EP2863953A1

EP2863953A1 - Active ingredient-containing solid dispersions based on diethylaminoethyl methacrylate copolymers

Info

Publication number: EP2863953A1
Application number: EP13730156.0A
Authority: EP
Inventors: Karl Kolter; Maximilian Angel; Matthias Karl; Silke Gebert; Michael Klemens MüLLER
Original assignee: BASF SE
Current assignee: BASF SE
Priority date: 2012-06-22
Filing date: 2013-06-11
Publication date: 2015-04-29
Also published as: CN104379174A; JP2015523356A; JP6189429B2; WO2013189776A1; CN104379174B

Abstract

Disclosed are solid dispersions consisting of hydrophobic active ingredients and cationic copolymers of N,N-diethylaminoethyl methacrylate and methyl methacrylate, the monomers being provided at a weight ratio of 35:65 to 55:45.

Description

Description The present invention relates to solid dispersions of hydrophobic drugs for pharmaceutical dosage forms based on a cationic copolymer of N, N-diethylaminoethyl methacrylate and methyl methacrylate in the weight ratio of the monomers from 35:65 to 55:45. The present invention further relates to the preparation and use of such solid dispersions for pharmaceutical dosage forms.

WO 00/05307, WO 02/067906 and WO 2004/019918 describe cationic aminoalkyl acrylate copolymers and their use as coating and binding agents. WO 2009/016258 discloses the preparation of the aqueous polymer dispersions of cationic polymers based on Ν, Ν-diethylaminoethyl methacrylate, as used in accordance with the invention, and their use for coating medicaments.

The term "solid dispersion" describes systems in which the active ingredient is embedded in the polymer matrix in the form of microdispersed domains Such systems are true solid dispersions in the sense that the disperse and continuous phases are solid phases.

Furthermore, the term "solid dispersion" also includes so-called "solid solutions" in which the active ingredient is molecularly embedded embedded in the solid polymer phase (the matrix). Such solid solutions, for example, when used in solid pharmaceutical dosage forms of a poorly soluble drug to an improved release of the drug. An important requirement of such solid solutions is that they are stable even over long periods of storage, that is, that the active ingredient does not crystallize out. Furthermore, the capacity of the solid solution, in other words the ability to form stable solid solutions with the highest possible active substance contents, is also important.

The use of so-called "solid dispersions" to improve the solubility and bioavailability of drugs and their preparation by solution or melt extrusion is well known, for example, from "Ch. Leuner, J. Dressman, Europe Journal of Pharmaceutics and Biopharmaceutics 50 (2000 ) 47-60 ". In this reference, the use of cationic amino acrylates such as Eudragit ^® E is generally described.

However, it has been found that Eudragit ^® E, which is also marketed as Eudragit ^® E PO, concerning something to be desired stability of the solid dispersion and the loading capacity of active ingredient can remain. Frequently, at higher drug loadings, drug crystals or larger drug domains are generated. However, the highest possible loading capacity is of great importance.

The object of the present invention was to prepare solid dispersions of hydrophobic active substances in cationic polymers which do not have these disadvantages.

Accordingly, solid dispersions of hydrophobic drugs and a cationic copolymer of Ν, Ν-diethylaminoethyl methacrylate and methyl methacrylate in the weight ratio of monomers of 35:65 to 55:45 were found.

Furthermore, a process for the preparation of active substance-containing solid dispersions of hydrophobic active ingredients, containing as matrix polymers by radical polymerization obtained cationic copolymers of Ν, Ν-diethylaminoethyl methacrylate and methyl methacrylate in a weight ratio of monomers from 35:65 to 55:45, which characterized characterized in that a liquid mixture of the matrix polymer and at least one hydrophobic agent is converted to a solid.

The liquid mixture may be in the form of a solution or melt. The liquid mixture is a homogeneous mixture.

Preferred matrix polymers are copolymers of Ν, Ν-diethylaminoethyl methacrylate and methyl methacrylate in the weight ratio of the monomers of 45:55.

The cationic matrix polymers can be obtained by free radical emulsion polymerization. With regard to the preparation of the matrix polymers based on N, N-

Diethylaminoethyl methacrylate by emulsion polymerization is expressly referred to the disclosure of WO 2009/016258.

The copolymer is preferably used as the matrix polymer is a commercially wässri- gene dispersion as Kollicoat ^® Smartseal 30 D, BASF SE in the form available. The weight average molecular weight is in the range of 200,000 daltons. The molecular weight can be determined by light scattering.

The cationic matrix polymers can also be used in partially neutralized form. For this purpose, 0.1 to 30, preferably 2 to 20 mol% of the basic groups can be partially neutralized with suitable acids. All physiologically well-tolerated inorganic or organic acids are suitable for this purpose.

Suitable inorganic acids are hydrochloric acid, sulfuric acid or phosphoric acid. Also suitable are monocarboxylic acids such as acetic acid, formic acid, propionic acid, methanesulfonic acid, ethanesulfonic acid, benzoic acid, salicylic acid, gentisic acid, glycolic acid, lactic acid, caproic acid, caprylic acid, capric acid, ascorbic acid, isoascorbic acid, nicotinic acid,

Hydroxyethanesulfonic acid, dichloroacetic acid, pyroglutamic acid, cinnamic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, gluconic acid, glucuronic acid, hippuric acid, tobionic acid, mandelic acid, naphthalenesulfonic acid, oleic acid, orotic acid, or tricarboxylic acids such as citric acid.

