U.S. patent application number 09/946205 was filed with the patent office on 2002-05-02 for pharmaceutical compositions containing carvedilol and hydrochlorothiazide.
Invention is credited to Heller, Rudolf.
Application Number | 20020052367 09/946205 |
Document ID | / |
Family ID | 8233041 |
Filed Date | 2002-05-02 |
United States Patent
Application |
20020052367 |
Kind Code |
A1 |
Heller, Rudolf |
May 2, 2002 |
Pharmaceutical compositions containing carvedilol and
hydrochlorothiazide
Abstract
A pharmaceutical combination preparation for the treatment of
cardiac and cardiovascular disorders, such as hypertension, angina
pectoris, cardiac insufficiency and illnesses associated therewith,
contains the active substances carvedilol, or a pharmaceutically
acceptable salt thereof, and hydrochlorothiazide, or a
pharmaceutically acceptable salt thereof, as well as
pharmaceutically usual additives.
Inventors: |
Heller, Rudolf; (Traunfeld,
AT) |
Correspondence
Address: |
HOFFMANN-LA ROCHE INC.
PATENT LAW DEPARTMENT
340 KINGSLAND STREET
NUTLEY
NJ
07110
|
Family ID: |
8233041 |
Appl. No.: |
09/946205 |
Filed: |
September 5, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
09946205 |
Sep 5, 2001 |
|
|
|
09447872 |
Nov 23, 1999 |
|
|
|
Current U.S.
Class: |
514/223.5 |
Current CPC
Class: |
A61P 9/10 20180101; A61P
9/12 20180101; A61K 31/54 20130101; A61P 9/04 20180101; A61P 9/00
20180101; A61K 9/28 20130101; A61K 9/2077 20130101; A61K 31/54
20130101; A61K 31/40 20130101; A61K 31/54 20130101; A61K 2300/00
20130101 |
Class at
Publication: |
514/223.5 |
International
Class: |
A61K 031/549 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 27, 1998 |
EP |
98122489.2 |
Claims
What is claimed is:
1. A tablet which comprises (i) carvedilol or a pharmaceutically
acceptable salt thereof, (ii) hydrochlorothiazide or a
pharmaceutically acceptable salt thereof, and (iii) at least one
pharmaceutically acceptable additive.
2. The tablet of claim 1, wherein the weight ratio of to (i)
hydrochlorothiazide or a pharmaceutically acceptable salt thereof,
to (ii) carvedilol or a pharmaceutically acceptable salt thereof,
is between about 1:0.5 and about 1:10.
3. The tablet of claim 1, wherein the tablet comprises (i) about 10
mg to about 50 mg of carvedilol or a pharmaceutically acceptable
salt thereof, and (ii) about 5 mg to about 30 mg
hydrochlorothiazide or a pharmaceutically acceptable salt
thereof.
4. The tablet of claim 1, wherein the at least one pharmaceutically
acceptable additive comprises a binder, disintegrant, glidant,
adsorption agent, separating agent, filler, or carrier.
5. The tablet of claim 1, wherein the tablet comprises from about
0% to about 50 % by weight lactose, from about 0% to about 50% by
weight saccharose, from about 0% to about 10% by weight magnesium
stearate, from about 0% to about 30% by weight cellulose, from
about 0% to about 10% by weight polyvinylpyrrolidone, from about 0%
to about 10% by weight polymeric cellulose compounds, from about 0%
to about 10% by weight silicon dioxide, and from about 0% to about
20% by weight cross-linked polyvinylpyrrolidone.
6. The tablet of claim 5, wherein the tablet comprises about 25 mg
carvedilol and about 12.5 mg hydrochlorothiazide.
7. The tablet of claim 6, wherein the tablet comprises about 25 mg
carvedilol, about 12.5 mg hydrochlorothiazide, about 28.06 mg
lactose monohydrate, about 25 mg saccharose, about 2.17 mg
magnesium stearate, about 10 mg microcrystalline cellulose, about
1.78 mg polyvinylpyrrolidone (25,000), about 5.32 mg silicon
dioxide, and about 20.17 mg cross-linked polyvinylpyrrolidone.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This is a divisional of copending application Ser. No.
