WO2022264004A1 - Composition pharmaceutique comprenant de l'itraconazole - Google Patents

Composition pharmaceutique comprenant de l'itraconazole Download PDF

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Publication number
WO2022264004A1
WO2022264004A1 PCT/IB2022/055460 IB2022055460W WO2022264004A1 WO 2022264004 A1 WO2022264004 A1 WO 2022264004A1 IB 2022055460 W IB2022055460 W IB 2022055460W WO 2022264004 A1 WO2022264004 A1 WO 2022264004A1
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WIPO (PCT)
Prior art keywords
itraconazole
pharmaceutical composition
oral pharmaceutical
solid oral
amount
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PCT/IB2022/055460
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English (en)
Inventor
Sushrut Kulkarni
Nitin Deshmukh
Ravindra SATPUTE
Kunal BAGUL
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Glenmark Pharmaceutical Limited
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Application filed by Glenmark Pharmaceutical Limited filed Critical Glenmark Pharmaceutical Limited
Priority to BR112023026118A priority Critical patent/BR112023026118A2/pt
Publication of WO2022264004A1 publication Critical patent/WO2022264004A1/fr
Priority to CONC2024/0000201A priority patent/CO2024000201A2/es

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin

Definitions

  • the invention relates to a stable solid oral pharmaceutical composition comprising itraconazole which provides reduction in pill burden in the treatment of fungal infections, including superficial infections, such as onychomycosis, as well as systemic fungal infections, for example, pulmonary or extrapulmonary blastomycosis, histoplasmosis, and aspergillosis.
  • the application also relates to a process for preparing the pharmaceutical composition comprising itraconazole.
  • Itraconazole is a broad spectrum triazole antifungal compound available for the treatment of fungal infections, including superficial infections, such as onychomycosis, as well as systemic fungal infections, for example, Blastomycosis, pulmonary and extrapulmonary, Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non-meningeal histoplasmosis, and Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy.
  • superficial infections such as onychomycosis
  • systemic fungal infections for example, Blastomycosis, pulmonary and extrapulmonary, Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non-meningeal histoplasmosis, and Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy.
  • Itraconazole is a highly variable drug with low bioavailability of 55%.
  • the maximum daily dose of conventional itraconazole capsules in life threatening situations is 600 mg (six capsules of 100 mg strength in three divided doses of 200 mg).
  • WO 2013/192566 discloses pharmaceutical compositions, such as solid oral dosage forms, comprising itraconazole, methods of making the compositions, and methods of using the same for treating disorders including, but not limited to, fungal infections. This patent application is silent on challenges of having high content of itraconazole and stability of the composition.
  • Some solid oral dosage forms containing magnesium stearate as lubricant are known for its hydrophobicity and possible negative effect on dissolution of active substances.
  • the article from Demuth et al discloses deteriorated dissolution of itraconazole in presence of magnesium stearate.
  • the invention in one embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising itraconazole in a solid dispersion with a matrix polymer and dissolution enhancing agent(s).
  • Another embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising (a) itraconazole, (b) matrix polymer and (c) dissolution enhancing agent(s).
  • a stable solid oral pharmaceutical composition comprising:
  • dissolution enhancing agent(s) selected from combination of (i) dibasic calcium phosphate and (ii) silicified microcrystalline cellulose or combination of (i) dibasic calcium phosphate and (ii) microcrystalline cellulose.
  • Another embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising itraconazole in a solid dispersion with a matrix polymer selected from hypromellose phthalate, copovidone, hypromellose acetate succinate, hypromellose, polymethacrylates, hydroxypropyl cellulose and cellulose acetate phthalate and dissolution enhancing agent(s) selected from combination of (i) dibasic calcium phosphate and (ii) silicified microcrystalline cellulose or combination of (i) dibasic calcium phosphate and (ii) microcrystalline cellulose.
  • a matrix polymer selected from hypromellose phthalate, copovidone, hypromellose acetate succinate, hypromellose, polymethacrylates, hydroxypropyl cellulose and cellulose acetate phthalate
  • dissolution enhancing agent(s) selected from combination of (i) dibasic calcium phosphate and (ii) silicified microcrystalline cellulose or combination
  • Another embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising (a) itraconazole in an amount of 50 mg to 300 mg, (b) matrix polymer selected from hypromellose phthalate, copovidone, hypromellose acetate succinate, hypromellose, polymethacrylates, hydroxypropyl cellulose and cellulose acetate phthalate and (c) dissolution enhancing agent(s) selected from combination of (i) dibasic calcium phosphate and (ii) silicified microcrystalline cellulose or combination of (i) dibasic calcium phosphate and (ii) microcrystalline cellulose.
