CA2232357A1 - A process for producing solid drug forms - Google Patents
A process for producing solid drug forms Download PDFInfo
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- CA2232357A1 CA2232357A1 CA 2232357 CA2232357A CA2232357A1 CA 2232357 A1 CA2232357 A1 CA 2232357A1 CA 2232357 CA2232357 CA 2232357 CA 2232357 A CA2232357 A CA 2232357A CA 2232357 A1 CA2232357 A1 CA 2232357A1
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- Prior art keywords
- extruder
- mixture
- acid
- mixing
- premix
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
Abstract
The invention concerns a method of producing medicaments in solid form by mixing at least one pharmacologically acceptable polymer binder, at least one pharmaceutical active substance and optionally conventional pharmaceutical additives, extruding the mixture and shaping the medicament, a pre-mixture being prepared from the components and fed into the extruder. The method according to the invention enables high-quality medicaments to be produced in a simple and careful manner.
Description
BASF Aktiengesellschaft 950021 O.Z. 00~0/~o309 A process for producing solid drug forms The present invention relates to a process for producing solid 5 drug forms by mixing at least one pharmacologically acceptable polymeric binder and at least one pharmaceutical active ingredient, with or without conventional pharmaceutical additives.
lO A simple continuous process for producing solid drug forms has been known for some time and entails a solvent-free melt of a polymeric binder which contains active ingredient being extruded, and the extrudate being shaped to the required drug form, for example in a calender with molding rolls, see EP-A-240 904, 15 EP-A-240 906 and EP-A-337 256. A problem with this continuous process is the accurate metering of all the individual components which is necessary to produce drugs. It did not appear practicable to produce a premix of the components and to feed this premix into the extruder because the risk of d~ ;ng of the 20 components and thus the production of drug forms of non-uniform composition is too great. In order to achieve adequate mixing, the components were fed singly into the extruder, specifically into an extruder having an efficient mixing effect, for example a multiscrew extruder. EP-A-337 256 proposes continuous metering of 25 the individual components into the hopper of an extruder. The metering is carried out by very precise differential weigh feeders. It is nevertheless impossible completely to avoid variations in metering because the differential weigh feeders must be operated volumetrically on charging. The result of this 30 is that at least part of the resulting drug forms does not meet the specifications.
Another disadvantage of the process described in EP-A-337 256 is the great complexity of the distribution of the powdered active 35 ingredient during mixing in the plastic zone of the extruder in order to be able to implement the required axial back-mixing. The coupling of the melting and mixing in the extruder makes it necessary, in order to achieve adequate mixing, for there to be a relatively long residence time in a zone with high shear. This 40 may lead to local overheating and damage to the product, especially on use of a shear- and temperature-sensitive active ingredient.
Finally, the process described in EP-A-337 256 also has the 45 disadvantage that the extruder must be starve fed, ie. the extruder must be operated at higher speeds than when operated CA 022323~7 1998 04-21 BASF Aktiengesellschaft 950021 O.Z. 0050/46309 from a full hopper. This leads to greater product damage, in particular in the mixing zones necessary for adequate mixing.
It is an object of the present invention to provide a simple and 5 mild process for producing solid drug forms.
We have found that this object is achieved when the extruder is fed with a premix of the components.
10 The present invention therefore relates to a process for producing solid drug forms by mixing at least one pharmacologically acceptable polymeric binder and at least one pharmaceutical active ingredient, with or without conventional pharmaceutical additives, melting the mixture in an extruder to a 15 plastic composition and shaping the drug form, wherein a premix is produced from the components and is fed into the extruder.
It is possible according to the invention to use both a dry premix and a premix of liquid and solid components. A premix of 20 liquid and solid products has the advantage that the solid ingredients have already been wetted. This generally results in more favorable flow properties.
The premix is prepared in a conventional mixer for solids. It is 25 possible, for example, to use mixing apparatus like that employed for mixing in plastic technology. Suitable equipment is described, for example, in "Mischen beim Herstellen und Verarbei-ten von Kunststoffen", H. Pahl, VDI-Verlag, 1986.
30 In the process according to the invention, the solid components do not, in contrast to conventional tablet production, have to be extremely finely divided because homogenization also takes place subsequently in the extruder.
35 The extruder is preferably fed directly with the premix from the full hopper so that accurate continuous metering of the complete mixture is unnecessary. If flow problems occur, such as bridging, adherence of the product in the hopper etc., suitable measures to improve flow can be provided. For example, it is possible to add 40 flow promoters or antiblocking agents as explained in detail hereinafter. It is additionally possible to provide mechanical measures such as the use of vibrators or agitators.
In the extrusion stage, the binder is softened and/or melted and 45 the plastic composition is homogeni~ed by longitudinal and transverse mixing in the extruder.
CA 022323~7 1998-04-21 M/~ q BASF Aktiengesellschaft 950021 O.Z. 0050/46309 The process according to the invention makes it possible to use a single-screw extruder, which is less costly and is associated with a smaller increase in temperature in the pressure buildup zone than the multiscrew extruders necessary for previous 5 processes. A single-screw extruder is particularly suitable when processing products with good feed properties. When there are high demands on constancy of output, it is expedient to provide a special extraction device, for example a gear pump.
10 A co-rotating, intermeshing screw machine is also advantageous as extruder, being capable of operation at a lower speed than in processes described in the prior art, owing to the charging from a full hopper, so that the risk of local overheating and thus damage to the product is reduced. This type of extruder is also 15 suitable for products with less good feed properties and is distinguished by a good mixing action. It may also be expedient to use in conjunction with this type of extruder a special extraction device, for example a gear pump.
20 It is also advantageous to employ as extruder a counter-rotating, intermeshing machine. An extruder of this type has better feed characteristics and a greater efficiency in the pressure buildup than a co-rotating extruder. The improved feed characteristics make more economic operation possible because there are limits on 25 the output of co-rotating extruders since the feed characteristics are worse and when binders with a relatively low apparent density are used. The greater efficiency in the pressure buildup results in a smaller rise in temperature in the pressure buildup zone compared with co-rotating extruders, so that the 30 temperature of the melt can be kept lower and damage to the product can be reduced. This type of extruder is therefore particularly suitable for shear- and temperature-sensitive products.
35 If there are special requirements for the homogenizing action and degassing, it is also possible and advantageous to employ multiscrew extruders (3 to 10 screws).
