Note: Descriptions are shown in the official language in which they were submitted.
BASF Aktiengesellschaft 970165 O.Z. 0050/48593
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 and, where
appropriate, at least one active ingredient and, where
appropriate, conventional additives to form a plastic mixture,
and shaping. The invention particularly relates to a process for
producing solid pharmaceutical 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, it is
15 disclosed in the book "Pharmazeutische Technologie", authors
Prof. Bauer, Frommig and Fuhrer, Thieme Verlag, pages 292 et
seq., that drug forms can be obtained from the melts by dry
granulation. The possibility of producing solidified melt
granules either by melt ng and shock solidification, by casting
20 and comminuting or by prilling in spray towers is described. One
problem with these processes is the accurate shaping which is
necessary for producing drugs. Irregular particles or fragments
are frequently produced so that the resulting shape by no means
corresponds to customary drug forms, and granules therefore have
25 only little importance as a drug form 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.
30 A considerably simpler continuous process for producing solid
pharmaceutical forms has been known for some time and entails
extruding a solvent-free melt of a polymeric binder containing
active ingredients, and shaping this extrudate to the required
drug form, for example in a calender with molding rolls, see
35 EP-A-240 904, EP-A-240 906 and EP-A-337 256 and EP-A-358105. 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 The use of polyoxazolines in various sectors, for example as
binders in pharmaceutical preparations, is known. WO 95/01383,
WO 95/01384, WO 95/06078 and WO 95/06079 disclose water- or
alcohol-soluble or dispersible elastomeric copolymers which
contain from l0 to 60% by weight of polyoxazolines with a degree
45 of polymerization of from l0 to 2000 as building block. The
copolymers can be used for hair care compositions and drugs for
topical administration.
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Investigations on polyoxazolines for their clearance and
biodistribution (Zalipsky et al., J. Pharm. Sci., 85, (1996),
133), toxicity (Kobayashi et al., Macromol. Chem. 184, (1983),
5 793) and pharmacokinetic properties (Goddard et al., J. Contr.
Rel. 10, (1989) 5) have been carried out and revealed that
polyoxazolines can be used to produce liposomes and as carrier
polymers for pharmaceutical active ingredients.
10 US-A-5 410 016 describes hydrogels from polymerized and
crosslinked macromers which contain hydrophilic oligomers, eg.
polyoxazolines, with biodegradable portions for use as drug
carriers for drug forms with controlled release for time-limited
protection of tissues, to prevent adhesions after surgical
15 operations and the like.
WO 94/03544 describes protein-compatible polymer blends of
water-soluble polymers and matrix polymers and their use as
s~able hydrophilic surfaces in vessels for storing protein
20 solutions. Poly(ethyloxazoline) is also suitable as water-soluble
poly~er.
WO 93/16687 discloses water-soluble macromers (prepolymers) which
have be~n modified with at least two substituents capable of
25 free-radical polymerization. Suitable macromers include
poly(ethyloxazolines). The macromers are subjected to a
photopolymerization in order to encapsulate biological materials
with gel formation.
30 US-A-5 536 505 discloses a matrix system which comprises a
homogeneous mixture of poly(2-ethyl-2-oxazoline), cellulose
acetate with a degree of substitution of about 0.5 to 3.0 and a
water-soluble active ingredient. The matrix system permits
controlled release of active ingredients.
The use of poly(ethyloxazoline) and poly(methacrylic acid) or
poly(acrylic acid) for forming polymer complexes whose solubility
in water can be controlled by an electric current as system for
pulsed release of active ingredient is described by Kwon et al.,
40 Proc. l9th Int. Symp. Contr. Rel. Bioact. Mater. (1992) 243 and
Kwon et al., Nature, 354 (1991) 291, and Bae et al., in
r~Polymeric Drugs and Drug Administration~, ACS Symp. Ser. 545,
(1994) 98.
