Note: Descriptions are shown in the official language in which they were submitted.
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R-RABEPRAZOLE COMPOSITIONS AND METHODS
FIELD OF THE INVENTION
This invention relates to compositions of matter
containing rabeprazole. The invention also relates to
methods of treating and preventing ulcers, treating
other conditions related to gastric hypersecretion, and
treating psoriasis.
BACKGROUND OF THE INVENTION
Racemic rabeprazole is an orally active, potent,
irreversible inhibitor of H+,K'-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+ into the
lumen in exchange for K+ 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+,K+-ATPase, a profound
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and prolonged inhibition of gastric acid secretion can
be achieved.
Proton pump inhibitors have also been reported as
useful in treating psoriasis. [See PCT application
W095/18612]
The Cmax of racemic rabeprazole is at about 4 to 5
hours in humans and the serum half-life is about 50
minutes to 1.5 hours depending on dose, but this does
not reflect the duration of the acid inhibitory effect,
which is about 24 hours. Racemic rabeprazole is
comparable to omeprazole in its effects on hepatic drug
metabolizing enzyme systems such as CYP 3A, although it
appears to be less inhibitory of CYP 2C19 than is
omeprazole and a more potent inducer of CYP lAl mRNA
than is pantoprazole.
No cardiovascular or obvious physical changes have
been so far reported in humans on administration of
racemic rabeprazole, but reports of clinical trials are
only recently beginning to appear. Most proton pump
inhibitors produce significantly elevated fasting serum
gastrin levels. 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. Gastroenterolocty 90, 391-399
(1986)]. Thus, despite its advantages, some adverse
effects of racemic rabeprazole 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
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to find a compound with the advantages of the racemic
mixture of rabeprazole which would not have the
aforementioned disadvantages.
SUMMARY OF THE INVENTION
This invention relates to the use of optically
pure R(+)rabeprazole 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 gastric acid secretion.
R(+)Rabeprazole inhibits the H+, K'-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. The invention also relates to a method
of treating psoriasis using optically pure R(+)
rabeprazole. Optically pure (+) rabeprazole 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 rabeprazole.
The invention also relates to certain
pharmaceutical compositions containing the R(+) isomer
of rabeprazole.
DETAILED DESCRIPTION OF THE INVENTION
The active compound of these compositions and
methods is an optical isomer of rabeprazole. The
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preparation of racemic rabeprazole is described in
United States Patent 5,045,552 and its equivalent
European application 268956. Chemically, the active
compound in the compositions and methods of the
invention is the (+) isomer of 2-[[[4-(3-
methoxypropoxy)-3-methyl-2-pyridinyl]methyl]sulfinyl-
[1H)-benzimidazole(I), hereinafter referred to as (+)-
rabeprazole.
N O
N
N
H3C O O
-CH3
(+) Rabeprazole, which is the subject of the
present invention, is not presently commercially
available.
The separation of racemic rabeprazole into R(+)
rabeprazole and S(-) rabeprazole by chromatography has
been described by Nochi et al [Chem. Pharm. Bull. 44,
1853-1857 (1996)], but the pharmacology and
pharmacodynamics have not been described for either
enantiomer. In addition to the chromatographic
separation of the racemate into its enantiomers,
asymmetric oxidation of the thioether precursor and
bioreduction of the racemate to eliminate the S(-)
enantiomer can be carried out in analogous fashion to
the procedure described for lansoprazole in PCT
applications WO 9602535 and 9617077; the disclosures of
both are incorporated herein by reference.
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It has now been discovered that the optically pure
(+) isomer of rabeprazole is a superior agent for
treating ulcers of the stomach, duodenum and esophagus,
gastroesophageal reflux diseases, Zollinger-Ellison
Syndrome, psoriasis and other disorders, including
those that would benefit from an inhibitory action on
H+,K+-ATPase in that it provides this effective
treatment while substantially reducing the adverse
effects of racemic rabeprazole including, but not
limited to, hepatocellular neoplasia, gastric
carcinoids, headache, diarrhea and skin alterations.