Compared with prior art processes, in the process according to 40 the invention the complexity of metering the components is considerably reduced and is restricted to the preparation of the premix. Despite this, the accuracy of metering is distinctly improved. Variations in the product quality are thereby avoided, which means that the process according to the invention provides 45 the required drug forms reliably and with the required specifications.
CA 022323~7 1998-04-21 1~1/ ~ U ~
BASF Aktiengesellschaft 950021 O.Z. 0050~46309 The premix comprises at least one pharmacologically suitable, thermoplastic, polymeric ~inder and at least one pharmaceutical active ingredient, with or without pharmaceutical additives (ancillary substances). On melting, the premix must become 5 extrudable, ie. pasty or a viscous liquid (thermoplastic). The glass transition temperature of the mixture is below the decomposition temperature of all the components present in the mixture. The binder should preferably be soluble or swellable in a physiological environment. Examples of suitable binders are:
polyvinylpyrrolidone (PVP), copolymers of N-vinylpyrro-lidone (NVP) and vinyl esters, especially vinyl acetate, copolymers of vinyl acetate and crotonic acid, partially hydrolyzed polyvinyl acetate, polyvinyl alcohol, 15 poly(hydroxyalkyl acrylates), poly(hydroxyalkyl methacrylates), polyacrylates and polymethacrylates (Eudragit types), copolymers of methyl methacrylate and acrylic acid, cellulose esters, cellulose ethers, especially methylcellulose and ethylcellulose, hydroxyalkylcelluloses, especially hydroxypropylcellulose, 20 hydroxyalkylalkylcelluloses, especially hydroxypropylethylcellulose, cellulose phthalates, especially cellulose acetate phthalate and hydroxypropylmethylcellulose phthalate, starch, starch derivatives, eg. maltodextrins, sugar alcohols, such as mannitol or palatinose and mannans, especially 25 galactomannans. The K values (according to H. Fikentscher, Cellu-lose-Chemie 13 (1932), 58-64 and 71-74) of the polymers are in the range from 10 to 100, preferably 12 to 70, in particular 12 to 35, and for PVP preferably 12 to 35, in particular 12 to 17.
30 Preferred polymeric binders are polyvinylpyrrolidone, copolymers of N-vinylpyrrolidone and vinyl esters, poly(hydroxyalkyl acrylates), poly(hydroxyalkyl methacrylates)~ polyacrylates, polymethacrylates, alkylcelluloses and hydroxyalkylcelluloses.
35 The polymeric binder must soften or melt in the complete mixture of all the components in the range from 50 to 180~C, preferably 60 to 130~C. The glass transition temperature of the mixture must therefore be below 180~C, preferably below 130~C. If necessary, it is reduced by conventional, pharmacologically acceptable 40 plasticizing ancillary substances. However, the mixture preferably contains no plasticizer. Examples of suitable plasticizers are:
long-chain alcohols, ethylene glycol, propylene glycol, glycerol, 45 trimethylolpropane, triethylene glycol, butanediols, pentanols, such as pentaerythritol, hexanols, polyethylene glycols, polypropylene glycols, polyethylene/propylene glycols, silicones, BASF Aktiengesellschaft 950021 O.Z. 0050/46309 aromatic carboxylic esters (eg. dialkyl phthalates, trimellitic esters, benzoic esters, terephthalic esters) or aliphatic dicarboxylic esters (eg. dialkyl adipates, sebacic esters, azelaic esters, citric- and tartaric esters), fatty acid esters, 5 such as glycerol mono-, di- or triacetate or sodium diethylsulfosuccinate. The plasticizer concentration is generally from 0.5 to 15, preferably O.S to 5, % of the total weight of the mixture.
10 Examples of conventional pharmaceutical ancillary substances, whose total amount can be up to 100% of the weight of the polymer, are extenders or bulking agents such as silicates or diatomaceous 15 earth, magnesium oxide, aluminum oxide, titanium oxide, stearic acid or its salts, eg. the magnesium or calcium salt, methylcellulose, sodium carboxymethylcellulose, talc, sucrose, lactose, cereal or corn starch, potato flour, polyvinyl alcohol, expecially in a concentration of from 0.02 to 50, preferably 0.20 20 to 20, % of the total weight of the mixture;
lubricants such as aluminum and calcium stearates, talc and silicones, in a concentration of from 0.1 to 5, preferably 0.1 to 3, % of the total weight of the mixture;
dyes, such as azo dyes, organic or inorganic pigments or dyes of natural origin, with inorganic pigments in a concentration of from 0.001 to 10, preferably 0.5 to 3, % of the total weight of the mixture being preferred;
flowability agents such as Ani~l or vegetable fats, especially in hydrogenated form and those which are solid at room temperature. These fats preferably have a melting point of 50~C or above. Triglycerides of C12, C14, C16 and C18 fatty acids are 35 preferred. Waxes, such as carnauba wax, can also be used. These fats and waxes can advantageously be admixed alone or together with mono- and/or diglycerides or phosphatides, especially lecithin. The mono- and diglycerides are preferably derived from the abovementioned fatty acid types. The total amount of fats, 40 waxes, mono- and diglycerides and/or lecithins is 0.1 to 30, preferably 0.1 to 5, % of the total weight of the composition for the particular layer;
stabilizers, such as antioxidants, light stabilizers, 45 hydroperoxide destroyers, radical scavengers, stabilizers against microbial attack.
CA 022323~7 1998-04-21 ~Yl/JU 1~--BASF AktiengesellsChaft 9S0021 0.Z. 0050/46309 It is furthermore possible to add wetting agents, preservatives, disintegrants, adsorbents and mold release and blowing agents (cf., for example, H. Sucker et al. Pharmazeutische Technologie, Thieme-Verlag, Stuttgart 1977).
Ancillary substances also mean for the purpose of the invention substances for producing a solid solution with the pharmaceutical active ingredient. Examples of these auxiliaries are pentaerythritol and pentaerythritol tetraacetate, polymers such 10 as polyethylene oxides and polypropylene oxides and their block copolymers (poloxamers)t phosphatides such as lecithin, homo- and copolymers of vinylpyrrolidone, surfactants such as polyoxyethylene 40 stearate, and citric and succinic acids, bile acids, sterols and others as indicated, for example, by J.L.
15 Ford, Pharm. Acta Helv. 61, 69-88 (1986) angegeben.
Additions of bases and acids to conrol the solubility of an active ingredient (see, for example, K. Thoma et al., Pharm. Ind.
