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

Description of the invention

The present invention relates to a multiparticulate form of a drug containing at least two types of granules differently coated, allowing the active ingredient to be uniformly released inside the intestines. The invention further relates to the use of the multiparticulate drug in the treatment of Crohn's disease or ulcerative colitis.

State of the art

Multiparticulate drug forms obtained by compressing a binder with granules containing the active ingredient coated with gastric acid-resistant methacrylate copolymers are disclosed in Beckert et al. (1996), "Compression of enteric-coated pellets to disintegrating tablets, International Journal of Pharmaceutics 143, pp. 13-23.

Also known for a long time (e.g. from EP-A 181 515 and DE-PS 1 617 751) are methacrylate copolymers containing monomers with quaternary ammonium groups, e.g. trimethylammoniumethyl methacrylate chloride, and their use in the production of a drug shell that slows down the release of active substances. The treatment takes place in an organic solution or with an aqueous dispersion system, for example by spraying onto the surface of the drug core or without the use of a solvent in the presence of a flow enhancer by application in a melt (see EP-A 0 727 205). EP-A 629 398 describes pharmaceutical preparations comprising a core with an active ingredient and an organic acid, the core being coated with two layers. The inner layer is formed by a release-slowing methacrylate copolymer with quaternary ammonium groups (EUDRAGIT® RS), and the outer layer is made up of a substance resistant to gastric juice, for example a copolymer of the EUDRAGIT® L30D-55 type (ethyl acrylate / methacrylic acid, 50:50). The release characteristics are described by delayed, rapid release of the active ingredient under conditions of elevated pH.

EP 0 704 207 A2 describes thermoplastic materials used in the preparation of a drug shell that are soluble in intestinal juice. They are copolymers composed of 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 acrylic acid and / or methacrylic acid alkyl esters.

EP 0 704 208 A2 describes coating agents and binders for drug shells soluble in intestinal juice. They are copolymers composed of 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 description covers both single-layer and multi-layer casings. These can include a core which includes, for example, an alkaline or water-sensitive active ingredient; they have a sealing layer made of another coating material, such as cellulose ether or cellulose ester, or of a cationic polymethacrylate, for example of the EUDRAGIT® type, including but not limited to EUDRAGIT® RS and RL; moreover, they are provided with the gastric acid-soluble casing mentioned above.

In GUPTA VK et al .: Statistical optimization of a novel multi-unit colonic delivery system containing multiple coatings of aqueous polymethacrylates (27^th International Symposium on Controlled release of Bioactive Materials and 3th Conssumer and Diversified Products Conference, Proceedings Book 2000, Paris, France, July 7-13, 2000, Deerfield, IL: CRS, US, 7 July 2000 (2000-07-07), pages 453-454) describes a multiparticulate drug form containing 5-aminosalicylic acid, the particles of which have a pH-independent inner coating containing Eudragit® RL and RS, as well as a pH-independent outer coating containing Eudragit® FS.

Multiparticulate drug forms in the form of capsules or compressed tablets are known in the art. Another known solution envisages the use of granules with a casing made of different polymers in the multiparticulate drug forms in order to thus obtain different release profiles of active substances.

Object of the invention

There is a need for drug forms that release the active ingredients inside the intestine in accordance with defined release profiles of the active ingredients.

The object of the invention is to provide a dosage form which hardly releases the active ingredient in the stomach and which allows the active ingredient to be released as uniformly and long as possible both in the small intestine and in the large intestine. The drug form of this

The type finds application in the treatment of inflammatory bowel conditions such as ulcerative colitis and, in particular, Crohn's disease.

The above object has been achieved with a multiparticulate drug form containing at least two types of granules A and B for use in the process of uniform release of the pharmaceutical active ingredient in the small intestine and the large intestine, granules A and B containing the active pharmaceutical ingredient inside the core, provided with different casings on the inside of the core. based on a polymer, enabling the release of active ingredients at different pH values, characterized by that Form A of the granules has a polymer-based inner shell that allows continuous release of the active ingredient and a gastric juice-resistant outer shell that dissolves rapidly in an environment with a pH above about 5.5, consisting of a methacrylate copolymer, which is 40-60% by weight methacrylic acid and 60-40% by weight methyl methacrylate or 60-40% by weight ethyl acrylate or HPMCP (hydroxypropylmethylcellulose phthalate) and form B of the granules has a polymer-based shell which during the USP release test within 6 hours it allows the release of less than 20% of the active ingredient in an environment with a pH of 6.8 and the release of more than 50% of the active ingredient in an environment with a pH of 7.2, wherein the polymeric shell of the form B granules is a methacrylate copolymer composed of 60 to 95% by weight of the radical polymerized C1 to C4 alkyl esters of acrylic acid or methacrylic acid and 5 to 40% by weight of methacrylate monomers with an acid group in the alkyl radical.

