Multi-particulate form of medicament, comprising at least two differently coated forms of pellet

ES 2 298 236 T3

DESCRIPTION

Multi-particle drug form, containing at least two differently coated granule forms.

The invention relates to a multi-particle drug form, which contains at least two differently coated granule forms, and enables widely uniform release throughout the entire region of the intestines. The invention further relates to a process for the production of the multi-particle drug form, as well as to the use of granule forms A and B for the production of the drug form.

State of the art

Multiparticulate drug forms, which are obtained by compression of a binding agent with granules coated with gastric juice resistant (meth) -acrylate copolymers, containing an active substance, are known from the quotation of Beckert and collaborators (1996), "Compression of enteric-coated pellets to disintegrating tablets", International Journal of Pharmaceutics 143, pages 13 - 23.

Copolymers of (meth) acrylates, which contain monomers with quaternary ammonium groups, e.g. trimethylammonium chloride-methyl methacrylate, and their use for drug-retardant coatings, have been known for a long time (e.g. , from European patent application document EP-A 181,515 or from German patent document DE-PS 1,617,751). The treatment is carried out in an organic solution or as an aqueous dispersion, eg. by spraying onto drug cores, or else without solvents in the presence of fluidizing agents, by application in the melt (see EP-A 0.727.205).

Document EP-A 629,398 describes pharmaceutical formulations, which have a core with an active substance and with an organic acid, the core being enveloped by two layers. The inner shell is formed in this case by a retardant (meth) acrylate copolymer with quaternary ammonium groups (EUDRAGIT^® RS), while the outer shell contains a coating resistant to gastric juices, for example a copolymer of the EUDRAGIT type^® L30D-55 (from ethyl acrylate and methacrylic acid, 50:50). The achieved release characteristic can be described as a rapid, time-delayed release of the active substance at a high pH value.

European patent application document EP 0,704,207 A2 describes certain thermoplastic synthetic materials for drug casings soluble in intestinal juices. In this case, they are copolymers based on 16 to 40% by weight of acrylic or methacrylic acid, 30 to 80% by weight of methyl acrylate and 0 to 40% by weight of other alkyl esters of acrylic acid and / or methacrylic acid.

EP 0,704,208 A2 describes coating agents and binders for soluble drug casings in intestinal juices. These are copolymers based on 10 to 25% by weight of methacrylic acid, 40 to 70% by weight of methyl acrylate, and 20 to 40% by weight of methyl methacrylate. The specification, next to single layer coatings, mentions multi-layer coating systems. These can be composed of a core, which contains, for example, a basic active substance or a water-sensitive active substance, they have an insulating layer based on a different coating material, such as a cellulose ether, a cellulose ester or a cationic polymethacrylate, e.g. of the EUDRAGIT type^®, among others also the EUDRAGIT^® RS and RL, and then they are further provided with the envelope soluble in intestinal juices, which has been mentioned above.

Gupka et al. (27th International Symposium on Controlled Release of Bioactive Materials and 3rd Comsumer and Diversified Products conference, Proceedings Book 2000, pages 453-454 [27th International Symposium on the Controlled Release of Bioactive Materials and 3^to Diversified Products and Consumer Conference, Act Book 2000, pages 453-454]) describe a multi-particle drug form, containing 5-amino-salicylic acid, the particles of which contain an internal, pH-independent coating with Eudragit RL and RS, as well as a pH-dependent outer coating with Eudragit FS.

Multi-particle drug forms in the shape of compressed capsules or tablets are well known. It is also known to incorporate, in multi-particle drug forms, granules with different polymeric coatings, to thus arrive at combined release profiles.

Problem and solution

There is a need for drug forms, which release the active substances in the intestinal tract, and in this context meet special release profiles of the active substances.

A medicinal form had to be made available, which delivers almost nothing of the active substance to the stomach and makes possible the most uniform and long-lasting delivery of the active substance, both in the small intestine and also in the region of the large intestine. The drug form must e.g.

ES 2 298 236 T3 be suitable for the therapy of inflammatory bowel diseases, such as ulcerative colitis and in particular Crohn's disease.