51, 98-101 (1989)) are also regarded as pharmaceutical ancillary 20 substances..
The only precondition for suitability of ancillary substances is adequate temperature stability.
25 Pharmaceutical active ingredients mean for the purpose of the invention all substances with a pharmaceutical effect and m;n;m~l side effects as long as they do not decompose under the processing conditions. The amount of active ingredient per dose unit and the concentration may vary within wide limits depending 30 on the efficacy and release rate. The only condition is that they are sufficient to achieve the required effect. Thus, the active ingredient concentration can be in the range from 0.1 to 95, preferably from 20 to 80, in particular from 30 to 70, % by weight. Combinations of active ingredients, eg.
35 ibuprofen/caffeine, can also be employed. Active ingredients for the purpose of the invention are also vitamins and minerals, and crop treatment agents and insecticides. The vitamins include the vitamins of the A group, of the B group, which means, besides Bl, B2, B6 and B12 and nicotinic acid and nicotinamide, also compounds 40 with vitamin B properties such as adenine, choline, pantothenic acid, biotin, adenylic acid, folic acid, orotic acid, pangamic acid, carnitine, p-aminobenzoic acid, myo-inositol and lipoic acid, and vitamin C, vitamins of the D group, E group, F group, H group, I and J groups, R group and P group. Active ingredients 45 for the purpose of the invention also include therapeutic peptides.
CA 022323~7 1998-04-21 JV~
BASF Aktiengesellschaft 950021 O.Z. 0050/46309 The process according to the invention is suitable, for example, for processing the following active ingredients:
acebutolol, acetylcysteine, acetylsalicylic acid, acyclovir, 5 alprazolam, alfacalcidol, allantoin, allopurinol, ambroxol, amikacin, amiloride, aminoacetic acid, amiodarone, amitriptyline, amlodipine, amoxicillin, ampicillin, ascorbic acid, aspartame, astemizole, atenolol, beclomethasone, benserazide, benzalkonium hydrochloride, benzocaine, benzoic acid, betamethasone, 10 bezafibrate, biotin, biperiden, bisoprolol, bromazepam, bromhexine, bromocriptine, budesonide, bufexamac, buflomedil, buspirone, caffeine, camphor, captopril, carbamazepine, carbidopa, carboplatin, cefachlor, cefalexin, cefatroxil, cefazolin, cefixime, cefot~x;me, ceftazidime, ceftriaxone, 15 cefuroxime, selegiline, chloramphenicol, chlorhexidine, chlorpheniramine, chlortalidone, choline, cyclosporin, cilastatin, cimetidine, ciprofloxacin, cisapride, cisplatin, clarithromycin, clavulanic acid, clomipramine, clonazepam, clonidine, clotrimazole, codeine, cholestyramine, cromoglycic 20 acid, cyanocobalamin, cyproterone, desogestrel, dexamethasone, dexpanthenol, dextromethorphan, dextropropoxiphen, diazepam, diclofenac, digoxin, dihydrocodeine, dihydroergotamine, dihydroergotoxin, diltiazem, diphenhydramine, dipyridamole, dipyrone, disopyramide, domperidone, dopamine, doxycycline, 25 enalapril, ephedrine, epinephrine, ergocalciferol, ergotamine, erythromycin, estradiol, ethinylestradiol, etoposide, Eucalyptus globulus, famotidine, felodipine, fenofibrate, fenoterol, fentanyl, flavine mononucleotide, fluconazole, flunarizine, fluorouracil, fluoxetine, flurbiprofen, furosemide, gallopamil, 30 gemfibrozil, gentamicin, Ginkgo biloba, glibenclamide, glipizide, clozapine, Glycyrrhiza glabra, griseofulvin, guaifenesin, haloperidol, heparin, hyaluronic acid, hydrochlorothiazide, hydrocodone, hydrocortisone, hydromorphone, ipratropium hydroxide, ibuprofen, imipenem, indomethacin, iohexol, iopamidol, 35 isosorbide dinitrate, isosorbide mononitrate, isotretinoin, ketotifen, ketoconazole, ketoprofen, ketorolac, labetalol, lactulose, lecithin, levocarnitine, levodopa, levoglutamide, levonorgestrel, levothyroxine, lidocaine, lipase, imipramine, lisinopril, loperamide, lorazepam, lovastatin, 40 medroxyprogesterone, menthol, methotrexate, methyldopa, methylprednisolone, metoclopramide, metoprolol, miconazole, midazolam, minocycline, minoxidil, misoprostol, morphine, multivitamin mixtures or combinations and mineral salts, N-methylephedrine, naftidrofuryl, naproxen, neomycin, 45 nicardipine, nicergoline, nicotinamide, nicotine, nicotinic acid, nifedipine, nimodipine, nitrazepam, nitrendipine, nizatidine, norethisterone, norfloxacin, norgestrel, nortriptyline, nystatin, CA 022323~7 1998-04-21 ..., ~v, ,_ BASF Aktiengesellschaft 950021 O.Z. 0050/46309 ofloxacin, omeprazole, ondansetron, pancreatin, panthenol, pantothenic acid, paracetamol, penicillin G, penicillin V, phenobarbital, pentoxifylline, phenoxymethylpenicillin, phenylephrine, phenylpropanolamine, phenytoin, piroxicam, 5 polymyxin B, povidone-iodine, pravastatin, prazepam, prazosin, prednisolone, prednisone, bromocriptine, propafenone, propranolol, proxyphylline, pseudoephedrine, pyridoxine, quinidine, ramipril, ranitidine, reserpine, retinol, riboflavin, rifampicin, rutoside, saccharin, salbutamol, salcatonin, 10 salicylic acid, simvastatin, somatotropin, sotalol, spironolactone, sucralfate, sulbactam, sulfamethoxazole, sulfasalazine, sulpiride, tamoxifen, tegafur, teprenone, terazosin, terbutaline, terfenadine,tetracycline, theophylline, thiamine, ticlopidine, timolol, tranexamic acid, tretinoin, 15 triamcinolone acetonide, triamterene, trimethoprim, troxerutin, uracil, valproic acid, vancomycin, verapamil, vitamin E, folinic acid, zidovudine.
Preferred active ingredients are ibuprofen (as racemate, 20 enantiomer or enriched enantiomer), ketoprofen, flurbiprofen, acetylsalicylic acid, verapamil, paracetamol, nifedipine or captopril.
