BG65878B1 - Multi-particulate form of medicament, comprising at least two differently coated forms of pellet - Google Patents

Abstract

The invention relates to a multifunctional dosage form suitable for uniform release of the active pharmaceutical ingredient in the small intestine and colon, comprising at least two forms of pellets A and B, which contain the active pharmaceutical ingredient in the core and have different polymer coatings, which determine the release of the active ingredient at different pH values, characterized in that flight form A is provided with an internal polymer coating that provides a sustained release of the active ingredient This ingredient has an exterior enteric coating that dissolves rapidly at a pH above about 5.5, and pellet form B is provided with an internal polymer coating which, in the USP release test, releases less than 20% of the active ingredient at pH 6.8. for 6 h and release more than 50% of the active ingredient at pH 7.2 for 6 h. The invention also relates to a method for the preparation of a multifunctional dosage form and to the use of pellet forms A and B for the preparation of the dosage form.

Description

(54) MULTILATERAL PHARMACEUTICAL FORM CONTAINING AT LEAST TWO DIFFERENT COVERED PELLET FORMS

Technical field

The invention relates to a multidrug formulation comprising at least two different coated pellet forms and allowing the release of the active ingredient to be substantially uniform throughout the intestinal tract. The invention further relates to a process for the preparation of a multidrug formulation and to the use of pellet forms A and B for the preparation of the dosage form.

BACKGROUND OF THE INVENTION

Multicomponent dosage forms obtained by compressing a binder with active ingredient-containing pellets coated with gastric juice-resistant / meth / acrylate copolymers are described by Beckert-et al. / 1996 /, “Compression of entericcoated pellets to disintegrating tablets” International Journal of Pharmaceuticals 143, pp. 13-23.

(Meth) acrylate copolymers, which include monomers with cluster ammonium groups, for example trimethylammoniummethyl [sic] methacrylate chloride, and their use for coatings of slow-release drugs, have been known for a long time / e.g. by EP-A 181 515 or by DE-C 1 617 751 /, The treatment is carried out in an organic solvent or in an aqueous dispersion, for example by spraying on the drug cores or in the absence of a solvent in the presence of flow assistants, means by melt application / see EP-A 0 727 205 /.

EP-A 629 398 describes pharmaceutical preparations having an active ingredient core and an organic acid, wherein the core has a two-layer coating. The inner coating in this case is formed by a slow release / meth / acrylate copolymer with quaternary ammonium groups / EUDRAGIT® RS /, while the outer coating has an enteric coating, for example a copolymer of type EUDRAGIT® L30D

55 (ethyl acrylate / methacrylic acid, 50: 50). The achieved release characteristics can be described by the rapid release of the active ingredient after a temporary delay at elevated pH.

EP 0 704 207 A2 describes thermoplastic coatings soluble in intestinal juice. These include copolymers of 16 to 40% by weight, acrylic or methacrylic acid, 30 to 80% by weight, methyl acrylate and 0 to 40% by weight, other acrylic acid and / or methacrylic acid alkyl esters.

EP 0 704 208 A2 describes coatings and binders for drug coatings soluble in intestinal juice. These include copolymers 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 mentions not only single-layer coatings, but also multi-layer coatings. They may consist of a core which includes, for example, an alkali-sensitive or water-active ingredient, has an adhesive layer of other coating material such as cellulose ether, cellulose ester or cationic polymethacrylate, for example of the type EUDRAGIT®, including EUDRAGIT® RS and RL, and further provided with the aforementioned coating soluble in intestinal juice.

Multiple dosage forms in the form of capsules or compressed tablets have been known for some time. It is also known to import pellets with different polymer coatings in multidrug formulations in order to achieve combined release profiles. Task and solution

There is a need for dosage forms that release the active ingredients into the intestinal tract and are further tailored to the release profiles of the specific active ingredient.

The invention provides a dosage form that releases the substantially inactive ingredient in the stomach and assists in the release of the active ingredient, which is as uniform and prolonged as possible in both the small intestine and the large intestine. Doctor

65878 The formulation is intended to be suitable, for example, for the treatment of inflammatory bowel diseases such as ulcerative colitis and, in particular, Crohn's disease.

The task is accomplished by a multi-drug formulation suitable for the uniform release of the active pharmaceutical ingredient in the small intestine and colon, comprising at least two pellet forms A and B containing an active pharmaceutical ingredient in the core and having different polymer coatings which determine the release of the active ingredient at different pH values, characterized in that the pellet form A is provided with an internal polymer coating that provides a continuous release of the act the outer ingredient, and has an exterior enteric coating that dissolves rapidly at pH above 5.5, and pellet form B is provided with an internal polymer coating which, in the USP release test, releases less than 20% of the active ingredient at pH 6.8 in for 6h and releases more than 50% of the active ingredient at pH 7.2 for 6h

The invention further relates to a method for the preparation of multidrug dosage form of the various pellet forms A and B, which are obtained by coating the active ingredient containing cores with the specified polymer coatings, blending together and converting to a multidimensional dosage form by introducing them in a capsule or by compressing them in a tablet unit in the presence of excipients.

