Process for the preparation of solid pharmaceutical forms

The invention relates to a process for the production of solid pharmaceutical forms which contain an N-vinylpyrrolid-2-one (NVP) polymer as a binder, by injection molding or extrusion and shaping.

The use of polyvinylpyrrolidone in pharmaceutical active ingredient mixtures in order to increase the biological absorption of active ingredient mixtures in the form of molecular dispersions is known, for example, from EP-A-214 092.

The usual tableting machines work in a clockwise process with a stamp and a die. The process requires intensively pre-mixed and specially prepared tableting compounds and is therefore multi-stage and complex. The production of solid pharmaceutical forms with targeted release of active ingredient is particularly complex. On the one hand, this may require measures for retardation, on the other hand measures to improve the absorption of active substances.

One way to improve the absorption of poorly soluble active ingredients is to use solid solutions of the active ingredients in water-soluble polymers. The previously known solid solutions of this type in NVP polymers were prepared via common solutions of active substance and polymer in an organic solvent by removing the solvent. In order to be able to dissolve both the hydrophobic active substance and the hydrophilic polymer, chlorinated hydrocarbons were generally required. Their practically complete removal is very complex. In order to avoid environmental pollution, the solvents must be removed from the exhaust air as completely as possible, which in turn is very expensive. Such methods are described for example in US 3,089,818; T. Tachibana and A. Nakamura, Colloid Journal and Journal of Polymers, Vol. 203 (1965), 130; JP-PS 24 379; M. Mayersohn et al. , J. Pharm. Sci. 55 (1966), 1323; DE-B-11 37 009; W. Scholten, Arzn. Research 14 (1964), 469.

The extrusion of active ingredient / polymer mixtures has already been described, cf. e.g. B. DE-A-12 29 248; EP-A-204 596; P. Speiser, Pharmaceutica Acta Helv., 41 (1966), p. 340, and 46 (1971), p. 31. In no case, however, were solvent-free NVP polymers melted, let alone extruded, without mixing with other polymers or with water, and in no case was the formation of a solid solution of a poorly water-soluble active ingredient in a water-soluble polymer described.

In R. Voigt, Textbook of pharmaceutical technology, 5th edition, Verlag Chemie, Weinheim, 1984, pages 221 and 222, the production of solid pharmaceutical preparations by injection molding or extrusion and shaping of active ingredient-thermoplastic mixtures is described in general terms, but without any specific information, especially about the type of polymers suitable for this. It was undoubtedly not a question of strongly hydrophilic polymers, such as NVP polymers, because these have so far not been processed in the pharmaceutical sector by dry melt, but have always been pasted with solvents (usually water), cf. e.g. GB 1 388 786.

The invention was based on the task of developing a simple process for the production of solid pharmaceutical forms, preferably with a targeted release of active substance over a period of time.

The object is achieved by a process for the production of solid pharmaceutical forms by mixing at least one active pharmaceutical ingredient with at least one meltable pharmacologically acceptable binder and, if appropriate, other customary pharmaceutical auxiliaries, at a temperature in the range from 50 to 180, preferably 60 to 160 ° C. , Injection molding or extrusion and molding, wherein the fusible binder used is a solvent-free NVP polymer with a water content of at most 3.5% by weight, which contains at least 20, preferably at least 60, in particular 100,% by weight of NVP polymerized in and all of its comonomers, if any, nitrogen and / or contain oxygen, and an NVP polymer being used at least when the glass transition temperature of the mixture is above 120 ° C., which was obtained by polymerization in an organic solvent or with an organic peroxide as a starter in aqueous solution, and the mixture does not contain any thermoplastics which are sparingly soluble in gastric juice (less than 10% soluble in 6 hours).

The NVP polymers should contain at least 20, preferably at least 60, in particular 100,% by weight of NVP in copolymerized form and a K value according to Fikentscher (Cellulose-Chemie, 13, 1932, pp. 58 to 64 and 71 to 74) of 10 to 70 , preferably 10 to 50, more preferably 12 to 40 and in particular 12 to 35, in the case of NVP homopolymers preferably 12 to 35, in particular 12 to 17.