09/447,872 filed Nov. 23 1999.
BACKGROUND OF THE INVENTION
[0002] 1. Field
[0003] The present invention is concerned with pharmaceutical
combination preparations that are suitable for treating cardiac and
cardiovascular disorders and the illnesses associated therewith.
Specifically, the present invention relates to pharmaceutical
combination preparations containing carvedilol and
hydrochlorothiazide as active substances.
[0004] 2. Description
[0005] Carvedilol, a compound of the formula: 1
[0006] is a .beta.-blocker with additional .alpha..sub.1-blocking
activity, which has been commercially available for several years
under the trade name Coreg.RTM. in the United States and
Dilatrend.TM. outside the United States.
[0007] Hydrochlorothiazide, a compound of the formula: 2
[0008] is a diuretic, which has been marketed for decades.
[0009] The combination of a .beta.-blocker with a diuretic has been
used successfully for treating cardiac and circulatory disorders
such as hypertension, angina pectoris, cardiac insufficiency and
illnesses associated therewith. Many studies have investigated the
advantages of combination therapy using carvedilol and
hydrochlorothiazide (e.g. Widmann et al., 1990, Eur J Clin
Pharmacol 38 (2):143-146; van der Does et al., 1990, Eur J Clin
Pharmacol 38 (2):147-152; McTavish et al., 1993, Drugs 45(2):
232-258). In all of these studies, the two active substances
carvedilol and hydrochlorothiazide were sequentially administered
in the form of individual tablets. A fixed combination of the two
active substances could not be realized until the present
invention.
[0010] A combined product was not earlier developed because the two
active substances, carvedilol and hydrochlorothiazide, have
different solubilities and, when granulated together, gave end
products with inadequate active substance release and
bioavailability. Thus, it was problematic to provide the two active
substances as a combination preparation, such as a tablet. An
object of the invention is to provide a solution to these
problems.
SUMMARY OF THE INVENTION
[0011] The subject invention provides a pharmaceutical combination
preparation containing the active substances (i) carvedilol, or a
pharmaceutically acceptable salt thereof, and (ii)
hydrochlorothiazide, or a pharmaceutically acceptable salt thereof,
and at least one pharmaceutically acceptable additive.
[0012] The preferred weight ratio of (i) hydrochlorothiazide, or a
pharmaceutically acceptable salt thereof, to (ii) carvedilol, or a
pharmaceutically acceptable salt thereof, is between about 1:0.5
and about 1:10. Typically, the preparation is in dosage form
containing (i) about 10 mg to about 50 mg of carvedilol, or a
pharmaceutically acceptable salt thereof, and (ii) about 5 mg to
about 30 mg of hydrochlorothiazide, or a pharmaceutically
acceptable salt thereof. The acceptable additive includes binders,
disintegrants, glidants, adsorption agents, separating agents,
fillers, and carriers. A more preferred pharmaceutical combination
preparation contains about 0 weight % to about 50 weight % lactose,
about 0 weight % to about 50 weight % saccharose, about 0 weight %
to about 10 weight % magnesium stearate, about 0 weight % to about
30 weight % cellulose, about 0 weight % to about 10 weight %
polyvinylpyrrolidone, about 0 weight to about 10 weight % polymeric
cellulose compounds, about 0 weight % to about 10 weight % highly
dispersed silicon dioxide and about 0 weight % to about 20 weight %
cross-linked polyvinylpyrrolidone. Most preferably, the preparation
is in solid dosage form.
[0013] The subject invention also provides method for treating of
cardiac and circulatory disorders which comprises administering an
effective amount of a pharmaceutical combination preparation in
dosage form containing the active substances (i) carvedilol, or a
pharmaceutically acceptable salt thereof, and (ii)
hydrochlorothiazide, or a pharmaceutically acceptable salt thereof,
and at least one pharmaceutically acceptable additive.
