EP2571493A1

EP2571493A1 - Preparations of biologically active substances with enlarged surface area based on amphiphilic copolymers

Info

Publication number: EP2571493A1
Application number: EP11720524A
Authority: EP
Inventors: Sebastian Koltzenburg; Karl Kolter; Jan Kurt Walter Sandler; Dejan Djuric; Ingo Bellin
Original assignee: BASF SE
Current assignee: BASF SE
Priority date: 2010-05-21
Filing date: 2011-05-20
Publication date: 2013-03-27
Also published as: WO2011144727A1; JP2013526561A; CN102905695A

Abstract

Preparations of biologically active substances based on amphiphilic copolymers with increased surface area.

Description

Preparations of biologically active substances with increased surface area based on amphiphilic copolymers

description

The present invention relates to solid preparations of biologically active substances having an enlarged surface based on thermoplastically processable amphiphilic copolymers, wherein at least one polyether-containing graft polymer is used as the amphiphilic copolymer. Furthermore, the invention relates to processes for the preparation of such preparations.

The enlargement of the surface is achieved by partial or complete foaming of the preparations.

It is well known that foamed plastics can be prepared by extrusion of volatile blowing agent-containing melts. It is also known which conditions can influence the morphology of the foams. Thus, M. Lee et al. In Polymer Engineering and Science, Vol. 38, no. 7, 1998, the extrusion of foamed polyethylene / polystyrene blends with supercritical carbon dioxide.

Furthermore, Han et al. in "Polymer Engineering and Science, Vol. 42, No. 11, 2094-2106" the foam extrusion of polystyrenes with supercritical carbon dioxide.

Further publications on this topic are: W. Michaeli et al., ANTEC 2007 / S. 3043-3045; Lee et al., Polym Int 49: 712-718 (2000).

WO 2007/051743 discloses the use of water-soluble or water-dispersible copolymers of N-vinyllactam, vinyl acetate and polyethers as solubilizers for pharmaceutical, cosmetic, food-processing, agrotechnical or other technical applications. This generally describes that the corresponding graft polymers can also be processed in the melt with the active ingredients.

From WO 2009/013202 it is known that such graft polymers of N-vinyl lactam, vinyl acetate and polyethers can be melted in the extruder and mixed with powdered or liquid active ingredients, wherein the extrusion at temperatures well below the melting point of the active ingredient is described. , From EP-A 0 932 393 it is known to obtain solid foamed pharmaceutical forms by extrusion and foaming of active-ingredient-containing polymer melts containing active ingredients and thermoplastic polymers such as homo- and copolymers of N-vinylpyrrolidone. These foamed dosage forms should have a significantly improved release of the active substance compared to the non-foamed extrudates.

WO 2005/023215 describes active-ingredient-containing platelet-shaped polymer particles which are obtained by melt extrusion and foaming of the melt with a gas. The polymers used are poly (vinylpyrrolidone-vinyl acetate) or Eudragit E1 1 -PO. The foamed platelet-shaped particles should enable a faster release of the active ingredient in an aqueous environment.

However, the hitherto known foam-like formulations of biologically active substances leave something to be desired in terms of the mechanical stability of the foams.

In addition, the dissolution behavior in the case of preparations of poorly water-soluble active substances is in need of improvement.

The object of the present invention was to find active substance-containing preparations which can be obtained by the attractive process of melt extrusion and enable improved release of the active ingredient. The task was also to provide a stable amorphous embedding of the active ingredients. The improvement of the mechanical properties of the formulations was also part of the object of this invention.

Accordingly, the preparations defined above were found. Furthermore, methods for producing such drug forms have been found.

The surface of the preparations is enlarged by partial or complete foaming of the preparation. "Partially or completely foamed" means according to the invention that a density of 1% to 99% of the density of the compact preparation is achieved by the foaming The evaluation of the foaming can be carried out optically with the aid of light or electron micrographs or can be carried out by means of a direct density determination In the following, "partly or completely foamed" is also jointly referred to as "foamed".

The solid, foamed active substance preparations according to the invention can contain as active substances all substances which can be incorporated into the polymer melt without decomposition under the processing conditions. Suitable amphiphilic copolymers are polyether-containing graft polymers. These are obtained by free-radical polymerization of vinyl monomers in the presence of the polyether component, which serves as a graft base. In particular, polyether graft polymers which are obtained by free-radically initiated polymerization of a mixture of i) from 30 to 80% by weight of N-vinyllactam are suitable for the preparation of the foamed preparations,

ii) 10 to 50 wt .-% of vinyl acetate and

iii) 10 to 50% by weight of a polyether, with the proviso that the sum of i), ii) and iii) is equal to 100% by weight. According to a variant of the method, the polyether copolymers are intimately mixed with sparingly water-soluble polymers and the sparingly water-soluble active ingredients, and the mixture is heated above the glass transition temperature of the copolymers.