The R(+) isomer of rabeprazole is also a superior agent
for treating ulcers and other disorders by virtue of
the greater predictability of dosage among patients, as
discussed below.
The present invention encompasses a method of
treating ulcers, which comprises administering to a
human in need of such therapy, an amount of (+)
rabeprazole, 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
rabeprazole.
The present invention also encompasses an oral
antiulcer composition for the treatment of a human in
need of antiulcer therapy, which comprises a
pharmaceutically acceptable carrier for oral
administration and a therapeutically effective amount
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of (+) rabeprazole, or a pharmaceutically acceptable
salt thereof, substantially free of its (-)
stereoisomer. Preferably the composition is in the
form of a tablet or capsule and the amount of (+)
rabeprazole in the tablet or capsule is 10, 30 or
50 mg.
The present invention further encompasses a method
of treating gastroesophageal reflux disease and of
treating conditions caused by or contributed to by
gastric hypersecretion. Conditions associated with
hypersecretion in humans may include, but are not
limited to, Zollinger-Ellison syndrome.
The present invention further encompasses a method
of treating psoriasis while substantially reducing the
adverse effects of racemic rabeprazole.
Utilizing the optically pure or substantially
optically pure isomer of (+) rabeprazole results in
enhanced efficacy, diminished adverse effects, and
accordingly, an improved therapeutic index. Moreover,
the R(+) enantiomer provides a desirable half-life and
shows less variation in the patient population between
so-called extensive metabolizers and poor metabolizers
than does racemic rabeprazole. It is therefore, more
desirable to use the (+) isomer of rabeprazole than to
administer the racemic mixture because predictability
of an effective and safe dose for an individual patient
is greater.
The term "adverse effects" includes, but is not
limited to, hepatocellular neoplasia, gastrin
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hypersecretion, gastric carcinoids, headache, diarrhea
and skin alterations.
The term "substantially free of its (-)
stereoisomer" as used herein means that the
compositions contain at least 90% by weight of (+)
rabeprazole and 10% by weight or less of (-)
rabeprazole. In a more preferred embodiment the term
"substantially free of the (-) isomer" means that the
composition contains at least 99o by weight of (+)
rabeprazole, and 1% or less of (-) rabeprazole. These
percentages are based upon the total amount of
rabeprazole in the composition. The terms
"substantially optically pure (+) isomer of
rabeprazole" or "substantially optically pure (+)
rabeprazole" and "optically pure (+) isomer of
rabeprazole" and "optically pure (+) rabeprazole" are
also encompassed by the above-described amounts.
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.
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.
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
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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.
The term "treating psoriasis" as used herein means
treating, alleviating or palliating the condition, and
thus providing relief from the symptoms of pruritis,
epidermal scaling, itching and burning.
The magnitude of a prophylactic or therapeutic
dose of (+) rabeprazole 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 (+) rabeprazole
for the conditions described herein is from about 5 mg
to about 200 mg in single or divided doses. Preferably
a daily dose range should be about 10 mg to about 50 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 15 mg and increased up
to about 50 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 responses) 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,
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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," "an amount
sufficient to alleviate gastric hypersecretion but
insufficient to cause said adverse effects" and "an
amount sufficient to treat psoriasis" are encompassed
by the above-described dosage amounts and dose
frequency schedule.
The relative activity, potency and specificity of
optically pure rabeprazole and racemic rabeprazole 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 (+) rabeprazole, (-) rabeprazole 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 7Ø Plasma gastrin levels are then
determined in a secand 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
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are made. These responses are then analyzed
statistically using Student's "t" test to assess
whether equivalent antisecretory doses show differences
in gastrin responses.
S Any suitable route of administration may be
employed for providing the patient with an effective
dosage of (+) rabeprazole. Rectal, parenteral
(subcutaneous, intramuscular, intravenous),
transdermal, and like forms of administration are
possible, but oral administration is preferred. Oral
dosage forms include tablets, troches, dispersions,
suspensions, solutions, capsules, and the like.