Similarly, the invention relates to the use of the described pellet forms A and B in the method according to the claims, for the preparation of a multidrug formulation which uniformly releases the active ingredient within the pH range from 6.8 to [sic] 7.2, corresponding to the conditions in the small intestine and in the large intestine, in particular for the treatment of Crohn's disease or ulcerative colitis.

SUMMARY OF THE INVENTION

The multifunctional dosage form may be in the form of a pellet-filled capsule, for example a gelatin capsule, or it may be in the form of a tablet in which the pellets are compressed together with the usual excipients to form a tablet unit.

The multidrug formulation is suitable for virtually uniform release of the active pharmaceutical ingredient in the small intestine and colon and includes at least two pellet forms, A and B, which contain the active pharmaceutical ingredient in the core but have different polymer coatings that determine the release of the active ingredient ingredient at different pH values. In vitro, in the USP release assay, (USP 23, method 2), at pH 6.8 and pH 7.2, combined profiles are obtained which are between the individual release curves for the two pellet forms A and B. In vivo, the release profile of pellet form A dominates the small intestine and release of the active ingredient from pellet form B begins in the large intestine.

The pellet cores consist entirely or partially of an active pharmaceutical ingredient. The cores are generally spherical or circular and have diameters ranging from about 0.3 to 2 mm. The polymer coatings are in the range of about 2 to 16 mg of polymer per cm ² of the core surface.

Pellet Form A

The pellet form A is provided with an internal polymer coating and an outer polymer coating.

Internal polymer coating

The inner polymer coating allows virtually regardless of the pH the sustained release of the active ingredient. The purpose is the release profile of the active ingredient by which, in the USP release test (USP 23, method 2), at pH 6.8, there is about 40 to 70%, preferably 40 to 60%, release of the active ingredient after 2h, and 60 to 100%, preferably 80 to 100%, release after 4j. This results from the average residence time in the small intestine, which is about 4h.

The inner polymer coating of pellet form A consists of a / meth / acrylate copolymer obtained from free-radical

65878 B1 polymerization: of the C1 to C4 alkyl esters of acrylic or methacrylic acid and (meth) acrylate monomers having a quaternary ammonium group in the alkyl radical.

Suitable / meth / acrylate copolymers are described in, for example, EP-A 181515 or DE-C 1617751. These polymers are soluble or capable of swelling regardless of pH values and are suitable for pharmaceutical coatings. A possible preparation method that may be mentioned is block polymerization in the presence of a free radical initiator dissolved in the monomer mixture. Similarly, the polymer can be obtained by solvent or precipitation polymerization. The polymer may thus be obtained in the form of a fine powder, which is achievable in the case of block polymerization by grinding, and in the case of solvent and precipitate polymerization, for example, by spray drying. The (meth) acrylate copolymer is comprised of 85 to 98%. by weight, polymerized by free radicals, C1 to C4-alkyl esters of acrylic or methacrylic acid and from 15 to 2% by weight, of (meth) acrylate monomers having a quaternary ammonium group in the alkyl radical.

The preferred C1- to C4-alkyl esters of acrylic or methacrylic acid are methyl acrylate, ethyl acrylate, butyl acrylate, butyl methacrylate and metal methacrylate. A particularly preferred (meth) acrylate monomer with a quaternary ammonium group is 2-trimethyl ammonium methyl methacrylate chloride.

Further, a suitable (meth) acrylate copolymer may be constituted, for example, from 85 to less than 93% by weight, C1 to C4 alkyl esters of acrylic and methacrylic acid and more than 7 to 15% by weight the weight of (meth) acrylate monomers with a quaternary ammonium group in the alkyl radical. Such (meth) acrylate monomers are commercially available and used for extended release coatings / of the type / EUDRAGIT® [sic] RL //.

A particularly suitable copolymer includes, for example, 60% by weight, methyl methacrylate, 30% by weight, ethyl acrylate and 10% by weight 2-trimethyl ammonium methyl methacrylate chloride (EUDRAGIT® RL).