  • Another embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising (a) itraconazole in an amount of 50 mg to 400 mg, (b) matrix polymer selected from hypromellose phthalate, copovidone, hypromellose acetate succinate, hypromellose, polymethacrylates, hydroxypropyl cellulose and cellulose acetate phthalate and (c) dissolution enhancing agent(s) selected from combination of (i) dibasic calcium phosphate and (ii) silicified microcrystalline cellulose or combination of (i) dibasic calcium phosphate and (ii) microcrystalline cellulose wherein a.
  • matrix polymer selected from hypromellose phthalate, copovidone, hypromellose acetate succinate, hypromellose, polymethacrylates, hydroxypropyl cellulose and cellulose acetate phthalate
  • dissolution enhancing agent(s) selected from combination of (i) dibasic calcium phosphate and (i
  • itraconazole is present in an amount from 20% w/w to 60% w/w, preferably from 30% w/w to 50% w/w and more preferably 40% w/w by total weight of the solid dispersion;
  • weight ratio of itraconazole to matrix polymer is in the range of about 1 : 1 to about 1 : 3 , or about 1 : 1.5, based on the weight of itraconazole;
  • dissolution enhancing agent(s) is preferably present in an amount from 10% w/w to 80% w/w, more preferably in an amount from 20% w/w to 70% w/w, most preferably in an amount from 30% w/w to 60% w/w by total weight of the composition;
  • dissolution enhancing agent(s) selected from combination of (i) dibasic calcium phosphate and (ii) silicified microcrystalline cellulose or combination of (i) dibasic calcium phosphate and (ii) microcrystalline cellulose wherein i. itraconazole is present in an amount from 50 mg or 65 mg or 100 mg or 130 mg or 150 mg or 195 mg or 200 mg or 250 mg or 260 mg or 300 mg or 400 mg ii. itraconazole is present in an amount from 20% w/w to 60% w/w, preferably from 30% w/w to 50% w/w and more preferably 40% w/w by total weight of the solid dispersion; iii.
  • weight ratio of itraconazole to matrix polymer is in the range of about 1 : 1 to about 1:3, or about 1: 1.5, based on the weight of itraconazole;
  • dissolution enhancing agent(s) is preferably present in an amount from 10% w/w to 80% w/w, more preferably in an amount from 20% w/w to 70% w/w, most preferably in an amount from 30% w/w to 60% w/w by total weight of the composition;
  • Another embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising (a) itraconazole in an amount of 50 mg, (b) matrix polymer selected from hypromellose phthalate, copovidone, hypromellose acetate succinate, hypromellose, polymethacrylates, hydroxypropyl cellulose and cellulose acetate phthalate and (c) dissolution enhancing agent(s) selected from combination of (i) dibasic calcium phosphate and (ii) silicified microcrystalline cellulose or combination of (i) dibasic calcium phosphate and (ii) microcrystalline cellulose.
  • Another embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising (a) itraconazole in an amount of 65 mg, (b) matrix polymer selected from hypromellose phthalate, copovidone, hypromellose acetate succinate, hypromellose, polymethacrylates, hydroxypropyl cellulose and cellulose acetate phthalate and (c) dissolution enhancing agent(s) selected from combination of (i) dibasic calcium phosphate and (ii) silicified microcrystalline cellulose or combination of (i) dibasic calcium phosphate and (ii) microcrystalline cellulose.
  • Another embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising (a) itraconazole in an amount of 100 mg, (b) matrix polymer selected from hypromellose phthalate, copovidone, hypromellose acetate succinate, hypromellose, polymethacrylates, hydroxypropyl cellulose and cellulose acetate phthalate and (c) dissolution enhancing agent(s) selected from combination of (i) dibasic calcium phosphate and (ii) silicified microcrystalline cellulose or combination of (i) dibasic calcium phosphate and (ii) microcrystalline cellulose.
  • Another embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising (a) itraconazole in an amount of 130 mg, (b) matrix polymer selected from hypromellose phthalate, copovidone, hypromellose acetate succinate, hypromellose, polymethacrylates, hydroxypropyl cellulose and cellulose acetate phthalate and (c) dissolution enhancing agent(s) selected from combination of (i) dibasic calcium phosphate and (ii) silicified microcrystalline cellulose or combination of (i) dibasic calcium phosphate and (ii) microcrystalline cellulose.
  • Another embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising (a) itraconazole in an amount of 130 mg, (b) matrix polymer, wherein itraconazole is dispersed in matrix polymer phase; wherein itraconazole is present in an amount from 20% w/w to 60% w/w, preferably from 30% w/w to 50% w/w and more preferably 40% w/w by total weight of the solid dispersion; wherein weight ratio of itraconazole to matrix polymer is in the range of about 1: 1 to about 1:3, or about 1: 1.5, based on the weight of itraconazole.
