U.S. patent application number 14/505415 was filed with the patent office on 2015-01-15 for oral preparation useful in measuring capacity to metabolize pyridine.
The applicant listed for this patent is OTSUKA PHARMACEUTICAL CO., LTD.. Invention is credited to Yoshiharu INOUE, Tadashi MUKAI.
Application Number | 20150017100 14/505415 |
Document ID | / |
Family ID | 37683305 |
Filed Date | 2015-01-15 |
United States Patent
Application |
20150017100 |
Kind Code |
A1 |
INOUE; Yoshiharu ; et
al. |
January 15, 2015 |
ORAL PREPARATION USEFUL IN MEASURING CAPACITY TO METABOLIZE
PYRIDINE
Abstract
An object of the present invention is to provide an oral
preparation that can be used to diagnose the existence or degree of
pyridine metabolic capacity disorder, pyrimidine metabolic rate,
etc., with high accuracy and with little variation due to
individual differences. The oral preparation is prepared using a
powder material obtained by mixing and pulverizing (a) an
isotope-labeled compound and/or a pyrimidine metabolite compound
and (b) a sugar and/or a sugar alcohol.
Inventors: |
INOUE; Yoshiharu;
(Tokushima, JP) ; MUKAI; Tadashi; (Tokushima,
JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
OTSUKA PHARMACEUTICAL CO., LTD. |
Tokyo |
|
JP |
|
|
Family ID: |
37683305 |
Appl. No.: |
14/505415 |
Filed: |
October 2, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11989286 |
Jan 24, 2008 |
8883121 |
|
|
PCT/JP2006/314591 |
Jul 24, 2006 |
|
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14505415 |
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Current U.S.
Class: |
424/9.1 |
Current CPC
Class: |
A61K 9/2018 20130101;
A61K 49/0004 20130101; A61K 51/1255 20130101; A61K 9/145 20130101;
A61K 9/1623 20130101 |
Class at
Publication: |
424/9.1 |
International
Class: |
A61K 49/00 20060101
A61K049/00; A61K 9/14 20060101 A61K009/14 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 25, 2014 |
JP |
2005-214762 |
Claims
1-18. (canceled)
19. An oral preparation produced using a powder material obtained
by mixing component (a) and component (b) and pulverizing a
resulting mixture, wherein a particle diameter at 50% of the powder
material is 5 to 20 .mu.m, (a) at least one isotope-labeled
compound selected from the group consisting of thymine, uracil and
a metabolite thereof, in which at least one of carbon atoms, oxygen
atoms, and nitrogen atoms is labeled with an isotope, and (b) at
least one sugar alcohol selected from the group consisting of
erythritol, mannitol, xylitol, sorbitol, maltitol, reducing
paratinose and lactitol.
20. An oral preparation according to claim 19, which contains the
component (a) in a proportion of 5 to 20 wt. %.
21. An oral preparation according to claim 19, wherein the
component (a) is isotope-labeled uracil.
22. An oral preparation according to claim 19, wherein the
component (b) is mannitol.
23. An oral preparation according to claim 19, wherein the
component (a) is isotope-labeled uracil and the component (b) is
mannitol.
24. An oral preparation according to claim 19, wherein the oral
preparation is a solid preparation.
25. An oral preparation according to claim 24, wherein the solid
preparation is subtle granules, granules, powders, tablets,
capsules or pills.
26. An oral preparation according to claim 19, wherein the oral
preparation is administered at the same time as or immediately
before or after ingestion of a test meal.
27. A process for producing an oral preparation, the process
comprising the steps of: (1) producing a powder material by mixing
component (a) and component (B) and pulverizing a resulting
mixture, wherein a particle diameter at 50% of the powder material
is 5 to 20 .mu.m, (a) at least one isotope-labeled compound
selected from the group consisting of thymine, uracil and a
metabolite thereof, in which at least one of carbon atoms, oxygen
atoms, and nitrogen atoms is labeled with an isotope, and (b) at
least one sugar alcohol selected from the group consisting of
erythritol, mannitol, xylitol, sorbitol, maltitol, reducing
paratinose and lactitol; and (2) formulating the powder material
obtained in the above step (1) into a preparation.
