Field of Invention

The present invention relates to an orally disintegrating pharmaceutical formulation comprising dronedarone or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. The background of the invention

Dronedarone is a noniodinated benzofuran derivative with antiarrhythmic properties. Dronedarone is an amiodarone analog that differs structurally from amiodarone in that the iodine moiety was removed and a methane sulfonyl group was added. These modifications reduce thyroid and other adverse effects and makes dronedarone less lipophilic, with a shorter half-life. The chemical name of dronedarone is N-[2-butyl-3-[4- [3-(dibutylamino)propoxy]benzoyl]-1 -benzofuran-5-yl]methanesulfonamide and has the structure shown in the following formula I.

Formula I : Dronedarone Formula II: Dronedarone hydrochloride

Dronedarone hydrochloride (shown in formula II) is an antiarrhythmic drug indicated to reduce the risk of hospitalization for atrial fibrillation (AF) in patients in sinus rhythm with a history of paroxysmal or persistent AF. It was approved by the FDA on 2009 and marketed under the brandname MULTAQ™. Recommended dose is one tablet of 400 mg twice a day with morning and evening meals. In prior art, dronedarone and pharmaceutically acceptable salts thereof are described in EP 0 471 609 B1 . US 7 323 493 B1 discloses tablet formulations of dronedarone HCI. There are also several patent applications which disclose orally administered dronedarone formulations, but none of them includes orally disintegrating tablets of dronedarone. Over the past decades, orally disintegrating tablets (ODTs) have gained considerable attention as a preferred alternative to conventional tablets due to improved efficacy, bioavailability, rapid onset of action, better patient compliance and acceptance. ODTs are solid dosage forms containing active ingredients which disintegrate rapidly through buccal mucosa. It is desirable in the treatment of a number of diseases including pediatric and geriatric treatments. They are also advantageous for administrations of medicaments to patients who are traveling or have little access to water or patients who have difficulties swallowing other dosage forms.

Because dronedarone is used mostly for elderly patients with atrial fibrillation with high risk, there is a need in the art for orally disintegrating tablet of dronedarone. However, it is not easy to develop orally disintegrating formulations for all active agents because of several different reasons and requirements such as disintegration, stability, compressibility and taste masking. Dosage form must disintegrate in the oral cavity with the existence of saliva in a short period of time. So those compositions should have a porous structure. However, these porous characteristic tend to be very sensitive to humidity and may be lead to stability problems.

To fulfill all these requirements, the orally disintegrating tablet formulation of dronedarone needs to be adapted in particular by a careful excipient selection give a suitable porous structure with suitable disintegrating time and high stability.

Detailed description of the invention

The present invention relates to an orally disintegrating pharmaceutical formulation comprising dronedarone or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

According to one embodiment, dronedarone or a pharmaceutically acceptable salt used in this present invention is dronedarone hydrochloride. According to this embodiment, dronedarone hydrochloride (HCI) is present in an amount of between 5 to 90 %, preferably between 20 to 75 % and more preferably it is 40 to 75 % by weight of total formulation. According to this embodiment, dronedarone hydrochloride present in an amount of between 50 to 1000 mg, preferably 200 to 800 mg and more preferably it is 400 to 800 mg.

To develop an orally disintegrating tablet, it is very crucial to achieve superior disintegration time in oral cavity of patients. Formulation must disintegrate in the oral cavity with the existence of saliva in a short period of time. In this invention, for the orally disintegrating formulation comprising dronedarone HCI, desired disintegration time is achieved. In one embodiment, the orally disintegrating formulation of dronedarone HCI is disintegrated in less than 1 min.

In one embodiment, the orally disintegrating formulation of this present invention comprises one or more pharmaceutically acceptable excipient selected from the group comprising super disintegrants, taste masking agents, diluents, lubricants, binders, glidants, sweeteners, flavouring agents, acidifying agents and alkalizing agents.