The problem is solved by a multi-particle drug form, which is suitable for the uniform release of a pharmaceutical active substance in the small intestine and in the large intestine, containing at least two forms A and B of granules, which in the core they contain a pharmaceutical active substance and have different polymeric coatings, which determine the release of the active substance at different pH values, characterized in that the granule form A is provided with an internal polymeric coating, which enables a continuous release of the active substance, and has an external coating, resistant to gastric juices, which dissolves rapidly above a value of pH of about 5.5, and consisting of a (meth) acrylate copolymer based on 40 to 60% by weight of methacrylic acid and 60 to 40% by weight of methyl methacrylate or 60 to 40% or by weight of ethyl acrylate, or an HPMCP (hydroxypropyl methyl cellulose phthalate), and granule form B is provided with a polymeric coating, which in the release test according to USP (US Pharmacopeia), releases less than 20% of the active substance at a pH of 6.8 within 6 hours, and at a pH of 7.2 within 6 hours more than 50% of the active substance, the coating being Form B polymer granules a (meth) acrylate copolymer, which is composed of 60 to 95% by weight of C alkyl esters_x to C₄ of acrylic acid or of methacrylic acid, polymerized by radicals, and from 5 to 40% or by weight of monomers of (meth) acrylates with an acid group in the alkyl radical.

The invention further relates to a process for the production of a multi-particle drug form, in which the different forms A and B of granules are produced by coating nuclei containing active substances with the indicated polymeric coatings, they are mixed with each other. , and by filling into a capsule or by compression to form a tablet unit, in the presence of adjuvants, they transform into a multi-particle drug form.

The invention also relates to the use of granule forms A and B, which have been described in the claimed process for the production of a multi-particle drug form with a uniform delivery of the active substance in the pH range of 6 , 8 and 7.2, in a manner corresponding to the circumstances prevailing in the small and large intestines, in particular for the treatment of Crohn's disease or ulcerative colitis.

Realization of the invention

The multiparticulate drug form can be in the shape of a capsule filled with granules, for example a gelatin capsule, or it can be a tablet, in which the granules have been compressed together with conventional adjuvants for give the tablet unit.

The multi-particle drug form is suitable for the widely uniform release of a pharmaceutical active substance in the small intestine and in the large intestine, and contains at least two forms A and B of granules, which in the core contain a substance active ingredient, but they have different polymeric coatings, which determine the release of the active substance at different pH values. In vitro, mixed profiles are obtained in the release test according to USP (USP 23, method 2) at a pH of 6.8 and a pH of 7.2, which are located between the individual lay curves. in freedom of the two forms A and B of granules. In vivo, the release of granule form A predominates in the small intestine, whereas in the large intestine region the release of the active substance from granule form B is employed.

The granule cores are wholly or partially composed of a pharmaceutical active substance. The cores are generally spherical or round and have diameters in the range of about 0.3 to 2 mm. Polymeric coatings are in the range of about 2 to 16 mg of a polymer per cm² surface area of ​​the nuclei.

Granule Form A

Granule Form A is provided with an inner polymeric coating and an outer polymeric coating.

Internal polymeric coating

The internal polymeric coating enables a continuous release of the active substance, which is largely independent of pH. A release profile of the active substance is intended, in which case in the release test according to USP (USP 23, method 2) at a pH of 6.8 after 2 hours it has been put into freedom approximately 40 to 70%, preferably 40 to 60%, and after 4 hours 60 to 100%, preferably 80 to 100% of the active substance has been released. This is deduced from the average length of stay in the small intestine, which is approximately 4 hours.

The internal polymeric coating of granule form A can be composed of a (meth) acrylate copolymer, based on alkyl esters from Q to C₄ of acrylic acid or of methacrylic acid, polymerized by radicals, and of monomers of (meth) acrylates with a quaternary ammonium group in the alkyl radical.

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Corresponding copolymers of (meth) acrylates are known, for example, from EP-A 181,515 or DE-PS 1,617,751. These are polymers that are soluble or swellable in a manner independent of the pH value, which are suitable for forming drug coatings. As a possible production process, mention should be made of the polymerization in substance in the presence of a radical-forming initiating agent, which is dissolved in the monomer mixture. Also, the polymer can be prepared by solution or precipitation polymerization. The polymer can thus be obtained in the form of a fine powder, which can be achieved, in the case of bulk polymerization, by grinding, and in the case of solution and precipitation polymerizations, e.g. by spray drying.

The (meth) acrylate copolymer is composed of 85 to 98% by weight of radical polymerized C1 to C4 alkyl esters of acrylic acid or methacrylic acid, and 15 to 2% by weight of (meth) monomers acrylates with a quaternary ammonium group on the alkyl radical.

Preferred C1 to C4 alkyl esters of methacrylic acid or methacrylic acid are methyl acrylate, ethyl acrylate, butyl acrylate, butyl methacrylate, and methyl methacrylate.

As (meth) acrylate monomer with quaternary ammonium groups, methyl 2-trimethylammonium methacrylate chloride is particularly preferred.

