U.S. patent application number 10/189453 was filed with the patent office on 2003-02-06 for pharmaceutical compositions for ulcer.
This patent application is currently assigned to Nicox S.A.. Invention is credited to Soldato, Piero Del.
Application Number | 20030027844 10/189453 |
Document ID | / |
Family ID | 11379187 |
Filed Date | 2003-02-06 |
United States Patent
Application |
20030027844 |
Kind Code |
A1 |
Soldato, Piero Del |
February 6, 2003 |
Pharmaceutical compositions for ulcer
Abstract
Pharmaceutical compositions for the therapy and the prevention
of ulcer and dyspepsia relapses comprising as essential components
the following components a) and b): component a): one or more
components selected from the conventional anti-ulcer products;
component b): organic compounds containing the --ONO.sub.2
function, or inorganic compounds containing the --NO group,
characterized in that they are NO nitric oxide donors.
Inventors: |
Soldato, Piero Del; (Milano,
IT) |
Correspondence
Address: |
ARENT FOX KINTNER PLOTKIN & KAHN
1050 CONNECTICUT AVENUE, N.W.
SUITE 400
WASHINGTON
DC
20036
US
|
Assignee: |
Nicox S.A.
|
Family ID: |
11379187 |
Appl. No.: |
10/189453 |
Filed: |
July 8, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10189453 |
Jul 8, 2002 |
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09622911 |
Aug 29, 2000 |
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6436975 |
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09622911 |
Aug 29, 2000 |
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PCT/EP99/01225 |
Feb 25, 1999 |
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Current U.S.
Class: |
514/338 ;
424/718; 514/509 |
Current CPC
Class: |
A61P 43/00 20180101;
A61K 31/00 20130101; A61P 1/04 20180101; A61P 1/00 20180101; A61P
1/14 20180101; Y10S 514/925 20130101 |
Class at
Publication: |
514/338 ;
514/509; 424/718 |
International
Class: |
A61K 031/4439; A61K
031/21; A61K 033/00 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 5, 1998 |
IT |
MI98A000443 |
Claims
1. Pharmaceutical compositions comprising as components the
following: component a): 13wherein in the (A) formula R=H,
OCH.sub.3, OCHF.sub.2; R.sub.1=CH.sub.3, OCH.sub.3; R.sub.2=H,
CH.sub.3; R.sub.3=CH.sub.3, CH.sub.2--CF.sub.3,
(CH.sub.2).sub.3--OCH.sub.3; component b): one or more organic
compounds containing the --ONO.sub.2 group, or one or more
inorganic compounds containing the --NO group, or mixtures thereof,
said compounds being characterized in that they are NO nitric oxide
donors, i.e., when they are brought into contact in vitro with
cells of the vasal endothelium, platelets, and after incubation of
5 minutes at a temperature of 37.degree. C., are capable to release
NO and to activate the cGMP synthesis (Guanosine cyclic
3',5'-(hydrogen phosphate)):
2. Pharmaceutical compositions according to claim 1, wherein the
molar ratio between the components a) and b) varies from 1:0.1 to
1:5.
3. Pharmaceutical compositions according to claim 1, wherein in
component a) the compounds are the following: formula (A):
R--OCH.sub.3, R.sub.1=CH.sub.3, R.sub.2=CH.sub.3, R.sub.3=CH.sub.3,
Omeprazole residue; as in Omeprazole, but with R=OCHF.sub.2,
R.sub.1=OCH.sub.3, R.sub.2=H, Pantoprazole residue; as in
Omeprazole, but with R=H, R.sub.2=H,
R.sub.3=(CH.sub.2).sub.3--OCH.sub.3, Rabeprazole residue; as in
Rabeprazole, but with R.sub.3=CH.sub.2--CF.sub.3, Lansoprazole
residue.
4. Pharmaceutical compositions according to claim 1, wherein the
isomers of one or more compounds of each component are used.
