KR100441109B1 - A solid mixture of cyclodextrin prepared by melt-extrusion - Google Patents

Abstract

The present invention relates to a process for the preparation of a solid mixture comprising one or more cyclodextrins and insoluble active ingredients, characterized in that it comprises a melt-extruding step of impregnating the cyclodextrin carrier with the active ingredient.

Description

A solid mixture of cyclodextrin prepared by melt-extrusion

The present invention relates to a process for preparing a solid mixture containing one or more active ingredients, preferably one or more substantially insoluble active ingredients, and one or more cyclodextrins by melt-extrusion. The present invention also relates to pharmaceutical compositions containing this mixture.

WO 94/11031, published May 5,1994, describes a process for making high quality enclosure compounds using extrusion techniques. This application mentions a method of extruding cyclodextrin along with the active ingredient. However, this application describes a method of feeding a wet mixture (i.e., containing water or other solvent) to an extruder.

A microgranule containing cyclodextrin obtained by extrusion-spheronisation in French Patent Application No. 2,705,677, published on Dec. 2, 1994, is described. The melt-spheronization technique is a technique using an agglomeration technique, namely, an extrusion method and a molding technique, that is, a sphericalization method. The French Patent Application are substantially β- cyclodextrin (Kleptose ^R), and microcrystalline cellulose described (Avicel ^R) and the forming method of the micro granules containing the ketoprofen and paracetamol as active ingredient. The extrusion technique used in this French patent application involves a method of preforming a wetting mass by pressing a wetting mass into a nozzle to form a long strand of extruded material. In this application, melt-extrusion is not mentioned at all.

EP 0,665,009, published April 24, 1994, as an international application, dislocates the crystalline state of a crystalline drug by extruding the crystalline material itself, i.e. without the use of any excipient such as cyclodextrin, Is described.

Uekama et al. Pharm. Pharmacolog., Vol. 44, No. 2, pages 73-8], spray-drying with hydroxypropyl -? - cyclodextrin to prepare amorphous nifedipine powder. There is no mention of melt-extrusion in this document.

Van Doorne et al., Pharm. Weekbl. Sci. Ed., 1988, vol. 10, No. 2, page (s) 80-85), suggests a method of forming a complex between? -Cyclodextrin and six antifungal imidazole derivatives. In this document, a gel and cream containing an antifungal agent was prepared by adding a 1.8% solution of? -Cyclodextrin instead of purified water. This reference also does not mention extrusion at all.

By Hostetler et al. Antimicrob. Chemother., 1993, vol 32, No 3, pages 459-463) describe the effect of hydroxypropyl- beta -cyclodextrin on the efficacy of oral itraconazole for interstitial cryptococcosis . In this document, the authors describe a method of dissolving itraconazole in hydroxypropyl -? - cyclodextrin to form a 100 ml solution. This document does not mention the extrusion process at all.

Mikami et al., Jpn. J. Med. Mycol., 1994, vol. 35, No. 3, page 263-267] describes the effect of carrier solvents on the efficacy of oral itraconazole for the treatment of aspergillosis of mice. This document does not mention the extrusion process at all.

Hydroxypropyl-beta-cyclodextrin is synthesized by the method described in Uekama et al. (&Quot; Effect of 2-hydroxypropyl-beta-cyclodextrin on Crystallization and Polymorphic Transition of Nifedipine in Solid State ", Pharmaceutical research, vol 11, -Cyclodextrin obtained by heating a mixture of cyclodextrins and immediately cooling to 0 占 폚 is described as a grit mixture of 2-hydroxypropyl-? -Cyclodextrin. This document does not mention how to extrude the mixture.

US 5,009,900 describes a greasy matrix useful for introducing and / or retaining and / or stabilizing volatile and / or unstable components in cooked or uncooked food. The glycidity matrix is a chemically modified starch having a dextrose equivalent weight of about 2 or less; Maltodextrin, corn syrup solids or polydextrose and mono- or disaccharides. This patent describes a method of forming a grit matrix by extrusion. However, cyclodextrins and therapeutically or pharmaceutically active ingredients are not specifically mentioned.

The above-mentioned documents do not describe the present invention at all.