  • Another embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising (a) itraconazole in an amount of 130 mg, (b) matrix polymer selected from hypromellose phthalate, copovidone, hypromellose acetate succinate, hypromellose, polymethacrylates, hydroxypropyl cellulose and cellulose acetate phthalate wherein itraconazole is dispersed in matrix polymer phase; wherein itraconazole is present in an amount from 20% w/w to 60% w/w, preferably from 30% w/w to 50% w/w and more preferably 40% w/w by total weight of the solid dispersion; wherein weight ratio of itraconazole to matrix polymer is in the range of about 1: 1 to about 1:3, or about 1: 1.5, based on the weight of itraconazole.
  • Another embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising (a) itraconazole in an amount of 200 mg, (b) matrix polymer selected from hypromellose phthalate, copovidone, hypromellose acetate succinate, hypromellose, polymethacrylates, hydroxypropyl cellulose and cellulose acetate phthalate and (c) dissolution enhancing agent(s) selected from combination of (i) dibasic calcium phosphate and (ii) silicified microcrystalline cellulose or combination of (i) dibasic calcium phosphate and (ii) microcrystalline cellulose.
  • Another embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising (a) itraconazole in an amount of 300 mg, (b) matrix polymer selected from hypromellose phthalate, copovidone, hypromellose acetate succinate, hypromellose, polymethacrylates, hydroxypropyl cellulose and cellulose acetate phthalate and (c) dissolution enhancing agent(s) selected from combination of (i) dibasic calcium phosphate and (ii) silicified microcrystalline cellulose or combination of (i) dibasic calcium phosphate and (ii) microcrystalline cellulose.
  • Another embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising (a) itraconazole in an amount of 400 mg, (b) matrix polymer selected from hypromellose phthalate, copovidone, hypromellose acetate succinate, hypromellose, polymethacrylates, hydroxypropyl cellulose and cellulose acetate phthalate and (c) dissolution enhancing agent(s) selected from combination of (i) dibasic calcium phosphate and (ii) silicified microcrystalline cellulose or combination of (i) dibasic calcium phosphate and (ii) microcrystalline cellulose.
  • Another embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising (a) itraconazole is present in an amount from 130 mg or 150 mg or 195 mg or 200 mg or 250 mg or 260 mg or 300 mg or 400 mg, (b) matrix polymer selected from hypromellose phthalate, copovidone, hypromellose acetate succinate, hypromellose, polymethacrylates, hydroxypropyl cellulose and cellulose acetate phthalate wherein itraconazole is dispersed in matrix polymer phase; wherein itraconazole is present in an amount from 20% w/w to 60% w/w, preferably from 30% w/w to 50% w/w and more preferably 40% w/w by total weight of the solid dispersion; wherein weight ratio of itraconazole to matrix polymer is in the range of about 1: 1 to about 1:3, or about 1: 1.5, based on the weight of itraconazole.
  • the weight ratio of itraconazole to matrix polymer is in the range of about 1 : 0.5 to about 1 : 5 based on the weight of itraconazole.
  • Another embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising itraconazole that minimises the number of capsules required for the therapeutically effective dose, ideally to fewer than 4 units, preferably two or three units.
  • Another embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising itraconazole in a solid dispersion with a matrix polymer and dissolution enhancing agent(s) wherein the said composition is devoid of magnesium stearate.
  • Another embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising itraconazole in a solid dispersion with a matrix polymer and dissolution enhancing agent(s) wherein the said composition is devoid of surfactant.
  • Another embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising itraconazole in a solid dispersion with a matrix polymer and dissolution enhancing agent(s), wherein itraconazole is present in an amount of 50 mg or 65 mg or 100 mg or 130 mg or 150 mg or 195 mg or 200 mg or 250 mg or 260 mg or 300 mg or 400 mg of itraconazole.
  • Another embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising itraconazole in a solid dispersion with a matrix polymer and dissolution enhancing agent(s), wherein itraconazole is present in an amount from 20% w/w to 60% w/w, preferably from 30% w/w to 50% w/w and more preferably 40% w/w by total weight of the solid dispersion.
  • Another embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising itraconazole in a solid dispersion with a matrix polymer and dissolution enhancing agent(s), wherein dissolution enhancing agent(s) is preferably present in an amount from 10% w/w to 80% w/w, more preferably in an amount from 20% w/w to 70% w/w, most preferably in an amount from 30% w/w to 60% w/w by total weight of the composition.
  • Another embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising itraconazole in a solid dispersion with a matrix polymer and dissolution enhancing agent(s), wherein itraconazole is present in an amount of 20% to 60%, and preferably from 30% to 50% and more preferably 40% by weight of the solid dispersion.
  • Another embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising itraconazole in a solid dispersion with a matrix polymer and dissolution enhancing agent(s), wherein weight ratio of itraconazole to matrix polymer is in the range of about 1 : 1 to about 1 : 3 , or about 1 : 1.5, based on the weight of itraconazole.