The inner shell based on the polymer of granules A is preferably made of a methacrylate copolymer, radical polymerization of C1 to C4 alkyl esters and / or methacrylic acid and methacrylate monomers with a quaternary ammonium group in the alkyl radical, the methacrylate copolymer being 40% by weight of ethyl acrylate and 60 to 80% by weight of methyl methacrylate, ethyl cellulose or polyvinyl acetate.

More preferably, for the inner casing based on the polymer of granules A, a methacrylate copolymer is used which comprises 85 to less than 93% by weight of C1 to C4 alkyl esters of acrylic acid or methacrylic acid and more than 7 to 15% by weight of methacrylate monomers with a quaternary ammonium group in an alkyl radical.

For the casing based on the polymer of granules B, a methacrylate copolymer is preferably used which comprises 10 to 30% by weight methyl methacrylate, 50 to 70% by weight methyl acrylate and 5 to 15% by weight methacrylic acid.

More preferably, granules B are additionally provided with an inner polymer-based shell, which allows a continuous release of the active ingredient.

Preferably, the active pharmaceutical ingredient is an aminosalicylate, sulfonamide, hormone, peptide, interferon or glucocorticoid.

It is also preferred that the active pharmaceutical ingredient is 5-aminosalicylic acid, olsalazine, sulfalazine, prednisone or budesonide.

Preferably, the multiparticulate form of the drug allows the active ingredient to be evenly released in an environment with a pH in the range of 6.8-7.2, which corresponds to the conditions prevailing in the small and large intestines.

The multiparticulate form of the drug as defined above finds use in the treatment of Crohn's disease or ulcerative colitis.

The multiparticulate form of the drug is produced by a process in which different types of granules A and B are produced by coating the cores containing the active ingredient with polymer-based shells, which are then mixed together and then encapsulated or pressed into a tablet in the presence of the substance. auxiliaries, thereby creating a multiparticulate form of the drug.

The multiparticulate drug form may be a capsule filled with granules, for example a gelatin capsule, or a tablet in which the granules have been pressed together using conventional excipients.

The multiparticulate form of the drug finds application in the case of substantially uniform release of the active pharmaceutical ingredient in the small intestine and in the large intestine. It comprises at least two types of granules, A and B, containing a pharmaceutical active ingredient in their core and having different polymer-based shells allowing the active ingredient to be released at different pH. In vitro, during the USP release test (USP 23, method 2) at a pH of 6.8 and 7.2, mixed profiles are obtained, which are the resultant of the release curves for both types of granules A and B. In vivo, the profile

The release form for granule A roughly describes the environment of the small intestine, while the release of the active ingredient from granules B begins within the large intestine.

The core of the granule is wholly or partially a pharmaceutical active ingredient. As a rule, the cores have a spherical shape with a diameter of about 0.3 to 2 mm. The weight of the polymer-based shell is from about 2 to 16 mg per cm² core surface.

Granule type A

Granules A were provided with a polymer-based inner shell and a polymer-based outer shell.

Polymer based inner sheath

The polymer-based inner shell allows the active ingredient to be released continuously, substantially independent of the surrounding pH. Ultimately, the release profile of the active ingredient for the USP release test (USP 23, method 2) allows release under pH conditions of 6.8 within 2 hours about 40 to 70% of the active ingredient, preferably 40 to 60%, and within 4 hours. hours 60 to 100% and preferably 80 to 100%. This corresponds to the average residence time in the small intestine of approximately 4 hours.

The inner polymer-based shell of granules A may be made of methacrylate copolymer, radical polymerized C1 to C4 alkyl esters and / or methacrylic acid, and methacrylate monomers with a quaternary ammonium group in the alkyl radical.

Suitable methacrylate copolymers are known, for example, from EP-A 181 515 or DE-PS 1 617 751. These are polymers which dissolve or bulge irrespective of the ambient pH value and which are used in the preparation of pharmaceutical casings. A suitable method of preparation is block polymerization in the presence of a free-radical initiator dissolved in the monomer mixture. It is also possible to produce the polymer by a solution polymerization or slurry polymerization process. In this way, the polymer can be obtained in a powdered form, which is carried out by grinding in the case of block polymerization, and in the case of solution or sediment polymerization, for example, by spray drying.

