CA2232135A1 - Solid mixtures of cyclodextrins prepared via melt-extrusion - Google Patents

Abstract

Process for preparing a solid mixture comprising one or more cyclodextrins and an insoluble active ingredient characterized in that said process comprises a melt-extrusion step, wherein the active ingredient is embedded into the cyclodextrin carrier.

Description

CA 0223213~ 1998-03-16 SOLID MIXTURES OF CYCLODFXTRINS PREPARED VIA MFT T-EXTRUSION

5 The present invention involves a process for preparing solid mixtures by melt-extrusion comprising one or more active ingredients. preferably one or more practically insoluble active ingredients and one or more cyclodextrins. The invention further concernspharmaceutical compositions comprising the above mixture.

lû WO 94/11031, published on May 5, 1994, discloses a method of manufacturing a high-quality enclosure compound using extrusion techniques. In this document the extrusion of cyclodextrins together with an active ingredient is mentioned. However, the document discloses the use of a wet mixture (i.e. including water or anothersolvent) to feed into the extruder.
French patent application 2,705,677 published on December 2, 1994 describes micro-granules obtained by extrusion-spheronisation cont~ining a cyclodextrin. The extrusion-spheronisation technique is the combination of an agglomeration technique, i.e. extrusion, and a shaping technique, i.e. the spheronisation. Said patent application 20 actually teaches the formation of microgranulates containing ~-cyclodextrin (Kleptose~9) and microcrystalline cellulose (Avicel~') and as active ingredientsketoprofen and parace~amol. The extrusion techniyue used in the above-mentioned patent application consists in preforming a humid mass by forcing said human mass through a nozzle thus forming long strands of extruded material. The document does 25 not mention melt-extrusion at all.

EP 0,665,009, published as international application on April 24, 1994, discloses a method of dislocating the crystalline condition of crystalline medicine by extruding said crystalline material as such, i.e. without any excipient such as cyclodextrins.
In J. Pharm. Pharmacolog., vol 44, No 2, pages 73-8, Uekarna et al sho~1v how amorphous nifedipine powders were prepared by spray-drying with hydroxypropyl-,13-cyclodextrins. The document does not mention melt-extrusion.

In Pharm. Weekbl. Sci. ~d., 1988, vol 10, No 2, page(s) 80-85, Van Doorne et al, the complex formation between 13-cyclodextrins and six antimicotic imill~7--1e derivatives was studied. In said study gels and creams comprising antimicotics were prepared W O 97/18839 PCT~EP96/05118 whereby a 1.8 % solution of ,(3-cyclodextrin was added instead of purified water. There is no mentioning of extrusion at all.

In J. Antimicrob. Chemother., 1993, vol 32, No 3, pages 459-463, Hostetler et al5 describe the effect of hydroxypropyl~ -cyclodextrin on the efficacy of oral itraconazole in dissemin~tP~l murine cryptococcosis. In said doc-lmPnt the authors describe how itraconazole is solubilized in hydroxypropyl-,l~-cyclodextrin resulting in a 100 ml solution. There is no mentioning at all of an extrusion process.

lU In Jpn. J. Med. Mycol., 1994, vol 35, No 3, page 263-267, Mikami et al describe the effect of carrier solvents on the efficacy of oral itraconazole therapy in aspergilossis in mice. Again this document discloses itraconazole being solubilized in hydroxypropyl-,13-cyclodextrin. There is no mentioning of extrusion techniques.

15 In~"Effect of 2-Hydroxypropyl-,~-cyclodextrin on Cryst~lli7~tion and Polymorphic Transition of Nifedipine in Solid State", Ph~rm~reutical research, vol 11, No 12, 1994, Uekama et al. describe a glassy mixtllre of 2-hydro~y~ -cyclodextrin obtained by heating said mixture and imm~ t~ly cooling said ~ ulc; to 0 degrees Celsius.
There is no teaching that this ~ LLule can be extruded.
US 5,009,900 describe glassy matrices that are useful for introducing and/or ret~inin~
and/or stabilizing the volatile and/or labile colnpol1ents in cooked and uncooked food products. These glassy matrices colll~.ise chemically modified starch having a dextrose equivalent not greater than about 2; maltodextrin, corn syrup solids or a 25 polydextrose, and a mono- or ~ cçh~ride The document does disclose extrusion to form glassy matrices. However, there is no specific mentioning of cyclodextrins and of thela~GuLically or pharmS~reutic~ly active ingredients.

