Note: Descriptions are shown in the official language in which they were submitted.
; BASF Aktiengesellschaft 970399 O.Z. 0050/48594
,: .
The production of solid dosage forms
The invention relates to a process for producing solid dosage
5 forms by mixing at least one polymeric binder, at least one
active ingredient and, where appropriate, conventional additives
to form a plastic mixture, and shaping the mixture. The invention
particularly relates to a process for producing solid
pharmaceutical dosage forms.
Classical processes for producing solid pharmaceutical forms,
especially tablets, are carried out batchwise and comprise a
plurality of stages. Pharmaceutical granules represent an
important intermediate therefor. Thus, for example, Bauer,
lS Frommig and Fuhrer, "Pharmazeutische Technologie~,
Georg-Thieme-Verlag, pages 292 et seq., reveal that drug forms
can be obtained from the melt by dry granulation. The possibility
of producing solidified melt granules either by melting and shock
solidification, by casting and comminuting or by prilling in
20 spray towers is described. One problem with these processes is
the accurate shaping which is necessary for producing drugs.
Irregular particles or fragments are produced, so that the
resulting shape by no means corresponds to customary drug forms,
and granules therefore have only little importance as a drug form
25 on their own. Production of desired solid drug forms requires the
use of further process steps such as compression in tabletting
machines. This is time-consuming and costly.
A considerably simpler continuous process for producing solid
30 pharmaceutical forms has been known for some time and entails
extruding a solvent-free melt of a polymeric binder containing
active ingredients, and shaping the extrudate to the required
drug form, for example in a calender with molding rolls, see
EP-A-240 904, EP-A-240 906, EP-A-337 256 and EP-A-358 105 (melt
35 extrusion). It is possible in this way to achieve specific
shaping. The polymeric binders employed are, in particular,
polymers of N-vinylpyrrolidone or copolymers thereof, eg. with
vinyl acetate.
40 Homo- and copolymers of N-vinylcaprolactam have been used in
conventional pharmaceutical dosage forms. Thus, US 3,900, 559
describes a dosage form for the sustained release of
methantheline from a matrix which comprises a water-insoluble,
gel-forming, hydrophilic terpolymer with N-vinyllactam as one
45 constituent. US 4,987,182 describes the production of a mixture
of polyvinylbutyral and a polyvinyllactam which is used as active
ingredient carrier. WO 96/17579 describes a binder for tablets
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which comprises a homo- or copolymer of an N-vinyllactam and a
polyacid. EP 756 820 A describes iodine-containing preparations
with improved stabillty which may comprise polyvinylcaprolactam
in the binder component. DE 44 34 986 A describes the preparation
5 of polyvinylcaprolactam. This is employed for producing slow-
release active ingredient preparations. DE 43 27514 A discloses a
copolymer of a water-insoluble monomer and a water-soluble
monomer which may be N-vinylcaprolactam. The copolymer can be
used as carrier for active ingredients and makes easier
10 incorporation of the components and controlled release possible.
DE 44 22 881 describes the use of copolymers of N-vinylcapro-
lactam with hydrophobic comonomers in formulations of active
ingredients with low water solubility. The formulations are in
15 the form of solutions or dispersions and have improved stability
and efficacy.
DE 35 17 080 describes a component for therapeutic active
ingredient delivery systems based on polymers which have
20 elastomeric properties and may be homo- or copolymers of
N-vinyllactams. These components are used in the active
ingredient reservoir layer for therapeutic active ingredient
delivery systems, for example medicinal plasters.
25 Dosage forms based on polymers of this type have the disadvantage
that they release the active ingredient too slowly for many
applications. It is therefore impossible to produce rapid-release
dosage forms, also called instant release formulations, without
taking additional measures, such as comminution of the dosage
30 form, to produce a large surface area.
It is an object of the present invention to provide dosage forms
which can be produced by melt extrusion and are capable of rapid
release of active ingredient.
