FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
COMPLETE SPECIFICATION
(SECTION 10)
PHARMACEUTICAL COMPOSITIONS CONTAINING ANTIFUNGAL AGENT."
Glenmark Pharmaceuticals Limited, an Indian Company,
registered under the Indian company's Act 1957 and
having its registered office at
B/2, Mahalaxmi Chambers, 22, Bhulabhai Desai Road
Post Box No. 26511
Mumbai - 400 026, India
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION: AND THE MANNER IN, WHICH IT IS TO BE PERFORMED
1 2 OCT ZOO

PHARMACEUTICAL COMPOSITIONS CONTAINING ANTIFUNGAL AGENT
PRIORITY
This application claims the benefit under Indian Provisional Application 1322/MUM/2005, filed on October 20, 2005, and entitled "PHARMACEUTICAL COMPOSITION COMPRISING ITRACONAZOLE", the contents of which are incorporated by reference herein.
BACKGROUND OF THE INVENTION
1. Technical Field
The present invention generally relates to pharmaceutical compositions containing at least an antifungal agent such as itraconazole and a process for its preparation.
2. Description of the Related Art
[0002] The present invention is directed to a pharmaceutical composition containing
at least an antifungal agent such as itraconazole. Itraconazole is a 1:1:1:1 racemic mixture of four diastereomers (two enantiomeric pairs), each possessing three chiral centers. Itraconazole (also known as (±)-l-[(R*)-sec-butyl]-4-[p-[4-[p-[[(2R*,4S*)-2-(2,4-dichlorophenyl)-2-( 1H-1,2,4-triazol-1 -ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl] -1 -piperazinyl]phenyl]-2-l,2,4-triazolin-5-one mixture with (±)-l-[(R*)-sec-butyl]-4-[p-[4-[p-[[(2S* ,4R*)-2-(2,4-dichlorophenyl)-2-(l H-1,2,4-triazol-1 -ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-l-piperazinyl]phenyl]-2-l,2,4-triazolin-5-one or (±)-l-[(RS)-sec-butyl]-4.[p.[4.[p.[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(l,H-l,2,4-triazol-l-ylmethyl)-l,3-dioxolan-4-yl]methoxy]phenyl]-l-piperazinyl]phenyl]-2-l,2,4-triazolin-5-one) may be represented by Formula I:
■2


cr
Itraconazole is a synthetic triazole antifungal agent. In vitro studies have demonstrated that itraconazole inhibits the cytochrome P450-dependent synthesis of ergosterol, which is a vital component of fungal cell membranes. Itraconazole is indicated for the treatment of fungal infections in immunocompromised and non-immunocompromised patients. Itraconazole is sold under the trade name Sporanox®. See, e.g., The Merck Index, Thirteenth Edition, 2001, p. 938, monograph 5266; and Physician's Desk Reference, "Sporanox," 59th Edition, p. 1753-1757(2005).
U.S. Patent No. 5,633,015 ("the '015 Patent"), herein incorporated by reference, discloses a bead having a 25-30 mesh sugar core (about 600 um to about 710 um) coated with an azole antifungal and a polymer, finished with a sealing film coat. The '015 Patent further discloses that the development of azole antifungals has been hampered by the fact that the azole antifungals are only very sparingly soluble in water. The '015 Patent describes the importance of the size of the cores, in that if the cores are too large, then there is less surface area available for applying the drug coating layer, which results in thicker coating layers. If the cores are too small, then there is a larger-total surface area available for coating resulting in thinner coating layers.
U.S. Patent No. 6,663,901 ("the '901 patent"), herein incorporated by reference, discloses a process for preparing pellets containing a central, rounded or spherical core having a 16-25 mesh (about 710 um to about 1180 um), a coating film of a water-soluble polymer and an antifungal agent, and a seal-coating layer, wherein the pellets have a residual concentration of dichloromethane of less than 600 ppm. The process in the '901 patent includes coating sugar cores by spraying them with a solution of an antifungal agent and a water-soluble polymer in an organic solvent containing methylene chloride and an alcohol in a fluidized-bed granulator,
3

