WO2009018547A1 - Extended release formulations containing an ion-channel-modulating compound for the prevention of arrhythmias - Google Patents

Extended release formulations containing an ion-channel-modulating compound for the prevention of arrhythmias Download PDF

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Publication number
WO2009018547A1
WO2009018547A1 PCT/US2008/072018 US2008072018W WO2009018547A1 WO 2009018547 A1 WO2009018547 A1 WO 2009018547A1 US 2008072018 W US2008072018 W US 2008072018W WO 2009018547 A1 WO2009018547 A1 WO 2009018547A1
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extended release
formulation
formulations
active ingredient
tablet
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PCT/US2008/072018
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French (fr)
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Conrad S. Winters
Taryn Boivin
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Cardiome Pharma Corp.
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Publication of WO2009018547A1 publication Critical patent/WO2009018547A1/en

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    • 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
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/282—Organic compounds, e.g. fats
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention is directed to extended release formulations of ion channel modulating compound or pharmaceutically acceptable salts thereof. 0 These extended release formulations are useful in preventing arrhythmia and other diseases, in particular atrial fibrillation, from occurring in mammals, preferably in humans, when orally administered thereto.
  • Arrhythmias are abnormal rhythms of the heart.
  • the term "arrhythmia" 5 refers to a deviation from the normal sequence of initiation and conduction of electrical impulses that cause the heart to beat. Arrhythmias may occur in the atria or the ventricles. Atrial arrhythmias are widespread and relatively benign, although they place the subject at a higher risk of stroke and heart failure. Ventricular arrhythmias are typically less common, but very often fatal. 0 Atrial fibrillation is the most common arrhythmia encountered in clinical practice. It has been estimated that 2.2 million individuals in the United States have paroxysmal or persistent atrial fibrillation. The prevalence of atrial fibrillation is estimated at 0.4% of the general population, and increases with age.
  • Atrial fibrillation is usually associate with age and general physical 5 condition, rather than with a specific cardiac event, as is often the case with ventricular arrhythmia. While not directly life threatening, atrial arrhythmias can cause discomfort and can lead to stroke or congestive heart failure, and increase overall morbidity.
  • AV atrioventricular
  • rhythm control seeks to convert the atrial fibrillation and then maintain normal sinus rhythm, thus attempting to avoid the morbidity associated with chronic atrial fibrillation.
  • the main disadvantage of the rhythm control strategy is related to the toxicities and proarrhythmic potential of the anti-arrhythmic drugs used in this strategy.
  • Most drugs currently used to prevent atrial or ventricular arrhythmias have effects on the entire heart muscle, including both healthy and damaged tissue. These drugs, which globally block ion channels in the heart, have long been associated with life-threatening ventricular arrhythmia, leading to increased, rather than decreased, mortality in broad subject populations. There is therefore a long recognized need for antiarrhythmic drugs that are more selective for the tissue responsible for the arrhythmia, leaving the rest of the heart to function normally. Such drugs are less likely to cause ventricular arrhythmias.
  • Vernakalant hydrochloride is the non-proprietary name adopted by the United States Adopted Name (USAN) council for the ion channel modulating compound having the following formula:
  • Vernakalant hydrochloride modifies atrial electrical activity through a combination of concentration-, voltage- and frequency-dependent blockade of sodium channels and blockade of ultra-rapidly activating (l Kur ) and transient outward (l t0 ) potassium channels. These combined effects prolong atrial refractoriness and rate-dependently slow atrial conduction.
  • This unique profile provides an effective anti-fibrillatory approach expected to be suitable for conversion of atrial fibrillation and the prevention of recurrence of atrial fibrillation.
  • the present invention is directed to extended release formulations for ion channel modulating compounds or pharmaceutically acceptable salts thereof.
  • extended release formulations are useful in the prevention of arrhythmia, particularly, atrial fibrillation and/or atrial flutter, in a mammal, preferably in a human, upon oral administration thereto.
  • these extended release formulations are useful in the prevention of the recurrence of arrhythmia in a mammal having previously undergone one or more arrhythmias or prevention of arrhythmia in a mammal during or following surgery, e.g., a cardiac surgery.
  • this invention provides extended release formulations comprising a therapeutically effective amount of an ion channel modulating compound and one or more pharmaceutically acceptable excipients.
  • this invention provides xtended release tablet formulations comprising a therapeutically effective amount of an ion channel modulating compound has the structure:
  • R 4 and R 5 are independently selected from hydroxy and Ci-C ⁇ alkoxy.
  • this invention provides extended release formulations comprising a therapeutically effective amount of vernakalant hydrochloride and one or more pharmaceutically acceptable excipients.
  • this invention provides extended release formulations comprising a therapeutically effective amount of vernakalant hydrochloride and one or more pharmaceutically acceptable excipients wherein at least one of the pharmaceutically acceptable excipients comprises a hydrophilic matrix polymer.
  • this invention provides for extended release tablet formulations comprising 300 mg of an ion channel modulating compound, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • this invention provides for extended release tablet formulations comprising about 250 or 300 mg of vernakalant or vernakalant hydrochloride and one or more pharmaceutically acceptable excipients.
  • this invention provides for extended release tablet formulations comprising about 250 or 300 mg of vernakalant or vernakalant hydrochloride and one or more pharmaceutically acceptable excipients wherein at least one pharmaceutically acceptable excipient comprises a hydrophilic matrix polymer.
  • the hydrophilic matrix polymer is hydroxypropyl methyl cellulose or polyethylene oxide.
  • this invention provides a extended release tablet formulation coated with a enteric coating composition comprising a (meth)acrylate copolymer.
  • the extended release tablet formulation comprises an ion channel modulating compound has the structure:
  • the ion channel modulating compound is vernakalant hydrochloride.
  • the enteric coating composition comprises a (meth)acrylate copolymer, Imwitor, thethyl citrate, and a polysorbate.
  • this invention provides for an extended release tablet formulation of an ion channel modulating compound wherein less than 1 % of the ion channel modulating compound, or a pharmaceutically acceptable salt thereof, is released over 6 hours in 0.1 N HCI solution and over a further 18 hours in phosphate buffer solution at pH 7.2.
  • the extended release tablet formulation comprises an ion channel modulating compound has the structure:
  • the ion channel modulating compound is vernakalant hydrochloride.
  • this invention provides for capsules comprising one or more extended release tablet formulations of this invention.
  • the capsule comprises an extended release tablet formulation of this invention coated with a enteric coating comprising a (meth)acrylate copolymer.
  • the enteric coating composition comprises a (meth)acrylate copolymer, Imwitor, triethyl citrate, and a polysorbate.
  • the capsule comprises an extended release tablet formulation of this invention coated with a taste masking coating composition comprising a polyvinyl alcohol (PVA) base.
  • PVA polyvinyl alcohol
  • the taste masking coating composition comprises PVA base hydroxypropyl methyl cellulose, dicalcium phosphate, an magnesium stearate.
  • the capsule comprises both an extended release tablet formulation of the invention coated with a enteric coating and an extended release tablet formulation of the invention coated with a taste masking coating.
  • this invention provides for a method of preventing an arrhythmia in a mammal, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of an extended release formulation or tablet of the invention.
  • this method is for the prevention of the recurrence of an arrhythmia in a mammal that has previously undergone one or more arrhythmia or for the prevention of arrhythmia in a mammal during or following surgery, e.g., a cardiac surgery.
  • the arrhythmia is atrial fibrillation and/or atrial flutter.
  • Figure 1 includes two graphs showing the Geometric Mean Plasma Concentration-Time Plots for Vernakalant and Cmpd. 2 in Stage 1 (Pharmacokinetic Population).
  • Original refers to the controlled release formulation.
  • Figure 2 includes two graphs showing Geometric Mean Plasma Concentration-Time Plots of Vernakalant and Cmpd. 2 in Stage 2 (Pharmacokinetic Population).
  • Figure 3 shows a comparison of Least Square Means of Pharmacokinetic Parameters for Vernakalant in Stage 1 and Stage 2 (Pharmacokinetic Population).
  • Figure 4 shows a comparison of Least Square Means of Pharmacokinetic Parameters for Cmpd. 2 in Stage 1 and Stage 2 (Pharmacokinetic Population).
  • Figure 5 provides a diagram of the metabolism of vernakalant in
  • This invention is directed to extended release formulations comprising a therapeutically effective amount of ion channel modulating compound, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • this invention is directed to extended release formulations comprising a therapeutically effective amount of vernakalant hydrochloride and one or more pharmaceutically acceptable excipients suitable for sustained release formulations, which, upon oral administration thereto, are effective in preventing the recurrence of arrhythmia in the mammal.
  • the extended release formulations of the invention have a slower release profile of the active ingredient than the controlled release formulations disclosed herein.
  • the extended release formulations of the invention are intended to be administered to a mammal, preferably a human, at risk of arrhythmia, such as, e.g., a mammal that has previously undergone one or more arrhythmias.
  • prevention preferably means keeping an arrhythmia from occurring in a mammal.
  • Prevention may also mean a lessening of the severity of an arrhythmia if an arrhythmia does occur.
  • Prevention may also mean postponing the time for onset of an arrhythmia.
  • Prevention may also mean lessening the probability that the mammal will suffer from an arrhythmia.
  • the arrhythmia to be prevented is atrial fibrillation.
  • the arrhythmia to be prevented is atrial flutter.
  • the subject in which arrhythmia is be prevented is any mammal.
  • the subject is a human.
  • the subject is any domestic animal, including, but not limited to cats, dogs, etc.
  • the subject is any farm animal, including, but not limited to pigs, cows, horses, etc.
  • the subject is considered at risk of arrhythmia.
  • the subject may have previously undergone one or more arrhythmias or is undergoing or has undergone a surgicial procedure associated with a risk of arrhythmia, e.g., a cardiac surgery, such as a coronary artery bypass graft (CABG) procedure.
  • AF atrial fibrillation
  • AFL atrial flutter
  • the extended release formulations of the invention comprise a therapeutically effective amount of an ion channel modulating compound, or a pharmaceutically acceptable salt thereof, as the active ingredient and one or more pharmaceutically acceptable excipients.
  • a "therapeutically effective amount” refers to that amount of active ingredient sufficient to effect the desired prevention of arrhythmia in the mammal to which a formulation of the invention has been administered.
  • pharmaceutically acceptable refers to those compounds, salts, excipients and compositions, which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of mammals, preferably humans, without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • a "pharmaceutically acceptable excipient” can be any pharmaceutically acceptable material, composition, or vehicle suitable for allowing the active ingredient to be released from the formulation in a sustained manner, including but not limited to, a liquid or solid filler, diluent, excipient, solvent or encapsulating material, which is involved in carrying or transporting the active ingredient to an organ, or portion of the body.
  • a pharmaceutically acceptable excipient must be compatible with the other ingredients of the formulation.
  • materials which can serve as pharmaceutically acceptable excipients include, but are not limited to, sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; tragacanth; malt; gelatin; talc; cocoa butter, waxes, animal and vegetable fats, paraffins, silicones, bentonites, silicic acid, zinc oxide; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid
  • extended release refers to the release of the active ingredient from the formulation in a sustained and regulated manner over a longer period of time than an immediate release formulation containing the same amount of the active ingredient would release during the same time period.
  • an immediate release formulation comprising vernakalant hydrochloride may release 80% of the active ingredient from the formulation within 15 minutes of administration to a human subject
  • an extended release formulation of the invention comprising the same amount of vernakalant hydrochloride would release 80% of the active ingredient within a period of time longer than 15 minutes, preferably within a period of time longer than 12 hours.
  • the extended release formulations of the invention release the active ingredient, preferably vernakalant hydrochloride, over a longer period of time in vivo than a comparative controlled release formulation containing the same amount of the active ingredient would over the same period of time.
  • a comparative controlled release formulation containing the active ingredient, vernakalant hydrochloride may release 80% of the amount of the active ingredient present in the formulation in vivo over a period of 4-6 hours after administration to a human subject whereas an extended release formulation of the invention may release 80% of the same amount of the active ingredient in vivo over a period of 6-24 hours, preferably over a period of 12-18 hours and more preferably over a period of 14-16 hours.
  • Extended release formulations of the invention therefore allow for less frequency of dosing to the mammal in need thereof than the corresponding controlled release formulations.
  • extended release formulations may improve the pharmacokinetic or toxicity profile of the active ingredient upon administration to the mammal in need thereof.
  • the ion channel modulating compounds, or pharmaceutically acceptable salts thereof, utilized in the formulations of the invention can be any ion channel modulating compound or pharmaceutical acceptable salt thereof. These ion channel modulating compounds are referred to herein as the "active ingredient" of the formulations disclosed herein.
  • the ion channel modulating compound is a compound described in U.S. Patent No. U.S. Patent No. 7,057,053. More preferably, the ion channel modulating compound is vernakalant hydrochloride, which compound has the following formula:
  • Vernakalant hydrochloride has been shown to be orally bioavailable in humans and animals ⁇ e.g., in dogs). The compound is rapidly absorbed, and has a linear pharmacokinetic profile in humans following a 10-minute infusion. The half-life of the compound in healthy volunteers has been shown to be approximately 2 hours compared to 3-4 hours in patients with recent onset atrial fibrillation.
  • Vernakalant hydrochloride is highly soluble in aqueous solution, and at a concentration of 20 mg/ml has a pKa of 9.5 and a pH of 5.7. It is anhydrous under current manufacturing process, and is stable under long term and accelerated conditions, such as when stored in a low-density polyethylene (LDPE) bag inside a LDPE-lined aluminum compound foil bag.
  • LDPE low-density polyethylene
  • the ion channel modulating compound is any isomeric or pharmaceutically acceptable salt form of vernakalant, as represented by the following formula (I):
  • the ion channel modulating compound is in a trans- or cis-configuration, as represented by Formulas (Ma) and (Mb), respectively:
  • the ion channel modulating compound is by the following formula (Ia):
  • the ion channel modulating compounds are represented by Formula (III):
  • Y is selected from a direct bond, O, S, and Ci-C 4 alkylene;
  • Ri 3 is selected from hydrogen, Ci-C ⁇ alkyl, Cs-Cscycloalkyl, aryl, and benzyl;
  • the ring of formula (IV) is formed from the nitrogen as shown as well as three to nine additional ring atoms independently selected from carbon, nitrogen, oxygen, and sulfur; where any two adjacent ring atoms may be joined together by single or double bonds, and where any one or more of the additional carbon ring atoms may be substituted with one or two substituents selected from hydrogen, hydroxy, Ci-C 3 hydroxyalkyl, oxo, C 2 -C 4 acyl, Ci-C 3 alkyl, C 2 -C 4 alkylcarboxy, Ci-C 3 alkoxy, CrC 2 oalkanoyloxy, or may be substituted to form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur; and any two adjacent additional carbon ring atoms may be fused to a C 3 -C 8 carbocyclic ring, and any one or more of the additional nitrogen ring atoms may be substituted with substituents selected from hydrogen
  • R3 and R 4 are independently attached to the cyclohexane ring shown in formula (III) at the 3-, A-, 5- or 6- positions and are independently selected from hydrogen, hydroxy, d-C ⁇ alkyl, and d-C ⁇ alkoxy;
  • R 5 , Re and Ri 4 are independently selected from hydrogen, d-C ⁇ alkyl, aryl and benzyl;
  • A is selected from C 5 -Ci 2 alkyl, a C 3 -Ci 3 carbocyclic ring, and ring systems selected from formulae (V), (Vl), (VII), (VIII), (IX) and (X):
  • R 7 , R 8 and R 9 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, thfluoromethyl, C 2 -C 7 alkanoyloxy, CrC 6 alkyl, d-C 6 alkoxy, C 2 -C 7 alkoxycarbonyl, d-C ⁇ thioalkyl and N(Ri 5 , Ri 6 ) where R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl, and Ci-C ⁇ alkyl;
  • Rio and Rn are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 -C 7 alkanoyloxy, Ci-C 6 alkyl, d-C ⁇ alkoxy, C2-C7alkoxycarbonyl, Ci-C 6 thioalkyl, and N(Ri 5 , Ri 6 ) where R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl, and Ci-C 6 alkyl;
  • R12 is selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 -C 7 alkanoyloxy, Ci-C 6 alkyl, d-C ⁇ alkoxy, C 2 -C 7 alkoxycarbonyl, Ci-C 6 thioalkyl, and N(Ri 5 , Ri 6 ) where Ri 5 and Ri 6 are independently selected from hydrogen, acetyl, methanesulfonyl, and Ci-C 6 alkyl; and Z is selected from CH, CH 2 , O, N and S, where Z may be directly bonded to "X" as shown in formula (III) when Z is CH or N, or Z may be directly bonded to R17 when Z is N, and Ri 7 is selected from hydrogen, Ci-C 6 alkyl, Cs-Cscycloalkyl, aryl and benzyl;
  • the ion channel modulating compound is one or more of the following compounds: (+)-frans-[2-(4-morpholinyl)-1 -(2-naphthenethoxy)]cyclohexane;
  • Certain compounds of the present invention contain at least two asymmetric carbon atoms and, thus, exist as enantiomers and diastereomers.
  • the present invention includes all enantiomeric and diastereomeric forms of the aminocyclohexyl ether compounds of the invention. Pure stereoisomers, mixtures of enantiomers and/or diastereomers, and mixtures of different compounds of the invention are included within the present invention. Thus, compounds of the present invention may occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention. A racemate or racemic mixture does not imply a 50:50 mixture of stereoisomers.
  • independently at each occurrence is intended to mean (i) when any variable occurs more than one time in a compound of the invention, the definition of that variable at each occurrence is independent of its definition at every other occurrence; and (ii) the identity of any one of two different variables ⁇ e.g., Ri within the set Ri and R2) is selected without regard the identity of the other member of the set.
  • substituents and/or variables are permissible only if such combinations result in stable compounds.
  • Acid addition salts refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like
  • organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid
  • Alkoxy refers to an O-atom substituted by an alkyl group, for example, methoxy [-OCH 3 , a Cialkoxy].
  • Alkoxyalkyl refers to a alkylene group substituted with an alkoxy group.
  • methoxyethyl [CH 3 OCH 2 CH 2 -] and ethoxymethyl (CH 3 CH 2 OCH 2 -] are both C 3 alkoxyalkyl groups.
  • Alkyl refers to a branched or unbranched hydrocarbon fragment containing the specified number of carbon atoms and having one point of attachment. Examples include n-propyl (a C ⁇ alkyl), /so-propyl (also a C ⁇ alkyl), and f-butyl (a C 4 alkyl).
  • Alkylene refers to a divalent radical which is a branched or unbranched hydrocarbon fragment containing the specified number of carbon atoms, and having two points of attachment.
  • An example is propylene [-CH 2 CH 2 CH 2 -, a C 3 alkylene].
  • Alkylcarboxy refers to a branched or unbranched hydrocarbon fragment terminated by a carboxylic acid group [-COOH]. Examples include carboxymethyl [HOOC-CH 2 -, a C 2 alkylcarboxy] and carboxyethyl [HOOC-CH 2 CH 2 -, a C 3 alkylcarboxy].
  • Aryl refers to aromatic groups which have at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl (also known as heteroaryl groups) and biaryl groups, all of which may be optionally substituted. Carbocyclic aryl groups are generally preferred in the compounds of the present invention, where phenyl and naphthyl groups are preferred carbocyclic aryl groups.
  • Alkyl refers to an alkylene group wherein one of the points of attachment is to an aryl group.
  • An example of an aralkyl group is the benzyl group [C 6 H 5 CH 2 -, a C 7 aralkyl group].
  • Cycloalkyl refers to a ring, which may be saturated or unsaturated and monocyclic, bicyclic, or tricyclic formed entirely from carbon atoms.
  • An example of a cycloalkyl group is the cyclopentenyl group (C 5 H 7 -), which is a five carbon (C 5 ) unsaturated cycloalkyl group.
  • Carbocyclic refers to a ring which may be either an aryl ring or a cycloalkyl ring, both as defined above.
  • Carbocyclic aryl refers to aromatic groups wherein the atoms which form the aromatic ring are carbon atoms. Carbocyclic aryl groups include monocyclic carbocyclic aryl groups such as phenyl, and bicyclic carbocyclic aryl groups such as naphthyl, all of which may be optionally substituted. "Heteroatom” refers to a non-carbon atom, where boron, nitrogen, oxygen, sulfur and phosphorus are preferred heteroatoms, with nitrogen, oxygen and sulfur being particularly preferred heteroatoms in the compounds of the present invention.
  • Heteroaryl refers to aryl groups having from 1 to 9 carbon atoms and the remainder of the atoms are heteroatoms, and includes those heterocyclic systems described in "Handbook of Chemistry and Physics," 49th edition, 1968, R. C. Weast, editor; The Chemical Rubber Co., Cleveland, OH. See particularly Section C, Rules for Naming Organic Compounds, B. Fundamental Heterocyclic Systems. Suitable heteroaryls include furanyl, thienyl, pyridyl, pyrrolyl, pyrimidyl, pyrazinyl, imidazolyl, and the like.
  • “Hydroxyalkyl” refers to a branched or unbranched hydrocarbon fragment bearing an hydroxy (-OH) group. Examples include hydroxymethyl
  • Thioalkyl refers to a sulfur atom substituted by an alkyl group, for example thiomethyl (CH 3 S-, a Cithioalkyl).
  • Moduleating in connection with the activity of an ion channel means that the activity of the ion channel may be either increased or decreased in response to administration of a compound or composition or method of the present invention. Thus, the ion channel may be activated, so as to transport more ions, or may be blocked, so that fewer or no ions are transported by the channel.
  • “Pharmaceutically acceptable salt” refers to salts of the compounds of the present invention derived from the combination of such compounds and an organic or inorganic acid (acid addition salts) or an organic or inorganic base (base addition salts).
  • the compounds of the present invention may be used in either the free base or salt forms, with both forms being considered as being within the scope of the present invention.
  • Representative ion channel modulating compounds are more specifically disclosed in U.S. Patent No. 7,057,053 and U.S. Patent No. 7,345, 087, both of which are incorporated in therein entirety herein by reference. Further, methods of synthesizing and producing the ion channel modulating compounds of the present invention are described, e.g., in U.S. Patent No. 7,259,184 and U.S. Patent Application Serial Nos. 10/838,470, 11/757,880, 11/690,361 , 1 1/719,737, and 1 1/455,280, all of which are incorporated herein by reference in their entirety.
  • the present invention provides methods of preventing arrhythmia in subjects or patients (e.g., mammals or warm-blooded animals, including humans and other animals) at risk for arrhythmia, by administering to such subjects an effective amount of a controlled release formulation of an ion channel modulating compound, such as, e.g. vernakalant hydrochloride.
  • the methods of the invention are used to prevent or postpone the onset or recurrence of an arrhythmia.
  • the subject is a CYP2D6 extensive metabolizer. It is also unerstood that the formulations and methods describe herein may also beused in the treatment of arrhythmia.
  • methods of the present invention may be used to prevent arrhythmia in a subject who previously underwent one or more arrhythmias, or in a subject at risk of an arrhythmia.
  • methods of the present invention are used to prevent a post-operative arrhythmia ⁇ e.g., following cardiac surgery such as CABG or valvular surgery).
  • methods of the present invention are used to prevent the recurrence of arrhythmia, i.e., a recurrent arrhythmia, in a subject having previously undergone one or more arrhythmias.
  • the methods may also be used to treat or prevent sustained atrial fibrillation (atrial fibrillation of longer than 72 hours and less than 6 months duration) and chronic atrial fibrillation.
  • the ion channel modulating agent e.g., vernakalant hydrochloride
  • the amount of ion channel modulating compound administered will generally range from a dosage of from about 0.1 to about 100 mg/kg/day, and typically from about 0.1 to 10 mg/kg where administered orally or intravenously for antiarrhythmic effect.
  • a dosage is 5 mg/kg or 7.5 mg/kg.
  • the ion channel modulating compound is administered at a dosage of about 50-2500 mg per day, 100-2500 mg/day, 300-1800 mg/day, or 500-1800 mg/day. In one embodiment, the dosage is between about 100 to 600 mg/day. In another embodiment, the dosage is between about 300 and 1200 mg/day. In particular embodiments, the ion channel compound is administered at a dosage of 100 mg/day, 300 mg/day, 600 mg/day, 1000 mg/day, 1200 mg/day, or 1800 mg/day, in one or more doses per day (i.e., where the combined doses achieve the desired daily dosage).
  • a dosage is 100 mg bid, 150 mg bid, 300 mg bid, 500 mg bid, 600 mg bid, or 900 mg b.i.d.
  • these dosages are administered orally to a subject at risk for arrhythmia, to prevent such arrhythmia. Examples of other suitable dosages and dosing regimes are also described, e.g., in U.S. Patent Application Nos. 1 1/667,139, 1 1/832,580, 60/916,129, and 60/953,431 .
  • the ion channel modulating compound is administered in repeat dosing, and the initial dosage and subsequent dosages may be the same or different.
  • an effective orally administered (i.e., oral) dosage of vernakalant hydrochloride for the prevention of an arrhythmia, (e.g., over 90 days) is greater than 300 mg b.i.d., or greater than 600 mg per day.
  • an effective oral dosage of vernakalant hydrochloride may be in the range greater than 300 mg b.i.d. and up to 900 mg b.i.d. In other embodiments, it may be in the range greater than 300 mg b.i.d. and up to 600 b.i.d.
  • an effective oral dosage of vernakalant hydrochloride is about 500 mg b.i.d., about 600 mg b.i.d., about 700 mg b.i.d., about 800 mg b.i.d., or about 900 mg b.i.d.
  • the ion channel modulating compound is administered long-term, chronically, or regularly, e.g., to prevent arrhythmia in a mammal.
  • Such long term or chronic administration may be, e.g., at least 90 minutes, at least 2 hours, at least 3 hours, at least 4 hours, at least 8 hours, at least 12 hours, at least 24 hours, at least 48 hours, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least one week, at least 2 weeks, at least one month, at least 2 months, at least 4 months, at least 6 months, at least one year, at least 2 years, or greater than 2 years.