We have found that this object is achieved by using an N-vinyl-
caprolactam-containing polymer as polymeric binder.
The present invention therefore relates to a process for
40 producing solid dosage forms by mixing at least one polymeric
binder, at least one active ingredient and, where appropriate,
conventional additives to form a plastic mixture, and shaping,
wherein a homo- or copolymer of N-vinylcaprolactam is used as
polymeric binder.
The novel process makes it possible to produce solid dosage forms
with rapid release of active ingredient (~instant release") in a
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simple and low-cost manner. The rapid release of the active
ingredient is surprising because N-vinylcaprolactam polymers in
the polymer art release the active ingredient only slowly, and
because plastic mixtures of the components result in very
5 compact, nonporous dosage forms with a small surface area, which
would suggest slow release of active ingredient.
Dosage forms mean herein all forms which are suitable for use as
drugs, plant treatment compositions, human and ~n;m~l foods and
10 for delivering fragrances and perfume oils. These include, for
example, tablets of any shape, pellets, granules, but also larger
forms such as cubes, blocks (bricks) or cylindrical forms, which
can be used, in particular, as human or ~n;m~l foods.
15 The dosage forms obtainable according to the invention generally
comprise:
a) 0.1-99% by weight, in particular 0.1-60% by weight (based on
the total weight of the dosage form) of an active ingredient,
b) 10-99.9% by weight, in particular 40-99.9% by weight of a
polymeric binder and
c) where appropriate additives.
The polymeric binder employed can be a homopolymer or a copolymer
of N-vinylcaprolactam. The copolymer contains at least 1% by
weight, preferably at least 10% by weight, particularly
preferably at least 25% by weight and, in particular, at least
30 50% by weight of N-vinylcaprolactam units.
As copolymer, the polymeric binder contains at least one other
copolymerizable monomer in an amount of from 0.5 to 99% by
weight, preferably 0.5 to 90% by weight, particularly preferably
35 0.5 to 75% by weight and, in particular, 0.5 to 50% by weight.
Suitable comonomers are, in particular, monoethylenically
unsaturated carboxylic acids having 3 to 30, in particular 3 to
8, carbon atoms, such as acrylic acid, methacrylic acid,
dimethylacrylic acid, ethacrylic acid, maleic acid, citraconic
40 acid, methylenemalonic acid, allylacetic acid, vinylacetic acid,
crotonic acid, fumaric acid, mesaconic acid and itaconic acid,
and the monoesters of said dicarboxylic acids with C1-C24-
alkanols. Acrylic acid, methacrylic acid, maleic acid or mixtures
of said carboxylic acid are preferred. The monoethylenically
45 unsaturated carboxylic acids may be employed in the form of the
free acid and, if available, the anhydrides or in partially or
completely neutralized form. The neutralization is preferably
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carried out using alkali metal or alkaline earth metal bases,
ammonia or amines, eg. sodium hydroxide, potassium hydroxide,
sodium carbonate, potassium carbonate, sodium bicarbonate,
magnesium oxide, calcium hydroxide, calcium oxide, gaseous or
5 aqueous ammonia, triethylamine, ethanolamine, diethanolamine,
morpholine, diethylenetriamine or tetraethylenepentamine.
