HK1111608B

HK1111608B - Pharmaceutical composition comprising a solid dispersion with a polymer matrix

Info

Publication number: HK1111608B
Application number: HK08102568.0A
Authority: HK
Inventors: Michel Bedos; Thierry Breul; Stephen Byard; Isabel Ribeiro Dos Santos
Original assignee: 赛诺菲-安万特
Priority date: 2004-09-17
Filing date: 2005-09-15
Publication date: 2013-05-03

Description

Pharmaceutical composition comprising a solid dispersion and a polymer matrix

The invention relates to novel pharmaceutical compositions comprising a solid dispersion of at least one active principle in a pharmaceutically acceptable polymer matrix comprising at least one continuous phase of polydextrose and at least one continuous phase of a polymer other than polydextrose.

Pharmaceutical compositions in which the active principle is in the form of a solid dispersion are well known to the person skilled in the art. They are generally used to improve the solubility of the active principle, to control its release rate or to improve its bioavailability.

Many active principle molecules have low oral bioavailability. Poor absorption following oral administration may be due to their low solubility in aqueous media (i.e., solubility in water at 25 ℃ less than 1mg/ml) and poor permeability. To improve the bioavailability of these molecules when administered orally, a number of techniques have been employed. This is the case with micronization, formation of salts and complexes, solubilization in liquids and solid dispersions.

The concept of solid dispersion was introduced by Sekiguchi and Obi in 1961 (chem. Pharm. Bull.9, (1961), 866- & 872), and then by Goldberg in 1965 (J. Pharm. Sci.54, (1965), 1145- & 1148) and by Chiou and Riegelmann in 1971 (J.Pharm. Sci.60(9), (1971)1281- & 1302).

In general, the expression "solid dispersion" denotes a matrix in the solid state, as opposed to the liquid or gaseous state, which contains at least two components, the first of which, for example, the pharmaceutically active principal component, is dispersed as homogeneously as possible in the other components, for example, a pharmaceutically acceptable matrix. Such "solid dispersion" will be more particularly referred to as "solid solution" when the distribution consists of a single phase: this dispersion is carried out at the molecular level, when the active principle is dissolved in a solid matrix and is in an amorphous state. Such a solid solution can readily form a liquid solution when it is contacted with a liquid medium, such as gastric medium. When the distribution does not consist of a single phase, the expression "solid dispersion" is used: this dispersion was carried out at the particle level (═ 50 nm). The active principle component is either completely dispersed in the crystalline state or partially dissolved therein.

There are mainly two methods of preparing "solid dispersions":

"solvent" method, which is based on the solubilization of the components (active principle and matrix) in a common solvent, followed by evaporation of the solvent;

"melting" process, which consists in melting the components (active principal component and matrix) at high temperature, and then cooling the mixture in order to be able to solidify it.

The "solvent" method has a number of drawbacks: the implementation is complex, in particular there are a number of steps associated with the handling of the solvent, which entail high costs and also environmental and public health problems (residual content of solvent).

The "melt" method does not have these drawbacks, but requires the use of high temperatures that may affect the chemical stability of the active principle and other components in the solid dispersion.

The solid dispersions contained in the pharmaceutical compositions of the prior art generally consist of the active principle dissolved or dispersed in a matrix of one or more pharmaceutically acceptable polymers.

Thus, patent applications EP 0240904 and EP 0240906(BASF AG) describe the preparation of solid pharmaceutical dosage forms by extrusion or injection molding, preferably using N-vinylpyrrolidone copolymers, in particular copovidone.

However, due to the exact fact that this low solubility is distributed along the gastrointestinal tract, the prior art compositions comprising solid dispersions do not always allow a particularly satisfactory increase in the bioavailability of active principle ingredients of low water solubility.

It has now been found, very surprisingly and unexpectedly, that new pharmaceutical compositions containing solid dispersions containing a particular polymer matrix can advantageously increase the bioavailability of the active principle compared to the solid dispersions already known.

The subject of the present invention is therefore a pharmaceutical composition comprising a solid dispersion comprising at least one active principle and a pharmaceutically acceptable polymer matrix, characterized in that said pharmaceutically acceptable polymer matrix comprises a mixture of (i) and (ii): (i) polydextrose in the form of a continuous polydextrose phase, (ii) at least one polymer other than polydextrose in the form of a continuous phase of said polymer, the proportion of polydextrose being at least 20% by weight and the proportion of said at least one polymer other than polydextrose being at least 20% by weight, based on the total weight of said pharmaceutically acceptable polymer matrix.

In particular, the pharmaceutical composition of the invention is characterized in that it is obtainable by a process comprising at least one step comprising preparing a mixture containing said at least one active principle, said polydextrose and said at least one polymer other than polydextrose in a screw mixer (dispositif a vism langouse) at a mixing temperature of about 50-250 ℃.

More specifically, the subject of the invention is a solid pharmaceutical composition comprising a solid dispersion containing at least one active principle and a pharmaceutically acceptable polymer matrix,

characterised in that said pharmaceutically acceptable polymer matrix comprises a mixture of (i) and (ii): (i) polydextrose in the form of a continuous polydextrose phase so as to facilitate the disintegration of the composition in an aqueous medium, (ii) at least one polymer other than polydextrose in the form of a continuous phase of such polymer, the proportion of polydextrose being at least 20% by weight, the proportion of at least one polymer other than polydextrose being at least 20% by weight, based on the total weight of said pharmaceutically acceptable polymer matrix,

characterized in that the pharmaceutical composition is obtainable by a process comprising at least one step comprising preparing a mixture comprising said at least one active principle ingredient, said polydextrose and said at least one polymer other than polydextrose in a screw mixer at a mixing temperature of about 50-250 ℃.

The pharmaceutical compositions of the present invention are very particularly suitable for oral administration.

According to the invention, the term "solid dispersion" is intended to mean a dispersion of at least one active principle in a pharmaceutically acceptable polymer matrix, in the form of a solid solution (in which the active principle is dispersed in the amorphous state, dissolved), or not (in which the active principle is dispersed in the crystalline state), or in an intermediate form (in which the active principle is partially dispersed in the amorphous state and partially dispersed in the crystalline state).

According to the invention, the term "continuous phase" of a given polymer (polydextrose, etc.) is intended to indicate that said polymer forms part of the polymer matrix and is not in a dispersed state, i.e. is dispersed throughout the three dimensions of the solid dispersion without interruption.

Thus, the pharmaceutically acceptable polymer matrix of the composition according to the invention comprises a mixture of at least two continuous polymer phases, i.e. a mixture of said polydextrose in the form of a first continuous phase and said at least one polymer other than polydextrose in the form of at least one further continuous phase, these different continuous polymer phases not being discretely dispersed from each other.

It has been noted that this characteristic structure of the composition of the invention is, on the one hand, the respective polymer content (at least 20% by weight, based on the total weight of the pharmaceutically acceptable polymer matrix) and, on the other hand, the result of the steps comprising a process for preparing the mixture of components of the solid dispersion using a screw mixer and at a mixing temperature of about 50-250 ℃ (shearing and plasticization of the mixture at this temperature using a screw mixer, for example of an extrusion or injection molding apparatus), without wishing to be bound by any theory.

According to the invention, it should be noted that in a pharmaceutical composition comprising a solid dispersion, in particular a bicontinuous solid dispersion, of the active principle in a polymer matrix containing a polymer other than polydextrose, also in the form of a continuous phase, the polydextrose in the form of a continuous polydextrose phase of the polymer matrix functions to promote disintegration of the pharmaceutical composition in an aqueous medium.

According to the present invention, the expression "promoting disintegration of the pharmaceutical composition" is intended to mean accelerating the disintegration of a solid dispersion in an aqueous medium. The disintegration ability was determined according to the disintegration test described in the European pharmacopoeia (la Pharmacopee eeuropene) section 2.9.1.

However, without wishing to be bound by any theory, the improved disintegration in the stomach due to the presence of the continuous polydextrose phase in the pharmaceutical composition according to the invention should advantageously allow to reduce the risk of local concentrations and therefore of precipitation of the active principle ingredient, in particular in the gastrointestinal tract.

Polydextrose (CAS No.068424044) is a water-soluble amorphous polymer containing glucose units randomly linked by glycosidic linkages of all types (mainly 1, 6), and a particularly low content of glucose and sorbitol units. In particular, patents US 3766165 and US 3876794 from Pfizer inc. Polydextrose is generally obtained by a process comprising a step of catalytic condensation reaction, using a mixture comprising D-glucose, sorbitol and an acidic catalyst, in particular citric acid or phosphoric acid.

Firstly in the food sector, in particular in the nutritional food sector, polydextrose was developed and used in view of its partial metabolic action and therefore its low caloric value. Polydextrose is mentioned, for example, in the Food chemical Specification (Food Chemicals Codex) (FCC, 4 th edition, 1996).

In the field of food applications, and also from now on, considering its use in the pharmaceutical field, for example as excipient (pharmaceutical excipients 2001, edited by Ray C Rowe, Paul J Sheskey and Paul J Weller, polydextrose monograph, 2001, 7 months and 27 days), polydextrose can advantageously be purified, in particular using conventional ion exchange resin separation techniques, in order to remove residual products therefrom, in order to further improve its organoleptic (acidity) and/or color properties (see for example EP 0458748 or EP 0473333).

Thus, according to the present invention, the term "polydextrose" is of course intended to mean polydextrose which is pharmaceutically acceptable. In particular, the purity of the pharmaceutically acceptable polydextrose is preferably at least 90% by weight polydextrose, the remaining components mainly comprising free glucose, sorbitol and levoglucosan (1, 6-anhydro-D-glucose) units and water, which purity can be determined on a dry matter basis by uv spectrophotometry.

