The technical field of the present invention relates to an oral pharmaceutical composition of poorly soluble azole antifungal compound having predictable release profile; and process of preparation thereof.
Azole antifungal compounds, in particular itraconazole is a broad-spectrum antifungal compound disclosed in US 4,267,179, and indicated for a wide variety of antifungal infections. Itraconazole is marketed as immediate release capsules (100mg), and oral and injectable solutions (10mg/ml), by Janssen Pharma under the trade name SPORANOX®.
The fact that azole antifungal compounds are poorly soluble in water hampers the development of efficacious pharmaceutical compositions. Considerable endeavors have been directed towards improving the solubility, and consequently the bioavailability of such compounds from oral pharmaceutical compositions. One of the common approaches of preparing pharmaceutical compositions of good bioavailability involves the incorporation of poorly soluble antifungal compound in hydrophilic polymer and applying over inert core.
European Patent EP 658103, assigned to Janssen Pharmaceutica discloses pharmaceutical compositions of poorly soluble antifungal compounds prepared on the basis of this technology. Particularly, it discloses beads which comprise a) a central, rounded or spherical core, b) a coating film of a hydrophilic polymer and an antifungal compound and c) a seal coating polymer layer, characterized in that the core has a diameter of about 600 pm to about 700 pm. European Patent EP 969821 and PCT application WO 00/03697, also discloses pharmaceutical compositions based on the same approach, wherein the cores have diameter of 250 urn to 355 pm and 710 urn to 1180 urn respectively. The seal coating polymer layer is applied to the drug coated cores to prevent sticking of the beads which would have the undesirable effect of a concomitant decrease of the dissolution rate and of the bioavailability. Preferably a thin layer of polyethylene glycol (PEG), in particular PEG 20000 is used as a seal coating polymer layer.
The related prior art thus highlights the importance of the size of central inert cores, providing a feeling to a person skilled in the art that the in vitro and in vivo release
profiles of the final compositions of poorly soluble azole antifungal compounds is highly dependent on the inert core particle size.
The inventors of the present invention have now surprisingly discovered that though a proper selection of central inert cores of particular size may ease processing, the processing parameters maintained during the fabrication of the pharmaceutical composition of azole antifungal compounds are the ones, which affect the release profiles and reproducibility of the compositions.
Hence, in one general aspect there is provided a process for the preparation of pharmaceutical composition of azole antifungal compound comprising multiple drug loaded core units, wherein the process comprises the steps of
a) loading central inert cores in a coater,
b) achieving and maintaining the bed temperature from about 20° C to about 35° C, and inlet air relative humidity from about 35 % to about 55 %,
c) coating with a drug layer comprising azole antifungal compound and hydrophilic polymer; and
d) drying the drug loaded cores at about 60° C to about 100° C.
In another general aspect there is provided a process for the preparation of pharmaceutical composition of itraconazole comprising multiple drug loaded core units, wherein the process comprises the steps of
a) loading central inert cores in a coater,
b) achieving and maintaining the bed temperature from about 20° C to about 35° C, and inlet air relative humidity from about 35 % to about 55 %,
c) coating with a drug layer comprising itraconazole and hydrophilic polymer; and
d) drying the drug loaded cores at about 60° C to about 100° C.
In another general aspect there is provided a process for the preparation of pharmaceutical composition of itraconazole comprising multiple drug loaded core units, wherein the process comprises the steps of:
a) loading central inert cores in a coater,
b) achieving and maintaining the bed temperature from about 20° C to about 35° C, and inlet air relative humidity from about 35 % to about 55 %,
c) coating with a drug layer comprising itraconazole and hydroxypropyl methylcellulose; and
d) drying the drug loaded cores at about 60° C to about 100° C.
In another general aspect there is provided a process for the preparation of pharmaceutical composition of itraconazole comprising multiple drug loaded core units, wherein the process comprises the steps of:
a) loading central inert cores having diameter of about 500 urn to about 600 urn, in a coater,
b) achieving and maintaining the bed temperature from about 20° C to about 35° C, and inlet air relative humidity from about 35 % to about 55 %,
c) coating with a drug layer comprising itraconazole and hydrophilic polymer; and
d) drying the drug loaded cores at about 60° C to about 100° C.
In another general aspect there is provided a pharmaceutical composition of azole antifungal compound comprising multiple drug loaded core units comprising
a) a central inert core,
b) uniform drug layer, free of air pockets comprising azole antifungal compound and hydrophilic polymer,
wherein coating of the inert core with drug layer is carried out by achieving and maintaining the bed temperature from about 20° C to about 35° C, and inlet air relative humidity from about 35 % to about 55 %, and drying the drug loaded cores at about 60° C to about 100° C.
