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WO2019147889A1 - Compositions et méthodes pour traiter une fibrillation auriculaire et/ou un flutter auriculaire chez un être humain - Google Patents

Compositions et méthodes pour traiter une fibrillation auriculaire et/ou un flutter auriculaire chez un être humain Download PDF

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Publication number
WO2019147889A1
WO2019147889A1 PCT/US2019/015079 US2019015079W WO2019147889A1 WO 2019147889 A1 WO2019147889 A1 WO 2019147889A1 US 2019015079 W US2019015079 W US 2019015079W WO 2019147889 A1 WO2019147889 A1 WO 2019147889A1
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Prior art keywords
human patient
dosage form
unitary dosage
vanoxerine
salt
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Arthur M. Brown
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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
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate

Definitions

  • Vanoxerine (1- [2- [bis (4-fluorophenyl)methoxy] ethyl] - 4- (3-phenylpropyl)piperazine) , its manufacture and/or certain pharmaceutical uses thereof are described in U.S. Pat. No.
  • Atrial flutter and/or atrial fibrillation are the most commonly sustained cardiac arrhythmias in clinical
  • ventricular proarrhythmias such as early afterdepolarizations (EADs) and delayed after depolarizations (DADs) and ventricular arrhythmias most notably polymorphic ventricular tachycardia called Torsade de Pointes (TdP) and less commonly monomorphic ventricular tachycardia and ventricular fibrillation.
  • EADs early afterdepolarizations
  • DADs delayed after depolarizations
  • ventricular arrhythmias most notably polymorphic ventricular tachycardia called Torsade de Pointes (TdP) and less commonly monomorphic ventricular tachycardia and ventricular fibrillation.
  • TdP Torsade de Pointes
  • Rate control requires anticoagulation therapy to avoid thromboembolism. This therapy has side effects most important excessive bleeding that seriously reduce quality of life and may be deadly. NSR does not have the thromboembolic risk and the side effects of anticoagulant therapy.
  • anti-arrhythmic agents are now available on the market, those having both satisfactory efficacy and a high margin of safety have not been obtained.
  • anti-arrhythmic agents of Class I according to the
  • Vmax maximum velocity of the upstroke of the action potential
  • ⁇ -adrenergenie receptor blockers and calcium channel (ICa) antagonists which belong to Class II and Class IV, respectively, have replaced digoxin for rate control. Both have serious side effects, ⁇ -blockers depress contractility and can produce heart failure in AF patients with structural heart disease. They also compromise airways in AF patients with respiratory disease. Calcium channel blockers have depressant effects on cardiac contractility and also depress AV conduction, which can lead to AV dissociation.
  • Anti-arrhythmic agents of Class III are drugs that cause a selective prolongation of the action potential duration (APD) without a significant depression of the maximum upstroke velocity (Vmax) . They therefore increase the wave length of the cardiac action potential increasing refractoriness, and so antagonize re-entry. Available drugs in this class are limited in number. Examples such as sotalol and amiodarone have been shown to possess interesting Class III properties (Singh B. N. , Vaughan Williams E. M. , "A Third Class of Anti-Arrhythmic
  • Amiodarone is not a selective Class III antiarrhythmic agent because it possesses multiple electrophysiological actions and is severely limited by side effects. (Nademanee, K. , "The Amiodarone Odyssey,” J. Am. Coll. Cardiol. (1992) 20:1063-1065). Drugs of this class are expected to be effective in preventing ventricular fibrillation. Selective Class III agents, by
  • Class III agents increase myocardial refractoriness via a prolongation of cardiac action potential duration (APD) .
  • APD cardiac action potential duration
  • prolongation of the cardiac action potential can be achieved by enhancing inward currents (i.e. Na+ or Ca2+ currents; hereinafter INa and ICa, respectively) or by reducing outward repolarizing potassium K+ currents.
  • inward currents i.e. Na+ or Ca2+ currents; hereinafter INa and ICa, respectively
  • ICa reducing outward repolarizing potassium K+ currents.
