Note: Descriptions are shown in the official language in which they were submitted.
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WO 97/02021 PCT/EP96/02893
ORAL PHARMACEUTICAL COMPOSITIONS WITH DELAYED RELEASE
OF REVERSIBLE PROTON PUMP INHIBITORS
f
Field of the Invention
The present invention relates to oral pharmaceutical
compositions in pellet or tablet form for reversible proton pump
inhibitors for combined use with antimicrobially-active
ingredients for the treatment of disorders caused by
Helicobacter.
Prior Art
Control of the microbe Helicobacter pylori, which is thought
to be responsible for certain gastric disorders, by combined use
of an antimicrobially-active ingredient which is active againat
Helicobacter pylori and of an agent which reduces gastric acid
has been regarded as the method of choice for some time.
Besides inhibitors of gastric acid secretion of the H2
receptor antagonist type, in recent times use has been made, with
more or less success, of compounds of the class of so-called
.irreversible proton pump inhibitors (such as pantoprazole,
. omeprazole or lansoprazole). Irreversible proton pump inhibitors
are substances which covalently, and thus irreversibly, bind too
the enzyme.~which is responsible for acid secretion in the
stomach, the H+/K+ ATPase.
Besides so-called irreversible proton pump inhibitors, which
essentially have a common basic chemical structure
(pyridinylmethylsulfinylbenzimidazoles), there are the so-called
~ reversible H+/K+ ATPase inhibitors which have different basic
chemical structures and which, as the name indicates, reversibly
~ bind to the enzyme responsible for gastric acid secretion. These
are called reversible proton pump inhibitors in connection with
the present invention. Reversible proton pump inhibitors ai:e
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disclosed, for example, in the documents DE-A-3917232,
EP-A-0399267, EP-A-0387821, JP-A-3031280, JP-A-2270873,
EP-A-0308917, EP-A-0268989, EP-A-0228006, EP-A-0204285, .
EP-A-0165545, EP-A-0125756, EP-A-0120589, EP-A-0509974,
DE-A-3622036, EP-A-0537532, EP-A-0535529, JP-A-3284686, r
JP-A-3284622, US-P-4,833,149, EP-A-0261912, WO-A-9114677,
WO-A-9315055, WO-A-9315071, WO-A-9315056, WO-A-9312090,
WO-A-9212969, WO-A-9118887, EP-A-0393926, EP-A-0307078,
US-P-5,041,442, EP-A-0266890, WO-A-9414795, EP-A-0264883,
EP-A-0033094, EP-A-0259174, EP-A-0330485, WO-A-8900570,
EP-A-0368158, WO-A-9117164, WO-A-9206979, WO-A-9312090,
WO-A-9308190, WO-A-9418199, DE-A-3011490, US-P-4;464,372,
EP-A-0068378 and WO-A-9424130.
Combined use of reversible proton pump inhibitors with
antimicrobially-active ingredients has a good effect against
Helicobacter in vitro. However, the clinical effect achieved
with this combined use is disappointing.
Szcrtimarv of the Invention
The action of an antimicrobially-active ingredient on
Helicobacter is surprisingly enhanced by administering a
reversible proton pump inhibitor in slow-release dosage form
(extended release form). It must be regarded as particularly
surprising that, in addition, administration of the slow-release
reversible proton pump inhibitor results in the onset of action
taking place significantly faster than on administration of a
non-slow-release reversible proton pump inhibitor. The duration
of treatment until Helicobacter is eradicated is shortened,
saving considerable amounts of antibiotic and acid inhibitor.
The invention thus relates to an oral pharmaceutical compo-
sition for treating a disorder caused by Helicobacter comprising a
reversible proton pump inhibitor in combination with at least one
antimicrobially-active ingredient, wherein at least part of the
reversible proton pump inhibitor is in slow-release form. Further
subject-matters are evident from the claims.
