U.S. patent application number 09/964442 was filed with the patent office on 2002-03-28 for orally administrable acid stable antiulcer benzimidazole derivatives.
This patent application is currently assigned to KOPRAN RESEARCH LABORATORIES LIMITED. Invention is credited to Deshpande, Jayant, Gupte, Rajan, Mali, Subhash, Ranbhan, Kamlesh.
Application Number | 20020038032 09/964442 |
Document ID | / |
Family ID | 11076226 |
Filed Date | 2002-03-28 |
United States Patent
Application |
20020038032 |
Kind Code |
A1 |
Mali, Subhash ; et
al. |
March 28, 2002 |
Orally administrable acid stable antiulcer benzimidazole
derivatives
Abstract
Orally administrable acid stable anti-ulcer benzimidazole
derivatives which are polymer based. The process of preparation
comprises condensing a benzimidazole with a biocompatible partially
orally biodegradable synthetic cross linked polymer in aqueous
medium at 5.degree.-80.degree. C. and pH 4-11 under inert
atmosphere. The weight percentage of benzimidazole with respect to
the polymeric benzimidazole is 1-50. The reaction mixture is cooled
and the product is isolated and dried at 25.degree.-45.degree. C.
There is also provided a formulation of the polymeric
benzimidazoles in combination with pharmaceutically acceptable
excipients.
Inventors: |
Mali, Subhash; (Navi Mumbai,
IN) ; Gupte, Rajan; (Navi Mumbai, IN) ;
Deshpande, Jayant; (Navi Mumbai, IN) ; Ranbhan,
Kamlesh; (Navi Mumbai, IN) |
Correspondence
Address: |
GREENBLUM & BERNSTEIN, P.L.C.
1941 ROLAND CLARKE PLACE
RESTON
VA
20191
US
|
Assignee: |
KOPRAN RESEARCH LABORATORIES
LIMITED
Maharashtra
IN
|
Family ID: |
11076226 |
Appl. No.: |
09/964442 |
Filed: |
September 28, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
09964442 |
Sep 28, 2001 |
|
|
|
PCT/IN00/00016 |
Feb 24, 2000 |
|
|
|
Current U.S.
Class: |
546/256 |
Current CPC
Class: |
A61K 31/787 20130101;
A61P 1/04 20180101 |
Class at
Publication: |
546/256 |
International
Class: |
C07D 43/14 |
Claims
1. Orally administrable acid stable anti-ulcer benzimidazole
derivatives of the formula I: 16wherein R.sub.6=H or CH.sub.3,
X=--OCOCH.sub.2COO--, 17or --CONHCH.sub.2NHCO--, R.sub.7=H,
CH.sub.3, C.sub.2H.sub.5 or CONH.sub.2, Y=OH or NH.sub.2,
E=--COO--, B is benzimidazole moiety of the formula IIA: 18wherein
each of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5=H, C.sub.1-12
alkyl C.sub.6-12 (un)substituted aryl, C.sub.1-8 alkoxy, C.sub.6-12
aryloxy, C.sub.1-5 alkoxy carbonyl, C.sub.6-12 aryloxy carbonyl,
C.sub.1-5 alkoxy alkyl, C.sub.6-12 alkoxyaryl, C.sub.1-5 haloalkyl,
C.sub.1-5 alkyl, C.sub.1-5 haloalkoxy alkyl or C.sub.6-12 aryl
thioethers, (un)substituted amines or diamines, (un)substituted
amides, halo, cyano, nitro, carboxylic acid or carbocyclic or O, N,
S containing heterocyclic ring systems or enantiomers thereof; and
pharmaceutically acceptable acid addition salts thereof.
2. Polymeric benzimidazoles as claimed in claim 1, wherein the
benzimidazole moiety is omeprazole.
3. Polymeric benzimidazoles as claimed in claim 1, wherein the
benzimidazole moiety is lansoprazole.
4. Polymeric benzimidazoles as claimed in claim 1, wherein the
benzimidazole moiety is pantoprazole.
5. A process for the preparation of orally administrable acid
stable anti-ulcer benzimidazole derivatives of the formula I:
19wherein R.sub.6=H or CH.sub.3, X=--OCOCH.sub.2COO--, or
--CONHCH.sub.2NHCO--, R.sub.7=H, CH.sub.3, C.sub.2H.sub.5 or
CONH.sub.2, Y OH or NH.sub.2, E=--COO--, B is benzimidazole moiety
of the formula IIA: 20wherein each of R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.5=H, C.sub.1-12 alkyl, C.sub.6-12 (un)substituted
aryl, C.sub.1-8 alkoxy, C.sub.6-12 aryloxy, C.sub.1-5 alkoxy
carbonyl C.sub.6-12 aryloxy carbonyl, C.sub.1-5 alkoxy alkyl,
C.sub.6-12 alkoxyaryl, C.sub.1-5 haloalkyl, C.sub.1-5 alkyl,
C.sub.1-5 haloalkoxy alkyl or C.sub.6-12 aryl thioethers,
(un)substituted amines or diamines, (un)substituted amides, halo,
cyano, nitro, carboxylic acid or carbocyclic or O, N, S containing
heterocyclic ring system or enantiomers thereof and
pharmaceutically acceptable acid addition salts thereof, the
process comprising: a) condensing a benzimidazole of the formula
II: 21wherein each of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5
is as defined above, with a biocompatible partially orally
biodegradable synthetic cross linked polymer of the formula III:
22wherein R.sub.6, R.sub.7, X and E each is as defined above and
Y'=O or N, in aqueous medium at 5.degree.-80.degree. C. and pH 4-11
under inert atmosphere and stirring; the weight percentage of the
benzimidazole with respect to the conjugate being 1-50; b) cooling,
isolating and drying the resulting polymeric benzimidazole at
25.degree.-45.degree. C.; and c) if desired, converting the
polymeric benzimidazole into pharmaceutically acceptable acid
addition salts.
