Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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Combination
The present invention relates to a combination comprising at least one NSAID
(non-steroidal
antiinflammatory drug) and at least one proton pump inhibitor for the
prevention and/or treatment
of tumours, to medicaments containing them and to their production.
The treatment of tumours, in spite of great advances which have been made in
the last few years, is
a still unsolved medical problem. In addition to the treatment of manifest
tumours, scientific
interest is also being aimed increasingly at the therapy of precancerous
changes. The aim is being
pursued here of delaying or of preventing the development of malignant
neoplasias.
Adenomatosis coli (syn.: familial adenomatous polyposis = FAP) is a neoplastic
syndrome with
formation of numerous large intestinal polyps. The disease occurs to an
increased extent familially
and is inherited autosomally dominantly. In symptomatic patients with FAP, the
carcinoma rate is
50 to 100%, in diseases detected by preventive medical checkups 10 to 15%.
While the proportion
of FAP patients makes up about 1% of the total number in the colonic carcinoma
family (Rustgi
AK. Hereditary gastrointestinal polyposis and nonpolyposis syndromes. N Engl J
Med 1994, 331,
1694-1702), adenomatous polyps are found in about 33% of the total population
at the age of
approximately 50 years and in about 50% at the age of 70 years (Williams AR,
Balasooriva BA,
Day DW. Polyps and cancer of the large bowel: a necropsy study in Liverpool.
Gut. 1982, 23,
835-842). Histologically, the neoplasias are adenomas. Often, involvements of
the small intestine
and neoplasms in the duodenum and papillae are also found. Diagnosis is
already possible
presymptomatically by means of a gene test. Because of the expectation of
carcinoma,
proctomucosectoiny and colectomy are generally carried out therapeutically
after diagnosis.
It was proved in studies that non-steroidal antiinflammatory drugs (NSAID) are
suitable for the
treatment of FAP and of adenomatous polyps and thus markedly reduce the risk
of bowel cancer
(Janne PA, Mayer RJ. Chemoprevention of colorectal cancer N Engl J Med 2000,
342, 1960-
1968; Steinbach G, Lynch PM, Phillips RKS, Wallace MH, Hawk E et al. The
effect of celecoxib,
a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med
2000, 342, 1946-
1952). O-Acetylsalicylic acid has a demonstrably prophylactic action against
the formation of
cancer of the large intestine, breast cancer and in experimental models
against lung cancer (Harris
R E, Kasbari S, Farrar WB. Prospective study of nonsteroidal anti-inflammatory
drugs and breast
cancer. Oncology Reports 1998, 6, 71-73; Rioux N., Castonguay A. Prevention of
NNK-induced
lung tumorigenesis in A/J mice by acetylsalicylic acid and NS-398. Cancer
research 1998, 58,
5354-5360). High doses or long-term administration of NSAIDs, however, can
cause undesired
side effects, for example in the gastrointestinal region (Wolfe MM,
Lichtenstein DR, Singh G.
Gastrointestinal Toxicity of nonsteroidal antiinflammatory drugs. N Eng] J Med
1999; 340:1888-
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1899 (Erratuin, N Engl J med 1999;341:548).).
The avoidance of medicament-related gastrointestinal side effects in the
gastrointestinal tract by
use of a combination consisting of the proton pump inhibitor pantoprazole and
an NSAID when
taking NSAIDs is described in WO 2005/074930.
Briefly, it was shown that the permanent administration of o-acetylsalicylic
acid for the
prophylaxis of diseases of the cardiovascular system or stroke can be carried
out even in patients
with an increased risk of gastrointestinal bleeding, for example in the case
of existing
gastrointestinal ulcers, without the feared bleeding occurring as side
effects, if o-acetylsalicylic
acid is combined with esomeprazole (Chan FKL, Ching JYL, Hung LCT, Wong VWS,
Leung
VKS et al. Clopidogel versus Aspirin and Esomeprazole to prevent recurrent
ulcer bleeding. N
Eng] J Med 2005, 352, 238-244).
The object of the present invention is the provision of a combination
comprising an NSAID for the
prevention and/or treatment of tumours, where NS AID-related adverse side
effects are reduced.
It has now been found that the combination according to the invention has
unexpected
advantageous effects and properties with respect to prevention and/or
treatment of tumours.
The present invention relates to a combination comprising at least one NSAID
as component A
and at least one proton pump inhibitor as component B for the prevention
and/or treatment of
tumours.
NSAID (non-steroidal antiinflammatory drugs) in the context of the invention
in general represent
all classes of substance mentioned under this term in the prior art. NSAID
represents, for example,
aceclofenac, acetaminophen, o-acetylsalicylic acid, alclofenac, alminprofen,
amfenac,
ampiroxicam, amtolmetinguacil, anirolac, antrafenine, azapropazone,
benorilate, bermoprofen,
bindarit, bromfenac, bucloxic acid, bucolom, bufexamac, bumadizon, butibufen,
butixirate,
carbasalate calcium, carprofen, cinmetacin, cinnoxicam, clidanac, clobuzarit,
deboxamet,
dexibuprofen, dexketoprofen, diclofenac, diflunisal, eltenac, enfenamic acid,
etersalate, etodolac,
etofenamate, feclobuzon, felbinac, fentiazac, fepradinol, flobufen,
floctafenine, flufenamic acid,
flunoxaprofen, flurbiprofen, flurbiprofen axetil, furpfenac, furprofen,
glucametacin, ibufenac,
ibuprofen, indobufen, indometacin, indometazin franesil, indoprofen,
ketoprofen, ketorolac,
lobenzarit, lonazolac, lornoxicam, loxoprofen, mefenamic acid, meloxicam,
mesalazine,
mofezolac, nabumetone, naproxen, niflumic, olsalazine, oxaprozine,
pelubiprofen,
phenylbutazone, pimeprofen, pirazolac, piroxicam, pirprofen, pranoprofen,
prifelone, prinomide,
proglumetacin, proquazone, protizinic acid, romazarit, salicylamide, salicylic
acid, salmistein,
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salnacedin, salsalate, sulindac, suprofen, talniflumate, tenidap, tenosal,
tenoxicam, tepoxalin,
tiaprofenic acid, tiaramide, tilnoprofen arbamel, timegadine, tinoridine,
tolfenamic acid, tolmetin,
ufenamate, ximoprofen, zaltoprofen and zoliprofen.
Preferred NSAIDs mentioned are acetaminophen, o-acetylsalicylic acid,
clidanac, diclofenac,
flurbiprofen, ibuprofen, ketoprofen and sulindac. A particularly preferred
NSAID is o-acetyl-
salicylic acid.
Proton pump inhibitors in the context of the invention in general represent
all classes of substance
mentioned under this term in the prior art. Proton pump inhibitors represent,
for example,
ranitidine, famotidine, pantoprazole, lanzoprazole, esomeprazole, omeprazole
and rabeprazole.
Preferred proton pump inhibitors mentioned are pantoprazole, rabeprazole,
lanzoprazole,
esomeprazole and omeprazole. Particularly preferred proton pump inhibitors are
lanzoprazole,
esomeprazole and omeprazole.