  • the matrix polymer is hypromellose phthalate.
  • Another embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising a) itraconazole in an amount of 130 mg in a solid dispersion with a matrix polymer wherein itraconazole is present in an amount from 20% w/w to 60% w/w by total weight of the solid dispersion; and b) dissolution enhancing agent(s).
  • Another embodiment relates to a stable solid oral pharmaceutical composition, wherein itraconazole is present in an amount from 30 % w/w to 50% w/w by total weight of the solid dispersion.
  • Another embodiment relates to a stable solid oral pharmaceutical composition, wherein itraconazole is present in an amount of about 40% w/w by total weight of the solid dispersion.
  • Another embodiment relates to a stable solid oral pharmaceutical composition, wherein matrix polymer selected from hypromellose phthalate, copovidone, hypromellose acetate succinate, hypromellose, polymethacrylates, hydroxypropyl cellulose and cellulose acetate phthalate.
  • matrix polymer selected from hypromellose phthalate, copovidone, hypromellose acetate succinate, hypromellose, polymethacrylates, hydroxypropyl cellulose and cellulose acetate phthalate.
  • Another embodiment relates to a stable solid oral pharmaceutical composition, wherein dissolution enhancing agent(s) is selected from combination of (i) dibasic calcium phosphate and (ii) silicified microcrystalline cellulose or combination of (i) dibasic calcium phosphate and (ii) microcrystalline cellulose.
  • Another embodiment relates to a stable solid oral pharmaceutical composition, wherein dissolution enhancing agent(s) is present in an amount from 10% w/wto 80% w/w by total weight of the composition.
  • Another embodiment relates to a stable solid oral pharmaceutical composition, wherein dissolution enhancing agent(s) is present in an amount from 20% w/w to 70% w/w by total weight of the composition.
  • Another embodiment relates to a stable solid oral pharmaceutical composition, wherein dissolution enhancing agent(s) is present in an amount from 30% w/w to 60% w/w by total weight of the composition.
  • the dissolution enhancing agent(s) is combination of (i) dibasic calcium phosphate and (ii) silicified microcrystalline cellulose in the ratio of 1 : 1 to 1:4.
  • the dissolution enhancing agent(s) is combination of (i) dibasic calcium phosphate and (ii) microcrystalline cellulose in the ratio of 1:1 to 1:4.
  • Another embodiment relates to a stable solid oral pharmaceutical composition comprising itraconazole in capsule dosage form.
  • step (ii) the solution from step (i) was spray-dried to form solid dispersion as a spray dried powder.
  • the spray dried solid dispersion was further dried in suitable dryer.
  • step (iii) the solid dispersion of itraconazole and matrix polymer was mixed properly with dissolution enhancing agent(s) and one or more pharmaceutically acceptable excipient like disintegrant, lubricant or glidant; (iv) the blend from step (iii) was filled in suitable capsules.
  • Another embodiment relates to method of producing a stable solid oral pharmaceutical composition of itraconazole by blending process.
  • Another embodiment relates to method of producing a stable solid oral pharmaceutical composition of itraconazole by roll compaction process.
  • stable solid oral pharmaceutical composition means a solid oral pharmaceutical composition which exhibits substantial chemical stability (assay / total impurity) of itraconazole and NLT 70% (Q) of labelled amount of itraconazole is dissolved in 60 minutes under specified dissolution conditions over a period of 3 months or 6 months or 9 months or 12 months or 24 months at ambient conditions (e.g., about 30°C and a relative humidity (RH) of about 75%) or at accelerated conditions (e.g., at about 40°C and about 75% RH).
  • ambient conditions e.g., about 30°C and a relative humidity (RH) of about 75%) or at accelerated conditions (e.g., at about 40°C and about 75% RH).
  • the dissolution conditions used are 0.5% SLS in Water / 75 RPM / 900ml /paddle and the limit is NLT 70% (Q) of labelled amount of itraconazole dissolved in 60 minutes.
  • Itraconazole as used herein includes the base form and pharmaceutically acceptable salts, solvates, hydrates, prodrugs, enantiomers, esters, polymorphs, complex, co-crystals thereof.
  • active ingredient (used interchangeably with “active” or “active agent” or “drug” or “medicament”) as used herein include itraconazole.
  • matrix polymer means a material that exhibits low hygroscopicity and high softening temperature comprising a polymer or a blend of two or more polymers.
  • low hygroscopicity we mean having an equilibrium water content ⁇ 10% at 50% relative humidity, as determined by Dynamic Vapour Sorption (DVS), disclosed in Bergren, M. S. Int. I. Pharm 103:103-114 (1994).
  • high softening temperature we mean that the material, in “as received” form (that is to say, without having been exposed to high humidity) exhibits a glass transition temperature (Tg) or melting point (Tm)>100°C., as determined by Differential Scanning Calorimetry (DSC).