The desired release characteristics can be achieved, for example, by the thickness of the coating layer of polymer coatings of the "EUDRAGIT® RL type" described above. This is achieved, for example, by 5 to 15% coverage of EUDRAGIT® RL on cores containing 0.8 to 1.2mm in diameter containing the active ingredient. The required release characteristics can also be achieved with another layer thickness by mixing a copolymer of 50-70% by weight, methyl methacrylate, 20-40% by weight, ethyl acrylate and 7-2% by weight , 2 Trimethyl ammonium methyl methacrylate chloride ('' EUDRAGIT® RS type ''). The particularly suitable copolymer comprises 65% by weight, methyl methacrylate, 30% by weight, ethyl acrylate and 5% by weight, 2-trimethyl ammonium methyl methacrylate chloride [sic] EUDRAGIT® RS. EUDRAGIT® RS and RL types can be mixed, for example, in a ratio of 10: 1 to 1:10. Higher proportions of the "EUDRAGIT® RL type" in the mixture are preferred, for example 60 to 90% by weight.

The inner polymer coating may also consist of a (meth) acrylate copolymer composed of 20 to 40% by weight of ethyl acrylate and 60 to 80% by weight of methyl methacrylate, ethyl cellulose or polyvinyl acetate.

Exterior polymer coating

The outer polymer coating is an enteric coating that dissolves rapidly only at pH values above about 5.5. Thus, the coating is intended to effectively prevent the release of the active ingredient in the stomach [sic], i.e. the release is predicted to be no more than 10, preferably 5%, according to USP 23. Upon passage through the small intestine, it is contemplated that the outer polymer layer will dissolve rapidly so that the release characteristics from now on are determined by the internal polymer cover. If the outer polymer coating is too thin, too much of the active ingredient is released into the stomach. If the outer polymer coating is applied in too thick a layer, it prevents the direct release of the active ingredient in the small intestine. Suitable layer thicknesses are, for example, in the range of 15 to 150microm, preferably,

65878 B1, for example, from 20 to 60 mg. Based on the weight of the core provided with the inner polymer coating and with a diameter of 0.8 to 1.25 mm, it is generally appropriate to apply a polymer (based on dry material) in the range of 8 to 40% by weight, preferably from 10 to 25% by weight.

The enteric polymer coating of Pellet Form A may be [lacuna] a (meth) acrylate copolymer containing acid groups and having, for example, acrylic acid residues, but preferably methacrylic acid. The (meth) acrylate copolymer consists of 40 to 100, preferably 45 to 99, in particular 85 to 95%, by weight, polymerized with the free radicals C1- to C4-alkyl esters of acrylic or methacrylic acid and can includes from 0 to 60, preferably from 1 to 55, and in particular from 5 to 15% by weight, of the (meth) acrylate monomers with the anionic group in the alkyl radical.

C1 to C4 alkyl acrylate esters. or methacrylic acid are, in particular, methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate and butyl acrylate. Suitable examples are also neutral / meth / acrylate copolymers of 20 to 40% by weight, ethyl acrylate and 60 to 80% by weight of methyl methacrylate / EUDRAGIT® NE type / if used in admixture with / meth / acrylate copolymers, containing acid groups. Particularly suitable (meth) acrylate copolymers are composed of 40 to 60% by weight of methacrylic acid and 60 to 40% by weight of methyl methacrylate or 60 to 40% by weight of ethyl acrylate / EUDRAGIT® L or EUDRAGIT® L100-55 types.

Anionic (meth) acrylate copolymers of from 20 to 40% by weight, methacrylic acid and 80 to 60% by weight, methyl methacrylate (EUDRAGIT® S type) are also generally suitable. (Meth) acrylate copolymers containing from 10 to 30% by weight, methyl methacrylate, 50 to 70% by weight, methyl acrylate and 5 to 15% by weight, methacrylic acid (EUDRAGIT® FS type) are also suitable.

The enteric coating of pellet form A may also consist of shellac, HPMCP / hydroxy propyl methyl cellulose phthalate / CAP / cellulose acetate phthalate / HPPS-AS / hydroxy propyl methyl cellulose acetate succinate / or polyvinyl acetate [sic]. However, care must be taken in each individual case to adjust the coating, for example, in accordance with the thickness of the layer and, where appropriate, to mix with other polymers in such a way that it dissolves rapidly after passing into thin films. gut.

Pellet Form B

Pellet Form B releases, at pH 6.8 according to the USP Release Test (USP 23, Method 2), not more than 10%, preferably not more than 5%, after 2h and not more than 20, preferably not more than 10 % of active ingredient after 4h. At pH 7.2, about 40 to 60% of the active ingredient is released after 3 hours, and about 80 to 100 [lacuna] are released after 60h.

The polymeric coating of pellet Form B may be a / meth / acrylate copolymer that is composed of 60 to 95% by weight of free radicals C1- to C4-alkyl esters of acrylic or methacrylic acid and 5 to 40%, stopped weight, (meth) acrylate monomers with an acid group in the apkyl radical.

Particularly suitable (meth) acrylate 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 kioepin (EUDRAGIT® FS type).

