U.S. patent application number 10/023968 was filed with the patent office on 2002-07-04 for pharmaceutical formulation and process.
This patent application is currently assigned to AstraZeneca AB.. Invention is credited to Lovgren, Kurt, Lundberg, Per Johan.
Application Number | 20020086029 10/023968 |
Document ID | / |
Family ID | 20397154 |
Filed Date | 2002-07-04 |
United States Patent
Application |
20020086029 |
Kind Code |
A1 |
Lundberg, Per Johan ; et
al. |
July 4, 2002 |
Pharmaceutical formulation and process
Abstract
A new oral pharmaceutical dosage form comprising a core material
that contains a proton pump inhibitor, one or more alkaline
reacting compounds and optionally pharmaceutical excipients having
a water soluble separating layer and an enteric coating layer. The
core material as such is alkaline reacting and the separating layer
between the alkaline reacting core material and the enteric coating
layer is formed in situ as a water soluble salt between the
alkaline reacting compound(s) and the enteric coating polymer. The
invention also describes a new efficient process for the
manufacture of such a dosage form comprising two functionally
different layers in one manufacturing step, and its use in
medicine.
Inventors: |
Lundberg, Per Johan;
(Molndal, SE) ; Lovgren, Kurt; (Molnlycke,
SE) |
Correspondence
Address: |
WHITE & CASE LLP
PATENT DEPARTMENT
1155 AVENUE OF THE AMERICAS
NEW YORK
NY
10036
US
|
Assignee: |
AstraZeneca AB.
|
Family ID: |
20397154 |
Appl. No.: |
10/023968 |
Filed: |
December 18, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10023968 |
Dec 18, 2001 |
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09413521 |
Oct 6, 1999 |
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09413521 |
Oct 6, 1999 |
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08612951 |
Mar 8, 1996 |
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08612951 |
Mar 8, 1996 |
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PCT/SE96/00161 |
Feb 9, 1996 |
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Current U.S.
Class: |
424/184.1 |
Current CPC
Class: |
A61K 31/435 20130101;
A61K 31/4439 20130101; A61K 9/2886 20130101; A61K 9/5073 20130101;
A61K 9/5078 20130101; A61K 9/1617 20130101; A61K 9/2081 20130101;
Y10S 514/925 20130101; A61P 1/04 20180101; A61K 31/4184 20130101;
A61K 31/444 20130101; A61K 9/5026 20130101; A61K 31/00 20130101;
A61K 31/4188 20130101; A61K 9/2866 20130101 |
Class at
Publication: |
424/184.1 |
International
Class: |
A61K 039/00; A61K
039/38 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 9, 1995 |
SE |
9500478-4 |
Claims
1. An oral pharmaceutical dosage form comprising a core material
that contains a proton pump inhibitor, one or more alkaline
reacting compound(s) and optionally pharmaceutically s acceptable
excipients having a water soluble separating layer and an enteric
coating layer characterized in that the core material is alkaline
reacting and that the separating layer is being formed in situ
during the enteric coating as a water soluble salt between the
enteric coating layer polymer(s) and the alkaline reacting
compound(s).
2. A dosage form according to claim 1, wherein the alkaline
reacting compounds are selected from the group of alkaline organic
substances, hydroxides of alkali metals or one of their alkaline
salts of phosphoric acid, carbonic acid or silicic acid, or an
alkaline ammonium salt.
3. A dosage form according to claim 2, wherein the alkaline
reacting substance is a hydroxide of an alkali metal or an alkaline
salt of phosphoric acid, carbonic acid or silicic acid, or an
alkaline ammonium salt.
4. A dosage form according to claim 2, wherein the alkaline
reacting compound is an alkaline organic substance, e.g. an amino
acid or a salt thereof, an alkaline amine or a derivative thereof,
or an alkaline salt of a weak organic acid.
5. A dosage form according to claim 2, wherein the alkaline organic
substance is an amino acid, e.g. lysine, arginine, ornitine or
histidine, or an alkaline amine or a derivative thereof, e.g.
N-methyl-D-glucamine or trometamine.
6. A dosage form according to claim 1, wherein the alkaline
reacting compounds are present in a concentration of more than 0.1
mmol/g dry ingredients in the alkaline part of the core
material.
7. A dosage form according to claim 1, wherein the enteric coating
polymer(s) is/are hydroxypropyl cellulose derivative(s), e.g.
hydroxypropylmethylcellulose acetate succinate.
8. A dosage form according to claim 1, wherein the enteric coating
polymer is copolymerized methacrylic acid/methacrylic acid methyl
esters.