  • long-term treatment is characterized as administration for 3 days or longer, since this is the approximate time in which ion channel modulating compounds reach steady state plasma levels with twice daily oral dosing.
  • the ion channel modulating compound is administered for at least one week to one year, which may be, e.g., following surgery or an arrhythmia. Such methods are particularly useful in preventing post-surgical arrhythmia or the recurrence or arrhythmia.
  • the ion channel modulating compound is administered to the mammal in two or more doses over the duration of administration.
  • the ion channel modulating compound is administered orally using an extended release formulation or tablet of this invention.
  • controlled release tablet formulations comprising an ion channel modulating compound, specifically vernakalant hydrochloride, and one or more pharmaceutically acceptable excipient were prepared.
  • Comparative controlled release tablet formulations comprising the active ingredient were made by incorporating the ion channel modulating compound, or its pharmaceutically effective salt, (collectively referred to herein as the "active ingredient"), preferably vernakalant hydrochloride, within a matrix system, including, but not limited to, a hydrophilic matrix system, a hydrophilic non-cellulose matrix system, a hydrophobic (plastic matrix system), or a hydrophilic/hydrophobic matrix system; within a fat-wax system; or within a film- coated particulate system.
  • a matrix system including, but not limited to, a hydrophilic matrix system, a hydrophilic non-cellulose matrix system, a hydrophobic (plastic matrix system), or a hydrophilic/hydrophobic matrix system; within a fat-wax system; or within a film- coated particulate system.
  • Hydrophilic matrix systems showed uniform and constant diffusion of the active ingredient from a tablet prepared with a hydrophilic, gelling polymer (i.e., a hydrophilic matrix system polymer) after the tablet is placed in an aqueous environment. Release of the active ingredient from the system was controlled by a gel diffusional barrier which is formed by a process that is usually a combination of gel hydration, diffusion of the active ingredient, and gel erosion.
  • a hydrophilic, gelling polymer i.e., a hydrophilic matrix system polymer
  • Hydrophobic (plastic) matrix systems utilized inert, insoluble polymers (i.e., hydrophobic matrix system polymers) and copolymers to form a porous skeletal structure in which the active ingredient is embedded. Controlled release was effected by diffusion of the active ingredient through the capillary wetting channels and pores of the matrix, and by erosion of the matrix itself.
  • Hydrophilic/hydrophobic matrix systems utilized a combination of hydrophilic and hydrophobic polymers that formed a soluble/insoluble matrix in which the active ingredient was embedded. Controlled release of the active ingredient was by pore and gel diffusion as well as tablet matrix erosion. The hydrophilic polymer was expected to delay the rate of gel diffusion.
  • the active ingredient was incorporated in a hot melt of a fat wax matrix, solidified, sized and compressed with appropriate tablet excipients. Controlled release of the active ingredient was effected by pore diffusion and erosion of the fat-wax system. The addition of a surfactant as a wicking agent helped water penetration of the system to cause erosion.
  • Film-coated particulate systems included time-release granulations, prepared by extrusion-spheronization process or by conventional granulation process that had been film-coated to produce differing species of controlled release particles with specific active ingredient release characteristics. Controlled release particles could be compressed together with appropriate excipients to produce tablets with the desired controlled release profile. The release of the active ingredient was by particle erosion in either acid (gastric) or alkaline (intestinal) pH.
  • Controlled release tablet formulations comprising the active ingredient could be manufactured by methods including, but not limited to, direct compression (dry blending the active ingredient with flowable excipients, followed by compression), wet granulation (application of a binder solution to powder blend, followed by drying, sizing, blending and compression), dry granulation or compaction (densifying the active ingredient or active ingredient/powder blend through slugging or a compactor to obtain flowable, compressible granules), fat-wax (hot melt) granulation (embedding the active ingredient in molten fatty alcohols, followed by cooling, sizing, blending and compression), and film-coating of particulates (dry blend, wet granulation, kneading, extrusion, spheronization, drying, film-coating, followed by blending of different species of film-coated spheres, and compression).
  • direct compression dry blending the active ingredient with flowable excipients, followed by compression
  • wet granulation application
  • a. Direct compression b. Wet densification of the active ingredient and Starch 1500 or Povidone K29/32 with purified water, followed by tray drying to a moisture level of 2-3% w/w/ and blending with direct compression excipients.
  • the desired amount of the active ingredient and the desired amount of Starch 1500, Povidone K29/32, Lactose Fast Flo, Anhydrous Emcompress or Carbopol 71 G were mixed by hand in a small polyethylene (PE) bag or a 500 ml_ high density polyethylene (HDPE) container for approximately one minute and then passed through a #30 mesh screen.
  • the resulting blend was then mixed with the desired amounts of the remaining excipients in the desired formulation, excluding magnesium stearate and stearic acid, for approximately 2 minutes in either a small PE bag or a 500 ml_ HDPE container.
  • Approximately 1 g of the resulting mixture was then mixed with the desired amount of magnesium stearate and stearic acid, passed through a #30 mesh screen, added back to the remaining resulting mixture and then blended for approximately one minute.
  • the resulting blend was then compressed into tablets at a final tablet weight of 630 mg or 675 mg (for tablets containing 300 mg active ingredient using a conventional bench top tablet press.
  • the desired amount of the pre-screened (#40 mesh) active ingredient and Starch 1500 were placed in a 4 quart V-shell and blended at 25 rpm for 3 minutes.
  • Magnesium stearate was then added to an equal amount of the resulting mixture, which was then blended in a small polyethylene bag for approximately 1 minute, passed through a #30 mesh screen by hand and returned to the resulting mixture.
  • the final resulting mixture was blended for 2 minutes at 25 rpm and then compressed into tablets at a final tablet weight of 630 mg (for tablets containing 300 mg active ingredient) using a conventional tablet press.
  • the desired amount of the active ingredient was mixed with the desired amount of Starch 1500 or Povidone K29/32 and the resulting mixture was passed through a #30 mesh screen. Purified water was added to the screened mixture until it reached a satisfactory densification end point.
  • the resulting wet mass was passed through a #12 mesh screen onto a tray and dried at 60° C for 2 to 3 hours until a moisture level of 2-3% w/w was obtained.
  • the resulting dry granules were passed through a #20 mesh screen into either a small PE bag or a 500 ml_ HDPE container.
  • To the screened dry granules was added the desired amounts of the remaining excipients of the formulation, excluding magnesium stearate and stearic acid. The contents were mixed for approximately 2 minutes.
  • Approximately 1 g of the resulting mixture was then mixed with the desired amounts of magnesium stearate and stearic acid, passed through a #30 mesh screen, added back to the remaining resulting mixture and then blended for approximately 1 minute.
  • the final resulting blend was compressed into tables at a final tablet weight of 630 mg or 675 mg (for tablets containing 300 mg active ingredient) using a conventional tablet press.
  • the desired amount of fat wax preferably cetostearyl alcohol or cetyl alcohol
  • the desired amounts of the active ingredient, Lactose Fast Flo and Prosolv SMCC90 were then added to the melted wax with continuous stirring and heating until completely dispersed. Alternately, only the desired amount of the active ingredient was dispersed in the melted wax.
  • the resulting granular-like particles were passed through a #20 mesh screen and placed in either a small PE bag or a 500 ml_ HDPE container.
  • the screened particles were blended with Lactose Fast Flo and Prosolv SMCC 90 for approximately 2 minutes in either a small PE bag or a 500 mL HDPE container. Approximately I g of each blend was mixed with the desired amounts of magnesium stearate and stearic acid, passed through a #30 mesh screen, returned to the blend, and mixed for approximately one minute. The final blend was compressed into tablets at weights of 630 mg or 675 mg (for tablets containing 300 mg active ingredient) using a conventional tablet press.
  • the desired amount of fat wax preferably, cetostearyl alcohol was melted at approximately 70° C in a mixer until the wax liquefied.
  • Prosolv SMCC90 were blended for approximately 1 minute in a double lined PE bag and set aside.
  • the desired amount of the active ingredient was added to the melted wax with continuous stirring and heating at approximately 70 0 C until the active ingredient was completely dispersed.
  • the blend of excipients was then added to the melted wax with stirring and maintaining heating between 40° C and 60° C until dispersion was complete.
  • the resulting granular-like particles were cooled to ambient temperature, passed through a #20 mesh screen and placed in a double lined PE bag.
  • the screened particles were then blended with stearic acid in a 4 quart V-shell for approximately 2 minutes at 25 rpm.
  • Magnesium stearate was added to an equal amount of the stearic acid blend, blended in a small PE bag for approximately 1 minute, passed through a #20 mesh screen by hand, returned to the stearic acid blend and the final mixture was blended for 3 minutes at 25 rpm.
  • the final blend was compressed into tablets at a weight of 630 mg or 675 mg (for tablets containing 300 mg of active ingredient) using a conventional tablet press.
  • Hydrophilic formulation #300-2 was prepared by reducing the calculated tablet weight of 675 mg of hydrophilic formulation #300-1 to 630 mg by reducing the amount of Lactose Fast Flo and Prosolv SMCC 90.
  • Table 8 provides for a controlled release tablet formulation of the invention comprising 300 mg of the active ingredient, vernakalant hydrochloride, in a hydrophilic (non-cellulose) matrix system.
  • Table 9 provides for a controlled release tablet formulation of the invention comprising 300 mg of the active ingredient, vernakalant hydrochloride, in a hydrophilic/hydrophobic matrix system.
  • Table 10 provides for a controlled release tablet formulation of the invention comprising 300 mg of the active ingredient, vernakalant hydrochloride, in a fat wax system. This formulation was prepared by methods disclosed herein.
  • the in vitro release profile of the comparative controlled release formulations described above may be empirically determined by examining the dissolution of the tablet formulations over time.
  • a method using a USP approved apparatus for dissolution or release test can be used to measure the rate of release in vitro.
  • Example 6 is provided as a guide in preparing the comparative controlled release formulations.
  • Table 11 provides the in vitro dissolution release percentages of the comparative controlled tablet formulations comprising 300 mg of the active ingredient.
  • TABLE 11 MEAN DISSOLUTION % RELEASE OF 300 MG COMPARATIVE CONTROLLED RELEASE FORMULATIONS
  • the in vivo pharmacokinetic profiles of the comparative controlled release formulations were determined as follows. The formulations were administered to dogs to determine the pharmacokinetic profile of each formulation. A single comparative controlled release tablet formulation was orally administered to a dog. Blood samples were collected via the jugular or cephalic vein at predose (0), 30, 60, 90, 120, 240, 360, 480, 600, 720 and 1440 minutes after administration. Concentration levels of the active ingredient in the plasma samples at each timepoint was determined using standard methods known to one skilled in the art.
  • a controlled release formulation should provide a broader pharmacokinetic curve while minimizing the C max when compared to the pharmacokinetic curve of a comparable immediate release formulation.
  • hydrophilic formulation #300-2 was administered as a double dose (600 mg of active ingredient) to six healthy male and female subjects. Blood was drawn at pre-dose (0 hours), 0.5, 1 , 1.5, 2, 3, 4, 6, 8, 10, 12, 16 and 24 hours post dose. The median pharmacokinetic parameters are shown in the following Table 15:
  • an extended release formulation which provides a longer T max and a reduced C ma ⁇ than the T max and C ma ⁇ obtained from the comparative controlled release formulations is desired (i.e., an extended release formulation with a slower active ingredient release rate).
  • various formulations were prepared and investigated as extended release formulations of the invention, as described futher below, to identify suitable combinations of active ingredient and excipients for extended release formulations.
  • the present invention provides extended release tablet formulations comprising an active ingredient, such as vernakalant hydrochloride, in combination with particular excipients. These tablet formulations may be uncoated or coated with either or both a taste masking coating and an enteric coating. In addition, one or more of these extended release tablet formulations may be present in a capsule.
  • an extended release tablet formulation of this invention comprises comprises a hydrophilic matrix polymer.
  • the hydrophilic matrix polymer is hydroxypropyl methyl cellulose or polyethylene oxide.
  • an extended release formulation of the present invention comprises between about 20% wt. and about 60% wt. hydrophilic matrix polymer, or between about 25% wt. and about 45% wt. hydrophilic matrix polymer.
  • a controlled release formulation comprises about 20% wt., about 30% wt., about 35% wt., about 40% wt., about 45% wt., about 50% wt., about 55% wt., or about 60% wt. hydrophilic matrix polymer.
  • this tablet formulation further comprises magnesium stearate.
  • the formulation comprises about 0.5% wt. to 2.0% wt. magnesium stearate. In one embodiment, the formulation comprises about 1.0 % wt. magnesium stearate.
  • an extended release formulation comprises dicalcium phosphate, e.g., A-Tab. In various embodiments, the formulation comprises about 5.0% wt. to about 50% wt., or about 10% wt. to about 30% wt. dicalcium phosphate. In certain embodiments, the formulation comprises about 10% wt., about 20% wt. or about 30% wt. dicalcium phosphate.
  • the combination of hydrophilic matrix polymer and dicalcium phosphate between about 40% wt. and 70% wt. or between about 50% wt. and 60% wt. of the formulation. In one embodiment, the combination of hydrophilic matrix polymer and dicalcium phosphate is about 55% wt. of the formulation.
  • this tablet formulation comprises vernakalant hydrochloride; hydroxypropyl methyl cellulose; dicalcium phosphate anhydrous; and magnesium stearate.
  • an extended release tablet formulation of this invention is coated with a enteric coating composition comprising a (meth)acrylate copolymer.
  • the enteric coating composition comprises a (meth)acrylate copolymer, Imwitor, triethyl citrate, and a polysorbate.
  • an extended release tablet formulation of this invention is coated with a taste masking coating composition comprising a polyvinyl alcohol (PVA) base.
  • PVA polyvinyl alcohol
  • the taste masking coating composition comprises PVA base hydroxypropyl methyl cellulose, dicalcium phosphate, an magnesium stearate.
  • this invention provides for capsules comprising one or more extended release tablet formulations of this invention.
  • the capsule comprises an extended release tablet formulation coated with a enteric coating comprising a (meth)acrylate copolymer.
  • the capsule comprises an extended release tablet formulation of this invention coated with a taste masking coating composition comprising a polyvinyl alcohol (PVA) base.
  • the capsule comprises both an extended release tablet formulation coated with a enteric coating and an extended release tablet formulation coated with a taste masking coating.
  • the extended release tablet formulations present in the capsule comprise vernakalant hydrochloride as the ion channel modulating agent.
  • they comprise vernakalant hydrochloride and hydroxypropyl methyl cellulose
  • they comprise vernakalant hydrochloride, hydroxypropl methyl cellulose, and magnesium stearate.
  • they comprise vernakalant hydrochloride, hydroxypropyl methyl cellulose, magnesium stearate, and dicalcium phosphate anhydrous.
  • any of the controlled release or extended release tablet formulations described herein may be coated with one or more of any of the coatings described herein.
  • the present invention provides extended release tablets and capsules comprising an effective amount of an ion channel modulating compound, such as vernakalant hydrochloride, when administered at a recommended dosage, including any of those dosages described herein.
  • a recommended dosage may include any number of extended release tablets or capsules.
  • a recommended dosage of about 500 mg vernakalant hydrochloride b.i.d. may be achieved by administered two tablets or capsuled comprising about 250 mg vernakalant hydrochloride b.i.d.
  • any of the specific extended release tablet formulations described herein e.g. those comprising 300 mg of vernakalant hydrochloride, may be readily adapted to include 250 mg vernakalant hydrochloride, by varying the amounts of each component therein and maintaining the same ratio of components by weight.
  • the extended release tablet formulations of an ion channel modulating compound, or capsules comprising these formulations have a release profile wherein less than 1 % of the ion channel modulating compound, or a pharmaceutically acceptable salt thereof, is released following 2 hours in 0.1 N HCI solution and 4 hours in phosphate buffer solution at pH 6.4.
  • an extended release formulation of the present invention releases a certain percentage of active ingredient, e.g., vernakalant, when placed in a dissolution medium, such as described in Example 7.
  • an extended release formulation releases less than about 35% to less than about 10% active ingredient (e.g., less than about 35%, 30%, 25%, 20%, 15%, or 10% active ingredient, including all ranges and integers in between) after incubation for about 2 hours at 37 0 C in 0.1 N HCI (i.e., Dissolution Medium 1 ).
  • an extended release formulation releases less than about 60% to less than about 25% active ingredient (e.g., 60%, 55%, 50%, 45%, 35%, 30%, or 25% active ingredient, including all ranges and integers in between) after incubation for about 6 hours at 37 0 C in 0.1 N HCI.
  • an extended release formulation releases less than about 85% to less than about 55% active ingredient (e.g., less than about 85%, 80%, 75%, 70%, 65%, 60%, 55%, including all ranges and integers in between) after incubation for about 6 hours at 37 0 C in 0.1 N HCI, followed by about 6 hours further incubation in 0.05 M Thbasic Sodium Phosphate Buffer adjusted to pH 7.2 ⁇ 0.05.
  • active ingredient e.g., less than about 85%, 80%, 75%, 70%, 65%, 60%, 55%, including all ranges and integers in between
  • an extended release formulation of the present invention demonstrates particular pharmacokinetic (PK) characteristics following administration (e.g., oral administration of 300mg extended release vernakalant) to an individual.
  • PK characteristics may be represented, for example, by maximum plasma concentration (C ma ⁇ ), time of maximum plasma concentration (t max ), area under the plasma concentration-time curve (AUC), C max /AUC ratio, and half-life (t 1/2 ), as described in Example 10.
  • PK characteristics may also be represented by mean plasma concentration, such as by the geometric mean, CV%, arithmetic mean, standard deviation, median, and minimum and maximum values.
  • an extended release formulation has an apparent mean half-life (ti /2 ) ranging from about 4 hours to about 10 or more hours (e.g., 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, or more hours, including all ranges and decimal components in between, e.g., 4.2, 4.3, 4.4, etc.) following administration to an individual.
  • an extended release formulation has a t max value ranging from about 3 hours to about 7 or 8 hours (e.g.., about 3, 4, 5, 6, 7, 8, or more hours, including all ranges and decimal components in between (e.g., 4.2, 4.3, 4.4, etc.).
  • an extended release formulation exhibits lower Cmax values and lower C m a ⁇ /AUC ⁇ n f ratios as compared to a non-extended release formulation, such as a controlled release formulation.
  • an extended release formulation has a mean C ma ⁇ value ranging from about 12 ng/ml to about 25 ng/ml, including all ranges, integers, and decimal components in between, following administration to an individual.
  • a non-extended release formulation typically exhibits a mean C ma ⁇ value of about 28 ng/ml or more.
  • an extended release formulation has a mean C max value ranging from about 90 ng/ml to about 150 ng/ml, including all ranges, integers, and decimal components in between (e.g., 90, 95, 100, 120, 125, 130, 140, 150, 90-120, 100-120, 120-150 ng/ml, etc.), following administration to an individual.
  • a non-extended release formulation typically exhibits a mean Cmax value of about 200 or 220 ng/ml or more.
  • an extended release formulation has a mean C ma ⁇ value ranging from about 195 ng/ml to about 220 ng/ml, including all ranges, integers, and decimal components in between, following administration to an indivual.
  • a non- extended release formulation typically exhibits a mean C ma ⁇ value of about 270 or 280 ng/ml or more.
  • an extended release formulation may exhibit a mean C m a ⁇ /AUC ⁇ nf ratio ranging from about 0.05 to about 0.12, including all ranges and decimal components in between, such as about 0.05 to about 0.10, 0.05 or 0.06 to about 0.10 or 0.09, 0.06 to about 0.08 or 0.07, among others.
  • Methocel K4M hydroxypropyl methyl cellulose
  • hydrophilic table formulation #300-2 at 19.0% total weight
  • Cetostearyl alcohol was used as the active ingredient release retardant in fat wax formulation #300-1 at 22.22%.
  • Both formulations contain around 15% Prosolv SMCC90 and around 15% lactose. It was determined that the presence of Prosolv SMCC90 and lactose would cause the increase in drug release rate.
  • Two formulation approaches were investigated in detail: matrix tablets and coated tablets. Hydrophilic matrix tablets containing hydroxypropyl methyl cellulose or polyethylene oxide as active ingredient release retardants were demonstrated to be viable delivery systems for the active ingredient, vernakalant hydrochloride.
  • HPMC Hydroxypropyl Methyl Cellulose
  • Calcium phosphate dibasic and polyethylene oxide were found to be the most effective in improving the compaction properties of hydroxypropyl methyl cellulose matrix tablets. iv). Three hydroxypropyl methyl cellulose matrix formulations containing 10%, 20% or 30% A-Tab (calcium phosphate dibasic) were selected for stability studies.
  • hydroxypropyl methyl cellulose based extended release formulations of the invention were developed as follows. 1 . Hydroxypropyl methyl cellulose
  • Methocel K4M, Methocel K15M and Methocel K100M are most commonly used for the preparation of extended release dosage forms.
  • the viscosity of 2% Methocel K4M, K15M and K100M solution in water at 2O 0 C is 4,000, 15,000 and 100,000 cps, respectively.
  • Slower active ingredient release is expected when Methocel K100M is used to replace Methocel K4M, starch 1500, Prosolv SMCC and lactose in the hydrophilic formulation #300-2.
  • vernakalant hydrochloride With the addition of alkaline agents, a certain percentage of vernakalant hydrochloride will be, theoretically, converted from the hydrochloride salt to the free base.
  • the free base form of vernakalant hydrochloride is anticipated to have a much slower solubility and diffusion rate than its hydrochloride salt. Therefore, addition of alkaline agents could theoretically effectively retard the release of the active ingredient.
  • Carbonate, phosphate and citrate salts are commonly used alkaline agents in extended release formulations. Sodium salt is more commonly used than potassium salt. These alkaline agents were added at levels ranging from 4.3 to 10.0 percent and were all within the range specified in the FDA inactive ingredient list. These salts are available as anhydrous or hydrate forms.
  • Carbopol is cross-linked polycarboxylic acid carbomer and it can form a strong gel in an alkaline aqueous environment in order to hinder the release of the active ingredient.
  • Carbopol 974P is the only grade of Carbopol approved for oral drug delivery
  • Formulations containing Carbopol as an active ingredient release retardant demonstrated very poor flow properties and poor compaction properties.
  • the presence of alkaline agents in the formulations actually increased the release rate of the active ingredient, vernakalant hydrochloride.
  • Methocel K100M CR (controlled release grade) was identified to be a suitable hydrophilic matrix polymer for extended release of the active ingredient, vernakalant hydrochloride. Extended release over 12 hours was successfully demonstrated by Extended Release Formulation #1.
  • Extended Release Formulation #1 tablets were prepared by manually compressing a physical blend of vernakalant hydrochloride, Methocel K100M and magnesium stearate on a rotary tablet press. Tablet hardness was around 20 Kp. Additional investigation was commenced to identify suitable filler excipients which could be incorporated into Extended Release Formulation #1 to improve its compaction properties when compressed into a tablet dosage form for oral administration. Accordingly, the effect of the following pharmaceutically acceptable filler excipients on the compaction properties of Extended Release Formulation #1 was investigated. All of these excipients have superior compaction properties when compressed on their own. a). Microcrystalline cellulose (Avicel PH 101 and Avicel PH
  • Avicel is the most commonly used filler excipients to improve the compaction properties of a tablet formulation.
  • the composition of formulations containing microcrystalline cellulose, Avicel is summarized in Table 31.
  • the average particle size of PH 101 is 50 ⁇ m and the average particle size of PH 105 is 20 ⁇ m. It was anticipated that Avicel PH 105 could improve the compaction properties more significantly than Avicel PH 101 since the particle size of Avicel PH 105 is smaller.
  • Ethyl cellulose is a water insoluble polymer used for the preparation of matrix tablets and is extremely compressible. It is also commercially available as premium and fine particle size grade. The fine particle size grade was selected for investigation because of its stronger solid state binding capacity as a result of its large specific surface area.
  • the composition of extended release formulations of the invention comprising ethyl cell use, Ethocel Std 10 FP, is summarized in Table 33.
  • CR denotes controlled release grade which is specially produced, ultra-fine particle size material.
  • Methocel K100M 100% of material is finer than 30 mesh and 99% is finer than 40 mesh.
  • Methocel K100M CR 90% of material is finer than 100 mesh.
  • Dicalcium phosphate anhydrous (A-Tab, Rhodia)
  • dicalcium phosphate anhydrous (A-Tab) was investigated as an excipient to increase the compaction property of Extended Release Formulation HPMC #1.
  • Table 35 The composition of extended release formulations of the invention comprising dicalcium phosphate anhydrous (A-Tab) is summarized in Table 35. TABLE 35: 300 MG EXTENDED RELEASE HPMC FORMULATIONS FURTHER COMPRISING DICALCIUM PHOSPHATE ANHYDROUS (A-TAB)
  • CR and A-Tab were mixed in a mortar and pestle.
  • the appropriate amount of magnesium stearate was added to the mixture and the resulting mixture was blended briefly.
  • the resulting powder blend was passed through a 30 mesh screen.
  • the resulting blend was manually compressed using a 11 mm, round, shallow concave tabletting tool to a tablet hardness of 20 Kp.
  • the tablets so formed exhibited good compaction properties when A-Tab was present in the formulation at 10%, 20% and 30% level. Furthermore, it was observed that A- Tab appeared to be more effective in improving the compaction properties of the powder blend than Avicel and Ethocel.
  • Polyethylene oxide has excellent compaction properties. At the same time, polyethylene oxide could potentially suppress the initial burst effect of the hydrophilic matrix formulations.
  • Coagulated grade polyethylene oxide was selected for detailed investigation. It is available from Dow Chemical as regular grade, fine particle size grade (90% pass through 60 mesh screen) and superfine grade (90% pass 100 mesh screen). Polyethylene oxide of smaller particle size can improve the compaction properties of the formulation to a greater extent because it has greater specific surface area.
  • superfine grade polyethylene oxide has been found to be very dusty and difficult to handle during the blending process because of its superfine particle size. Therefore, fine particle size grade was selected for investigation.
  • composition of extended release formulations of the invention comprising fine particle size grade polyethylene oxide coagulated (PoIyOx WSR) is summarized in Table 39.
  • vernakalant hydrochloride Methocel K100M CR and A-Tab were mixed in a mortar and pestle.
