Note: Descriptions are shown in the official language in which they were submitted.
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METHOD FOR PRODUCING SOLID, SPHERICAL FORMS CONTAINING
PHARMACEUTICAL ACTIVE AGENTS IN A BINDER MATRIX
The present invention relates to a process for producing solid
spherical moldings which comprise at least one pharmaceutical
active ingredient homogeneously dispersed in a binder matrix by
mixing the ingredients to form a melt and subsequently shaping.
EP-A 240 904, EP-A 240 906 and EP-A 358105 disclose that
pharmaceutical active ingredients can be processed together with
polymeric binders by melt extrusion to give various types of
solid drug forms. The shaping takes place in these cases by
calendering or hot cut using rotating knives.
However, shaping processes of this type are less suitable for
shaping low-viscosity melts as obtained, for example, with
formulations comprising sugar alcohols as matrix. In addition,
such low-viscosity melts also have a tendency to be tacky, which
likewise makes shaping by the above-mentioned processes.
difficult.
EP-A 012 192 discloses an apparatus for extruding free-flowing
compositions, and this can preferably be employed for
granulation. In this apparatus, the free-flowing composition is
converted into drops by means of rotating perforated cylinders.
Corresponding apparatuses are commercially available under the
name Rotoformer~ (supplied by Sandvik).
WO 93/25074 describes the formulation of crop protection agents
by extrusion and shaping with the aid of such a Rotoformer. The
formulations obtainable in this way are cloudy, mostly soft
powder granules.
It is an object of the present invention to provide a process for
producing solid spherical drug forms which also makes it possible
to process low-viscosity melts and results in drug forms with
good product properties.
We have found that this object is achieved by a process for
producing solid spherical moldings which comprise at least one
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pharmaceutical active ingredient homogeneously dispersed in an
ancillary substance matrix by mixing the ingredients to form a
melt and subsequently shaping, wherein at least one
pharmaceutical active ingredient is processed with at least one
melt-processable matrix ancillary substance, forming a
homogeneous melt with a viscosity of less than 5000 mPas, and
°
. 0050/48825
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shaping the melt into drops with the aid of a rotating perforated
roll which are subsequently solidified by cooling.
The process according to the invention is suitable for all active
ingredients which do not decompose under the processing
conditions.
The process according to the invention is suitable, for example,
for formulating the following substances or their physiologically
acceptable salts, it also being possible to generate the salts in
situ in the extruder:
- Antiinfectives
Aciclovir, aminoglycosides, amphotericin B, azole antimyco-
tics, clotrimazole, itraconazole, sepraconazole, clindamycin,
cephalosporins, chloramphenicol, erythromycin, 5-fluoroura-
cil, etoposide, flucytosine, ganciclovir, griseofulvin, gyra-
se inhibitors, isoniazid, lincosamides, mebendazole, meflo-
quine, metronidazole, nitroimidazoles, novobiocin, platinum
compounds, polymyxin B, praziquantel, pyrimethamine, rifampi-
cin, saquinavir, streptomycin, sulfonamides, tetracyclines,
trimethoprim, vancomycin, zidovudine;
- Antipyretics, analgesics, antiinflammatory agents, paraceta-
mol, ibuprofen, ketoprofen, oxaprozin, acetylsalicyl acid,
morphine, propoxyphene, phenylbutazone;
- Antibiotics
Rifampicin, griseofulvin, chloramphenicol, cycloserine, eryt
hromycin, penicillins such as penicillin G, streptomycin, te
tracycline;
- Antiepileptics
Hydantoins, carbamazepine;