28. A process according to claim 27, wherein the oral preparation
contains the component (a) in a proportion of 5 to 20 wt. %.
29. A process according to claim 27, wherein the component (a) is
isotope-labeled uracil.
30. A process according to claim 27, wherein the component (b) is
mannitol.
31. A process according to claim 27, wherein the component (a) is
isotope-labeled uracil and the component (b) is mannitol.
32. A process according to claim 27, wherein the oral preparation
is a solid preparation.
33. A process according to claim 32, wherein the solid preparation
is subtle granules, granules, powders, tablets, capsules or
pills.
34. A process according to claim 27, wherein the oral preparation
is administered at the same time as or immediately before or after
ingestion of a test meal.
Description
TECHNICAL FIELD
[0001] The present invention relates to an oral preparation that
can be effectively used to assess, with high accuracy, the
existence or degree of a pyridine metabolic capacity disorder;
pyrimidine-metabolic rate; etc. The present invention also relates
to a process for producing the oral preparation.
BACKGROUND ART
[0002] 5-Fluorouracil (hereinafter sometimes referred to as
"5-FU"), various derivatives thereof (such as tegafur, carmofur,
doxifluridine, etc.), and like fluorouracil drugs are widely used
as anticancer drugs at present. It is known that 5-FU administered
to the body is first degraded by the action of dihydropyrimidine
dehydrogenase (hereinafter sometimes referred to as "DPD"), which
is the first enzyme in the pyrimidine metabolic pathway. It is
therefore believed that the concomitant use of a drug that inhibits
DPD enzymatic activity is effective in sustaining the effects of
fluorouracil drugs such as 5-FU and the like. On the other hand, it
is known that when a fluorouracil drug such as 5-FU is administered
to a subject with DPD deficiency or reduced DPD activity, the drug
is not metabolized in a normal manner and results in an abnormally
high fluorouracil drug concentration in the blood, thereby causing
severe side effects (e.g., myelosuppression, digestive symptoms,
etc).
[0003] Thus, in order to effectively exhibit the action of
fluorouracil drugs or prevent the side effects of fluorouracil
drugs, diagnosis of pyrimidine-metabolic capacity, i.e., the
existence, degree, etc., of a pyrimidine metabolic disorder in the
subject, before administration of a fluorouracil drug is believed
to be important.
[0004] A method for diagnosing pyrimidine metabolic activity in a
subject has been reported in which an isotope-labeled pyrimidine
compound is administered to the subject, and the excretion behavior
of the isotope-labeled metabolic product discharged from the body
is measured so as to determine the pyrimidine metabolic capacity,
i.e., the existence, degree, etc., of a pyrimidine metabolic
disorder in the subject (e.g., Patent Document 1). Granules and
subtle granules containing isotope-labeled pyrimidine compounds and
carriers are already known as pyrimidine metabolic capacity
diagnosis preparations for use in the above method.
[0005] However, isotope-labeled pyrimidine compounds, such as
.sup.13C-uracil, have, as well as low solubility,
characteristically high cohesiveness, although bulk powders of such
compounds themselves are fine particles of several microns.
Therefore, granules and subtle granules prepared from
isotope-labeled pyrimidine compounds as such by standard methods do
not rapidly dissolve, and partly because of this, the compounds
have disadvantages such as a slow and non-uniform absorption rate
in the living body and variation in the absorption rate due to
individual differences. Therefore, in order to realize pyrimidine
metabolic capacity diagnosis with higher accuracy, it is desired to
overcome the above defects so that variation in the excretion time
and amount of the isotope-labeled metabolic products can be reduced
and the non-uniformity of diagnosis accuracy due to individual
differences can be decreased.
Patent Document 1: International Publication No. WO 02/072153,
pamphlet
DISCLOSURE OF THE INVENTION
Problems to be Solved by the Invention
[0006] An object of the present invention is to provide an oral
preparation that can be used to diagnose the existence, degree,
etc., of a pyridine metabolic capacity disorder, with high accuracy
and with little variation due to individual differences.