  • the appropriate amount of magnesium stearate was added to the mixture and the resulting mixture was blended briefly.
  • the resulting powder blend was passed through a 30 mesh screen.
  • the resulting blend was manually compressed using a 11 mm, round, shallow concave tabletting tool to a tablet hardness of 20 Kp. Good compaction properties were observed for all four formulations.
  • Polyethylene oxide (PEO) was found to be an excellent hydrophilic active ingredient release retardant for the preparation of extended release formulations of the active ingredient, vernakalant hydrochloride. Initial burst in the release of the active ingredient was less in polyethylene oxide matrix tablets, in comparison with the hydroxypropyl methyl cellulose matrix tablets. Polyethylene oxide matrix tablets also demonstrated better compaction properties than the hydroxypropyl methyl cellulose matrix tablets. 1. Comparison of Different Grades of Polyethylene Oxide (PoIvOx)
  • Polyethylene oxide (PEO) is a homopolymer of ethylene oxide. It is miscible with water at any ratio. Different grades of polyethylene oxide NF (Dow Chemical) are listed in Table 43. Polyethylene oxide grade WSR N-301 , polyethylene oxide grade WSR coagulated and polyethylene oxide grade WSR 303 were selected for the initial evaluation. The objectives were to evaluate the effect of polyethylene oxide molecular weight on the release rate of the active ingredient.
  • WSR N-301 , WSR coagulated and WSR 303 are available in three different grades: regular, FP (fine particles, >90% pass through 60 mesh) and SFP (superfine particles, >90% pass through 100 mesh).
  • regular fine particles, >90% pass through 60 mesh
  • SFP fine particles, >90% pass through 100 mesh.
  • the compaction properties of polyethylene oxide improved with a decrease in particle size. Therefore, polyethylene oxide of SFP grade was used for the initial formulation evaluation.
  • compositions of the formulations containing the different grades of polyethylene oxide are presented in Table 44.
  • vernakalant hydrochloride and polyethylene oxide were mixed in a mortar and pestle.
  • the appropriate amount of magnesium stearate was added to the mixture and the resulting mixture was blended briefly.
  • the resulting powder blend was passed through a 30 mesh screen.
  • the resulting blend was manually compressed using a 11 mm, round, shallow concave tabletting tool to a tablet hardness of 20 Kp. Excellent compaction properties was observed for all three formulations.
  • the release rate of the active ingredient was similar when polyethylene oxide WSR 301 , polyethylene oxide WSR 303 or polyethylene oxide WSR coagulated grades were used in that the release rate of the active ingredient was essentially constant over the initial 8 hours.
  • vernakalant hydrochloride and polyethylene oxide were mixed in a mortar and pestle.
  • the appropriate amount of magnesium stearate was added to the mixture and the resulting mixture was blended briefly.
  • the resulting powder blend was passed through a 30 mesh screen.
  • the resulting blend was manually compressed using a 11 mm, round, shallow concave tabletting tool to a tablet hardness of 20 Kp. Good compaction properties were observed for the formulation.
  • aqueous dispersion based on Eudragit FS 3OD was applied onto the tablets of the formulation HPMC #33 to impart enteric delivery properties to the formulation.
  • the composition of the aqueous coating dispersion is presented in Table 52.
  • the solid content of the final dispersion was 20%.
  • the coating parameters is summarized in Table 53.
  • Tablets samples were collected at 4.0%, 6.6% and 8.4% coating levels.
  • the dissolution results of coated tablets (6.6% coating and 8.4% coating) and uncoated tablets are presented in Tables 54 and 55.
  • Solid content of the final dispersion is 20%.
  • Extended release formlations can also be prepared according to Tables 65- 67.
  • Polyvinyl alcohol (PVA) base Opadry Il (Colorcon) or Opadry was applied to the core tablet formulation (which was prepared by similar methods disclosed herein) for taste masking.
  • Eudragit FS 30 D was applied to deliver the active ingredient to the colon region.
  • Capsules were also prepared containing one 150 mg tablet coated with Opadry Il and one 150 mg tablet coated with Eudragit FS 30 D. All of the formulations contained Methocel K100M CR and A-Tab at 10%, 20% or 30% (w/w).
  • A-Tab (dicalcium phosphate, anhydrous) 20.00 17.80 75.00
  • A-Tab (dicalcium phosphate, anhydrous) 30.00 26.70 112.50
  • composition of the Opadry® Il coating dispersion is presented in
  • Opadry Il Prior to Eudragit FS 30 D coating, Opadry Il was applied as a sub-coat. An Opadry clear coating (Table 69) was then applied as an over-coat after
  • Opadry over coat was applied to prevent sticking between Eudragit coated tablets during the curing.
  • Opadry clear was selected for the top coat instead of Opadry Il because Opadry clear could be applied at a lower product temperature.
  • Solid content of the coating dispersion is 7%.
  • the 300 mg dose tablets were coated with Opadry Il at a 4% weight gain level. Each batch of 150 mg dose tablets was divided in half. One half was coated with Opadry Il at a 4% weight gain level. The other half were coated with Opadry Il at a 2% weight gain level, then with Eudragit FS 30 D at an 8% weight gain level, and finally with Opadry clear at a 2% weight gain level.
  • the coating parameters are indicated in Table 70:
  • Paddle speed 150 rpm Sampling timepoints 0, 1 , 2, 4, 8, 12, 16 and 24 hours
  • Dissolution medium 0-2 hr 0.1 N HCI solution
  • Example 7 Formulation Storage Stability and Dissolution Testing was performed on three different 300mg Vernakalant tablet formulations manufactured according to Formulation #1 , Formulation #4, and Formulation #7 (see Tables 56, 59, and 62, respectively). Testing was also performed on three different 300mg 2-in-1 Vernakalant capsule formulations, each capsule comprising a combination of two 150mg Vernakalant tablet Formulations. These three different 2-in-1 capsule formulations were manufactured according to (i) Formulations #2/#3, (ii) Formulations #5/#6, and (iii) Formulations #8/#9.
  • the tablets and capsules were stored for up to 6 months at either 30°C/65% relative humidity (RH) or 40°C/75% RH.
  • Samples taken at 0 (initial), 1 , 3, and 6 months were tested in in vitro dissolution assays and were also analyzed by chromatography for Vernakalant content, water content, and the presence or absence of Vernakalant degradation products.
  • Vernakalant tablets or capsules from the initial, 1 , 3, and 6 month timepoints were tested in an in vitro dissolution assay.
  • the dissolution assay was performed using the following ingredients: Dissolution Medium Stage 1 : 0.1 N HCI Dissolution Medium Stage 2: 0.2 M Tribasic Sodium Phosphate Buffer To perform the dissolution, tablets or capsules from each time point were placed in dissolution vessels containing 750ml Dissolution Medium Stage 1 at 37 0 C using USP apparatus 2. Samples were collected at the 2 hour and 6 hour time points. After sampling of the 6 hour timepoint, 250ml of Dissolution Medium Stage 2 was added to each vessel and the pH was adjusted to 7.2 ⁇ 0.05 with 2N sodium hydroxide or 2N hydrochloric acid. Samples were then collected at the 12 hour and 24 hour timepoints.
  • the paddles were stopped and any remaining dosage form was crushed using long arm tweezers or a glass stirring rod. After dispersal of the dosage form, the paddle speed was increased to 250 rpm for 30 minutes. The "infinity" sample was collected at this time point.
  • the samples from the 2 hour, 6 hour, 12 hour, 24 hour and infinity time points were analyzed by chromatography as compared to a Vernakalant hydrochloride stock standard (-0.3 mg/ml).
  • the standard was prepared by dissolving -30 mg vernakalant hydrochloride in 100ml 0.1 N HCI and mixing well.
  • the chromatography data was used to calculate the percent vernakalant (active ingredient) released for each time point. The results are set forth below in Tables 71 through 82.
  • Atrial Fibhllation/Atrial Flutter The following study was conducted to evaluate, inter alia, the efficacy of a controlled release formulation comprising vernakalant hydrochloride in human subjects with sustained atrial fibrillation (atrial fibrillation of longer than 72 hours and less than 6 months duration.
  • the time to first documented recurrence of symptomatic sustained atrial fibrillation or atrial flutter was longer in subjects receiving the active ingredient than subjects receiving placebo. 43.1 % of placebo subjects were in sinus rhythm on Day 28 compared to 61.6% of subjects treated with 300 mg. b.i.d. of active ingredient and 62.4% of subjects treated with 600 mg b.i.d. of active ingredient.
  • vernakalant hydrochloride oral
  • AF sustained symptomatic atrial fibrillation
  • This study demonstrated statistically significant efficacy for the patient group receiving 500 mg b.i.d. of vernakalant hydrochloride (oral) as compared to placebo.
  • the safety data from the interim analysis also suggested that vernakalant hydrochloride (oral) was well-tolerated in the AF patient population studied during this dosing period.
  • Vernakalant hydrochloride (oral) tablets were prepared from a blend of vernakalant hydrochloride drug substance with tablet excipients, including silicified microcrystalline cellulose, hydroxypropyl methyl ether cellulose
  • HPMC Hypromellose or HPMC
  • pregelatinized starch lactose monohydrate
  • stearic acid lactose monohydrate
  • magnesium stearate magnesium stearate
  • Tablets were compressed as weight multiples from a common formula, to afford 150 mg, 200 mg, or 300 mg of vernakalant hydrochloride drug substance per tablet.
  • the tablets were encapsulated in opaque white gelatin capsule shells. Capsules containing the 150 mg and 200 mg tablets were backfilled with lactose monohydrate to approximate similar capsule weights across dose strengths.
  • the composition of the vernakalant hydrochloride (oral) tablets is shown in Table 83.
  • the composition of vernakalant hydrochloride (oral) encapsulated tablets is shown in Table 84.
  • tVernakalant hydrochloride is the monohydrochlohde salt.
  • the salt factor is
  • fA blend of pharmaceutical gelatins may be used; when bovine gelatin is used, it is alkaline processed, pharmaceutical grade, and in full compliance with all pharmaceutical regulatory requirements.
  • Subjects with sustained AF were randomized to placebo or vernakalant hydrochloride for up to 90 days.
  • Subjects treated with vernakalant hydrochloride received either 150 mg b.i.d, 300 mg b.i.d., or 500 mg b.i.d.
  • the extended release formulations tested in Stage 1 differed in their percent polymer content, with a higher polymer content expected to translate to a slower release rate.
  • the polymer in the controlled release formulation was chemically identical to that in the extended release formulations but had a lower molecular weight and therefore different physical properties. It was expected that the higher molecular weight polymer used in the extended release formulations would hydrate and erode more slowly than the polymer in the controlled release formulation.
  • Stage 2 of the study was designed to demonstrate the effect of an enteric coating on the PK profile of vernakalant. Tablets that are enteric-coated will not dissolve below a pH of 7, thereby not releasing their contents until the tablet enters the ascending colon, and thus delaying the release along the gastrointestinal tract.
  • This study was a phase I, open-label, randomized, two-stage, crossover, single-dose, single center, formulation comparison study. Healthy male volunteers who were genotyped as CYP2D6 extensive metabolizers (EMs) were eligible to participate in the study. A total of 29 healthy male volunteers who met all of the inclusion criteria and none of the exclusion criteria were enrolled in this study.
  • EMs extensive metabolizers
  • Stage 1 of the study subjects received single doses of 300 mg vernakalant (oral) administered as a controlled release formulation (encapsulated tablet) and as three film-coated extended release formulations (designated Formulation 25CR, 35CR and 45CR), in a 4-pehod, 4-sequence cross-over manner.
  • Study medication was supplied as tablets or capsules of 300 mg vernakalant (oral), and was to be administered orally with 100 ml_ water.
  • the formulations tested in Stage 1 included the following 4 dosage forms:
  • Controlled release formulation (K4M polymer) (encapsulated tablet) o 300 mg vernakalant hydrochloride o 120 mg hydroxypropyl methyl cellulose (K4M) o 30 mg pregelatinized starch o 90 mg silicified microcrystalline cellulose o 81 mg of lactose monohydrate o 4.5 mg stearic acid o 4.5 mg magnesium stearate
  • Formulation 35CR was selected for further evaluation in Stage 2.
  • Subjects in Stage 2 received single 300 mg doses of the original controlled release formulation (encapsulated tablet), Formulation 35CR as a film-coated tablet (same 35CR formulation used in Stage 1 ), and Formulation 35CR as a gelatin capsule (consisting of an enteric-coated tablet and a film-coated tablet), administered in a 3-period, 6-sequence cross-over manner.
  • the enteric coating used is described in Table 52, and the film coating was Opadry II.
  • the formulations tested in Stage 2 included the following 3 dosage forms:
  • Formulation 35CR administered as a film-coated tablet (same 35CR formulation used in Stage 1 )
  • Formulation 35CR administered as a gelatin capsule containing an enteric-coated tablet of 165 mg vernakalant HCI (150 mg vernakalant free base) and a film-coated tablet of 165 mg vernakalant HCI (150 mg vernakalant free base)
  • the extended release formulation tablets had 300 mg vernakalant free base
  • the controlled release formulation had 300 mg vernakalant HCI (approximately 272 mg vernakalant free base).
  • the 35CR capsule administered in Stage 2 included an enteric-coated tablet and a film-coated tablet surrounded by a hard gelatin capsule shell.
  • AEs treatment-emergent adverse events
  • SAEs serious adverse events
  • Plasma samples for PK analysis were collected predose (within 2 hours prior to dosing) and at 1 , 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours postdose for each dosing period. Plasma samples for PK analysis were also collected in the case of an SAE.
  • the plasma PK parameters were determined for vernakalant and its metabolites (Cmpd. 4, Cmpd. 2, Cmpd. 3; Figure 5), and included maximum plasma concentration (C max ), time of maximum plasma concentration (t max ), area under the plasma concentration-time curve (AUC), C m a ⁇ /AUC ratio, and half-life (Un)- Linear and semi-log plots of time-concentration profiles were produced by subject and by using the geometric mean plasma concentration value at each time point for each formulation. Plasma concentration data was summarized with the number of observations, geometric mean, CV%, arithmetic mean, standard deviation, median, and minimum and maximum values. The PK analysis for Stage 1 was completed prior to proceeding to Stage 2. Results
  • a total of 29 subjects were enrolled in the study, with 17 subjects in Stage 1 and 12 subjects in Stage 2. All subjects in this study were male (as required by the study inclusion criteria) and over 80% of the subjects were black or African American. All subjects were genotyped as CYP2D6 extensive metabolizers (EMs), with the exception of one, who was an intermediate metabolizer. The study population ranged from 22-49 years of age (mean age of 35 years) and had a mean BMI of 26 kg/m 2 . The demographics were similar for subjects in Stage 1 and in Stage 2. All randomized subjects received at least one dose of study drug. A total of 25 subjects completed the study (15 in Stage 1 and 10 in Stage 2). Four subjects (two in each study stage) were discontinued from study drug and did not complete the study.
  • EMs extensive metabolizers
  • One subject (last dosing period and formulation: Period 1 , original) voluntarily withdrew from the study and left the clinical facility against medical advice after being notified that a family member was ill.
  • One subject (last dosing period and formulation: Period 2, 35CR capsule) was withdrawn due to non-compliance with study requirements, as the subject had a positive drug screen at check-in in Period 3.
  • One subject in each study stage was withdrawn from the study due to adverse events (AEs).
  • One subject (last dosing period and formulation: Period 2, 45CR) experienced an AE of dermatitis and one subject (last dosing period and formulation: Period 2, 35CR) had an AE of tachycardia and a serious AE of tachyarrhythmia.
  • Stage 1 the controlled release formulation and extended release formulations showed a similar time course of increase in vernakalant plasma concentration following study drug administration, with the exception of the 45CR formulation, which tended to show a modest delay in the time of maximum plasma concentration (t max ).
  • Plasma concentrations of vernakalant were detectable by one hour for all formulations in both Stage 1 and Stage 2.
  • Maximum plasma concentrations (C ma ⁇ ) of vernakalant were observed between 2 and 6 hours for the controlled release formulation and between 2 and 4 hours for the 25CR, 35CR, and 45CR extended release formulations in Stage 1.
  • Stage 2 maximum plasma concentrations of vernakalant were seen between 3 and 6 hours for the controlled release formulation, between 2 and 4 hours for the 35CR tablet, and between 3 and 10 hours for the 35CR capsule.
  • the maximum plasma concentration of vernakalant was highest for the controlled release formulation, and similar among the 25CR, 35CR, and 45CR extended release formulations in Stage 1.
  • the 35CR capsule displayed a significantly lower C ma ⁇ than the other formulations, but maintained higher plasma levels out to 24 hours.
  • the mean plasma concentration-time profiles showed a more gradual increase in plasma concentration and much lower plasma drug concentrations following drug administration in both Stage 1 and Stage 2 than the vernakalant mean plasma concentration-time profiles.
  • Plasma concentrations of Cmpd. 2 were approximately 10-15% of those measured for the parent compound vernakalant.
  • Cmpd. 2 plasma concentrations were detectable by one hour for all formulations in Stage 1 and for the 35CR tablet in Stage 2.
  • Cmpd. 2 was detected by 2 hours for the controlled release formulation and for the 35CR capsule in Stage 2.
  • Maximum plasma concentrations of Cmpd. 2 were observed between 2 and 8 hours for the controlled release formulation and between 2 and 4 hours for the 25CR, 35CR, and 45CR formulations in Stage 1. In Stage 2, maximum plasma concentrations of Cmpd.
  • the extended release formulations showed similar total exposure (AUC mf ) values as the controlled release formulation.
  • AUC mf total exposure
  • the 3 extended release formulations displayed a trend towards decreasing C ma ⁇ and C m a ⁇ /AUC ratio with increasing polymer content (i.e., 25CR, 35CR, 45CR). Additionally, as the polymer content increased, the apparent half-life (Un) was prolonged.
  • the 35CR capsule in Stage 2 had a longer apparent Un (9.54 hours) and later t max (6 hours) compared to the other formulations. The lowest C ma ⁇ and C m a ⁇ /AUC ratio were seen with the 35CR capsule, consistent with a more marked delayed release profile.
  • the mean AUC ⁇ as t was greater than the mean AUC ⁇ n f. This occurred because the mean AUC ⁇ n f could not be calculated in all subjects due to the shape of the terminal elimination slope. In addition, subjects who did not have a calculable AUC ⁇ n f had a very high AUC ⁇ as t- This resulted in a higher mean AUC ⁇ as t than otherwise would have been the case.
  • the metabolite Cmpd. 2 appeared in plasma with a median t max ranging from 3 to 5 hours for most formulations. For the 35CR capsule in Stage 2, the median t max was 7 hours.
  • the C max and AUC ⁇ nf for Cmpd. 2 were approximately 10-15% of those values measured for the parent compound vernakalant.
  • the AUCmf showed some variability, but was similar across formulations.
  • the C ma ⁇ , Cmax/AUCmf ratio, and apparent ty 2 for Cmpd. 2 followed a similar trend to the values reported for vernakalant in both Stage 1 and Stage 2.
  • the C max was similar among all formulations in Stage 1 (but highest for the controlled release formulation), and in Stage 2, the C ma ⁇ for the 35CR capsule and 35CR tablet were approximately 50% and 70% that of the controlled release formulation.
  • the C max /AUC mf ratio was highest for the controlled release formulation and lowest for the 35CR capsule.
  • vernakalant and Cmpd. 2 were detected by 1 and 2 hours, respectively, for all formulations.
  • Maximum plasma concentrations of both vernakalant and Cmpd. 2 were observed between 2 and 6 hours with the controlled release and film-coated extended release formulations; however, the 35CR capsule showed maximum concentrations between 3 and 10 hours postdose.
  • Plasma concentrations of Cmpd. 2 were approximately 10-15% of those measured for vernakalant.
  • Stage 1 all extended release formulations tended to show improved sustained release characteristics as compared to the controlled release formulation by exhibiting lower C ma ⁇ (but similar AUC ⁇ n f) and longer apparent U /2 values as the polymer content increased (i.e., 25CR, 35CR, 45CR), as well as a trend toward lower C m a ⁇ /AUC ⁇ nf ratios.
  • the 35CR formulation was selected for further evaluation in Stage 2.
  • the 35CR capsule (containing the enteric-coated tablet) in Stage 2 had greater sustained release characteristics as compared to the other formulations, by exhibiting the slowest release rate (delayed t max ), with the lowest C max and C m a ⁇ /AUC ⁇ nf ratio, and the longest Un-
  • Stage 1 Other common treatment- emergent AEs (each occurring in 2 subjects) were supraventricular extrasystoles, dyspepsia, nausea, increased blood creatine phosphokinase, increased white blood cells (WBC) in urine, and rash.
  • WBC white blood cells
  • Stage 2 Four subjects (24%) in Stage 1 and 10 subjects (83%) in Stage 2 had treatment-emergent AEs that were considered to be related to study drug.
  • the incidence of treatment-related AEs was highest for the 45CR formulation (19%), and lower for the controlled release formulation (12%) and the 25CR and 35CR formulations (7%).
  • Stage 2 the incidence of treatment- related AEs was lowest for the 35CR capsule (42%), and similar among the controlled release (60%) and 35CR (58%) formulations.
  • the most common treatment-related AE was ventricular extrasystoles, occurring in 5 subjects (17%). All of the ventricular extrasystole events were captured on telemetry monitoring, and were asymptomatic, mild in severity, required no treatment, and resolved spontaneously. Other common treatment-related AEs included supraventricular extrasystoles and increased WBC in urine, each occurring in 2 subjects (7%).
  • Stage 1 it was expected that the higher molecular weight polymers (as used in the extended release film-coated formulations) would hydrate and erode more slowly than the lower molecular weight polymer used in the controlled release formulation (encapsulated tablet), translating to a slower release rate.
  • the safety analysis revealed that the incidence of treatment-emergent AEs in Stage 1 was lowest for the 35CR formulation (13%), and similar across all other formulations (20-25%).

Abstract

Extended release formulations comprising a therapeutically effective amount of an ion channel modulating compound, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients suitable for extended release formulations are disclosed.

Description

EXTENDED RELEASE FORMULATIONS CONTAINING AN ION-CHANNEL-MODULATING COMPOUND FOR THE PREVENTION OF ARRHYTHMIAS
CROSS-REFERENCE TO RELATED APPLICATION
This application claims the benefit under 35 U. S. C. § 1 19(e) of U.S. 5 Provisional Patent Application No. 60/953,431 filed August 1 , 2007, where this provisional application is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
The present invention is directed to extended release formulations of ion channel modulating compound or pharmaceutically acceptable salts thereof. 0 These extended release formulations are useful in preventing arrhythmia and other diseases, in particular atrial fibrillation, from occurring in mammals, preferably in humans, when orally administered thereto.
BACKGROUND OF THE INVENTION
Arrhythmias are abnormal rhythms of the heart. The term "arrhythmia" 5 refers to a deviation from the normal sequence of initiation and conduction of electrical impulses that cause the heart to beat. Arrhythmias may occur in the atria or the ventricles. Atrial arrhythmias are widespread and relatively benign, although they place the subject at a higher risk of stroke and heart failure. Ventricular arrhythmias are typically less common, but very often fatal. 0 Atrial fibrillation is the most common arrhythmia encountered in clinical practice. It has been estimated that 2.2 million individuals in the United States have paroxysmal or persistent atrial fibrillation. The prevalence of atrial fibrillation is estimated at 0.4% of the general population, and increases with age. Atrial fibrillation is usually associate with age and general physical 5 condition, rather than with a specific cardiac event, as is often the case with ventricular arrhythmia. While not directly life threatening, atrial arrhythmias can cause discomfort and can lead to stroke or congestive heart failure, and increase overall morbidity. There are two general therapeutic strategies used in treating subjects with atrial fibrillation. One strategy is to allow the atrial fibrillation to continue and to control the ventricular response rate by slowing the conduction through the atrioventricular (AV) node with digoxin, calcium channel blockers or beta- blockers; this is referred to as rate control. The other strategy, known as rhythm control, seeks to convert the atrial fibrillation and then maintain normal sinus rhythm, thus attempting to avoid the morbidity associated with chronic atrial fibrillation. The main disadvantage of the rhythm control strategy is related to the toxicities and proarrhythmic potential of the anti-arrhythmic drugs used in this strategy. Most drugs currently used to prevent atrial or ventricular arrhythmias have effects on the entire heart muscle, including both healthy and damaged tissue. These drugs, which globally block ion channels in the heart, have long been associated with life-threatening ventricular arrhythmia, leading to increased, rather than decreased, mortality in broad subject populations. There is therefore a long recognized need for antiarrhythmic drugs that are more selective for the tissue responsible for the arrhythmia, leaving the rest of the heart to function normally. Such drugs are less likely to cause ventricular arrhythmias.
Ion channel modulating compounds selective for the tissue responsible for arrhythmia are described in U.S. Patent No. U.S. Patent No. 7,057,053. Of particular interest to the present invention is the ion channel modulating compound known as vernakalant hydrochloride. Vernakalant hydrochloride is the non-proprietary name adopted by the United States Adopted Name (USAN) council for the ion channel modulating compound having the following formula:
Figure imgf000004_0001
and a chemical name of (3R)-1 -[(1 R,2R)-2-(3,4- dimethoxyphenyl)ethoxy]cyclohexyl]pyrrolidin-3-ol hydrochloride. Vernakalant hydrochloride modifies atrial electrical activity through a combination of concentration-, voltage- and frequency-dependent blockade of sodium channels and blockade of ultra-rapidly activating (lKur) and transient outward (lt0) potassium channels. These combined effects prolong atrial refractoriness and rate-dependently slow atrial conduction. This unique profile provides an effective anti-fibrillatory approach expected to be suitable for conversion of atrial fibrillation and the prevention of recurrence of atrial fibrillation.
There therefore exists a need for extended release tablet formulations of vernakalant hydrochloride for the prevention of the recurrence of arrhythmia in mammals, preferably in humans.
