FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION: ITRACONAZOLE ORAL DOSAGE FORM
2. APPUCANT(S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALS: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra
(East), Mumbai-400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides pharmaceutical formulation of itraconazole or pharmaceutically acceptable salt thereof. The formulation is in the form of central inert core coated with an active agent along with pharmaceutical^ acceptable excipients, characterised such that the formulation does not contain a seal coat.
The following specification particularly describes the invention and the manner in which it is to be performed.
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4. DESCRIPTION
Itraconazole is a synthetic triazole antifungal agent, a 1:1:1:1 racemic mixture of four
diastereomers (two enantiomeric pairs), each possessing three chiral centers.
Chemically, itraconazole is (±)-1-[(R*)-sec-butyl]-4-[p-[4-[p-[[(2R*,4S*)-2-(2,4-
dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-clioxolan-4-yl]methoxy]phenyl]-1-
piperazinyl] phenyl]-delta2-1,2,4-triazolin-5-one mixture with (±)-1-[(R*)-sec-butylJ-4-[P-
[4-[p-[l(2S*4R*)-2-(2,4,-dichlorophenyl)-2-(1 H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-
yl]methoxy] phenyl]-1-piperazinyl]phenyl]-delta2-1,2,4-triazolin-5-one or (±)-1-[(RS)-sec-
butyl]-4-[p-[4-[p-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1 H-1,2,4-triazol-1 -ylmethyl)-1,3,-
dioxolan-4-yl]methoxy]phenyl]-1 -piperazinyl]phenyl]-delta2-1,2,4-triazolin-5-one of
formula 1. It is insoluble in water, very slightly soluble in alcohols, and freely soluble in dichloromethane. It has a pKa of 3.70 and a log (n-octanol/water) partition coefficient of 5.66 at pH 8.1. Itraconazole is indicated for the treatment of the following fungal infections in immunocompromised and non- immunocompromised patients: Blastomycosis, pulmonary and extrapulmonary; Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non-meningeal histoplasmosis; Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy; and Onychomycosis due to dermatophytes (tinea unguium) of the toenail with or without fingernail involvement.