Means for Solving the Problems
[0007] The present inventors conducted extensive research to solve
the above problems, and found that an oral preparation prepared
using a powder material obtained by mixing and pulverizing (a) an
isotope-labeled compound and/or a metabolite thereof, and (b) a
sugar and/or a sugar alcohol, enables pyrimidine metabolic capacity
diagnosis with high accuracy and with little variation due to
individual differences. The present invention has been achieved by
further improvements based on this finding.
[0008] The present invention provides the following oral
preparations, production processes for the same, etc.
[0009] Item 1. An oral preparation produced from a powder material
obtained by mixing and pulverizing (a) a pyrimidine compound and/or
a metabolite thereof, in which at least one of carbon atoms, oxygen
atoms, and nitrogen atoms is labeled with an isotope, and (b) a
sugar and/or a sugar alcohol.
[0010] Item 2. An oral preparation according to item 1, wherein a
particle diameter at 50% of the powder material is 40 .mu.m or
less.
[0011] Item 3. An oral preparation according to item 1, which
contains the component (a) in a proportion of 5 to 20 wt. %.
[0012] Item 4. An oral preparation according to item 1, wherein the
component (a) is isotope-labeled uracil.
[0013] Item 5. An oral preparation according to item 1, wherein the
component (b) is mannitol.
[0014] Item 6. An oral preparation according to item 1, wherein the
component (a) is isotope-labeled uracil and the component (b) is
mannitol.
[0015] Item 7. An oral preparation according to item 1, which is a
granular preparation.
[0016] Item 8. An oral preparation according to item 7, which is
produced by extrusion granulation of the powder material.
[0017] Item 9. An oral preparation according to item 7, wherein the
granular preparation has a mean particle diameter of 1400 .mu.m or
less.
[0018] Item 10. An oral preparation according to item 1, which is a
preparation for diagnosing pyrimidine-metabolic capacity.
[0019] Item 11. An oral preparation according to item 1, which is a
preparation for determining gastric emptying capacity.
[0020] Item 12. An oral preparation according to item 1, which is a
preparation for diagnosing dyspepsia.
[0021] Item 13. A process for producing an oral preparation, the
process comprising the steps of:
[0022] (1) producing a powder material by mixing and pulverizing
(a) a pyrimidine compound and/or a metabolite thereof, in which at
least one of carbon atoms, oxygen atoms, and nitrogen atoms is
labeled with an isotope, and (b) a sugar and/or a sugar alcohol;
and
[0023] (2) formulating the powder material obtained in the above
step (1) into a preparation.
[0024] Item 14. A process according to item 13, wherein a particle
diameter of the powder material produced in the step (1) is of 40
.mu.m or less.
[0025] Item 15. A process according to item 13, wherein the oral
preparation contains the component (a) in a proportion of 5 to 20
wt. %.
[0026] Item 16. A process according to item 13, wherein the
component (a) is isotope-labeled uracil.
[0027] Item 17. A process according to item 13, wherein the
component (b) is mannitol.
[0028] Item 18. A process according to item 13, wherein the
component (a) is isotope-labeled uracil and the component (b) is
mannitol.
[0029] Item 19. A process according to item 13, wherein the oral
preparation has a granular form.
[0030] Item 20. A process according to item 19, wherein the step
(2) is a step of formulating the powder material obtained in the
step (1) into a preparation by extrusion granulation.
[0031] Item 21. A process according to item 19, wherein the oral
preparation is a granular preparation having a mean particle
diameter of 1400 .mu.m or less.
[0032] Item 22. A process according to item 13, wherein the oral
preparation is a preparation for diagnosing pyrimidine metabolic
capacity.
[0033] Item 23. A process according to item 13, wherein the oral
preparation is a preparation for determining gastric emptying
capacity.
[0034] Item 24. A process according to item 13, wherein the oral
preparation is a preparation for diagnosing dyspepsia.
[0035] Item 25. Use of a powder material obtained by mixing and
pulverizing (a) a pyrimidine compound and/or a metabolite thereof,
in which at least one of carbon atoms, oxygen atoms, and nitrogen
atoms is labeled with an isotope, and (b) a sugar and/or a sugar
alcohol, for producing a preparation for diagnosing pyrimidine
metabolic capacity.