Further examples of suitable comonomers are the esters of the
abovementioned carboxylic acids with Cl-C24-alkanols, C2-C4-diols,
10 mono- and di-Cl-C4-alkylamino-C2-C4-alkanols, and the amides,
mono- and di-Cl-C4-alkylamides and nitriles of these carboxylic
acids, eg. methyl acrylate, ethyl acrylate, methyl methacrylate,
ethyl methacrylate, hydroxyethyl acrylate, hydroxypropyl
acrylate, hydroxybutyl acrylate, hydroxyethyl methacrylate,
15 hydroxypropyl methacrylate, hydroxyisobutyl acrylate,
hydroxyisobutyl methacrylate, monomethyl maleate, dimethyl
maleate, monoethyl maleate, diethyl maleate, 2-ethylhexyl
acrylate, 2-ethylhexyl methacrylate, stearyl acrylate, stearyl
methacrylate, behenyl acrylate, behenyl methacrylate octyl
20 acrylate, octyl methacrylate, acrylamide, methacrylamide,
N,N-dimethylacrylamide, N-tert-butyl acrylamide, acrylonitrile,
methacrylonitrile, dimethylaminoethyl acrylate, diethylaminoethyl
acrylate, diethylaminoethyl methacrylate and the salts of the
last-mentioned monomers with carboxylic acids or mineral acids or
25 the quaternized products.
Also suitable as copolymerizable monomers are acrylamidoglycolic
acid, vinylsulfonic acid, allylsulfonic acid, methallylsulfonic
acid, styrenesulfonic acid, 3-sulfopropyl acrylate, 3-sulfopropyl
30 methacrylate and acrylamidomethylpropanesulfonic acid, and
phosphono-containing monomers such as vinylphosphonic acid,
allylphosphonic acid and acrylamidomethylpropanephosphonic acid.
Further suitable copolymerizable monomers are N-vinylpyrrolidone,
N-vinylimidazole, N-vinyl-2-methylimidazole, N-vinyl-4-methylimi-
35 dazole, diallylammonium chloride and vinyl esters such as vinylacetate and vinyl propionate, and vinylaromatic compounds such as
styrene. It is, of course, also possible to employ mixtures of
said monomers.
40 The homo- and copolymers are prepared by known processes, eg. of
solution, precipitation, suspension or inverse suspension
polymerization, or of emulsion or inverse emulsion
polymerization, using compounds which form free radicals under
the polymerization conditions.
The polymerizations are normally carried out at from 30 to 200~C,
preferably 40 to 110~C. Examples of suitable initiators are azo
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and peroxy compounds, and the conventional redox initiator
systems such as combinations of hydrogen peroxide and reducing
compounds, eg. sodium sulfite, sodium bisulfite, sodium
formaldehyde sulfoxylate and hydrazine.
The copolymers have K values of at least 7, preferably 10 to 100,
particularly preferably 10 to 50. The K values are determined via
the method of H. Fikentscher, Cellulose-Chemie, 13 (1932) 58-64
and 71-74, in a~ueous solution or in an organic solvent at 25~C,
10 at concentrations which are from 0.1% to 5%, depending on the K
value range.
Besides the polymeric binders described above, it is possible to
employ in particular up to 30% by weight, based on the total
15 weight of the binder, of other binders such as polymers,
copolymers, cellulose derivatives, starch and starch derivatives.
Suitable examples are:
Polyvinylpyrrolidone (PVP), copolymers of N-vinylpyrrolidone
20 (NVP) and vinyl acetate or vinyl propionate, copolymers of vinyl
acetate and crotonic acid, partially hydrolyzed polyvinyl
acetate, polyvinyl alcohol, poly(hydroxyalkyl acrylates),
poly(hydroxyalkyl methacrylates), polyacrylates and
polymethacrylates (Eudragit types), copolymers of methyl
25 methacrylate and acrylic acid, polyacrylamides, polyethylene
glycols, polyvinylformamide (partially or completely hydrolyzed
where appropriate), cellulose esters, cellulose ethers,
especially methyl cellulose and ethyl cellulose,
hydroxyalkylcelluloses, especially hydroxypropylcellulose,
30 hydroxyalkylalkylcelluloses, especially
hydroxypropylethylcellulose, cellulose phthalates, especially
cellulose acetate phthalate and hydroxypropylmethylcellulose
phthalate, and m~nn~ns, especially galactom~nn~ns. Of these,
polyvinylpyrrolidone, copolymers of N-vinylpyrrolidone and vinyl
35 esters, poly(hydroxyalkyl acrylates), poly(hydroxyalkyl
methacrylates), polyacrylates, polymethacrylates, alkylcelluloses
and hydroxyalkylcelluloses are particularly preferred.