6. A process as claimed in claim 5, wherein the benzimidazole is
omeprazole.
7. A process a claimed in claim 5, wherein the benzimidazole is
lansoprazole.
8. A process as claimed in claim 5, wherein the benzimidazole is
pantoprazole.
9. A process as claimed in claim 5, wherein the weight percentage
of the benzimidazole with respect to the conjugate is 20.
10. A process as claimed in claim 5, wherein the condensation
temperature is 30.degree. C.
11. A process as claimed in claim 5, wherein the condensation pH is
6-11.
12. A process as claimed in claim 5, wherein the isolation is
carried out by filtration.
13. A process as claimed in claim 5 wherein the drying is carried
out in a tray dryer at 30.degree.-50.degree. C.
14. A formulation of orally administrable acid stable anti-ulcer
benzimidazole derivatives of the formula I: 23wherein R.sub.6=H or
CH.sub.3, X=--OCOCH.sub.2COO--, or --CONHCH.sub.2NHCO--, R.sub.7=H,
CH.sub.3, C.sub.2H.sub.5 or CONH.sub.2, Y=OH or NH.sub.2,
E=--COO--, B is benzimidazole moiety of the formula IIA: 24wherein
each of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5=R C.sub.1-12
alkyl C.sub.6-12 (un)substituted aryl, C.sub.1-8 alkoxy, C.sub.6-12
aryloxy, C.sub.1-5 alkoxy carbonyl, C.sub.6-12 aryloxy carbonyl,
C.sub.1-5 alkoxy alkyl C.sub.6-12 alkoxyaryl, C.sub.1-5 haloalkyl,
C.sub.1-5 alkyl, C.sub.1-5 haloalkoxy alkyl or C.sub.6-12 aryl
thioethers, (un)substituted amines or diamines, (un)substituted
amides, halo, cyano, nitro, carboxylic acid or carbocyclic or O, N,
S containing heterocyclic ring systems or enantiomers thereof; and
pharmaceutically acceptable acid addition salts thereof in
combination with pharmaceutically acceptable excipients.
15. A formulation as claimed in claim 14, wherein the benzimidazole
moiety is omeprazole.
16. A formulation as claimed in claim 14, wherein the benzimidazole
moiety is lansoprazole.
17. A formulation as claimed in claim 14, wherein the benzimidazole
moiety is pantoprazole.
Description
[0001] "This is a continuation of International Application No.
PCT/IN 00/00016, filed Feb. 24, 2000, the contents of which are
expressly incorporated by reference herein in its entirety. The
International Application is not published and will be published
under PCT Article 21(2) in English."
TECHNICAL FIELD
[0002] The benzimidazole derivatives are polymeric benzimidazoles
of the formula 1: 1
[0003] wherein R.sub.6H or CH.sub.3, X=--OCOCH.sub.2COO--, 2
[0004] or --CONHCH.sub.2NHCO--, R.sub.7=H, CH.sub.3, C.sub.2H.sub.5
or CONH.sub.2, Y=OH or NH.sub.2, E=--COO--, B is benzimidazole
moiety of the formula IIA: 3
[0005] wherein each of R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.5=H, C.sub.1-12 alkyl, C.sub.6-1.sub.2 (un)substituted aryl
C.sub.1-8 alkoxy, C.sub.6-12 aryloxy, C.sub.1-5 alkoxy carbonyl
C.sub.6-12 aryloxy carbonyl, C.sub.1-5 alkoxy alkyl, C.sub.6-12
alkoxyaryl, C.sub.1-5 haloalkyl, C.sub.1-5 alkyl, C.sub.1-5
haloalkoxyl alkyl or C.sub.6-12 aryl thioethers, (un) substituted
amines or diamines, (un)substituted amides, halo, cyano, nitro,
carboxylic acid or carbocyclic or O, N, S containing heterocyclic
ring systems or enantiomers thereof.
[0006] This invention also relates to pharmaceutically acceptable
acid addition salts of the acid stable antiulcer polymeric
benzimidazoles, process for the preparation thereof and formulation
comprising the same.
[0007] The compounds of the invention on oral administration
inhibit exogenously or endogenously stimulated gastric acid
secretion and thus may be used in the treatment/prevention of
peptic ulcers, gastro intestinal inflammatory diseases like
duodenal/gastric ulcer or gastritis or other gastro intestinal
disorders.