drying the resulting cores in vacuo by irradiating the 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.
Accordingly, there remains a need for improved pharmaceutical compositions containing an azole antifungal that eliminate and reduce the drawbacks of the prior art in an economical and time consuming manner on a commercial scale.
SUMMARY OF THE INVENTION
In accordance with one embodiment of the present invention, a pharmaceutical composition is provided comprising a core having a coating film comprising a hydrophilic polymer and an antifungal agent, wherein there is absent a seal-coating polymer layer over the coating film, having a dissolution at 30 minutes greater than or equal to about 70%, at 45 minutes greater than or equal to about 80%, at 60 minutes of greater than or equal to about 95%, as measured using the type II paddle method at 100 rpm according to the US Pharmacopoeia, in a dissolution medium comprised of 900 ml of a'Simulated Gastric Fluid medium.
DEFINITIONS
The term "aspect ratio" as used herein shall be understood to mean an average value of the major axis/minor axis of crystal particles.
The term "treating" or "treatment" of a state, disorder or condition as used herein means: (1) preventing or delaying the appearance ^f 9J.in.ical symptoms of the state, disorder or condition developing in a mammal that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof, or (3)
4

relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms. The benefit to a subject to be treated is either statistically significant or at least perceptible to the patient or to the physician.
The term "therapeutically effective amount" as used herein means the amount of a compound that, when administered to a mammal for treating a state, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.
The term "delivering" as used herein means providing a therapeutically effective amount of an active ingredient to a particular location within a host means causing a therapeutically effective blood concentration of the active ingredient at the particular location. This can be accomplished, e.g., by topical, local or by systemic administration of the active ingredient to the host.
The term "buffering agent" as used herein means a compound used to resist a change in pH upon dilution or addition of acid of alkali^ Such compounds include, by way of example and without limitation, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and sodium citrate anhydrous and dehydrate and other such material known to those of ordinary skill in the art.
The term "sweetening agent" as used herein means a compound used to impart sweetness to a preparation. Such compounds include, by way of example and without limitation, aspartame, dextrose, glycerin, mannitol, saccharin sodium; sorbitol, sucrose, fructose and other such materials known to those of ordinary skill in the art.
The term "binders" as used herein means substances used to cause adhesion of powder particles in tablet granulations. Such compounds include, by way of example and without limitation, acacia alginic acid, tragacanth, carboxymethylcellulose sodium, poly
5

(vinylpyrrolidone), compressible sugar (e:g.,jNuTab), ethylcellulose, gelatin, liquid glucose, methylcellulose, povidone and pregelatinized starch, combinations thereof and other material known to those of ordinary skill in the art.
When needed, other binders may also be included in the present invention. Exemplary binders include starch, poly(ethylene glycol);,; guar gum, polysaccharide, bentonites, sugars, invert sugars, poloxamers (PLURQNIG™ F68, PLURONIC™ F127), collagen, albumin, celluloses in nonaqueous solvents, combinations thereof and the like. Other binders include, for example, poly(propylene glycol), polyoxyethylene-polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, poly(ethylene oxide), microcrystalline cellulose, poly(vinylpyrrolidone), combinations thereof and other such materials known to those of ordinary skill in the art.
The term "diluent" or "filler" as used herein means inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the preparation of tablets and capsules. Such compounds include, by way of example and without limitation, dibasic calcium phosphate, kaolin, sucrose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, starch, combinations thereof and other such materials known to those of ordinary skill in the art;; ■■ M L
The term "glidant" as used herein means agents used in tablet and capsule formulations to improve flow-properties during tablet compression and to produce an anti-caking effect. Such compounds include, by way of example and without limitation, colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, combinations thereof and other such materials known to those of ordinary skill in the art.
The term "lubricant" as used herein means.substances used in tablet formulations to reduce friction during tablet compression. Such compounds include, by way of example and without limitation, calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate, combinations thereof and other such materials known to those of ordinary skill in the art.
6