None of the above mentioned documents disclose the present invention.
Although WO 94/11031 and French patent application 2,705,677 disclose extrusion of mixtures of cyclodextrins and actives ingredients, said documents do not mention the use of meltextrusion. The technique described in WO 94/l 1031 and French patent application 2,705,~77 has a main disadvantage, that a humid mass needs to be prepared 35 which requires adding to the cyclodextrin and the active ingredient a certain amount of water and in most cases others solvents such as ethanol or methanol. Removing the water and/or other solvents is often a troublesome production step, which often leads to CA 0223213~ 1998-03-16 W O 97/18839 PCT~EP96/05118 irreproducibility because not all of the solvent can be removed. Moreover, with practically insoluble active ingredients the amounts of water and/or adjuvant solvents needed make the above technique unpractical on a production scale. Another disadvantage of the technique described in the prior art is that the drying step can induce unwanted cryst~ll;7zltion of the active ingredient.

T~es~ p~o~lems are soived in the ptesent invention by t~ use of a melt-extrusionprocess to form solid mixtures comprising one or more cyclodextrins and insoluble active ingredients.

The present process is advantageously applicable when said active ingredient is sensitive to a solvent such as water or an organic solvent, because it does not require any solvent. The term "sensitive" used herein means that the active ingredient is readily (e.g. within about one hour) influenced by a solvent to such an extent that its 15 physical, chemical and/or biological ~lu},e,Lies are subsL~lially modified or changed.

The present process is further advantageous because it does not require a drying step, during which insoluble active ingredients often tend to crystallize.

20 The ter.n "insoluble" hereinabove and hereinunder refers to three categories of compounds, i.e. the "very slightly soluble", "practically insoluble" and "insoluble".
The terms "very slightly soluble", "practically insoluble" or "insoluble" are to be understood as defined in the United States Pharmacopeia 23, NF 18 (l995) page 7, i.e.
25 a "very slightly soluble" compound requires from lO00 to lO,000 parts of solvent for l part of solute; a "practically insoluble" or "insoluble" compound requires more than lO,000 parts of solvent for l part of solute. The solute referred to in these cases are water or aqueous solutions.
30 Three examples of this type of insoluble compounds are: itraconazole, loviride and (~)-ethyl (R*,~*)-4-[5-[ l -[ I -L(4-chlorophenyl)hydroxymethyl]propyl~- 1 ,5-dihydro-S-oxo-4~-1,2,4-triazol~-yl]-2-pyridinyl~-1-pipe~ ineczlrboxylate (hereinafter referred to as compound l).

35 Itraconazole is an art-known antifungal. ~oviride is an art-known anti-retrovirally active compound, particularly useful in treating HIV-infected patients.

CA 0223213~ 1998-03-16 Ethyl (R*,R*)-4-[5-[ 1 -t I -[(4-chlorophenyl)hydroxymethyl]propyl3- 1 ,5-dihydro-5-oxo-4~-1,2,~triazol-4-yl]-2-pyridinyl]-1-piL~e.d~illecarboxylate is described ascompound No. 3, in WO 95/27704 published on October 19, 1995.

5 The compounds that are suitable to be used in this technique are compounds that show no appreciable decomposition at the temperatures needed to melt and extrude the mixture of said one or more active ingredients with the cyclodextrin or cyclodextrins.

The term "active ingredient" further refers to compounds or mixtures of compounds 10 which are pharm~e~ltically or therapeutically or cocm~ti~llly active for treating humans or :~nim~l.c.