The molecular weight of the polydextrose that can be used in the composition according to the invention is preferably at most 22000g/mol, as determined in a known manner by means of gel permeation chromatography (or "exclusion chromatography") equipped with a refractometric detector.

In particular, the average molecular weight of the polydextrose that can be used in the composition of the present invention is 150-.

Among the polydextrose which can be used in the composition according to the invention, mention may be made in particular of the polydextrose sold by the company Pfizer under the names "polydextrose A" and "polydextrose K", having an average molecular weight of 1200-Such asII', more particularly "Ultra^TM"marketing polydextrose, their average molecular weight is 182-" 5000- ".

Of course, in order to constitute a continuous polydextrose phase, according to the present invention, the term "polydextrose" may comprise a single given polydextrose or a mixture of several polydextroses, in particular those mentioned above.

The polymer "other than polydextrose" comprised in the polymer matrix of the composition according to the invention may be any polymer usable in the solid dispersions of the prior art, and of course also comprises polymers other than polydextrose as defined above.

Of course, the polymer other than polydextrose may comprise a mixture of several polymers other than polydextrose, which are different from each other but miscible.

In particular, said at least one polymer other than polydextrose is chosen from the following:

cellulose-type polymers, for example alkylcelluloses, in particular methylcelluloses, such as hydroxyalkylcelluloses, in particular hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxybutylcelluloses and low-substituted hydroxypropylcelluloses, for example hydroxyalkylalkylcelluloses, in particular hydroxyethylmethylcellulose and hydroxypropylmethylcelluloses, for example carboxyalkylcelluloses, in particular carboxymethylcellulose, for example carboxyalkylcellulose salts, in particular carboxymethylcellulose sodium, for example carboxyalkylalkylcelluloses, in particular carboxymethylethylcelluloses, and for example esters of cellulose derivatives, in particular hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate and cellulose acetate phthalate;

vinyl homopolymers and copolymers, such as N-vinylpyrrolidone polymers, in particular polyvinylpyrrolidone, copovidone and polyvinyl alcohol;

acrylic and methacrylic polymers, e.g. ofCompany under the trade nameIn particularE100 andthose sold by L100-55;

chemically modified starches, in particular starches derived from starches extracted from corn, potato, rice, wheat or tapioca;

-pectin;

-chitin derivatives, such as chitosan;

natural polymers such as gum tragacanth, gelatin, sodium alginate, amylopectin, gum acacia, guar gum, agar-agar and xanthan gum,

polyoxyalkylenes, such as polyethylene oxide, polypropylene oxide and copolymers of ethylene oxide and propylene oxide;

and mixtures thereof.

More particularly, the at least one polymer other than polydextrose is chosen from the following: methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxybutylcellulose, low-substituted hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, carboxymethylethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate, polyvinylpyrrolidone, copovidone, polyvinyl alcohol, acrylic and methacrylic polymers, for example, fromCompany under the trade nameIn particularE100 andpolymers sold under the trade names L100-55, starch derived from starch extracted from corn, potato, rice, wheat or tapioca, pectin, chitosan, gum tragacanth, gelatin, sodium alginate, amylopectin, gum acacia, guar gum, agar, and the likeEsters, xanthan gum, polyethylene oxide, polypropylene oxide, copolymers of ethylene oxide and propylene oxide, and mixtures thereof.

The polymers other than polydextrose that can be used in the composition according to the invention are chosen in particular from hydrophilic polymers other than polydextrose and their mixtures, more particularly from the following:

hydroxypropyl cellulose, e.g. available under the trade name AqualonHydroxypropyl cellulose for sale;

hydroxyethyl cellulose, e.g. available under the trade name AqualonHydroxyethyl cellulose for sale;

cationic copolymers of dimethylaminoethyl methacrylate and neutral methacrylic acid esters, e.g.Company under the trade nameE100, said copolymer;

anionic copolymers of methacrylic acid and methacrylic acid esters, e.g.Company under the trade nameL100-55;

hydroxypropyl methylcellulose acetate succinate, for example under the trade name Shin-EtsuHydroxypropyl methylcellulose acetate succinate sold;

-polyethylene glycol, preferably polyethylene glycol with a molecular weight higher than 1500;

copolyvinylpyrrolidone, i.e. from BASF under the trade name Kollidon VACopolymer sold [ 60% poly (N-vinylpyrrolidone) -40% vinyl acetate]，

And mixtures thereof.

It may be observed that, more particularly when the at least one polymer other than polydextrose is a hydrophilic polymer other than polydextrose as defined above, the at least one polymer other than polydextrose as defined above may be in particular soluble in the fraction of polydextrose contained in the pharmaceutically acceptable polymer matrix: the continuous phase of the at least one polymer other than polydextrose may thus be in the form of a solid solution of polydextrose in the at least one polymer other than polydextrose, this continuous phase being distinct from the continuous polydextrose phase. The composition according to the invention is therefore characterized in that, in particular when the at least one polymer other than polydextrose is a hydrophilic polymer other than polydextrose as defined above, the at least one polymer other than polydextrose is in the form of a continuous phase of solid solution of polydextrose in the at least one polymer other than polydextrose, this continuous phase being distinct from the continuous polydextrose phase.

According to a particular embodiment of the invention, the polymeric matrix of the composition according to the invention comprises only two continuous polymeric phases, namely a first continuous polydextrose phase and a second continuous phase of said at least one polymer other than polydextrose, and therefore the pharmaceutical composition according to the invention is characterized by a polymeric matrix of bicontinuous structure consisting essentially of a continuous polydextrose phase and a continuous phase of said at least one polymer other than polydextrose.

The expression "bicontinuous structure" is generally known to describe a structure in which a majority of the molecules of two different compounds (or different phases) constitute a domain that extends uninterrupted in three dimensions (according to Lindman et al, 1989). Such a bicontinuous structure is thus characterized by a separation surface, a so-called interface, across the entire sample, dividing it into two distinct adjacent but interwoven labyrinths. Thus, the two sub-volumes (or subspaces) of each part of this interface occupied by each compound (or phase) are continuous (according to Schwarz and Gomper, 2002). The two labyrinths can then be used independently of one another, passing through the sample from one part to the other: it is thus possible for each compound (or phase) to connect any two points located within the compound (or phase) by means of a path that is traversed only by this same compound (or this same phase).

The use of extrusion to obtain bicontinuous polymeric solid structures is described in the literature, in fields other than pharmaceuticals, in particular in patent application WO 0110949, and in the pharmaceutical field, in particular in Dollinger and Sawan, Polymer Preprints, 1990, 31: 211-212, which describes the use of PLA/PE-PVAc mixtures in which the PE-PVAc phase functions to strengthen/strengthen the matrix.

The Demonstration of bicontinuous structures in liquid media by NMR measurements of the self-diffusion coefficient is well described in the literature, for example K.P. Datema et al, Magnetic Resonance in Chemistry, Vol.30, 760-767(1992), the Demonstration of bicontinuous structures in microemulsions using an automatic NMR self-diffusion measurement mode, or B.Lindman et al, colloidal and surface, 38(1989), 205-224, the Demonstration of bicontinuous structures in microemulsions. In the case of solid media composed of Polymer blends, a number of studies have been published on the theoretical prediction of the bicontinuous structure obtained (Interfacial and topological measurements of bicontinuous Polymer morphology (polymers) as published in Physical reviews, vol.64010803(2001), h.jinnai et al, Physical reviews, Polymer polymers, or J Lyngaae-Jorgensen et al, Polymer (Polymer)44(2003), structured Polymer blends in bicontinuous phase as published in 1661-1669); and microscopic Observation or porosity measurement of the structure of the polymer blend did not make these predictions worthwhile (J.H. Laurer et al, Macromolecules 1998, 31, 7546-.

In order to demonstrate the continuity of the solid phase in the heterogeneous solid mixture, it is possible to use solid Nuclear Magnetic Resonance (NMR) analysis techniques, in particular to measure the relaxation times of the proton nuclei. In this NMR analysis, the nucleus is excited to an energy state above its equilibrium state. These excited nuclei lose energy through interactions between adjacent nuclear spins (spin-spin interactions) and with the surrounding medium (spin-lattice interactions). Measuring these relaxation processes of molecular proton nuclei enables experimentally observing the molecular mobility of such molecules in their environment. Two parameters that can be experimentally measured using this technique are:

- "T1", corresponding to the relaxation time of the protons within the fixed label, measured in seconds, which characterizes a domain (or phase) of about 50nm, and

- "T1 ρ" or "T1 Rho", corresponding to the relaxation time of protons within the rotating mark, measured in milliseconds, characterizes a domain (or phase) of 5-50 nm.

In the case of a solid polymer mixture, if a single value for T1 is obtained, this indicates that the polymer mixture is homogeneous and it is not possible to separate discrete domains of a phase having a size greater than 50nm dispersed in another phase: the mixture is then a solid solution on the order of 50 nm.

Similarly, if a single value for T1Rho is obtained, this indicates that the polymer mixture is homogeneous and it is not possible to separate discrete domains of a phase having a size greater than 5 nm dispersed in another phase: the mixture is then a solid solution of the order of 5 nm.