The compounds contained in the combination according to the invention can also
be employed in
the form of their salts, solvates and solvates of the salts, if they are not
already salts, solvates and
solvates of the salts.
The compounds contained in the combination according to the invention,
depending on their
structure, can also exist in stereoisomeric forms (enantiomers,
diastereomers). The invention
therefore comprises the enantiomers or diastereomers and their respective
mixtures.
If the compounds contained in the combination according to the invention can
occur in tautomeric
forms, the present invention comprises all tautomeric forms.
Preferred salts in the context of the present invention are physiologically
acceptable salts of the
compounds according to the invention. Also comprised, however, are salts which
themselves are not
suitable for pharmaceutical applications but can be used, for example, for the
isolation or purification
of the compounds according to the invention.
Physiologically acceptable salts of the compounds according to the invention
comprise acid addition
salts of mineral acids, carboxylic acids and sulphonic acids, e.g. salts of
hydrochloric acid,
hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid,
ethanesulphonic acid,
toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid,
acetic acid, trifluor-
oacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric
acid, fumaric acid, maleic acid
and benzoic acid.
Physiologically acceptable salts of the compounds according to the invention
also comprise salts of
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customary bases, such as, by way of example and preferably, alkali metals
salts (e.g. sodium and
potassium salts), alkaline earth metal salts (e.g. calcium and magnesium
salts) and ammonium salts
derived from ammonia or organic amines having 1 to 16 C atoms, such as, by way
of example and
preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine,
monoethanolamine,
diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol,
procaine,
dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-
methylpiperidine.
Solvates in the context of the invention are designated as those forms of the
compounds according to
the invention which form a complex in the solid or liquid state by
coordination with solvent
molecules. Hydrates are a special form of the solvates, in which the
coordination takes place with
water.
The combination according to the invention can be used for the prevention
and/or treatment of
tumours.
Tumours in the context of the invention are cancerous diseases of the organs
of warm-blooded
organisms and their precursors, in particular tumours, in which therapeutic
effects can be achieved
by inhibition of Cox-I and/or Cox-2. These are carcinomas of the
gastrointestinal tract and its
appended organs such as the liver, pancreas, in particular of the small
intestine, of the large
intestine, of the rectum, and of their precursors. Precursors are understood
as meaning changes
which are still not cancer, preferably intestinal polyps, for example
adenomatous intestinal polyps.
Other tumours in the context of the invention are carcinomas of the lungs,
tumours of the skin, in
particular melanoma, carcinoma of the prostate, carcinoma of the breast,
skeletal tumours,
lymphatic tumours, tumours of the ovaries, tumours of the endocrine system and
tumours of the
central nervous system.
Preferably, the combination according to the invention can be used for the
prevention and/or
treatment of carcinomas of the lungs, carcinomas of the breast, tumours of the
ovaries and
carcinomas of the gastrointestinal tract such as, for example, of the small
intestine, of the large
intestine and of the rectum.
In addition, the combination according to the invention can be used for the
prevention and/or
treatment of familial adenomatous polyposis (FAP), familially cumulative
tumours without
polyposis (Hereditary Non-Polyposis Colorectal Carcinoma - HNPCC), and primary
or secondary
chemoprevention and therapy of colorectal carcinoma.
Prevention is understood as meaning both primary and secondary prevention.
Primary prevention
is understood in this connection as meaning the protection of patients from a
first disease which
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results in organ damage. Secondary prevention is understood in this connection
as meaning the
protection of patients, who are already suffering from organ damage as a
result of a tumour, from a
fresh tumour.
When using the combination according to the invention, a synergistic effect
which is not to be
expected is observed in the action. Thus the amounts of the active substances
employed in the
combination can be reduced in comparison to monotherapy. Likewise, when using
an amount of
active substance equivalent in comparison to monotherapy, a better action
which is not to be
expected can be observed.
The synergistic effect of the combination according to the invention is
preferably observed if the
combination according to the invention comprises 0.1 to 20 mg/kg, in
particular 0.5 to 15 mg/kg,
of active substance of the component A and 0.01 to 15 mg/kg, in particular
0.05 to 10 mg/kg of
active substance of the component B, in each case based on kg of body weight
of the patient on
oral administration.
In addition, the synergistic effect of the combination according to the
invention is preferably
observed if the combination according to the invention comprises as the NSAID
o-acetylsalicylic
acid in a dose of 25 to 1500 mg, preferably in a dose of 75 to 750 mg, and as
the proton pump
inhibitor omeprazole in a dose of 5 to 100 mg, preferably in a dose of 15 to
50 mg, particularly
preferably in a dose of 20 to 40 mg, pantoprazole in a dose of 5 to 100 mg,
preferably in a dose of
15 to 50 mg, particularly preferably in a dose of 20 to 40 mg, lansoprazole in
a dose of 5 to
100 mg, preferably in a dose of 10 to 50 mg, particularly preferably in a dose
of 15 to 30 mg, or
esomeprazole in a dose of 5 to 100 mg, preferably in a dose of 15 to 50 mg,
particularly preferably
in a dose of 20 to 40 mg.
A combination comprising as component A o-acetylsalicylic acid and as
component B
pantoprazole, lansoprazole, esomeprazole or omeprazole is preferred. A
combination comprising
as component A o-acetylsalicylic acid and as component B lansoprazole or
omeprazole is
particularly preferred.
The synergistic effect of the combinations according to the invention is
preferably observed if the
components A and B of the combination according to the invention are present
in a ratio of 2:1 to
100:1, preferably 2:1 to 40:1, based on A and B.
"Ratio" within the meaning of the invention is understood as meaning the
weight ratio of the
individual components, if not stated otherwise.
If appropriate, it may be necessary to depart from the amounts mentioned,
namely depending on
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the body weight or the type of administration route, on individual behaviour
towards the
medicaments, the manner of their formulation and the time or interval in which
administration
takes place. Thus in some cases it may be adequate to manage with less than
the abovementioned
minimum amount, while in other cases the upper limit mentioned above has to be
exceeded. In the
case of the administration of relatively large amounts, it may be advisable to
divide these into a
number of individual doses over the course of the day.
If appropriate, it may be expedient to supplement the combination according to
the invention by
addition of one or more further components. Examples which may be mentioned
are vitamin C,
vitamin E and folic acid. These other components can be added individually or
alternatively
together.
The combination according to the invention is furthermore distinguished by a
surprisingly good
tolerability.
The combination according to the invention is preferably employed in human
medicine, but is also
suitable for veterinary medicine, in particular for the treatment of mammals.
The combinations according to the invention can be administered parenterally,
topically or orally,
preferably topically or orally, particularly preferably orally.
The present invention further relates to the use of the combination according
to the invention for
producing administration forms for the prevention and/or treatment of tumours.
"Combinations" within the meaning of the invention are not only understood as
meaning
administration forms which contain all components (fixed combinations), and
combination packs
which contain the components separately from one another, but also components
which are
administered simultaneously or staggered in terms of time, provided they are
employed for the
treatment or prophylaxis of the same disease. The individual components can
then be present in
different administration forms (e.g. in different tablets and/or capsules),
which are then employed
siinultaneously or staggered in terms of time for the treatment or prophylaxis
of the same disease.