  • Tg glass transition temperature
  • Tm melting point
  • DSC Differential Scanning Calorimetry
  • Suitable matrix polymers for use in the invention include: hypromellose phthalate (hydroxypropylmethylcellulose phthalate, HPMCP), copovidone, hypromellose acetate succinate (hydroxypropylmethylcellulose acetate succinate, HPMCAS), , hypromellose (hydroxypropylmethylcellulose, HPMC), polymethacrylates (poly(methacrylic acid, methyl methacrylate 1:1; poly(methacrylic acid, ethyl acrylate) 1:1), hydroxypropyl cellulose (HPC), and cellulose acetate phthalate (CAP).
  • HPMCP hypromellose phthalate
  • copovidone hypromellose acetate succinate
  • HPMCAS hydroxypropylmethylcellulose acetate succinate
  • HPMC hypromellose (hydroxypropylmethylcellulose, HPMC)
  • polymethacrylates poly(methacrylic acid, methyl methacrylate 1:1; poly(methacrylic acid, ethyl acryl
  • dissolution enhancing agent(s) means combination of specific pharmaceutically acceptable excipients which aid in the increase of dissolution of solid oral pharmaceutical composition comprising itraconazole. It was found that use of these combination of specific excipents selected from combination of (i) dibasic calcium phosphate and (ii) silicified microcrystalline cellulose or combination of (i) dibasic calcium phosphate and (ii) microcrystalline cellulose significantly increased the dissolution of solid oral pharmaceutical composition comprising itraconazole.
  • “dissolution enhancing agent(s)” are dibasic calcium phosphate or dicalcium phosphate or dibasic calcium phosphate (anhydrous), microcrystalline cellulose, silicified microcrystalline cellulose (PROSOLV ® SMCC 50), AVICEL ® DG (Microcrystalline Cellulose + Dicalcium Phosphate, Anhydrous; 75:25).
  • AVICEL ® DG is a synergistic combination of 75 percent microcrystalline cellulose and 25 percent anhydrous dibasic calcium phosphate, produced using a spray-dried, co-processing technology.
  • the “dissolution enhancing agent(s)” is combination of two different excipients, where dibasic calcium phosphate is common and the other excipient can be microcrystalline cellulose or other suitable excipient.
  • the various pharmaceutically acceptable excipients selected from the group of diluents, disintegrants, binders, lubricants, glidants. Additional excipients may be included in the formulation.
  • Suitable diluents include, for example, lactose, sugar, starches, modified starches, mannitol, sorbitol, calcium sulphate, xylitol, lactitol and the like.
  • Suitable binders include, for example, gum acacia, gum tragacanth, guar gum, pectin, wax binders, methylcellulose, carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, gelatine, polyvinylpyrolbdone (PVP), sodium alginate and the like.
  • PVP polyvinylpyrolbdone
  • Suitable disintegrants include, for example, crosscarmellose sodium, crospovidone, sodium starch glycollate and the like.
  • Suitable lubricants include, for example, sodium stearyl fumarate, polyethylene glycol, talc and the like.
  • Suitable glidant include, for example, colloidal silicon dioxide and the like.
  • Additional conventional excipients include preservatives, stabilisers, anti-oxidants, antiadherents or glidants.
  • one or more diluents will be present in an amount of l%w/w to 70 %w/w by total weight of the composition. In certain embodiments, one or more disintegrants will be present in an amount of l%w/w to 20%w/w and especially 4% w/w to 10% %w/w by total weight of the composition.
  • solid dispersion means systems in which itraconazole is dispersed in matrix polymer.
  • the definition of a solid dispersion does not encompass physical mixtures from dry or wet mixing or dry blending operations.
  • the method for preparing solid dispersions are known in the art and typically comprise the steps of dissolving the drug and the matrix polymer in a common solvent and evaporating the solvent.
  • the solvent can be routinely selected according to the polymer used. Examples of solvents are: acetone, acetone/dichloromethane, methanol/dichloromethane, dichloromethane / ethanol, acetone/water, acetone/methanol, acetone/ethanol, dichloromethane/ethanol or ethanol/water.
  • Methods for evaporating solvent include rotary evaporation, spray drying, lyophilisation and thin film evaporation. Alternatively, solvent removal may be accomplished by cryogenic freezing followed by lyophilisation. Other techniques may be used such as melt extrusion, solvent controlled precipitation, pH controlled precipitation, supercritical fluid technology and cryogenic co milling.
  • the solid dispersion composition of itraconazole with particular types of matrix polymer increased the bioavailability of itraconazole compared to the conventional capsule product.
  • the increased bioavailability could be useful in enabling a reduction in the daily dose of itraconazole required to achieve comparable biological exposure seen with a conventional formulation, e.g. a conventional capsule of itraconazole.
  • a conventional formulation e.g. a conventional capsule of itraconazole.
