BG107147A - Multi-particulate form of medicament, comprising at least two differently coated forms of pellet. - Google Patents

Abstract

The invention relates to a multi-particulate form of medicament, suitable for the uniform release of a pharmaceutical agents in the upper intestine and the lower intestine, containing at least two forms of pellets, A and B, the core of which contains a pharmaceutical agent and with different polymer coatings which permit the release of the agent at different pH values. Said forms are characterised in that pellet form A is provided with an inner polymer coating, permitting a sustained release of agent and an external coating, resistant to gastric juice, which rapidly dissolves at a pH above 5.5. Pellet form B is provided with a polymer coating, which releases less than 20% of the agent at pH 6.8 in 6 hours according to the USP release test and at pH 7.2 releases more than 50% in 6 hours. The invention further relates to a method for the production of the multi-particulate form of medicament and the use of pellet forms A and B for the production of the form of medicament. 13 claims

Description

MULTILATERAL MEDICINAL FORM CONTAINING AT LEAST TWO DIFFERENT COVERED PELLET FORMS

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 multifaceted dosage form and to the use of pellet forms A and B for the preparation of the dosage form.

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

(Meth) acrylate copolymers, which include quaternary ammonium group monomers, for example trimethylammoniummethyl [sic] methacrylate chloride, and their use for slow release coatings have been known for a long time / e.g. EP-A 181 515 or 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 EUDRAGIT® type, inter alia

pp. ·· • ·

• ·

EUDRAGIT® RS and RL, and additionally are then 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 promotes the release of the active ingredient, which is as uniform and prolonged as possible in the small intestine and colon. The dosage form 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 solved by the consequence of a multi-form dosage form suitable for 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,

4. characterized in that the pellet form A is provided with an internal polymeric coating that provides a sustained release of the active ingredient, and has an external enteric coating that dissolves rapidly at pH above 5.5, and the pellet form B is provided with an internal a polymer coating which, in the USP release test, releases less than 20% of the active ingredient at pH 6.8 for 6 hours and releases more than 50% of the active ingredient at pH 7.2 for 6 hours.

The invention further relates to a method for the preparation of a multifunctional formulation of the various pellet forms A and B, which are prepared by coating the active ingredient containing cores with the specified polymer coatings, blending together and converting to a multicomponent dosage form by capsule insertion 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 colon, in particular for the treatment of Croy's disease or ulcerative colitis.

SUMMARY OF THE INVENTION

The multifunctional formulation may be in the form of a pellet-filled capsule, for example a gelatin capsule, or

5 may be in the form of a tablet in which the pellets are compressed together with the usual excipients until the tablet unit is obtained.

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 an active pharmaceutical ingredient in

the core, but have different polymer coatings that determine the release of the active 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 form 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 an 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 active ingredient after 2 hours, and at 60 to 100%, preferably 80 to 100%, release after 4 hours. This stems from the average residence time in the small intestine, which is about 4 hours.

The internal polymeric coating of pellet form A consists of a (meth) acrylate copolymer derived from the free-radical polymerization of the C1- to C4-alkyl esters of acrylic or methacrylic acid and (meth) acrylate monomers with a quaternary ammonium group in the alkyl radical.

Suitable / meth / acrylate copolymers are described in, for example, EPA 181 515 or DE-C 1 617 751. They are polymers that are soluble or swellable regardless of pH values and suitable for pharmaceutical coatings. A possible preparation method that may be mentioned is block copolymerization 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 composed of 85 to 98% by weight, polymerised by free radicals, C1 to C4-alkyl esters of acrylic or methacrylic acid and from 15 to 2% by weight, (meth) acrylate monomers with quaternary ammonium a 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 methyl methacrylate.

A particularly preferred (meth) acrylate monomer with a quaternary ammonium group is 2-trimethyl ammonium methyl methacrylate chloride.

A further suitable (meth) acrylate copolymer may be constituted, for example, from 85 to less than 93% by weight, C1 to C4-alkyl acrylic and methacrylic acid esters and more than 7 to 15% by weight, / 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 "EUDRAGIT® RL type" polymer coatings described above. This is achieved, for example, by 5 to 15% coverage of EUDRAGIT® RL on cores containing 0.8 to 1.2 mm 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 • · · · · · · 40 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Chloride / “EUDRAGIT® RS type” /. The particularly suitable copolymer comprises 65% by weight of methyl methacrylate, 30% by weight of ethyl acrylate and 5% by weight of 2-trimethyl ammonium methyl methacrylate chlorine. d [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 internal polymer coating may also consist of a W / meth / acrylate copolymer of 20 to 40% by weight, 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 prevent the active ingredient from being released into 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 envisaged that the outer polymer layer will dissolve rapidly so that the release characteristics from that point on are determined by the internal polymer coating . 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 150 µm, preferably, for example, 20 to 60 µm. Based on

J * ·· the weight of the core, provided with the inner polymer coating and having a diameter of 0.8 to 1.25 mm, is generally appropriate to apply a polymer (based on dry material) in the range of 8 to 40% by weight, preferably from 10 up to 25% by weight.