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Detaibr
Reversible proton pump inhibitors are, for the purpose of
the present invention, those active ingredients which reversibly
bind to the enzyme responsible for gastric acid secretion, H+,/K+
ATPase. Examples of reversible proton pump inhibitors tire
- enumerated in the previously-noted documents. Examples of
reversible proton pump inhibitors are, e.g., 8-(2-
methoxycarbonylamino-6-methylbenzylamino)-2,3-dimethyl-
imidazo[1,2-a]pyridine (hereinafter B94o1-011), 3-hydroxymethyl-
8-(2 -methoxycarbonylamino-6-methylbenzyloxy)-2
methylimidazo[1,2-a]pyridine, 3-hydroxymethyl-8- (2-
methoxycarbonylamino-6-methylbenzyloxy)-2-methylimidazo[1,2-
a]pyridine, 8-(2-methoxycarbonylamino-6-methylbenzyloxy)-2,3-di-
methylimidazo[1,2-a]pyridine, 8-(2-tert-butoxycarbonylamino-~6-
methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine, 8-(2-tezt-
butoxycarbonylamino-6-methylbenzyloxy)-2,3-dimethylimidazo[1,2-
a]pyridine, 8-(2-ethoxycarbonylamino-6-methylbenzylamino) -2,3-
dimethylimidazo[1,2-a]pyridine,~8-(2-isobutoxycarbonylamino-6-
methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine, 8-(2-
isopropoxycarbonylamino-6-methylbenzylamino) -2,3-dimethyl-
imidazo[1,2-a]pyridine, 8-(2-tert-butoxycarbonylamino-6-
methylbenzylamino)-3-hydroxymethyl-2-methylimidazo[1,2-
a]pyridine, 8-(2-tert-butoxycarbonylamino-6-methylbenzyloxy)-3-
hydroxymethyl-2-methylimidazo[1,2-a]pyridine, 8-{2-[(2 -
methoxyethoxy)carbonylamino]-6-methylbenzyloxy}-2-
methylimidazo[1,2-a]pyridine-3-methanol, 8-(2-[(2 -
methoxyethoxy)carbonylamino]-6-methylbenzylamino}-2-
methylimidazo[1,2-a]pyridine-3-methanol, 8-{2-[(2 -
methoxyethoxy)carbonylamino]-6-methylbenzylamino}-2,3-
dimethylimidazo[1,2-a]pyridine, 8- {2-[(2-methoxyethoxy)-
carbonylanino]. -6-methylbenzyloxy}-2-methylimidazo[1,2-
a]pyridine-3-methanol, 8-(2-[(2 -methoxyethoxy) carbonylamino]-6-
methylbenzyloxy}-2,3-dimethylimidazo[1,2-a]pyridine, 3-
hydroxymethyl-2-methyl-8-benzyloxyimidazo-[1,2-a]pyridine,
3-hydroxymethyl-2-trifluoromethyl-8-benzyloxyimidazo-
[1,2-a]pyridine, 1,2-dimethyl-3-cyanomethyl-F3-
benzyloxyimidazo[1,2-a]pyridine, 2-methyl-3-cyanomethyl-8-
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benzyloxyimidazo[1,2-a]pyridine, 3-butyryl-8-methoxy-4-(2-
methylphenylamino)quinoline and 3-butyryl-8-hydroxyethoxy-4- (2-
methylphenylamino) quinoline.
Reversible proton pump inhibitors can, in this connection,
be present as such, in the form of their salts and/or their
solvates (e.g. hydrates), etc. Particularly suitable salts are
(because all reversible proton pump inhibitors are substances
with a basic reaction) all acid-addition salts. Particular
mention may be made of the pharmacologically-acceptable salts of
inorganic and organic acids customarily used in~pharmaceutical
technology, including water-soluble and water-insoluble acid-
addition salts with acids, such as hydrochloric acid,
hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid,
acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-
hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid,
malefic acid, lauric acid, malic acid, fumaric acid, succinic
acid, oxalic acid, tartaric acid, embonic acid, stearic acid,
toluenesulfonic acid, methanesulfonic acid and 3-hydroxy-2-
naphthoic acid, the acids being used in the preparation of the
salt in a ratio of amounts which are equimolar or different
therefrom - depending on whether the acid is mono- or polybasic
and depending on the salt required.