(Meth) acrylate copolymers of 20 to 40% by weight, methacrylic acid and 80 to 60%, straight weight methyl methacrylate (EUDRAGIT® S type) are similarly suitable. Pellet Form B is preferably provided with only one polymer coating, but if the release profile in the colon needs to be modified, like Pellet Form A, it may additionally be provided with an internal polymer coating resulting in virtually independent of the pH value of continuous release of the active ingredient. This can be used if it is necessary to prolong the release of the active ingredient in the colon to 6, to 12 or more than 24h

Active ingredients

The formulation according to the invention is sub

65878 Bl suitable for the introduction into the body of a large number of active pharmaceutical ingredients to be released into the small intestine and large intestine, and in particular those active ingredients which may preferably be administered in a slow release form, such as anti-diabetic agents, analgesics, anti-inflammatory agents, antirheumatic agents, antihypertensive agents, antihypertensive agents, psychoaggressive drugs, tranquilizers, vomiting agents, muscle relaxants, glucocorticoids, with anti-ulcerative colitis or Crohn's disease agents, anti-allergic agents, antibiotics, anti-epileptics, anticoagulants, antifungals, antitussives, anti-arteriosclerosis agents, diuretics, proteins, peptides, enzymes, enzyme inhibitors, anti-sorption , immunotherapeutic agents and cytokines, laxatives, lipid-lowering agents, anti-migraine agents, mineral products, otologists, anti-parkinsonism agents, thyroid therapeutics, sp ammolytics, plaque aggregation inhibitors, vitamins, cytostatics and metastasis inhibitors, phytopharmaceuticals, chemotherapeutic agents and amino acids.

Examples of suitable active ingredients are acarbose, antigens, beta-blockers, non-steroidal antirheumatic agents [sic], cardiac glycosides, acetylsalicylic acid, virusostatics, acyclovir, cisplatin, aginomycin, alpha- and beta-simepic, [sic] dimepic, allopurinol, alprostadil, prostaglandins, amantadine, ambroxol, amlodipine, methotrexate, S-amino salicylic acid [sic], amitriptyline, amoxicillin, anastrozole, atenolol, azathioprine, balsalazide, beclomethasam, diabetamazepam, beclomethasam and derivatives, budesonide, bufesamac, buprenorphine, methadone, calcium salts, potassium salts, magnesium salts, candesartan, carbamazepine, captopril, cephalosporins, cetirizine, cenodeoxycholinic acid, ursodeoxycholinic acid, ursodeoxycholinic acid, ursodeoxycholinic acid clindamycin, chlobutinol. clonidine, cstimoxazole, codeine, caffeine, vitamin D and its derivatives, cholestyramine, chromoglycic acid, coumarin and coumarin derivatives, cysteine, cytarabine, cyclophosphamide, cyclosporine, cyproterone, cytarabine [sic], dapiprazole, desoglazolester, , dimenhydrinate, dimethyl sulfoxide, dimethicone, dipyridary [sic], domperidone and domperidane [sic] derivatives, dopamine, doxazosin, doxorubisin [sic], doxylamine, dapiprazole [sic], benzodiazepines, diclofenac, glycosidine, dicosine, glycoside ions, enalapril, epinephrine, epoetin and epoetin derivatives, morphinans, calcium antagonists testosterone and testosterone derivatives, androgen and aldrogen derivatives, etenzamide, etofenamate, ethofibrate, fenofibrate, ethophylline, etoposide, famciclovir, famotidine, felodipine, fenofibrate, fentanyl, fenticonazol, giraz fluconazine, fluorocarcinol, fluorouricil, fluoxetine, fluobetrofen, fluutastine, pholytropin, formoterol, phosphorin, goutine such as anti-diabetic agents for oral administration, glucagon, glucosamine and glucosamine derivatives, glutathione, glycerol and glycerol derivatives, hypothalamic hormones, goserelin, gyrase inhibitors [sic], guanetidine, halofantrine, hapoperidol and heparin derivatives, hyaluronic acid, hydralazine, hydrochlorothiazide and hydrochlorothiazide derivatives, salicylates, hydroxyzine, idarubicin, ifosfamide, imipramine, indomethacin, indoramin, insulin, interferons, iodine and iodine derivatives, isoconazole, isoprenaline, glucitol and glutsitolni derivatives, itraconazole, ketoconazole. ketoprofen, ketotifen, lacidipine, lansoprazole, levodopa, levomethadone, troid hormones, lipoic acid