The active substances of components A and B can be converted into the
customary formulations in
the form of medicaments or administration forms in a known manner, where these
can be liquid or
solid formulations. Examples are tablets, sugar-coated tablets, pills,
capsules, granules, aerosols,
syrups, emulsions, suspensions, juices, ointments, creams, powders and
solutions. Moreover,
impregnated plasters or dressings can be used with the combination according
to the invention.
Procedures for the production of these administration forms comprising the
combination according
to the invention are known to the person skilled in the art.
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Since the combinations according to the invention are highly tolerable and in
some cases
efficacious even in low doses, very different formulation variants can be
realized. Thus, on the one
hand, the possibility of formulating the individual components separately
exists. In this case, the
individual components A and B do not definitely have to be taken at the same
time, but on the
other hand taking staggered in terms of time can be advantageous for the
achievement of optimum
effects. In the case of a separate administration of this type, it is obvious
to combine the
formulations of the individual components, for example tablets or capsules,
together at the same
time in a suitable primary pack. In the primary pack, the components are in
each case situated in
separate containers, which can be, for example, tubes, vials or blister packs.
A separate packaging
of this type of the components in a common primary pack is also designated as
a kit.
Further suitable formulation variants for the combinations according to the
invention are
preferably also fixed combinations. "Fixed combination" is understood here as
meaning those
administration forms in which the components are present together in a fixed
quantitative ratio.
Fixed combinations of this type can be realized in the already mentioned
liquid or solid
formulations, for example as solutions, capsules or tablets.
The combinations according to the invention are dosed up to 3 times daily;
those combinations are
preferred which allow administration I to 2 times daily.
The active substances of the components A and B are particularly suitable for
formulation in a
fixed combination in the form of a solid peroral administration form. It is
generally known that the
compliance in patients is dependent to a crucial extent on the factors number
of administration
forms per taking time and size and weight of the (solid peroral)
pharmaceutical form. Therefore
both the number of the various medicaments to be taken separately should be
kept as low as
possible (advantage of a fixed combination), and the size and the weight of a
fixed peroral
administration form should be as small as possible with full therapeutic
potency, in order to make
taking as pleasant as possible for the patient. Fixed combinations in the form
of solid peroral
pharmaceutical formulations having minimum size and minimum weight can thus be
realized. The
fixed combinations according to the invention accordingly offer a patient
compliance which is as
high as possible and thereby improve the safety and reliability of a treatment
decisively.
By combination of the components A and B and modification of the composition
or of the
functionality, the release of active substance can be controlled. For example
by means of delayed
release of active substance (retardation) of a component, the abovementioned
decoupling of the
onset of action in terms of time can also be realized in fixed combinations.
The solid peroral administration forms mentioned here are produced by the
general standard
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processes. Ingredients are those which are pharmaceutically accepted and
physiologically
harmless, for example: as fillers, cellulose derivatives (e.g.
microcrystalline cellulose), sugars (e.g.
lactose), sugar alcohols (e.g. mannitol, sorbitol), inorganic fillers (e.g.
calcium phosphate), binding
agents (e.g. polyvinylpyrrolidone, gelatin, starch and cellulose derivatives),
and all further
excipients which are needed for the production of pharmaceutical formulations
with the desired
properties, e.g. lubricants (magnesium stearate), e.g. disintegrants (e.g.
crosslinked
polyvinyl pyrrol idone, sodium carboxymethylcellulose), e.g. wetting agents
(e.g. sodium
laurylsulphate), e.g. retarding agents (e.g. cellulose derivatives,
polyacrylic acid derivatives), e.g.
stabilizers, e.g. flavourings, e.g. colour pigments.
Liquid formulations are likewise produced according to standard methods using
pharmaceutically
customary excipients and contain the active substances in either dissolved or
suspended form.
Typical administration volumes of these pharmaceutical preparations are I to
10 ml. Examples of
excipients in these liquid formulations are: solvents (e.g. water, alcohol,
natural and synthetic oils,
e.g. medium-chain triglycerides), solubilizers (e.g. glycerol, glycol
derivatives), wetting agents
(e.g. polysorbate, sodium laurylsulphate), and further excipients which are
needed for the
production of pharmaceutical formulations with the desired properties, e.g.
viscosity-enhancing
agents, e.g. pH corrigents, e.g. sweeteners and flavourings, e.g.
antioxidants, e.g. stabilizers, e.g.
preservatives.
The main constituents of the shells of capsule formulations are, for example,
gelatin or hydroxy-
propylmethylcellulose.
Pharmaceutical excipients, as are familiar to the person skilled in the art,
are also described, for
example, in the following handbook: "Handbook of Pharmaceutical Excipients",
Wade, A. &
Weller, P.J., American Pharmaceutical Association, Washington, 2nd edition
1994.
For the use of the two components A and B according to the invention for the
treatment of the
disease states mentioned, the oral administration route is preferred. The
present invention further
relates to medicaments which contain the components A and B, customarily
together with one or
more inert, non-toxic, pharmaceutically suitable excipients.
For oral administration, administration forms functioning according to the
prior art, releasing the
components A and B according to the invention rapidly and/or in modified form,
which contain the
two components in crystalline (ground or micronized) and/or amorphous and/or
dissolved form are
suitable. Influence can be brought to bear on the absorption from the
gastrointestinal tract, for
example, by means of the rate of solution and thus the particle size of the
components A and B
employed. Among these suitable administration forms are (enteric-)coated or
uncoated tablets,
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hard capsules made of gelatin, HPMC, pullulan or other materials, soft gelatin
capsules, powders,
granules and pellets. Depending on the half-life, the stability of the
components A and B, of the
site of absorption and/or of a desired decoupling of the onset of action in
terms of time, further
controlled-release formulations are suitable. These include, for example,
structured tablets, erosion
matrix tablets, tablets or mini-tablets having a diffusion-controlling
coating, capsules containing
pellets, granules or tablets having a diffusion-controlling coating, capsules
containing eroding
pellets, granules or tablets and osmotic-release tablets. A more accurate
description of selected
systems of the rapid-release and of the controlled-release formulations and
their production is
given below.
The components A and B used according to the invention can be converted to the
administration
forms mentioned. This can be done in a manner known per se by mixing with
inert, non-toxic,
pharmaceutically suitable excipients.
For the processing of the component A in combination with component B to give
a joint oral
administration form (fixed combination), all abovementioned administration
forms are suitable. In
the case of mutual impairment of the stability, the two components can be
separated spatially in
the pharmaceutical form. For this, separate granules or pellets, for example,
are filled into capsules
or two granulates are compressed to give a 1-layer/2-layer or a jacket-core
tablet. In addition, it is
also possible to coat at least one of the two components or a powder, granules
or a pellet
preparation which contains at least one of the two components with polymer and
subsequently to
process it further to give a tablet or capsule.