  • the solid dispersion formulations of the invention exhibit increased bioavailability and by increasing drug loading it is likely to require fewer dose units compared to conventional itraconazole formulations.
  • Another embodiment relates to a stable solid oral pharmaceutical composition comprising itraconazole in a solid dispersion with a matrix polymer and dissolution enhancing agent(s).
  • Another embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising (a) itraconazole, (b) matrix polymer and (c) dissolution enhancing agent(s).
  • a matrix polymer selected from hypromellose phthalate, copovidone, hypromellose acetate succinate, hypromellose, polymethacrylates, hydroxypropyl cellulose and cellulose acetate phthalate
  • dissolution enhancing agent(s) selected from combination of (i) dibasic calcium phosphate and (ii) silicified microcrystalline cellulose or combination of (i) dibasic calcium phosphate and (ii) microcrystalline
  • Another embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising itraconazole in a solid dispersion with a matrix polymer selected from hypromellose phthalate, copovidone, hypromellose acetate succinate, hypromellose, polymethacrylates, hydroxypropyl cellulose and cellulose acetate phthalate and dissolution enhancing agent(s) selected from combination of (i) dibasic calcium phosphate and (ii) silicified microcrystalline cellulose or combination of (i) dibasic calcium phosphate and (ii) microcrystalline cellulose.
  • a matrix polymer selected from hypromellose phthalate, copovidone, hypromellose acetate succinate, hypromellose, polymethacrylates, hydroxypropyl cellulose and cellulose acetate phthalate
  • dissolution enhancing agent(s) selected from combination of (i) dibasic calcium phosphate and (ii) silicified microcrystalline cellulose or combination
  • Another embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising (a) itraconazole in an amount of 50 mg to 300 mg, (b) matrix polymer selected from hypromellose phthalate, copovidone, hypromellose acetate succinate, hypromellose, polymethacrylates, hydroxypropyl cellulose and cellulose acetate phthalate and (c) dissolution enhancing agent(s) selected from combination of (i) dibasic calcium phosphate and (ii) silicified microcrystalline cellulose or combination of (i) dibasic calcium phosphate and (ii) microcrystalline cellulose.
  • Another embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising (a) itraconazole in an amount of 65 mg, (b) matrix polymer selected from hypromellose phthalate, copovidone, hypromellose acetate succinate, hypromellose, polymethacrylates, hydroxypropyl cellulose and cellulose acetate phthalate and (c) dissolution enhancing agent(s) selected from combination of (i) dibasic calcium phosphate and (ii) silicified microcrystalline cellulose or combination of (i) dibasic calcium phosphate and (ii) microcrystalline cellulose.
  • Another embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising (a) itraconazole in an amount of 130 mg, (b) matrix polymer selected from hypromellose phthalate, copovidone, hypromellose acetate succinate, hypromellose, polymethacrylates, hydroxypropyl cellulose and cellulose acetate phthalate and (c) dissolution enhancing agent(s) selected from combination of (i) dibasic calcium phosphate and (ii) silicified microcrystalline cellulose or combination of (i) dibasic calcium phosphate and (ii) microcrystalline cellulose.
  • Another embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising (a) itraconazole in an amount of 130 mg, (b) matrix polymer, wherein itraconazole is dispersed in matrix polymer phase; wherein itraconazole is present in an amount from 20% w/w to 60% w/w, preferably from 30% w/w to 50% w/w and more preferably 40% w/w by total weight of the solid dispersion; wherein weight ratio of itraconazole to matrix polymer is in the range of about 1: 1 to about 1:3, or about 1: 1.5, based on the weight of itraconazole.
  • Another embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising (a) itraconazole in an amount of 130 mg, (b) matrix polymer selected from hypromellose phthalate, copovidone, hypromellose acetate succinate, hypromellose, polymethacrylates, hydroxypropyl cellulose and cellulose acetate phthalate wherein itraconazole is dispersed in matrix polymer phase; wherein itraconazole is present in an amount from 20% w/w to 60% w/w, preferably from 30% w/w to 50% w/w and more preferably 40% w/w by total weight of the solid dispersion; wherein weight ratio of itraconazole to matrix polymer is in the range of about 1: 1 to about 1:3, or about 1: 1.5, based on the weight of itraconazole.
  • Another embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising itraconazole that minimises the number of capsules required for the therapeutically effective dose, ideally to fewer than 4 units, preferably two or three units.
  • Another embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising itraconazole in a solid dispersion with a matrix polymer and dissolution enhancing agent(s) wherein the said composition is devoid of magnesium stearate.
  • Another embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising itraconazole in a solid dispersion with a matrix polymer and dissolution enhancing agent(s) wherein the said composition is devoid of surfactant.