The term "disintegrant" as used herein means a compound used in solid dosage forms to promote the disruption of the solid mass into smaller particles which are more readily dispersed or dissolved. Exemplary disintegrants include, by way of example and without limitation, starches such as corn starch, potato starch, pre-gelatinized and modified starched thereof, sweeteners, clays, such as bentonite, microcrystalline cellulose (e.g. Avicel™), carsium (e.g. Amberlite™), alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, tragacanth, combinations thereof and other such materials known to those of ordinary skill in the art.
The term "wetting agent" as used herein means a compound used to aid in attaining intimate contact between solid particles and liquids. Exemplary wetting agents include, by way of example and without limitation, gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetqrnacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, (e.g., TWEEN™s), polyethylene glycols, polyoxyethylene stearates colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxyl propylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP). Tyloxapol (a nonionic liquid polymer of the alkyl aryl polyether alcohol type, also known as superinone or triton) is another useful wetting agent, combinations thereof and other such materials known to those of ordinary skill in the art.
Most of these excipients are described in detail in, e.g., Howard C. Ansel et al., Pharmaceutical Dosage Forms and Drug delivery Systems, (7th Ed. 1999); Alfonso R. Gennaro et al., Remington: The Science and-Practice of Pharmacy, (20th Ed. 2000); and A. Kibbe, Handbook of Pharmaceutical Excipients, (3rd Ed. 2000), which are incorporated by reference herein.
7

BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is a graphical representation of the release profile over time of the pharmaceutical composition of Example 1 versus Sporanox (4NG686) and Sporanox (4MG646).
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The pharmaceutical compositions of the present invention includes at least a core region having a coating film of a hydrophilic polymer and an azole antifungal agent, wherein there is absent a seal-coating polymer layer over the coating film.
Suitable cores can be obtained from pharmaceutically acceptable materials having the appropriate dimensions, e.g., about 20 to about 25 mesh (about 710 um to about 850 um), and include, but are not limited to, polymers such as plastic resins; inorganic material such as silica, glass, hydroxyapatite, salts, e.g., sodium chloride, potassium chloride or magnesium carbonate, and the like; organic material such as activated carbon and the like; acids such as citric acid, fumaric acid, tartaric acid, ascorbic acid and the like; and saccharides and derivatives thereof. Preferably the core material include saccharides such as sugars, oligosaccharides, polysaccharides ,and thehv; derivatives, for example, glucose, rhamnose, galactose, lactose, sucrose, mannitol, sorbitol, dextrin, maltodextrin, cellulose, sodium carboxymethyl cellulose, starches ! (maize; rice, potato, wheat, tapioca) and the like. A particularly preferred material suitable for use as cores is about 20 to about 25 mesh sugar cores (USP 22/NF XVII, p. 1989) which include about 62.5% to about 91.5% (w/w) sucrose, the remainder being starch and possibly also dextrines, and which are pharmaceutically inert or neutral. These cores are also known as neutral pellets.
The hydrophilic polymer for use in theicoating film may be a polymer that has an apparent viscosity of about 1 to about 100 mPa.s when dissolved in a 2% aqueous solution at 20°C. For example, the hydrophilic polymer can be an alkylcellulose such as methylcellulose and
8

the like, hydroxyalkylcelluloses such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxybutylcellulose and the like, hydroxyalkyl alkylcelluloses such as hydroxyethyl methylcellulose, hydroxypropyl methylcellulose and the like, carboxyalkylcelluloses such as carboxymethylcellulose and the like, alkali metal salts of carboxyalkylcelluloses such as sodium carboxymethylcellulose and the like, carboxyalkylalkylcelluloses such as ..carboxymethylethylcellulose and the like, carboxyalkylcellulose esters, starches.,, pectjnes such as sodium carboxymefhylamylopectine and the like, chitine derivates such as chitosan and the like, polysaccharides such as alginic acid and the like, alkali metal and ammonium salts thereof, carrageenans, galactomannans, tragacanth, agar-agar, gummi arabicum, guar gummi and xanthan gummi, polyacrylic acids and the salts thereof, polymethacrylic acids and the salts thereof, methacrylate copolymers, polyvinylalcohol, polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate, polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide and the like.
In one embodiment, a hydrophilic polymer in the drug coating layer includes a hydroxypropyl methylcellulose (Methocel®, Pharmacoat®), methacrylate (Eudragit E®), hydroxypropylcellulose (Klucel®), or a polyvidone. A preferred hydrophilic polymer is a hydroxypropyl methylcellulose';or. ^PMC': wherein the HPMC contains sufficient hydroxypropyl and methoxy groups;,;to;render jt hydrophilic, e.g., a hydroxypropyl molar substitution from about 0.05 to about 3.0 and a methoxy degree of substitution of from about 0.8 to about 2.5. Methoxy degree of substitution as used herein refers to the average number of methyl ether groups present per anhydroglucose unit of the cellulose molecule. Hydroxypropyl molar substitution as used herein refers to the average number of moles of propylene oxide which have reacted with eaqh: anhydroglucose unit of the cellulose molecule. Hydroxypropyl methylcellulose is the United States Adopted Name for hypromellose (see, e.g., Martindale, The Extra Pharmacopoeia^ 29th edition, page 1435). Preferably a hydroxypropyl methylcellulose with low viscosity, e.g., about 5 mPa.s, is used, e.g. hydroxypropyl methylcellulose 2910 5 mPa.s wherein in the four digit number "2910", the first two digits represent the approximate percentage of methoxyl groups and the third and
9