Another suitable (meth) acrylate copolymer can be constituted, for example, from 85 to less than 93% by weight of C1 to C4 alkyl esters of acrylic acid or methacrylic acid, and from more than 7 to 15% by weight of (meth) acrylate monomers with a quaternary ammonium group on the alkyl radical. Such (meth) acrylate monomers are commercially common and have long been used for retardant coatings (of the EUDRAGIT® RL type).

A suitable copolymer in particular contains, for example, 60% by weight of methyl methacrylate, 30% by weight of ethyl acrylate and 10% by weight of 2-trimethylammonium chloride-methyl methacrylate (EUDRAGIT^® RL).

The desired release profile can be achieved eg by the coating layer thickness of polymeric coatings of the "EUDRAGIT® RL type" described above. This is achieved, for example, in the case of a coating containing 5 to 15% EUDRAGIT^® RL, on cores containing active substances, with a diameter of 0.8 to 1.2 mm. The desired release characteristic can also be achieved, in the cases of other layer thicknesses, by adding a copolymer, based on 50-70% by weight of methyl methacrylate, of 20-40% by weight of ethyl acrylate and 7-2% by weight of methyl 2-trimethylammonium methacrylate chloride ("of the EUDRAGIT® RS type"). A particular suitable copolymer may be 65% by weight of methyl methacrylate, 30% by weight of ethyl acrylate and 5% by weight of 2-trimethylammonium chloride-methyl methacrylate (EUDRAGIT® RS). The EUDRAGIT® RL and RS types can be mixed eg in the ratios of 10 by 1 to 1 by 10. Higher proportions of the "EUDRAGIT® RL type" are preferred, eg 60 to 90% in weight, in the mix.

The internal polymeric coating can also be composed of a (meth) acrylate copolymer based on 20 to 40% by weight of ethyl acrylate and 60 to 80% by weight of methyl methacrylate, ethylcellulose or a poly (acetate). vinyl).

External polymeric coating

The outer polymeric coating is a gastric juice resistant coating that dissolves rapidly just above a pH of about 5.5. The coating must therefore largely prevent a release of the active substance in the stomach, that is to say that the stomach, according to USP 23, should be at most 10, preferably only 5%. As it passes into the small intestine, the outer polymeric coating must dissolve rapidly, so the release characteristic is determined from this point on by the inner polymeric coating.

If the outer polymeric coating is too thin, too much of the active substance will already be released in the stomach. If the outer polymeric coating is applied too thickly, it will prevent the immediate release of the active substance in the small intestine. Suitable layer thicknesses are, for example, in the range 15 to 150 pm, preferably, for example, 20 to 60 pm. Based on the weight of the core with a diameter of 0.8 to 1.25 mm, which is provided with the internal polymeric coating, as a rule an applied amount of the polymer (based on the dry substance) in the range of 8 to 40% by weight, preferably 10 to 25% by weight.

The gastric juice resistant polymeric coating of granule form A can be composed of copolymers of (meth) acrylates based on 40 to 60% by weight of methacrylic acid and 60 to 40% by weight of methyl methacrylate or of 60 to 40% by weight of ethyl acrylate (of the EUDRAGIT types ^® L or EUDRAGIT^® L100-55).

The gastric juice resistant polymeric coating of granule form A may be composed of a HPMCP (hydroxypropyl methyl cellulose phthalate).

ES 2 298 236 T3

In any case, care must be taken that the coating adjusts, for example with regard to the layer thickness and possibly to the mixing with other different polymers, in such a way that it dissolves quickly after having passed into the small intestine.

Form B granules

Granule form B releases at pH 6.8, in the release test according to USP (USP 23, method 2), after 2 hours, no more than 10%, preferably not more than 5%, and after 4 hours not more than 20%, preferably not more than 10%, of the active substance. At a pH of 7.2, approximately 40 to 60%, and after 60 hours approximately 80 to 100%, of the active substance are released after 3 hours.

The polymeric coating for granule form B is a (meth) acrylate copolymer, which is composed of 60 to 95% by weight of Ci to C alkyl esters₄ of acrylic acid or of methacrylic acid, polymerized by radicals, and from 5 to 40% by weight of monomers of (meth) acrylates with an acid group in the alkyl radical.

Copolymers of (meth) acrylates, which consist of 10 to 30% by weight of methyl methacrylate, 50 to 70% by weight of methyl acrylate and 5 to 15% by weight of methacrylic acid ( of the EUDRAGIT® FS type).

Also suitable are copolymers of (meth) acrylates based on 20 to 40% by weight of methacrylic acid and 80 to 60% by weight of methyl methacrylate (of the EUDRAGIT type^® S).