BACKGROUND ART
[0008] Antiulcer benzimidazoles of the formula II: 4
[0009] wherein each of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5
is as defied above, are known to be unstable at neutral or acidic
pH of the gastric fluid and undergo decomposition in
gastrointestinal fluid on oral administration resulting in loss of
activity. Therefore, these compounds are not directly orally
ingested. Instead, they are formulated for use by enteric coating
or by N-substitution with non-polymeric substituents followed by
enteric coating [U.S. Pat. Nos. 4,045,563, 5,039,806 and 5,948,773,
PCT Publications Nos WO 95/32957, WO 94/27988 and WO 91/19711, EP
Patents Nos 176308 and 0045200 and J. Med. Chem., 34,1049(1991)
John Sih et al].
[0010] Enteric coated formulations in the form of tablet comprise
an initial barrier coating on the active with polymers such as
hydroxy propyl methyl cellulose, polyvinyl pyrrolidone or the like,
followed by acid resistant coating with polymers such as cellulose
acetate phthalate, hydroxy propyl methyl phthalate, polyvinyl
acetate phthalate or copolymer of methacrylic acid and ethyl
acrylate. The method of preparing enteric coated tablets involves
provision of multiple coatings and numerous unit operations such as
communition, blending, pelletisation, pan coating, drying, spray
coating and/or fluid bed coating/drying because of which it is
cumbersome, time consuming and expensive. Benzimidazole actives
being sensitive to light, moisture and organic solvents such as
dichloromethane, acetone or isopropyl alcohol there are chances of
decomposition of the actives during pelletisation thereof. The
biologically active compound from such enteric coated formulation
is directly released in neutral pH in the intestinal fluid
bypassing contact with acidic gastric fluid, where a good
percentage of the active is decomposed due to its instability in
neutral pH. Thus the bioavailabilty of benzimidazole actives from
enteric coated formulations thereof is low. Anti-ulcer
benzimidazoles are not known or reported to have been formulated
into other oral dosage forms such as syrup or suspension.
[0011] Bioactives other than benzimidazoles covalently conjugated
with synthetic polymers directly or through a reactive functional
group are known and reported. For example, progesterone has been
conjugated with aliphatic polyesters such as
poly-[.epsilon.-Caprolactone), poly-[.epsilon.-(+,-)-Calactone],
polypivalolactone and poly-(+,-)-dilactide through an ester linkage
[(Biomed. Mater. Res, Pitt et al, 1969, 13, 497); (Polymer
conjugates with Anticancer Activity, Advances in Polymer Science, D
Putnam et al., 1995, Vol 122, page 55-123, Springer Verlag
Berline)]. These polymer-conjugates are administered by subdermal
route.
[0012] U.S. Pat. No. 4,587,046 describes covalent conjugation of
naturally occuring catecholamines and autocoid moieties with
monodisperse amino acid polymers or peptides having an alkyl group
through ester/amide linkages. These conjugates are administered
parenterally.
[0013] U.S. Pat. No. 5,783,178 describes conjugation of actives
like vinca alkaloids, mitomycims, bleomycins, fluconazole,
amphotericin B, paclitaxel derivatives, cytokines, erythroprotein
or polynucleotides with block copolymer of ethyleneoxy monomer or a
mixture of ethyleneoxy and the --OCH(CH)CH.sub.2-- monomers through
bifunctional linking group. Tris system is mainly used as targeted
drug delivery system.
[0014] U.S. Pat. No. 5,510,418 describes covalent conjugation of
glycosaminoglycan with polyethylene glycol through an ether linkage
and is useful for hard/soft tissue augmentation. These
polymer-conjugates are to be administered by parenteral route.
[0015] Biphenylamine derivatives have been conjugated with
polymethacrylic acid. Release of the biphenyl amine derivative from
the conjugate was reported only after intraperitoneal
injection.
[0016] U.S. Pat. No. 5,889,078 describes conjugates of biologically
active compounds such as cytostatic fluoro uracil with homopolymer
of acrylic acids through ester or amide linkages. These polymer
conjugates are mainly used as drug delivery system by parenteral
route wherein the polymeric backbone after release of the
bioactives is difficult to be excreted from the biological
system.
[0017] U.S. Pat. No. 5,037,883 describes conjugate of active such
as anticancer daunomycin with copolymer of N-(2-hydroxypropyl)
acrylamide, N-methacrylamide, N-methacrylic acid and/or
N-methacryloylated amino acid through peptide group. These
polymer-conjugates are administered by parenteral route.
[0018] U.S. Pat. No.5,976,527 describes conjugates of proteins such
as albumin, immunoglobulins, blood clotting factors and peptide
hormones with polmethylmethacrylate or polymeth acrylamide
comprising reactive oxirane groups, which after immobilisation are
used for interaction with biological systems. These conjugate
systems are mainly used for diagnostic purposes and as sorbents for
pollutants.
[0019] Benzimidazole compounds substituted with polymer at the
nitrogen thereof are not known or reported.