9. A dosage form according to claim 1, wherein the proton pump
inhibitor is a compound of the general formula I or a
pharmaceutically acceptable salt thereof or a pure enantiomer
thereof in neutral form or in the form of an alkaline salt 3wherein
N in the benzimidazole moiety means that one of the carbonators
substituted by R.sub.6-R.sub.9 optionally may be exchanged for a
nitrogen atom without any substituents; R.sub.1, R.sub.2 and
R.sub.3 are the same or different and selected from hydrogen, alkyl
alkoxy optionally substituted by fluorine, alkylthio, alkoxyalkoxy,
dialkylamino, piperidino, morpholino, halogen, phenyl and
phenylalkoxy; R.sub.4 and R.sub.5 are the same or different and
selected from hydrogen, alkyl and aralkyl; R'.sub.6 is hydrogen,
halogen, trifluoromethyl, alkyl and alkoxy; R.sub.6-R.sub.9 are the
same or different and selected from hydrogen, alkyl alkoxy,
halogen, halo-alkoxy, alkylcarbonyl, alkoxycarbonyl, oxazolyl
trifluoroalkyl or adjacent groups R.sub.6-R.sub.9 form ring
structures which may be further substituted; R.sub.10 hydrogen or
forms an alkylene chain together with R.sub.3 and R.sub.11 and
R.sub.12 are the same or different and selected from hydrogen,
halogen or alkyl and alkyl groups, alkoxy groups and moities
thereof may be branched and straight C.sub.1-C.sub.9-chains or
comprise cyclic alkyl groups, for example cycloalkylalkyl.
10. A dosage form according to claim 1, wherein the proton pump
inhibitor is omeprazole or an alkaline salt thereof.
11. A dosage form according to claim 1, wherein the proton pump
inhibitor is a pure enantiomer of omeprazole or an alkaline salt
thereof.
12. A dosage form according to claim 1, wherein the proton pump
inhibitor is lansoprazole, one of its pure enantiomers or a
pharmaceutically acceptable salt thereof.
13. A dosage form according to claim 1, wherein the proton pump
inhibitor is pantoprazole, one of its pure enantiomers or a
pharmaceutically acceptable salt thereof.
14. A dosage form according to claim 1, wherein the alkaline
reacting core material is individual pellets intended for a capsule
formulation or a tableted multiple unit dosage form.
15. A dosage form according to claim 1, wherein the alkaline
reacting core material is a tablet.
16. A dosage form according to claim 1, wherein individually
enteric coated pellets are compressed into a tableted multiple unit
dosage form.
17. A process for the preparation of an oral, enteric coated
pharmaceutical dosage form comprising a core material that contains
a proton pump inhibitor, one or more alkaline reacting compounds
and optionally pharmaceutically acceptable excipients having a
water soluble separating layer and an enteric coating layer
characterized in that an alkaline reacting core material is
prepared and coated with an enteric coating polymer wherein a
separating layer between the core material and the enteric coating
layer is formed in situ by a reaction between the enteric coating
polymer(s) and the alkaline reacting compound(s) in the core
material during the application of the enteric coating onto the
alkaline reacting core material.
18. An oral, pharmaceutical dosage form comprising a proton pump
inhibitor as defined in any of claims 1-16 for use in inhibiting
gastric acid secretion in mammals and man.
19. A method for inhibiting gastric acid secretion in mammals and
man by administering to a host in need thereof a dosage form
comprising a therapeutically effective dose of a proton pump
inhibitor as defined in any of claims 1-16.
20. Use of an oral pharmaceutical dosage form defined in any of
claims 1-16 for the manufacture of a medicament useful in the
treatment of gastric acid related diseases.
Description
FIELD OF THE INVENTION
[0001] The present invention refers to new pharmaceutical
formulations comprising acid labile heterocyclic compounds with
gastric inhibitory effect, in the following referred to as proton
pump inhibitors. The new formulations are intended for oral use.
Furthermore, the present invention refers to a new method for the
manufacture of such a formulation and, the use of the new
formulations in medicine.
BACKGROUND OF THE INVENTION
[0002] The proton pump inhibitors are for example compounds of the
general formula I 1
[0003] wherein
[0004] N in the benzimidazole moiety means that one of the carbon
atoms substituted by R.sub.6-R.sub.9 optionally may be exchanged
for a nitrogen atom without any substituents;
[0005] R.sub.1, R.sub.2 and R.sub.3 are the same or different and
selected from hydrogen, alkyl, alkoxy optionally substituted by
fluorine, alkylthio, alkoxyalkoxy, dialkylamino, piperidino,
morpholino, halogen, phenyl and phenylalkoxy;
[0006] R.sub.4 and R.sub.5 are the same or different and selected
from hydrogen, alkyl and aralkyl;
[0007] R'.sub.6 is hydrogen, halogen, trifluoromethyl, alkyl and
alkoxy;
[0008] R.sub.6-R.sub.9 are the same or different and selected from
hydrogen, alkyl alkoxy, halogen, halo-alkoxy, alkylcarbonyl,
alkoxycarbonyl, oxazolyl trifluoroalkyl, or adjacent groups
R.sub.6-R.sub.9 form ring structures which may be further
substituted;
[0009] R.sub.10 is hydrogen or forms an alkylene chain together
with R.sub.3 and
[0010] R.sub.11 and R.sub.12 are the same or different and selected
from hydrogen, halogen or alkyl and alkyl groups, alkoxy groups and
moities thereof may be branched and straight C.sub.1-C.sub.9-chains
or comprise cyclic alkyl groups, for example cycloalkylalkyl.
