Specification
Field of the Invention:
The present invention relates to controlled release formulation for the delivery 01 an
anti-arrhythmic drug. The controlled release formulation comprises of dronedarone
or pharmaceutically acceptable salts, esters, metabolites, prodrugs or enantiolTiers
thereof.
Background of the Invention:
Cardiac arrhythmia is a. term for any large and heterogeneous group of conditions Iti
which there is abnormal electric activity in the heart. An arrhythmia is a disordei' of
the heart rateheart rate (pulse) or heart rhythm, such as beating too fast
(tachycardia), too slow (bradycardia), or irregularly. Arrhythmias can be lifethreatening
medical emergencies which can result in cardiac arrest and sudden
death.
Normally, the four chambers of the heart contract in very specific and coordinated
manner. The electrical impulse that signals the heart to contract in a synchronizeo
manner begins in the sinoatrial node (SA node) which is heart's natural pacemaker
The signal leaves the SA node and travels through the two upper chambers (atna:
Then the signal passes through the atrioventricular node (AV node). Finally it passes
through the lower chambers (ventricles). This path enables the chambers to contract
in a coordinated fashion. Problems can occur anywhere along this conduclion
system, causing various arrhythmias. The examples include: Bradycardia - a slow
heart rate due to problems with the SA node's pacemaker ability, or an interruptio!i In
energy movement (conduction) through the natural electrical pathways of the hedrt
Supraventricular tachycardia - a fast heart rate that originates in the upper chamhers
(atria). The most common are atrial fibrillation or flutter (a rapid heart rate that is not
regular).and atrioventricular nodal reentry tachycardia (AVNRT). VentricLiiar
tachycardia - a fast heart rate that originates in the lower chambers (ventricles).
The method of cardiac rhythm management depends firstly on whether or not U'le
affected person is stable or unstable. Treatments may include physical maneuvers
medications, electricity conversion, or electro or cryo cautery. When an arrhythmia IS
2
serious, urgent treatment may be required to restore a normal rhythm. This !flay
include: electrical "shock" therapy (defibrillation or cardioversion), implantinq a
temporary pacemaker to interrupt the arrhythmia medications given through a vein
(intravenous). Medications are generally used to prevent and/or manage arrhythmia
There are many classes of antiarrhythmic medications, with different mechanisms of
action which include Sodium Channel Blockers (Class I) e.g. Class IA -QuinieJIlile
(Quinidex), Procainamide (Pronestyl), Disopyramide (Norpace); Class IB- Lidoccliine
(Xylocaine), Tocainide (Tonocard), Mexiletine (Mexitil); Class IC- Encairwje
(Enkaid), Flecainide (Tambocor); Beta-Adrenergic Blockers (Class II)-Propranolol
(Inderal), Acebutolol (Sectral), Esmolol (Brevibloc), Sotalol (Betapace); Drugs "hat
Prolong Repolarization (Class 111)- Dronedarone (Multaq), Amiodarone (Cordaror1e)
Calcium Channel Blockers (Class IV)- Verapamil (Calan, Isoptin), Diltiazem
(Cardizem), Mebefradil (Posicor); Miscellaneous- Adenosine (Adenocard), Digoxin
(Lanoxin).
Dronedarone hydrochloride is N-{2-butyl-3-[4-(3-dibutylaminopropoxy) benz:l\/l)
benzofuran-5-yl} methane sulfonamide, hydrochloride.
The effects of Dronedarone most likely result from its electrophysiological properties
belonging to all four Vaughan-Williams classes. Dronedarone is a multichannel
blocker inhibiting the potassium currents (including IK (Ach), IKur, IKr, IKs) and thus
prolonging cardiac action potential and refractory periods (Class III). It also inhibits
the sodium currents (Class Ib) and the calcium currents (Class IV). It non
competitively antagonizes adrenergic activities (Class II). Dronedarone works by
altering currents passing through potassium, sodium, and calcium channels, theret)y
3
prolonging conduction in the heart. This helps maintain a regular heart rhythm or
sinus rhythm and slows the heart rate.