  • Another embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising itraconazole in a solid dispersion with a matrix polymer and dissolution enhancing agent(s), wherein itraconazole is present in an amount of 50 mg or 65 mg or 100 mg or 130 mg or 150 mg or 195 mg or 200 mg or 250 mg or 260 mg or 300 mg or 400 mg of itraconazole.
  • Another embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising itraconazole in a solid dispersion with a matrix polymer and dissolution enhancing agent(s), wherein itraconazole is present in an amount from 20% w/w to 60% w/w, preferably from 30% w/w to 50% w/w and more preferably 40% w/w by total weight of the solid dispersion.
  • Another embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising itraconazole in a solid dispersion with a matrix polymer and dissolution enhancing agent(s), wherein dissolution enhancing agent(s) is preferably present in an amount from 10% w/w to 80% w/w, more preferably in an amount from 20% w/w to 70% w/w, most preferably in an amount from 30% w/w to 60% w/w by total weight of the composition.
  • Another embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising itraconazole in a solid dispersion with a matrix polymer and dissolution enhancing agent(s), wherein itraconazole is present in an amount of 20% to 60%, and preferably from 30% to 50% and more preferably 40% by weight of the solid dispersion.
  • Another embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising itraconazole in a solid dispersion with a matrix polymer and dissolution enhancing agent(s), wherein weight ratio of itraconazole to matrix polymer is in the range of about 1 : 1 to about 1 : 3 , or about 1 : 1.5, based on the weight of itraconazole.
  • the matrix polymer is hypromellose phthalate.
  • the dissolution enhancing agent(s) is combination of (i) dibasic calcium phosphate and (ii) silicified microcrystalline cellulose in the ratio of 1 : 1 to 1:4.
  • the dissolution enhancing agent(s) is combination of (i) dibasic calcium phosphate and (ii) microcrystalline cellulose in the ratio of 1 : 1 to 1:4.
  • Another embodiment relates to a stable solid oral pharmaceutical composition comprising itraconazole in capsule dosage form.
  • Another embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising: a) itraconazole in a solid dispersion with a matrix polymer selected from hypromellose phthalate, copovidone, hypromellose acetate succinate, hypromellose, polymethacrylates, hydroxypropyl cellulose and cellulose acetate phthalate; b) dissolution enhancing agent(s) selected from combination of (i) dibasic calcium phosphate and (ii) silicified microcrystalline cellulose or combination of (i) dibasic calcium phosphate and (ii) microcrystalline cellulose wherein i.
  • a matrix polymer selected from hypromellose phthalate, copovidone, hypromellose acetate succinate, hypromellose, polymethacrylates, hydroxypropyl cellulose and cellulose acetate phthalate
  • dissolution enhancing agent(s) selected from combination of (i) dibasic calcium phosphate and (i
  • itraconazole is present in an amount from 50 mg or 65 mg or 100 mg or 130 mg or 150 mg or 195 mg or 200 mg or 250 mg or 260 mg or 300 mg or 400 mg ii. itraconazole is present in an amount from 20% w/w to 60% w/w, preferably from 30% w/w to 50% w/w and more preferably 40% w/w by total weight of the solid dispersion; iii. weight ratio of itraconazole to matrix polymer is in the range of about 1 : 1 to about 1:3, or about 1: 1.5, based on the weight of itraconazole; iv.
  • dissolution enhancing agent(s) is preferably present in an amount from 10% w/w to 80% w/w, more preferably in an amount from 20% w/w to 70% w/w, most preferably in an amount from 30% w/w to 60% w/w by total weight of the composition;
  • Another embodiment relates to a stable solid oral pharmaceutical composition
  • a stable solid oral pharmaceutical composition comprising: a) itraconazole in a solid dispersion with a matrix polymer selected from hypromellose phthalate, copovidone, hypromellose acetate succinate, hypromellose, polymethacrylates, hydroxypropyl cellulose and cellulose acetate phthalate; b) dissolution enhancing agent(s) selected from combination of (i) dibasic calcium phosphate and (ii) silicified microcrystalline cellulose or combination of (i) dibasic calcium phosphate and (ii) microcrystalline cellulose wherein i.
  • a matrix polymer selected from hypromellose phthalate, copovidone, hypromellose acetate succinate, hypromellose, polymethacrylates, hydroxypropyl cellulose and cellulose acetate phthalate
  • dissolution enhancing agent(s) selected from combination of (i) dibasic calcium phosphate and (i
  • itraconazole is present in an amount from 50 mg or 65 mg or 100 mg or 130 mg or 150 mg or 195 mg or 200 mg or 250 mg or 260 mg or 300 mg or 400 mg ii. itraconazole is present in an amount from 20% w/w to 60% w/w by total weight of the solid dispersion; iii. weight ratio of itraconazole to matrix polymer is in the range of about 1 : 1 to about 1 :3 based on the weight of itraconazole; iv. dissolution enhancing agent(s) is preferably present in an amount from 20% w/w to 70% w/w by total weight of the composition.
