Multiparticulate albaconazole compositions

Abstract

The present invention provides an oral solid pharmaceutical composition in the form of a multiparticulate composition comprising albaconazole, a process for the preparation of the composition of the invention and its use in therapy.

Description

[Technical field]

[0001] The present invention provides an oral solid pharmaceutical composition in the form of albaconazole-containing pellets, a process for the preparation of said composition and its use in therapy. [Background technology]

[0002] Albaconazole was first described in WO97 / 05130A1 as one of a variety of novel pyrimidone derivatives with antifungal activity, which can be used for various therapeutic applications. The above document describes various oral pharmaceutical compositions containing pyrimidone derivatives, such as tablets, dispersible powders or granules, and liquids. Also mentioned are preparations for vaginal or rectal administration. Representative pyrimidone derivative-containing formulations described in WO97 / 05130A1 are tablets, hard gelatin capsules, syrups, aerosols, and two different injection formulations. However, none of these formulations have been tested by any method, and WO97 / 05130A1 does not provide experimental data for any of the dosage forms disclosed.

[0003] Document WO2008 / 021049A2 describes various crystalline forms of albaconazole and their use in pharmaceutical preparations.However, the preparations containing albaconazole crystalline forms are only mentioned generally without specific examples.Therefore, there is no information about how specific albaconazole polymorphs behave in specific pharmaceutical preparations, and no experimental data is provided for the disclosed dosage forms.

[0004] Document WO2010 / 138674A1 discloses a method for the treatment or prevention of a fungal condition in a patient, comprising topically applying to the patient a dose selected from the group consisting of nail lacquer, enamel, paint, solution, lotion, cream, gel, aerosol foam and aerosol spray forms. The active ingredient is a pyrimidone derivative, such as albaconazole. No pharmaceutical composition for oral administration is mentioned in this document.

[0005] Pharmaceutical compositions containing albaconazole for oral administration are disclosed and described, for example, in the document "Clinical Pharmacology: Advances and Applications 2013:5 23-31". This document describes a comparison of tablet and capsule formulations to determine bioavailability, bioequivalence, safety and tolerability. The capsule formulation tested contained microcrystalline cellulose pellets coated with a mixture of albaconazole and aminomethacrylate copolymer, talc, colloidal SiO2, hydrochloric acid, absolute alcohol, and purified water. However, there are no further reports on these formulations, and no methods for their preparation are disclosed. However, the use of aminomethacrylate copolymer suggests the formation of a solid dispersion.

[0006] However, there remains a need to provide pharmaceutical compositions for oral administration comprising albaconazole that are simple in composition and nevertheless provide suitable dissolution behavior allowing good to excellent bioavailability, and there is also a need to provide such pharmaceutical compositions on a large scale for industrial purposes and not limited to laboratory quantities only.

[0007] This is not easy to achieve, since albaconazole is very hydrophobic, has low flowability, and is prone to hydrolysis in the presence of aqueous solutions.These physicochemical properties make it very difficult to obtain an oral composition containing albaconazole with a good solubility profile and good bioavailability.

[0008] To circumvent the hydrophobicity issue of albaconazole, the active pharmaceutical ingredient (API) was first used in amorphous form when testing various excipients. Simple blends with excipients such as mannitol, sodium lauryl sulfate, croscarmellose sodium, colloidal anhydrous silica, or mixtures thereof were attempted, but resulted in formulations that were not wettable or formed aggregates. Furthermore, high variability was observed in dissolution tests, and sometimes even particles remained in solution. Generally, these simple blends did not result in a uniform and homogenous composition.

[0009] Therefore, wet granulation (using water as the granulation liquid) tests were conducted and the formulation was developed. The wet granulation technique was expected to improve the dissolution behavior and overcome the problems observed in the simple blend. However, hydrophobicity was still an issue even with the addition of surfactants in the formulation, and aggregation was still observed during the dissolution test.

[0010] As previous techniques did not give the desired results, the hot melt technique was attempted, which is said to have the potential to improve dissolution in complex cases. Here, the appropriate excipients were heated to their melting point and then albaconazole was added to the melt. The formed dispersion was then cooled to obtain a solid dispersion, which was obtained as granules. The use of excipient Gelucire 44 / 14 (32-lauroyl macrogol glyceride) in a ratio of 1:4 albaconazole:Gelucire 44 / 14 showed promising results with approximately 87% of the albaconazole dissolved after 45 minutes in 0.1 N HCl. These promising results were obtained for a dosage form containing 40 mg of albaconazole. However, the resulting formulation was waxy and difficult to handle, and the amount of Gelucire 44 / 14 required was too high to obtain a dosage form suitable for oral administration, making high doses unfeasible.

