WO2005002553A2

WO2005002553A2 - Fluconazole capsules with improved release

Info

Publication number: WO2005002553A2
Application number: PCT/HU2004/000071
Authority: WO
Inventors: Pál FEKETE; Judit Virgula; Éva FURDYGA; Magdolna LEVENTISZNÉ HUSZÁR; Imre Klebovich; Katalin BALOGHNÉ NEMES
Original assignee: EGIS Gyógyszergyár Rt.
Priority date: 2003-07-02
Filing date: 2004-06-30
Publication date: 2005-01-13
Also published as: PL380995A1; SK50132006A3; CZ200657A3; EA200600085A1; CN1812783A; UA82532C2; WO2005002553A3; HU0302030D0; BG109430A; EP1648451A2; HU227142B1; EA008585B1; HUP0302030A2

Abstract

The object of the invention is to provide fluconazole containing capsules with improved active ingredient release. The in vitro dissolution as well as in vivo absorption of the fluconazole capsules according to the invention is faster and more consistent than those of commercial compositions containing fluconazole. The invention is based on the fact that granulation of fluconazole particles with an agent capable to provide hydrophilic surface, e.g. lactose, to said particles results in fast an consistent release of the active ingredient. In this way, capsules according to the invention are suitable to provide enhanced absorption of said active ingredient.

Description

FLUCONAZOLE CAPSULESWITHIMPROVED RELEASE

Fluconazole is an important representative of the wide spectrum triazole antifungal medicinal active ingredients, which is mainly administered orally.

Chemically fluconazole is 2,4-difluoro-(α),(α)-bis-(lH-l,2,4- triazole-1- yl- methyl)-benzylalcohol. Its chemical structure corresponds to the empirical formula and molecular weight of Ci3H₁₂F₂N₆O and 306.3 g/mol, respectively. Fluconazole is white, crystalline solid, which is poorly soluble in water.

Fluconazole is administered in the therapy in form of tablets or capsules in strengths of 50 mg, 100 mg, 150 mg or 200 mg. Tablets containing fluconazole as active ingredient are marketed in the United States. In Europe, fluconazole containing capsules are introduced.

TECHNICAL BACKGROUND OF THE INVENTION

According to the state of the art, the fluconazole containing medicinal preparations marketed by the originator (Pfizer) contain the following auxiliary agents:

Diflucan® capsules lactose, maize starch, magnesium stearate, silicone dioxide, sodium lauryl sulfate.

(Source: Rote Liste) Diflucan® tablets microcrystalline cellulose, anhydrous calcium phosphate, povidone, sodium croscarmellose, FD4C Red No. 40 aluminium pigment, magnesium stearate. (Source: Physicians' Desk Reference)

Pharmacokinetic studies revealed that after oral administration, fluconazole is rapidly absorbed from the gastrointestinal tract. Its metabolism is not significant in the liver. No first pass effect occurs. Absolute bioavailability of fluconazole is approximately 90 %. Peak plasma concentration (c_max) of fluconazole increase linearly with the administered dose (linear pharmacokinetics). Peak plasma concentration occures 1 to 2 hours after administration.

Due to the aforementioned pharmacokinetic properties of fluconazole, the active ingredient should be rapidly released from the medicinal preparation in order to prevent delayed absorption of said active ingredient as an effect pharmaceutical formulation.

However, it is known for those skilled in the art that production of immediate release medicinal preparation containing fluconazole is not straightforward.

In the international publication document WO 93/18757, preparation of fluconazole containing immediate release preparation is disclosed, wherein said preparation is manufactured by formulating a tablet containing menthol and obtaining a porous tablet structure by having menthol sublimed.

According to the publication of Hostetler and co-workers, use of hydroxypropyl-beta-cyclodextrin as a solubility-enhancing agent, which has prevailed for other active ingredients, can not be used for the formulation of fluconazole (Antimicrob. Agents Chemother. 1992, 36(2), 477-80).

Inappropriate dissolution rate of fluconazole preparation results in high deviation of peak plasma concentration results during a bioequivalence study, which, in turn, causes inconsistency in study results. For example, in the study of Moraes and coworkers, the deviation of peak plasma concentration values was 27.5 % (Ther. Drug Monit. 1999, 21(2), 200-207).

FIELD OF THE INVENTION

Therefore there is a long-felt need for a fluconazole containing medicinal preparation, which provides for the fast and consistent dissolution in vitro as well as fast and consistent absorption in vivo.