In particular, dicarboxylic acids having a chain length of 3 to 10 carbon atoms are suitable. Suitable dicarboxylic acids are, in particular, unbranched dicarboxylic acids which have terminal acid groups. Suitable dicarboxylic acids are also those which are substituted by one or two hydroxy groups.

According to the invention, are used for the partial neutralization preferably dicarboxylic acids having a first pKa of greater than 2 and a second _pK a of greater. 4 Particular preference is given to using dicarboxylic acids which have a first pK _s value of greater than 2.5 and a second pK _s value of greater than 5. The pK _s value is the negative decadic logarithm of the acid constant. Suitable dicarboxylic acids which carry no further substituents in addition to the acid groups are the saturated alkanedicarboxylic acids malonic acid, succinic acid, glutaric acid, adipic acid or sebacic acid. Suitable alkanedicarboxylic acids substituted with one or two hydroxy groups are malic acid (2-hydroxy-succinic acid) or tartaric acid (2,3-dihydroxysuccinic acid). The unsaturated dicarboxylic acid is especially fumaric acid.

It is also possible to use mixtures of such dicarboxylic acid.

Thus, it may be advisable to mix dicarboxylic acids which produce a particularly good resistance of the coatings with those acids which produce a particularly good redispersibility of the powders. Suitable mixtures are, for. B adipic acid with sulfuric acid or succinic acid with oxalic acid.

Partial neutralization in the context of the invention means that 2 to 25, preferably 4 to 16, mol% of the diethylaminoethyl groups are present in salt form. Particular preference is given to using dicarboxylic acids, such as adipic acid or succinic acid.

The term "hydrophobic active ingredient" means according to the invention that an active ingredient at 20 ° C. in water has a solubility of less than 0.25% (m / m), preferably less than 0.1%, particularly preferably less than 0.01%.

The solid dispersions obtained by the process according to the invention are amorphous. "Amorphous" means that the crystalline contents of hydrophobic substance less than 5 wt.

%, based on the total weight of the solid dispersion.

The solid dispersions obtained according to the invention can be analyzed for amorphicity or X-ray diffraction (XRD) and Differential Scanning Calorimetry (DSC) Absence of crystallinity. Such an amorphous state may also be referred to as an X-ray amorphous state. "The evaluation is preferably carried out by means of XRD, DSC can also be used to investigate whether crystalline fractions are present, crystalline fractions can be identified by sharp melting points Heating rate of 20 K / min.

For the purpose of screening, the assessment of the crystalline fractions can also be carried out by light microscopy. Suitable light microscopes with a resolution of 167 line pairs / mm, which corresponds to a smallest resolvable object structure of 3 μηη.

According to the invention, the resulting solid may be present in solid form as a film or granules or powder depending on the embodiment. In principle, the processes of the film method, spray drying and melt extrusion are suitable for the preparation of the solid dispersions, the solid dispersions being converted into the solid form by transferring a liquid mixture in the form of a solution or melt containing a hydrophobic active ingredient and the matrix polymer. According to one embodiment, all ingredients of the preparations are first dissolved in a suitable solvent and then the solvent is removed. This can be done via all kinds of drying processes, e.g. via spray drying, film method (evaporation of the solvent), fluidized bed drying, drying using supercritical gases, freeze-drying. The solution can also be processed into thin films.

According to a further embodiment, the solid preparations are prepared by extrusion. The polymers can be fed to the extruder both in powder form and in the form of solutions or dispersions. The dispersions or solutions of the polymer can be converted into a solid form by removing the dispersing agent or solvent in the extruder in the molten state and cooling the melt.

The methods mentioned are described in more detail below: The film method represents a method in which a clear solution of the polymer and the

Drug is formed into a thin film which solidifies by evaporation of the solvent. Clear solution means that there is no cloudiness on normal inspection. This method is particularly suitable as a screening method to easily determine the loading limits of the solid dispersions. For the screening method, the film can be produced by pouring the solution with the appropriate concentrations of polymer and active ingredient onto glass plates and using a doctor blade to make the film. draws. Usually, the films are drawn down to layer thicknesses of 50 to 200 μm. The resulting films are then dried by removal of the solvent and solidified. Preferably, the removal of the solvent is carried out under vacuum, for example at 1 hPa to 100hPa. The drying can be carried out, for example, in a vacuum drying cabinet or comparable vacuum devices. In addition, the removal of the solvent can be effected by the action of temperature.

For the screening process, the films produced are then stored for a defined period of time - usually 14 days - under controlled climatic conditions. The climatic conditions are at 23 ° C / 53% rel. Humidity.

Subsequently, the films can be examined microscopically at a magnification of 40 times). Clear films are a sign of amorphous systems. Cloudy films indicate larger crystalline proportions.

In principle, films can also be produced for use in commercial dosage forms. In this case, the solution of polymer and active ingredient is likewise poured out with suitable casting devices onto suitable surfaces and drawn out to the desired layer thickness or applied to rolls and dried.

Suitable solvents are in principle all solvents which dissolve the polymers and the hydrophobic active ingredients equally well.

According to a further embodiment of the invention, the spray-drying is suitable for the preparation of the solid dispersions. To prepare the polymer-active substance mixture, the substances are weighed into a suitable container. The appropriate amount of solvent is added and stirred until complete dissolution of the polymer and drug. Suitable solvents are, for example, acetone, dichloromethane, ethanol, propanol, methanol, isopropanol, dimethylformamide, ethyl acetate, methyl ethyl ketone, tetrahydrofuran, dioxane, diethyl ether.