65878 Bl linen and lipoic acid derivatives, lisinopril, lisuride, lofepramine, lomustine, loperamide, loratadine, maprotilin, mebendazole, mebeverine, meclozin, mefenamic acid, mefloquine, meloxicam, mepindolol, mtrobemazine, mepromazol, metroemazol, metroemazol methotrexate, methylphenidate, methyl-prednisolone, methixene, metoclopramide, metoprolol, metronidazole, mianserin, miconazole, minocycline, minoxidil, misoprostol, mitomycin, mizolastine, moexipril, morphine and morphinicurol, irophin, iroxin laxone, tilidine, naproxen, narcotic, natamycin, neostigmine, nicergoline, nicetamide, nifedipine, niflumic acid, nimodipine, nimorazole, nimustin, nizoldipine, adrenaline and adrenaline derivatives, norfloxacin, novamin sulfine, nascapine, nascapine , omoconazole, ondansetron, oxaceprol, oxacillin, oxyconazole, oxymetazoline, pantoprazole, paracetamol, paroxetine, penciclovir, penicillins for oral administration, pentazocin, pentifillin, pentoxifylline, perphenazine, petzentin, petzentin, petzentin iramine, barbituric acid derivatives, phenylbutazone, phenytoin, pimozide, pindolol, piperazine, piracetam, pirenzepine, pyribedil, piroxicam, pramipexole, pravastatin, prazosin, procaine, promazin, propiverinol, propranolinol, propranolinol, propranolinol, propranolinol ketiapine, kinapril, kinaprilat, ramipril, ranitidine, reproterol, reserpine, ribavirin, rifampicin, risperidone, ritonavir, ropinirole, roxatidine, roxithromycin, ruskogenin, rutoside and rutoside derivatives, sabadalamin, sabadalamin, sabadalamin, sabadalamin ertacazole, sertindol, sertralion [sic], silicates, sildenafil [sic], simvastatin, sitholol, spaglenoic acid, sparfloxacin, spiramol, sufrol, suptal , sulthamycin, sulthiam, sumatriptan, suxamethonium chloride, tacrine, tacrolimus, tgliolol, tamoxifen, taurolidine, tazarotene, temazepam, teniposide, tenoxicam, terazosin, terbinafine, terbutaline, terfenadine, terlithipril n, theophylline, butyzin, thiamazole, phenothiazines, thiotepa, tiagabine, thiapride, propionic acid derivatives, ticlopidine, timolol, tinidazole, thioconazole, thioguanine, thioxolone, tiropramide, tolizanyltolazolin, tolazepine, tolizaniline , antioestrogens, tramadol, tramazolin, trandolapril, tranylcypromine, trapidil, trazodone, triamcinolone and triamcinolone derivatives, triamterene, trifluperidol, trifluridine, trimethoprim, trimipramine, trifelamin, trifos, trifos, trifos pin, troxerutin, tulobuterol, tyramine, thyrotricin, urapidil, ursodeoxycholic acid [sic], henodeoxycholic acid [sic], valacyclovir, valproic acid, vancomycin, vecuronium chloride, Viagra, venlafaxine, virenpaxine, vincristine, vindesine, vinorelbine, vinpocetine, vykidil, warfarin, xanthinol nicotinate, xipamide, zafirlukast, zalcitabine, zidovudine, zolmitriptan, zolpidem, zoplicon [sic], zotipine and the like.

The active ingredients may optionally also be used in the form of their pharmaceutically acceptable salts or derivatives, and in the case of chiral active ingredients it may be possible to use both optically active isomers and racemates or mixtures of diastereoisomers. Optionally, the compositions of the invention also include two or more active pharmaceutical ingredients.

The active ingredients that have been specifically mentioned as being suitable for the treatment of ulcerative colitis and Crohn's disease are those that are intended to be released as continuously as possible into the intestine, especially sooner or only in the colon. The active pharmaceutical ingredient may be one aminosalicylate, sulfonamide or glucocorticoid and those specifically mentioned are 5-aminosalicylic acid, olsalazine, sulfalazine [sic], prednisone or budesonide.

The following lists summarize the active ingredients suitable for the treatment of ulcer7

65878 Bl colitis and Crohn's disease.

Active ingredients for the treatment of ulcerative colitis mesalazine sulfazalazine betamethasone beta-dehydrogenphosphate hydrocortisone acetate cromoglycine acid dexamethasone olsalazine caretin methylpredizolene, carol resin methylpredenzolone

Other suitable active ingredients balsalazide peptides for oral administration / e.g. RDP 58 / interleukin 6 interleukin 12 ilodecakin / interleukin 10 / nicotine tartrate

5-ASA Conjugates / CPR 2015 / Monoclonal Antibodies to Interleukin 12 Diethyldihydroxyhospermine / DEONONO / Diethyl Chospermine / DEHOP / Cholecystokinin / CCA / Antagonist / CR 1795 / Amino Acid Fragment of 40 kd peptide from stomach1 / natalizumab infliximab / REMICADE /

N- deacetylated lysoglycospingolipid / WILD 20 / azelastines tranilast sudysmase phosphorothioate antisense oligonucleotide / ISIS 2302 / tazophelones ropivacaine lipoxygenase inhibitor / A 69412 / sucralfate

Forms of application

The described drugs (for oral administration) may be in the form of a tablet made from compressed pellets or in the form of pellets that are encapsulated, for example, composed of gelatin, starch or cellulose derivatives.

