KR19990067009A - 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 containing one or more cyclodextrins and insoluble active ingredients, comprising a melt-extrusion step of impregnating the active ingredient into a cyclodextrin carrier.

Description

Solid mixture of cyclodextrin prepared by melt-extrusion

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

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

Microgranules containing cyclodextrins obtained by extrusion-spheronisation are described in French Patent Application No. 2,705,677 published on December 2, 1994. Melt-spherification is a technique using agglomeration techniques, that is, an extrusion method and a molding technique, that is, a spheroidization method. This French patent application describes substantially how to form microgranules containing β-cyclodextrin (Kleptose ^R ) and microcrystalline cellulose (Avicel ^R ) and ketoprofen and paracetamol as active ingredients. The extrusion technique used in this French patent application involves a method of preforming a wet mass by injecting the wet mass into a nozzle to form a long strand of extruded material. No mention is made of melt-extrusion in this application.

EP 0,665,009, published on April 24, 1994, as an international application, dislocates the crystalline state of crystalline medicine by extruding the crystalline material on its own, ie without using any excipients such as cyclodextrins. The method of making is described.

Uekama et al., J. Pharm. Pharmacolog., Vol 44, No2, pages 73-8, describes a method for preparing amorphous nifedipine powder by spray-drying with hydroxypropyl-β-cyclodextrin. 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, suggest a method for forming a complex between β-cyclodextrin and six antifungal imidazole derivatives. In this document, gels and creams containing antifungal agents were prepared by adding 1.8% β-cyclodextrin solution in place of purified water. This document also mentions nothing about extrusion.

Hoster et al., J. Antimicrob. Chemother., 1993, vol 32, No3, pages 459-463, describe the effect of hydroxypropyl-β-cyclodextrin on the efficacy of oral itraconazole on scattered rat cryptococcosis. . In this document the author describes a method for dissolving itraconazole in hydroxypropyl-β-cyclodextrin to form 100 ml of solution. No mention is made of the extrusion process in this document.

Mikami et al., Jpn. J. Med. Mycol., 1994, vol 35, No3, pages 263-267, describe the effect of carrier solvents on the efficacy of oral itraconazole treatment on aspergilossis in mice. No mention is made of the extrusion process in this document.

2-hydroxypropyl-β by Uekama et al., "Effect of 2-hydroxypropyl-β-cyclodextrin on Crystallization and Polymorphic Transition of Nifedipine in Solid State", Pharmaceutical research, vol 11, No 12, 1994]. A glissified mixture of 2-hydroxypropyl-β-cyclodextrin obtained by heating a mixture of cyclodextrins and immediately cooling to 0 ° C. is described. This document does not mention how to extrude the mixture.

US 5,009,900 describes glissiness matrices useful for introducing, maintaining, and / or stabilizing volatile and / or labile ingredients in cooked or uncooked foods. This glissiness matrix can be selected from the group consisting of chemically modified starches having dextrose having an equivalent weight of about 2 or less; Maltodextrin, corn syrup solids or polydextrose and mono- or disaccharides. This patent describes a method for extruding to form a glissic matrix. However, no special mention is made of cyclodextrins and therapeutically or pharmaceutically active ingredients.

All of the above-mentioned documents do not describe the invention.

WO 94/11031 and French Patent Application No. 2,705,677 describe the extrusion of the cyclodextrin and the active ingredient but do not mention how to use melt extrusion. The technique described in WO 94/11031 and French patent application 2,705,677 requires the addition of a certain amount of water and / or other solvents such as ethanol or methanol to the cyclodextrin and the active ingredient in order to produce the wet mass. There are major disadvantages. Often difficult process steps are involved to remove water and other solvents, which are not reproducible because not all solvents can be removed. In addition, when using substantially insoluble active ingredients, the amount of water and / or co-solvents required makes the technique infeasible 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 forming a solid mixture containing one or more cyclodextrins and insoluble active ingredients using a melt-extrusion process.

The present invention does not require any solvent and can be advantageously applied when the active ingredient is sensitive to solvents such as water or organic solvents. As used herein, the term "sensitive" means that the active ingredient is readily affected (eg within about 1 hour) to the extent that its physical, chemical and / or biological properties are significantly modified or altered.

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

Above and after, the term “insoluble” means a compound of the subcategory, ie “very slightly soluble”, “substantially insoluble” and “insoluble”.