45 WO 94/20073 discloses lipid-polymer conjugates in which a
vesicle-forming lipid is covalently connected to a water- and
solvent-soluble polymer in order to increase the half-life of
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liposomes in the bloodstream. Polyoxazolines are among the water-
and solvent-soluble polymers which can be used.
W0 92/06678 describes biocompatible microcapsules which can be
5 used for implanting exogenous material, the microcapsules having
an outer layer of a water-soluble nonionic polymer such as
poly(ethylene oxide) to prevent cells adhering to the surface of
the microcapsules. Also suitable in place of poly(ethylene oxide)
are other water-soluble polymers such as poly(ethyloxazoline).
Shenouda et al., Int. J. Pharmac., 61 (1990) 127 describe the
partial coating of hydroxypropylmethylcellulose capsules with
polyoxazolines for release of active ingredients from the
capsules at a constant rate. The use of a matrix of
15 hydroxypropylmethylcellulose and poly(ethyloxazoline) do not
result in these release characteristics.
Chun et al., Proc. 23rd Int. Symp. Contr. Rel. Bioact. Mater.
(1996) 343 describe influencing the shape and size cf alginate
20 microspheres by introducing or coating with various substances
including poly(ethyloxazoline), and the effect thereof on the
release of active ingredients. Alginate microspheres with added
polymer were smaller than microspheres of pure alginate.
25 However, the production of these dosage forms such as
microcapsules and microparticles, and the introduction of the
active ingredient, are very complicated and thus time-consuming
and costly.
30 It is an object of the present invention to provide a simple and
low-cost process for producing solid dosage forms, especially
drug forms.
We have found that this object is achieved by producing the
35 dosage forms by converting the binder into the plastic state, in
particular by melt extrusion, with use of polyoxazolines as
binders.
The present invention therefore relates to a process for
40 producing solid dosage forms by mixing at least one polymeric
binder, where appropriate at least one active ingredient and,
where appropriate, conventional additives to form a plastic
mixture, and shaping, wherein homo- and/or copolymers of
2-substituted oxazolines are used as polymeric binder.
The terms detailed below have the following meanings for the
purpose of the present invention:
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Alkyl is straight-chain or branched alkyl generally having 1 to
30 carbon atoms, preferably Cl-C2l-alkyl and, in particular,
Cl-C6-alkyl. Examples of alkyl groups are methyl, ethyl, n-propyl,
5 isopropyl, n-butyl, n-hexyl, 2-ethylhexyl, n-nonyl, n-dodecyl,
cetyl and stearyl.
Alkenyl is straight-chain or branched alkenyl having 3 to 20, in
particular 3 to 8, carbon atoms. Examples are hexenyl and oleyl.
Aryl is preferably phenyl or naphthyl.
Acyl is preferably -COH or COCl-Cl8-alkyl, in particular
COCl-C6-alkyl.
Heterocyclyl is an aromatic or nonaromatic group having 5 or
6 ring atoms with l, 2 or 3 heteroatoms which are selected,
independently of one another, from O, S and N. Examples of
aromatic heterocyclic groups are pyrrolyl, imidazolyl, thiazolyl,
20 triazolyl, furyl, thienyl, oxazolyl, isoxazolyl, pyridyl and
pyrimidinyl. Examples of nonaromatic heterocyclic groups are
pyrrolidinyl, tetrahydrofuryl, morpholinyl, piperidinyl and
piperazinyl.
25 The novel process makes it possible to produce solid dosage forms
in a simple and low-cost manner. The advantageous properties of
the polyoxazolines are not impaired by conversion into the
plastic state.
30 Dosage forms mean herein all forms which are suitable for use as
drugs, plant treatment compositions, human and animal foods and
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
35 can be used, in particular, as human or animal foods.
The dosage forms obtainable according to the invention generally
comprise:
40 a) 0-99% by weight, in particular 0.1-60% by weight (based on
the total weight of the dosage form) of an active ingredient,
b) 1-100% by weight, in particular 40-99.9% by weight of a
polymeric binder and
c) where appropriate additives.