Such medicinal preparations are characterized by short time interval to reach peak plasma concentration (t_max: time to reach peak plasma concentration after administration), high peak plasma concentration (c_max) and low interindividual deviation of the aforementioned two pharmacokinetic variables.

In the pharmaceutical development phase, said pharmacokinetic variables can be estimated on the basis of the active ingredient dissolution rate. In the first step, medicinal preparations having rapid and consistent in vitro dissolution rate are developed. Advantages of such preparations to the one having moderately slow dissolution are the following: - time required for absorption is short, since it is governed dominantly by the properties of the active ingredient, - the interindividual difference in the time required for absorption is low, because modulating effect of the formulation is negligible, - the possibility of interference during the absorption of the active ingredient is lower, because the time required for complete absorption is short. Such interferences include, but are not limited to changes in peristaltic motion due to nausea or diarrhea, intake of medicines influencing drug absorption and, food ingestion. Under certain treatment protocols and in some diseases, incomplete absorption of the drug may result in the failure of achieving the desired therapeutical effect. For example, in vaginal candidiasis, fluconazole is administered in monodose, i.e. only one dose of the drug is ingested. Another critical application is the fungal infection of the nail (onychomycosis), wherein the drug is taken once a week.

Our studies carried out for the development of immediate release capsules showed that methods known in the state of the art are ineffective when dissolution rate of fluconazole containing tablets is to be increased. Such methods include decreasing the particle size of the active ingredient (DE 23 55 204, HU 200 926), detergents in the formulation (EP 462 067) or using special disintegrants or silicone dioxide (HU 196 710).

SUMMARY OF THE INVENTION

The object of the present invention is to provide rapidly and consistently dissolving capsules containing fluconazole, comprising fluconazole [2,4-diflouro-(α),(α)-bis-(lH- 1,2,4- triazol-l-ylmethyl)benzylalcohol], granulated with an agent capable of providing hydrophilic superficial character for the granules and optionally with a surfactant, said granules admixed with other optional filling or auxiliary agents.

The basis of our invention is the recognition that a hydrophilic coating layer fashioned on the surface of fluconazole particles of hydrophobic nature significantly increase the dissolution rate of said hydrophobic fluconazole particles.

On the one hand, the aforementioned hydrophilic layer residing on the surface of hydrophobic particles inhibits said particles to stick together in the dissolving medium, which process can result in diminished wetted surface during the dissolution process, and in conclusion, in diminished dissolution rate. On the other hand, said hydrophilic layer facilitates the hydration of the individual particles producing rapid and consistent superficial wetting of said hydrophilically coated particles and also rapid dissolution thereof.

According to the present invention, a process is provided for the manufacture of fluconazole capsules, wherein said fluconazole particles are coated with an agent providing hydrophilic character to the particles and optionally with a surfactant and granules resulting from the above mentioned process are optionally admixed with one or more filling agents or another pharmaceutically acceptable auxiliary agents.

We experienced surprisingly that a carbohydrate of low molecular weight as hydrophilic agent is suitable for ensuring the favourable dissolution of fluconazole capsules when sprayed on the surface of the active ingredient at least in an amount of 5 weight%, more favourable in an amount of 10-20 weight%, calculated on the basis of the weight of the active ingredient. Capsules prepared in this manner exhibit faster and more consistent in vitro dissolution and provide fast absorption and more consistent blood plasma concentration when compared to preparations known in the art.

DETAILED DESCRIPTION OF THE INVENTION

Fluconazole capsules according to the present invention are comprising fluconazole containing granules produced by granulating fluconazole with 5-20 weight% of an agent capable to provide hydrophilic superficial character for the granules and optionally with 0.1-1 weight% surfactant calculated on the basis of said active ingredient, optionally admixed with 10-60 weight% filling agent, 5-30 weight% disintegrant, 0.1-2 weight% lubricant and 0.1-2 weight% glidant calculated on the basis of the filling weight of said capsule, wherein the fluconazole content of the capsule fill is 30-85 weight%, calculated on the basis of the filling weight.

Said fluconazole containing granules having a hydrophilic superficial layer are prepared by spraying the aqueous solution of an agent capable to provide hydrophilic character onto the fluconazole particles and by evaporating the water.

Agents capable to provide hydrophilic character are substances which form a hydrophylic layer on particles when sprayed onto said particles directly or in solution, thus facilitating the wetting of said particles and increasing dissolution rate. These agents include carbohydrates of low molecular weight, such as sugar alcohols and sugars. Preferable sugar alcohols are mannitol, sorbitol or maltitol, while preferable sugars include lactose, glucose, fructose or saccharose; the most preferably, lactose is used. Lactose is preferable since in its presence no stability problems are anticipated.