OBJECTS OF INVENTION
[0020] An object of the invention is to provide orally
adininistrable acid stable anti-ulcer benzimidazole derivatives and
pharmaceutically acceptable salts thereof, having increased
bioavailability.
[0021] Another object of the invention is to provide orally
administrable acid stable anti-ulcer benzimidazole derivatives and
pharmaceutically acceptable salts thereof, which are not enteric
coated.
[0022] Another object of the invention is to provide orally
administrable acid stable anti-ulcer benzimidazole derivatives and
pharmaceutically acceptable salts thereof which have activity
comparable to unsubstituted benzimidazoles.
[0023] Another object of the invention is to provide orally
administrable acid stable anti-ulcer benzimidazole derivatives and
pharmaceutically acceptable salts thereof which me capable of being
clinically used.
[0024] Another object of the invention is to provide a process for
the preparation of orally administrable acid stable anti-ulcer
benzimidazole derivatives and pharmaceutically acceptable salts
thereof which results in products having increased
bioavailability.
[0025] Another object of the invention is to provide a process for
the preparation of orally administrable acid stable anti-ulcer
benzimidazole derivatives and pharmaceutically acceptable salts
thereof, which results in products that are not enteric coated and
is therefore simple, less time consuming less expensive, easy and
convenient to carry out.
[0026] Another object of the invention is to provide a process for
the preparation of orally administrable acid stable anti-ulcer
benzimidazole derivatives and pharmaceutically acceptable salts
thereof, which results in products having activity comparable to
the unsubstituted benzimidazoles.
[0027] Another object of the invention is to provide a process for
the preparation of orally administrable acid sable anti-ulcer
benzimidazole derivatives and pharmaceutically acceptable salts
thereof, which results in products capable of being used
clinically.
[0028] Another object of the invention is to provide a formulation
of orally administrable acid stable anti-ulcer benzimidazole
derivatives and pharmaceutically acceptable salts thereof, having
increased bioavailability.
[0029] Another object of the invention is to provide a formulation
of orally administrable acid stable anti-ulcer polymeric
benzimidazoles and pharmaceutically acceptable salts thereof, which
are not enteric coated.
[0030] Another object of the invention is to provide a formulation
of orally administrable acid stable anti-ulcer benzimidazole
derivatives and pharmaceutically acceptable salts thereof, which
have activity comparable to the unsubstituted benzimidazoles.
[0031] Another object of the invention is to provide a formulation
of orally administrable acid stable anti-ulcer benzimidazole
derivatives and pharmaceutically acceptable salts thereof which are
capable of being used clinically.
DISCLOSURE OF THE INVENTION
[0032] According to the invention there is provided orally
administrable acid stable anti-ulcer benzimidazole derivatives of
the Formula I 5
[0033] wherein R.sub.6=H or CH.sub.3, X=--OCOCH.sub.2COO--, 6or
CONHCH.sub.2NHCO--, R.sub.7=H, CH.sub.3, C.sub.2H.sub.5 or
CONH.sub.2, Y=OH or NH.sub.2, E=--COO--, B is benzimidazole moiety
of the formula IIA: 7
[0034] wherein each of R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.5=H, C.sub.1-12 alkyl, C.sub.6-12 (un)substituted aryl,
C.sub.1-8 alkoxy; C.sub.6-12 aryloxy, C.sub.1-5 alkoxy carbonyl,
C.sub.6-12 aryloxy carbonyl C.sub.1-5 alkoxy alkyl, C.sub.6-12
alkoxyaryl, C.sub.1-5 haloalkyl C.sub.1-5 alkyl, C.sub.1-5
haloalkoxy alkyl or C.sub.6-12 aryl thioethers, (un) substituted
amines or diamines (un)substituted amides, halo, cyano, nitro,
carboxylic acid or carbocyclic or O, N, S containing heterocyclic
ring systems or enantiomers thereof, and pharmaceutically
acceptable acid addition salts thereof.
[0035] According to the invention there is also provided a process
for the preparation of orally adininistrable acid stable anti-ulcer
benzimidazole derivatives of the formula I: 8
[0036] wherein R.sub.6=H or CH.sub.3, X=--OCOCH.sub.2COO--, 9
[0037] or --CONHCH.sub.2NHCO--, R.sub.7=H, CH.sub.3, C.sub.2H.sub.5
or CONH.sub.2, Y=OH or NH.sub.2, E=--COO--, B is benzimidazole
moiety of the formula IIA: 10
[0038] wherein each of R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.5=H, C.sub.1-12 alkyl, C.sub.6-12 (un)substituted aryl,
C.sub.1-8 alkoxy, C.sub.6-12 aryloxy, C.sub.1-5 alkoxy carbonyl,
C.sub.6-12 aryloxy carbonyl, C.sub.1-5 alkoxy alkyl, C.sub.6-12
alkoxyaryl, C.sub.1-5 haloalkyl, C.sub.1-5 alkyl, C.sub.1-5
haloalkoxy alkyl or C.sub.6-12 aryl thioethers, (un)substituted
amines or diamines, (un)substituted amides, halo, cyano, nitro,
carboxylic acid or carbocyclic or O, N, S containing heterocyclic
ring systems or enantiomers thereof; and pharmaceutically
acceptable acid addition salt, thereof, the process comprising:
[0039] a) condensing a benzimidazole of the formula II: 11
[0040] wherein each of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5
is defined above, with a biocompatible partially orally
biodegradable synthetic cross linked polymer of the formula III:
12
[0041] wherein R.sub.6, R.sub.7, X and E each is as defined above
and Y'=O or N, in aqueous medium at 5.degree.-80.degree. C. and pH
4-11 under inert atmosphere and stirring the weight percentage of
the benzimidazole with respect to the conjugate being 1-50;
[0042] b) cooling, isolating and drying the resulting polymeric
benzimidazole at 25.degree.-45.degree. C.; and
[0043] c) if desired, converting the polymeric benzimidazole into
pharmaceutically acceptable acid addition salts.
