U.S. patent application number 10/256518 was filed with the patent office on 2003-05-08 for methods and compositions for treating gastric disorders with optically pure (-) pantoprazole.
This patent application is currently assigned to SEPRACOR INC.. Invention is credited to Gray, Nancy M..
Application Number | 20030086968 10/256518 |
Document ID | / |
Family ID | 21990236 |
Filed Date | 2003-05-08 |
United States Patent
Application |
20030086968 |
Kind Code |
A1 |
Gray, Nancy M. |
May 8, 2003 |
Methods and compositions for treating gastric disorders with
optically pure (-) pantoprazole
Abstract
Methods and compositions are disclosed utilizing optically pure
(-) pantoprazole for the treatment of ulcers in humans while
substantially reducing the concomitant liability of adverse effects
associated with the racemic mixture of pantoprazole. The optically
pure (-) isomer is also useful for the treatment of
gastroesophageal reflux. (-) Pantoprazole is an inhibitor of
H.sup.+ release and is therefore useful in the treatment of other
conditions related to gastric hypersecretion such as
Zollinger-Ellison Syndrome.
Inventors: |
Gray, Nancy M.;
(Marlborough, MA) |
Correspondence
Address: |
HESLIN ROTHENBERG FARLEY & MESITI PC
5 COLUMBIA CIRCLE
ALBANY
NY
12203
US
|
Assignee: |
SEPRACOR INC.
84 waterford Drive
Marlborough
MA
01752
|
Family ID: |
21990236 |
Appl. No.: |
10/256518 |
Filed: |
September 26, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10256518 |
Sep 26, 2002 |
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09783683 |
Feb 14, 2001 |
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09783683 |
Feb 14, 2001 |
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09268388 |
Mar 15, 1999 |
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09268388 |
Mar 15, 1999 |
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08772944 |
Dec 23, 1996 |
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5888535 |
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08772944 |
Dec 23, 1996 |
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08416442 |
Apr 3, 1995 |
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08416442 |
Apr 3, 1995 |
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08054318 |
Apr 27, 1993 |
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Current U.S.
Class: |
424/465 ;
514/338 |
Current CPC
Class: |
A61P 1/04 20180101; A61K
31/4439 20130101; A61K 31/44 20130101 |
Class at
Publication: |
424/465 ;
514/338 |
International
Class: |
A61K 031/4439 |
Claims
What is claimed is:
1. A method of treating ulcers in a human which comprises
administering to said human an amount of (-) pantoprazole, or a
pharmaceutically acceptable salt thereof, substantially free of its
(+) stereoisomer, said amount being sufficient to alleviate or
palliate said ulcers.
2. The method of claim 1 wherein (-) pantoprazole is administered
parenterally, transdermally, or orally as a tablet or a
capsule.
3. The method of claim 2 wherein the amount of (-) pantoprazole or
a pharmaceutically acceptable salt thereof administered is from
about 5 mg to about 125 mg per day.
4. The method of claim 3 wherein the amount administered is from
about 10 mg to about 100 mg per day.
5. The method of claim 4 wherein the amount administered is from
about 20 mg to about 80 mg per day.
6. The method of claim 1 wherein the amount of (-) pantoprazole or
a pharmaceutically acceptable salt thereof is greater than
approximately 90% by weight of the total weight of
pantoprazole.
7. The method of claim 1 wherein the amount of said (-)
pantoprazole or a pharmaceutically acceptable salt thereof,
substantially free of its (+) stereoisomer, is administered
together with a pharmaceutically acceptable carrier.
8. The method according to claim 1, wherein (-) pantoprazole is
administered as a sodium salt.
9. A method of treating ulcers in a human while substantially
reducing the concomitant liability of adverse effects associated
with racemic pantoprazole which comprises administering to a human
in need of such antiulcer therapy an amount of (-) pantoprazole, or
a pharmaceutically acceptable salt thereof, substantially free of
its (+) stereoisomer, said amount being sufficient to alleviate or
palliate said ulcers but insufficient to cause said adverse
effects.
10. A pharmaceutical composition for the treatment of a human in
need of ulcer therapy which comprises an amount of (-) pantoprazole
or a pharmaceutically acceptable salt thereof, substantially free
of its (+) stereoisomer, said amount being sufficient to alleviate
said ulcers.