[0011] Examples of proton pump inhibitors according to formula I
are 2
[0012] The proton pump inhibitors used in the dosage forms of the
invention may be used in neutral form or in the form of an alkaline
salt, such as for instance the Mg.sup.2+, C.sup.2+, Na.sup.+,
K.sup.+ or Li.sup.+ salts, preferably the Mg.sup.2+ salts. Further
where applicable, the compounds listed above may be used in racemic
form or in the form of a substantially pure enantiomer thereof, or
alkaline salts of the racemates or the single enantiomers.
[0013] Suitable proton pump inhibitors are for example disclosed in
EP-A1-0005129, EP-A1-174 726, EP-A1-166 287, GB 2 163 747 and
WO90/06925, WO91/19711, WO91/19712, and further especially suitable
compounds are described in WO94/27988 and WO95/01977.
[0014] These proton pump inhibitors are, as already mentioned,
useful for inhibiting gastric acid secretion in mammals and man. In
a more general sense, they may be used for prevention and treatment
of gastric-acid related diseases in mammals and man, including e.g.
reflux esophagitis, gastritis, duodenitis, gastric ulcer and
duodenal ulcer. Furthermore, they may be used for treatment of
other gastrointestinal disorders where gastric acid inhibitory
effect is desirable e.g. in patients on NSAID therapy, in patients
with Non Ulcer Dyspepsia, in patients with symptomatic
gastro-esophageal reflux disease, and in patients with gastrinomas.
They may also be used in patients in intensive care situations, in
patients with acute upper gastrointestinal bleeding, pre- and
postoperatively to prevent aspiration of gastric acid and to
prevent and treat stress ulceration. Further, they may be useful in
the treatment of Helicobacter infections and diseases related to
these.
[0015] These proton pump inhibitors are, however, susceptible to
degradation/transformation in acidic reacting and neutral media.
The degradation is catalyzed by acidic reacting compounds and the
proton pump inhibitors are usually stabilized in mixtures with
alkaline reacting compounds.
[0016] In respect to the stability properties of the proton pump
inhibitors mentioned above, it is obvious that a proton pump
inhibitor in an oral solid dosage form must be protected from
contact with the acidic reacting gastric juice and the active
substance must be transferred in intact form to that part of the
gastrointestinal tract where pH is less acidic, neutral or alkaline
and where rapid absorption of the pharmaceutically active
substance, i.e. the proton pump inhibitor, can occur.
[0017] A pharmaceutical dosage form of these proton pump inhibitors
is best protected from contact with acidic gastric juice by an
enteric coating layer. In U.S. Pat. No. 4,853,230 such enteric
coated preparations of different acid labile substances are
described. Said preparations contain an alkaline core material
comprising the active substance, a separating layer and an enteric
coating layer.
[0018] Ordinary enteric coating layers, however, comprise compounds
which contain acidic groups. If covered with such an enteric
coating layer, the acid labile substance may rapidly decompose by
direct or indirect contact with the acidic groups resulting in
discoloration of the content and loss in content of the active
compound with the passage of time. The discoloration can be avoided
by applying some type of separating layer between the core material
comprising the susceptible proton pump inhibitor and the enteric
coating layer.
[0019] Thus, there are a lot of patent applications describing such
a separating layer between a core material comprising the
pharmaceutically active substance and an enteric coating layer. See
for instance, U.S. Pat. No. 4,786,505, EP 0,277,741 and EP
0,342,522. The prior art techniques to apply at least two different
layers on a pellet core or a tablet comprising an acid labile
compound is rather complicated and there is a demand for finding
new processes and formulations to simplify the manufacturing of
such enteric coated articles comprising acid labile substances.
SUMMARY OF THE INVENTION
[0020] According to one aspect of the invention a new
pharmaceutical dosage form is provided in the form of an enteric
coated tablet. Alternatively, individually enteric coated units are
prepared and filled into a capsule, a sachet or included in a
tableted multiple unit dosage form.
[0021] The present invention is characterized by the presence of a
separating layer between an alkaline reacting core material
comprising a pharmaceutically active acid labile substance and an
enteric coating layer, wherein the separating layer comprises a
water soluble salt of an enteric coating polymer.
[0022] According to a second aspect the present invention provides
a process for the manufacture of two functionally different layers
in one manufacturing step. By such a process a separating layer
comprising a water soluble salt of an enteric coating polymer is
obtained, as well as the enteric coating layer itself.
[0023] Thus, the present invention simplifies the preparation of
enteric coated articles comprising a separating layer between a
core material and an enteric coating layer by providing a new
process for the manufacture of such dosage forms. According to said
process the separating layer is formed by an in situ reaction
between the enteric coating polymer and the alkaline core material
comprising the pharmaceutically active substance.
BRIEF DESCRIPTION OF THE FIGURES
[0024] FIG. 1 is a photo showing a cross-section of a tablet
manufactured according to the invention described in the present
specification.