[0011] A solution to obtain high doses with hot melt technology was found by using a mixture of Gelucire 44 / 14 and a diluent such as mannitol, lactose monohydrate or a mixture thereof. However, these compositions manufactured with hot melt technology showed problems under the prescribed storage conditions. After one month of storage at 40°C and 75% relative humidity (RH), the composition turned into a compact waxy material, did not meet the required specifications, and barely dissolved albaconazole. A similar problem was observed after one month of storage at 30°C and 60% RH, but to a lesser extent. Also, even under the mildest conditions of 25°C and 60% RH, after six months the dissolution rate was considerably reduced, making it nearly impossible to meet the requirements for a dosage form with the desired bioavailability. Summary of the Invention

[0012] The present inventors have now developed a multiparticulate composition comprising pellets coated with an albaconazole-containing composition that is simple in composition and easily available on a large scale, and that provides an albaconazole formulation with good dissolution behavior and bioavailability.

[0013] In one particular embodiment, the albaconazole in the albaconazole-containing composition is in solid form.Preferably, the solid form of albaconazole can be amorphous or crystalline, more preferably crystalline.It has been observed that under the specified stability test conditions, the multiparticulate composition containing crystalline albaconazole maintains the crystalline solid form of drug substance, which means that crystalline albaconazole is stable and does not change its crystalline form into another crystalline form.

[0014] A manufacturing process for preparing the coated pellets of the present invention has also been developed.

[0015] A first aspect of the present invention provides a method for producing a method for manufacturing a semiconductor device comprising the steps of: a) a plurality of substantially spherical, inert particles, each having a diameter between 300 and 800 μm; b) a coating on each of said plurality of particles comprising albaconazole, a coating agent, and a plasticizer. The present invention relates to a multiparticulate pharmaceutical composition comprising:

[0016] A second aspect of the invention provides a method for preparing a multiparticulate pharmaceutical composition according to the first aspect.

[0017] A third aspect of the invention relates to a multiparticulate composition according to the first aspect for use in the treatment of a fungal infection.

[0018] A fourth aspect of the invention relates to the use of a composition according to the first aspect for the manufacture of a medicament for the treatment of a fungal infection.

[0019] A fifth aspect of the invention relates to a method for treating a fungal infection by administering a composition according to the first aspect to a subject in need thereof. [Brief description of the drawings]

[0020] [Figure 1] XRD diffraction pattern of albaconazole form III. [Diagram 2] XRD diffraction pattern of albaconazole form IV. [Diagram 3] XRD diffraction pattern of albaconazole form VI. [Figure 4] XRD diffraction pattern of amorphous albaconazole. [Diagram 5] Dissolution profiles comparing Albaconazole Capsules (Amorphous) and Albaconazole Capsules (Crystalline). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] definition The term "about" as used herein refers to a statistically meaningful range of a value, typically within 10%. Such a range can be within the experimental error typical of standard methods used to measure and / or determine a given value or range. In one embodiment, the range is within 5% of the indicated value. In another embodiment, the range is within 1% of the indicated value. In yet another embodiment, the range is within 0.5% of the indicated value.

[0022] As used herein, the term "pharmacologically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for contact with the tissues of animals, especially humans, and are free of undue toxicity, irritation, allergic response, or other significant complications and commensurate with a reasonable benefit / risk ratio.

[0023] As used herein, the term "treating" includes, unless otherwise specified, remission, cure, and / or maintaining cure of a disease or disorder (i.e., preventing or delaying recurrence). Treatment after a disorder has begun aims to reduce, alleviate, ameliorate, or completely eliminate the disorder and / or symptoms associated therewith, prevent worsening, slow the rate of progression, or prevent a disorder from recurring once eliminated (i.e., preventing recurrence).

[0024] As used herein, the term "multiparticulate pharmaceutical composition" refers to a pharmaceutical composition in the form of a plurality of solid units, each of which is a solid unit.

[0025] As used herein, the term "coating" refers to the deposition and / or adsorption, preferably uniform, of at least one coating material onto a substrate. Preferably, the coating material is a thin, uniform film applied onto the substrate.

[0026] The term "inert particles" as used herein refers to particles that do not have therapeutic activity of their own, regardless of the materials used in different aspects and / or embodiments. The particles may be in the form of spheres or pellets.

[0027] The inventors have surprisingly found that by coating substantially spherical inert particles having a diameter between 300 and 800 μm with a mixture comprising albaconazole, a coating agent and a plasticizer, an oral solid pharmaceutical composition having good flowability, stability and dissolution properties can be prepared.