There may specifically be the formation of solid solutions. The 25 term "solid solutions" is familiar to the skilled worker, for example from the literature cited at the outset. In solid solutions of pharmaceutical active ingredients in polymers, the active ingredient is present in the form of a molecular dispersion in the polymer.
The resulting mixture is solvent-free, ie. it contains neither water nor an organic solvent.
The shaping of the mixture is carried out by conventional 35 methods. Examples of conventional methods are:
Hot granulation, which results in lenticular pellets with a diameter of 1 to 10 mm;
40 Cold granulation, which results in cylindrical products with a length to diameter ratio of 1 to 10 and a diameter of 0.5 to lO mm;
Calendering in a calender with two molding rolls, as described, 45 for example, in EP-A-240 904;
CA 022323~7 1998-04-21 lVll J ~ 1 ~'t 8ASF Aktiengesellschaft 950021 O.Z. 0050/46309 Extrusion and shaping of the still plastic extrudate between a belt and a roll or between two belts or between two rolls, as described in EP-A-358 105.
5 Solid pharmaceutical forms which can be produced by the process according to the invention are, in particular, pellets, granules and uncoated or coated tablets. The resulting forms, in particular the granules, can also subsequently be ground to powders and employed in this form, for example in hard gelatin 10 capsules. Granules can also be compressed to tablets in a conventional way. The resulting drug forms can finally also be provided in a conventional way with film coatings which control the release of active ingredient or mask the flavor. Suitable materials for such coatings are polyacrylates such as the 15 Eudragit types, cellulose esters such as the hydroxypropylmethyl-cellulose phthalates, and cellulose ethers, such as ethylcellulose, hydroxypropylmethylcellulose or hydroxypropyl-cellulose.
20 The process according to the invention thus also makes it possible to produce drug forms by conventional methods such as compression of granules to tablets, but without the disadvantages of these conventional processes.
25 The following examples illustrate the invention without restricting it.
Example 1 300 kg of polyvinylpyrrolidone with a K value of 30, 6 kg of 30 Aerosil 90, 54 kg of mannitol and 240 kg of ibuprofen were metered into a solids mixer tKrauss Maffei type MT 0.75/200) consisting of a conical container which is arranged vertically and in which there is a mixing screw, and were mixed discontinuously. This entailed the mixing screw executing two 35 rotational movements, a fast one round its own axis and a slow one round the container axis.
This solid mixture was metered at a throughput of 15 kg/h via a weigh feeder continuously into a co-rotating ZSK30 extruder (Wer-40 ner & Pfleiderer). The extruder was fed from the full hopperduring this. There was no d~m;x;ng of the dry premix.
In the extruder, the mixture was melted, conveyed and homogenized to a plastic composition by longitudinal and transverse mixing, 45 and extruded, applying the following conditions, Section 1: 43~C
Section 2: 57~C
CA 022323~7 1998-04-21 BASF Aktiengesellschaft 950021 o.Z. 0050/46309 Section 3: 120~C
Section 4: 100~C
Section 5: 100~C
Head : 100~C
5 Die : 100~C
The extrudate of the composition was subjected to cold-cut granulation and subsequently continuous pelleting.
10 Transparent pellets were obtained.
They show a release of more than 70 % in 30 minutes, measured at pH 7.2, which complies with the requirements of USP XXII.
15 Example 2 300 kg of polyvinylpyrrolidone with a K value of 30, 6 kg of Aerosil 90, 54 kg of maltodextrins and 240 kg of ibuprofen were metered into a solids mixer as in Example 1 and mixed discontinuously.
This solid mixture was metered at a throughput of 15 kg/h via a weigh feeder continuously into a co-rotating ZSK30 extruder (Wer-ner & Pfleiderer). The extruder was fed from the full hopper during this. A compressed air vibrator was used to prevent 25 bridging. There was no ~m; ~; ng of the dry premix.
In the extruder, the mixture was melted, conveyed and homogenized by longitudinal and transverse mixing to a plastic composition, and was extruded, under the conditions indicated in Example 1.
The composition was extruded as ribbon and shaped in a calender with two molding rolls to oblong tablets which release the active ingredient as bolus dose. The resulting tablets show a release of > 70 % in 30 minutes, measured at pH 7.2, which complies with the 35 requirements of USP XXII.
Example 3 100 kg/h polyvinylpyrrolidone with a K value of 30, 2 kg/h Aerosil 90, 18 kg/h maltodextrins and 80 kg/h ibuprofen were 40 metered continuously into a continuously operating solids mixer (Gericke type GAC-307) and mixed.
This solid mixture was continuously metered into a co-rotating ZSK83 extruder (Werner & Pfleiderer). The extruder was fed from 45 the full hopper during this.
CA 022323~7 1998-04-21 BASF Aktiengesellschaft 950021 O.Z. 0050/46309 J
In the extruder, the mixture was melted, conveyed and homogenized by longitudinal and transverse mixing to a plastic composition, and was extruded, under the conditions indicated in Example 1.
5 The extrudate of this composition was subjected to cold-cut granulation and subsequently continuous pelleting.
~/ ~ v ~ .
lO A simple continuous process for producing solid drug forms has been known for some time and entails a solvent-free melt of a polymeric binder which contains active ingredient being extruded, and the extrudate being shaped to the required drug form, for example in a calender with molding rolls, see EP-A-240 904, 15 EP-A-240 906 and EP-A-337 256. A problem with this continuous process is the accurate metering of all the individual components which is necessary to produce drugs. It did not appear practicable to produce a premix of the components and to feed this premix into the extruder because the risk of d~ ;ng of the 20 components and thus the production of drug forms of non-uniform composition is too great. In order to achieve adequate mixing, the components were fed singly into the extruder, specifically into an extruder having an efficient mixing effect, for example a multiscrew extruder. EP-A-337 256 proposes continuous metering of 25 the individual components into the hopper of an extruder. The metering is carried out by very precise differential weigh feeders. It is nevertheless impossible completely to avoid variations in metering because the differential weigh feeders must be operated volumetrically on charging. The result of this 30 is that at least part of the resulting drug forms does not meet the specifications.
Another disadvantage of the process described in EP-A-337 256 is the great complexity of the distribution of the powdered active 35 ingredient during mixing in the plastic zone of the extruder in order to be able to implement the required axial back-mixing. The coupling of the melting and mixing in the extruder makes it necessary, in order to achieve adequate mixing, for there to be a relatively long residence time in a zone with high shear. This 40 may lead to local overheating and damage to the product, especially on use of a shear- and temperature-sensitive active ingredient.