On the other hand, if in the case of a solid mixture of two polymers, two values for T1Rho are obtained, this means that the mixture is composed of two different phases (or domains). In the latter case, if the value of T1Rho contributed to a polymer does not vary with its concentration in the mixture, it can be concluded therefrom that this polymer constitutes a continuous phase consisting solely of this polymer. On the other hand, if the value of T1Rho contributed to the polymer varies with its concentration in the mixture, it can be concluded therefrom that: this polymer is part of a composition of phases consisting of two polymers dispersed in one another, the dispersion being of the order of 5-50nm, i.e. of the order of one polymer molecule, and in this case the mixture being a solid solution of one polymer in the other.

Thus, according to a particular embodiment, the pharmaceutical composition of the invention is characterized in that said pharmaceutically acceptable polymeric matrix has a bicontinuous structure consisting essentially of said polydextrose continuous phase and of said at least one polymeric continuous phase other than polydextrose.

More particularly, the pharmaceutical composition of the invention is characterized in that said pharmaceutically acceptable polymeric matrix has a bicontinuous structure consisting essentially of said polydextrose continuous phase and of said at least one polymeric continuous phase other than polydextrose, chosen from hydrophilic polymers as described previously and mixtures thereof, i.e. more particularly chosen from hydroxypropyl cellulose, hydroxyethyl cellulose, cationic copolymers of dimethylaminoethyl methacrylate and neutral methacrylic acid esters, anionic copolymers of methacrylic acid and methacrylic acid esters, hydroxypropyl methylcellulose acetate succinate, polyethylene glycol, copovidone and mixtures thereof.

As indicated previously, it has been noted that the characteristic structure of the compositions according to the invention is caused in particular by the respective content of polymer (at least 20% by weight based on the total weight of the said pharmaceutically acceptable polymer matrix).

In particular, the pharmaceutical composition according to the invention is characterized in that the proportion of polydextrose is about 20 to 80% by weight, based on the total weight of the pharmaceutically acceptable polymer matrix, and in that the proportion of the at least one polymer other than polydextrose is about 20 to 80% by weight.

According to a particular embodiment, in the polymer matrix of the pharmaceutical composition of the invention, the ratio by weight of polydextrose to the at least one polymer other than polydextrose is between about 20: 80 and 50: 50.

In the pharmaceutical composition of the invention, the proportion of said pharmaceutically acceptable polymer matrix may in particular be from about 50 to 99.9% by weight, based on the total weight of the composition.

According to the present invention, the term "active principle" is intended to mean a drug which, after administration, causes a prophylactic or therapeutic response, as well as a combination of two or more such substances.

The compositions of the invention may contain any active principle known to the person skilled in the art, whatever the envisaged therapeutic application.

However, of course, such active principle components should be suitable for the conditions comprising said step of preparing the mixture in a screw mixer at a mixing temperature of about 50-250 ℃.

The active principle may be in the form of a pharmaceutically acceptable solvated or unsolvated salt or in the form of a complex, in particular with a cyclodextrin, in particular hydroxypropyl- β -cyclodextrin.

More particularly, the compositions of the invention are suitable for the administration of active principle ingredients which are poorly soluble in water. Thus, in particular, the at least one active principle may have a moderate solubility in aqueous media, i.e. a solubility in water at 25 ℃ of less than 10mg/ml, a low solubility in aqueous media, i.e. a solubility in water at 25 ℃ of less than 1mg/ml, or even a very low solubility in aqueous media, i.e. a solubility in water at 25 ℃ of less than 0.1 mg/ml.

In the composition of the invention, the at least one active principle is dispersed in the pharmaceutically acceptable polymer matrix either in an amorphous state, or in a crystalline state, preferably predominantly in an amorphous state, the presence of the active principle in the amorphous state being particularly advantageous for its dissolution in liquid solutions.

According to the invention, the term "predominantly amorphous" is intended to mean that more than 50% of the total mass of the at least one active principle dispersed in the pharmaceutically acceptable matrix is amorphous.

The amorphous or crystalline arrangement of the active principal component can be analyzed by differential enthalpy analysis or by X-ray diffraction studies, but also by microscopic techniques.

As active principal components that can be used in the composition of the present invention, there may be mentioned, in particular:

-N-piperidino-5- (4-bromophenyl) -1- (2, 4-dichlorophenyl) -4-methylpyrazole-3-carboxamide;

-N-piperidino-5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -4-methylpyrazole-3-carboxamide;

-amiodarone (or 2-n-butyl-3- [3, 5-diiodo-4-diethylaminoethoxybenzoyl ] benzofuran) or a pharmaceutically acceptable salt thereof, in particular the hydrochloride;

-dronedarone (drondarone) (or 2-n-butyl-3- [4- (3-di-n-butylaminopropoxy) benzoyl ] -5-methylsulphonamidobenzofuran) and pharmaceutically acceptable salts thereof, in particular the hydrochloride;

-2- [1- (7-chloroquinolin-4-yl) -5- (2, 6-dimethoxyphenyl) -1H-pyrazole-3-carbonyl ] amino-adamantane-2-carboxylic acid;

-isopropyl 2-n-butyl-3- [4- [3- (dibutylamino) propyl ] benzoyl ] -1-benzofuran-5-carboxylate and pharmaceutically acceptable salts thereof, in particular the fumarate salt;

-7-chloro-N, N, 5-trimethyl-4-oxo-3-phenyl-3, 5-dihydro-4H-pyridazino [4, 5-b ] indole-1-acetamide,

and combinations of these active principal ingredients.

The proportion of the active principle depends inter alia on the intrinsic solubility of the active principle, the required effective dose and the desired dissolution profile.

In the compositions of the invention, the proportion of the active principle is in particular from about 0.1 to 50% by weight, based on the total weight of the composition. An equivalent dose of the active principle ingredient is about 1mg to 1 g per unit dose.

The pharmaceutical compositions of the present invention may also contain any of the components known to those skilled in the art for pharmaceutical compositions, particularly those for pharmaceutical compositions containing solid dispersions. In particularThe pharmaceutical composition according to the invention is characterized in that the mixture prepared in the screw mixer may also contain at least one component selected from plasticizers, mold release or lubricating agents, fluidizing agents, antioxidants, preservatives, dyes, flavors, sweeteners, wetting agents, buffers, adsorbents, absorbents, absorption promoters, in particular vitamin E (d-alpha-tocopheryl polyethylene glycol 1000 succinate), such as that sold under the name EastmanProducts marketed by Vitamin E TPGS, bioadhesives, disintegrants and mixtures thereof.

As indicated previously, it has been noted that the characteristic structure of the composition of the invention is not only caused by the respective contents of the polymers (at least 20% by weight based on the total weight of the pharmaceutically acceptable polymer matrix) but also by the steps comprising a process for preparing a mixture of the components of the solid dispersion using a screw mixer at a mixing temperature of about 50-250 ℃ (at which temperature shearing and plasticization of the mixture is performed using a screw mixer, for example of an extrusion or injection molding apparatus).

More particularly, the mixing temperature is about 80-200 deg.C, more particularly about 100-160 deg.C.

The mixing temperature is particularly adjusted so that it is above the glass transition temperature of the mixture, and this mixing may be carried out for a time sufficient to plasticize the mixture, dissolve the active principle and thus form in particular the polydextrose and the continuous phase of the polymer other than polydextrose, substantially free of inhomogeneities. The formation of these continuous phases can be verified, for example, by measuring the relaxation times of the protons using solid state NMR, as described previously and illustrated in the examples below.

Preferably, this mixing temperature is adjusted to a temperature suitable for the active principle. This temperature can be lowered, for example, to avoid excessively intense disintegration of the active principle of a given polymer matrix, according to techniques known to those skilled in the art, in particular by introducing at least one plasticizer, such as triethyl citrate, ethylene glycol, triethylene glycol, polyethylene glycol, polypropylene glycol, copolymers of ethylene glycol and propylene glycol, poloxamers or water, to lower the glass transition temperature of the polymer matrix.

In particular, this mixing temperature can be achieved using a heating device fitted to the screw mixer.

The components of the mixture to be prepared in the screw mixer, i.e. at least the at least one active principle, the polydextrose and the at least one polymer other than polydextrose, may be added to the screw mixer individually and/or as a mixture of at least a part thereof.

For example, the components may be added as a single homogeneous pre-mix or "physical mixture" prepared in a conventional mixer, such as a Turbula type mixer, at room temperature (about 25 ℃).

According to another embodiment, the polymer other than polydextrose may be added to said screw mixer in the form of a mixture of at least a part of the total polydextrose of the composition according to the invention, at least a part of the total amount of said at least one active principle and at least a part of the total amount of one or more possible additives, this mixture being in particular in the form of a simple physical mixture or in the form of a solid dispersion or in the form of a solid solution, the remaining components of the composition according to the invention, i.e. at least the remaining polydextrose, the remaining said at least one active principle and the remaining one or more possible additives, being added to the screw mixer together with this mixture to obtain the composition according to the invention. In contrast thereto, of course, the polydextrose can be added to said screw mixer in the form of a mixture of at least a part of the total amount of polymer other than the polydextrose, at least a part of the total amount of said at least one active principle and at least a part of the total amount of one or more possible additives, this mixture being in particular in the form of a simple physical mixture or in the form of a solid dispersion or in the form of a solid solution, the remaining components of the composition of the invention, i.e. at least the remaining said polymer other than the polydextrose, the remaining said at least one active principle and the remaining one or more possible additives, being added to the screw mixer together with this mixture to obtain the composition of the invention.

The screw mixer may thus be chosen in particular from known devices for plastic extrusion (single-screw or multi-screw extruders) or injection molding. Different screw geometries may be suitable, in particular according to the composition of the mixture.

According to one embodiment of the invention, the screw mixer is a twin-screw mixer (dispositif abbe-vis mlangeuse), one advantage of which is in particular that it provides greater shear forces on the mixture. Such twin screw mixers can be operated in either co-or counter-rotating mode.