Examples of suitable antimicrobially-active ingredients
(active against Helicobacter pylori) are enumerated in European
Patent Application EP-A-282131. These active ingredients
include, for example, bismuth salts (such as bismuth subcitrate
or bismuth subsalicylate), sulfonamides, nitrofurans (such as
nitrofurazone, nitrofurantoin or furazolidone), metronidazole,
tinidazole, nimorazole or antibiotics. Examples of antibiotics
which may be mentioned in this connection are, arranged according
to particular classes of active ingredient: aminoglycosides,
such as gentamicin, neomycin, kanamycin, amikacin or
streptomycin; macrolides, such as erythromycin, azithromycin,
clarithromycin, clindamycin or rifampicin; penicillins, such as
penicillin G, penicillin V, ampicillin, mezlocillin or
amoxicillin; polypeptides, such as bacitracin or polymyxinl
tetracyclines, such as tetracyline, chlorotetracycline,
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oxytetracycline, minocycline or doxycycline; carbapenems, such
as imipenem, loracarbef, meropenem or panipenem: cephalosporins,
such as cefalexin, cefoxitin, cefuroxime axetil, cefotaxime,
cefpodoxime proxetil, cefaclor, cefadroxil or cephalothin; gyrase
inhibitors, such as ciprofloxacin, norfloxacin, ofloxacin or
_ pefloxacin; or other different antibiotics, such as
chloramphenicol. Particularly worthy of mention in taxis
connection is also the combination of a plurality of
antimicrobially-active ingredients, for example the combination
of a bismuth salt and/or tetracycline with metroriidazole, or the
combination of amoxicillin or clarithromycin with metronidazole.
Particularly worthy of mention in this connection
is also administration of a reversible proton pump inhibitor
together with a plurality of antimicrobially-active ingredients,
for example with the combination of a bismuth salt and/or
tetracycline with metronidazole, or with the combination of
amoxicillin or clarithromycin or with metronidazole.
The dosage of the active ingredients depends greatly on the
nature of the reversible proton pump inhibitor used and of the
antimicrobially-active ingredients) used. A typical dosage of
a reversible proton pump inhibitor as disclosed, for example, in
WO-A-9418199 can be regarded as a daily dose of from about 0.01
to about 20, preferably from 0.05 to 5, and in particular from
0.1 to 1:5, mg/kg of body weight, where appropriate in the form
of a plurality of single doses. Penicillins, such as
amoxicillin, are administered in a daily dose of from about 5 to
40, preferably from 10 to 20, mg/kg of body weight.
Antimicrobially-active ingredients which may be
emphasized 'are erythromycin, azithromycin, clarithromycin,
clindamycin, rifampicin, ampicillin, mezlocillin, amoxicillin,
tetracycline, minocycline, doxycycline, imipenem, meropenem,
cefalexin, cefuroxime axetil, cefpodoxime proxetil, cefaclor,
cefadroxil, ciprofloxacin, norfloxacin, ofloxacin and pefloxacin.
Clarithromycin and amoxicillin may be mentioned <~s
antimicrobially-active ingredients which should be particularly
emphasized.
Combined administration means (for the purpose of the
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present invention) fixed and, in particular, free combinations,
i.e. the slow-release reversible proton pump inhibitor and the
antimicrobially-active ingredient are present together in one
dosage unit, or slow-release reversible proton pump inhibitor and
antimicrobially-active ingredient, which are present in separate
dosage units, are administered in direct succession or at a
relatively large time interval: a relatively large time interval
means within a time span of up to a maximum of 24 hours. For use
as separate dosage units, these are preferably made available
together in one pack. For example, the two dosage units are
packed together in blister packs which are designed with regard
to the relative arrangement of the two dosage units with respect
to one another, the inscription and/or coloring in a manner known
per se so that the times for taking the individual components
(dosage regimen) of the two dosage units are evident to a
patient.
A dosage unit means, in particular, those medicinal dosage
forms in which slowing or extending of reversible proton pump
inhibitor release is achieved with as few problems as possible.
These include, i n particular, tablets, coated tablets or pellets,
and microtablets in capsules, with the dosage form advantageously
being designed so that the two active ingredient components
(reversible proton pump inhibitor on the one hand and
antimicrobially-active ingredient on the other hand) are
released, or made available effectively for the body, in
such a way that an optimal active-ingredient profile (and thus
action profile) is achieved.
For slowing release, various types and degrees of retarding
release may be used to ensure a reversible proton pump inhibitor
plasma level which persists as long as possible and is sufficient
for raising pH.