The liquid to be dried can then be converted by sputtering with removal of the solvent in a solid. In principle, atomization can take place via nozzles or via rotating disks. Single or multi-fluid nozzles, such as, for example, two-fluid nozzles, are suitable as nozzles. A heated inert gas flowing in cocurrent dries the distributed droplets to form solid particles with particle diameters in the range of 5-100 μm. Nitrogen is preferably used as the drying gas. In the entry area of the spray dryer, the drying gas is preferably fed tangentially. The separation of the dry product particles can take place in a cyclone or a filter. The Temperature of the drying gas may be 30 to 150 ° C. The atomization pressure may be 0.1 to 20 MPa. The spray drying can also be designed in the form of an agglomerative spray drying (eg FSD technology), which leads to larger agglomerates of 100-1000μηι.

According to a further embodiment of the invention, the solid dispersions are prepared by means of a screw extruder. In principle, the usual extruder types are suitable for the extrusion process. Preference is given to using twin-screw extruders. However, multi-shaft extruders with more than two screws are also suitable. The suitable extruder for this purpose usually comprise a housing, a drive unit with gear and a process unit, which consists of the or the extruder shafts equipped with the screw elements, in which case modular construction is assumed. Conventional screw elements are conveying elements, kneading disks, backflow elements or elements with specific geometries that influence the influencing of specific parameters. The person skilled in such elements are known and he can set with some preliminary tests suitable screw geometries. It is also important to ensure that the shear load is not too high. Usually, it is also advisable to set a larger free volume in the feed zone, and then to reduce the pitch in the further course.

The individual zones of the extruder are usually heatable or coolable. The temperature setting depends on the glass transition temperature of the mixture of cationic polymer, hydrophobic active substance to be extruded and other possible admixtures. The temperature setting can be done by controlling the cylinder internal temperature. The temperature which is set in detail depends on the decomposition temperature of the components and on the melting point of the active ingredient.

To prepare the liquid mixture, the mixture of the components hydrophobic active ingredient and matrix polymer and optionally other excipients is heated to temperatures above the glass transition temperature of the mixture. The glass transition temperature of the mixture can be determined by DSC at a heating rate of 20 K / min.

The temperature of the individual extruder zones may vary between 30 and 200 ° C, preferably 40 to 180 ° C, meaning the in-cylinder temperatures. In the first zone, the temperature is chosen low and increased in the subsequent zones until it is so far above the glass transition temperature of the mixture that a homogeneous melt is formed. Homogeneous melts have a clear appearance. Which temperature profile is chosen in detail depends on the composition of the formulation.

The formulations for extrusion can be fed to the extrusion process in different ways. The following methods A-E can basically be used:

If additional solvent is added, the solvents mentioned in connection with the production of films can be used.

The liquid mixture produced in the extruder in the form of a melt of matrix polymer, hydrophobic active ingredient and optionally further auxiliaries can be extruded via one or more nozzles.

The round nozzles used can have a diameter of 0.5 to 5 mm. Other nozzle shapes, such as slot dies can also be used, especially if a larger material throughput is desired.

The resulting solidified extrudate strands can be processed to granules with a granulator and these can in turn be further comminuted (ground) into a powder. The granules or powder can be filled into capsules or pressed into tablets using conventional tableting excipients. In this case, further release-controlling adjuvants can also be used. It is also possible to use water, organic solvents, buffer substances or plasticizers during the extrusion. In particular, water or volatile alcohols are suitable for this purpose. This method allows the reaction at a lower temperature. The amounts of solvent or plasticizer are usually between 0 and 30% by weight of the extrudable mass. The water or solvent can already be removed by a degassing point in the extruder under normal pressure or by applying a vacuum. alternative These components evaporate as the extrudate exits the extruder and the pressure reduces to normal pressure. In the case of less volatile components, the extrudate can be post-dried accordingly. At the time of extrusion of the melt through the nozzles, the melts are preferably free of solvents. This means that the solvent content is less than 1 wt .-%.

In a particular variant of the production process, directly after the extrusion, the thermoplastic composition is calendered to form a tablet-like tablet, which is the final dosage form. In this variant, it may be useful to add other ingredients, e.g. Polymers for adjusting the glass transition temperature and the melt viscosity, disintegrants, solubilizers, plasticizers, dyes, flavorings, sweeteners, etc. already before or during the extrusion add. In principle, these substances can also be used if the extrudate is first comminuted and then pressed into tablets.

The amorphous solid dispersions obtained according to the invention can have a loading of hydrophobic active ingredient of from 2 to 60% by weight, based on the total weight of the solid dispersion. The content of hydrophobic active ingredient is preferably from 10 to 50% by weight, particularly preferably from 20 to 50% by weight. The content of cationic matrix polymer of diethylaminoethyl methacrylate and methyl methacrylate may be 5 to 95% by weight. In addition, the dispersions may contain other pharmaceutical additives. The amount of further additives may be from 0.1 to 60% by weight, based on the total preparation. The addition (up to 50% by weight of the polymer matrix) of hydrophilic polymers can influence the rate of disintegration of the resulting extrudates during release. By increasing the hydrophilicity, faster wetting and faster disintegration in the release can be achieved. Hydrophilic polymers with low molecular weights are particularly suitable for this purpose (<100,000 daltons). Hydrophilic polymers of higher molecular weight (> 100,000 daltons). may be considered as a stabilizer for the resulting solid solution as they increase the rigidity of the matrix and prevent the crystallization of the drug from supersaturated solutions. As a result, stable supersaturated solid solutions can be prepared, which have a particularly high proportion of drug.