[0014] Another aspect of the subject invention is a process for
producing a solid dosage form pharmaceutical combination
preparation containing carvedilol, or a pharmaceutically acceptable
salt thereof, and hydrochlorothiazide, or a pharmaceutically
acceptable salt thereof. The process comprises (i) forming a press
mass containing a carvedilol, or pharmaceutically acceptable salt
thereof, granulate and a hydrochlorothiazide carvedilol, or
pharmaceutically acceptable salt thereof, granulate and (ii)
compressing the press mass to form the solid dosage form
pharmaceutical combination preparation. The two granulates each
having a granulate moisture content between about 6% and about 20%
and a bulk density between about 0.1 g/ml and about 1.5 g/ml. The
granuate moisture content and the bulk density of the two
granulates do not vary from each other by more than about 30%.
[0015] The granulate moisture content of the carvedilol, or
pharmaceutically acceptable salt thereof, granulate and the
hydrochlorothiazide, or pharmaceutically acceptable salt thereof,
granulate is preferably between about 10% and about 15%. The bulk
density of both the carvedilol, or pharmaceutically acceptable salt
thereof, granulate and the hydrochlorothiazide, or pharmaceutically
acceptable salt thereof, granulate is preferably between about 0.4
g/ml and about 0.75 g/ml. Compressing is generally accomplished
using a tablet press to form tablets. The process can further
comprise coating the solid dosage form with a pharmaceutically
acceptable aqueous film suspension. The coating of the solid dosage
form is typically first performed at a rate of about 30 g to about
50 g of film suspension per minute during the first about 30
minutes to about 70 minutes and then performed at a rate of about
60 g to about 90 g of film suspension per minute until the film
coating has finished. Pharmaceutically acceptable solid dosage form
combination preparations prepared using the described process are
also part of the invention. The amount of the disintegrant in the
dosage form is typically at least 5 weight %.
[0016] Another aspect of the invention is a light-protecting film
suspension for use in coating solid dosage form pharmaceutical
preparations. This light-protecting film preferably comprises:
about 10 weight % to about 50 weight % poly(ethyl acrylate, methyl
acrylate) 2:1, 800,000; about 1 weight % to about 10 weight %
sodium citrate; about 1 weight % to about 25 weight %
methylhydroxypropylcellulose; about 0 weight % to about 20 weight %
macrogol 10,000; about 5 weight % to about 40 weight % talc; about
2 weight % to about 25 weight % titanium dioxide; about 0 weight %
to about 10 weight % indigocarmine color lacquer; about 0 weight %
to about 2 weight % polysorbate; and about 0 weight % to about 1.0
weight % dimethicone.
DETAILED DESCRIPTION OF THE INVENTION
[0017] The present invention will now be described in terms of its
preferred embodiments. These embodiments are set forth to aid in
understanding the invention but are not to be considered
limiting.
[0018] The present invention is concerned with pharmaceutical
combination preparations containing the active substances
carvedilol, or a pharmaceutically acceptable salt thereof, and
hydrochlorothiazide, or a pharmaceutically acceptable salt thereof,
as well as pharmaceutically usual additives. Moreover, the present
invention is concerned with the use of this combination preparation
for the treatment of cardiac and circulatory disorders such as
hypertension, angina pectoris, cardiac insufficiency and illnesses
associated therewith.
[0019] The term "pharmaceutical combination preparation" refers to
a pharmaceutically acceptable dosage form which simultaneously
contains two or more active substances.
[0020] Pharmaceutically acceptable salts of the compounds of the
formulas (I) and (II) include alkali salts, such as Na or K salts,
alkaline earth metal salts, such as Ca and Mg salts, as well as
salts with organic or inorganic acids, such as, for example,
hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid,
phosphoric acid, citric acid, formic acid, maleic acid, acetic
acid, succinic acid, tartaric acid, methanesulphonic acid or
toluenesulphonic acid, which are non-toxic for living
organisms.