  • IK consists of two pharmacologically and kinetically distinct K+ current subtypes, IK, (rapidly
  • IK is the product of the human ether-a-go-go gene (hERG) .
  • hERG cDNA in cell lines leads to production of the hERG current which is almost identical to IKr, (Curran et al., "A Molecular Basis for Cardiac Arrhythmia: hERG Mutations Cause Long QT Syndrome," Cell (1995) 80 (5) : 795-803) .
  • Class III anti-arrhythmic agents currently in use of development including d-sotalol, dofetilide (UK-68,798) , almokalant (H234/09) , E-4031 and methanesulfonamide-N- [1 ' -6- cyano-1 ,2 ,3,4-tetrahydro-2-naphthalenyl) -3- ,4-dihydro-4- hydroxyspiro [2H-l-benzopyran-2 , 4 ' -piperidin] -6yl ] , (+) - , monochloride (MK-499) predominantly, if not exclusively, block IKr.
  • amiodarone is a blocker of IKs (Balser J. R.
  • Dronedarone is an amiodarone derivative presently in restricted use clinically (Zimetbaum, "Dronedarone for atrial fibrillation—an odyssey,” N.E.J.M.
  • Reentrant excitation has been shown to be a prominent mechanism underlying supraventricular arrhythmias in man.
  • Reentrant excitation requires a critical balance between slow conduction velocity and sufficiently brief refractory periods to allow for the initiation and maintenance of multiple reentry circuits to coexist simultaneously and sustain AF.
  • Most selective Class III antiarrhythmic agents currently in development, such as d-sotalol and dofetilide predominantly, if not exclusively, block IKr, the rapidly activating component of IK found both in atria and ventricle in man.
  • torsade de pointes TdP
  • acquired long QT syndrome a specific type of polymorphic ventricular tachycardia which is commonly associated with excessive prolongation of the electrocardiographic QT interval , hence termed "acquired long QT syndrome”
  • Cardiovasc. Cardiol. 20 (Suppl. 2) :S17-S22) .
  • the pro-arrhythmic tendency led to suspension of the SWORD trial when d-sotalol had a higher mortality than placebo controls.
  • IKs supraventricular tachyarrhythmias
  • Class III anti-arrhythmic agents are that their effect increases or becomes more manifest at or during bradycardia or slow heart rates, and this contributes to their potential for proarrhythmia.
  • these agents or drugs lose most of their effect. This loss or
  • ranolazine Another drug under consideration is ranolazine. This drug was developed for treatment of angina pectoris. It blocks the late inward sodium current and reduces AP duration (Kloner RA, et al., "Efficacy and safety of ranolazine in patients with chronic stable angina," Postgrad Med. (2013) 125 (6) :43-52) . Its use has been proposed with Class III hERG blockers such as dronedarone in the hope that block of late INa will offset block of hERG.
  • VX vanoxerine
  • vanoxerine at 90 mg effectively terminated AFL and after further doses of 180 and 270 mg at hourly intervals rendered it noninducible. It also suppressed inducibility of nonsustained AF. These effects occurred at consistent plasma drug levels.
  • the mean vanoxerine plasma level at the point of noninducibility was 84 ng/mLor 160 riM total, with a narrow range of 76-99 ng/mL.
  • the free VX level was 0.16 nM. Vanoxerine' s insignificant or minimal effects on measured electrophysiologic parameters are consistent with little proarrhythmic risk.
  • VX is 99.8% bound by plasma proteins (Lacerda et al, 2010; Obejero-Paz et al, 2015) and mean free concentrations for the 100, 200 and 300 mg doses are 0.11, 0.46 and 1.1 nM respectively. VX blocks hERG in in vitro studies at an IC50 Of 10 nM (Obejero-Paz, 2015) .
