Note: Descriptions are shown in the official language in which they were submitted.
CA 02257547 1999-O1-12
Process for producing solid dosage forms
The invention relates to a process for producing solid dosage
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
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 melting and shock solidification, by casting
and comminuting or by grilling 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
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.
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
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, e.g. with vinyl
acetate.
The use of polyamides in medical technology and pharmacy is known
to the skilled worker. Implants, the transdermal administration
of medicinal substances, dialysis membranes and drug coatings
represent only a few examples from the versatile application
areas for polyamides.
CA 022S7547 1999-O1-12
2
WO 96/21427 A1 describes, for example, the possibility of
employing polyamides as biodegradable, water-insoluble,
polyamide-containing copolymers in liquid drug formulations with
controlled release of active ingredient.. These polymers contain
the active ingredient in dissolved, dispersed or suspended form.
The use of polyamides in solid pharmaceutical compositions is
mentioned in W0 93/24154 A1. These compositions are based on
melt-spun polymers whose predominantly amorphous nature is
ZO intended to ensure rapid and constant release of active
ingredient.
A process for producing medicinal pills and tablets is described
In DE-A-1 766 546. This involves a shaping step in which the
carrier substance is converted into a melt containing the active
ingredient in dispersed and/or dissolved form, this melt is
placed in the trough-like space of a pair of rotating rolls, the
rolls being provided on their outer surfaces with cavities to
receive the coating composition and being cooled in order to
allow the liquid coating composition to solidify in cavities, and
the medicinal products obtained in this way leave the cavities.
The carrier substance may also comprise thermoplastics such as
polyvinyl chloride, polyethylene, polypropylene, polyamides,
p~lystyrene, polyvinylidene chloride, acrylonitrile/butadiene/
styrene or acrylonitrile/styrene.
Polyamide-containing compositions with delayed release of active
ingredient are mentioned in EP 381 445 A2 and EP 381 446 A1.
These comprise topical compositions for dental or oral treatment
in which the respective active ingredient is embedded in
cellulose or a hydrophobic polymer.
Polymers with sulfonate groups are described in DE 40 37 518 A1
as suitable component for producing particular resin particles
with a narrow size distribution and essentially spherical shape.
Resin particles of this type can be used in particular for
electrophotographic toners. A use as carrier for medicinal
products is mentioned in passing.
However, the production of the above compositions is in many
cases very complicated and thus time-consuming and costly and, in
most cases, results in dosage forms with rapid release
characteristics.
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It is an object of the present invention to provide a simple and
low-cost process for producing solid dosage forms, especially
drug forms, with delayed release of active ingredient.
We have found that this object is achieved by producing the
dosage forms by melt extrusion and, moreover, using polyamides
with sulfonate groups as binders.
The present invention therefore relates to a process for
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 polyamides with sulfonate groups
are used as polymeric binders.
The novel process makes it possible to produce solid dosage forms
in a simple and low-cost manner. The advantageous properties of
the polyamides with sulfonate groups are not impaired by the
conversion into the plastic state. In addition, the novel process
surprisingly results in dosage forms with very slow release of
active ingredient (slow release formulations), whereas the
polyamides previously used resulted in dosage forms with rapid
release of active ingredient. It is thus possible to achieve any
required release profiles by admixtures with rapid-release
auxiliaries. In addition, owing to the high glass transition
temperature, it is possible to produce hard, tack-free dosage
forms which have good storage stability even at high
temperatures.
Dosage forms mean herein a11 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
can be used, in particular, as human or animal foods.
The dosage forms obtainable according to the invention generally
comprise:
a) 0 to 90% by weight, in particular 0.1 to 60% by weight (based
on the total weight of the dosage form) of an active
ingredient,
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b) 10 to 100% by weight, in particular 40 to 99.9% by weight, of
a polymeric binder and
c) where appropriate additives.
If the dosage form is employed for human or animal food purposes,
the active ingredient may be absent, i.e. the dosage form may
comprise up to 100% of the polymeric binder.
The polymeric binders used according to the invention are
polyamides with sulfonate groups. The sulfonate groups can be
introduced with one or more of the monomers employed to construct
the polyamides. Moreover these monomers may have one or more
sulfonate groups. The molar proportion of monomers with sulfonate
groups is, as a rule, at least 0.5 mol% and preferably not more
than 50 mol%. 5 to 35 mol% are particularly preferred, especially
10 to 30 mol%.