[0021] The phrase "drying loss" of granulates refers to the
gravimetric determination of the weight difference between original
granulate and the granulate dried to constant weight. Drying can be
effected, for example, in a drying oven at elevated temperatures,
with an infra-red lamp, with a microwave apparatus, with a hot air
blower, etc.
[0022] Measurement of the granulate moisture in the present
specification was effected with a SUPERMATIC rapid hygrometer from
the firm Foss Electric (accuracy .+-.0.25%). The measurement
principle is based on the measurement of the dielectric constants
of the measured material. A sample amount of 250 g was used.
[0023] In a preferred embodiment of the combination preparation in
accordance with the invention the weight ratio of
hydrochlorothiazide or a pharmaceutically acceptable salt thereof
to carvedilol or a pharmaceutically acceptable salt thereof lies
between 1:0.5 and 1:10, preferably between 1:0.5 and 1:5,
especially at 1:2.
[0024] A preferred combination preparation in accordance with the
invention contains between 10 mg and 50 mg, preferably 25 mg, of
carvedilol or a pharmaceutically acceptable salt thereof and
between 5 mg and 30 mg, preferably 12.5 mg, of hydrochlorothiazide
or a pharmaceutically acceptable salt thereof in an oral dosage
form.
[0025] The combination preparations in accordance with the
invention may contain additives such as binders, plasticizers,
diluents, carriers, glidants, antistatics, adsorbing agents,
separating agents, dispersants, drageeing lacquers, de-foamers,
film formers, emulsifiers, disintegrants and fillers in the tablets
and/or the coating. Tablets or granulates, for example, can contain
flavor-improving additives as well as substances usually used as
preservatives, stabilizers, moisture-retainers and emulsifiers,
salts for varying the osmotic pressure, buffers and other
additives.
[0026] The additives mentioned above can comprise organic or
inorganic substances, e.g. water, sugar, salts, acids, bases,
alcohols, organic polymeric compounds, and the like. Lactose,
saccharose, magnesium stearate, various celluloses and substituted
celluloses, polymeric cellulose compounds, highly dispersed silicon
dioxide, maize starch, talc and various polymeric
polyvinylpyrrolidone compounds are preferred additives. For
example, polyvinylpyrrolidones, which are not cross-linked, with a
molecular weight of 8,000 to 630,000, preferably 25,000, and
cross-linked polyvinylpyrrolidones with a molecular weight greater
than 1,000,000 can be used. It is a prerequisite that all additives
used in the production are non-toxic and advantageously do not
alter the bioavailability of the active substances.
[0027] Solid dosage forms which contain about 0-50 weight %
lactose, about 0-50 weight % saccharose, about 0-10 weight %
magnesium stearate, about 0-30 weight % cellulose, about 0-10
weight % polyvinylpyrrolidone, about 0-10 weight % polymeric
cellulose compounds, about 0-10 weight % highly dispersed silicon
dioxide, and about 0-20 weight % cross-linked polyvinylpyrrolidone
as additives are especially preferred.
[0028] A combination preparation in accordance with the invention
which contains about 25 mg of carvedilol, about 12.5 mg of
hydrochlorothiazide, about 25.0 mg of saccharose, about 28.06 mg of
lactose, about 1.78 mg of polyvinylpyrrolidone, about 20.17 mg of
cross-linked polyvinylpyrrolidone, about 10-0 mg of
microcrystalline cellulose, about 5.32 mg of highyl dispersed
silicon dioxide and about 2.17 mg of magnesium stearate per 130 mg
solid dosage form is especially preferred.
[0029] Further, it has surprisingly been found that the process
used for the production of the combination preparations permits the
two active substance granulates to be pressed to a stable tablet in
one operation.
[0030] The active substances and additives required for the
production of the combination preparation in accordance with the
invention are known (Carvedilol: EP 0004920; hydrochlorothiazide:
Pharmaceutically Active Substances; Syntheses, Patents, Uses, A.