The granule form B is preferably provided with only a polymeric coating, but when the release profile in the large intestine is to be modified, it can also be provided, as well as the granule form A, additionally with a polymeric coating. internal, which conditions a release, largely continuous and independent of the pH, of the active substance. This may be appropriate when it is necessary to prolong the release of the active substance in the large intestine (the colon) to 6 to 12 or up to 24 hours.

Active substances

The formulation according to the invention is suitable for the administration of a large number of pharmaceutical active substances, which must be released in the small and large intestines, and in particular of the active substances that can advantageously be administered in one form. delayed, such as antidiabetic, analgesic, antiphlogistic, antirheumatic, antihypotonic, antihypertonic, psychotropic, tranquilizer, antiemetic, muscle relaxants, glucocorticoids, agents for the treatment of ulcerative colitis or Crohn's disease, antiallergics, antibiotics, antiepileptics, anticoagulants, antifungals, antitussives, agents for arteriosclerosis, diuretics, proteins, peptides, enzymes, enzyme inhibitors, agents for the treatment of gout, hormones and their inhibitory substances, cardiac glycosides, immunotherapeutic agents and cytokines, laxatives, hypolipidemic agents, anti-migraine agents, formulations of mineral substances, otological agents, agents against Parkinson's disease, therapeutic agents for the thyroid gland, spasmolytics, inhibitors of the aggregation of thrombocytes, vitamins, cytostatics and inhibitors of metastasis, phytopharmaceuticals, chemotherapeutic agents and amino acids.

Examples of active substances that come into question are acarbose, antigens, beta receptor blockers, non-steroidal antirheumatic agents, cardiac glycosides, acetylsalicylic acid, virustatic agents, aclarubicin, acyclovir, cisplatin, actinomycin, alpha- and beta-sympathomimetic agents, (omeprazole , allopurinol, alprostadil, prostaglandins, amantadine, ambroxol, amlodipine, methotrexate, S-amino-salicylic acid, amitriptyline, amoxicillin, anastrozole, atenolol, azathioprine, balsalazide, beclomethasone, betahistine, bezafibrate, bicalutamide, diazepam and derivatives of diazepam, budesonide, bufexamac, buprenorphine, methadone, calcium salts, potassium salts, magnesium salts, candesartan, carbamazepine, captopril, kethnodeoxyzporin, cethopric acid, cephanodeoxyzporin, ursodeoxycholic, theophylline and theophylline derivatives, trypsins, cimetidine, clarithromycin, clavulanic acid, clindamycin, clobutinol, clonidine, cotrimoxazole, codeine, caffeine, vitamin D and derivatives of vitamin D, cholestyramine, chromoglycic acid, coumarin and derivatives of coumarin, cysteine, cytarabine, cyclophosphamide, cyclosporine, cyproterone, cytarabine, dapiprazole, desogestrel, desonide, dihydralazine, diltiazem, ergot alkaloids, dimethyl sulfoxide, dimethyl sulfoxide, dimethyl sodium sulfoxide, dimethyl sulfoxide, dimethyl sulfoxide , dipyridamole, domperidone and derivatives of domperidone, dopamine, doxazosin, doxorubizine, doxylamine, dapiprazole, benzodiazepines, diclofenac, glycoside antibiotics, desipramine, econazole, ACE inhibitors, enalapril, ephedrine, epinephrine, epoetin and epoetin derivatives, morphinan, calcium antagonists, irinotecan, modafinil, orlistat, peptide antibiotics, phenytoin, riluzole, risedronate, sildenafil, topiramate, macrolide antibiotics, estrogens and derivatives of estrogens, gestagens and gestagen derivatives, testosterone and testosterone derivatives, androgens and androgen derivatives, etenzamide, etofenamate, etofibrate, fenofibrate, etofilina, etoposide, famciclovir, famotidine, felodipine, fenofibrate, fentanyl, fenticonazole, gyrase inhibitors, fluconazole, fludarabine, flunarizine, fluorouracil, fluoxetine, flurbiprofen, ibuprofen, flutamide, fluvastatin, follitropicide, gallopamine, phosphoxylamine, fossilropic acid, , gemfibrozil, gentamicin, ginkgo, hypericon or St. John's wort, glibenclamide, urea derivatives as oral antidiabetics, glucagon, glucosamine and glucosamine derivatives, glutathione, glycerol and glycerol derivatives, hypothalamic hormones, goserelin, gyrase inhibitors, guanethidine, halofantrin, haloperidol, heparin and derivatives of heparin, hyaluronic acid, hydralazine, hydrochlorothiazide and derivatives of hydrochlorothiazide, hydrochlorothiazide, ifhydrochlorothiazide, hydrochlorothiazide, ifyridine iodine derivatives, hydrochlorothiazide, salizine-iodine derivatives, hydrochlorothiazide, salizinicylates , indomethacin, indoramine,