11. The composition of claim 10 wherein said amount of (-)
pantoprazole is sufficient to alleviate ulcers but insufficient to
cause adverse effects associated with the administration of racemic
pantoprazole.
12. The composition according to claim 10 wherein (-) pantoprazole
is administered as a sodium salt.
13. The composition according to claim 10 adapted for oral
administration.
14. The composition according to claim 10 adapted for parenteral
delivery.
15. The composition according to claim 10 wherein (-) pantoprazole
or a pharmaceutically acceptable salt thereof, substantially free
of its (+) stereoisomer, is administered together with a
pharmaceutically acceptable carrier.
16. A method of treating gastroesophageal reflux disease in a human
which comprises administering to said human an amount of (-)
pantoprazole, or a pharmaceutically acceptable salt thereof,
substantially free of its (+) stereoisomer, said amount being
sufficient to alleviate symptoms of gastroesophageal reflux.
17. The method of claim 16 wherein (-) pantoprazole is administered
parenterally, transdermally, or orally as a tablet or a
capsule.
18. The method of claim 17 wherein the amount of (-) pantoprazole
or a pharmaceutically acceptable salt thereof administered is from
about 5 mg to about 125 mg per day.
19. The method of claim 18 wherein the amount administered is from
about 10 mg to about 100 mg per day.
20. The method of claim 19 wherein the amount administered is from
about 20 mg to about 80 mg per day.
21. The method of claim 16 wherein the amount of (-) pantoprazole
or a pharmaceutically acceptable salt thereof is greater than
approximately 90% by weight of the total weight of
pantoprazole.
22. The method of claim 16 wherein the amount of said (-)
pantoprazole or a pharmaceutically acceptable salt thereof,
substantially free of its (+) stereoisomer, is administered
together with a pharmaceutically acceptable carrier.
23. The method according to claim 16, wherein (-) pantoprazole is
administered as a sodium salt.
24. A method of treating gastroesophageal reflux disease in a
human, while substantially reducing the concomitant liability of
adverse effects associated with racemic pantoprazole, which
comprises administering to a human in need of such therapy an
amount of (-) pantoprazole, or a pharmaceutically acceptable salt
thereof, substantially free of its (+) stereoisomer, said amount
being sufficient to alleviate symptoms of gastroesophageal reflux
but insufficient to cause said adverse effects.
25. A pharmaceutical composition for the treatment of a human in
need of therapy for gastroesophageal reflux disease which comprises
an amount of (-) pantoprazole or a pharmaceutically acceptable salt
thereof, substantially free of its (+) stereoisomer, said amount
being sufficient to alleviate said gastroesophageal reflux.
26. The composition of claim 25 wherein said amount of (-)
pantoprazole is insufficient to cause adverse effects associated
with the administration of racemic pantoprazole.
27. The composition according to claim 25 wherein (-) pantoprazole
is administered as a sodium salt.
28. The composition according to claim 25 adapted for oral
administration.
29. The composition according to claim 25 adapted for parenteral
delivery.
30. The composition according to claim 25 wherein (-) pantoprazole
or a pharmaceutically acceptable salt thereof, substantially free
of its (+) stereoisomer, is administered together with a
pharmaceutically acceptable carrier.
31. A method of treating a condition caused by or contributed to by
gastric hypersecretion in a human which comprises administering to
said human an amount of (-) pantoprazole, or a pharmaceutically
acceptable salt thereof, substantially free of its (+)
stereoisomer, said amount being sufficient to alleviate said
gastric hypersecretion.
32. The method according to claim 31 wherein said condition is
Zollinger-Ellison Syndrome.
33. The method of claim 31 wherein (-) pantoprazole is administered
parenterally, transdermally, or orally as a tablet or a
capsule.
34. The method of claim 33 wherein the amount of (-) pantoprazole
or a pharmaceutically acceptable salt thereof administered is from
about 5 mg to about 125 mg per day.
35. The method of claim 34 wherein the amount administered is from
about 10 mg to about 100 mg per day.
36. The method of claim 35 wherein the amount administered is from
about 20 mg to about 80 mg per day.
37. The method of claim 31 wherein the amount of (-) pantoprazole
or a pharmaceutically acceptable salt thereof is greater than
approximately 90% by weight of the total weight of
pantoprazole.