The polyether copolymers are readily soluble in water, which means that 1 part of copolymer dissolves in 1 to 10 parts of water at 20 ° C.

According to one embodiment of the invention, preferred polyether copolymers obtained from: i) 30 to 70% by weight of N-vinyllactam

ii) 15 to 35% by weight of vinyl acetate, and

iii) from 10 to 35% by weight of a polyether.

Particularly preferably used polyether copolymers are obtainable from: i) 40 to 60 wt .-% N-vinyl lactam

ii) 15 to 35% by weight of vinyl acetate

iii) 10 to 30 wt .-% of a polyether

Very particularly preferably used polyether copolymers are obtainable from i) 50 to 60 wt .-% N-vinyl lactam

ii) 25 to 35% by weight of vinyl acetate, and

iii) 10 to 20 wt .-% of a polyether. The proviso that the sum of components i), ii), and iii) is equal to 100% by weight also applies to the preferred and particularly preferred compositions. Suitable N-vinyllactam are N-vinylcaprolactam or N-vinylpyrrolidone or mixtures thereof. Preference is given to using N-vinylcaprolactam.

The graft is polyether. Suitable polyethers are preferably polyalkylene glycols. The polyalkylene glycols may have molecular weights of from 1000 to 100,000 D [daltons], preferably from 1500 to 35,000 D, more preferably from 1,500 to 10,000 D. The molecular weights are determined on the basis of the measured according to DIN 53240 OH number.

Particularly preferred polyalkylene glycols are polyethylene glycols. Also suitable are polypropylene glycols, polytetrahydrofurans or polybutylene glycols obtained from 2-ethyloxirane or 2,3-dimethyloxirane.

Suitable polyethers are also random or block copolymers of polyalkylene glycols obtained from ethylene oxide, propylene oxide and butylene oxides, such as, for example, polyethylene glycol-polypropylene glycol block copolymers. The block copolymers may be of the AB or ABA type.

The preferred polyalkylene glycols also include those which are alkylated at one or both OH end groups. Suitable alkyl radicals are branched or unbranched C 1 -C 22 -alkyl radicals, preferably C 1 -C -alkyl radicals, for example methyl, ethyl, n-butyl, isobutyl, pentyl, hexyl, octyl, nonyl , Decyl, dodecyl, tridecyl or octadecyl radicals.

General processes for the preparation of the polyether copolymers according to the invention are known per se. The preparation is carried out by free-radically initiated polymerization, preferably in solution, in nonaqueous, organic solvents or in mixed nonaqueous / aqueous solvents. Suitable production processes are described, for example, in WO 2007/051743 and WO 2009/013202, to the disclosure of which reference is expressly made with regard to the preparation process.

The term "sparingly soluble in water" is understood according to the invention as follows: The term "sparingly soluble in water" according to the invention comprises sparingly soluble to practically insoluble substances and means that for a solution of the substance to be dissolved in water at 20 ° C at least 100 bis 1000 g of water per g of substance is needed. In the case of practically insoluble substances, at least 10,000 g of water are required per g of substance. In the following description, the term "poorly soluble" is used abbreviated to "sparingly soluble in water". The present preparations are particularly suitable for the formulation of pharmaceutical active substances, in particular for sparingly soluble active substances.

Suitable active ingredients are, for example:

Acebutolol, acetylcysteine, acetylsalicylic acid, acyclovir, alprazolam, albumin, alfacalcidol, allantoin, allopurinol, ambroxol, amikacin, amiloride, aminoacetic acid, amiodarone, amitriptyline, amlodipine, amoxicillin, ampicillin, ascorbic acid, aspartame, astemizole, atenolol, acemetacin, beclometasone, Benserazide, benzalkonium hydroxide, benzocaine, benzoic acid, betametasone, bezafibrate, biotin, biperiden, bisoprolol, bromazepam, bromhexine, bromocriptine, budesonide, bufexamac, buflomedil, buserspiro, caffeine, camphor, captopril, carbamazepine, carbidopa, carboplatin, cefachlor, cefalexin , Cefadroxil, Cefazolin, Cefixime, Cefotaxime, Ceftazidine, Ceftriaxone, Cefuroxime, Chloramphenicol, Chlorhexidine, Chlorpheniramine, Chlortalidone, Choline, Ciclosporin, Cilastatin, Cimetidine, Ciprofloxacin, Cisapride, Cisplatin, Clarithromycin, Clavulanic Acid, Clomipramine, Clonazepam, Clonidine, Clotrimazole, clozapine, co-serine, colestyramine, cromoglicinic acid, cyanocobalamin, cyproterone, D esogestrel, dexamethasone, dexpanthenol, dextromethorphan, dextropropoxyphene, diazepam, diclofenac, digoxin, dihydrocodeine, dihydroergotamine, diltiazem, diphenhydramine, dipyridamole, dipyrone, disopyramide, domperidone, dopamine, doxycycline, enalapril, enrofloxacin, ephedrine, epinephrine, ergocalciferol, ergotamine, erythromycin, Estradiol, ethinyl estradiol, etoposide, eucalyptus globulus, famotidine, felodipine, fenofibrate, fenoterol, fentanyl, flavin mononucleotide, fluconazole, flunarizine, fluorouracil, fluoxetine, flurbiprofen, flutamide, furosemide, gemfibrozil, gentamicin, ginkgo biloba, glibenclamide, glipizide, glycyrrhiza glabra Guaifenesin, haloperidol, heparin, hyaluronic acid, hydrochlorothiazide, hydrocodone, hydrocortisone, hydro- morphone, hydroxytetracycline, ipratropium hydroxides, ibuprofen, imipenem, indomethacin, lohexol, lopamidol, isosorbide dinitrates, isosorbide mononitrates, isotretinoin, ketotifen, ketoconazole, ketoprofen, ketorolac , Labetalon, Lactulose, Lec ithin, levocarnitine, levodopa, levoglutamide, levonorgestrel,

Levothyroxine, Lidocaine, Lipase, Lisinopril, Loperamide, Lorazepam, Lovastatin, Medroxyprogesterone, Menthol, Methotrexate, Methyldopa, Methylprednisolone, Metoclopramide, Metoprolol, Miconazole, Midazolam, Minocycline, Minoxidil, Misoprostol, Morphine, Multivitamins and Minerals, Nystatin, N-Methylephedrine, Naftidrofuryl, naproxen, neomycin, nicardipine, nicergoline, nicotinamide, nicotine, nicotinic acid, nifedipine, nimodipine, nitrendipine, nizatidine, norethisterone, norfloxacin, norgestrel, nortriptyline, ofloxacin, omeprazole, ondansetron, pancreatin, panthenol, pantoprazole, pantothenic acid, paracetamol, Penicillin G, Penicillin V, Phenobarbital, Pentoxifylline, Phenylephrine, Phenylpropanolamine, Phenytoin, Piroxicam, Polymy- xin B, povidone-iodine, pravastatin, prazepam, prazosin, prednisolone, prednisone, proglumetacin, propafenone, propranolol, pseudoephedrine, pyridoxine, quinidine, ramipril, ranitidine, reserpine, retinol, riboflavin, rifavicin, rionavir, rutoside, saccharin, salbutamol, salcatonin , Salicylic Acid, Sildenafil, Simvastatin, Somatropin, Sotalol, Spironolactone, Sucralfate, Sulbactam, Sulfamethoxazole, Sulpiride, Tamoxifen, Tegafur, Tenoxicam, Teprenone, Terazosin, Terbutaline, Terfenadine, Theophylline, Thiamine, Tiaprofenic Acid, Ticlopidine, Timolol, Tranexamic Acid, Tretinoin, Triamcinolone Acetonides, triamterenes, trimethoprim, troxerutin, uracil, valproic acid, vancomycin, verapamil, vitamin E, folinic acid, zidovudine, zotepin. Vitamins can also be formulated according to the invention. These include the vitamins of the A group, the B group, which in addition to B1, B2, B6 and B12 and nicotinic acid and nicotinamide including compounds with vitamin B properties are understood, such. Adenine, choline, pantothenic acid, biotin, adenylic acid,

Folic acid, orotic acid, pangamic acid, carnitine, p-aminobenzoic acid, myo-inositol and alpha-lipoic acid, furthermore vitamins of the C group, D group, E group, F group, H group, I and J group, K group and P group.

As active ingredients are also pesticides, other biocides or veterinary substances into consideration.

In addition to the amphiphilic copolymers, other thermoplastically processable polymers can also be added to the preparations.

Other thermoplastically processable polymers for the polymer matrix according to the invention are amorphous, thermoplastic polymers.