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If the dosage form is employed for human or animal food purposes,
the active ingredient may be absent, ie. the dosage form may
comprise up to 100% of the polymeric binder.
5 The polymeric binders used according to the invention are
oxazoline homopolymers and/or copolymers of various oxazolines or
oxazolines and other monomers (comonomers). The copolymers
preferably contain at least 10% by weight, in particular at least
20% by weight and, particularly preferably, at least 50% by
10 weight of oxazoline units. Examples of suitable comonomers are
monoethylenically unsaturated carboxylic acids such as acrylic
acid or methacrylic acid.
The copolymerlzation of oxazolines is described, for example, in
15 US 4,016,192.
The polymers us~d according to the invention preferably comprise
oxazoline units of the formula
~ ~ R
where R is alkyl which may be interrupted by one or more oxygen
atoms (between which there are at least 2 carbon atoms) or
alkenyl, aryl, cycloalkyl or heterocyclyl, where R may have 1, 2
or 3 substituents which are selected, independently of one
30 another, from alkyl, halogen, OH, alkoxy, acyl, acyloxy, COR1,
SO2R1, amino, monoalkylamino, dialkylamino, nitro, aryl or
heterocyclyl, where R1 is OH, OC1-C6-alkyl, NH2, NHC1-C6-alkyl or
N(C1-C6-alkyl)2, or the abovementioned substituents which are,
however, linked to the oxazoline ring via O, S, NR2, P(OR2)2,
35 SioR3, Si(R3)3, where R2 is H or C1-C6-alkylj and the R3 radicals
are, independently of one another, C1-C6-alkyl.
R is preferably alkyl and hydroxyalkyl having 1 to 30, in
par-icular 1 to 21, carbon atoms. R is particularly preferably
40 methyl, ethyl, hydroxyethyl, hydroxypropyl, stearyl or cetyl.
A review of the synthesis of oxazolines and the polymerization
thereof is to be found in Henkel-Referata 28/1992, 43-47.
45 The polyoxyazolines are obtained in a manner known per se by
cationic ring-opening polymerization to form units of the formula
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CH2 - CH2 - N 3
CO
R
In the chemical structure, the polyoxazolines used according to
10 the invention as binders are N-acylated polyethyleneimines. They
can be converted by hydrolysis, with elimination of the acyl
group, into polyethyleneimines which are distinguished, by
comparison with polymers obtained by polymerization of
ethyleneimine, by a high degree of linearity. The degree of
15 polymerization of polyoxazolines can be adjusted virtually as
desired via the amount of catalyst employed. The preparation is
normally carried out as solution or bulk polymerization with
trifluoromethanesulfonic ester or methyl para-toluenesulfonate or
other known catalysts suitable for cationic polymerization.
The copolymers can be prepared by, on the one hand,
copolymerizing various oxazolines and, on the other hand,
copolymerizing oxazolines with other suitable monomers with
sufficiently high nucleophilicity.
Besides the polymeric binders described above, it is possible to
_employ in particular up to 30% by weight, based on the total
weight of the binder, of other binders such as polymers,
copolymers, cellulose derivatives and starch. Suitable examples
30 are:
Polyvinylpyrrolidone (PVP), copolymers of N-vinylpyrrolidone
(NVP) and vinyl esters, especialy vinyl acetate, copolymers of
vinyl acetate and crotonic acid, partially hydrolized polyvinyl
35 acetate, polyvinyl alcohol, poly(hydroxyalkyl acrylates),
poly(hydroxyalkyl methacrylates), polyacrylates and
polymethacrylates (Eudragit types), copolymers of methyl
methacrylate and acrylic acid, polyacrylamides, polyethylene
glycols, polyvinyl formamide (partially or completely hydrolyzed
40 where appropriate), cellulose esters, cellulose ethers,
especially methyl cellulose and ethyl cellulose,
hydroxyalkylcelluloses, especially hydroxypropylcellulose,
hydroxyalkylalkylcelluloses, especially
hydroxypropylethylcellulose, cellulose phthalates, especially
45 cellulose acetate phthalate and hydroxypropylmethylcellulose
phthalate, and m~nn~ns, especially galactomannans. Of these,
polyvinylpyrrolidone, copolymers of N-vinylpyrrolidone and vinyl
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esters, poly(hydroxyalkyl acrylates)~ poly(hydroxyalkyl
methacrylates), polyacrylates, polymethacrylates, alkylcelluloses
and hydroxyalkylcelluloses are particularly preferred.