[0036] Item 26. Use of a powder material obtained by mixing and
pulverizing (a) a pyrimidine compound and/or a metabolite thereof,
in which at least one of carbon atoms, oxygen atoms, and nitrogen
atoms is labeled with an isotope, and (b) a sugar and/or a sugar
alcohol, for producing a preparation for determining gastric
emptying capacity.
[0037] Item 27. Use of a powder material obtained by mixing and
pulverizing (a) a pyrimidine compound and/or a metabolite thereof,
in which at least one of carbon atoms, oxygen atoms, and nitrogen
atoms is labeled with an isotope, and (b) a sugar and/or a sugar
alcohol, for producing a preparation for diagnosing dyspepsia.
Effects of the Invention
[0038] The oral preparation of the present invention is produced by
formulating a powder material obtained by mixing and pulverizing
(a) an isotope-labeled compound and/or a metabolite thereof and (b)
a sugar and/or a sugar alcohol, into a preparation. With such
formulation, the oral preparation of the present invention makes it
possible to diagnose pyrimidine metabolic capacity and gastric
emptying capacity with high accuracy and with little variation due
to individual differences. As a result, the behavior of an
isotope-labeled metabolic product can be correctly determined by
one or a small number of measurements, 20 to 30 minutes after
administration of the preparation, so that the time required for
the determination and the number of measurements can be reduced,
thereby decreasing the burden on patients.
BRIEF DESCRIPTION OF THE DRAWINGS
[0039] [FIG. 1]A figure showing the behavior of degradation
(metabolism) of pyrimidine compounds (uracil, 5-fluorouracil
(5-FU), and thymine) by a series of pyrimidine metabolizing enzymes
(dihydropyrimidine dehydrogenase (DPD), dihydropyrimidinase
(DHPase), and .beta.-ureidopropionase (.beta.-UPase)).
[0040] [FIG. 2]A figure comparing the results of observing, over
time, the behavior of .sup.13CO.sub.2 excreted in the expired air
of three healthy subjects (Subjects A, B, and C) to whom the
granular preparation of Example 2 has been administered.
[0041] [FIG. 3]A figure comparing the results of observing, over
time, the behavior of .sup.13CO.sub.2 excreted in the expired air
of three healthy subjects (Subjects A, B, and C) to whom the
granular preparation of Comparative Example 2 has been
administered.
[0042] [FIG. 4]A figure-showing, over time, the behavior of
.sup.13CO.sub.2 excreted in the expired air of 20 patients
suspected of having gastroparesis, to whom the preparation of
Example 1 has been administered in Test Example 5.
[0043] [FIG. 5]A figure showing the plasma 2-.sup.13C uracil
concentration in patients divided into three groups (normal gastric
emptying capacity, reduced gastric emptying capacity, and
insufficient gastric emptying capacity) based on the results shown
in FIG. 4, 20 minutes after administration of the preparation of
Example 1.
BEST MODE FOR CARRYING OUT THE INVENTION
[0044] The present invention is described below in detail.
[0045] The oral preparation of the present invention contains an
isotope-labeled pyrimidine compound and/or a metabolite thereof
(hereinafter these are sometimes referred to as "Component
(a)").
[0046] The pyrimidine compound for use in the present invention may
be any of a wide variety of compounds having a pyrimidine skeleton,
and is preferably a compound that serves as a substrate for a
pyrimidine metabolizing enzyme, and in particular dihydropyrimidine
dehydrogenase (DPD), which is the first enzyme in the pyrimidine
metabolic pathway in the living body. Specific examples of such
pyrimidine compounds include uracil, thymine, and derivatives
thereof. The derivatives of uracil and thymine are not limited as
long as they serve as substrates for DPD, and as long as their
final metabolic products formed via the pyrimidine metabolic
pathway are discharged in excrement such as expired air, urine, or
sweat. Specific examples of such derivatives include halides of
uracil, such as 5-fluorouracil, 5-bromouracil, etc.; halides of
thymine, such as 5-fluorothymine, 5-bromothymine, etc.; and the
like. Preferable examples of pyrimidine compounds include uracil,
thymine, and 5-fluorouracil.
