FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
CONTROLLED RELEASE FORMULATION OF AMIODARONE
SALT"
We, BA RESEARCH INDIA LIMITED, of BA Research House, Opposite "Pushparaj Towers", Nr. Judges Bungalows, Bodakdev, Ahmedabad-380 054, Gujarat, India
The following specification particularly describes the nature of the invention and the manner in which it is to be performed.

FIELD OF INVENTION
Novel pharmaceutical dosage forms which provides for therapeutic amount of a pharmaceutical^ acceptable salt of Amiodarone that releases the drug in spaced apart "pulses." The dosage forms are comprised of first and second dosage units, with each dosage unit having a different drug release profile. The dosage forms may comprise capsules housing compressed tablets or drug-containing beads, granules, or particles or may comprise a single tablet with the first and second dosage units incorporated therein.
BACKGROUND OF THE INVENTION
Antiarrhythmic agents are employed to treat patients suffering from, inter alia, cardiac
contractions that are too rapid, too slow or asynchronous. Generally, antiarrhythmic agents
are classified according to the Vaughan Williams' classification. For example, beta
adrenoreceptor-blocking agents are classified as "Class II" antiarrhythmic agents and
potassium channel blocking agents are classified as "Class III" antiarrhythmic agents.
Amiodarone [(2-butyl-3-benzofuranyl){4-[2-(diethylamino)ethoxy]-3,5-
diiodophenyl}methanone] salts fall within a class of antiarhythmatic drugs with predominantly class HI oral administration. It is used for the treatment of arrhythmias including wide range of cardiac tachyarrhythmias including both ventricular and supraventricular arrhythmias. Amiodarone HC1 is provided commercially in tablet form as 'Cordaronel'. Very little work have been carried out in developing alternate solid formulations of Amiodarone though it has been in the market from the sixties. We herein describe a novel formulation of Amiodarone which releases the drug in pulses allowing for greater amount time when the drug is available and also release the drug in u controlled manner.
EMBODIMENTS OF THE PRESENT INVENTION:
Thus, it is the primary object of the present invention to provide a pharmaceutical dosage form for Amiodarone salts.
In an embodiment of the present invention is provided a pharmaceutical dosage form that provides an initial rapid release of a therapeutically effective dose of an antiarrhythmic agent followed by so-called "delayed release" pulses such that a second dose of the active agent is released from the dosage form. By incorporating both an immediate release dosage unit and one or more delayed release dosage units of the active agent, the dosage form mimics a multiple dosing profile without repeated dosing.
In an embodiment, each dosage unit may comprise two or more compressed tablets, or may be comprised of a plurality of beads, granules or particles, providing that each dosage
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unit has a different drug release profile. The immediate release dosage unit releases drug substantially immediately following oral administration to provide an initial dose. The delayed release dosage unit releases drug approximately 8 hours to 12 hours following oral administration to provide a second dose.
In a further embodiment is provided suitable dosage form of Amiodarone salts for the treatment of cardiac arrhythmias.
DETAILED DESCRIPTION OF THE INVENTION
The invention provides pharmaceutical dosage forms that provide the pulsatile delivery of Amiodarone salts. By "pulsatile" is meant that a plurality of drug doses are released at spaced apart intervals of time. Generally, upon ingestion of the dosage form, release of the initial dose is substantially immediate, i.e., the first drug release "pulse" occurs within about one hour of ingestion. This initial pulse is followed by a first time interval during which very little or no drug is released from the dosage form, after which a second dose is then released. The duration of the nearly drug release-free time interval will vary depending upon the dosage form design e.g., a twice daily dosing profile, a three times daily dosing profile, etc. For dosage forms providing a twice daily dosage profile, the nearly drug release-free interval has a duration of approximately 8 hours to 12 hours between the first and second dose.
The dosage form may be in the form of a capsule wherein each dosage unit in the capsule may comprise a plurality of drug-containing beads, granules or particles. As is known in the art, drug-containing "beads" refer to beads made with drug and one or more excipients or polymers. Drug-containing beads can be produced by applying drug to an inert support, e.g., inert sugar beads coated with drug or by creating a "core" comprising both drug and one or more excipients. As is also known, drug-containing "granules" and "particles" comprise drug particles that may or may not include one or more additional excipients or polymers. In contrast to drug-containing beads, granules and particles do not contain an inert support. Granules generally comprise drug particles and require further processing. Generally, particles are smaller than granules, and are not further processed. Although beads, granules and particles may be formulated to provide immediate release, beads and granules are generally employed to provide delayed release.
For dosage forms mimicking a twice a day dosing profile, a first group beads, granules or particles releases drug substantially immediately following ingestion of the dosage form, while a second group of beads or granules preferably releases drug approximately 8 hours to less than 14 hours following ingestion of the dosage form.