5 The polymeric binder must soften or melt in the complete mixture
of all the components in the range of from 50 to 200~C, preferably
60 to 130~C. The glass transition temperature of the mixture must
therefore be below 200~C, preferably below 130~C. If necessary, it
is reduced by conventional pharmacologically acceptable
10 plasticizing 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 mixture preferably contains no plasticizer.
15 Examples of such plasticizers are:
Long-chain alcohols, ethylene glycol, propylene glycol, glycerol,
trimethylolpropane, triethylene glycol, butanediols, pentanols
such as pentaerythritol, hexanols, polyethylene glycols,
20 polypropylene glycols, polyethylene/propylene glycols, silicones,
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
25 such as glycerol mono-, di- or triacetate or sodium diethyl
sulfosuccinate. The concentration of plasticizer is generally
from 0.5 to 15, preferably 0.5 to 5, % of the total weight of the
mixture.
30 Conventional pharmaceutical auxiliaries, whose total amount can
be up to 100% of the weight of the polymer, are, for example,
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,
35 methylcellulose, sodium carboxymethylcellulose, talc, sucrose,
lactose, cereal or cornstarch, potato flour, polyvinyl alcohol,
in particular in a concentration of from 0.02 to 50, preferably
0.20 to 20, % of the total weight of the mixture.
40 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.
Flowability agents such as ~nim~] or vegetable fats, especially
45 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, Cl4, C16 and C18 fatty acids are
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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
5 derived from the abovementioned fatty acid types. The total
amount of fats, waxes, mono-, diglycerides and/or lecithin is
from 0.1 to 30, preferably 0.1 to 5, % of the total weight of the
composition for each layer.
10 Dyes, such as azodyes, 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
total weight of the mixture.
15 Stabilizers such as antioxidants, light stabilizers,
hydroperoxide destroyers, radical scavengers, stabilizers against
microbial attack.
It is also possible tc add wetting agents, preservatives,
20 disintegrants, adsorbents, release agents and propellants (cf.,
for example, H. Sucker et al., Pharmazeutische Technologie,
Thieme-Verlag, Stuttgart 1978).
Auxiliaries include for the purpose of the invention substances
25 for producing a solid solution of the active ingredient. Examples
of these auxiliaries are pentaerythritol and pentaerythritol
tetraacetate, polymers such as polyethylene oxides and
polypropylene oxides and their block copolymers (poloxamers),
phosphatides such as lecithin, homo- and copolymers of
30 vinylpyrrolidone, surfactants such as polyoxyethylene
40 stearate, and citric and succinic acids, bile acids, sterols
and others as indicated, for example, in J. L. Ford, Pharm. Acta
Helv. 61 (1986) 69-88.
35 Auxiliaries are also regarded as being bases and acids added to
control the solubility of an active ingredient (see, for example,
K. Thoma et al., Pharm. Ind. 51 (1989) 98-101).
The only precondition for the suitability of auxiliaries is
40 adequate thermal stability.