[0047] Usable pyrimidine compounds include, in addition to the
above compounds, which serve as direct substrates for DPD,
compounds that serve as indirect substrates for the enzyme, i.e.,
precursors (including prodrugs), which are metabolized or degraded
in vivo into substrates for DPD (such as uracil, thymine,
5-fluorouracil, etc.). Examples of such precursors include
precursors of uracil, such as cytosine, uridine, and phosphates
thereof (e.g., uridylic acid); precursors of thymine, such as
5-methylcytosine, thymidine, and phosphates thereof (e.g.,
thymidylic acid); and precursors (prodrugs) of 5-fluorouracil, such
as tegafur, carmofur, doxifluridine, etc.
[0048] The metabolite of a pyrimidine compound is a compound that
corresponds to a metabolic intermediate of the pyrimidine compound
and that serves as a substrate for a pyrimidine metabolizing
enzyme, and in particular dihydropyrimidinase (hereinafter
sometimes referred to as "DHPase"), which is the second enzyme in
the pyrimidine metabolic pathway in the living body, or
.beta.-ureidopropionase (hereinafter sometimes' referred to as
".beta.-UPase"), which is the third enzyme. Specific examples of
metabolites of pyrimidine compounds include dihydrouracil,
dihydrothymine, and derivatives thereof (e.g., halides of
dihydrouracil, such as 5-fluorodihydrouracil and the like), which
serve as substrates for DHPase; and .beta.-ureidopropionic acid,
.beta.-ureidoisobutyric acid, and derivatives thereof (e.g.,
halides of .beta.-ureidopropionic acid, such as
fluoro-.beta.-ureidopropionic acid, and halides of
.beta.-ureidoisobutyric acid), which serve as substrates for
.beta.-UPase.
[0049] In the present invention, Component (a) is preferably a
pyrimidine compound, more preferably uracil, thymine, or
5-fluorouracil, and still more preferably 5-fluorouracil.
[0050] In the pyrimidine compound and/or metabolite thereof for use
in the present invention, at least one of the carbon atoms, oxygen
atoms, and nitrogen atoms in the molecule is labeled with an
isotope. The isotope is not limited, and specific examples include
.sup.13C, .sup.14C, .sup.18O, and .sup.15N. The isotope may be
radioactive or non-radioactive, but .sup.13C, .sup.18O, or
.sup.15N, which are non-radioactive, are preferable from the
viewpoint of safety.
[0051] The pyrimidine compound and/or metabolite thereof for use in
the present invention may have one isotope in the molecule or may
have two or more isotopes of the same or different elements.
Although not limitative, it is preferable that a carbon atom or
oxygen atom in the pyrimidine compound or metabolite thereof be
labeled so that at least part (C or O) of CO.sub.2 produced via the
pyrimidine metabolic pathway is labeled with an isotope. Examples
of such pyrimidine compounds include those having an
isotope-labeled carbon atom at the 2-position of the pyrimidine
skeleton. Specific examples include 2-.sup.13C-labeled uracil and
2-.sup.13C-labeled fluorouracil.
[0052] The method for labeling a pyrimidine compound and/or a
metabolite thereof with an isotope as mentioned above is not
limited, and a wide variety of conventional methods can be employed
(Sasaki, "5.1 Application of Stable Isotopes in Clinical
Diagnosis"; Kagaku no Ryoiki (Journal of Japanese Chemistry) 107,
"Application of Stable Isotopes in Medicine, Pharmacy, and
Biology", Nankodo, pp. 149-163 (1975); Kajiwara, "RADIOISOTOPES",
41, 45-48 (1992); etc.). Some of such isotope-labeled pyrimidine
compounds and metabolites thereof are commercially available, and
these commercial products are conveniently usable.
[0053] The proportion of Component (a) in the oral preparation of
the present invention is, for example, usually 5 to 20 wt. %,
preferably 6 to 18 wt. %, and more preferably 8 to 15 wt. %.
[0054] The oral preparation of the present invention contains, in
addition to Component (a), a sugar and/or a sugar alcohol
(hereinafter these are sometimes referred to as "Component
(b)").
[0055] The sugar for use in the present invention is not limited as
long as it is pharmaceutically acceptable. Examples of such sugars
include glucose, galactose, fructose, xylose, arabinose, mannose,
and like monosaccharides; maltose, isomaltose, cellobiose, lactose,
sucrose, trehalose, and like disaccharides; etc. Among these,
glucose and sucrose are preferable.