fourth digits the approximate percentage composition of hydroxypropoxyl groups. The value 5 mPa.s is a value indicative of the apparent viscosity of a 2% aqueous solution at 20° C.
In another embodiment, suitable HPMC include those having a viscosity from about 1 to about 100 mPa.s, and preferably from about 3 to about 15 mPa.s, and most preferably about 5 mPa.s The most preferred type of HPMC having a viscosity of 5 mPa.s., is the commercially available HPMC 2910 5 mPa.s.
Suitable antifungal agents for use; as drugs, in, the drug coating layer are lipophilic azole antifungals such as in particular itraconazole.
The cores for use in the compositions of the present invention may further contain various additives such as, for example, thickening agents, lubricants, surfactants, preservatives, complexing and chelating agents, electrolytes and the like and mixtures thereof.
The coated cores of the present invention can conveniently be formulated into various pharmaceutical dosage forms tablets or capsules,; Suitable dosage forms will include at least an effective antifungal amount of the cores as described hereinbefore, for example, 100 mg of the active ingredient is available per dosage form. Preferably, the cores are filled in hard-gelatin capsules such that an amount of, for example, 100 mg of the active ingredient is available per dosage form. For example, hard-gelatin capsules of size 0 are suitable for formulating cores containing about 20. to about ,25 percent by weight itraconazole, equivalent to about 100 mg active ingredient.
Tablets containing the compositions according to the present invention may be produced by any standard tabletting technique, e.g. by wet granulation, dry granulation or direct compression. For example, dry granulation procedures include mixing the solid excipients (except lubricants), compacting the mixture in a compactor (e.g. a roller compactor) or double compression, milling the compacted mass screening the milled granules, mixing with a lubricant and compressing the mixture into tablets. Direct compression procedures generally
10

comprise mixing the solid excipients in one or more stages and compressing the uniform mixture into tablets. After tablet formation, the tablets may optionally be coated with the controlled release coating discussed hereinabove. The tablets can be of any size and shape. Tablet excipients can also be included, and may be, for example, diluents, retardants, and lubricants, as well as other pharmaceutically acceptable excipients. These excipients may be present in the core region and/or any other region of the formulation. Generally, diluents according to the present invention are inert materials that can be added to the active ingredient to make them more acceptable. Diluents are fillers designed to make up the required bulk of the tablet when the drug dosage itself is inadequate to produce this bulk. Tablet formulations may contain diluents for secondary reasons, such as. to provide better tablet properties such as improved cohesion, to permit use of direct compression manufacturing, or to promote flow. Suitable dosage forms include an effective antifungal amount of pellets as described hereinbefore.
The coated cores of the present invention may be generally prepared in the following manner: a drug coating solution is prepared! by dissolving into a suitable solvent system appropriate amounts of an itraconazole and a hydrophilic polymer. A suitable solvent system includes, but is not limited to, a mixture of methylene: chloride and an absolute alcohol. The mixture should contain at least about 50% by weight of methylene chloride acting as a solvent for the drug substance. As hydroxypropyl methylcellulose does not dissolve completely in methylene chloride, at least about 10% alcohol has to be added. Preferably a relatively low ratio of methylene chloride/alcohol is used in the coating solution.
The coating solution is then applied onto the scores by any technique known to one skilled in the art, spraying, dipping, etc. As one skilled in the art will readily appreciate, when spraying the coating solution onto the cores, the spraying rate should be regulated carefully as to low a spraying rate can cause some spray drying of the drug coating solution and result in a loss of product whereas to high a spraying rate will cause over wetting with subsequent agglomeration. Since agglomeration is the: most serious problem in coating the cores, lower
11

spraying rates may be used initially, to be increased as the coating process proceeds and the coated cores grow larger.
The drug coating and the subsequent drying in the present pharmaceutical composition was achieved without the use of microwave and radiofrequency radiation. In a preferred embodiment, a dryer used includes, but is not limited to, spray dryer and/or freeze dryer, roller/flaker - dryer and/or pan Dryer and/or tray dryer and/or fluid bed dryer. In a preferred embodiment, a fluid bed processor is used as dryer.
The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the claims.
EXAMPLE
The ingredients and the percent w/w formula of the composition of this example are set forth in Table 1.
TABLE 1