According to a particularly preferred embodiment of the invention, the screw mixer is an extrusion device, for example from Thermo Haake under the trade name PolydriveA device for sale. More particularly, said step comprising preparing said mixture in an extrusion device may advantageously be followed by at least one step comprising shaping the extruded mixture at the temperature of the extruded mixture or after cooling the extruded mixture to a suitable shaping temperature, this step being selected from the group consisting of calendering, spinning, cutting steps and combinations of these steps.

According to another particularly preferred embodiment of the invention, the screw mixer is an injection molding device, such as the injection molding machine sold under the trade name "spring 11" by the company Erinca. If necessary, the mixing step in the screw mixer may be carried out first, followed by a mixing step comprising mixing at a suitable temperature, in particular at room temperature (about 25 ℃) toScrew mixers, e.g.The step of physical mixing between the temperatures of the mixers, for a time sufficient to obtain a homogeneous physical mixture (usually a few minutes), in particular in order to facilitate the feeding of said screw mixers.

Regardless of the screw mixer used, the pharmaceutical composition of the invention is more particularly characterized in that, after cooling to a suitable temperature sufficient to solidify the resulting mixture, said process further comprises at least one step selected from the group consisting of grinding and cutting steps and combinations of these steps.

Of course, the composition may contain coatings, such as those known to the skilled person, in particular for improving the appearance and/or taste and/or for providing a modified release of the active principle.

In particular, the disintegration of the pharmaceutical composition, facilitated in particular by polydextrose in the form of a continuous phase, as explained previously, does not of course exclude immediate or modified release (slow or sustained release), or a combination of these release types, by fragments of the disintegrated composition, using formulation techniques known to those skilled in the art, in particular modified release coating techniques.

Thus, the pharmaceutical composition according to any one of the preceding claims may be more particularly characterized in that it is obtainable by a process which also comprises at least one modified-release coating step.

The invention also relates to a solid pharmaceutical dosage form, characterized in that it contains at least one pharmaceutical composition as described above, in particular a solid pharmaceutical dosage form for oral administration.

More particularly, the subject of the present invention is a pharmaceutical tablet characterized in that it can be obtained by a process comprising at least one step comprising grinding and cutting at least one pharmaceutical composition as described previously and a combination of these steps, followed by at least one compaction or compaction step, and optionally followed by a coating step as described previously.

Another subject of the present invention is a pharmaceutical capsule characterized in that it can be obtained by a process comprising, after a grinding, cutting step or a combination of these steps, at least one step of filling at least one pharmaceutical composition, and optionally a coating step as described previously.

Another subject of the present invention is a molded pharmaceutical tablet, characterized in that it consists of a pharmaceutical composition obtained with an injection molding device, optionally followed by a coating step as described previously.

Finally, the invention also relates to the use of polydextrose for the manufacture by extrusion or injection molding of pharmaceutical compositions containing a solid dispersion of at least one active principle in a pharmaceutically acceptable polymer matrix containing a mixture of polydextrose in the form of a continuous polydextrose phase and at least one polymer other than polydextrose in the form of a continuous polymer phase, the proportion of polydextrose being at least 20% by weight and the proportion of at least one polymer other than polydextrose being at least 20% by weight, based on the total weight of said polymer matrix.

Figure 1 is a graph obtained according to the in vitro disintegration test (example 4, part 4.1; table 4) showing the disintegration time (in minutes) of a moulded tablet (preparations 1 to 7 of example 4) as a function of the percentage of polydextrose in a polydextrose and copolyvinylpyrrolidone polymer matrix, based on the total weight of this polymer matrix.

Figure 2 is a graph obtained according to the in vitro disintegration test (example 4 part 4.2; table 5) showing the disintegration time (in minutes) of the moulded tablets (preparations 7-12) as a function of the percentage of polydextrose in the polydextrose and Eudragit E100 polymer matrix, based on the total weight of this polymer matrix.

Figure 3 is a graph obtained from in vitro disintegration tests (example 4, part 4.3; table 6) showing the disintegration time (in minutes) of molded tablets (preparations 7 and 13-15) as a function of the percentage of polydextrose in the polydextrose and Aqoat ASMG polymer matrix, based on the total weight of this polymer matrix.

Figure 4 is a graph obtained according to the in vitro disintegration test (example 4, part 4.4; table 7) showing the disintegration time (in minutes) of the moulded tablets (preparations 7 and 16-18) as a function of the percentage of polydextrose in the polydextrose and Klucel EF polymer matrix, based on the total weight of this polymer matrix.

FIG. 5 is a set of points showing proton relaxation time values (T1; in seconds) for molded tablets containing a matrix of polydextrose and copovidone (preparations 19 and 2-7) as described in example 5.

FIG. 6 shows two sets of dots, each set of dots showing proton relaxation time values (T1 Rho; in milliseconds) for molded tablets containing a matrix of polydextrose and copovidone (preparations 19 and 2-7) as described in example 5. The diamond-shaped set of dots corresponds to the polydextrose relaxation time (T1 Rho) value and the square-shaped set of dots corresponds to the copovidone relaxation time (T1 Rho) value.

The following examples are intended to illustrate the invention and should not be construed as limiting the scope of the invention in any way.

The weight percentages indicated in these examples are weight percentages expressed in terms of total weight, unless explicitly stated otherwise.

In the following, the term "active principle A" is intended to denote the active principle N-piperidino-5- (4-bromophenyl) -1- (2, 4-dichlorophenyl) -4-methylpyrazole-3-carboxamide.

Example 1: molded tablet comprising a polymer matrix of polydextrose and copovidone (50: 50) and 0.5% active principle

A physical mixture was prepared containing 0.5% by weight of active principle A, 49.75% by weight of a mixture of the active principle A and of the substance of the BASF type with the trade name KollidonCo-polyvinylpyrrolidone is sold under the trade name Litesse, 49.75% by weight by DaniscoPolydextrose is sold. Use at room temperature (about 25 ℃ C.)The mixer physically mixed for 45 minutes to give a homogeneous physical mixture.

This physical mixture was fed to an injection molding machine of the Sprinter type 11 from Erinca. The operating parameters were as follows:

barrel temperature of the first heating zone: 120 ℃;

barrel temperature of the second heating zone: 140 ℃;

-nozzle temperature: 160 ℃;

-hot runner temperature: 160 ℃.

The mold used was one that gave a molded tablet substantially the same size and shape as the size 0 capsule.

After cooling to room temperature, the molded tablets thus obtained, containing a polymer matrix of polydextrose and copovidone (polydextrose: copovidone weight ratio 50: 50), had an average mass of 1053mg, each containing a dose of about 5mg of active principle ingredient A.

Comparative example 1: molded tablet formulation comprising a matrix of copovidone polymer and 0.5% active principle

Preparing a physical mixture containing 05% by weight of active principle A and 99.5% by weight of BASF, with the trade name KollidonCommercially available copolyvinylpyrrolidone. Physical mixing was performed at room temperature (about 25 ℃) for 60 minutes using a Turbula mixer to give a homogeneous physical mixture.

This physical mixture was fed to an injection molding machine of the Sprinter model 11 from the company ernca. The operating parameters were as follows:

barrel temperature of the first heating zone: 120 ℃;

barrel temperature of the second heating zone: 150 ℃;

-nozzle temperature: 160 ℃;

-hot runner temperature: 160 ℃.

The mold used was one that gave a molded tablet having substantially the same size and shape as the size 0 capsule.

After cooling to room temperature, the molded tablets thus obtained containing the copovidone polymer matrix had an average mass of 939mg, each containing a dose of 5mg of active principle A.

Comparative example 2: molded tablet comprising a polydextrose polymer matrix and 0.5% active principle ingredient

A physical mixture was prepared containing 0.5% by weight of active principle A and 99.5% by weight of Daniseo, Inc. under the name LitessePolydextrose is sold. Use at room temperature (about 25 ℃ C.)The mixer physically mixed for 45 minutes to give a homogeneous physical mixture.

barrel temperature of the first heating zone: 120 ℃;

barrel temperature of the second heating zone: 155 ℃;

-nozzle temperature: 160 ℃;

-hot runner temperature: 160 ℃.

After cooling to room temperature, the molded tablets containing the polydextrose polymer matrix thus obtained had an average mass of 1150mg, each containing a dose of about 5mg of active principle ingredient a.

Example 2: in vitro dissolution test

Using the molded tablets prepared in example 1 and comparative examples 1 and 2 above, the dissolution of active principal ingredient a was investigated.

Dissolution kinetics were determined in a paddle apparatus at 37 ℃ with 75rpm paddle agitation using a simulated gastrointestinal dissolution medium of ph6.5 consisting of: one quarter volume of enzyme-free simulated gastric media according to USP XXI in pharmacopoeia (Pharmacopeia) (2 g/l sodium chloride pH adjusted to pH 1.2 with 11.6M hydrochloric acid) and three quarters volume of enzyme-free simulated intestinal media according to USP XXI in pharmacopoeia (6.8 g/l potassium dihydrogen phosphate pH adjusted to 7.5 with 10M sodium hydroxide). 1ml of a sample was taken at a prescribed time, each sample was filtered with a 5 μm membrane in advance, and then analyzed by liquid chromatography to determine the concentration of the active principal ingredient A dissolved in the dissolution medium.

To obtain an average of the percent dissolution over time, three measurements were made each time.

The results (average values) are listed in table 1 below. They are expressed as the percentage of active principle a dissolved at the rate of 2 tablets moulded per cartridge containing 500ml of dissolution medium.