[0025] FIG. 2 is a schematic drawing of the photo disclosed in FIG.
1. The tablet has an enteric coating layer (3), which has been
applied on an alkaline core material (1) comprising the
pharmaceutically active substance. Between the enteric coating
layer (3) and the core material (1) there is a separating layer (2)
shown. The separating layer (2) is on the photo inked by a
fluorescent colour.
DETAILED DESCRIPTION OF THE INVENTION
[0026] One object of the present invention is to provide a new
enteric coated pharmaceutical formulation comprising a core
material that contains a proton pump inhibitor, one or more
alkaline reacting compound(s) and optionally pharmaceutically
acceptable excipients, which formulation has a water soluble
separating layer and an enteric coating layer and wherein the core
material is alkaline and the separating layer is being formed in
situ during the enteric coating as a salt between the enteric
coating polymer(s) and an alkaline reacting compound(s) in the core
material.
[0027] Another object of the present invention is to provide a new
process for the manufacture of such enteric coated pharmaceutical
formulations comprising a core material of a proton pump inhibitor
wherein a separating layer is formed in situ during the enteric
coating by a reaction between the enteric coating polymer(s) and
one or more alkaline reacting compound(s) in the core material,
i.e. thereby a salt is formed between the enteric coating
polymer(s) and the alkaline reacting compound(s).
[0028] The new pharmaceutical dosage form according to the
invention is further characterized in the following way. Compacted
tablets or individual cores (in the form of small tablets, small
beads, granules or pellets) contain the proton pump inhibitor in
the form of a racemate or one of its single enantiomers or an
alkaline salt of said compound or one of its single enantiomers.
The tablets or individual cores, that also comprise one or more
alkaline reacting compound(s) which is in the position to form a
water soluble salt by a reaction with an enteric coating material,
are coated with one or more enteric coating layers.
[0029] The separating layer is formed in situ by a reaction between
the enteric coating polymer(s) and the alkaline reacting
compound(s) in the core material during the enteric coating
process.
[0030] The core material for the manufacture of enteric coated
pellets can be prepared according to two main principles. Firstly,
seeds can be layered with the proton pump inhibitor, alkaline
reating compound(s) and necessary excipients to give an alkaline
reacting core material, or the alkaline reacting core material can
be prepared as substantially homogeneous cores or tablets
comprising the proton pump inhibitor and the alkaline reacting
compound(s).
[0031] The alkaline reacting compound(s) in the core material or
tablet cores, necessary for an in situ reaction with the enteric
coating polymer, is a substance in the position to form a water
soluble salt with an enteric coating polymer. Such alkaline
reacting compounds are for instance amino acids, such as lysine,
arginine, ornitine, histidine, organic buffering compounds such as
trometamine (i.e. Tris-buffer), N-amino sugars such as
N-methyl-D-glucamine (i.e. Meglumine ), N-ethyl-D-glucamine (i.e.
Eglumine ), glucosamine, disodium-N-stearoyl-glutamate,
heterocyclic amine derivatives such as piperazine or its
hexahydrate, N-methylpiperazine, morpholine,
1-(2-hydroxyethyl)pyrrolidine, alkali salts of citric acid,
tartaric acid, caproic acid or fatty acids, alkali metal
phosphates, silicates or carbonates, sodium, potassium, magnesium,
calcium or aluminium hydroxides and organic amines such as
ethylamine, dicyclohexyl amine or triethanolamine, or alkaline
ammonium salts.
[0032] The core material as such should be an alkaline reacting
core material, i.e. the amount of alkaline reacting compound(s)
available in the core material should be enough to form a salt
between the enteric coating polymer(s) and the alkaline reacting
compound(s).
[0033] Thus, the concentration of alkaline reacting compound(s) in
the core material (before applying the enteric coating polymer) is
from approximately 0.1 mmol/g dry ingredients in the alkali
containing part of the core material up to approximately 15 mmol/g,
preferably the concentration shall be more than 0.3 mmol/g dry
ingredients in the alkaline part of the core material.
[0034] The upper limit range is only restricted by the need to
include a pharmaceutically active ingredient and excipients such as
binders etc in the alkaline core material. The concentration of
alkaline reacting compound(s) may be illustrated as follows. For a
core material where, for instance, 10% w/w of a proton pump
inhibitor and 5% w/w of excipients (binders, surfactants etc) are
to be included, 85% w/w remains to possible disposition to the
alkaline reacting compound(s). For such a core material, this means
that, if the alkaline reacting compound is sodium bicarbonate which
has the rather low molecular weight of 84 u, the concentration of
the alkaline material in the core material will be
[(85/84)/100].times.1 000, i.e. approximately 9.9 mmol/g in the
alkali containing part/layer.
