The technical field of the present invention relates to oral pharmaceutical composition of poorly soluble azole antifungal compounds having acceptable in vitro and in vivo performance. It also relates to process of preparation of above pharmaceutical compositions.
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 to about 700 urn. 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 to 355 urn and 710 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 above concept is carried further in European Patent EP 1103252, assigned to Liconsa and disclosing an oral pharmaceutical composition comprising a) an inert core and b) a single soluble active layer obtained from a solution comprising an active principle having
antifungal activity, an hydrophilic polymer and a non-ionic surfactant. It is believed that the incorporation of the non-ionic surfactant surprisingly prevents particle agglomeration.
However, there still exists a need for alternative pharmaceutical compositions of azole antifungal compounds which are easy to prepare using commonly used excipients and are economical.
We have now developed alternative pharmaceutical compositions of azole antifungal compounds having the problem of sticking of the drug coated cores to a negligible level, without the application of a separate seal coating polymer layer or non-ionic surfactant.
Hence, in one general aspect there is provided a pharmaceutical composition of azole antifungal compound comprising
a) drug coated cores, wherein the said drug coated core comprises
i) a central inert core, and
ii) at least one active layer comprising azole antifungal compound and hydrophilic polymer; and
b) antisticking-aid.
In another general aspect there is provided a pharmaceutical composition of azole antifungal compound comprising
a) drug coated cores, wherein the said drug coated core comprises
i) a central inert core, and
ii) at least one active layer comprising itraconazole and hydrophilic polymer; and
b) antisticking-aid.
In another general aspect there is provided a process for the preparation of a pharmaceutical composition of azole antifungal compound wherein the said process comprises the steps of:
a) coating central inert cores with at least one active layer comprising azole antifungal compound and hydrophilic polymer;
b) blending with antisticking-aid; and
c) processing into solid dosage form.
In another general aspect there is provided a process for the preparation of a pharmaceutical composition of azole antifungal compound wherein the said process comprises the steps of:
a) coating central inert cores with at least one active layer comprising itraconazole and hydrophilic polymer;
b) blending with antisticking-aid; and
c) processing into solid dosage form.
In another general aspect there is provided use of a pharmaceutical composition of azole antifungal compound comprising
a) drug coated cores, wherein the said drug coated core comprises
i) a central inert core, and
ii) at least one active layer comprising azole antifungal compound and hydrophilic polymer; and
b) antisticking-aid;
for the treatment of fungal infection in a mammal.
In another general aspect there is provided use of a pharmaceutical composition of azole antifungal compound comprising
a) drug coated cores, wherein the said drug coated core comprises
i) a central inert core, and
ii) at least one active layer comprising itraconazole and hydrophilic polymer; and
b) antisticking-aid;
for the treatment of fungal infection in a mammal.
In another general aspect more than one active layer may be applied over the central inert cores. In particular two active layers may be applied. The ratio of azole antifungal compound in the first and second active layers may vary in the range of about 50:50 to about 99:1.
The pharmaceutical compositions of the present invention avoid the application of a separate seal coat layer over the active layer. This reduces the time and cost of production. The agglomeration of the drug coated cores is effectively reduced with the use of an antisticking-aid. Mere blending of drug coated cores with the antisticking-aid have been found to ease processing into solid dosage forms of desired dissolution rate and bioavailability.
Examples of central inert cores include pharmaceutical^ acceptable inert cores available commercially or from inert material by process of extrusion-spheronization, granulation and the like.
Specific examples of commercially available inert pellets include sugar spheres, non-pariel seeds, celpheres and the like. Alternatively inert pellets 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 include 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 to 1200 urn.
The term "itraconazole" as used herein includes the free base form and the pharmaceutically acceptable acid addition salts of itraconazole, or of one of its stereoisomers, or of a mixture of two or more of its stereoisomers. In particular, (±)-(cis) form of the free base form may be used. 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.
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 carboxymethylamylopectine; chitine derivates such as chitosan, acrylic and methacrylic acid derivatives and copolymers; polyvinylalcohol; povidone, copovidone and copolyvidone; polyalkylene 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 to 15 cps. may be used. It has been observed that the ratio of itraconazole and hydrophilic polymer in the active layer is critical and should be evaluated with care. 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 to about 1:0.75, in particular about 1:1.