WO 94/11031 and French Patent Application 2,705,677 describe the extrusion of a mixture of cyclodextrin and active ingredient, but do not mention how to use melt extrusion. The techniques described in WO 94/11031 and French Patent Application 2,705,677 are the major drawbacks of adding cyclodextrin and other solvents such as ethanol or methanol in most cases to water and a certain amount of cyclodextrin to the active component . To remove water and / or other solvents is often accompanied by a demanding process step, which is not reproducible since not all solvents can be removed. Also, when using substantially insoluble active ingredients, the amount of water and / or co-solvent required can render the technique impractical on an industrial scale. Another disadvantage of the prior art is that the drying step may unnecessarily crystallize the active ingredient.

These problems are solved by the present invention by using a melt-extrusion process to form a solid mixture containing one or more cyclodextrins and insoluble active ingredients.

Since the present invention does not require any solvent, it can be advantageously applied when the active ingredient is sensitive to a solvent such as water or an organic solvent. As used herein, the term " sensitive " means that the active ingredient is affected by the solvent to such an extent that its physical, chemical and / or biological properties are easily modified (e.g.

The present invention is also advantageous because it does not require a drying step where the insoluble active ingredient may crystallize.

As used above and hereinafter, the term " insoluble " means a semicomponent compound, i.e., "very slightly soluble", "substantially insoluble" and "insoluble".

The term " very slightly soluble ", " substantially insoluble ", or " insoluble ", as defined in United States Pharmacopoeia 23, NF 18 (1995) page 7, Requires a negative solvent; &Quot; Substantially insoluble " or " insoluble " compound means that more than 10,000 parts solvent is required per part solute. Herein, the solute means water or an aqueous solution.

The insoluble compounds of this type include but are not limited to itraconazole, rovilide and (±) -ethyl (R ^* , R ^* ) -4- [5- [1- [1- (4-chlorophenyl) hydroxymethyl] 4-triazol-4-yl] -2-pyridinyl] -1-piperazinecarboxylate (hereinafter referred to as compound 1) .

Itraconazole is an antifungal agent known in the art. Lobilide is an antiretrovirally active compound known in the art which is particularly useful for treating HIV-infected patients.

(R ^* , R ^* ) -4- [5- [1- [1- [4-chlorophenyl) hydroxymethyl] propyl] -1,5-dihydro-5-oxo-4H -1,2,4-triazol-4-yl] -2-pyridinyl] -1-piperazinecarboxylate is described as compound 3 in WO 95/27704 published Oct. 19, 1995 .

Compounds suitable for use in the art are compounds that are not degraded at the temperatures necessary to melt and extrude the mixture of one or more active ingredients with the cyclodextrin (s).

The term " active ingredient " refers to a compound or mixture of compounds that is pharmaceutically or therapeutically or cosmetically active in treating humans or animals.

The present invention provides a process for preparing a solid mixture containing one or more cyclodextrin and (insoluble) active ingredients, comprising a melt-extruding step of combining one or more cyclodextrins with one or more active ingredients do.

Melt-extrusion is a polymer extrusion technique that involves impregnating the active ingredient with one or more carriers. In this technique, the active ingredient and the excipient are melted in the extruder and impregnated with the thermoplastic and heat-meltable polymers. The formed melt mass is then pressed into one or more nozzles into thermoplastic strand (s).

The extruder consists of an inlet, a cylindrical " barrel ", a die and a screw (s). A schematic diagram thereof is shown in Fig.

Most of the inlets are funnel-shaped.

The barrel may include one or more barrel units through which the screw (s) are deployed.

As the extruder, there can be used two general types, namely a uniaxial screw extruder having one screw and a multi-screw extruder having two or more screws. While the present invention can be carried out using both types of extruders, it is preferred to use a multi-screw extruder, in particular a twin screw extruder. Biaxial screw extruders (and multiaxial screw extruders) are more efficient because multiple interfering screws interfere with follow-up motion of the active components and intermeshing of the screws produces high physical energy .

A useful mode of operation of the screw is to operate the screw in a corotating manner.

The screw (s) may have different shapes, such as, for example, a trapezoidal cut screw, a trapezoidal cut screw, a trapezoidal reverse cut screw, a ball screw, a dough paddle, Can be used.

The filler fed to the extruder through the inlet is sheared by the screw in the barrel as it is advanced by the screw (s), mixed and extruded from the orifice (s) of the die. The temperature of the barrel or barrel unit can be controlled by a heating element or, in some cases, by a cooling element.

The rotational speed of the screw can be fixed within the allowable range of the extruder used.

The skilled artisan can select screw arrangements and can combine unit screws. The main function of the screw is to transport, grind and mix the extruded material.