Finally, the process described in EP-A-337 256 also has the 45 disadvantage that the extruder must be starve fed, ie. the extruder must be operated at higher speeds than when operated CA 022323~7 1998 04-21 BASF Aktiengesellschaft 950021 O.Z. 0050/46309 from a full hopper. This leads to greater product damage, in particular in the mixing zones necessary for adequate mixing.
It is an object of the present invention to provide a simple and 5 mild process for producing solid drug forms.
We have found that this object is achieved when the extruder is fed with a premix of the components.
10 The present invention therefore relates to a process for producing solid drug forms by mixing at least one pharmacologically acceptable polymeric binder and at least one pharmaceutical active ingredient, with or without conventional pharmaceutical additives, melting the mixture in an extruder to a 15 plastic composition and shaping the drug form, wherein a premix is produced from the components and is fed into the extruder.
It is possible according to the invention to use both a dry premix and a premix of liquid and solid components. A premix of 20 liquid and solid products has the advantage that the solid ingredients have already been wetted. This generally results in more favorable flow properties.
The premix is prepared in a conventional mixer for solids. It is 25 possible, for example, to use mixing apparatus like that employed for mixing in plastic technology. Suitable equipment is described, for example, in "Mischen beim Herstellen und Verarbei-ten von Kunststoffen", H. Pahl, VDI-Verlag, 1986.
30 In the process according to the invention, the solid components do not, in contrast to conventional tablet production, have to be extremely finely divided because homogenization also takes place subsequently in the extruder.
35 The extruder is preferably fed directly with the premix from the full hopper so that accurate continuous metering of the complete mixture is unnecessary. If flow problems occur, such as bridging, adherence of the product in the hopper etc., suitable measures to improve flow can be provided. For example, it is possible to add 40 flow promoters or antiblocking agents as explained in detail hereinafter. It is additionally possible to provide mechanical measures such as the use of vibrators or agitators.
In the extrusion stage, the binder is softened and/or melted and 45 the plastic composition is homogeni~ed by longitudinal and transverse mixing in the extruder.
CA 022323~7 1998-04-21 M/~ q BASF Aktiengesellschaft 950021 O.Z. 0050/46309 The process according to the invention makes it possible to use a single-screw extruder, which is less costly and is associated with a smaller increase in temperature in the pressure buildup zone than the multiscrew extruders necessary for previous 5 processes. A single-screw extruder is particularly suitable when processing products with good feed properties. When there are high demands on constancy of output, it is expedient to provide a special extraction device, for example a gear pump.
10 A co-rotating, intermeshing screw machine is also advantageous as extruder, being capable of operation at a lower speed than in processes described in the prior art, owing to the charging from a full hopper, so that the risk of local overheating and thus damage to the product is reduced. This type of extruder is also 15 suitable for products with less good feed properties and is distinguished by a good mixing action. It may also be expedient to use in conjunction with this type of extruder a special extraction device, for example a gear pump.
20 It is also advantageous to employ as extruder a counter-rotating, intermeshing machine. An extruder of this type has better feed characteristics and a greater efficiency in the pressure buildup than a co-rotating extruder. The improved feed characteristics make more economic operation possible because there are limits on 25 the output of co-rotating extruders since the feed characteristics are worse and when binders with a relatively low apparent density are used. The greater efficiency in the pressure buildup results in a smaller rise in temperature in the pressure buildup zone compared with co-rotating extruders, so that the 30 temperature of the melt can be kept lower and damage to the product can be reduced. This type of extruder is therefore particularly suitable for shear- and temperature-sensitive products.
35 If there are special requirements for the homogenizing action and degassing, it is also possible and advantageous to employ multiscrew extruders (3 to 10 screws).
Compared with prior art processes, in the process according to 40 the invention the complexity of metering the components is considerably reduced and is restricted to the preparation of the premix. Despite this, the accuracy of metering is distinctly improved. Variations in the product quality are thereby avoided, which means that the process according to the invention provides 45 the required drug forms reliably and with the required specifications.
CA 022323~7 1998-04-21 1~1/ ~ U ~
BASF Aktiengesellschaft 950021 O.Z. 0050~46309 The premix comprises at least one pharmacologically suitable, thermoplastic, polymeric ~inder and at least one pharmaceutical active ingredient, with or without pharmaceutical additives (ancillary substances). On melting, the premix must become 5 extrudable, ie. pasty or a viscous liquid (thermoplastic). The glass transition temperature of the mixture is below the decomposition temperature of all the components present in the mixture. The binder should preferably be soluble or swellable in a physiological environment. Examples of suitable binders are:
polyvinylpyrrolidone (PVP), copolymers of N-vinylpyrro-lidone (NVP) and vinyl esters, especially vinyl acetate, copolymers of vinyl acetate and crotonic acid, partially hydrolyzed polyvinyl acetate, polyvinyl alcohol, 15 poly(hydroxyalkyl acrylates), poly(hydroxyalkyl methacrylates), polyacrylates and polymethacrylates (Eudragit types), copolymers of methyl methacrylate and acrylic acid, cellulose esters, cellulose ethers, especially methylcellulose and ethylcellulose, hydroxyalkylcelluloses, especially hydroxypropylcellulose, 20 hydroxyalkylalkylcelluloses, especially hydroxypropylethylcellulose, cellulose phthalates, especially cellulose acetate phthalate and hydroxypropylmethylcellulose phthalate, starch, starch derivatives, eg. maltodextrins, sugar alcohols, such as mannitol or palatinose and mannans, especially 25 galactomannans. The K values (according to H. Fikentscher, Cellu-lose-Chemie 13 (1932), 58-64 and 71-74) of the polymers are in the range from 10 to 100, preferably 12 to 70, in particular 12 to 35, and for PVP preferably 12 to 35, in particular 12 to 17.
30 Preferred polymeric binders are polyvinylpyrrolidone, copolymers of N-vinylpyrrolidone and vinyl esters, poly(hydroxyalkyl acrylates), poly(hydroxyalkyl methacrylates)~ polyacrylates, polymethacrylates, alkylcelluloses and hydroxyalkylcelluloses.