The present invention provides a process for plepa~ g a solid mixture COLll~lliSillg one or more cyclodextrins and an (insoluble) active ingredient, comprising a melt-extrusion 15 step wherein one or more cyclodextrins are combined with the one or more active ingredients.

Melt-extrusion is a polymer extrusion technique which involves embedding an active ingredient in one or more carriers. In this technique the active ingredient and 20 excipients are molten in the extruder and hence emhed~ in thermoplastic and thermomelting polymers. The resulting molten mass is then forced through one or more nozzles resulting in a thermoplastic strand or strands.

An extruder comprises an inlet structure, a cylindrical structure called "barrel", a die 25 and a screw or screws. A schematic overview is shown in Figure l.

The inlet structure mostly is funnel shaped.

The barrel may comprise one or more barrel units and the screw or screws extend 30 through them.

Extruders are available in two general types, namely a single-screw extruder comprising one screw and a multi-screw extruder comprising two or more screws.
VVhile this invention can be carried out using either type of extruder, the use of a multi-35 screw extruder, particularly a twin-screw extruder is pic,r~ ,d. A twin-screw extruder (and a multi~screw extruder) is more efficient in that the plural screws interferring with CA 0223213~ 1998-03-16 PCT~EP96/0~118 .
each other precludes follow-up movement of the active ingredient and, moreover, the intermeshing of the screws provides a high energy output physically.

An interesting mode of operating the screws is to operate them in a corotating mode.

The screw or screws may have different shapes such as, for example, a trapezoidal screw, a trapezoidal cut screw, trapezoidal reverse cut screw, ball screw, kneading paddle and these may be used in the desired combination.

10 The load fed into the extruder via the inlet structure is forced by the-screw or screws to advance, shorn and blended by the screw within the barrel and extruded from the orifice or orifices of the die. The temperature of the barrel or of the barrel units can be controlled via a heating element or even if necessary by a cooling element.

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

A person skilled in the art is able to select the screw geometry and combination of unit screws. The principal function of the screw is to transport, crush and knead the20 m~terj~l that is being extruded.

The orifice configuration may be circular, elliptical, rectangular or hexagonal.
Hence, said melt-extrusion step comprises the following substeps:
25 a) mixing one or more cyclodextrins with the active ingredient or active ingredients, b) optionally mixing additives, c) heating the thus obtained mixture until melting of one of the components, d) forcing the thus obtained mixture through one or more nozzles;
e) cooling the mixture till it solidifies.
If desired, as mentioned above, the thermomelting mixture comprising one or more,. cyclodextrins and active ingredient(s) may comprise any suitable additive. When, for instance, the cyclodextrin(s) or the active ingredient(s) or one of the other possible additives is apt to be oxidized, an anti-oxidizing agent may be incul~ulated, preferably 35 in small amounts, such as. for instance lOO to SOOO ppm when compared to the total weight of the mixture. Furthermore, conventional auxiliary additives such as pigments~
flavors, stabilizers, preservatives and buffers may be added.

If necessary conventional pharmacologically acceptable plasticizers, such as long chain alcohols, ethylene glycol, propylene glycol, thriethylene glycol, butanediols, pentanols, hexanols, polyethylene glycols, aromatic carboxylates (e.g. dialkyl phthz~l~tes,5 trimelli~te~, benzoates or terephth~l~te~s), ~iph~tic dicarboxylates or fatty acid esters can also be added. Preferably however, a plasticizer is not nçe~leA

The term "melting" should be broadly interpreted. "Melting" can also refer to the fact that some transition is made to a glassy state, in which it is possible for one component lû oi the Illi~UlG to get embedded into the other. In particular cases, one component will melt and the other component(s) will dissolve in the melt thus forming solid solutions, which show advantageous dissolution ~io~e,lies.