The composition of the methacrylate copolymer comprises 85 to 98% by weight of the radical polymerized C1 to C4 alkyl esters of acrylic acid or methacrylic acid and 15 to 2% by weight of methacrylate monomers with a quaternary ammonium group in the alkyl radical.

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

2-trimethylammoniumethyl methacrylate chloride is particularly preferably used as the methacrylate monomer with quaternary ammonium groups.

A further methacrylate copolymer which may be used includes, for example, 85 to less than 93% by weight of C1 to C4 alkyl esters of acrylic acid or methacrylic acid and more than 7 to 15% by weight of methacrylate monomers with a quaternary ammonium group in the alkyl radical. These types of methacrylate monomers have been commercially available and have long been used in the production of casings that slow the release of active ingredients (EUDRAGIT® RL type).

A particularly preferred copolymer contains, for example, 60% by weight of methyl methacrylate, 30% by weight of ethyl acrylate and 10% by weight of 2-trimethylammoniumethyl methacrylate chloride (EUDRAGIT® RL).

Advantageous properties for the release of the active ingredient can be obtained, for example, by using a shell based on a polymer of the type "EUDRAGIT® RL described above, with a suitable thickness. This includes, for example, a 5 to 15% layer made of EUDRAGIT® RL covering a core containing an active ingredient with a diameter of 0.8 to 1.2 mm. The desired release properties of the active ingredient can also be obtained in the case of layers of different thickness by admixing a copolymer, which consists of 50-70% by weight of methyl methacrylate, 20-40% by weight of ethyl acrylate and 7-2% by weight of 2-trimethylammoniumethyl methacrylate chloride (EUDRAGIT® type) RS). A particularly preferred copolymer comprises 65% by weight of methyl methacrylate, 30% by weight of ethyl acrylate and 5% by weight of 2-trimethylamonoethyl methacrylate chloride (EUDRAGIT® RS). EUDRAGIT® RL and RS can, for example, be mixed in a ratio of 10 to 1 to 1 to 10. Preferred solutions provide for a higher content of EUDRAGIT® RL, for example 60 to 90% by weight of the mixture.

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The polymer-based inner shell may also include a methacrylate copolymer that includes 20 to 40% by weight of ethyl acrylate and 60 to 80% by weight of methyl methacrylate, ethyl cellulose, or polyvinyl acetate.

Polymer based outer sheath

The polymer-based outer casing is a gastric juice-resistant casing which dissolves quickly only above a pH of 5.5. The casing is thus intended to prevent the secretion of the active ingredient in the stomach, i.e. according to USP 23 it should be kept up to 10, preferably up to 5%. After entering the small intestine, the polymer-based outer casing should dissolve quickly, so that the active ingredient release process henceforth takes place depending on the properties of the polymer-based inner casing. If the polymer-based outer casing is found to be too thin, too much active ingredient will already be released in the stomach. If the polymer-based outer casing is too thick, it prevents the direct release of the active ingredient in the small intestine. A suitable layer thickness is in the range 15-150 µm, preferably 20-60 µm, for example. Depending on the weight of the core provided with a polymer-based inner sheath with a diameter of 0.8 to 1.25 mm, it is usually preferred to use a polymer (in terms of dry weight) of 8 to 40% by weight, preferably 10 to 25% by weight. % by weight.

The gastric acid-resistant shell of granule A polymer may comprise a methacrylate copolymer containing acid groups including acrylic acid residues, and preferably methacrylic acid residues.

The methacrylate copolymer comprises 40 to 100, preferably 45 to 99 and particularly preferably 85 to 95% by weight of the radical polymerized C1 to C4 alkyl esters of acrylic acid or methacrylic acid and 0 to 60, preferably 1 to 55, particularly preferably 5 to 15% by weight of methacrylate monomers with an anionic group in the alkyl radical.

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

Useful, for example, are neutral methacrylate copolymers comprising 20 to 40% by weight of ethyl acrylate and 60 to 80% by weight of methyl methacrylate (EUDRAGIT® NE type), as long as they are used in combination with acid group containing methacrylate copolymers.

Particularly preferred methacrylate copolymers consist of 40-60% by weight of methacrylic acid and 60-40% by weight of methyl methacrylate or 60-40% by weight of ethyl acrylate (EUDRAGIT® L or EUDRAGIT® L100-55 type).

Substantially anionic methacrylate copolymers, consisting of 20-40% by weight of methacrylic acid and 80-60% by weight of methyl methacrylate (type

EUDRAGIT® S).

Moreover, methacrylate copolymers can be used, consisting of 10-30% by weight of methyl methacrylate, 50 to 70% by weight of methyl acrylate and 5-15% by weight of methacrylic acid (EUDRAGIT® FS type).