Optionally, further enhancement of the dissolution rate of fluconazole particles can be achieved using a surfactant. Surfactants generally used in oral pharmaceutical preparations can be applied, such as non-ionic surfactants, which include among others polyethylene-fatty acid esters or ethers, sugar-esters; anionic surfactants including sodium lauryl sulfate or sodium dioctyl-sulfosuccinate. The amount of the surfactant is usually 0.1-1 weight%. Preferably, sodium lauryl sulfate can be used. Depending on the desired strength of the capsules, filling agents can be used to facilitate formulation. Filling agents used in the capsules according to the present invention are selected from those usually applied in capsule production. These agents include inorganic substances, such as calcium hydrogenphosphate dihydrate and organic substances. As organic filling agents, carbohydrates, e.g. carbohydrates of low molecular weight, sugars, e.g. fructose, glucose, or the most preferably, lactose; sugar alcohols, e.g. mannitol, sorbitol or maltitol; cellulose derivatives, e.g. microcrystalline cellulose could be used in an amount of 10-60 % calculated on the weight of the preparation.

The composition according to the present invention can contain further auxiliary agents.

Said auxiliary agents include lubricants useful in automated capsule filling process. Said lubricant's role is to decrease the friction between the particles of the formulation and the filling tubes. Lubricants known in the state of the art could be used in the production of the capsules according to the present invention. Such lubricants include stearic acid, hydrogenated vegetable oils, paraffins, alkali earth metal salts of stearic acid, such as magnesium stearate or calcium stearate. Amount of the lubricant is between 0.1-2.0 weight% calculated on the basis of the weight of preparation. Preferably, calcium or magnesium stearate, the most preferably, magnesium stearate can be used.

Since the fill of the capsules is compressed during the automated filling process, capsules according to the present invention can contain a disintegrant to enhance dispersion of the capsule fill in an aqueous medium after administration. Disintegrants generally used in the pharmaceutical technology can be used in the composition of the present invention, e.g. starch, starch derivatives, partially hydrolyzed starch or starch derivatives, e.g. sodium carboxymethyl starch, cellulose derivatives, e.g. sodium carboxymethyl cellulose, polivinyl-pyrrollidone. Preferably starch, more preferably, partially hydrolyzed, cross-linked starch can be applied. Usual amount of the disintegrant is 0.5-30 weight% calculated on the basis of the weight of the composition.

Further ingredients used in the composition according to the present invention include colloidal silicone dioxide. Colloidal silicone dioxide has multiple effect. It is useful to improve the gliding property of the powder mixture and the precision of metering. Said compound may shorten the disintegration time of the capsules due to its hydrophilic character and may accelerate the dissolution of the active ingredient. Colloidal silicone dioxide is added in a powder-mixing procedure in an amount of 0.1-2 weight% calculated on the basis of the weight of the composition.

Further object of the present invention is to provide a process for the manufacture of capsules containing fluconazole with rapid and consistent dissolution property, characterized in that a solution containing an agent capable to provide hydrophilic surface property and optionally a surfactant is sprayed onto the surface of fluconazole [2,4-diflouro-(α),(α)-bis-(l H- 1 ,2,4-triazole- 1 - ylmethyl)benzylalcohol] particles, the resulting treated particles are mixed and homogenized with filling and auxiliary agents and filled into capsules. According to a preferable embodiment, solution of 5-20 weight% agent capable to provide hydrophilic surface property and optionally 0.1-1 weight⁰/- surfactant calculated on the basis of the weight of fluconazole is sprayed onto the surface of fluconazole particles comprising 30-85 % of the weight of the medicinal composition, the resulting coated particles are admixed and homogenized with 10-60 % filling agent, 5-30 % disintegrant, 0.1- 2.0 % lubricant and 0.1-2 % glidant, wherein amounts of said filling agent, disintegrant, lubricant and glidant are calculated on the basis of the desired weight of the composition, and filling the resulting mixture into capsules.

