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Title: Preparations for
evaluating eliminative ability of stomach
United States Patent: 7,018,613
Issued: March 28, 2006
Inventors: Nakagawa; Shinsuke (Tokushima,
JP); Yamada; Keigo (Tokushima, JP); Miyake; Masateru (Tokushima, JP);
Inada; Makoto (Tokushima, JP); Ikei; Nobuhiro (Tokushima, JP); Noda;
Atsunari (Tokushima, JP); Nonomura; Hideji (Tokushima, JP)
Assignee: Otsuka Pharmaceutical Co., Ltd.
(Tokyo, JP)
Appl. No.: 275072
Filed: April 25, 2001
PCT Filed: April 25, 2001
PCT NO: PCT/JP01/03549
371 Date: February 25, 2003
102(e) Date: February 25, 2003
PCT PUB.NO.: WO01/82979
PCT PUB. Date: November 8, 2001
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Executive MBA in Pharmaceutical Management, U. Colorado
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Abstract
Preparations whereby reduction or
acceleration of the gastric emptying rate can be noninvasively evaluated:
and a method of evaluating the gastric emptying rate by using these
preparations. Thus, reduction or acceleration of the gastric emptying rate
can be safely and conveniently examined. Namely, theses preparations are
useful in objectively diagnosing the gastric motor function, as well as in
evaluating and judging the drug effect or therapeutic effect of a drug
concerning the gastric motor function on individual patients.
DISCLOSURE OF THE
INVENTION
It is an object of the present invention
to provide a preparation that allows the easy and noninvasive measurement
of the gastric emptying function. More concretely, it is an object of the
present invention to provide a preparation that allows the measurement and
evaluation of the gastric emptying rate using the expired air.
Furthermore, it is also an object of the present invention to provide a
simple method for measuring the gastric emptying rate using the
abovementioned preparation. Moreover, it is also an object of the present
invention to provide a method for diagnosing and evaluating the gastric
emptying function (gastric motor function) in examined subjects, and a
method for evaluating the pharmacological effects and therapeutic effects
of drugs relating to the gastric motor function in individual subjects,
utilizing the abovementioned method for measuring the gastric emptying
rate.
Generally, when food is consumed and enters the stomach, it is gradually
physically pulverized into small particles as a result of being subjected
to the effects of gastric contractions (gastric peristalsis), as well as
the effects of acids and enzymes. Then, at the point in time at which the
food has been converted into particle with a size of approximately 1 to 2
mm, this food is transferred into the intestines via the pylorus. The
present inventors focused on the mechanism of the gastric digestion and
evacuation, to develop a method for the simple measurement of the gastric
emptying rate. As a result, the present inventors found that in the case
of a preparation (a stomach-soluble type <a disintegrate-release type
sustained-release preparation>) that is prepared so that is gradually
disintegrated and dissolved inside the stomach, there is a correlation
between the endogastric elution behavior of the components of the
preparation and the gastric emptying rate (gastric movement). On the basis
of this finding, the present inventors confirmed that the gastric emptying
rate can easily be measuring the elution behavior of the
disintegrate-release type sustained-release preparation. Furthermore, the
present inventors confirmed that, when a labeled compound excreted in the
exhalation as carbon dioxide gas following metabolization is used in
preparation of the abovementioned sustained-release preparation, the
gastric emptying rate can be measured in a noninvasive manner from the
excretion behavior of the labeled compound or metabolites thereof.
The first preparation of the present invention (hereafter referred to as
"a stomach-soluble preparation") was perfected on the basis of such
findings. Specifically, the first preparation of the present invention ("a
stomach-soluble preparation") is a preparation for measuring the gastric
emptying rate as described in items 1 through 9 below:
Item 1. A preparation for measuring the gastric emptying rate comprising a
composition containing a compound (labeled compound) that is labeled with
either an isotope of C or O, or with isotopes of both, and that is
converted into labeled CO2 in the body and excreted in the
exhalation, this preparation being a disintegrate-release type
sustained-release preparation.
Item 2. The preparation for measuring the gastric emptying rate according
to item 1, wherein the behavior of the preparation following oral
administration to the subject is such that:
(i) the preparation remains inside the
stomach for a certain period of time after entering the stomach, without
being immediately discharged from the stomach,
(ii) the surface of the preparation is
gradually eroded by the gastric contraction so that the preparation is
disintegrated, and as this erosion and disintegrate occurs, the labeled
compound is gradually eluted into the stomach, and
(iii) the eluted labeled compound is
converted into labeled carbon dioxide gas inside the stomach and excreted
in the exhalation, or is absorbed, metabolized and excreted in the
exhalation as labeled carbon dioxide gas.