The pharmaceutical formulation of the antimicrobially-active
ingredients) is carried out in a manner which is familiar per
se to the skilled worker for the individual active ingredients.
The rapid release of part of the reversible proton pump
inhibitor and retarding release of another part is optionally
achieved, for example, by layered tablets or multilayer tablets,
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in which part of the reversible proton pump inhibitor is present
in an outer coating in a form without slowing release; this is
followed by another coating containing the antimicrobially-active
ingredient and then the core with the reversible proton pump
inhibitor whose release is slowed in a suitable manner.
The details of how to achieve slowing release are familiar
to the skilled worker on the basis of his expert knowledge. The
skilled worker is likewise familiar with suitable ancillary
substances and vehicles for the required dosage forms
(pharmaceutical formulations). Besides solvents, tablet
ancillary substances and other active ingredient excipients it
is possible to use, for example, tablet-coating compositions,
plasticizers, antioxidants, preservatives, dyes, etc. Where
incompatibilities between the active ingredients or between the
active ingredients and ancillary substances are to be expected,
suitable separating layers must be provided where appropriate.
The oral pharmaceutical compositions according to
the invention are distinguished from the prior art by controlled
release of active ingredients and increased stability.
Besides filler and binder, other ancillary ~substances, :in
particular lubricants and nonstick agents, and tabl~at
disintegrants, are used in the manufacture of the tablet core:a.
A suitable binder is, in particular, polyvinylpyrrolidone :in
various degrees of polymerization. Examples of lubricants and
nonstick agents are higher fatty acids and their alkali-metal and
alkaline-earth-metal salts, such as calcium stearate. Suitable
tablet disintegrants are, in particular, chemically-inert agent:a.
Preferred tablet disintegrants include cross-linkEad
polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulossa
and sodium starch glycolate.
Examples of suitable film-forming polymers, in respect oi:
the water-insoluble release-slowing intermediate layers) to be
applied to the pellet or tablet core, include ethylcellulose,
polyvinyl acetate, ammonio methacrylate copolymer type A (e. g.
Eudragit~ RL) and type B (Eudragit~ RS) etc. The release rate can
be controlled not only by incorporating suitable water-soluble
pore formers such as PEG, lactose, mannitol, sorbitol, HPMC, et<:. ,
but also by the thickness of the coating layer applied.
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The solvents or dispersants used for the release-controlling
polymer dispersion are non-aqueous organic solvents, such as
alcohols, ketones, halogenated hydrocarbons or mixtures of such ,
solvents. -
It is possible in a similar way to use osmotic systems with
semipermeable membranes of cellulose acetate, cellulose acetate -
butyrate or cellulose acetate propionate (as described in US-A
3845770, US-A 3916899, US-A 4036227, US-A 4093708, US-A 4096238,
US-A 4135514 and US-A 4142526) to control the release of active
ingredients. These can be coated with aqueous.dispersions of
enteric lacquers without changing the release rate.
Examples of suitable polymers for the enteric coating are
methacrylic acid/methyl methacrylate copolymer or methacrylic
acid/ethyl methacrylate copolymer (Eudragit~ L) or cellulose
derivatives, such as carboxymethylethylcellulose (CMEC, Duodcel),
cellulose acetate phthalate (CAP), cellulose acetate trimellitate
(CAT), hydroxypropylmethylcellulose phthalate (HP50, HP55),
hydroxypropylmethylcellulose acetate succinate (HPMCAS) or
polyvinyl acetate phthalate, to which it is also possible to add,
if desired, plasticizes (such as propylene glycol) and/or other
additives and ancillary substances (e.g. buffer; base, such as,
preferably, aluminum hydroxide; or pigment). The layers are
applied in conventional ways using equipment customary for these
purposes.
Susceptibility of Commercial Application
The combined use according to the invention of a slow-
release reversible proton pump inhibitor with an antimicrobially-
active ingredient meets all the requirements for a pharmaceutical
product or combination pharmaceutical product for the treatment
of gastric disorders attributable to the microbe, Helicobacter
pylori. The particular advantages connected with the combined
use of the slow-release drug form with an antimicrobially-active
ingredient which may be mentioned are: the rapid onset of ;
action with pH values as far as neutral in the lumen of the
stomach and in the wall of the stomach and an optimal displaying
of the effect of the antimicrobially-active ingredient. The
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_ g _
short duration of treatment which can be achieved increases the
compliance, which is extremely important for antibiotic
treatments.