Ingredient Qty/capsule(in mg)
Drug Coating -J;. * ■ ' ■ :
Sugar spheres 20/25# (710-850^1) 192.0
Itraconazole 100.0
HPMC 2910 (Methocel E-5 LV) 150.0
Methylene chloride ; ivr q.s.
Absolute alcohol q.s.
Filling in capsules ;
Capsule shells of size '0' 90.0
12

Manufacturing Process
Itraconazole was dissolved in methylene chloride under stirring to form an itraconazole solution. Next, HPMC 2910 was dispersed in absolute alcohol under stirring. The HPMC dispersion was added to the itraconazole solution and stirred until a clear solution was obtained. Sugar spheres were loaded into a Fluid Bed Processor. The coating solution was sprayed onto the sugar spheres using the bottom spray technique . In the bottom spray technique, the granulation/coating of small particles can be performed in a fluid bed processor by spraying a suitable solvent or a binder solution from the bottom of equipment onto the solid particles suspended in air stream. This technique is well known in the art and the equipment is available commercially. After completion of the spraying, the drug loaded cores were dried in the Fluid Bed Processor itself. After drying, the cores were filled in a size '0' hard gelatin capsule shells using a manual capsule filling machine or automatic capsule filling machine. The weight of the pellets is adjusted in such a way that each capsule contains itraconazole active equivalent to 100 mg.
The pharmaceutical composition of itraconazole was then tested for its dissolution profile against Sporanox (Batch No. 4NG686) and Sporanox (Batch Number 4MG646) in a Simulated Gastric Fluid (SGF) medium ;(900ml) by using USP II apparatus at 100 rotations per minute (RPM). The SGF was prepared without pepsin, a gastric enzyme. SGF pH of about 1.2 was prepared as per the USP NF 26 guidelines. 2 g sodium chloride was weighed and added to a suitable container, and 7 ml HCL and sufficient water were then added to reach 900 ml. The dissolution profiles are set forth below in Table 2 and a graphical representation is shown in Figure 1
13

Table 2

Assay
10 min 15 mim 30 min 45 min 60 min
Sporanox (4NG686) 21 33 65 83 91 99.30%
Sporanox (4MG646) 21 31 58 77 89 102.50%
Itraconazole pellets 29 44 71 88 96 99.10%
Results clearly show that the release in the case of the invention makes it bioequivalent to the existing Sporanox® product.
It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the claims appended hereto.
14

FEATURES AND ADVANTAGES:
1. A pharmaceutical composition comprising a core having a film coating of hydrophilic
polymer and an antifungal agent, and having a dissolution at least 70% in 60 minutes, as
measured using the type II paddle method at 100 rpm according to the US Pharmacopoeia, in
a dissolution medium comprised of 900 ml of a Simulated Gastric Fluid medium.
2. The pharmaceutical composition of Feature 1, wherein the core is a central, rounded or spherical core having a diameter from s about 710 to about 1180 um (16-25 mesh).
3. The pharmaceutical composition of Features 1 and 2, wherein the antifungal agent is itraconazole.
4. The pharmaceutical composition of Features 1-3, wherein the hydrophilic polymer comprises HPMC 2910 (Methocel E-5 LV):
5. The pharmaceutical composition of Features 1-4, further comprising one or more pharmaceutically acceptable excipients.

Taranpreet Lamba. (Sr. Manager-IPM)
Glenmark Pharmaceuticals Limited
15
Dated this Twelth (12th), day of October, 2006

ABSTRACT
A pharmaceutical composition comprising a core having a film coating of hydrophilic polymer and an antifungal agent, and having a dissolution at 60 minutes greater than or equal to about 70%, as measured using the type II paddle method at 100 rpm according to the US Pharmacopoeia, in a dissolution medium comprised of 900 ml of a Simulated Gastric Fluid medium.

Dated this Twelth (12,n), day of October, 2006

Taranpreet Lamba. (Sr. Manager-IPM)
Glenmark Pharmaceuticals Limited

12 OCT 2006.