38. The method of claim 31 wherein the amount of said (-)
pantoprazole or a pharmaceutically acceptable salt thereof,
substantially free of its (+) stereoisomer, is administered
together with a pharmaceutically acceptable carrier.
39. The method according to claim 31, wherein (-) pantoprazole is
administered as a sodium salt.
40. A method of treating a condition caused by or contributed to by
gastric hypersecretion in a human, while substantially reducing the
concomitant liability of adverse effects associated with racemic
pantoprazole, which comprises administering to a human, in need of
such therapy, an amount of (-) pantoprazole, or a pharmaceutically
acceptable salt thereof, substantially free of its (+)
stereoisomer, said amount being sufficient to alleviate said
gastric hypersecretion but insufficient to cause said adverse
effects.
41. A composition for the treatment of a condition caused by or
contributed to by gastric hypersecretion in a human which comprises
an amount of (-) pantoprazole or a pharmaceutically acceptable salt
thereof, substantially free of its (+) stereoisomer, said amount
being sufficient to alleviate said condition.
42. The composition of claim 41 wherein said amount of (-)
pantoprazole is insufficient to cause adverse effects associated
with the administration of racemic pantoprazole.
43. The composition according to claim 41 wherein said condition is
Zollinger-Ellison Syndrome.
44. The composition according to claim 41 wherein (-) pantoprazole
is administered as a sodium salt.
45. The composition according to claim 41 adapted for oral
administration.
46. The composition according to claim 41 adapted for parenteral
delivery.
47. The composition according to claim 41 wherein (-) pantoprazole
or a pharmaceutically acceptable salt thereof, substantially free
of its (+) stereoisomer, is administered together with a
pharmaceutically acceptable carrier.
Description
BACKGROUND OF THE INVENTION
[0001] This invention relates to novel compositions of matter
containing optically pure (-) pantoprazole. These compositions
possess potent activity in treating ulcers of the stomach, duodenum
and esophagus, gastroesophageal reflux diseases, Zollinger-Ellison
Syndrome, and other disorders including those that would benefit
from an inhibitory action on gastric acid secretion. (-)
Pantoprazole inhibits the H.sup.+, K.sup.+-ATPase associated with
the gastric proton pump and the resulting secretion of gastric acid
by parietal cells providing therapy in diseases associated with
gastric hyperacidity. Optically pure (-) pantoprazole provides this
treatment while substantially reducing adverse effects, including,
but not limited to, hepatocellular neoplasia, gastrin
hypersecretion, gastric neoplasms or carcinoids, headache, diarrhea
and skin alterations which are associated with the administration
of the racemic mixture of pantoprazole. Also disclosed are methods
for treating the above described conditions in a human while
substantially reducing the adverse effects that are associated with
the racemic mixture of pantoprazole by administering the (-) isomer
of pantoprazole to said human.
[0002] The active compound of these compositions and methods is an
optical isomer of pantoprazole. The preparation of racemic
pantoprazole is described in U.S. Pat. No. 4,758,579. The medicinal
chemistry of pantoprazole is described by Kohl et al. [J. Med.
Chem. 35, 1049-1057 (1992)], Kromer et al. [J. Pharm. Exp. Ther.
254, 129-135 (1990)], Simon et al. [Aliment. Pharmacol. Therap. 4,
239-245 (1990)], Beil et al. [Europ. J. Pharmacol. 218, 265-271
(1992)], and Kromer et al. [Pharmacology 41, 333-337 (1990)].
Chemically, the active compound is the (-) isomer of
5-(difluoromethoxy)-2-[[3,4-dimethoxy-2-pyridinyl)methyl]su-
lfinyl]-1H-benzimidazole(I), hereinafter referred to as
pantoprazole. 1
[0003] (-) Pantoprazole, which is the subject of the present
invention, is not presently commercially available; only the 1:1
racemic mixture is commercially available as its sodium salt.
[0004] Many organic compounds exist in optically active forms,
i.e., they have the ability to rotate the plane of plane-polarized
light. In describing an optically active compound, the prefixes D
and L or R and S are used to denote the absolute configuration of
the molecule about its chiral center(s). The prefixes d and l or
(+) and (-) are employed to designate the sign of rotation of
plane-polarized light by the compound, with (-) or l meaning that
the compound is levorotatory. A compound prefixed with (+) or d is
dextrorotatory. There is no correlation between nomenclature for
the absolute stereochemistry and for the rotation of an enantiomer.