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
45 particular, pharmaceutical active ingredients (for humans and
animals), active ingredients for plant treatment, insecticides,
active ingredients of human and animal foods, fragrances and
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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
5 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
10 group, the B group, by which are meant besides Bl, B2, B6 and Bl2
and nicotinic acid and nicotinamide also compounds 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,
15 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
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
following active ingredients:
acebutolol, acetylcysteine, acetylsalicylic acid, aciclovir,
25 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,
30 bezafibrate, biotin, biperiden, bisoprolol, bromazepam,
bromhexine, bromocriptine, budesonide, bufexamac, buflomedil,
buspirone, caffeine, camphor, captopril, carbamazepine,
carbidopa, carboplatin, cefachlor, cefalexin, cefadroxil,
cefazoline, cefixime, cefotaxime, ceftazidime, ceftriaxone,
35 cefuroxime, selegiline, chloramphenicol, chlorhexidine,
chlorpheniramine, chlortalidone, choline, cyclosporin,
cilastatin, cimetidine, ciprofloxacin, cisapride, cisplatin,
clarithromycin, clavulanic acid, clomipramine, clonazepam,
clonidine, clotrimazole, codeine, cholestyramine, cromoglycic
40 acid, cyanocobalamin, cyproterone, desogestrel, dexamethasone,
dexpanthenol, dextromethorphan, dextropropoxiphene, diazepam,
diclofenac, digoxin, dihydrocodeine, dihydroergotamine,
dihydroergotoxin, diltiazem, diphenhydramine, dipyridamole,
dipyrone, disopyramide, domperidone, dopamine, doxycycline,
45 enalapril, ephedrine, epinephrine, ergocalciferol, ergotamine,
erythromycin, estradiol, ethinylestradiol, etoposide, Eucalyptus
globulus, famotidine, felodipine, fenofibrate, fenoterol,
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fentanyl, flavin mononucleotide, fluconazole, flunarizine,
fluorouracil, fluoxetine, flurbiprofen, furosemide, gallopamil,
gemfibrozil, gentamicin, Gingko biloba, glibenclamide, glipizide,
clozapine, Glycyrrhiza glabra, griseofulvin, guaifenesin,
5 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,
10 lactulose, lecithin, levocarnitine, levodopa, levoglutamide,
levonorgestrel, levothyroxine, lidocaine, lipase, imipramine,
lisinopril, loperamide, lorazepam, lovastatin,
medroxyprogesterone, menthol, methotrexate, methyldopa,
methylprednisolone, metoclopramide, metoprolol, miconazole,
15 midazolam, minocycline, minoxidil, misoprostol, morphine,
multivitamin mixtures or combinations and mineral salts,
N-methylephedrine, naftidrofuryl, naproxen, neomycin,
nicardipine, nicergoline, nicotinamide, nicotine, nicotinic acid,
nifedipine, nimodipine, nitrazepam, nitrendipine, nizatidine,
20 norethisterone, norfloxacin, norgestrel, nortriptyline, nystatin,
ofloxacin, omeprazole, ondansetron, pancreatin, panthenol,
pantothenic acid, paracetamol, penicillin G, penicillin V,
phenobarbital, pentoxifylline, phenoxymethylpenicillin,
phenylephrine, phenylpropanolamine, phenytoin, piroxicam,
25 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,
30 salicylic 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,
35 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,
40 acetylsalicylic acid, verapamil, paracetamol, nifedipine or
captopril.
The novel dosage forms are particularly suitable, because of the
relatively low glass transition temperature of from 60 to 80~C for
45 the polyoxazolines used according to the invention as binders,
for thermally sensitive active ingredients. These include, for
example, enzymes such as pancreatin, lipases ...
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11
The novel process is also advantageous for producing solid dosage
forms for thermally sensitive crop protection agents.
5 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
the formation of the melt. For example, the components can be
10 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.
However, it has proven preferable, especially when sensitive
15 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
mixers with very short resid~nce times. The active ingredient(s)
20 can for this purpose be employed in solid form or in solution or
dispersion.
The components are generally employed as such in the production
process. However, they can also be used in liquid form, ie. as
25 solution, suspension or dispersion.