In another general aspect, drug loaded units prepared above may be further coated with a seal coat layer comprising seal coating polymer, and processed into solid dosage forms having the desired amount of azole antifungal compound.
Experiments were carried out by preparing (as per the procedure given in the examples) itraconazole coated inert cores at different bed temperatures and inlet air relative humidities (Test I, II, III). In vitro release profiles of the coated cores prepared above and that of SPORANOX® beads (beads removed from the capsule) (in pH 6.8 Phosphate buffer with 0.2% SLS, 900 ml, paddle type, 150 rpm). The results of the dissolution are represented below in Table 1. Further, sections of Test I, II, and SPORANOX® beads were cut and viewed under microscope (beads were sectioned
using MICRO™ and viewed under NICON MICROSCOPE Model - Eclipse 80 I, figures provided are at 400 magnification), and are represented herein as Figures 1, 2, and 3.
(Table Removed)
The inventors of the present invention have surprisingly observed that the release profile of azole antifungal compound from drug loaded inert cores is highly dependent upon the surface characteristics of the drug layer. Drug loaded cores having uniform drug layers (Figure 2 and 3), free of air pockets produced predetermined and reproducible release profiles; which is a prerequisite for desirable in vivo performance and clinical benefits. On the other hand, presence of air pockets (Figure 1) provided high initial drug release, the release in overall being highly erratic. Formation of uniform drug layer, free of air pockets was found to be dependent upon the bed temperature and the inlet air relative humidity. Too high bed temperature and/or too low inlet air relative humidity causes fast evaporation of the solvents from the drug layers, resulting in the formation of air pockets. Uniform drug layers, free of air pockets may be produced by achieving and maintaining the bed temperature from about 20° C to about 35° C, and inlet air relative humidity from about 35 % to about 55 %. The optimum bed temperature and inlet air relative humidity may vary with the selection of inert cores of particular size, which can be determined by routine experimentation.
Examples of central inert cores include pharmaceutically acceptable inert cores available commercially or from inert material by process of extrusion-spheronization, granulation and the like.
Specific examples of commercially available inert cores include sugar spheres, non-pariel seeds, celpheres and the like. Alternatively inert cores may be prepared from
pharmaceutically acceptable inert soluble, insoluble or swellable material, with or without pharmaceutically acceptable excipient. Specific examples of insoluble inert material include sand (silicon dioxide), glass, microcrystalline cellulose (celpheres) or plastic (polystyrene). On the other hand soluble inert material includes sugar selected from glucose, mannitol, lactose, xylitol, dextrose, sucrose and the like. Swellable inert material includes hydroxypropyl methylcellulose and the like. The inert core may be of any geometric shape, in particular spheres for ease of uniform coating. The inert core diameter may vary from about 100 urn to about 1200 urn.
The term "azole antifungal compound" includes any poorly soluble antifungal compound having the azole group in its structure such as itraconazole, saperconazole, voriconazole, and the like. It covers free base form and the pharmaceutically acceptable acid addition salts thereof. The acid addition forms may be obtained by reaction of the base form with an appropriate acid. Examples of appropriate acids include inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric acid; nitric acid; phosphoric acid; and organic acids such as acetic, propanoic hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic, butanedioic, (Z)-bulenedioic. (E)-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxy-butanedioic, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic acids. The term also covers isomers, enantiomers, and prodrugs. In particular the azole antifungal compound is itraconazole.
Hydrophilic polymer used in the active layer may include cellulose derivatives such as methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose hydroxybutylcellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, carboxymethylethylcellulose; starches; pectines such as sodium carboxymethylamylopectin; chitin derivates such as chitosan, acrylic and methacrylic acid derivatives and copolymers; polyvinylalcohol; povidone, copovidone and copolyvidone; polyafkylene oxides such as polyethylene oxide and polypropylene oxide; and copolymers of ethylene oxide and propylene oxide. In particular, hydroxypropyl methylcellulose having viscosity in the range of 3 cps to 15 cps may be used. When hydroxypropyl methylcellulose is used as a hydrophilic polymer, the w/w ratio of itraconazole and hydroxypropyl methylcellulose may vary from about 0.75:2.0 to about 2.0:0.75.
The seal coat layer may comprise one or more seal coating polymer including polyethylene glycol, ethyl cellulose, acrylic polymers like Eudragit E 100, shellac, cellulose derivatives, and the like. In particular, polyethylene glycol may be used. The seal coating layer may be applied over the drug coated cores up to a weight build up of about 1.0 % to about 5.0 %.
The term "coater" as used herein includes any conventionally used coating equipment in the art of pharmaceutical dispensing. In particular, a fluidized bed coater may be used.