35 The polymeric binder must soften or melt in the complete mixture of all the components in the range from 50 to 180~C, preferably 60 to 130~C. The glass transition temperature of the mixture must therefore be below 180~C, preferably below 130~C. If necessary, it is reduced by conventional, pharmacologically acceptable 40 plasticizing ancillary substances. However, the mixture preferably contains no plasticizer. Examples of suitable plasticizers are:
long-chain alcohols, ethylene glycol, propylene glycol, glycerol, 45 trimethylolpropane, triethylene glycol, butanediols, pentanols, such as pentaerythritol, hexanols, polyethylene glycols, polypropylene glycols, polyethylene/propylene glycols, silicones, BASF Aktiengesellschaft 950021 O.Z. 0050/46309 aromatic carboxylic esters (eg. dialkyl phthalates, trimellitic esters, benzoic esters, terephthalic esters) or aliphatic dicarboxylic esters (eg. dialkyl adipates, sebacic esters, azelaic esters, citric- and tartaric esters), fatty acid esters, 5 such as glycerol mono-, di- or triacetate or sodium diethylsulfosuccinate. The plasticizer concentration is generally from 0.5 to 15, preferably O.S to 5, % of the total weight of the mixture.
10 Examples of conventional pharmaceutical ancillary substances, whose total amount can be up to 100% of the weight of the polymer, are extenders or bulking agents such as silicates or diatomaceous 15 earth, magnesium oxide, aluminum oxide, titanium oxide, stearic acid or its salts, eg. the magnesium or calcium salt, methylcellulose, sodium carboxymethylcellulose, talc, sucrose, lactose, cereal or corn starch, potato flour, polyvinyl alcohol, expecially in a concentration of from 0.02 to 50, preferably 0.20 20 to 20, % of the total weight of the mixture;
lubricants such as aluminum and calcium stearates, talc and silicones, in a concentration of from 0.1 to 5, preferably 0.1 to 3, % of the total weight of the mixture;
dyes, such as azo dyes, organic or inorganic pigments or dyes of natural origin, with inorganic pigments in a concentration of from 0.001 to 10, preferably 0.5 to 3, % of the total weight of the mixture being preferred;
flowability agents such as Ani~l or vegetable fats, especially in hydrogenated form and those which are solid at room temperature. These fats preferably have a melting point of 50~C or above. Triglycerides of C12, C14, C16 and C18 fatty acids are 35 preferred. Waxes, such as carnauba wax, can also be used. These fats and waxes can advantageously be admixed alone or together with mono- and/or diglycerides or phosphatides, especially lecithin. The mono- and diglycerides are preferably derived from the abovementioned fatty acid types. The total amount of fats, 40 waxes, mono- and diglycerides and/or lecithins is 0.1 to 30, preferably 0.1 to 5, % of the total weight of the composition for the particular layer;
stabilizers, such as antioxidants, light stabilizers, 45 hydroperoxide destroyers, radical scavengers, stabilizers against microbial attack.
CA 022323~7 1998-04-21 ~Yl/JU 1~--BASF AktiengesellsChaft 9S0021 0.Z. 0050/46309 It is furthermore possible to add wetting agents, preservatives, disintegrants, adsorbents and mold release and blowing agents (cf., for example, H. Sucker et al. Pharmazeutische Technologie, Thieme-Verlag, Stuttgart 1977).
Ancillary substances also mean for the purpose of the invention substances for producing a solid solution with the pharmaceutical active ingredient. Examples of these auxiliaries are pentaerythritol and pentaerythritol tetraacetate, polymers such 10 as polyethylene oxides and polypropylene oxides and their block copolymers (poloxamers)t phosphatides such as lecithin, homo- and copolymers of vinylpyrrolidone, surfactants such as polyoxyethylene 40 stearate, and citric and succinic acids, bile acids, sterols and others as indicated, for example, by J.L.
15 Ford, Pharm. Acta Helv. 61, 69-88 (1986) angegeben.
Additions of bases and acids to conrol the solubility of an active ingredient (see, for example, K. Thoma et al., Pharm. Ind.
51, 98-101 (1989)) are also regarded as pharmaceutical ancillary 20 substances..
The only precondition for suitability of ancillary substances is adequate temperature stability.
25 Pharmaceutical active ingredients mean for the purpose of the invention all substances with a pharmaceutical effect and m;n;m~l side effects as long as they do not decompose under the processing conditions. The amount of active ingredient per dose unit and the concentration may vary within wide limits depending 30 on the efficacy and release rate. The only condition is that they are sufficient to achieve the required effect. Thus, the active ingredient concentration can be in the range from 0.1 to 95, preferably from 20 to 80, in particular from 30 to 70, % by weight. Combinations of active ingredients, eg.
35 ibuprofen/caffeine, can also be employed. Active ingredients for the purpose of the invention are also vitamins and minerals, and crop treatment agents and insecticides. The vitamins include the vitamins of the A group, of the B group, which means, besides Bl, B2, B6 and B12 and nicotinic acid and nicotinamide, also compounds 40 with vitamin B properties such as adenine, choline, pantothenic acid, biotin, adenylic acid, folic acid, orotic acid, pangamic acid, carnitine, p-aminobenzoic acid, myo-inositol and lipoic acid, and vitamin C, vitamins of the D group, E group, F group, H group, I and J groups, R group and P group. Active ingredients 45 for the purpose of the invention also include therapeutic peptides.