ES 2 298 236 T3 insulin, interferons, iodine and iodine derivatives, isoconazole, isoprenaline, glucitol and glucitol derivatives, itraconazole, ketoconazole, ketoprofen, ketotifen, lacidipine, lansoprazole, levodopa, levomethadone, thyroid gland hormones, liponic acid derivatives of liponic acid, lisinopril, lisuride, lofepramine, lomustine, loperamide, loratadine, maprotiline, mebendazole, mebeverine, meclozine, mefenamic acid, mefloquine, meloxicam, mepindolol, mepromabate, meropenem, Mesalazine, Mesuximide, Metamizole, Metformin, Methotrexate, Methylphenidate, Methylprednisolone, Metixen, Metoclopramide, Metoprolol, Metronidazole, Mianserin, Miconazole, Minocycline, Minoxidil, Misoprostol, Mitomycin, Mizolastine, Moexiphon, Morphonafalin, Morfaloxipril, N derivatives of Morfaloxiprillin tilidine, naproxen, narcotine, natamycin, neostigmine, nicergoline, nicetamide, nifedipine, niflumic acid, nimodipine, nimorazole, nimustine, nisoldipine, adrenaline and adrenaline derivatives, norfloxacin, novaminsulfone, noscapine, nystatin, ofloxacin, olanzapine, olsalazin, omeprazole, omoconazole, ondansetron, oxaceprole, oxacillin, oxy-nazole, oxymetazoline, pantoprazole, acetaminophen, paroxetine, pencyclovir, pentiphilin, pentifilin, pencillin, oxyclovir, pentiphilin, penicillin, oxyclovir from plants, phenazone, pheniramine, barbituric acid derivatives, phenylbutazone, phenytoin, pimozide, pindolol, piperazine, piracetam, pirenzepine, piribedil, piroxicam, pramipexole, pravastatin, prazosin, procaine, promazine, propiverine, propranolol, propiphenazone, prostaglandins, prothionamide, proxyphylline, quetiapine, quinapril, quinaprilat, ramipril, ranitidine, reproterol, reserpine, ribavirin, rifampin, ropyruscovirin, ritidonazin, ropyruscovirperin, ritidonazin, ropyruscovirin, ritidynicin, ropyruscovir rutoside and rutoside derivatives, sabadilla, salbutamol, salmeterol, scopolamine, selegiline, sertaconazole, sertindole, sertralion, silicates, sildenafil, simvastatin, sitosterin, sotalol, spaglumic acid, sparfloxacin, spectinomycin, spiramycin, spirapril, spironolactone, stavudine, streptomycin, sucralfate, sufentanil, sulbactam, sulfonamides, sulfasalazine, sulpiride, sultamicillin, sultiam, sumatriptan, tacrifolidine, tamusenolide chloride, sumatriptan, tamusenolide , tazarotene, temazepam, teniposide, tenoxicam, terazosin, terbinafine, terbutaline, terfenadine, terlipressin, tertatolol, tetracyclines, tetrizoline, theobromine, theophylline, Butizin, thiamazole, phenothiazines, thiotepa, tiagabine, tiapride, propionic acid derivatives, ticlopidine, timolol, tinidazole, thioconazole, thioguanine, thioxolone, thyropramide, tizanidine, tolazoline, tolbutamide, tolcapone, topotecanol, tolisnaphrogens , tramazoline, trandolapril, tranylcypromine, trapidil, trazodone, triamcinolone and derivatives of triamcinolone, triamterene, trifluperidol, trifluridine, trimethoprim, trimipramine, tripelennamine, tripolidine, triphosphamide, tromantadine, tromethamine, tropalpin, troxerutin, tulobuterol, tyramine, thyrothricin, urapidil, ursodeoxycholic acid, chenodeoxycholic acid, valacyclovir, valproic acid, vancomycin, vecuronium chloride, vida, viagra, venblastiligabaxin, virapidyl , vincamine, vincristine, vindesine, vinorelbine, vinpocetine, viquidil, warfarin, xanthinol nicotinate, xipamide, zafirlukast, zalcitabine, zidovudine, zolmitriptan, zolpidem, zoplicone, zotepine and the like.