5. Pharmaceutical compositions according to claim 1, wherein said
pharmaceutical compositions comprise organic or inorganic salts of
component a).
6. Pharmaceutical compositions according to claim 1, wherein said
pharmaceutical compositions comprise nitrate salts of component
a).
7. Pharmaceutical compositions according to claim 5, wherein the
salts of component a) contain at least one anion mole/compound
mole.
8. Pharmaceutical compositions according to claim 6, wherein the
salts of component a) contain at least one anion mole/compound
mole.
9. Pharmaceutical compositions according to claim 1, wherein the
organic compounds containing the --ONO.sub.2 groups usable in
component b) are selected from the following ones: clonitrate,
erytrityltetranitrate, mannitol hexanitrate, nicorandyl,
nitroglycerin, pentaerythritoltetranitr- ate, pentrinitrol,
propatylnitrate trolnitrate phosphate and prostaglandin
nitroderivatives.
10. Pharmaceutical compositions according to claim 1 wherein the
inorganic compounds containing the --NO group of component b) are
selected from the following: nitrate salts of alkaline,
earth-alkaline or III group metals and nitroprussiate salts.
11. Pharmaceutical compositions according to claim 10 wherein the
nitrate salts are sodium or potassium nitrate.
12. Pharmaceutical compositions according to claim 1 for oral,
parenteral or transdermic administration.
13. Pharmaceutical compositions according to claim 12 wherein the
component b) is administered contemporaneously, subsequently or
previously to component a).
14. A method of treating a patient with ulcer or dyspepsia
relapses, said method comprising administering a therapeutically
effective amount of the pharmaceutical composition according to
claim 1.
15. Pharmaceutical compositions obtainable by combining the
compositions according to claim 1 with conventional
gastroprotective agents.
16. Compositions according to claim 15 wherein the conventional
gastroprotective agents are selected from prostaglandins, bismuth
salts and antibiotics.
17. A method of treating a patient with ulcer or dyspepsia
relapses, said method comprising administering a therapeutically
effective amount of the pharmaceutical composition according to
claim 15.
18. Pharmaceutical compositions according to claim 2, wherein the
molar ratio between the components a) and b) varies from 1:0.5 to
1:2.
Description
[0001] The present invention relates to compositions to be used in
the therapy and in the prevention of the ulcer relapses and, in
general of the dyspepsias. More particularly it relates to
compositions having an improved gastroprotective activity combined
with an high acid secretion inhibition activity.
[0002] The products known in the art and those commercialized and
used in the ulcer therapy are compounds which perform an
anti-secretory activity (acid secretion inhibition). See for
instance "New Guide to Medicine & Drugs" Brit. Medical Assoc.
Editor, 1997, pages 108-109. Known products having higher
therapeutic efficacy show an high anti-secretory activity and are
used, both in the acute and in the long-term (6 months and more)
therapies. The drawback of these products is that they have a poor
gastroprotective activity, when present. From a practical point of
view this means that the gastric protection is not optimal and
causes inconveniences especially in the long-term therapy. In this
case the presence of frequent relapses due to the enfeeblement of
gastric mucosa is noticed.
[0003] To overcome these inconveniences is is known in the art to
add to said medicaments other anti-ulcer medicaments having a
gastroprotective action: prostaglandins, bismuth salts (e.g.
bismuth citrate) and antibiotics. In such way the removal of
ulcerous pathology is achieved. However these combinations are not
sastisfactory as to their tolerability in general. For example it
is well known that prostglandins produce side effects (diarrhoea)
towards the intestinal tract; bismuth salts frequently produce
nausea and heart-burn. Antibiotics produce undesired
gastrointestinal effects.
[0004] The need was felt to have available compositions active in
the ulcer and gastric dyspesia treatment having improved
therapeutic characteristic and tolerability, general and local, in
particular having an improved gastroprotective activity combined
with an high anti-secretion activity.
[0005] The Applicant has unexpectedly and surprisingly found
pharmaceutical anti-ulcer compositions having an improved
therapeutic activity and tolerability.