The polymeric binder must soften or melt in the total mixture of all components in the range from 50 to 180, preferably 60 to 130 ° C., so that the composition can be extruded. The glass transition temperature of the mixture must in any case be below 180, preferably below 130 ° C. If necessary, it is supplemented by customary pharmacologically acceptable plasticizing auxiliaries such as long-chain alcohols, ethylene glycol, propylene glycol, trimethylolpropane, triethylene glycol, butanediols, pentanols, hexanols, polyethylene glycols, aromatic carboxylic acid esters (eg dialkyl phthalates, trimellitic acid esters, benzoic acid esters, derephthalic acid esters, terephthalic acid esters, terephthalic acid esters, terephthalic acid esters, terephthalic acid esters, terephthalic acid esters, terephthalic acid esters, for example, terephthalic acid esters, terephthalic acid esters, terephthalic acid esters) Dialkyl adipates, sebacic acid esters, azelaic acid esters, citric and tartaric acid esters) or fatty acid esters. The plasticizer preferably makes up no more than 20% by weight of the polymer. Particularly preferred are NVP polymers that do not require such additives, that is to say that they melt or soften in the desired temperature range in a mixture with the active ingredient and, if appropriate, conventional pharmaceutical auxiliaries, even without special plasticizing additives. Melting or softening below a certain temperature may be necessary in view of possible thermal and / or oxidative damage not only to the active ingredient but also to the NVP polymer. This could turn yellow during extrusion, which is why the extrusion of NVP polymers has so far not been common. However, the risk is low at extrusion temperatures below 180 ° C., especially below 130 ° C., if the polymer was not prepared in aqueous solution with hydrogen peroxide as the starter, but in an organic solvent, or in water with an organic peroxide as starter, for example according to the method according to German patent application P 36 42 633.4 or according to the method of US 4,520,179 and 4,520,180.

If the K value is above 17, in particular above 30 or even 40 (up to a maximum of 70) and no strongly softening component is present, only copolymers with a glass transition temperature Tg below 120, preferably below 100 ° C., or the NVP are suitable - Polymer (including homopolymer) must not have been produced in water with H₂O₂ as a starter. This would result in polymer end groups which lead to yellowing at a higher temperature.

Possible comonomers are: unsaturated carboxylic acids, for example methacrylic acid, crotonic acid, maleic acid, itaconic acid, and their esters with alcohols having 1 to 12, preferably 1 to 8, carbon atoms, furthermore hydroxyethyl or hydroxypropyl acrylate and methacrylate, (meth) acrylamide, the anhydrides and half esters of maleic and itaconic acid (the half ester preferably being formed only after the polymerization), N-vinylcaprolactam and vinyl propionate.

Preferred comonomers are acrylic acid and in particular vinyl acetate. NVP polymers are therefore preferred which contain either only NVP or vinyl acetate as the only comonomer or at least 10, preferably at least 30% by weight, of these in copolymerized form. Vinyl acetate and vinyl propionate can be completely or partially saponified after the polymerization.

By "solvent-free" it is meant that no organic solvent, especially no chlorinated hydrocarbon, is added. In addition, no thermoplastic that is sparingly soluble in gastric juice should be mixed in, and the water content of the NVP polymer (through spontaneous absorption of moisture from the air; no deliberate addition of water!) Should not exceed 3.5% by weight. Higher water contents are detrimental in that they evaporate the water after the polymer / active substance strand emerges from the nozzle and lead to porous moldings which may even burst on the surface.