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

The C1- to C4-alkyl esters of acrylic 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), HPPC-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 consent, USP release test (USP 23, method 2), not more than 10%, preferably * not more than 5%, after 2 hours and not more than 20, preferably not more than of 10%, of the active ingredient after 4 hours. 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 60 hours.

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%, by weight , (meth) acrylate monomers with an acid group in the alkyl 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 acid (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, which results in virtually independent of pH value of continuous release of the active ingredient. This can be used if necessary to prolong the release of the active ingredient in the colon to 6, to 12 or more than 24 hours.

Active ingredients

The formulation according to the invention is suitable for the introduction into the body of a large number of active pharmaceutical ingredients which must be released into the small intestine and into the large intestine, and in particular those active ingredients, which may preferably be introduced in the slow release formulation , such as anti-diabetic agents, analgesics, anti-inflammatory agents, anti-rheumatic agents, antihypertensive agents, antihypertensive agents, psychoactive drugs, tranquilizers, vomiting agents, muscle us • · • ·

relaxants, glucocorticoids, ulcerative colitis or Crohn's disease, anti-allergic agents, antibiotics, anti-epileptics, anticoagulants, antifungals, antitussives, anti-arteriosclerosis agents, diuretics, proteins, peptides, enzymes, enzymes, enzymes, enzymes, enzymes inhibitors, cardiac glycosides, immunotherapeutic agents and cytokines, laxatives, lipid-lowering agents, anti-migraine agents, mineral products, otologists, anti-Parkinsonism agents, thyro other therapeutic agents, antispasmodics, plaque aggregation inhibitors, vitamins, cytostatics and metastasis inhibitors, phytopharmaceuticals, chemotherapeutic agents and amino acids.

Examples of suitable active ingredients are acarbose, antigens, beta-beta receptors, non-steroidal antirheumatic agents [sic], cardiac glycosides, acetylsalicylic acid, virusostatics, acyclovir, cisplatin, actinomycin, alpha- and beta-sicepicipicamipicamipicamipic , allopurinol, alprostadil, ppostaglandins, amantadine, ambroxol, amlodipine, methotrexate, amino salicylic acid [sic], amitriptyline, amoxicillin, anastrozole, atenolol, azathioprine, balsalazidine, beclomethazine, beclomethasin 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, ··

14 *.

Chloridine, kstimoxazole, codeine, caffeine, vitamin D and its derivatives, cholestyramine, chromoglycic acid, coumarin and coumarin derivatives • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · , cysteine, cytarabine, cyclophosphamide, cyclosporin, cyproterone, cytarabine [sic], dapiprazole, desogestrel, desonide, dihydralazine, diltiazem, ergot alkaloids, dimenhydrinate, dimethyl sulfoxide, dimethicone, dipicimidar, dipicimidar , doxazosin, doxorubisin [sic], doxylamine, dapiprazole [sic], benzodiazepines, diclofenac, glycosidic antibiotics, dosipramine, econazole,

ACE inhibitors, enalapril, epinephrine, epoetin, and epoetin derivatives, morphinans, calcium antagonists , testosterone and testosterone derivatives, androgen and iadrogenic derivatives, etenzamide, etofenamate, ethofibrate, fenofibrate, ethophilin, etoposide, famciclovir, famotidine, felodipine, fenofibrate, fentanyl, fenticonazole, gyrazine fluconazine such as antidiabetic agents for oral administration, glucagon, glucosamine and glucosamine derivatives, glutathione, glycerol and glycerol derivatives, hypothalamic hormones, goserelin, gyrase inhibitors [sic], guanetidine, halofantrine, heparin and heparin, hyaluronic acid, hydralazine, hydrochlorothiazide, salicylates, hydroxyzine, isopharidine, isomethyl, indoors , ketoconazole, ketoprofen, ketotifen, lacidipine, lansoprazole, levodopa, levomethadone, tlroid hormones, lipoic acid and lipoic acid derivatives, lisinopril, lisuride, lofepramine, lomustine, loperamide, loratad in, maprotilin, mebendazole, mebeverine, meklozin, mefenamic acid, mefloquine, meloxicam, mepindolol, meprobamate, meropenem, mesalazine, meuximide, metamizole, metformin, methotrexate, methylphenidino, metoproxin, metoproxin , minocycline, minoxidil, misoprostol, mitomycin, misolastin, moexipril, morphine and morphine derivatives, evening primrose / evening primrose /, nalbuphine, naloxone, tilidine, naproxen, narcotine, natamycin, neostigmine, nitserginolin, nitzergin, elin, nimodazine, nimustin, adolin, adrenaline and norfloxacin, novin sulfone, noscapine, olanzapine, olazalzin, ozacol, ozacepine penciclovir, penicillins for oral administration, pentazocin, pentifylline, pentoxifylline, perphenazine, pethidine, plant extracts, phenazone, phenyramine, barbituric acid derivatives, phenylbutazone, phenytoin, pimozide, pindolol, piperazine, piperazine am pirenzepine, piribedil,