[0006] It is an object of the present invention pharmaceutical
compositions comprising as essential components the following:
component a): one or more components selected from the following
classes: 1
[0007] wherein in the (A) class compounds
[0008] R.dbd.H, OCH.sub.3, OCHF.sub.2;
[0009] R.sub.1.dbd.CH.sub.3, OCH.sub.3;
[0010] R.sub.2.dbd.H, CH.sub.3;
[0011] R.sub.3.dbd.CH.sub.3, CH.sub.2--CF.sub.3,
(CH.sub.2).sub.3--OCH.sub- .3;
[0012] wherein in the (2) class compounds:
[0013] R.sup.I.sub.3, R.sup.I.sub.4 equal to or different from each
ocher, are respectively free valence, hydrogen,
--N.dbd.C(NH.sub.2).sub.2, --CH.sub.2--N(CH.sub.3).sub.2;
[0014] Y.dbd.S, N--R.sup.I.sub.6, CR.sup.I.sub.7R.sup.I.sub.8;
[0015] X.dbd.O, S, N--R.sup.I.sub.1;
[0016] R.sup.I.sub.2.dbd.H, CH.sub.3;
[0017] n=0, 1;
[0018] Z=N--CN, N--SO.sub.2NH.sub.2, CH--NO.sub.2 or 2
[0019] R.sup.I.sub.5.dbd.H, --NH--CH.sub.3, NH.sub.2;
[0020] R.sup.I.sub.6, R.sup.I.sub.7, R.sup.I.sub.8, R.sup.I.sub.1,
equal to or different from each other, are hydrogen, free
valence;
[0021] component b): one or more organic compounds containing the
--ONO.sub.2 function, or one or more inorganic compounds containing
the --NO group, or mixtures thereof, said compounds being
characterized in that they are NO nitric oxide donors, i.e. when
they are brought into contact in vitro with cells of the vasal
endothelium, platelets, etc., and after incubation of 5 minutes at
a temperature of 37.degree. C., are capable to release NO and to
activate the cGMP synthesis (Guanosine cyclic 3',5'-(hydrogen
phosphate)), as shown by the used specific tests which will be
described in detail further on.
[0022] The present invention compositions are obtainable by
directly mixing the components a) and b).
[0023] The molar ratio between the components a) and b) can vary
within wide limits, from 1:0.1 to 1:5, preferably from 1:0.5 to
1:2.
[0024] As regards the component a), the preferred (A) compounds are
the following:
[0025] when R.dbd.OCH.sub.3, R.sub.1.dbd.CH.sub.3,
R.sub.2.dbd.CH.sub.3, R.sub.3.dbd.CH.sub.3, Omeprazole residue;
[0026] as in Omeprazole, but with R.dbd.OCHF.sub.2,
R.sub.1.dbd.OCH.sub.3, R.sub.2.dbd.H, Pantoprazole residue;
[0027] as in Omeprazole, but with R.dbd.H, R.sub.2.dbd.H,
R.sub.3.dbd.(CH.sub.2).sub.3--OCH.sub.3, Rabeprazole residue;
[0028] as in Rabeprazole, but with R.sub.3.dbd.CH.sub.2--CF.sub.3,
Lansoprazole residue;
[0029] in component a) the preferred compounds of formula (B) are
the following:
[0030] when in formula (B) X.dbd.N--R.sup.I.sub.1 with
R.sup.I.sub.1 free valence, Y.dbd.N--R.sup.I.sub.6 with
R.sup.I.sub.6.dbd.H, R.sup.I.sub.3.dbd.H, R.sup.I.sub.4 is free
valence and forms with R.sup.I.sub.1 a double bond,
R.sup.I.sub.2.dbd.CH.sub.3, n.dbd.1,
R.sup.I.sub.5.dbd.--NH--CH.sub.3, Z.dbd.N--CN, Cimetidine
residue;
[0031] when X.dbd.N--R.sup.I.sub.1, with R.sup.I.sub.1 free
valence, Y.dbd.S,
[0032] R.sup.I.sub.3.dbd.--N.dbd.C(NH.sub.2).sub.2, R.sup.I.sub.4
is free valence and forms with R.sup.I.sub.1 a double bond,
R.sup.I.sub.2.dbd.H, n.dbd.1 R.sup.I.sub.5.dbd.H, Z=(VII.sub.A),
Ebrotidine residue;
[0033] as in Ebrotidine but with n=0, R.sup.I.sub.5=NH.sub.2 and