Surfactant may optionally be sprayed onto the surface of fluconazole particles together with the agent capable to produce a hydrophilic surface property. Spraying is preferably performed in the fluidized state, since this method provides fast evaporation of water. According to a preferable embodiment, the solution to be sprayed contains 10-40 weight% agent capable to produce a hydrophilic surface on the surface of the said hydrophobic active ingredient particles and optionally 0.1-1 weight% surfactant. In a more preferable embodiment, amounts of the agent capable to provide hydrophilic surface is 15-25 weight%, while the amount of the surfactant is 0.1-0.5 weight%. The agent capable to provide hydrophilic surface property on the fluconazole particles and optionally the surfactant are dissolved in water. The temperature of water is between 25 and 90°C, preferably between 40 and 70°C, the most preferably, between 55 and 65°C. The solution is thermostated during spraying at temperature between 25 and 90°C, preferably 40-70°C, the most preferably, between 55 and 65°C. The temperature of fluidizing air is between 25 and 80°C, preferably 40 and 70°C, the most preferably, 55 and 65°C. The pressure required for adequate spraying and the air volumetric flow rate could be determined by a person skilled in the art and according the apparatus used. Subsequent to spraying, the fluidized drying is continued until the humidity of the resulting granules decrease to 0.2-4%, preferably 0.5-3%, the most preferably, 1-2 %. The dried granules are screened using a sieve of 0.5 to 1.5 mm, preferably 0.6-1.2 mm, the most preferably, 0.8- 1.0 mm mesh. Granules are optionally admixed with filling agent and other auxiliary agents, homogenized and filled into capsules.

In order to further demonstrate the favourable properties of the fluconazole containing capsules according to the present invention, in vitro dissolution profile and in vivo absorption of fluconazole capsules of 150 mg strength prepared according to Example 3 are compared to a commercial fluconazole containing capsule prepared by Pfizer, known as the original developer of the fluconazole containing preparation.

Table 1

Dissolution of fluconazole capsules (150 mg strength) prepared according to Example 3

Batch Number: 120250200

The test was performed in a paddle apparatus according to Ph. Eur. at 50 rpm. The dissolving medium was 500 ml 0.1 M HCl. Samples were analyzed by high-performance liquid chromatography.

Table 2

Batch Number: 9026913 Dissolution of Diflucan® (Pfizer) capsules (150 mg strength) containing fluconazole prepared by the originator The test was performed in a paddle apparatus according to Ph. Eur. at 50 rpm.' The dissolving medium was 500 ml 0.1 M HCl. Samples were analyzed by high-performance liquid chromatography.

Results of in vitro dissolution tests show that capsules produced according to Example 3 of the present invention exhibit significantly higher dissolution rate in the initial 30 minutes of dissolution than the original preparation (Diflucan ® capsules). Furthermore, more consistency between dosage units with regard to said dissolution rate test was concluded, which was shown by comparing deviations of the dissolved amount of the active ingredient obtained in said dissolution test.

In vivo dissolution differences between said two preparations has been also demonstrated in a single dose, crossover, randomized comparative pharmacokinetic study performed in 28 healthy male individuals.

Table 3 demonstrates the maximum plasma concentration (c_max) and time required to reach maximum plasma concentration (t_max) together with their deviation, maximum and minimum values obtained in the above mentioned pharmacokinetic study.

Table 3

Pharmacokinetic parameters of Diflucan® capsules (Pfizer) and capsules prepared according to present invention (Example 3) Batch Numbers: Capsules according to present invention: 120250200 Diflucan® (Pfizer) capsules: 9026913

Maximum plasma concentrations measured were significantly higher in case of the composition according to the present invention (ANON A, p>0.05) than for Diflucan® capsules. Median time required to reach maximum plasma concentration (t_max) was 1.5 hour for the composition according to the present invention, while that for the Diflucan® capsules was 2.0 hours. However, while the mathematical mean was equal to the median for the composition according to the present invention (1.5 hours), it was 3.0 hours for Diflucan® capsules. Furthermore, relative standard deviation of the time required to reach maximum plasma concentration (t_max) was only about 50% for the composition according to the present invention to that for Diflucan® capsules. These facts demonstrate that absorption rate of the composition according to the present invention was significantly enhanced, which phenomenon was accompanied by decreased interindividual deviation in time required to reach peak plasma concentration, signifying increased consistency in absorption. (RSD 53.3 % vs. 100 %). Less consistent absorption of Diflucan® capsules are also demonstrated by excessive minimum and maximum values of the time required to reach peak plasma concentration. Namely, it could be observed that higher mean and median values in case of Diflucan® capsules are the consequence of an extremely long absorption time amounting 10-12 hours. Pharmacokinetic parameters therefore prove the faster and more consistent release and absorption of active ingredient in case of the composition of the present invention in vivo, which is inevitably advantageous from the therapeutical point of view. Similar conclusion can be drawn from the plasma concentration values measured during the absorption phase (i.e. first three hours following drug administration). Plasma concentration values are higher in all cases after administration of the composition of the present invention than for Diflucan ® capsules, while deviations of plasma concentrations are lower for the composition according to the present invention (Table 4). Lower relative standard deviations obtained for the composition according to the present invention than those for Diflucan® capsules for each plasma sampling time after administration proved the more consistent absorption of the composition according to the present invention.