The available dosage for Dronedarone is 400 mg oral tablet to be administered tWice
a day with meals. Dronedarone hydrochloride (Multaq®; Sanofi-Aventis) was
approved to reduce the risk of cardiovascular hospitalization in patients Wlttl
paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent
episode of AF/AFL and associated cardiovascular risk factors (i.e., age > 70
hypertension, diabetes, prior cerebrovascular accident, left atrial diameter ~ 50 nnrn
or left ventricular ejection fraction [LVEF] < 40%), who are in sinus rhythm or wrlO
will be cardioverted). Dronedarone is also found to be useful in prevention of stnJke
or transient ischemic attack, prevention of permanent atrial fibrillation, prevention of
cardioversion, regulating potassium levels in blood, for prevention of caroii:1C
arrhythmia and increased creatinine level, reducing death rate after infarction w'ld
reducing death rate after infarction. The primary advantage of dronedarone is Its
comparatively lower side- effect profile vis-a-vis amiodarone. Due to hlqt1
presystemic first pass metabolism the absolute oral bioavailability is only 4
(fasting) which increases to approx. 15% when administered with a high fat meal.
US5223510 assigned to Sanofi discloses dronedarone specifically.
US7:323493 assigned to Sanof; Aventis relates to a solid pharmaceutical
composition for oral administration characterized in that it comprises a benzofwan
derivative with antiarrhythmic activity, or one of the pharmaceutically acceptable
salts thereof, as an active principle, and a pharmaceutically acceptable noniol!lc
hydrophilic surfactant optionally in combination with one or more pharmaceutical
excipients.
US 2007/0243257 filed by Sanofi Aventis relates to a solid pharmaceutical
composition comprising a solid dispersion containing at least one active principle
and a pharmaceutically acceptable polymer matrix, characterized in that selid
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pharmaceutically acceptable polymer matrix comprises a blend of (i) polydextrose if'
the form of a continuous polydextrose phase, in order to promote the disintegration
of the composition in an aqueous medium, and (ii) at least one polymer other than
polydextrose, in the form of a continuous phase of this polymer, whereby It'le
polydextrose is in a concentration of at least 20 wt % and the at least one polymer
other than polydextrose is in a concentration of at least 20 wt % in relation to line
total weight of said pharmaceutically acceptable polymer matrix.
US 2008/0139645 filed by Sanofi Aventis relates to a solid pharmaceutical
composition for oral administration characterized in that it comprises a benzofuran
derivative with antiarrhythmic activity, or one of the pharmaceutically acceptable
salts thereof, as an active principle, and a pharmaceutically acceptable noniol1lc
hydrophilic surfactant optionally in combination with one or more pharmaceutlcai
excipients.
Although number of approaches have been disclosed in the prior art for preparinq a
formulation comprising dronedarone none describe a controlled relase formulation of
dronedarone. There exists a need for controlled release formulation of Dronedarone
which controls the release of Dronedarone in such a manner that therapeutically
effective concentration is maintained in the blood for an extended period of tlnle
keeping the drug concentration in the blood substantially constant. Dronedarone has
low solubility in aqueous media andl or at low pH, also at higher pH conditioll it
precipitates out. As a result it has low in-vivo bioavailability. The use of controlle(j
release formulations of Dronedarone would improve the bioavailability and rile
patient compliance with reduction in number of dosages to be taken per day.
Summary of the Invention:
One embodiment discloses a controlled release formulation of dronedarone
comprising: dronedarone, a controlled release polymer and pharmaceuticallv
acceptable excipients.
5
Another embodiment discloses a controlled release formulation comprising:
(i) Dronedarone, controlled release polymer and pharmaceutically acceptable
excipients,
(ii) Controlled release coating.
Another embodiment discloses a controlled release formulation of dronedarone
comprising dronedarone along with pharmaceutically acceptable excipients and
controlled release coating.
Another embodiment discloses a controlled release formulation comprising:
(i) Dronedarone and pharmaceutically acceptable excipients,
(ii) One or more coating optionally comprising dronedarone.
Another embodiment discloses a controlled release formulation of dronedarone
wherein the controlled release polymer used may be bioadhesive.
Brief Description of the Drawings:
Drug release for examples 1, 7 and 12 are reproduced in the attached Fig. 1
Detailed Description of the Invention:
A controlled release formulation of dronedarone or pharmaceutically acceptatJle
salts, esters, metabolites, prodrugs or enantiomers thereof and pharmaceutically
acceptable excipients.
The term "formulation" as used herein refers to the drug with pharmaceutically
acceptable excipients. This includes orally administrable formulations as well as
formulations administrable by other means.
"Controlled release formulation" as used herein are those whose drug release
characteristics of time course and/or location are chosen to accomplish therapeutic
6
or convenience objectives not offered by conventional, immediate release dosa~Je
forms.
"Controlled release formulation" or dosage forms which exhibit a "controlled release'
used herein is defined to mean formulations that release the drug at a controlled rate
and provide plasma concentrations of the drug that remain controlled with tirne
within the therapeutic range of the drug over a 24-hour period. "Controlled release'
is defined to mean release of the drug gradually or in a controlled manner per unit
time. For example, the controlled rate can be a constant rate providing plasma
concentrations of the drug that remain invariant with time within the therapeutic
range of drug over at least a 24-hour period.