As used herein, the term "super-disintegrant" is defined as the pharmaceutical ingredient that provides improved compressibility, stability as well as achieves disintegration substantially faster than the conventional disintegrants. According to this embodiment, the term "super-disintegrant" is selected from the group comprising crospovidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose (L-HPC), povidone, alginic acid and alginates, cross-linked alginic acid, croscarmellose sodium, sodium carboxymethyl starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, docusate sodium, soy polysaccharide, guar gum, gellan gum, xanthan gum, magnesium alumina silica, polyacrylin potasium, poloxamer, sodium dodecyl sulphate, sodium lauryl sulphate, calcium silicate, sodium glycine carbonate and ion exchange resins. It is difficult to develop orally disintegrating formulations because of several different reasons and requirements such as stability and solubility besides suitable disintegration time. Those formulations should have a porous structure to achieve rapid disintegration. However, these porous characteristic tend to be very sensitive to humidity and may be lead to instability problems. According to this embodiment, using super disintegrant in a specific amount is essential, because it affects density and amount of porous in the structure. Porous structure should both provide rapid disintegration in oral cavity and not to cause stability problems. In this invention it is surprisingly found that to achieve these properties, suitable amount of super disintegrant is 2.5 to 40 % and preferably 2.5 to 25 % by weight of total formulation.

In one embodiment, synergistically the ratio of dronedarone to super disintegrant is also affects the compressibility. In the orally disintegrating pharmaceutical formulation of this present invention, the certain ratio of dronedarone to super disintegrants is in the range of between 1 and 30 (w/w), preferably 1 and 15 (w/w) and more preferably 2 and 10 (w/w).

Suitable taste-masking agents may include but not limited to PVA (polyvinyl alcohol) based coating, polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat IR), butyl methacrylate and methyl methacrylate (Eudragit E 100) (Poly(butyl methacrylate-co-(2- demethylaminoeethyl)methacrylate-co-methyl methacrylate)) , ethylcellulose dispersions (Surelease), Kerry-HPC, polyethylene glycol, polyvinylprolidone, polyvinylprolidone-vinyl acetate copolymer (PVP-VA) and all kinds of OpadryTM, as well as pigments, dyes, titanium dioxide, iron oxide, talc or polymethylmetacrylate copolymers (Eudragit).

Suitable diluents are selected from the group comprising mannitol, xylitol, microcrystalline cellulose (MCC), lactose, corn starch dibasic calcium phosphate, xylitol, spray-dried lactose, sorbitol, sucrose, trehalose, isomalt, LudiFlash® (mannitol, crospovidon and polivinyl acetate), starch, calcium phosphate anhydrate, calcium phosphate dihydrate, calcium phosphate trihydrate, tribasic calcium phosphate, calcium carbonate, calcium sulfate, dicalcium sulfate, sodium chloride, carboxymethyl cellulose calcium, powdered cellulose, cellulose acetate, pregelatinized starch, lactose monohydrate, sodium carbonate, sodium bicarbonate, isomalt, heavy magnesium carbonate, maltodextrine, mixture of sucrose - maltodextrine, dextrose, lactitol, calcium carbonate, sugars, magnesium carbonate, polysaccharides, trehalose, inorganic salts, Pharmabursl® (mannitol, sorbitol,crospovidone and silica; aspartame; and magnesium stearate), Panexcea® (mikrokristalin seluloz, HPMC ve krospovidon), F-Melt® (D- mannitol, xylitol, microcrystalline cellulose, crospovidone, magnesium aluminometasilicate) and mixtures thereof. Suitable lubricants are selected from the group comprising sodium stearyl fumarate, magnesium stearate, sodium lauryl sulphate, zinc stearate, calcium stearate, mineral oil, talc, polyethylene glycol, glyceryl monostearate, glyceryl palmitostearate, magnesium lauryl sulphate, fumaric acid, zinc stearate, stearic acid, hydrogenated natural oils, silica, paraffin and mixtures thereof.

Suitable binders are selected from the group comprising polyvinylpyrrolidone (PVP) (Kollidon) (povidone K30), carnauba wax, hydroxypropyl methyl cellulose (HPMC), pullulan, polymethacrylate, glyceryl behenate, hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), methyl cellulose (MC), hydroxyethyl cellulose, sodium carboxymethyl cellulose (Na CMC), carboxymethyl cellulose calcium, ethyl cellulose and other cellulose derivatives, polymetacrylates, polyethylene oxide, polyvinyl alcohol, polycarbophil, polyvinyl acetate and their copolymers, gelatin, starch, xanthan gum, guar gum, alginate, carrageen, kollagen, agar, pectin, hyaluronic acid, carbomer, chitosan, cellulose acetate phthalate, hydroxypropyl starch, hydroxyethyl methyl cellulose, polaxomer, polyethylene glycol (PEG), sugars, glycose syrups, natural gums, tragacanth gum, polyacrylamide, aluminum hydroxide, benthonite, laponite, setostearyl alcohol, polyoxyethylene-alkyl ethers, acacia mucilage, polydextrose and mixtures thereof.