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In another embodiment, the individual dosage units are compacted in a single tablet, and may represent integral but discrete segments thereof (e.g., layers), or may be present as a simple admixture. For example, drug-containing beads, granules or particles with different drug release profiles (e.g., immediate and delayed release profiles) can be compressed together into a single tablet using conventional tableting means.
In a further alternative embodiment, a dosage form is provided that comprises an inner drug-containing core and at least one drug-containing layer surrounding the inner core. An outer layer of this dosage form contains an initial, immediate release dose of the drug.
As will be appreciated by those skilled in the art and as described in the pertinent texts and literature, a number of methods are available for preparing drug-containing tablets, beads, granules or particles that provide a variety of drug release profiles. Such methods include, but are not limited to, the following:
- coating a drug or drug-containing composition with an appropriate coating material, typically although not necessarily a incorporating a polymeric material;
- increasing drug particle size;
- placing the drug within a matrix; and
- forming complexes of the drug with a suitable complexing agent.
The delayed release dosage units in any of the above embodiments can be prepared, for example, by coating a drug or a drug-containing composition with a selected coating material. The drug-containing composition may be, e.g., a tablet for incorporation into a capsule, a tablet for use as an inner core in a "coated core" dosage form, or a plurality of drug-containing beads, particles or granules, for incorporation into either a tablet or capsule. Preferred coating materials are comprised of bioerodible, gradually hydrolyzable, gradually water-soluble, and/or enzymatically degradable polymers, and may be conventional "enteric" polymers. Enteric polymers, as will be appreciated by those skilled in the art, become soluble in the higher pH environment of the lower gastrointestinal tract or slowly erode as the dosage form passes through the gastrointestinal tract, while enzymatically degradable polymers are degraded by bacterial enzymes present in the lower gastrointestinal tract, particularly in the colon. Suitable coating materials for effecting delayed release include, but are not limited to, cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, methylcellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate and carboxymethylcellulose sodium; acrylic acid polymers and copolymers, preferably formed from acrylic acid, methacrylic acid,
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methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate, and other methacrylic resins that are commercially available under the tradename Eudragit® and the like. Combinations of different coating materials may also be used. Multi-layer coatings using different polymers may also be applied.
The preferred coating weights for particular coating materials may be readily determined by those skilled in the art by evaluating individual release profiles for tablets, beads and granules prepared with different quantities of various coating materials. Generally, however, a coating weight of approximately 5 wt. % to 50 wt. % is used to achieve an approximately 6 hour to less than 14 hour delay in release of the active agent.
The coating composition may include conventional additives, such as plasticizers, pigments, colorants, stabilizing agents, glidants, etc. A plasticizer is normally present to reduce the fragility of the coating, and will generally represent about 10 wt. % to 50 wt. % relative to the dry weight of the polymer. Examples of typical plasticizers are, but not limited to, polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, triethyl acetyl citrate, castor oil and acetylated monoglycerides. A stabilizing agent is preferably used to stabilize particles in the dispersion. Typical stabilizing agents are nonionic emulsifiers such as sorbitan esters, polysorbates and polyvinylpyrrolidone. Glidants are recommended to reduce sticking effects during film formation and drying, and will generally represent approximately 25 wt. % to 100 wt. % of the polymer weight in the coating solution. One effective glidant is talc. Other glidants such as magnesium stearate and glycerol monostearates may also be used. Pigments such as titanium dioxide may also be used. Small quantities of an anti-foaming agent, such as a silicone (e.g., simethicone), may also be added to the coating composition.
The delayed release dosage units may be coated with the delayed release polymer coating using conventional techniques, e.g., using a conventional coating pan, an airless spray technique, fluidized bed coating equipment (with or without a Wurster insert), or the like. For detailed information concerning materials, equipment and processes for preparing tablets and delayed release dosage, reference may be made to Pharmaceutical Dosage Forms: Tablets, eds. Lieberman et al. (New York: Marcel Dckkcr, Inc., 1989), and to Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 6[sup]th Ed. (Media, Pa: Williams & Wilkins, 1995).
The immediate release dosage unit of the dosage form-i.e., a tablet, a plurality of drug-containing beads, granules or particles, or an outer layer of a coated core dosage form-contains a therapeutically effective quantity of the active agent with conventional
