Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
1998-02-24
2001-02-13
Webman, Edward J. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S488000
Reexamination Certificate
active
06187342
ABSTRACT:
The present invention relates to solid drug forms obtainable by extrusion and subsequent shaping of a solvent-free melt, comprising, besides one or more active ingredients,
A) 2-90% by weight of a melt-processable, water-soluble polymer,
B) 5-89.9% by weight of isomalt, and
C) 0-5% by weight of lecithin,
where the stated amounts are based on the total weight of the drug form.
The invention furthermore relates to a process for producing such drug forms.
Formulations containing active ingredients and produced by melt extrusion are generally known.
The extrusion of melts, containing active ingredients, of water-soluble polymers, preferably copolymers of vinylpyrrolidone, is described, for example, in EP-A 240 904 and EP-A 240 906.
The melt extrusion process can be applied to a large number of active ingredients. It is possible specifically to influence the properties of the produced formulations, such as the rate of dissolution of the drug form in the gastrointestinal tract, by using different ancillary substances.
If it is wished to produce solid drug forms with rapid release, it is necessary to use ancillary substances which have a high rate of dissolution in accordance with correspondingly high solubility in water and which, moreover, must not adversely affect the melt-processability of the polymer melt containing active ingredients. Generally employed to date for this purpose have been sugar alcohols such as mannitol or sorbitol or sugars such as lactose.
However, a disadvantage of known compositions is that they are, in some cases, poorly processable, caused by a great tendency to stick during shaping, especially during calendering. In addition, these compositions are frequently still unsatisfactory in respect of release rate. An additional factor is that the lack of mechanical strength of the tablets, because of great embrittlement and thus the occurrence of fissuring, means that improvements are still necessary.
It is an object of the present invention to find drug forms which display rapid release of active ingredient with, at the same time, very good processability and high stability of the drug form.
We have found that this object is achieved by the drug forms defined at the outset.
Suitable active ingredients according to the invention are all those having sufficient thermal stability under the conditions of the melt extrusion process.
Examples of suitable active ingredients are acebutolol, acetylcysteine, acetylsalicylic acid, aciclovir, albrazolam [sic], alfacalcidol, allantoin, allopurinol, ambroxol, amikacin, amiloride, aminoacetic acid, amiodarone, amitriptyline, amlodipine, amoxicillin, ampicillin, ascorbic acid, aspartame, astemizole, atenolol, beclometasone, benserazide, benzalkonium hydrodrochloride [sic], benzocaine, benzoic acid, betametasone, bezafibrate, biotin, biperiden, bisoprolol, bromacepam [sic], bromhexine, bromocriptine, budesonide, bufexamac, buflomedil, buspirone, caffeine, camphor, captopril, carbamazepine, carbidopa, carboplatin, cefaclor, cefalexin, cefatroxil, cefazolin, cefixime, cefotaxime, ceftazidine, ceftriaxone, cefuroxime, celediline [sic], chloramphenicol, chlorhexidine, chlorpheniramine, chlortalidone [sic], choline, ciclosporin, cilastatin, cimetidine, ciprofloxacin, cisapride, cisplatin, claithromycin, clavulanic acid, clomibramine [sic], clonazepam, clonidine, clotrimazole, codeine, colestyramine, cromoglicic acid, cyanocobalamin, cyproterone, desogestrel, dexamethasone, dexpanthenol, dexthromethorphan [sic], dextropropoxiphene, diazepam, diclofenac, digoxin, dihydrocodeine, dihydroergotamine, dihydroergotoxin, diltiazem, diphenhydramine, dipyridamole, dipyrone, disopyramide, domperidonen dopamine, doxocycline [sic], enalapril, ephedrine, epinephrine, ergocalciferol, ergotamine, erythromycin, estradiol, ethinylestradinol, etoposide, Eucalyptus Globulus, famotidine, felodipine, fenofibrate, fenoterol, fentanyl, flavin