[0028] Thus, a first aspect of the present invention provides a method for producing a method for treating a cancer cell comprising the steps of: a) a plurality of substantially spherical, inert particles, each having a diameter between 300 and 800 μm; b) a coating on each of said plurality of particles comprising albaconazole, a coating agent, and a plasticizer. The present invention relates to a multiparticulate pharmaceutical composition comprising:

[0029] In a second aspect, the present invention provides a method for producing a pharmaceutical composition comprising the steps of: i) providing an aqueous solution comprising a coating agent and a plasticizer; ii) optionally adding a surfactant to the solution of step i); iii) dispersing albaconazole in the solution resulting from step i) or, if step ii) is present, from step ii) to form a suspension; iv) optionally sieving the suspension of step iii) to remove particles with a size greater than 90 μm; v) coating a plurality of spherical inert particles having a diameter between 300 and 800 μm with the suspension resulting from step iii) or, if step iv) is present, from step iv), vi) optionally drying the product obtained from step v), vii) Optionally, filling the product obtained from step v) into capsules. The present invention relates to a method for preparing a multiparticulate composition of the first aspect, comprising:

[0030] In an embodiment of the first or second aspect of the present invention, the substantially spherical inert particles before being coated have a diameter between 300 and 800 μm, preferably between 400 and 750 μm, more preferably between 450 and 750 μm, even more preferably between 500 and 710 μm, and most preferably between 580 and 680 μm.

[0031] Preferably, the substantially spherical inert particle is a neutral inert particle that does not have acidic or alkaline properties, and comprises or is selected from the group consisting of sugar particles, cellulose particles or silicon dioxide particles.More preferably, the substantially spherical inert particle is a sugar particle.The advantage of the above-mentioned substantially spherical inert particle is that compared with simple blending, the specific surface area on which albaconazole is present is increased, and thus the dissolution of albaconazole is improved.Sugar particles are preferred because they can reduce the manufacturing cost of the entire process, and therefore the final product and the composition containing the final product can be provided to a wider range of the general public.

[0032] In the context of the present invention, the term "substantially spherical" refers to the sphericity coefficient (Ψ W ) is used to designate particles with a sphericity coefficient between 0.9 and 1.1, more preferably between 0.95 and 1.05, where the sphericity coefficient is the ratio between the surface area of ​​a sphere having the same volume as the particle and the surface area of ​​the particle: Psi W =d V 2 / d S 2 (In the formula, d V and d S are the equivalent diameters of a sphere with equal volume and surface area, respectively.) (Part. Part. Syst. Character. 1996, 13, 368-373).

[0033] In the context of the present invention, sugar particles are particles comprising sucrose and starch.

[0034] In the context of the present invention, cellulose particles are particles comprising microcrystalline cellulose, preferably made of microcrystalline cellulose.

[0035] In the context of the present invention, silicon dioxide particles are particles which comprise silicon dioxide, preferably particles made of silicon dioxide.

[0036] The starch present in said sugar particles is selected from the group consisting of natural starches such as corn starch, maize starch and potato starch and mixtures thereof. Preferably, the starch is corn starch.

[0037] In another embodiment of the first and / or second aspect of the invention, the substantially spherical sugar particles comprise sucrose and starch, preferably the sugar particles comprise at least 60% by weight sucrose, the remainder i.e. up to about 40% by weight being starch, more preferably the sugar particles comprise 62-92% by weight sucrose and 8-38% by weight starch, preferably corn starch.

[0038] In another embodiment of the first and / or second aspect of the invention, the coating is prepared from a suspension comprising albaconazole, a coating agent and a plasticizer. Preferably, the resulting coated inert particles comprise (i) 3.5-30% by weight, preferably 5-30% by weight, more preferably 6-30% by weight, even more preferably 6-25% by weight, and most preferably 10-25% by weight of albaconazole; (ii) 0.1-17% by weight, preferably 2-15% by weight, more preferably 5-15% by weight, even more preferably 8-14% by weight, and most preferably 9-12% by weight of the coating agent; and (iii) 0.1-5% by weight, preferably 0.5-5% by weight, more preferably 1-4% by weight, even more preferably 2-3.5% by weight, and most preferably 2.5-2.9% by weight of the plasticizer; the remaining weight percentage of the coated inert particles comprising such inert particles and optional ingredients. All weight percentages given herein are based on 100 mg of coated particles.

[0039] The coating agent can be any cellulose ether, and is preferably selected from the group consisting of or including hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose calcium, povidone and other water-soluble povidone-derived polymers or combinations thereof.More preferably, the coating agent is hydroxypropylmethylcellulose.These coating agents maintain the solid form of albaconazole.