The orifice structure may be circular, elliptical, rectangular, or hexagonal.

The melt-extrusion step

a) mixing one or more cyclodextrins with the active ingredient (s)

b) optionally mixing the additives,

c) heating the obtained mixture until one of the components is melted,

d) after press fitting the resulting mixture through one or more nozzles,

e) cooling the mixture to solidification.

Optionally, as mentioned above, the heat-meltable mixture containing one or more cyclodextrins and the active ingredient (s) may contain suitable additives. For example, if the cyclodextrin (s) or active ingredient (s) or one other possible additive is susceptible to oxidation, the antioxidant is preferably added in minor amounts, for example from 100 to 5000, ppm. < / RTI > In addition, conventional auxiliary additives such as pigments, flavors, stabilizers, preservatives and buffers can be added.

If necessary, conventional pharmacologically acceptable plasticizers such as long chain alcohols, ethylene glycol, propylene glycol, triethylene glycol, butanediol, pentanol, hexanol, polyethylene glycol, aromatic carboxylates such as dialkyl phthalate, Trimellitates, benzoates or terephthalates), aliphatic dicarboxylates or fatty acid esters may also be added. However, preferably no plasticizer is required.

The term " melting " should be interpreted broadly. &Quot; Melting " also refers to a state in which some transition to the vitreous state takes place, where one component in the mixture can be impregnated with the other component. In a particular case, one component will melt and the other component (s) dissolve in the melt to form a solid solution, which exhibits favorable dissolution properties.

It is another advantage of the present invention that such a solid solution can be formed. One of ordinary skill in the art will recognize that mixing two or more solids, i.e., one or more cyclodextrins and the active ingredient (s), and subsequently melting these solids components, is accomplished by first contacting these solids components with water or other solvent Are known to form different products from those obtained by extrusion.

The properties of the melt extruded mixture of the present invention are that they contain substantially less water or other solvents than the mixture extruded in other ways.

Preferably, the melt extruded mixture of the present invention does not contain water or solvent except for water or a solvent which may be contained in the crystal structure of the active ingredient.

The temperature inside the extruder is an important parameter. If different barrel units are present, different temperatures may be applied. Those skilled in the art will employ the preferred form of the cyclodextrin (s) or the complete mixture to be extruded, and their behavior can be measured by a melting point meter, for example a Kofler hot bench, a hot stage type microscope or a type The required temperature can be determined by observing as a function of temperature using a DSC 7 series-differential scanning calorimeter such as Perkin Elmer.

Cooling can be performed without any auxiliary means. That is, it is most often sufficient to cool the thermoplastic strand exiting the extruder to the ambient temperature of the product. Of course, cooling assist means may also be used.

When the thermoplastic strand is cooled, the strand may be comminuted to obtain a mixture of the cyclodextrin (s) and the active ingredient in powder form.

Those skilled in the art know that milling may affect the physical properties of the extrudate. Friction occurs during pulverization, and since the high shear force is applied to the pulverized raw material, the temperature of the raw material may rise. Temperature and mechanical forces or shear forces can change the physical state of the material to be ground. Those skilled in the art will have sufficient means to control temperature and shear forces at will, and thus the milling process can be controlled.

The two processes, melt extrusion and milling, can be combined to have one configuration as shown in Fig. One or more cyclodextrins and a mixture of one or more active ingredients are fed through a funnel-like inlet with possible other additives. The mixture is then melt-extruded and the mixture is passed through a nozzle to a conveyor belt. The extrudate is cooled while being conveyed to the conveyor belt. The cooled molten extrudate is fed into a chopper to make pellets. This pellet is further crushed if necessary.

The powder material still has favorable properties (high bioavailability, dissolution rate, etc.) and can be used in a conventional manner to produce pharmaceutical, therapeutic or cosmetic solid dosage forms.

A further advantage of the present invention is that the active ingredient and the cyclodextrin can be converted to amorphous or a solid solution is formed. Those skilled in the art will appreciate that such a change in physical state from crystalline to amorphous or solid solutions is highly advantageous for dissolution.

The fact that the melt extruded mixture contains an amorphous material or a solid solution or consists essentially of an amorphous material or a solid solution can be measured or inspected using differential scanning calorimetry. If the crystalline material is present in the melt extruded mixture, the differential scanning calorimeter will exhibit an endothermic melting peak. If the amorphous material or solid solution is predominantly present in the melt extruded mixture, the differential scanning calorimeter will not exhibit an endothermic melting peak. The molten extrudate can be visually observed to distinguish the amorphous material from the solid solution. If the melt extrudate is opaque, the cyclodextrin (s) and active ingredient are all in an amorphous form. When the melt extrudate is transparent, a solid solution is formed.