The hydrophilic polymers are usually water-soluble, at least in a certain pH range. Water-soluble in this context means that dissolve at 20 ° C at least 0.1 g in 1 ml. Suitable hydrophilic polymers are, for example: polyvinylpyrrolidones having K values of 12 to 90, N-vinylpyrrolidone copolymers, for example copolymers with vinyl esters such as vinyl acetate or vinyl propionate, in particular copolymers of N-vinylpyrrolidone and vinyl acetate in a weight ratio of 60:40, polyvinyl alcohols, hydroxyalkylated cellulose derivatives such as hydroxypropylcellulose (HPC) or hydroxypropylmethylcellulose (HPMC), hydroxyalkylated and carboxyalkylated cellulose derivatives, acrylic acid-methacrylic acid copolymers.

Furthermore, polyethylene glycols having average molecular weights are from 1000 to 6000. Furthermore, graft polymers are polyethylene glycol and polyvinyl alcohol units as are commercially available as Kollicoat IR ^®, Fa. BASF, to buy or mixtures of such graft polymers with polyvinyl alcohol. Furthermore, graft copolymers of polyethylene glycol and N-vinylcaprolactam and vinyl acetate units doped thereon are suitable, such as the commercially available Soluplus®, BASF SE.

To adjust the glass transition temperature of the formulation, water-soluble polymers of high glass transition temperature, e.g. Polyvinylpyrrolidone with K values of 17 - 120, hydroxyalkyl or hydroxalkyl can be used. Too high a glass transition temperature of the formulation can be lowered by adding plasticizers. For this purpose, in principle, all plasticizers are suitable, which are also used for pharmaceutical coatings, such. Triethyl citrate, tributyl citrate, acetyl tributyl citrate, triacetin, propylene glycol, polyethylene glycol 400, dibutyl sebacate, glycerol monostearate, lauric acid, cetylstearyl alcohol. Such plasticizers can be used in amounts of from 0.1 to 20% by weight, based on the total weight of the dispersion.

Furthermore, surfactants which reduce the melt viscosity and thus the extrusion temperature can also be incorporated into the formulations. These substances can also positively influence the possible crystallization and bring about a better wetting of the formulation and a faster dissolution. Suitable substances are ionic and nonionic surfactants such as Kolliphor El ™ HS 15 (Macrogol 15 hydroxystearate), Tween ^® 80, polyoxyethylated fatty acid derivatives such as Kolliphor El ™ RH 40 (polyoxyl 40 Hydrogenated Castor Oil, USP), Kolliphor El ™ EL (Polyoxyl 35 Castor Oil , USP), poloxamers, docusate sodium or sodium lauryl sulfate.

It may also be advisable to add to the solid dispersions antioxidants in amounts of from 0.1 to 10% by weight, based on the total weight of the solid dispersion. Antioxidants which are suitable according to the invention in water are sparingly soluble antioxidants, ie antioxidants whose solubility in water at 20 ° C. is not more than 1 g / l.

Particularly suitable antioxidants are the lipophilic substances tocopherol, tocopherol acetate, ascorbyl palmitate, ascorbyl stearate, t-butylhydroquinone, t-butylhydroxyanisole, t-butylhydroxytoluene, octyl gallate or dodecyl gallate or combinations thereof.

The preparations obtained by these processes can be used in principle in all areas in which only sparingly soluble or insoluble substances in water should either be used in aqueous preparations or should have their effect in an aqueous environment. For the purposes of the present invention, hydrophobic active substances are preferably to be understood as meaning biologically active substances such as pharmaceutical active ingredients for humans and animals, cosmetic or agrochemical active substances or dietary supplements or dietary active substances.

Further suitable as solubilizing hydrophobic agents and dyes such as inorganic or organic pigments into consideration. Suitable biologically active substances according to the invention are, in principle, all solid active compounds which have a melting point which is below the decomposition point under extrusion conditions of the copolymers. The copolymers can generally be extruded at temperatures up to 200 ° C. The lower temperature limit depends on the composition of the mixtures to be extruded and the sparingly soluble substances to be processed in each case.

The active ingredients can come from any indication.

Examples include benzodiazepines, antihypertensives, vitamins, cytostatic drugs - especially taxol, anesthetics, neuroleptics, antidepressants, antiviral agents such as anti-HIV agents, antibiotics, antimycotics, anti-dementia, fungicides, chemotherapeutics, urologics, antiplatelet agents, sulfonamides, anticonvulsants, Hormones, immunoglobulins, serums, thyroid medicines, psychotropic drugs, Parkinson's and other antihyperkinetics, ophthalmics, neuropathy preparations, calcium metabolism regulators, muscle relaxants, anesthetics, lipid-lowering agents, liver therapeutics, coronary agents, cardiacs, immunotherapeutics, regulatory peptides and their inhibitors, hypnotics, sedatives, gynecologics , Gout, fibrinolytics, enzyme preparations and transport proteins, enzyme inhibitors, emetics, circulation-promoting agents, diuretics, diagnostics, corticoids, cholinergics, biliary tract therapeutics, antiasthmatics, broncholytics, beta-receptor blockers, Cal cien antagonists, ACE inhibitors, atherosclerosis agents, antiphlogistics, anticoagulants, antihypotonics, antihypoglycaemic agents, antihypertensives, antifibrinolytics, antiepileptics, antiemetics, antidotes, antidiabetic agents, antiarrhythmics, antianemics, antiallergics, anthelmintics, analgesics, analeptics, aldosterone antagonists, weight loss agents.