[0040] The plasticizer comprises or is selected from the group consisting of polyethylene glycol, polysorbate, triacetin, triethyl citrate or combinations thereof. More preferably, the plasticizer is polyethylene glycol. The use of a plasticizer helps to obtain a good coating with improved dissolution profile and release of albaconazole.

[0041] In another embodiment of the first and / or second aspect of the invention, the coated inert particles further comprise 0-1 wt. %, preferably 0.1-1 wt. %, more preferably 0.2-0.7 wt. %, most preferably 0.3-0.5 wt. % of a surfactant. A surfactant amount within the above ranges improves the dissolution of albaconazole. The weight percentages given here are based on 100 mg of coated particles.

[0042] In another embodiment of the first and / or second aspect of the invention, the surfactant is sodium lauryl sulfate, polyoxyethylene sorbitan fatty acid esters (also known as Tweens), sorbitan ethers / esters (also known as Spans) or combinations thereof. Sodium lauryl sulfate (SLS) is preferred as it shows no interactions with other components of the coating and is inert in this respect.

[0043] In another embodiment of the first and / or second aspect of the present invention, albaconazole is used in either amorphous or crystalline form.Preferably, crystalline form albaconazole is used because it has better stability performance in coating and reduced impurity profile than amorphous.Also, it has been observed that crystalline albaconazole dissolves earlier and faster than amorphous albaconazole.The known crystalline forms of albaconazole that can be used in the present invention are forms I, II, III, IV, V and VI disclosed in EP2650291A1, and preferably albaconazole crystalline form III, IV or VI.

[0044] Albaconazole forms III, IV and VI may be prepared as described in EP2650291.

[0045] Highly relevant 2-θ (±0.2°) peak positions for Form III in a characteristic X-ray powder diffraction (XRPD) pattern (described in EP2650291A1) include at least one of 4.08, 5.73, 6.22, 7.77, 8.15, 8.80, 11.25, 11.47, 12.44, 13.09, 15.57, 17.63, 18.66, 20.85, 26.65 and 27.12°. Preferably, crystalline Form III has a characteristic X-ray powder diffraction (XRPD) pattern that may include at least one 2-theta position selected from the group consisting of about 4.08, 5.73, 6.22, 7.77, 8.15, 8.80, 11.25, 11.47, 12.44, 13.09, 14.33, 14.68, 14.89, 15.57, 16.35, 16.68, 17.27, 17.63, 18.66, 19.32, 20.85, 22.12, 22.49, 23.58, 24.63, 25.02, 26.65, 27.12, 28.74, 29.11, 29.81, 31.35, and 33.48+ / -0.2 positions.

[0046] Highly relevant 2-θ (±0.2°) peak positions for Form IV in a characteristic X-ray powder diffraction (XRPD) pattern (described in EP2650291A1) include at least one of 4.15, 7.5, 8.33, 9.61, 11.16, 12.49, 13.29, 13.64, 14.41, 16.90, 18.74, 24.78, and 25.11°. Preferably, crystalline Form IV has a characteristic X-ray powder diffraction (XRPD) pattern that may include at least one 2-theta position selected from the group consisting of about 3.74, 4.15, 7.5, 8.33, 9.61, 11.16, 11.61, 12.49, 13.29, 13.64, 14.41, 15.43, 15.74, 16.90, 17.71, 18.25, 18.74, 19.30, 20.43, 21.78, 23.20, 24.26, 24.78, 25.11, 26.03, 26.86, 27.25, 28.00, 29.05, 30.07, 30.91, and 32.05+ / -0.2 positions.

[0047] Highly relevant 2-θ (±0.2°) peak positions for Form VI in a characteristic X-ray powder diffraction (XRPD) pattern (described in EP2650291A1) include at least one of 10.1, 14.5, 16.0, 21.1, 24.8, and 25.7°. Preferably, crystalline Form VI has a characteristic X-ray powder diffraction (XRPD) pattern that may include at least one 2-theta position selected from the group consisting of about 10.1, 12.1, 13.3, 14.5, 15.0, 16.0, 16.6, 17.0, 17.4, 18.8, 19.2, 19.7, 21.1, 22.3, 23.9, 24.2, 24.8, 25.7, 26.7, 27.6, 28.6, 28.9, 29.3, 29.7, 30.0, 30.5, 30.8, 31.3, 33.3, 33.7, 34.3, 35.0, 35.5, 36.5, 36.7, 37.4, and 39.5+ / -0.2 positions.

[0048] Most preferably, albaconazole Form III is used since it has shown excellent dissolution results combined with low impurities during stability studies and has also been shown to be the most reliable solid form within the coating over time.