The active substances can be used if desired also in the form of their pharmaceutically acceptable salts or derivatives, in the case of chiral active substances both optically active isomers and also racemates or mixtures of diastereoisomers can be used. If desired, the compositions according to the invention can also contain two or more pharmaceutical active substances.

As active substances, which are suitable for the therapy of ulcerative colitis and Crohn's disease, mention should be made in particular of those which must be released as constantly as possible in the intestine, in particular shortly before, or only in the region of the large intestine. The pharmaceutical active substance can be an aminosalicylate, a sulfonamide or a glucocorticoid, in particular 5-amino-salicylic acid, olsalazine, sulfalazine, prednisone or budesonide are to be mentioned.

The table below lists active substances suitable for the therapy of ulcerative colitis and Crohn's disease.

Active substances for the therapy of ulcerative colitis

Mesalazine

Sulfasalazine

Betamethasone 21-hydrogen phosphate

21-hydrocortisone acetate

Chromoglycic acid

Dexamethasone

Olsalazine-Na

Budesonide

Bismuth nitrate, karaya gum

Methylprednisolone 21-hydrogensuccinate

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Prednisone

Myrrh, coffee charcoal, chamomile flower extract

A 10% suspension of human placenta.

Other suitable active substances

Balsalazide

Orally administered peptides (eg RDP 58)

Interleukin 6

Interleukin 12

Ilodecacin (interleukin 10)

Nicotine tartrate

Conjugated with 5-ASA (CPR 2015)

Monoclonal antibodies against interleukin 12

Diethyl-dihydroxy-homospermine (DEHOHO)

Diethyl homospermine (DEHOP)

Cholecystokinin (CCK) antagonist (CR 1795)

Fragment with 15 amino acids of a 40 kd peptide from gastric juice (BPC 15)

Glucocorticoid analog (CBP 1011)

Natalizumab

Infliximab (REMICADE)

N-deacetylated lysoglycosphingolipid (WILD 20)

Azelastine

Tranilast

Sudismasa

Antisense oligonucleotide phosphorothioate (ISIS 2302)

Tazofelone

Ropivacaine

5-lipoxygenase inhibitor (A 69412)

Sucralfate

Forms of application

The drug form (for oral use) described can be presented as a tablet based on compressed granules or in the form of granules, which are packed inside a capsule, eg based on gelatin, starch or cellulose derivatives.

Usual pharmaceutical adjuvants

In the production of the drug form it is possible to use, in a manner known per se, pharmaceutically customary auxiliary substances. These builders can be contained in the core or in the coating agent.

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Dryness adjusting agents (anti-adhesive agents)

Dryness adjusting agents have the following properties: they have large specific surfaces, are chemically inert, are well capable of bleeding, and are finely divided. Because of these properties, they decrease the tack of polymers, which as functional groups contain polar comonomers.

Examples of dryness adjusting agents are:

Aluminum oxide, magnesium oxide, kaolin, talc, silicic acid (Aerosiles), barium sulfate and cellulose.

Separating agents

Examples of parting agents are:

Fatty acid esters or fatty acid amides, long chain aliphatic carboxylic acids, fatty alcohols as well as their esters, montanic or paraffin waxes and metal soaps; Glycerol monostearate, stearyl alcohol, behenic acid esters of glycerol, cetyl alcohol, palmitic acid, carnauba wax, beeswax, etc. are to be mentioned in particular. The customary quantitative proportions are in the range from 0.05% by weight to 5%, preferably 0.1 to 3% by weight, based on the copolymer.

Other common pharmaceutical adjuvants

In this context, for example, stabilizers, colorants, antioxidants, wetting agents, pigments, gloss agents, etc. are to be mentioned. They serve primarily as processing aids and must be able to guarantee a safe and reproducible production process as well as good long-term storage stability. Other customary pharmaceutical adjuvants can be present in amounts of 0.001% by weight to 100% by weight, preferably 0.1 to 10% by weight, based on the polymeric coating.

Plasticizers: Substances suitable as plasticizers generally have a molecular weight of between 100 and 20,000 and contain one or more hydrophilic groups in the molecule, eg hydroxyl, ester or amino groups. Citrates, phthalates, sebacates and castor oil are suitable. Examples of suitable plasticizers are citric acid alkyl esters, glycerol esters, phthalic acid alkyl esters, sebacic acid alkyl esters, sucrose esters, sorbitan esters, dibutyl sebacate and polyethylene glycols from 4,000 to 20,000. Preferred plasticizers are tributyl citrate, triethyl citrate, acetyl triethyl citrate, dibutyl sebacate, and diethyl sebacate. The amounts used are between 1 and 35, preferably between 2 and 10%, by weight, based on the (meth) acrylate copolymer.