  • HERG IC50/Effective Therapeutic Plasma Concentrations for the 100, 200 and 300 mg oral doses are 10/0.11, 10/0.46 and 10/1.1 or 91, 22 and 9.1. Only the 100 mg dose can be considered safe with respect to TdP (Redfern et al, 2003) .
  • SMs between 30 and 100 are in a gray zone with respect to TdP while SMs below 30 are frequently associated with TdP.
  • the exceptions to the 30-100 SM range and SMs below 30 may be MICE drugs but SMs below 100 are unacceptable in the presence of significant structural heart disease.
  • vanoxerine that can be used to prevent the recurrence of cardiac arrhythmia in mammalian patients, such as humans, that have previously suffered at least one episode of cardiac arrhythymia.
  • a random, double-blind, placebo-controlled, single center Phase 2A study was conducted to determine the preliminary safety and efficacy of a single capsule of 100 mg of vanoxerine orally administered to subjects with recent onset atrial flutter (AFL) and/or atrial
  • AF fibrillation
  • NYHA Classes 1 and 2 minimal structural heart disease
  • Conversion rate was ⁇ 50% in two hrs while the conversion rate for placebo was 0%.
  • the average free vanoxerine concentration at Cmax for converters was 0.077 nM.
  • a later dose-ranging multi-center (Israel and Russia) , random, double-blind, placebo-controlled Phase 2A) study looked at the safety and efficacy of single oral doses at 200, 300 and 400 mg of vanoxerine restricted to human patients with ⁇ A Classes 1 and 2. This study showed a dose- dependent efficacy ranging from ⁇ 60-80% in conversion of AF/AFL to NSR whereas the spontaneous placebo rate was ⁇ 20%.
  • vanoxerine is suitable for treating human patients.
  • Preliminary studies have suggested that daily use of a drug over 7, 10, and 14 days may lead to increased heart rate and systolic blood pressure when taking concentrations of 75, 100, 125, and 150 mg of vanoxerine a day. This is quite undesirable in patients suffering cardiac
  • cardiac arrhythmia is a progressive disease and patients who suffer from a first cardiac arrhythmia are pre-disposed to suffering from additional episodes of cardiac arrhythmia. Any cardiac arrhythmia involves risk with regard to mortality and morbidity, and so terminating the cardiac arrhythmia in a timely and safe manner is a critical need for these patients.
  • Embodiments of the present invention disclosed herein relate to compositions and methods for terminating an episode of atrial fibrillation in a human patient suffering from an episode of atrial fibrillation.
  • the human patient has the following characteristics: (i) the human patient does not have structural heart disease meeting ⁇ A Functional Classifications 3 or 4; (ii) the human patient has a body weight between 45 kg and 110 kg; (iii) the human patient is a candidate for electrical conversion to normal sinus rhythm; (iv) the human patient is hemodynamically stable with SBP > 90 mmHg and DBP ⁇ 105 mmHg, and ventricular rate of 60 bpm or greater; (v) the human patient has a serum potassium level of at least 4.0 m
  • instructions may optionally be provided to orally consume a second unitary dosage form containing about 50 mg to about 100 mg of vanoxerine, or an equivalent amount of a salt thereof, and one or more pharmaceutically acceptable inert excipients, not less than six (6) hours after consuming the first unitary dosage form.
  • An additional aspect of the inventions disclosed herein relates to a method for treating a human patient
  • the method consisting essentially of orally consuming once a day a unitary dosage form containing about 50 mg to about 100 mg of vanoxerine, or an equivalent amount of a salt thereof, and one or more pharmaceutically acceptable inert excipients, wherein the human patient has the following characteristics: (i) the human patient does not have structural heart disease meeting ⁇ A Functional
  • the human patient has a body weight between 45 kg and 110 kg; (iii) the human patient is a candidate for electrical conversion to normal sinus rhythm; (iv) the human patient is hemodynamically stable with SBP > 90 mmHg and DBP ⁇ 105 mmHg, and ventricular rate of 60 bpm or greater; (v) the human patient has a serum potassium level of at least 4.0 mEq/L; and (vi) the human patient has a screening and/or baseline QTc ⁇ 450 msec; and further wherein the human patient: (i) has not previously suffered a myocardial infarction or stroke; (ii) is not hypomagnesemic; and (iii) has not exhibited symptoms of congestive heart failure and/or angina within the previous 90 days; and further wherein the human patient has been undergoing the current episode of atrial fibrillation for not more than 24 hours.