Particularly preferred of the abovementioned pharmaceutical preparations are those which are orally administrable formulations. For the preparation of pharmaceutical dosage form such as tablets, the extrudates can be mixed with conventional pharmaceutical excipients. These are substances from the class of fillers, plasticizers, solubilizers, binders, silicates as well as explosives and adsorbents, lubricants, superplasticizers, Dyes, stabilizers such as antioxidants, wetting agents, preservatives, mold release agents, flavors or sweeteners, preferably fillers, plasticizers and solubilizers.

As fillers, e.g. inorganic fillers such as oxides of magnesium, aluminum, silicon, titanium or calcium carbonate, calcium or magnesium phosphates or organic fillers such as lactose, sucrose, sorbitol, mannitol may be added.

Suitable plasticizers are, for example, triacetin, triethyl citrate, glycerol monostearate, low molecular weight polyethylene glycols or poloxamers.

As additional solubility promoters are surfactants with a HLB (HydrophilicLipophilicBalance) greater than 1 1, for example, with 40 ethylene oxide-ethoxylated hydrogenated castor oil (Kolliphor ™ RH 40), with 35 ethylene oxide units ethoxylated castor oil (Kolliphor ™ EL), polysorbate 80 , Poloxamers or sodium lauryl sulfate.

As lubricants, stearates of aluminum, calcium, magnesium and tin, as well as magnesium silicate, silicones and the like can be used.

As flow agents, for example, talc or colloidal silica can be used.

Suitable binders are, for example, microcrystalline cellulose.

As disintegrants can be cross-linked polyvinylpyrrolidone or cross-linked sodium carboxymethylstarch. Stabilizers may be ascorbic acid or tocopherol.

Dyes are e.g. Iron oxides, titanium dioxide, triphenylmethane dyes, azo dyes, quinoline dyes, indigotine dyes, carotenoids to color the dosage forms, opacifying agents such as titanium dioxide or talc, in order to increase the light transmittance and to save dyes.

In addition to the application in cosmetics and pharmacy, the preparations according to the invention are also suitable for use in the food industry, for example for the incorporation of nutrients, auxiliaries or additives which are sparingly soluble in water or insoluble in water. fat-soluble vitamins or carotenoids. Examples include drinks colored with carotenoids.

The use of the preparations according to the invention in agrochemicals may include, inter alia, formulations containing pesticides, herbicides, fungicides or insecticides, especially those preparations of crop protection agents used as spray or pouring broths. With the aid of the method according to the invention so-called solid solutions with sparingly soluble substances can be obtained. Solid solutions according to the invention are systems in which no crystalline components of the sparingly soluble substance are observed.

Examples

According to the invention, the matrix polymer used was a polymer prepared analogously to Example 1 of WO 2009/016258, obtained from methyl methacrylate and diethylaminoethyl methacrylate, in the weight ratio of 55:45, which is commercially available as Kollicoat® Smartseal 30D as aqueous dispersion. Molar ratio diethylaminoethyl methacrylate: methyl methacrylate 3: 7; Tg: in the range of 63 ° C (measured by DSC at a heating rate of 20 ° K / min); Weight average (determined by SEC light scattering in the range of 200,000 daltons).

The polymer was used either as a freeze-dried or as a spray-dried powder.

In some examples, the polymer was also used in partially neutralized form:

Partial neutralization degree 6 mol: 6 mol% of the basic groups partially neutralized with adipic acid Partial neutralization degree 8 mol: 8 mol% of the basic groups partially neutralized with succinic acid

The Eudragit® EPO used for comparison is a basic copolymer of dimethylaminoethyl acrylate, butyl acrylate and methyl methacrylate in a molar ratio of 2: 1: 1.

Processl: film method

General rule

To prepare the polymer-active substance mixture, the substances were weighed in the respective amounts into a 50 ml penicillin glass.

Concentration polymer active solvent

[% By weight] [g] [g] [g]

Blank 2,00 - 18,00

5 2.00 0.1 1 17.89

10 2.00 0.22 17.78

15 2.00 0.35 17.65

20 2,00 0,50 17,50

25 2.00 0.67 17.33

30 2.00 0.86 17.14 35 2.00 1, 08 16.92

40 2.00 1, 34 16.66

45 2.00 1, 63 16.37

50 2,00 2,00 16,00

All mixtures were stirred for 24 h on a magnetic stirrer until the constituents dissolved. After visually evaluating the solution (clear solution), the solution was drawn out on a glass plate using a 120 μm knife. The resulting film was dried for 0.5 h at room temperature of 22 +/- 2 ° C in a fume hood and then for 0.5 h in a vacuum oven at 50 ° C and 1 MPa. The determination of the loading limit of the active ingredient in the polymer was carried out visually after storage for 7 days at 23 ° C / 54% rel. Humidity by microscopic observation. Clear films (without drug crystals) indicate molecularly disperse solutions and turbid films (with drug crystals) indicate crystalline systems.

Process 2: spray drying

General rule

To prepare the polymer-active substance mixture, the substances were weighed into a corresponding storage vessel. The appropriate amount of solvent is added and stirred until complete dissolution of the polymer and the active ingredient. For the fenofibrate formulations was used as a solvent acetone, in which itraconazole formulations was dissolved with dichloromethane and in the formulations with naproxen was dissolved with acetone. The solids content of the spray solution was 20 wt .-% in all experiments. Spray drying was performed on a laboratory scale.