Dicarboxylic acids with sulfonate groups are particularly
suitable for constructing the polyamides employed according to
the invention. If other dicarboxylic acids besides these
dicarboxylic acids with sulfonate groups are used, the ratio of
the molar proportions of dicarboxylic acids'with sulfonate groups
to other dicarboxylic acids is, as a rule, 1:99 to 99:1,
preferably 10:90 to 70:30 and, in particular, 20:80 to 60:40.
The polyamides with sulfonate groups which are preferably used
are obtainable from
A1) 0 to 90 mol% of at least one monoamino carboxylic acid, the
lactam thereof or monoamino carboxylic acid/lactam mixtures,
A2) 5 to 50 mol% of at least one primary or secondary diamine,
A3) 0.5 to 49.5 mol% of at least one dicarboxylic acid with
sulfonate groups and, where appropriate,
A4) 0.5 to 49.5 mol% of at least one other dicarboxylic acid,
where the total of the molar proportions of monomers A3) and
A4) essentially corresponds to the molar proportion of
monomer A2).
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It is particularly preferred to use polyamides with sulfonate
groups which are obtainable from
A1) 0 to 50 mol% of at least one monoamino carboxylic acid, the
5 lactam thereof or monoamino carboxylic acid/lactam mixtures,
A2) 45 to 50 mol% of at least one primary or secondary diamine,
A3) 5 to 35 mol% of at least one dicarboxylic acid with sulfonate
groups and, where appropriate,
A4) 15 to 45 mol% of at least one other dicarboxylic acid, where
the total of the molar proportions of monomers A3) and A4)
essentially corresponds to the molar proportion of monomer
A2).
Very particularly preferred polyamides with sulfonate groups are
obtainable from
A1) 0 to 45 mol% of at least one monoamino carboxylic acid, the
lactam thereof or monoamino carboxylic .acid/lactam mixtures,
A2) 47.5 to 50 mol% of at least one primary or secondary diamine,
A3) 10 to 30 mol% of at least one dicarboxylic acid with
sulfonate groups and, where appropriate,
35
A4) 20 to 40 mol% of at least one other dicarboxylic acid, where
the total of the molar proportions of.monomers A3) and A4)
essentially corresponds to the molar proportion of monomer
A2).
If present, the proportion of component A1 is at least 0.5 mol%.
Advantageous polyamides are obtainable from only monomers A2),
A3) and A4) described above. In this case, the molar proportion
of monomer A2) is 50 mol%. The molar proportions of monomers A3)
and A4) vary within the limits stated above, with the total
likewise being 50 mol%.
It is particularly advantageous if at least two different
diamines are used to prepare the novel polymers.
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Suitable monomers A1) are the monoamino carboxylic acids and
their lactams known for preparing polyamides. They are preferably
C2-C1z-monoamino carboxylic acids and, in particular, monoamino
carboxylic acids of the general formula H2N-R1-COON, in which R1
is a straight-chain or branched, saturated or unsaturated,
aliphatic, cycloaliphatic or aromatic radical. Radicals R1 of this
type may also be substituted one or more times by groups selected
independently from hydroxyl or C1_4-alkoxy. Examples of suitable
monoamino carboxylic acids and lactams are w-aminoundecanoic
acid, pyrrolidone, e-caprolactam, laurolactam, caprylolactam or
enantholactam.
Examples of suitable monomers A2) are primary C2-C18-diamines, in
particular those of the formula H2N-R2-NH2, in which R2 is a
Straight-chain or branched, saturated and unsaturated, aliphatic
radical having 2 to 18, preferably having 2 to 14, and in
particular, having 5 to 11 carbon atoms, which may also be
substituted one or more times by groups selected independently
from hydroxyl or C1_4-alkoxy, a saturated or unsaturated
cycloaliphatic radical having 5 to 8 and preferably 6 carbon
atoms, which may also be substituted one or more times by groups
selected independently from hydroxyl, C1_4-alkyl or C1_4-alkoxy, a
plurality of, and in particular two, cycloaliphatic radicals
which are linked togethex and are of the type identified above,
an aromatic radical having 6 to 18, preferably 6 to 12, carbon
atoms and, in particular, a phenyl radical, which may also be
substituted one or more times by groups selected independently
from hydroxyl, C1_4-alkyl or C1_4-alkoxy, or a plurality of, and in
particular two, aromatic radicals which are linked together and
are of the type identified above. Aliphatic and cycloaliphatic
radicals are preferred.