Suitable glidants are selected from the group comprising colloidal anhydrose silica, colloidal silicon dioxide (Aerosil), talc, aluminum silicate, powdered cellulose, calcium phosphate tribasic, hydrophobic colloidal silica, magnesium oxide, magnesium trisilicate, magnesium silicate and mixtures thereof.

Suitable sweeteners may include but not limited to sucralose, erythritol, thaumatin, mogroside, inuline, acesulfame-K, aspartame, saccharin or its sodium and calcium salts, sodium cyclamate, sucrose, fructose, glucose, sorbitol, menthol, peppermint, cinnamon, chocolate, vanillin and fruit essences such as cherry, orange, strawberry, grape or mixtures thereof. Suitable flavouring agents may include but not limited menthol, peppermint, cinnamon, chocolate, vanillin and fruit essences such as cherry, orange, strawberry, grape etc. and mixtures thereof. Suitable acidifying agents may include but not limited to citric acid, fumaric acid, adipic acid, acetic acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, sulfuric acid, tartaric acid and mixtures thereof.

Suitable alkalizing agents may include but not limited to sodium bicarbonate, sodium glycine carbonate, ammonia solution, ammonium carbonate, diethanolamine, diisopropanolamine, potassium hydroxide, sodium carbonate, sodium borate, sodium hydroxide, trolamine and mixtures thereof.

In this present invention, orally disintegrating formulations comprising dronedarone HCI has been designed made up of the following:

- 5.00 90.00 % by weight of dronedarone HCI,

- 2.50 40.00 % by weight of super disintegrant,

- 0.00 25.00 % by weight of binder,

- 0.50 60.00 % by weight of diluent,

- 0.01 3.00 % by weight of sweetener,

- 0.10 5.00 % by weight of flavouring agent,

- 0.01 5.00 % by weight of glidant,

- 0.10 10.00 % by weight of lubricant,

- optionally, taste masking agent.

Example 1 :

ingredients amount (%)

dronedarone HCI 5.00 - 90.00

mannitol 0.50 - 60.00

crospovidone 2.50 - 40.00

polyvinylpyrrolidone (PVP) 0.10 - 25.00

sucralose 0.01 - 3.00

colloidal anhydrose silica 0.10 - 1 .00

sodyum stearyl fumarate 0.10 - 10.00

flavouring agent 0.10 - 5.00 The production of the formulation is carried out as follows: Dronedarone HCI, mannitol and 50% of crospovidone are taken into granulator and mixed. Granulation is achieved in suitable amount of water and PVP mixture and granules are dried in fluid bed dryer or oven. Dried granules are sieved and sucralose, colloidal anhydrose silica, 50% of crospovidone and flavouring agent are mixed. Sodium stearyl fumarate is added to mixture then mixed. Then, the mixture is pressed into tablets.

Example 2:

The production of the formulation is carried out as follows: Dronedarone HCI, sucralose, sodium starch glycolate, xylitol, colloidal anhydrose silica and flavouring agent are mixed. Then, sodium stearyl fumarate is added and mixed. The mixture is pressed into tablets.

Example 3: ingredients amount (%)

dronedarone HCI 5.00 - 90.00

mannitol 0.50 - 60.00

xylitol 0.50 - 60.00

Low substituted

hydroxypropyl cellulose 2.50 - 40.00

(L-HPC)

sucralose 0.01 - 3.00

colloidal anhydrose silica 0.10 - 1 .00

sodyum stearyl fumarate 0.10 - 10.00

flavouring agent 0.10 - 5.00 The production of the formulation is carried out as follows: Dronedarone HCI, mannitol, xylitol, L-HPC and sucralose are mixed. Then, colloidal anhydrose silica and flavouring agent are added and mixed. Then, sodyum stearyl fumarate is added and mixed. The mixture is pressed into tablets.