The curves of the differential scanning calorimeter are shown in Figs. 2 to 7. Fig.

Useful embodiments of the present invention are melt extruded mixtures composed primarily of amorphous materials.

A more useful embodiment of the present invention is a melt extruded mixture consisting essentially of an amorphous material.

A still more useful embodiment of the present invention is a melt extruded mixture consisting essentially of a solid solution of the active ingredient (s) in the cyclodextrin (s).

A preferred embodiment of the present invention is a melt extruded mixture consisting essentially of a solid solution of the active ingredient (s) in the cyclodextrin (s).

Yet another advantage of the present invention is that the powdered material can be simply mixed with excipients and compressed into pharmaceutical, therapeutic or cosmetic forms of, for example, tablets or other solids, Or the granulation step may be omitted during the formation of the cosmetic composition.

Depending on the nature of the melt extruded mixture, the unit dosage form may be immediate release or sustained release, depending on the pellet size of the melt extruded mixture or the mesh of the powder of the melt extruded mixture, as well as other adjuvants added to the unit dosage form.

In some cases, such solid pharmaceutical forms may be subjected to conventional coating treatments to improve appearance and / or flavor (coating tablets) or further to control the release of the active ingredient.

Suitable tablets may have the following composition and may be prepared in a conventional manner. The amount presented depends on the dosage required for pharmaceutical, therapeutic or cosmetic activity.

Composition A

100 to 500 mg of the pulverized melt extrudate

100 to 300 mg of microcrystalline cellulose

10 to 200 mg of crospovidone

1 to 5 mg of colloidal silicon dioxide

Strontex 2 to 10 mg

Composition B

100 to 500 mg of the pulverized melt extrudate

Microcall (TM) (1) 200 to 300 mg

70 to 200 mg of crospovidone

20 to 50 mg of talc

Strontex 7 to 10 mg

1 to 5 mg of colloidal silicon dioxide

2 to 10 mg of magnesium stearate

The cyclodextrins used in the above-mentioned compositions include pharmaceutically acceptable unsubstituted and substituted cyclodextrins, more particularly alpha, beta or gamma -cyclodextrins, or pharmaceutically acceptable derivatives thereof, .

Substituted cyclodextrins that may be used in the present invention include the polyethers described in U.S. Patent No. 3,459,731. Generally, unsubstituted cyclodextrins are preferably reacted with alkylene oxides in the presence of an alkaline catalyst under overpressure and elevated temperature.

The average molar substitution degree (MS) is used to determine the average number of moles of substituent per unit of glucose since the hydroxy moiety of the cyclodextrin can itself be substituted by an alkylene oxide capable of reacting with other alkylene oxide molecules . The MS may be greater than 3 and is not theoretically limited.

Additional substituted cyclodextrins are those in which the hydrogen of one or more cyclodextrin hydroxy groups is replaced by a substituent selected from the group consisting of C _1-6 alkyl, hydroxyC _1-6 alkyl, carboxyC _1-6 alkyl or C _1-6 alkyloxycarbonylC _{1 Lt; /} RTI > alkyl or mixed ethers thereof. Particularly substituted cyclodextrins are those in which the hydrogen of one or more cyclodextrin hydroxy groups is replaced by C _1-3 alkyl, hydroxyC _2-4 alkyl or carboxyC _1-2 alkyl, more particularly methyl, ethyl, hydroxyethyl, Hydroxybutyl, carboxymethyl or carboxyethyl. ≪ / RTI >

In the above definitions, the term " C _1-6 alkyl " means a straight chain having 1 to 6 carbon atoms such as methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, And branched saturated hydrocarbon radicals.

The ether can be prepared by reacting the starting cyclodextrin with a suitable O-alkylating agent or a mixture thereof at a concentration such that the desired cyclodextrin ether is obtained. This reaction is preferably carried out in a suitable solvent in the presence of a suitable base. In this ether, the degree of substitution (DS) is the average number of hydroxy functional groups substituted per glucose unit and DS is 3 or less.