[0044] According to the invention, there is also provided a
formulation of orally administrable acid stable anti-ulcer
benzimidazole derivatives of the formula I: 13
[0045] wherein R.sub.6=H or CH.sub.3, X=--OCOCH.sub.2COO--, 14
[0046] or --CONHCH.sub.2NHCO--, R.sub.7=H, CH.sub.3, C.sub.2H.sub.5
or CONH.sub.2, Y=OH or NH.sub.2, E=--COO--, B is benzimidazole
moiety of the formula IIA: 15
[0047] wherein each of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5
=H C.sub.1-12 alkyl, C.sub.6-12 (un)substituted aryl, C.sub.1-8
alkoxy, C.sub.6-12 aryloxy, C.sub.1-5 alkoxy carbonyl C.sub.6-12
aryloxy carbonyl, C.sub.1-5 alkoxy alkyl, C.sub.6-12 alkoxyaryl,
C.sub.1-5 haloalkyl, C.sub.1-5 alkyl C.sub.1-5 haloalkoxy alkyl or
C.sub.6-12 aryl thioethers, (un)substituted amines or diamines,
(un) substituted amides, halo, cyano, nitro, carboxylic acid or
carbocyclic or O, N, S containing heterocyclic ring systems or
enantiomers thereof, and pharmaceutically acceptable acid addition
salts thereof, in combination with pharmaceutically acceptable
excipients.
[0048] The compounds of the formula II may be racemic or
enantiomeric.
[0049] Preferably the compound of the formula II may be
5-methoxy-2[(4-methoxy-3,5-dimethyl-2-pyridinyl)sulfinyl]-1H-benzimidazol-
e i.e. lansoprazole, wherein R.sub.1=CH.sub.3, R.sub.2=OCH.sub.3,
R.sub.3=CH.sub.3 R=OCH.sub.3, R.sub.5=H; or 5-(difluoro
methoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole
ie pantoprazole, wherein R.sub.1=H, R.sub.2=OCH.sub.3,
R.sub.3=OCH.sub.3, R.sub.4=OCHF.sub.2, R.sub.5=H; or
2[[[3-methyl-4-(2,2,2-trifluoroethoxy)--
2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole ie lansoprazole,
wherein R.sub.1=H, R.sub.2=OCH.sub.2CF.sub.3, R.sub.3=CH.sub.3,
R.sub.4=H, R.sub.5=H. The polymers may be formed in known maimer by
polymerisation of monomers such as acrylic acid, substituted
acrylic acids, acrylamide, substituted acrylamides, acrylonitrile,
substituted acrylonitriles, esters of acrylic or substituted
acrylic acids, styrene, vinyl styrene, vinyl anhydride or
derivatives thereof, preferably acrylic acid, methacrylic acid,
acrylamide, methacrylamide, acrylonitrile, ethyl acrylate, methyl
acrylate, butyl acrylate, hydroxyethylmethyl acrylate or
2-hexylethylmethacrylate.
[0050] Preferably Y' in the polymer of the formula III is oxygen
atom and Y in the polymeric benzimidazole of the formula 1 is
hydroxyl group.
[0051] Pharmaceutically acceptable acid addition salts of the
conjugate may be hydrochloride, hydrobromide, hydroiodide, sulfate,
phosphate, nitrate, perchlorate, formate, acetate, propionate,
succinate, glycolate, lactate, tartarate, citrate, ascorbate,
piruvate or alginate prepared in a known manner by treating the
polymeric benzimidazole with acid such as hydrochloric acid,
hydrobromic acid, hydroiodic acid, sulphuric acid, phosphoric acid,
nitric acid, perchloric acid, formic acid, acetic acid, propionic
acid, succinic acid, glycolic acid, lactic acid, tartaric acid.
citric acid, ascorbic acid, pyruvic acid, or alginic acid
respectively.
[0052] The weight percentage of the benzimidazole of the formula II
may be preferably 20% with respect to the conjugate.
[0053] The condensation pH may be preferably 6-11.
[0054] The temperature for condensation may be preferably
10.degree.-40.degree. C.
[0055] Isolation of the polymeric benzimidazole may be by
filtration, decantation or centrifugation, preferably
filtration.