The gastric acid-resistant pellet polymer A-based shell may be shellac, HPMCP (hydroxypropylmethyl cellulose phthalate), CAP (cellulose acetate phthalate), HPMC-AS (hydroxypropylmethyl cellulose acetate succinite) or polyvinyl acetate phthalate.

Nevertheless, in any case, care must be taken that the casing is selected, for example, in terms of thickness and possibly mixing with other polymers in such a way that it dissolves quickly when it enters the small intestine.

Granule type B

During the DSP release test (DSP 23 method 2), the granules B allow the release of no more than 10%, preferably no more than 5% of the active ingredient within 2 hours, and no more than 4 hours within 4 hours. 20%, preferably not more than 10% of active ingredient. At a pH of 7.2, about 40 to 60% of the active ingredient is released within 3 hours and about 80 to 100% of the active ingredient is released within 60 hours.

The shell based on the polymer of granules B may be made of a methacrylate copolymer composed of 60 to 95% by weight of C1 to C4 alkyl esters of acrylic acid or methacrylic acid subjected to radical polymerization, and 5 to 40% by weight of methacrylate monomers with an acid group in the alkyl radical .

PL 201 766 B1

Particularly preferred methacrylate copolymers 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 (EUDRAGIT® FS).

Also suitable are methacrylate copolymers with a content of 20 to 40% by weight of methacrylic acid and 80 to 60% by weight of methyl methacrylate (EUDRAGIT® S).

The granules B preferably include only one polymer-based shell, but may also - if the release profile in the large intestine needs to be changed - like granules A, additionally have a polymer-based inner shell, which allows the active ingredient to be continuously released independently of the pH indicator. This solution may prove to be advantageous when it is necessary to extend the release time of the active ingredient to 6-12 or 24 hours.

Active ingredients

The formulation according to the invention finds application in the administration of many active pharmaceutical ingredients which are released in the small intestine and large intestine, and in particular those active ingredients which are preferably administered in a slow release form, such as antidiabetic drugs, analgesics, anti-inflammatory drugs , anti-rheumatic drugs, preparations for increasing blood pressure, preparations for lowering blood pressure, psychopharmacological drugs, sedatives, antiemetics, muscle relaxants, glucocorticoids, drugs used in the treatment of ulcerative colitis or Crohn's disease, antiallergic drugs, antibiotics, antiepileptic drugs, anticoagulants, antifungal agents, antitussive drugs, preparations for hardening of the arteries, proteins, diuretics peptides, enzymes, enzyme inhibitors, preparations used in the treatment of gout, hormones and their inhibitors, cardiac glycosides, immunotherapy drugs and cytokines, laxatives, lipid lowering drugs, anti-migraine drugs, minerals, otological preparations, drugs for Parkinson's disease, drugs for thyroid disease, spasmolytic drugs, platelet aggregation inhibitors, vitamins, cytostatic drugs, metastasis inhibiting agents, phytopharmaceuticals, chemotherapeutic agents, and amino acids.