On account of the pH-dependent instability of component B, coating of the
formulation stage
containing this component (e.g. active substance crystals, granules, pellets
or mini-tablets; see
later) or of the entire formulation with an enteric coating is preferred.
Coatings within the meaning
of this invention are in particular film coatings. The process of lacquering
generally follows
standard processes and makes the addition of further excipients necessary. For
the enteric film
coating, film-forming agents (e.g. cellulose acetate phthalate,
polymethacrylic acid derivatives [=
EUDRAGITS L and S] or hydroxypropylmethylcellulose phthalate), plasticizers
(e.g.
polyethylene glycols, triacetin, glycerol, dibutyl phthalate),
colourants/pigments (e.g. titanium
dioxide, iron oxide) and release agents (e.g. talc, highly disperse silica,
silica gel, magnesium
stearate, glycerol monostearate) are distinguished. The coating is carried out
by spraying on a
suspension, preferably based on water. Replacement of the water by a suitable
organic solvent is
possible. Appropriate lacquering can be carried out in a different position in
the production
process. If only the formulation stage discussed above is enteric-coated,
further lacquering, for
example in the form of a sugar or film coating, can moreover take place at the
end of the
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production process. The preferred film-forming agents in this position are,
for example, modified
celluloses, polymethacrylates and polyvinylpyrrolidone.
In certain cases of the combinations mentioned, a delayed controlled release
of the components A
and/or B can be particularly advantageous. This can lead to an improved
pharmacological effect,
reduce the occurrence of undesired side effects or contribute to
simplification of treatment for the
patient. The invention therefore also relates to formulations which contain
both components and
release both components or one of the two components in controlled form. Here,
both component
A and component B, only component A or only component B can be released in
controlled form,
while in the latter two cases the other component is rapidly released.
A) Rapid-release formulations
The fixed combination according to the invention is, inter alia, a formulation
rapidly releasing the
components A and/or B. "Rapid-release formulation" is understood as meaning a
formulation of
the type (e.g. tablet, capsule, sachet) which releases > 80% of its contained
active substance doses
within 30 minutes (blade stirrer apparatus according to USP; UV detection;
release medium
900 ml of 0.1 N hydrochloric acid or acetate buffer pH 4.5 surfactant; speed
of rotation 75 rpm).
Consequently, the fixed combination within the meaning of this invention can
be administered up
to three times daily; a combination which allows administration I to 2 times
daily is preferred.
Various systems are suitable for the achievement of a rapid active substance
release. For example
powders and/or granules and/or pellets which are subsequently filled into
capsules or sachets, 1-
layer/2-layer or jacket-core tablets, film tablets, sugar-coated tablets or
soft gelatin capsules are
distinguished.
For example, the production of an administration form comprising the fixed
combination
according to the invention of the components A and B can be carried out by
filling a mixture of
both components directly into a capsule with addition of suitable excipients
and/or formulating to
give a tablet. Suitable excipient additives are, inter alia, fillers,
disintegrating agents and glidants.
Examples for the excipient groups mentioned can be - as fillers: cellulose
derivatives (e.g.
microcrystalline cellulose) and starches (native or modified, e.g. potato
starch), sugars (e.g.
lactose) and sugar alcohols (e.g. mannitol, sorbitol) and inorganic fillers
(e.g. calcium phosphate,
magnesium oxide) and buffer substances; as disintegrants: starch derivatives
(e.g. crosslinked
sodium carboxymethylstarch, sodium starch glycolate), cellulose derivatives
(e.g. crosslinked
sodium carboxymethylcellulose) or crosslinked polyvinylpyrrolidone; as
glidants (understood here
as the generic term for flow-regulating agents/lubricants/mould-release
agents): magnesium
stearate, calcium stearate, stearic acid, talc and highly disperse silica. In
order to make possible a
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uniform distribution of the two substances in the mixture, the two components
A and B, for
example, can be mixed with one another first and the excipients can be added
thereto in stages.
The present invention also relates to further processing of the active
substance/excipient mixture
already described to give granules. For granulation, according to the
invention the known
conventional processes in the form of fluidized bed agglomeration, rotor
granulation and wet
extrusion are suitable as wet granulation processes and roll compaction is
suitable as a dry
granulation process. A preferred wet granulation process is fluidized bed
agglomeration. In wet
granulation, water or a suitable organic solvent, for example ethanol, acetone
or isopropanol, or a
mixture of water with a suitable organic solvent can generally be employed as
solvent. The
addition of hydrophilizing agents in the form of surfactants (e.g. sodium
laurylsulphate,
polysorbates) is possible. Additionally to the already mentioned excipient
groups, the use of
binding agents, for example sugars, sugar alcohols, starches, cellulose
derivatives, alginates,
pectins, polyethylene glycols and polyvinylpyrrolidones can take place. The
addition of antistatics,
in particular in the case of finer active substance batches, is also possible.
Here, polyethylene
glycols, sodium laurylsulphate, highly disperse silica/alumina or dicalcium
phosphate, for
example, suggest themselves. The granules produced can be filled directly
(sachet/capsule) or
formulated further to give tablets.
Independently of the chosen production pathway (direct mixing or granulation),
the resulting
pharmaceutical form, that is a capsule, tablet or alternatively even the
granules (in the case of
sachet filling), can be provided with an enteric coating for stability
reasons.
Moreover, the preparation of the fixed combination can also be carried out by
the production of
two mixtures/granulates independent of one another, which are combined in an
additional process
step and filled thereafter (capsule/sachet) and/or formulated to give a
tablet. Each individual
production step can be characterized by the addition of suitable excipients.
The preferred
granulation process both for component A and component B is a dry granulation
process.
Processing to give the final pharmaceutical form is carried out after
combination of the two
granulates.
The utilization of this production pathway allows both the separate enteric
lacquering of one or
both granulates of components A and B before their combination/further
processing and an enteric
lacquering of the pharmaceutical form resulting at the end (combined granules,
capsule or tablet).
The production of a rapid-release administration form, comprising the fixed
combination
according to the invention of the components A and B, can also be carried out
by absorbing both
components on neutral pellets. For the production of rapid-release pellets
using the above-
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mentioned components A and/or B, neutral pellets of sucrose or
microcrystalline cellulose, for
example, can be coated with a mixture of the active substances, customary
binding agents and
further customary excipients. If, per component, one batch of pellets is
produced, the pellet batches
comprising the components A and B are subsequently combined to give one stage.
These pellets
can be filled into capsules and/or sachets or processed further to give
tablets.
If this production path is taken, there are again the options to enterically
lacquer one or both pellet
batches separately of one another, to coat the pellets after combination to
give one batch or to
enterically lacquer the pharmaceutical form (capsule/tablet) resulting after
further processing of
the pellet batches.
The present invention likewise relates to the production of a fixed
combination in the form of a 2-
layer or jacket-core tablet. This is in particular of advantage if an
incompatibility is expected
between the two components to be processed. Moreover, this process offers the
possibility of
employing various excipients or stabilizers (e.g. antioxidants or buffer
substances) in the
respective layer or in the core or the shell, depending on the component. For
the production of a 2-
layer tablet, a press having two filling and press stations is suitable in
particular. Each component
is fed to one of the filling stations in each case as a direct mixture with
suitable excipients or in the
form of granules. In the case of the production of a jacket-core tablet, after
pressing of the cores a
feed and centring unit for a 2-layer press is additionally needed, which
guarantees the correct
introduction of the cores into the jacket.