The possible formation of these solid solutions is one of the further advantages of the 15 present invention. It will be appreciated by a person skilled in the art that mixing two or more solids, i.e. one or more cyclodextrins and the active ingredient or ingredients, and subsequently melting these solids together will give rise to d~rre~cl~- products than when the said solids are first brought into contact with water or another solvent and then extruded.
A characteristic of the melt extruded mixtures of the present invention is the fact that they contain substantially less water or any other solvent than mixtures being extruded in an other way.

25 Preferably the present melt extruded Illi;~lw~S contain no water or solvent, apart from the water or solvent that eventually is contained in the crystal structure of the active ingredient.

It will be appreciated that the te,l,pc.alu,G inside the extruder is an important parameter.
30 When different barrel units are present, different ~ eldLules can be applied. A
person skilled in the art is able to establish the required I~ Gldtures by taking the desired type of cyclodextrin or cyclodextrins or even the complete IlliX~Ule that is going to be extruded and observing the behaviour as a function of tel~ alulG with the aid of a m~-ltin~ point mP~nringillsllull~llL, such as a Kofler hot bench, a microscope hot 35 stage type or a dir~elGnLial sc~nning calolillleter, e.g. type DSC 7 Series - Perkin Elmer.

CA 0223213~ 1998-03-16 W O 97/18839 PCT~EP96/05118 The cooling can be performed without using any auxiliary means, i.e. it most often suffices to let the thermoplastic strand coming out of the extruder cool down to the ambient temperature of the production site. Of course, cooling aids may be used.
5 Once these thermoplastic strands are cooled down these strands can be milled to obtain a powdered form of the mixture of cyclodextrin or cyclodextrins and the active ingredient.

A person skilled in the art will appreciate that the milling can influence the physical 10 characteristics of the extrudate. During milling the te~llperalule of the material can rise because of the friction and also high shear forces are exerted on the material that is to be milled. Both te~ eld~ult; and mechanical or shear forces can result in a transition of the physical state of the material that is to be milled. A person skilled in the art has sufficient means at his disposal to control temperature and shear forces and thus to 15 control the milling process.

The two processes, i.e. melt extrusion and milling can be combined into one configuration as is shown in Figure 1. The mixture of one or more cyclodextrins and one or more active ingredients in combination with possible other additives is feed via 20 a funnel like inlet. The Illi~Lule is then melt-extruded and the mixture is forced through a noz zle onto a conveyor belt. While being transported on the conveyor belt theextrudate cools down. The cooled melt extrudate is fed into a chopper which forms pellets. These pellets may be further milled if required.

25 This powdered material still has the beneficial L,lol)e.lies (high bioavailability, dissolution rate, etc.) and it can be used in the conventional way to prepare pharm~ceu~ic~l, therapeutical or cosmetical solid dosage forms.

An additional advantage of the present invention is that the active ingredient as well as 3Q the cyclodextrins may be transformed in a amorphous form or even that a solid solution is formed. A person skilled in the art will appreciate that this modification of physical state from crystalline to amorphous or to solid solutions is highly advantageous for the dissolution.

35 The fact whether the melt extruded mixture contains amorphous material or contains a solid solution or consists essentially of amorphous material or a solid solution can be measured or checked using differential scanning calorimetry. When there is crystalline CA 0223213~ l99X-03-16 W O 97/18839 PCT~EP96/05118 material present in the melt extruded mixture a differential sc~nning calorimeter will show an endothermic melting peak. When amorphous material or a solid solution ismainly present in the melt extruded mixture a differential sc~nning calorimeter will not show an endotherrnic melting peak. Visua} inspection of the melt extrudate allows for 5 a distinction between amorphous material and a solid solution. In case the melt extrudate is opaque then both the cyclodextrin(s) and the active ingredient are in a amorphous form. In case melt extrudate is clear then a solid so}ution was formed.

Curves of differential sc:-nning calorimetry are shown in Figures 2 to 7.
Interesting embodiments of the present invention are these melt extruded mixtures which consist mainly of amorphous material.

More interesting emborlim~nt.~ of the present invention are these melt extruded 15 mixtures which consist essentially of amorphous material.