Thus, D-lactic acid is the same as (-) lactic acid, and L-lactic
acid is (+). For a given chemical structure, these chiral compounds
exist as a pair of enantiomers which are identical except that they
are non-superimposable mirror images of one another. A specific
stereoisomer may also be referred to as an enantiomer, and a
mixture of such isomers is often called an enantiomeric or racemic
mixture.
[0005] Stereochemical purity is of importance in the field of
pharmaceuticals, where 12 of the 20 most prescribed drugs exhibit
chirality. A case in point is provided by the L-form of the
beta-adrenergic blocking agent, propranolol, which is known to be
100 times more potent than the D-enantiomer.
[0006] Furthermore, optical purity is important since certain
isomers may actually be deleterious rather than simply inert. For
example, it has been suggested that the D-enantiomer of thalidomide
was a safe and effective sedative when prescribed for the control
of morning sickness during pregnancy, while the corresponding
L-enantiomer has been believed to be a potent teratogen.
[0007] The separation of racemic pantoprazole into (+) pantoprazole
and (-) pantoprazole is described in German application 4,035,455,
but no pharmacology of the individual enantiomers is reported.
[0008] Racemic pantoprazole had been in clinical trials in Europe
and the United States under the sponsorship of two pharmaceutical
manufacturers, but the United States and British sponsor withdrew
in 1991 due to concerns about hepatocellular neoplasia seen in rats
in a two year carcinogenicity study. Trials continue in Europe and
initial reports indicate 90-100% ulcer healing in patients
suffering from duodenal ulcers after four weeks of 20 to 80 mg of
racemic pantoprazole per day.
[0009] Racemic pantoprazole sodium is an orally active, potent,
irreversible inhibitor of H.sup.+, K.sup.+-ATPase. The compound is
one of the class of compounds known as gastric "proton pump"
inhibitors. These compounds are weak organic bases which diffuse
passively from the plasma into the acid-containing intracellular
canaliculi of gastric parietal cells. At the low pH found in the
lumen of these canaliculi, the protonated compounds rearrange to
form pyridinium sulfenamides, which react with sulfhydryl groups
present on the ATPase localized in the membranes lining the
intracellular canaliculi. The alkylation of the sulfhydryl inhibits
the ability of the enzyme to catalyze the secretion of H.sup.+ into
the lumen in exchange for K.sup.+ ions. This inhibition results in
an overall reduction in hydrochloric acid secretion by the parietal
cells into the cavity of the stomach, thus increasing intragastric
pH. As a consequence of reduced acidity in the stomach, the
activity of the proteolytic enzyme pepsin is also markedly
decreased. Because the proton pump is the final step in acid
production and the compounds of this class combine covalently with
the associated H.sup.+, K.sup.+-ATPase, a profound and prolonged
inhibition of gastric acid secretion can be achieved.
[0010] The potency of pantoprazole in vitro as an inhibitor of
aminopyrine uptake, which is an index of acid secretion in isolated
gastric glands, is similar to that of omeprazole, a structurally
related antiulcer agent. Pantoprazole is, however, more chemically
stable under neutral and moderately acidic conditions than is
omeprazole. This may increase pantoprazole's selectivity for the
acid secreting parietal cells, where low pH conditions exist in the
intracellular canaliculi. In intact animals, pantoprazole is active
in inhibiting gastric acid secretion in both rats and dogs.
Specifically, the intravenous and oral doses required to reduce
endogenous acid secretion in pylorus-ligated rats by 50% are in the
1-3 .mu.mole/kg range. The calculated oral/intravenous (p.o./i.v.)
ratio is approximately 2, suggesting good oral bioavailability.
Racemic pantoprazole is also effective at doses less than
5.mu.mole/kg in inhibiting exogenously stimulated acid secretion
induced by a variety of agonists, indicating general activity of
the drug in inhibiting acid secretion. The serum half-life of
racemic pantoprazole is 1.1 to 1.5 hours in humans. Compared to
omeprazole, racemic pantoprazole is a weaker inhibitor of hepatic
drug metabolizing enzyme systems in intact rats and rat microsomal
enzyme preparations. The intravenous LD.sub.50 values are 632 (rat)
and 975 (mice) .mu.mole/kg; oral LD.sub.50 in mice is 1,893 and in
rats >2,467 .mu.mol/kg. The p.o./i.v. LD.sub.50 ratio of the
compound in mice is about 2 and the rat LD.sub.50 values are at
least two to three orders of magnitude greater than the
corresponding doses required to produce half-maximal inhibition of
endogenous acid secretion in this species.