Aggregates common in pharmacy

The usual excipients in pharmacy may be used in a manner known per se for the preparation of the dosage form. These excipients may be present in the core or in the coating agent.

Siccatives / non-sticking agents /:

Siccats have the following properties: they have a large specific surface area, are chemically inert, do not dust, and include fine particles. Because of these properties, they reduce the adhesiveness of polymers containing polar comonomers as functional groups.

Examples of desiccants are: alumina, magnesium oxide, kaolin, talc, silica (Aerosils), barium sulfate and cellulose.

Release agents

Examples of release agents are: fatty acid or fatty acid esters, aliphatic, long-chain carboxylic acids, fatty alcohols and their esters, mountain waxes or paraffin waxes and metal soaps; special attention should be paid to glycerol monostearate, stearyl alcohol, glycerol ester and bechenic acid [sic], cetyl alcohol, palmitic acid, cannabis [sic] wax, beeswax and so on. The usual amounts are in the range of 0.05%. , by weight, to 5, preferably from 0.1 to 3%, by weight, based on the copolymer.

Other excipients common in pharmacy

For example, stabilizers, colorants, antioxidants, moisturizers, pigments, glosses and the like should be mentioned. They are used specifically as processing aids and are designed to provide [sic] a reliable and reproducible production process and good long-term storage stability. Additional excipients, obi

65878 Pharmaceutical blends may be present in amounts of 0.001% by weight to 100% by weight, preferably from 0.1 to 10% by weight, based on the polymer coating.

Plasticizers: Substances suitable for plasticizers typically have a molecular weight of between 100 and 20,000 and contain one or more hydrophilic groups in the molecule, such as hydroxyl, ester or amino groups. Citrates, phthalates, sebacates, castor oil are suitable. Examples of suitable plasticizers are alkyl citrates, glycerol esters, alkyl phthalates, alkyl sebacates, sugar esters, sorbitan esters, dibutyl sebacate, and polyethylene glycols 4000 to 20,000. The amounts used are between 1 and 35, preferably 2 to 10% by weight, in percent [sic], of the base / meth / acrylate copolymer.

Pellets containing the active ingredient

Pellets containing the active ingredient can be obtained by applying the active ingredient through a layering process. This is accomplished by homogenizing the active ingredient together with other excipients (releasing agents where appropriate plasticizers) and dissolving or suspending them in a binder (eg EUDRAGIT L 30 D-55). A fluidized bed method may be used to apply the fluid to placebo pellets or other suitable carrier materials, by evaporation of the solvent or of the suspending agent / Intemational Journal of Pharmaceutics 143, pp. 13-23 /. The preparation method may be followed by a drying step. The active ingredient can be applied in multiple layers.

Another possibility of preparing pellets containing active ingredient is the extrusion / spheronization method. This can be accomplished, for example, as follows: lactose (20%) and active ingredient (80%); mesalazine = 5ASA / were mixed in a high-speed mixer (DIOSNA type P10, Osnabruck, Germany), and an aqueous solution containing the Kollidon 25 excipient was added in small portions until a homogeneous composition was obtained. The wet powder mixture is sieved. The pellets are then formed using Spheronizer type 15 (Caleva, Ascot, UK).

Coating with the FS [sic] polymer is carried out in Glatt coater / WSG5 or GPCG1 type, Glatt GmbH, Binzen (Lorrach, Germany). The 20% dry weight basis is applied to the pellets using the nebulization method in a manner known per se.

Some active ingredients, for example, acetylsalicylic acid, are commercially available in the form of active ingredient crystals and can be used in this form in place of pellets containing the active ingredient.

Film coatings containing the active ingredient, pellets are typically applied in a fluidized bed device. Examples of formulations are mentioned in this specification. The film-forming agents are usually mixed with plasticizers and release agents using a suitable method. The film-forming agents in this case may be in the form of a solution or suspension. Film-forming inert fillers may similarly be dissolved or suspended. Organic or aqueous solvents or dispersants may be used. In addition, stabilizers may be used to stabilize the dispersion (for example: Tween 80 or other suitable emulsifiers or stabilizers).