Kleemann et al., 2.sup.nd Edition, published by Georg Thieme, 1982,
page 469) or are commercially available or can be produced in
accordance with known methods.
[0031] The process for the production of the combination
preparation in accordance with the invention can comprise the steps
described hereinafter, but is not limited to these individual
steps:
[0032] a) the production of a carvedilol granulate;
[0033] b) the production of a hydrochlorothiazide granulate;
[0034] c) the processing of a carvedilol granulate and a
hydrochlorothiazide granulate to a press mass, with the two
granulates each having a granulate moisture content between 6 and
20% and a bulk density between 0.1 and 1.5 g/ml and the granuate
moisture content and the bulk density of the two granulates in each
case not varying from one another by more than 30%, preferably
20%;
[0035] d) the production of a solid dosage form, preferably a
tablet, from the press mass obtained under c).
[0036] The carvedilol granulate is preferably produced by fluidized
bed granulation, the hydrochlorothiazide granulate preferably by
granulation in a high speed mixer-granulator (e.g. DIOSNA P
450).
[0037] The granulate moisture content of the carvedilol granulate
and of the hydrochlorothiazide granulate preferably lies between 10
and 15%.
[0038] The bulk density of the two granulates preferably lies
between 0.4 and 0.75 g/ml.
[0039] In a particular embodiment the combination peparation, as
well as a carvedilol preparation alone, can be provided with a
light-protecting film.
[0040] As carvedilol is an active substance which is particularly
sensitive to light, a distinct brown coloration of the active
substance can occur not only in the case of the pure active
substance but also in the case of carvedilol-containing medicaments
in different dosages when these forms are exposed to light.
[0041] Under a "light-protecting film" there is to be understood a
coating based on an aqueous film suspension applied to the dosage
form, preferably by spraying.
[0042] The film suspension preferably contains about 10-50 weight %
poly(ethyl acrylate, methyl acrylate) 2:1, 800,000, about 1-10
weight % sodium citrate, about 1-25 weight %
methylhydroxypropylcellulose, about 0-20 weight % macrogol 10,000,
about 5-40 weight % talc, about 2-25 weight % titanium dioxide,
about 0-10 weight % indigocarmine color lacquer, about 0-2 weight %
polysorbate and about 0-1.0 weight % dimethicone.
[0043] A light-protecting film which contains about 2.348 mg of
poly(ethyl acrylate, methyl acrylate) 2:1, 800,000, about 0.308 mg
of sodium citrate, about 1.018 mg of methylhydroxypropylcellulose,
about 0.644 mg of macrogol 10,000, about 1.624 mg of talc, about
0.950 mg of titanium dioxide, about 0.170 mg of indigocarmine color
lacquer, about 0.034 mg of polysorbate and about 0.004 mg of
dimethicone per 7 g of film suspension is especially preferred.
[0044] All polysorbates (polyoxyethylene derivatives) of the
polysorbate 20 to polysorbate 85 type, preferably polysorbate 80,
can be used for the film coating.
[0045] Although the light-protecting film described above is used
for the film coating of oral dosage forms, such as e.g. tablets,
containing carvedilol, not only as a single but also as a
combination preparation, it is, of course, also suitable for
tablets containing other light-sensitive active substances.
[0046] In a further embodiment the invention also includes a
process for the application of a light-protecting film.
[0047] Since carvedilol is not very water soluble,
carvedilol-containing medicaments typically contain an especially
high content of disintegrant (15-20 weight % cross-linked
polyvinylpyrrolidone). It is known to the skilled artisan that the
direct application of an aqueous suspension to a tablet with a
disintegrant content of more than 5 weight % in one operation is
typically associated with problems because a reaction can occur
between water from the film suspension and disintegrant from the
tablet, which softens the surface of the tablet. It has now
surprisingly been found that by the inventive process described
below, an aqueous suspension, preferably an aqueous
light-protecting suspension, such as the aforementioned film
suspension, can be applied in one operation to a tablet having a
disintegrant content of more than 5%.