Granules containing an active substance

Granules containing an active substance can be prepared by applying an active substance through a layering process. For this, the active substance is homogenized together with other auxiliary substances (separating agents and possibly plasticizers) and is dissolved or suspended in a binder (eg EUDRAGIT L 30 D-55). By means of a fluidized (turbulent) bed process, the liquid can be applied on granules of a placebo or other suitable support or vehicle materials, the solvent or suspending agent being evaporated (bibliography: International Journal of Pharmaceutics 143, pages 13-23). After the production process, a drying stage can follow. The active substance can be applied in several layers.

Alternatively, granules containing an active substance can be produced by means of an extrusion and spheronization process. This can be done eg. as follows: lactose (20%) and an active substance (80%; mesalazine = 5-ASA) were mixed in a high speed mixer (High Speed ​​Mixer, DIOSNA type P10, Osnabrück, Germany) and added in small quantities an aqueous solution containing the adjuvant Kollidon 25, until a homogeneous mass had been obtained. The wet powder mixture was sieved. Granules were then formed from these with the aid of a Spheronizer type 15 spheronizer (from Caleva, Ascot, UK).

Coating with the FS polymer was carried out in a Glatt coater (type WSG5 or GPCG1, Glatt GmbH, Binzen / Lorrach, Germany). A 20% coat (based on dry weight) was applied to the granules with the top spray method (in English Top Spray) in a manner which was per se usual.

Certain active substances, eg acetylsalicylic acid, are commercially available in the form of active substance crystals and can be used in this form instead of granules containing an active substance.

Film coatings on granules containing active substances are usually applied in fluidized bed apparatus. Examples of recipes are mentioned in this application. Film-forming agents are usually mixed with plasticizers and release agents, according to an appropriate procedure. In this case, the film-forming agents can be presented as a solution or suspension. The film-forming aids can also be dissolved or suspended. Solvents can be used

ES 2 298 236 T3 or organic or aqueous dispersants. For stabilization of the dispersion, additional stabilizing agents can be used (Example: Tween 80 or other appropriate emulsifying agents and respectively stabilizers).

Examples of parting agents are glycerol monostearate or other suitable derivatives of fatty acids, derivatives of silicic acids or talc. Examples of plasticizers are propylene glycol, phthalates, polyethylene glycols, sebacates or citrates, as well as other substances mentioned in the literature.

General conditions for release tests (eg USP 23): pH 1.2: simulated gastric juice without pepsin (SGF-sp), pH 6.8 and pH 7.2: phosphate buffer according to DAB ( German Pharmacopoeia) 10. ERWEKA apparatus type DT 80 (flat blades = English paddle); 900 ml of an assay medium at 37 ° C, 100 rpm. The tests were carried out in each case in triplicate.

Production of multi-particle drug forms

The production of the multi-particle drug form is carried out by mixing the different forms A and B of granules, depending on the amount of active substance contained, in the 1: 1 ratio or in a different ratio, filled into a capsule or by compression to form a tablet unit in the presence of adjuvants in the multi-particle drug form.

The production of multi-particle drug forms by compressing a conventional pharmaceutically binding agent with particles containing an active substance is described in detail, eg. in the quote by Beckert et al., (1996), "Compression of enteric-coated pellets to disintegrating tablets", International Journal of Pharmaceutics 143, pages 13-23, and in the document International patent application WO 96/01624.

The mixtures for the production of tablets from coated particles are formulated by mixing the granules with binding agents suitable for the formation of tablets, if necessary by the addition of substances promoting disintegration and if necessary the addition of agents lubricants. The mixing can take place in suitable machines. Mixers that lead to damage to the coated particles are unsuitable, eg. plowshare mixers. In order to achieve appropriate and short disintegration times, a special order of succession may be necessary when adding the adjuvants to the coated particles. By pre-mixing with the particles coated with the lubricating or separating agent from the magnesium stearate (demoulding) molds, the surface of magnesium stearate can be made waterproof and therefore sticking and sticking are avoided.

Suitable tabletting mixtures usually contain 3 to 15% by weight of a disintegration aid, eg Kollidon CL, and eg 0.1 to 1% by weight of a lubricating agent. and mold release such as magnesium stearate. The proportion of the binding agent is determined depending on the requested proportion of coated particles.

Typical examples are eg Cellactose®, microcrystalline cellulose, calcium phosphates, Ludipress®, lactose or other suitable sugars, calcium sulfates or starch derivatives. Substances with a low bulk density are preferred.