The terms "very slightly soluble", "substantially insoluble" or "insoluble" are defined in U.S. Pharmacopoeia 23, NF 18 (1995), page 7, ie, "very slightly soluble" compounds ranging from 1000 to 10,000 for one part of the solute. A negative solvent is required; By “substantially insoluble” or “insoluble” compound is meant that at least 10,000 parts of solvent are required for one part of the solute. Here, solute means water or aqueous solution.

Insoluble compounds of this type include itraconazole, lobbyide and (±) -ethyl (R ^* , R ^* )-4- [5- [1- [1-[(4-chlorophenyl) hydroxymethyl] propyl]- There are three examples of 1,5-dihydro-5-oxo-4H-1,2,4-triazol-4-yl] -2-pyridinyl] -1-piperazinecarboxylate (hereafter referred to as compound 1). .

Itraconazole is an antifungal agent known in the art. Roviride is an antiretrovirally active compound known in the art, particularly useful for treating patients infected with HIV.

(±) -ethyl (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 October 19, 1995. .

Compounds suitable for use in the present technology are compounds that do not decompose at the temperatures necessary to melt and extrude a mixture of one or more active ingredients and cyclodextrin (s).

The term "active ingredient" means a compound or mixture of compounds that is pharmaceutically or therapeutically or cosmetically active in treating a human or animal.

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

Melt-extrusion is a polymer extrusion technique that includes impregnating an active ingredient into one or more carriers. In this technique, the active ingredients and excipients are melted in an extruder and impregnated with thermoplastic and thermomelt polymers. The formed melt mass is then press fit into one or more nozzles into thermoplastic strand (s).

The extruder consists of an inlet, a cylindrical "barrel", a die and screw (s). A schematic diagram of this is shown in FIG. 1.

The inlets are mostly funnel shaped.

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

As the extruder, two general types, a single screw extruder having one screw and a multi screw extruder having two or more screws can be used. The present invention can be carried out using both types of extruders, but preference is given to using multi-screw extruders, in particular twin screw extruders. Biaxial screw extruders (and multi-screw extruders) are more efficient because a plurality of mutually interfering screws interfere with the follow-up movement of the active ingredient and the intermeshing of the screws physically produces high energy. .

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

The screw (s) may have different forms such as, for example, trapezoidal screws, trapezoidal cut screws, trapezoidal reverse cut screws, ball screws, dough paddles, which may be combined as desired Can be used.

The charge fed to the extruder through the inlet is sheared by the screw in the barrel while advancing by the screw (s), mixed and then extruded from the orifice (s) of the die. The temperature of the barrel or barrel unit can be adjusted by means of a heating element or optionally a cooling element.

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

Those skilled in the art can choose screw arrangements and combine unit screws. The main function of the screw is to transport, grind and mix the extrusion raw material.

The orifice structure can be round, oval, rectangular or hexagonal.

The melt-extrusion step

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

b) optionally mixing the additives,

c) the resulting mixture is heated until one of the components melts,

d) the obtained mixture is press-fitted through one or more nozzles,

e) a lower step of cooling the mixture until it solidifies.

If desired, 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 antioxidants are preferably in small amounts, eg 100 to 5000, based on the total weight of the mixture. It can be impregnated in ppm. In addition, conventional auxiliary additives such as pigments, flavors, stabilizers, preservatives and buffers may be added.

If desired, conventional pharmacologically acceptable plasticizers such as long chain alcohols, ethylene glycol, propylene glycol, triethylene glycol, butanediol, pentanol, hexanol, polyethylene glycol, aromatic carboxylates (e.g. dialkyl phthalates, Trimellitate, benzoate or terephthalate), aliphatic dicarboxylates or fatty acid esters may also be added. However, preferably no plasticizer is required.

The term "melt" should be interpreted broadly. "Melt" also means a state in which some transition to the glassy state occurs, wherein one component of the mixture may be impregnated with the other component. In special cases, one component will melt and the other component (s) dissolve in the melt to form a solid solution, which exhibits favorable dissolution properties.

Being able to form such a solid solution is one of the other advantages of the present invention. Those skilled in the art will appreciate that mixing two or more solids, ie one or more cyclodextrins and the active ingredient (s), and subsequently melting these solid components first contacts these solid components with water or another solvent It is understood that it will form a different product than that obtained by extrusion.

A property of the melt extruded mixtures of the present invention is 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 contains no water or solvent except water or 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 can be applied. Those skilled in the art adopt the desired form of the cyclodextrin (s) or the complete mixture to be extruded, and their behavior is determined by melting point measuring instruments, such as Kofler hot bench, hot stage type microscope or type. The required temperature can be determined by observing as a function of temperature using a differential scanning calorimeter, such as the DSC 7 Series-Perkin Elmer.