In the cyclodextrin derivatives for use in the composition according to the invention, the DS is preferably from 0.125 to 3, especially from 0.3 to 2, more particularly from 0.3 to 1, the MS is from 0.125 to 10, in particular from 0.3 to 3, 0.3 to 1.5.

Particularly useful in the present invention are? -Cyclodextrin ethers, such as those described in M. et al. Dr Nogradi, Drugs of the Future, Vol. 9, No. 8, p. 577-578 (1984)] and polyethers such as hydroxypropyl [beta] -cyclodextrin and hydroxyethyl [beta] -cyclodextrin. The alkyl ether may be a methyl ether having a degree of substitution of from about 0.125 to 3, for example from about 0.3 to 2. The hydroxypropylcyclodextrin can be formed, for example, by the reaction of beta-cyclodextrin and propylene oxide, and the MS is about 0.125 to 10, for example about 0.3 to 3.

The newer type of substituted cyclodextrin is sulfobutyl cyclodextrin. This form is also included in the present invention.

The ratio of active ingredient to cyclodextrin can vary widely. For example, a ratio of 1/100 to 100/1 may be used. The useful ratio of active ingredient to cyclodextrin is from about 1/10 to 10/1. A more useful ratio of active ingredient to cyclodextrin is about 1/5 to 5/1. The most useful ratio is about 1/3 to 3/1. The preferred ratio is about 1/1.

Sometimes cyclodextrin mixtures of different forms (?,?, R) or different substituents (2-hydroxypropyl or methyl) or different degrees of substitution can be used to reduce the melting point.

1 schematically shows a configuration for carrying out the present invention.

Figure 2 is a differential scanning calorimetric curve (DSC curve) of unbranched batch No. 1 material (see Example 1).

Figure 3 is a differential scanning calorimetric curve of batch # 1 batch material (see Example 1).

4 is a differential scanning calorimetric curve of the No. 2 batch material (see Example 1).

Figure 5 is a differential scanning calorimetric curve of batch # 3 material (see Example 1).

Figure 6 is a differential scanning calorimetric curve of batch material # 4 (see Example 1).

7 is a differential scanning calorimetric curve of batch material No. 5 (see Example 1).

Example 1

An extruded sample of the active ingredient and hydroxypropyl -? - cyclodextrin (HP-β-CD) was obtained using an MP19 APV Baker twin screw extruder (available from APV Baker Company) having a die with an orifice diameter of 3 mm do. The process parameters for each experiment are shown in Table 1. This type of extruder has an L / D ratio of 15 and 4D FS - 4x30 FP - 4x60 FP - 4x90 P - 4x60 RP - 2.5D FS - 2x30 FP - 2x60 FP - 2x90 P - 3x60 RP - 3 DFS Means a transport element having a length four times greater than the diameter of a screw of a feed screw type, 4x30 FP means four forward piles positioned at an angle of 30 degrees with each other, and 4x60 RP means a reverse Quot;) < / RTI >

In an extruder of this type, the mixture is rotated at a delivery speed v2 by a feed screw rotating at a constant feed rate v1 (the feed rate rotating 10 times per minute corresponds to a feed rate of 1.5 kg per hour) Is fed onto a biaxial conveyor screw having a diameter of 18 mm. This speed is the rotation speed (revolutions per minute).

The mixture is then conveyed to the first heating zone t1. Here, the conveying speed is reduced by the difference in the structure of the biaxial conveying screw. That is, the rotational carrier speed v2 is the same, but the material does not advance rapidly.

Subsequently, the molten mass is conveyed to the second heating zone t2 by the biaxial conveyor screw having the prescribed structure, in which the conveying speed is again reduced by the difference in the structure of the biaxial conveyor screw.

After the second heating, the heat-meltable mixture is transferred to the nozzle of the apparatus.

* rpm = revolutions per minute

- t1: the temperature of the first heating zone

- t2: the temperature of the second heating zone

- t _p : Barrel internal temperature

- v1: Supply screw speed

- v2: screw carrier speed (rotation)

In each case, a mixture of the active ingredient and 2-hydroxypropyl-beta -CD provides a solid solution.

Example 2

An extruded sample of the active ingredient and dimethyl- beta -cyclodextrin (DM- beta -CD) is obtained using an MP19 APV Baker type extruder having the process parameters shown in Table 2.

(1) The device is operated manually without the feed screw.

In each case a mixture of the active ingredient and DM- [beta] -CD.