Z=N--SO.sub.2NH.sub.2, Famotidine residue;
[0034] as in Ebrotidine but with
R.sup.I.sub.3=--CH.sub.2--N(CH.sub.3).sub- .2,
R.sup.I.sub.5=--NH--CH.sub.3 and
[0035] Z=CH--NO.sub.2, Nizatidine residue;
[0036] as in Nizatidine, but with X=oxygen,
Y=CR.sup.I.sub.7R.sup.I.sub.8 with R.sup.I.sub.7 hydrogen and
R.sup.I.sub.8 free valence, R.sup.I.sub.4 is a free valence and
forms with R.sup.I.sub.9 a double bond, Ranitidine residue.
[0037] In the preparation of the invention compositions also the
isomers of one or more compounds of each component can be used.
[0038] The components belonging to (A) and (B) classes are prepared
according to methods described in "The Merck Index 12.sup.th Ed."
(1996), herein incorporated by reference.
[0039] In the formula (A) compounds of component a) also the
compounds having the following intramolecular ring are comprised,
obtainable by treating the precursors in an acid aqueous medium
(ref. "A Textbook of Drug Design and Development", Harwood academic
publisher, 1991, pag. 140): 3
[0040] wherein N.sup.AI and C.sup.AII are, respectively, the
nitrogen and the carbon atom in 1 and 2 position of the pyridine
ring or formula (A) and C.sup.B2 and N.sup.B3 the carbon and
nitrogen atom, respectively, in 2 and 3 position of the imydazole
ring (1 position of the imydazole ring is that of the proton
nitrogen).
[0041] Instead of the formula (A) and (B) compounds of component a)
the corresponding salts with organic or inorganic salts, obtainable
by reactions known to the skilled in the art, can be used. Examples
of usable inorganic ions are the following: hydrochlorides,
nitrates, sulphates, phosphates, etc.; among the organic ones
maleates, oxalates, acetates, succinates, etc. can be mentioned.
Compositions containing nitrates are preferred.
[0042] The salts with the preferred compounds of the component a)
are those corresponding to the preferred compounds of formula (A)
or (B).
[0043] In the compositions according to the present invention salts
of the compound of the above formulas contain at least one anion
mole/compound mole. Preferably the ratio between the anion and
compound moles is unitary. Salts having a higher molar ratio are
obtained when in the molecule other basic enough aminic groups to
be salified are present.
[0044] For example the salts of the class (A) and (B) compound with
nitric acid are prepared according to the following methods.
[0045] When the substance to be salified is available as free base
or as a corresponding salt soluble in an organic solvent, which
preferably does not contain hydroxyl groups, for example
acetonitrile, ethyl acetate, tetrahydrofuran, etc., the salt is
prepared by dissolving the substance in the solvent at a
concentration preferably equal or higher than 10% w/v, by adding
the amount of concentrated nitric acid corresponding to the moles
of salifiable aminic groups present in the compound. The nitric
acid is preferably diluted in the same solvent. Preferably during
and after the addition the mixture is cooled to temperatures in the
range 20.degree. C.-0.degree. C. The product is generally recovered
by filtration and washed with the solvent.
