FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
[Section 10, and Rule 13]
PHARMACEUTICAL COMPOSITION OF BENZOFURAN COMPOUNDS
Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near Dinesh
Hall, Ahmedabad 380 009, Gujarat, India
The following specification describes the nature of the invention.

Pharmaceutical composition of Benzofuran compounds
FIELD OF THE INVENTION:
The present invention relates to a pharmaceutical composition for oral administration which, comprises a benzofuran derivative or pharmaceutically acceptable salts thereof, as an active principle, and cyclodextrin or its derivative, optionally in combination with one or more pharmaceutically acceptable excipient. Present invention also encompasses the process for preparing the said pharmaceutical composition.
BACKGROUND:
Benzofuran compounds are useful as medicines, particularly for the treatment of pathological syndromes of the cardio-vascular system. It has been found that these compounds possess remarkable pharmacological properties since they are capable of prolonging the action potential and the refractory period of the cells of the myocardium. Furthermore, most of the compounds have also shown bradycardiac, anti-hypertensive and anti-adrenergic properties. These properties are capable of making the compounds very useful in the treatment of certain pathological syndromes of the cardiovascular system, in particular in the treatment of angina pectoris, hypertension, arrhythmias and cerebral circulatory insufficiency.
Dronedarone, in the form of its hydrochloride, exhibits a limited solubility in an aqueous medium: at ambient temperature, it is 0.5 mg/ml at pH=4.85. In the pH range from 1.5 to 5, this solubility is virtually constant and then becomes virtually negligible at pH values of greater than 5.5.

Amiodarone hydrochloride, its solubility at room temperature is from 0.3 to 0.9 mg/ml in the pH range from 3 to 4, and is a few ug/ml at pH = 7.
Thus benzofurans such as Dronedarone and Amiodarone poses challenge for preparation of pharmaceutical composition, which gives desired plasma profile.
US 7323493 disclosed a pharmaceutical composition of dronedarone using a non-ionic surfactant to overcome the problem of solubility. In the stomach, the acidic conditions which are favourable to solubilization of dronedarone (pH less than 5), but, on the other hand, risks encountering a medium of pH=6 to 7 once it enters the intestine, i.e. a non-solubilizing medium in which dronedarone will precipitate. This difference observed after administration with or without food, since the bioavailability of dronedarone hydrochloride is increased after the intake of food, in particular fats, which can greatly modify the precipitation kinetics of this active principle and also help to place it in emulsion form. Since the absorption of food gives rise to the secretion of bile salts, which are anionic surfactants, it showed that presence of anionic surfactant is a favorable influence on the solubilization of dronedarone hydrochloride.
However the effect of surfactant over the intestinal membrane is more complex. It has been shown that most surfactants interact with the absorbing membranes (Bermejo, D. M. and Ruiz-Garcia, A., Business Briefing: Pharmatech 2003; pages 1-7). Permeability enhancement and local damage are closely related sequelae of the interaction of surfactants with the intestinal wall (Swenson, E.S., Milisen, W.B., Curatolo, W., Pharm. Res. 1994 Aug; 11(8), pages 1132-42). Ingested surfactants may facilitate penetration or absorption of potentially toxic or pathogenic compounds, which in turn may result in adverse effects on the other organs (Lieberman, H.A., Rieger, M. M. and Banker, G. S., Eds., Pharmaceutical Dosage Forms: Disperse Systems, 2nd ed, Vol. 1 , page 261). The surfactant can facilitate their own entry and