The term controlled release formulation may be used interchangeably Wlttl
prolonged release formulation, programmed release formulation, timed release
formulation, modified release formulation, site specific release formulation, sustained
release formulation, extended release formulation, slow release formulatbi
pulsatile release formulation, delayed release formulation. The controlled release
formulations can be orally disintegrating extended release formulation, osmotic
dosage form, bioadhesive formulation, gastroretentive formulation and other such
dosage forms.
As used herein the term dronedarone includes all forms of dronedarone I'
pharmaceutically acceptable salts, esters, solvates, hydrates, metabolites, prodru9s
or isomers thereof. The most preferred form is dronedarone hydrochloride.
The controlled release formulation may be in the form of tablets (single layerec]
tablets, multilayered tablets, mini tablets, bioadhesive tablets, floating formulation
caplets, matrix tablets, tablet within a tablet, mucoadhesive tablets, modified releasl:;
tablets, pulsatile release tablets, gastroretentive tablets and timed release tablets:
pellets, beads, granules, spheroids, particles, compact, powders, capsules
7
microcapsules, tablets in capsules, microspheres, matrix formulations, fj(j
microencapsulation.
The term "pharmaceutically-acceptable excipients" as used herein includes cny
physiologically inert, pharmacologically inactive material known to one skilled in tile
art, which is compatible with the physical and chemical characteristics
Oronedarone.
One embodiment discloses a
dronedarone, controlled release
excipients.
controlled release formulation
polymer and pharmaceutically
comprisiilg
acceptaule
The controlled release formulation of dronedarone may contain one or more tha r
one controlled release polymer.
Other embodiment discloses a controlled release formulation compris
dronedarone having particle size (090) less than 100 microns. Preferably the partkle
size (090) of dronedarone is less than 60 microns and more preferably particle s .?t?
(090) less than 30 micron.
The controlled release polymer may be selected from water soluble polymer, water
insoluble polymer, waxy material or combination thereof.
The water soluble polymer may be selected from alkyl celluloses such as mett,
cellulose; hydroxyalkyl celluloses, for example, hydroxymethyl cellulose
hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxybutyl cellulosl'
hydroxyalkyl alkyl celluloses such as hydroxyethyl methyl cellulose ard
hydroxypropyl methyl cellulose; sodium or calcium carboxymethyl cellulose, meth'!
ethyl cellulose, ethylhydroxy ethylcellulose, carboxyalkyl cellulose esters; carbomers
; glycerol fatty acid esters, sorbitan esters, lecithins, other natural, semi-synthetic, r
synthetic di-, oligo-, and polysaccharides such as galactomannans, tragacanth, agel!
8
guar gum, gum arabic, pectin, acacia, karaya, locust bean gum, xanthan 9 rn
pullulan, collagen, casein, carrageenan, aligns, polycarbophil, ammonia alginate
sodium, calcium, potassium alginates, propylene glycol alginate, scleroglucan nd
polyfructans, maltodextrin; methacrylate copolymers; polyvinyl alcoiol
polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate
combinations of polyvinyl alcohol and polyvinylpyrrolidone; and polyalkylene OXij8S
such as polyethylene oxide and polypropylene oxide and copolymers of ethylene
oxide and propylene oxide, carboxyvinyl polymers, sodium alginate, sodlurn
hyluronate, sodium carmellose, calcium carmellose, sodium carboxymethyl starch
gelatin, starch, crosslinked starch, microcrystalline cellulose, ceratonia, chitin
poly(hydroxyalkyl methacrylate), polyvinyl alcohol having a low acetate residuE]! a
swellable mixture of agar and carboxymethyl cellulose, crosslinked polyvinyl alconoi
and poly N-vinyl-2-pyrrolidone and mixtures and blends thereof.