SUMMARY OF THE INVENTION The present invention is directed to extended release formulations for ion channel modulating compounds or pharmaceutically acceptable salts thereof. These extended release formulations are useful in the prevention of arrhythmia, particularly, atrial fibrillation and/or atrial flutter, in a mammal, preferably in a human, upon oral administration thereto. In particular embodiments, these extended release formulations are useful in the prevention of the recurrence of arrhythmia in a mammal having previously undergone one or more arrhythmias or prevention of arrhythmia in a mammal during or following surgery, e.g., a cardiac surgery.
Accordingly, in one aspect this invention provides extended release formulations comprising a therapeutically effective amount of an ion channel modulating compound and one or more pharmaceutically acceptable excipients.
In another aspect, this invention provides xtended release tablet formulations comprising a therapeutically effective amount of an ion channel modulating compound has the structure:
Figure imgf000005_0001
including isolated enantiomeric, diastereomeric and geometric isomers thereof and mixtures thereof, or a solvate or pharmaceutically acceptable salt thereof; wherein R4 and R5 are independently selected from hydroxy and Ci-Cβalkoxy.
In another aspect, this invention provides extended release formulations comprising a therapeutically effective amount of vernakalant hydrochloride and one or more pharmaceutically acceptable excipients.
In another aspect, this invention provides extended release formulations comprising a therapeutically effective amount of vernakalant hydrochloride and one or more pharmaceutically acceptable excipients wherein at least one of the pharmaceutically acceptable excipients comprises a hydrophilic matrix polymer. In another aspect, this invention provides for extended release tablet formulations comprising 300 mg of an ion channel modulating compound, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
In another aspect, this invention provides for extended release tablet formulations comprising about 250 or 300 mg of vernakalant or vernakalant hydrochloride and one or more pharmaceutically acceptable excipients.
In another aspect, this invention provides for extended release tablet formulations comprising about 250 or 300 mg of vernakalant or vernakalant hydrochloride and one or more pharmaceutically acceptable excipients wherein at least one pharmaceutically acceptable excipient comprises a hydrophilic matrix polymer. Preferably, the hydrophilic matrix polymer is hydroxypropyl methyl cellulose or polyethylene oxide.
In another aspect, this invention provides a extended release tablet formulation coated with a enteric coating composition comprising a (meth)acrylate copolymer. In particular embodiments, the extended release tablet formulation comprises an ion channel modulating compound has the structure:
Figure imgf000006_0001
including isolated enantiomeric, diastereomeric and geometric isomers thereof and mixtures thereof, or a solvate or pharmaceutically acceptable salt thereof; wherein R4 and R5 are independently selected from hydroxy and Ci-Cβalkoxy. In related embodiments, the ion channel modulating compound is vernakalant hydrochloride.
In one aspect, the enteric coating composition comprises a (meth)acrylate copolymer, Imwitor, thethyl citrate, and a polysorbate.
In a further aspect, this invention provides for an extended release tablet formulation of an ion channel modulating compound wherein less than 1 % of the ion channel modulating compound, or a pharmaceutically acceptable salt thereof, is released over 6 hours in 0.1 N HCI solution and over a further 18 hours in phosphate buffer solution at pH 7.2. In particular embodiments, the extended release tablet formulation comprises an ion channel modulating compound has the structure:
Figure imgf000007_0001
including isolated enantiomeric, diastereomeric and geometric isomers thereof and mixtures thereof, or a solvate or pharmaceutically acceptable salt thereof; wherein R4 and R5 are independently selected from hydroxy and Ci-C6alkoxy. In related embodiments, the ion channel modulating compound is vernakalant hydrochloride.
In related aspects, this invention provides for capsules comprising one or more extended release tablet formulations of this invention.
In one aspect, the capsule comprises an extended release tablet formulation of this invention coated with a enteric coating comprising a (meth)acrylate copolymer. In one embodiment, the enteric coating composition comprises a (meth)acrylate copolymer, Imwitor, triethyl citrate, and a polysorbate.
In another aspect, the capsule comprises an extended release tablet formulation of this invention coated with a taste masking coating composition comprising a polyvinyl alcohol (PVA) base. In one embodiment, the taste masking coating composition comprises PVA base hydroxypropyl methyl cellulose, dicalcium phosphate, an magnesium stearate.
In another aspect, the capsule comprises both an extended release tablet formulation of the invention coated with a enteric coating and an extended release tablet formulation of the invention coated with a taste masking coating.
In another aspect, this invention provides for a method of preventing an arrhythmia in a mammal, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of an extended release formulation or tablet of the invention. In particular embodiments, this method is for the prevention of the recurrence of an arrhythmia in a mammal that has previously undergone one or more arrhythmia or for the prevention of arrhythmia in a mammal during or following surgery, e.g., a cardiac surgery. Preferably, the arrhythmia is atrial fibrillation and/or atrial flutter.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
Figure 1 includes two graphs showing the Geometric Mean Plasma Concentration-Time Plots for Vernakalant and Cmpd. 2 in Stage 1 (Pharmacokinetic Population). Original" refers to the controlled release formulation.
Figure 2 includes two graphs showing Geometric Mean Plasma Concentration-Time Plots of Vernakalant and Cmpd. 2 in Stage 2 (Pharmacokinetic Population).
Figure 3 shows a comparison of Least Square Means of Pharmacokinetic Parameters for Vernakalant in Stage 1 and Stage 2 (Pharmacokinetic Population).
Figure 4 shows a comparison of Least Square Means of Pharmacokinetic Parameters for Cmpd. 2 in Stage 1 and Stage 2 (Pharmacokinetic Population). Figure 5 provides a diagram of the metabolism of vernakalant in
CYP2D6 extensive metabolizers (EMs) and poor metablolizers (PMs). DETAILED DESCRIPTION OF THE INVENTION
This invention is directed to extended release formulations comprising a therapeutically effective amount of ion channel modulating compound, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. In particular, this invention is directed to extended release formulations comprising a therapeutically effective amount of vernakalant hydrochloride and one or more pharmaceutically acceptable excipients suitable for sustained release formulations, which, upon oral administration thereto, are effective in preventing the recurrence of arrhythmia in the mammal. The extended release formulations of the invention have a slower release profile of the active ingredient than the controlled release formulations disclosed herein.
Accordingly, the extended release formulations of the invention are intended to be administered to a mammal, preferably a human, at risk of arrhythmia, such as, e.g., a mammal that has previously undergone one or more arrhythmias.
As used herein, unless the context makes clear otherwise, "prevention," and similar words such as "prevented," "preventing", etc, preferably means keeping an arrhythmia from occurring in a mammal. Prevention, as used herein, may also mean a lessening of the severity of an arrhythmia if an arrhythmia does occur. Prevention, as used herein, may also mean postponing the time for onset of an arrhythmia. Prevention, as used herein may also mean lessening the probability that the mammal will suffer from an arrhythmia. In one version of the invention, the arrhythmia to be prevented is atrial fibrillation. In another version, the arrhythmia to be prevented is atrial flutter.
Generally, the subject in which arrhythmia is be prevented is any mammal. In one version, the subject is a human. In another version, the subject is any domestic animal, including, but not limited to cats, dogs, etc. In another version, the subject is any farm animal, including, but not limited to pigs, cows, horses, etc. In particular aspects of the invention, the subject is considered at risk of arrhythmia. For example, the subject may have previously undergone one or more arrhythmias or is undergoing or has undergone a surgicial procedure associated with a risk of arrhythmia, e.g., a cardiac surgery, such as a coronary artery bypass graft (CABG) procedure. Postoperative arrhythmias such as atrial fibrillation (AF) and atrial flutter (AFL) are common after cardiac surgery, such as CABG, valvular surgery, or both.
As set forth above in the Summary of the Invention, the extended release formulations of the invention comprise a therapeutically effective amount of an ion channel modulating compound, or a pharmaceutically acceptable salt thereof, as the active ingredient and one or more pharmaceutically acceptable excipients. As used herein, a "therapeutically effective amount" refers to that amount of active ingredient sufficient to effect the desired prevention of arrhythmia in the mammal to which a formulation of the invention has been administered. As used herein, "pharmaceutically acceptable" refers to those compounds, salts, excipients and compositions, which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of mammals, preferably humans, without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. As used herein, and described in more detail below, a "pharmaceutically acceptable excipient" can be any pharmaceutically acceptable material, composition, or vehicle suitable for allowing the active ingredient to be released from the formulation in a sustained manner, including but not limited to, a liquid or solid filler, diluent, excipient, solvent or encapsulating material, which is involved in carrying or transporting the active ingredient to an organ, or portion of the body. Each pharmaceutically acceptable excipient must be compatible with the other ingredients of the formulation. Some examples of materials which can serve as pharmaceutically acceptable excipients include, but are not limited to, sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; tragacanth; malt; gelatin; talc; cocoa butter, waxes, animal and vegetable fats, paraffins, silicones, bentonites, silicic acid, zinc oxide; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and any other compatible substances routinely employed in pharmaceutical formulations and any substance identified herein as a pharmaceutically acceptable excipient. As used herein, "extended release" refers to the release of the active ingredient from the formulation in a sustained and regulated manner over a longer period of time than an immediate release formulation containing the same amount of the active ingredient would release during the same time period. For example, an immediate release formulation comprising vernakalant hydrochloride may release 80% of the active ingredient from the formulation within 15 minutes of administration to a human subject, whereas an extended release formulation of the invention comprising the same amount of vernakalant hydrochloride would release 80% of the active ingredient within a period of time longer than 15 minutes, preferably within a period of time longer than 12 hours. Furthermore, the extended release formulations of the invention release the active ingredient, preferably vernakalant hydrochloride, over a longer period of time in vivo than a comparative controlled release formulation containing the same amount of the active ingredient would over the same period of time. As a non-limiting example, a comparative controlled release formulation containing the active ingredient, vernakalant hydrochloride, may release 80% of the amount of the active ingredient present in the formulation in vivo over a period of 4-6 hours after administration to a human subject whereas an extended release formulation of the invention may release 80% of the same amount of the active ingredient in vivo over a period of 6-24 hours, preferably over a period of 12-18 hours and more preferably over a period of 14-16 hours. Extended release formulations of the invention therefore allow for less frequency of dosing to the mammal in need thereof than the corresponding controlled release formulations. In addition, extended release formulations may improve the pharmacokinetic or toxicity profile of the active ingredient upon administration to the mammal in need thereof.
Active Ingredient The ion channel modulating compounds, or pharmaceutically acceptable salts thereof, utilized in the formulations of the invention can be any ion channel modulating compound or pharmaceutical acceptable salt thereof. These ion channel modulating compounds are referred to herein as the "active ingredient" of the formulations disclosed herein. Preferably, the ion channel modulating compound is a compound described in U.S. Patent No. U.S. Patent No. 7,057,053. More preferably, the ion channel modulating compound is vernakalant hydrochloride, which compound has the following formula:
Figure imgf000012_0001
Vernakalant Hydrochloride Vernakalant hydrochloride has been shown to be orally bioavailable in humans and animals {e.g., in dogs). The compound is rapidly absorbed, and has a linear pharmacokinetic profile in humans following a 10-minute infusion. The half-life of the compound in healthy volunteers has been shown to be approximately 2 hours compared to 3-4 hours in patients with recent onset atrial fibrillation.
Vernakalant hydrochloride is highly soluble in aqueous solution, and at a concentration of 20 mg/ml has a pKa of 9.5 and a pH of 5.7. It is anhydrous under current manufacturing process, and is stable under long term and accelerated conditions, such as when stored in a low-density polyethylene (LDPE) bag inside a LDPE-lined aluminum compound foil bag. More generally, the ion channel modulating compound is any isomeric or pharmaceutically acceptable salt form of vernakalant, as represented by the following formula (I):
Figure imgf000013_0001
(I) including isolated enantiomeric, diastereomehc and geometric isomers thereof and mixtures thereof, or a solvate or pharmaceutically acceptable salt thereof.
In more specific forms of Formula (I), the ion channel modulating compound is in a trans- or cis-configuration, as represented by Formulas (Ma) and (Mb), respectively:
Figure imgf000013_0002
(Ha) (lib) or a solvate or pharmaceutically acceptable salt thereof.
In more general terms of Formula (I), the ion channel modulating compound is by the following formula (Ia):
Figure imgf000013_0003
(Ia)
including isolated enantiomeric, diastereomeric and geometric isomers thereof and mixtures thereof, or a solvate or pharmaceutically acceptable salt thereof; wherein R4 and R5 are independently selected from hydroxy and Ci-Cβalkoxy. In further embodiments, the ion channel modulating compounds are represented by Formula (III):
Figure imgf000014_0001
(III) or an isomer or pharmaceutical acceptable salt thereof, wherein, independently at each occurrence,
X is selected from -C(R6,Ri4)-Y-, and -C(Ri3)=CH-; Y is selected from a direct bond, O, S, and Ci-C4alkylene; Ri3 is selected from hydrogen, Ci-Cβalkyl, Cs-Cscycloalkyl, aryl, and benzyl;
Ri and R2, when taken together with the nitrogen atom to which they are directly attached in formula (III), form a ring denoted by formula (IV):
Figure imgf000014_0002
(IV)
wherein the ring of formula (IV) is formed from the nitrogen as shown as well as three to nine additional ring atoms independently selected from carbon, nitrogen, oxygen, and sulfur; where any two adjacent ring atoms may be joined together by single or double bonds, and where any one or more of the additional carbon ring atoms may be substituted with one or two substituents selected from hydrogen, hydroxy, Ci-C3hydroxyalkyl, oxo, C2-C4acyl, Ci-C3alkyl, C2-C4alkylcarboxy, Ci-C3alkoxy, CrC2oalkanoyloxy, or may be substituted to form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur; and any two adjacent additional carbon ring atoms may be fused to a C3-C8carbocyclic ring, and any one or more of the additional nitrogen ring atoms may be substituted with substituents selected from hydrogen, Ci-C6alkyl, C2-C4acyl, C2-C4hydroxyalkyl and C3-Csalkoxyalkyl; or Ri and R2, when taken together with the nitrogen atom to which they are directly attached in formula (III), may form a bicyclic ring system selected from 3-azabicyclo[3.2.2]nonan-3-yl, 2-aza-bicyclo[2.2.2]octan-2-yl,
3-azabicyclo[3.1.0]-hexan-3-yl, and 3-azabicyclo[3.2.0]-heptan-3-yl;
R3 and R4 are independently attached to the cyclohexane ring shown in formula (III) at the 3-, A-, 5- or 6- positions and are independently selected from hydrogen, hydroxy, d-Cβalkyl, and d-Cβalkoxy;
R5, Re and Ri4 are independently selected from hydrogen, d-Cβalkyl, aryl and benzyl;
A is selected from C5-Ci2alkyl, a C3-Ci3carbocyclic ring, and ring systems selected from formulae (V), (Vl), (VII), (VIII), (IX) and (X):
Figure imgf000015_0001
(V)
where R7, R8 and R9 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, thfluoromethyl, C2-C7alkanoyloxy, CrC6alkyl, d-C6alkoxy, C2-C7alkoxycarbonyl, d-Cβthioalkyl and N(Ri5, Ri6) where R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl, and Ci-Cβalkyl;
Figure imgf000016_0001
(Vl) (VII)
where Rio and Rn are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, Ci-C6alkyl, d-Cβalkoxy, C2-C7alkoxycarbonyl, Ci-C6thioalkyl, and N(Ri5, Ri6) where R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl, and Ci-C6alkyl;
Figure imgf000016_0002
(VIM)
where R12 is selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, Ci-C6alkyl, d-Cβalkoxy, C2-C7alkoxycarbonyl, Ci-C6thioalkyl, and N(Ri5, Ri6) where Ri5 and Ri6 are independently selected from hydrogen, acetyl, methanesulfonyl, and Ci-C6alkyl; and Z is selected from CH, CH2, O, N and S, where Z may be directly bonded to "X" as shown in formula (III) when Z is CH or N, or Z may be directly bonded to R17 when Z is N, and Ri7 is selected from hydrogen, Ci-C6alkyl, Cs-Cscycloalkyl, aryl and benzyl;
Figure imgf000016_0003
(IX) (X) including isolated enantiomeric, diastereomehc and geometric isomers thereof, and mixtures thereof.
In more specific embodiments of Formula (III), the ion channel modulating compound is one or more of the following compounds: (+)-frans-[2-(4-morpholinyl)-1 -(2-naphthenethoxy)]cyclohexane;
(-)-frans-[2-(4-morpholinyl)-1 -(2-naphthenethoxy)]cyclohexane;
(+)-frans-[2-(4-morpholinyl)-1 -(1 -naphthenethoxy)]cyclohexane;
(-)-frans-[2-(4-morpholinyl)-1 -(1 -naphthenethoxy)]cyclohexane;
(+)-frans-[2-(4-morpholinyl)-1 -(4-bromophenethoxy)]cyclohexane; (-)-frans-[2-(4-morpholinyl)-1 -(4-bromophenethoxy)]cyclohexane;
(+)-frans-[2-(4-morpholinyl)-1 -[2-(2-naphthoxy)ethoxy)]cyclohexane;
(-)-frans-[2-(4-morpholinyl)-1 -[2-(2-naphthoxy)ethoxy)]cyclohexane;
(+)-frans-[2-(4-morpholinyl)-1 -[2-(4-bromophenoxy)ethoxy]]cyclohexane;
(-)-frans-[2-(4-morpholinyl)-1 -[2-(4-bromophenoxy)ethoxy]]cyclohexane; (+)-frans-[2-(4-morpholinyl)-1 -(3,4-dimethoxyphenethoxy)]cyclohexane;
(-)-frans-[2-(4-morpholinyl)-1-(3,4-dimethoxyphenethoxy)]cyclohexane;
(+)-frans-[2-(1 -pyrrolidinyl)-1 -(1 -naphthenethoxy)]cyclohexane;
(-)-frans-[2-(1 -pyrrolidinyl)-1 -(1 -naphthenethoxy)]cyclohexane;
(+)-frans-[2-(4-morpholinyl)-1 -(2-(benzo[b]thiophen-3-yl)ethoxy)]-cyclohexane; (-)-frans-[2-(4-morpholinyl)-1 -(2-(benzo[b]thiophen-3-yl)ethoxy)]cyclohexane;
(+)-frans-[2-(4-morpholinyl)-1 -(2-(benzo[b]thiophen-4-yl)ethoxy)]-cyclohexane;
(-)-frans-[2-(4-morpholinyl)-1 -(2-(benzo[b]thiophen-4-yl)ethoxy)]-cyclohexane;
(+)-frans-[2-(4-morpholinyl)-1 -(3-bromophenethoxy)]cyclohexane;
(-)-frans-[2-(4-morpholinyl)-1 -(3-bromophenethoxy)]cyclohexane; (+)-frans-[2-(4-morpholinyl)-1 -(2-bromophenethoxy)]cyclohexane;
(-)-frans-[2-(4-morpholinyl)-1 -(2-bromophenethoxy)]cyclohexane;
(+)-frans-[2-(4-morpholinyl)-1 -(3-(3,4-dimethoxyphenyl)-1 -propoxy)]- cyclohexane;
(-)-frans-[2-(4-morpholinyl)-1 -(3-(3,4-dimethoxyphenyl)-1-propoxy)]cyclohexane; (1 R,2R)/(1 S,2S)-2-(4-morpholinyl)-1 -(3,4-dichlorophenethoxy)-cyclohexane;
(1 R,2R)/(1 S,2S)-2-(3-ketopyrrolidinyl)-1 -(1 -naphthenethoxyj-cyclohexane;
(1 R,2R)/(1 S,2S)-2-(1 -acetylpiperazinyl)-1 -(2-naphthenethoxy)-cyclohexane; (1 R,2R)/(1 S,2S)-2-(3-ketopyrrolidinyl)-1 -(2,6-dichlorophenethoxy)-cyclohexane;
(1 R,2R)/(1 S,2S)-2-[1 ,4-dioxa-7-azaspiro[4.4]non-7-yl]-1 -(1 - naphthenethoxy)cyclohexane;
(1 R,2S)/(1 S,2R)-2-(4-morpholinyl)-1 -[(2-trifluoromethyl)phenethoxy]- cyclohexane;
(1 R,2R)/(1 S,2S)-2-(3-ketopyrrolidinyl)-1 -[3-(cyclohexyl)propoxy]-cyclohexane;
(1 R,2R)/(1 S,2S)-2-(3-acetoxypyrrolidinyl)-1 -(1 -naphthenethoxy)-cyclohexane;
(1 R,2R)/(1 S,2S)-2-(3-hydroxypyrrolidinyl)-1 -(2,6-dichlorophenethoxy)- cyclohexane; (1 R,2R)/(1S,2S)-2-(3-ketopyrrolidinyl)-1 -(2,2-diphenylethoxy)-cyclohexane;
(1 R,2R)/(1 S,2S)-2-(3-th iazol id inyl )-1 -(2,6-dichlorophenethoxy)-cyclohexane; and
(1 R,2S)/(1 S,2R)-2-(3-ketopyrrolidinyl)-1 -(1 -naphthenethoxyj-cyclohexane; including isolated enantiomeric and diastereomeric isomers thereof, and mixtures thereof; and pharmaceutically acceptable salts thereof.
Certain compounds of the present invention contain at least two asymmetric carbon atoms and, thus, exist as enantiomers and diastereomers.
Unless otherwise noted, the present invention includes all enantiomeric and diastereomeric forms of the aminocyclohexyl ether compounds of the invention. Pure stereoisomers, mixtures of enantiomers and/or diastereomers, and mixtures of different compounds of the invention are included within the present invention. Thus, compounds of the present invention may occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention. A racemate or racemic mixture does not imply a 50:50 mixture of stereoisomers.
The phrase "independently at each occurrence" is intended to mean (i) when any variable occurs more than one time in a compound of the invention, the definition of that variable at each occurrence is independent of its definition at every other occurrence; and (ii) the identity of any one of two different variables {e.g., Ri within the set Ri and R2) is selected without regard the identity of the other member of the set. However, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, the following terms are defined to have following meanings, unless explicitly stated otherwise: "Acid addition salts" refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
"Acyl" refers to branched or unbranched hydrocarbon fragments terminated by a carbonyl -(C=O)- group containing the specified number of carbon atoms. Examples include acetyl [CH3C=O-, a C2acyl] and propionyl [CH3CH2C=O-, a C3acyl].
"Alkanoyloxy" refers to an ester substituent wherein the ether oxygen is the point of attachment to the molecule. Examples include propanoyloxy [(CH3CH2C=O-O-, a C3alkanoyloxy] and ethanoyloxy [CH3C=O-O-, a C2alkanoyloxy].
"Alkoxy" refers to an O-atom substituted by an alkyl group, for example, methoxy [-OCH3, a Cialkoxy].
"Alkoxyalkyl" refers to a alkylene group substituted with an alkoxy group. For example, methoxyethyl [CH3OCH2CH2-] and ethoxymethyl (CH3CH2OCH2-] are both C3alkoxyalkyl groups.
"Alkoxycarbonyl" refers to an ester substituent wherein the carbonyl carbon is the point of attachment to the molecule. Examples include ethoxycarbonyl [CH3CH2OC=O-, a C3alkoxycarbonyl] and methoxycarbonyl [CH3OC=O-, a C2alkoxycarbonyl]. "Alkyl" refers to a branched or unbranched hydrocarbon fragment containing the specified number of carbon atoms and having one point of attachment. Examples include n-propyl (a Cβalkyl), /so-propyl (also a Cβalkyl), and f-butyl (a C4alkyl).
"Alkylene" refers to a divalent radical which is a branched or unbranched hydrocarbon fragment containing the specified number of carbon atoms, and having two points of attachment. An example is propylene [-CH2CH2CH2-, a C3alkylene].
"Alkylcarboxy" refers to a branched or unbranched hydrocarbon fragment terminated by a carboxylic acid group [-COOH]. Examples include carboxymethyl [HOOC-CH2-, a C2alkylcarboxy] and carboxyethyl [HOOC-CH2CH2-, a C3alkylcarboxy].
"Aryl" refers to aromatic groups which have at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl (also known as heteroaryl groups) and biaryl groups, all of which may be optionally substituted. Carbocyclic aryl groups are generally preferred in the compounds of the present invention, where phenyl and naphthyl groups are preferred carbocyclic aryl groups.
"Aralkyl" refers to an alkylene group wherein one of the points of attachment is to an aryl group. An example of an aralkyl group is the benzyl group [C6H5CH2-, a C7aralkyl group]. "Cycloalkyl" refers to a ring, which may be saturated or unsaturated and monocyclic, bicyclic, or tricyclic formed entirely from carbon atoms. An example of a cycloalkyl group is the cyclopentenyl group (C5H7-), which is a five carbon (C5) unsaturated cycloalkyl group.
"Carbocyclic" refers to a ring which may be either an aryl ring or a cycloalkyl ring, both as defined above.
"Carbocyclic aryl" refers to aromatic groups wherein the atoms which form the aromatic ring are carbon atoms. Carbocyclic aryl groups include monocyclic carbocyclic aryl groups such as phenyl, and bicyclic carbocyclic aryl groups such as naphthyl, all of which may be optionally substituted. "Heteroatom" refers to a non-carbon atom, where boron, nitrogen, oxygen, sulfur and phosphorus are preferred heteroatoms, with nitrogen, oxygen and sulfur being particularly preferred heteroatoms in the compounds of the present invention.
"Heteroaryl" refers to aryl groups having from 1 to 9 carbon atoms and the remainder of the atoms are heteroatoms, and includes those heterocyclic systems described in "Handbook of Chemistry and Physics," 49th edition, 1968, R. C. Weast, editor; The Chemical Rubber Co., Cleveland, OH. See particularly Section C, Rules for Naming Organic Compounds, B. Fundamental Heterocyclic Systems. Suitable heteroaryls include furanyl, thienyl, pyridyl, pyrrolyl, pyrimidyl, pyrazinyl, imidazolyl, and the like. "Hydroxyalkyl" refers to a branched or unbranched hydrocarbon fragment bearing an hydroxy (-OH) group. Examples include hydroxymethyl
(-CH2OH, a Cihydroxyalkyl) and 1 -hydroxyethyl (-CHOHCH3, a C2hydroxyalkyl).