The method according to the invention is suitable, for example, for processing the following active ingredients: Betamethasone, thioctic acid, sotalol, salbutamol, norfenefrin, silymarin, dihydergotamine, buflomedil, etofibrrat, indomethacin, oxazepam, β-acetyldigoxin, piroxicam, haloperidol, ISMN, amitriptyline, nifitripinolinol, diflipinolinol, diflipinolinopin, diclipinolinol, diclipinolinopin Clonidine, fenofibrate, allopurinol, pirenzepin, levothyroxine, tamoxifen, metildigoxin, o- (β-hydroxyethyl) rutoside, propicillin, aciclovir mononitrate, paracetamol, naftidrofuryl, pentoxifylline, propafenone, Acebutolol, L-thyroxine, tramadol, bromocriptine, loperamide, ketotifen, fenoterol, Ca-dobelisate, propranolol, minocycline, nicergoline, ambroxol, metoprolol, β-sitosterol, enalapril hydrogen maleate, bezafibrate, ISDN, gallopamilotinate, xanzepine, xanophenolate, xanatexinzepine, xanoline xanthate, xanolinate, xanoline, xanine, xanoline, xanine, xanoline, xanine, xanine, xanoline, xanine, xanine, xanoline, xanine, xanine, xanoline, xanine, xanine, xanoline, xanine, xanine, xanoline, xanine, xanine, xinoline, xanine, xanine, xinoline, xanine, xine Dexapanthenol, pindolol, lorazepam, diltiazem, piracetam, phenoxymethylpenicillin, furosemide, bromazepam, flunarizine, erythromycin, metoclopramide, acemetacin, ranitidine, biperiden, metamizole, doxepin, Dipotassium chlorazepate, tetrazepam, estramustine phosphate, terbutaline, captopril, maprotiline, prazosin, atenolol, glibenclamide, cefaclor, etilefrin, cimetidine, theophylline, hydromorphone, ibuprofen, primidone, clobazam, oxaceroidoxalone, 5-oxacepridoxalone, 5-oxacepridoxalone, 5-oxypersprolate, 5 mg Hymechromon, Etofyllinclofibrat, Vincamin, Cinnarizin, Diazepam, Ketoprofen, Flupentixol, Molsidomin, Glibornurid, Dimetinden, Melperon, Soquinolol, Dihydrocodein, Clomethiazol, Clemastin, Glisoxepid, Kallidinogenase, oxyfedrine, baclofen, carboxymethylcysteine, thioridacin, betahistine, L-tryptophan, myrtol, bromelaine, prenylamine, salazosulfapyridine, astemizole, sulpiride, benzerazide, dibenzepine, acetylsalicylic acid, miconazetolifin, colinosolifin, colinosolifin, colonylolonolinate, colonazolifinate Fluorocortolone, mexiletine, amoxicillin, terfenadrin, mucopolysaccharide poly sulfuric acid ester, triazolam, mianserin, tiaprofenic acid, amezinium metal sulfate, mefloquine, probucol, quinidine, Carbamazepine, Mg-L-aspartate, penbutolol, piretanide, amitriptyline, cyproterone, sodium valproinate, mebeverine, bisacodyl, 5-amino salicylic acid, dihydralazine, magaldrate, phenprocoumon, amantadine, naproxen, carteolol, famotidine, methyldopin Nadolol, levomepromazine, doxorubicin, medofenoxate, azathioprine, flutamide, norfloxacin, fendiline, prajmalium bitartrate, aescin.

Solid solutions of the following active ingredients are particularly preferred: Acetaminophen (= paracetamol), acetohexamide, acetyldigoxin, acetylsalicylic acid, acromycin, anipamil, benzocaine, β-carotene, chloramphenicol, chlordiazepoxide, chlormadinone acetate, chlorothiazide, cinnarizine, clonazepam, codeine, dexiaxinaminone, dexiaxinaminone, dexiaxinoxinone, dexiaxinoxinone, Flunitrazepam, furosemide, gramicidin, griseofulvin, hexobarbital, hydrochlorothiazide, hydrocortisone, hydroflumethiazide, indomethazine, ketoprofen, lonetil, medazepam, mefruside, Methandrostenolone, methylprednisolone, methylsulfadiazine (= sulfaperin), nalidixic acid, nifedipine, nitrazepam, nitrofurantoin, nystatin, estradiol, papaverine, phenacetin, phenobarbital, phenylbutazone, phenytoin, streptomycin, sulfonolamone, spironolamone, Sulfamethoxydiazine (= sulfameter), sulfaperin, sulfathiazole, sulfisoxazole, testosterone, tolazamide, tolbutamide, trimethoprim, tyrothricin.

The term “solid solutions” is familiar to the person skilled in the art, for example from the literature cited at the beginning. In solid solutions of active pharmaceutical ingredients in polymers, the active ingredient is present in the polymer in a molecularly dispersed manner.

The formation of solid solutions of the active substances mentioned in NVP polymers was not foreseeable and is all the more surprising since many active substances which are sparingly soluble in water in other polymers do not form solid solutions (with a molecularly disperse distribution), but rather are incorporated in the form of solid particles in the respective polymer, which can be recognized by electron microscopy. In the case of crystalline active substances, they also show a Debye-Scherrer diagram, in contrast to the solid solutions.

If, in addition to the water-soluble, meltable binder to be used according to the invention, the first-mentioned should make up at least 50, preferably at least 70% by weight of all meltable binders used.

Solid pharmaceutical forms in the sense of the invention are, for example, tablets, coated tablets, granules and suppositories.

Pharmaceutical active substances in the sense of the invention are understood to mean all substances with a pharmaceutical effect and as few side effects as possible, provided that they do not decompose under the processing conditions. The amount of active ingredient per dose unit and the concentration can vary within wide limits depending on the effectiveness and rate of release. The only requirement is that they are sufficient to achieve the desired effect. The active substance concentration can thus be in the range from 0.1 to 95, preferably from 20 to 80, in particular 30 to 70,% by weight. Combinations of active substances can also be used. Active substances in the sense of the invention are also vitamins. Active substances which are sparingly soluble in water mean those whose absorption in the gastrointestinal tract is normally unsatisfactory because of their insufficient solubility.