According to the preceding comments, the separate enteric lacquering of only
one or both
granulates of the components A and B or an enteric lacquering of the resulting
2-layer tablet, an
enteric lacquering of only the core or an enteric lacquering of the resulting
jacket-core tablet is
possible.
The present invention also relates to the production of a fixed combination
using melt extrusion, a
process which likewise follows standard processes. Here, component A, for
example, can be
employed in the form of one of the already described active
substance/excipient mixtures or
granulates, while component B is first processed to give a melt extrudate. For
the process of melt
extrusion, the use of one/a number of polymer(s), plasticizers and carriers is
necessary. Suitable
polymers can be, for example, hydroxypropylcellulose or polyvinylpyrrolidone.
Possible
plasticizers are, inter alia, triethyl citrate, benzoic acid and succinic
acid. The term vehicles is
understood here as meaning excipients such as, for example, sugar alcohols, in
particular mannitol,
microcrystalline cellulose and crosslinked sodium carboxymethylcellulose. The
melt extrudate
obtained is either rounded to give pellets or comminuted after its production,
preferably to a
particle size < 0.3 15 [mm], and can subsequently be processed further with
the powder/granulate
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mixture comprising the component A. Here, direct filling as granules
(sachet/capsule) or
compaction to give tablets (1-layer or 2-layer tablets) can take place.
Addition of lubricants is
advisable under these conditions.
Moreover, the production of the fixed combination can also be carried out by
the production of
two melt extrudates independent of one another, which are combined in an
additional process step
and filled therein and/or formulated to give a tablet (1-layer or 2-layer
tablets). Each individual
production step can be characterized by the addition of suitable excipients.
After melt extrusion
has taken place, either rounding to give pellets or comminution of the melt
extrudate follows,
preferably to a particle size < 0315 mm. The pellets/granules thus obtained
are mixed. The mixed
extrusion pellets can be packed directly (sachet/capsule) or the mixed
granules can be compressed
to give tablets.
Moreover, this invention also relates to the production of a fixed combination
by the joint melt
extrusion of both active substances in an active substance-excipient mixture.
After melt extrusion
has taken place, either rounding to give pellets or comminution of the melt
extrudate follows,
preferably to a particle size < 0.315 mm. The pellets thus obtained can be
packed directly
(sachet/capsule) or the granules can be compressed to give tablets.
Independently of the preferred production procedure, there are various options
for the enteric
lacquering which is to be carried out: the extrudates obtained (granules or
pellets) can be coated
separately of one another or alternatively lacquered after mixing them or the
resulting
pharmaceutical forms (capsule/tablet) can be coated.
B) Formulations having controlled active substance release
Corresponding to the rapid-release tablets, the controlled active substance
release is likewise
defined by means of the release rate of the components A and/or B from the
formulation. For the
determination of the average release rate according to the definition of the
invention, the
pharmaceutical formulations of the present invention are tested in the
"Apparatus 2" of the USP
(test medium 900 ml of phosphate buffer pH 6.8 surfactant; speed of rotation
75 rpm; UV
detection). A formulation shows controlled active substance release if, for
the delayed release
component(s), a release rate of 80% in more than 45 minutes, preferably
between 80% in 2 hours
to 80% in 16 hours, results.
Various systems are suitable for the achievement of controlled active
substance release. These can
be subdivided into, for example, enveloping forms, diffusion-controlled
pellets, which are filled
into capsules or sachets or can be compressed to give tablets, into matrix
tablets, into 2- or 1-layer
tablets or into osmotic release systems. Depending on the desired release
profile (dependent on the
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properties of the active substances, in particular the stability, the half-
life and the indication), both
components or alternatively only one can be processed in the controlled-
release form.
For the formulation of the components A and B in controlled-release form,
single crystals of the
active substances, active substance-containing granule particles or pellets
can be provided with a
coating and subsequently filled into capsules or processed to give tablets.
Tablets themselves can
also be enveloped. Excipients used are fats, waxes and various polymers.
Should the coating
consist of digestible or non-digestible fats or fat-like substances, the
digestible substances
employed can be, for example, glycerol monostearate, glycerol monopalmitate,
stearic acid,
diglycol stearate or glycerol trioleate and the non-digestible substances
employed can be, for
example, carnauba wax, beeswax and cetystearyl alcohol. The formation of pores
can be controlled
by addition of water-soluble excipients and the release rate can be controlled
by means of their
size. Possible pore-forming agents for controlling the pore size are, inter
alia, soluble polymers,
such as, for example, polyethylene glycols, polyvinylpyrrolidones,
hydroxypropylmethylcelluloses,
carboxymethylcelluloses or their salts, methylcelluloses, dextrins,
maltodextrins, cyclodextrins,
dextrans or other soluble compounds, such as, for example, salts (sodium
chloride, potassium
chloride, ammonium chloride etc.), urea, sugar (glucose, sucrose, fructose,
lactose etc.), sugar
alcohols (mannitol, sorbitol, lactitol etc.).
If necessary, enteric lacquering of the resulting pharmaceutical form follows.
For the formulation of the components A and B in controlled-release form for
subsequent filling
into a capsule/a sachet or for subsequent tabletting, diffusion-controlling
pellets are in particular
suitable. For the production of the diffusion-controlling pellets containing
one of the above-
mentioned active substances, neutral pellets of sucrose or microcrystalline
cellulose, for example,
are coated with a mixture of the active substance, customary binding agents
and further customary
excipients and subsequently coated with a diffusion lacquer, which can contain
a plasticizer. The
binding agents used are preferably hydroxypropylmethylcellulose or
polyvinylpyrrolidone.