[0049] As described in EP2650291, the XRPD patterns of Form III and Form IV were measured at room temperature using a Philips X'Pert diffractometer equipped with a θ / 2θ goniometer, a Cu tube (CuKα radiation, λ=1.5419A) operated at 50 kV and 40 mA, divergence slit=1 / 4°, solar slit=0.04 rad, anti-scatter slit=1 / 4°, receiving slit=0.10 mm, and a two-dimensional curved graphite monochromator. Data were collected in the 2θ range of 2-35° using a step-scan method with step size=0.02° and time per step=20 s. Meanwhile, the XRPD pattern of Form VI was measured using either: (1) an Inel XRG-3000 diffractometer equipped with a CPS (Curved Position Sensitive) detector with a 2θ range of 120°. Real-time data was collected using Cu-Kα radiation. The tube voltage and amperage were set to 40 kV and 30 mA, respectively. The monochromator slit was set to 5 mm × 160 μm. The patterns are displayed from 2.5 to 40° 2θ. Samples were prepared for analysis by packing them into thin-walled glass capillaries. Each capillary was mounted on a goniometer head that was motorized so that the capillary could be rotated during data acquisition. Samples were analyzed for 300 s. Calibration of the instrument was performed using silicon standards. Alternatively, (2) XRPD analysis was performed using Cu Kα radiation using a Shimadzu XRD-6000 X-ray powder diffractometer. This instrument is equipped with a long fine-focus X-ray tube. The tube voltage and amperage were set to 40 kV and 40 mA, respectively. The divergence and scattering slits were set to 1° and the receiving slit was set to 0.15 mm. Diffracted radiation was detected with a Nal scintillation detector. A theta-2theta continuous scan at 1° / min (0.4 sec / 0.02° step) from 2.5 to 40°2theta was used. Samples were spun at a speed of 25 rpm. A silicon standard was analyzed to confirm instrument alignment. Data were collected and analyzed using an XRD-6100 / 7000 v.5.0. Samples were prepared for analysis by placing them in an aluminum holder with a silicon well.

[0050] In the context of the present invention, the most preferred coating agent, hydroxypropyl methylcellulose, has a viscosity between about 0.5 mPa·s and about 50 mPa·s. Preferably, the hydroxypropyl methylcellulose has a viscosity between about 1 mPa·s and about 10 mPa·s, more preferably between about 2 mPa·s and about 8 mPa·s, most preferably between about 4 mPa·s and about 6 mPa·s. The viscosity values ​​indicated correspond to the measured viscosity of a 2% w / w aqueous solution of hydroxypropyl methylcellulose at 20° C., measured according to the USP method. Preferred hydroxypropyl methylcellulose may be selected from the group consisting of cellulose ethers graded as E5LV, E15LV, E50LV, and K100LV, preferably K100LV.

[0051] In the context of the present invention, the most preferred plasticizers are polyethylene glycols having a viscosity of 2700-3500 mPas in a 50% solution at 20° C., measured according to ISO 6388, and / or a molecular weight calculated from the OH number of 16000-25000 g / mol. Such polyethylene glycols are also known as polyethylene glycol 20000.

[0052] In an embodiment of the first or second aspect of the present invention, the multiparticulate pharmaceutical composition may be used to fill capsules or sachets, preferably capsules, or even to manufacture tablets.Preferably, the composition is filled into hard capsules, such as hard gelatin capsules or HPMC capsules.The size of the capsule depends on the dosage used, but may preferably be selected from size 1, size 00 or size 0L.

[0053] The dose of albaconazole used may be any therapeutically effective dose. Preferably, the dose may be 1-400mg, more preferably 10-200mg, even more preferably 10-150mg. In particular, the dose of albaconazole may be selected from the amounts of 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145 or 150mg and any combination thereof. Most preferred are doses of albaconazole selected from 20, 25, 40, 50, 75, 80 and / or 100mg.

[0054] The multiparticulate compositions of the present invention may further comprise pharma- ceutically acceptable excipients within the coating. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, sweeteners, colorants and flavoring agents.

[0055] Suitable diluents may be selected from the group consisting of cellulose derivatives, such as cellulose powder, microcrystalline cellulose, or silicified microcrystalline cellulose, natural starches, such as corn starch and potato starch, pregelatinized starch, and mixtures thereof.

[0056] Suitable binders may be selected from the group consisting of povidone, copovidone, gelatin, polyethylene oxide, alginic acid, modified corn starch, and / or mixtures thereof.

[0057] Suitable glidants may be selected from the group consisting of calcium silicate, magnesium silicate, corn starch, colloidal silicon dioxide, silicon hydrogel, talc, sodium stearyl fumarate, and / or mixtures thereof.