The term "antisticking-aid" as used herein comprises one or more lubricant/glidants and/or cushioning beads. Examples of lubricants/glidants include talc, colloidal silicon dioxide, magnesium sterate, steraic acid, glyceryl behenate, and the like. Incorporation of cushioning beads into the antisticking-aid synergistically reduces the tendency of drug coated cores to form agglomerates. Examples of cushioning beads include all inert cores as described herein. In particular, sugar spheres may be used.
The pharmaceutical composition of azole antifungal compound may be prepared by processes known in the prior art, e.g. by comminuting, mixing, granulation, sizing, filling, molding, spraying, immersing coating, compressing etc.
In one of the embodiments, pharmaceutical composition of azole antifungal compound
may be prepared by a process comprising the steps of:
a) coating central inert cores with an active layer comprising itraconazole and hydrophilic
polymer;
b) blending with antisticking-aid; and
c) processing into solid dosage form.
In one of the embodiments, pharmaceutical composition of azole antifungal compound may be prepared by a process comprising the steps of:
a) coating central inert cores with two active layers comprising itraconazole and hydrophilic polymer;
b) blending with antisticking-aid; and
c) processing into solid dosage form.
The active layers may be applied over the central inert cores as solution/ dispersion of coating ingredients using any conventional technique known in the prior art such as spray coating in a conventional coating pan or fluidized bed processor; dip coating and the like.
Alternatively the layers over the central inert core may also be applied using hot melt technique.
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.
The active layers, central inert cores and antisticking-aid may further comprise one or more pharmaceutically inert excipients to aid in processing or performance as known in the prior art.
The drug coated cores prepared by any of the above methods may be blended with other pharmaceutically inert excipients (if required) and compressed into tablet or filled into capsule/sachet, using techniques known in the art for these purposes. The final tablet or capsule may optionally be coated with film-forming polymers, if desired.
The term "pharmaceutically inert excipient" as used herein include surfactants, binders, diluents, disintegrants, 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
Table 1. Capsule composition
(Table Removed)
Procedure:
1. Itraconazole and hydroxypropyl methylcellulose were dissolved in a mixture of methylene chloride and ethanol.
2. PEG was dissolved (only for Example 1) under continuous stirring in the solution of step 1.
3. Talc was added to the above solution, and properly stirred to prepare a homogenous dispersion.
4. Celpheres were loaded in a fluidized bed processor, and layered with the
dispersion of step 3.
5. Drug loaded spheres were then dried in a vacuum tray dryer and blended with the antisticking-aid.
6. The blend of step 5 was finally filled into suitable sized capsules, to obtain a dose of 100 mg itraconazole per capsule.
Table 2. Capsule composition
(Table Removed)
Table 3. Capsule composition
(Table Removed)
Procedure (Example 3-9):
1. Itraconazole and hydroxypropyl methylcellulose portions of the first drug layer were dissolved in a mixture of methylene chloride and ethanol.
2. Sugar spheres/celpheres were loaded in a fluidized bed processor, and layered with the solution of step 1.
3. The drug loaded spheres were dried in a vacuum tray dryer.
4. Itraconazole and hydroxypropyl methylcellulose portions of the second drug layer were dissolved in a mixture of methylene chloride and ethanol.
5. Talc, PEG (Examples 3, 6, 8 and 9), castor oil (Example 5) and colloidal silicon dioxide (Example 4 and 7) were added to the solution of step 4, and properly stirred to prepare a homogenous dispersion.
6. Drug loaded spheres of step 2 were further layered with the dispersion of step 5.
7. Drug loaded beads were then dried in a vacuum tray dryer and blended with the antisticking-aid.
8. The blend of step 7 was finally filled into suitable sized capsules, to obtain a dose of 100 mg itraconazole per capsule.

WE CLAIM:
1. A pharmaceutical composition of azole antifungal compound comprising
a) drug coated cores, wherein the said drug coated core comprises
i) a central inert core, and
ii) at least one active layer comprising azole antifungal compound and
hydrophilic polymer; and
b) antisticking-aid.