The polymeric binder must soften or melt in the complete mixture
40 of all the components in the range of from 50 to 180~C, preferably
60 to 130~C, to form a plastic mixture. 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 plasticizing
45 auxiliaries. The amount of plasticizer does not exceed 30% of the
total weight of binder and plasticizer in order to form
storage-stable drug forms which show no cold flow. However, the
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mixture preferably contains no plasticizer.
Examples of such plasticizers are:
5 Long-chain alcohols, ethylene glycol, propylene glycol, glycerol,
trimethylolpropane, triethylene glycol, butanediols, pentanols
such as pentaerythritol, hexanols, polyethylene glycols,
polypropylene glycols, polyethylene/propylene glycols, silicones,
aromatic carboxylic esters (eg. dialkyl phthalates, trimellitic
lO esters, benzoic esters, terephthalic esters) or aliphatic
dicarboxylic esters (eg. dialkyl adipates, sebacic esters,
azelaic esters, citric and tartaric esters), fatty acid esters
such as glycerol mono-, di- or triacetate or sodium diethyl
sulfosuccinate. The concentration of plasticizer is generally
15 from 0.5 to 15, preferably 0.5 to 5, % of the total weight of the
mixture.
Conventional pharmaceutical auxiliaries, whose total amount can
be up to 100% of the weight of the polymer, are, for example,
20 extenders and bulking agents such as silicates or diatomaceous
earth, magnesium oxide, aluminum oxide, titanium oxide, stearic
acid or its salts, eg. the magnesium or calcium salt,
methylcellulose, sodium carboxymethylcellulose, talc, sucrose,
lactose, cereai or corn starch, potato flour, polyvinyl alcohol,
25 in particular in a concentration of from 0.02 to 50, preferably
0.20 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
30 3, % OL the total weight of the mixture.
Flowability agents such as animal 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
35 above. Triglycerides of C12, Cl4, Cl6 and C18 fatty acids are
preferred. It is also possible to use waxes such as carnauba wax.
These fats and waxes may be admixed advantageously alone or
together with mono- and/or diglycerides or phosphatides,
especially lecithin. The mono- and diglycerides are preferably
40 derived from the abo~ementioned fatty acid types. The total
amount of fats, waxes, mono-, diglycerides and/or lecithlns is
from 0.1 to 30, preferably 0.1 to 5, % of the total weight of the
composition for each layer.
45 Dyes, such as azo dyes, organic or inorganic pigments or dyes of
natural origin, with preference for inorganic pigments in a
concentration of from 0.001 to 10, preferably 0.5 to 3, % of the
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total weight of the mixture.
Stabilizers such as antioxidants, light stabilizers,
hydroperoxide destroyers, radical scavengers, stabilizers against
5 microbial attack.
It is also possible to add wetting agents, preservatives,
disintegrants, adsorbents, release agents and propellants (cf.,
for example, H. Sucker et al., Pharmazeutische Technologie,
10 Thieme-Verlag, Stuttgart 1978).
Auxiliaries include for the purpose of the invention substances
for producing a solid solution of the active ingredient. Examples
of these auxiliaries are pentaerythritol and pentaerythritol
15 tetraacetate, polymers such as polyethylene oxides and
polypropylene oxides and their block copolymers (poloxamers),
phosphatides such as lecithin, homo- and copolymers of
vinylpyrrolidone, surfactants such as polyoxyethylene
40 stearate, and citric and succinic acids, bile acids, sterols
20 and others as indicated, for example, in J. L. Ford, Pharm. Acta
Helv. 61 (1986) 69-88.
Auxiliaries are also regarded as being bases and acids added to
control the solubility of an active ingredient (see, for example,
25 K. Thoma et al., Pharm. Ind. 51 (1989) 98-101).
The only precondition for the suitability of auxiliaries is
adequate thermal stability.
