U.S. patent application number 10/489856 was filed with the patent office on 2005-09-08 for granulate or powder for producing coating or binding agents for medicaments.
Invention is credited to Gryczke, Andreas, Meier, Christian, Petereit, Hans-Ulrich, Roth, Erna.
Application Number | 20050197434 10/489856 |
Document ID | / |
Family ID | 31197526 |
Filed Date | 2005-09-08 |
United States Patent
Application |
20050197434 |
Kind Code |
A9 |
Petereit, Hans-Ulrich ; et
al. |
September 8, 2005 |
Granulate or powder for producing coating or binding agents for
medicaments
Abstract
The invention relates to a process for the production of
granules or powders, suitable as coating agents and binders for
oral or dermal pharmaceutical forms, for cosmetics or food
supplements, consisting essentially of (a) a copolymer, consisting
of free radical- polymerized C1- to C4-esters of acrylic or
methacrylic acid and further (meth)acrylate monomers which contain
functional tertiary amino groups, (b) 3 to 25% by weight, based on
(a), of an emulsifier having an HLB of at least 14, (c) 5 to 50% by
weight, based on (a), of a C.sub.12- to C.sub.18-monocarboxylic
acid or of a C.sub.12- to C.sub.18- hydroxyl compound, where the
components (a), (b) and (c) are simultaneously or successively
blended or mixed with one another, optionally with addition of a
pharmaceutical active compound and/or further customary additives,
fused in a heatable mixer, mixed, the melt is cooled and comminuted
to give granules or powders.
Inventors: |
Petereit, Hans-Ulrich;
(Darmstadt, DE) ; Meier, Christian; (Darmstadt,
DE) ; Roth, Erna; (Darmstadt, DE) ; Gryczke,
Andreas; (Strasse, DE) |
Correspondence
Address: |
OBLON, SPIVAK, MCCLELLAND, MAIER & NEUSTADT, P.C.
1940 DUKE STREET
ALEXANDRIA
VA
22314
US
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 0249035 A1 |
December 9, 2004 |
|
|
Family ID: |
31197526 |
Appl. No.: |
10/489856 |
Filed: |
March 23, 2004 |
PCT Filed: |
July 8, 2003 |
PCT NO: |
PCT/EP03/07319 |
Current U.S.
Class: |
524/394; 264/216;
264/331.18; 526/319 |
Current CPC
Class: |
A61K 9/1682 20130101;
A61K 9/1694 20130101; A61K 9/1635 20130101; A61K 9/2846 20130101;
A61K 9/5026 20130101 |
Class at
Publication: |
524/394; 264/216;
264/331.18; 526/319 |
International
Class: |
B29C 039/14; C08J
005/00; C08K 005/04; C08J 003/00 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 27, 2002 |
DE |
102 39 999.9 |
Claims
1. A process for the production of granules or powders, suitable as
coating agents and binders for oral or dermal pharmaceutical forms,
for cosmetics or food supplements, consisting essentially of (a) a
copolymer, consisting of free radical-polymerized C1- to C4-esters
of acrylic or methacrylic acid and further (meth)acrylate monomers
which contain functional tertiary amino groups, (b) 3 to 25% by
weight, based on (a), of an emulsifier having an HLB of at least
14, (c) 5 to 50% by weight, based on (a), of a C.sub.12- to
C.sub.18-monocarboxylic acid or of a C.sub.12- to C.sub.18-hydroxyl
compound, where the components (a), (b) and (c) are simultaneously
or successively blended or mixed with one another, optionally with
addition of a pharmaceutical active compound and/or further
customary additives, fused in a heatable mixer, mixed, the melt is
cooled and comminuted to give granules or powders.
2. The process as claimed in claim 1, wherein the heatable mixer
employed is an extruder.
3. The process as claimed in claim 2, wherein with a double screw
extruder is employed.
4. The process as claimed in claim 1, wherein extrusion is carried
out at temperatures in the range from 80 to 160.degree. C.
5. Granules or powder, suitable as a readily water- dispersible or
fusible precursor for a coating agent and binder for oral or dermal
pharmaceutical forms, for cosmetics or food supplements,
characterized in that it can be produced as claimed in claim 1.
6. A pharmaceutical agent, comprising: the granules or powders as
claimed in claim 5 and a moisture-sensitive pharmaceutically active
compound from the active compound classes of the analgesics,
anti-rheumatics, active compounds for the treatment of gastric
ulcers, antibiotics, antihypotensives, antidepressants, thyroid
therapeutics, anti Parkinson active compounds, anxiolytics,
peptides, phospohordiesterase inhibitors, proteins, cardiovascular
agents or neuroleptics or their salts.
7. A pharmaceutical agent as claimed in claim 6, wherein the
moisture-sensitive pharmaceutical active compound present is
acetylsalicylic acid, carbenoxolone, cefalotin, epinefrine,
imipramine, potassium iodide, ketoprofen, levodopa, nitrazepam,
nitroprusside, oxitetracycline HCl, promethazine, omeprazole or
other benzimidazole derivatives, ranitidine or streptomycin or
their salts.
8. A pharmaceutical agent as claimed in claim 5; wherein said
powder or granules coats a moisture-sensitive pharmaceutical active
compound.
9. A taste-isolating coating, which comprises the powder or
granules as claimed in claim 5.
10. A pharmaceutical binding agents which comprises the powder or
granules as claimed in claim 5; wherein the pharmaceutical binding
agent is obtained by a means of wet or melt granulation.
11. An article, comprising: two or more types of granules or
powders as claimed in claim 5, wherein the granules or powders in
each case containing a different color pigment and being processed
by mixing to give a coating agent and binder.
Description
[0001] The invention relates to a powder or granules for the
production of coating agents and binders for pharmaceutical
forms.
[0002] Prior art
[0003] U.S. Pat. No. 4,705,695 describes a process for the coating
of pharmaceutical formulations with an aqueous coating agent
comprising a water-soluble (meth)acrylate copolymer having tertiary
amino groups, and a water- insoluble, neutral polymer as a binder.
The solubility of the (meth)acrylate copolymer consisting, for
example, of equal proportions of methyl methacrylate and
dimethylaminoethyl methacrylate, is brought about by stirring in in
powder form with particle sizes below 0.25 mm in water with
simultaneous addition of an acid. The binder employed is an
insoluble copolymer, e.g. of methyl methacrylate and ethyl acrylate
(70:30). The production of the coating solution is relatively
complicated. Because of the content of acid, the coating has an
unpleasant taste. Appropriate films dissolve both in artificial
gastric juice and in water in less than two minutes.