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pharmaceutical excipients. The immediate release dosage unit may or may not be coated, and may or may not be admixed with the delayed release dosage unit or units (as in an encapsulated mixture of immediate release drug-containing granules, particles or beads and delayed release drug-containing granules or beads). A preferred method for preparing immediate release tablets (e.g., as incorporated into a capsule) is by compressing a drug-containing blend, e.g., blend of granules, prepared using a direct blend, wet-granulation or dry-granulation process. Immediate release tablets may also be molded rather than compressed, starting with a moist material containing a suitable water-soluble lubricant.
However, preferred tablets herein are manufactured using compression rather than molding. A preferred method for forming immediate release drug-containing blend is to mix drug particles directly with one or more excipients such as diluents (or fillers), binders, disintegrants, lubricants, glidants, colorants or the like. As an alternative to direct blending, a drug-containing blend may be prepared by using a wet-granulation or dry-granulation processes. Beads containing the active agent may also be prepared by any one of a number of conventional techniques, typically starting from a fluid dispersion. For example, a typical method for preparing drug-containing beads involves blending the active agent with conventional pharmaceutical excipients such as microcrystalline cellulose, starch, polyvinylpyrrolidone, methylcellulose, talc, metallic stearates, silicone dioxide, or the like. The admixture is used to coat a bead core such as a sphere having a size of approximately 20 to 60 mesh.
An alternative procedure for preparing drug beads is by blending drug with one or more pharmaceutically acceptable excipients, such as microcrystalline cellulose, lactose, cellulose, polyvinyl pyrrolidone, talc, magnesium stearate, a disintegrant, etc., extruding the blend, sphcronizing the extrudate, drying and optionally coating to form the immediate release beads.
Optional pharmaceutically acceptable excipients present in the drug-containing tablets, beads, granules or particles include, but are not limited to, diluents, binders, lubricants, disintegrants, colorants, stabilizers, surfactants and the like. Diluents, also termed "fillers," are typically necessary to increase the bulk of a solid dosage form so that a practical size is provided for compression of tablets or formation of beads and granules. Suitable diluents include, for example, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch, silicone dioxide, titanium oxide, magnesium aluminum silicate and powder sugar. Binders are used to impart cohesive
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qualities to a solid dosage formulation, and thus ensure that a tablet or bead or granule remains intact after the formation of the dosage forms. Suitable binder materials include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as acacia, tragacanth, sodium alginate, cellulose and synthetic polymers such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, polyacrylic acid/polymethacrylic acid and polyvinylpyrrolidone. Lubricants are used to facilitate tablet manufacture; examples of suitable lubricants include, for example, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, and polyethylene glycol, talc, and mineral oil. Disintegrants are used to facilitate dosage form disintegration or "breakup" after administration, and are generally starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropyl cellulose, pregelatinized starch, clays, cellulose, alginine, gums or cross linked polymers, such as cross-linked PVP. Stabilizers are used to inhibit or retard drug decomposition reactions which include, by way or example, oxidative reactions. Surfactants may be anionic, cationic, amphoteric or nonionic surface active agents. Suitable anionic surfactants include, but not limited to those containing carboxylate, sulfonate and sulfate ions. Examples for anionic surfactants are sodium, potassium, ammonium of long chain alkyl sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzene sulfonate. Cationic surfactants include, but not limited quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride,. Examples for nonionic surfactants are, but not limited to, ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, PEG-150 laurate, PEG-400 monolaurate, polysorbates, If desired, the tablets, beads granules or particles may also contain minor amount of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, preservatives, and the like.
The amount of active agent released in each dose will be a therapeutically effective amount, and will depend upon the dosage form itself (e.g., a dosage form having a twice daily dosing profile).
The amount of Amiodarone in the dosage form may vary between 400 mg to 800 mg. In the present invention twice a day dosage profile is envisaged and accordingly, the active agent in immediate release form represent about 40 wt. % to 60 wt. %, of the total active agent in one dosage form, while, correspondingly, the active agent in the delayed release
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form generally represents about 60 wt. % to 40 wt. %, of the total active agent in one dosage form.
It is to be understood that while the invention has been described in conjunction with the preferred specific embodiments thereof, that the description above as well as the examples that follow are intended to illustrate and not limit the scope of the invention. Other aspects, advantages and modifications within the scope of the invention will be apparent to those skilled in the art to which the invention pertains. EXAMPLES 1: Preparation of Immediate Release Granulation