  • Another embodiment relates to a method of producing a stable solid oral pharmaceutical composition of itraconazole comprising: (i) a suitable amount itraconazole with a desired amount of at least one matrix polymer was dissolved in methylene chloride and ethanol with continuous stirring;
  • step (ii) the solution from step (i) was spray-dried to form solid dispersion as a spray dried powder.
  • the spray dried solid dispersion was further dried in suitable dryer.
  • step (iv) the blend from step (iii) was filled in suitable capsules.
  • Another embodiment relates to method of producing a stable solid oral pharmaceutical composition of itraconazole by blending process. Another embodiment relates to method of producing a stable solid oral pharmaceutical composition of itraconazole by roll compaction process.
  • the solid oral pharmaceutical composition can be in provided form of capsule, tablet, powder, sachet and the like, and particularly a capsule.
  • the composition can also comprise one or more additional antifungal agents.
  • Example 1 Example 2
  • Example 3 (Mg / Capsule) (Mg / Capsule) (Mg / Capsule)
  • step (1) The solution from step (1) was spray-dried to form solid dispersion as a spray dried powder.
  • the spray dried solid dispersion was further dried in suitable dryer;
  • step (1) The solution from step (1) was spray-dried to form solid dispersion as a spray dried powder.
  • the spray dried solid dispersion was further dried in suitable dryer;
  • the dried drug-polymer solid dispersion iron step (2) was blended properly with excipients of Stage B and filled in suitable capsules.
  • step (1) The solution from step (1) was spray-dried to form solid dispersion as a spray dried powder.
  • the spray dried solid dispersion was further dried in suitable dryer; 3.
  • the dried drug-polymer solid dispersion iron step (2) was blended properly with excipients of Stage B and filled in suitable capsules.
  • step (1) The solution from step (1) was spray-dried to form solid dispersion as a spray dried powder.
  • the spray dried solid dispersion was further dried in suitable dryer;
  • step (3) The dried drug-polymer solid dispersion from step (2) was roll compacted with excipients from Stage B in roll compactor. The compacted mass was milled and screened. 4. The blend from step (3) was mixed properly with excipients of Stage C and filled in suitable capsules.
  • step (1) The solution from step (1) was spray-dried to form solid dispersion as a spray dried powder.
  • the spray dried solid dispersion was further dried in suitable dryer;
  • the dried drug-polymer solid dispersion iron step (2) was blended properly with excipients of Stage B and filled in suitable capsules.
  • step (2) The solution from step (1) is spray-dried to form solid dispersion as a spray dried powder.
  • the spray dried solid dispersion was further dried in suitable dryer; 3.
  • the dried drug-polymer solid dispersion from step (2) is blended properly with excipients of Stage B and filled in suitable capsules.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne une composition pharmaceutique orale solide stable comprenant de l'itraconazole qui permet de réduire la charge des pilules dans le traitement d'infections fongiques, y compris des infections superficielles, telles que l'onychomycose, ainsi que des infections fongiques systémiques, par exemple, la blastomycose pulmonaire ou extrapulmonaire, l'histoplasmose et l'aspergillose. L'invention concerne également un procédé de préparation de la composition pharmaceutique comprenant de l'itraconazole.
PCT/IB2022/055460 2021-06-13 2022-06-13 Composition pharmaceutique comprenant de l'itraconazole WO2022264004A1 (fr)

Priority Applications (2)

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BR112023026118A BR112023026118A2 (pt) 2021-06-13 2022-06-13 Composição farmacêutica que compreende itraconazol e seu método de produção
CONC2024/0000201A CO2024000201A2 (es) 2021-06-13 2024-01-11 Composición farmacéutica que comprende itraconazol

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IN202121026278 2021-06-13
IN202121026278 2021-06-13

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002100407A1 (fr) * 2001-06-12 2002-12-19 Smartrix Technologies Inc. Granules d'itraconazole: formulations pharmaceutiques pour administration orale et procede de preparation de ces dernieres
US20050226924A1 (en) * 2004-04-13 2005-10-13 Kyu-Hyun Lee Composition comprising itraconazole for oral administration
CN105126110A (zh) * 2015-07-29 2015-12-09 中山大学 伊曲康唑的固体分散体及其制备方法和应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002100407A1 (fr) * 2001-06-12 2002-12-19 Smartrix Technologies Inc. Granules d'itraconazole: formulations pharmaceutiques pour administration orale et procede de preparation de ces dernieres
US20050226924A1 (en) * 2004-04-13 2005-10-13 Kyu-Hyun Lee Composition comprising itraconazole for oral administration
CN105126110A (zh) * 2015-07-29 2015-12-09 中山大学 伊曲康唑的固体分散体及其制备方法和应用

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