[0046] When on the contrary the substance is not very soluble, or
it is available as a not very soluble salt in the above mentioned
solvents, the corresponding mixtures with hydroxylated solvents may
be used. Examples of such solvents are methyl alcohol, ethyl
alcohol and water. Precipitation can be quickened by diluting then
the so obtained mixture, after the addition of nitric acid, with an
apolar solvent.
[0047] When the starting product is salified with hydrochloric
acid, it is possible to prepare the nitric acid salt directly
adding silver nitrate to the solution. After filtering silver
chloride, the solution is concentrated and treated as above
indicated to recover the nitrate salt.
[0048] When the starting product is a salt, it is also possible to
liberate the corresponding base by a treatment with a sodium or
potassium bicarbonate or carbonate saturated solution, or with a
sodium or potassium hydroxide diluted solution. The base is then
extracted by a suitable organic solvent (for example halogenated
solvents, esters, ethers), which is then dried. The organic
solution is evaporated and then one proceeds according to the
preceding preperation methods, by dissolving the base in
acetonitrile or in the other above mentioned solvents.
[0049] For the component b), the organic compounds containing the
--ONO.sub.2 groups which can be used are, as an example, the
following, which are reported in The Merck Index 11th Ed. -1989 and
prepared by the known methods, for instance those mentioned in the
same reference, herein incorporated by reference:
[0050] chlonitrate (3-chloro-1,2-propanediol dinitrate) (Merck No.
2390) having the formula C.sub.3H.sub.5ClN.sub.2O.sub.6 and
structural formula 4
[0051] erythrityltetranitrate (1,2,3,4 butantetroltetranitrate)
(Merck No. 3622) having the formula C.sub.4H.sub.6N.sub.4O.sub.12
and structural formula 5
[0052] mannitol hexanitrate (Merck No. 5630) having the formula
C.sub.6H.sub.5N.sub.6O.sub.18 and structural formula 6
[0053] nicorandyl (N-[2-(nitroxy)ethyl]-3-pyridine-carboxamide)
(Merck No. 6431) having the formula C.sub.9H.sub.9N.sub.3C.sub.4
and structural formula 7
[0054] nitroglycerin (1,2,3 propanetriol trinitrace) (Merck No.
6528) having the formula C.sub.3H.sub.5N.sub.3O.sub.9 and
structural formula 8
[0055] pentaerythritoltetranitrate
(2,2-bis[(nitroxy)-methyl]-1,3-propaned- ioldinitrate) (Merck No.
7066) having the formula C.sub.5H.sub.8N.sub.4O.s- ub.12 and
structural formula 9
[0056] pentrinitrol
(2,2-bis[(nitroxy)methyl]-1,3-propanediolmononitrate) (Merck No.
7094) having the formula C.sub.5H.sub.9N.sub.3O.sub.10 and
structural formula 10
[0057] propatylnitrate
(2-ethyl-2-[(nitroxy)methyl]-1,3-propanedioldinitra- te) (Merck No.
7821) having the formula C.sub.6H.sub.11N.sub.3O.sub.9 and
structural formula 11
[0058] trolnitratephosphate (2,2',2"-nitryltrisethanoltrinitrate
phosphate) (1:2 salt) (Merck No. 9682) having the formula
C.sub.6H.sub.18N.sub.4O.sub.17P.sub.2 and structural formula 12
[0059] Other compounds containing the --ONO.sub.2 group which can
be used are prostglandin nitroderivatives described in the PCT/EP
Application 98/03645 in the Applicant's name. This patent
application is herein incorporated by reference both for compounds
and preparation processes.
[0060] Among the inorganic compounds containing the --NO group can
be mentioned:
[0061] nitrate salts of alkaline, earth-alkaline or III group
metals, for example with aluminum, sodium and potassium nitrates
are preferred;
[0062] nitroprussiate salts, such as for example:
sodiumnitroprussiate (pentakis
(cyano-C)nitrosylferrate(2-)disodium) (Merck No. 8600), having the
formula Na.sub.2[Fe(CN).sub.5NO].