  • a second unitary dosage form containing about 50 mg to about 100 mg of vanoxerine, or an equivalent amount of a salt thereof, and one or more pharmaceutically acceptable inert excipients may be consumed not less than six (6) hours after consuming the first unitary dosage form.
  • Yet another aspect of the inventions disclosed herein includes a unitary oral dosage form for use by a human patient undergoing an episode of atrial fibrillation and/or atrial flutter, without also inducing torsades de pointes or
  • the dosage containing about 50 mg to about 100 mg of vanoxerine, or an equivalent amount of a salt thereof, and one or more pharmaceutically acceptable inert excipients, wherein the human patient has the following
  • the human patient does not have structural heart disease meeting NYHA Functional Classifications 3 or 4 ;
  • the human patient has a body weight between 45 kg and 110 kg;
  • the human patient is a candidate for electrical conversion to normal sinus rhythm;
  • the human patient is hemodynamically stable with SBP > 90 mmHg and DBP ⁇ 105 mmHg, and ventricular rate of 60 bpm or greater;
  • the human patient has a serum potassium level of at least 4.0 mEq/L; and
  • the human patient has a screening and/or baseline QTc ⁇ 450 msec; and further wherein the human patient: (i) has not previously suffered a myocardial infarction or stroke; (ii) is not
  • kits for the treatment a human patient who is undergoing an episode of atrial fibrillation and/or atrial flutter without also inducing torsades de pointes or ventricular fibrillation in that patient, the kit comprising a plurality of unitary dosage forms, each of said unitary dosage forms
  • vanoxerine containing between about 50 mg to about 100 mg of vanoxerine, or an equivalent amount of a salt thereof, and one or more
  • the human patient has the following characteristics: (i) the human patient does not have structural heart disease meeting ⁇ A Functional Classifications 3 or 4; (ii) the human patient has a body weight between 45 kg and 110 kg; (iii) the human patient is a candidate for electrical conversion to normal sinus rhythm; (iv) the human patient is hemodynamically stable with SBP > 90 mmHg and DBP ⁇ 105 mmHg, and ventricular rate of 60 bpm or greater; (v) the human patient has a serum potassium level of at least 4.0 mEq/L; and (vi) the human patient has a screening and/or baseline QTc ⁇ 450 msec; and further wherein the human patient: (i) has not previously suffered a myocardial infarction or stroke; (ii) is not hypomagnesemic; and (iii) has not exhibited symptoms of congestive heart failure and/or angina within the previous 90 days; and further wherein the human patient has been
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of and/or for consumption by human beings without excessive toxicity,
  • the term "subject” means a human (or human child) which is afflicted with, suffering from and/or undergoing an episode of atrial fibrillation.
  • treatment naive in
  • controlling is intended to refer to all processes wherein there may be a slowing, interrupting, arresting, or stopping of the progression of the diseases and conditions described herein, but does not
  • unitary dosage form means a single pharmaceutical dosage form which is capable of being orally consumed by a subject, and which can be readily handled and packaged, remaining as a physically and chemically stable unitary dose comprising about 50 mg to about 100 mg of
  • vanoxerine or an equivalent amount of pharmaceutically
  • administer refers to the actions of a medical professional or caregiver in providing a unitary dosage form to a patient for the patient to consume.
  • self- administering or “self-administer” refer to the actions of a patient actually consuming a unitary dosage form.