[0035] One or more enteric coating layers are applied onto the
prepared core material or tablets by using a suitable aqueous
coating technique. The enteric coating material is dispersed and/or
dissolved in an aqueous vehicle. As enteric coating polymer(s) one
or more, separately or in combination, of the following can be
used; methacrylic acid copolymers, cellulose acetate phthalate,
hydroxypropyl methylcellulose phthalate, hydroxypropyl
methylceuulose acetate succinate, polyvinyl acetate phthalate,
cellulose acetate trimellitate, carboxymethylethylcellulose,
shellac or other suitable enteric coating polymer(s).
[0036] The enteric coating layer(s) may contain pharmaceutically
acceptable plasticizers to obtain desired mechanical properties,
such as flexibility and hardness of the enteric coating layer(s).
The amount of plasticizer is optimized for each enteric coating
formulation, in relation to selected enteric coating polymer(s),
selected plasticizer(s) and the applied amount of said polymer(s).
The mechanical properties of the enteric coating are especially
important for a tableted multiple unit dosage form, i.e. the
individually enteric coated units must withstand the compression
into a tableted multiple unit dosage form without any significant
effect on the acid resistance. Suitable plasticizers are for
instance, but not restricted to, triacetin, citric acid esters,
phthalic acid esters, dibutyl sebacate, cetyl alcohol, polyethylene
glycols, polysorbates or other plasticizers.
[0037] The preparation of the core material containing the proton
pump inhibitor and alkaline reacting compound(s) is described more
in detail below. The individually enteric coated cores can be
constituted according to different principles.
[0038] The active substance, the proton pump inhibitor, used as a
racemate or one of its single enantiomers or an alkaline salt of
said compound or one of its single enantiomers, mixed with the
alkaline reacting compound(s) is applied on seeds and are used for
further processing.
[0039] The seeds, which are to be layered with the active
substances, can be water insoluble seeds comprising different
oxides, celluloses, organic polymers and other materials, alone or
in mixtures or water soluble seeds comprising different inorganic
salts, sugars, non-pareils and other materials, alone or in
mixtures. Further, the seeds may comprise active substance in the
form of crystals, agglomerates, compacts etc. The size of the seeds
is not essential for the present invention but may vary between
approximately 0.1 and 2 mm. The seeds layered with active substance
are produced either by powder or solutior'suspension layering using
for instance granulating or spray coating/layering equipment.
[0040] Before the seeds are layered, the active substance is mixed
with alkaline reacting compound(s) and further components to obtain
preferred handling and processing properties and suitable
concentration of the active substance. Pharmaceutical constituents
such as fillers, binders, lubricants, disintegrating agents,
surfactants and other pharmaceutically acceptable additives, can be
used. Binders are for example celluloses such as hydroxypropyl
methylcellulose, hydroxypropyl cellulose and carboxymethylcellulose
sodium, polyvinylpyrrolidone, sugars, starches and other
pharmaceutically acceptable substances with cohesive properties.
Suitable surfactants are found in the groups of pharmaceutically
acceptable non-ionic or ionic surfactants such as a for instance
sodium lauryl sulfate or polysorbates.
[0041] Alternatively, the active substance mixed with alkaline
compound(s) and further mixed with suitable constituents can be
formulated into tablets or individual cores. Said tablets or cores
may be produced by compression/extrusion/spheronization or balling
utilizing different processing equipments. The manufactured tablets
or cores can further be layered with additional ingredients
comprising active substance and alkaline reacting compound(s)
and/or be used for further processing.
[0042] The active substance may optionally be mixed with alkaline
pharmaceutically acceptable substance (or substances) for further
stabilisation. Such substances can be chosen among, but are not
restricted to, substances such as for instance the above mentioned
alkaline reacting compounds or other alkaline reacting substances
known by the skilled person in the art to be useful as stabilizers
for acidic susceptable substances.
[0043] Alternatively, the aforementioned alkaline reacting core
material can be prepared by the use of spray drying or spray
congealing technique.
[0044] The prepared alkaline reacting core material in the form of
tablets or pellets are spray coated with an aqueous enteric coating
polymer dispersion/solution. The process parameters such as inlet
air temperature, air flow, atomizer air flow and spraying rate are
adjusted with respect to the equipment used for the process as well
as the specific enteric coating polymer(s). The inlet air
temperature must not be such that the enteric coating polymer(s)
will block in the spraying nozzles.
[0045] The invention is described more in detail by the following
examples, which are not intended to limit the scope of the
invention.
EXAMPLE 1
[0046] Tablets containing lansoprazole and arginine are produced
according to the following procedure. Firstly, dry ingredients are
thoroughly mixed and then granulated with a solution in a
laboratory mixer. The dried granules are mixed with lubricants etc.
in a final mixing step.
1 Concentration Dry ingredients for granulation (mmol/g dry
ingredients in (for approx. 4000 tablets) the alkaline tablet core)
Lansoprazole 40.4 g L-arginine (passing 120 mesh) 365.4 g 4.2
Microcrystalline cellulose 38.5 g Granulating solution Distilled
water 173 g Corn starch 7.7 g
[0047] The solution is poured over the premixed powder mass during
mixing. The wet granules are dried on a tray in a drying cabinet.