Likewise, other natural, synthetic or semisynthetic polymers such as, for
example, methylcellulose,
hydroxypropylcellulose, sodium carboxymethylcellulose, polyacrylic acids,
polyvinyl alcohols or
gelatin can be employed. A suitable diffusion lacquer is particularly
ethylcellulose. However, other
materials such as poly[(methacrylic acid)(ethyl acrylate)] (1:1) or other
acrylates, cellulose acetate
or cellulose acetate butyrate can also be used. Suitable plasticizers are,
inter alia, phthalic acid
derivatives (e.g. dimethyl phthalate, diethyl phthalate, dibutyl phthalate),
citric acid derivatives
(e.g. triethyl citrate, tributyl citrate, acetyltriethyl citrate), other
esters (e.g. diethyl sebacate,
triacetin), fatty acids and derivatives (glycerol monostearate, acetylated
fatty acid glycerides,
castor oil and other native oils, miglyol), or polyols (glycerol, 1,2-
propanediol, polyethylene glycol
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of differing chain length). In addition, the type and amount of the
plasticizer are adjusted such that
the above-defined release according to the invention and the necessary
stability of the pellets are
achieved. The adjustment of the above-defined release is further carried out
by control of the pore
size of the diffusion lacquer and/or its thickness. The proportion of the pore-
forming agent in the
amount of lacquer here is 0 to 50% by weight. The adherence of a certain
weight ratio of active
substance-coated pellets to diffusion membrane and of a certain ratio of the
diffusion lacquer to
amount of plasticizer is crucial here for pellet production. Some of the
plasticizer employed can
evaporate during the lacquering and subsequent malleablizing. On changing the
peripheral
conditions, a change in the amount of coating to diffusion lacquer is
necessary. Thus a higher
amount of coating is necessary, for example, if the desired release rate is
reduced, the amount of
the pore-forming agent is increased or in the case of certain plasticizers the
proportion of
plasticizer is reduced. A lower amount of coating is necessary if the desired
release rate is
increased, the amount of the pore-forming agent is reduced or in the case of
certain plasticizers the
proportion of plasticizer is increased. The diffusion pellets can be produced,
inter alia, by
suspending or dissolving the components A and B in water and thickening with a
concentrated
hydroxypropylmethylcellulose solution. The suspension or solution thus
obtained is absorbed on
neutral pellets in a spray process in a fluidized bed unit. The coating of the
pellets with a diffusion
membrane follows, preferably in a fluidized bed unit by spraying on, for
example, an aqueous
ethylcellulose dispersion or organic ethylcellulose solution, which contains a
suitable,
physiologically tolerable plasticizer. The pellets are subsequently
malleablized at temperatures of
50 to 125 C, preferably 60 to 110 C. Here, higher malleablizing temperatures
lead to the fact that,
for the achievement of the release according to the invention, rather lower
lacquer application
amounts are sufficient and the resulting pellets are physically more stable on
storage. The
thickness of the diffusion membrane, plasticizer type, amount of plasticizer
and pellet size are
chosen such that the above-described release rate is achieved. The quantity of
pellets of both
components corresponding to the daily dose is filled into a hard gelatin
capsule or a sachet or
further processed to give tablets. In addition to the described coating of
neutral pellets, other
methods of pellet production are also possible, such as wet extrusion with
subsequent rounding,
rotor granulation, fluidized bed agglomeration or melt extrusion with
subsequent rounding.
Alternatively, mini-tablets having a diameter of 1- 4 mm can also be produced.
Subsequently, the
active substance-containing pellets or mini-tablets are coated with a
diffusion membrane as
described.
If necessary, an enteric lacquer is added.
For the formulation of both components in a fixed combination and controlled-
release form, tablets
are likewise suitable which contain the components A and B in a matrix of a
water-swellable
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polymer. The size of these tablets can be dimensioned such that one or more
tablets find room in
the interior of a capsule or of a sachet. The tablets can be filled into the
capsule in uncoated form
or coated with a lacquer beforehand, for example a lacquer insoluble in
gastric juice.
Tablets which contain both components in a matrix of a water-swellable polymer
can be produced
as follows. These "matrix formulations" expediently contain 0.1 to 70% by
weight, preferably 0.2
to 60% by weight of the active substances. The proportion of the matrix of the
water-swellable
polymer is expediently 10 to 95% by weight, preferably 20 to 60% by weight.
Pharmaceutical
preparations according to the invention in the form of erosion tablets are
particularly preferred.
These tablets are characterized in that, in addition to customary excipients
and vehicles and
tabletting excipients, they contain a certain amount of water-swellable,
hydrogel-forming
polymers, where these polymers must have a viscosity of at least 15,
preferably at least 50, cps
(measured as a 2% strength aqueous solution at 20 C). Customary excipients and
vehicles are, for
example, lactose, microcrystalline cellulose, mannitol or calcium phosphate.
Customary tabletting
excipients are, for example, magnesium stearate, talc or highly disperse
silica. In the case of
magnesium stearate, these are expediently present in an amount of 0.5 to 3% by
weight, in the case
of highly disperse silica expediently in an amount of 0.1 to 1% by weight. The
water-soluble,
hydrogel-forming polymers employed are preferably hydroxy-propylcelluloses,
hydroxypropylmethylcelluloses, methylcelluloses, carboxymethylcellulose,
alginates,
galactomannans, polyacrylic acids, polymethacrylic acids or copolymers of
inethacrylic acid and
methyl methacrylate, guar, agar, pectin, tragacanth, gum arabic, xanthan or
mixtures of these
substances. The use of hydroxypropylmethylcelluloses is particularly
preferred. Here, the erosion
tablets according to the invention should contain at least 10% by weight of a
hydroxypropylmethylcellulose type based on the mass of a tablet, whose
viscosity (measured as a
2% strength aqueous solution at 20 C) is at least 15, preferably at least 50,
cps. The
pharmaceutical formulation which comprises the active substance in a matrix of
a water-swellable
polymer is produced by mixing the active substance, the polymer and suitable
excipients and
vehicles and customary tabletting excipients and directly tabletting. A prior
dry granulation in the
form of roll compaction is just as possible as the carrying out of a wet
granulation, in which the
active substance, the water-swellable polymer and suitable vehicles are
granulated in the fluidized
bed. When using rotor granulation, if appropriate the utilization of ethanol-
water mixtures is
necessary. In the case of matrix tablets, the amount and viscosity of the
water-swellable polymer
are chosen such that tablets with the above-described average release rates
result for both
components. The dry granules are screened, mixed with a lubricant, such as,
for example,
magnesium stearate, and tabletted. The tablet is optionally subsequently
lacquered, if necessary
with an enteric coating. For the subsequent filling of a capsule, erosion
tablets with a diameter of
3 mm to 7 mm are preferred; an optionally enteric lacquering is also possible
in this position.
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The present invention likewise relates to a pharmaceutical formulation in
which the components A
and B are present in a 2-layer tablet. This consists either of two controlled-
release layers or of one
controlled-release and one rapid-release layer. The formulation of the in each
case controlled-
release layer is geared to the principles which were presented above for the
matrix formulation.
For the formulation of the in each case rapid-release layer cf. section A) of
the present invention.
For tabletting, in particular a 2-layer press provided with 2 filling and
press stations is in particular
suitable. The tablet is optionally subsequently lacquered; if necessary this
lacquering can be
carried out using an enteric coating. In order to prevent an initial release
rate of one of the two
components which is too high, the two-layer tablet can also be provided with a
third, active
substance-free layer.
Moreover, the components A and B can also be processed to give a 1-layer
tablet. A suitable
controlled-release formulation for subsequent incorporation into a 1-layer
tablet is in particular the
diffusion-controlling pellets already described. Either two types of diffusion-
controlling pellets or
one type of diffusion-controlling pellets are mixed with the active substance
to be combined in
rapid-release form and further excipients, vehicles and tabletting excipients
and compressed to
give a l-layer tablet. Granulation of the rapid-release active substance and
the subsequent
lacquering of the tablet are also possible.
If necessary, an enteric lacquer is to be added.
A further embodiment of the present invention is the "osmotic pharmaceutical
release system".