[0011] Although no cardiovascular or obvious physical changes have
been observed in humans on short-term administration of racemic
pantoprazole, fasting serum gastrin levels are significantly
elevated. This is cause for concern because prolonged elevated
serum gastrin appears to be associated with diffuse and focal
enterochromaffin-like cell hyperplasia and focal neoplasia
(carcinoids) in rats. [Larsson et al. Gastroenterology 90, 391-399
(1986)]. Thus, despite its advantages, some adverse effects of
racemic pantoprazole may remain, including, but not limited to,
some incidence of hepatocellular neoplasia and gastric carcinoids
on long-term therapy, and headache, diarrhea and skin alterations
on acute therapy. It would therefore be particularly desirable to
find a compound with the advantages of the racemic mixture of
pantoprazole which would not have the aforementioned
disadvantages.
SUMMARY OF THE INVENTION
[0012] It has now been discovered that the optically pure (-)
isomer of pantoprazole is an effective agent for treating ulcers of
the stomach, duodenum and esophagus, gastroesophageal reflux
diseases, Zollinger-Ellison Syndrome and other disorders, including
those that would benefit from an inhibitory action on H.sup.+,
K.sup.+-ATPase. The optically pure (-) isomer of pantoprazole
provides this effective treatment while substantially reducing the
adverse effects of racemic pantoprazole including, but not limited
to, hepatocellular neoplasia, gastric carcinoids, headache,
diarrhea and skin alterations. The present invention also includes
methods for treating the above described conditions in a human
while substantially reducing the adverse effects that are
associated with the racemic mixture of pantoprazole by
administering the optically pure (-) isomer of pantoprazole to said
human.
DETAILED DESCRIPTION OF THE INVENTION
[0013] The present invention encompasses a method of treating
ulcers, which comprises administering to a human in need of such
therapy, an amount of (-) pantoprazole, or a pharmaceutically
acceptable salt thereof, substantially free of its (+)
stereoisomer, said amount being sufficient to alleviate the
symptoms of ulcers. The method substantially reduces the
concomitant liability of adverse effects associated with the
administration of the racemic compound by providing an amount which
is insufficient to cause the adverse effects associated with the
racemic mixture of pantoprazole.
[0014] The present invention also encompasses an antiulcer
composition for the treatment of a human in need of antiulcer
therapy, which comprises an amount of (-) pantoprazole, or a
pharmaceutically acceptable salt thereof, substantially free of its
(+) stereoisomer, said amount being sufficient to alleviate said
ulcers. Preferably the amount is insufficient to cause the adverse
effects associated with racemic pantoprazole.
[0015] The present invention further encompasses a method of
treating gastroesophageal reflux disease in a human, which
comprises administering to a human in need of-such therapy, an
amount of (-) pantoprazole, or a pharmaceutically acceptable salt
thereof, substantially free of its (+) stereoisomer, sufficient to
alleviate said gastroesophageal reflux. The method substantially
reduces the concomitant liability of adverse effects associated
with the administration of racemic pantoprazole by providing an
amount which is insufficient to cause adverse effects associated
with the administration of racemic pantoprazole.
[0016] In addition, the present invention encompasses a composition
for the treatment of a human having gastroesophageal reflux
disease, which comprises an amount of (-) pantoprazole, or a
pharmaceutically acceptable salt thereof, substantially free of its
(+) isomer, said amount being sufficient to alleviate or palliate
said disorder. Preferably the amount is insufficient to cause
adverse effects associated with the administration of racemic
pantoprazole.
[0017] A further aspect of the present invention includes a method
of treating a condition caused by or contributed to by gastric
hypersecretion in a human, which comprises administering to a human
in need of such therapy, an amount of (-) pantoprazole, or a
pharmaceutically acceptable salt thereof, substantially free of its
(+) stereoisomer, sufficient to alleviate said gastric
hypersecretion. The method substantially reduces the concomitant
liability of adverse effects associated with the administration of
racemic pantoprazole by providing an amount which is insufficient
to cause adverse effects associated with the administration of
racemic pantoprazole. Conditions associated with hypersecretion in
humans may include, but are not limited to, Zollinger-Ellison
syndrome.