FORMULA 1
U. S. Patent No. 5,633,015 (the '015 Patent) discloses a bead comprising a central, rounded or spherical core; a coating film of a hydrophilic polymer and an
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antifungal agent selected from the group consisting of itraconazole and saperconazole, and a seal-coating polymer layer, the core has a diameter of from about 600 to about 700 mu.m (25-30 mesh).
U. S. Patent No. 6,663,901 discloses a process for preparing pellets, comprising coating sugar cores by spraying them with a solution of an antifungal agent and a water-soluble polymer in an organic solvent comprising methylene chloride and an alcohol in a fluidized-bed granulator equipped with a bottom spray insert; drying the resulting coated cores in vacuo by irradiating said cores with microwave or radiofrequency radiation; and seal-coating the dried cores by spraying them with a solution of a seal-coating polymer in an organic solvent comprising methylene chloride and an alcohol in a fluidized-bed granulator equipped with a bottom spray insert, the pellets have a residual concentration of dichloromethane of less than 600 ppm.
U. S. Patent No. 6,365,188 discloses a process for preparing a solid mixture for pharmaceutical, therapeutic or cosmetic forms comprising one or more cyclodextrins and itraconazole and the process includes melt-extrusion step.
U. S. Patent No. 6,737,082 discloses a pellet form oral pharmaceutical composition, comprising an inert core, having a particle size between 50 and 600 mu.m and a single coating layer having an active principle including an antifungal compound selected from the group consisting of itraconazole and saperconazole, a hydrophilic polymer and a non-ionic surfactant sprayed onto said inert core.
U.S. Patent No. 6,039,981 discloses an antifungal composition for oral administration comprising a fused mixture of itraconazole and phosphoric acid, a pharmaceutically acceptable carrier and a surfactant.
U. S. Application No. 20050142188 discloses a pellet comprising a central, rounded or spherical core having a diameter from about 710 to about 1180mu.m
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(16-25 mesh); a coating film of a water-soluble polymer and an antifungal agent, and a seal-coating polymer layer, wherein the residual concentration of dichloromethane in said pellet is less than 600 ppm.
U. S. Application No. 20050074494 discloses pellet consisting essentially of an inert starting seed; an antifungal agent; a binder :and an alkaline agent.
According to the '015 Patent, the dosage form is in the form of central spherical bead, active drug containing layer coated on the said inert core and a seal coat surrounding the said active layer as shown in figure 1. The specification further says that inert cores which are too small in size have a larger total surface available for coating resulting in a thinner coating layers and further they have a considerable tendency to agglomerate during the coating process which leads to undesirable effect of a concomitant decrease of the dissolution rate. The patent further suggests that applying seal coating polymer layer to the drug coated core prevents sticking of the beads. Seal coating polymer layer is nothing but the inert thin layer of polyethylene glycol surrounding the active drug-containing layer.
The present invention is now directed to a solid oral dosage form of itraconazole or pharmaceutically acceptable salt thereof. Itraconazole, a drug from the class of azole antifungal agent, possesses low aqueous solubility, which in turn results in poor bioavailability. The present invention now helps to solve the problems of solubility and bioavailability of this antifungal compound.
The new formulation of the present invention is characterized by the fact that it consists of beads comprising an inert core coated with layer of active compound along with pharmaceutically acceptable excipients such that it does not contain any seal coat or inert layer surrounding the active layer as shown in figure 2. The size of the inert core ranges between 25# to 40#.
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In one of the aspects of the present invention there is provided a solid oral dosage form of itraconazole or salt thereof comprising an inert core wherein the said inert core has a particle size between 25# to 40#.
In another aspect of the present invention there is provided a solid oral dosage form of itraconazole or salt thereof, wherein the dosage form comprises of:
1) a central inert core;
2) a coating of active compound along with pharmaceutically acceptable excipients surrounding the said inert core,
wherein the said inert core has a particle size between 25# to 30# and characterized by the fact that the dosage form is without any seal coat.
In yet another aspect of the present invention there is provided a solid oral dosage form of itraconazole or salt thereof, wherein the dosage form comprises of:
1) a central inert core;
2) a coating of active compound along with pharmaceutically acceptable excipients surrounding the said inert core,
wherein the said inert core has a particle size between 35# to 40# and characterized by the fact that the dosage form is without any seal coat.
In yet another aspect of the present invention there is provided a solid oral dosage form of itraconazole or salt thereof, wherein the dosage form comprises of:
1) 25-60% by weight of an inert core material;
2) 15- 45% by weight of itraconazole or salt thereof;
3) 15-30% by weight of hydrophillic polymer;
4) 0-5% by weight of polyethylene glycol; and
5) 0-5% by weight of non-ionic surfactant.
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Therapeutically effective amount of itraconazole or salt thereof is used for the preparation of the dosage form. The inert cores are the neutral spherical beads which can be made up of one or more of saccharides or derivatives thereof such as polysaccharides, sugars such as mannitol, sorbitol, lactose, sucrose, maltodextrin, sodium carboxymethylcellulose, starches such as maize starch, rice starch and the like. These materials are pharmaceutically acceptable and have dimensions of about 25# to 40# and more specifically 25# -30# or 35# -40#. This dimension size represents optimum size for formulation and further for drying step.
The coating solution is made up of active compound itraconazole or salt thereof along with one or more hydrophillic polymers, surfactants dissolved in a mixture of organic solvent, water and pharmaceutically acceptable excipients. The organic solvents comprises one or more of methylene chloride, isopropyl alcohol, ethanol, methanol, dichloromethane and the like. The residual solvent level in drug coated cores are within the limits set out by the International Conference on Harmonisation (ICH).
The hydrophillic polymers are water soluble polymers with low viscosity and comprises one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, methacrylates and the like.
The surfactant comprises one or more from Tween80, Cremophor EL, Poloxamer 188, Poloxamer 407, propylene glycol esters, glycerol esters, (mono-di-tri-)acetylated sorbitan, (mono, di-tri)acetylated saccharose, polyoxyethylene sorbitan esters of fatty acids, polyoxyethylene alkyl ethers of fatty chain, and polyoxyethylene-polyoxypropylene copolymers and the like. The non-ionic surfactant such as poloxamer 188 is the preferred agent. The use of surfactant in the present invention helps to enhance the solubility and dissolution rate of itraconazole or salt thereof.
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The drug coating layer further may contain polyethylene glycol along with other pharmaceutically acceptable excipients. The presence of polyethylene glycol in the active drug containing layer helps to increase the solubility of the otherwise very low aqueous solubility drug itraconazole, further it also helps to reduce the particle sticking. The present invention uses polyethylene glycol 6000. The dosage form is free of any seal coat or inert layer surrounding the active drug containing layer, which reduces the cost and time required for the development of the dosage form.
The present invention further may contain various pharmaceutical^ acceptable additives such as lubricants, thickening agents, surfactants, chelating agents, preservatives, complexing agents and the like.
The preferred solid oral dosage form may be capsule. The drug-coated beads are filled into hard gelatin capsules.
The dosage form may be prepared by the processes known in the art. Itraconazole, Hypromellose 2910, poloxamer 188 and Polyethylene glycol 6000 are dissolved in methylene chloride-isopropyl alcohol-water mixture. This drug solution is coated over the sugar spheres using fluidized bed coater (FBC) equipment by wruster technique. The beads are dried using FBC. The beads may be further lubricated by mixing with talc. Drug layered beads are filled in empty hard gelatin capsules.
The dosage form may have dissolution of about 60% or more in first one hour and 90% or more in next one hour when measured in a USP Type II apparatus at 100 rpm and using simulated gastric fluid (SGF) without enzymes at 37°C ±2.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those
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skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLES
Table 1 provides composition of present invention.
Table 2 provides the dissolution data of the capsules prepared as per the Formula provided in Table 1. For determination of drug release rate, Simulated Gastric Fluid (SGF) without enzymes in 900 ml of medium using USP Type 2 Apparatus (rpm 100) was used.
Table 1