30 Active ingredients mean for the purpose of the invention all
substances with a physiological effect as long as they do not
decompose under the processing conditions. These are, in
particular, pharmaceutical active ingredients (for humans and
animals), active ingredients for plant treatment, insecticides,
35 active ingredients of human and animal foods, fragrances and
perfume oils. The amount of active ingredient per dose unit and
the concentration may vary within wide limits depending on the
activity and the release rate. The only condition is that they
suffice to achieve the desired effect. Thus, the concentration of
40 active ingredient can be in the range from 0.1 to 95, preferably
from 20 to 80, in particular 30 to 70, % by weight. It is also
possible to employ combinations of active ingredients. Active
ingredients for the purpose of the invention also include
vitamins and minerals. The vitamins include the vitamins of the A
45 group, the B group, by which are meant besides B1, B2, B6 and Bl2
and nicotinic acid and nicotinamide also compounds with vitamin B
properties such as adenine, choline, pantothenic acid, biotin,
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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, K group and P group. Active ingredients for the purpose
5 of the invention also include therapeutic peptides. Plant
treatment agents include, for example, vinclozolin, epoxiconazole
and quinmerac.
The novel process is suitable, for example, for processing the
10 following active ingredients:
acebutolol, acetylcysteine, acetylsalicylic acid, aciclovir,
alprazolam, alfacalcidol, allantoin, allopurinol, ambroxol,
amikacin, amiloride, aminoacetic acid, amiodarone, amitriptyline,
15 amlodipine, amoxicillin, ampicillin, ascorbic acid, aspartame,
astemizole, atenolol, beclomethasone, benserazide, benzalkonium
hydrochloride, benzocaine, benzoic acid, betamethasone,
bezafibrate, biotin, biperiden, bisoprolol, bromazepam,
bromhexine, bromocriptine, budesonide, bufexamac, buflomedil,
20 buspirone, caffeine, camphor, captopril, carbamazepine,
carbidopa, carboplatin, cefachlor, cefalexin, cefadroxil,
cefazoline, cefixime, cefot~ime, ceftazidime, ceftriaxone,
cefuroxime, selegiline, chloramphenicol, chlorhexidine,
chlorpheniramine, chlortalidone, choline, cyclosporin,
25 cilastatin, cimetidine, ciprofloxacin, cisapride, cisplatin,
clarithromycin, clavulanic acid, clomipramine, clonazepam,
clonidine, clotrimazole, codeine, cholestyramine, cromoglycic
acid, cyanocobalamin, cyproterone, desogestrel, dexamethasone,
dexpanthenol, dextromethorphan, dextropropoxiphene, diazepam,
30 diclofenac, digoxin, dihydrocodeine, dihydroergotamine,
dihydroergotoxin, diltiazem, diphenhydramine, dipyridamole,
dipyrone, disopyramide, domperidone, dopamine, doxycycline,
enalapril, ephedrine, epinephrine, ergocalciferol, ergotamine,
erythromycin, estradiol, ethinylestradiol, etoposide, Eucalyptus
35 globulus, famotidine, felodipine, fenofibrate, fenoterol,
fentanyl, flavin mononucleotide, fluconazole, flunarizine,
fluorouracil, fluoxetine, flurbiprofen, furosemide, gallopamil,
gemfibrozil, gentamicin, Gingko biloba, glibenclamide, glipizide,
clozapine, Glycyrrhiza glabra, griseofulvin, guaifenesin,
40 haloperidol, heparin, hyaluronic acid, hydrochlorothiazide,
hydrocodone, hydrocortisone, hydromorphone, ipratropium
hydroxide, ibuprofen, imipenem, indomethacin, iohexol, iopamidol,
isosorbide dinitrate, isosorbide mononitrate, isotretinoin,
ketotifen, ketoconazole, ketoprofen, ketorolac, labetalol,
45 lactulose, lecithin, levocarnitine, levodopa, levoglutamide,
levonorgestrel, levothyroxine, lidocaine, lipase, imipramine,
lisinopril, loperamide, lorazepam, lovastatin,
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medroxyprogesterone, menthol, methotrexate, methyldopa,