"Thioalkyl" refers to a sulfur atom substituted by an alkyl group, for example thiomethyl (CH3S-, a Cithioalkyl). "Modulating" in connection with the activity of an ion channel means that the activity of the ion channel may be either increased or decreased in response to administration of a compound or composition or method of the present invention. Thus, the ion channel may be activated, so as to transport more ions, or may be blocked, so that fewer or no ions are transported by the channel.
"Pharmaceutically acceptable salt" refers to salts of the compounds of the present invention derived from the combination of such compounds and an organic or inorganic acid (acid addition salts) or an organic or inorganic base (base addition salts). The compounds of the present invention may be used in either the free base or salt forms, with both forms being considered as being within the scope of the present invention.
Representative ion channel modulating compounds are more specifically disclosed in U.S. Patent No. 7,057,053 and U.S. Patent No. 7,345, 087, both of which are incorporated in therein entirety herein by reference. Further, methods of synthesizing and producing the ion channel modulating compounds of the present invention are described, e.g., in U.S. Patent No. 7,259,184 and U.S. Patent Application Serial Nos. 10/838,470, 11/757,880, 11/690,361 , 1 1/719,737, and 1 1/455,280, all of which are incorporated herein by reference in their entirety.
Methods of Preventing Arrhythmia
In certain embodiment, the present invention provides methods of preventing arrhythmia in subjects or patients (e.g., mammals or warm-blooded animals, including humans and other animals) at risk for arrhythmia, by administering to such subjects an effective amount of a controlled release formulation of an ion channel modulating compound, such as, e.g. vernakalant hydrochloride. In particular embodiments, the methods of the invention are used to prevent or postpone the onset or recurrence of an arrhythmia. In one embodiment, the subject is a CYP2D6 extensive metabolizer. It is also unerstood that the formulations and methods describe herein may also beused in the treatment of arrhythmia.
In particular embodiments, methods of the present invention may be used to prevent arrhythmia in a subject who previously underwent one or more arrhythmias, or in a subject at risk of an arrhythmia. For example, methods of the present invention are used to prevent a post-operative arrhythmia {e.g., following cardiac surgery such as CABG or valvular surgery). In another embodiment, methods of the present invention are used to prevent the recurrence of arrhythmia, i.e., a recurrent arrhythmia, in a subject having previously undergone one or more arrhythmias. In particular embodiments, the methods may also be used to treat or prevent sustained atrial fibrillation (atrial fibrillation of longer than 72 hours and less than 6 months duration) and chronic atrial fibrillation. In particular embodiments, the ion channel modulating agent, e.g., vernakalant hydrochloride, is provided to a subject orally. In particular embodiments, the amount of ion channel modulating compound administered will generally range from a dosage of from about 0.1 to about 100 mg/kg/day, and typically from about 0.1 to 10 mg/kg where administered orally or intravenously for antiarrhythmic effect. In particular embodiments, a dosage is 5 mg/kg or 7.5 mg/kg. In various embodiments, the ion channel modulating compound is administered at a dosage of about 50-2500 mg per day, 100-2500 mg/day, 300-1800 mg/day, or 500-1800 mg/day. In one embodiment, the dosage is between about 100 to 600 mg/day. In another embodiment, the dosage is between about 300 and 1200 mg/day. In particular embodiments, the ion channel compound is administered at a dosage of 100 mg/day, 300 mg/day, 600 mg/day, 1000 mg/day, 1200 mg/day, or 1800 mg/day, in one or more doses per day (i.e., where the combined doses achieve the desired daily dosage). In related embodiments, a dosage is 100 mg bid, 150 mg bid, 300 mg bid, 500 mg bid, 600 mg bid, or 900 mg b.i.d. In particular embodiments, these dosages are administered orally to a subject at risk for arrhythmia, to prevent such arrhythmia. Examples of other suitable dosages and dosing regimes are also described, e.g., in U.S. Patent Application Nos. 1 1/667,139, 1 1/832,580, 60/916,129, and 60/953,431 . In particular embodiments, the ion channel modulating compound is administered in repeat dosing, and the initial dosage and subsequent dosages may be the same or different.
In certain embodiments, an effective orally administered (i.e., oral) dosage of vernakalant hydrochloride for the prevention of an arrhythmia, (e.g., over 90 days) is greater than 300 mg b.i.d., or greater than 600 mg per day. For example, an effective oral dosage of vernakalant hydrochloride may be in the range greater than 300 mg b.i.d. and up to 900 mg b.i.d. In other embodiments, it may be in the range greater than 300 mg b.i.d. and up to 600 b.i.d. In one embodiment, an effective oral dosage of vernakalant hydrochloride is about 500 mg b.i.d., about 600 mg b.i.d., about 700 mg b.i.d., about 800 mg b.i.d., or about 900 mg b.i.d. In particular embodiments, the ion channel modulating compound is administered long-term, chronically, or regularly, e.g., to prevent arrhythmia in a mammal. Such long term or chronic administration may be, e.g., at least 90 minutes, at least 2 hours, at least 3 hours, at least 4 hours, at least 8 hours, at least 12 hours, at least 24 hours, at least 48 hours, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least one week, at least 2 weeks, at least one month, at least 2 months, at least 4 months, at least 6 months, at least one year, at least 2 years, or greater than 2 years. In one embodiment, long-term treatment is characterized as administration for 3 days or longer, since this is the approximate time in which ion channel modulating compounds reach steady state plasma levels with twice daily oral dosing.
In related embodiments related to preventing a disease or disorder, e.g., an arrythmia, the ion channel modulating compound is administered for at least one week to one year, which may be, e.g., following surgery or an arrhythmia. Such methods are particularly useful in preventing post-surgical arrhythmia or the recurrence or arrhythmia. In various embodiments, the ion channel modulating compound is administered to the mammal in two or more doses over the duration of administration. In certain embodiments, the ion channel modulating compound is administered orally using an extended release formulation or tablet of this invention.
Comparative Controlled Release Tablet Formulations
For purposes of comparison only, the preparation of controlled release tablet formulations comprising an ion channel modulating compound, specifically vernakalant hydrochloride, and one or more pharmaceutically acceptable excipient were prepared.
A. Excipients for the Controlled Release Tablet Formulations
Exemplary excipients used in the controlled release formulations of the active ingredient disclosed herein are listed in Tables 1 to 5 below, along with their chemical/ brand name and function.
TABLE 1 : EXCIPIENTS FOR A CONTROLLED RELEASE FORMULATION UTILIZING A HYDROPHILIC MATRIX SYSTEM
Figure imgf000024_0001
Figure imgf000025_0001
TABLE 2: EXCIPIENTS FOR A CONTROLLED RELEASE FORMULATION UTILIZING A HYDROPHOBIC MATRIX SYSTEM
Figure imgf000026_0001
TABLE 3: EXCIPIENTS FOR A CONTROLLED RELEASE FORMULATION
UTILIZING A FAT-WAX SYSTEM
Figure imgf000026_0002
Figure imgf000027_0001
TABLE 4: EXCIPIENTS FOR A CONTROLLED RELEASE FORMULATION UTILIZING A HYDROPHILIC/HYDROPHOBIC MATRIX SYSTEM
Figure imgf000027_0002
Figure imgf000028_0001
TABLE 5: EXCIPIENTS FOR A CONTROLLED RELEASE FORMULATION UTILIZING A FILM-COATED PARTICULATE SYSTEM
Figure imgf000028_0002
Figure imgf000029_0001
B. Preparation of the Comparative Controlled Release Formulations
Comparative controlled release tablet formulations comprising the active ingredient were made by incorporating the ion channel modulating compound, or its pharmaceutically effective salt, (collectively referred to herein as the "active ingredient"), preferably vernakalant hydrochloride, within a matrix system, including, but not limited to, a hydrophilic matrix system, a hydrophilic non-cellulose matrix system, a hydrophobic (plastic matrix system), or a hydrophilic/hydrophobic matrix system; within a fat-wax system; or within a film- coated particulate system.
Hydrophilic matrix systems showed uniform and constant diffusion of the active ingredient from a tablet prepared with a hydrophilic, gelling polymer (i.e., a hydrophilic matrix system polymer) after the tablet is placed in an aqueous environment. Release of the active ingredient from the system was controlled by a gel diffusional barrier which is formed by a process that is usually a combination of gel hydration, diffusion of the active ingredient, and gel erosion.
Hydrophobic (plastic) matrix systems utilized inert, insoluble polymers (i.e., hydrophobic matrix system polymers) and copolymers to form a porous skeletal structure in which the active ingredient is embedded. Controlled release was effected by diffusion of the active ingredient through the capillary wetting channels and pores of the matrix, and by erosion of the matrix itself.
Hydrophilic/hydrophobic matrix systems utilized a combination of hydrophilic and hydrophobic polymers that formed a soluble/insoluble matrix in which the active ingredient was embedded. Controlled release of the active ingredient was by pore and gel diffusion as well as tablet matrix erosion. The hydrophilic polymer was expected to delay the rate of gel diffusion.
In fat-wax systems, the active ingredient was incorporated in a hot melt of a fat wax matrix, solidified, sized and compressed with appropriate tablet excipients. Controlled release of the active ingredient was effected by pore diffusion and erosion of the fat-wax system. The addition of a surfactant as a wicking agent helped water penetration of the system to cause erosion.
Film-coated particulate systems included time-release granulations, prepared by extrusion-spheronization process or by conventional granulation process that had been film-coated to produce differing species of controlled release particles with specific active ingredient release characteristics. Controlled release particles could be compressed together with appropriate excipients to produce tablets with the desired controlled release profile. The release of the active ingredient was by particle erosion in either acid (gastric) or alkaline (intestinal) pH.
Controlled release tablet formulations comprising the active ingredient could be manufactured by methods including, but not limited to, direct compression (dry blending the active ingredient with flowable excipients, followed by compression), wet granulation (application of a binder solution to powder blend, followed by drying, sizing, blending and compression), dry granulation or compaction (densifying the active ingredient or active ingredient/powder blend through slugging or a compactor to obtain flowable, compressible granules), fat-wax (hot melt) granulation (embedding the active ingredient in molten fatty alcohols, followed by cooling, sizing, blending and compression), and film-coating of particulates (dry blend, wet granulation, kneading, extrusion, spheronization, drying, film-coating, followed by blending of different species of film-coated spheres, and compression).
The methods for manufacturing these controlled release tablet formulations included, but are not limited, to the following methods: a. Direct compression. b. Wet densification of the active ingredient and Starch 1500 or Povidone K29/32 with purified water, followed by tray drying to a moisture level of 2-3% w/w/ and blending with direct compression excipients. c. Fat-wax (hot melt). In one version of the direct compression method, the desired amount of the active ingredient and the desired amount of Starch 1500, Povidone K29/32, Lactose Fast Flo, Anhydrous Emcompress or Carbopol 71 G were mixed by hand in a small polyethylene (PE) bag or a 500 ml_ high density polyethylene (HDPE) container for approximately one minute and then passed through a #30 mesh screen. The resulting blend was then mixed with the desired amounts of the remaining excipients in the desired formulation, excluding magnesium stearate and stearic acid, for approximately 2 minutes in either a small PE bag or a 500 ml_ HDPE container. Approximately 1 g of the resulting mixture was then mixed with the desired amount of magnesium stearate and stearic acid, passed through a #30 mesh screen, added back to the remaining resulting mixture and then blended for approximately one minute. The resulting blend was then compressed into tablets at a final tablet weight of 630 mg or 675 mg (for tablets containing 300 mg active ingredient using a conventional bench top tablet press. In another version of the direct compression method, the desired amount of the pre-screened (#40 mesh) active ingredient and Starch 1500 were placed in a 4 quart V-shell and blended at 25 rpm for 3 minutes. To the resulting blend was added the desired amounts of pre-screened (#30 mesh) Prosolv SMCC 90, Lactose Fast Flow, Methocel K4M and stearic acid (pre-screened through a #40 mesh) and the resulting mixture was mixed for 5 minutes at 25 rpm.
Magnesium stearate was then added to an equal amount of the resulting mixture, which was then blended in a small polyethylene bag for approximately 1 minute, passed through a #30 mesh screen by hand and returned to the resulting mixture. The final resulting mixture was blended for 2 minutes at 25 rpm and then compressed into tablets at a final tablet weight of 630 mg (for tablets containing 300 mg active ingredient) using a conventional tablet press. In a version of the wet densification method, the desired amount of the active ingredient was mixed with the desired amount of Starch 1500 or Povidone K29/32 and the resulting mixture was passed through a #30 mesh screen. Purified water was added to the screened mixture until it reached a satisfactory densification end point. The resulting wet mass was passed through a #12 mesh screen onto a tray and dried at 60° C for 2 to 3 hours until a moisture level of 2-3% w/w was obtained. The resulting dry granules were passed through a #20 mesh screen into either a small PE bag or a 500 ml_ HDPE container. To the screened dry granules was added the desired amounts of the remaining excipients of the formulation, excluding magnesium stearate and stearic acid. The contents were mixed for approximately 2 minutes. Approximately 1 g of the resulting mixture was then mixed with the desired amounts of magnesium stearate and stearic acid, passed through a #30 mesh screen, added back to the remaining resulting mixture and then blended for approximately 1 minute. The final resulting blend was compressed into tables at a final tablet weight of 630 mg or 675 mg (for tablets containing 300 mg active ingredient) using a conventional tablet press.
In a version of the fat wax (hot melt) method, the desired amount of fat wax, preferably cetostearyl alcohol or cetyl alcohol, was placed in a stainless steel container, which was then heated on until the wax completely liquifies (i.e., completely melts). The desired amounts of the active ingredient, Lactose Fast Flo and Prosolv SMCC90 were then added to the melted wax with continuous stirring and heating until completely dispersed. Alternately, only the desired amount of the active ingredient was dispersed in the melted wax. The resulting granular-like particles were passed through a #20 mesh screen and placed in either a small PE bag or a 500 ml_ HDPE container. In the case of the melted wax containing only the active ingredient, the screened particles were blended with Lactose Fast Flo and Prosolv SMCC 90 for approximately 2 minutes in either a small PE bag or a 500 mL HDPE container. Approximately I g of each blend was mixed with the desired amounts of magnesium stearate and stearic acid, passed through a #30 mesh screen, returned to the blend, and mixed for approximately one minute. The final blend was compressed into tablets at weights of 630 mg or 675 mg (for tablets containing 300 mg active ingredient) using a conventional tablet press.
In another version of the fat wax (hot melt) method, the desired amount of fat wax, preferably, cetostearyl alcohol was melted at approximately 70° C in a mixer until the wax liquefied. The desired amounts of Lactose Fast Flo and
Prosolv SMCC90 were blended for approximately 1 minute in a double lined PE bag and set aside. The desired amount of the active ingredient was added to the melted wax with continuous stirring and heating at approximately 700C until the active ingredient was completely dispersed. The blend of excipients was then added to the melted wax with stirring and maintaining heating between 40° C and 60° C until dispersion was complete. The resulting granular-like particles were cooled to ambient temperature, passed through a #20 mesh screen and placed in a double lined PE bag. The screened particles were then blended with stearic acid in a 4 quart V-shell for approximately 2 minutes at 25 rpm. Magnesium stearate was added to an equal amount of the stearic acid blend, blended in a small PE bag for approximately 1 minute, passed through a #20 mesh screen by hand, returned to the stearic acid blend and the final mixture was blended for 3 minutes at 25 rpm. The final blend was compressed into tablets at a weight of 630 mg or 675 mg (for tablets containing 300 mg of active ingredient) using a conventional tablet press.
The following Examples are provided as a guide to assist in the preparation of the comparative controlled release formulations.
EXAMPLE 1
300 mg Comparative Controlled Release Tablet Formulations Hydrophilic Matrix System
The following Table 6 provides for a controlled release tablet formulation comprising 300 mg of the active ingredient, vernakalant hydrochloride, in a hydrophilic matrix system. TABLE 6: 300 MG COMPARATIVE HYDROPHILIC FORMULATIONS
Figure imgf000034_0001
EXAMPLE 2 300 mg Comparative Controlled Release Tablet Formulations
Hydrophilic Matrix System
The following Table 7 provides for a controlled release tablet formulation of the invention comprising 300 mg of the active ingredient, vernakalant hydrochloride, in a hydrophilic matrix system. Hydrophilic formulation #300-2 was prepared by reducing the calculated tablet weight of 675 mg of hydrophilic formulation #300-1 to 630 mg by reducing the amount of Lactose Fast Flo and Prosolv SMCC 90.
TABLE 7: 300 MG COMPARATIVE HYDROPHILIC FORMULATION
Figure imgf000035_0001
EXAMPLE 3 300 mg Comparative Controlled Release Tablet Formulations
Hydrophilic (Non-Cellulose) Matrix System
The following Table 8 provides for a controlled release tablet formulation of the invention comprising 300 mg of the active ingredient, vernakalant hydrochloride, in a hydrophilic (non-cellulose) matrix system.
TABLE 8: 300 MG COMPARATIVE HYDROPHILIC (NON-CELLULOSE)
FORMULATION
Figure imgf000036_0001
EXAMPLE 4 300 mg Comparative Controlled Release Formulations
Hydrophilic/Hydrophobic Matrix System
The following Table 9 provides for a controlled release tablet formulation of the invention comprising 300 mg of the active ingredient, vernakalant hydrochloride, in a hydrophilic/hydrophobic matrix system.
TABLE 9: 300 MG COMPARATIVE HYDROPHILIC/HYDROPHOBIC
FORMULATION
Figure imgf000037_0001
EXAMPLE 5 300 mg Comparative Controlled Release Formulations
Fat Wax System
The following Table 10 provides for a controlled release tablet formulation of the invention comprising 300 mg of the active ingredient, vernakalant hydrochloride, in a fat wax system. This formulation was prepared by methods disclosed herein.
TABLE 10: 300 MG COMPARATIVE FAT WAX FORMULATIONS
Figure imgf000038_0001
C. In vitro Release Profile of the Comparative Controlled Release Formulations
The in vitro release profile of the comparative controlled release formulations described above may be empirically determined by examining the dissolution of the tablet formulations over time. A method using a USP approved apparatus for dissolution or release test can be used to measure the rate of release in vitro.
The following Example 6 is provided as a guide in preparing the comparative controlled release formulations.
EXAMPLE 6 In-vitro Dissolution of Comparative Controlled Release Tablet Formulations
The following Table 11 provides the in vitro dissolution release percentages of the comparative controlled tablet formulations comprising 300 mg of the active ingredient. TABLE 11 : MEAN DISSOLUTION % RELEASE OF 300 MG COMPARATIVE CONTROLLED RELEASE FORMULATIONS
Figure imgf000039_0001
D. In vivo Pharmacokinetic Profiles of the Comparative Controlled Release Formulations Administered to Dogs
The in vivo pharmacokinetic profiles of the comparative controlled release formulations were determined as follows. The formulations were administered to dogs to determine the pharmacokinetic profile of each formulation. A single comparative controlled release tablet formulation was orally administered to a dog. Blood samples were collected via the jugular or cephalic vein at predose (0), 30, 60, 90, 120, 240, 360, 480, 600, 720 and 1440 minutes after administration. Concentration levels of the active ingredient in the plasma samples at each timepoint was determined using standard methods known to one skilled in the art. The concentration levels were plotted on a standard pharmacokinetic curve (time in minutes versus concentration in ng/mL) and the area under the curve from time = 0 to time = 1440 minutes (AUCo-t), the area under the curve from time = 0 to infinity (AUCιnf), the Cmax (peak blood plasma concentration level of the active ingredient) and Tmax (time after administration of the formulation when peak plasma concentration level occurs) were calculated. In general, a controlled release formulation should provide a broader pharmacokinetic curve while minimizing the Cmax when compared to the pharmacokinetic curve of a comparable immediate release formulation. The following Table 12 presents the plasma concentrations of the active ingredient, vernakalant hydrochloride, in dogs that received a comparative hydrophilic controlled release tablet formulation comprising 300 mg of the active ingredient, (i.e., hydrophilic formulation #300-2); a comparative fat wax controlled release tablet formulation of the invention comprising 300 mg of the active ingredient (i.e., fat wax formulation #300-1 ); a comparative hydrophilic/hydrophobic controlled release tablet formulation of the invention comprising 300 mg of the active ingredient (i.e., hydrophobic formulation #300- 1 ), and a comparative hydrophilic (non-cellulose) tablet formulation of the invention comprising 300 mg of the active ingredient (i.e., hydrophilic (non- cellulose) formulation #300-1 ). Concentrations are given as μg/mL and are an average obtained from n = 3 dogs unless otherwise indicated.
TABLE 12: PLASMA CONCENTRATIONS OF ACTIVE INGREDIENT IN DOGS AFTER ORAL ADMINISTRATION OF COMPARATIVE CONTROLLED
RELEASE FORMULATIONS
Figure imgf000040_0001
Figure imgf000041_0001
ND = No detection, * n=2, ** n=1
From the above concentration averages, the area under the curve (AUCmf), Tmax and Cmax were calculated and their ratio determined (AUCmf/Cmax), as shown in Table 13 below.
TABLE 13: PHARMACOKINETIC PARAMETERS IN DOGS
Figure imgf000041_0002
E. In vivo Pharmacokinetic Profiles of the Comparative Controlled Release Formulations Administered to Humans Comparative hydrophilic formulation #300-2 and comparative fat Wax formulation #300-2 were each administered as one dose (300 mg of active ingredient) to six healthy male and female subjects (six subjects per formulation). Blood was drawn at pre-dose (0 hours), 0.5, 1 , 1.5, 2, 3, 4, 6, 8, 10, 12, 16 and 24 hours post dose. The median pharmacokinetic parameters of each formulation are shown in the following Table 14:
TABLE 14: PHARMACOKINETIC PARAMETERS OF 300 MG ACTIVE
INGREDIENT
Figure imgf000042_0001
Based on the above results, hydrophilic formulation #300-2 was administered as a double dose (600 mg of active ingredient) to six healthy male and female subjects. Blood was drawn at pre-dose (0 hours), 0.5, 1 , 1.5, 2, 3, 4, 6, 8, 10, 12, 16 and 24 hours post dose. The median pharmacokinetic parameters are shown in the following Table 15:
TABLE 15: PHARMACOKINETIC PARAMETERS OF 600 MG ACTIVE
INGREDIENT
Figure imgf000042_0002
Extended Release Formulations of the Invention
Based on the above results, an extended release formulation which provides a longer Tmax and a reduced Cmaχ than the Tmax and Cmaχ obtained from the comparative controlled release formulations is desired (i.e., an extended release formulation with a slower active ingredient release rate). Accordingly, various formulations were prepared and investigated as extended release formulations of the invention, as described futher below, to identify suitable combinations of active ingredient and excipients for extended release formulations. As a result, the present invention provides extended release tablet formulations comprising an active ingredient, such as vernakalant hydrochloride, in combination with particular excipients. These tablet formulations may be uncoated or coated with either or both a taste masking coating and an enteric coating. In addition, one or more of these extended release tablet formulations may be present in a capsule.
In particular embodiments, an extended release tablet formulation of this invention comprises comprises a hydrophilic matrix polymer. Preferably, the hydrophilic matrix polymer is hydroxypropyl methyl cellulose or polyethylene oxide. In various embodiments, an extended release formulation of the present invention comprises between about 20% wt. and about 60% wt. hydrophilic matrix polymer, or between about 25% wt. and about 45% wt. hydrophilic matrix polymer. In related embodiments, a controlled release formulation comprises about 20% wt., about 30% wt., about 35% wt., about 40% wt., about 45% wt., about 50% wt., about 55% wt., or about 60% wt. hydrophilic matrix polymer.
In particular embodiments, this tablet formulation further comprises magnesium stearate. In various embodiments, the formulation comprises about 0.5% wt. to 2.0% wt. magnesium stearate. In one embodiment, the formulation comprises about 1.0 % wt. magnesium stearate. In particular embodiments, an extended release formulation comprises dicalcium phosphate, e.g., A-Tab. In various embodiments, the formulation comprises about 5.0% wt. to about 50% wt., or about 10% wt. to about 30% wt. dicalcium phosphate. In certain embodiments, the formulation comprises about 10% wt., about 20% wt. or about 30% wt. dicalcium phosphate. In certain embodiments, the combination of hydrophilic matrix polymer and dicalcium phosphate between about 40% wt. and 70% wt. or between about 50% wt. and 60% wt. of the formulation. In one embodiment, the combination of hydrophilic matrix polymer and dicalcium phosphate is about 55% wt. of the formulation.
In one embodiment, this tablet formulation comprises vernakalant hydrochloride; hydroxypropyl methyl cellulose; dicalcium phosphate anhydrous; and magnesium stearate.
In certain embodiments, an extended release tablet formulation of this invention is coated with a enteric coating composition comprising a (meth)acrylate copolymer. In one embodiment, the enteric coating composition comprises a (meth)acrylate copolymer, Imwitor, triethyl citrate, and a polysorbate.
In other embodiments, an extended release tablet formulation of this invention is coated with a taste masking coating composition comprising a polyvinyl alcohol (PVA) base. In one embodiment, the taste masking coating composition comprises PVA base hydroxypropyl methyl cellulose, dicalcium phosphate, an magnesium stearate.
In related aspects, this invention provides for capsules comprising one or more extended release tablet formulations of this invention. For example, in one embodiment, the capsule comprises an extended release tablet formulation coated with a enteric coating comprising a (meth)acrylate copolymer. In another embodiment, the capsule comprises an extended release tablet formulation of this invention coated with a taste masking coating composition comprising a polyvinyl alcohol (PVA) base. In addition, in particular embodiments, the capsule comprises both an extended release tablet formulation coated with a enteric coating and an extended release tablet formulation coated with a taste masking coating. In particular embodiments, the extended release tablet formulations present in the capsule comprise vernakalant hydrochloride as the ion channel modulating agent. In one embodiment, they comprise vernakalant hydrochloride and hydroxypropyl methyl cellulose In a related embodiment, they comprise vernakalant hydrochloride, hydroxypropl methyl cellulose, and magnesium stearate. In a furher related embodiment, they comprise vernakalant hydrochloride, hydroxypropyl methyl cellulose, magnesium stearate, and dicalcium phosphate anhydrous.