[0058] Suitable lubricants may be selected from the group consisting of magnesium stearate, calcium stearate, zinc stearate, glyceryl behenate, mineral oil, stearic acid, and / or mixtures thereof.

[0059] In an embodiment of the second aspect, the aqueous solution used in step iii) comprises a) 2-15 wt. %, preferably 3-10 wt. %, more preferably 4.5-7 wt. % of a coating agent, b) 0.1-5 wt. %, preferably 0.5-3 wt. %, more preferably 1.0-2.0 wt. % of a plasticizer, and c) 0-1 wt. %, preferably 0.1-0.8 wt. %, more preferably 0.15-0.5 wt. % of a surfactant, all percentages here being based on the total weight of the solution obtained in step i) or step ii).

[0060] In an embodiment of the second aspect, albaconazole is dispersed in the solution of step i) or step ii) such that the weight ratio of albaconazole to solution, expressed as "weight ratio = kg albaconazole / kg solution", when a surfactant (or wetting agent) is also present, is comprised between 0.05 and 0.2, preferably between 0.08 and 0.12.

[0061] In an embodiment of the second aspect, the coating suspension used in step v) is used such that the weight ratio of coating suspension to inert particles, expressed as "ratio = kg coating suspension / kg inert particles", is comprised between 1 and 9, preferably between 2 and 6, most preferably between 2.5 and 4.5. If the weight ratio is less than 1, the resulting coated particles are not homogeneous enough, so that high variability may occur. On the other hand, if the weight ratio is more than 9, problems may occur with the dissolution of albaconazole, because the coating layer is too thick.

[0062] A further advantage of the compositions according to the invention is that their preparation does not require organic solvents, making the preparation process more sustainable and environmentally friendly, as well as more economical since expensive work-up and recycling of organic solvents is not required.

[0063] Another advantage of the composition according to the present invention is that there is only one coating layer containing active ingredient, and there is no need to coat additional layers such as protective layer or other functional layer.Therefore, the composition can be simply and easily maintained.

[0064] In an embodiment of the second aspect, drying of the product resulting from the coating step is carried out at a temperature of the dried product between 35 and 65°C, most preferably between 45 and 55°C.

[0065] The composition according to the present invention and / or the dosage form produced from said composition, such as tablets or capsules, can be stored in any form of packaging available on the market. Such packaging can include blister packs, sachets, bottles or vials. The packaging can include systems or additives to protect the pharmaceutical composition from humidity, light or other harmful effects, can include tamper-resistant or child-resistant systems or features, and can be made of any material considered necessary to protect against humidity, light, oxidation or any other harmful environmental effects. For example, this can include standard polyethylene packaging, and the more protective aluminum blister packaging currently on the market, etc. EXAMPLES

[0066] Example 1 A multiparticulate pharmaceutical composition of the present invention was prepared using the following ingredients:

[0067] [Table 1]

[0068] A multiparticulate composition was prepared as follows: 1.007 Kg of hydroxypropyl methylcellulose (5 mPas) and 0.2573 Kg of polyethylene glycol 20,000 were slowly added to the mixing vessel under stirring (1,000-2,000 rpm) to obtain a solution. The solution was allowed to stand and degas. 0.0382 Kg of sodium lauryl sulfate was then added under stirring (500-1,000 rpm) until completely dissolved. To the resulting solution, 1.905 Kg of albaconazole (Form III) was added under stirring for about 1 hour to obtain a homogenous suspension. The suspension was filtered through a 90 μm sieve to remove undesirable large particles. As a result, 20.02 Kg of filtered suspension was obtained.

[0069] A fluidized bed coating apparatus (SAR Labortecnic SA) was prepared with the following specifications: (Wurster gun / 0.8 mm nozzle / fiber filter 100 μm). 6,000 kg of sugar spheres 600 were weighed and heated at 60° C. for 2 minutes. Then, the fan flow rate was set at 313 to 400 m 3 / h, inlet air temperature 65-85°C, product temperature 45-55°C, and outlet air temperature 30-85°C.

[0070] The coating was done in four stages with the following specifications: Phase 1: Pump speed (%, ml / min) = 14-15, 23-28 Grinding pressure (%, bar) = 45, 1.94 Time(min)=15min Phase 2: Pump speed (%, ml / min) = 20-21, 31-37 Grinding pressure (%, bar) = 55, 2.94 Time(min)=120 min Phase 3: Pump speed (%, ml / min) = 25-28, 43-49 Grinding pressure (%, bar) = 65, 2.94 Time(min)=45 min Phase 4: Pump speed (%, ml / min) = 31-33, 52-54 Grinding pressure (%, bar) = 65, 2.94 Time (min) = approx. 235 min (until coating suspension is exhausted)

[0071] The apparatus was emptied and the contents were sieved through a 1,000 μm sieve to yield 8.905 Kg of product.