methylprednisolone, metoclopramide, metoprolol, miconazole,
midazolam, minocycline, minoxidil, misoprostol, morphine,
multivitamin mixtures or combinations and mineral salts,
5 N-methylephedrine, naftidrofuryl, naproxen, neomycin,
nicardipine, nicergoline, nicotinamide, nicotine, nicotinic acid,
nifedipine, nimodipine, nitrazepam, nitrendipine, nizatidine,
norethisterone, norfloxacin, norgestrel, nortriptyline, nystatin,
ofloxacin, omeprazole, ondansetron, pancreatin, panthenol,
10 pantothenic acid, paracetamol, penicillin G, penicillin V,
phenobarbital, pentoxifylline, phenoxymethylpenicillin,
phenylephrine, phenylpropanolamine, phenytoin, piroxicam,
polymyxin B, povidone-iodine, pravastatin, prazepam, prazosin,
prednisolone, prednisone, bromocriptine, propafenone,
15 propranolol, proxyphylline, pseudoephedrine, pyridoxine,
quinidine, ramipril, ranitidine, reserpine, retinol, riboflavin,
rifampicin, rutoside, saccharin, salbutamol, salcatonin,
salicylic acid, simvastatin, somatropin, sotalol, spironolactone,
sucralfate, sulbactam, sulfamethoxazole, sulfasalazine,
20 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, vitamin E, folinic acid, zidovudine.
Preferred active ingredients are ibuprofen (as racemate,
enantiomer or enriched enantiomer), ketoprofen, flurbiprofen,
acetylsalicylic acid, verapamil, paracetamol, nifedipine or
captopril.
To produce the solid dosage forms, a plastic mixture of the
components (melt) is prepared and then subjected to a shaping
step. There are various ways of mixing the components and forming
the melt. The mixing can take place before, during and/or after
35 the formation of the melt. For example, the components can be
mixed first and then melted or be mixed and melted
simultaneously. The plastic mixture is often then homogenized in
order to disperse the active ingredient thoroughly.
40 However, it has proven preferable, especially when sensitive
active ingredients are used, first to melt the polymeric binder
and, where appropriate, make a premix with conventional
pharmaceutical additives, and then to mix in (homogenize) the
sensitive active ingredient(s) in the plastic phase in intensive
45 mixers with very short residence times. The active ingredient(s)
can for this purpose be employed in solid form or in solution or
dispersion.
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The components are generally employed as such in the production
process. However, they can also be used in liquid form, ie. as
solution, suspension or dispersion.
5 Suitable solvents for the liquid form of the components are
primarily water or a water-miscible organic solvent or a mixture
thereof with water. However, it is also possible to use organic
solvents which are immiscible or miscible with water. Suitable
water-miscible solvents are, in particular, Cl-C4-alkanols such as
10 ethanol, isopropanol or n-propanol, polyols such as ethylene
glycol, glycerol and polyethylene glycols. Suitable
water-immiscible solvents are alkanes such as pentane or hexane,
esters such as ethyl acetate or butyl acetate, chlorinated
hydrocarbons such as methylene chloride, and aromatic
15 hydrocarbons such as toluene and xylene. Another solvent which
can be used is liquid C02.
The solvent used in the individual case depends on the component
to he taken up and the properties thereof. For example,
20 pharmaceutical active ingredients are frequently used in the form
of a salt -~hich is, in general, soluble in water. Water-soluble
active ingredients can therefore be employed as aqueous solution
or, preferably, be taken up in the aqueous solution or dispersion
of the binder. A corresponding statement applies to active
25 ingredients which are soluble in one of the solvents mentioned,
if the liquid form of the components used is based on an organic
solvent.