2. The pharmaceutical composition of azole antifungal compound according to claim 1 wherein two active layers are applied over the central inert core.
3. The pharmaceutical composition of azole antifungal compound according to claim 2 wherein the ratio of azole antifungal compound in first and second active layers over the central inert core, may vary from about 50:50 to about 99:1.
4. The pharmaceutical composition of azole antifungal compound according to claim 3 wherein the ratio of azole antifungal compound in first and second active layers over the central inert core may vary from about 80:20 to about 95:5.
5. The pharmaceutical composition of azole antifungal compound according to claim 1 wherein azole antifungal compound is selected from the group consisting of the free base form and the pharmaceutically acceptable acid addition salts of itraconazole, or of one of its stereoisomers, or of a mixture of two or more of its stereoisomers.
6. The pharmaceutical composition of azole antifungal compound according to claim 5 wherein azole antifungal compound is free base form of itraconazole.
7. The pharmaceutical composition of azole antifungal compound according to claim 1 wherein inert core is a commercially available product selected from the group consisting of sugar sphere, non pareil seed, and celphere.
8. The pharmaceutical composition of azole antifungal compound according to claim 7 wherein inert core is sugar sphere.
9. The pharmaceutical composition of azole antifungal compound according to claim 1 wherein inert core may be prepared from insoluble, soluble or swellable inert material.
10. The pharmaceutical composition of azole antifungal compound according to claim 9 wherein inert core is prepared from an insoluble material.
11.The pharmaceutical composition of azole antifungal compound according to claim 10 wherein insoluble material is selected from the group consisting of sand (silicon dioxide), glass, microcrystalline cellulose, Starch and plastic (polystyrene).
12.The pharmaceutical composition of azole antifungal compound according to claim 9 wherein inert core is prepared from a soluble material.
13. The controlled release multiple unit system according to claim 12 wherein soluble material is selected from the group consisting of sugars such as glucose, mannitol, lactose, xylitol, sucrose, and dextrose.
14.The pharmaceutical composition of azole antifungal compound according to claim 9 wherein inert core is prepared from a swellable material.
15.The pharmaceutical composition of azole antifungal compound according to claim 14 wherein swellable material is hydroxypropyl methylcellulose.
16.The pharmaceutical composition of azole antifungal compound according to claim 9 wherein inert core is prepared by the method of extrusion-spheronization.
17.The pharmaceutical composition of azole antifungal compound according to claim 9 wherein inert core is prepared by the method of granulation.
18.The pharmaceutical composition of azole antifungal compound according to claim 1
wherein hydrophilic polymer is selected from the group consisting of cellulose
derivatives such as methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose hydroxybutylcellulose, hydroxyethyl methylcellulose,
hydroxypropyl methylcellulose, carboxymethylcellulose, sodium
carboxymethylcellulose, carboxymethylethylcellulose; starches; pectines such as sodium carboxymethylamylopectine; chitine derivates such as chitosan, acrylic and methacrylic acid derivatives and copolymers; polyvinylalcohol; povidone, copovidone and copolyvidone; polyalkylene oxides such as polyethylene oxide and polypropylene oxide; and copolymers of ethylene oxide and propylene oxide.
19. The pharmaceutical composition of azole antifungal compound according to claim 18 wherein hydrophilic polymer is hydroxypropyl methylcellulose.
20. The pharmaceutical composition of azole antifungal compound according to claim 19 wherein w/w ratio of azole antifungal compound and hydroxypropyl methylcellulose may vary from about 0.75:2 to about 1:0.75.
21.The pharmaceutical composition of azole antifungal compound according to claim 20
wherein w/w ratio of azole antifungal compound and hydroxypropyl methylcellulose is
1:1. 22.The pharmaceutical composition of azole antifungal compound according to claim 1
wherein the antisticking-aid comprises one or more lubricant/glidant, and/or cushioning
bead. 23.The pharmaceutical composition of azole antifungal compound according to claim 22
wherein lubricant/glidant is selected from the group consisting of talc, colloidal silicon
dioxide, magnesium sterate, stearic acid, glyceryl behenate etc.