The mixing of the active ingredient or the active ingredients with the binders and, if appropriate, further customary galenical additives can be carried out before or after the melting of the polymeric binder by the methods customary in industry. Mixing in the extruder with a mixing compartment, preferably a twin-screw extruder, or in the screw region of an injection molding machine is preferred.

The shaping can be carried out by injection molding or by extrusion and subsequent shaping of the still plastic strand, for example by hot cutting into granules or shaping into tablets, for example by passing the strand between two counter-rotating rollers with opposing depressions in the roller shell, the design of which determines the tablet shape. Cold cutting can also be considered, if necessary with subsequent compression of the granules into tablets. The term "extrusion" includes - at least in the sense of the invention - the injection molding.

The NVP polymer can be adjusted so strongly or so weakly hydrophilically, depending on the intended use, that the tablets produced therefrom dissolve in the mouth (buccal tablet) or in the stomach or only in the intestine (quickly or delayed), depending on the type and amount of comonomers swell so that they release the active ingredient. They are sufficiently swellable if they absorb more than 10% by weight of water when stored at 90% relative humidity. If it is desired for binders containing carboxyl groups that they only release the active substance in the alkaline environment of the intestine, the above statement of water absorption only applies to the neutralized form (salt form) of the polymer (in which the protons of the carboxyl groups are wholly or partly by ammonium, Sodium or potassium ions are replaced).

Customary pharmaceutical auxiliaries, the total amount of which may be up to 100% by weight, based on the polymer, are, for example, extenders such as silicates or silica, stearic acid or their salts with, for example, magnesium or calcium, methyl cellulose, sodium carboxymethyl cellulose, talc, sucrose, lactose , Cereal or corn starch, potato flour, polyvinyl alcohol, also wetting agents, preservatives, disintegrants, adsorbents, colorants, flavorings (see e.g. H. Sucker et al., Pharmaceutical Technology, Thieme-Verlag, Stuttgart 1978).

If desired, the solid pharmaceutical form can also be provided with a conventional coating to improve the appearance and / or taste (dragee) or to further delay the release of the active ingredient. For orally ingested tablets with delayed release of active ingredient, it can be advantageous if the tablet is manufactured in a closed-cell porous form according to one of the known techniques, so that it floats in the stomach and thus remains there for a longer time.

In the case of solid pharmaceutical forms with rapid release of active ingredient, the method according to the invention allows the pharmaceutical form to be designed much more freely than the conventional tablet pressing technique. For example, engravings can be affixed for identification, or almost any shape can be produced, which also represents a unique identification for the visually impaired. Certain shapes, e.g. the hemisphere can also be suitable for achieving a specific drug release characteristic. By extrusion and hot or cold cutting of the strand, very small-sized and uniformly shaped granules can be produced in a simple manner, for example for multiple-unit molds.

The parts and percentages given in the examples relate to the weight. The drug release time was determined using the half-change test method.

example 1

45 Parts of a copolymer with a K value of 30 consisting of 60% by weight of N-vinylpyrrolidone and 40% by weight of vinyl acetate, 5 parts of stearyl alcohol and 50 parts of theophylline were processed into dragee cores in an injection molding machine. The processing temperature was 100 ° C. The dragee cores obtained in this way were stable against mechanical influences and showed no abrasion during transport and packaging. The active ingredient was tested in the half-change test, cf. eg R. Voigt, textbook of pharm. Technology, 5. Ed., Verl. Chemie, Weinheim; Deerfield Beach, Florida; Basel, 1984, p. 627, completely released within 6 to 8 hours in connection with the paddle method according to USP 21.

Example 2

50 Parts of the copolymer from Example 1 and 50 parts of theophylline were processed in an injection molding machine into oblong tablets of 1 cm in length. The processing temperature was 120 ° C. The tablets thus obtained were also stable against mechanical influences and released the active ingredient completely within 1 to 2 hours.

Example 3

47.5 parts of a copolymer with a K value of 30 consisting of 60% by weight of N-vinylpyrrolidone and 40% by weight of vinyl acetate, 2.5 parts of crosslinked polyvinylpyrrolidone (PVP) as tablet disintegrant and 50 parts of theophylline were mixed and extruded in a twin-screw extruder. The temperature of the five shots was 120 ° C each. The nozzle had a temperature of 130 ° C. The still plastic strand was pressed into oblong tablets using the device described in German parallel application P 36 12 211.4. The tablets were stable against mechanical influences. The drug release time was 30 to 45 min.