Item 3. The preparation for measuring the gastric emptying rate according
to item 1 or item 2, wherein the preparation can expand to a size that
does not pass through the pylorus for a certain period of time following
oral administration.
Item 4. The preparation for measuring the gastric emptying rate according
to any of items 1 through 3, which comprises an anti-disintegrator in
addition to a labeled compound.
Item 5. The preparation for measuring the gastric emptying rate according
to item 4, wherein the anti-disintegrator is at least one member selected
from a group consisting of water-soluble high-molecular weight compound,
fat and oil, and sugars.
Item 6. The preparation for measuring the gastric emptying rate according
to item 4 or item 5, wherein the anti-disintegrator is at least one member
selected from a group consisting of hydroxypropylcellulose,
hydroxypropylmethylcellulose, ethylcellulose, cellulose acetate phthalate,
hardened oil, carnauba wax, sugars and sugar alcohol.
Item 7. The preparation for measuring the gastric emptying rate according
to any of items 1 through 6, wherein the isotope is at least one member
selected from a group consisting of 13C, 14C and
18O.
Item 8. The preparation for measuring the gastric emptying rate according
to any of items 1 through 7, wherein the labeled compound is at least one
member selected from a group consisting of alkali metal salt, alkaline
earth metal salt and ammonium salt of carbonic acid, alkali metal
hydrogencarbonate, alkaline earth metal hydrogencarbonate and ammonium
hydrogencarbonate
Item 9. The preparation for measuring the gastric emptying rate according
to any of items 1 through 8, wherein the labeled compound is at least one
member selected from a group consisting of acetic acid, glycine, octanoic
acid and alkali metal salts thereof.
Furthermore, the preparation has a form for oral administration such as
tablet, capsule, pill, powder, granule or the like.
As a result of further research based on the abovementioned findings, the
present inventors found that if a labeled compound that generates carbon
dioxide gas as result of dissolution or a metabolic reaction is used in
manufacturing of a preparation that dissolves in the intestines, the
preparation is be dissolved in intestine or be subjected to further
metabolization, and excreted in the exhalation as labeled carbon dioxide
gas. The inventors also found that the gastric emptying rate can be
measured noninvasively by tracking the behavior of the labeled carbon
dioxide gas excreted in the exhalation, and that as a result, the gastric
emptying function can easily be evaluated.
There are generally two types of gastric and intestinal motor patterns
(motor mode) in humans and animals, i.e., a fasting mode and an ingestion
mode. The present inventors confirmed that the gastric emptying rate can
be measured in accordance with these various motor modes by appropriately
selecting the size of the abovementioned intestine-soluble preparation.
The second preparation of the present invention (hereafter referred to as
"an intestine-soluble preparation") was perfected on the basis of such
findings. Specifically, the second preparation of the present invention
("a intestine-soluble preparation") is a preparation for measuring the
gastric emptying rate as described in items 10 through 15 below:
Item 10. A preparation for measuring the gastric emptying rate comprising
a composition containing a compound (labeled compound) that is labeled
with either an isotope of C or O, or with isotopes of both, and that is
converted into labeled CO2 in the body and excreted in the
exhalation, the preparation being coated by an enteric coating.
Item 11. The preparation for measuring the gastric emptying rate according
to item 10, wherein the behavior of the preparation following oral
administration to the subject being such that:
(1) the preparation remains inside the
stomach for a certain period of time after entering the stomach, without
being discharged from the stomach,
(2) the preparation is discharged from
the stomach by the gastric housekeeper movement, and
(3) the preparation is then dissolved in
the intestines, and the labeled compound eluted from the interior of the
preparation is converted into labeled carbon dioxide inside the intestines
or absorbed and metabolized, and is excreted in the exhalation.
Item 12. The preparation for measuring the gastric emptying rate according
to item 10, wherein the behavior of the preparation following oral
administration to the subject being such that:
(1) the preparation enters the stomach,
(2) the preparation is discharged from
the stomach by the gastric movement to discharge food, and
(3) the preparation is dissolved in the
intestines, and the labeled compound eluted from the interior of the
preparation is converted into labeled carbon dioxide inside the intestines
or absorbed and metabolized, and is excreted in the exhalation.
Item 13. The preparation for measuring the gastric emptying rate according
to any of items 10 through 12, wherein the isotope is at least one member
selected from a group consisting of 13C, 14C and
18O.