Examples of release agents are glycerol monostearate or other suitable fatty acid derivatives, silicic acid derivatives or talc. Examples of plasticizers are propylene glycol, phthalates, polyethylene glycols, sebacates or citrates and other substances mentioned in the literature. The general conditions for release tests are / eg, USP 23 /: pH 1.2: simulated gastric fluid without pepsin / SGE-spZ, pH 6.8 and pH 7.2: phosphate buffer supplemented with DAB 10. ECUECtype DT 80 device / paddle / [sic ]; 900 ml of test medium at 37 ° C, 100 rpm. Each test is performed three times.

Preparation of multicomponent dosage forms

The multidrug formulation is prepared by blending different

65878 The blank pellet forms A and B, for example in a 1: 1 ratio or in another ratio, depending on the amount of active ingredient present, are encapsulated or compressed into a tablet unit in the presence of excipients to form the multifunctional formulation. The preparation of multidrug formulations by compressing a binder that is customary in pharmacy with the active ingredient containing pellets is described in detail by, for example, [lacuna] Beckert et al. / 1996 / “Compression of enteric-coated pellets to disintegrating tablets”, International Journal of Pharmaceutics 143, pp. 13-23 and in WO 1996/001624.

Mixtures for the preparation of coated particle tablets are prepared by mixing the pellets with suitable tabletting binders, if necessary, disintegrating promoters are added and lubricants are added if necessary. Mixing can take place in suitable devices. Inappropriate mixers are those that cause damage to the coated particles. A special sequence of addition of excipients to the coated particles may be necessary in order to achieve suitable short disintegration times. The premixing of the [sic] coated particles with an oiling agent or a loose magnesium stearate release agent is capable of rendering their surface hydrophobic and thus avoiding adhesion.

Mixtures suitable for tabletting typically contain 3 to 15% by weight of a disintegrant, e.g., Kollidon CL, and, for example, 0.1 to 1%, by weight of an oily and loose release agent such as magnesium stearate. The binder content is determined by the required content of coated particles. Typical binders are, for example, Cellactose ®, microcrystalline cellulose, calcium phosphates, Ludipress ®, lactose or other suitable sugars, calcium sulphates or starch derivatives. Low volume substances are preferred.

Typical disintegrating aids are cross-linked starch derivatives or cellulose derivatives, and cross-linked polyvinylpyrrolidone. Similarly cellulose derivatives are also suitable. The use of disintegrating aids may be omitted by selecting a suitable binder.

Typical lubricants and loose release agents are magnesium stearates or other suitable salts of fatty acids or substances mentioned in the literature for this purpose / for example, lauric acid, calcium stearate, talc and the like. similar. The use of an lubricant and a release agent in the mixture may be omitted if suitable devices are used (for example, an external lubricating tablet press) or compositions.

The mixture may, where appropriate, be mixed with an adjuvant to improve the flowability of, for example, highly dispersed silica, talc and the like. similar.

Tableting can be accomplished in conventional tablet presses, eccentric or rotary tablet presses, with pressures ranging from 5 to 40kN, preferably 1020kN. Tablet presses can be provided with external oiling systems. Form filling systems are used where appropriate, which avoid filling the form with stirring blades.

Application rate means the proportion of dry matter of the atomized functional film-forming polymer in percent by weight. It is above 15 to 38, preferably preferably 18 to 36, and most preferably 20 to 30% by weight, based on the weight of the particle.

Particulate content means the weight of the coated particles, as a proportion of the total weight of the dosage form, the compressed tablet [sic], in percent by weight. The particulate content of the dosage form is 35-90, especially preferably 40 to 70%, by weight. Particulate content of 70 to 90% by weight can be achieved in particular by using so-called soft pellets in place of sugar pellets.

65878 Bl

Examples of carrying out the invention

Example 1: Pellet Form A, Internal Polymer Coating Commercially available cores containing the active ingredient 5aminosalicylic acid, with a diameter in the range 0.8 to 1.25 mm, are coated with 12% by weight of copolymer 60% by weight, methyl methacrylate, 30% by weight ethyl acrylate and 10% by weight 2-trimethylammonium methyl methacrylate chloride (EUDRAGIT® RL).

To this end, 3 0g talc, 12g triethyl citrate and 268g water were added to 200g 30% dispersion of the copolymer (EUDRAGIT® RL 30D) (20.45 [sic] solid content). The cores are coated in a fluidized bed apparatus / STREA 1, Aeromatic-Fielder AG, Budendorf, Switzerland / with a nozzle arrangement and a nozzle diameter of 0.8 mm and a jet pressure of 1.4 to 1.5 bar, 500g pellets, air temperature at inlet 32- 36 ° C, outlet air temperature 25-30 ° C, spray rate 2.4 g / min

Example 2: Pellet Form A, outer polymer coating.