Examples of suitable active ingredients are acarbose, antigens, beta blockers, non-steroidal anti-inflammatory agents, cardiac glycosides, acetylsalicylic acid, virostatic preparations, aclarubicin, acyclovir, cisplatin, actinomycin, alpha and beta sympathomimetic drugs, dmeprazole, allopadilanthinol, alagadinol, prostadinol ambroxol, amlodipine, methotrexate, s-aminosalicylic acid, amitriptyline, amoxicillin, anastrozole, atenolol, azathioprine, balsalazide, beclometasone, betahistine, bezafibrate, bicalutamide, diazepam and its derivatives, budesonide, bufexamac, buprenorphine, methadone, calcium salts, potassium salts, magnesium salts, candesartan, carbamazepine, captopril, cephalosporin, cetirizine, chenodesic acid, chenodesic acid and itsoxychodesine , trypsin, cimetidine, clarithromycin, clavulanic acid, clindamycin, clobutinol, clonidine, cotrimoxazole, codeine, caffeine, vitamin D and its derivatives, colestyramine, cromoglycan, coumarin and its derivatives, cysteine, cytarabine, cyclophosphamide, cyclosporin, cyproterone, cytosine arabinoside, dapiprazole, desogestrel, desonide, dihydralazine, diltiazem, ergot alkaloids, dimenhydrinate, dimethylsulfoxide, dimethicone, dipsoridimine, diphyridamol, doxoridine doxylamine, dapiprazole, benzodiazepine, diclofenac, glycoside antibiotics, desipramine, econazole, ACE inhibitors, enalapril, ephedrine, epinephrine, epoetin and its derivatives, morphinan, calcium antagonists, irinotecan, modafinil, orlistat, peptide antibiotics, phenytoin, riluzole, resdronate, sildenafil, topiramate, macrolide antibiotics, estrogen and its derivatives, progestogen and its derivatives, testosterone and its derivatives, androgen and its derivatives, etenzamide, etofibrate , fenofibrate, ethophylline, etoposide, famciclovir, famotidine, felodipine, fentanyl, fenticonazole, gyrase inhibitors, fluconazole, fludarabine, flunarizine, fluorouracil, fluoxetine, flurbiprofen, ibuprofen, flutamide, fluvastatin, follitropin, formoterol, fosfomycin, furosemide, fusidic acid, gallopamil, ganciclovir, gemfibrozil, gentamicin, ginkgo, St.John's wort, glibenclamide, urea derivatives as oral antidiabetic drugs, glycerolosamine and its glucathione derivatives, hypothalamic hormones, goserelin, gyrase inhibitors, guanethidine, halofantrine, haloperidol, heparin and its derivatives, hyaluronic acid, hydralazine, hydrochlorothiazide and its derivatives, salicylate, hydroxyzine, idarubicin, ifosfamide, imipramine, indomethacin, indoramine, insulin, interferon, iodine and its derivatives, isoconazole, isoprenaline, glucitol and derivatives, itraconazole, ketoconazole, ketoprofen, ketotifen, lacidoprazolium, levodoparazolyc , lipoic acid and its derivatives, lisinopril, lisuride, lofepramine, lomustine, loperamide, flonidan, maprotiline, mebendazole, mebeverine, meclosine, mefacit, mefloquine, meloxicam, mepindolol,

PL 201 766 B1 meprobamate, meropenem, mesalazine, mesuximide, metamizole, metformin, methotrexate, methylphenidate, methylprednisolone, metixen, metoclopramide, metoprolol, metronidazole, mianserin, miconazole, minocycline, minoxidil and its mesoxidil derivative, myconazole, mycoprostinoliphin, mithomiciphinolastin , primrose, nalbuphine, naloxone, tilidine, naproxen, narcotic, natamycin, neostigmine, nicergoline, nicetamide, nifedipine, niflumic acid, nimodipine, nimorazol, nimustin, nisoldipin, adrenaline and its derivatives, norfloxacin, novaminsulfon, noscapine, nystatin, ofloxacin, olanzapine, olsalazine, omeprazole, omoconazole, ondansetron, oxaceprol, oxacillin, oxiconazole, oxymetazoline, pantoprazole, paroxacetinyphylcycin, pentilycin, paroxacetinyphycin, pentilycin perphenazine, pethidine, plant extracts, phenazone, pheniramine, barbituric acid derivatives, phenylbutazone, phenytoin, pimozide, pindolol, piperazine, piracetam, pirenzepine, piribedil, piroxicam, pramipexole, pravastatin, prazosin, procaine, promazine, propiverin, propranolol, propyphenazone, prostaglandin, protionamide, proxyphyllin, quetiapine, quinapril, quinaprilat, ramipril, ranitidine, rampiridin, rprisperidin, rprisperidin, rprisperidin, riboteroliprin. roxatidine, roxithromycin, ruscogenin, rutoside and its derivatives, sabadil, salbutamol, salmeterol, scopolamine, selegiline, sertaconazole, sertindol, sertralione (zoloft), silicates, sildenafil, simvastatin, sitosterin, sotalol, spaglumic acid, sparfloxacin, spectinomycin, spiramycin, spirapril, spironolactone, stavudin, streptomycin, sucralfate, sufentanil, sulbactam, sulfonamides, sulfasalazine, sultamicillinium chloride, sultamicillinium chloride, sultamicillinium chloride tacrolimus, taliolol, tamoxifen, taurolidin, tazarotene, temazepam, teniposide, tenoxicam, terazosin, terbinafine, terbutaline, terfenadine, terlipressin, tertatolol, tetracycline, tetrisoline, theobromine, theophylline, butizin, thiamazole, phenothiazine, thiotepa, thiagabine, tiapride, propionic acid derivatives, ticlopidine, timolol, tinidazole, thioconazole, thioguanine, thioxolone, tiropramide, tiropramide, tizolanidine, tizolecanidine torasemide, antiestrogens, tramadol, tramazolin, trandolapril, tranylcypromine, trapidil, trazodone, triamcinolone and its derivatives, triamterene, trifluperidol, trifluridine, trimethoprim, trimipramine, tripelenamine, triprolidin, triphosphamide, tromantadine, trometamol, tropalpin, troxerutin, tulobuterol, tyramine, tyrothricin, urapidil, ursodeoxycholic acid, chenodeoxycholic acid, valaciclovir, valproic acid, vancomycin, vecuronium, vecuronium, vecuronium chloride, vilaginium, vecuronium chloride, vilaginium chloride, vilramine chloride, viagra vincristine, vindesine, vinorelbine, vinpocetine, viquidil, warfarin, xanthinol nicotinate, xipamid, zafirlukast, zalcitabine, zidovudine, zolmitriptan, zolpidem, zopiclone, zotepine and the like.