Table 1: dissolution of active principle A in moulded tablets containing a matrix of a copolymer of vinylpyrrolidone and/or polydextrose polymer

According to these results, the molded tablets containing a copolymer of vinylpyrrolidone and polydextrose (50: 50) polymer matrix according to the invention provide a solubility of the active principle ingredient A of at least 30 minutes which is significantly higher than the results obtained with the molded tablets containing only a copolymer of vinylpyrrolidone and only a polymer of polydextrose, respectively.

Example 3: in vivo study of bioavailability

Molded tablets according to the invention, which contain a polydextrose and copovidone (50: 50) polymer matrix and 0.5% active principle, were again prepared in the following manner.

A physical mixture was prepared containing 0.5% by weight of active principle A, 49.75% by weight of a mixture of BASF with the trade name Kollidon VACo-polyvinylpyrrolidone is sold under the trade name Litesse, 49.75% by weight by DaniscoPolydextrose is sold. Use ofThe mixer was physically mixed at room temperature (about 25 ℃) in 2 steps for 30 minutes to give a homogeneous physical mixture.

barrel temperature of the first heating zone: 120 ℃;

barrel temperature of the second heating zone: 140 ℃;

-nozzle temperature: 160 ℃;

-hot runner temperature: 160 ℃.

The mold used was one that was able to obtain molded tablets that were substantially the same size and shape as the size 0 capsules.

After cooling to room temperature, the molded tablets thus obtained containing polydextrose and copovidone polymer (polydextrose: copovidone weight ratio 50: 50) had an average mass of 1084mg and contained about 5mg of active principle ingredient A dose per tablet of the molded tablet.

In vivo study

A bioavailability study of active principle a at a dose of 10mg was carried out on 12 young common male volunteers. A dose of 10mg of active principle a consists of 2 moulded tablets of 5mg prepared as described in example 3 above.

In this test, a control capsule prepared by a wet granulation process having the following unit composition was also used as a control:

table 2: composition of control capsules

Active principal ingredient A	5mg
		Corn starch	80mg
Lactose monohydrate	279mg
		Hydroxypropyl methylcellulose	10mg
Sodium dodecyl sulfate	2mg
		Croscarmellose sodium	20mg
Magnesium stearate	4mg
		Size 0 orange capsules	1

The active principle A at a dose of 10mg consists of 2 control capsules of 5 mg.

The study included 4 cycles of oral administration, separated by 7 days. Blood samples were taken from each test subject prior to oral administration and then at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48, 72, 120 and 168 hours after oral administration. The content of active principal component A in each sample was determined by an effective LC-MS/MS method with a limit of quantitation of 1 ng/ml. The bioavailability of the active principle component a was determined at each administration by measuring the calculated AUC (expressed in ng.h/ml) from 0 to 120 hours after administration. The average values of the results obtained are listed in table 3 below.

Table 3: in vivo study of bioavailability

Pharmaceutical dosage form	C max(ng/ml)	T max(h)	AUC_0-120(ng.h/ml)
				Molded tablet of example 3	134	1.5	1408
Contrast capsule	41	1.5	906

From this study result it can be concluded that for an empty stomach, the molded tablet of the invention (example 3) gives an AUC and thus a bioavailability of the active principle a which is 1.55 times greater than the bioavailability obtained with the control capsule.

Example 4: functional-in vitro disintegration test for polydextrose

4.1 Co-vinylpyrrolidone and polydextrose matrix-in vitro disintegration test the following preparation examples 1-7 (without active principle) were carried out.

Preparation example 1: molded tablets containing a matrix of a copovidone polymer to a sprayer of the Erinca company Sprinter 11 model, feed BASF company under the trade nameCo-vinylpyrrolidone sold by VA 64. The operating parameters were as follows:

barrel temperature of the first heating zone: 130 ℃;

barrel temperature of the second heating zone: 139 ℃;

-nozzle temperature: 141 ℃;

-hot runner temperature: 170 deg.C.

The mold used was such that a molded tablet substantially the same size and shape as the size 0 capsule could be obtained.

After cooling to room temperature, the molded tablets thus obtained with the matrix of the copovidone polymer had an average mass of 988 mg.

Preparation example 2: molded tablet comprising polydextrose and copovidone (20: 80) polymer matrix

A physical mixture was prepared containing 80% by weight of a mixture having the trade name BASFCo-polyvinylpyrrolidone sold by VA 64 and sold under the trade name Litesse by 20% by weight of DaniscoPolydextrose is sold. Use at room temperature (about 25 ℃ C.)The mixer physically mixed for 45 minutes to give a homogeneous physical mixture.

The mixture was fed to an injection molding machine of the Sprinter model 11 of the company ernca. The operating parameters were as follows:

barrel temperature of the first heating zone: 130 ℃;

barrel temperature of the second heating zone: 140 ℃;

-nozzle temperature: 160 ℃;

-hot runner temperature: 160 ℃.

After cooling to room temperature, the molded tablets thus obtained, containing a polymer matrix of polydextrose and copovidone (polydextrose: copovidone weight ratio 20: 80), had an average mass of 1002 mg.

Preparation example 3: moulded tablets containing a polydextrose and a copovidone (33: 67) polymer matrix

A physical mixture was prepared containing 67% by weight of a mixture having the trade name BASFCo-polyvinylpyrrolidone sold by VA 64 and sold under the trade name Litesse by 33% by weight of DaniscoPolydextrose is sold. Use at room temperature (about 25 ℃ C.)The mixer physically mixed for 35 minutes to give a homogeneous physical mixture.

barrel temperature of the first heating zone: 130 ℃;

barrel temperature of the second heating zone: 140 ℃;

-nozzle temperature: 160 ℃;

-hot runner temperature: 160 ℃.

After cooling to room temperature, the molded tablets thus obtained, containing polydextrose and copovidone polymer matrix (polydextrose: copovidone weight ratio 33: 67), had an average mass of 1034 mg.

Preparation example 4: molded tablet comprising polydextrose and copovidone (50: 50) polymer matrix

A physical mixture was prepared containing 50% by weight of a mixture having the trade name BASFCo-polyvinylpyrrolidone sold by VA 64 and sold under the trade name Litesse by 50% by weight of DaniscoPolydextrose is sold. Use at room temperature (about 25 ℃ C.)The mixer physically mixed for 30 minutes to give a homogeneous physical mixture.

barrel temperature of the first heating zone: 120 ℃;

barrel temperature of the second heating zone: 140 ℃;

-nozzle temperature: 160 ℃;

-hot runner temperature: 160 ℃.

After cooling to room temperature, the molded tablets thus obtained, containing polydextrose and copovidone polymer matrix (polydextrose: copovidone weight ratio 50: 50), had an average mass of 1117 mg.

Preparation example 5: molded tablet comprising a polydextrose and copovidone (67: 33) polymer matrix

A physical mixture was prepared containing 33% by weight of a mixture having the trade name BASFCo-polyvinylpyrrolidone sold by VA 64 and 67% by weight of the copolymer of Danisco under the name LitessePolydextrose is sold. Use at room temperature (about 25 ℃ C.)The mixer physically mixed for 40 minutes to give a homogeneous physical mixture.

barrel temperature of the first heating zone: 130 ℃;

barrel temperature of the second heating zone: 140 ℃;

-nozzle temperature: 160 ℃;

-hot runner temperature: 160 ℃.

After cooling to room temperature, the molded tablets thus obtained, containing polydextrose and copovidone polymer matrix (polydextrose: copovidone weight ratio 67: 33), had an average mass of 1099 mg.

Preparation example 6: molded tablet comprising a polydextrose and copovidone (80: 20) polymer matrix

A physical mixture was prepared containing 20% by weight of a mixture having the trade name BASFCo-polyvinylpyrrolidone sold by VA 64 and sold under the trade name 80% by weight by the company DaniscoPolydextrose is sold. Use at room temperature (about 25 ℃ C.)The mixer physically mixed for 120 minutes to give a homogeneous physical mixture.

barrel temperature of the first heating zone: 130 ℃;

barrel temperature of the second heating zone: 140 ℃;

-nozzle temperature: 160 ℃;

-hot runner temperature: 160 ℃.

After cooling to room temperature, the molded tablets thus obtained, containing polydextrose and copovidone polymer matrix (polydextrose: copovidone weight ratio 80: 20), had an average mass of 1144 mg.

Preparation example 7: molded tablets containing polydextrose polymer matrix

Injection moulding machine model Sprinter 11 from Erinca, Inc. is fed with a product under the name Litesse from Danisco IncPolydextrose is sold. The operating parameters were as follows:

barrel temperature of the first heating zone: 120 ℃;

barrel temperature of the second heating zone: 145 ℃;

-nozzle temperature: 150 ℃;

-hot runner temperature: 160 ℃.

After cooling to room temperature, the molded tablets thus obtained, containing the polydextrose polymer matrix, had an average mass of 1186 mg.

In vitro testing of molded tablets containing a matrix of copovidone and polydextrose

The ability of the molded tablets containing a polydextrose and/or copovidone polymer matrix of the above-mentioned preparation examples 1-7 to disintegrate in demineralized water as a disintegration medium at a temperature of 37+/-2 ℃ was investigated according to the tablet disintegration test conditions described in the european pharmacopoeia section 2.9.1.

To derive therefrom the mean value of the disintegration time in minutes, three measurements were carried out each time.

These results are listed in table 4 below and are the subject of figure 1.