[0056] The sugar alcohol for use in the present invention is not
limited as long as it is pharmaceutically acceptable. Specific
examples of sugar alcohols include erythritol, mannitol, xylitol,
sorbitol, maltitol, reducing paratinose, lactitol, etc. Among
these, mannitol, xylitol, and erythritol are preferable, and
mannitol is more preferable.
[0057] In the present invention, Component (b) is preferably a
sugar alcohol, more preferably mannitol, xylitol, or erythritol,
and still more preferably mannitol.
[0058] The proportion of Component (b) in the oral preparation of
the present invention is, for example, usually 80 to 95 wt. %,
preferably 82 to 94 wt. %, and more preferably 85 to 92 wt. %,
based on the total weight of the preparation.
[0059] The ratio of Component (b) to Component (a) in the oral
preparation of the present invention is, for example, 400 to 1900
parts by weight, preferably 450 to 1550 parts by weight, and more
preferably 550 to 1150 parts by weight, of Component (b), per 100
parts by weight of Component (a). The combined use of Components
(a) and (b) in such a ratio further improves the accuracy of
pyrimidine metabolic disorder diagnosis.
[0060] The oral preparation of the present invention is produced by
formulating a powder material containing Components (a) and (b)
into a preparation. The powder material used for preparing the oral
preparation of the present invention is obtained by mixing
Components (a) and (b) in the above ratio and pulverizing the
resulting mixture.
[0061] The oral preparation of the present invention may have the
same composition as the powder material after pulverization, or may
contain other components in addition to the powder material.
Therefore, the proportions of Components (a) and (b) in the powder
material are suitably selected according to the proportions of
Components (a) and (b) in the final form of the oral preparation,
the preparation steps for the oral preparation, etc.
[0062] The powder material may be obtained by mixing and
pulverizing pharmaceutically acceptable additives together with
Components (a) and (b), as long as the effects of the present
invention are not impaired. Such additives are the same as those
that can be added when formulating the powder material into a
preparation. Specific examples of such additives are given
hereinafter.
[0063] The particle diameter of the powder material is not limited
as long as the particle diameter is a result from mixing and
pulverizing Components (a) and (b), but in order to increase the
accuracy of pyrimidine metabolic capacity diagnosis, it is
desirable that the particle diameter at 50% be 40 .mu.m or less,
preferably 30 .mu.m or less, and more preferably 5 to 20 .mu.m.
[0064] Preferable examples of the powder material are powder
materials having a particle size distribution such that the
particle diameter at 50% is 40 .mu.m or less and the particle
diameter at 90% is 200 Cm or less; more preferable examples are
those having a particle size distribution such that the particle
diameter at 50% is 30 .mu.m or less, and the particle diameter at
90% is 100 .mu.m or less; and still more preferable examples are
those having a particle size distribution such that the particle
diameter at 50% is 5 to 20 .mu.m, and the particle diameter at 90%
is 10 to 70 .mu.m. Use of a powder material having such particle
size distribution to prepare the oral preparation enables Component
(a) to be absorbed in the living body at a rapid and uniform rate,
thereby making it possible to diagnose pyrimidine metabolic
capacity with higher accuracy.
[0065] As used herein, the meanings of the particle diameter at 50%
and particle diameter at 90% of the powder material are as follows:
the volume of the particles of the powder material is integrated in
order from the particle with the smallest particle diameter, until
the integrated volume accounts for 50% or 90% of the total volume
of the particles of the powder material, and the particle diameter
of the last particle integrated is the particle diameter at 50% or
90%. The particle diameter at 50% and particle diameter at 90% can
be measured using a dry laser method (measurement conditions: a
focal distance of 100 mm, a number of averaging processes of 10, an
averaging interval of 5 milliseconds, and an air pressure of 0.4
MPa).
[0066] The pulverizing treatment used for the preparation of the
powder material is not limited, but pulverizing treatment using a
dry mill is preferable. Specific examples of dry mills include
hammer mills, pin mills, jet mills, etc.