Water insoluble polymer may be selected from cellulose acylate; cellulose eO!
ether; cellulose diacylate; cellulose triacylate; cellulose acetate; cellulose diacetate
cellulose triacetate; mono-, di- and tricellulose alkan, mono-, di- and tricelluluse
aroyl; ethyl cellulose; cellulose acetate; cellulose acetate butyrate; cellulose ace':ate
phthalate; cellulose acetate trimellitate; glyceryl monooleate; glyceryl monosteardte
glyceryl palmitostearate; polyvinyl acetate phthalate; hydroxypropylmethylcelluluse
phthalate; hydroxypropylmethylcellulose acetate succinate; poly(alkyl methacrylate)
poly (vinyl acetate); poly vinyl alcohols; polyacrylamide derivatives ammonlc
methacrylate copolymers, poly acrylic acid and poly acrylate and methacry:,Cite
copolymers, aminoacryl-methacrylate copolymer, polyvinyl acetaldiethylarnflo
acetate, copolymers of maleic anhydride and styrene, ethylene, propylene Dr
isobutylene, polyacrylamides, polyox( polyethylene oxides), diesters of polygluc:Hl
cellulose butyrate, cellulose propionate, shellac, chitosan, oleyl alcohol, ze n
hydrogenated castor oil and the like.
Waxy material may be selected from carnauba wax; beeswax; chinese wax
spermaceti; lanolin; bayberry wax; white wax; yellow wax; candelilla w x
9
microcrystalline wax; castor wax; esparto wax; Japan wax; jojoba oil; cotton seec Dr
corn oil, hydrogenated cotton seed oil, ouricury wax; rice bran wax; ceresin wa>:es
montan wax; ozokerite; peat waxes; paraffin wax; polyethylene waxes; ,1ilej
polyglycerol fatty acid esters.
One embodiment discloses a controlled release formulation of dronedar:iIle
comprising: dronedarone, a controlled release polymer and pharmaceuticdilV
acceptable excipients.
Another embodiment discloses a controlled release formulation of dronedarurle
wherein the controlled release polymer used may be bioadhesive.
The bioadhesive polymers may be selected from proteins (e.g., hydrophilic protei S i
such as carbomers, pectin, zein, modified zein, casein, gelatin, gluten, ser,un
albumin and collagen; chitosan; oligosaccharides; polysaccharides such ciS
cellulose, dextrans, tamarind seed polysaccharide, gellan, carrageenan, xanthdJ!
gum, gum arabic, hyaluronic acid, polyhyaluronic acid, alginic acid and sodiun,
alginate; glyceryl monooleate; polyamides;, polycarbonates; polyalkylenics
polyalkylene glycols; polyalkylene oxides; polyalkylene terephthalates; polyvi
alcohols; polyvinyl ethers; polyvinyl esters; polyvinyl halides; polyvinylpyrrolido!le
polyglycolides; polysiloxanes; polyurethanes; polystyrene; polymers of acrylic B'ld
methacrylic esters; polylactides; poly(butyric acid); poly(valeric acid); poly(lactide-cll
glycolide); polyanhydrides; polyorthoesters; poly(fumaric acid); poly(maleic aCIO)
poly(methyl vinyl ether/maleic anhydride); polycarbophil and blends or copolymers 01
mixtures thereof.
The controlled release formulation may further contain one or more pharmaceuticcl Iy
acceptable excipients such as binders; diluents; lubricants; disintegrating agenl::,
glidants; stabilizers; osmotic agents; dissolution enhancing agents; and surface
active agents.
10
Examples of binders include, potato starch; pregelatinized starch; modified steilch
gelatin; wheat starch; corn starch; celluloses such as methyl cellul'lse
hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, etllV
cellulose and sodium carboxy methyl cellulose; hydroxypropyl Sta
polymethacrylates; carbomers; natural gums such as acacia, alginic acid and !lua!
gum; lactose (anhydrous, monohydrate, spraydried); liquid glucose; dextrin; SOCIWTl
alginate; kaolin; povidone; syrup; polyethylene oxide; polyvinyl pyrrolidone; .J()ly
vinyl alcohol; poly-N-vinyl amide; polyethylene glycol; sucrose; polydextrose; gelatin
poly propylene glycol; tragacanth; ceratonia; glyceryl behenate; hydrogenc:.Itea
vegetable oil; zein; castor oil; paraffin; higher aliphatic alcohols; higher alipb.Cltlc
acids; long chain fatty acids; fatty acid esters; agar; chitosan; maltodeXlrlf!
magnesium aluminum silicate; inulin and wax-like materials such as fatty alcohols
fatty acid esters, fatty acid glycerides, hydrogenated fats, hydrocarbons, stearic ard
copovidone; dextrates, sunflower oil and stearyl alcohol.