The dried granules are milled to pass a 1.0 mm sieve. The granules
are mixed with
2 Talc 3.1 g Sodium dodecyl sulphate 20.8 g Microcrystalline
cellulose 19.2 g Magnesium stearate 5.0 g
[0048] in a laboratory mixer, and then compressed into tablets
having a size of 7 mm .O slashed. and a weight of approximately 125
mg. The obtained tablets have a content of lansoprazole of 10 mg
per tablet.
[0049] Obtained tablets are spray coated with the enteric coating
dispersion defined below, in a Wurster equipped fluidized bed.
3 Enteric coating dispersion Water 80.0 g Triethylcitrate 1.3 g
Na-laurylsulphate 0.2 g Hydroxypropylmethylcellulose acetate
succinate LF 6.3 g Talc 1.9 g
[0050] This single coating step resulted in tablets having two
polymeric layers with different characteristics. The inner layer is
not soluble in acetone, as the outer layer, but soluble in water.
FIG. 1, obtained with confocal laser scanning microscopy (CLSM)
shows a cross-section of the tablet where the separating layer is
easily detected as a layer having an intense fluorescence.
[0051] The separating layer is spontaneously formed in situ during
the process, as a salt between the alkaline reacting compound and
the enteric coating polymer.
EXAMPLE 2
[0052] Core material containing the magnesium salt of
(-)-omeprazole and the alkaline reacting compound trometamine
(=tris-buffer) is prepared by extrusion and spheronization.
[0053] The powder mass is mixed in a laboratory mixer and then
water is added.
4 Concentration (mmol/g dry ingredients in Powder mixture the
alkaline core material) Magnesium salt of (-)- 400 g omeprazole
Microcrystalline cellulose 300 g Trometamine 1000 g 4.1 PVP-XL 100
g Mannitol pwd 195 g Hydroxypropyl methylcellulose 5 g 6 cps Water
q.s.
[0054] The powder mixture is mixed with the water and the wet mass
is mixed to obtain a suitable consistency of the mass.
[0055] Extrusion is performed with an extruder fitted with 1.0 mm
screen. The extrudate is formed into pellets on a spheronizer and
dried in a fluidized bed drier.
[0056] 200 g of the obtained pellets are spray coated with the
enteric coating dispersion described below, in a Wurster equipped
fluidized bed.
5 Enteric coating dispersion Water 93.9 g Polyethylene glycol 400
4.6 g Eudragit .TM. L30D-55 151.5 g
[0057] This single coating step resulted in pellets having two
polymeric layers with different characteristics. The inner layer is
not soluble in acetone as the outer layer, but soluble in water.
The separating layer is spontaneously formed in situ during the
process, as a salt between the alkaline reacting compound and the
enteric coating polymer.
[0058] Enteric coated pellets having a separating layer are
obtained. These pellets may be filled in capsules or sachets for
oral administration.
EXAMPLE 3
[0059] Core material containing omeprazole and N-methyl-D-glucamine
(=meglumine) is prepared by extrusion and spheronization of the
below described composition using the same procedure as in Example
2;
6 Concentration (mmol/g dry ingredients in Powder mixture the
alkaline core material) Omeprazole 100.0 g Microcrystalline
cellulose 50.0 g Meglumine 500.0 g 2.6 Mannitol pwd 297.0 g Sodium
starch glycolate 48.0 g Sodium laurylsulphate 5.0 g Water q.s.
[0060] Obtained dried pellets/cores are spray coated with the
enteric coating dispersion described below, in a Wurster equipped
fluidized bed.
7 Enteric coating dispersion Water 93.9 g Polyethylene glycol 400
4.6 g Eudragit .TM. L30D-55 151.5 g
[0061] This single coating step resulted in tablets having two
polymeric layers with different characteristics. The inner layer is
not soluble in acetone, as the outer one, but soluble in water. The
separating layer is spontaneously formed in situ during the
process, as a salt between the alkaline reacting compound and the
enteric coating polymer.
[0062] The obtained pellets having a separating layer and an
enteric coating layer, are suitable for filling into hard gelatine
capsules or sachets for oral administration.
EXAMPLE 4
[0063] Core material containing magnesium salt of omeprazole and
N-methyl-D-glucamine (meglumine ) is prepared by layer coating in a
Wurster equipped fluidized bed on sugar seeds. For this operation
the following materials are used;
8 Concentration (mmol/g dry ingredients in Substance Amount the
alkali containing layer) Water purified 102 g Ethanol 99% (w/v) 102
g HPMC 6 cps 2 g N-methyl-D-glucamine 3.3 g 0.37 Magnesium salt of
omeprazole 40 g Non Pareille 500 g
[0064] First the water and ethanol were mixed whereafter the HPMC
was dissolved in the obtained solution. N-methyl-D-glucamine and
magnesium salt of omeprazole were dissolved/suspended in the
solution. The sugar cores (Non Pareille) were used as starting
seeds for the formation of core material. A peristaltic pump was
used to feed the spraying suspension, which was fed with a velocity
of 3.9 g/min.