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
30 solvents which are immiscible or miscible with water. Suitable
water-miscible solvents are, in particular, C1-C4-alkanols such zs
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,
35 esters such as ethyl acetate or butyi acetate, chlorinated
hydrocarbons such as methylene chloride, and aromatic
hydrocarbons such as toluene and xylene. Another solvent which
can be used is liquid C02.
40 The solvent used in the individual case depends on the component
to be taken up and the properties thereof. For example,
pharmaceutical active ingredients are frequently used in the form
of a salt which is, in general, soluble in water. Water-soluble
active ingredients can therefore be employed as aqueous solution
45 or, preferably, be taken up in the aqueous solution or dispersion
of the binder. A corresponding statement applies to active
ingredients which are soluble in one of the solvents mentioned,
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12
if the liquid form of the components used is based on an organic
solvent.
It is possible where appropriate to replace melting by
5 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
10 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
15 agitator, eg. kneaders (like those of the type to be mentioned
below).
A particularly suitable mixing apparatus is one employed for
mixing ir. p'astics technology. Suitable apparatuses are
20 described, for example, in "Mischen beim Herstellen und
Verarbeiten von Kunststoffen", H. Pahl, VDI-Verlag, 1986.
Particularly suitable mixing apparatuses are extruders and
dynamic and static mixers, and stirred vessels, single-shaft
stirrers with stripper mechanisms, especially paste mixers,
25 multishaft stirrers, especially PDSM mixers, solids mixers and,
preferably, mixer/kneader reactors (eg. ORP, CRP, AP, DTB
supplied by List or Reactotherm supplied by Krauss-Maffei or
Ko-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
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
35 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
40 components can be introduced in a free feed, eg. via a weigh
feeder. Plastic compositions can be fed in directly from an
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
active ingredient and, where appropriate, the additive(s) ranges
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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
5 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
lO 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.
15 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
20 solvent, the extruders are generally equipped with an evaporating
section. Particularly preferred extruders are those of the ZKS
series from Werner & Pfleiderer.
It is also posible according to the invention to produce
25 multilayer pharmaceutical forms by coextrusion, in which case a
plurality of mixtures of the components described above is fed
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.
They may be in open or closed form, in particular as open or
closed multilayer tablets.
35 At least one of the layers contains at least one pharmaceutical
active ingredient. It is also possible for another active
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
40 ingredient can be controlled.
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
45 depends on the required pharmaceutical form. Examples of suitable
dies are those with a flat orifice, called a slit die, and dies
with an annular orifice. The design of the die depends on the
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polymeric binder used and the required pharmaceUtiCal form.
The 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
10 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
15 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 ccextrusion, open or closed
20 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
way. Micropastilles can be produced by the Rotoform-Sandvik
process. These dosage forms can be rounded and/or provided with a
25 coating by conventional methods in a subsequent process step.
Examples of materials suitable for film coatings are
polyacrylates such as the Eudragit types, cellulose esters such
as the hydroxypropylcellulose phthalates, and cellulose ethers,
such as ethylcellulose, hydroxypropylmethylcellulose or
30 hydroxypropylcellulose.
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
35 solutions of active ingredients in polymers, the active
ingredient is in the form of a molecular dispersion in the
polymer.
The following examples are intended to illustrate the novel
40 process without restricting it, however.
Examples
To produce the solid dosage forms, the stated amounts of crop
45 protection agent or drug, polymeric binder (polyethyloxazoline;
Mw ~ 400,000), nonionic surfactant and ionic dispersant are
introduced, either mixed or separately, into a corotating,
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closely intermeshing twin screw extruder (Werner und Pfleiderer
ZSK 30) and extruded through 12 temperature zones. The speed of
the screws was varied in the range from 100 to 300 rpm, and the
temperature was in the range from 30 to 80~C in the feed sections
5 and 80 to 160~C in the plasticizing sections. The exact conditions
are indicated in the individual examples. The output was 2 to
4 kg per hour and the residence time was 1 to 2 minutes. The
active ingredient, the polymer and the additives were fed via
weigh feeders to the extruder inlet and were melted. The nonionic
10 surfactant was, where appropriate, then fed in as liquid and
incorporated with mixing and kneading elements. If required, the
melt was degassed before the addition. The melt discharged from
the extruder through a die was, after cooling, crushed, ground
and graded by screening. The 400 to 500 ~m screen fraction was
15 used for the use tests. The conditions are summarized in the
following Table 1.