Table 4

Plasma concentration of fluconazole after single oral administration of capsules according to the present invention (150 mg) and for Diflucan ® (Pfizer) capsules

OO

Such results were unexpected since according to the teachings of patent specification HU 196 710, immediate release fluconazole containing preparations could be produced by a greatly specialized technology resulting in porous tablets only.

Experiments were conducted to evaluate the processes according to the state of the art to produce fluconazole containing capsules with fast and consistent release of the active ingredient. Effect of the particle size of the active ingredient and use of auxiliary agents were studied.

In order to evaluate the effect of the particle size of the active ingredient on the dissolution rate, available active ingredient was milled to a certain extent and the active ingredient fractions of different particle size were formulated to yield capsules containing 50 mg fluconazole. Capsules were prepared by homogenizing the active ingredient and auxiliary agents in a gravity mixer and the resulting mixture was filled into hard gelatine capsules. Results of the experiments are summarized in Table 5 and Table 6.

Table 5 Composition of fluconazole capsuels

Table 6 Effect of particle size on the dissolution of fluconazole capsules

t

From the experiments it could be concluded that decreasing the particle size of the fluconazole active ingredient result neither in increase of dissolution rate or consistency of dissolution, i.e. decrease of the relative standard deviation between dosage units. From the technical viewpoint, decrease in the particle size in the active ingredient resulted a decrease in the gliding property of the powder mixture, thus increasing the mass deviation (poor uniformity of mass). This phenomenon was clearly identifiable for batches 9811011 and 9811012.

Since it is known from the state of the art that increase of dissolution rate could be achieved by applying surfactant or hydrophilic colloidal silicone dioxide in increased amounts, we examined separately the effect of applying double amount of the surfactant sodium lauryl sulfate and the effect of using tenfold amount of hydrophilic silicone dioxide on the dissolution rate of the fluconazole capsules. Composition of capsules is summarized in Table 7. The filling powder mixture was prepared by dry homogenization and was filled into hard gelatin capsules. Dissolution testing was performed according to the provisions of Ph. Eur. The test was performed in a paddle apparatus according to Ph. Eur. at 50 rpm. The dissolving medium was 500 ml 0.1 M HCl. Samples were analyzed by high-performance liquid chromatography. Results of the dissolution test are summarized in Table 8. Table 7 Composition of fluconazole capsules

t l-

Table 8 Effect of the amount of surfactant and hydrophilic colloidal auxiliary agent on dissolution rate

to ^

From the experiments we concluded that the increase in the amount of surfactant or hydrophilic colloidal silicone dioxide did not result in the desired increase of the consistency of initial dissolution rate. Surprisingly, increase in the amount of sodium lauryl sulfate resulted in the decrease of the initial dissolution rate.

According to the aforesaid experiments, the fast and consistent dissolution for the fluconazole active ingredient can not be achieved by applying techniques known from the state of the art.

Opposingly, we found that immediate release oral fluconazole compositions can be prepared by using the apparatus and equipments of pharmaceutical technology known from the prior art.

On the basis of the qualitative composition of the original preparation, aqueous solution of a portion of the lactose used as filling agent in the original preparation together with sodium lauryl sulfate is sprayed onto the particles of the active ingredient, admixed and homogenized with starch, magnesium stearate and hydrophilic colloidal silicone dioxide and filled into hard gelatine capsules. In this way, fluconazole capsules characterized by fast and consistent absorption are obtained.

Experiments were performed to clarify the effect of auxiliary agents present in the composition, wherein surfactant, colloidal silicone dioxide and the filling agent were omitted from the composition (Example 4). Dissolution of the active ingredient was rapid and consistent in this case as well. Amount of fluconazole present in the composition can vary between 30-85 weight% on the basis of the mass of the composition, taking into account the amount of other ingredients. Considering that fluconazole may be applied in monodose, which may be as high as 200 mg, it is advantageous to produce fluconazole capsules containing at least 40 weight% fluconazole.

Our invention is further demonstrated in the following examples without restricting the invention to the examples in any way.