Particularly suitable polymers are water-soluble, melt-processable homo- or copolymers of N-vinylpyrrolidone or mixtures thereof

Polymers. The polymers usually have glass transition temperatures in the range of 80 to 190, preferably 90 to 175 ° C. Suitable homopolymers are, for example, polymers having Fikentscher K values in the range of 10 to 30. Suitable copolymers may include, as comonomers, unsaturated carboxylic acids, e.g. Methacrylic acid, crotonic acid, maleic acid, itaconic acid, and esters thereof with alcohols having 1 to 12, preferably 1 to 8 carbon atoms, further 25

Hydroxyethyl or hydroxypropyl acrylate and methacrylate, (meth) acrylamide, the anhydrides and half esters of maleic acid and itaconic acid (wherein the half ester is preferably formed only after the polymerization), or vinyl monomers such as N-vinylcaprolactam, vinyl acetate, vinyl butyrate and vinyl propionate

or mixtures of the comonomers mentioned. Thus, for example, Terpolymers of N-vinylpyrrolidone, vinyl acetate and vinyl propionate.

Preferred comonomers are acrylic acid and, most preferably, vinyl acetate. The comonomers may be contained in amounts of from 20 up to 70% by weight. Very particularly preferred according to the invention are copolymers which are obtained from 60% by weight of N-vinylpyrrolidone and 40% by weight of vinyl acetate. Suitable polymers are, for example, homopolymers or copolymers of vinyl chloride, polyvinyl alcohols, polystyrene, polyhydroxybutyrates or copolymers of ethylene and vinyl acetate.

Furthermore, the active compound preparations may also contain starches, degraded starches, casein, pectin, chitin, chitosan, gelatin or shellac as matrix components, which can be processed in the melt with the addition of conventional plasticizers.

Furthermore, the preparations according to the invention may contain the usual pharmaceutical auxiliaries, such as fillers, lubricants, mold release agents,

Flow regulators, plasticizers, dyes and stabilizers in amounts up to 50 wt .-%. These and the quantities given below

are in each case based on the total weight of the preparation (= 100%).

As fillers are e.g. the oxides of magnesium, aluminum, silicon and titanium and lactose, mannitol, sorbitol, xylitol, pentaerythritol and its derivatives, the amount of filler being in the range from 0.02 to 50, preferably 0.2 to 20,% by weight.

As flow control agents, e.g. the mono-, di- and triglycerides of long-chain fatty acids such as C12, C14, C1S and C1S fatty acids, waxes such as carnauba wax and the lecithins, the amount being in the range from 0.1 to 30, preferably 0, 1 to 5 wt.% Is.

As plasticizers, e.g. in addition to low molecular weight polyalkylene oxides such as polyethylene glycol, polypropylene glycol and polyethylene propylene glycol also

15 polyhydric alcohols such as propylene glycol, glycerol, pentaerythritol and sorbitol and Natriumdiethylsulfosuccinat, mono-, di- and triacetate of glycerol and Polyethylenglykolstearinsäureester called. The amount of plasticizer is about 0.5 to 15, preferably 0.5 to 5 wt .-%.

As lubricants, e.g. Stearates of aluminum or calcium and talc and silicones mentioned, wherein their amount is in the range of 0.1 to 5, preferably 0.1 to 3 wt .-%.

Examples of stabilizers which may be mentioned are light stabilizers, antioxidants, free-radical scavengers and microbial attack stabilizers, their amount preferably being in the range from 0.01 to 0.05% by weight.

In order to prepare the preparations according to the invention, the active ingredient component can either be premixed with the polymer and then extruded, or be metered in during the extrusion of the blowing agent-containing polymer melt.

The proportions of the individual components in the preparation can be varied within wide limits. Depending on the effective dose and release rate

of the active ingredient may amount thereof 0.1 to 90 wt .-% of the active ingredient preparation. The amount of the polymer may be 10 to 99.9 wt .-%. In addition, 0 to 50 wt .-% of one or more auxiliaries may be included. The production of foamed active substance preparations according to the invention is preferably carried out by extrusion of a melt which, in addition to one or more active ingredients, contains at least one amphiphilic copolymer and optionally further thermoplastically processable polymers and optionally conventional excipients, the melt being impregnated with volatile, physiologically acceptable propellant.

Suitable volatile, physiologically acceptable blowing agents are gaseous blowing agents such as carbon dioxide, nitrogen, air, noble gases such as helium or argon, propane, butane, dimethyl ether, ethyl chloride, chlorofluorohydrocarbons, difluoroethane or nitrous oxide (nitrous oxide), carbon dioxide and / or nitrogen being preferred. the. Very particular preference is given to carbon dioxide. The gaseous propellant can be used subcritically, but the use in the supercritical state is preferred.