Item 14. The preparation for measuring the gastric emptying rate according
to any of items 10 through 13, wherein the labeled compound is at least
one compound selected from a group consisting of alkali metal salt,
alkaline earth metal salt and ammonium salt of carbonic acid, alkali metal
hydrogencarbonate, alkaline earth metal hydrogencarbonate, and ammonium
hydrogencarbonate.
Item 15. The preparation for measuring the gastric emptying rate according
to any of items 10 through 14, wherein the labeled compound is at least
one compound selected from a group consisting of acetic acid, glycine,
octanoic acid and alkali metal salts thereof.
The abovementioned preparation can be prepared in a form for oral
administration such as tablet, capsule, pill, powder, granule or the like.
Furthermore, the present invention provides a method for measuring the
gastric emptying rate using at least one preparation for measuring the
gastric emptying rate, i.e., either the first preparation or the second
preparation described above. In concrete terms, the method can be
performed by orally administering any of the stomach-soluble preparations
described in the abovementioned items 1 through 9 or the intestine-soluble
preparations described in the abovementioned items 10 through 15 to the
subject, and then measuring the behavior of the labeled compound in the
body, or measuring the amount or behavior of a labeled compound
(metabolite) excreted from the body. Preferably, this involves measurement
of the amount or behavior of labeled CO2 excreted in the
exhalation.
The gastric emptying rate of the subject can be evaluated by utilizing
such a method. Accordingly, the present invention also provides a
diagnostic evaluation method for the gastric emptying rate of humans or
animals. In concrete terms, this method can be performed by orally
administering any of the stomach-soluble preparations described in the
abovementioned items 1 through 9 or the intestine-soluble preparations
described in the abovementioned items 10 through 15 to a subject for whom
a reduction or acceleration of the gastric emptying function is suspected,
and then comparing the behavior of the labeled compound inside the body or
the amount or behavior of a labeled compound excreted from the body, with
the behavior of the labeled compound inside the body or amount or behavior
of a labeled compound excreted from the body that is obtained for a
healthy subject using the same preparation for measuring the gastric
emptying rate. Preferably, the method is performed by comparing the amount
or behavior of labeled CO2 excreted in the exhalation for the
abovementioned healthy subject and subject in which a reduction or
acceleration of the gastric emptying function is suspected. Furthermore,
the evaluation of the abovementioned gastric emptying rate can be
performed more accurately by using two separate preparations, i.e., the
stomach-soluble preparation and the intestine-soluble preparation, in
combination.
Furthermore, in the case of drugs relating to the gastric motor function,
the pharmacological effect or therapeutic effect on individual subjects
can be evaluated by utilizing the abovementioned method. Accordingly, the
present invention also relates to a method for evaluating the
pharmacological effect or therapeutic effect of drugs relating to the
gastric motor function. In concrete terms, this method can be performed by
orally administering any of the stomach-soluble preparations described in
the abovementioned items 1 through 9 or the intestine-soluble preparations
described in the abovementioned items 10 through 15 to the subject before
and after the administration of a drug relating to the gastric motor
function, measuring the behavior of the labeled compound inside the body
or the amount or behavior of a labeled compound (matabolite) excreted from
the body, and comparing the results obtained before the administration of
the drug with the results obtained after the administration of the drug.
Preferably, the method of the present invention is performed by comparing
the amount or behavior of labeled CO2 gas excreted in the
exhalation prior to the administration of the abovementioned drug with the
amount or behavior of labeled CO2 gas excreted in the
exhalation following the administration of the abovementioned drug.
Furthermore, the evaluation of the pharmacological effect or therapeutic
effect of the abovementioned drug can be performed more accurately by
using two preparations, i.e., a stomach-soluble preparation and an
intestine-soluble preparation, in combination.
Claim 1 of 20 Claims
1. A preparation for measuring
the gastric emptying rate comprising a composition containing a compound
that is labeled with at least one of the isotopes of C and O and that is
converted into labeled CO2 in the body and excreted in the
exhalation,
the preparation being coated by an enteric coating and having a mean size of
1 mm or greater, wherein the behavior of the preparation following oral
administration to a subject being such that:
(1) the preparation remains inside the stomach after entering the stomach,
without being discharged from the stomach,
(2) the preparation is discharged from the stomach by the gastric
housekeeper movement, and
(3) the preparation is dissolved in the intestines, and the labeled compound
eluted from the interior of the preparation is converted into labeled carbon
dioxide inside the intestines or absorbed and metabolized, and is excreted
in the exhalation.
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