piroxicam, pramipexole, pravastatin, prazosin, procaine, promazine, propiverine, propranolol, propifenazone, prostaglandins [sic], prothionamide, proxyphilin, ketiapine, kinapril, kinaprilat, ramipril, ranitidine, riproperin, reservation , roxatidine, roxithromycin, ruskogenin, rutoside and rutoside derivatives, sabadila, salbutamol, salmeterol, scopolamine, selegiline, sertaconazole, sertindol, sertralion [sic], silicates, sildenafil [sic], simvastalatin, silystalatin, sivastalatin spectinomycin, spiroline, sulphate, sulphate, sulphate tenoxicam, terazosin, terbinafine, terbutaline, terfenadine, terlipressin, tertatolol, tetracyclines, terizolin, theobromine, theophylline, butyzine, thiamazole, phenothiazines, thiotepa, tiagabine, thiapride, propionic acid derivatives, thiolopidine, thiolampin, thiol Tiozolin, Tiozolin, Tiozolin, Tiazolidine, Tetazolin, Tetazolin, Tetazolin, Tazolidine , trimethoprim, trimipramine, tripelenamine, triprolidine, triphosphamide, tromantadine, trometamol, tropalpine, troxerutin, tulobuterol, tyramine, thyrotricin, urapidil, ursodeoxycholic acid [sic], henodeoxycholic acid ovir, valproic acid , 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 mentioned specifically as 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. Active pharmaceutical _x ingradiient may be an aminosalicylate, a sulfonamide or a glucocorticoid, and those which are specifically mentioned are 5aminosalitsilova acid olzalazin, sulphasalazine [sic], prednisone or budesonide.

The following lists summarize the active ingredients suitable for the treatment of ulcerative colitis and Crohn's disease.

Active ingredients for the treatment of ulcerative colitis mesalazine sulfazalazine betamethasone 21-dehydrogenphosphate ·· tf · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Hydrocortisone 21-acetate cromoglycic acid dexamethasone olzalazine Na budesonide bismuthrate, brown resin methylprednisolone 21-Hydrogen succinate prednisone peace / myhrr /, coffee charcoal, chamomile color% human placenta suspension

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 against interleukin 12 diethyldihydroxyhomospermine / DEHOHO / diethylhomospermine / DEHOP / cholecystokinin / CCA / antagonist / CR 1795 / amino acid fragment of 40 kd peptide / 40Cd peptide / 40Cd peptide / 40Cd peptide / natalizumab infliximab / REMICADE /

N- deacetylated lysoglycospingolipid / WILD 20 / · · · · · · · · · · · · · · · · · · · ·

azelastines tranilast sudysmaz phosphorothioate antisense oligonucleotide / ISIS 2302 / tazophelones ropivacaine lipoxygenase inhibitor / A 69412 / sucralfate

Forms of application

The medicines described (for oral administration) may be in the form of a tablet made from compressed pellets or in the form of a capsule-coated pellet, 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. Due to these properties, they reduce the adhesiveness of polymers containing polar comonomers as functional groups.

Examples of siccatives are:

alumina, magnesium oxide, kaolin, talc, silica (Aerosils), barium sulphate and cellulose.

Release Means • ·

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 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

Mention should be made, for example, of stabilizers, colorants, antioxidants, moisturizers, pigments, glosses and the like. They are used in particular as processing aids and are intended to provide [sic] a reliable and reproducible manufacturing process and good long-term storage stability. Additional excipients customary in pharmacy 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, for example 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,

20 * ..

esters of sorbitan, dibutyl sebacate and polyethylene glycols

4000 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 2 to 10%, by weight in percent [sic], based on / meth / acrylate copolymer.

Pellets containing the active ingredient

Pellets containing the active ingredient may be prepared

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, with the evaporation of the solvent or the suspending agent / literature: International 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 the active ingredient is the extrusion / spheronization method. This can be accomplished, for example, as follows: lactose (20%) and active ingredient (80%); mesalazine = 5 ASA / were mixed in a high-speed mixer (DIOSNA type P10, Osnabrock, 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% layer (based on dry weight) 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 crystals of the W active ingredient 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. Inert film fillers can similarly be dissolved or suspended. Organic or aqueous solvents or dispersants may be used. In addition, dispersion stabilizers (for example: Tween 80 or other suitable emulsifiers or stabilizers) may be used.