  • Cardiac arrhythmias include atrial, junctional, and ventricular arrhythmias, heart blocks, sudden arrhythmic death syndrome, and include bradycardias, tachycardias, re-entrant, and fibrillations. These conditions, including the following specific conditions: atrial flutter, atrial fibrillation, multifocal atrial tachycardia, premature atrial contractions, wandering atrial pacemaker, supraventricular tachycardia, AV nodal reentrant tachycardia, junctional rhythm, junctional tachycardia, premature junctional contraction, premature
  • ventricular contractions ventricular bigeminy, accelerated idioventricular rhythm, monomorphic ventricular tachycardia, polymorphic ventricular tachycardria, and ventricular
  • fibrillation and combinations thereof, are all capable of severe morbidity and death if left untreated.
  • the methods and compositions described herein are particularly useful for the treatment of atrial fibrillation.
  • a first embodiment of the inventions disclosed herein is a method of treating a human patient undergoing an episode of atrial fibrillation and/or atrial flutter without also inducing torsades de pointes or ventricular fibrillation in said patient, the method consisting essentially of providing instructions to a human patient to orally consume a unitary dosage containing about 50 mg to about 100 mg of vanoxerine, or an equivalent amount of a salt thereof, and one or more pharmaceutically acceptable inert excipients.
  • instructions may also be provided to orally consume a second unitary dosage form not less than six (6) hours after the first unitary dosage form is consumed.
  • instructions may be provided to orally consume a second unitary dosage form not less than twenty-four (24) hours after the first unitary dosage form is consumed.
  • a second embodiment of the inventions disclosed herein is a method for treating a human patient undergoing an episode of atrial fibrillation and/or atrial flutter without also inducing torsades de pointes or ventricular fibrillation in said patient, the method consisting essentially of orally consuming a unitary dosage form containing about 50 mg to about 100 mg of vanoxerine, or an equivalent amount of a salt thereof, and one or more pharmaceutically acceptable inert excipients.
  • a second unitary dosage form may be orally consumed not less than six (6) hours after the first unitary dosage form is consumed.
  • instructions may be provided to orally consume a second unitary dosage form not less than twenty-four (24) hours after the first unitary dosage form is consumed.
  • a third embodiment of the inventions disclosed herein includes a unitary oral dosage form for use by a human patient containing between about 50 mg and aboutlOO mg of vanoxerine, or an equivalent amount of a salt thereof, and one or more
  • a fourth embodiment of the inventions disclosed herein includes a kit for the treatment a human patient who is undergoing an episode of atrial fibrillation and/or atrial flutter without also inducing torsades de pointes or ventricular fibrillation in that patient, the kit comprising a plurality of unitary dosage forms, each of said unitary dosage forms
  • vanoxerine containing about 50 mg to about 100 mg of vanoxerine, or an equivalent amount of a salt thereof, and one or more
  • the human patient has the following characteristics: (i) the human patient does not have structural heart disease meeting YHA Functional Classifications 3 or 4; (ii) the human patient has a body weight between 45 kg and 110 kg; (iii) the human patient is a candidate for electrical conversion to normal sinus rhythm; (iv) the human patient is hemodynamically stable with SBP > 90 mmHg and DBP ⁇ 105 mmHg, and ventricular rate of 60 bpm or greater; (v) the human patient has a serum potassium level of at least 4.0 mEq/L; and (vi) said the human patient has a screening and/or baseline QTc ⁇ 450 msec; and further wherein the human patient: (i) has not previously suffered a myocardial infarction or stroke; (ii) is not hypomagnesemic; and (iii) has not exhibited symptoms of congestive heart failure and/or angina within the previous 90 days; and further wherein the human patient
  • the unitary dosage form containing vanoxerine may be in the form of a tablet or a capsule containing the requisite amount of vanoxerine, or an equivalent amount of a salt of vanoxerine, and such pharmaceutically acceptable excipients as may be necessary to produce the final unitary dosage form. Any and all excipients must be inert, organoleptically acceptable, and compatible with vanoxerine or the pharmaceutically salt thereof being employed.
  • a suitable unitary dosage form containing vanoxerine may be prepared in the form of a tablet.