Typical disintegration aids (disintegrating agents) are crosslinked derivatives of starches or cellulose as well as a crosslinked polyvinylpyrrolidone. Likewise, certain cellulose derivatives are suitable. By choosing a suitable binding agent, the use of disintegration aids can be dispensed with.

Typical lubricating and mold release agents are magnesium stearates or other suitable fatty acid salts or substances reported in the literature for this purpose (eg lauric acid, calcium stearate, talc, etc.). In the case of the use of suitable machines (eg an externally lubricated tablet press) or of suitable formulations, the use of a lubricating and mold release agent can be omitted.

Optionally, an auxiliary agent for improving flowability (eg highly dispersed derivatives of silicic acids, talc, etc.) may optionally have been added to the mixture.

Tableting can be carried out in conventional rotary or eccentric tableting presses with compression forces in the range of 5 to 40 kN, preferably 10-20 kN. Tablet presses can be provided with systems for external lubrication. Eventually, special systems are used to fill matrices, which avoid the filling of matrices by means of stirring blades.

By the amount applied is meant the proportion of the spray applied dry substance of the functional film-forming polymer, in% by weight. It is greater than 15 to 38, particularly preferably 18 to 36, in particular 20 to 30,% by weight, based on the weight of the particles.

By the proportion of the particles is meant the proportion by weight of the coated particles in the total weight of the drug form, of the compressed tablets, in% by weight. The proportion of the particles of the form

ES 2 298 236 T3 drug is 35-90, particularly preferably 40 to 70% by weight. Particle ratios of 70 to 90% by weight can be achieved in particular when so-called soft cores are used instead of sugar granules.

Examples

Example 1

Form A granules, internal polymeric coating

Commercially available cores, containing the active substance 5-amino-salicylic acid, with a diameter in the range of 0.8 to 1.25 mm, are coated with a 12% coating based on a copolymer of 60% by weight of methyl methacrylate, 30% by weight of ethyl acrylate and 10% by weight of methyl 2-trimethylammoniomethacrylate chloride (EUDRAGIT^® RL).

For this, 200 g of a 30% dispersion of the copolymer (EUDRAGIT^® RL 30D) are added 30 g of talc, 12 g of triethyl citrate and 268 g of water (content of solids, 20.4 5). Coating of the cores is carried out in a fluidized bed apparatus (STREA 1, Aeromatic-Fielder AG, Bubendorf, Switzerland) with an arrangement of nozzles in the bottom spray mode [in English "Bottom Spray Mode"] and with a nozzle diameter of 0.8 nm and an atomization pressure of 1.4 to 1.5 bar. 500 g of the granules, inlet air temperature 32-36 ° C, outlet air temperature 25 - 30 ° C, atomization rate 2.4 g / min.

Example 2

Granule Form A, external polymeric coating

The coated cores from Example 1 are provided with an external polymeric coating based on a copolymer of (meth) acrylate based on 50% by weight of methacrylic acid and 50% by weight of ethyl acrylate (EUDRAGIT® L100-55 or respectively a dispersion of EUDRAGIT® L 30 D-55).

For this, to 166 g of a 30% dispersion of the aforementioned copolymer (EUDRAGIT® L30D-55), 25 g of talc, 5 g of triethyl citrate and 204 g of water are added (solids content 20.4 %). Coating of the cores is carried out, as indicated in Example 1, in a fluidized bed apparatus. An applied quantity of polymer of 20% (dry substance of the polymer based on the coated granule) is sprayed on.

Example 3

Granule Form B

Granules containing an active substance are coated as in Example 1, but with a (meth) acrylate copolymer, which is composed of 25% by weight of methyl methacrylate, 65% by weight of methyl acrylate and 10% by weight of methyl acrylate. % by weight of methacrylic acid (EUDRAGIT® FS).

For this, to 166 g of a 30% dispersion of the aforementioned copolymer (EUDRAGIT® FS 30 D) are added 4 g of glycerol monostearate, 2 g of a Polysorbat 80.2.5 g of triethyl citrate and 185 g of water (content of solids of the atomized dispersion 20%). Coating of the cores is carried out as indicated in Example 1 in a fluidized bed apparatus. An applied quantity of polymer of 20% (dry substance of the polymer, based on the coated granule) is sprayed on.

Example 4

Recipe for a multi-particle drug form based on granule forms A and B according to Examples 2 and 3

Recipe for tablets

Form A of granules Form B of granules Cellactose

Kollidon CL

Magnesium stearate

250.0 g

250.0 g

417.5 g

80.0 g

2.5 g

The mixture can be directly compressed in a suitable tablet press by applying eg a compression force of 15 kN to form tablets.