[0056] The polymeric benzimidazole may be dried in a tray dryer or
vacuum tray dryer, preferably tray dryer, preferably at
30.degree.-50.degree. C.
[0057] The excipients may be lactose, magnesium stearate, methyl
cellulose, distilled water, microcrystalline cellulose,
maltodextrin, glycerin, flavouring agents or other excipients known
in the aft.
[0058] The polymeric benzimidazoles of the invention are novel and
are found to be acid stable due to the polymeric N-substitution.
Therefore, they do not disintegrate in the gastrointestinal fluid
ad are suitable for oral administration without enteric coating.
Since they do not disintegrate in the gastrointestinal fluid, their
bioavailability is increased as compared to enteric coated
benzimidazoles and their activities are comparable to those of
unsubstituted benzimidazoles. Because the process for the
preparation of the compounds of the invention eliminates enteric
coating, it is simple, less time consuming, less expensive, easy
and convenient to carry out. Upon oral administration, under the
influence of enzymes/chemicals in the gastrointestinal fluid, the
polymeric benzimidazole cleaves at the hydrolysable group (E) to
release a N-substituted benzimidazole derivative (ie the
benzimidazole along with a part of the polymer) having anti-ulcer
activity. The remaining part of the polymer is inert, non-toxic and
non-absorbable in the gastro intestinal fluid and is excreted from
the body as such or as nonabsorbable metabolites thereof Therefore
the polymeric benzimidazole conjugates of the invention are safe
for clinical use. The polymeric benzimidazoles of the invention may
be formulated into tablets or capsules besides other oral dosage
forms such as syrup or suspension.
[0059] The following experimental examples are illustrative of the
invention but not limitative of the scope thereof.
EXAMPLE 1
[0060] The copolymer (5.0 g) prepared using acrylonitrile, glycidyl
acrylate and glycol dimethacrylate was mixed with omeprazole [1.25
g] dissolved in aqueous medium at pH 9.5. The reaction mixture was
stirred at 30.degree. C. for 18 hours. The product was filtered
washed with water (100 ml.times.5) aid dried under vacuum at
45.degree. C. for 12 hours to obtain 6.1 g of the
polymer-substituted omeprazole.
EXAMPLE 2
[0061] The copolymer (5.0 g) prepared using glycidyl methacrylate
and acrylamide was mixed with omeprazole (1.25 g) dissolved in
aqueous medium at pH 9.8. The reaction mixture was stirred at
30.degree. C. for 18 hours. The product was filtered washed with
water (100 ml.times.5) and dried under vacuum at 45.degree. C. for
12 hours to obtain 5.92 g of the polymer-substituted
omeprazole.
EXAMPLE 3
[0062] The copolymer (5.0 g) prepared using glycidyl methacrylate
and glycol dimethacrylate was mixed with omeprazole (1.25 g)
dissolved in aqueous madium at pH 10.4. The reaction mixture was
stirred at 30.degree. C. for 18 hours. The product was filtered
washed with water (100 ml.times.5) and dried under vacuum at
45.degree. C. for 12 hours to obtain 6.05 g of the
polymer-substituted omeprazole.
EXAMPLE 4
[0063] The procedure of Example 2 was followed using omeprazole
(2.5 g) and pH 10.2 instead of omeprazole (1.25 g) and pH 9.8 to
obtain 6.45 g of the polymer-substituted omeprazole.
EXAMPLE 5
[0064] The procedure of Example 3 was followed using omeprazole
(2.5 g) instead of omeprazole (1.25 g) to obtain 6.32 g of the
polymer-substituted omeprazole.
EXAMPLE 6
[0065] The procedure of Example 2 was followed using lansoprazole
(3.0 ) instead of omeprazole (1.25 g) to obtain 5.8 g of the
polymer-substituted lansoprazole.
EXAMPLE 7
[0066] The procedure of Example 2 was followed using pantoprazole
(3.0 g) instead of omeprazole (1.25 g) to obtain 5.9 g of the
polymer-substituted pantoprazole.
EXAMPLE 8
[0067] Tablets containing the following ingredients:
1 Polymeric benzimidazole 100.0 g of Example2 Lactose 70.0 g
Magnesium stearate 1.5 g Methyl cellulose 0.6 g Crosspovidone 5.5 g
Distilled water q.s
[0068] were prepared by mixing to form a wet mass and forcing the
wet mass through a sieve, granulating and drying on an oven. After
drying, the granulate was mixed with crosspovidone and magnesium
stearate. The dry mixture was pressed into tablet (1000 tablets)
Each tablet containing 100 mg of active substance using 5 mm
diameter punches.
EXAMPLE 9
[0069] Suspension containing the following ingredients were
prepared:
2 Polymeric benzimidazole 2.0 g of Example 2 Glycerin 55.0 g Pharma
grade sugar 320.0 g Maltodextrin 0.5 g Flavouring agent 0.5 g
Ethanol 5.0 ml Distilled water 100.0 ml
EXAMPLE 10
[0070]
3 Capsules containing: Polymeric benzimidazole 100.0 g of Example 2
Anhdrous lactose 300.0 g Microcrystalline cellulose 20.0 g
Magnesium sterate 0.5 g
[0071] were mixed in geometrical order using planatory mixer. The
blend was sieved and filled into capsules.