CA 022323~7 1998-04-21 JV~
BASF Aktiengesellschaft 950021 O.Z. 0050/46309 The process according to the invention is suitable, for example, for processing the following active ingredients:
acebutolol, acetylcysteine, acetylsalicylic acid, acyclovir, 5 alprazolam, alfacalcidol, allantoin, allopurinol, ambroxol, amikacin, amiloride, aminoacetic acid, amiodarone, amitriptyline, amlodipine, amoxicillin, ampicillin, ascorbic acid, aspartame, astemizole, atenolol, beclomethasone, benserazide, benzalkonium hydrochloride, benzocaine, benzoic acid, betamethasone, 10 bezafibrate, biotin, biperiden, bisoprolol, bromazepam, bromhexine, bromocriptine, budesonide, bufexamac, buflomedil, buspirone, caffeine, camphor, captopril, carbamazepine, carbidopa, carboplatin, cefachlor, cefalexin, cefatroxil, cefazolin, cefixime, cefot~x;me, ceftazidime, ceftriaxone, 15 cefuroxime, selegiline, chloramphenicol, chlorhexidine, chlorpheniramine, chlortalidone, choline, cyclosporin, cilastatin, cimetidine, ciprofloxacin, cisapride, cisplatin, clarithromycin, clavulanic acid, clomipramine, clonazepam, clonidine, clotrimazole, codeine, cholestyramine, cromoglycic 20 acid, cyanocobalamin, cyproterone, desogestrel, dexamethasone, dexpanthenol, dextromethorphan, dextropropoxiphen, diazepam, diclofenac, digoxin, dihydrocodeine, dihydroergotamine, dihydroergotoxin, diltiazem, diphenhydramine, dipyridamole, dipyrone, disopyramide, domperidone, dopamine, doxycycline, 25 enalapril, ephedrine, epinephrine, ergocalciferol, ergotamine, erythromycin, estradiol, ethinylestradiol, etoposide, Eucalyptus globulus, famotidine, felodipine, fenofibrate, fenoterol, fentanyl, flavine mononucleotide, fluconazole, flunarizine, fluorouracil, fluoxetine, flurbiprofen, furosemide, gallopamil, 30 gemfibrozil, gentamicin, Ginkgo biloba, glibenclamide, glipizide, clozapine, Glycyrrhiza glabra, griseofulvin, guaifenesin, haloperidol, heparin, hyaluronic acid, hydrochlorothiazide, hydrocodone, hydrocortisone, hydromorphone, ipratropium hydroxide, ibuprofen, imipenem, indomethacin, iohexol, iopamidol, 35 isosorbide dinitrate, isosorbide mononitrate, isotretinoin, ketotifen, ketoconazole, ketoprofen, ketorolac, labetalol, lactulose, lecithin, levocarnitine, levodopa, levoglutamide, levonorgestrel, levothyroxine, lidocaine, lipase, imipramine, lisinopril, loperamide, lorazepam, lovastatin, 40 medroxyprogesterone, menthol, methotrexate, methyldopa, methylprednisolone, metoclopramide, metoprolol, miconazole, midazolam, minocycline, minoxidil, misoprostol, morphine, multivitamin mixtures or combinations and mineral salts, N-methylephedrine, naftidrofuryl, naproxen, neomycin, 45 nicardipine, nicergoline, nicotinamide, nicotine, nicotinic acid, nifedipine, nimodipine, nitrazepam, nitrendipine, nizatidine, norethisterone, norfloxacin, norgestrel, nortriptyline, nystatin, CA 022323~7 1998-04-21 ..., ~v, ,_ BASF Aktiengesellschaft 950021 O.Z. 0050/46309 ofloxacin, omeprazole, ondansetron, pancreatin, panthenol, pantothenic acid, paracetamol, penicillin G, penicillin V, phenobarbital, pentoxifylline, phenoxymethylpenicillin, phenylephrine, phenylpropanolamine, phenytoin, piroxicam, 5 polymyxin B, povidone-iodine, pravastatin, prazepam, prazosin, prednisolone, prednisone, bromocriptine, propafenone, propranolol, proxyphylline, pseudoephedrine, pyridoxine, quinidine, ramipril, ranitidine, reserpine, retinol, riboflavin, rifampicin, rutoside, saccharin, salbutamol, salcatonin, 10 salicylic acid, simvastatin, somatotropin, sotalol, spironolactone, sucralfate, sulbactam, sulfamethoxazole, sulfasalazine, sulpiride, tamoxifen, tegafur, teprenone, terazosin, terbutaline, terfenadine,tetracycline, theophylline, thiamine, ticlopidine, timolol, tranexamic acid, tretinoin, 15 triamcinolone acetonide, triamterene, trimethoprim, troxerutin, uracil, valproic acid, vancomycin, verapamil, vitamin E, folinic acid, zidovudine.
Preferred active ingredients are ibuprofen (as racemate, 20 enantiomer or enriched enantiomer), ketoprofen, flurbiprofen, acetylsalicylic acid, verapamil, paracetamol, nifedipine or captopril.
There may specifically be the formation of solid solutions. The 25 term "solid solutions" is familiar to the skilled worker, for example from the literature cited at the outset. In solid solutions of pharmaceutical active ingredients in polymers, the active ingredient is present in the form of a molecular dispersion in the polymer.
The resulting mixture is solvent-free, ie. it contains neither water nor an organic solvent.
The shaping of the mixture is carried out by conventional 35 methods. Examples of conventional methods are:
Hot granulation, which results in lenticular pellets with a diameter of 1 to 10 mm;
40 Cold granulation, which results in cylindrical products with a length to diameter ratio of 1 to 10 and a diameter of 0.5 to lO mm;
Calendering in a calender with two molding rolls, as described, 45 for example, in EP-A-240 904;
CA 022323~7 1998-04-21 lVll J ~ 1 ~'t 8ASF Aktiengesellschaft 950021 O.Z. 0050/46309 Extrusion and shaping of the still plastic extrudate between a belt and a roll or between two belts or between two rolls, as described in EP-A-358 105.
5 Solid pharmaceutical forms which can be produced by the process according to the invention are, in particular, pellets, granules and uncoated or coated tablets. The resulting forms, in particular the granules, can also subsequently be ground to powders and employed in this form, for example in hard gelatin 10 capsules. Granules can also be compressed to tablets in a conventional way. The resulting drug forms can finally also be provided in a conventional way with film coatings which control the release of active ingredient or mask the flavor. Suitable materials for such coatings are polyacrylates such as the 15 Eudragit types, cellulose esters such as the hydroxypropylmethyl-cellulose phthalates, and cellulose ethers, such as ethylcellulose, hydroxypropylmethylcellulose or hydroxypropyl-cellulose.
20 The process according to the invention thus also makes it possible to produce drug forms by conventional methods such as compression of granules to tablets, but without the disadvantages of these conventional processes.
25 The following examples illustrate the invention without restricting it.
Example 1 300 kg of polyvinylpyrrolidone with a K value of 30, 6 kg of 30 Aerosil 90, 54 kg of mannitol and 240 kg of ibuprofen were metered into a solids mixer tKrauss Maffei type MT 0.75/200) consisting of a conical container which is arranged vertically and in which there is a mixing screw, and were mixed discontinuously. This entailed the mixing screw executing two 35 rotational movements, a fast one round its own axis and a slow one round the container axis.
This solid mixture was metered at a throughput of 15 kg/h via a weigh feeder continuously into a co-rotating ZSK30 extruder (Wer-40 ner & Pfleiderer). The extruder was fed from the full hopperduring this. There was no d~m;x;ng of the dry premix.