It is possible where appropriate to replace melting by
30 dissolving, suspending, or dispersing in the abovementioned
solvents, if desired and/or necessary with the addition of
suitable auxiliaries such as emulsifiers. The solvent is then
generally removed to form the melt in a suitable apparatus, eg.
an extruder. This will be comprised by the term mixing
35 hereinafter.
The melting and/or mixing takes place in an apparatus customary
for this purpose. Particularly suitable ones are extruders or
containers which can be heated where appropriate and have an
40 agitator, eg. kneaders (like those of the type to be mentioned
below).
A particularly suitable mixing apparatus is one employed for
mixing in plastics technology. Suitable apparatuses are
45 described, for example, in "Mischen beim Herstellen und
Verarbeiten von Kunststoffen", H. Pahl, VDI-Verlag, 1986.
Particularly suitable mixing apparatuses are extruders and
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dynamic and static mixers, and stirred vessels, single-shaft
stirrers with stripper mechanisms, especially paste mixers,
multishaft stirrers, especially PDSM mixers, solids mixers and,
preferably, mixer/kneader reactors (eg. ORP, CRP, AP, DTB
5 supplied by List or Reactotherm supplied by Krauss-Maffei or
Ro-Kneter supplied by Buss), trough mixers and internal mixers or
rotor/stator systems (eg. Dispax supplied by IKA).
In the case of sensitive active ingredients it is preferable
10 first for the polymeric binder to be melted in an extruder and
then for the active ingredient to be admixed in a mixer/kneader
reactor. On the other hand, with less sensitive active
ingredients, a rotor/stator system can be employed for vigorously
dispersing the active ingredient.
- The mixing apparatus is charged continuously or batchwise,
depending on its design, in a conventional way. Powdered
components can be introduced in a free feed, eg. via a weigh
feeder. Plastic compositions can be fed in directly from an
20 extruder or via a gear pump, which is particularly advantageous
if the viscosities and pressures are high. Liquid media can be
metered in by a suitable pump unit.
The mixture obtained by mixing and/or melting the binder, the
25 active ingredient and, where appropriate, the additive(s) ranges
from pasty to viscous (plastic) or fluid and is therefore
extrudable. 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
30 swellable in a physiological medium.
The steps of mixing and melting in the process can be carried out
in the same apparatus or in two or more separately operating
apparatuses. The preparation of a premix can take place in one of
35 the conventional mixing apparatuses described above. A premix of
this type can then be fed directly, for example, into an extruder
and subsequently extruded, where appropriate with the addition of
other components.
40 It is possible in the novel process to employ as extruders single
screw machines, intermeshing screw machines or else multiscrew
extruders, especially twin screw extruders, corotating or
counterrotating and, where appropriate, equipped with kneading
disks. If it is necessary in the extrusion to evaporate a
45 solvent, the extruders are generally equipped with an evaporating
section. Particularly preferred extruders are those of the ZKS
series from Werner & Pfleiderer.
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It is also possible according to the invention to produce
multilayer pharmaceutical forms by coextrusion, in which case a
plurality of mixtures of the components described above is fed
5 together to an extrusion die so as to result in the required
layered structure of the multilayer pharmaceutical form. It is
preferable to use different binders for different layers.
Multilayer drug forms preferably comprise two or three layers.
10 They may be in open or closed form, in particular as open or
closed multilayer tablets.
At least one of the layers contains at least one pharmaceutical
active ingredient. It is also possible for another active
15 ingredient to be present in another layer. This has the advantage
that two mutually incompatible active ingredients can be
processed or that the release characteristics of the active
ingredient can be controlled.