  • the inert ingredients used in the preparation of tablets are generally known by and available to those skilled in the art.
  • suitable tablets may be prepared by mixing the requisite amount of vanoxerine, or an equivalent amount of a pharmaceutically acceptable salt thereof, with an inert diluent, such as lactose or calcium phosphate, in the presence of a disintegrating agent, such as potato starch or macrocrystalline cellulose, and a lubricating agent, such as magnesium stearate or talc, and then tableting the mixture by known methods.
  • Tablets may also be prepared by wet granulation and subsequent compression.
  • a mixture containing the requisite amount of vanoxerine, or an equivalent amount of a pharmaceutically acceptable salt thereof, and at least one diluent, and optionally a part of the disintegrating agent, is granulated together with an aqueous, ethanolic or aqueous- ethanolic solution of the binding agents in appropriate
  • Tablets may also be prepared by the direct compression of the mixture containing the requisite amount of vanoxerine, or an equivalent amount of a pharmaceutically acceptable salt thereof, together with the needed additives.
  • the tablets may be transformed to dragees by using protective, flavoring and dyeing agents such as sugar, cellulose derivatives (methyl- or ethylcellulose or sodium carboxymethylcellulose) , polyvinylpyrrolidone, calcium phosphate, calcium carbonate, food dyes, aromatizing agents, iron oxide pigments and the like which are commonly used in the pharmaceutical industry, and then used to fill capsule shells.
  • protective, flavoring and dyeing agents such as sugar, cellulose derivatives (methyl- or ethylcellulose or sodium carboxymethylcellulose) , polyvinylpyrrolidone, calcium phosphate, calcium carbonate, food dyes, aromatizing agents, iron oxide pigments and the like which are commonly used in the pharmaceutical industry, and then used to fill capsule shells.
  • vanoxerine or pharmaceutically acceptable salt thereof
  • the desired additives may simply be added directly as dried powders to a suitable capsule shell, such as a hard or soft gelatin capsule.
  • the vanoxerine or pharmaceutically acceptable salt thereof
  • the vanoxerine may preferably be mixed with one or more of the desired additives using dry granulation or wet granulation and then an appropriate amount of the resulting mixture may be added to a suitable capsule shell.
  • the amount of vanoxerine contained in a unitary dosage form for oral consumption a human patient is between about 50 mg and about 100 mg of vanoxerine, or an equivalent amount of a pharmaceutically acceptable salt thereof. More preferably, each unitary dosage form contains about 100 mg of vanoxerine or an equivalent amount of a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt of vanoxerine used in the unitary dosage form is vanoxerine hydrochloride.
  • Suitable unitary dosage forms of vanoxerine, or a pharmaceutically acceptable salt thereof can be prepared by wet mixing vanoxerine (or a pharmaceutically acceptable salt
  • the final mixture is compressed into a tablet. In other embodiments, the final mixture is added to capsule shells.
  • a suitable manufacturing process comprises the steps of: (a) dry blending vanoxerine (or a pharmaceutically acceptable salt thereof) and one or more excipients to form a dry mixture; (b) wetting the dry mixture with water, preferably with purified water, to form a wet granulation mixture; (c) drying the wet granulation mixture to form a dried granulation mixture; (d) milling the dried
  • the final blended mixture is compressed into tablets. In other preferred embodiments, the final blended mixture is compressed into tablets. In other preferred
  • the final blended mixture is added to capsule shells .
  • step (a) vanoxerine or a
  • Blenders appropriate for large scale dry blending include twin shell blenders, double cone blenders, and ribbon blenders. Ribbon blenders have the advantage of being used in continuous-production procedures. High-speed, high shear mixers may also be used and offer the advantage of shorter mixing times.
  • the dry mixture may also be granulated, milled into a fine powder, passed through a mesh screen, or micronized, if necessary.
  • the dry mixture may also be granulated, milled into a fine powder, passed through a mesh screen, or micronized, if necessary.