[0004] WO 00/05307 describes a process for the production of a
coating agent and binder for oral or dermal pharmaceutical forms
consisting of (a) 35 - 98% by weight of a copolymer, consisting of
free radical- polymerizable C1- to C4-esters of acrylic or
methacrylic acid and further (meth)acrylate monomers which have
functional tertiary amino groups and (b) 1 - 50% by weight of a
plasticizer and 1 - 15% by weight of an emulsifier having an HLB of
at least 14 where the components (a), (b) and (c) are blended with
one another with or without addition of water and optionally with
addition of a pharmaceutical active compound and further customary
additives and the coating agent and binder is produced by fusing,
casting, spreading or spraying, the copolymer (a) being
incorporated in powder form with a mean particle size of 1 - 40
.mu.m.
[0005] A copolymer corresponding to WO 00/05307 of methyl
methacrylate, butyl methacrylate, and dimethylamino- ethyl
methacrylate in the ratio 25:25:50 having a mean particle size of
15 .mu.m is on the market under the name EUDRAGIT.RTM. EPO
(Registered trademark of Rohm GmbH & Co. KG) and thus prior
art.
[0006] The formulation in the defined powder form in combination
with plasticizer and emulsifier makes it possible to convert the
corresponding copolymers into stable aqueous solutions or
dispersions without the addition of acids. There is the advantage
that a bitter intrinsic taste of the coating agent which otherwise
occurs can be avoided. The coating agents and binders are moreover
scarcely soluble in water, but dissolve rapidly in artificial
gastric juice. They are therefore suitable, in particular, for
taste-isolating formulations which disintegrate rapidly in the
gastric juice.
[0007] A further development of WO 00/05307 has been made known by
the publications of Roth et al. ("Improved Moisture Protection with
New Aqueous Aminomethacrylate Copolymer Formulations", CRS, Annual
Meeting 2002 in Seoul (Korea) Jul. 2002) and Petereit "new aspects
of moisture protection and insulation of solid dosage forms with
EUDRAGIT.RTM. EPO" 33th International EUDRAGIT.RTM. Workshop 2001
(Darmstadt, 27-28 Sep. 2001).
[0008] It is reported that the addition of C12 - C18-fatty acids or
alcohols brings about moisture protection. The addition of, for
example, 10% by weight of sodium lauryl sulfate and 15% by weight
of stearic acid to EUDRAGIT.RTM. EPO in dispersed form is
especially recommended.
[0009] Object and achievement
[0010] The invention originates essentially from the EUDRAGIT.RTM.
EPO formulations mentioned at the outset with addition of C12 -
C18-fatty acids or alcohols and emulsifiers such as, for example,
sodium lauryl sulfate. Coating agents and binders produced
therefrom advantageously have only a low water vapor permeability
(moisture protection action). The publications of Roth et al. and
Petereit recommend the dispersion of the individual components
present as powders under stirring conditions. The use of the
pulverulent components has the disadvantage that an undesirable
formation of powder dusts always accompanies it, which as a rule is
undesirable in the case of the end user. It was therefore regarded
as an object to make available an intermediate which can be
processed easily and with markedly reduced dust development by the
end user to give a coating agent and binder.
[0011] The object is achieved by a
[0012] process for the production of granules or powder, suitable
as a coating agent and binder for oral or dermal pharmaceutical
forms, for cosmetics or food supplements, consisting essentially
of
[0013] (a) a copolymer, consisting of free radical-polymerized C1-
to C4-esters of acrylic or methacrylic acid and further
(meth)acrylate monomers which contain functional tertiary amino
groups,
[0014] (b) 3 to 25% by weight, based on (a), of an emulsifier
having an HLB of at least 14,
[0015] (c) 5 to 50% by weight, based on (a), of a C.sub.12- to
C.sub.18- monocarboxylic acid or of a C.sub.12- to
C.sub.18-hydroxyl compound,
[0016] where the components (a), (b) and (c) are simultaneously or
successively blended or mixed with one another, optionally with
addition of a pharmaceutical active compound and/or further
customary additives, fused in a heatable mixer, mixed, the melt is
cooled and comminuted to give granules or powder.
[0017] Owing to the extrusion process of the components (a), (b)
and (c), and optionally additionally added pharmaceutical active
compounds and/or further customary additives, a molecular matrix
obviously results which, after comminution, substantially affords
dust-free processable powder or granules. The end user can easily
process the granules or powder further in a customary manner. The
powder or granules save the prestocking, weighing and the
incorporation of many individual components, since these are
already present in the specified amounts. The dust development
using the powders or granules according to the invention is
avoided. It is surprising that even copolymers as in component (a),
which are present in powder form having a mean particle size of
over 40 .mu.m, and which in this form as a rule necessitate
relatively long dispersion times, of, for example, a number of
hours, can be converted in this way into a rapidly dispersible
form. It is even more surprising, however, that using the present
invention even granules, for example, having particle sizes of 0.5
- 5 mm, can be converted into a rapidly dispersible form.
[0018] Carrying out the invention
[0019] Component (a)
[0020] The copolymers (a) consist essentially or completely of free
radical-polymerized C1- to C4-esters of acrylic or methacrylic acid
and further (meth)acrylate monomers which contain functional
tertiary amino groups.
[0021] Suitable monomers having functional tertiary amino groups
are listed in U.S. pat. No. 4,705,695, column 3, line 64 to column
4, line 13. In particular, dimethylaminoethyl acrylate,
2-dimethylaminopropyl acrylate, dimethyl- aminopropyl methacrylate,
dimethylaminobenzyl acrylate, dimethylaminobenzyl methacrylate,
(3-dimethylamino-2,2- dimethly)propyl acrylate,
dimethylamino-2,2-dimethly)- propyl methacrylate,
(3-diethylamino-2,2-dimethly)- propyl acrylate and
diethylamino-2,2-dimethly)propyl methacrylate may be mentioned.
Dimethylaminoethyl methacrylate is particularly preferred.
[0022] The content of the monomers having tertiary amino groups in
the copolymer can advantageously be between 30 and 70% by weight,
preferably between 40 and 60% by weight. The proportions of the C1-
to C4-esters of acrylic or methacrylic acid is 70-30% by weight.
Methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl
acrylate, ethyl acrylate, butyl acrylate may be mentioned.
[0023] A (meth)acrylate copolymer having tertiary amino groups
corresponding to the component (a) can be built up, for example,
from 20-30% by weight of methyl methacrylate, 20-30% by weight of
butyl methacrylate and 60-40% by weight of dimethylaminoethyl
methacrylate. The proportion of component (a) in the formulation is
preferably 50-90% by weight.
[0024] The copolymers (a) are obtained in a manner known per se by
free-radical substance, solution, bead or emulsion polymerization.
They are brought into a form which is miscible dry or in the melt
with the components (b) and (c) before processing by means of
suitable grinding, drying or spraying processes. In particular, the
granule or powder form is suitable for further processing. Suitable
implements for this are familiar to the person skilled in the art,
e.g. die- face pelletizers, strand pelletizers, air jet mills,
pinned disk mills, fan mills. Optionally, appropriate sieving steps
can be included. A suitable mill for large industrial amounts for
the production of powders is, for example, an opposed jet mill
(Multi No. 4200), which is operated at about 6 bar overpressure.
Suitable powders can, for example, mean particle sizes of 1-40
.mu.m (EUDRAGIT.RTM. EPO type) or between 40 .mu.m to 50 .mu.m.
Granules can, for example, be rounded, lenticular or cylindrical
with particle sizes of 0.5 to 50 mm, preferably 1 to 5 mm
(EUDRAGIT.RTM. E type).
[0025] Component (b)
[0026] Emulsifiers or surfactants are surface-active substances
having lyobipolar character, i.e. nonpolar, lipophilic and polar,
hydrophilic centers must be present in their molecule (P.H. List,
Arzneiformenlehre [Pharmaceutical form theory], Wissenschaftliche
Verlagsgesellschaft mbH Stuttgart, 1982, chap. 6.2.). Depending on
molecular structure, a distinction is made between ionic and
nonionic emulsifiers.
[0027] The HLB is a measure of the hydrophilicity or lipo-
philicity of nonionic surfactants introduced in 1950 by Griffin. It
can be determined experimentally by the phenol titration method
according to Marszall; cf. "Parfumerie, Kosmetik" [Perfumery,
cosmetics], volume 60, 1979, pp. 444-448; further references in
Rompp, Chemie-Lexikon [Chemical encyclopedia], 8th ed. 1983, p.
1750. See furthermore, for example, U.S. Pat. No. 4,795,643
(Seth)).
[0028] An HLB (hydrophilic/lipophilic balance) can only be
determined exactly with nonionic emulsifiers. With anionic
emulsifiers, this value can be determined arithmetically, but is
virtually always above or far above 14.
[0029] Emulsifiers (b) having an HLB of above 14 are understood
according to the invention as meaning hydrophilic, nonionic
emulsifiers having an HLB range of at least 14, and likewise
hydrophilic, anionic emulsifiers and their salts which have an
arithmetical HLB of above 14. Emulsifiers having HLBS of less than
14, such as, for example, glycerol monostearate can admittedly
additionally also be present, but do not replace the emulsifiers
(b) having HLBs of at least 14.
[0030] Suitable emulsifiers (b) are, for example, sodium lauryl
sulfate and sodium cetylstearyl sulfate, sucrose stearate and
polysorbate 80. The emulsifiers (b) are present in amounts of 1-25,
preferably 5-10, % by weight based on component (a). Of course, the
use of emulsifier mixtures is also possible.
[0031] The addition of the emulsifiers (b) to the formulation can
be performed in a known manner, directly, in aqueous solution or
after thermal pretreatment of the mixture.
[0032] Depending on type (lipophilic or hydrophilic) and amount
added, the emulsifiers can influence the functionality of the
polymer layer.
[0033] Component (c)
[0034] Component (c): 5 to 50, preferably 10 to 20, % by weight,
(based on component (a)), of a C.sub.12- to C.sub.18-
monocarboxylic acid or of a C.sub.12- to C.sub.18-hydroxyl
compound. Component (c) is crucial for the surprisingly low water
vapor permeability of the formulations.
[0035] Unbranched C.sub.12- to C.sub.18-monocarboxylic acid or a
C.sub.12- to C.sub.18-hydroxyl compounds are preferred. If
appropriate, branched derivatives of the substances mentioned can
also be suitable.
[0036] C.sub.12- to C.sub.18-monocarboxylic acids are, for example,
in particular, lauric acid and myristic acid. Palmitic acid and
stearic acid are preferred.
[0037] C.sub.12- to C.sub.18-hydroxyl compound, in particular
alkanols having a terminal hydroxyl group such as, for example,
lauryl alcohol or stearyl alcohol.
[0038] Further additives
[0039] Customary additives are preferably added to the formulation
according to the invention during the production of the granules or
powders. The additives can also additionally be added to the
coating agent and binder during processing. In principle, of
course, all substances employed must be toxicologically harmless
and in particular be able to be used in medicaments without risk
for patients.
[0040] Amounts employed and use of the customary additives in
pharmaceutical coatings or coverings are familiar to the person
skilled in the art. Customary additives can be, for example,
mold-release agents, pigments, stabilizers, antioxidants,
pore-forming agents, penetration promoters, lustering agents,
aromatic substances or flavorings. They are used as processing aids
and should guarantee a safe and reproducible production process and
good long-term storage stability or they achieve additional
advantageous properties in the pharmaceutical form. They are added
to the polymer preparations before processing and can influence the
permeability of the coatings, which can optionally be utilized as
an additional control parameter.
[0041] Mold-release agents:
[0042] Mold-release agents as a rule have lipophilic properties and
as a rule are added to the spray suspensions. They prevent
agglomeration of the cores during the making into a film.
Preferably, talc, Mg stearate or Ca stearate, ground silicic acid,
kaolin or nonionic emulsifiers having an HLB of between 3 and 8 are
employed. Customary amounts employed for mold- release agents in
the coating agents and binders according to the invention are
between 0.5 to 100% by weight based on the copolymer (a).