Osmotic pharmaceutical release systems of this type are known in principle in
the prior art and are
treated in detail, for example, in R. W. Baker, Osmotic Drug Delivery: A
Review of the Patent
Literature, Journal of Controlled Release 1995, 35: 1-21 or in R.K. Verma et
al., Osmotic Pumps
in Drug Delivery, Critical Reviews in Therapeutic Drug Carrier Systems 2004,
21: 477-520. The
pharmaceutical formulation as an osmotic pharmaceutical release system
preferably consists of
a) a core which contains the components A and B, optionally a hydrophilic
polymeric swelling
agent and optionally a water-soluble substance for the induction of osmosis,
and
b) a shell which is permeable for water and impermeable for the components A
and B of the
active substance-containing core, and
c) an opening through the shell b) for the transport of the constituents
contained in the core into
the surrounding body fluid.
This special osmotic pharmaceutical release system is described in principle
in the prior art, for
example in DE 2 328 409 or US 3,485,770. With respect to the materials for the
shell, reference
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may be made to EP 0 277 092 and US 3,916,899 and US 3,977,404 mentioned there.
With respect to suitable hydrophilic polymeric swelling agents reference may
be made to the
polymeric swelling agents mentioned in EP 0 277 092 and WO 96/40080. For
example, ethylene
oxide homopolymers (polyethylene glycol) with various degrees of
polymerization with molecular
weights between 100 000 to 8 000 000 and vinylpyrrolidone/vinyl acetate
copolymers and further
water-swellable polymers mentioned in US 3,865,108, US 4,002,173 and US
4,207,893 can be
used. Water-soluble substances for the induction of osmosis are in principle
all water-soluble
substances whose use in pharmacy is harmless, which are mentioned as water-
soluble excipients,
for example, in the pharmacopoeias or in "Hager's Handbuch der
Pharmazeutischen Praxis"
[Hager's Handbook of Pharmaceutical Practice], 1990-1995, Springer Verlag and
Remington's
Pharmaceutical Sciences. Special water-soluble substances are salts of
inorganic or organic acids
or non-ionic organic substances with high water solubility such as, for
example, carbohydrates
such as sugars etc. The production of an opening in the shell of the tablet is
known per se in the
prior art and described, for example, in the US patent specifications US
3,485,770 and US
3,916,899. The release rate is adjusted by the type and amount of the
semipermeable material
forming the shell, by the type and amount of the hydrophilic polymeric
swelling agent optionally
contained and of the optionally present water-soluble substance for the
induction of osmosis. The
components A and B of the present invention can be introduced into an osmotic
pharmaceutical
release system in different ways. For the controlled release of both
components, these are mixed
with the excipients and compressed to give a joint active substance layer. If
only one component is
to be released in controlled form, the components not to be released in
controlled form can either
be incorporated separately into the lacquer shell of the tablet, or it is
compressed to give a separate
active substance layer, which is first pumped free from the pharinaceutical
release system before
the control led-re lease component.
If necessary, an enteric coating is additionally to be applied.
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Working examples:
Example 1:
80 mg of o-acetylsalicylic acid and 20 mg of omeprazole are used for the
production of a tablet, if
necessary with addition of further excipients.
Example 2:
600 mg of o-acetylsalicylic acid and 15 mg of lanzoprazole are used for the
production of a tablet,
if necessary with addition of further excipients.
Example 3:
80 mg of o-acetylsalicylic acid and 40 mg of omeprazole are used for the
production of a tablet, if
necessary with addition of further excipients.
Example 4:
600 mg of o-acetylsalicylic acid and 30 mg of lanzoprazole are used for the
production of a tablet,
if necessary with addition of further excipients.
Example 5:
100 mg of o-acetylsalicylic acid and 20 mg of omeprazole are used for the
production of a tablet, if
necessary with addition of further excipients.
Example 6:
500 mg of o-acetylsalicylic acid and 15 mg of lanzoprazole are used for the
production of a tablet,
if necessary with addition of further excipients.
Example 7:
100 mg of o-acetylsalicylic acid and 40 mg of omeprazole are used for the
production of a tablet, if
necessary with addition of further excipients.
Example 8:
500 mg of o-acetylsalicylic acid and 30 mg of lanzoprazole are used for the
production of a tablet,
if necessary with addition of further excipients.
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Example 9:
500 mg of o-acetylsalicylic acid and 40 mg of omeprazole are used for the
production of a tablet, if
necessary with addition of further excipients.
Example 10:
100 mg of o-acetylsalicylic acid and 15 mg of lanzoprazole are used for the
production of a tablet,
if necessary with addition of further excipients.
Example 11:
500 mg of o-acetylsalicylic acid and 20 mg of omeprazole are used for the
production of a tablet, if
necessary with addition of further excipients.
Example 12:
100 mg of o-acetylsalicylic acid and 30 mg of lanzoprazole are used for the
production of a tablet,
if necessary with addition of further excipients.
Example 13:
Rapid-release dry-compacted fixed formulation
400.0 g of o-acetylsalicylic acid are homogeneously mixed with 150.0 g of
lanzoprazole, 162.5 g
of Avicel PH 101 V, 100.0 g of maize starch, 100.0 g of sucrose and 75.0 g of
AcDiSol and
compacted. The resulting briquettes are screened in 2 stages and subsequently
mixed with 12.5 g
of magnesium stearate. The finished mixture is compressed in a rotary press to
give 200.0 mg of
heavy tablets in the format 9 mm WR 15 and these are subsequently provided
with an enteric
coating consisting of 28.0 g of Eudragit L30D , 20.0 g of talc and 2.0 g of
triethyl citrate,
dissolved or suspended in 200.0 g of water. The 200 mg heavy tablet cores
contain 80 mg of
o-acetylsalicylic acid and 30 mg of lansoprazole.
Example 14:
2-Layer tablet
640.0 g of o-acetylsalicylic acid are homogeneously mixed with 56.0 g of
Avicel PH 101, 56.0 g of
maize starch and 48.0 g of ascorbic acid and compacted. The resulting
briquettes are screened in 2
stages.
60.0 g of omeprazole are homogeneously mixed with 28.0 g of sucrose, 80.5 g of
Avicel PH 101 ,
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20.0 g of AcDiSol and 12.0 g of magnesium carbonate and compacted. The
resulting briquettes
are screened in 2 stages. The granules obtained are dissolved or suspended
with a mixture of
22.5 g of Eudragit L30D , 20.0 g of talc and 2.5 g of glycerol monostearate,
in 180.0 g of water,
enteric lacquered in the fluidized bed and subsequently mixed with 2.0 g of
magnesium stearate.
625.0 mg of the o-acetylsalicylic acid-containing and 165.0 mg of the
omeprazole-containing
granules are compressed in a 2-layer press to give 790.0 mg of heavy tablets
in the format
19x9 mm WR 5.7. These tablet cores contain 500 mg of o-acetylsalicylic acid
and 40 mg of
omeprazole. Subsequently, they are dissolved or suspended in 154.2 g of water
with a mixture of
7.5 g of hydroxypropylmethylcellulose 15 cp, 2.5 g of PEG 3350 and 2.5 g of
titanium dioxide, and
lacquered.