- Antitussives and antiasthmatics
Diphenhydramine;
- Antirheumatics
Chloroquine, indomethacin, gold compounds, phenylbutazone,
oxyphenbutazone, penicillamine;
- Hypnotics
Barbiturates, phenobarbital, zolpidem, dioxopiperidines, ur-
Bides;
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- Psychopharmaceuticals, neuroleptics
Perazine, promazine, sulpiride, thioridazine, chlorpromazine,
meprobamate, triflupromazine, melperone, clozapine, risperi-
done, reserpine;
- Tranquilizers;
- Antidepressants
Imipramine, paroxetine, viloxazine, moclobemide;
- Psychostimulants;
- Psychotomimetics;
- Diuretics
Potassium canrenoate, loop diuretics, furosemide, hydrochlo-
rothiazide, spironolactone, thiazides, triamterene;
- Hormones
Androgens, antiandrogens, gestagens, glucocorticoids, estro-
gens, cortisol, dexamethasone, prednisolone, testosterone,
Adiuretin, oxytocin, somatropin, insulin;
- Immunosuppressants
Ciclosporin;
- Bronchodilators;
- Muscle relaxants, tranquilizers
Carisoprodol, tetrazepam, diazepam, chlordiazepoxide;
- Enzymes
Lipase, phytase;
- Anti-gout agents
Allopurinol, colchicine;
- Anticoagulants
Coumarins;
- Antiepileptics
Phenytoin, phenobarbital, primidone, valproic acid, carbama-
zepine;
- Antihistamines
Chlorphenoxamine, dimenhydrinate;
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- Antimimetics;
- Antihypertensives, antiarrhythmics
Lidocaine, procainamide, quinidine, calcium antagonists, gly-
cerol trinitrate, isosorbide dinitrate, isosorbide 5-mononi-
trate, pentaerythrityl tetranitrate, nifedipine, diltiazem,
felodipine, verapamil, reserpine, minoxidil, captopril, ena-
lapril, lisinopril;
- Sympathomimetics
Norfenefrine, oxedrine, midodrine, phenylephrine, isoprenali-
ne, salbutamol, clenbuterol, ephedrine, tyramine, ~-hlockers
such as alprenolol, metoprolol, bisoprolol;
- Antidiabetics
Biguanides, sulfonylureas, carbutamide, tolbutamide, glibenc-
lamide, metformin, acarbose, troglitazone;
- Iron preparations;
- Vitamins
Vitamin C, B, A, D, folic acid;
- ACE inhibitors
Captopril, ramipril, enalapril;
- Anabolics;
- Iodine compounds;
- X-ray contrast agents;
- CNS-active compounds;
- Antiparkinson agents
Biperiden, benzatropine, amantadine, opioid analgesics, bar-
biturates, benzodiazepines, disulfiram, lithium salts, theo-
phylline, valproate, neuroleptics;
- Cytostatics;
- Antispasmolytics;
- Vasodilators
Naftidrofuryl, pentoxifylline.
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It is also possible to obtain preparations of the bioactive
substances in the form of solid solutions. The term "solid
solutions" is familiar to the skilled worker (see Chiou and
Riegelman, J. Pharm. Sci. ~Q, 1281-1302 (1971)). In solid
5 solutions of pharmaceutical active ingredients in polymers or
other matrices, the active ingredient is in the form of a
molecular dispersion in the matrix.
Preferred active ingredients are non-steroidal antirheumatic
agents, opioids and vitamins. Ibuprofen and tramadol
hydrochloride are particularly preferred.
The amount of active ingredients in the complete preparation may
vary within wide limits depending on the activity, rate of
release and solubility. Thus, the active ingredient content may
be from 0.1 to 90, preferably 5 to 70, % of the total weight of
the preparation. The only condition is that the melts can be
processed by the process according to the invention.
The active ingredient is in the form of a homogeneous dispersion,
preferably as "solid solution", i.e. molecular dispersion, in an
ancillary substance matrix.
Suitable components for the ancillary substance matrix may be
polymeric or else low molecular weight binders as long as they
are melt-processable without decomposition and do not give
together with the active ingredient, and other additives where
appropriate, solid forms prone to cold flow.