[0043] Pigments: Pigments incompatible with the coating agent are
in particular those pigments which, when they are added directly to
the (meth)acrylate copolymer dispersion, e.g. by stirring in, in
customary use amounts of, for example, 20 to 400% by weight based
on the dry weight of the (meth)acrylate copolymer, lead to the
destabilization of the dispersion, coagulation, to demixing
phenomena or similarly undesirable effects. Furthermore, the
pigments to be used are, of course, nontoxic and suitable for
pharmaceutical purposes. For this, for example, also see: Deutsche
Forschungs- gemeinschaft [German research association], Farbstoffe
fur Lebensmittel [Colorants for foodstuffs], Harald Boldt Verlag
KG, Boppard (1978); Deutsche Lebensmittel- rundschau 74, No. 4, p.
156 (1978); Arzneimittel- farbstoffverordnung [Pharmaceutical
colorants order] AmFarbV of 08.25.1980.
[0044] Pigments incompatible with the coating agent can be, for
example, aluminum oxide pigments. Incompatible pigments are, for
example, Orange Yellow, Cochineal Red lake, color pigments based on
aluminum oxide or azo dyes, sulfonic acid dyes, Orange Yellow S
(E100, C.I. 15985, FD&C Yellow 6), indigocarmine (E132, C.I.
73015, FD&C Blue 2), tartrazine (E 102, C.I. 19140, FD&C
Yellow 5), Ponceau 4R (E 125, C.I. 16255, FD&C Cochineal Red
A), Quinoline Yellow (E 104, C.I. 47005, FD&C Yellow 10),
erythrosine (E 127, C.I. 45430, FD&C Red 3), azorubine (E 122,
C.I. 14720, FD&C carmoisine), amaranth (E 123, C.I. 16185,
FD&C Red 2), Brilliant Acid Green (E 142, C.I. 44090, FD&C
Green S).
[0045] The E numbers of the pigments indicated refer to EU
numbering. For this see also "Deutsche Forschungs- gemeinschaft,
Farbstoffe fur Lebensmittel, Harald Boldt Verlag KG, Boppard
(1978); Deutsche Lebensmittel- rundschau 74, No. 4, p. 156 (1978);
Arzneimittel- farbstoffverordnung [Pharmaceutical colorants order]
AmFarbV of 08.25.1980. The FD&C numbers refer to the
registration in Food, Drugs and Cosmetics by U.S. Food and Drug
Administration (FDA) described in: U.S. Food and Drug
Administration, Center for Food Safety and Applied Nutrition,
Office of Cosmetics and Colors: Code of Federal Regulations - Title
21 Color Additive Regulations Part 82, Listing of Certified
Provisionally Listed Colors and Specifications (CFR 21 Part
82).
[0046] Plasticizers
[0047] Further additives can also be plasticizers. Customary
amounts are between 0 and 50, preferably 0 to 20, in particular 0
to 10, % by weight. Particularly preferably, however, at most 5% by
weight or no plasticizer is contained, since the formulations are
frequently already elastic enough due to the presence of the
components (c) and additional plasticizer can lead to undesirable
tackiness.
[0048] Depending on type (lipophilic or hydrophilic) and amount
added, plasticizers can influence the functionality of the polymer
layer. By means of physical interaction with the polymer,
plasticizers achieve a lowering of the glass transition temperature
and promote, depending on the amount added, making into a film.
Suitable substances as a rule have a molecular weight between 100
and 20,000 and contain one or more hydrophilic groups in the
molecule, e.g. hydroxyl, ester or amino groups.
[0049] Examples of suitable plasticizers are alkyl citrates,
glycerol esters, alkyl phthalates, alkyl sebacates, sucrose esters,
sorbitan esters, diethyl sebacate, dibutyl sebacate and
polyethylene glycols 200 to 12,000. Preferred plasticizers are
triethyl citrate (TEC), acetyl-triethyl citrate (ATEC) and dibutyl
sebacate (DBS). Esters which as a rule are liquid at room
temperature, such as citrates, phthalates, sebacates or castor oil,
are furthermore to be mentioned. Preferably, citric acid esters and
sebacic acid esters are used.
[0050] The addition of the plasticizer to the formulation can be
performed in a known manner, directly, in aqueous solution or after
thermal pretreatment of the mixture. Mixtures of plasticizers can
also be employed.
[0051] Processing to give granules or powders
[0052] The components (a), (b) and (c) are optionally blended or
mixed with one another simultaneously or successively with addition
of a pharmaceutical active compound and/or further customary
additives. The components are then fused in a heatable mixer, mixed
and the melt is cooled and comminuted to give granules or
powders.
[0053] It is possible, for example, to dry the components (a), (b)
and (c), and the pharmaceutical active compound and/or further
customary additives optionally present, for example to mix them
with one another in a gravity mixer or in a mechanical mixer. It is
also possible, however, to feed the components (a), (b) and (c),
and the pharmaceutical active compound and/or further customary
additives optionally present, on their own or as a component
mixture, directly to a heatable mixer, e.g. an extruder, via
continuously operating automatic feeders. It is also possible to
meter the components (b) and (c), and the pharmaceutical active
compound and/or further customary additives optionally present into
the melt of the component (a) on their own or as a component
mixture dry or if appropriate in the fused state.
[0054] The mixture is preferably fused in an extruder and extruded
by means of an extruder, e.g. extruded at temperatures in the range
from 80 to 160, preferably 100 to 150.degree. C. It can be a
single-screw or a double- screw extruder, at whose end the
extrudate emerges, for example, as a melt strand. The extrudate
obtained is comminuted to give granules or powder. This can be
carried out, for example, by means of a hot chip granulator, an
extrudate granulator and/or grinding in a mill, e.g. a pinned disk
mill. The extrudate can, for example, be drawn off via a withdrawal
belt and fed to an extrudate granulator, which cuts up the strand
into pieces 1 to 5 mm long. In the case of granules, the mean grain
size can be, for example, in the range from 0.5 to 5 mm, preferably
1 to 3 mm. Suitable powder sizes can be in the range from 1 to 500
.mu.m, preferably 100 to 500 .mu.m.
[0055] The further processing of the powder or granules according
to the invention
[0056] The invention accordingly relates to granules or powders
which can be produced by means of extrusion and subsequent
comminution of the extrudate and are suitable as a precursor which
is easily dispersible in water or fusible, or as an intermediate,
for a coating agent and binder for oral or dermal pharmaceutical
forms.