Example 15:
Capsule in combination with dry compaction and melt extrusion
400.0 g of o-acetylsalicylic acid are homogeneously mixed with 40.0 g of
Avicel PH 101 and
40.0 g of maize starch and compacted. The resulting briquettes are screened in
2 stages.
40.0 g of pantoprazole are homogeneously mixed and extruded with 40.0 g of
mannitol and
440.0 g of HPC-SL. The resulting strand is cut to give cylinders and these are
rounded off.
In each case 97.2 mg of the roll granulate comprising o-acetylsalicylic acid
are filled into capsules
together with 130,0 mg of pellets comprising pantoprazole. Each capsule
contains 81 mg of
o-acetylsalicylic acid and 10 mg of pantoprazole. The capsules are dissolved
or suspended in
166.0 g of water with a mixture of 20.0 g of Eudragit L30D , 19.5 g of talc
and 2.0 g of triethyl
citrate, and lacquered (enteric coating).
Colony formation assay
The following are used: 96 well plates, previously: cell culture-treated
(351172 BD Biosciences),
DMEM/F12 powder medium (42400-010 Invitrogen), or RPMI powder medium (51800-
019
Invitrogen), Sea Plaque agarose (50100 Cambrex) (USA: Biowhittaker BMA 50100,
125 grams),
Cell-Titer Blue (Ord. # G8080, 20m] / G8081, 100 ml / G8082, 1Ox100m1,
Promega), cells: A549
(ATCC# CCL 185); HCT 116 (ATCC# CCL 247).
First, a bottom layer is temperature controlled at 44 C with double-
concentrated agar (Eppendorf
Thermo-Mixer). Then, 50 1 of bottom agar/well are plated out and incubated at
room temperature
for about 30 min. The application of the top layer containing the tumour cells
(HCT 116) then
takes place. For this, the cell suspension is rapidly and thoroughly mixed 1:1
with bottom agar
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(44 C) in a 50m1 Falcon. 50 l of the mixture of top agar/cells are plated out
without contacting
the bottom agar in this process and incubated at room temperature for about 30
min. Finally, 80 1
of DMEM/F12 (standard medium) per well are added as the final layer, without
contacting the soft
agar in this process. Addition of substance is carried out 24h after
inoculation. The substances are
dissolved in DMSO here in the concentrations indicated below and 10 p1/well
are added.
Incubation is carried out for 2 weeks in the presence of IOmM Hepes buffer.
Evaluation is carried
out by means of the CTB assay according to the instructions of the
manufacturer (Promega) and
the calculation of the IC50 is carried out with the aid of the program
GraphPad Prism.
Table 1: Activity of o-acetylsalicylic acid, lanzoprazole or omeprazole or the
respective
combinations on tumour cells (HCT I 16 colonic carcinoma cells) in the soft
agar colony formation
assay. (PPI: proton pump inhibitor - specification in the table column)
Soft agar assay
IC50 calculation with Prism: Sigmoidal dose-response (variable slope),
bottom=O
HCT116
Omeprazole Lansoprazole
o- ceysaicyicact o ceysaicylcaci
Combination with IC50 [mM] IC50 [mM]
Component B see above 62.5 M 0.55 0.30
Component B see above 31.3 M 0.96 0.49
Component B see above 15.6 M 0.77 1.65
1.26 1.93
meprazo e ansoprazo e
Combination with IC50 [ M] IC50 [ M]
o-Acetylsalicylic acid 1.25 mM 68 84
o-Acetylsalicylic acid 0.625 mM 116 67
o-Acetylsalicylic acid 0.313 mM 99 91
o-Acetylsalicylic acid 0.156mM 126 108
129 107
Table 2: Activity of o-acetylsalicylic acid and lanzoprazole or combinations
on human lung
carcinoma cells (A549) in the soft agar colony formation assay.
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Combination with o-Acetylsalicylic acid IC50 [mM]
Lanzoprazole 125 M 1.04
Lanzoprazole 62.5 M 1.67
Lanzoprazole 31.3 M 2.09
Lanzoprazole 15.6 M 2.00
3.11
Lanzoprazole
Combination with IC50 [[tM]
o-Acetylsalicylic acid 2.5 mM 44
o-Acetylsalicylic acid 1.25 mM 88
o-Acetylsalicylic acid 0.625 mM 117
o-Acetylsalicylic acid 0.313 mM 128
o-Acetylsalicylic acid 0.156 mM 141
- 145
The growth of tumour cell colonies is markedly more strongly inhibited by the
combination of
o-acetylsalicylic acid with the proton pump inhibitors lanzoprazole or
omeprazole than by
o-acetylsalicylic acid on its own.
Migration assay:
The migration assay is carried out with DLD I cells (ATCC# CCL 221). The cells
are cultured in
RPMI 1640/glutamine 1 /o/Glutamax 1% /(FCS 10%) and used for the assay at a
confluence of
about 80%. First, 750 l each of medium + 10% FCS, l OnM IL-8 and 20nM SDF-1
are introduced
into a 24-well Companion Plate. The plate is temperature controlled at 37 C.
The cells are then
trypsinized from culture bottles, stopped with medium + 10% FCS, centrifuged,
washed once with
medium without FCS, resuspended and counted in a Neubauer chamber. 8 M
individual batches
are then employed (without Fluoroblock) and coated with 500 l each of cells
(corresponds to
5x105 cells/well). Substances are prepared in DMSO in the concentrations
indicated below and
then added to the medium of the Companion Plate (3.75 1) and to the cells in
the batches (2.5 1).
After a migration period of 48h, the medium is removed from the batches and
these are washed in
a fresh Companion Plate with 500 l each of prewarmed D-PBS (Gibco).
Subsequently, the
batches are placed in a new Companion Plate with 200 l each of prewarmed
Accutase and
incubated for 10 minutes at 37 C without shaking and a further 5 minutes at
600 rpm in an
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Eppendorf Thermomixer. The batches are then removed and in each case 150 1
from the
Companion Plate (bottom cells) are added to white 96 well MTP and processed
with CellTiter-Glo
(Promega #G7571) according to the instructions of the manufacturer.
Measurement is carried out
in a Lumibox at 0.5% sensitivity. The evaluation is carried out with Excel and
GraphPad Prism.
Table 3: Influence of a combination of o-acetylsalicylic acid and the proton
pump inhibitor
lanzoprazole on the migration behaviour of DLD-1: colon carcinoma cells.
Conc. [mM] of o-acetylsalicylic o-Acetylsalicylic o-Acetylsalicylic acid
acid/lanzoprazole acid* Lanzoprazole* + lanzoprazole*
0.313 / 0.031 79 41 24
0.625 / 0.031 82 41 23
1.25 / 0.031 35 41 10
*The percentage of the migrated cells in the lower chamber relative to the
untreated control is
indicated in [%].
An inhibitory effect on the migration behaviour of tumour cells is found. As a
result of the
combination, markedly fewer DLD-1 cells reach the bottom chamber than with o-
acetylsaticylic
acid on its own.