Examples of suitable polymeric matrix components are:
Homo- or copolymers of N-vinylpyrrolidone such as
polyvinylpyrrolidone (PVP), copolymers of N-vinylpyrrolidone with
vinyl esters, in particular with vinyl acetate, or else with
vinyl propionate. The K values (according to H. Fikentscher,
Cellulose-Chemie 13 (1932), pages 58-64 and 71-74) are in the
range from 10 to 100, preferably 12 to 70, in particular 12 to
35. The K values for PVP are particularly preferably in the range
from 10 to 40.
Copolymers of vinyl acetate and,crotonic acid, partially
hydrolyzed polyvinyl acetate or polyvinyl alcohol.
Cellulose derivatives, such as, for example, cellulose ethers, in
particular methylcellulose, ethylcellulose,
hydroxyalkylcelluloses, especially hydroxypropylcellulose,
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hydroxyalkylalkylcelluloses, in particular
hydroxypropylmethylcellulose and hydroxypropylethylcellulose.
Cellulose esters such as cellulose phthalates, in particular
cellulose acetate phthalate and hydroxypropylmethylcellulose
phthalate, in addition mannans, especially galactomannans.
Also suitable as polymeric binders are polymers based on
acrylates or methacrylates, for example the polyacrylates and
polymethacrylates, copolymers of acrylic acid and methyl
methacrylate or polyhydroxyalkyl acrylates or methacrylates,
known as Eudragit types.
Likewise suitable are polylactides, polyglycolides,
polylactide/polyglycolides, polydioxanes, polyanhydrides,
polystyrenesulfonates, polyacetates, polycaprolactones,
poly(ortho)esters, polyamines, polyhydroxyalkanoates or
alginates.
Suitable matrix components can also be natural or semi-synthetic
binders such as starches, degraded starches, for example
maltodextrin, in addition gelatin which may, depending on
requirements, have basic or acidic characteristics, chitin or
chitosan. Gelatins are preferred.
Low molecular weight binders are also suitable according to the
invention as matrix ancillary substances, in particular sugar
alcohols such as, for example, sorbitol, mannitol, xylitol or,
particularly preferably, isomalt. Trehalose is also preferred,
and displays a cryoprotective effect.
It is also possible to employ fats or waxes as binders. Thus,
suitable examples of binders are polyethylene glycols or.
polypropylene glycols with molecular weights in the range from
300 to 100,000.
Particularly preferred binders are the homo- and copolymers of
N-vinylpyrrolidone, sugar alcohols and gelatin.
It is, of course, also possible to employ mixtures of said
binders, in particular also mixtures of melt-processable polymers
with sugar alcohols.
The binder must soften or melt in the complete mixture of all the
components in the range from 40 to 180°C, preferably 60 to
130°C.
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It is also possible for the melt to be mixed with a solvent which
may, as well as its dissolving properties, also display a
plasticizing effect in the melt. Solvents of this type are, in
particular, monohydric or polyhydric alcohols or water or
5 mixtures of alcohols and water. Water is the preferred
plasticizing solvent. It may be advisable to add the plasticizing
solvent in amounts of from 0.5 to 30% by weight. By adding the
solvent it is possible to adjust the melt viscosity specifically
and thus influence the detachment behavior on the die or die
10 plate. The solvent can be removed during the solidification in
the cold liquid medium, which represents a freeze-drying. The
melts processed according to the invention have a viscosity at~
120°C below 5000 mPas, preferably 1000 to 4000 mPas (measured with
a rotational viscometer with shear rates in the range 10-100°/s).
The forms produced by the process according to the invention may
additionally contain the ancillary substances customary for the
stated uses in the amounts customary for this purpose.
Examples of ancillary substances for drugs are bulking agents,
lubricants, mold release agents, plasticizers, blowing agents,
stabilizers, dies, extenders, flowability agents and mixtures
thereof. However, the ancillary substances for drugs must never
restrict the idea according to the invention of a drug form which
gradually dissolves or at least erodes and disintegrates in the
digestive fluids and becomes surrounded with a gel layer.