[0057] The granules or powders can be processed further at room or
elevated temperature with or without addition of water and
optionally with addition of pharmaceutical active compounds and/or
further customary additives which are still not contained in a
manner known per se by fusing, casting, spreading, spraying or
granulating to give coating agents and binders. In this process,
the making into a film of the coating agent and binder is a
prerequisite for the functional effect in the resulting
pharmaceutical forms.
[0058] The conversion of the granules or powders into a dispersion
by introduction into water and stirring at room temperature is
preferred. Alternatively, higher shear forces or elevated
temperatures, e.g. 50 to 70.degree. C., can be used. Under these
conditions, the dispersing time can be, for example, 45 to 120
min.
[0059] The solids content of the resulting dispersion is between 5
and 30% by weight, preferably between 10 and 20% by weight). The
viscosity of the dispersion depends on the concentration of the
solid. As a rule, it is under 1 Pa*s.
[0060] Two or more types of granules or powders, which in each case
contain various color pigment, can be processed by means of mixing
to give a coating agent and binder. This has the advantage that
colored mixtures can be produced. In this way, color shades can be
generated which cannot be produced using individual color
pigments.
[0061] The making into a film takes place, independently of the
application process, by supply of energy. This can take place by
means of convection (heat), radiation (infrared or microwaves) or
conduction. Water employed for application as a suspending agent
evaporates here, if appropriate a vacuum can also be applied in
order to accelerate the evaporation. The temperature necessary for
the making into a film depends on the combination of the components
employed.
[0062] Further processing of the powders or granules according to
the invention for the production of binders:
[0063] Use as binders is carried out, for example, by spraying the
aqueous polymer suspension onto active compound- free cores
(nonpareils) with simultaneous addition of powdered active
compounds or their mixtures. A further embodiment is the spraying
on of the aqueous polymer suspension together with active compounds
dissolved or suspended therein.
[0064] The granules or powders can also be processed further as
binders by processing by means of wet or melt granulation.
[0065] Further processing of the formulation according to the
invention for the production of coating agents:
[0066] The granules or powders can be used as moisture- isolating
and/or as taste-isolating coating agents.
[0067] Preformed supports for the coatings are capsules, tablets,
granules, pellets, crystals of regular or irregular shape. The size
of granules, pellets or crystals is between 0.01 and 2.5 mm, that
of tablets between 2.5 and 30.0 mm. Capsules consist of gelatin,
starch or cellulose derivatives.
[0068] Powders and crystals as a rule contain 100% of the
biologically active substance. Preformed carriers contain from
approximately 0.1 to up to 99% of the biologically active substance
or of the pharmaceutical active compound, and to 1 to 99.9% by
weight of further pharmaceutical excipients.
[0069] Customary production processes are direct compression,
compression of dry, moist or sintered granules, extrusion and
subsequent rounding, wet or dry granulation or direct pelleting
(e.g. to plates) or by binding of powders (powder layering) to
active compound-free spheres (nonpareils) or active compound-
containing particles.
[0070] In addition to the active compound, they can contain further
pharmaceutical excipients: binders, such as cellulose and its
derivatives, polyvinylpyrrolidone (PVP), humectants, disintegration
promoters, lubricants, disintegrants, (meth)acrylates, starch and
its derivatives, sugar solubilizers or others.
[0071] Of particular importance is the disintegration time of the
cores, which influences the release of the active compound. Today,
shorter disintegration times of under 5, or under 10, min are
strived for in the disintegration test according to Ph. Eur. Longer
disintegration times are problematic because additional coatings
further delay the release of the active compound and can put the
therapeutic effect in question. Today, a disintegration time of 30
min is regarded as a threshold value. Testing is carried out in
water and artificial gastric juice (0.1 N HCl).
[0072] The cores employed are homogeneous or have a laminated
structure. If engravings are inlaid into the surfaces, these should
be covered by coatings if possible but only slightly filled in. The
layer thickness of the polymer powder employed according to the
invention varies greatly ahd depends on the processing procedure or
the amount of additives. It is between 1 and 100 .mu.m, preferably
between 10 and 50 .mu.m. On customary tablets, one polymer
application corresponds to from 0.5 to 5% by weight.
[0073] Coated microparticles can be compressed to give
disintegrating tablets according to K. Lehmann et al., Drugs made
in Germany 37, 2, 53-60 (1994) and T.E. Beckert et al,
International Journal of Pharmaceutics 143, (1996), 13-23, without
significant influence on the function of the polymer.
[0074] The function of the polymer layer made into a film in the
final pharmaceutical form can be varied:
[0075] Protection from harmful environmental influences due to
moisture, gases, light etc.
[0076] Odor or taste isolation,
[0077] marking by color
[0078] mechanical stabilization
[0079] isolation of incompatible ingredients
[0080] avoidance of adherence to the mucous membranes.
[0081] temporarily delayed release of active compound
[0082] pH-controlled release of active compound
[0083] isolation of cores from further coatings
[0084] The low viscosity of the polymer mixture in aqueous
dispersions is advantageous even at high solids contents of up to
30%, since engravings on the surface of tablets are reproduced in
detail.
[0085] The good protective and isolating action of the polymer
mixture according to the invention with, at the same time, a small
influence on tablet disintegration is particularly advantageous.
Even at low polymer applications of 1% by weight, a taste isolation
of more than 30 sec is already achieved. Thicker coatings with a
copolymer of methyl methacrylate, butyl methacrylate and
dimethylaminoethyl methacrylate in the ratio 25:25:50
(EUDRAGIT.RTM. E or EUDRAGIT.RTM. EPO) improve the taste
concealment, but without prolonging the disintegration time in 0.1
N HCl. The reliable covering of colored cores by coatings having a
high pigment content is likewise advantageous. One particular
embodiment is the embedding of a second active compound in the
coating on an active compound-containing core.
[0086] Application to the formulation according to the invention
for production on supports
[0087] The formulation according to the invention can be applied in
powder form, as a melt or in aqueous suspension by means of
granulation, casting, spreading or by means of spray application.
Water is used here mainly as a vehicle in order to apply thin
coatings uniformly to spherical cores, e.g. by spraying. Spreading
processes are moreover employed for coatings. The process employed
depends mainly on the carrier chosen. Dry powders are applied by
spreading or dusting, if appropriate also using electrostatic
forces. The making into a film can be carried out by action of
heat. For carrying out it is crucial here that uniform, continuous
layers result.