Ingredient Quantity w/w(%)
Amiodarone HC1 53.3
Sodium carboxymethylcellulose 1.0
Microcrystalline cellulose 9.5
Magnesium stearate 0.2
Corn starch 30
Other excipients 6
The blend is prepared by mixing Amiodarone HC1 powder, microcrystalline cellulose starch in a granulating bowl. The powder blend is then granulated with water to form a wet mass. The wet granules are dried in a conventional oven or in a fluid bed dryer. The dried granulation is milled using a conventional pharmaceutical mill or screened through a 20 to 24 mesh. The resulting screened granulation is blended with the other excipients
The granulation blend is compressed into tablets using conventional tableting equipment. ii) Preparation of Delayed Release Tablets

Ingredient Quantity w/w(%)
Hydroxymethyl cellulose 45
Hydroxypropylmethyl cellulose 15
Talc 20
Polyethylene glycol 8
Polysorbate-80 5
Water qs
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A stainless steel vessel is charged with water and talc and mixed till a suspension is formed. A second vessel is charged with hydroxymethyl cellulose and polyethylene glycol. The mixture is slowly agitated and to it was added hydroxypropylmethyl cellulose and Polysorbate-80 until a uniform solution is obtained.. The talc suspension is added to the second vessel and stirred to form the polymeric coating formulation. A conventional coating pan or a fluidized bed coater is then charged with 5 kg of tablets as prepared in step 1 above and coated with the coating formulation described above until the desired dissolution profile is obtained. Example 2 Preparation of Immediate Release Granulation

Ingredient Quantity w/w(%)
Amiodarone HC1 55
Hydroxyethyl cellulose 0.8
Microcrystalline cellulose 7.5
Magnesium stearate 0.2
Corn starch 30
Other excipients 7.5
The tablets were prepared as per Example 1
ii) Preparation of Delayed Release Tablets

Ingredient Quantity w/w(%)
Hydroxymethyl cellulose 40
Hydroxypropylmethyl cellulose 20
Talc 20
Dimethyl phthalate 7
Polysorbate-80 6
Water qs
The delayed release tablet was prepared according to the Example 1 described above.
Pharmacokinetic study:
In vivo dissolution differences between said between the aforesaid two preparations
were demonstrated in a single dose, crossover, randomized comparative pharmacokinetic
study performed in 34 healthy volunteers.
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It was found that
16 % subjects achieved Tmax earlier in test product compare to reference product;
68 % of subjects have higher Cmax compare to ref product
Thus, it was found that among the test population, 53 % of subjects had earlier
Tmax and higher Cmax in test product compare to reference product thereby
demonstrating that the absorption rate of the present formulation has significantly improved
over the test product.
While the invention has been described by way of examples and in terms of the
preferred embodiments, it is to be understood that the invention is not limited to the disclosed
embodiments. On the contrary, it is intended to cover various modifications as would be
apparent to those skilled in the art. Therefore, the scope of the appended claims should be
accorded the broadest interpretation so as to encompass all such modifications.
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We claim
1. A pulsatile release dosage form for treatment of conditions responsive to the
administration of Amiodarone HC1, comprising:
(a) an immediate release dosage unit comprising a first dose of the active agent that is released-substantially immediately following oral administration of the dosage form to a patient;
(b) a delayed release dosage unit comprising a second dose of the active agent and a means for delaying release of the second dose until approximately 6 hours to less than 14 hours following oral administration of the dosage form.

2. The dosage form of claim 1, wherein the dosage units are comprised of drug-containing beads, granules or particles compressed in a single tablet.
3. The dosage form of claim 1, wherein the immediate release dosage unit comprises an outer layer surrounding an inner core, said inner core comprising the delayed release dosage unit.
4. The dosage form of claim 1-3, wherein the second dose is released approximately 10 hours to 12 hours following oral administration.
5. The dosage form of any preceding claims, wherein each dosage unit contains approximately 40 wt. % to 60 wt. % of the total active agent in the dosage form.
6. The dosage form of claim 1, wherein the means for delaying release comprises a matrix of a delayed release polymeric material
7. The dosage form of claim 46, wherein the polymeric material is selected from the group consisting of cellulosic polymers, acrylic acid polymers and copolymers or combinations thereof.
8. The dosage form of claim 1, wherein at least one of the immediate release, delayed release and optional second delayed release dosage units further comprises a diluent or a binder or a lubricant.
9. A pharmaceutical formulation of Amiodarone HC1 as is hereinbefore dedcribed.
Dated this the 27th day of July 2007

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ABSTRACT
CONTROLLED RELEASE FORMULATION OF AMIODARONE SALT
Novel pharmaceutical dosage forms which provides for therapeutic amount of a pharmaceutically acceptable salt of Amiodarone that releases the drug in spaced apart "pulses."
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