The liquid to be dried was atomized by means of two-fluid nozzle. A co-flowing, heated gas (here nitrogen) dries the dispersed droplets into solid particles with particle diameters in the range of 5-20 μηη. In the entrance area of the spray dryer, the drying gas is supplied tangentially. The separation of the dry product particles takes place in a cyclone.

Process 3: Extrusion

General rule

The twin-screw extruder used to prepare the formulations described in the Examples below had a screw diameter of 16 mm and a length of 40D. The extruder consisted of 10 heatable zones including nozzle. The screw configuration was chosen so that kneading elements were used in zones 5 and 7, otherwise conveying elements. The nozzle (zone 10) was also heated.

The extrusion examples below describe the process parameters used. The specified zone temperatures are the internal cylinder temperature.

Characterization of the products obtained

Characterization of the solid dispersions was carried out by visual inspection, X-ray diffraction (XRD) and Differential Scanning Calorimetry (DSC).

Visual examination of the stable solid solutions reveals no amorphous constituents. The visual inspection can be done with a light microscope both with and without polarizing filter at 40x magnification

The prepared solid solutions from the extrusion process and from the spray drying were tested for crystallinity and / or amorphicity by XRD or DSC using the following equipment and conditions:

XRD

Measuring instrument: Diffractometer D 8 Advance with 9-fold sample changer (Fa.Bruker / AXS)

Type of measurement: θ- Θ Geometry in reflection

Angular range 2 theta: 2-40 °

Increment: 0.02 °

Measuring time per angle step: 2.4s

Divergence Slit: Göbel mirror with 1, 0 mm plug

Antiscattering Slit: target gap

Detector: Sol-X detector

Temperature: room temperature

Generator setting: 40 kV / 50 mA

DSC

Meter: Q2000 (TA Instruments, USA)

Drying: Dry the samples overnight at 40 ° C under vacuum and then weigh them into a 20 bar pressure-tight crucible

Heating rate: 20 K / min Characterization of solid solutions by means of drug release

The prepared solid solutions from the extrusion process and the spray drying were investigated by means of manual or semi-automatic drug release:

Manual release of active ingredient from itraconazole extrudates (method 1)

Drug release was carried out by USP apparatus (paddle method) 2, 700 mL 0.08 N HCl, 37 ° C, 50 rpm (BTWS 600, Pharmatest). The extrudates were cut by means of a granulator to a length of 3 mm and fed in this form of release. In each case, 100 mg of active ingredient (non-sink conditions) were used per release vat. Detection of the released active substance was carried out manually after specified times and after filtration through a 10 μm filter by UV-VIS spectroscopy (Agilent 8453 UV-VIS Spectrometer, Agilent).

Release of active ingredient from itraconazole extrudates (method 2)

The drug release was carried out by USP apparatus (paddle method) 2, 700 mL 0.08 N HCl, 37 ° C, 75 rpm (BTWS 600, Pharmatest). The extrudates were cut by means of a granulator to a length of 3 mm and fed in this form of release. In each case, 100 mg of active ingredient (non-sink conditions) were used per release vat. Detection of the released drug was semi-automatic at fixed times and after filtration through a 45 μηη filter by UV-VIS spectroscopy (Agilent 8453 UV-VIS spectrometer, Agilent). Release of the drug from the danazol extrudates (method 3)

The active substance release was performed according to USP apparatus (Paddle method) 2, 700 mL of 0.08 N HCl with 0.1% Tween ^® 80, 37 ° C, 100 rpm (600 BTWS, Pharma Test). The extrudate strands were cut by means of a granulator to a length of 3 mm. The divided extrudate strands were comminuted with a MF 10 basic mill (sieve: 0.5 mm, IKA Werke) and fed in this form of release. In each case 100 mg of active ingredient (non-sink conditions) were used per release vat. The detection of the released drug was semi-automatic after specified times and after filtration through a 45 μηη filter by UV-VIS spectroscopy (Agilent 8453 UV-VIS spectrometer, Agilent). Release of active substances from the spray-drying products (method 4)

The drug release was carried out by USP apparatus (paddle method) 2, 700 mL 0.08 N HCl, 37 ° C, 75 rpm (BTWS 600, Pharmatest). The products by spray drying were filled into gelatin capsules (size: 0) and fed in this form of release. To prevent the capsules from floating, they were weighted with a platinum wire. In each case 100 mg of active ingredient (non-sink conditions) were used per release vat. The detection of the released active substance was semi-automatic according to established time and after filtration through a 45 μηι filter by UV-VIS spectroscopy (Agilent 8453 UV-VIS spectrometer, Agilent).

example 1

Loading capacity of Kollicoat ^® Smartseal and partially neutralized Kollicoat ^® Smartseal with

different active ingredients compared to Eudragit ^® EPO. The concentrations in the films given here are based on the loading capacity of the molecule-dispersed active substance, ie, no crystals of the active ingredient are yet to be observed in the film. Higher loadings lead to crystalline proportions.

DMF dimethylformamide

CI2CH2 dichloromethane

Kollicoat ^® Smartseal and Kollicoat ^® Smartseal (partially neutralized) dissolve active ingredients as a solid solution significantly better than Eudragit ^® EPO. Example 2

2925 g of Kollicoat ^® Smartseal (freeze-dried) and 75 g of butyl hydroxy toluene were weighed in a Turbulamischbehälter and mixed for 10 minutes in the Turbula T10B. This mixture was dosed into the extruder with the gravimetric dosing unit DDW-MD2-DDSR20-10 (Brabender technology) and the active ingredient fenofibrate with the gravimetric dosing unit Mini Twin MT1 (Brabender technology).

