.
  • macromolecules include biological polymers such as antibodies and proteins or synthetic polymers such as polyvinylpyrrolidone, and polyethylene glycol.
  • Complexes can also be formed between drugs and small molecules.
  • the association constant will be greater and the complex more stable.
  • smaller molecules include zinc, optionally suspended in a gelatin solution or an oil solution.
  • An alternative dosage form for an intramuscular injection is an aqueous suspension. By varying viscosity and particle size a stable suspension of active ingredient can be afforded.
  • Another common approach to decreased dissolution rate is to decease the saturation solubility of the drug. This is accomplished through the formation of less soluble salts and prodrug derivatives and by employing polymorphic crystal forms of the active
  • intramuscular injection include sesame, olive, arachnis, maize, almond, cotton seed and caster oil. With oil
  • Emulsions comprising oil-in-water emulsions or water- in-oil emulsions may also be used.
  • Implants comprise a drug-barring polymeric device which is inserted subcutaneously or in various body cavities.
  • the polymer material which is used must, of course, be biocompatible and nontoxic and are typically chosen from among hydrogels, silicones, polyethylenes, ethylene-vinyl acetate copolymers, and biodegradable
  • Hydrogels generally are a polymeric material that exhibit the ability to swell in water and retain greater than 20 percent of that water within its structure, but which will not dissolve in water. Small molecular weight substances are capable of diffusing through hydrogels.
  • hydrogels include polyhydroxyalkyl methacrylates, polyacrylamide and polymethacrylamide, polyvinylpyrrolidone, polyvinyl alcohol, and various combinations thereof
  • Additional implantable systems include
  • subcutaneous devices and intravaginal devices.
  • Percutaneous drug absorption generally includes the use of microporous membranes as the rate controlling
  • Microporous membranes are films varying in
  • pore sizes ranging from several micrometers to a few angstroms.
  • material from which such membranes are made include regenerated cellulose, cellulose nitrates/acetate, cellulose triacetate, polypropylene, polycarbonate and polytetrafluoroethylene.
  • the barrier properties of these various films depend upon the method of preparation, the medium with which the pores are filled, pore diameter, percent porosity, and tortuosity.
  • Nanoparticles are examples of systems known collectively as colloidal drug delivery systems.
  • Other members in this group include microcapsules, nanocapsules, macromolecular complexes, polymeric beads, microspheres and liposomes.
  • a nanoparticle is a particle
  • nanoparticles containing dispersed drug with a diameter of 200-500 nm.
  • Materials used in the preparation of nanoparticles are sterilisable, nontoxic and biodegradable. Examples include albumen, ethylcellulose, casein and gelatin. Typically, they are prepared by procedures similar to the coacervation method of microencapsulation.
  • Liposomes generally, are phospholipids that when dispersed with aqueous media swell, hydrate and form
  • Phospholipids can also form a variety of structures other than liposomes when dispersed in water depending on the molar ration of lipid to water. At low ratios, the liposome is the
  • the actual physical characteristics of the liposomes depend on pH, ionic strength and the presence of divalent cations. They show low permeability to ionic and polar substances but at elevated temperatures undergo a phase transition which alters their permeability.
  • Polar drugs are trapped in the aqueous spaces and nonpolar drugs bind to the lipid bilayer of vesicle. Polar drugs are released when the bilayer is broken or by permeation, but nonpolar drugs remain affiliated with the bilayer until it is disrupted by temperature or exposure to lipoproteins.
  • the liposome acts as the carrier or the active agent.
  • the formulations of the present invention may be formulated as nonimmediate (i.e. sustained) release tablets, capsules, injection solutions for parenteral use, gel, suspensions or elixirs for oral use or suppositories.
  • the compositions are formulated in a unit dosage form, each dosage containing an amount of active ingredient suitable to afford a subject from 0.01 to 3.0 mg, more usually 0.05 to 2.0 mg, of the active ingredient.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic or prophylatic effect, related to the desired daily or divided dose, in association with one or more suitable pharmaceutical
  • the unit dosage form may contain from 0.01 to 5.0 mg of the active ingredient.
  • a preferred formulation of the invention is an oral or implantable nonimmediate release formulation comprising 0.01 to 3.0 mg or 0.05 to 2.0 mg of active ingredient together with a pharmaceutically acceptable carrier therefor in a unit dosage form. Most preferred is an oral nonimmediate release formulation.
  • the nonimmediate release formulations of the present invention should provide a prophylatic or
  • temporal delivery refers to controlling the rate of drug delivery.
  • Nonimmediate release formulations of the present invention should afford one or more of the following
  • Patent compliance is a necessary and important component in the success of all self-administered drug therapy. It is anticipated the nonimmediate release
  • a geometric mean for time to maximum plasma concentration should be from about 2.5 hours to about 5.0 hours, preferably 2.5 - 4.0 hours, with a geometric mean plasma elimination half- life of from about 6.0 hours to about 16.0 hours, preferably 7.0 - 15.0 hours.
  • t max time to maximum plasma concentration
  • Moxonidine is currently commercially available in at least Germany and Austria as 0.2, 0.3 and 0.4 mg dosage immediate release formulation tablets as an antihypertensive agent. Set forth below is the complete formulation of the currently marketed 0.3 mg tablet. For the 0.2 mg and 0.4 mg tablet, the amount of lactose is adjusted to accommodate the higher or lower active ingredient content.
  • moxonidine to patients with essential hypertension can produce significant reductions in blood pressure 24 hours after dosing, without an excessive incidence of symptomatic hypotension.