24. The pharmaceutical composition of azole antifungal compound according to claim 23 wherein lubricant/glidant is a combination of colloidal silicon dioxide and talc.
25. The pharmaceutical composition of azole antifungal compound according to claim 22 wherein cushioning bead is selected from the group consisting of inert cores described in claims 7 to 15.
26.The pharmaceutical composition of azole antifungal compound according to claim 25
wherein cushioning bead is sugar sphere. 27. The pharmaceutical composition of azole antifungal compound according to claim 23
and 25 wherein antisticking-aid is a combination of talc, colloidal silicon dioxide and
sugar sphere. 28.The pharmaceutical composition of azole antifungal compound according to claim 1
wherein pharmaceutical composition is a solid dosage form selected from the group
consisting of tablet, capsule and sachet. 29.The pharmaceutical composition of azole antifungal compound according to claim 28
wherein solid dosage form is capsule. 30.The pharmaceutical composition of azole antifungal compound according to claim 28
wherein solid dosage form may further comprise one or more pharmaceutically inert
excipients. 31.The pharmaceutical composition of azole antifungal compound according to claim 30
wherein pharmaceutically inert excipient is selected from the group consisting of
surfactants, binders, diluents, disintegrants, lubricants, glidants, plasticizers, stabilizers
and coloring agents. 32.A process for the preparation of a pharmaceutical composition of azole antifungal
compound wherein the said process comprises the steps of:
a) coating central inert cores with at least one active layer comprising azole antifungal compound and hydrophilic polymer;
b) blending with antisticking-aid; and
c) processing into solid dosage form.
33.The process for the preparation of a pharmaceutical composition of azole antifungal compound according to claim 32 wherein two active layers are applied over the central inert core.
34.The process for the preparation of a pharmaceutical composition of azole antifungal compound according to claim 33 wherein the ratio of azole antifungal compound in first and second active layers over the central inert core, may vary from about 50:50 to about 99:1.
35.The process for the preparation of a pharmaceutical composition of azole antifungal compound according to claim 34 wherein the ratio of azole antifungal compound in first and second active layers over the central inert core may vary from about 80:20 to about 95:5.
36. The process for the preparation of a pharmaceutical composition of azole antifungal compound according to claim 32 wherein azole antifungal compound is selected from the group consisting of the free base form and the pharmaceutically acceptable acid addition salts of itraconazole, or of one of its stereoisomers, or of a mixture of two or more of its stereoisomers.
37. The process for the preparation of a pharmaceutical composition of azole antifungal compound according to claim 36 wherein azole antifungal compound is free base form of itraconazole.
38.The process for the preparation of a pharmaceutical composition of azole antifungal
compound according to claim 32 wherein active layer is applied as a
solution/dispersion. 39.The process for the preparation of a pharmaceutical composition of azole antifungal
compound according to claim 38 wherein solution/dispersion is prepared in solvents
selected from the group consisting of methylene chloride, isopropyl alcohol, acetone,
methanol, ethanol, and mixtures thereof. 40.The process for the preparation of a pharmaceutical composition of azole antifungal
compound according to claim 32 wherein active layer is applied using hot melt
technique.
41.The process for the preparation of a pharmaceutical composition of azole antifungal compound according to claim 32 wherein solid dosage form is selected from the group of tablet, capsule and sachet. 42.The process for the preparation of a pharmaceutical composition of azole antifungal
compound according to claim 41 wherein solid dosage form is capsule. 43. Use of a pharmaceutical composition of azole antifungal compound comprising a) drug coated cores, wherein the said drug coated core comprises i) a central inert core, and
ii) at least one active layer comprising azole antifungal compound and hydrophilic polymer; and b) antisticking-aid; for the treatment of fungal infection in a mammal. 44.The use of a pharmaceutical composition of azole antifungal compound according to claim 43 wherein azole antifungal compound is selected from the group consisting of the free base form and the pharmaceutical^/ acceptable acid addition salts of itraconazole, or of one of its stereoisomers, or of a mixture of two or more of its stereoisomers. 45. The use of a pharmaceutical composition of azole antifungal compound according to claim 44 wherein azole antifungal compound is free base form of itraconazole.