It is understood that any of the controlled release or extended release tablet formulations described herein may be coated with one or more of any of the coatings described herein.
In further embodiments, the present invention provides extended release tablets and capsules comprising an effective amount of an ion channel modulating compound, such as vernakalant hydrochloride, when administered at a recommended dosage, including any of those dosages described herein. A recommended dosage may include any number of extended release tablets or capsules. For example, in one embodiment, a recommended dosage of about 500 mg vernakalant hydrochloride b.i.d. may be achieved by administered two tablets or capsuled comprising about 250 mg vernakalant hydrochloride b.i.d. The skilled artisan will appreciate that any of the specific extended release tablet formulations described herein, e.g. those comprising 300 mg of vernakalant hydrochloride, may be readily adapted to include 250 mg vernakalant hydrochloride, by varying the amounts of each component therein and maintaining the same ratio of components by weight.
In certain embodiments, the extended release tablet formulations of an ion channel modulating compound, or capsules comprising these formulations, have a release profile wherein less than 1 % of the ion channel modulating compound, or a pharmaceutically acceptable salt thereof, is released following 2 hours in 0.1 N HCI solution and 4 hours in phosphate buffer solution at pH 6.4. In certain embodiments, an extended release formulation of the present invention releases a certain percentage of active ingredient, e.g., vernakalant, when placed in a dissolution medium, such as described in Example 7. For example, in certain aspects, an extended release formulation releases less than about 35% to less than about 10% active ingredient (e.g., less than about 35%, 30%, 25%, 20%, 15%, or 10% active ingredient, including all ranges and integers in between) after incubation for about 2 hours at 370C in 0.1 N HCI (i.e., Dissolution Medium 1 ). In certain aspects, an extended release formulation releases less than about 60% to less than about 25% active ingredient (e.g., 60%, 55%, 50%, 45%, 35%, 30%, or 25% active ingredient, including all ranges and integers in between) after incubation for about 6 hours at 370C in 0.1 N HCI. In certain aspects, an extended release formulation releases less than about 85% to less than about 55% active ingredient (e.g., less than about 85%, 80%, 75%, 70%, 65%, 60%, 55%, including all ranges and integers in between) after incubation for about 6 hours at 370C in 0.1 N HCI, followed by about 6 hours further incubation in 0.05 M Thbasic Sodium Phosphate Buffer adjusted to pH 7.2±0.05.
In certain embodiments, an extended release formulation of the present invention demonstrates particular pharmacokinetic (PK) characteristics following administration (e.g., oral administration of 300mg extended release vernakalant) to an individual. PL characteristics may be represented, for example, by maximum plasma concentration (Cmaχ), time of maximum plasma concentration (tmax), area under the plasma concentration-time curve (AUC), Cmax/AUC ratio, and half-life (t1/2), as described in Example 10. PK characteristics may also be represented by mean plasma concentration, such as by the geometric mean, CV%, arithmetic mean, standard deviation, median, and minimum and maximum values.
In certain aspects, an extended release formulation has an apparent mean half-life (ti/2) ranging from about 4 hours to about 10 or more hours (e.g., 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, or more hours, including all ranges and decimal components in between, e.g., 4.2, 4.3, 4.4, etc.) following administration to an individual. In certain aspects, an extended release formulation has a tmax value ranging from about 3 hours to about 7 or 8 hours (e.g.., about 3, 4, 5, 6, 7, 8, or more hours, including all ranges and decimal components in between (e.g., 4.2, 4.3, 4.4, etc.).
In certain embodiments, an extended release formulation exhibits lower Cmax values and lower Cmaχ/AUCιnf ratios as compared to a non-extended release formulation, such as a controlled release formulation. In certain aspects, an extended release formulation has a mean Cmaχ value ranging from about 12 ng/ml to about 25 ng/ml, including all ranges, integers, and decimal components in between, following administration to an individual. Merely by comparison, in these instances a non-extended release formulation typically exhibits a mean Cmaχ value of about 28 ng/ml or more. In certain aspects, an extended release formulation has a mean Cmax value ranging from about 90 ng/ml to about 150 ng/ml, including all ranges, integers, and decimal components in between (e.g., 90, 95, 100, 120, 125, 130, 140, 150, 90-120, 100-120, 120-150 ng/ml, etc.), following administration to an individual. In these instances, a non-extended release formulation typically exhibits a mean Cmax value of about 200 or 220 ng/ml or more. In certain aspects, an extended release formulation has a mean Cmaχ value ranging from about 195 ng/ml to about 220 ng/ml, including all ranges, integers, and decimal components in between, following administration to an indivual. In these instances, a non- extended release formulation typically exhibits a mean Cmaχ value of about 270 or 280 ng/ml or more. In certain embodiments, an extended release formulation may exhibit a mean Cmaχ/AUCιnf ratio ranging from about 0.05 to about 0.12, including all ranges and decimal components in between, such as about 0.05 to about 0.10, 0.05 or 0.06 to about 0.10 or 0.09, 0.06 to about 0.08 or 0.07, among others.
As noted above, Methocel K4M (hydroxypropyl methyl cellulose) was used as the active ingredient release retardant in hydrophilic table formulation #300-2 at 19.0% total weight. Cetostearyl alcohol was used as the active ingredient release retardant in fat wax formulation #300-1 at 22.22%. Both formulations contain around 15% Prosolv SMCC90 and around 15% lactose. It was determined that the presence of Prosolv SMCC90 and lactose would cause the increase in drug release rate. Two formulation approaches were investigated in detail: matrix tablets and coated tablets. Hydrophilic matrix tablets containing hydroxypropyl methyl cellulose or polyethylene oxide as active ingredient release retardants were demonstrated to be viable delivery systems for the active ingredient, vernakalant hydrochloride. A. Hydroxypropyl Methyl Cellulose (HPMC) Based Hydrophilic Extended Release Formulations
At the initial stage of the extended release formulation development, efforts were focused on the development of a hydrophilic matrix tablet by modifying the existing hydrophilic formulation #300-2 using the following approaches. i). Decrease the percent of active ingredient in the tablets by increasing the target tablet weight from 630 mg to 700 mg. ii). Replace Methocel K4M with Methocel K100M (Dow Chemical) to decrease the hydration rate. iii). Increase hydroxypropyl methyl cellulose content in the formulation by replacing Starch 1500, Prosolv SMCC and lactose with hydroxypropyl methyl cellulose (Methocel). iv). Incorporate alkaline agents in the formulation to convert vernakalant hydrochloride to vernakalant base during the dissolution process
The key results of these studies are summarized as follows: i). The presence of alkaline agents in the formulation was not effective in decreasing active ingredient release rate. ii). The desired in vitro dissolution profile was achieved when Methocel K4M, Starch 1500, Prosolv SMCC and lactose were replaced with Methocel K100M. However, the formulation was poorly compressible. iii). Microcrystalline cellulose, ethyl cellulose, calcium phosphate dibasic, hydroxypropyl cellulose, polyethylene oxide were evaluated as diluents to improve the compaction properties of hydroxypropyl methyl cellulose matrix tablets. Calcium phosphate dibasic and polyethylene oxide were found to be the most effective in improving the compaction properties of hydroxypropyl methyl cellulose matrix tablets. iv). Three hydroxypropyl methyl cellulose matrix formulations containing 10%, 20% or 30% A-Tab (calcium phosphate dibasic) were selected for stability studies.
The hydroxypropyl methyl cellulose based extended release formulations of the invention were developed as follows. 1 . Hydroxypropyl methyl cellulose
Hydroxypropyl methyl cellulose (Methocel) is available in a variety of grades. Methocel K4M, Methocel K15M and Methocel K100M are most commonly used for the preparation of extended release dosage forms. The viscosity of 2% Methocel K4M, K15M and K100M solution in water at 2O0C is 4,000, 15,000 and 100,000 cps, respectively. Slower active ingredient release is expected when Methocel K100M is used to replace Methocel K4M, starch 1500, Prosolv SMCC and lactose in the hydrophilic formulation #300-2.
2. The Addition of Alkaline Agents The formulations detailed in Table 16 through Table 23 were prepared to investigate the use of Methocel K100M as an active ingredient release retardant and the effect of alkaline agents on the release of vernakalant hydrochloride in hydroxypropyl methyl cellulose matrix tablets.
With the addition of alkaline agents, a certain percentage of vernakalant hydrochloride will be, theoretically, converted from the hydrochloride salt to the free base. The free base form of vernakalant hydrochloride is anticipated to have a much slower solubility and diffusion rate than its hydrochloride salt. Therefore, addition of alkaline agents could theoretically effectively retard the release of the active ingredient. Carbonate, phosphate and citrate salts are commonly used alkaline agents in extended release formulations. Sodium salt is more commonly used than potassium salt. These alkaline agents were added at levels ranging from 4.3 to 10.0 percent and were all within the range specified in the FDA inactive ingredient list. These salts are available as anhydrous or hydrate forms. For the purpose of the dissolution experiments, the anhydrous forms were used. Based on the dissociation constants of anions, phosphate salt should provide the highest pH at the same molar concentration. TABLE 16: COMPOSITION OF 300 MG EXTENDED RELEASE FORMULATION HPMC #1
Figure imgf000050_0001
TABLE 17: COMPOSITION OF 300 MG EXTENDED RELEASE FORMULATION HPMC #2 FURTHER COMPRISING AN ALKALINE AGENT
Figure imgf000050_0002
TABLE 18: COMPOSITION OF 300 MG EXTENDED RELEASE FORMULATION HPMC #3 FURTHER COMPRISING AN ALKALINE AGENT
Figure imgf000050_0003
Figure imgf000051_0001
TABLE 19: COMPOSITION OF 300 MG EXTENDED RELEASE FORMULATION HPMC #4 FURTHER COMPRISING AN ALKALINE AGENT
Figure imgf000051_0002
TABLE 20: COMPOSITION OF 300 MG EXTENDED RELEASE FORMULATION HPMC #5 FURTHER COMPRISING AN ALKALINE AGENT
Figure imgf000051_0003
TABLE 21 : COMPOSITION OF 300 MG EXTENDED RELEASE FORMULATION HPMC #6 FURTHER COMPRISING AN ALKALINE AGENT
Figure imgf000052_0001
TABLE 22: COMPOSITION OF 300 MG EXTENDED RELEASE FORMULATION HPMC #7 FURTHER COMPRISING AN ALKALINE AGENT
Figure imgf000052_0002
TABLE 23: COMPOSITION OF 300 MG EXTENDED RELEASE FORMULATION HPMC #8 FURTHER COMPRISING AN ALKALINE AGENT
Figure imgf000053_0001
Dissolution properties for the formulations listed in Tables 16 through 23 are shown in Tables 24 and 25.
As seen in the following Tables 24 and 25, the desired release profile
(extended release over 12 hours) could be achieved by replacing Methocel
K4M, starch 1500, Prosolv SMCC and lactose in the existing formulation with Methocel K100M. It was also concluded that the presence of alkaline agents did not result in desirable decrease in the release rate of the active ingredient, vernakalant hydrochloride.
TABLE 24: DISSOLUTION PROFILE DATA OF 300 MG EXTENDED RELEASE FORMULATIONS COMPRISING METHOCEL K100M AND AN ALKALINE AGENT (CITRATE OR CARBONATE SALTS)
Figure imgf000053_0002
TABLE 25: DISSOLUTION PROFILE DATA OF 300 MG EXTENDED
RELEASE HPMC FORMULATIONS COMPRISING METHOCEL K100M AND
AN ALKALINE AGENT (PHOSPHATE SALTS)
Figure imgf000054_0001
3. The Addition of a Carbomer with the Alkaline Agents
The use of a carbomer in the formulations containing alkaline agents was also investigated. Carbopol is cross-linked polycarboxylic acid carbomer and it can form a strong gel in an alkaline aqueous environment in order to hinder the release of the active ingredient.
The formulations of the invention containing Carbopol and an alkaline agent are listed in Tables 26 through 29. The dissolution results for these formulations are presented in Table 30.
TABLE 26: COMPOSITION OF 300 MG EXTENDED RELEASE HPMC FORMULATION (HPMC #9) FURTHER COMPRISING A CARBOMER AND
AN ALKALINE AGENT
Figure imgf000055_0001
* Carbopol 974P is the only grade of Carbopol approved for oral drug delivery
TABLE 27: COMPOSITION OF 300 MG EXTENDED RELEASE HPMC FORMULATION (HPMC #10) FURTHER COMPRISING A CARBOMER AND
AN ALKALINE AGENT
Figure imgf000055_0002
TABLE 28: COMPOSITION OF 300 MG EXTENDED RELEASE HPMC FORMULATION (HPMC #11 ) FURTHER COMPRISING A CARBOMER AND
AN ALKALINE AGENT
Figure imgf000056_0001
TABLE 29: COMPOSITION OF 300 MG EXTENDED RELEASE HPMC FORMULATION (HPMC #12) FURTHER COMPRISING A CARBOMER AND
AN ALKALINE AGENT
Figure imgf000056_0002
TABLE 30: DISSOLUTION PROFILE DATA OF 300 MG EXTENDED
RELEASE HPMC FORMULATIONS FURTHER COMPRISING A CARBOMER
(CARBOPOL) AND AN ALKALINE AGENT
Figure imgf000057_0001
Formulations containing Carbopol as an active ingredient release retardant demonstrated very poor flow properties and poor compaction properties. The presence of alkaline agents in the formulations actually increased the release rate of the active ingredient, vernakalant hydrochloride.
4. Optimization of Hydroxypropyl Methyl Cellulose Tablet Formulations of the Invention
Based on the above results, Methocel K100M CR (controlled release grade) was identified to be a suitable hydrophilic matrix polymer for extended release of the active ingredient, vernakalant hydrochloride. Extended release over 12 hours was successfully demonstrated by Extended Release Formulation #1.
Extended Release Formulation #1 tablets were prepared by manually compressing a physical blend of vernakalant hydrochloride, Methocel K100M and magnesium stearate on a rotary tablet press. Tablet hardness was around 20 Kp. Additional investigation was commenced to identify suitable filler excipients which could be incorporated into Extended Release Formulation #1 to improve its compaction properties when compressed into a tablet dosage form for oral administration. Accordingly, the effect of the following pharmaceutically acceptable filler excipients on the compaction properties of Extended Release Formulation #1 was investigated. All of these excipients have superior compaction properties when compressed on their own. a). Microcrystalline cellulose (Avicel PH 101 and Avicel PH
105. FMC Inc).
Avicel is the most commonly used filler excipients to improve the compaction properties of a tablet formulation. The composition of formulations containing microcrystalline cellulose, Avicel, is summarized in Table 31. The average particle size of PH 101 is 50 μm and the average particle size of PH 105 is 20 μm. It was anticipated that Avicel PH 105 could improve the compaction properties more significantly than Avicel PH 101 since the particle size of Avicel PH 105 is smaller.
TABLE 31 : 300 MG EXTENDED RELEASE HPMC FORMULATIONS FURTHER COMPRISING MICROCRYSTALLINE CELLULOSE (AVICEL)
Figure imgf000058_0001
The above formulations were prepared as follows:
The appropriate amounts of vernakalant hydrochloride, Methocel K100M and Avicel were mixed together using a mortar and pestle. The appropriate amount of magnesium stearate was added and the resulting mixture was blended briefly. The resulting powder blend was passed through a 30 mesh screen. The resulting blend was manually compressed using a 11 mm, round, shallow concave tabulating tool to a tablet hardness of 20 Kp. During the testing of the hardness of the tablets so formed, capping or lamination was observed for all three formulations. The dissolution data for the formulations listed in Table 31 are presented in Table 32 (dissolution data for Extended Release Formulation HPMC #1 is shown for comparison purposes).
TABLE 32: DISSOLUTION PROFILE DATA OF 300 MG EXTENDED RELEASE FORMULATIONS COMPRISING MICROCRYSTALLINE
CELLULOSE (AVICEL)
Figure imgf000059_0001
As noted above, extended release of the active ingredient, vernakalant hydrochloride, over a 12 hour period was observed for all three extended release formulations comprising microcrystalline cellulose (Avicel). However, when compared to Extended Release Formulation #1 , the release rate of the active ingredient increased with the percentage of Avicel present in these formulations. b). Ethyl cellulose (Ethocel Std 10 FP, Dow Chemical)
As seen above, the presence of microcrystalline cellulose, Avicel, increased the release rate of the active ingredient. It was deemed necessary to investigate another active ingredient release retardant to improve the compaction properties of Extended Release Formulation #1. Ethyl cellulose is a water insoluble polymer used for the preparation of matrix tablets and is extremely compressible. It is also commercially available as premium and fine particle size grade. The fine particle size grade was selected for investigation because of its stronger solid state binding capacity as a result of its large specific surface area. The composition of extended release formulations of the invention comprising ethyl cell use, Ethocel Std 10 FP, is summarized in Table 33.
TABLE 33: 300 MG EXTENDED RELEASE HPMC FORMULATIONS FURTHER COMPRISING ETHYL CELLULOSE (ETHOCEL)
Figure imgf000060_0001
CR denotes controlled release grade which is specially produced, ultra-fine particle size material. For Methocel K100M, 100% of material is finer than 30 mesh and 99% is finer than 40 mesh. For Methocel K100M CR, 90% of material is finer than 100 mesh.
The above formulations were prepared as follows:
The appropriate amounts of vernakalant hydrochloride, Methocel K100M or Methocel K100M CR and Ethocel Std 10 FP were mixed in a mortar and pestle. The appropriate amount of magnesium stearate was added to the mixture and the resulting mixture was blended briefly. The resulting powder blend was passed through a 30 mesh screen. The resulting blend was manually compressed using a 11 mm, round, shallow concave tabletting tool to a tablet hardness of 20 Kp. The tablets so formed exhibited good compaction properties. The dissolution data for the formulations listed in Table 33 are presented in Table 34 (dissolution data for Extended Release Formulation HPMC #1 is shown for comparison purposes).
TABLE 34: DISSOLUTION PROFILE DATA OF 300 MG EXTENDED RELEASE HPMC FORMULATIONS FURTHER COMPRISING ETHYL
CELLULOSE (ETHOCEL)
Figure imgf000061_0001
As shown above in Table 34, the release rate of the active ingredient increased with the increase in Ethocel FP level and the extended release of the active ingredient over a period of 12 hours was observed even with Ethocel FP at 30% level. It was also concluded that there was no difference in the release profile of the active ingredient when Methocel K100M was replaced with Methocel K100M CR. However, when compared to Extended Release Formulation HPMC #1 , the release rate of the active ingredient increased with the presence of Ethocel in these formulations. c). Dicalcium phosphate anhydrous (A-Tab, Rhodia) In addition to the foregoing extended formulations of the invention, dicalcium phosphate anhydrous (A-Tab) was investigated as an excipient to increase the compaction property of Extended Release Formulation HPMC #1. The composition of extended release formulations of the invention comprising dicalcium phosphate anhydrous (A-Tab) is summarized in Table 35. TABLE 35: 300 MG EXTENDED RELEASE HPMC FORMULATIONS FURTHER COMPRISING DICALCIUM PHOSPHATE ANHYDROUS (A-TAB)
Figure imgf000062_0001
The above formulations were prepared as follows: The appropriate amounts of vernakalant hydrochloride, Methocel K100M
CR and A-Tab were mixed in a mortar and pestle. The appropriate amount of magnesium stearate was added to the mixture and the resulting mixture was blended briefly. The resulting powder blend was passed through a 30 mesh screen. The resulting blend was manually compressed using a 11 mm, round, shallow concave tabletting tool to a tablet hardness of 20 Kp. The tablets so formed exhibited good compaction properties when A-Tab was present in the formulation at 10%, 20% and 30% level. Furthermore, it was observed that A- Tab appeared to be more effective in improving the compaction properties of the powder blend than Avicel and Ethocel. The dissolution data for three of the extended release formulations of the invention listed in Table 35 are presented in Table 36 (dissolution data for Extended Release Formulation HPMC #1 is shown for comparison purposes). TABLE 36: DISSOLUTION PROFILE DATA OF 300 MG EXTENDED RELEASE HPMC FORMULATIONS COMPRISING DICALCIUM PHOSPHATE
ANHYDROUS (A-TAB)
Figure imgf000063_0001
The above results indicate that the presence of dicalcium phosphate anhydrous increased the release rate of the active ingredient in the three formulations as compared to the release rate of the active ingredient in Extended Release Formulation HPMC #1. d). Hvdroxypropyl cellulose (Klucel EF, Aqualon) In addition to the foregoing extended formulations of the invention, hydroxypropyl cellulose (Klucel) was investigated as an excipient to increase the compaction property of Extended Release Formulation HPMC #1. The composition of extended release formulations of the invention comprising hydroxypropyl cellulose is summarized in Table 37.
TABLE 37: 300 MG EXTENDED RELEASE HPMC FORMULATIONS FURTHER COMPRISING HYDROXYPROPYL CELLULOSE (KLUCEL)
Figure imgf000064_0001
The above formulations were prepared as follows:
The appropriate amounts of vernakalant hydrochloride, Methocel K100M CR and A-Tab were mixed in a mortar and pestle. The appropriate amount of magnesium stearate was added to the mixture and the resulting mixture was blended briefly. The resulting powder blend was passed through a 30 mesh screen. The resulting blend was manually compressed using a 11 mm, round, shallow concave tabulating tool to a tablet hardness of 20 Kp. The tablets exhibited good compaction properties when Klucel was present in the formulation at the 20% level.
The dissolution data for one of the formulations listed in Table 37 is presented in Table 38 (dissolution data for Extended Release Formulation HPMC #1 is shown for comparison purposes). TABLE 38: DISSOLUTION PROFILE DATA OF 300 MG EXTENDED RELEASE HPMC FORMULATIONS COMPRISING HYDROXYPROPYL
CELLULOSE (KLUCEL)
Figure imgf000065_0001
The above results indicate that the presence of 20% hydroxypropyl cellulose in the formulation did not increase the release rate of the active ingredient as compared to the release rate of the active ingredient in Extended Release Formulation HPMC #1. e). Polyethylene oxide, (PoIvOx WSR, Dow Chemical) As shown above, the use of microcrystalline cellulose (Avicel), ethyl cellulose (Ethocel), or dicalcium phosphate dibasic anhydrous (A-Tab) in the formulations of the invention to improve the compaction properties of the formulations resulted in an increase in the release rate of the active ingredient within the first 4 hours. This initial burst effect is generally attributed to the fact that the hydrophilic matrix can not hydrate fast enough to retard the release of the active ingredient.
The effect of polyethylene oxide (PoIyOx WSR) on the release of the active ingredient in Extended Release Formulation HPMC #1 was also investigated. Polyethylene oxide has excellent compaction properties. At the same time, polyethylene oxide could potentially suppress the initial burst effect of the hydrophilic matrix formulations. Coagulated grade polyethylene oxide was selected for detailed investigation. It is available from Dow Chemical as regular grade, fine particle size grade (90% pass through 60 mesh screen) and superfine grade (90% pass 100 mesh screen). Polyethylene oxide of smaller particle size can improve the compaction properties of the formulation to a greater extent because it has greater specific surface area. On the other hand, superfine grade polyethylene oxide has been found to be very dusty and difficult to handle during the blending process because of its superfine particle size. Therefore, fine particle size grade was selected for investigation.
The composition of extended release formulations of the invention comprising fine particle size grade polyethylene oxide coagulated (PoIyOx WSR) is summarized in Table 39.
TABLE 39: 300 MG EXTENDED RELEASE HPMC FORMULATIONS FURTHER COMPRISING POLYETHYLENE OXIDE (POLYOX WSR, COAGULATED, FINE
PARTICLE)
Figure imgf000066_0001
The above formulations were prepared as follows:
The appropriate amounts of vernakalant hydrochloride, Methocel K100M CR and A-Tab were mixed in a mortar and pestle. The appropriate amount of magnesium stearate was added to the mixture and the resulting mixture was blended briefly. The resulting powder blend was passed through a 30 mesh screen. The resulting blend was manually compressed using a 11 mm, round, shallow concave tabletting tool to a tablet hardness of 20 Kp. Good compaction properties were observed for all four formulations.
Dissolution data for the formulations listed in Table 39 is presented in Table 40. TABLE 40: DISSOLUTION PROFILE DATA OF 300 MG EXTENDED RELEASE HPMC FORMULATIONS COMPRISING POLYETHYLENE OXIDE
(POLYOX WSR)
Figure imgf000067_0001
* Percentage calculated by crushing sample until all the active ingredient was extracted.
As shown above in Table 40, the dissolution rate of the formulations remained the same with the addition of polyethylene oxide during the initial phase of the dissolution (first 4 hours). f). Comparison of Different Molecular Weight of Hvdroxypropyl Methyl Cellulose (Methocel)
The effect of the molecular weight of Methocel K15M versus Methocel K100M on the release rate of the active ingredient, vernakalant hydrochloride, from formulations of the invention further comprising dicalcium phosphate anhydrous (A-Tab) was investigated. The compositions of these formulations are shown in Table 41.
TABLE 41 : 300 MG EXTENDED RELEASE HPMC FORMULATIONS FURTHER
COMPRISING DICALCIUM PHOSPHATE ANHYDROUS (A-TAB) (COMPARING
METHOCEL K15M TO METHOCEL K100M)
Figure imgf000068_0001
The dissolution results of these formulations are presented in Table 42.
TABLE 42: DISSOLUTION PROFILE DATA OF 300 MG EXTENDED RELEASE HEMP FORMULATIONS COMPARING METHOCEL K15M TO
METHOCEL K100M
Figure imgf000068_0002
* Percentage calculated by crushing sample until all the active ingredient was extracted.