Examples of diluents include microcrystalline cellulose; lactose, cellulose powdelea
cellulose silicified, cellulose acetate, methyl cellulose, microcrystalline lactcse
dibasic or tribasic calcium phosphate; saccharides; confectioner's supar
compressible sugar; confectioner's sugar; sugar spheres; dextrates; dexl ,n
dextrose; fructose; maltose; sodium chloride; lactitol; maltodextrin; mannitol
sucrose; fructose; glyceryl palmitostearate; semithicone; Magnesium alumir13
hydroxypropyl starch; sodium starch glycolate; sodium starch glucolate; sodilllTI
carboxymethylcellulose; carboxymethyl cellulose calcium; sodium carboxymethyl
starch; ion-exchange resins such as polacrillin potassium; microcrystalline cellulose
11
starches and pregelatinized starch; formalin-casein; clays such as bentonitE' 0'
veegum; guar gum; celluloses or cellulose derivatives; sodium alginate; calciunl
alginate; alginic acid; chitosan; magnesium aluminum silicate ; colloidal silicon
dioxide.
The lubricants may be selected from Mg, AI, Ca or Zn stearate; polyethylene glyco'
polyvinyl alcohol; glyceryl behenate; glyceryl monostearate; Glyce
palmitostearate; potassium benzoate; sodium benzoate; mineral oil; sodium steary:
fumarate; palmitic acid, myristic acid; stearic acid; hydrogenated vegetable CII!
hydrogenated castor oil; talc; hydrogenated soybean oil; stearyl alcohol; leucrle
sodium lauryl sulfate; ethylene oxide polymers; poloxamer; octyldodecanol; Sod.H1l
stearyl fumarate and colloidal silica.
The stabilizers may be selected from naturally occuring as well as synthetic
phospholipids, their hydrogenated derivatives and mixtures thereof; organic aC!(Js
like acetic acid, tartaric acid, citric acid, fumaric acid, lactic acid, and mixtures
thereof sphingolipids and glycosphingolipids; physiological bile salts such as sodi !Tcholate, sodium dehydrocholate, sodium deoxycholate, sodium glycocholate (-1
sodium taurocholate; saturated and unsaturated fatty acids or fatty alcohu!s
etho.xylated fatty acids or fatty alcohols and their esters and ethers; alkyla!
polyether alcohols such as tyloxapol; esters and ethers of sugars or sugar alcoh()ls
with fatty acids or fatty alcohols; acetylated or ethoxylated mono- and diglyceridc:s
synthetic biodegradable polymers like block co-polymers of polyoxyethylene cHlO
polyoxypropyleneoxide; ethoxylated sorbitanesters or sorbitanethers; amino acids
polypeptides and proteins such as gelatine and albumin; or combination thereof.
The glidants may be selected from magnesium trisilicate; powdered celluloi'.,e
starch; talc; tribasic calcium phosphate; calcium silicate; magnesium silic81e
magnesium trisilicate; colloidal silicon dioxide; and silicon hydrogels.
12
Dissolution enhancing agents may be selected from, but are not limited to, orgdll
acids, inorganic acids or combination thereof. The organic acids include, but nol
limited to citric acid, fumaric acid, malic acid, maleic acid, tartaric acid, succinic aCI()
oxalic acid, aspartic acid, mandelic acid, glutaric acid, and glutamic acid.
inorganic acids include but not limited to hydrochloric acid, phosphoric acid, nitriC
acid, and sulfuric acid.
The surface active agents used may be hydrophilic, hydrophobic or combinall
esparto wax; Japan wax; jojoba oil; cotton seed oil, corn oil, hydrogenated cotten
seed oil, ouricury wax; rice bran wax; ceresin waxes; montan wax; ozokerite; pedt
waxes; paraffin wax; polyethylene waxes; and polyglycerol fatty acid esters an(]
pharmaceutically acceptable excipients.
6. A controlled release formulation of dronedarone comprising
(1) Dronedarone and pharmaceutically acceptable excipients and
(2) Controlled release coating.
33
7. The controlled release formulation of claim 6 wherein the controlled rele:lse
coating comprises of controlled release polymer.
8. The controlled release formulation of Claim 6 wherein the controlled relea~,e
polymers includes hydrophilic polymers, hydrophobic polymers or waxes.
9. The controlled release formulation of Claim 6 wherein the controlled release
coating may be functional coating, moisture barrier coating, enteric polym,:,nc
coating, sustained release coating and the like.
10. A controlled release formulation of dronedarone comprising
(1) Dronedarone and pharmaceutically acceptable excipients and
(2) One or more coating optionally comprising dronedarone.
11. The controlled release formulation of claim 10 wherein one or more coatinu is
selected from controlled release or enteric or immediate release.
12. The controlled release formulation of claim 10 wherein the coating comprses
of water soluble polymer, water insoluble polymer, waxy material or combinat:o!
thereof as exemplified in example 13 or 14.