[0048] The specific procedure at the beginning of the film coating
is critical for the process: The spray rate must be so low at the
beginning on the one hand to permit the formation of a film on the
tablet surface and on the other hand to remove the water of the
film suspension as rapidly as possible from the tablet surface.
This procedure is additionally assisted by the supply of large
amounts of air and a high air supply temperature in the drageeing
kettle. As soon as this critical phase of the film coating has been
completed, i.e. a thin film has formed over the entire tablet, the
spray rate can be increased to an extent which is usual in the case
of conventional film coatings. The film coating can be carried out
to the end using this increased spray rate. The aforementioned
inventive film coating procedure is also facilitated and assisted
by the composition of the film suspension.
[0049] The tablets to be film coated are added to a drageeing
kettle (e.g. a 50 kg drageeing kettle from the firm BRUCKS, Model
XI) and film coated with the light-protecting suspension (film
coating e.g. with a binary spray nozzle from the firm WALTHER,
PILOT type, Model WA).
[0050] The following data refer to a film coating using the
aforementioned drageeing kettle and binary spray nozzles. However,
these values can be readily varied by the artisan depending on the
equipment used.
[0051] During the first 30 to 70, preferably 50, minutes the film
coating of the solid dosage form is effected with 30 to 50 g,
preferably with 40 g, of film suspension per minute and
subsequently until the film coating has finished with 60 to 90 g,
preferably with 74 g, of film suspension per minute. In a process
variant, after 40 to 60 minutes, the spray rate can also be
increased continuously to the maximum value of 60 to 90 g per
minute.
[0052] The film coating process described above can be used for the
film coating of any pharmaceutically acceptable solid dosage form,
such as tablets, with a disintegrant content of more than 5%. Thus,
for example, a pharmaceutically acceptable solid dosage form
containing 0-20 weight % carvedilol, 0-50 weight % lactose, 0-50
weight % saccharose, 0-10 weight magnesium stearate, 0-30 weight
cellulose, 0-10 weight polyvinylpyrrolidone, 0-10 weight highly
dispersed silicon dioxide and 0-20 weight cross-linked
polyvinylpyrrolidone can also be coated with a pharmaceutically
acceptable aqueous film suspension. The combination preparations
produced and film coated according to the process in accordance
with the invention have a surprisingly long stability.
[0053] Oral administration is the preferred form of administration
for the combination preparation in accordance with the invention.
Preferred dosage forms include tablets, capsules and dragees.
However, tablets are most preferred. The dosage in which the
combination preparation in accordance with the invention is
administered depends on the age and the requirements of the patient
and on the route of administration. In general, dosages of about
10-50 mg of carvedilol and about 5-30 mg of hydrochlorothiazide per
day come into consideration.
[0054] The following Examples are intended to illustrate the
preferred embodiments of the present invention, without limiting
them.
EXAMPLE 1
[0055] Production of a Carvedilol Granulate
[0056] a) Production of the Suspension
[0057] 64,500 g of purified water are placed in a kettle and 15,000
g of sieved lactose D80, 7,500 g of sieved saccharose and 1,500 g
of polyvinylpyrrolidone 25,000 (e.g. Kollidon 25) are added thereto
and dissolved while stirring for 30 minutes. Subsequently, 3,000 g
of highly dispersed silicon dioxide (e.g. Aerosil 200) and 37,500 g
of finely crystalline carvedilol are added to the above solution
and stirred for 30 minutes until a homogeneous suspension is
produced. The suspension is pumped over a colloid mill and a hand
sieve into a different container. The suspension is stirred
continuously until the fluidized bed granulation has finished in
order to prevent settling.