mononucleotide, fluconazole, flunarizine, fluorouracil, fluoxetine, flurbiprofen, furosemide, gallopamil, gemfibrozil, gentamincin [sic], Ginkgo Biloba [sic], glibenclamide, glipizide, glozapine [sic], Glycyrrhiza Glabra, griseofulvin, guaifenesin, haloperidol, heparin, hyaluronic acid, hydrochlorothiazide, hydrocodone, hydrocortisone, hydromorphone, ibratropium [sic] hydroxide, ibuprofen, imipenem, indomethacin, iohexol, iopamidol, isosorbide dinitrate, isosorbide mononitrate, isotretionin [sic], ketotifen, ketoconazole, ketoprofen, ketorolac, labatalon [sic], lactulose, lecithin, levocarnitine, levodopa, levoglutamide, levonorgestrel, levothyroxine, lidocaine, lipase, lipramine [sic], lisinopril, loperamide, lorazepam, lovastatin, medroxyprogesterone, menthol, methotrexate, methyldopa, methylprednisolone, metoclopramide, metoprolol, miconazole, midazolam, minocycline, minoxidil, misoprostol, morphine, multivitamin and minerals, N-methylephedrine, naftidrofuril, naproxen, neomycin, nicardipine, nicergoline, nicotinamide, nicotine, nicotinic acid, nifedipine, nimodipine, nitrazepam, nitrendipine, nizatidine, norethisterone, norfloxacin, norgestrel, nortriptyline, nystatin, ofloxacin, omeprazole, ondansetron, pancreatin, panthenol, pantothenic acid, paracetamol, penicillin G, penicillin V, phenobarbital, phenoxifylline [sic], phenoxymethylpenicillin, phenylephrine, phenylpropanolamine, phenytoin, piroxicam, polymyxin B, povidone-iodine, pravastatin, prazepam, prazosin, prednisolone, prednisone, promocriptine [sic], propafenone, propranolol, proxyphylline, pseudoephedrine, pyridoxine, quinidine, ramipril, ranitidine, reserpine, retinol, riboflavin, rifampicin, rutoside, saccharin, salbutamol, salcatonin, salicyl [sic] acid, simvastatin, somatropin, sotalol, spironolactone, sucralfate, sulbactam, sulfamethoxazole, sulfasalazine, sulpiride, tamoxifen, tegafur, teprenone, terazosin, terbutaline, terfenadine, tetracycline, theophylline, thiamine, ticlopidine, timolol, tranexamic acid, tretinoin, triamcinolone acetonide, triamterene, trimethoprim, troxerutin, uracil, valproic acid, vancomycin, verapamil, vitamins [sic] E, volinic [sic] acid, zidovudine.
Especially suitable active ingredients according to the invention are those which are suitable for the production of rapid-release forms (instant-release forms).
The preferred active ingredient is verapamil or its physiologically tolerated salts, particularly preferably vearapamil hydrochloride. Paracetamol is also preferred.
Melt-processable, water-soluble polymer components A) which may be mentioned are:
alkylcelluloses such as methylcellulose
hydroxymethylcelluloses such as hydroxymethyl-, hydroxyethyl-, hydroxypropyl- and hydroxybutylcellulose,
hydroxyalkylmethylcelluloses such as hydroxyethylmethyl- and hydroxypropylmethylcellulose,
polyvinylpyrrolidone,
copolymers of N-vinylpyrrolidone and vinyl acetate with up to 50% by weight of vinyl acetate,
carboxyalkylcelluloses such as carboxymethylcelluloses,
polysaccharides such as alginic acid and its alkali metal and ammonium salts,
polyethylene glycols
and mixtures of such water-soluble polymers.
The component A) should, in the complete mixture of all the components, soften or melt in the range from 50 to 180° C., preferably 80 to 140° C., so that the composition can be extruded. Processability at these temperatures can, where appropriate, be achieved by adding plasticizers.
“Water-soluble” means that at least 0.5 g, preferably at least 2 g, of the polymer dissolves, where appropriate also colloidally, in 100 g of water at 20° C.
Preferred polymer components A) are, besides polyvinylpyrrolidone, the polyethylene glycols and, particularly preferably, a copolymer obtained by free-radical polymerization of 60% by weight of N-vinylpyrrolidone and 40% by weight of vinyl acetate. Hydroxypropylcelluloses are also preferred.
The drug forms contain as an ancillary substance isomalt which is also known under the brand name Palatinit®. Is
Breitenbach Jorg
Neumann Jorg
Rosenberg Joerg
Zeidler Jurgen
BASF - Aktiengesellschaft
Keil & Weinkauf
Webman Edward J.
LandOfFree
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