If desired, the active ingredients can be used in the form of their pharmaceutically acceptable salts or derivatives, and in the case of chiral active ingredients, both optically active isomers and racemic compounds, and mixtures of diastereoisomers can be used. The compositions of the invention may also include two or more active pharmaceutical ingredients.

Among the active ingredients which find use in the treatment of ulcerative colitis and Crohn's disease, mention should be made in particular of those which are released as continuously as possible in the intestines, in particular shortly before or only inside the large intestine. The active pharmaceutical ingredient may be an aminosalicylate, a sulfonamide or a glucocorticoid, in particular 5-aminosalicylic acid, olsalazine, sulfalazine, prednisone or budesonide.

Active ingredients for the treatment of ulcerative colitis and Crohn's disease are listed below.

Active ingredients used in the treatment of ulcerative colitis mesalazine sulfasalazine betamethasone dihydrogenphosphate (Bethamethason-21-dihydrogenophosphat) hydrocortisone acetate (Hydrocortison-21-acetate) cromoglycan (Cromoglicinsaure) dexamethasone olsalazine-hydrosalazine-hydro-bismuth-bismuth-bismuth-bismuthated gum-nitrate hydrogensonide prednisone myrrh, arabic coffee, chamomile flower extract, 10% suspension of human placenta.

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Other active ingredients that are used balsalazide oral peptides (e.g. RDP 58) interleukin 6 interleukin 12 ilodecakin (interleukin 10) nicotine tartrate conjugated 5-aminosalicylic acid (CPR 2015) monoclonal antibodies against interleukin 12 diethyldihydroxyhomospermin (DEHOHO) diethylhomospermin (DEHOP) antagonist of the cholecystokinin (CR) 1795 (CRK Peptidokinin) fragment 40 kd gastric (BPC 15) glucocorticoid analogue (CBP 1011) natalizumab infliximab (REMICADE)

N-deacetylated lysoglycosphingolipid (WILD 20) azelastine tranilast sudismase antisense phosphorothioate oligonucleotide (ISIS 2302) tazofelone ropivacaine 5-lipoxygenase inhibitor (A 69412) sucralfate

The form of the drug administered

The described drug forms for internal use may be tablets made of compressed granules or granules placed in capsules, containing gelatin, starch or cellulose derivatives.

Auxiliary substances used in pharmacy

In the process of manufacturing the dosage form, pharmaceutical auxiliaries can be used in a manner known per se. These substances can be included in the core or the coating agent.

Drying agents

The drying agents are characterized by the following properties: large specific surface, chemically inactive, liquid, fine particles. Due to the above properties, they reduce the adhesion of polymers containing polar comonomers as functional groups.

Examples of drying agents:

alumina, magnesium oxide, kaolin, talc, silica (aerosil), barium sulfate and cellulose.

Release agents

Examples of release agents:

fatty acid esters or fatty amides, aliphatic long-chain carboxylic acids, fatty alcohols and their esters, montan or paraffin waxes and metallic soaps; mention should be made in particular of glycerol monostearate, stearyl alcohol, glycerol ester of behenic acid, cetyl alcohol, palmitic acid, carnauba wax, beeswax, etc. Typically the amount of agents of this type is 0.05-5% by weight, preferably 0.1- 3% by weight relative to the copolymer.

Other auxiliary substances used in pharmacy

Mention should be made, for example, of stabilizing agents, dyes, antioxidants, wetting agents, pigments, polishing agents, etc. They are used in particular as processing aids, guaranteeing safe and reproducible preparation and long-term stability of the stored product. The other pharmaceutical excipients may be used in an amount of from 0.001 wt% to 100 wt%, preferably 0.1-10 wt% based on the polymer-based shell.