Cycloaliphatic or aromatic radicals which are linked together are
linked together by either a bond or a divalent radical, it being
possible for the divalent radical to be, in particular, a
C1-C4-alkylene group such as a methylene, 1,1-, 1,2-ethylene,
1,1-, 1,2-, 1,3- and 2,2-propylene group, -0-, -S-, -S02-, C(0)
and an alkylene group of the type identified above which is
Interrupted by -0-, -S-, -S02- or C(O).
Aliphatic radicals are preferably alkylene or alkenylene groups
which may also be interrupted one or more times by -O-, -S-, -S02-
or C(o).
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Cycloaliphatic radicals are preferably cycloalkyl or cycloalkenyl
groups which may also be interrupted one or more times by -0-,
-S-, -S02- or C(O).
Examples of suitable primary diamines are alkylenediamines or
cycloalkyldiamines such as 1,2-ethanediamine, 1,5-pentanediamine,
di(4-aminocyclohexyl)methane, 2,2-di(4-aminocyclohexyl)propane,
di(3-methyl-4-aminocyclohexyl)methane or, preferably,
hexamethylenediamine. Also suitable are 2,2,4-trimethyl-
hexamethylenediamine, 2-butyl-2-ethyl-1,5-pentanediamine,
2-methylpentamethylenediamine or 4,7-dioxadecane-1,10-diamine.
Also suitable as monomers A2) are secondary diamines, for example
those derived from a primary diamine of the type described above
by replacement of at least one amine hydrogen by a suitable
substituent such as C1-C3-alkyl.
Preferred secondary diamines are cyclic diamines of the general
formula
2~
R
HN ~ ~NH
R2.,
in which R2' and R2" may, independently of one another, have the
meanings indicated above for R2. An example of a diamine of this
type is piperazine.
Suitable monomers A3) with sulfonate groups are those in which
the sulfo group is in salt form, e.g. as salt of an alkali metal
such as lithium, sodium or potassium, or of an.ammonium group
which is optionally substituted by one to 4 aliphatic or aromatic
groups. Suitable monomers with sulfonate groups are sulfonic acid
salts of CQ-C2o- and, preferably, C4-C12-dicarboxylic acids.
Particularly suitable dicarboxylic acids are those of the general
formula HOOC-R3-COON, in which R3 may have the meanings mentioned
above for R2.
R3 is preferably an aromatic radical. This includes phenyl,
naphthyl or diphenyl radicals and two phenyl radicals linked
together by a divalent radical. Examples of such divalent
radicals are indicated above.
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The sulfonate groups can be linked to R3 directly or via a
C1-C4-alkylene bridge. One example of aliphatic dicarboxylic acids
with sulfonate groups is sulfosuccinic acid. Suitable aromatic
dicarboxylic acids with sulfonate groups are based, for example,
on phthalic acid, isophthalic acid, terephthalic acid, 1,4- and
2,6-naphthalenedicarboxylic acid, 3,3'- and
4,4'-diphenyldicarboxylic acid, 3,3'- and 4,4'-diphenylmethane-
dicarboxylic acid or 2-phenoxyterephthalic acid. As a rule, the
aromatic dicarboxylic acids have one or two sulfonate groups.
These can be linked to any positions not substituted by carboxyl
groups, directly, for example as in 5=sulfoisophthalic acid, or
via a divalent bridge, for example as in 5-sulfopropoxy-
isophthalic acid. A salt of 5-sulfoisophthalic acid, in
particular the sodium salt, is particularly preferred.
Suitable and preferred monomers A4) are C2-C16-dicarboxylic acids
and, in particular, dicarboxylic acids of the general formula
HOOC-R4-COON. The definition of the radical R3 applies in
principle to the radical R4 except that R4 has no sulfonate group.
Examples of aliphatic dicarboxylic acids are azelaic acid,
dodecanedicarboxylic acid or, preferably, adipic acid or sebacic
acid. Examples of suitable aromatic dicarboxylic acids are
isophthalic acid or terephthalic acid, which may also be
substituted, such as, for example, 3-tert-butylisophthalic acid,
also 3,3'- or 4,4'-diphenyldicarboxylic acid, 3,3'- or
4,4'-diphenylmethanedicarboxylic acid, di(3- or 4-carboxyphenyl)
sulfone, 1,4- or 2,6-naphthalenedicarboxylic acid or
2-phenoxyterephthalic acid.