[0063] The invention components b) containing the --ONO.sub.2
groups or the --NO group which produce the invention results, as
already said, must meet the test in vitro described in detail
hereinunder.
[0064] Specifically the test relates to the nitric oxide generation
from the NO-donors described in the present invention, among which,
for instance nitroglicerin, nicorandyl, nitroprussiate, etc., when
they are put in the presence of endothelial cells (method a) or
platelets (method b):
[0065] a) Endothelial Cells
[0066] Cells of the human umbilical vein, spread on plate, with a
10.sup.3 cells/plate density have been incubated with scalar
concentrations of NO-donor (1-100 .mu.g/ml) for 5 minutes. The
incubation medium (physiologic solvent, for example Tyrode) has
been then analyzed to determine the capability to generate NO,
by:
[0067] 1) the nitric oxide disclosure by chemiluminiscence;
[0068] 2) cGMP determination (cyclic GMP No. 2715 of the above
mentioned Merck).
[0069] As regards the chemiluminiscence analysis, an amount
equivalent to 100 .mu.l was injected in the reaction chamber of a
chemiluminiscence analyzer containing glacial acetic acid and
potassium iodide. Nitrites/nitrates present in the medium under
these conditions are converted into NO which is then determined
after its reaction with ozone, with consequent light generation. As
it usually occurs in the devices measuring the chemiluminiscence,
the produced luminiscence is directly proportional to the generated
NO levels and can be measured by the suitable photomultiplier unit
of a chemiluminiscence analyzer.
[0070] The photomultiplier converts the incident light into
electric voltage, which is then quantitatively recorded. On the
basis of a calibration curve, prepared with scalar nitrite
concentrations, it was possible to quantitatively determine the
generated NO concentration. For example, from the incubation of 100
.mu.M of nicorandyl, an amount equal to about 10 .mu.M of NO was
generated.
[0071] As regards the cGMP determination, a portion of the
incubation medium (equal to 100 .mu.l) was centrifuged at 1000
revolutions per 20 seconds. The supernatant was discharged and the
sediment treated with iced phosphate buffer (pH 7,4). The cGMP
level produced were tested, by specific immuno-enzymatic reactants.
From such experiments it resulted that, under these experimental
conditions, the incubation with one of the various tested NO-donors
caused a significant cGMP increase with respect to the values
obtained in absence of a NO donor. For example, after incubation
with 100 .mu.M of sodium nitroprussiate, an increase of about 20
times the value obtained with the incubation of only the vehicle
without NO donor was recorded.
[0072] b) Platelets
[0073] Washed human platelets, prepared analogously with what
described by Radomski et al, (Br.J. Pharmacol. 92, 639-1987), were
used. 0.4 ml aliquots were incubated with scalar NO-donor
concentrations (1-100 .mu.g/ml) for 5 minutes. The incubation
medium (e.g. Tyrode) was then analyzed to determine the capability
to generate NO, by determination of nitric oxide by
chemiluminiscence and cGMP, with the modalities described in the
previous paragraph, for the analyses carried out on the endothelial
cells. As to the determination by chemiluminiscence, also in this
case, on the basis of a calibration curve, prepared with scalar
nitrite concentrations, it was possible to quantitatively determine
the generated NO concentration. For example, after incubation of
100 .mu.M of nicorandyl, an amount equal to 35 82 M of NO was
generated.
[0074] As regards the cGMP determination, also in these
experimental conditions it resulted that the incubation with one of
the various NO-donors tested caused a cGMP significant increase
with respect to the values obtained in absence of a NO-donor. For
example, after incubation with 100 .mu.M of sodium nitroprussiate,
an increase of about 30 times the value obtained with the
incubation of only the vehicle without NO-donor was recorded.
[0075] In conclusion, from said tests it results that all the
NO-donors according to the present invention, after incubation with
endothelial cells or platelets for 5 minutes, are capable to
generate NO, and to activate the cGMP synthesis in a
concentration-depending way, as Determined by the used specific
tests.