Even more interesting embodiments of the present invention are those melt extruded mixtures which consist mainly of a solid solution of the active ingredient or active ingredients in the cyclodextrin or the cyclodextrins.
Preferred embo~im~nt~ of the present invention are those melt extruded mixtures which consist essentially of a solid solution of the active ingredient or active ingredients in the cyclodextrin or the cyclo~1Pxtrins.

25 Another advantage of the present invention is that the granulation step in forrning pharm~re.l1ical, therapeutical or cosmetical compositions can be omitted, because the powdered material can simply be mixed with other excipients and compressed into, for in~f:~nce~ tablets or another solid pharrn~(~elltical, therapeutical or cosmetical form.

30 Depending upon the characteristics of the melt extruded mixture, the size of the pellets of said melt extruded mixture or the mesh of the powder of said melt extruded mixture and, of course, dependent upon the other auxiliaries that are added to the unit dosage forms the unit dosage form may give immediate release or sustained release.

35 If desired, said solid pharm~eutic:~l form may also be provided with a conventional coating to improve the appearance and/or the flavor (coated tablets) or additionally to target the release of the active ingredient.

CA 0223213~ 1998-03-16 W O 97/18839 PCT~EP96/05118 g_ Suitable tablets may have the following compositions and may be prepared in a conventional way. The amounts given are of course dependent upon the dose required for the pharmaceutical, therapeutic or cosmetic activity.

Composition A
milled melt extrudatelO0 - 500 mg microcrystalline cellulose lO0 - 300 mg crospovidone 10 - 200 mg colloidal silicon dioxide l - 5 mg sterotex 2 - lO mg Composition B
milled melt extrudatelO0 - 500 mg Microcelac (TM) (l~200 - 300 mg crospovidone 70 - 200 mg talc 20 - 50 mg sterotex 7 - lOmg colloidal silicon dioxide l - 5 mg m~gne~ium stearate2 - l 0 mg The cyclodextrin to be used in the aforementioned compositions include the pharm~ce~tically acceptable unsubstituted and substituted cyclodextrins known in the art, more particularly oc, ,13 or~ycyclodextrins or the pharm~re-ltically acceptable derivatives thereof.

Substituted cyclodextrins which can be used in the invention include polyethers described in U.S. Patent 3,459,73 l . In general, unsubstituted cyclodextrins are reacted with an alkylene oxide, preferably under superatmospheric pressure and at an elevated temperature, in the presence of an alkaline catalyst.
Since a hydroxy moiety of the cyclodextrin can be substituted by an alkylene oxide which itself can react with yet another molecule of alkylene oxide, the average molar ~ub~ ulion (MS) is used as a measure of the average number of moles of the substituting agent per glucose unit. The MS can be greater than 3 and theoretically has no limit.

CA 0223213~ 1998-03-16 W O 97/18839 PCT~EP96/~5118 Further substituted cyclodextrins are ethers wherein the hydrogen of one or morecyclodextrin hydroxy groups is replaced by Cl 6alkyl, hydroxyCI 6alkyl, carboxy-C1 6alkyl or C1 6alkyloxycarbonylCI 6alkyl or mixed ethers thereof. In particular such substituted cyclodextrins are ethers wherein the hydrogen of one or more 5 cyclodextrin hydroxy groups is replaced by C 1 3alkyl, hydroxyC2 4alkyl or carboxyCl_2alkyl or more in particular by methyl, ethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxy-methyl or carboxyethyl.

In the foregoing definitions the term "Cl 6alkyl~' is meant to include straight and 10 branched saturated hydrocarbon radicals, having from 1 to 6 carbon atoms, such as, methyl, ethyl, 1-methylethyl, l,1-dimethylethyl, propyl, 2-methylpropyl, butyl, pentyl, hexyl and the like.