  • the pharmacokinetics and pharmacodynamics in CHF patients are compared to a previous report in patients with essential hypertension following a single 0.25 mg dose (Kirch et al., J. Clin. Pharmacol, 30, 1088-1095 (1990)).
  • Moxonidine was administered in a randomized, double-blind, placebo-controlled Phase 2 clinical trail in patients with functional New York Heart Association (NYHA) Class II -III CHF. Only patients receiving a stable dose of an angiotensin converting enzyme ACE inhibitor or who failed previous ACE therapy were eligible. Patients could also be receiving digitalis, diuretics and other drugs used as CHF therapy, provided the dose was stable prior to start of the study. The study consisted of a 2-week single-blind
  • Unstable angina pectoris defined as angina at rest
  • severe stable angina more than two attacks per day on average
  • Cerebrovascular disease for example, Cerebrovascular disease
  • rheumatoid arthritis for example, systemic lupus erythematosus, polyarteritis nodosa, scleroderma.
  • Dosage groups for the trial were studied sequentially. Six moxonidine dosage groups were evaluated. Dosage groups were defined by a starting level of moxonidine and up to two dosage increases at 1-week intervals. The study drug was given initially on a once-a-day regimen.
  • a week is defined as 5 to 9 days.
  • Visits 3, 6, and 8 are 8-hour evaluation days (referred to as Study Days 1, 2, and 3), on which the daily dose of study medication was withheld until administration at the medical clinic, after which the patients were followed up for 8 hours. During that time, physiologic observations were made, adverse events elicited, and blood samples drawn for clinical laboratory measurements and neuroendocrine mediator and study drug concentration assays. At Visits 4 and 5, the patients received their medication dose in the medical clinic and remained for observation in the clinic for 4 hours following dosage administration.
  • the dosage size was progressively larger from the first to the sixth group. For each group the starting dose was smallest, with a maximum of two subsequent dose progression steps at 1-week intervals.
  • Moxonidine and placebo tablets were provided to the hospital pharmacy and dispensed to patients in a number sufficient for each visit interval. Tablets of 0.1 mg of moxonidine and tablets of placebo were identical in appearance and combined in the proper proportions to assure desired dosages (including twice daily dosing if required), ease of compliance, and maintenance of the blind.
  • dose in this protocol refers to the combination of study drug tablets taken on a single day. The current commercial formulations were used with lactose content adjusted to accommodate the presence or absence of active ingredient as described above.
  • Visit 3 (Study Day 1) is one of the three 8- hour evaluation days during this protocol on which study medication was taken at the medical clinic and the patient was followed up for 8 hours for safety assessments and laboratory measurements.
  • the medication dose was administered at the medical clinic and patients were observed for four hours following administration of the medicine dose.
  • Visits 6 and 8 (Study Days 2 and 3) were also 8 -hour evaluation days at which the daily dose was withheld for administration at the medical clinic, after which the patient was followed for up to 8 hours. On each of the 4-hour and 8-hour evaluation days, patients did not take their daily medication until administered at the medical clinic.
  • Visits 3 through 7 patients were provided sufficient
  • Study drug or placebo was taken once a day early in the morning as a single dose (6 tablets), unless evidence of symptomatic hypotension justified dividing the dose, with the result that the regimen was twice daily.
  • Plasma concentration analysis at approximately 0, 0.5, 1, 1.5, 2, 4, 6, and 8 hours after study drug administration on the three Study Days (Visits 3, 6, and 8). Plasma concentrations were determined using a gas chromatography/mass spectrometry analytical method. Generally, aliquots of human plasma (1.0 ml) are fortified with 25.0 ⁇ l (10 pg/ ⁇ l working internal solution) of internal standard (Clonidine.HCl). Each sample is extracted into ethyl acetate under basic conditions, the organic layer is removed, and the plasma discarded. Samples are back extracted with 0.5 M HCl and the organic layer is discarded. Samples are then extracted into methylene chloride under basic conditions, the aqueous layer is discarded and the organic layer is taken to dryness under a stream of nitrogen. The dried sample residues are derivatized with 3,5
  • concentrations of moxonidine in plasma predict negligible accumulation of moxonidine following repeated administration to CHF patients, even with a BID regimen.
  • Predicted peak to trough rations for BID dosing is 20:1.
  • SSBP Standing Systolic Blood Pressure
  • Table 4 shows the absolute and percentage changes from predose baseline in standing systolic blood pressure at Study Day 1 (visit 6). There were 6 patients who received placebo, and 9 who received moxonidine, 0.1 mg. The peak effect was at 2 hours after drug administration. A trend of increasing SSBP was observed in the placebo group (avg. 6.7 mm Hg). The change may have been due to the decay of effect of the morning dose of ACE inhibitor taken prior to coming to the clinic. Compared to placebo, moxonidine produced a reduction in SSBP, the average difference being -15.6 mm Hg. (-11.9%).
  • HTN hypertensive
  • Table 5 shows the absolute and percentage changes in norepinephrine plasma concentration from predose baseline to 2 hours after dosing (0.1 mg) in the groups of patients. These values are obtained using standard clinical laboratory
  • Moxonidine at 0.1 mg produced a maximum reduction in mean PNE 2 hours after dosing at Visit 3. Two hours after dosing, PNE was reduced by over 30% relative to placebo.
  • moxonidine on PNE on Visits 3 and 6 in a representative subject demonstrated the patient did not respond to a 0.1 mg dose on Visit 3, but responded intensely to a 0.3 mg dose in Visit 6.
  • pre-dose PNE on Visit 6 was elevated relative to baseline.
  • Visit 6 baseline PNE was elevated relative to Visit 3 baseline PNE in 5 of 8 patents receiving moxonidine, but only 1 of 5 subj ects receiving placebo.