[0067] The oral preparation of the present invention is produced by
adding, as required, additives such as excipients, binders, pH
adjusters, disintegrators, absorption enhancers, lubricants,
colorants, corrigents, flavors, etc., to the powder material, and
formulating the resulting mixture into a preparation via a
treatment such as granulation or another forming procedure, which
is selected according to the form of the preparation. When the oral
preparation of the present invention is a powder preparation, the
powder material as such can be used as the oral preparation in the
final form.
[0068] Specific examples of additives that can be used for
formulation include lactose, starch, refined white sugar, dextrin,
mannitol, xylitol, sorbitol, erythritol, calcium dihydrogen
phosphate, sodium chloride, glucose, calcium carbonate, kaolin,
crystalline cellulose, silicate, and like excipients; water,
ethanol, simple syrup, glucose solutions, starch solutions, gelatin
solutions, carboxymethylcellulose, carboxymethylcellulose sodium,
shellac, methylcellulose, hydroxypropylmethylcellulose,
hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol,
gelatin, dextrin, pullulan, and like binders; citric acid, citric
anhydride, sodium citrate, sodium citrate dihydrate, anhydrous
sodium monohydrogen phosphate, anhydrous sodium dihydrogen
phosphate, sodium hydrogen phosphate, anhydrous sodium dihydrogen
phosphate, and like pH adjusters; carmellose calcium,
low-substituted hydroxypropycellulose, carmellose, croscarmellose
sodium, carboxymethyl starch sodium, crospovidone, and like
disintegrators; polysorbate 80, quaternary ammonium bases, sodium
lauryl sulfate, and like absorption enhancers; purified talc,
stearate, polyethylene glycol, colloidal silicic acid, sucrose
fatty acids, hydrogenated oils, and like lubricants; yellow iron
oxide, yellow iron sesquioxide, iron sesquioxide, .beta.-carotene,
titanium oxide, food colors (e.g., Food Blue No. 1), copper
chlorophyll, riboflavin, and like colorants; ascorbic acid,
aspartame, sweet hydrangea leaf, sodium chloride, and like
corrigents; and the like.
[0069] The form of the oral preparation of the present invention is
not limited as long as it is a solid preparation, and subtle
granules, granules, powders, tablets (including naked tablets and
coated tablets), capsules, pills, and other forms can be selected
as desired. Among these, to further enhance the effects of the
present invention, granular preparations such as subtle granules
and granules, and in particular granular preparations produced by
extrusion granulation, are preferred.
[0070] When the oral preparation of the present invention is a
granular preparation, the mean particle diameter of the preparation
is, for example, usually 1400 .mu.m or less, preferably 50 to 1200
.mu.m, and more preferably 100 to 1000 .mu.m. When the granular
preparation has such a particle diameter, the granular preparation
enables pyrimidine metabolic capacity diagnosis with higher
accuracy. The particle diameter of the preparation can be measured
using a vibration sieve method (specifically, using a measurement
apparatus Robot Shifter RPS-95 (Seishin Enterprise Co., Ltd.) at a
vibration level of 5, a shift time of 5 minutes, and a pulse
interval of 1 second).
[0071] After administering the oral preparation of the present
invention, the pyrimidine metabolic capacity, i.e., the existence
or degree of a pyrimidine metabolic disorder, pyrimidine metabolic
rate, etc., in a subject, can be assessed by measuring the
excretion behavior of the isotope-labeled metabolic product
excreted from the body. Therefore, the oral preparation of the
present invention can be used as a preparation for determining
pyrimidine metabolic capacity. Further, as described hereinafter,
since gastric emptying capacity can also be assessed based on the
assessment results of pyrimidine metabolic capacity, and
specifically the results of measuring pyrimidine metabolic rate,
the oral preparation of the present invention can also be used as a
preparation for determining gastric emptying capacity. Embodiments
of the preparation for determining pyrimidine metabolic capacity
and the preparation for determining gastric emptying capacity are
specifically described below.
Preparation for Determining Pyrimidine Metabolic Capacity
[0072] Since the oral preparation of the present invention can be
used to determine pyrimidine metabolic capacity with respect to the
existence, degree, etc., of a pyrimidine metabolic disorder, the
preparation is useful for the detection, measurement, and diagnosis
of a pyrimidine metabolic disorder. Specific conditions, method,
etc., for using the oral preparation of the present invention as a
preparation for determining pyrimidine metabolic capacity are as
follows.