[0072] Biological activity
[0073] Wistar albino rats of either sex, fed on standard rat chow
diet were divided into the groups of 10 animals each. The
distribution of animals in groups, the sequence of trials and the
treatment allotted to each group were randomized. Gastric
ulceration was produced by pylorus ligation and absolute ethanol
administration. In these methods, animals were fasted for 36 hrs
before the experiment. Coprohagy was prevented by fasting the
animals in cages with grating as the floor. Duodenal ulceration was
produced by cysteamine and in this model fasting is not required
and hence food and water were made available as libidum till the
start of the experiment. The animals were sacrificed using
anaesthetic ether after the completion of experiments; the stomachs
were removed, opened along the greater curvature, washed with
saline and examined with 6.4* (cm diameter) binocular magnifier.
Lesions were assessed by two observers unaware of the experimental
protocol.
[0074] Drug treatment schedule
[0075] Drugs used were polymeric benzimidazoles of Examples 1 to 7
(1.5 mg to 10 mg/kg, peroral ie p.o) and unsubstituted and
unenteric coated omeprazole (manufactured by us, 0.40 mg/kg p.o).
They were administered per orally, 30 minutes after the drug
treatment the animals were subjected to any ulcerogenic
procedure.
[0076] Pylorus ligated rats
[0077] Rats were anaesthetized with anaesthetic ether and the
portion of abdomen was opened by a small midline incision below the
xiphoid process. Pylorus portion of the stomach was lifted and
ligated. During the process care was taken to avoid the traction of
the pylorus or damage to its blood supply. The stomach was isolated
from the body and its contents were collected, measured and
centrifuged. The supernatant was used immediately for biochemical
analysis for total acidity. Immediately after the removal of the
contents from the stomach, they were examined for lesions in the
stomach portion which were measured and expressed in terms of ulcer
index calculated as the total ulcerated area divided by the total
mucosal area.
[0078] Ethanol induced gastric mucosal damage
[0079] Rats were given 1.0 ml of 100% ethyl alcohol (p.o) by gavage
needle, 30 minutes after the administration of test compound. Two
hours after ethanol administration all rats were sacrificed. The
area of the glandular portion of the stomach was measured in
millimeters. Then the area of the gastric mucosal damage was
calculated in square millimeters and the severity of the gastric
mucosal injury was expressed as percentage of the surface area of
the glandular stomach.
[0080] Cystemanine-HCl induced duodenal ulcers in rats
[0081] Wistar albino rats of either sex were used. Food and water
were available and libidum; throughout the study. Duodenal ulcers
were induced by two administrations of cysteamine hydrochloride 400
mg/kg p.o, in 10% aqueous solution at an interval of 4 hour. The
drugs under study were administered 30 minutes before each dose of
cysteamine hydrochloride. All the animals were sacrificed 24 hours
after the first dose of cysteamine and duodenum were excised
carefully and opened along the antimesenteric side. The mean ulcer
area was obtained by measuring the dimensions of the duodenal
ulcer(s) in square millimeters.
[0082] Results
[0083] Effect on ulcer index and total acid output in pylorus
ligated rats
[0084] Pylorus ligation for 19 hours produced accumulation of
gastric secretory volume and increase in the total acid output of
the gastric juice as shown in Table 1.
4TABLE 1 Effect of polymeric benzimidazoles of Examples 1 to 7 and
omeprazole on total acid output and intensity of gastric lesions in
plorus ligated rats as calculated by [mean + Standard Error Mean ie
SEM] Polymeric mg/kg .times. days Total acid output benzimidazole
of (p.o) meq/L/100 g Ulcer index Control 0 .times. 0 186.41 .+-.
19.05 2.88 .+-. 0.18 Example 1 2 .times. 1 60.5 .+-. 4.1 1.09 .+-.
0.51 10 .times. 1 71.32 .+-. 4.5 1.15 .+-. 0.34 Example 2 2 .times.
1 65.8 .+-. 6.3 1.28 .+-. 0.32 10 .times. 1 61.15 .+-. 6.9 1.17
.+-. 0.42 Example 3 2 .times. 1 71.15 .+-. 2.5 1.35 .+-. 0.37 10
.times. 1 69.81 .+-. 24 1.33 .+-. 0.39 Example 4 1.5 .times. 1
72.36 .+-. 6.81 1.18 .+-. 0.23 10 .times. 1 68.11 .+-. 6.53 1.24
.+-. 0.39 Example 5 1.5 .times. 1 55.14 .+-. 5.81 1.21 .+-. 0.51 10
.times. 1 54.06 .+-. 6.52 1.15 .+-. 0.67 Example 6 1.5 .times. 1
77.15 .+-. 6.3 1.25 .+-. 0.45 10 .times. 1 68.53 .+-. 6.9 1.15 .+-.