Such ethers can be ~.~aled by reacting the starting cyclodextrin with an ~ iate 15 Q-alkylating agent or a mixture of such agents in a concentration being selected so that the desired cyclodextrin ether is obtained. The said reaction is preferably conducted in a suitable solvent in the presence of an app.o~~iate base. With such ethers, the degree of snbstit~ltion (DS) is the average number of ~ L;I..~ hydroxy functions per glucose unit, the DS being thus 3 or less.
In the cyclodextrin derivatives for use in the compositions according to the present invention, the DS preferably is in the range of 0.125 to 3, in particular 0.3 to 2, more in particular 0.3 to 1 and the MS is in the range of 0.125 to lO, in particular of 0.3 to 3 and more in particular 0.3 to 1.5.
Of particular utility in the invention are the ,(3-cyclodextrin ethers, e.g. dimethyl-~-cyclodextrin as described in Drugs of the Future, Vol. 9, No. 8, p. 577-578 by M.
Nogradi (1984) and polyethers, e.g. hydroxypropyl ~-cyclodextrin and hydroxyethyl ,B-cyclodextrin, being examples. Such an alkyl ether may be a methyl ether with a degree of sllbstit ltion of about 0.125 to 3, e.g. about 0.3 to 2. Such a hydroxypropylcyclodextrin may for example be formed from the reaction between ~I~-cyclodextrin an propylene oxide and may have a MS value of about 0.125 to 10, e.g. about 0.3 to 3.

A more novel type of substituted cyclodextrins is sulfobutylcyclodextrines. These type are also envisaged in the present invention.

CA 02232l3~ l99X-03-l6 The ratio of active ingredient over cyclodextrin may vary widely. For example ratios of l/lO0 to lO0/l may be applied. Interesting ratios of active ingredient over cyclodextrin range from about l/lO to lO/l. More interesting ratios of active ingredient over cyclodextrin range from about l/5 to 5/l. Most interesting ratios range from about l/3 to 3/l. Preferred ratio is aa~oout l/l.

The use of a mixture of cyclodextrinc, either different types (a"(3, ~y) or ~lirr~l~;nt substitution (2-hydlu~ yl or methyl) or different substitution grades in sometimes recommendable to decrease the melting point.
Description of the drawin~s Figure l is a schematic representation of a configuration for carrying out the present invention.
Figure 2 is a differential sc~nning calorimetry curve (DSC curve) of non-milled Batch No l material. (see Example l) Figure 3 is a differential sc:~nning calorimetry curve of milled Batch No 1 material (see Example l) Figure 4 is a differential scanning calorimetry curve of Batch No 2 material (see Example l) Figure 5 is a differential sczlnn;ng calorimetry curve of of Batch No 3 material ~see Example l) Figure 6 is a differential scz~nning calorimetry curve of of Batch No 4 material (see Example l~
3~
Figure 7 is a differential sc~nnin~ calorimetry curve of of Batch No 5 material (see Bxample l) ~xample l Extruded samples of active ingredient with hydroxypropyl-,B-cyclodextrin (HP-~3--CD) were obtained using a Twin Screw Extruder type MP19 APV Baker (commercially available from the company APV Baker) with a die having a orifice of 3 mm. The process parameters for each individual experiment are shown in the table l. This type of extruder has a L/D ratio of lS and a screw pattern: 4D FS - 4x30 FP - 4x60 FP -4x90 P - 4x60 RP - 2.5D FS - 2x30 FP - 2x60 FP - 2x90 P - 3x60 RP - 3 DFS. (4D
refers to a transportelement having a length of 4 times the screw diameter of the feed screw type; 4x30 FP refers to 4 forward paddles positioned with mutual angle of 30 CA 0223213~ 1998-03-16 W O 97/18839 PCTrEP96/05118 degrees, 4x60 RP refers to a working zone having reverse paddles positioned with a mutual angle of 60 degrees) ~n this type of extruder the mixture is fed by a feeding screw turning a constant feeding speed (vl) ( A feeding speed of 10 revolutions per minute amounts to a feeding speed ~, of 1,5 kg per hour) onto the twin transporter screws having a ~ m~-ter of 18 mm turning at a transporter speed (v2). These speeds are rotationa} speeds (revolutions per minute).