[0088] For application processes according to the prior art see,
for example, Bauer, Lehmann, Osterwald, Rothgang, "berzogene
Arzneiformen" [Coated pharmaceutical forms] Wissenschaftliche
Verlagsgesellschaft mbH Stuttgart, chap. 7, pp. 165-196.
[0089] Properties relevant for application, tests required and
specifications are listed in pharmacopeia.
[0090] Details can be taken from the customary textbooks, e.g.:
[0091] Voigt, R. (1984): Lehrbuch der pharmazeutischen Technologie
[Textbook of pharmaceutical technology]; Verlag Chemie Weinheim -
Beerfield Beach/Florida - Basle.
[0092] Sucker, H., Fuchs, P., Speiser, P.: Pharmazeutische
Technologie [Pharmaceutical technology]; Georg Thieme Verlag
Stuttgart (1991), in particular chapters 15 and 16, pp.
626-642.
[0093] Gennaro, A.R. (Editor), Remington's Pharmaceutical Sciences,
Mack Publishing Co., Easton Pennsylvania (1985), Chapter 88, pp.
1567-1573.
[0094] List, P. H. (1982): Arzneiformenlehre [Pharma- ceutical form
theory], Wissenschaftliche Verlags- gesellschaft mbH,
Stuttgart.
[0095] Water vapor permeability
[0096] While coating agents and binders according to WO 00/05307
have water vapor permeabilities measured according to DIN 53 122 in
the range of 400 (g/m.sup.2/d) or above, the water vapor
permeabilities of the coating agents and binders produced from the
powders or granules according to the invention are at most 350
(g/m.sup.2/d), preferably at most 300 (g/m.sup.2/d), particularly
preferably at most 200 (g/m.sup.2/d). In particular, the powders or
granules according to the invention can in many cases also be
processed further with extensive or complete relinquishment of
customary plasticizers. This is advantageous, since it is always
attempted to keep the number of components in pharmaceutical
formulations low.
[0097] Biologically active substances:
[0098] The pharmaceuticals employed within the meaning of the
invention are intended to be used on or in the human or animal body
in order
[0099] 1. to cure, to alleviate, to prevent or to recognize
diseases, illnesses, bodily defects or pathological symptoms.
[0100] 2. to allow the condition, the state or the functions of the
body or mental states to be recognized.
[0101] 3. to replace active compounds or body fluids produced by
the human or animal body.
[0102] 4. to ward off, to eliminate or to render harmless
pathogens, parasites or exogenous substances or
[0103] 5. to influence the condition, the state or the functions of
the body or mental states.
[0104] Customary pharmaceuticals can be taken from the reference
works, such as, for example, the Rote Liste or the Merck index.
[0105] The formulation according to the invention is suitable for
the administration of fundamentally any desired pharmaceutical
active compounds, which can preferably be administered in isolated
or protected form, such as antidepressants, beta-receptor blockers,
anti- diabetics, analgesics, antiinflammatories, anti- rheumatics,
antihypotensives, antihypertensives, psychopharmaceuticals,
tranquillizers, antiemetics, muscle relaxants, glucocorticoids,
agents for the treatment of ulcerative colitis or Crohn's disease,
antiallergics, antibiotics, antiepileptics, anti- coagulants,
antimycotics, antitussives, arterio- sclerosis agents, diuretics,
enzymes, enzyme inhibitors, gout agents, hormones and their
inhibitors, cardiac glycosides, immunotherapeutics and cytokines,
laxatives, hypolipidemics, gastrointestinal therapeutics, migraine
agents, mineral preparations, otologicals, Parkinson agents,
thyroid therapeutics, spasmolytics, platelet aggregation
inhibitors, vitamins, cytostatics and metastasis inhibitors,
phytopharmaceuticals, chemotherapeutics and amino acids.
[0106] Examples of suitable active compounds are acarbose,
nonsteroidal antirheumatics, cardiac glycosides, acetylsalicylic
acid, virustatics, aclarubicin, acyclovir, cisplatin, actinomycin,
alpha- and beta- sympathomimetics, (allopurinol, alosetrone,
alprostadil, prostaglandins, amantadine, ambroxole, amlodipine,
methotrexate, S-aminosalicylic acid, amitriptyline, amlodipine,
amoxicillin, anastrozole, atenolol, atorvastatin, azathioprine,
balsalazide, beclomethasone, betahistine, bezafibrate,
bicalutamide, diazepam and diazepam derivatives, budesonide,
bufexamac, buprenorphine, methadone, calcium salts, potassium
salts, magnesium salts, candesartan, carbamazepine, captopril,
cefalosporins, celetoxib, cetirizine, chenodeoxycholic acid,
ursodeoxycholic acid, theophylline and theophylline derivatives,
trypsins, cimetidine, clarithromycin, clavulanic acid, clindamycin,
clobutinol, clonidine, cotrimoxazole, codeine, caffeine, vitamin D
and derivatives of vitamin D, colestyramine, cromoglicic acid,
coumarin and coumarin derivatives, cysteine, cytarabine,
cyclophosphamide, ciclosporin, cyproterone, cytarabine,
dapiprazole, desogestrel, desonide, dihydralazine, diltiazem, ergot
alkaloids, dimenhydrinate, dimethyl sulfoxide, dimeticone,
dipyridamoi, domperidone and domperidan derivatives, donepzil,
dopamine, doxazosine, doxorubizin, doxylamine, dapiprazole,
benzodiazepines, diclofenac, glycoside antibiotics, desipramine,
econazole, ACE inhibitors, enalapril, ephedrine, epinephrine,
epoetin and epoetin derivatives, morphinans, calcium antagonists,
irinotecan, modafinil, orlistate, peptide antibiotics, phenytoin,
riluzoles, risedronate, sildenafil, topiramate, macrolide
antibiotics, esomeprazole, estrogen and estrogen derivatives,
gestagen and gestagen derivatives, testosterone and testosterone
derivatives, androgen and androgen derivatives, ethenzamide,
etofenamate, etofibrate, fenofibrate, etofylline, etoposide,
famciclovir, famotidine, felodipine, fenofibrate, fentanyl,
fenticonazole, gyrase inhibitors, fluconazole, fludarabine,