0.32 Example 7 1.5 .times. 1 59.58 .+-. 7.19 1.41 .+-. 0.32 10
.times. 1 52.65 .+-. 5.5 1.37 .+-. 0.51 Omeprazole 0.4 .times. 1
72.93 .+-. 7.17 0.88 .+-. 0.10
[0085] The benzimidazole active content in the compounds of
Examples 1 to 7 was 20-30%.
[0086] Conclusion: The results of Table I showed that polymeric
benzimidazoles of Examples 1 to 7 (both the doses) produced
decrease in ulcer index and total acid output. The activities of
the polymeric benzimidazoles of Examples 1 to 7 were comparable to
those of omeprazole.
[0087] Effect on absolute ethanol induced gastric mucosal
damage
[0088] Oral administration of absolute ethanol produced blackish S
elongated bands of hemorrhagic lesions in the corpus mucosa along
the long axis of the stomach within 2 hours. Polymeric
benzimidazoles of Examples 1 to 7 when administered in the doses
1.5 mg to 2 mg/kg p.o decreased the area of gastric mucosal lesions
when compared to ethanol treated rats in control, as shown in Table
2.
5TABLE 2 Effect of polymeric benzimidazoles of Examples 1-7 on
gastric mucosal injury induced by absolute ethanol in 7 rats Area
of gastric lesions % of polymeric (mg/kg .times. days) (mm.sup.2)
untreated benzimizcle (p.o) (% of the glandular stomach) rats of
Control 0 .times. 0 34.62 .+-. 1.44 100 Example 1 (2 .times. 1)
3.85 .+-. 0.19 11.12 Example 2 (2 .times. 1) 4.51 .+-. 0.22 12.99
Example 3 (2 .times. 1) 3.51 .+-. 0.81 10.14 Example 4 (1.5 .times.
1) 1.55 .+-. 0.6 4.48 Example 5 (1.5 .times. 1) 1.73 .+-. 0.32 4.99
Example 6 (1.5 .times. 1) 1.95 .+-. 0.48 5.63 Example 7 (1.5
.times. 1) 1.79 .+-. 0.32 5.17
[0089] The benzimidazole active content in the compounds of
Examples 1 to 7 was 20-30%.
[0090] The results of Table 2 were significantly different from
those of control conditions as indicated by P<0.05.
[0091] Effect on cysteamine induced duodenal ulcer model
[0092] Administration of cysteamine caused some mortality in rats
within 24 hour. The rats when died had perforated ulcers. Polymeric
benzimidazoles of Examples 1-7 (1.5 mg and 2 mg/kg) decreased
significantly the mean ulcer area when compared to those in rats in
control. However mortality was reduced in the animals treated with
polymeric benzimidazole of Examples, to 7 as shown in Table 3.
6TABLE 3 Effect of polymeric benziniidazoles of Examples 1-17 on
cysteamine induced duodenal ulcer 7 rats models: (mean + SEM)
Polymeric (mg/kg .times. days) Mean Ulcer Area benzimidazole of
(p.o) (mm.sup.2) Control (0 .times. 0) 13.94 .+-. 1.27 Example 1 (2
.times. 1) 6.55 .+-. 0.3 Example 2 (2 .times. 1) 7.13 .+-. 0.43
Example 3 (2 .times. 1) 6.85 .+-. 0.51 Example 4 (1.5 .times. 1)
6.34 .+-. 0.62 Example 5 (1.5 .times. 1) 6.13 .+-. 0.35 Example 6
(1.5 .times. 1) 6.83 .+-. 0.33 Example 7 (1.5 .times. 1) 6.53 .+-.
0.47
[0093] The benzimidazole active content in the compounds of
Examples 1 to 7 was 20-30%.
[0094] The results of Table 3 were significantly different from
those of control conditions as indicated by P<0.05.
[0095] Expressions of results and statistics
[0096] The results were analyzed statistically using the unpaired
students T test. The value of P less then 5% (P<0.05) was
considered to be statistically significant.
[0097] In-Vitro studies
[0098] In-vitro digestion of polymeric benzimidazole of Examples
1-5 using simulated gastric and intestinal fluids for 2 and 7 hrs
respectively PA 37.degree. C., did not show the release of
Omeprazole (tested by HPLC procedure given for omeprazole in
USP-23). Similarly, polymeric benzimidazoles of Examples 6 and 7
after digestion, did not show release of lansoprazole and
pantoprazole (USP-23) respectively. Therefore it should be assumed
that the drugs released were derivatives (modified forms) of
omepraole, lansoprazole and pantoprazole respectively.
[0099] In-vivo screening of the polymeric benzimidazole of Example
1-7 in rats by pylorus ligation, ethanol induced cytoprotective
property and antiduodenal ulcer property reveals significant proton
pump inhibiting property at 1.5-2 mg/kg body weight dose.
[0100] Conclusions
[0101] Polymeric benzimidazoles of Examples 1-7 show significant
antiulcer activity in rats in all the three experimental models,
viz. pylorus ligated rats, ethanol induced gastric mucosal injury
and cysteamine induced duodenal ulcer. Activities were comparable
with that of omeprazole in pylorus ligated rats model.
* * * * *