  • the dosing regimen should produce a significant suppression of PNE at trough following chronic dosing, without excessive reductions in blood pressure at time of peak effect.
  • noncompliance with a multiple dosing regimen can result in a failure to obtain the benefits of the active agent and may exacerbate the high peak to trough effect ratios.
  • moxonidine should also be improved by a nonimmediate release formulation.
  • the sustained release of the active compound is based on the principle of a hydrocolloid matrix.
  • the matrix is formed by hydroxypropylmethylcellulose, HPMC 2208 (15000 mPas, at 2%, 20°C).
  • HPMC 2208 15000 mPas, at 2%, 20°C.
  • a mixture of Lactose and Calcium phosphate was used as carrier.
  • the liberation of the active compound was controlled by varying the ratios between these three components.
  • the batch analysis tests showed a high sensitivity of the formula to variations of the mixing time. Increased mixing times tend to lead to an uneven lubricant distribution which caused insufficient tablet hardness.
  • Example 1 Because of the delayed therapeutic effect with Example 1 (data not included), it was decided to combine a sustained release formulation with an initial dose. As data
  • the “Eyetablet” is a special kind of presscoated tablet: A circular biconvex kernel (6 mm in diameter) is pressed into a circular coat "U” shaped in cross-section and 9 mm in diameter, without the kernel being completely covered.
  • the coat contains the initial dose (0.1 mg) in an immediate release form. It disintegrates within 30-95 seconds because of a high content of disintegration enhancers
  • the kernel carries the sustained form (0.535 mg) .
  • Example 2 The tablets were coated for humidity protection.
  • Example 2 The tablets were coated for humidity protection.
  • Example 3-1 through 3-5 were prepared and coated as described in 3-6.
  • aqueos coating of the kernels with a 12.5% suspension by means of a spray gun (0.8 mm nozzle).
  • Example 1 The formulation of Example 1 was compared to a 0.25 mg immediate release tablet (Comparative Example A) in a study with eight hypertensive patients. Plasma concentrations were determined using known GC/MS methodology.
  • Example 1 With the formulation of Example 1, the maximum plasma concentration was reached 2-3 hours after administration. The higher dose, compared to Example A, caused a 60% increase of the plasma concentration maxima (2.25 ⁇ 1 ng). These kinetic data correspond to the blood pressure decrease. Example 1 led to a 50% higher maximum decrease of the systolic and the diastolic blood pressure compared to Example A, that occurred 5-6 hours after administration. The action period, defined as the period of time for which a diastolic blood pressure decrease greater than or equal to 10 mm Hg was not
  • Example 2 In a clinical study with four healthy volunteers the "Eyetablet" of Example 2 was compared to a 0.25 mg immediate release tablet (Comparative Example A) with regard to the kinetic behaviour. Plasma concentrations were determined using known GC/MS methodology. See for Example Kirch, et al., J . Clin . Pharmacol., 30, 1088-1095 (1990); Trenk, et al., J. Clin. Pharmacol., 27, 988-993 (1987); and Kirch, et al.,
  • Example 3-6 formulation A study with two volunteers was carried out concerning only kinetic data of the Example 3-6 formulation which is reported below along with the limited clinical kinetic data obtained as described above.
  • the objectives of this study were (1) to provide data for the comparison of the bioavailability of four different controlled release formulations of moxonidine after single dose administrations and (2) to test the food effect for one of the formulations in five additional subjects.
  • Example 4-1, 4-2 and 6 with 0.3 mg moxonidine per tablet and the formulation of Example 5 contained 0.1 mg moxonidine were used.
  • the study was conducted in an open, randomized, 7 day wash-out design consisting of 5 study periods with single dose administration after an overnight fast. The first four study periods were carried out in a four-way crossover design including the formulations of Comparative Example B, Example 6, Example 4-2 and Example 5. In the fifth period, the same subjects received the formulation of Example 4-1 as single dose administration.
  • the study population consisted of 10 healthy fasted subjects of either sex.
  • the formulation of Example 6 was also tested in a parallel group of 5 additional subjects who were dosed after the United States Food and Drug Administration (FDA) high fat breakfast.
  • FDA United States Food and Drug Administration
  • Plasma concentrations of moxonidine were determined using a GC-MS method with a limit of quantitation (LOQ) of 0.025 ng/ml described below.
  • C max The maximum plasma concentration (C max ) for each formulation was obtained from the content-adjusted data series.
  • the plateau time t 50VCmax corresponds to the time span during which plasma
  • concentrations are higher than 50% of C max .
  • Formulation B was calculated in the following two ways
  • F rel (1) AUC 0-inf Example /AUC 0-inf comparat ive B
  • concentrations for one subject showed at 6 and 12 h exceptionally high values with corresponding high impact on the PK parameters and the mean values. These two concentrations were excluded from the data set and from the PK analysis.
  • the intrasubject variability seen for moxonidine in this study was generally lower for AUC than for C max .
  • Half of the subjects showed a relatively large variability in C max .
  • For AUC, one subject showed higher variability compared to the other subjects.
  • Example 6 0.3 mg
  • Example 5 0.1 mg given in 3 tablets
  • All formulations of the present invention also achieved a reduction of the intersubject variability for C max and very good relative bioavailability. Furthermore, exceptionally few adverse effects were observed with all formulations of the present invention.
  • Example 6 No statistically significant differences were seen between the formulations of Example 6, containing 0.3 mg moxonidine and Example 5 given as 3 tablets with 0.1 mg each.
  • the formulation of Example 4-1 showed higher plasma levels and faster absorption than the formulations of Examples 4-2 and 6 and resulting in higher relative bioavailability.