The mixture was extruded under the following conditions with the twin-screw extruder having a screw diameter of 16 mm and a length of 40D:

• Zone temperature 1. Cylinder: 45 ° C; 2nd cylinder: 85 ° C

• Zone temperature from the 3rd cylinder: 150 ° C

• Screw speed 50 rpm

· Throughput: 500 g / h

• Nozzle diameter 3 mm

The preparation with a mass fraction of 34% (w / w) fenofibrate was examined by XRD and found to be amorphous.

Example 3

2925 g of Kollicoat ^® Smartseal (freeze-dried) and 75 g of butyl hydroxy toluene were weighed in a Turbulamischbehälter and 10 minutes in the Turbula mixed T1 OB. This mixture was dosed into the extruder with the gravimetric dosing unit DDW-MD2-DDSR20-10 (Brabender technology). 250 g of Kollicoat ^® Smartseal mixture (Kollicoat ^® Smartseal with butylated hydroxytoluene) and 250 g of itraconazole were weighed into a Turbulamischbehälter and mixed for 10 minutes in Turbula T2C. This active ingredient mixture was metered into the extruder via a second gravimetric metering system Mini Twin MT1 (Brabender technology).

The mixture was extruded under the following conditions with the twin-screw extruder having a screw diameter of 16 mm and a length of 40D: zone temperature 1st cylinder: 50 ° C; 2nd cylinder: 100 ° C

• Zone temperature from 3rd cylinder to 10 cylinder: 160 ° C

• Screw speed 50 rpm Throughput: 400 g / h

Nozzle diameter 3 mm

The solid solutions were assayed by XRD and found to be amorphous to 38% itraconazole. The release (method 1) of the active ingredient from an extrudate in 0.08 N HCl after 2 h was 89% (Figure 1).

Figure 1: drug release of itraconazole from the Kollicoat ^® Smartseal extrudate in 0.08 N HCl at 50 rpm

Example 4

The corresponding amount of the respective polymer (Kollicoat ^® Smartseal, Kollicoat ^®

Smartseal mol neutralized 8, Eudragit ^® EPO) and the active ingredient corresponding carbamates zepin were weighed into a Turbulamischbehälter (total amount of polymer + active ingredient in each case 400 g) and 10 minutes in Turbula T2C was mixed. This mixture was dosed into the extruder with the gravimetric dosing unit DDW-MD2-DDSR20-10 (Brabender technology). The mixture was extruded under the following conditions with the twin-screw extruder having a screw diameter of 16 mm and a length of 40D:

Zone temperature 1st cylinder: 40 ° C; 2nd cylinder: 80 ° C

Zone temperature from the 3rd cylinder to cylinder 10: 160 ° C

Screw speed 200 rpm

Throughput: 1000 g / h

Nozzle diameter 3 mm

The prepared preparations were analyzed by DSC for amorphous and crystalline drugs in the formulation.

Polymer carbamazepine (% w / w)

10 15 20 25 30 35 40 45 50

Kollicoat ^® AAAK

Smartseal

Kollicoat ^® AKKK

Smartseal 8

mol partial neutralized

Eudragit ^® AKKK

EPO

amorphous formulation (without active substance crystals)

crystalline formulation (with active ingredient crystals)

Comparison of the results of the solid solution (amorphous formulations) with carbamazepine from the extrusion compared to the film method.

Kollicoat ^® Smartseal and Kollicoat ^® Smartseal 8 mol partially neutralized show higher loadings of carbamazepine in the extrusion and in the film method compared to the loadability of Eudragit ^® EPO.

Example 5

Smartseal mol neutralized 6, Eudragit ^® EPO) and the corresponding active ingredient itraconazole were weighed into a Turbulamischbehälter (total amount of polymer + active ingredient in each case 400 g) and 10 minutes in Turbula T2C was mixed. This mixture was dosed into the extruder with the gravimetric dosing unit DDW-MD2-DDSR20-10 (Brabender technology).

• zone temperature 1st cylinder: 50 ° C; 2nd cylinder: 90 ° C

· Zone temperature from 3rd cylinder to 9th cylinder: 160 ° C

• Zone temperature 10. Cylinder: 150 ° C

• Screw speed 200 rpm

• Throughput: 1000 g / h

• Nozzle diameter 3 mm The produced formulations were visually examined and evaluated for amorphous (clear extrudate) and crystalline active ingredients in the formulation (onset of haze).

amorphous formulation (without active substance crystals)

crystalline formulation (with active ingredient crystals)

Comparison of the results of the solid solution (amorphous formulations) with itraconazole from the extrusion to the film method.

Kollicoat ^® Smartseal and Kollicoat ^® Smartseal 6 mol partially neutralized show higher loadings of itraconazole in the extrusion and in the film method compared to the loadability of Eudragit ^® EPO.