Softeners

Substances used as plasticizers typically have a molecular weight of 100-20,000, and the molecule comprises one or more hydrophilic groups, for example hydroxyl, ester or amino groups. Citrates are used here,

Phthalates, sebacates and castor oil. Examples of plasticizers that find use herein are citric acid alkyl esters, glycerin esters, phthalic acid alkyl esters, sebacic acid alkyl esters, sucrose esters, sorbitan esters, dibutyl sebacate, and polyethylene glycols 4,000 to 20,000. Preferred plasticizers are tributyl citrate, tributyl citrate. , acetyltriethyl citrate, dibutyl sebacate and diethyl sebacate. They are used in an amount of 1 to 35% by weight, preferably 2-10% by weight, based on the methacrylate copolymer.

Granules containing the active ingredient

Granules containing the active ingredient can be prepared by applying the active ingredient in a layering process. According to this method, the active ingredient is homogenized with other adjuvants (release agents and, optionally, plasticizers), followed by a dissolving or suspending process in a binder (e.g. EUDRAGIT L 30 D-55). A fluidized bed reactor can be used to apply the liquid to placebo granules or other carriers, the solvent or dispersion medium being then evaporated (International Journal of Pharmaceutics 143, pp. 13-23). After the end of the manufacturing process, a drying step may be included. The active ingredient may be applied in multiple layers.

An alternative method is to produce the active ingredient granules by an extrusion / rounding process. It can be carried out, for example, as follows: lactose (20%) and the active ingredient (80%, mesalazine = 5-ASA) were mixed together using a high-shear stirrer (DIOSNA P10, Osnabriick, Germany), and then a little aqueous solution containing excipient of the Kollidon 25 type until a homogeneous composition is obtained. The wet powder mixture was sieved. The pellets were then formed from the resulting material with the aid of Spheronizer 15 (Caleva, Ascot, UK).

Coating with FS polymer was carried out in a Glatt-Coater WSG5 or GPCG1 coater (Glatt GmbH, Binzen / Lorrach, Germany). 20% of the layer (based on dry weight) was sprayed onto the granules in the usual manner.

Certain active ingredients, for example acetylsalicylic acid, are commercially available as crystals. They can also be used in this form, i.e. instead of granules containing the active ingredients.

The shells of the granules containing the active ingredient are typically applied using a fluid bed apparatus. Exemplary formulations useful herein are listed herein. Binding agents are typically mixed with plasticizers and release agents by an appropriate method. Binders can be in the form of a solution or a suspension. It is also possible to include in the solution or suspension suitable auxiliary substances supporting the casing production process. It is possible to use organic or aqueous solvents or dispersants. It is also possible to use additional stabilizers to stabilize the dispersion process (for example: Tween 80 or other emulsifiers or stabilizers).

Examples of release agents are glycerol monostearate and other suitable fatty acid derivatives, silicic acid derivatives, and talc. Examples of plasticizers are propylene glycol, phthalates, polyethylene glycols, sebacates or citrates, and other substances reported in the literature.

General conditions for a release test (e.g. USP 23):

pH 1.2: artificial gastric juice without pepsin (SGF-sp), pH 6.8 and pH 7.2: phosphate buffer in accordance with DAB 10. Apparatus ERWEKA DT 80 (mixer); 900 ml of test medium at 37 ° C, 100 rpm. Each of the tests was performed in triplicate.

Preparation of multiparticulate forms of drugs

The multiparticulate drug form is prepared by mixing different types of granules A and B, for example in a 1: 1 or other ratio, depending on the amount of active ingredient, and placing them in a capsule or compressing them into a tablet in the presence of excipients.

The preparation of a multiparticulate drug form by compressing a pharmaceutical binder with particles containing the active ingredient is described in detail in, for example, Beckert et al. (1996) "Compression of enteric-coated pellets to disintegrating tablets, International Journal of Pharmaceutics 143, pp. 13-23 and WO 96/01624.

The mixtures for the tablet production process from the coated particles are prepared by mixing the granules with suitable binders used in the tabletting process, possibly with disintegration aid and possibly lubricants.

PL 201 766 B1

The mixing process can take place with the use of appropriate devices. Agitators which should not be used here are those which damage the coated particles, for example a ploughshare mixing blade. In order to obtain a sufficiently short disintegration time, it may be necessary to consider the order in which the excipients are added to the coated particles. By premixing the coated particles with a lubricant or release agent, magnesium stearate, a hydrophobic surface can be obtained, thus preventing sticking.

The mixture used in the tabletting process typically comprises 3 to 15% by weight of a disintegrant, for example Kollidon CL, and for example 0.1 to 1% by weight of a lubricant and release agent such as magnesium stearate. The amount of binder is determined by the desired content of the coated particles.