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PCT/US1997/009914 1996-06-06 1997-06-05 Formulation and method for treating congestive heart failure WO1997046241A1 (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
HU0003885A HUP0003885A2 (hu) 1996-06-06 1997-06-05 Készítmény pangásos szívelégtelenség kezelésére
PL97330637A PL330637A1 (en) 1996-06-06 1997-06-05 Agent for and method of treating hypostatic cardiac insufficiency
JP10500901A JP2000511906A (ja) 1996-06-06 1997-06-05 鬱血性心不全を治療するための製剤および方法
EP97928011A EP0914128A1 (en) 1996-06-06 1997-06-05 Formulation and method for treating congestive heart failure
BR9709546A BR9709546A (pt) 1996-06-06 1997-06-05 Formulação e método para tratamento de insuficiéncia cardíaca digestiva
AU32331/97A AU3233197A (en) 1996-06-06 1997-06-05 Formulation and method for treating congestive heart failure
IL12696697A IL126966A0 (en) 1996-06-06 1997-06-05 Formulation and method for treating congestive heart failure
NO985695A NO985695L (no) 1996-06-06 1998-12-04 Formulering og fremgangsmÕte for Õ behandle kongestiv hjerteinfarkt
EA199900006A EA199900006A1 (ru) 1996-06-06 1999-01-06 Препарат и способ для лечения застоной сердечной недостаточности