Cooling can be performed without any auxiliary means. That is, it is most often enough to cool the thermoplastic strands exiting the extruder to ambient temperature in the production section. Of course, cooling aids can also be used.

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

One skilled in the art knows that grinding may affect the physical properties of the extrudate. Friction occurs during grinding, and because the high shear force is applied to the raw materials to be crushed, the temperature of the raw materials can rise. Temperature and mechanical or shear forces can change the physical state of the raw material being ground. Those skilled in the art have sufficient means to adjust the temperature and shear forces at will, and thus control the grinding process.

The two processes, melt extrusion and grinding, can be combined to have one configuration as shown in FIG. A mixture of one or more cyclodextrins and one or more active ingredients is fed through a funnel inlet along with other possible additives. The mixture is then melt-extruded and the mixture is sent through a nozzle to a conveyor belt. The extrudate is cooled while being conveyed to the conveyor belt. The cooled melt extrudate is fed into a chopper to pellet. This pellet is further ground if necessary.

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

Another advantage of the present invention is that the active ingredient and cyclodextrin can be converted to amorphous or a solid solution is formed. Those skilled in the art know that such a change in physical state from crystalline to amorphous or solid solution is very 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 examined using a differential scanning calorimeter. Differential scanning calorimetry will show endothermic melting point peaks if crystalline material is present in the melt extruded mixture. Differential scanning calorimetry will not show an endothermic melting point peak if there is mainly amorphous material or solid solution in the melt extruded mixture. The melt extrudate can be visually observed to distinguish between the amorphous material and the solid solution. If the melt extrudate is opaque, then both the cyclodextrin (s) and the active ingredient are in amorphous form. If the melt extrudate is transparent, a solid solution is formed.

The curve of the differential scanning calorimeter is shown in FIGS.

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

Even more useful embodiments of the present invention are melt extruded mixtures consisting essentially of amorphous material.

Even more useful embodiments of the present invention are melt extruded mixtures consisting primarily of a solid solution of the active ingredient (s) in the cyclodextrin (s).

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

Another advantage of the present invention is that the powdered material can be simply mixed with excipients and compressed, for example, into pharmaceutical, therapeutic or cosmetic forms of tablets or other solids, for example in pharmaceutical, therapeutic Or a 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 powder of the melt extruded mixture and also other auxiliaries added to the unit dosage form.

If desired, these solid pharmaceutical forms may be subjected to conventional coatings to improve their appearance and / or flavor (coating tablets) or further control the release of the active ingredient.

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

Composition A

100 to 500 mg of ground melt extrudate

Microcrystalline cellulose 100 to 300 mg

Crospovidone 10-200 mg

1-5 mg of colloidal silicon dioxide

Sterotex 2-10 mg

Composition B

100 to 500 mg of ground melt extrudate

200-300 mg of microceram (TM) (1)

Crospovidone 70-200 mg

Talc 20-50 mg

Sterotex 7-10 mg

1-5 mg of colloidal silicon dioxide

Magnesium Stearate 2-10 mg

Cyclodextrins used in the above-mentioned compositions include pharmaceutically acceptable and unsubstituted and substituted cyclodextrins known in the art, more particularly α, β or γ-cyclodextrins or pharmaceutically acceptable derivatives thereof. Included.

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

Since the hydroxy moiety of the cyclodextrin can be substituted by an alkylene oxide that can react with other alkylene oxide molecules on its own, the average molar substitution (MS) is used to determine the average mole of substituents per unit of glucose. . MS can be greater than 3 and is not limited in theory.

Additional substituted cyclodextrins are those in which one or more of the cyclodextrin hydroxy groups are hydrogenated with C _1-6 alkyl, hydroxyC _1-6 alkyl, carboxyC _1-6 alkyl or C _1-6 alkyloxycarbonylC _{1 -6} ether substituted by alkyl or mixed ethers thereof. Particularly substituted cyclodextrins are those in which one or more of the cyclodextrin hydroxy groups are hydrogenated with C _1-3 alkyl, hydroxyC _2-4 alkyl or carboxyC _1-2 alkyl, more particularly methyl, ethyl, hydroxyethyl, hydroxy Ether substituted by oxypropyl, hydroxybutyl, carboxymethyl or carboxyethyl.

In the above definition, the term "C _1-6 alkyl" is a straight chain of 1 to 6 carbon atoms such as methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, 2-methylpropyl, butyl, pentyl, hexyl, and the like. And branched saturated hydrocarbon radicals.