that of other material into the body, which thus enters in to the systemic circulation. Polysorbate 60 or 80 affects the integrity of intestinal mucosa (Lieberman, H.A., Rieger, M.M. and Banker, G.S., Eds., Pharmaceutical Dosage Forms: Disperse Systems, 2n ed., Vol. 1, page 261). Management of cardiovascular diseases, being a long term therapy, use of surfactants in the formulation of benzofuran compounds need to be judiciously avoided. Thus there is a long felt need to have a composition of benzofuran that is safe and efficacious.
The inventors of the present invention have surprisingly found pharmaceutical compositions of benzofuran derivative and cyclodextrin or its derivative with improved dissolution.
SUMMARY OF THE INVENTION:
The first embodiment of the present invention is to provide a pharmaceutical composition comprising benzofuran derivative or pharmaceutically acceptable salts thereof, as an active principle, and cyclodextrin or its derivative, optionally in combination with one or more pharmaceutical excipient.
Another embodiment of the present invention is to provide a pharmaceutical composition comprising benzofuran derivative or pharmaceutically acceptable salts thereof, as an active principle, and β-cyclodextrin, optionally in combination with one or more pharmaceutical excipient;
Another embodiment of the present invention is to provide a pharmaceutical composition comprising dronedarone or pharmaceutically acceptable salts thereof, as an active principle, and β-cyclodextrin or its derivative, optionally in combination with one or more pharmaceutical excipient.

Another embodiment of the present invention is to provide a pharmaceutical composition comprising dronedarone or pharmaceutically acceptable salts thereof, as an active principle, and hyroxypropyl p-cyclodextrin (HPpCD), optionally in combination with one or more pharmaceutical excipient.
Another embodiment of the present invention is to provide a pharmaceutical composition comprising amiodarone or pharmaceutically acceptable salts thereof, as an active principle, and hyroxypropyl P-cyclodextrin (HPpCD), optionally in combination with one or more pharmaceutical excipient.
Another embodiment of the present invention is to provide a pharmaceutical composition comprising;
a) dronedarone or pharmaceutically acceptable salts thereof;
b) cyclodextrin or its derivative; and
c) optionally one or more pharmaceutical excipient.
In yet another embodiment, the pharmaceutical composition of the present invention can be processed by wet granulation or dry granulation or direct compression or any other technique known to a skilled person.
In yet another embodiment, the pharmaceutical compositions of the present invention may be formulated optionally with one or more therapeutic agent{s).
BRIEF DESCRIPTION OF THE FIGURES:
Figure 1 is a comparative release profile of MULTAQ® vs Dronedarone 400mg (Uncoated tablet) of example 1
Figure 2 is a comparative release profile of MULTAQ® vs Dronedarone 400mg {Coated tablet) of example 1

DETAIL DESCRIPTION OF THE INVENTION:
The present invention relates to a pharmaceutical composition for oral administration which comprises a benzofuran derivative or pharmaceutically acceptable salts thereof, as an active principle, and cyclodextrin or its derivative, optionally in combination with one or more pharmaceutical excipient.
The term "benzofuran derivative" as used herein is understood to denote a benzofuran compound chosen from those described in US 3248401 and US 5223510 and EP 338746, as well as in patent applications WO 88/07996, WO 89/02892, WO 90/02743 and WO 94/29289. Of all of these compounds, mention may preferably be made of dronedarone and the pharmaceutically acceptable salts thereof described in US 5223510, as well as amiodarone and the pharmaceutically acceptable salts thereof described in US 3248401.
The term "pharmaceutical composition" or "dosage form" as used herein refers to any suitable physical form of the drug containing fixed dose of the active ingredient. Composition of the present invention includes without limitation a wider variety of dosage form like e.g. tablets, capsules, sachets, granules, pellets, powders etc. The tablet dosage form may be in chewable dosage form. More preferably the pharmaceutical composition of present invention is in the form of tablet.
"Cyclodextrin" or its derivatives used in the compositions of the invention, can be of sulphobutyl ether derivative of P-cyclodextrin, dimethyl p-cyclodextrin, trimethyl β-cyclodextrin, and their mixtures. However, it is preferable to use hydroxypropyl β-cyclodextrin. The p-cyclodextrin derivative may be present in an amount ranging from 0.5% to 25%, preferably 0.5% to 20%, most preferably 0.5 to 15% by weight of the pharmaceutical composition.