The mixture is then transported into a first heating zone (tl). Here the rate of transport ~liminiched by a dirre-ence of the configuration of the twin transporter screws i.e. the rotational transporter speed v2 remains the same but the material does not progress as quickly.

~ubsequently, the molten mass is transported by again normal configuration twin transporter screws to a second heating zone (t2) where the rate of transport is again ~1imini.ched by a difference of configuration of the twin transporter screws.

After this second heating the thermomelting mixture is transported to the nozzle of the 20a~dl dlus .
Table I
mixture Batch. t1 t2 tp v1 v2 No (~C) (~C) (~C)(rpm)* (rpm)*
compound 1 1 1 256 283 280 10 100 HP-,B-CD 3 itraconazole 1 2 263 265 279 10 20 HP-13-CD ~ 1 itraconazole 1 3 264 265 280 10 20 lov ride 1 4 274 285 292 10 80 HP-.~-CD
lov-ide 1 5 258 265 274 10 20 25 * rpm = revolutions per minute - t 1: temperature of the first heating zone - t2: tt;ll,pcldture of the second heating zone CA 0223213~ 1998-03-16 W O 97118839 PCT~EP96/05118 - tp: temperature inside the barrel - vl: rate of feeding screw - v2: twin transporter screws speed(rotational).

5 In every case the mixture of active ingredient and 2-hydroxypropyl-,~-CD gave a solid solution.

Example 2 Extruded samples of active ingredient with dimethyl-,B-cyclodextrin (DM-,13-CD) were 10 obtained using extruder type MP19 - APV Baker with the process parameters as shown in the table 2.

Table 2 mixture Batch. tl t2 tp v1 (1) V2 No. (~C) (~C) (~C)(rpm)* (rpm)*
compound 1 1 6 241 245 254 0 20 DM-~-CD ~ 1 itraconazole 1 7 239 240 253 O 20 loviride 1 8 248 250 263 ~ 20 DM-,B-CD ~ 1 * rpm = revolutions per minute (1) The apparatus was fed m~nn~lly, without using the feeding screw.
In every case the mixture of active ingredient and DM-,B-CD.
20 - tl: ~ el~Lul~; of the first heating zone - t2: temperature of the second heating zone - tp: temperature inside the barrel - v1: feeding screw speed (rotational) - v2: twin transporter screw speed (rotational).
Fxample 3 The dissolution of the melt extrudate of Batch No 1 was compared with the dissolution of the "physical mixture" (i.e. the mixture of the two component in the ratio as shown for Batch No. 1, but not melt extruded).

CA 0223213~ 1998-03-16 W O 97/18839 PCT~EP96/05118 An amount of 100 mg of milled melt extrudate of Batch No I was added to a volume of gO0 ml of artificial gastric juice at a le~llpeldture of 37 degrees Celsius. The stirring method used was the peddle method with a peddle moving at 100 rotations per minute.
Using UV spectrometry the relative amount of dissolved extrudate was measured 5 during 1 hour.

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

The results of this dissolution process are shown in Table 3 Ta~le 3 time mixture milled extrudate Batch No I corresponding physical (minutes) (% of total amount dissolved) (% of total amount dissolved) 0 0.00 0.00 62.10 1.71 lS 70.20 14.67 72.63 2 1 .06 74 07 26. 10 74.25 28.35 E~xample 4 15 The melting behaviour was measured by using differential sç~nning calorimetry. The calorimeter used is the Perkin-Elmer 7 Series Thermal Analysis System. In all cases the rate of heating was set at 20 degrees Celsius per minute.

Figure 2 shows the DSC curve of melt extrudate of Batch No 1 before milling The 20 curve shows no endothermic or exothermic peaks and it was established by visual inspection that the molten material was a clear solution, thus in~iic~tin~ that the non-milled melt extrudate of Batch No 1 is a solid solution.

Figure 3 shows the DSC curve of melt extrudate of Batch No 1 after milling. The 25 curve shows no endothermic or exothermic peaks and it was established by visual inspection that the molten material was a clear solution, thus in-lic:~ting that the milled melt extrudate of Batch No 1 is a solid solution.