It is of course true for a11 monomer groups that mixtures of the
particular monomers can also be employed.
The polyamides with sulfonate groups can be prepared in a manner
known per se.
The preferred mode of preparation which may be mentioned is the
batch process (discontinuous mode of preparation). This entails
the aqueous monomer solution being heated in an autoclave to
temperatures from 240 to 300C over the course of 0.5 to 3 h,
during which a pressure of from 10 to 50 bar, in particular 15 to
30 bar, is reached and is kept constant for up to 4 h by
releasing excess steam. The autoclave is then decompressed to
atmospheric pressure at constant temperature within a period of
from 0.5 to 3 h. The polymer melt is subsequently removed from
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the autoclave, cooled with air or nitrogen and subsequently
granulated.
The copolyamide obtained in this way usually has a viscosity
number between 25 and 110 ml/g, preferably from 30 to 80 ml/g,
measured on a 0.5% by weight solution in 96% strength sulfuric
acid.
The copolymers generally have K values of at least 7, preferably
10 to 250. The polymers may have K values of up to 300. The K
values are determined by the method of H. Fikentscher,
Cellulosechemie, Volume 13, 58-64 and 71-74 (1932), in aqueous
solution or in an organic solvent at 25C and at concentrations
which are between 0.1% and 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
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
(NVP) and vinyl esters, especially vinyl acetate, copolymers of
vinyl acetate and crotonic acid, partially hydrolyzed polyvinyl
acetate, polyvinyl alcohol, polyvinylformamide, partially or
completely hydrolyzed polyvinylformamide, poly(hydroxyalkyl
acrylates), poly(hydroxyalkyl methacrylates), polyacrylates and
polymethacrylates (Eudragit types), copolymers of methyl
methacrylate and acrylic acid, polyacrylamides, polyethylene
glycols, cellulose esters, cellulose ethers, especially methyl .
cellulose and ethyl cellulose, hydroxyalkylcelluloses, especially
hydroxypropylcellulose, hydroxyalkylalkylcelluloses, especially
hydroxypropylethylcellulose, cellulose phthalates, especially
cellulose acetate phthalate and hydroxypropyl
methylcellulose phthalate, and mannans, especially
galactomannans. Of these, polyvinylpyrrolidone, copolymers of
N-vinylpyrrolidone and vinyl esters, poly(hydroxyalkyl
acrylates), poly(hydroxyalkyl methacrylates), polyacrylates,
p~l~ethacrylates, alkylcelluloses and hydroxyalkylcelluloses are
particularly preferred.
The polymeric binder must soften or melt in the complete mixture
of a11 the components in the range from 50 to 180C, preferably 60
to 130C. The glass transition temperature of the mixture must
therefore be below 180C, preferably below 130C. If necessary, it
is reduced by conventional pharmacologically acceptable
plasticizing auxiliaries. The amount.of plasticizer does not
CA 02257547 1999-O1-12
lU
exceed 30% of the total weight of binder and plasticizes in order
to form storage-stable drug forms which show no cold flow.
However, the mixture preferably contains no plasticizes.
Examples of such plasticizers are:
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 (e. g. dialkyl phthalates, trimellitic
esters, benzoic esters, terephthalic esters) or aliphatic
dicarboxylic esters (e. g. 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 plasticizes is generally
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,
extenders and bulking agents such as silicates or diatomaceous
earth, magnesium oxide, aluminum oxide, titanium oxide, stearic
acid or its salts, e.g. the magnesium or calcium salt, methyl
cellulose, sodium carboxymethylcellulose, talc, sucrose, lactose,
cereal or corn starch, 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.
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 animal or vegetable fats, especially
in hydrogenated form and those which are solid at room
temperature. These fats preferably have a melting point of 50C or
above. Triglycerides of C12, C14, Cls 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
derived from the abovementioned fatty acid types. The total
amount of fats, waxes, mono-, diglycerides and/or lecithins is
from 0.1 to 30, preferably 0.1 to 5, % of the total weight of the
composition for each layer.
Dyes, such as azo dyes, organic or inorganic pigments or dyes of
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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.
Stabilizers such as antioxidants, light stabilizers, hydro-
peroxide destroyers, radical scavengers, stabilizers against
microbial attack.