Example 1 Capsules of the following composition were produced in a laboratory scale.

Sodium lauryl sulfate is dissolved in about 450 g purified water and heated to approx. 60°C, and in this solution is lactose monohydrate is dissolved under stirring. The active ingredient is transferred to a Glatt GPCG 1 fluid bed granulating apparatus and said solution is sprayed onto the particles of the active ingredient, while the temperature of the solution is kept between 40-60°C. Subsequently the coated particles were dried in the same apparatus and are regranulated using a 0.8 mm mesh manual sieve. Granules and Aerosil 200 are homogenized in an Engelsmann drum mixer for 5 minutes, then lactose (DCL 11) and pregelatinized starch (Starch 1500) is added; the homogenization is continued for 5 minutes. A portion of approx. 200 g is removed from the homogenate obtained in the above described process and used for preparing a pre-blend with the magnesium stearate. The pre-blended mixture has been reloaded to the homogenizing container and the whole mass of the blend was homogenated for further 2 minutes.The final blend was filled into capsules. Dissolution data of the capsule

Example 2 Capsules of the following composition were produced on a pilot plant scale.

Sodium lauryl sulfate is dissolved in purified water, the solution is heated to 60°C and lactose monohydrate is added. The mixture is stirred until complete dissolution. The active ingredient is transferred into the fluidizing container of a Glatt GPCG 15 apparatus and is fluidized at 60°C air temperature. The granulating solution is sprayed onto the particles of the active ingredient at a pressure of 250 kPa. Subsequently the mixture is dried until its humidity is less than 2 %. Dried granules are regranulated using a Diaf granulating apparatus. Weight of the granules was determined and amounts of the components of the outer phase were calculated on the basis of the actual weight of the granules. The appropriate amount of the sieved Aerosil 200 and the granules are transferred into the drum mixer and are homogenized for 5 minutes. Subsequently the actual amount of lactose (DLC- 11) and pregelatinized starch (Starch 1500) are added and homogenized for further 5 minutes. Approximately 500 g of the pre-blend prepared in the above described manner was removed and was mixed with the actual amount of sieved magnesium stearate in a bowl manually. This mixture is transferred into the drum mixer and homogenized for further 2 minutes. The homogenized blend is filled into hard gelatin capsules of „0" size. Dissolution data of the capsule

Example 3 In order to provide test preparation for the pharmacokinetic study of the composition according to the present invention, 150mg capsules were produced on a 100.000 ea batch scale.

Apparatus, equipment

Bill of materials

Ingredient Charge

Inner phase

Fluconazole 15.0000 kg

Granulating solution

Lactose monohydrate 1.8000 kg

Sodium lauryl sulfate 0.0375 kg

Purified water 6.5000 kg

Outer phase

Lactose DCL 11 12.5000 kg

Maize starch Sta -RX 1500 5.3300 kg

Aerosil 200 0.0355 kg

Magnesium stearate 0.2800 kg

Capsules of 150 mg were produced using the process described in Example 2.

Dissolution data of the capsules prepared by the aforementioned process are summarized in Table 1.

Example 4 Capsules of the following composition were produced on a laboratory scale.

Lactose monohydrate is dissolved in approx.400 g water heated approximately 60°C under stirring. The active ingredient is transferred into a Glatt GPCG 1 fluid bed granulating apparatus and the solution is sprayed onto the particles, while the temperature of the solution was kept between 40 and 60°C. Coated particles are dried in the same apparatus and regranulated using a manual sieve of. 0.8 mm mesh. Granules and pregelatinized starch (Starch 1500) are homogenized for 5 minutes in an Engelsmann drum mixer. Approximately 200 g of the blend obtained in this manner is removed and mixed with the pre-weighed magnesium stearate. This pre-mix was reloaded to the homogenizing drum and homogenized for further 2 minutes. The final blend was filled into hard gelatin capsules of „0" size with an average filling weight of 233.0 mg. Active ingredient content of the capsules is 150 mg. Dissolution testing

Claims

What we claim is:

1. Fluconazole containing capsules with fast and consistent active ingredient release comprising fluconazole [2,4- diflouro-(α),(α)-bis-(lH- 1 ,2,4-triazol- 1 -yl- methyl)benzylalcohol] particles granulated with an agent capable to produce hydrophilic surface character on said particles and optionally with a surfactant and optionally admixed with further filling and auxiliary agents.