CA 0223213~ 1998-03-16 W O 97/18839 PCT~EP96/05118 Figure 4 shows the DSC curve of meltextrudate of Batch No 2 before milling. The curve shows no endotherrnic or exothermic peaks and it was established by visualinspection that the molten material was not a clear solution, thus indicating that the non-milled melt extrudate of Batch No 2 is a mixture of amorphous material.

~ Figure S shows the DSC curve of meltextrudate of Batch No 3 before milling. The curve shows a small endothermic peak. The data on said small peak are as follows:
Xl = 117.~00 degrees Celsius, X2 = 143.200 degrees Celsius, Peak at 132.695 degrees Celsius, Area is 38.126 mJ, ~H is 3.768 J/g, Height is 1.520 mW and the onset is at 10 125.816 degrees Celsius. Said small peak is very probably due to an hll~uliLy in the cyclo-le~trin.c It was established that the non-milled melt extrudate of Batch No 3 is a mixture of amorphous material.

Figure 6 shows the DSC curve of meltextrudate of Batch No 4 before milling The 15 curve shows a few small endothermic peaks. Hence, it was established that the non-milled melt extrudate of Batch No 4 is a mixture of amorphous material co.~i..i..g small amounts of crystalline material Figure 7 shows the D~C curve of meltextrudate of Batch No 5 before milling, The 20 curve shows no endothermic or exothermic peaks and it was established by visual inspection that the molten material was not a clear solution, thus indicating that the non-milled melt extrudate of Batch No 5 is a mixture of amorphous material.

F~z~ml?le 5 25 The melt extrudate of Batch No. 1 was milled and sieved. By mixing the a~lu~liate amounts a tablet having the following compûsition was prepared in an art-known way:

milled extrudate batch No 1 480 mg microcrystalline cellulose 218 mg 3û Aerosil 3 mg m~gnPsium stearate 5 mg crospovidone 144 mg

Claims (12)

Claims

1. Process for preparing a solid mixture consisting one or more cyclodextrins and one or more active ingredients characterized in that said process encompasses a melt-extrusion step, wherein the active ingredient is embedded into the cyclodextrin carrier.

2. A process as claimed in claim 1, wherein the melt-extrusion process comprises the following substeps:
a) mixing one or more cyclodextrins with one or more active ingredients, and b) optionally mixing additives;
c) heating the thus obtained mixture until melting of one of the components;
d) forcing the thus obtained mixture through one or more nozzles;
e) cooling the mixture till it solidifies.

3. A solid mixture obtainable by the process as described in any of claims 1 or 2, with the proviso that nifedipine in combination with 2-hydroxypropyl-.beta.-cyclodextrin is excluded.

4. A solid mixture as claimed in claim 3 characterized in that the active ingredient or active ingredients are insoluble according to the definition of US Pharmacopeia.

5. A solid mixture as claimed in claims 3 or 4, wherein substantially only one type of cyclodextrin is present.

6. A solid mixture as claimed in any of claims 3 to 5 wherein a cyclodextrin is hydroxypropyl-.beta.-cyclodextrin.

7. A solid mixture as claimed in any of claim 3 to 5 wherein a cyclodextrin is dimethyl-.beta.-cyclodextrin.

8. A solid mixture as claimed in any of claims 3 to 7, wherein the active ingredient is itraconazole.

9. A solid mixture as claimed in any of claims 3 to 7 wherein the active ingredient is loviride.

10. A solid mixture as claimed in any of claims 3 to 7 wherein the active ingredient is (~)-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.

11. A pharmaceutical composition comprising milled melt extrudate and other excipients.

12. A process for preparing a pharmaceutical composition as claimed in claim 11 characterized by milling appropriately the solid mixture as claimed in any of claims 4 to 10, intimately mixing the thus obtained powdered material with otherpharmaceutically acceptable excipients and further processing into pharmaceutical dosage forms.