[0072] [Table 2-1]

[0073] [Table 2-2]

[0074] [Table 3]

[0075] [Table 4]

[0076] Comparative Example 2: An albaconazole composition was prepared using wet granulation. For a capsule composition with a net weight of 300 mg, 40 mg of albaconazole was mixed with 224 mg of mannitol and 30 mg of croscarmellose sodium, and the resulting mixture was granulated with water containing 6 mg of sodium lauryl sulfate. After manual sieving, the granules were filled into gelatin capsules size 1. Dissolution testing in 0.1 N HCl showed poor dissolution behavior, with aggregates still observed after 45 minutes.

[0077] Comparative Example 3: Gelucire 44 / 14 (32-lauroyl macrogol glyceride) was heated to 65°C until melted, after which albaconazole was slowly added under stirring. The dispersion of albaconazole in the molten excipients was cooled to room temperature. Solid granules were finally obtained, sieved through a 500 μm sieve and filled into gelatin capsules size 1 at 40 mg albaconazole / capsule. Albaconazole:Gelucire 44 / 14 ratios of 1:2, 1:3, and 1:4 were prepared and the dissolution in 0.1 N HCl was measured after 45 minutes. The 1:2 and 1:3 preparations showed poor dissolution behavior with aggregation even after 45 minutes. The 1:4 preparation was properly dissolved, with approximately 87% of the albaconazole dissolved after 45 minutes. However, it was not possible to prepare a high dose of albaconazole per capsule since high amounts of excipients made the overall composition too waxy.

[0078] Comparative Example 4: A composition of albaconazole, Gelucire 44 / 14, mannitol and lactose monohydrate was prepared in the ratio of albaconazole: Gelucire 44 / 14: mannitol: lactose monohydrate = 1:2.5:2.5:2.5 in order to reduce the amount of Gelucire 44 / 14. For this purpose, albaconazole was blended with mannitol and lactose monohydrate, followed by the addition of Gelucire. The mixture was heated to 65°C under stirring in order to melt the Gelucire, finally obtaining an albaconazole dispersion. The obtained dispersion was cooled to room temperature and sieved through a 200 μm sieve. Finally, a solid granule was obtained and filled into gelatin capsule size 00 to obtain 80 mg albaconazole / capsule. The capsules thus obtained were packed in a paper envelope (60 g / m 2 ), aluminum (20 μm) and polyethylene (30 g / m 2 ) and then subjected to standard stability studies.

[0079] Dissolution testing in 0.1N HCl after 45 minutes revealed the following: After 6 months at 25°C / 60% RH, the amount of albaconazole dissolved decreased to approximately 64%. After one month at -30°C / 60% RH, the amount of albaconazole dissolved had decreased to approximately 25%, which was outside the acceptable range. After 1 month at -40°C / 75% RH the amount of albaconazole dissolved had decreased to approximately 6%, which is outside the acceptable range, and the capsule contents had turned into a compact waxy material.

[0080] Analysis method: 1) Dissolution test: Analytical procedure: European Pharmacopoeia (Ph.Eur.) <2.9.3>; UV / Vis Test conditions: - Paddle device - Stirring speed: 100rpm - Dissolution medium: 0.1N hydrochloric acid 0.1 N Hydrochloric Acid: Using a pipette, transfer 8.5 ml of hydrochloric acid to a 1,000 ml graduated flask and dilute to volume with HPLC grade water. - Volume of dissolution medium: 900ml - Elution time: 45 min - Temperature of dissolution medium: 37±0.5℃

[0081] 2) Related Content: Analytical procedure: European Pharmacopoeia <2.2.29>; HPLC Chromatography system: - Column: Luna C18(2) 5μm, 150×4.6mm. - Mobile phase: Acetonitrile / 0.5% phosphoric acid as follows:

[0082] [Table 5]

[0083] - Flow rate: 1.0ml / min - Detection wavelength: 210nm - Injection volume: 20μl - Column temperature: 30℃ - Retention time of albaconazole: approx. 20.0 min - Chromatogram time: 29 min

[0084] Test solution: Crush the contents (pellets) of at least 5 capsules and from the resulting powder, accurately weigh out approximately 150 mg and transfer to a 25 ml graduated flask. Add approximately 20 ml of acetonitrile HPLC grade and sonicate for approximately 10 minutes. After cooling, dilute to volume with acetonitrile HPLC grade. Filter through a 0.45 μm Millex HV-PVDF filter or similar filter and discard the first drop of filtrate (perform in triplicate).

[0085] Individual related substances below the quantification limit (QL = 0.015%) and the peak corresponding to placebo were not quantified.