[0058] b) Fluidized Bed Granulation
[0059] 30,000 g of finely ground saccharose and 15,000 g of
cross-linked polyvinylpyrrolidone (e.g. Plasdone XL) are placed in
the pan of the fluidized bed granulator (e.g. GLATT-WSG 150). The
suspension obtained under a) is introduced using a tube pump
(internal tube diameter: 10 mm) via a 2.2 mm binary nozzle
(1.sup.st material: suspension; 2.sup.nd material: purified
compressed air of 6 bar). The spray granulation takes place with an
air supply temperature of about 80.degree. C. and a product
temperature of about 34.degree. C. to 37.degree. C. The moisture
content of the spent air amounts to 50 to 70% of the relative
humidity, the spraying time amounts to about 120 minutes.
[0060] c) Sieving
[0061] After the fluidized bed granulation the granulate is passed
through a sieve with a mesh size of 1.2 mm.
[0062] d) Final Mixing
[0063] 8,250 g of cross-linked polyvinylpyrrolidone (e.g. Plasdone
XL) and 3,000 g of highly dispersed silicon dioxide (e.g. Aerosil
200) are passed through a sieve with a mesh size of 1.2 mm and
homogenized with the granulate in a mixer (e.g. a plowshare mixer
from the firm LDIGE). Then, 2,250 g of magnesium stearate are
passed through a sieve with a mesh size of 1.2 mm and the sieved
magnesium stearate is mixed briefly with the granulate and the
granulate yield is established (target weight: 123,000 g).
Subsequently, the IPC values (IPC in process control) of the final
mixture are determined, with it being necessary to achieve the
following target values:
1 Granulate moisture 11.5-12.5% Drying loss (microwave) 2.0--3.0%
Bulk density 0.50-0.65 g/ml
EXAMPLE 2
[0064] Production of a Hydrochlorothiazide Granulate
[0065] a) Production of the Granulation Solution
[0066] 1,040 g of polyvinylpyrrolidone 25,000 (e.g. Kollidon 25
having a mean average mol wt of approximately 25,000) are dissolved
in 9,620 g of water while stirring.
[0067] b) Granulation of the Active Substance and Additives
[0068] 19,500 g of hydrochlorothiazide and 28,340 g of lactose are
mixed in a mixer-granulator (e.g. DIOSNA) for 4 minutes.
Thereafter, 10,660 g of the granulation solution from a) are
sprayed into the mixer with a spray pressure of 2 bar and
granulated in the mixer-granulator for 5 minutes. The mist
granulate is dried to a defined final moisture content at an air
inlet temperature of 75.degree. C.
[0069] c) Granulate Sieving
[0070] The dried granulate from b) is passed through a pharma sieve
with a mesh size of 1.25 mm [and] subsequently the granulate
moisture is determined. The target value lies at 9.5 to 11.0%.
Subsequently, the granulate weight is determined (target weight:
74,880 g).
[0071] d) Production of the Final Mixture
[0072] 15,600 g of microcrystalline cellulose together with 7,280 g
of cross-linked polyvinylpyrrolidone (e.g. Plasdone XL), 2,080 g of
highly dispersed silicon dioxide (e.g. Aerosil 200) and 1,040 g of
magnesium stearate are passed through a pharma sieve with a mesh
size of 1.25 mm. This sieved material and the sieved granulate from
c) are added to a pharma mixer and mixed for 30 seconds. The
finished mixture is discharged into a pharma container and the
yield is determined. Subsequently, the IPC values of the final
mixture are determined, with it being necessary to achieve the
following target values:
2 Granulate moisture 10.0-11.0% Drying loss (microwave) 1.5-2.5%
Bulk density 0.50-0.65 g/ml
EXAMPLE 3
[0073] Production of a Carvedilol-hydrochlorothiazide Press
Mass
[0074] a) Mixing of the Press Mass
[0075] 70,340 g of hydrochlorothiazide granulate and 120,160 g of
carvedilol granulate are placed in a suitable pharma mixer (e.g.
plowshare mixer LODIGE) and homogeneously mixed. The mixing time
amounts to 3 minutes. The finished mixture is filled into an
air-tight container through which light cannot pass and the yield
is determined (target weight: 19,500 g). Subsequently, the IPC
values of the final mixture are determined, with it being necessary
to achieve the following target values:
3 Granulate moisture 11.0-12.0% Drying loss (microwave) 2.0-3.0%
Bulk density 0.50-0.65 g/ml
EXAMPLE 4
[0076] Production of the Tablets
[0077] The press mass is pressed using a computer-controlled high
performance rotary tablet press (e.g. KILIAN TX 40 with automatic
pressing force control as well as regulation and control of the
tablet weight) to tablets, which are stored in container through
which light cannot pass.