Table 4: disintegration in vitro testing of molded tablets containing Co-vinylpyrrolidone and polydextrose base

Molded tablet	Copolyvinylpyrrolidone% of Polymer matrix	Polydextrose% of Polymer matrix	Disintegration time (mean value; in minutes)
				Preparation example 1	100	0	56.4
Preparation example 2	80	20	48
				Preparation example 3	67	33	35.7
Preparation example 4	50	50	29
				Preparation example 5	33	67	21.3
Preparation example 6	20	80	15
				Preparation example 7	0	100	9.5

According to these results, the addition of polydextrose to the copovidone, in the form of a mixture of two respective continuous phases of these two polymers (non-discretely dispersed in one another), makes it possible to reduce the disintegration time of the molded tablets.

4.2 E100 and polydextrose matrix-in vitro disintegration test the following preparation examples 8-12 (without active principle) were carried out.

Preparation example 8: comprises polydextrose andmolded tablets of E100 (55: 45) Polymer matrix

Preparing a physical mixture containing 45% by weightCompany under the trade nameE100, and 55 wt% Danisco under the trade name LitessePolydextrose is sold. Use at room temperature (about 25 ℃ C.)The mixer physically mixed for 30 minutes to give a homogeneous physical mixture.

barrel temperature of the first heating zone: 140 ℃;

barrel temperature of the second heating zone: 150 ℃;

-nozzle temperature: 160 ℃;

-hot runner temperature: 180 ℃ is carried out.

After cooling to room temperature, the product thus obtained contains polydextrose ande100 Polymer matrix (polydextrose:)E100 weight ratio 55: 45) have an averageThe mass is 1015 mg.

Preparation example 9: comprises polydextrose andmolded tablets of E100 (60: 40) Polymer matrix

Preparing a physical mixture comprising 40% by weightCompany under the trade nameAcrylic and methacrylic polymers sold as E100, and 60% by weight of Danisco under the name LitessePolydextrose is sold. Use at room temperature (about 25 ℃ C.)The mixer physically mixed for 30 minutes to give a homogeneous physical mixture.

barrel temperature of the first heating zone: 140 ℃;

barrel temperature of the second heating zone: 150 ℃;

-nozzle temperature: 160 ℃;

-hot runner temperature: 180 ℃ is carried out.

After cooling to room temperature, the product thus obtained contains polydextrose ande100 Polymer base (polydextrose:)E100 weight ratio 60: 40) has an average mass of 1048 mg.

Preparation example 10: comprises polydextrose andmolded tablets of E100 (67: 33) Polymer matrix A physical mixture was prepared containing 33% by weightCompany under the trade nameE100, and 67 wt% Danisco under the trade name LitessePolydextrose is sold. Use at room temperature (about 25 ℃ C.)The mixer physically mixed for 60 minutes to give a homogeneous physical mixture.

barrel temperature of the first heating zone: 140 ℃;

barrel temperature of the second heating zone: 150 ℃;

-nozzle temperature: 160 ℃;

-hot runner temperature: 180 ℃ is carried out.

After cooling to warm temperature, the product thus obtained contains polydextrose ande100 Polymer base (polydextrose:)E100 weight ratio 67: 33) has an average mass of 1057 mg.

Preparation example 11: comprises polydextrose andmolded tablets of E100 (75: 25) Polymer matrix

Preparing a physical mixture comprising 25% by weightCompany under trade nameE100, and 75% by weight of Danisco under the name LitessePolydextrose is sold. Use at room temperature (about 25 ℃ C.)The mixer physically mixed for 30 minutes to give a homogeneous physical mixture.

barrel temperature of the first heating zone: 130 ℃;

barrel temperature of the second heating zone: 140 ℃;

-nozzle temperature: 160 ℃;

-hot runner temperature: 180 ℃ is carried out.

The mold used was one that gave a mold of substantially the same size and shape as the size 0 capsule.

After cooling to room temperature, the product thus obtained contains polydextrose ande100 Polymer base (polydextrose:)E100 weight ratio 75: 25) has an average mass of 1119 mg.

Preparation example 12: comprises polydextrose andmolded tablets of E100 (90: 10) polymer matrix

Preparing a physical mixture containing 10% by weightCompany under the trade nameAcrylic and methacrylic polymers sold as E100, and 90% by weight of Danisco under the name LitessePolydextrose is sold. Use at room temperature (about 25 ℃ C.)The mixer physically mixed for 30 minutes to give a homogeneous physical mixture.

barrel temperature of the first heating zone: 130 ℃;

barrel temperature of the second heating zone: 140 ℃;

-nozzle temperature: 160 ℃;

-hot runner temperature: 180 ℃ is carried out.

After cooling to room temperature, the product thus obtained contains polydextrose ande100 Polymer base (polydextrose:)E100 weight ratio 90: 10) has an average mass of 1188 mg.

Comprises In vitro disintegration testing of E100 and polydextrose-based coated molded tablets

The formulations of preparation examples 7 to 12 containing polydextrose and/or the like were investigated according to the conditions of the tablet disintegration test described in the European pharmacopoeia 2.9.1, sectionThe ability of molded tablets of the E100 polymer matrix to disintegrate in demineralized water as disintegration medium at temperatures of 37+/-2 ℃.

In order to obtain therefrom an average value of the disintegration time in minutes, measurements were carried out three times each time.

These results are listed in table 5 below and are the subject of figure 2.

Table 5: comprises In vitro disintegration testing of molded tablets of E100 and polydextrose matrix

Based on these results, the followingThe addition of polydextrose to E100, in the form of a mixture of two respective continuous phases of these two polymers (non-discretely dispersed from each other), makes it possible to reduce the disintegration time of the molded tablets.

4.3 ASMG and polydextrose matrix-in vitro disintegration test the following preparations 13-15 (without active principle) were carried out.

Preparation example 13: comprises polydextrose andmolded tablets of ASMG (75: 25) polymer matrix

A physical mixture was prepared containing 25% by weight of Shin-Etsu under the trade name Shin-EtsuHydroxypropyl methylcellulose acetate succinate sold by ASMG, and 75% by weight of the company Danisco under the name LitessePolydextrose is sold. Use at room temperature (about 25 ℃ C.)The mixer physically mixed for 40 minutes to give a homogeneous physical mixture.

barrel temperature of the first heating zone: 125 ℃;

barrel temperature of the second heating zone: 145 ℃;

-nozzle temperature: 160 ℃;

-hot runner temperature: 170 deg.C.

After cooling to room temperature, the product thus obtained contains polydextrose andASMG polymer (polydextrose:ASMG weight ratio 75: 25) has an average mass of 1182 mg.

Preparation example 14: comprises polydextrose andmolded tablets of ASMG (80: 20) polymer matrix

A physical mixture was prepared containing 20% by weight of Shin-Etsu under the trade name Shin-EtsuHydroxypropyl methylcellulose acetate succinate, which is well-established AS MG, and 80% by weight of Danisco under the trade name LitessePolydextrose is sold. Use at room temperature (about 25 ℃ C.)The mixer physically mixed for 40 minutes to give a homogeneous physical mixture.

barrel temperature of the first heating zone: 130 ℃;

barrel temperature of the second heating zone: 140 ℃;

-nozzle temperature: 145 ℃;

-hot runner temperature: at 150 ℃.

After cooling to room temperature, the product thus obtained contains polydextrose andASMG polymer base (polydextrose:)ASMG weight ratio 80: 20) has an average mass of 1101 mg.

Preparation example 15: comprises polydextrose andmolded tablets of ASMG (85: 15) polymer matrix

Preparing a physical blendThe mixture contains 15 wt.% Shin-Etsu under the trade nameHydroxypropyl methylcellulose acetate succinate sold by ASMG, and 85% by weight of Danisco under the trade name LitessePolydextrose is sold. Use at room temperature (about 25 ℃ C.)The mixer physically mixed for 40 minutes to give a homogeneous physical mixture.

barrel temperature of the first heating zone: 130 ℃;

barrel temperature of the second heating zone: 140 ℃;

-nozzle temperature: 145 ℃;

-hot runner temperature: at 150 ℃.

After cooling to room temperature, the product thus obtained contains polydextrose andASMG Polymer matrix (polydextrose:)ASMG weight ratio 85: 15) has an average mass of 1122 mg.

Comprising hydroxypropyl methylcellulose acetate succinate ( ASMG) and glucose-based molded tablet

The compositions of preparation examples 7 and 13-15 containing polydextrose and/or the like were investigated according to the conditions of tablet disintegration test described in the European pharmacopoeia 2.9.1, sectionAbility of molded tablets of ASMG polymer matrix to disintegrate in demineralized water as a disintegration medium at a temperature of 37+/-2 ℃.

These results are listed in table 6 below and are the subject of figure 3.

Table 6: in vitro disintegration testing of molded tablets having hydroxypropyl methylcellulose acetate succinate and polydextrose matrix

Based on these results, the followingThe addition of polydextrose to the ASMG, in the form of a mixture of two respective continuous phases of these two polymers (non-discretely dispersed from each other), makes it possible to reduce the disintegration time of the moulded tablets.

4.4 hydroxypropyl cellulose and polydextrose base

The following preparation examples 16 to 18 (containing no active principal ingredient) were carried out.

Preparation example 16: molded tablet comprising polydextrose and hydroxypropyl cellulose polymer matrix (50: 50; containing 2% by weight vitamin E polyethylene glycol succinate)

A physical mixture is prepared containing 49% by weight of hydroxypropylcellulose, such as that available from Aqualon under the trade name AqualonHydroxypropyl cellulose sold by EF; 49% by weight of Danisco, under the trade name LitessePolydextrose for sale; and 2% by weight of Eastman company under the trade nameVitamin E polyethylene glycol succinate sold by Vitamin E TPGS. Physical mixing was carried out using a Rayneri reverse screw blade mixer at a temperature of about 50 ℃ for about 15 minutes to give a homogeneous physical mixture.

barrel temperature of the first heating zone: 125 ℃;

barrel temperature of the second heating zone: at 146 ℃;

-nozzle temperature: 155 ℃;

-hot runner temperature: 160 ℃.