The term "solid dosage form" as used herein includes multiple drug coated core processed into tablet, capsule, sachet and the like.
In one of the embodiments itraconazole capsule may be prepared by a process comprising the steps of
a) loading central inert cores in a fluidized bed coater;
b) achieving and maintaining the bed temperature from about 20° C to about 35° C, and inlet air relative humidity from about 35 % to about 55 %,
c) preparing a solution of itraconazole and hydrophilic polymer in one or more solvent;
d) coating the central cores with the solution of step c);
e) drying the drug coated cores;
f) preparing a solution of seal coating polymer in one or more solvent;
g) coating the dried coated cores with the solution of step 0; h) filing the coated cores in capsule shells of suitable size.
Example of solvents used for preparing a solution/dispersion of azole antifungal compound and hydrophilic polymer may include methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, and mixtures thereof. In particular a mixture of methylene chloride and ethanol may be used.
Drug coated inert cores may be dried in suitable dryers selected based upon the solvents used, and the diameter of the inert cores selected. In particular, Tray dryer, Hot air oven, Fluidized bed dyer/processor may be used. In general, the drug coated
cores may be dried at about 60° C to about 100° C for about 12 hours to about 36 hours.
The pharmaceutical composition may further comprise one or more pharmaceutically inert excipients to aid in processing or performance as known in the prior art.
The term "pharmaceutically inert excipient" as used herein includes surfactants, binders, diluents, lubricants, glidants, plasticizers, stabilizers and coloring agents.
Examples of surfactants include both non-ionic and ionic (cationic, anionic and zwitterionic) surfactants suitable for use in pharmaceutical compositions. Specific examples include polyethoxylated fatty acids and its derivatives, for example polyethylene glycol 400 distearate, polyethylene glycol - 20 dioleate, polyethylene glycol 4 -150 mono dilaurate, polyethylene glycol -20 glyceryl stearate; alcohol - oil transesterification products, for example polyethylene glycol - 6 corn oil; polyglycerized fatty acids, for example polyglyceryl - 6 pentaoleate; propylene glycol fatty acid esters, for example propylene glycol monocaprylate; mono and diglycerides for example glyceryl ricinoleate; Sterol and sterol derivatives, for example sitosterol; sorbitan fatty acid esters and its derivatives, for example polyethylene glycol - 20 sorbitan monooleate, sorbitan monolaurate; vegetable oils, for example castor oil, hydrogenated vegetable oil: polyethylene glycol alkyl ether or phenols, for example polyethylene glycol - 20 cetyl ether, polyethylene glycol - 10 - 100 nonyl phenol; sugar esters, for example sucrose monopalmitate; polyoxyethylene - polyoxypropylene block copolymers known as "poloxamer"; ionic surfactants, for example sodium caproate, sodium glycocholate, soy lecithin, sodium stearyl fumarate, propylene glycol alginate, octyl sulfosuccinate disodium, palmitoyl carnitine; and the like.
Examples of binders include methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and the like.
Examples of diluents include calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, cellulose-microcrystalline, cellulose powdered,
dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners and mixtures thereof.
Examples of lubricants and glidants include colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, glyceryl behenate and the like.
Examples of plasticizers include polyethylene glycol, triethyl citrate, triacetin, diethyl phthalate, dibutyl sebacate and the like.
Examples of stabilizers include antioxidants, buffers, acids and the like. Examples of coloring agents include any FDA approved color for oral use.
The invention is further illustrated by the following examples but they should not be construed as limiting the scope of the invention any way.
Examples Composition
(Table Removed) Includes 10 % overages
Procedure:
a) Non pareil seeds were loaded in a fluidized bed coater.
b) The bed temperature and inlet air relative humidity were adjusted and maintained from about 27° C to about 30° C and from about 35 % to about 45 % respectively.
c) Itraconazole and hydroxypropyl methylcellulose were dissolved in a mixture of methylene chloride and ethanol (60:40 w/w) to form an 8 % w/w solution.
d) The non pareil seeds were coated with the solution of step c) and dried under vacuum at 80° C for 36 hours.
e) Polyethylene glycol was dissolved in a mixture of methylene chloride and ethanol (60:40 w/w) to form a 10 % w/w solution.
f) The coated cores of step d) were coated with the seal coating solution of step e).
g) The seal coated cores of step f) were filled into capsules of size "0", so that each capsule comprised 100 mg itraconazole.
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wherein coating of the inert core with drug layer is carried out by achieving and maintaining the bed temperature from about 20° C to about 35° C, and inlet air relative humidity from about 35 % to about 55 %, and drying the drug loaded cores at about 60° C to about 100° C.
9. The pharmaceutical composition of azole antifungal compound and process of preparation thereof, as described and illustrated in the examples and figures herein.