The pharmaceutical compositions of the present
invention comprise (+) rabeprazole as the active
ingredient, or a pharmaceutically acceptable salt
thereof, and may also contain a pharmaceutically
acceptable carrier, and optionally, other therapeutic
ingredients.
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 and is unstable at low pH,
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 of aluminum, calcium, lithium,
magnesium, potassium, sodium, titanium and zinc or
organic salts made from lysine, N,N'-
dibenzylethylenediamine, chloroprocaine, choline,
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diethanolamine, ethylenediamine, meglumine (N-
methylglucamine) and procaine. Sodium salts are
preferred.
The compositions of the present invention include
suspensions, solutions, elixirs 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. It has been found that the inclusion of
mannitol and of basic salts of calcium and magnesium in
the compositions allows the preparation of tablets and
capsules that retain good stability. If desired,
tablets and granules may be coated by standard aqueous
or nonaqueous techniques. Oral dosage forms suitable
for rabeprazole are described in US patent 5,035,899
and in PCT applications W096/01624, W097/12580 and
W097/25030, the disclosures of which are incorporated
herein by reference.
In addition to the common dosage forms set out
above, the compounds of the present invention may also
be administered by controlled release formulations,
which are well known in the art. Compositions suitable
for rectal administration are described in European
Application 645140, the disclosure of which is
incorporated herein by reference.
Pharmaceutical compositions of the present
invention suitable for oral administration may be
presented as discrete units such as capsules, cachets,
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or tablets, 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-
s 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.
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 10
mg, about 30 mg or about 50 mg of (+) rabeprazole for
oral administration.
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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 - Tablets
Composition per tablet:
R(+) rabeprazole 30 mg
Precipitated calcium carbonate 50 mg
Corn Starch 40 mg
Lactose 73.4 mg
Hydroxypropylcellulose 6 mg
Magnesium stearate (0.05 ml)
Total 200.0 mg
EXAMPLE 1
R(+) Rabeprazole, precipitated calcium carbonate,
corn starch, lactose and hydroxypropylcellulose are
mixed together, water is added, and the mixture is
kneaded, then dried in vacuum at 40o C, for 16 hours,
ground in a mortar and passed through a 16-mesh sieve
to give granules. To this is added magnesium stearate
and the resultant mixture is made up into tablets each
weighing 200 mg on a rotary tableting machine.
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Example 2 - Granules
Composition per tablet :
R(+) rabeprazole 30 mg
Magnesium carbonate 20 mg
Corn Starch 80 mg
Microcrystalline cellulose 20 mg
Carboxymethylcellulose calcium 10 mg
Hydroxypropylcellulose 10 mg
Pluronic F68 4 mg
Lactose 26 mg
Water (0.05 ml)
Total 200 mg
EXAMPLE 2
The ingredients above are mixed well in the
proportions shown, water is added, and the mixture is
kneaded and granulated in an extruder granulator
(screen size 1.0 mm ~). The granules are immediately
converted to spherical form in a spheronizer. The
spherical granules are then dried under vacuum at 400
C. for 16 hours and passed through round sieves to give
12- to 42-mesh granules.
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Example 3 - Capsules
Enteric coating composition:
Eudragit L-30D 138 mg (solids 41.4 mg?
Talc 4.1 mg
Polyethylene glycol
5000 12.4 mg
Tween 80 2.1 mg
Water 276 ~C1
Composition of enteric granules:
Granules of Example 5 200 mg
Enteric coat 60 ma
Total 260 mg
Composition her capsule:
Enteric granules 260 mg
No. 1 hard capsule 76 ma
Total 336 mg
EXAMPLE 3
Enteric granules are produced by coating the
granules obtained in Example 2 with the enteric coating
composition shown using a fluidized bed granulator
under conditions such that the inlet air temperature is
50o C. and the granule temperature is about 40o C.
Number 1 hard capsules are filled with the enteric
granules thus obtained in an amount of 260 mg per
capsule using a capsule filling machine.
An enteric coating, such as the polyacrylate
Eudragit L~ and Eudragit S° series, is applied by spray
coating the tablets, preferably with an aqueous
dispersion of the coating polymer. 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.
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