The release (method 2) of itraconazole (30 + 45% w / w) mol neutralized and from the extrudates with Kollicoat ^® Smart Seal, 30% (w / w) Kollicoat ^® Smartseal 6 Eudragit ^® EPO with 25, 30.35% ( w / w) Itraconazole in 0.08 N HCl show a rapid and complete release of the drug after 1.5 h. Formulation release after

90 min [% w / w]

30% itraconazole in Kollicoat ^® Smartseal 99

45% itraconazole in Kollicoat ^® Smartseal 98

30% itraconazole in Kollicoat ^® Smartseal 6 mol partially neutralized 97

25% itraconazole in Eudragit ^® EPO 99

30% itraconazole in Eudragit ^® EPO 98

35% itraconazole in Eudragit ^® EPO 101

Example 6

The corresponding amount of the respective polymer (Kollicoat ^® Smartseal, Eudragit ^® EPO) and the corresponding drug danazol was weighed into a Turbulamischbehalter (total amount of polymer + active ingredient was 400 g each) and 10 minutes in Turbula T2C mixed. This mixture was dosed into the extruder with the gravimetric dosing unit DDW-MD2-DDSR20-10 (Brabender technology).

• zone temperature 1st cylinder: 40 ° C; 2nd cylinder: 80 ° C

· Zone temperature from 3rd cylinder to cylinder 10 .: 180 ° C

• Screw speed 200 rpm

• Throughput: 1000 g / h

• Nozzle diameter 3 mm The preparations were analyzed with XRD for amorphous and crystalline active substances in the formulation.

amorphous formulation (without active substance crystals)

crystalline formulation (with active ingredient crystals) The release (method 3) of 25% (w / w) Danazol shows from the ground extrudates Kollicoat ^® Smartseal and Eudragit ^® EPO in 0.08 N HCl with 0.1% Tween ^® 80 Figure 2. Recrystallization Danazols relies the Eudragit ^® EPO extrudate from 5 minutes, with Kollicoat ^® Smartseal extrudate over 14 minutes and can therefore be extended for 9 minutes. The maximum release of danazol in this formulation can be further increased to 40%. It is expected that a larger area under the release curve of Kollicoat Smartseal will also result in greater bioavailability.

The release curves are shown in Figure 2: release of danazol from Kollicoat ^® Smartseal and Eudragit ^® EPO extrudates (ground) in 0.08 N HCl with 0.1% Tween ^® 80 at 100 rpm

Example 7

Loading capacity of Kollicoat ^® Smartseal with various active ingredients in spray drying. Performed spray-drying experiments on a laboratory scale:

1 . Itraconazole: Kollicoat ^® Smartseal with 40 + 50% (w / w) itraconazole

2. fenofibrate: Kollicoat ^® Smartseal 40 + 50% (w / w) fenofibrate

3. Naproxen: Kollicoat ^® Smartseal 40 + 50% (w / w) naproxen experimental conditions:

Active ingredient loading loading loading

Film method Spray drying Spray drying

[%] [DSC,%] [XRD,%]

Itraconazole 50 50 50

Fenofibrate 50 40 -

Naproxen 50 50 50 Kollicoat ^® Smartseal dissolves high concentrations of the active substances itraconazole, fenofibrate and naproxen as a solid solution in spray drying, comparable to the results from the film method.

The release (method 4) of itraconazole (40 + 50% w / w) from Kollicoat ^® Smartseal (spray drying) in 0.08 N HCl shows a rapid and complete release of the active substance after 2 h (Figure 3).

The active substance release of itraconazole is shown in Figure 3: Release of itraconazole from Kollicoat ^® Smartseal, prepared by the method of spray-drying, in 0.08 N HCl at 75 rpm

Claims

claims

1 . Solid dispersions of hydrophobic agents and cationic copolymers

Ν, Ν-Diethylaminoethylmethacrylat and methyl methacrylate in the weight ratio of the monomers from 35:65 to 55:45.

2. Solid dispersions according to claim 1, containing cationic copolymers of N, N-

Diethylaminoethylmethacrylat and methyl methacrylate in the weight ratio of the monomers of 45:55.

3. Solid dispersions according to claim 1 or 2, containing 10 to 50 wt .-% of a hydrophobic active ingredient.

4. Solid dispersions according to any one of claims 1 to 3, containing 20 to 50 wt .-% of a hydrophobic active ingredient.

5. Solid dispersions according to one of claims 1 to 4, containing further pharmaceutical additives.

6. Solid dispersions according to one of claims 1 to 5, containing plasticizer.

7. Solid dispersions according to any one of claims 1 to 6, containing antioxidants.

8. A process for the preparation of solid dispersions of hydrophobic agents and cationic copolymers of Ν, Ν-diethylaminoethyl methacrylate and methyl methacrylate in the weight ratio of the monomers from 35:65 to 55:45 according to any one of claims 1 to7, characterized in that comprising a liquid mixture produces hydrophobic agents and cationic copolymer and the liquid mixture is converted into the solid form.

9. The method according to claim 8, characterized in that the liquid mixture is in the form of a solution or a melt.

10. The method according to claim 8, characterized in that one carries out the transfer of the liquid mixture in the solid form by spray drying.

1 1. A method according to claim 8, characterized in that the liquid mixture is prepared in a screw extruder with heating and solidified after extrusion by cooling.

12. The method according to claim 8, characterized in that one carries out the conversion into the solid form by shaping the liquid mixture into a film and solidifies it.

13. The method according to any one of claims 8 to 12, in which the cationic copolymer is used partially neutralized.

14. The method according to any one of claims 8 to 13, in which the cationic copolymer is used to 2 to 15 mol%, based on the cationic groups, partially neutralized.

15. The method according to any one of claims 8 to 13, in which the cationic copolymer is used partially neutralized with a C3-Cio-dicarboxylic acid.

16. Use of solid dispersions according to one of claims 1 to 15, as pharmaceutical, cosmetic, agrochemical preparations, dietetic preparations or preparations of food supplements.