As shown above in Table 42, both Methocel formulations had approximately the same active ingredient release characteristics. B. Polyethylene Oxide Based Hydrophilic Extended Release Formulations of the Invention
Polyethylene oxide (PEO) was found to be an excellent hydrophilic active ingredient release retardant for the preparation of extended release formulations of the active ingredient, vernakalant hydrochloride. Initial burst in the release of the active ingredient was less in polyethylene oxide matrix tablets, in comparison with the hydroxypropyl methyl cellulose matrix tablets. Polyethylene oxide matrix tablets also demonstrated better compaction properties than the hydroxypropyl methyl cellulose matrix tablets. 1. Comparison of Different Grades of Polyethylene Oxide (PoIvOx)
Polyethylene oxide (PEO) is a homopolymer of ethylene oxide. It is miscible with water at any ratio. Different grades of polyethylene oxide NF (Dow Chemical) are listed in Table 43. Polyethylene oxide grade WSR N-301 , polyethylene oxide grade WSR coagulated and polyethylene oxide grade WSR 303 were selected for the initial evaluation. The objectives were to evaluate the effect of polyethylene oxide molecular weight on the release rate of the active ingredient.
TABLE 43: MOLECULAR WEIGHT OF DIFFERENT GRADES OF POLYETHYLENE OXIDE (POLYOX)
Figure imgf000069_0001
Figure imgf000070_0001
WSR N-301 , WSR coagulated and WSR 303 are available in three different grades: regular, FP (fine particles, >90% pass through 60 mesh) and SFP (superfine particles, >90% pass through 100 mesh). The compaction properties of polyethylene oxide improved with a decrease in particle size. Therefore, polyethylene oxide of SFP grade was used for the initial formulation evaluation.
The compositions of the formulations containing the different grades of polyethylene oxide are presented in Table 44.
TABLE 44: 300 MG EXTENDED RELEASE PEO FORMULATIONS
Figure imgf000070_0002
The above formulations were prepared as follows:
The appropriate amounts of vernakalant hydrochloride and polyethylene oxide were mixed in a mortar and pestle. The appropriate amount of magnesium stearate was added to the mixture and the resulting mixture was blended briefly. The resulting powder blend was passed through a 30 mesh screen. The resulting blend was manually compressed using a 11 mm, round, shallow concave tabletting tool to a tablet hardness of 20 Kp. Excellent compaction properties was observed for all three formulations.
The dissolution results of these formulations are presented in Table 45.
TABLE 45: DISSOLUTION PROFILE DATA OF 300 MG EXTENDED RELEASE PEO FORMULATIONS
Figure imgf000071_0001
As can be seen above in Table 45, the release rate of the active ingredient, vernakalant hydrochloride, was similar when polyethylene oxide WSR 301 , polyethylene oxide WSR 303 or polyethylene oxide WSR coagulated grades were used in that the release rate of the active ingredient was essentially constant over the initial 8 hours.
2. The Addition of Carbomer and Alkaline Agents The addition of a carbomer (Carbopol 974P) and an alkaline agent to the PEO extended release formulations was investigated. The compositions of these formulations are listed in Tables 46-49:
TABLE 46: COMPOSITION OF 300 MG EXTENDED RELEASE PEO FORMULATION FURTHER COMPRISING CARBOMER AND ALKALINE
AGENT (PEO #4)
Figure imgf000071_0002
Figure imgf000072_0001
TABLE 47: COMPOSITION OF 300 MG EXTENDED RELEASE PEO FORMULATION FURTHER COMPRISING CARBOMER AND ALKALINE
AGENT (PEO #5)
Figure imgf000072_0002
TABLE 48: COMPOSITION OF 300 MG EXTENDED RELEASE PEO FORMULATION FURTHER COMPRISING CARBOMER AND ALKALINE
AGENT (PEO #5)
Figure imgf000072_0003
TABLE 49: COMPOSITION OF 300 MG EXTENDED RELEASE PEO FORMULATION FURTHER COMPRISING CARBOMER AND ALKALINE
AGENT (PEO #4)
Figure imgf000073_0001
The dissolution properties of these formulations are shown in Table 50.
TABLE 50: DISSOLUTION PROFILE DATA OF 300 MG EXTENDED RELEASE PEO FORMULATIONS FURTHER COMPRISING CARBOMER
AND ALKALINE AGENT
Figure imgf000073_0002
As shown above in Table 50, the addition of alkaline agents to the PEO formulations was not effective in decreasing the release rate of the active ingredient. C. Enteric Active Ingredient Delivery (Eudragit Coated Tablets)
Regional absorption data indicates that the active ingredient, vernakalant hydrochloride, is well absorbed along the length of the gastrointestinal tract. It is also freely soluble at all physiological pH's. Vernakalant hydrochloride released in the upper gastrointestinal tract is rapidly and extensively absorbed. Coating with a enteric coating would delay the start of the absorption process. If the total dose is coated, then there is the potential for reduction in total amount of drug absorbed. Dividing the required dosage amount between coated and uncoated tablets allows for absorption in the upper gastrointestinal tract from the uncoated matrix tablet and in the lower gastrointestinal tract from the enteric-coated matrix tablet.
An aqueous dispersion of Eudragit FS 3OD, an anionic pH-dependent (meth)acrylate copolymer, was successfully applied to tablets to prepare the tablets for enteric drug delivery. Composition of the core tablet formulation investigated for a coated extended release formulation is listed in Table 51.
TABLE 51 : COMPOSITION OF CORE 150 MG EXTENDED RELEASE TABLET FORMULATION (HPMC #33)
Figure imgf000074_0001
The above formulation was prepared as follows:
The appropriate amounts of vernakalant hydrochloride and polyethylene oxide were mixed in a mortar and pestle. The appropriate amount of magnesium stearate was added to the mixture and the resulting mixture was blended briefly. The resulting powder blend was passed through a 30 mesh screen. The resulting blend was manually compressed using a 11 mm, round, shallow concave tabletting tool to a tablet hardness of 20 Kp. Good compaction properties were observed for the formulation.
An aqueous dispersion based on Eudragit FS 3OD was applied onto the tablets of the formulation HPMC #33 to impart enteric delivery properties to the formulation. The composition of the aqueous coating dispersion is presented in Table 52.
TABLE 52: COMPOSITION OF EUDRAGIT FS 30 D COATING DISPERSION
Figure imgf000075_0001
The solid content of the final dispersion was 20%. The coating parameters is summarized in Table 53.
TABLE 53: PROCESSING PARAMETERS FOR EUDRAGIT FS 3OD
COATING
Figure imgf000075_0002
Pump Speed (rpm) Started with 6 and gradually increased to 8
Tablets samples were collected at 4.0%, 6.6% and 8.4% coating levels. The dissolution results of coated tablets (6.6% coating and 8.4% coating) and uncoated tablets are presented in Tables 54 and 55.
TABLE 54: DISSOLUTION PROFILE DATA OF 150 MG EXTENDED RELEASE EUDRAGIT FS 30 D COATED FORMULATIONS
Figure imgf000076_0001
* Percentage calculated by crushing sample until all the active ingredient was extracted. It was determined that enteric delivery of the active ingredient could be achieved with the aqueous coating of Eudragit FS 3OD dispersion at 6.6% coating level. Less than 1 % of active ingredient was released following 2 hours in 0.1 N HCI solution and 4 hours in phosphate buffer solution at pH 6.4.
Tablets containing Eudragit FS 3OD at 8.4% level remained intact through the acid stage and buffer stage at pH 6.4. In certain embodiments, a coating level in the range of 5-10% or 6-9%, or about 8% may be used. The composition of the Eudragit FS 30 D coating dispersions presented above in Table 52 was modified for the preparation of lead prototype formulations for stability studies. The composition of the modified coating dispersion is presented below in Table 55. TABLE 55: COMPOSITION OF OPTIMIZED EUDRAGIT FS 30 D COATING
DISPERSION
Figure imgf000077_0001
Solid content of the final dispersion is 20%.
D. Additional Coated Extended Release Formulations of the Invention
In addition to the foregoing extended release formulations, the following coated extended release formulations were prepared, as set forth in Tables 56- 64. Extended release formlations can also be prepared according to Tables 65- 67. Polyvinyl alcohol (PVA) base Opadry Il (Colorcon) or Opadry was applied to the core tablet formulation (which was prepared by similar methods disclosed herein) for taste masking. Eudragit FS 30 D was applied to deliver the active ingredient to the colon region. Capsules were also prepared containing one 150 mg tablet coated with Opadry Il and one 150 mg tablet coated with Eudragit FS 30 D. All of the formulations contained Methocel K100M CR and A-Tab at 10%, 20% or 30% (w/w).
TABLE 56: COMPOSITION OF COATED EXTENDED RELEASE
FORMULATION #1
Figure imgf000077_0002
Figure imgf000078_0001
TABLE 57: COMPOSITION OF COATED EXTENDED RELEASE
FORMULATION #2
Figure imgf000078_0002
TABLE 58: COMPOSITION OF COATED EXTENDED RELEASE
FORMULATION #3
Figure imgf000078_0003
Figure imgf000079_0001
TABLE 59: COMPOSITION OF COATED EXTENDED RELEASE
FORMULATION #4
Figure imgf000079_0002
TABLE 60: COMPOSITION OF COATED EXTENDED RELEASE
FORMULATION #5
Figure imgf000079_0003
Figure imgf000080_0001
TABLE 61 : COMPOSITION OF COATED EXTENDED RELEASE
FORMULATION #6
Wt.% of Wt.% of Final mg per Final
Component Core Coated Tablet Coated Tablet
Vernakalant Hydrochloride 44.20 39.34 165.75
Methocel KI OOM CR 34.80 30.97 130.50
A-Tab (dicalcium phosphate, anhydrous) 20.00 17.80 75.00
Magnesium Stearate 1.00 0.89 3.75
Opadry Il coating 1.78 7.50
Eudragit FS30 D coating 7.26 30.60
Opadry Clear coating 1.96 8.26
Total 100.00 100.00 421.36
TABLE 62: COMPOSITION OF COATED EXTENDED RELEASE
FORMULATION #7
Figure imgf000080_0002
Figure imgf000081_0001
TABLE 63: COMPOSITION OF COATED EXTENDED RELEASE
FORMULATION #8
Figure imgf000081_0002
TABLE 64: COMPOSITION OF COATED EXTENDED RELEASE
FORMULATION #9
Wt.% Wt.% of Final mg per Final
Component of Core Coated Tablet Coated Tablet
Vernakalant Hydrochloride 44.20 39.34 165.75
Methocel KI OOM CR 24.80 22.07 93.00
A-Tab (dicalcium phosphate, anhydrous) 30.00 26.70 112.50
Magnesium Stearate 1.00 0.89 3.75
Opadry Il coating 1.78 7.50
Eudragit FS30 D coating 7.26 30.60
Opadry Clear coating 1.96 8.26
Total 100.00 100.00 421.36 TABLE 65: COMPOSITION OF COATED EXTENDED RELEASE
FORMULATION #10
Figure imgf000082_0001
TABLE 66: COMPOSITION OF COATED EXTENDED RELEASE
FORMULATION #11
Figure imgf000082_0002
TABLE 67: COMPOSITION OF COATED EXTENDED RELEASE
FORMULATION #12
Figure imgf000083_0001
The composition of the Opadry® Il coating dispersion is presented in
Table 65. Opadry Il used was PVA-based because it offered a better moisture protection. The composition of two different Eudragit FS 30 D coating dispersions used are presented above in Table 52 and 54.
Prior to Eudragit FS 30 D coating, Opadry Il was applied as a sub-coat. An Opadry clear coating (Table 69) was then applied as an over-coat after
Eudragit FS coating. Opadry over coat was applied to prevent sticking between Eudragit coated tablets during the curing. Opadry clear was selected for the top coat instead of Opadry Il because Opadry clear could be applied at a lower product temperature.
TABLE 68: COMPOSITION OF OPADRY Il COATING DISPERSION
Figure imgf000083_0002
Solid content of the coating dispersion is 10%. TABLE 69: COMPOSITION OF OPADRY CLEAR TOP COATING SOLUTION
Figure imgf000084_0001
Solid content of the coating dispersion is 7%.
The 300 mg dose tablets were coated with Opadry Il at a 4% weight gain level. Each batch of 150 mg dose tablets was divided in half. One half was coated with Opadry Il at a 4% weight gain level. The other half were coated with Opadry Il at a 2% weight gain level, then with Eudragit FS 30 D at an 8% weight gain level, and finally with Opadry clear at a 2% weight gain level. The coating parameters are indicated in Table 70:
TABLE 70: COATING PARAMETERS
Figure imgf000084_0002
E. In vitro Dissolution Studies of Extended Release Formulations of the Invention
All the in vitro dissolution release results of the extended release formulations disclosed above (except those coated with Eudragit FS 30 D) were collected using the following dissolution conditions: Apparatus USP apparatus 2
Dissolution medium 0.1 N hydrochloric acid solution
Medium volume 900 ml_
Medium temperature 370C
Paddle speed 150 rpm Sampling timepoints 0, 1 , 2, 4, 8, 12, 16 and 24 hours
Sampling volume 5 ml_
Sample analysis UV-Vis at 278 nm
All the above disclosed in vitro dissolution release results of the extended release formulations coated with Eudragit FS 30 D for enteric delivery were collected using the following dissolution conditions: Apparatus USP apparatus 2
Dissolution medium 0-2 hr: 0.1 N HCI solution
2-6 hr: USP phosphate buffer (PBS) at pH 6.8 6-30 hr: USP phosphate buffer at pH 7.5 Total medium replacement at each stage
Medium volume 900 ml_
Medium temperature 370C
Paddle speed 150 rpm
Sampling timepoints* End of acid stage, end of PBS at 6.4 stage Buffer stage: 1 , 2, 4, 8, 12 and 24 hours
Sampling volume 5 ml_
Sample analysis UV-Vis at 278 nm
Example 7 Formulation Storage Stability and Dissolution Testing Storage stability and dissolution testing was performed on three different 300mg Vernakalant tablet formulations manufactured according to Formulation #1 , Formulation #4, and Formulation #7 (see Tables 56, 59, and 62, respectively). Testing was also performed on three different 300mg 2-in-1 Vernakalant capsule formulations, each capsule comprising a combination of two 150mg Vernakalant tablet Formulations. These three different 2-in-1 capsule formulations were manufactured according to (i) Formulations #2/#3, (ii) Formulations #5/#6, and (iii) Formulations #8/#9.
To test the storage stability of these formulations, the tablets and capsules were stored for up to 6 months at either 30°C/65% relative humidity (RH) or 40°C/75% RH. Samples taken at 0 (initial), 1 , 3, and 6 months were tested in in vitro dissolution assays and were also analyzed by chromatography for Vernakalant content, water content, and the presence or absence of Vernakalant degradation products. Vernakalant tablets or capsules from the initial, 1 , 3, and 6 month timepoints were were tested in an in vitro dissolution assay. The dissolution assay was performed using the following ingredients: Dissolution Medium Stage 1 : 0.1 N HCI Dissolution Medium Stage 2: 0.2 M Tribasic Sodium Phosphate Buffer To perform the dissolution, tablets or capsules from each time point were placed in dissolution vessels containing 750ml Dissolution Medium Stage 1 at 370C using USP apparatus 2. Samples were collected at the 2 hour and 6 hour time points. After sampling of the 6 hour timepoint, 250ml of Dissolution Medium Stage 2 was added to each vessel and the pH was adjusted to 7.2±0.05 with 2N sodium hydroxide or 2N hydrochloric acid. Samples were then collected at the 12 hour and 24 hour timepoints. After collecting the 24 hour timepoint, the paddles were stopped and any remaining dosage form was crushed using long arm tweezers or a glass stirring rod. After dispersal of the dosage form, the paddle speed was increased to 250 rpm for 30 minutes. The "infinity" sample was collected at this time point.
The samples from the 2 hour, 6 hour, 12 hour, 24 hour and infinity time points were analyzed by chromatography as compared to a Vernakalant hydrochloride stock standard (-0.3 mg/ml). The standard was prepared by dissolving -30 mg vernakalant hydrochloride in 100ml 0.1 N HCI and mixing well.
The chromatography data was used to calculate the percent vernakalant (active ingredient) released for each time point. The results are set forth below in Tables 71 through 82.
TABLE 71 : DISSOLUTION OF EXTENDED RELEASE TABLET FORMULATION #1 AFTER STORAGE AT 3O0C AND 65% RELATIVE
HUMIDITY (RH)
Figure imgf000087_0001
TABLE 72: DISSOLUTION OF EXTENDED RELEASE TABLET FORMULATION #1 AFTER STORAGE AT 4O0C AND 75% RELATIVE
HUMIDITY (RH)
Figure imgf000087_0002
TABLE 73: DISSOLUTION OF EXTENDED RELEASE TABLET FORMULATION #4 AFTER STORAGE AT 3O0C AND 65% RELATIVE
HUMIDITY (RH)
Figure imgf000088_0001
TABLE 74: DISSOLUTION OF EXTENDED RELEASE TABLET FORMULATION #4 AFTER STORAGE AT 4O0C AND 75% RELATIVE
HUMIDITY (RH)
Figure imgf000088_0002
TABLE 75: DISSOLUTION OF EXTENDED RELEASE TABLET FORMULATION #7 AFTER STORAGE AT 3O0C AND 65% RELATIVE
HUMIDITY (RH)
Figure imgf000088_0003
TABLE 76: DISSOLUTION OF EXTENDED RELEASE TABLET FORMULATION #7 AFTER STORAGE AT 4O0C AND 75% RELATIVE
HUMIDITY (RH)
Figure imgf000089_0001
TABLE 77: DISSOLUTION OF EXTENDED RELEASE 2-IN-1 CAPSULE
HAVING COMBINED TABLET FORMULATIONS #2 & #3 AFTER STORAGE
AT 3O0C AND 65% RELATIVE HUMIDITY (RH)
Figure imgf000089_0002
TABLE 78: DISSOLUTION OF EXTENDED RELEASE 2-IN-1 CAPSULE
HAVING COMBINED TABLET FORMULATIONS #2 & #3 AFTER STORAGE AT 4O0C AND 75% RELATIVE HUMIDITY (RH)
Figure imgf000089_0003
Figure imgf000090_0001
TABLE 79: DISSOLUTION OF EXTENDED RELEASE 2-IN-1 CAPSULE
HAVING COMBINED TABLET FORMULATIONS #5 & #6 AFTER STORAGE
AT 3O0C AND 65% RELATIVE HUMIDITY (RH)
Figure imgf000090_0002
TABLE 80: DISSOLUTION OF EXTENDED RELEASE 2-IN-1 CAPSULE
HAVING COMBINED TABLET FORMULATIONS #5 & #6 AFTER STORAGE
AT 4O0C AND 75% RELATIVE HUMIDITY (RH)
Figure imgf000090_0003
TABLE 81 : DISSOLUTION OF EXTENDED RELEASE 2-IN-1 CAPSULE
HAVING COMBINED TABLET FORMULATIONS #8 & #9 AFTER STORAGE AT 3O0C AND 65% RELATIVE HUMIDITY (RH)
Figure imgf000090_0004
Figure imgf000091_0001
TABLE 82: DISSOLUTION OF EXTENDED RELEASE 2-IN-1 CAPSULE
HAVING COMBINED TABLET FORMULATIONS #8 & #9 AFTER STORAGE
AT 4O0C AND 75% RELATIVE HUMIDITY (RH)
Figure imgf000091_0002
EXAMPLE 8
Prevention of Recurrence of Atrial Fibhllation/Atrial Flutter The following study was conducted to evaluate, inter alia, the efficacy of a controlled release formulation comprising vernakalant hydrochloride in human subjects with sustained atrial fibrillation (atrial fibrillation of longer than 72 hours and less than 6 months duration.
Subjects received the first treatment on Day 1 and were monitored for the first 3 days of dosing. Subjects who were still in atrial fibrillation on the third day of dosing were electrically converted to sinus rhythm. Subjects who converted to sinus rhythm without intervention (other than study medication) or who were successfully electrocardioverted continued with study medication for a total of 28 days of study treatment administration.
A total of 221 subjects were enrolled in the study, 75 subjects received placebo, 71 subjects received twice daily one capsule containing one controlled release tablet formulation (300 mg b.i.d. of active ingredient), hydrophilic formulation #300-2, 75 subjects received twice daily one capsule containing two controlled release tablet formulations (600 mg b.i.d. of active ingredient), hydrophilic formulation #300-2. The majority of the study subjects were male (61.4%) and Caucasian (100%), with a mean age of 64 ± 10 years (range 32-83 years). A total of 171 subjects were converted to sinus rhythm by Day 3 of the study and continued to received study medication through Day 28. The time to first documented recurrence of symptomatic sustained atrial fibrillation or atrial flutter was longer in subjects receiving the active ingredient than subjects receiving placebo. 43.1 % of placebo subjects were in sinus rhythm on Day 28 compared to 61.6% of subjects treated with 300 mg. b.i.d. of active ingredient and 62.4% of subjects treated with 600 mg b.i.d. of active ingredient.
This study demonstrated the ability of controlled release hydrophilic formulation #300-2 to reduce the short term recurrence of atrial fibrillation in subjects with sustained atrial fibrillation (atrial fibrillation of longer than 72 hours and less than 6 months duration).
EXAMPLE 9
ORAL VERNAKALANT HYDROCHLORIDE PREVENTS RECURRENCE OF ATRIAL FIBRILLATION
OVER 90 DAYS
The safety, tolerability, pharmacokinetics, and preliminary efficacy of vernakalant hydrochloride (oral) over 90 days of dosing in patients with sustained symptomatic atrial fibrillation (AF; AF duration > 72 hours and < 6 months) was demonstrated in a randomized, double-blind, placebo-controlled, dose-ranging study. This study demonstrated statistically significant efficacy for the patient group receiving 500 mg b.i.d. of vernakalant hydrochloride (oral) as compared to placebo. The safety data from the interim analysis also suggested that vernakalant hydrochloride (oral) was well-tolerated in the AF patient population studied during this dosing period.
Vernakalant hydrochloride (oral) tablets were prepared from a blend of vernakalant hydrochloride drug substance with tablet excipients, including silicified microcrystalline cellulose, hydroxypropyl methyl ether cellulose
(Hypromellose or HPMC), pregelatinized starch, lactose monohydrate, stearic acid, and magnesium stearate. Tablets were compressed as weight multiples from a common formula, to afford 150 mg, 200 mg, or 300 mg of vernakalant hydrochloride drug substance per tablet. For the purpose of blinding clinical trial materials, the tablets were encapsulated in opaque white gelatin capsule shells. Capsules containing the 150 mg and 200 mg tablets were backfilled with lactose monohydrate to approximate similar capsule weights across dose strengths. The composition of the vernakalant hydrochloride (oral) tablets is shown in Table 83. The composition of vernakalant hydrochloride (oral) encapsulated tablets is shown in Table 84.
Table 83. Composition of Vernakalant Hydrochloride (Oral) Tablets
Figure imgf000093_0001
tVernakalant hydrochloride is the monohydrochlohde salt. The salt factor is
1 .10.
Table 84. Composition of Vernakalant Hydrochloride (Oral) Encapsulated
Tablets
Figure imgf000093_0002
Figure imgf000094_0001
fA blend of pharmaceutical gelatins may used; when bovine gelatin is used, it is alkaline processed, pharmaceutical grade, and in full compliance with all pharmaceutical regulatory requirements. tUsed in 150 mg and 200 mg dosage strengths only. Subjects with sustained AF were randomized to placebo or vernakalant hydrochloride for up to 90 days. Subjects treated with vernakalant hydrochloride received either 150 mg b.i.d, 300 mg b.i.d., or 500 mg b.i.d. After the first 3 days, patients still in atrial fibrillation were electrically cardioverted. Successfully cardioverted patients continued to receive vernakalant (oral) or placebo for the remainder of the 90-day trial and were monitored throughout the dosing period.
A Kaplan-Meier analysis of the 446 patients included in the study demonstrated a significant efficacy benefit for the 500 mg b.i.d. dosing group as compared to placebo (two-sided, p<0.05). Median time to recurrence of atrial fibrillation was greater than 90 days for the 500 mg b.i.d. dosing group, compared to 39 days for the placebo group. 52% of patients in the 500mg b.i.d. dosing group (n=110) completed the study in normal heart rhythm as compared to 39% of patients receiving placebo (n=118). The interim efficacy analysis for the 150 mg b.i.d. (n=110) and 300 mg b.i.d. (n=108) dosing groups had not achieved statistical significance at the 90 day timepoint.
The safety data for all dosing groups suggests that vernakalant (oral) was well-tolerated within the interim safety population (n=537), which includes patients randomized who did not enter the maintenance phase of the study. During the dosing period under analysis, there was no difference in the incidence of serious adverse events between treatment groups. Potentially drug-related serious adverse events occurred in 1 % of placebo patients, 2% of patients in the 150 mg b.i.d. dosing group, 0% of patients in the 300 mg b.i.d. dosing group and 1 % of patients in the 500 mg b.i.d. dosing group. There were no cases of drug-related "Torsades de Pointes", a well-characterized arrhythmia which is an occasional side effect of some current anti-arrhythmic drugs. There were 2 deaths during this period, both unrelated to vernakalant hydrochloride (oral), comprising a patient in the 150 mg b.i.d. dosing group who died of cervical cancer at day 79, and a patient in the placebo group who died at day 86 after suffering an ischemic stroke.
EXAMPLE 10 Pharmacokinetic and Safety Studies of Controlled Release and Extended Release Formulations
The following study was performed to compare the pharmacokinetics of an original controlled release formulation of vernakalant (oral) to three extended (sustained) release formulations, and to compare the controlled release formulation to a film-coated and enteric-coated extended release formulation, in single dose administrations to healthy male volunteers under fasting conditions, in order to determine which formulation provides the most appropriate extended release characteristics for further development.
The study included two stages, Stage 1 and Stage 2. The extended release formulations tested in Stage 1 differed in their percent polymer content, with a higher polymer content expected to translate to a slower release rate. The polymer in the controlled release formulation was chemically identical to that in the extended release formulations but had a lower molecular weight and therefore different physical properties. It was expected that the higher molecular weight polymer used in the extended release formulations would hydrate and erode more slowly than the polymer in the controlled release formulation. Stage 2 of the study was designed to demonstrate the effect of an enteric coating on the PK profile of vernakalant. Tablets that are enteric-coated will not dissolve below a pH of 7, thereby not releasing their contents until the tablet enters the ascending colon, and thus delaying the release along the gastrointestinal tract. Overall Study Design and Plan
This study was a phase I, open-label, randomized, two-stage, crossover, single-dose, single center, formulation comparison study. Healthy male volunteers who were genotyped as CYP2D6 extensive metabolizers (EMs) were eligible to participate in the study. A total of 29 healthy male volunteers who met all of the inclusion criteria and none of the exclusion criteria were enrolled in this study.