[0065] The Wurster apparatus was equipped with a 60 mm high
insertion tube, having a diameter of 50 mm, positioned to leave a
10 mm slit below it. A spraying nozzle having a 0.8 mm opening was
used. The atomizing air flow was 2.3 Nm.sup.3/h and air pressure
used was 1.9 bar. The inlet air temperature was 50.degree. C. and
flow used 43 m.sup.3/h.
[0066] After the core formation step, 100 grams of the obtained
core material was film-coated by spraying with an enteric coating
dispersion as described below, using the same equipment as in the
core formation step.
9 Enteric coating dispersion Water purified 183 g Triethyl citrate
2.9 g Sodium laurylsulphate 0.4 g Hydroxypropyl methylcellulose
14.4 g acetate succinate LF Talc 4.3 g
[0067] First the triethyl citrate was dissolved in the water, and
thereafter the sodium laurylsulphate was added. The
hydroxypropylmethylcellulose acetate succinate was dispersed in the
solution, and then the talc was added. The dispersion was fed with
a rate of 3.8 g/min.
[0068] Inlet air temperature used was 42.degree. C. and flow was
set to 40 Nm.sup.3/h. Atomizing air flow used was 2.1 Nm.sup.3/h ,
obtained with a pressure of 1.7 bar.
[0069] After finalizing the spraying, the inlet air temperature is
rised to 60.degree. C. and the product is kept at this temperature
for appr. 5 minutes.
[0070] This single film-coating step resulted in cores having two
polymeric coating layers with different characteristics. The inner
layer is not soluble in acetone, as the outer layer, but soluble in
water. Using confocal laser scanning microscopy to study a
cross-section of the cores from this example, the presence of an
inner layer was confirmed.
[0071] The separating layer is spontaneously formed in situ during
the process, as a salt between the alkaline reacting compound and
the enteric coating polymer.
EXAMPLE 5
[0072] A rotogranulator was used to produce spherical core units
containing pantoprazole. As starting material inert sugar seeds
(Non-Pareille) with an average size between 0.6 to 0.71 mm _527 was
used. The sugar seeds were coating layered with the powder mixture
described below, by spraying a 5% solution of HPMC 6 cps in
water.
[0073] The obtained core material containing pantoprazole was dried
at 40.degree. C. for 16 hours in vacuum and then sieved to give
granules between 0.6 mm to 1.25 mm .O slashed..
10 Starting material Non-Pareille 110 parts by weight Concentration
(mmol/g dry ingredients in Powder mixture Amount the alkali
containing layer) Pantoprazole 29.3 parts by weight L-Lysine 22.0 "
0.88 Sucrose 36.7 " Corn starch 42.5 " Microcrystalline 36.7"
cellulose Solution Hydroxypropyl 2.9 " methylcellulose Water (58.7
")
[0074] 250 g of the core material produced in this way was spray
coated with an enteric coating dispersion in a Wurster equipped
fluidized bed apparatus. The dispersion was made by adding the
mentioned ingredients in stated order, while stirring.
11 Dispersion Water 626.8 g Triethylcitrate 9.8 g
Sodium-laurylsulphate 1.5 g Hydroxypropylmethylcellulose 49.2 g
acetate succinate LF Talc 14.8 g
[0075] Enteric coated pellets having a water soluble separating
layer were obtained. These pellets may be filled in capsules or
sachets for oral administration.
EXAMPLE 6
[0076] Omeprazole tablets, 6 mm in diameter containing 20 mg of
omeprazole were prepared by mixing and granulating dry powder
ingredients with water in a Kenwood mixer. For this operation the
following materials are used;
12 Concentration (mmol/g dry ingredients in the alkaline Substance
Amount tablet core) Omeprazole 40.0 g Mannitol pwd 68.0 g
Microcrystalline cellulose 35.0 g Polyvinylpyrrolidone cross-linked
30.0 g Hydroxypropylcellulose low-substituted 20.0 g L-arginine 5.3
g 0.14 Sodium laurylsulphate 2.0 g Water purified q.s. approx 50 g
Sodium stearylfumarate (SSF) 1.0 g
[0077] The dry powders except for SSF were mixed to homogeneity.
This mixture was moistened with the water and the wet mass dried on
a tray in a drying oven. The obtained granules were milled to pass
a screen with 0.8 mm apertures. Then the lubricant SSF was mixed
with the granules using the same Kenwood mixer as before.
[0078] Cores having an average weight of 101 mg were compressed on
a tableting machine equipped with 6 mm diameter punches.
[0079] After the core formation step, 50 grams of the obtained
cores were film-coated by spraying an aqueous enteric coating
dispersion as described below, using a Wurster equipped fluidized
bed.
13 Enteric coating dispersion Substance Amount Water purified 183 g
Triethyl citrate 2.9 g Sodium laurylsulphate 0.4 g
Hydroxypropylmethylcellulose 14.4 g acetate succinate LF Talc 4.3
g
[0080] This single film-coating step resulted in cores having two
polymeric coating layers with different characteristics. The inner
layer is not soluble in acetone, as the outer layer, but soluble in
water.