[0076] It has now surprisingly been found that the present
invention compositions allow to improve, compared with the known
above mentioned combinations, the total pharmaco-toxi-cological
behaviour of the compounds forming the component a), increasing the
therapeutic efficacy and their general and local tolerability in
the ulcer and gastric dyspepsia treatment, with improved
gastroprotective activity.
[0077] The present invention compositions are formulated in the
corresponding pharmaceutical compositions according to well known
techniques in the field together with the conventional excipients;
see for example the volume "Remington's Pharmaceutical Sciences 15a
Ed."
[0078] The administering of the present invention compositions can
be carried out by oral, parenteral or transdermic way. The
component b) can generally be administered contemporaneously,
subsequently or previously to the component a). The (A) and (B)
compound doses of component a) are the conventional ones for these
compounds.
[0079] It is a further object of the invention compositions
obtainable by combining the pharmaceutical compositions according
to the present invention with conventional gastroprotective agents.
As examples, prostaglandins, bismuth salts, active antibiotics
towards pathogenic microorganisms in the gastrointestinal mucosa
can be mentioned.
[0080] It has surprisingly been found that the gastroprotective
activity of the invention compositions is very high. This makes it
possible to avoid the undesired effects of known gastroprotectives
when they are used in combination with compounds or formulations of
the invention compounds. It has indeed been found that the amount
of the known gastroprotective agents, in the combination of the
invention, is lower compared with those known and does not cause
undesirable side effects. The skilled in the field is able to
easily determine the maximum amount of conventional
gastroprotective agents to be combined with the invention
pharmaceutical compositions, since this corresponds to the absence
of typical side effects of the known gastroprotective agents. In
any case the amount of conventional gastroprotective agents to be
used in the combination is lower than that used in combinations
described in the art.
[0081] The following examples have the purpose to illlustrate the
invention and must not be considered as limitative of the same.
EXAMPLE 1
[0082] Pharmaceutical Composition
[0083] Mixture formed by:
1 Component a) cimetidine 50 g. componente b) KNO.sub.3 20 g.
[0084] Amounts of this mixture corresponding to 70 mg/kg, or
multiples, to be supplied to animals, are then weighed.
[0085] Pharmacological Tests
EXAMPLE 2
[0086] Acute Toxicity
[0087] To a group of 10 rats weighing 20 g each a single dose equal
to 280 mg/kg of the Example 1 composition was supplied by oral way
in a carboxymethylcellulose aqueous suspension 2% w/v.
[0088] The animals are kept under obsevation for 14 days. In no one
of the group animals the toxic syntom presence was noticed.
EXAMPLE 3
[0089] Anti-Ulcer Activity
[0090] The anti-ulcer activity is evaluated according to the
experimental model described in the paper of A. Robert et Al.
"Cytoprotection by prostaglandins in rats. Prevention of gastric
necrosis produced by alcohol, HCl, NaOH, hypertonic NaCl and
thermal injury" Gastroenterology 77, 433-43 1979.
[0091] To 3 groups of 10 rats each, kept with empty stomach since
the previous night, 15 minutes before the supply of absolute
ethanol (1 ml), by oral way are supplied:
[0092] 5 ml/Kg of carboxymethylcellulose aqueous suspension 2%.
[0093] 50 mg/Kg of cimetidine in 5 ml/Kg of carboxymethylcellulose
aqueous suspension 2%.
[0094] 70 mg/Kg of the Example 1 composition in 5 ml/Kg of
carboxymethylcellulose aqueous suspension 2%.
[0095] One hour later the animals are sacrificed and the gastric
lesion incidence is evaluated. The results are reported in Table 1
and they show that the combination cimetidine and potassium nitrate
shows an improved gastroprotective activity with respect to
cimetidine.
2 TABLE I Gastric Damage Treatment (%) Vehicle 100 Cimetidine 50
mg/Kg 100 Composition Ex. 1 70 mg/Kg 60
* * * * *