The melt is preferably produced in the extruder, more preferably in a twin-screw extruder. The mixing of the active substance or substances

with the polymers and, if appropriate, further additives may be carried out before or after the melting of the polymers by the methods customary in the art.

Especially in the case of temperature-sensitive active substances, it is advisable to add them only after the thermoplastic has melted. The melt can

be obtained at temperatures of 20 to 200, preferably 70 to 200 ° C, wherein the suitable temperature depends mainly on the glass transition temperature of the added polymers. Depending on the mixture components present in the melt, the extrusion can also be carried out at temperatures below the glass transition temperature of the amphiphilic copolymer. Also, the blowing agent can reduce the necessary for the achievement of a melt temperatures due to its viscosity-reducing effect.

Usually, the polymers will melt at temperatures above their glass transition temperature.

The impregnation of the melt with the blowing agent is preferably carried out under pressure. Under these conditions, between 1 and 15% by weight of the melt can be melted. of the propellant. The introduction of the gas can be carried out at pressures of up to 30 MPa, preferably at pressures between 0.1 to 20 MPa. In this case, up to 20% by weight of gas are injected into the melt - preferably 1 to 20 wt .-%.

By impregnating with softening blowing agents such as CO2, the viscosity of the melt is lowered, so that the extrusion of the blowing agent-containing melt can be carried out at lower temperatures than with a corresponding blowing agent-free melt. This property of the blowing agent-containing polymer melt favors the incorporation of thermolabile active ingredients.

Prior to extrusion through the die, the blowing agent-containing melt is cooled to temperatures in the range of up to 70 ° C above the glass transition temperature of the mixture. Preferably, the temperature at the nozzle 10 to 40 ° C above the glass transition temperature of the recipe. Particularly preferred is a temperature range between 15 and 30 ° C.

For particularly temperature-sensitive active ingredients, the addition to the melt is recommended after the blowing agent admixture and the temperature has dropped. The process according to the invention can be carried out in a single extruder with different temperature zones. However, preference is given

a tandem extrusion plant consisting of two coupled together

Extruders, wherein the first extruder, in which the melting of the polymer and the blowing agent loading of the melt takes place, is preferably a twin-screw extruder with good mixing action, and the second extruder is a single-shaft extruder with low shear and high cooling capacity.

The still plastic strand emerging from the extruder nozzle expands to a foam under the normal pressure present outside the extruder.

The degree of foaming and thus the morphology of the active ingredient preparation can be controlled by the amount of added blowing agent and the extrusion temperature. A high degree of foaming results in a lower density and thus a high dissolution rate of the active ingredient form. If higher densities are desired, a high propellant content which is favorable for the preparation can be lowered by degassing directly to the nozzle gap to the extent that a product which is only slightly foamed is obtained. The foamed active compound preparation is subsequently shaped into the respective desired active substance forms, for example by pelleting, granulation or tabletting by known processes. The solid active compound preparations usually have densities in the range from 20 to 1000 g / l, preferably 25 to 600 g / l, particularly preferably 30 to 500 g / l.

The foams can be open-celled or closed-celled. The preparations according to the invention have an increased surface area in comparison with conventional extrudates.

It is also possible to produce multilayer partially or completely foamed active substance-containing forms by coextrusion. In this case, at least two masses each containing at least one of said thermoplastic binders, of which at least one contains an active ingredient and of which at least one is impregnated in the manner already described with a gaseous physiologically acceptable propellant, coextruded and then to the desired Dosage form deformed.

Prior to coextrusion, the mass is prepared separately for each layer of the drug form. For this purpose, the respective starting components are processed in a separate extruder under the conditions already described for the above process variant conditions to active ingredient-containing melts. It can be worked for each layer under each material-specific optimal conditions. For example, a different processing temperature can be selected for each layer. The respective compositions can also be impregnated with different amounts of blowing agent, for example, so that layers with different degrees of foaming are formed.

The molten or plastic masses from the individual extruders are filled in a common coextrusion, formed and discharged. The shape of the coextrusion depends on the desired drug form. For example, tools with a flat outlet gap, so-called slot die tools, and tools with annular gap-shaped outlet cross section are suitable.

The nozzle design is carried out depending on the polymeric binder used and the desired shape. After discharge from the coextrusion tool, shaping takes place to the desired active ingredient or drug form. In this case, a variety of shapes depending on the coextrusion tool and the type of shaping can be generated. For example, it is possible to produce open multi-layer tablets from a strand which emerges from a slot die and which in particular has two or three layers by punching or cutting, for example by means of a glowing wire. Alternatively, open multilayer tablets can be delivered via a die having an annular cross-section via a hot break, ie by cutting or chopping the strand immediately after leaving the die, or preferably via a cold cut, ie by cutting or chopping the strand after at least partial cooling , to be separated.