2. Fluconazole containing capsules providing fast and consistent active ingredient release according to claim 1, comprising 30-85 % fluconazole calculated on the basis of the weight of said composition granulated with 5-20 % agent capable to produce hydrophilic layer on the surface of fluconazole particles and optionally with 0.1-1 % surfactant, both amount calculated on the basis of the weight of fluconazole, and admixed optionally with 10-60 % filling agent, 5-30 % disintegrant, 0.1-2.0 % lubricant and 0.1-2.0 % glidant, each calculated on the basis of the weight of the composition.

3. Fluconazole containing capsules providing fast and consistent active ingredient release according to claim 1, comprising 30-60 % fluconazole calculated on the basis of the weight of said composition, granulated with 10-20 % agent capable to produce hydrophilic layer on the surface of said fluconazole particles and optionally with 0.1-1 % surfactant, both amount calculated on the basis of the weight of fluconazole, and admixed optionally with 20-50 % filling agent, 10-25 % disintegrant, 0.5-1.5 % lubricant and 0.2-1.0 % glidant, each calculated on the basis of the weight of the composition.

4. Fluconazole containing capsules providing fast and consistent active ingredient release according to claim 1, comprising 40-50 % fluconazole calculated on the basis of the weight of said composition granulated with 10-15 % agent capable to produce hydrophilic layer on the surface of said fluconazole particles and optionally with 0.2-0.5 % surfactant, both amount calculated on the basis of the weight of fluconazole, and admixed optionally with 30-40 % filling agent, 10-15 % disintegrant, 0.5-1.0 % lubricant and 0.1-0.5 % glidant, each amount calculated on the basis of the weight of the composition.

5. Capsules according to any of claim 1 to 4, wherein the agent capable to produce hydrophilic layer on the surface of fluconazole particles is a carbohydrate of low molecular weight.

6. Capsules according to any of claim 1 to 4 containing an organic or inorganic filling agent.

7. Capsules according to claim 6, wherein the inorganic filling agent is calcium hydrogenphosphate.

8. Capsules according to claim 6, wherein the organic filling agent is selected from carbohydrate of cellulose derivatives, preferably from carbohydrates of low molecular weight.

9. Capsules according to claim 5 or claim 8, wherein the carbohydrate of low molecular weight is selected from sugars or sugar alcohols.

10. Capsules according to claim 9, wherein the sugar is selected from lactose, glucose, fructose, being preferably lactose.

11. Capsules according to any of claims 1 to 4, wherein the surfactant is of anionic type, preferably sodium lauryl sulfate.

12. Capsules according to any of claims 1 to 4, wherein the disintegrant is starch or starch derivative, preferably pregelatinized starch.

13. Capsules according to any of claims 1 to 4, wherein the lubricant is alkali earth metal stearate, hydrogenated vegetable oils or paraffin, preferably magnesium stearate.

14. Capsules according to any of claims 1 to 4, wherein the glidant is colloidal silicone dioxide.

15. Fluconazole containing capsules providing fast and consistent active ingredient release according to claim 1, comprising 40-50 % fluconazole calculated on the basis of the weight of said composition, granulated with 10-15 % lactose and optionally with 0.2-0.5 % sodium lauryl sulfate, both amount calculated on the basis of the weight of fluconazole, and admixed optionally with 30-40 % lactose, 10-15 % pregelatinized starch, 0.5-1.0 % magnesium stearate and 0.1-0.5 % colloidal silicone dioxide, each amount calculated on the basis of the weight of the composition.

16. Process for the preparation of fluconazole capsules with fast and consistent active ingredient release, characterized in that a solution of an agent capable to produce hydrophilic surface and optionally of a surfactant is sprayed onto the surface of fluconazole [2,4-diflouro-(α),(α)-bis-(lH-l,2,4- triazol-l-yl-methyl)benzylalcohol] particles, particles treated in the aformentioned manner are optionally admixed and homogenized with further filling and auxiliary agents and filled into capsules.

17. Process for the preparation of fluconazole capsules with fast and consistent active ingredient release according to claim 16, characterized in that solution comprising 5-20 % agent capable to provide hydrophilic surface and optionally 0.1-1 % surfactant calculated on the basis of the weight of fluconazole particles is sprayed onto the surface of said particles comprising 30-85% weight of the capsule fill and particles treated in this manner are optionally homogenized with 10-60 % filling agent, 5-30 % disintegrant, 0.1-2.0 % lubricant, 0.1-2.0 % glidant, each weight calculated on the basis of the preparation, and filled into capsules.