SN Ingredient Quantity (%)
Example 1 Example 2
1 Sugar spheres (25# -30#) Sugar spheres (35# -40#) 42.50
2 Itraconazole Itraconazole 25.00
3 Hypromellose2910 Hypromellose 2910 27.50
4 Polyethylene glycol 6000 Polyethylene glycol 6000 2.50
5 Poloxamer188 Poloxamer 188 2.50
6 Methylene chloride Methylene chloride q. s.
7 Isopropyl alcohol Isopropyl alcohol q.s.
8 Water Water q. s.
Encapsulation Empty hard Gelatin capsules
Procedure - Itraconazole, Hypromellose 2910, poloxamer 188 and Polyethylene glycol 6000 are dissolved in methylene chloride-isopropyl alcohol-water mixture. This drug solution is coated over the sugar spheres using fluidized bed coater (FBC) equipment by wruster technique. The beads are dried using FBC. Drug layered beads are filled in empty hard gelatin capsules for the fill weight of 400mg/capsule.
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Table 2: The release pattern of the dosage form of present invention and Sporanox®.

Samplingpoints (minutes) Cumulative percent dissolved
Sporanox® Trial 1
10 15 7
20 37 26
30 58 43
45 76 55
60 88 66
90 96 80
120 100 90
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WE CLAIM:
1. A solid oral dosage form of itraconazole or salt thereof comprising an inert core wherein the said inert core has a particle size between 25# to 40#.
2. A solid oral dosage form of itraconazole or salt thereof, wherein the dosage form comprising:

1) a central inert core;
2) a coating of active compound along with pharmaceutically acceptable excipients surrounding the said inert core,
wherein the said inert core has a particle size between 25# to 30# and characterized by the fact that the dosage form is without any seal coat.
3. A solid oral dosage form of itraconazole or salt thereof, wherein the dosage
form comprising:
1) a central inert core;
2) a coating of active compound along with pharmaceutically acceptable excipients surrounding the said inert core,
wherein the said inert core has a particle size between 35# to 40# and characterized by the fact that the dosage form is without any seal coat.
4. A solid oral dosage form of itraconazole or salt thereof, wherein the dosage
form comprising:
1) 25-60% by weight of an inert core material;
2) 15- 45% by weight of itraconazole or salt thereof;
3) 15-30% by weight of hydrophillic polymer;
4) 0-5% by weight of polyethylene glycol; and
5) 0-5% by weight of non-ionic surfactant.
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5. A solid oral dosage form according to claims 1, 2, 3 and 4, wherein the inert
core is sugar sphere.
6. A solid oral dosage form according to claims 2 and 3, wherein the
pharmaceutically acceptable excipients include hydrophillic polymer, surfactant,
lubricants, thickening agents, surfactants, chelating agents, preservatives,
complexing agents and the like.
7. A solid oral dosage form according to claim 6, wherein the hydrophillic polymer is selected form the group consisting one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, methacrylates and the like.
8. A solid oral dosage form according to claim 6, wherein the surfactant is selected from the group consisting one or more of propylene glycol esters, glycerol esters, (mono-di-tri-)acetylated sorbitan, (mono, di-tri)acetylated saccharose, polyoxyethylene sorbitan esters of fatty acids, polyoxyethylene alkyl ethers of fatty chain, and polyoxyethylene-polyoxypropylene copolymers and the like.
9. A method for obtaining a solid oral dosage form as claimed in claims 1, 2 and 3, comprising the steps of:

1) preparing a coating solution comprising itraconazole or salt thereof along with other pharmaceutically acceptable excipients;
2) coating a core with a solution comprising itraconazole or salt thereof along with other pharmaceutically acceptable excipients;
3) drying said coating.
10. A solid oral dosage form according to claims 1, 2 and 3, wherein the dosage
form may have dissolution of about 60% or more in first one hour and 85% or
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more in next one hour when measured in a USP Type II apparatus at 100 rpm and using simulated gastric fluid (SGF) without enzymes at 37°C ±2.05.


Dated this 26th day of February, 2007

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