The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.
Throughout this specification and the appended claims it is to be understood that the words "comprise" and "include" and variations such as "comprises", "comprising", "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
Dronedarone may be present in the range of 200-1000 mg per unit dosage form.
The pharmaceutical compositions as described herein may also comprise one or more pharmaceutical^ acceptable excipient selected from carrier / diluent, disintegrant, binder, lubricant, opacifier, film forming agent, plasticizer, glidant, and others known to the skilled person in the art.
Diluent / Carrier is selected from the group comprising of microcrystalline cellulose (MCC), silicified MCC, lactose, starch, pregelatinized starch, sugar, mannitol, sorbitol, dextrates, dextrin, maltodextrin, dextrose, calcium carbonate, calcium sulfate, dibasic calcium phosphate dehydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide and the mixture thereof. The diluent / carrier may be used in a concentration of about 0% to 30% by weight of the pharmaceutical composition.
Disintegrant may be selected from the group comprising of croscarmellose sodium, sodium starch glycolate, starch, pregelatinized starch, partially pregelatinized starch, sodium carboxymethyl cellulose, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, Low - substituted hydroxy propyl cellulose and the mixture

thereof. The disintegrant may be present in an amount ranging from 0% to 20% by weight of the pharmaceutical composition.
Binder may be selected from the group comprising of hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomers, dextrin, ethyl cellulose, methylcellulose, shellac, zein, gelatin, polymethacrylates, polyvinyl pyrrolidone, pregelatinized starch, sodium alginate, gums, synthetic resins and the mixtures thereof. The binder may be present in an amount ranging from 0% to 15% by weight of the pharmaceutical composition.
Lubricant / Glidant may be selected from the group comprising of talc, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; sodium stearyl fumarate, colloidal silicon dioxide, finely divided silicon dioxide, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate, polyethylene glycols, starch, sodium stearyl fumarate, mineral oil, magnesium trisilicate and the mixtures thereof. The lubricant / glidant may be present in an amount ranging from 0% to 5% by weight of the pharmaceutical composition.
Film forming agent may be selected the group comprising of hydroxypropylmethylcellulose (hypromellose), polyvinylpyrrolidone, gelatin, hydroxypropylcellulose, polyethylene oxide, hydroxyethylcellulose, sodium alginate and the mixture thereof. The film forming agent may be used in seal coat, drug coat, separating coat, film coat and such like.
Plasticizer may be selected the group comprising of citrate esters (e.g., triethylcitrate, triacetin); fatty acid esters (eg., butyl stearate, glycerol monostearate, steryl alcohal); sebacate esters (eg., dibutyl sebacate); phthalate esters (eg., diethyl phthalate, dibutyl phthalate); low molecular weight poly(alkylene oxides); polyethylene glycols, polypropylene glycols, poly(ethylene/propylene glycols); glycerol, pentaerythritol,

glycerol monoacetate, diacetate or triacetate; propylene glycol; sodium diethyl sulfosuccinate; triacetin; mineral oil; castor oil, vitamin E TPGS and the therapeutic compound itself. The plasticizer can be present in concentration from about 0.005% to 1% by weight of the pharmaceutical composition.
Opacifying agent may be selected from a group comprising of titanium dioxide, iron oxides, and the like.
This pharmaceutical composition can be in any solid pharmaceutical form which is suitable for oral administration, such as a tablet, a granule, a gelatin capsule or a powder in a unit sachet.
In one of the embodiment, the pharmaceutical composition of the present invention can be processed by wet granulation or dry granulation or direct compression or any other technique known to a skilled person.
One of the preferred embodiment of the present invention provides a process for the preparation of pharmaceutical composition of benzofuran, which comprises the following steps:
1. Sift benzofuran compound, cyclodextrin or its derivative, optionally combination with one or more pharmaceutical excipient.
2. Prepare binder solution by dissolving suitable binder in an aqueous / non aqueous solvent and granulate the above sifted materials using Binder solution to form wet granules.
3. Dry the granules of step 2, followed by sizeing, using appropriate sieve.
4. Blend the granules of Step 3 in, followed by lubrication in appropriate blender.