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-sp /, pH 6.8 and pH 7.2: phosphate buffer supplemented with DAB 10. ER VEKA type DT 80 device "/ paddle / [sic]; 900 ml of test medium at 37 ° C, 100 rpm. Each test is performed three times.

Preparation of multidrug dosage forms

The multidrug formulation is prepared by

Mixing the various pellet forms A and B, for example in a ratio of 1: 1 or in another ratio, depending on the amount of active ingredient present, are enclosed in a capsule 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. _w / 1996 / “Compression of enteric-coated pellets to disintegrating tablets”,

International Journal of Pharmaceutics 143, pp. 13-23 and in WO 96/01624.

Mixtures for the preparation of coated particle tablets are prepared by mixing the pellets with suitable tablet 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. Special

.. 23 ..

• · ···· * · · · _ · · · *. . · · · ...... · ·. ···· ···· .J ………….

a 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. 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. Use of lubricating and releasing agent • · • ·: ·; ; · · · · • · .. · · · · · · ·

.. · · · · · · · The mixture may be omitted if suitable devices are used (for example, an external oiling tablet press) or formulations.

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 40 kN, preferably 10-20 kN. Tablets C presses may be provided with external lubrication systems. Where appropriate, mold filling systems are used which avoid filling the mold 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, in particular preferably 18 to 36, and in particular 20 to 30% by weight, based on the weight of the particle.

Particle 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 particle content of the dosage form is 35-90, especially preferably 40 to 70%, relative to the 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.

EXAMPLES • ·

Example 1: Pellet Form A, inner polymer coating

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

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

Example 2: Pellet Form A, Exterior Polymer Coating The coated cores of Example 1 are [lacuna] with an exterior polymer coating of / meth / acrylate copolymer of 50% by weight methacrylic acid and 50% by weight ethyl acrylate / EUDRAGIT® L1OO-55 or EUDRAGIT® L 30 D-55 / dispersion.

To this end, 25 g of talc, 5 g of triethyl citrate and 204 g of water were added to 166 g 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 / 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, 4 g of glycerol monostearate, 2 g of polysorbate 80, 2.5 g of triethyl citrate and 185 g of water are added to 166 g of a 30% dispersion of the aforementioned copolymer / EUDRAGIT® FS 30 D / / 20% solids content dispersive substance for atomization. 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 multidrug formulation comprising pellet form A and B according to Examples 2 and 3.

Composition of the tablet:

Pellet Form A 250.0 g

Pellet Form B 250.0g

Cellactose 417.5g

Kollidon CL 80.0 g

Magnesium stearate 2.5 g

The mixture can be compressed into tablets directly into a suitable tablet press using, for example, a pressure of 15 kN.

Claims (6)

Patent Claim "" 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 that dissolves rapidly at pH above about 5.5, and pellet form B is provided with an internal polymer coating which, under the USP release test, releases less than 20% of the active ingredient at pH 6.8 for 6 hours and releases more than 50% of the active ingredient at pH 7.2 for 6 hours. 2. A multi-compound dosage form according to claim 1, characterized in that the enteric polymer coating of pellet form A may also consist of acid groups (meth / acrylate copolymer, shellac, HPMCP / hydroxy propyl methyl cellulose phthalate), CAP (cellulose acetate phthalate), HPPS-AS (hydroxy propyl methyl cellulose acetate succinate) or polyvinyl acetate [sic] phthalate. The multidrug formulation according to claim 2, wherein the / 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 is used for enteric polymer coating of pellet form A. 4. The multidrug formulation according to claim 1 or 2, characterized in that the inner polymer coating of pallet form A consists of a / meth / acrylate copolymer obtained from the free-radical polymerization of the C1 to C4 alkyl esters of 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 ethyl acrylate and 60 to 80% by weight of methyl methacrylate, ethylcellulose or polyvinyl acetate. 5. The multidrug formulation according to claim 4, 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 / meth / acrylate monomers with quaternary ammonium group in the alkyl radical, was used for the internal polymer coating of pellet form A. 6. A multi-compound dosage form according to one or more of claims 1 to 5, characterized in that the (meth) acrylate [sic] copolymer is comprised of 60 to 95% by weight of the C1- to C4-alkyl esters of acrylic or methacrylic acid and 5 to 40% by weight of (meth) -acrylate monomers with an acid group in the alkyl radical was used for polymer coating of pellet B.