Closed drug forms, i. Shapes in which the active substance-containing layer is completely surrounded by a drug-free layer are obtained, in particular, via a tool having an annular cross-section through the treatment of the strand in a suitable squeezing device.

It is advantageous if, when the outer layer has already cooled, the inner layer of the multilayer tablet is still plastically deformable on entering the squeezing device. In particular tablets, preferably oblong tablets, dragees, lozenges and pellets can be produced in this way.

According to a further variant of the method, foamed active substance-containing molds can be produced by extruding a melt comprising at least one thermoplastic amphiphilic copolymer in addition to one or more active substances, which still molds the plastic melt and then compressing the solid active substance-containing mold one of the abovementioned gaseous blowing agents impregnated, for example, in a conventional autoclave at pressures in the range of 10 to 300 bar, preferably 50 to 200 bar and then expanded.

When relaxing to normal pressure, the impregnated mold expands to a partially or fully foamed form.

The degree of foaming depends on the duration of the impregnation process and can be set as desired. This variant of the method is preferably suitable for

Production of partially foamed molds which have an outer foamed casing and a non-foamed core and thus have a step-shaped release profile. The foamed forms can also be provided with a conventional drug-permeable Ü-coating, so easily floating

Swimming forms can be obtained. Such swimming forms can be used for pharmaceutical purposes or even for veterinary or agricultural products, for example for the production of slowly sinking fish feed. The solid, foamed active substance preparations obtained according to the invention, which contain the active ingredient homogeneously dispersed in the polymeric matrix, dissolve very rapidly and thus allow the rapid release of the active ingredient. By the method according to the invention, the foamed

Active ingredient preparations can be obtained in a simple and economical manner. It is also advantageous that can be extruded at significantly lower temperatures than without blowing agent by the viscosity-reducing effect of the blowing agent, so that the active ingredients are thermally less stressed. In the preparations according to the invention the active substance is embedded in amorphous form. Amorphous means that no more than 3% by weight of the active ingredient, measured by DSC, is in crystalline form. The DSC measurements are usually carried out at a heating rate of 20 K / min. The use of a solubilizing polymer offers significant advantages over previously known polymers for melt extrusion. Due to the solubilizing effect, solid solutions can also be achieved with particularly sparingly soluble active ingredients. The higher specific surface area of the solid solutions due to the foaming offers an even faster release of active substance than with non-foamed solid solutions. Surprisingly, they are solubilizing

Polymer produced foams not together, even if larger amounts of lipophilic drugs are incorporated. This would have been expected because lipophilic additives such. As silicones in aqueous foams lead to a dramatic collapse of the foam structure.

The gas used as a temporary plasticizer during the extrusion is no longer detectable in the final product, so that a higher stability could be expected compared to solid solutions with permanent plasticizers, since the latter preparations show a lower rigidity.

The highest possible rigidity, however, is very desirable with regard to the ability of the foamed products to be ground. Products with higher rigidity are more brittle, break more easily and are less prone to deformation during the grinding process. Therefore, porous substructures are better preserved. The foamed preparations according to the invention have good rigidity. Examples

The twin-screw extruder used to prepare the formulations described in the examples below had screw diameters of 16 mm and a length of 40D. The entire extruder was made up of 8 individually heatable cylinder blocks. The first two cylinders were tempered at 20 ° C or at 70 ° C for better material intake. The third cylinder was set at a constant temperature, where the gas was introduced through a nozzle directly into the extruder. The gas used was CO2, which was introduced by means of a dosing pump.

The temperature of the following cylinders was adjusted in the process so that a temperature resulted at the nozzle, which can be up to 70 ° C above the glass transition temperature of the mixture. The foamed extrudate was ground after cooling with an analytical mill (IKA A10) for 30 s. For further experiments, the sieve fraction was used, which was smaller than 250μηη after grinding.

The polymer foams produced were examined for crystallinity and amorphicity by means of XRD (X-ray diffractometry) and DSC (Differential Scanning Calorimetry) 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: 2-80 °

Increment: 0.02 °

Measuring time per angle step: 4.8s

Divergence Slit: Göbel mirror with 0.4 mm plug

Antiscattering Slit: target gap

Detector: Sol-X detector

Temperature: room temperature

Generator setting: 40kV / 50mA

DSC

DSC Q 2000 of the company TA-Instruments

Parameter:

Weighing approx. 8.5 mg

Heating rate: 20K / min

The milled foams were filled into hard gelatin capsules. The drug was released by USP apparatus (paddle method) 2, 37 ° C, 50 rpm (BTWS 600, Pharmatest) in 0.1 molar hydrochloric acid for 2 h. The detection of the released active ingredient was carried out by UV spectroscopy (Lambda-2, Perkin Elmer). The drawn samples were diluted with methanol immediately after filtration to prevent crystallization of the poorly soluble drug.