It is also possible to add wetting agents, preservatives,
disintegrants, adsorbents, release agents dispersing additives,
propellants and defoamers (cf., for example, H. Sucker et al.,
Pharmazeutische Technologie, Thieme-verlag, Stuttgart Z978).
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
tetraacetate, polymers such as polyethylene oxides and poly-
propylene oxides and their block copolymers (poloxamers),
phosphatides such as lecithin, homo- and copolymers of vinyl-
pyrrolidone, 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.
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
adequate thermal stability.
Active ingredients mean for the purpose of the invention a11
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,
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
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
group, the B group, by which are meant besides B1, B2. Bs and B12
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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,
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,
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,
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,
cefuroxime, selegiline, chloramphenicol, chlorhexidine,
chlorpheniramine, chlortalidone, choline, cyclosporin,
cilastatin, cimetidine, ciprofloxacin, cisapride, cisplatin,
clarithromycin, clavulanic acid, clomipramine, clonazepam,
clonidine, clotrimazole, codeine, cholestyramine, cromoglycic
acid, cyanocobalamin, cyproterone, desogestrel, dexamethasone,
dexpanthenol, dextromethorphan, dextropropoxiphene, diazepam,
diclofenac, digoxin, dihydrocodeine, dihydroergotamine,
dihydroergotoxin, diltiazem, diphenhydramine, dipyridamole,
dipyrone, disopyramide, domperidone, dopamine, doxycycline,
enalapril, ephedrine, epinephrine, ergocalciferol, ergotamine,
erythromycin, estradiol, ethinylestradiol, etoposide, Eucalyptus
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,
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,
lactulose, lecithin, levocarnitine, levodopa, levoglutamide,
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levonorgestrel, levothyroxine, lidocaine, lipase, imipramine,
lisinopril, loperamide, lorazepam, lovastatin, medroxy
progesterone, menthol, methotrexate, methyldopa, methyl
prednisolone, metoclopramide, metoprolol, miconazole, 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, norethisterone,
norfloxacin, norgestrel, nortriptyline, nystatin, ofloxacin,
omeprazole, ondansetron, pancreatin, panthenol, 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, 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, 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
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.
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 ingredients) in the plastic phase in intensive
mixers with very short residence times. The active ingredients)
CA 02257547 1999-O1-12
' 14
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, i.e, as
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
solvents which are immiscible or miscible with water. Suitable
water-miscible solvents are, in particular, C1-C4-alkanols such as
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
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 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
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,
if the liquid form of the components used is based on an organic
solvent.
It is possible where appropriate to replace melting by
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, e.g.
an extruder. This will be comprised by the term mixing
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
agitator, e.g. 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
CA 02257547 1999-O1-12
14
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, i.e. as
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
solvents which are immiscible or miscible with water. Suitable
water-miscible solvents are, in particular, C1-C4-alkanols such as
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
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 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
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,
if the liquid form of the components used is based on an organic
solvent.
It is possible where appropriate to replace melting by
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, e.g.
an extruder. This will be comprised by the term mixing
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
agitator, e.g. 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
CA 02257547 1999-O1-12
16
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
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.
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
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
depends on the required pharmaceutical form. Examples of suitable
dies are those with a flat orifice, called slit dies, and dies
with an.annular orifice. The design of the die depends on the
polymeric binder used and the required pharmaceutical form.
The resulting mixture is preferably solvent-free, i.e. 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
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
results in lenticular dosage forms (tablets) with a diameter of
from 1 to 10 mm, while cold-cut 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
CA 02257547 1999-O1-12
17
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
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
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
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
process without restricting it, however.
Example l
520 g of a polyamide from 16.67 mol% of sodium 5-sulfoisophthalic
acid, 16.67 mol% of isophthalic acid, 33.33 mol% of
hexamethylenediamine and 33.33% of s-caprolactam (K .value 21.0; 1%
strength in dimethylformamide; Mn (end group analysis): 6000-7000;
Tg - 149~C) are extruded with 480 g of verapamil hydrochloride
under the conditions indicated hereinafter and calendered to give
500 mg oblong tablets by the process described in EP-A-240 904.
Section 1: 94~C
Section 2: 150~C
Section 3: 123~C
Section 4: 100~C
Section 5: 81~C
Dye: 79~C
The release after 8 h was 10% [USP paddle method (pH change)].