After cooling to room temperature, the molded tablets thus obtained, containing polydextrose, hydroxypropyl cellulose and vitamin E polyethylene glycol succinate polymer matrix (polydextrose to hydroxypropyl cellulose weight ratio 50: 50), had an average mass of 1051 mg.

Preparation example 17: molded tablets containing polydextrose and hydroxypropyl cellulose polymer matrix (67: 33, containing 2% by weight vitamin E polyethylene glycol succinate)

A physical mixture is prepared containing 32.3% by weight of hydroxypropyl cellulose, such as that sold under the trade name AqualonHydroxypropyl cellulose sold by EF; 65.7% by weight of Danisco, under the trade name LitessePolydextrose for sale; and 2% by weight of Eastman company under the trade nameVitamin E polyethylene glycol succinate sold by Vitamin E TPGS. Physical mixing was carried out using a Rayneri reverse screw blade mixer at a temperature of about 50 ℃ for about 15 minutes to give a homogeneous physical mixture.

barrel temperature of the first heating zone: 130 ℃;

barrel temperature of the second heating zone: 140 ℃;

-nozzle temperature: 150 ℃;

-hot runner temperature: at 150 ℃.

After cooling to room temperature, the molded tablets thus obtained, containing polydextrose, hydroxypropyl cellulose and vitamin E polyethylene glycol succinate polymer matrix (polydextrose to hydroxypropyl cellulose weight ratio 67: 33), had an average mass of 1126 mg.

Preparation example 18: molded tablet comprising polydextrose and hydroxypropyl cellulose polymer matrix (80: 20; containing 2% by weight vitamin E polyethylene glycol succinate)

A physical mixture is prepared containing 19.6% by weight of hydroxypropyl cellulose, such as that available from Aqualon under the trade name AqualonHydroxypropyl cellulose sold by EF; 78.4% by weight Danisco, under the name LitessePolydextrose for sale; and 2% by weight of Eastman company under the trade nameVitamin E polyethylene glycol succinate sold by Vitamin E TPGS. Physical mixing was carried out using a Rayneri reverse screw blade mixer at a temperature of about 50 ℃ for about 15 minutes to give a homogeneous physical mixture.

barrel temperature of the first heating zone: 130 ℃;

barrel temperature of the second heating zone: 140 ℃;

-nozzle temperature: 150 ℃;

-hot runner temperature: at 150 ℃.

After cooling to room temperature, the molded tablets thus obtained, containing polydextrose, hydroxypropyl cellulose and vitamin E polyethylene glycol succinate polymer matrix (polydextrose to hydroxypropyl cellulose weight ratio 80: 20), had an average mass of 1146 mg.

Comprising hydroxypropyl cellulose (A) EF) and polydextrose matrix in vitro disintegration testing of molded tablets

The compositions of preparation examples 7 and 16-18 containing polydextrose and/or the like were investigated according to the conditions of tablet disintegration test described in the European pharmacopoeia 2.9.1, sectionThe ability of molded tablets of EF polymer matrix to disintegrate in demineralized water as disintegration medium at temperatures of 37+/-2 ℃.

These results are listed in table 7 below and are the subject of figure 4.

Table 7: comprises hydroxypropyl cellulose and polydextrose²In vitro disintegration testing of matrix molded tablets

According to these results, hydroxypropylcelluloseThe addition of polydextrose to EF, in the form of a mixture of two respective continuous phases of these two polymers (non-discretely dispersed from each other), makes it possible to reduce the disintegration time of the molded tablets.

Example 5: solid state NMR analysis of proton relaxation time of molded tablets containing a matrix of polydextrose and copovidone

The following preparation example 19 (containing no active principal ingredient) was also carried out.

Preparation example 19: molded tablets containing a matrix of a copolymer of vinylpyrrolidone Polymer to an injection molding machine model Sprinter 11 from Erinca corporation was fed BASF corporation under the trade name Kollidon VACommercially available copolyvinylpyrrolidone. The operating parameters were as follows:

barrel temperature of the first heating zone: 120 ℃;

barrel temperature of the second heating zone: 160 ℃;

-nozzle temperature: 160 ℃;

-hot runner temperature: 170 deg.C.

After cooling to room temperature, the molded tablets thus obtained, containing a matrix of a copolymer of vinylpyrrolidone and polyvinylpyrrolidone, had an average mass of 972 mg.

_{Solid state NMR analysis}

Table 8 below reports the proton relaxation times T1 and T1Rho of the molded tablets of preparation examples 2-7 and 19 above, containing a matrix of copovidone and/or polydextrose, as measured by solid state NMR. These results are the subject of figures 5 and 6, figure 5 showing T1 in seconds as a function of the percentage of polydextrose contained in the matrix and figure 6 showing T1Rho in milliseconds as a function of the percentage of polydextrose contained in the matrix.

The proton relaxation times T1 and T1Rho were measured by solid state NMR according to the method described in the Investigation of the physical stability of amorphous drugs and drug polymer melts by temperature-variable solid state NMR, published by Forster et al, pharmacy, Vol.58(2003), pages 761-762, but with varying amounts of polydextrose and polyvinylpyrrolidone in the polymer matrix at constant temperature and simultaneously. Each value described is the average of the results obtained after 3 trials.

From these results for each mixture of polydextrose and copovidone (see fig. 5), a single proton relaxation time value was obtained: t is₁(expressed in seconds) this means that it is not possible to distinguish the co-existing copovidone and polydextrose phases on the 50nm scale (measurement sensitivity). In other words, it is not possible to distinguish discrete domains of one phase dispersed in another, the size of this domain being greater than 50 nm. Thus, on this scale, neither the polydextrose nor the copovidone phases are discontinuous, which corresponds to the macromolecular scale of these two polymers. It is also noted that the value of T1 varies with the composition of the matrix and reflects the proportion of polydextrose present in the matrix.

Table 8: proton relaxation time (T1 in seconds and T1Rho in milliseconds) values for molded tablets containing a matrix of polydextrose and copovidone

Molded tablet	Polydextrose% of Polymer matrix	Copolyvinylpyrrolidone% of Polymer matrix	T1(s)	T1Rho polydextrose (ms)	T1Rho copolyvinylpyrrolidone (ms)
						Preparation example 19	0	100	2.0	-	18.6
Preparation example 2	20	80	3.3	4.0	12.9
						Preparation example 3	33	67	4.0	3.6	11.1
Preparation example 4	50	50	4.1	3.3	9.4
						Preparation example 5	67	33	5.6	3.5	9.4
Preparation example 6	80	20	6.1	3.9	9
						Preparation example 7	100	0	6.0	3.7	-

According to these results (see fig. 6), two proton relaxation time values were obtained for each mixture of polydextrose and copovidone: t1Rho (expressed in milliseconds), which means that two different phases can be distinguished on the 5-50nm scale (measurement sensitivity), which corresponds to the molecular scale of polydextrose and copovidone. These results also indicate that two phase compositions are observed. T1Rho attributed to polydextrose remained essentially unchanged, regardless of the composition of the analyzed matrix, indicating that one of the phases consisted solely of polydextrose. The T1Rho attributed to copovidone varied with the composition of the analyzed matrix until this matrix contained 50% polydextrose and then remained unchanged for a proportion of polydextrose greater than 50%. This means that the copolymerized vinylpyrrolidone phase dissolves the polydextrose until saturation (50% polydextrose). Thus, for both of these blended and melted polymers, at the molecular level, two polymer phases coexist, one phase consisting solely of polydextrose, the other being a solid solution of polydextrose in the copolyvinylpyrrolidone.

Thus, these results demonstrate that:

at the macromolecular level, there is no discrete phase of one polymer dispersed in another (T1 has a single value), so the matrix is continuous;

the molded tablets containing a matrix of polydextrose and copovidone consist of two polymer phases differing on the molecular level, namely a phase of polydextrose only and a polymer phase consisting of a solid solution of polydextrose in copovidone;

at molecular weight level, the phase consisting of polydextrose only is continuous (no change in T1Rho attributed to polydextrose as a function of matrix composition).

In summary, the molded tablets of matrix consisting of a mixture of molten polydextrose and copovidone do not contain any discontinuous structure and they consist of two distinct polymeric phases, one of which (only the polydextrose phase) is continuous. It can therefore be deduced that the other phases, which are composed of a solid solution of polydextrose in copolyvinylpyrrolidone, are therefore themselves continuous. The molded tablets containing a matrix of polydextrose and copovidone consist of two distinct and continuous phases, so that their physical result is bicontinuous.

Example 6: a moulded tablet comprising polydextrose and a copolymeric vinylpyrrolidone (20: 80) polymer matrix, containing 12.41% by weight of the active principle 2-butyl-3- [4- [3- (dibutylamino) propyl ] ester]Benzoyl radical]-1-benzofuran-5-carboxylic acid isopropyl fumarate

A physical mixture was prepared containing 12.41% by weight of the active principle 2-butyl-3- [4- [3- (dibutylamino) propyl group]Benzoyl radical]Isopropyl-1-benzofuran-5-carboxylate, 68.08% by weight of BASF, trade name Kollidon VACo-polyvinylpyrrolidone sold under the trade name Litesse, 17.51% by weight of DaniscoPolydextrose sold under the trade name Eastman corporation at 2.00% by weightVitamin E polyethylene glycol succinate sold by Vitamin E TPGS. Physical mixing was carried out at about 50 ℃ for about 15 minutes using a Rayneri reverse propeller blade mixer to give a homogeneous physical mixture.

barrel temperature of the first heating zone: 130 ℃;

barrel temperature of the second heating zone: 140 ℃;

-nozzle temperature: 140 ℃;

-hot runner temperature: at 140 ℃.