The coated cores of Example 1 are [lacuna] with an outer polymer coating of (meth) acrylate copolymer of 50% by weight methacrylic acid and 50% by weight ethyl acrylate (EUDRAGIT® L100-55 or EUDRAGIT® L 30 D-55 dispersion). To this end, 25g of talc, 5g of triethyl citrate and 204g of water were added to 166g of a 30% dispersion of the aforementioned copolymer (EUDRAGIT® L 30 D-55) (20.4% solids content). The cores were coated as indicated in Example 1 in a fluidized bed device. 20% polymer (dry polymeric substance to the coated pellet) was applied by spraying.

EXAMPLE 3 Pellet Form B The active ingredient-containing pellets were coated as in Example 1 but with a / meth / acrylate copolymer of 25% by weight, methyl methacrylate, 65% by weight, methyl acrylate and 10% by weight , methacrylic acid / EUDRAGIT® FS /. To this end, 4g glycerol monostearate, 2g polysorbate 80.2.5g triethyl citrate and 185g water were added to 166g 30% dispersion of the above-mentioned copolymer / EUDRAGIT® FS 30 D / / 20% solids content in the dispersion spray. The cores were coated as indicated in Example 1 in a fluidized bed apparatus. A spray of 20% polymer (dry polymeric substance to the coated pellet) was applied. Example 4: Composition of a multidrug formulation comprising pellet forms A and B according to Examples 2 and 3.

Composition of the tablet: Pellet Form A 250.0 g Pellet Form B 250.0 g Cellactose 417.5 g KollidonCL 80.0 g Magnesium stearate 2.5 g

Claims

Claims (10)

Claims A multifunctional dosage form suitable for uniform release of the active pharmaceutical ingredient in the small intestine and colon, comprising at least two pellets A and B containing an active pharmaceutical ingredient in the core and having different polymer coatings which determine the release of the active ingredient at different pH values, characterized in that the pellet form A is provided with an internal polymer coating that provides a sustained release of the active ingredient and has an exterior an enteric coating which dissolves rapidly at pH above about 5.5 and which consists of a (meth) acrylate copolymer of 40 to 60% by weight of methacrylic acid and 60 to 40% by weight of methyl methacrylate or 60 to 40% by weight of ethyl acrylate or HPMCP (hydroxy propyl methyl cellulose phthalate) and pellet form B is provided with a polymer coating which, in the USP release test, releases less than 20% of the active ingredient at pH 6.8 for 6h and releases more than 50% of the active ingredient at pH 7.2 for 6h, wherein the polymer the coating of pellet form B is a / meth / acrylate copolymer which is composed of 60 to 95% by weight of free radical polymerization C1- to C4-alkyl acrylic or methacrylic acid esters and 5 to 40% by weight / meth Acrylate monomers with an acid group in the alkyl radical. 65878 Bl 2. The multidrug formulation according to claim 1, characterized in that the inner polymer coating of the pellet form A consists of a (meth) acrylate copolymer obtained from the free-radical polymerization of the C1- to C4-alkyl esters of the acrylic or methacrylic acid and (meth) acrylate monomers with a quaternary ammonium group in the alkyl radical, (meth) acrylate copolymer of 20 to 40% by weight of ethyl acrylate and 60 to 80% by weight of methyl methacrylate, ethylcellulose or polyvinyl acetate. A multi-compound dosage form according to claim 2, characterized in that the (meth) acrylate copolymer is 85 to less than 93% by weight of the C1 to C4 alkyl esters of acrylic or methacrylic acid and more than 7 to 15 % by weight of (meth) acrylate monomers with quaternary ammonium group in the alkyl radical, was used for the internal polymer coating of pellet form A. A multi-compound dosage form according to claim 1, characterized in that the (meth) acrylate copolymer containing 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 is used for polymer coating of pellet form B. 5. The multidrug formulation according to claim 1 or 4, characterized in that the pellet form B is further provided with an internal polymer coating that facilitates the continuous release of the active ingredient. A multidrug formulation according to one or more of claims 1 to 5, characterized in that the active pharmaceutical ingredient that is present is amino salicylate, sulfonamide, hormone, peptide, interferon or glucocorticoid. The multidrug formulation according to claim 6, wherein the active pharmaceutical ingredient is 5-aminosalicylic acid, olsalazine, sulfalazine, prednisone or budesonide. 8. A method for the preparation of a multidrug formulation according to one or more of claims 1 to 7, characterized in that the various pellet forms A and B are prepared by coating the active ingredient cores with said polymer coatings, mixed together and are converted into a multidrug formulation by capsule application or compression into a tablet unit in the presence of excipients. Use of pellet forms A and B according to one or more of claims 1 to 7 in the method according to claim 8, for the preparation of a multidrug dosage form with uniform release of the active ingredient in the pH range from 6.8 to 7.2, corresponding to conditions in the small intestine and colon. Use according to claim 9, characterized in that the multidrug formulation is suitable for the treatment of Crohn's disease or ulcerative colitis.