Examples of bulking agents are inorganic bulking agents such as
the oxides of magnesium, aluminum, silicon, titanium etc. in a
concentration of from 0.02 to 50, preferably 0.20 to 20, % of the
total weight of the drug form.
Examples of lubricants are stearates of aluminum, calcium and
magnesium, and talc and silicones in a concentration of from 0.1
to 5, preferably from 0.1 to 3, % of the total weight of the
form.
Examples of disintegration promotors which can be employed are
sodium carboxymethyl starch or crospovidone. It is also possible
to employ wetting agents such as sodium lauryl sulfate or sodium
docusate.
Examples of plasticizers comprise low molecular weight
poly(alkylene oxides), such as, for example, polyethylene
glycols), polypropylene glycols), poly(ethylene/propylene
glycols); organic plasticizers with a relatively low molecular
weight such as glycerol, pentaerythritol, glycerol monoacetate,
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diacetate or triacetate, propylene glycol, sodium diethyl
sulfosuccinate etc., added in concentrations of from 0.5 to 15,
preferably from 0.5 to 5, % of the total weight of the drug form.
Examples of dies are known azo dies, organic and inorganic
pigments or coloring matter of natural origin.
Inorganic pigments are preferred in concentrations of from 0.001
to 10, preferably from 0.5 to 3, % of the total weight of the
drug form.
It is also possible to add other additives which improve the flow
properties of the mixture or act as mold release agents, such as,
for example, animal or vegetable fats, preferably in their
hydrogenated form, especially those which are solid at room
temperature. These fats preferably have a melting point of 50°C or
above. Triglycerides of the C12, Ci4. Cis and C18 fatty acids are
preferred. The same function can also be carried out by waxes
such as, for example, carnauba wax. These additives can be added
alone without the addition of bulking agents or plasticizers.
These fats and waxes can advantageously be admixed alone or
together with mono- and/or diglycerides or phosphatides, in
particular lecithin. The mono- and diglycerides are preferably
derived from the fat types described above, i.e. C12, C14, Cis and
C18 fatty acids. The total amount of fats, waxes, mono- and
diglycerides and/or lecithins is 0.1 to 30, preferably 0.1 to 50,
% of the total weight of the drug form.
Examples of flow regulators which can be used are Aerosils or
talc.
It is also possible to add stabilizers such as, for example,
antioxidants, light stabilizers, hydroperoxide destroyers,
radical scavengers and stabilizers against microbial attack.
Ancillary substances also mean for the purpose of the invention
substances for producing a solid solution with the pharmaceutical
active ingredients. Examples of these ancillary substances are
pentaerythritol and pentaerythritol tetraacetate, polymers such
as, for example, polyethylene oxides or 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 and others as indicated, for example,
in J.L. Ford, Pharm. Acta iielv. ~1, 69-88 (1986).
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Pharmaceutical ancillary substances are also regarded as being
additions of bases or acids to control the solubility of an
active ingredient (see, for example, K. Thoma et al., Pharm. Ind.
98-101 (1989)).
The mixing of the bioactive substance with the ancillary
substances can take place in a manner known per se. The
components can be mixed first and then melted and homogenized.
However, it may be advisable, especially with active ingredients
which are thermally unstable or sensitive to shear forces, first
to melt and mix the ancillary substances and then mix in the
active ingredient.
The melting and mixing take place in an apparatus customary for
this purpose. Generally suitable mixing and melting apparatuses
are those employed in plastics technology. Suitable apparatuses
are described, for example, in ~~Mischen beim Herstellen and
Verarbeiten von Kunststoffen", H. Pahl, VDI-Verlag, 1986.