Example 4

50 Parts of a K 52 copolymer of 30% by weight of N-vinylpyrrolidone and 70% by weight of vinyl acetate and 50 parts of theophylline were mixed and extruded in a twin-screw extruder. The temperature of the five shots was 30, 60, 100, 100 and 120 ° C. The nozzle was also heated to 120 ° C. The still plastic strand was pressed as in Example 3 to form mechanically stable oblong tablets. The active ingredient was released completely within 8 hours.

Example 5

47.5 parts of a copolymer with a K value of 30 consisting of 60% by weight of N-vinylpyrrolidone and 40% by weight of vinyl acetate, 2.5 parts of stearyl alcohol and 50 parts of theophylline were melted in an injection molding machine at 100 ° C. and processed to dragee cores. The mold was left at room temperature. The tablet cores thus produced were stable against mechanical influences. The active ingredient was released completely within 6 hours.

For Examples 6 to 11, a mixture of 50% by weight of an NVP homopolymer (PVP) with a K value according to Fikentscher 12 to 60 and 50% by weight of theophylline was processed in a single-screw extruder at the following temperatures:<tables id="tabl0001" num="0001"><img file="EP0240904B1_D0001.tif" /></tables>

In Examples 6 and 7, the active ingredient (in artificial gastric juice) dissolved from the tablets thus obtained within less than 30 minutes. completely, in Examples 8 and 9 within 1 to 2 hours, in Example 10 after more than 2 hours. In Example 11, the PVP contained 10% by weight of stearyl alcohol. In this case the release time was 8 hours.

Examples 12 to 14

36 Parts of a copolymer of K value 30 from 60% by weight of N-vinylpyrrolidone and 40% by weight of vinyl acetate, 4 parts of stearyl alcohol, 40 parts of theophylline and 20 parts Example 12: Starch Example 13: Lactose Example 14: Sucrose were mixed in a 6-shot twin-screw extruder and shaped into tablets as in Example 1. The temperature of the shots was 90, 100, 110, 120, 130, 130 ° C, that of the nozzle 135 ° C. The active ingredient dissolved completely from the tablets within 6 hours.

Example 15

50 Parts of the copolymer of Examples 12 to 14 and 50 parts of lithium carbonate were processed on the same device and at the same temperatures as in Examples 12 to 14 into tablets which released the active ingredient (in artificial gastric juice) completely within 15 to 20 minutes.

Example 16

50 Parts of the copolymer of Examples 12 to 14 and 50 parts of verapamil were shaped into tablets according to Examples 12 to 14. The drug release time here was about 3 hours.

The copolymers used to prepare solid solutions had the following compositions and K values:<ul id="ul0001" list-style="none"><li>A) 60% by weight NVP and 40% vinyl acetate; K value approx. 33.</li><li>B) 100% by weight NVP; K value 30.</li><li>C) 100% by weight NVP; K value 12.</li><li>D) 100% by weight NVP; K value 17.</li></ul>

The polymers B, C and D were prepared in accordance with the German patent application P 36 42 633.4 in water with an organic peroxide as a starter.

Example 17

3rd Parts of copolymer A and 1.5 parts of benzocaine were premixed in a ploughshare mixer and extruded in a simple, 6-shot extruder at the following temperatures in the individual shots, counted towards the nozzle: 30, 30, 40, 50, 60, 70 ° C. The nozzle temperature was also 70 ° C. The extrudate consisted of a solid solution, as shown by the Debye-Scherrer photograph, which did not contain the slightest indication of crystallinity. The same procedure was followed for the other examples (table) in an analogous manner.<tables id="tabl0002" num="0002"><img file="EP0240904B1_D0002.tif" /></tables><tables id="tabl0003" num="0003"><img file="EP0240904B1_D0003.tif" /></tables>

Example 50

Examples 18, 19 and 20 were repeated on an injection molding machine with a nozzle temperature of 130.degree. Tablets consisting of solid solutions were obtained.

Example 51

Vitamin C as an active ingredient was mixed in a weight ratio of 1: 1 with the following NVP polymers in a twin-screw extruder and extruded at the temperatures indicated in the table in sections 1 to 6 and the nozzle and added according to German parallel application P 36 12 211.4 via a calender Tablets shaped.<ul id="ul0002" list-style="none"><li>a) copolymer of 60% by weight of NVP and 40% by weight of vinyl acetate; K value approx. 33.</li><li>b) 90% by weight of copolymer according to (a) and 10% by weight stearyl alcohol.</li><li>c) homopolymer of NVP; K value 17.</li></ul><tables id="tabl0004" num="0004"><img file="EP0240904B1_D0004.tif" /></tables>

In all three cases, the vitamin was released in water within 1 to 2 hours. In the processing described, it remained 100% intact and was protected in this form against the effects of light and atmospheric oxygen during prolonged storage.