Preparation of Polymer 1

In a stirred apparatus, the template was heated without the subset of feed 2 under an atmosphere of IS to 77 ° C. When the internal temperature of 77 ° C was reached, the portion of feed 2 was added and grafted on for 15 min. Subsequently, feed 1 was added in 5 h and feed 2 in 2 h. After all feeds had been added, the reaction mixture was postpolymerized for a further 3 hours. After postpolymerization, the solution was adjusted to a solids content of 50% by weight.

Original: 25 g of ethyl acetate

104.0 g PEG 6000,

1.0 g of feed 2

Feed 1: 240 g of vinyl acetate

456 g of vinylcaprolactam

240 g of ethyl acetate

Feed 3: 10.44 g of tert-butyl perpivalate (75% by weight in Aliphatengem

67.90 g of ethyl acetate

Subsequently, the solvent was removed by a spray method to obtain a powdery product. The K value was 16, measured 1 wt .-% strength in ethanol. The glass transition temperature of the polymer determined by DSC was 70 ° C.

Example 1:. Polymer 1 + 5.5 wt ^'% C0 ₂

• Throughput polymer: 18.95 kg / h

• C0 ₂ injection: 1 .05 kg / h

• Melt temperature in front of the nozzle: 135 ° C

· Melt pressure in front of the nozzle: 160 bar Example 2: Polymer 1 + 8.4 wt.% C0 ₂

• Throughput polymer: 18.45 kg / h

• C0 ₂ injection: 1 .55 kg / h

• Melt temperature in front of the nozzle: 120 ° C

• Melt pressure in front of the nozzle: 130 bar

Example 3: Polymer 1 + 1.1 wt.% C0 ₂

• Throughput polymer: 18 kg / h

• C02 injection: 2 kg / h

• Melt temperature in front of the nozzle: 107 ° C

• Melt pressure in front of the nozzle: 135 bar

Example 4: Polymer 1 + Fenofibrate + CO2

Polymer 1 and 20% by weight of fenofibrate (melting point 81 ° C.), based on the total amount of polymer + active compound, were weighed out and mixed for 60 minutes in a V-Blender.

• Throughput mixture (polymer + fenofibrate): 18.75 kg / h

• C0 ₂ injection: 1 .25 kg / h

· Melt temperature in front of the nozzle: 80 ° C

• Melt pressure in front of the nozzle: 135 bar

The foamed extrudates were analyzed by XRD and by DSC and found to be amorphous. The release of the drug in 0.1 normal HCl after 2 h was 100%. After 6 months storage at 30 ° C, the preparations were still amorphous.

Example 5: Polymer 1 + cinnarizine + CO2 polymer 1 and 20% by weight of cinnarizine (melting point 122 ° C.), based on the total amount of polymer + active compound, were weighed out and mixed for 60 minutes in a V-Blender.

Throughput mixture (polymer + cinnarizine): 18.75 kg / h

· C0 ₂ injection: 1 .25 kg / h

• Melt temperature in front of the nozzle: 105 ° C

• Melt pressure in front of the nozzle: 130 bar The foamed extrudates were analyzed by XRD and by DSC and found to be amorphous. The release of the drug in 0.1 normal HCl after 70 minutes 95%. After 6 months storage at 30 ° C, the preparations were still amorphous.

Example 6: Polymer 1 + itraconazole + CO2

Polymer 1 and 40% by weight of itraconazole (melting point 166 ° C.), based on the total amount of polymer + active compound, were weighed out and mixed for 60 minutes in a V-Blender.

• Throughput mixture (polymer + itraconazole): 18.9 kg / h

• C0 ₂ injection: 1 .1 kg / h

· Melt temperature in front of the nozzle: 120 ° C

• Melt pressure in front of the nozzle: 130 bar

The foamed extrudates were analyzed by XRD and by DSC and found to be amorphous. The release of the drug in 0.1 normal HCl after 2 h was 90%. After 6 months storage at 30 ° C, the preparations were still amorphous.

Example 7: Polymer 1 + danazol + CO2 polymer 1 and 20% by weight of danazol (melting point 225 ° C.), based on the total amount of polymer + active compound, were weighed out and mixed for 60 minutes in a V-Blender.