[0018] In addition, the invention encompasses a composition for the
treatment of a condition caused by or contributed to by gastric
hypersecretion in a human which comprises an amount of (-)
pantoprazole or a pharmaceutically acceptable salt thereof,
substantially free of its (+) stereoisomer, the amount being
sufficient to alleviate the condition. Preferably the amount is
insufficient to cause adverse effects associated with the
administration of racemic pantoprazole.
[0019] The available racemic mixture of pantoprazole (i.e., a 1:1
racemic mixture of the two enantiomers) exhibits antiulcer activity
through its selective, potent, and irreversible inhibition of
H.sup.+, K.sup.+-ATPase, thus providing therapy and a reduction of
symptoms in a variety of conditions and disorders related to
hypersecretion; however, this racemic mixture, while offering the
expectation of efficacy, causes adverse effects which are serious
enough to have caused curtailment of clinical trials. Utilizing the
optically pure or substantially optically pure isomer of (-)
pantoprazole results in enhanced efficacy, diminished adverse
effects, and accordingly, an improved therapeutic index. It is
therefore, more desirable to use the (-) isomer of pantoprazole
than to administer the racemic mixture.
[0020] The term "adverse effects" includes, but is not limited to,
hepatocellular neoplasia, gastrin hypersecretion, gastric
carcinoids, headache, diarrhea and skin alterations.
[0021] The term "substantially free of its (+) stereoisomer" as
used herein means that the compositions contain at least 90% by
weight of (-) pantoprazole and 10% by weight or less of (+)
pantoprazole. In a more preferred embodiment the term
"substantially free of the (+) isomer" means that the composition
contains at least 99% by weight of (-) pantoprazole, and 1% or less
of (+) pantoprazole. In the most preferred embodiment, the term
"substantially free of its (+) stereoisomer" as used herein means
that the composition contains greater than 99% by weight of (-)
pantoprazole. These percentages are based upon the total amount of
pantoprazole in the composition. The terms "substantially optically
pure (-) isomer of pantoprazole" or "substantially optically pure
(-) pantoprazole" and "optically pure (-) isomer of pantoprazole"
and "optically pure (-) pantoprazole" are also encompassed by the
above-described amounts.
[0022] The term "treating ulcers" as used herein means treating,
alleviating or palliating such conditions, and thus providing
relief from the symptoms of nausea, heartburn, post-prandial pain,
vomiting, and diarrhea.
[0023] The term "a method for treating gastroesophageal reflux
diseases in a human" as used herein means treating, alleviating or
palliating the conditions that result from the backward flow of the
stomach contents into the esophagus.
[0024] The term "treating a condition caused, or contributed to, by
gastric hypersecretion in a human" as used herein means treating,
alleviating or palliating such disorders associated with
hypersecretion, thus providing, relief from the symptoms of the
aforementioned conditions. Zollinger-Ellison Syndrome is among the
conditions caused by or contributed to by hypersecretion.
[0025] The chemical synthesis of the racemic mixture of
pantoprazole can be performed by the method described in U.S. Pat.
No. 4,758,579 cited above. The (-) isomer of pantoprazole may then
be obtained from its racemic mixture by resolution of the
enantiomers of pantoprazole or precursors thereto using
conventional means such as an optically active resolving base.
German application 4,035,455 (Kohl et al.), which is incorporated
herein by reference, discloses a method for resolving the racemic
pantoprazole by forming an alkoxymethylamine with fenchyl
chloromethyl ether. Other standard methods of resolution known to
those skilled in the art including, but not limited to, simple
crystallization and chromatographic resolution, can also be used.
(See for example, E. L. Eliel, Stereochemistry of Carbon Compounds,
McGraw Hill (1962) and [Wilen and Lochmuller "Tables of Resolving
Agents" Journal of Chromatography 113, 283-302 (1975)].
Alternatively, the prochiral sulfide may be enantiospecifically
oxidized to the (-) sulfoxide by processes known in the art.