EXAMPLE 5
[0078] Protection of Carvedilol-containing Medicaments from Light
by Film Coating
[0079] a) Production of the Film Suspension:
[0080] 364 g of Pharmacoat (=methylhydroxypropylcellulose), 230 g
of macrogol 10,000 (polyethylene glycol, approximate average mol wt
of 10,000), 110 g of sodium citrate, 979 g of talc, 339 g of
titanium dioxide, 12 g of Tween (polysorbate 80), 61 g of
indigocarmine color lacquer and 4 g of dimethicone are dissolved in
6,900 g of hot water (30-60.degree. C.) while stirring. The
homogeneous solution is passed twice through a colloid mill. 401 g
of Eudragit NE 30 D are added immediately before the film
coating.
[0081] b) Film Coating:
[0082] 60-70 kg of dust-free tablets from Example 3 are placed in a
drageeing kettle and film coated with the suspension from a). The
cores are sprayed from above, with the distance of the spray nozzle
from the core bed being about 60-70 cm. A binary nozzle (compressed
air/liquid) with a diameter of 1.8 mm is used for this purpose. The
sprayed air pressure (purified compressed air) amounts to 3 bar,
the temperature of the input air amounts to 70.degree. C., the
amount of input air amounts to 350-500 m.sup.3/h and the amount of
spent air amounts to 700-1,000 m.sup.3/h. A tube pump is used to
introduce the liquid, with the PVC pipe having an external diameter
of 8 mm and an internal diameter of 4 mm. The pump speed is 10 rpm
during the first 50 minutes and is subsequently 25 rpm. Based on
the film suspension, the pump speed is 40 g suspension/minute
during the first 50 minutes and subsequently (about a further 100
minutes) it is increased stepwise up to 74 g suspension/minute. The
rotation velocity of the kettle is 12 rpm during the first 50
minutes and is thereafter 18 rpm. The kettle inclination lies at 60
degrees.
EXAMPLE A
[0083] Tablets containing the following ingredients can be produced
according to the process described above:
4 Active substances Carvedilol 25.000 mg Hydrochiorothiazide 12.500
mg Additives Saccharose Ph.Eur. 25.000 mg Lactose 1 H.sub.2O
Ph.Eur. 28.060 mg Polyvinylpyrrolidone 25,000 Ph.Eur. 1.780 mg
Cross-linked polyvinylpyrrolidone NF 20.170 mg Microcrystalline
cellulose Ph.Eur. 10.000 mg Highly dispersed silicon dioxide
Ph.Eur. 5.320 mg Magnesium stearate Ph.Eur. 2.170 mg Film coating
Poly(ethyl acrylate, methyl acrylate) 2:1, 2.248 mg 800,000 average
mol wt Sodium citrate Ph.Eur. 0.308 mg Methylhydroxypropylcellulose
Ph.Eur. 1.018 mg Macrogol 10,000 0.644 mg Talc Ph.Eur. 1.624 mg
Titanium dioxide Ph.Eur. 0.950 mg Indigocarmine color lacquer 0.170
mg Polysorbate 80 PhiEur. 0.034 mg Dimethicone 0.004 mg
[0084] Upon reading the present specification, various alternative
embodiments will become obvious to the skilled artisan. These
embodiments are to be considered within the scope and spirit of the
invention, which is only to be limited by the claims that follow
and their equivalents.
* * * * *