• Throughput mixture (polymer + danazol): 18.75 kg / h

· C0 ₂ injection: 1 .25 kg / h

• Melt temperature in front of the nozzle: 130 ° C

• Melt pressure in front of the nozzle: 135 bar

The foamed extrudates were analyzed by XRD and by DSC and found to be amorphous. The release of the drug in 0.1 normal HCl after 2 h was 90%. After 6 months storage at 30 ° C, the preparations were still amorphous. Example 8: Polymer 1 + Piroxicam + CO2

Polymer 1 and 30% by weight of piroxicam (melting point 199 ° C.), based on the total amount of polymer + active compound, were weighed in and mixed for 60 minutes in a V-Blender.

• Throughput mixture (polymer + piroxicam): 18.85 kg / h

• C0 ₂ injection: 1 .15 kg / h

• Melt temperature in front of the nozzle: 135 ° C

· Melt pressure in front of the nozzle: 140 bar

The foamed extrudates were analyzed by XRD and by DSC and found to be amorphous. The release of the drug in 0.1 normal HCl after 2 hours was 69%. After 6 months storage at 30 ° C, the preparations were still amorphous.

Example 9: Polymer 1 + Felodipine + CO2

Polymer 1 and 40% by weight of felodipine (melting point 145 ° C.), based on the total amount of polymer + active compound, were weighed out and mixed for 60 minutes in a V-Blender.

• Throughput mixture (polymer + felodipine): 18.9 kg / h

• C0 ₂ injection: 1 .1 kg / h

· Melting temperature in front of the nozzle: 1 10 ° C

• Melt pressure in front of the nozzle: 130 bar

The foamed extrudates were analyzed by XRD and by DSC and found to be amorphous. The release of the drug in 0.1 normal HCl after 2 hours was 91%. After 6 months storage at 30 ° C, the preparations were still amorphous.

Example 10: Polymer 1 + carbamezipin + CO2 polymer 1 and 40% by weight of carbametapine (melting point 192 ° C.), based on the total amount of polymer + active compound, were weighed out and mixed for 60 minutes in a V-Blender.

• Throughput mixture (polymer + carbamezipin): 18.9 kg / h

· C0 ₂ injection: 1 .1 kg / h

• Melt temperature in front of the nozzle: 130 ° C

• Melt pressure in front of the nozzle: 132 bar The foamed extrudates were analyzed by XRD and by DSC and found to be amorphous. The release of the drug in 0.1 normal HCl after 2 h was 78%. After 6 months storage at 30 ° C, the preparations were still amorphous.

Example 1 1: Polymer 1 + Clotrimazole + CO2

Polymer 1 and 15% by weight of clotrimazole (melting point 148 ° C.), based on the total amount of polymer + active compound, were weighed out and mixed for 60 minutes in a V-Blender.

• Throughput mixture (polymer + clotrimazole): 18.7 kg / h

• C0 ₂ injection: 1 .3 kg / h

• Melt temperature in front of the nozzle: 105 ° C

· Melt pressure in front of the nozzle: 135 bar

The foamed extrudates were analyzed by XRD and by DSC and found to be amorphous. The release of the drug in 0.1 normal HCl after 2 h was 63%. After 6 months storage at 30 ° C, the preparations were still amorphous.

Claims

claims

Preparations according to claim 1, wherein the preparations are present partially or completely foamed.

Preparations according to Claim 1 or 2 comprising, as amphiphilic copolymers, polyether copolymers obtained by free-radical polymerization of from 30 to 70% by weight of N-vinyllactam, from 15 to 35% by weight of vinyl acetate, and from 10 to 35% by weight of a polyether.

Preparations according to one of claims 1 to 3, comprising polyether copolymers obtained from 40 to 60 wt .-% N-vinyl lactam, 15 to 35 wt .-% vinyl acetate and 10 to 30 wt .-% of a polyether.

Preparations according to one of claims 1 to 4, containing further thermoplastically processable polymers.

Process for the preparation of preparations according to one of Claims 1 to 5, characterized in that a melt comprising the biologically active substance, at least one amphiphilic copolymer and, if appropriate, further auxiliaries and, as blowing agent, a volatile physiologically acceptable gas are extruded and expanded.

A method according to claim 6, characterized in that the melt is loaded at a gas pressure of 1 to 30 MPa with the volatile physiologically harmless gas.

A method according to claim 6 or 7, characterized in that the concentration of the gas in the melt is one to 15 wt .-%.

Method according to one of claims 6 to 8, characterized in that the melt can be obtained at temperatures of 20 to 200 ° C.

10. The method according to any one of claims 6 to 9, characterized in that the melt at temperatures of 70 to 200 ° C can be obtained.