Particularly suitable apparatuses are extruders and dynamic and
static mixers, and stirred vessels, single-shaft stirrers with
stripper mechanisms, especially paste mixers, multi-shaft
stirrers, solids mixers and, preferably, mixer/kneader reactors,
trough mixers, internal mixers or rotor/stator systems. The
mixing and melting particularly preferably take place in a
single-screw or multi-screw extruder, in particular a twin-screw
extruder, and this can also be preceded by mixing chambers. The
mixing and melting can also take place in apparatuses in which
the energy is supplied in the form of microwaves or ultrasound.
The charging of the mixing and melting apparatus can take place
continuously or batchwise in a conventional way. Powdered
components can be fed in freely, for example through a weigh
feeder. Plastic compositions can, for example, be fed in directly
from an extruder or be fed in via a gear pump. Liquid components
can be metered in through suitable pumping units. It is also
possible according to the invention to feed in low-viscosity
pastes or gels with a high dispersing medium content, with water
preferably being used as dispersing medium.
The mixtures are processed to melts preferably at temperatures
from 20 to 280°C, particularly preferably from 25 to 180°C.
For the shaping, the still plastic melt is converted with the aid
of rotating perforated rolls into drops which are then solidified
by cooling.
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According to the invention, the plastic mixture is first extruded
using a suitable extruder to give a continuous strand. It is
moreover possible for any solvents and residual moisture present
to be stripped off by means of a vacuum pump during the
5 extrusion. The shape of the extrusion die depends on the required
shape. The melt is preferably extruded through round-section
dies, with the plastic mixture being extruded as a strand with
circular cross-section and discharged into the Rotoformer~ or
into an analogous apparatus suitable for producing pastilles.
The plastic melt is in these cases passed through rotating
perforated rolls and converted into drops in this way.
The apparatus suitable for making pastilles consists in
particular of a rotating, heatable roll which has orifices and
which is surrounded by a perforated casing. The roll and
perforated casing preferably move in opposite directions.
The process according to the invention is explained below by
means of examples.
General procedure
The amounts, stated in each of the examples, of active ingredient
and matrix ancillary substances were mixed in a co-rotating,
closely intermeshing twin-screw extruder (ZSK 40 from Werner &
Pfleiderer, Stuttgart). The temperature in the extruder zones was
(in ~C): Zone 1/80; Zone 2/110; Zone 3/150; Zone 4/150; Zone
6/150; Zone 7/150. The screws rotated at ?0 rpm. The throughput
was 20 kg/h with residence times of 1-2 min. The melt emerging
through a die on the extruder head was introduced through a gear
pump into the roll of the Rotoformer~ (type 50.211, Sandvik
Process Systems GmbH, Stuttgart). The rotoformer consists of a
rotating, heated roll which has a perforated casing through whose
perforation the still plastic extrudate was discharged onto a
cooled conveyor belt. The perforated casing had 3720 holes (d = 1
mm), and the capacity of the roll is about 2 kg of melt. The
distance between the perforated casing and the cooling belt was 3
mm. The cooling belt had a length of 4 m and a width of 400 mm.
The temperature of the roll was kept at 150 to 170°C, the
temperature of the belt was adjusted to 20°C by cooling with
water, and the belt moved at 30 m/min.
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Example 1
Ibuprofen 50 Gew.-%
PVP K30 50 Gew.-%
Example 2:
Ibuprofen 40 Gew.-%
PVP K30 55 Gew.-%
10Copolyvidones 5 Gew.-%
Example 3
Ibuprofen 26 Gew.-%
15Isomalt 74 Gew.-%
(Palatinit~)
Temperature of the extruder
zones:
in C 20, 80, 120, 80, 80 (die)
80,
20
Example 4
Tramadol hydrochloride 20 Gew.-%
Isomalt 80 Gew.-%
25
Example 5
Ibuprofen 20 Gew.-%
Na ibuprofenate 44 Gew.-%
30PVP K30 22 Gew.-%
Hydroxypropylmethylcellulose
m.w. with a viscosity
of 4000 mPas 14 Gew.-%
(Methocel~ K4M, from Colorcon Dow)
35
45