Table 1:
20 Exam- Active Poly- Lutensol Addition Tempera- Speed
ple ingre- ethyloxa- AT 25a) ture, Sec-
dient zoline tions 1-12 rpm
No. % by wt % by wt % by wt % by wt ~C
1 50 50 30, 80, 200
Kresoxim- go_go
methyl
2 50 40 10 30, 80, 150
Kresoxim- 85-85
methyl
3 50 40 5 5, Tamol 30, 80, 150
Kresoxim- NHb) 85-85
methyl
4 50 40 5 5, Wettol 30, 80, 150
Kresoxim- NT1C) 85-85
methyl
5, Ufoxan 30, 80, 150
Kresoxim- 3Ad) 85-85
methyl
6 50 50 30, 80, 200
Vinclozo- 90-90
lin
40 7 50 40 10 30, 80, 150
Vinclozo- 85-85
lin
8 50 40 5 5, Tamol 30, 80, 150
Vinclozo- NH 85-85
lin
9 50 40 5 5, Wettol 30, 80, 150
Vinclozo- NT1 85-85
lin
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Exam- Active Poly- Lutensol Addition Tempera- Speed
ple ingre- ethyloxa- AT 25a) ture, Sec-
dient zoline tions 1-12 rpm
No. % by wt % by wt % by wt % by wt ~C
5 10 50 40 5 5, Ufoxan 30, 80, 150
Vinclozo- 3A 85-85
lin
Sections
1-7
1 11 20 80 20, 50,
~ bact. 90, 90,
lipase 80, 80, 90
12 10 90 20, 50,
pan- 90, 80-80,
creatin 95
15 a) nonionic surfactant based on ethoxylated fatty alcohols,
alkylphenols, fatty amines and alkyl glucosides
b) condensate of naphthalenesulfonic acid and formaldehyde
c) sodium alkylnaphthalenesulfonate
d) ligninsulfonate
1.0 g of the 400-500 ~m screen fractions of Examples 1-10 was in
each case added to 1000 ml of deionized water. The resulting
dispersion was stirred at 3 rpm for 5 minutes (IKA magnetic
stirrer, RET-G, Janke & Kunkel GmbH, Staufen; 1 l glass vessel 0
25 10 cm, T = 20~C). It was then filtered through a 160 ~m wire
screen. The residue on the screen as a % of the initial weight
was:
Example Residue [%]
1 8.2
2 2.1
3 1.5
4 2.8
1.3
6 5-3
7 0.8
8 0.3
9 0.5
1.1
The experiments demonstrate that the novel granules rapidly form
a fine dispersion in water. They are therefore suitable for spray
and distributor applications in agriculture.
Example 13
50% by weight of verapamil hydrochloride and 50% by weight of
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polyethyloxazoline (Mw ~ 400,000) were extruded under the
conditions indicated below (Werner und Pfleiderer ZSK 30 twin
screw extruder) and calendered to 500 mg forms.
Section 1 30~C
Section 2 50~C
Section 3 60~C
Section 4 80~C
Section 5 60~C
Die 60~C
The release after 1 hour was 100% (USP paddle method (pH
change)).
15 Example 14
72% by weight of paracetamol and 28% by weight of
polyethyloxazoline (Mw ~ 400,000) were extruded under the
conditions indicated below (Werner und Pfleiderer ZSK 30 twin
20 screw extruder) and calendered to 500 mg forms.
Section 1 30~C
Section 2 60~C
Section 3 80~C
Section 4 80~C
Section 5 80~C
Die 80~C
The release after 1 hour was 100% (USP paddle method (pH
30 change))~
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