Typical binders are, for example, Cellactose®, microcrystalline cellulose, calcium phosphate, Ludipress®, lactose or other suitable sugars, calcium sulfates or starch derivatives. Substances with a low bulk density are preferred here.

Typical disintegrants (disintegrants) are derivatives of cross-linked starch or cellulose, as well as cross-linked polyvinylpyrrolidone. Cellulose derivatives are also used here. Disintegrants can also be dispensed with by appropriately selecting the binder.

Typical lubricants and release agents are magnesium stearate and other suitable fatty acid salts and other substances reported in the literature (e.g., lauric acid, calcium stearate, talc, etc.). The lubricant and the release agent can also be dispensed with by appropriately selecting devices (for example a tablet press with an external lubrication system) or formulations.

If necessary, a flow aid (for example highly dispersed silicic acid derivatives, talc, etc.) can be added to the mixture.

The tabletting process can be carried out using conventional tablet presses, eccentric or rotary tablet presses, with a pressing force of 5-40 kN, preferably 10-20 kN. The tablet presses may be equipped with an external lubrication system. Optionally, special die filling systems can be used to avoid the use of a die filling system with the use of an agitator blade.

The term "applied amount" means the percentage by weight of the dry weight of the sprayed functional film-forming polymer. It is above 15, reaching 38% by weight, preferably 18-36% by weight and particularly preferably 20-30% by weight, based on the weight of the particle.

The term "fraction of particles" means the weight of the coated particles relative to the total weight of the drug form of the compressed tablet, expressed in% by weight. The proportion of the particles in the drug form is 35-90% by weight, preferably 40-70% by weight. A particle fraction of 70-90% by weight can in particular be obtained by using so-called soft cores in place of sugar granules.

Example 1: Granules A, Polymer-Based Inner Sheath Commercially available cores containing the active ingredient 5-aminosalicylic acid with a diameter ranging from 0.8 to 1.25 mm are coated with a 12% copolymer shell containing 60% by weight of methyl methacrylate, 30% by weight of ethyl acrylate and 10% by weight of 2-trimethylamonoethyl methacrylate chloride (EUDRAGIT® RL).

For this purpose, 30 g of talc, 12 g of triethyl citrate and 268 g of water were added to 200 g of a 30% copolymer dispersion (EUDRAGIT® RL SOD) (solids content 20.45). The cores were coated using a fluid bed apparatus (STREA 1, Aeromatic-Fielder AG, Bubendorf, Switzerland) having a bottom-spray nozzle assembly, the nozzle diameter being 0.8 mm and the spray pressure being 140 -150 kPa. 500 g of granules were used, inlet air temperature was 32-36 ° C, exhaust air temperature was 25-30 ° C, spray rate 2.4 g / min.

Example 2: granules A, polymer based outer shell

The coated cores described in Example 1 were coated with a polymer-based outer sheath consisting of a methacrylate copolymer comprising 50% by weight methacrylic acid and 50% by weight ethyl acrylate (EUDRAGIT® L100-55 or EUDRAGIT® L30 D-55 dispersion system).

For this purpose, 25 g of talc, 5 g of triethyl citrate and 204 g of water were added to 166 g of the dispersion of 30% copolymer mentioned above (EUDRAGIT® L30D-55) (solids content 20.4% ). The cores were coated as shown in Example 1 using a fluid bed apparatus. 20% polymer (dry weight of polymer versus coated granules) was sprayed.

Example 3: granules B.

The active-containing granules were coated as described in Example 1 with a methacrylate copolymer consisting of 25% by weight methyl methacrylate, 65% by weight methyl acrylate and 10% by weight methacrylic acid (EUDRAGIT® FS).

For this purpose, 4 g of glycerol monostearate, 2 g of polysorbate 80, 2.5 g of triethyl citrate and 185 g of water were added to 166 g of the 30% copolymer dispersion mentioned above (EUDRAGIT® FS 30D) (solids content in the system dispersion: 20%). The cores were coated as shown in Example 1 using a fluid bed apparatus. 20% polymer (dry weight of polymer relative to the coated granules) was sprayed.

Example 4: A multiparticulate drug formulation comprising granules A and B as discussed in Examples 2 and 3

<td colspan="2">The composition of the tablet</td>

<td>Granules A</td><td>250.0 g</td>

<td>Granules B</td><td>250.0 g</td>

<td>Cellactose</td><td>417.5 g</td>

<td>Kollidon CL</td><td>80.0 g</td>

<td>Magnesium stearate</td><td>2.5 g</td>

<td colspan="2">This mixture may be directly compressed into a tablet using an appropriate</td>

There are presses for the production of tablets with a pressing force of 15 kN.