flunarizine, fluorouracil, fluoxetin, flurbiprofen, ibuprofen,
flutamide, fluvastatin, follitropin, formoterol, fosfomicin,
furosemide, fusidic acid, galantamine, gallopamil, ganciclovir,
gemfibrozil, gentamicin, ginkgo, St John's wort, glibenclamide,
urea derivatives as oral antidiabetics, glucagon, glucosamine and
glucosamine derivatives, glutathione, glycerol and glycerol
derivatives, hypothalamus hormones, goserelin, gyrase inhibitors,
guanethidine, halofantrin, haloperidol, heparin and heparin
derivatives, hyaluronic acid, hydralazine, hydrochlorothiazide and
hydrochloro- thiazide derivatives, salicylates, hydroxyzine,
idarubicin, ifosfamide, imipramine, indometacin, indoramine,
insulin, interferon, iodine und iodine derivatives, isoconazole,
isoprenaline, glucitol and glucitol derivatives, itraconazole,
ketoconazole, ketoprofen, ketotifen, lacidipine, lansoprazole,
levodopa, levomethadone, thyroid hormones, lipoic acid and lipoic
acid derivatives, lisinopril, lisuride, lofepramine, lomustine,
loperamide, loratadine, maprotiline, mebendazole, mebeverine,
meclozine, mefenamic acid, mefloquin, meloxicam, mepindolol,
meprobamate, meropenem, mesalazine, mesuximide, metamizole,
metformin, methotrexate, methylphenidate, methylprednisolone,
metixen, metoclopramide, metoprolol, metronidazole, mianserine,
miconazole, minocycline, minoxidil, misoprostol, mitomycin,
mizolastine, moexipril, morphine and morphine derivatives, evening
primrose, nalbuphine, naloxone, tilidine, naproxen, narcotine,
natamycin, neostigmine, nicergoline, nicethamide, nifedipine,
niflumic acid, nimodipine, nimorazole, nimustine, nisoldipine,
adrenalin and adrenalin derivatives, norfloxacin, novamine sulfone,
noscapine, nystatin, ofloxacin, olanzapine, olsalazine, omeprazole,
omoconazole, ondansetrone, orlistate, oseltamivir, oxaceprol,
oxacillin, oxiconazole, oxymetazoline, pantoprazole, paracetamol,
paroxetin, penciclovir, oral penicillins, pentazocine,
pentifylline, pentoxifylline, perphenazine, pethidine, plant
extracts, phenazone, pheniramine, barbituric acid derivatives,
phenylbutazone, phenytoin, pimozide, pindolol, piperazine,
piracetam, pirenzepine, piribedil, piroxicam, pramipexol,
pravastatin, prazosine, procaine, promazine, propiverine,
propranolol, propyphenazone, prostaglandins, protionamide,
proxyphylline, quetiapin, quinapril, quinaprilate, ramipril,
ranitidine, reproterol, reserpine, ribavirin, rifampicin,
risperidone, ritonavir, ropinirol, rosiglitazone, roxatidine,
roxithromycin, ruscogenin, rutoside and rutoside derivatives,
sabadilla, salbutamol, salmeterol, scopolamine, selegiline,
sertaconazole, sertindole, sertralion, sildenafil, silicates,
simvastatin, sitosterol, sotalol, spaglumic acid, sparfloxacin,
spectinomycin, spiramycin, spirapril, spironolactone, stavudine,
streptomycin, sucralfate, sufentanil, sulbactam, sulfonamides,
sulfasalazine, sulpiride, sultamicillin, sultiam, sumatriptan,
suxamethonium chloride, tacrin, tacrolimus, tadalafil, taliolol,
tamoxifen, taurolidine, tazarotene, tegaserod, temazepam,
teniposide, tenoxicam, terazosine, terbinafine, terbutaline,
terfenadine, terlipressin, tertatolol, tetracyclines, tetryzoline,
theobromine, theophylline, butizine, thiamazole, phenothiazines,
thiotepa, tiagabin, tiapride, propionic acid derivatives,
ticlopidine, timolol, tinidazole, tioconazole, tioguanine,
tioxolone, tiropramide, tizanidine, tolazoline, tolbutamide,
tolcapone, tolnaftate, tolperisone, topotecan, torasemide,
anti6strogens, tramadol, tramazoline, trandolapril,
tranylcypromine, trapidil, trazodone, triamcinolone and
triamcinolone derivatives, triamterene, trifluperidol,
trifluridine, trimethoprim, trimipramine, tripelennamine,
triprolidine, trifosfamide, tromantadine, trometamol, tropalpine,
troxerutin, tulobuterol, tyramine, tyrothricin, urapidil,
ursodeoxycholic acid, chenodeoxycholic acid, valacyclovir,
valdecoxib, valproic acid, vancomycin, vardenafil, vecuronium
chloride, venlafaxin, verapamil, vidarabine, vigabatrine,
viloxazine, vinblastine, vincamine, vincristine, vindesine,
vinorelbine, vinpocetin, viquidil, warfarin, xantinol nicotinate,
xipamide, zafirlukast, zalcitabin, zanamivir, zidovudine,
zolmitriptan, zolpidem, zoplicon, zotepine and the like.
[0107] The active compounds can, if desired, also be used in the
form of their pharmaceutically acceptable salts or derivatives, and
in the case of chiral active compounds both optically active
isomers and racemates or diastereoisomer mixtures can be employed.
If desired, the compositions according to the invention can also
contain two or more pharmaceutical active compounds.
[0108] Examples of particularly preferred active compounds are
acetylsalicylic acid, carbenoxolone, cefalotin, epinefrine,
imipramine, potassium iodide, ketoprofen, levodopa, nitrazepam,
nitroprusside, oxitetracycline HCl, promethazine, omeprazole or
other benzimidazole derivatives and streptomycin.
[0109] Particularly preferred are moisture-sensitive pharma-
ceutical active compounds from the active compounds classes of the
analgesics, antirheumatics, active compounds for the treatment of
gastric ulcers, antibiotics, antihypotensives, antidepressants,
thyroid therapeutics, Anti Parkinson active compounds, anxiolytics,
peptides, phospohordiesterase inhibitors, proteins, cardiovascular
agents or neuroleptics or their salts is present.
[0110] Moisture-sensitive pharmaceutical active compounds are, for
example, acetylsalicylic acid, carbenoxolone, cefalotin,
epinefrine, imipramine, potassium iodide, ketoprofen, levodopa,
nitrazepam, nitroprusside, oxitetracycline HCl, promethazine,
omeprazole or other benzimidazole derivatives, ranitidine or
streptomycin or their salts.