The ether can be prepared by reacting the starting cyclodextrin at a concentration such that a suitable O-alkylating agent or mixture thereof 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 substituted hydroxy functional groups per unit of glucose and DS is 3 or less.

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

Particularly useful in the present invention are β-cyclodextrin ethers, for example M. Chem. Drugs of the Future by Vol. Nogradi, Vol. 9, No. 8, p. 577-578 (1984), dimethyl-β-cyclodextrin and polyethers such as hydroxypropyl β-cyclodextrin and hydroxyethyl β-cyclodextrin. The alkyl ether may be methyl ether having a degree of substitution of about 0.125 to 3, for example about 0.3 to 2. Hydroxypropyl cyclodextrins can be formed, for example, by reaction of β-cyclodextrins with propylene oxide, and MS is about 0.125 to 10, for example about 0.3 to 3.

A newer form of substituted cyclodextrin is sulfobutylcyclodextrin. This form is also included in the present invention.

The active ingredient ratio to cyclodextrin can vary widely. For example, a ratio of 1/100 to 100/1 can be used. A useful ratio of active ingredient to cyclodextrin is 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. Preferred ratio is about 1/1.

Sometimes cyclodextrin mixtures of different forms (α, β, γ) or different substituents (2-hydroxypropyl or methyl) or different degrees of substitution may be used to reduce the melting point.

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

FIG. 2 is a differential scanning calorimetry curve (DSC curve) of batch 1 material (see Example 1) which is not ground.

3 is a differential scanning calorimetry curve of ground No. 1 batch material (see Example 1).

4 is a differential scanning calorie curve of batch material 2 (see Example 1).

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

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

7 is a differential scanning calorific curve of batch material 5 (see Example 1).

Example 1

An extrusion sample of hydroxypropyl-β-cyclodextrin (HP-β-CD) was obtained using an MP19 APV Baker type twin screw extruder (commercially available from the APV Baker Company) with a die having 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 (where 4D is 4x30 FP means four forward paddles located at an angle of 30 ^° to each other, and 4x60 RP means reverse paddles located at an angle of 60 ^{° to} each other. Means an operating region with

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

The mixture is then conveyed to the first heating zone t1. The conveying speed is reduced here by the structural difference 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 a biaxial carrier screw having a defined structure, wherein the conveying speed is again reduced by the structural difference of the biaxial carrier screw.

After the second heating the hot melt mixture is transferred to the nozzle of the apparatus.

mixture Batch number t1 (℃) t2 (℃) t _p (℃) v1 (rpm) ^* v2 (rpm) ^* Compound 1 / HP-β-CD = 1/3 One 256 283 280 10 100 Itraconazole / HP-β-CD = 1/1 2 263 265 279 10 20 Itraconazole / HP-β-CD = 1/3 3 264 265 280 10 20 Roviride / HP-β-CD = 1/1 4 274 285 292 10 80 Roviride / HP-β-CD = 1/3 5 258 265 274 10 20

^* Rpm = revolutions per minute

t1: temperature of the first heating zone

t2: temperature of the second heating zone

-t _p : Temperature inside barrel

-v1: feed screw speed

-v2: Biaxial Carrier Screw Speed (Rotation)

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

Example 2

MP19 APV Baker type extruders with the process parameters shown in Table 2 were used to obtain extrusion samples of the active ingredient and dimethyl-β-cyclodextrin (DM-β-CD).

mixture Batch number t1 (℃) t2 (℃) t _p (℃) v1 (1) (rpm) ^* v2 (rpm) ^* Compound 1 / DM-β-CD = 1/1 6 241 245 254 0 20 Itraconazole / DM-β-CD = 1/1 7 239 240 253 0 20 Roviride / DM-β-CD = 1/1 8 248 250 263 0 20

^* Rpm = revolutions per minute

(1) The device is operated manually without supply screw.

In each case a mixture of the active ingredient and DM-β-CD.

t1: temperature of the first heating zone

t2: temperature of the second heating zone

-t _p : Temperature inside barrel

-v1: Feed screw speed (rotation)

-v2: Biaxial Carrier Screw Speed (Rotation)

Example 3

The solubility of the melt extrudate in batch 1 was compared with that of the “physical mixture” (ie, a mixture of two components having the same ratio as batch 1 but not melt extruded). 100 mg of the ground melt extrudates in one batch are added to 900 ml of artificial gastric juice at a temperature of 37 ° C. The stirring method used is a paddle method using a paddle rotating 100 times per minute. Relative amounts of dissolved extrudate were measured for 1 hour using UV spectroscopy.