Examples
The following formulation examples explain the invention in
detail without restricting it.
Example 1
Tablets:
I. Production of uncoated core:
a) B9401-011 (hemimalate) 119.8 mg
b) Sodium carboxymethylstarch 21.0 mg
c) Microcrystall~ne cellulose
(e.g.: Avicel PH 101) - 21.0 mg
d) Maize starch 19.4 mg
e) Magnesium stearate 5.0 mg
186.2 mg
a) is mixed with b), c,) and part of d). A paste
is prepared with the remainder of d). The latter is used
for granulation of the powder mixture in a suitable
mixer. The granules are dried in a drying oven or
fluidized bed. e) is added to the dried granules, and the
granules are compressed in a suitable tabletting machine.
II. Release-slowing layer
f) Ethylcellulose 9.85 mg
g) Lactose micronized 2.37 mg
h) Propylene glycol 0.98 mg
14. 00 mg
ig
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f) is dissolved in 165 ml of isopropanol, h) is
stirred in for a sufficient length of time using a suitable
agitator to form a solution (A). g) is suspended in 165 ml of
isopropanol using a rotor-stator agitator to form a fine
suspension (B). (A) and (B ) are combined.
The tablet cores obtained under I are coated
to an adequate layer thickness with the suspension obtained
above in suitable apparatus.
Example 2
Tablets:
I. Production of uncoated core:
Production of the cores takes place as in Example I, I.
II. Release-slowing layer:
f) Polyvinyl acetate
10.38 mg
g) Lactose micronized 2.59 mg
h) Propylene glycol 1.03 mg
13 .13 mg
f) is dissolved in 150 ml of a 1:1
acetone/chloroform mixture. h) is stirred in for a sufficient
length of time,'.using a suitable agitator to prepare a
solution (A) .
g) is suspended in 150 ml of a 1:1
acetone/chloroform mixture, using rotor-stator agitator to
prepare a fine dispersion (B). (A) and (B) are combined.
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The tablet cores obtained under I are coated to a
sufficient layer thickness with the thus-obtained dispersion
in suitable apparatus.
Example 3
Pellets:
I. Starter pellets
a) Sucrose pellets (0.7-0.85 mm) 95,0.0 g
b) Hydroxypropylmethylcellulose
2910 (USP) 40.0 g~
c) Propylene glycol 10.0 g
a) is sprayed with an aqueous solution of
b) and c) in a fluidized bed (Wurster method).
II. Active pellets
d) B9401-011 (Hemimalate) 403.0 g
e) Hydroxypropylmethylcellulose
2910 (USP) 403.0 g
f) Propylene glycol 201.5 g
d), e) , f) are successively dissolved in 4 liters
of purified water and sprayed onto 900 g of the pellets
obtained under I in a fluidized bed (Wurster method).
III. Slow-release pellets
A release-slowing layer is applied in analogy
to the procedure described for tablets in a pan or fluidized
w
bed.
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Example 4
Pellets:
I. Active pellets
a) B9401-011 (Hemimalate) 403.0 g
b) Microcrystalline cellulose
(Avicel PH101) 117.0 g
c) Na carboxymethylcellulose 18.0 g
a) and b) are premixed dry and subsequently
moistened to a paste-like consistency with a solution of Na
carboxymethylcellulose in water in a conventional kneader or
high-speed mixer. The resulting composition is then extruded
and shaped into pellets by the extruder/rounder method
familiar to the skilled worker. The moistened pellets are
dried in suitable equipment (drying oven, fluidized bed,
etc.).
III. Slow-release pellets:
The release-slowing layer is applied in analogy
to the procedure described for tablets in a pan or fluidized
bed.
The invention and its advantages are readily
understood from the foregoing description. As is apparent,
various changes can be made in the products and methods
without departing from the spirit and scope of the invention
;.
or sacrificing its material advantages. The products and
processes hereinbefore described are merely illustrative of
preferred embodiments of the invention.