[0026] The magnitude of a prophylactic or therapeutic dose of (-)
pantoprazole in the acute or chronic management of disease will
vary with the severity of the condition to be treated and the route
of administration. The dose and perhaps the dose frequency will
also vary according to the age, body weight and response of the
individual patient. In general, the total daily dose range for (-)
pantoprazole for the conditions described herein is from about 5.0
mg to about 125 mg in single or divided doses. Preferably a daily
dose range should be about 10 mg to about 100 mg in single or
divided doses while most preferably a daily dose range should be
about 20 mg to about 80 mg in single or divided doses. In managing
the patient, the therapy should be initiated at a lower dose,
perhaps at about 10 mg to about 25 mg and increased up to about 80
mg or higher depending on the patient's global response. It is
further recommended that children and patients over 65 years and
those with impaired renal or hepatic function, initially receive
low doses, and that they be titrated based on individual
response(s) and blood level(s). It may be necessary to use dosages
outside these ranges in some cases as will be apparent to those
skilled in the art. Further, it is noted that the clinician or
treating physician will know how and when to interrupt, adjust, or
terminate therapy in conjunction with individual patient response.
The terms "an amount sufficient to alleviate or palliate ulcers but
insufficient to cause said adverse effects," "an amount sufficient
to alleviate the symptoms of gastroesophageal reflux but
insufficient to cause said adverse effects," and "an amount
sufficient to alleviate gastric hypersecretion but insufficient to
cause said adverse effects" are encompassed by the above-described
dosage amounts and dose frequency schedule.
[0027] Any suitable route of administration may be employed for
providing the patient with an effective dosage of (-) pantoprazole.
For example, oral, rectal, parenteral (subcutaneous, intramuscular,
intravenous), transdermal, and like forms of administration may be
employed. Dosage forms include tablets, troches, dispersions,
suspensions, solutions, capsules, patches, and the like.
[0028] The pharmaceutical compositions of the present invention
comprise (-) pantoprazole as the active ingredient, or a
pharmaceutically acceptable salt thereof, and may also-contain a
pharmaceutically acceptable carrier, and optionally, other
therapeutic ingredients.
[0029] The terms "pharmaceutically acceptable salts" or "a
pharmaceutically acceptable salt thereof" refer to salts prepared
from pharmaceutically acceptable non-toxic bases. Since the
compound of the present invention is a weak acid (pK.sub.a=8.2),
salts may be prepared from pharmaceutically acceptable non-toxic
bases including inorganic and organic bases. Suitable
pharmaceutically acceptable base addition salts for the compound of
the present invention include metallic salts made from aluminum,
calcium, lithium, magnesium, potassium, sodium and zinc or organic
salts made from lysine, N,N'-dibenzylethylenediamine,
chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine
(N-methylglucamine) and procaine. Sodium salts are particularly
preferred.
[0030] The compositions of the present invention include
suspensions, solutions, elixirs, aerosols, or solid dosage forms.
Carriers such as starches, sugars, and microcrystalline cellulose,
diluents, granulating agents, lubricants, binders, disintegrating
agents, and the like are suitable in the case of oral solid
preparations (such as powders, capsules, and tablets), and oral
solid preparations are preferred over the oral liquid
preparations.
[0031] Because of their ease of administration, tablets and
capsules represent the most advantageous oral dosage unit forms, in
which case solid pharmaceutical carriers are employed. If desired,
tablets may be coated by standard aqueous or nonaqueous
techniques.
[0032] In addition to the common dosage forms set out above, the
compounds of the present invention may also be administered by
controlled release means and delivery devices such as those
described in U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809;
3,598,123; and 4,008,719, the disclosures of which are hereby
incorporated by reference.
[0033] Pharmaceutical compositions of the present invention
suitable for oral administration may be presented as discrete units
such as capsules, cachets, tablets, or aerosol sprays, each
containing a predetermined amount of the active ingredient, as a
powder or granules, or as a solution or a suspension in an aqueous
liquid, a non-aqueous liquid, an oil-in-water emulsion, or a
water-in-oil liquid emulsion. Such compositions may be prepared by
any of the methods of pharmacy, but all methods include the step of
bringing into association the active ingredient with the carrier
which constitutes one or more necessary ingredients. In general,
the compositions are prepared by uniformly and intimately admixing
the active ingredient with liquid carriers or finely divided solid
carriers or both, and then, if necessary, shaping the product into
the desired presentation.
[0034] For example, a tablet may be prepared by compression or
molding, optionally, with one or more accessory ingredients.