In the extruder, the mixture was melted, conveyed and homogenized to a plastic composition by longitudinal and transverse mixing, 45 and extruded, applying the following conditions, Section 1: 43~C
Section 2: 57~C
CA 022323~7 1998-04-21 BASF Aktiengesellschaft 950021 o.Z. 0050/46309 Section 3: 120~C
Section 4: 100~C
Section 5: 100~C
Head : 100~C
5 Die : 100~C
The extrudate of the composition was subjected to cold-cut granulation and subsequently continuous pelleting.
10 Transparent pellets were obtained.
They show a release of more than 70 % in 30 minutes, measured at pH 7.2, which complies with the requirements of USP XXII.
15 Example 2 300 kg of polyvinylpyrrolidone with a K value of 30, 6 kg of Aerosil 90, 54 kg of maltodextrins and 240 kg of ibuprofen were metered into a solids mixer as in Example 1 and mixed discontinuously.
This solid mixture was metered at a throughput of 15 kg/h via a weigh feeder continuously into a co-rotating ZSK30 extruder (Wer-ner & Pfleiderer). The extruder was fed from the full hopper during this. A compressed air vibrator was used to prevent 25 bridging. There was no ~m; ~; ng of the dry premix.
In the extruder, the mixture was melted, conveyed and homogenized by longitudinal and transverse mixing to a plastic composition, and was extruded, under the conditions indicated in Example 1.
The composition was extruded as ribbon and shaped in a calender with two molding rolls to oblong tablets which release the active ingredient as bolus dose. The resulting tablets show a release of > 70 % in 30 minutes, measured at pH 7.2, which complies with the 35 requirements of USP XXII.
Example 3 100 kg/h polyvinylpyrrolidone with a K value of 30, 2 kg/h Aerosil 90, 18 kg/h maltodextrins and 80 kg/h ibuprofen were 40 metered continuously into a continuously operating solids mixer (Gericke type GAC-307) and mixed.
This solid mixture was continuously metered into a co-rotating ZSK83 extruder (Werner & Pfleiderer). The extruder was fed from 45 the full hopper during this.
CA 022323~7 1998-04-21 BASF Aktiengesellschaft 950021 O.Z. 0050/46309 J
In the extruder, the mixture was melted, conveyed and homogenized by longitudinal and transverse mixing to a plastic composition, and was extruded, under the conditions indicated in Example 1.
5 The extrudate of this composition was subjected to cold-cut granulation and subsequently continuous pelleting.
~/ ~ v ~ .
Claims (5)
1. A process for producing solid drug forms by mixing at least one pharmacologically acceptable polymeric binder and at least one pharmaceutical active ingredient, with or without conventional pharmaceutical additives, extruding the mixture obtained and shaping the drug form, wherein a premix is produced from the components and is fed into the extruder.
2. A process as claimed in claim 1, wherein the extruder is fed from a hopper which is essentially completely filled.
3. A process as claimed in claim 1 or 2, wherein a binder selected from among polyvinylpyrrolidone, polyacrylates, polymethacrylates, polyhydroxyacrylates, polyhydroxymethacrylates, alkylcelluloses and hydroxyalkylcelluloses is used.
4. A process as claimed in any of the preceding claims, wherein a co-rotating extruder is used as extruder.
5. A process as claimed in any of the preceding claims, wherein a mixture of polyvinylpyrrolidone and ibuprofen without plasticizer and pharmaceutical additives is used as premix.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19539360.0 | 1995-10-23 | ||
| DE1995139360 DE19539360A1 (en) | 1995-10-23 | 1995-10-23 | Process for the production of solid dosage forms |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2232357A1 true CA2232357A1 (en) | 1997-05-01 |
Family
ID=7775507
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2232357 Abandoned CA2232357A1 (en) | 1995-10-23 | 1996-10-22 | A process for producing solid drug forms |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0859602A1 (en) |
| JP (1) | JPH11513696A (en) |
| CN (1) | CN1200034A (en) |
| CA (1) | CA2232357A1 (en) |
| DE (1) | DE19539360A1 (en) |
| NO (1) | NO981798L (en) |
| WO (1) | WO1997015290A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8470347B2 (en) | 2000-05-30 | 2013-06-25 | AbbVie Deutschland GmbH and Co KG | Self-emulsifying active substance formulation and use of this formulation |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19840256A1 (en) | 1998-09-03 | 2000-03-09 | Basf Ag | Widely applicable, continuous method for preparing coated solid dosage forms, comprises extruding mixture of drug and thermoplastic binder then applying coating composition in liquid or vapor form |
| DE19901383A1 (en) | 1999-01-15 | 2000-07-20 | Knoll Ag | Process for the preparation of different solid dosage forms |
| EP2098222A4 (en) * | 2006-10-31 | 2012-12-26 | Kaneka Corp | Physiologically active substance-containing granular composition and method of producing the same |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4413350A1 (en) * | 1994-04-18 | 1995-10-19 | Basf Ag | Retard matrix pellets and process for their production |
| US5965161A (en) * | 1994-11-04 | 1999-10-12 | Euro-Celtique, S.A. | Extruded multi-particulates |
-
1995
- 1995-10-23 DE DE1995139360 patent/DE19539360A1/en not_active Withdrawn
-
1996
- 1996-10-22 CA CA 2232357 patent/CA2232357A1/en not_active Abandoned
- 1996-10-22 JP JP9516268A patent/JPH11513696A/en active Pending
- 1996-10-22 WO PCT/EP1996/004584 patent/WO1997015290A1/en not_active Application Discontinuation
- 1996-10-22 EP EP96934782A patent/EP0859602A1/en not_active Withdrawn
- 1996-10-22 CN CN 96197794 patent/CN1200034A/en active Pending
-
1998
- 1998-04-22 NO NO981798A patent/NO981798L/en not_active Application Discontinuation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8470347B2 (en) | 2000-05-30 | 2013-06-25 | AbbVie Deutschland GmbH and Co KG | Self-emulsifying active substance formulation and use of this formulation |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0859602A1 (en) | 1998-08-26 |
| NO981798D0 (en) | 1998-04-22 |
| DE19539360A1 (en) | 1997-04-24 |
| JPH11513696A (en) | 1999-11-24 |
| NO981798L (en) | 1998-04-22 |
| CN1200034A (en) | 1998-11-25 |
| WO1997015290A1 (en) | 1997-05-01 |
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