In Stage 1 of the study, subjects received single doses of 300 mg vernakalant (oral) administered as a controlled release formulation (encapsulated tablet) and as three film-coated extended release formulations (designated Formulation 25CR, 35CR and 45CR), in a 4-pehod, 4-sequence cross-over manner. Study medication was supplied as tablets or capsules of 300 mg vernakalant (oral), and was to be administered orally with 100 ml_ water. The formulations tested in Stage 1 included the following 4 dosage forms:
• Controlled release formulation (K4M polymer) (encapsulated tablet) o 300 mg vernakalant hydrochloride o 120 mg hydroxypropyl methyl cellulose (K4M) o 30 mg pregelatinized starch o 90 mg silicified microcrystalline cellulose o 81 mg of lactose monohydrate o 4.5 mg stearic acid o 4.5 mg magnesium stearate
• Formulation 25CR (25% K100M polymer) controlled release (film-coated tablet) (Table 62)
• Formulation 35CR (35% K100M polymer) controlled release (film-coated tablet) Table 59)
• Formulation 45CR (45% K100M polymer) controlled release (film-coated tablet) (Table 56) Based on the pharmacokinetic (PK) and safety data obtained from Stage
1 (as well as ease of manufacture), Formulation 35CR was selected for further evaluation in Stage 2. Subjects in Stage 2 received single 300 mg doses of the original controlled release formulation (encapsulated tablet), Formulation 35CR as a film-coated tablet (same 35CR formulation used in Stage 1 ), and Formulation 35CR as a gelatin capsule (consisting of an enteric-coated tablet and a film-coated tablet), administered in a 3-period, 6-sequence cross-over manner. The enteric coating used is described in Table 52, and the film coating was Opadry II. The formulations tested in Stage 2 included the following 3 dosage forms:
• Original controlled release formulation (K4M polymer) (encapsulated tablet)
• Formulation 35CR, administered as a film-coated tablet (same 35CR formulation used in Stage 1 )
• Formulation 35CR, administered as a gelatin capsule containing an enteric-coated tablet of 165 mg vernakalant HCI (150 mg vernakalant free base) and a film-coated tablet of 165 mg vernakalant HCI (150 mg vernakalant free base) In both Stage 1 and Stage 2, the extended release formulation tablets had 300 mg vernakalant free base, whereas the controlled release formulation had 300 mg vernakalant HCI (approximately 272 mg vernakalant free base). The 35CR capsule administered in Stage 2 included an enteric-coated tablet and a film-coated tablet surrounded by a hard gelatin capsule shell. Subjects arrived at the clinic the evening before dosing and fasted overnight (for at least 10 hours) prior to dosing, and remained in a fasted state until 4 hours postdose. No water was permitted from one hour prior until one hour after dosing, with the exception of 100 ml_ ambient temperature water administered at dosing. At approximately 4, 8, 12, and 24 hours postdose, standardized meals with beverages were provided. Subjects were required to abstain from alcohol, caffeine, grapefruit products, and xanthine-containing foods for 48 hours prior to dosing and throughout their stay at the clinic. In both Stage 1 and Stage 2, safety was assessed by monitoring treatment-emergent adverse events (AEs) and serious adverse events (SAEs) throughout the study and for 7±2 days after the last dose; continuous telemetry monitoring from predose to 8 hours postdose; vital signs and 12-lead electrocardiograms (ECGs) from predose to 24 hours postdose; and clinical chemistry, hematology, and urinalysis predose and at 24 hours postdose. Plasma samples for PK analysis were collected predose (within 2 hours prior to dosing) and at 1 , 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours postdose for each dosing period. Plasma samples for PK analysis were also collected in the case of an SAE. The plasma PK parameters were determined for vernakalant and its metabolites (Cmpd. 4, Cmpd. 2, Cmpd. 3; Figure 5), and included maximum plasma concentration (Cmax), time of maximum plasma concentration (tmax), area under the plasma concentration-time curve (AUC), Cmaχ/AUC ratio, and half-life (Un)- Linear and semi-log plots of time-concentration profiles were produced by subject and by using the geometric mean plasma concentration value at each time point for each formulation. Plasma concentration data was summarized with the number of observations, geometric mean, CV%, arithmetic mean, standard deviation, median, and minimum and maximum values. The PK analysis for Stage 1 was completed prior to proceeding to Stage 2. Results
A total of 29 subjects were enrolled in the study, with 17 subjects in Stage 1 and 12 subjects in Stage 2. All subjects in this study were male (as required by the study inclusion criteria) and over 80% of the subjects were black or African American. All subjects were genotyped as CYP2D6 extensive metabolizers (EMs), with the exception of one, who was an intermediate metabolizer. The study population ranged from 22-49 years of age (mean age of 35 years) and had a mean BMI of 26 kg/m2. The demographics were similar for subjects in Stage 1 and in Stage 2. All randomized subjects received at least one dose of study drug. A total of 25 subjects completed the study (15 in Stage 1 and 10 in Stage 2). Four subjects (two in each study stage) were discontinued from study drug and did not complete the study. One subject (last dosing period and formulation: Period 1 , original) voluntarily withdrew from the study and left the clinical facility against medical advice after being notified that a family member was ill. One subject (last dosing period and formulation: Period 2, 35CR capsule) was withdrawn due to non-compliance with study requirements, as the subject had a positive drug screen at check-in in Period 3. One subject in each study stage was withdrawn from the study due to adverse events (AEs). One subject (last dosing period and formulation: Period 2, 45CR) experienced an AE of dermatitis and one subject (last dosing period and formulation: Period 2, 35CR) had an AE of tachycardia and a serious AE of tachyarrhythmia.
The mean plasma concentration-time plots for vernakalant and Cmpd. 2 for each formulation in Stage 1 and Stage 2 are shown in Figures 1 and 2. Plasma levels of Cmpd. 4 and Cmpd. 3 were below the limit of quantitation (<5.00 ng/mL), and as a result, no pharmacokinetic analyses were performed for these metabolites.
In Stage 1 , the controlled release formulation and extended release formulations showed a similar time course of increase in vernakalant plasma concentration following study drug administration, with the exception of the 45CR formulation, which tended to show a modest delay in the time of maximum plasma concentration (tmax). Plasma concentrations of vernakalant were detectable by one hour for all formulations in both Stage 1 and Stage 2. Maximum plasma concentrations (Cmaχ) of vernakalant were observed between 2 and 6 hours for the controlled release formulation and between 2 and 4 hours for the 25CR, 35CR, and 45CR extended release formulations in Stage 1. In Stage 2, maximum plasma concentrations of vernakalant were seen between 3 and 6 hours for the controlled release formulation, between 2 and 4 hours for the 35CR tablet, and between 3 and 10 hours for the 35CR capsule. The maximum plasma concentration of vernakalant was highest for the controlled release formulation, and similar among the 25CR, 35CR, and 45CR extended release formulations in Stage 1. In Stage 2, the 35CR capsule displayed a significantly lower Cmaχ than the other formulations, but maintained higher plasma levels out to 24 hours.
For the metabolite Cmpd. 2, the mean plasma concentration-time profiles showed a more gradual increase in plasma concentration and much lower plasma drug concentrations following drug administration in both Stage 1 and Stage 2 than the vernakalant mean plasma concentration-time profiles. Plasma concentrations of Cmpd. 2 were approximately 10-15% of those measured for the parent compound vernakalant. Cmpd. 2 plasma concentrations were detectable by one hour for all formulations in Stage 1 and for the 35CR tablet in Stage 2. Cmpd. 2 was detected by 2 hours for the controlled release formulation and for the 35CR capsule in Stage 2. Maximum plasma concentrations of Cmpd. 2 were observed between 2 and 8 hours for the controlled release formulation and between 2 and 4 hours for the 25CR, 35CR, and 45CR formulations in Stage 1. In Stage 2, maximum plasma concentrations of Cmpd. 2 were seen between 2 and 8 hours for the controlled release formulation, between 2 and 6 hours for the 35CR tablet, and between 3 and 10 hours for the 35CR capsule. After reaching the maximum value, plasma levels of Cmpd. 2 gradually declined, becoming undetectable by approximately 16 hours postdose for most formulations. The 45CR formulation in Stage 1 and the 35CR capsule in Stage 2 had detectable levels of Cmpd. 2 up to 24 hours postdose. The maximum plasma concentration of Cmpd. 2 was similar among all formulations in Stage 1. In Stage 2, the 35CR capsule had a Cmax that was approximately half that of the controlled release formulation. A graphical comparison of the PK parameters (least square means) for each formulation in Stage 1 and Stage 2 is provided for vernakalant and Cmpd. 2 (Figures 3 and 4). Addtionally, the PK parameters for vernakalant and Cmpd. 2 for each formulation are summarized in Table 85 (least square means) and Table 86 (geometric means and medians).
TABLE 85. LEAST SQUARE MEANS OF PHARMACOKINETIC PARAMETERS FOR
VERNAKALANT AND COMPD. 2
Least Square Geometric Mean (95% Confidence Interval)
Cmax AUCinf
Formulation N Cmax' t-1/2
(ng/mL) (ng.h/rriL) AUCinf (h)
Vernakalant
Stage 1
Original 15 279.4a 2104.6 0.1334 2.65
(228.5, 341.7) (1598.6, 2770.8) (0.1145, 0.1553) (1.86, 3.77)
25CR 15 217.4 1885.9 0.1157 4.07
(177.4, 266.3) (1432.2, 2483.4) (0.0993, 0.1348) (2.86, 5.79)
35CR 14 203.5b 1841.1 0.1102 4.33
(1394.8, 2430.2) (0.0940, 0.1291 ) (3.00, 6.26) Least Square Geometric Mean (95% Confidence Interval)
AUCinf
Formulation N Cmax Cmax' t-1/2
(ng/mL) (ng.h/mL) AUCinf (h)
(166.1,249.3)
45CR 13 196.2a 1892.7 0.1089 5.01
(160.5,239.9) (1431.1,2503.3) (0.0925,0.1281) (3.43, 7.33)
Stage 2
Original 9 221.5C 1660.0 0.1332 2.68
(166.7,294.3) (1208.5, 2280.3) (0.1086,0.1634) (1.90,3.78)
35CR 11 143.2d 1444.9 0.1005 5.23
(108.4, 189.1) (1085.7, 1922.9) (0.0853,0.1183) (4.00, 6.83)
35CR capsule 8 96.2d 1415.0 0.0646 9.54
(72.9, 127.1) (1033.0, 1938.1) (0.0528,0.0791) (6.79,
13.41)
Cmpd.2
Stage 1
Original 14 30.4a 281.4 0.1094 3.80
(22.4,41.2) (204.0,388.1) (0.0923,0.1296) (2.85, 5.06)
25CR 15 24.7 262.4 0.0950 5.37
(18.2,33.6) (190.6,361.2) (0.0806,0.1120) (4.07, 7.09)
35CR 15 21.2 260.0 0.0824 7.04
(15.6,28.8) (188.9,358.0) (0.0698,0.0971) (5.34, 9.29)
45CR 14 21.0a 263.7 0.0795 8.17
(15.5,28.5) (191.2,363.7) (0.0670, 0.0942) (6.14,
10.89)
Stage 2
Original 8 28.0C 232.1 0.1182 3.19
(20.7, 38.0) (151.5,355.8) (0.0957, 0.1460) (2.33, 4.35)
35CR 10 18.8d 238.0 0.0767 7.92
(14.0,25.3) (158.4,357.6) (0.0632,0.0931) (5.99,
10.47)
35CR capsule 8 13.5d 222.3 0.0622 8.10
(10.1, 18.1) (141.1,350.0) (0.0493, 0.0785) (5.70, 11.51) a N=16 b N=15 c N=10 d N=12
Source: Appendix Table 14.2.3.1 and 14.2.0 S.3
TABLE 86. SUMMARY OF PHARMACOKINETIC PARAMETERS FOR VERNAKALANTAND CMPD.2
Geometric Mean (%CV) Median (Range)
Formulation N 'last AUC last Mast tn
(ng/mL) (ng.h/mL) (h) (h)_ Vernakalant
Stage 1
Original 16 12.5 2085.7 20.0 3.0
(68.8) (46.4) (12.0-24.0) (2.0-6.0)
25CR 15 13.3 1711.3 3.0 t OJA\ A π)
(51.6) (50.6)
(12.0-24.0) (2.0-4.0)
35CR 15 15.1 1645.7 3.0
Z O4Λ . nU
(93.7) (49.3)
(12.0-24.0) (2.0-4.0)
45CR 16 19.0 1591.2 3.5
24 0
(98.4) (45.5)
(12.0-24.0) (2.0-4.0)
Stage 2
Original 10 11.0 1552.5 16.0 3.5
(56.1 ) (65.5) (12.0-24.0) (3.0-6.0)
35CR 12 13.5 1221.9 24.0 3.0
(115.3) (59.8) (10.0-24.0) (2.0-4.0)
35CR capsule 12 20.4 1126.6 24.0 6.0
(55.2) (48.5) (24.0-24.0) (3.0-10.0)
Cmpd. 2
Stage 1
Original 16 7.2 224.3 12.0 3.0
(27.3) (71.1 ) (10.0-24.0) (2.0-8.0)
25CR 15 6.3 193.8 12.0 3.0
(19.4) (82.3) (8.0-24.0) (2.0-4.0)
35CR 15 6.2 171.8 16.0 3.0
(21.2) (74.1 ) (10.0-24.0) (2.0-4.0)
45CR 16 6.9 170.4 16.0 3.0
(39.4) (92.9) (8.0-24.0) (2.0-4.0)
Stage 2
Original 10 7.3 203.0 12.0 5.0
(21.8) (74.6) (10.0-16.0) (2.0-8.0)
35CR 12 6.5 145.0 14.0 3.0
(23.6) (91.1 ) (8.0-24.0) (2.0-6.0)
35CR capsule 12 6.4 120.9 16.0 7.0
(34.1 ) (172.2) (10.0-24.0) (3.0-10.0)
Source: Appendix Table 14.2.2.1 and 14.2.2.3
The extended release formulations showed similar total exposure (AUCmf) values as the controlled release formulation. In Stage 1 , the 3 extended release formulations displayed a trend towards decreasing Cmaχ and Cmaχ/AUC ratio with increasing polymer content (i.e., 25CR, 35CR, 45CR). Additionally, as the polymer content increased, the apparent half-life (Un) was prolonged. The 35CR capsule in Stage 2 had a longer apparent Un (9.54 hours) and later tmax (6 hours) compared to the other formulations. The lowest Cmaχ and Cmaχ/AUC ratio were seen with the 35CR capsule, consistent with a more marked delayed release profile.
In some cases, the mean AUCιast was greater than the mean AUCιnf. This occurred because the mean AUCιnf could not be calculated in all subjects due to the shape of the terminal elimination slope. In addition, subjects who did not have a calculable AUCιnf had a very high AUCιast- This resulted in a higher mean AUCιast than otherwise would have been the case.
The metabolite Cmpd. 2 appeared in plasma with a median tmax ranging from 3 to 5 hours for most formulations. For the 35CR capsule in Stage 2, the median tmax was 7 hours. The Cmax and AUCιnf for Cmpd. 2 were approximately 10-15% of those values measured for the parent compound vernakalant. The AUCmf showed some variability, but was similar across formulations. The Cmaχ, Cmax/AUCmf ratio, and apparent ty2 for Cmpd. 2 followed a similar trend to the values reported for vernakalant in both Stage 1 and Stage 2. The Cmax was similar among all formulations in Stage 1 (but highest for the controlled release formulation), and in Stage 2, the Cmaχ for the 35CR capsule and 35CR tablet were approximately 50% and 70% that of the controlled release formulation. The Cmax/AUCmf ratio was highest for the controlled release formulation and lowest for the 35CR capsule. Pharmacokinetic Conclusions
To summarize, following oral dosing, vernakalant and Cmpd. 2 were detected by 1 and 2 hours, respectively, for all formulations. Maximum plasma concentrations of both vernakalant and Cmpd. 2 were observed between 2 and 6 hours with the controlled release and film-coated extended release formulations; however, the 35CR capsule showed maximum concentrations between 3 and 10 hours postdose. Plasma concentrations of Cmpd. 2 were approximately 10-15% of those measured for vernakalant.
In Stage 1 , all extended release formulations tended to show improved sustained release characteristics as compared to the controlled release formulation by exhibiting lower Cmaχ (but similar AUCιnf) and longer apparent U/2 values as the polymer content increased (i.e., 25CR, 35CR, 45CR), as well as a trend toward lower Cmaχ/AUCιnf ratios. There was considerable variability in the PK parameters between subject profiles; however, based on the PK (and safety) profile from Stage 1 (as well as ease of manufacture), the 35CR formulation was selected for further evaluation in Stage 2. The 35CR capsule (containing the enteric-coated tablet) in Stage 2 had greater sustained release characteristics as compared to the other formulations, by exhibiting the slowest release rate (delayed tmax), with the lowest Cmax and Cmaχ/AUCιnf ratio, and the longest Un-
For Cmpd. 2, the pharmacokinetics generally followed the same trend as for vernakalant. Safety Results
Overall, vernakalant (oral) was well tolerated for all formulations studied. A total of 48 treatment-emergent AEs were reported by 19 subjects (66%) in this study. There was a lower incidence of treatment-emergent AEs for subjects in Stage 1 (8 subjects, 47%) versus Stage 2 (1 1 subjects, 92%). In Stage 1 , the incidence of treatment-emergent AEs was lowest for the 35CR formulation (13%) and similar across all other formulations (20-25%). In Stage 2, the incidence of treatment-emergent AEs was lowest for the 35CR capsule (50%), and slightly higher for the controlled release (60%) and 35CR (67%) formulations. The most common treatment-emergent AE was ventricular extrasystoles, which occurred in 5 subjects (17%). Other common treatment- emergent AEs (each occurring in 2 subjects) were supraventricular extrasystoles, dyspepsia, nausea, increased blood creatine phosphokinase, increased white blood cells (WBC) in urine, and rash. Four subjects (24%) in Stage 1 and 10 subjects (83%) in Stage 2 had treatment-emergent AEs that were considered to be related to study drug. In Stage 1 , the incidence of treatment-related AEs was highest for the 45CR formulation (19%), and lower for the controlled release formulation (12%) and the 25CR and 35CR formulations (7%). In Stage 2, the incidence of treatment- related AEs was lowest for the 35CR capsule (42%), and similar among the controlled release (60%) and 35CR (58%) formulations. The most common treatment-related AE was ventricular extrasystoles, occurring in 5 subjects (17%). All of the ventricular extrasystole events were captured on telemetry monitoring, and were asymptomatic, mild in severity, required no treatment, and resolved spontaneously. Other common treatment-related AEs included supraventricular extrasystoles and increased WBC in urine, each occurring in 2 subjects (7%).
There were no deaths in this study. Two subjects were withdrawn from the study due to AEs. One subject had an AE of tachycardia and an SAE of tachyarrhythmia, both occurring on the same day, after the second administration of study drug (35CR) (both events were detected from the subject's telemetry report). The Investigator assessed the AE of tachycardia to be of moderate severity and the SAE of tachyarrhythmia to be severe; both events were considered to be probably related to study drug. One subject (who had a pre-existing history of eczema) had an AE of dermatitis that began approximately one day after the second administration of study drug (45CR). The Investigator assessed the event of dermatitis to be of moderate severity and possibly related to study drug.
There were no clinically significant changes or trends observed in any vital signs. One subject had abnormal 12-lead ECG findings that were considered to be clinically significant, which were reported as an AE of atrioventricular block first degree. Clinically significant findings in urinalysis
(leukocyte esterase), serum chemistry (creatine kinase), and hematology (WBC count) resulted in AEs for three subjects, respectively. One subject had an abnormal clinically significant physical examination finding, which corresponded with the AE (dermatitis) reported for this subject that led to study drug discontinuation. Conclusions
In Stage 1 , it was expected that the higher molecular weight polymers (as used in the extended release film-coated formulations) would hydrate and erode more slowly than the lower molecular weight polymer used in the controlled release formulation (encapsulated tablet), translating to a slower release rate. The results demonstrated that the extended release formulations tended to show improved sustained release characteristics compared to the controlled release formulation by exhibiting lower maximum plasma concentrations (but similar total exposure) and longer apparent half-lives as the polymer content increased (i.e., 25CR, 35CR, 45CR), as well as a trend toward lower Cmax/AUCmf ratios. The safety analysis revealed that the incidence of treatment-emergent AEs in Stage 1 was lowest for the 35CR formulation (13%), and similar across all other formulations (20-25%).
There were no significant trends in safety parameters or any significant differences between the extended release formulations investigated in Stage 1. Although there was variability between subject profiles with respect to various PK and safety parameters, the PK and safety data from Stage 1 (as well as ease of manufacture) suggested that the 35CR formulation would be most appropriate for further evaluation in Stage 2.
In Stage 2, it was anticipated that an enteric-coating would further delay the release of the tablet's contents. The PK analysis revealed that the 35CR gelatin capsule (containing the enteric-coated tablet) had greater sustained release characteristics compared to the 35CR film-coated tablet and the controlled release formulation encapsulated tablet. The 35CR gelatin capsule exhibited the slowest release rate (delayed tmax), with the lowest Cmaχ and Cmax/AUCmf ratio, and the longest half-life, compared to the other formulations. The safety results showed that the incidence of treatment-emergent AEs in Stage 2 was lowest for the 35CR gelatin capsule (50%), and higher for the controlled release formulation encapsulated tablet (60%) and the 35CR film- coated tablet (67%).
While vernakalant (oral) administered at single doses of 300 mg appeared to be safe and well tolerated in healthy males for all formulations studied, increasing the polymer content led to improved sustained release characteristics. Overall, the 35CR gelatin capsule (containing both an enteric-coated tablet and a film-coated tablet) demonstrated a superior sustained release profile compared to all other formulations.
* * * * * All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification are incorporated herein by reference in their entireties. Although the foregoing invention has been described in some detail to facilitate understanding, it will be apparent that certain changes and modifications may be practiced within the scope of the appended claims. Accordingly, the described embodiments are to be considered as illustrative and not restrictive, and the invention is not to be limited to the details given herein, but may be modified within the scope and equivalents of the appended claims.

Claims

WHAT IS CLAIMED IS
1. An extended release tablet formulation comprising a therapeutically effective amount of an ion channel modulating compound, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
2. The extended release tablet formulation of Claim 1 wherein the ion channel modulating compound has the structure:
Figure imgf000108_0001
including isolated enantiomeric, diastereomeric and geometric isomers thereof and mixtures thereof, or a solvate or pharmaceutically acceptable salt thereof; wherein R4 and R5 are independently selected from hydroxy and Ci-Cβalkoxy.
3. The extended release tablet formulation of Claim 2 wherein the ion channel modulating compound or pharmaceutically acceptable salt thereof is vernakalant hydrochloride.
4. The extended release tablet formulation of Claim 3 wherein at least one of the pharmaceutically acceptable excipients is a hydrophilic matrix system polymer selected from the group consisting of carbomer, hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose.
5. The extended release tablet formulation of Claim 4 wherein the hydrophilic matrix system polymer is hydroxypropyl methyl cellulose.
6. The extended release tablet formulation of Claim 4 wherein at least one of the pharmaceutically acceptable excipients is magnesium stearate.
7. The extended release tablet formulation of Claim 6 comprising: vernakalant hydrochloride; hydroxypropyl methyl cellulose; dicalcium phosphate anhydrous; and magnesium stearate.
8. The extended release tablet formulation of any one of Claims 1-7 wherein the tablet formulation is coated with a enteric coating composition comprising a (meth)acrylate copolymer.
9. The extended release tablet formulation of Claim 8 wherein the enteric coating composition comprises: the (meth)acrylate copolymer;
Imwitor; triethyl citrate; and a polysorbate.
10. The extended release tablet formulation of any one of Claims 1-9 wherein less than 1 % of the ion channel modulating compound, or a pharmaceutically acceptable salt thereof, is released following 2 hours in 0.1 N HCI solution and 4 hours in phosphate buffer solution at pH 6.4.
11. A capsule comprising the extended release tablet formulation of any one of Claims 8-10.
12. The capsule of Claim 11 , further comprising an extended release tablet formulation of any one of claims 1 -7 wherein the tablet formulation is coated with a taste masking coating composition comprising a polyvinyl alcohol (PVA) base.
13. The capsule of Claim 12, wherein the taste masking coating composition comprises: the PVA base; hydroxypropyl methyl cellulose dicalcium phosphate; and magnesium stearate.
14. A method of preventing an arrhythmia in a mammal, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of an extended release formulation of any one of Claims 1 to 10 or a capsule of any one of Claims 11 -13.
15. The method of Claim 14 wherein the arrhythmia is atrial fibrillation.
16. The method of Claim 14 wherein the mammal is a human.
17. The method of Claim 14 wherein the human has previously undergone one or more arrhythmias.
18. The method of Claim 14 wherein the extended release formulation is the extended release formulation of Claim 3.
19. The method of Claim 14 wherein the extended release formulation is a extended release formulation of Claim 8.
20. The method of Claim 14 wherein the tablet is a tablet of Claim 12.
PCT/US2008/072018 2007-08-01 2008-08-01 Extended release formulations containing an ion-channel-modulating compound for the prevention of arrhythmias WO2009018547A1 (en)

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KR20200100376A (en) * 2019-02-18 2020-08-26 충북대학교 산학협력단 Tablet for delayed release of pirfenidone or pharmaceutically acceptable salts thereof comprising polymer and channeling agent

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EP2462933A1 (en) * 2007-05-04 2012-06-13 Cardiome Pharma Corp. Controlled release oral formulations of ion channel modulating compounds and related methods for preventing arrhythmia
EP2468278A1 (en) * 2007-05-04 2012-06-27 Cardiome Pharma Corp. Controlled release oral formulations of ion channel modulating compounds and related methods for preventing arrhythmia
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