5. Compress the lubricated blend to tablets using suitable punches &
compression machine, followed by optionally coating. The invention will be further illustrated by the following example, however, without restricting its scope to these embodiments.
EXAMPLE 1: Pharmaceutal composition of Dronedarone 400mg

S.No. Ingredient Function Mg/tablet
■1 Dronedarone hydrochloride Active Ingredient 426.00
2 Lactose Diluent 41.65
3 Pregelatinised starch Diluent 45.50
4 Crospovidone Disintegrant 65.00
5 Hydroxy propyl β-cyclodextrin Solubilizer 40.00
6 Hydroxy propyl methyl cellulose Binder 26.00
7 Colloidal silicon dioxide Glidant 2.60
8 Magnesium stearate Lubricant 3.25
9 HPMC (Metho E 15) Film forming agent 3.80
10 Talc Glidant 4.15
11 Colloidal Silicon Dioxide Glidant 0.58
12 PEG 6000 Plasticizer 0.57
13 Titanium dioxide Opacifier 0.90
Procedure:
1. Dronedarone hydrochloride, Lactose, pregelatinized starch, Crospovidone and Hydroxy propyl β-cyclodextrin were sifted. 2. Binder solution was prepared by dissolving Hydroxy propyl methyl cellulose in purified water and granulate the material of step 1 with the binder solution.

3. Granules of step 3 were dried in Fluid bed dryer, followed by sizing in oscillating granulator.
4. Granules of Step 3 were blended along with silicon dioxide, followed by lubrication with magnesium stearate in a blender.
5. Lubricated blend was compressed to tablets, followed by coating using Hydroxypropyl methyl Cellulose, Talc, Colloidal Silicon Dioxide, Titanium Dioxide and PEG 6000.
Dissolution (Media: Phosphate buffer, pH 4.5) of the above prepared batch was compared with Multaq® (400 mg). (See Table 1 & Figure 1)
Table 1

Drug Release (%)
Time (Min.) Multaq® Dronedarone
400mg
(Uncoated tablet) Dronedarone
400mg (Coated tablet)
5 6.3 10.32 1.23
10 17.5 19.70 6.22
15 28.9 29.07 14.18
30 58.2 52.70 41.87
45 77.6 72.35 65.02
60 87.1 89.22 82.67
90 92.2 97.67 97.88
120 92.5 98.17 98.03

Figure 1


We Claim:
1. A pharmaceutical composition comprising benzofuran derivative or
pharmaceutically acceptable salts thereof, cyclodextrin or its derivative and
optionally one or more pharmaceutical excipient.
2. The pharmaceutical composition according to claim 1, wherein pharmaceutical composition is tablet, capsule, sachet, granules, pellets or powder.
3. The pharmaceutical composition according to claim 2, wherein pharmaceutical composition is tablet, which is coated or uncoated.
4. The pharmaceutical composition according to claim 1, wherein benzofuran derivative is selected from Dronedarone and Amiodarone.
5. The pharmaceutical composition according to claim 1, wherein cyclodextrin or it derivative is selected from sulphobutyl ether derivative of P-cyclodextrin, dimethyl p-cyclodextrin, trimethyl p-cyclodextrin, hydroxypropyl p-cyclodextrin and mixture thereof.
6. The Pharmaceutical composition according to claim 1, wherein one or more pharmaceutical excipient is selected from diluent, disintegrant, binder, lubricant, opacifier, film forming agent, plasticizer and glidant
7. The pharmaceutical composition according to claim 1, wherein cyclodextrin or its derivative is present in amount of 0.5% to 25% w/w.
8. A pharmaceutical composition comprising
a) dronedarone or pharmaceutically acceptable salts thereof;

b) cyclodextrin or its derivative; and
c) optionally one or more pharmaceutical excipient.
9. The pharmaceutical composition according to claim 8, wherein cyclodextrin is
hydroxypropyl P-cyclodextrin and mixture thereof.
10. A pharmaceutical composition of benzofuran derivative as herein described,
particularly with reference to the foregoing examples.