  • the dry mixture may also be granulated, milled into a fine powder, passed through a mesh screen, or micronized, if necessary.
  • the resulting dry mixture is then wetted with a wetting agent to form a wet granulation mixture in step (b) .
  • the wetting agent is typically added over time, usually from about 1 to about 15 minutes, with continuous mixing.
  • the wetting agent is added to the blender used in the dry blending step.
  • the wet granulation is carried out in a high shear granulator.
  • the wetting agent is an aqueous-based solution.
  • the wetting agent is water without any additional solvents, and in particular, without organic solvents. More preferably, the water is purified water.
  • the type and amount of wetting agent, rate of addition of wetting agent, and the mixing time influences the structure of the granules.
  • the different types of granules such as pendular, funicular, capillary, etc. , can be manipulated to achieve the desired density, porosity, texture and dissolution pattern of the granules, which in turn, determines the compressibility, hardness, disintegration and consolidation characteristics of the dried mixture.
  • the wet granulation mixture is then dried in step (c) to form a dried granulation mixture with an appropriate moisture content.
  • the drying means include a fluid bed or tray dryers. Fluid bed drying yield shorter drying times, in the range from 1 to 3 hours, while tray drying
  • the wet granulation mixture is dried in a fluid bed, for preferably about 1-3 hours.
  • Fluid bed drying has the added advantages of better temperature control and decreased costs.
  • the method of drying, drying time, and moisture content are critical to avoid decomposition, chemical migration, and other adverse physical characteristics of dried mixture which can affect the dosage form performance.
  • the dried granulation mixture is subsequently milled in step (d) to form a milled granulation mixture.
  • the particle size of the dried granulation mixture is reduced to achieve an appropriate particle size distribution for the subsequent processes.
  • milling is achieved using a high shear impact mill (such as Fitzpatrick) or a low shear screening mill (such as Comil) .
  • the dried granulation mixture may also be screened to select the desired granule size.
  • the lubricant was blended with the dried granulation mixture to give a final blended mixture.
  • a V blender or bin blenders are used.
  • a preferred blender is a V-shell PK blender.
  • a gentle blending is preferred, such that each granule covered with the lubricant, while minimizing the breaking up of the granules. Increased breaking of the granules results in fine powder, or "fines".
  • a high fine content results in variations of weight and density during compression into a tablet, as well as increases the need for cleaning of the compression machinery.
  • the final blended mixture is then prepared in a unitary dosage form suitable for once a day oral administration.
  • Suitable unitary dosage forms include tablets, capsules, pills, troches, cachets, and the like.
  • the final blended mixture is compressed into a tablet.
  • the compression machinery typically contains two steel punches within a steel die cavity. The tablet is formed when pressure is exerted on the dried granulation mixture by the punches in the cavity, or cell.
  • Tableting machines include single-punch machines, rotary tablet machines, gravity feed, and powder assisted machines. Preferably, gravity feed or powder assisted machines are used.
  • Rotary machines operating at high speeds suitable for large-scale production include double rotary machines and single rotary machines. Tablets can also include sugar-coated tablets, film-coated tablets, enteric-coated tablets, multiple-compressed tablets, controlled-release tablets, tablets for solution, effervescent tablets or buccal and sublingual tablets.
  • Compressed tablets may be characterized by a number of specifications, including diameter size, shape, thickness, weight, hardness, friability, disintegration time, and
  • the tablets preferably have
  • the final blended mixture is enclosed in capsules, preferably hard gelatin capsules.
  • the hard gelatin capsules are commercially available, and are generally made from gelatin, colorants, optionally an opacifying agent such as titanium dioxide, and typically contain 12-16% water.
  • the hard capsules can be prepared by filling the longer end of the capsule with the final blended mixture, and slipping a cap over the top using mG2, Zanasi, or Hofliger and Karg (H&K) machines .
  • the present invention provides for a process of preparing a solid dose form of
  • vanoxerine or a pharmaceutically acceptable salt thereof, by dry mixing vanoxerine (or a pharmaceutically acceptable salt thereof) with the excipients.