20 The shaping takes place by coextrusion with the mixtures from the
individual extruders or other units being fed into a common
coextrusion die and extruded. The shape of the coextrusion die
depends on the required pharmaceutical form. Examples of suitable
dies are those with a flat orifice, called a slit die, and dies
25 with an annular orifice. The design of the die depends on the
polymeric binder used and the required pharmaceutical form.
Thz resulting mixture is preferably solvent-free, ie. it contains
neither water nor an organic solvent.
The plastic mixture is, as a rule, subjected to final shaping.
This can result in a large number of shapes depending on the die
and mode of shaping. For example, if an extruder is used, the
extrudate can be shaped between a belt and a roll, between two
35 belts or between two rolls, as described in EP-A-358 105, or by
calendering in a calender with two molding rolls, see, for
example, EP-A-240 904. Other shapes can be obtained by extrusion
and hot- or cold-cut of the extrudate, for example small-particle
and uniformly shaped pellets. Hot-cut pelletization usually
40 results in lenticular dosage forms (tablets) with a diameter of
from 1 to 10 mm, while strip pelletization normally results in
cylindrical products with a length to diameter ratio of from 1 to
10 and a diameter of from 0.5 to 10 mm. It is thus possible to
produce monolayer but also, on use of coextrusion, open or closed
45 multilayer dosage forms, for example oblong tablets, coated
tablets, pastilles and pellets. The resulting granules can also
be ground to a powder and compressed to tablets in a conventional
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way. Micropastilles can be produced by the Rotoform-Sandvik
process. These dosage forms can be rounded and/or provided with a
coating by conventional methods in a subsequent process step.
Examples of materials suitable for film coatings are
5 polyacrylates such as the Eudragit types, cellulose esters such
as the hydroxypropylcellulose phthalates, and cellulose ethers,
such as ethylcellulose, hydroxypropylmethylcellulose or
hydroxypropylcellulose.
10 In specific cases there may be formation of solid solutions. The
term solid solutions is familiar to the skilled worker, for
example from the literature cited at the outset. In solid
solutions of active ingredients in polymers, the active
ingredient is in the form of a molecular dispersion in the
15 polymer.
The following examples are intended to illustrate the novel
process without restricting it, however.
20 Examples
Example 1
520 g of polyvinylcaprolactam (K value 40; 1% strength in
25 ethanol) were extruded with 480 g of verapamil hydrochloride
under the conditions indicated below and calendered to give
500 mg oblong tablets.
Section 1 52~C
Section 2 85~C
Section 3 130~C
Section 4 108~C
Section 5 92~C
Die 85~C
The release after 1 hour was 100% (USP paddle method (pH
change)).
Example 2
500 g of copolymer of 50% by weight vinylcaprolactam and 50% by
weight vinylpyrrolidone (K value 65; 1% strength in water) were
extruded with 480 g of verapamil hydrochloride under the
conditions indicated below to give 500 mg oblong tablets, and
45 were granulated.
Section 1 47~C
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14
Section 286~C
Section 3132~C
Section 4112~C
Section 5101~C
Die 100~C
The release after 1 hour was 67% and after 2 hours was 100% (USP
paddle method (pH change)).
lO Example 3
500 g of copolymer of 50% by weight vinylcaprolactam and 50% by
weight vinylpyrrolidone (K value 65; 1% strength in water) were
extruded with 500 g of vinclozolin under the conditions indicated
15 below, and were cooled and granulated.
Section 1 60~C
Section 2 96~C
Section 3140~C
Section 4150~C
Section 5129~C
Die 100~C
Transparent, X-ray-amorphous, water-dispersible granules were
25 obtained.
Example 4
500 g of polyvinylcaprolactam (K value 40; 1% strength in
30 ethanol) were extruded with 500 g of epoxyconazole under the
conditions indicated below, and were cooled and calendered.
Section 1 60~C
Section 2 90~C
Section 3120~C
Section 4135~C
Section 5120~C
Die 100~C
40 Transparent, X-ray-amorphous, water-dispersible granules were
obtained.
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