After cooling to room temperature, the molded tablets thus obtained with a polymer matrix of polydextrose and copovidone (polydextrose: copovidone weight ratio 20: 80) had an average mass of 969mg and contained a dose of about 100mg of the active main ingredient isopropyl 2-butyl-3- [4- [3- (dibutylamino) propyl ] benzoyl ] -1-benzofuran-5-carboxylate per tablet of the molded tablet.

Differential enthalpy analysis (single glass transition temperature, equal to 86 ℃) and X-ray diffraction studies can conclude that: the active principle isopropyl 2-butyl-3- [4- [3- (dibutylamino) propyl ] benzoyl ] -1-benzofuran-5-carboxylate is not in crystalline form in this composition (i.e. no crystalline form is detected).

Example 7: a moulded tablet comprising polydextrose and a copolymeric vinylpyrrolidone (20: 80) polymer matrix, which contains 10.03% by weight of the active principle component 7-chloro-N, N, 5-trimethyl-4-oxo-3-phenyl-3, 5-dihydro-4H-pyridazino [4, 5-b ]]Indole-1-acetamides

A physical mixture was prepared containing 10.03% by weight of the active principle 7-chloro-N, N, 5-trimethyl-4-oxo-3-phenyl-3, 5-dihydro-4H-pyridazino [4, 5-b ]]Indole-1-acetamide, 71.97% by weight BASF, sold under the trade name Kollidon VACo-polyvinylpyrrolidone is sold under the trade name Litesse with 17.99% by weight DaniscoPolydextrose is sold. Use at room temperature (about 25 ℃ C.)The mixer physically mixed for 40 minutes to give a homogeneous physical mixture.

barrel temperature of the first heating zone: 150 ℃;

barrel temperature of the second heating zone: 170 ℃;

-nozzle temperature: 180 ℃;

-hot runner temperature: 180 ℃ is carried out.

After cooling to room temperature, the molded tablets thus obtained with the polymer matrix of polydextrose and copovidone (polydextrose: copovidone weight ratio 20: 80) had an average mass of 985mg and contained a dose of about 100mg of the active main ingredient 7-chloro-N, N, 5-trimethyl-4-oxo-3-phenyl-3, 5-dihydro-4H-pyridazino [4, 5-b ] indole-1-acetamide per molded tablet.

Differential enthalpy analysis (single glass transition temperature at 99 ℃) and X-ray diffraction studies can observe: the active principle 7-chloro-N, 5-trimethyl-4-oxo-3-phenyl-3, 5-dihydro-4H-pyridazino [4, 5-b ] indole-1-acetamide is not in crystalline form in such compositions (i.e. no crystalline form is detected).

Claims

1. A solid pharmaceutical composition comprising a solid dispersion comprising at least one active principle and a pharmaceutically acceptable polymer matrix, characterized in that said pharmaceutically acceptable polymer matrix comprises a mixture of (i) and (ii) wherein the polymer matrix is in the form of a bicontinuous phase: (i) polydextrose in the form of a continuous polydextrose phase and (ii) a polymer other than polydextrose in the form of a continuous phase of such polymer, the proportion of polydextrose being at least 20% by weight based on the total weight of said pharmaceutically acceptable polymer matrix, this example of said one other than polydextrose being at least 20% by weight, wherein said one other than polydextrose is selected from the group consisting of copolyvinylpyrrolidone/vinyl acetate, butyl methacrylate-dimethylaminoethyl methacrylate-methyl methacrylate copolymer, hydroxypropyl methylcellulose acetate or hydroxypropyl cellulose and mixtures thereof,

wherein the solid pharmaceutical composition is prepared at a mixing temperature of 50-250 ℃.

2. Pharmaceutical composition according to claim 1, characterized in that it is obtainable by a process comprising at least one step which comprises preparing a mixture comprising said at least one active principle, said polydextrose and said one polymer other than polydextrose in a screw mixer and at a mixing temperature of 80-200 ℃.

3. Pharmaceutical composition according to claim 1 or 2, characterized in that the polydextrose is selected from the group consisting of pharmaceutically acceptable polydextrose and mixtures thereof, having a molecular weight of at most 22000 g/mol.

4. Pharmaceutical composition according to claim 1 or 2, characterized in that the proportion of polydextrose is 20-80% by weight and the proportion of the one polymer other than polydextrose is 20-80% by weight, based on the total weight of the pharmaceutically acceptable polymer matrix.

5. Pharmaceutical composition according to claim 1 or 2, characterized in that in the polymer matrix the ratio by weight of polydextrose to the one polymer other than polydextrose is between 20: 80 and 50: 50.

6. Pharmaceutical composition according to claim 1 or 2, characterized in that the proportion of said pharmaceutically acceptable polymer matrix is 50-99.9% by weight, based on the total weight of the composition.

7. Pharmaceutical composition according to claim 1 or 2, characterized in that in the pharmaceutically acceptable polymer matrix the at least one active principle is mainly amorphous, wherein "mainly amorphous" means that more than 50% of the total mass of the at least one active principle dispersed in the pharmaceutically acceptable matrix is amorphous.

8. Pharmaceutical composition according to claim 1 or 2, characterized in that the active principle is selected from:

-2-n-butyl-3- [3, 5-diiodo-4-diethylaminoethoxybenzoyl ] benzofuran or a pharmaceutically acceptable salt thereof;

-2-n-butyl-3- [4- (3-di-n-butylaminopropoxy) benzoyl ] -5-methanesulfonamido benzofuran and its pharmaceutically acceptable salts;

-isopropyl 2-n-butyl-3- [4- [3- (dibutylamino) propyl ] benzoyl ] -1-benzofuran-5-carboxylate and pharmaceutically acceptable salts thereof;

and combinations of these active principal ingredients.

9. The pharmaceutical composition of claim 8, wherein the pharmaceutically acceptable salt of 2-n-butyl-3- [3, 5-diiodo-4-diethylaminoethoxybenzoyl ] benzofuran is the hydrochloride salt thereof.

10. The pharmaceutical composition of claim 8, wherein the pharmaceutically acceptable salt of 2-n-butyl-3- [4- (3-di-n-butylaminopropoxy) benzoyl ] -5-methanesulfonamido benzofuran is the hydrochloride salt thereof.

11. The pharmaceutical composition according to claim 8, wherein the pharmaceutically acceptable salt of isopropyl 2-n-butyl-3- [4- [3- (dibutylamino) propyl ] benzoyl ] -1-benzofuran-5-carboxylate is the fumarate salt thereof.

12. Pharmaceutical composition according to claim 1 or 2, characterized in that the proportion of the active principle is 0.1 to 50% by weight, based on the total weight of the composition.

13. Pharmaceutical composition according to claim 1 or 2, characterized in that the mixture prepared in the screw mixer further contains at least one component selected from the group consisting of plasticizers, mold release agents or lubricants, fluidizing agents, antioxidants, preservatives, dyes, fragrances, sweeteners, wetting agents, buffers, adsorbents, absorbents, absorption promoters, bioadhesives, disintegrants and mixtures thereof.

14. The pharmaceutical composition according to claim 1 or 2, characterized in that the screw mixer is a twin-screw mixer.

15. The pharmaceutical composition according to claim 1 or 2, characterized in that the screw mixer is an extrusion device.

16. The pharmaceutical composition according to claim 15, characterized in that after said step comprising preparing said mixture in an extrusion device, at least one step comprising shaping the extruded mixture at the temperature of the extruded mixture or after cooling the extruded mixture to a suitable shaping temperature is followed, this step being selected from the group consisting of calendering, spinning and cutting steps and combinations of these steps.

17. The pharmaceutical composition according to claim 1 or 2, characterized in that the screw mixer is an injection molding device.

18. The pharmaceutical composition according to claim 1 or 2, characterized in that the pharmaceutical composition is obtainable by a process further comprising at least one step selected from the group consisting of grinding and cutting steps and combinations thereof, after cooling to a suitable temperature sufficient to solidify the resulting mixture.

19. Pharmaceutical composition according to claim 1 or 2, characterized in that it is obtainable by a process further comprising at least one coating step for modified release.

20. Solid pharmaceutical dosage form, characterized in that it contains at least one pharmaceutical composition according to any one of the preceding claims.

21. Pharmaceutical tablet, characterized in that it is obtainable by a process comprising at least one step of compacting or compacting at least one pharmaceutical composition according to claim 18.

22. Pharmaceutical tablet according to claim 21, characterized in that it is obtainable by a process which further comprises at least one coating step for modified release.

23. Pharmaceutical capsule, characterized in that it can be obtained by a process comprising at least one step of filling at least one pharmaceutical composition according to claim 18.

24. Pharmaceutical capsule, characterized in that it can be obtained by a process comprising at least one step of filling at least one pharmaceutical composition according to claim 18 or 19.

25. A molded pharmaceutical tablet, characterized in that it consists of a pharmaceutical composition according to claim 17.

26. A molded pharmaceutical tablet, characterized in that it consists of a pharmaceutical composition according to claim 17 or 19.

27. Use of polydextrose for the manufacture of a pharmaceutical composition according to any of the preceding claims 1 to 19 by extrusion or injection moulding.