18. Process for the preparation of fluconazole capsules with fast and consistent active ingredient release according to claim 16, characterized in that solution comprising 10-20 % agent capable to provide hydrophilic surface and optionally 0.1-1 % surfactant calculated on the basis of the weight of fluconazole particles is sprayed onto the surface of said particles comprising 30-60% weight of the capsule fill and particles treated in this manner are optionally homogenized with 10-50 % filling agent, 10-25 % disintegrant, 0.5-1.5 % lubricant, 0.1-1.0 % glidant, each weight calculated on the basis of the preparation, and filled into capsules.

19. Process for the preparation of fluconazole capsules with fast and consistent active ingredient release according to claim 16, characterized in that solution comprising 10-15 % agent capable to provide hydrophilic surface and optionally 0.2- 0.5 % surfactant calculated on the basis of the weight of fluconazole particles is sprayed onto the surface of said particles comprising 40-50% weight of the capsule fill and particles treated in this manner are optionally homogenized with 30-40 % filling agent, 10-15 % disintegrant, 0.5-1.0 % lubricant, 0.1-0.5 % glidant, each weight calculated on the basis of the preparation, and filled into capsules.

20. Process for the preparation of fluconazole capsules with fast and consistent active ingredient release according to claim 16, characterized in that solution comprising 10-15 % lactose and optionally 0.2-0.5 % sodium lauryl sulfate calculated on the basis of the weight of fluconazole particles is sprayed onto the surface of said particles comprising 40- 50% weight of the capsule fill and particles treated in this manner are optionally homogenized with 30-40 % lactose as filling agent, 10-15 % pregelatinized starch as disintegrant, 0.5-1.0 % magnesium stearate as lubricant, 0.1-0.5 % colloidal silicone dioxide as glidant, each weight calculated on the basis of the preparation, and filled into capsules.

21. Process according to any of claims 16 to 19, characterized in that the agent capable to provide hydrophilic surface is a carbohydrate of low molecular weight.

22. Process according to any of claims 16 to 19, characterized in that an organic or inorganic filling agent is used.

23. Process according to claim 22, characterized in that an inorganic filling agent, preferably calcium hydrogenphosphate is used.

24. Process according to claim 23, characterized in that an organic filling agent belonging to carbohydrates or cellulose derivatives, preferably a carbohydrate of low molecular weight is used.

25. Process according to claim 21 or claim 24, characterized in that a sugar or sugar alcohol is used as carbohydrate of low molecular weight.

26. Process according to claim 25, characterized in that preferably lactose, glucose, fructose or saccharose, the most preferably, lactose is used as sugar.

27. Process according to any of claims 16 to 19, characterized in that as surfactant, preferably an anionic surfactant, the most preferably, sodium lauryl sulfate is used.

28. Process according to any of claims 16 to 19, characterized in that preferably starch, the most preferably, pregelatinized starch is used as disintegrant.

29. Process according to any of claims 16 to 19, characterized in that preferably alkali earth metal salts of stearic acid, hydrogenated vegetable oils or paraffins are used as lubricant.

30. Process according to any of claims 16 to 19, characterized in that colloidal silicone dioxide is used as glidant.

31. Process according to any of claims 16 to 20, characterized in that the temperature of the water used for the dissolution of the agent capable to provide a hydrophilic surface and optionally for the dissolution of surfactant is between 25 and 90 °C and the temperature of the solution of said agents is kept between 25 and 90 °C during spraying.

32. Process according to any of claims 16 to 20, characterized in that the temperature of the water used for the dissolution of the agent capable to provide a hydrophilic surface and optionally for the dissolution of surfactant is between 40 and 70 °C and the temperature of the solution of said agents is kept between 40 and 70 °C during spraying.

33. Process according to any of claims 16 to 20, characterized in that the temperature of the water used for the dissolution of the agent capable to provide a hydrophilic surface and optionally for the dissolution of surfactant is between 55 and 65 °C and the temperature of the solution of said agents is kept between 55 and 65 °C during spraying.

34. Process according to any of claims 16 to 20, characterized in that spraying is carried out in a fluid bed granulating apparatus.

35. Process according to claim 34, characterized in that the temperature of the air stream used for fluidization is kept preferably between 25 and 80 °C, more preferably, between 40 and 70°C, the most preferably, between 55 and 65°C.

36. Process according to claim 35, characterized in that the granules are dried in the fluid bed apparatus until the humidity of said granules decreases between 0.2 to 4 %, preferably 0.5 to 3.0 %, the most preferably, between 1 and 2 %.