- t1: the temperature of the first heating zone

- t2: the temperature of the second heating zone

- t _p : Barrel internal temperature

- v1: Feed screw speed (rotation)

- v2: screw carrier speed (rotation)

Example 3

The solubility of the melt extrudate in batch # 1 was compared to the solubility of the " physical mixture " (i.e., the mixture of the two components that had the same ratio as batch one but were not melt extruded). 100 mg of the ground melt extrudate of batch 1 is added to 900 ml of artificial gastric juice at a temperature of 37 캜. The stirring method used is a paddle method using paddles rotating at 100 revolutions per minute. The relative amount of dissolved extrudate was determined using UV spectroscopy for 1 hour.

The same procedure was carried out for " physical mixture ".

The results of the dissolution process are shown in Table 3 below.

Example 4

The degree of melting was measured using a differential scanning calorimeter. The calorimeter used is the Perkin-Elmer 7 series thermal analysis system. In all cases, the heating rate was fixed at 20 [deg.] C per minute.

Fig. 2 shows the DSC curve of batch melt extrudate No. 1 before milling. This curve indicates that there is no endothermic and exothermic peak, and it was observed that the molten material was a transparent solution visually, suggesting that the melt extrudate in the unbranched batch No. 1 is a solid solution.

Figure 3 shows the DSC curve of the batch melt extrudate once after milling. This curve indicates that there is no endothermic and exothermic peak, and it was observed that the molten material was visually a clear solution, suggesting that the melt extrudate in the batch 1 batch is a solid solution.

4 shows the DSC curve of the batch melt extrudate No. 2 prior to milling. This curve indicates that there is no endothermic and exothermic peak, and it was observed that the molten material was visually insoluble in solution, suggesting that the melt extrudate in the unbranched batch No. 2 is a mixture of amorphous materials.

Fig. 5 shows the DSC curve of the batch melt extrudate three times prior to milling. This curve shows a small endothermic peak. The data for this small peak are as follows: X1 = 117.600 占 폚, X2 = 143.200 占 폚, 132.695 占 폚 peak, area 38.126 mJ,? H 3.768 J / g, height 1.520 mW and start operating at 125.816 占 폚. This small peak appears to be probably due to impurities in the cyclotetramine. It is clear that the melt extrudate of batch 3, which is not ground, is a mixture of amorphous materials.

6 shows the DSC curve of the batch melt extrudate of No. 4 prior to milling. This curve represents several small endothermic peaks. Thus, it is certain that the melt extrudate of batch 4, which has not been pulverized, is a mixture of amorphous material containing a small amount of crystalline material.

7 shows the DSC curve of the batch melt extrudate of No. 5 prior to milling. This curve shows that there is no endothermic and exothermic peak and it was observed that the molten material was visually insoluble in the solution, suggesting that the melt extrudate in the unbranched batch No. 5 is a mixture of amorphous materials.

Example 5

The melt extrudate of batch 1 is pulverized and sieved. Mixing appropriate amounts to produce tablets having the following composition in a manner known in the art:

480 mg < RTI ID = 0.0 >

218 mg of microcrystalline cellulose

Aerosil 3 mg < RTI ID = 0.0 >

Magnesium stearate 5 mg

Crospovidone 144 mg

Claims (8)

A process for preparing a solid mixture comprising cyclodextrin and itraconazole, characterized in that it comprises a melt-extrusion step in which itraconazole is impregnated with a cyclodextrin carrier and no solvent is used. The method of claim 1, wherein the melt- a) mixing the cyclodextrin with itraconazole, b) heating the resulting mixture until one of the components has melted, c) The resulting mixture is injected through a nozzle, d) cooling the mixture to solidification. 3. The process according to claim 2, further comprising a lower step of mixing the additive subsequent to the lower step a). A solid mixture obtained by the process as claimed in any one of claims 1, 2 and 3. 5. The solid mixture of claim 4 wherein only one type of cyclodextrin is present. The solid mixture according to claim 4, wherein the cyclodextrin is hydroxypropyl -? - cyclodextrin or dimethyl -? - cyclodextrin. A pharmaceutical composition for an antifungal agent comprising the solid mixture of claim 4 and other excipients in powdered form. Characterized in that the solid mixture as claimed in claim 4 is ground and the resulting powder material is thoroughly mixed with other pharmaceutically acceptable excipients and then further processed into a pharmaceutical dosage form, A method for preparing a pharmaceutical composition for an antifungal agent comprising the solid mixture of claim 4 and other excipients.