[0086] The compositions of the present invention may be used to treat a fungal infection in a patient by orally administering the composition to the patient.

Claims

1. a) a plurality of particles, each having a diameter between 300 and 800 μm, that are substantially spherical and inert; and b) a coating on each of said plurality of particles comprising albaconazole, a coating agent, a plasticizer, and a surfactant. Including, A multiparticulate pharmaceutical composition wherein said coating agent is hydroxypropyl methylcellulose, said plasticizer is polyethylene glycol, and said surfactant is sodium lauryl sulfate.

2. 10. The multiparticulate composition of claim 1, wherein the plurality of substantially spherical, inert particles have a diameter, before being coated, between 400 and 750 μm, preferably between 450 and 750 μm, more preferably between 500 and 710 μm, and most preferably between 580 and 680 μm.

3. 3. A multiparticulate composition according to any one of claims 1 to 2, wherein the plurality of substantially spherical, inert particles comprises or is selected from the group consisting of sugar particles, cellulose particles or silicon dioxide particles; preferably each of the plurality of substantially spherical, inert particles is a sugar particle comprising sucrose and starch, preferably at least 60% by weight sucrose and up to 40% by weight starch, preferably corn starch.

4. 3. A multiparticulate composition according to any one of claims 1 to 2, wherein the coating comprises, relative to 100 mg of coated particles, (i) 3.5 to 30%, preferably 5 to 30%, more preferably 6 to 30%, even more preferably 6 to 25%, and most preferably 10 to 25% by weight of albaconazole; (ii) 0.1 to 17%, preferably 2 to 15%, more preferably 5 to 15%, even more preferably 8 to 14%, and most preferably 9 to 12% by weight of coating agent; and (iii) 0.1 to 5%, preferably 0.5 to 5%, more preferably 1 to 4%, even more preferably 2 to 3.5%, and most preferably 2.5 to 2.9% by weight of plasticizer.

5. 3. A multiparticulate composition according to any one of claims 1 to 2, wherein the coating comprises 0.1 to 1%, preferably 0.2 to 0.7%, and more preferably 0.3 to 0.5% by weight of the surfactant, relative to 100 mg of coated particles.

6. 3. A multiparticulate composition according to any one of claims 1 to 2, wherein albaconazole is used in a solid form selected from the group comprising or consisting of crystalline Form III, crystalline Form IV, crystalline Form VI or an amorphous form; preferably, albaconazole is used in crystalline Form III.

7. A pharmaceutical composition comprising a capsule containing the multiparticulate composition of any one of claims 1-2.

8. The following steps: i) providing an aqueous solution of a coating agent and a plasticizer; ii) adding a surfactant to the solution of step i); iii) dispersing albaconazole in the solution resulting from step i) or from step ii) to form a suspension; iv) optionally sieving the suspension of step iii) to remove particles with a size greater than 90 μm; v) coating a plurality of spherical inert particles having a particle size between 300 and 800 μm with the suspension resulting from step iii) or from step iv) if present, vi) optionally drying the product obtained from step v); vii) optionally filling the product obtained from step v) into capsules. A method for preparing a multiparticulate composition according to any one of claims 1 to 2, comprising:

9. 9. The method of claim 8, wherein the aqueous solution used in step iii) comprises a) 2 to 15 wt. %, preferably 3 to 10 wt. %, and more preferably 4.5 to 7 wt. % of a coating agent, b) 0.1 to 5 wt. %, preferably 0.5 to 3 wt. %, and more preferably 1.0 to 2.0 wt. % of a plasticizer, and c) 0.1 to 0.8 wt. %, and preferably 0.15 to 0.5 wt. % of a surfactant.

10. 9. A method according to claim 8, wherein albaconazole is dispersed in the solution of step i) or ii) such that the weight ratio of albaconazole to solution, expressed as "weight ratio = kg albaconazole / kg solution", is comprised between 0.05 and 0.2, preferably between 0.08 and 0.

12.

11. 9. The method according to claim 8, wherein the coating suspension used in step v) is used in a weight ratio of coating suspension to inert particles, expressed as "ratio = kg coating suspension / kg inert particles", between 1 and 9, preferably between 2 and 6, most preferably between 2.5 and 4.

5.

12. 9. The method according to claim 8, wherein the drying step vi) of the product resulting from the coating step v) is carried out at a temperature of the dried product between 35 and 65°C, most preferably between 45 and 55°C.

13. A composition according to any one of claims 1 to 2 for use in the treatment of fungal infections.

14. Use of a composition according to any one of claims 1 to 2 for the manufacture of a medicament for the treatment of a fungal infection.

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