[0111] Administration forms:
[0112] In principle, the pharmaceutical forms described can be used
directly by means of oral administration. The granules, pellets, or
particles produced according to the invention can be filled into
gelatin capsules, sachets or into suitable multidose containers
having a metering device. They are taken in solid form or suspended
in liquids. By means of compression from, optionally after
admixture of further excipients, tablets which disintegrate after
taking and which usually release coated subunits are obtained.
Likewise conceivable is the embedding of agglomerates in
polyethylene glycol or lipids for the production of suppositories
or vaginal pharmaceutical forms. Coated tablets are packed in
blister packs or multidose containers and removed by the patient
directly before taking.
[0113] Classes of active compounds and substances which often can
produce a bitter taste and can advantageously be formulated using
the coating agents and binders according to the invention are, for
example:
[0114] Analgesics and antirheumatics:
[0115] paracetamol, diclofenac, aceclofenac, ibuprofen, ketoprofen,
flubiprofen, levacetylmethadol, oxycodone
[0116] Psychopharmaceuticals:
[0117] prometazine, donepezil, modafinil, nefazodone, reboxetin,
sertindole, sertralin
[0118] Antibiotics:
[0119] erythromicyn, roxithromycin, clarithromycin, grepafloxacin,
ciprofloxacin, levofloxacin, sparfloxacin, trovafloxacin,
nevirapine
[0120] Beta-blockers
[0121] propanolol, metoprolol, bisoprolol, nebivolol
[0122] Antidiabetics:
[0123] metformine, miglitol, repaglinide
[0124] H1 antihistaminics:
[0125] diphenhydramine, fexofenadine, mizolastine
[0126] H2 antihistaminics
[0127] cimetidine, nizatidine, ticlopidine, cetridine,
ranitidine,
[0128] Vitamins:
[0129] thiamine nitrate; Others: quinidine sulfate, amiloprilose
HCl, pseudoephedrine HCl, sildenafil, topiramate, granisetrone,
rebamipides, quinine HCl.
EXAMPLES
[0130] EUDRAGIT.RTM. E 100: copolymer of methyl methacrylate, butyl
methacrylate, and dimethylaminoethyl methacrylate in the ratio
25:25:
[0131] P=parts by weight=% by weight
Example 1
[0132] Production of colorless granules which can be rapidly
dispersed.
[0133] 15 parts (P) of stearic acid are mixed with 7 P of sodium
lauryl sulfate in a suitable mixer and subsequently extruded with
100 P of EUDRAGIT.RTM. E 100 in a synchronous 18 mm double screw
extruder, whose screws are provided with compounding elements, at
temperatures between 105 to 140.degree. C. with a throughput of
about 1.6 kg/h. The extrudate is drawn off via a withdrawal belt
and fed to an extrudate granulator, which comminutes the extrudate
into pieces about 3.05 mm (0.12 inch) long. The mean diameter of
the granule grains obtained is 2 mm and is dependent on the
withdrawal rate of the extrudate.
[0134] 15 P of the granules thus obtained can be dispersed in 100 P
of purified water within 60 min at 63.degree. C. by means of a
magnetic stirrer. The film cast from this dispersion is
homogeneous.
Example 2
[0135] Production of yellow granules which can be rapidly
dispersed.
[0136] 15 P of stearic acid are mixed with 10 P of sodium lauryl
sulfate and 15 P of SICOVIT Yellow 10 (E 172) in a suitable mixer
and subsequently extruded with 100 P of EUDRAGIT.RTM. E 100 in a
synchronous 18 mm double screw extruder, whose screws are provided
with compounding elements, at temperatures between 105 to
140.degree. C. with a throughput of about 1.6 kg/h. The extrudate
is drawn off via a withdrawal belt and fed to an extrudate
granulator, which comminutes the extrudate into pieces about 3.05
mm (0.12 inch) long. The mean diameter of the granule grains
obtained is 2 mm and is dependent on the withdrawal rate of the
extrudate.
[0137] 15 P of the granules thus obtained can be dispersed in 100 P
of purified water within 60 min at 63.degree. C. by means of a
magnetic stirrer. The film cast from this dispersion is
homogeneous.
Example 3
[0138] Production of blue granules which can be rapidly
dispersed.
[0139] 15 P of stearic acid are mixed with 10 P of sodium lauryl
sulfate and 15 P of SICOPHARM indigotin lake (E 132) in a suitable
mixer and subsequently extruded with 100 P of EUDRAGIT.RTM. E 100
in a synchronous 18 mm double screw extruder, whose screws are
provided with compounding elements, at temperatures between 105 to
140.degree. C. with a throughput of about 1.6 kg/h. The extrudate
is drawn off via a withdrawal belt and fed to an extrudate
granulator, which comminutes the extrudate into pieces about 3.05
mm (0.12 inch) long. The mean diameter of the granule grains
obtained is 2 mm and is dependent on the withdrawal rate of the
extrudate.
[0140] 15 P of the granules thus obtained can be dispersed in 100 P
of purified water within 60 min at 63.degree. C. by means of a
magnetic stirrer. The film cast from this dispersion is
homogeneous.
Example 4
[0141] Production of taste-isolated quinidine sulfate tablets
[0142] For the production of the spray dispersion, 532 g of
completely demineralized water warmed to 63.degree. C. are
introduced. 111.72 g of the granules described in example 2 are
added to the water and dispersed with stirring for about 60 min.
11.17 g of talc are added to the dispersion as a mold release
agent. Using the spray dispersion obtained, 3000 g of quinidine
sulfate cores (.O slashed. 10 mm) are sprayed with a supply of warm
air. The product temperature is between 25 and 33.degree. C. The
coated cores were subsequently dried on racks at 40.degree. C. for
two hours. The film coating obtained is uniform (and) of good
covering power and shows its imperviousness by a taste isolation of
greater than 30 min.
Example 5
[0143] Production of a dispersion from two different colored
granules
[0144] 7.5 P each of the granules described in examples 2 and 3 are
dispersed in 100 P of purified water at 63.degree. C. for about 60
min. The dispersion thus obtained has a homogeneous green color.
The film cast from this dispersion is, after drying, likewise
satisfying with a homogeneous color shade.
* * * * *