The same procedure was followed for the "physical mixture".

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

Time mixture (minutes) Crushed extrudate in batch 1 (% total dissolved) Corresponding physical mixture (% total dissolved) 0 0.00 0.00 5 62.10 1.71 15 70.20 14.67 30 72.63 21.06 45 74.07 26.10 60 74.25 28.35

Example 4

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

2 shows the DSC curve of batch 1 melt extrudates prior to milling. This curve indicates that there is no endothermic and exothermic peaks, and it was observed that the molten material was a clear solution visually, indicating that the melt extrudate in batch 1, which was not comminuted, was a solid solution.

3 shows the DSC curve of batch 1 melt extrudates after grinding. This curve indicates that there is no endothermic and exothermic peaks, and it was observed that the molten material was a clear solution visually, indicating that the melt extrudates of the ground batch 1 were a solid solution.

4 shows the DSC curve of the two batch melt extrudates prior to grinding. This curve indicates the absence of endothermic and exothermic peaks and was visually observed to be a solution in which the molten material was not clear, suggesting that the two batches of unpulverized melt extrudate were a mixture of amorphous material.

5 shows the DSC curve of the three batch melt extrudates before grinding. This curve shows a small endothermic peak. The data for this small peak are as follows: peak at X1 = 117.600 ° C, X2 = 143.200 ° C, 132.695 ° C, area 38.126 mJ, ΔH 3.768 J / g, height 1.520 mW, starting at 125.816 ° C. This small peak is probably due to impurities in the cyclodextrin. It is certain that the melt extrudate of batch 3, which is not comminuted, is a mixture of amorphous materials.

6 shows the DSC curve of batch 4 melt extrudates prior to milling. This curve shows some small endothermic peaks. Thus, it is certain that the melt extrudate of batch 4, which is not comminuted, is a mixture of amorphous materials containing small amounts of crystalline material.

7 shows the DSC curve of the batch 5 melt extrudate before grinding. This curve indicates the absence of endothermic and exothermic peaks and was visually observed to be a solution in which the molten material was not clear, suggesting that the 5 batches of unmelted melt extrudate were a mixture of amorphous material.

Example 5

The batch of melt extrudates are ground and sieved. Mixing the appropriate amount produces a tablet having the following composition in a manner known in the art:

480 mg of ground extrudate in batch 1

Microcrystalline Cellulose 218 mg

Aerosil 3 mg

Magnesium Stearate 5mg

Crospovidone 144 mg

Claims (12)

A method of making a solid mixture containing one or more cyclodextrins and one or more active ingredients, characterized by comprising a melt-extrusion step of impregnating the active ingredient into a cyclodextrin carrier. The process of claim 1 wherein the melt-extrusion process a) mixing one or more cyclodextrins with one or more active ingredients, b) optionally mixing the additives, c) the resulting mixture is heated until one of the components melts, d) the obtained mixture is press-fitted through one or more nozzles, e) a lower step of cooling the mixture until it solidifies. A solid mixture obtainable by the method as claimed in claim 1, wherein nifedipine is not combined with 2-hydroxypropyl-β-cyclodextrin. 4. The solid mixture of claim 3, wherein the active ingredient (s) is insoluble according to the definition of the US Pharmacopoeia. The solid mixture of claim 3 or 4 wherein substantially only one type of cyclodextrin is present. The solid mixture according to any one of claims 3 to 5, wherein the cyclodextrin is hydroxypropyl-β-cyclodextrin. The solid mixture according to any one of claims 3 to 5, wherein the cyclodextrin is dimethyl-β-cyclodextrin. 8. A solid mixture according to any one of claims 3 to 7, wherein the active ingredient is itraconazole. 8. A solid mixture according to any one of claims 3 to 7, wherein the active ingredient is lobbyide. 8. The active ingredient according to claim 3, wherein the active ingredient is (±) -ethyl (R ^* , R ^* )-4- [5- [1- [1-[(4-chlorophenyl) hydroxy Methyl] propyl] -1,5-dihydro-5-oxo-4H-1,2,4-triazol-4-yl] -2-pyridinyl] -1-piperazinecarboxylate. A pharmaceutical composition containing milled melt extrudate and other excipients. A solid mixture as claimed in any one of claims 4 to 10 is suitably ground and the powdered material obtained is thoroughly mixed with other pharmaceutically acceptable excipients and then further processed into a pharmaceutical dosage form. To prepare a pharmaceutical composition as claimed in claim 11.