  • the mixture is compressed into a tablet.
  • the mixture is added to capsule shells.
  • the process comprises the steps of: (a) dry blending of vanoxerine (or a pharmaceutically acceptable salt thereof) and one or more excipients to form a dry mixture; (b) mixing a lubricant in the dry mixture to give a final blended mixture; (c) preparing the final blended mixture in a solid dosage form suitable for oral administration.
  • the final blended mixture is compressed into tablets. In other preferred embodiments, the final blended mixture is compressed into tablets. In other preferred
  • the final blended mixture is added to capsule shells .
  • step (a) vanoxerine, or a
  • vanoxerine or a pharmaceutically acceptable salt thereof
  • vanoxerine is thoroughly dry blended with the diluent (s) ,
  • disintegrant (s) and a binder to form a uniform dry mixture.
  • Blenders appropriate for large scale dry blending include twin shell blenders, double cone blenders, V blenders or bin
  • a preferred blender is a V-shell PK blender. Highspeed, high shear mixers may also be used. The dry mixture may also be granulated, milled into a fine powder, passed through a mesh screen, or micronized, if necessary.
  • the lubricant was blended with the dry mixture to give a final blended mixture.
  • a V blender or bin blenders are used.
  • a preferred blender is a V-shell PK blender.
  • the final blended mixture is then compressed into tablets or added to capsule shells as desired.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des compositions et des méthodes de terminaison d'un épisode de fibrillation auriculaire et/ou de flutter auriculaire sans induire également des torsades de pointes ou de fibrillation ventriculaire chez un patient humain subissant un épisode de fibrillation auriculaire et/ou de flutter auriculaire. De telles méthodes comprennent la consommation par voie orale d'une seule forme posologique unitaire contenant environ 50 mg à environ 100 mg de vanoxérine, ou une quantité équivalente d'un sel de celle-ci.
PCT/US2019/015079 2018-01-26 2019-01-25 Compositions et méthodes pour traiter une fibrillation auriculaire et/ou un flutter auriculaire chez un être humain Ceased WO2019147889A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030162793A1 (en) * 2002-02-22 2003-08-28 Brown Arthur M. Methods for preventing or treating cardiac arrhythmia
US20120010216A1 (en) * 2010-07-06 2012-01-12 Brown Arthur M Pharmaceutical compositions containing vanoxerine
US20160038482A1 (en) * 2013-04-26 2016-02-11 Laguna Pharmaceuticals, Inc. Vanoxerine for self-administration for terminating acute episodes of cardiac arrhythmia in mammals

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030162793A1 (en) * 2002-02-22 2003-08-28 Brown Arthur M. Methods for preventing or treating cardiac arrhythmia
US20120010216A1 (en) * 2010-07-06 2012-01-12 Brown Arthur M Pharmaceutical compositions containing vanoxerine
US20160038482A1 (en) * 2013-04-26 2016-02-11 Laguna Pharmaceuticals, Inc. Vanoxerine for self-administration for terminating acute episodes of cardiac arrhythmia in mammals

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
"Safety and Efficacy of Vanoxerine for Conversion of Atrial Fibrillation or Flutter to Normal Sinus Rhythm (COR-ART", 22 December 2015 (2015-12-22), XP055629049 *
"Safety and Efficacy of Vanoxerine for the Conversion of Subjects With Recent Onset Atrial Fibrillation or Flutter to Normal Sinus Rhythm (RESTORE SR", CLINICAL TRIALS.GOV, 17 October 2016 (2016-10-17), XP055629047 *
DITTRICH ET AL.: "COR-ART: A multicenter, randomized, double-blind, placebo-controlled dose- ranging study to evaluate single oral doses of vanoxerine for conversion of recent-onset atrial fibrillation or flutter to normal sinus rhythm", HEART RHYTHM, vol. 12, no. 6, 2015, pages 1105 - 1112 *

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