Compressed tablets may be prepared by compressing in a suitable
machine the active ingredient in a free-flowing form such as powder
or granules, optionally mixed with a binder, lubricant, inert
diluent, surface active agent or dispersing agent. Molded tablets
may be made by molding in a suitable machine, a mixture of the
powdered compound moistened with an inert liquid diluent.
Desirably, each tablet contains from about 10 mg to about 100 mg of
the active ingredient, and each cachet or capsule contains from
about 10 mg to about 100 mg of the active ingredient. Most
preferably, the tablet, cachet or capsule contains either one of
three dosages, about 20 mg, about 40 mg or about 80 mg of (-)
pantoprazole sodium salt for oral administration.
[0035] The invention is further defined by reference to the
following examples describing in detail the preparation of the
compositions of the present invention, as well as their utility. It
will be apparent to those skilled in the art that many
modifications, both to materials and methods, may be practiced
without departing from the purpose and interest of this
invention.
EXAMPLES
Example 1
[0036] The relative activity, potency and specificity of optically
pure pantoprazole and racemic pantoprazole both as gastric
antisecretory agents and plasma gastrin elevating agents can be
determined by a pharmacological study in animals according to the
method of Decktor et al..[J. Pharmacol. Exp. Ther. 249, 1-5
(1989)]. The test provides an estimate of relative activity,
potency and, through a measure of specificity, an estimate of
therapeutic index. Fasted rats, implanted with a gastric cannula,
receive single oral or parenteral doses of (-) pantoprazole, (+)
pantoprazole or racemate, 1 hour before collection of gastric juice
over a four hour period. Acid output and pH are then determined on
each sample. Dose response evaluations are performed with each
compound to determine the lowest dose which inhibits acid output by
at least 95% and maintains gastric pH above 7.0. Plasma gastrin
levels are then determined in a second group of rats treated with
the doses selected in the first series of tests. Blood samples are
taken for analyses over the five hour period after dosing, and both
peak level as well as area-under-the-curve analyses of the gastrin
responses are made. These responses are then analyzed statistically
using Student's "t" test to assess whether equivalent antisecretory
doses show differences in gastrin responses.
Example 2
[0037]
1 ORAL FORMULATION Capsules: Quantity per capsule in mg Formula A B
C (-) Pantoprazole sodium 20 40 80 salt Lactose 152 132 142
Cornstarch 27.5 27.5 27.5 Magnesium Stearate 0.50 0.50 0.50
Compression Weight 200 200 250
[0038] The (-) pantoprazole, lactose and cornstarch are blended
until uniform and then the magnesium stearate is blended into the
resulting powder, which is sieved and filled into suitably sized,
two-piece, hard gelatin capsules using conventional machinery.
Other doses may be prepared by altering the fill weight and, if
necessary, changing the capsule size to suit.
Example 3
[0039]
2 ORAL FORMULATION Tablets: Quantity per tablet in mg Formula A B C
(-) Pantoprazole sodium 20 40 80 salt Lactose 147 127 137
Cornstarch 5 5 5 Water (per thousand Tablets)* 48 mL 48 mL 48 mL
Cornstarch 27.5 27.5 27.5 Magnesium Stearate 0.50 0.50 0.50
Compression Weight 200 200 250 *The water evaporates during
manufacture
[0040] The (-) pantoprazole is blended with the lactose until a
uniform blend is formed. The smaller quantity of cornstarch is
blended with the water to form the resulting corn starch paste.
This is then mixed with the uniform blend until a uniform wet mass
is formed. The remaining cornstarch is added to the resulting wet
mass and mixed until uniform granules are obtained. The granules
are then screened through a suitable milling machine, using a 1/4
inch stainless steel screen. The milled granules are dried in a
suitable drying oven until the desired moisture content is
obtained. The dried granules are then milled through a suitable
milling machine, magnesium stearate is blended in, and the
resulting mixture is compressed into tablets of the desired shape,
thickness, hardness and disintegration. Tablets of other strengths
may be prepared by altering the ratio of active ingredient to the
excipients or to the final weight of the tablet. An enteric
coating, such as the polyacrylate Eudragit L.RTM. and Eudragit
S.RTM. series, is applied by spray coating the tablets, preferably
with an aqueous dispersion of the coating polymer.
* * * * *