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Cited By (4)

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Publication number Priority date Publication date Assignee Title
WO2000044355A1 (en) * 1999-01-29 2000-08-03 Eli Lilly And Company Moxonidine salts
WO2000045820A1 (de) * 1999-02-01 2000-08-10 Solvay Pharmaceuticals Gmbh Verwendung von moxonidin zur behandlung nach herzinfarkt
EP0951907B1 (de) * 1998-04-06 2003-03-05 Solvay Pharmaceuticals GmbH Verwendung von Moxonidin als Thermogenese stimulierend wirksames Arzneimittel
EP1894927A1 (en) * 2006-08-31 2008-03-05 Chemagis Ltd. The use of moxonidine salts for purification of moxonidine

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100812287B1 (ko) * 2007-01-03 2008-03-13 주식회사 챠콜코리아 내면에 반사층을 갖는 신호등 갓

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FR2441625A1 (fr) * 1978-11-15 1980-06-13 Beiersdorf Ag (d2-imidazolinyl-2 amino)-5 pyrimidines, procede pour les preparer, et medicaments qui en contiennent
EP0246549A2 (de) * 1986-05-22 1987-11-25 LTS Lohmann Therapie-Systeme GmbH & Co. KG Transdermales Arzneimittel
EP0305726A1 (de) * 1987-09-02 1989-03-08 Michael Dr. Horstmann Transdermales therapeutisches System
DE3904795A1 (de) * 1989-02-17 1990-08-23 Beiersdorf Ag Pharmazeutisches praeparat und diagnoseverfahren
DE4325491A1 (de) * 1993-07-29 1995-02-02 Boehringer Ingelheim Kg Verwendung von zentral wirksamen alpha-2-Agonisten zur Hemmung des Postaggressionsstoffwechsels
EP0689837A2 (de) * 1994-07-01 1996-01-03 Kali-Chemie Pharma GmbH Antihyperglykämisch wirksame Arzneimittel
EP0768087A2 (en) * 1995-08-15 1997-04-16 Eli Lilly And Company Treating substance abuse withdrawal

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FR2441625A1 (fr) * 1978-11-15 1980-06-13 Beiersdorf Ag (d2-imidazolinyl-2 amino)-5 pyrimidines, procede pour les preparer, et medicaments qui en contiennent
EP0246549A2 (de) * 1986-05-22 1987-11-25 LTS Lohmann Therapie-Systeme GmbH & Co. KG Transdermales Arzneimittel
EP0305726A1 (de) * 1987-09-02 1989-03-08 Michael Dr. Horstmann Transdermales therapeutisches System
DE3904795A1 (de) * 1989-02-17 1990-08-23 Beiersdorf Ag Pharmazeutisches praeparat und diagnoseverfahren
DE4325491A1 (de) * 1993-07-29 1995-02-02 Boehringer Ingelheim Kg Verwendung von zentral wirksamen alpha-2-Agonisten zur Hemmung des Postaggressionsstoffwechsels
EP0689837A2 (de) * 1994-07-01 1996-01-03 Kali-Chemie Pharma GmbH Antihyperglykämisch wirksame Arzneimittel
EP0768087A2 (en) * 1995-08-15 1997-04-16 Eli Lilly And Company Treating substance abuse withdrawal

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Publication number Priority date Publication date Assignee Title
EP0951907B1 (de) * 1998-04-06 2003-03-05 Solvay Pharmaceuticals GmbH Verwendung von Moxonidin als Thermogenese stimulierend wirksames Arzneimittel
WO2000044355A1 (en) * 1999-01-29 2000-08-03 Eli Lilly And Company Moxonidine salts
WO2000045820A1 (de) * 1999-02-01 2000-08-10 Solvay Pharmaceuticals Gmbh Verwendung von moxonidin zur behandlung nach herzinfarkt
AU774855B2 (en) * 1999-02-01 2004-07-08 Abbott Laboratories Gmbh Use of moxonidine for postmyocardial infarction treatment
US7041303B2 (en) 1999-02-01 2006-05-09 Solvay Pharmaceuticals Gmbh Use of moxonidine for postmyocardial infarction treatment
EP1894927A1 (en) * 2006-08-31 2008-03-05 Chemagis Ltd. The use of moxonidine salts for purification of moxonidine

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AU3233197A (en) 1998-01-05
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NO985695L (no) 1999-02-04
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CA2256720A1 (en) 1997-12-11
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CZ397698A3 (cs) 1999-05-12
CN1226166A (zh) 1999-08-18
PL330637A1 (en) 1999-05-24

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