[0081] The separating layer is spontaneously formed in situ during
the process, as a salt between the alkaline reacting compound and
the enteric coating polymer.
EXAMPLE 7
[0082] Tablets, 7 mm in diameter containing omeprazole and
disodiumhydrogenphosphate was prepared by mixing and granulating
dry powder ingredients with a water solution containing sodium
laurylsulphate, in a Kenwood mixer. For this operation the
following materials are used:
14 Concentration (mmol/g dry ingredients in Substance Amount the
alkaline tablet core) Omeprazole 80.0 g Mannitol pwd 88 g
Microcrystalline cellulose 132 g L-HPC 53 g
Disodiumhydrogenphosphate 104 g 1.12 dihydrate Granulation liquid
Water purified 80 g Sodium laurylsulphate 3 g Water purified q.s.
Final mixing Sodium stearylfumarate (SSF) 10 g Polyvinylpyrrolidone
crosslinked 50 g
[0083] The dry powders except for SSF were mixed to homogenity.
This mixture was moistened first with the granulation liquid and
then with water until satisfactory consistency of the mass. The wet
mass was dried on a tray in a drying oven. The obtained granules
were milled to pass a screen with 0.8 mm apertures and then the
lubricant SSF and the disintegrating agent polyvinylpyrrolidone
crosslinked were mixed with the obtained granules using the same
Kenwood mixer as before.
[0084] Cores having an average weight of 130 mg were compressed on
a tableting machine equipped with 7 mm diameter punches.
[0085] After the core formation step, 50 grams of the obtained
cores were film-coated by spraying with an aqueous enteric coating
dispersion as described below, using a Wurster equipped fluidized
bed.
15 Enteric coating dispersion Water purified 183 g Triethyl citrate
2.9 g Sodium laurylsulphate 0.4 g Hydroxypropyl methylcellulose
14.4 g acetate succinate LF Talc 4.3 g
[0086] This single film-coating step resulted in cores having two
polymeric coating layers with different characteristics. The inner
layer is not soluble in acetone, as the outer layer, but soluble in
water. The separating layer is spontaneously formed in situ during
the process, as a salt between the inorganic alkaline reacting
compound and the enteric coating polymer.
REFERENCE EXAMPLES 1 AND 2
[0087] Placebo tablets, 6 mm in diameter was prepared by mixing and
granulating dry powder ingredients with water in a Kenwood mixer.
For this operation the following materials are used;
16 Concentration (mmol/g dry ingredients Amount containing layer)
Substance Ref. Ex. 1 Ref. Ex. 2 Ref Ex. 1 Ref. Ex. 2 Mannitol pwd
161.5 g 141.3 g Microcrystalline 38.5 g 38.5 g cellulose
Na.sub.2HPO.sub.4 .times. 2H.sub.2O -- 20.2 g -- 0.56 Water
purified q.s. 45 g 45 g approx Sodium stearylfumarate 1.0 g 1.0 g
(SSF)
[0088] The dry powders except for SSF were mixed to homogeneity.
This mixture was moistened with the water and the wet mass dried on
a tray in a drying oven. The obtained granules were milled to pass
a screen with 0.8 mm apertures. Then the lubricant SSF was mixed
with the granules using the same Kenwood mixer as before.
[0089] Cores having an average weight of 93-94 mg were compressed
on a tableting machine equipped with 6 mm diameter punches.
[0090] After the core formation step, 50 grams of each kind of the
obtained cores were (separately) film-coated by spraying an aqueous
enteric coating dispersion according to below, using a Wurster
equipped fluidized bed.
17 Enteric coating dispersion Substance Amount Water purified 183 g
Triethyl citrate 2.9 g Sodium laurylsulphate 0.4 g
Hydroxypropylmethylcellulose 14.4 g acetate succinate LF Talc 4.3
g
[0091] These reference examples show that presence of the alkaline
material in the core material composition is necessary for the
formation of an in situ formed spontaneously developed separating
layer.
[0092] For Reference Ex. 1, this single film-coating step resulted
in cores having only one coating layer, being soluble in acetone.
No separating layer was spontaneously formed.
[0093] For Reference Ex. 2, this single film-coating step resulted
in cores having two polymeric coating layers with different
characteristics. The inner layer is not soluble in acetone, as the
outer layer, but soluble in water. The separating layer is
spontaneously formed in situ during the process, as a salt between
the alkaline reacting compound and the enteric coating polymer.
[0094] By using confocal laser scanning microscopy to study a
cross-section of the cores from the Reference example 2, the
presence of an inner layer was confirmed. In contrast, examining a
cross-section of a core from Reference example 1, no inner layer
was seen.
[0095] The best mode to practice the invention is by the
formulations described in Examples 1 and 2.
[0096] The different active substances, i.e. proton pump
inhibitors, are prepared according to information disclosed in the
Patent specifications mentioned in page 6 of this
specification.
* * * * *