[0073] When the oral preparation of the present invention is
administered to a subject with normal pyrimidine metabolic
capacity, in whom or which the series of pyrimidine metabolizing
enzymes (DPD, DPHase, and .beta.-UPase) function normally in the
living body (hereinafter sometimes referred to as a "healthy
subject"), the pyrimidine compound contained as Component (a) in
the preparation is metabolically degraded into metabolic products
such as .beta.-alanine, F-.beta.-alanine, .beta.-aminoisobutyric
acid, NH.sub.3, CO.sub.2, etc., as shown in FIG. 1.
[0074] The final metabolic product CO.sub.2 thus formed by
metabolism is excreted in expired air, and .beta.-alanine,
F-.beta.-alanine, or .beta.-aminoisobutyric acid is excreted mainly
in urine. Of the final metabolic products thus excreted, at least
one of CO.sub.2 and a final metabolic product selected from
.beta.-alanine, F-.beta.-alanine, and .beta.-aminoisobutyric acid
is labeled with an isotope, depending on the isotope-labeled site
of the pyrimidine compound and/or metabolite thereof used as
Component (a). Such an isotope label is used as an index to measure
the excretion behavior (the behavior of excretion amount or
excretion rate over time) of these final metabolic products using,
as a test sample, expired air when CO.sub.2 is labeled, or urine
when .beta.-alanine, F-.beta.-alanine, .beta.-aminoisobutyric acid,
or ammonia is labeled.
[0075] The pyrimidine metabolic capacity of the subject can be
determined from the thus measured excretion behavior (the behavior
of excretion amount or excretion rate over time) of the
isotope-labeled metabolic product.
[0076] When the oral preparation of the present invention is used
for determining pyrimidine metabolic capacity, the dose of the oral
preparation of the present invention is not limited, but is
preferably an amount corresponding to 1 to 2000 mg, and preferably
10 to 300 mg, of Component (a).
[0077] When using the oral preparation of the present invention for
determining pyrimidine metabolic capacity, it is preferable to use
as Component (a) a pyrimidine compound and/or a metabolite thereof
that causes isotope-labeled CO.sub.2 to be excreted in expired air
as a result of metabolism. Using such a preparation, the pyrimidine
metabolic capacity of a subject can be determined from the
excretion behavior (the behavior of excretion amount and excretion
rate over time) of isotope-labeled CO.sub.2, which can be found by
administering the preparation to the subject and measuring
isotope-labeled CO.sub.2 excreted in the expired air of the
subject.
[0078] When the preparation contains, as an active ingredient, a
pyrimidine compound that forms an isotope-labeled compound other
than isotope-labeled CO.sub.2, such as .beta.-alanine,
fluoro-.beta.-alanine, .beta.-aminoisobutyric acid, or the like,
excrement such as urine, sweat or the like is used in place of
expired air as a test sample.
[0079] When expired air is used as a test sample, the method for
measuring isotope-labeled CO.sub.2 contained in expired air varies
depending on whether the isotope used is radioactive or
non-radioactive. Conventional analytic methods are usable,
including a liquid scintillation-counter method, mass spectrometry,
infrared spectrometry, emission spectrometry, magnetic resonance
spectrometry, etc. From the viewpoint of measurement accuracy,
infrared spectrometry and mass spectrometry are preferable. When
excrement such as urine, sweat, or the like is used as the test
sample, the isotope-labeled pyrimidine compound (or an
isotope-labeled pyrimidine metabolite), isotope-labeled metabolic
intermediates, and isotope-labeled metabolic products contained in
the test sample can be separated simultaneously and analyzed at the
same time by the combined use of separation techniques, such as
liquid chromatography, gas chromatography, etc. Thus, the excretion
behavior of the isotope-labeled metabolites can be selectively
measured.
[0080] The pyrimidine metabolic capacity in a subject can be
assessed by, for example, comparing the excretion behavior (the
behavior of the excretion amount or excretion rate over time) of an
isotope-labeled metabolic product in the subject, which is measured
as described above, with the excretion behavior of the
isotope-labeled metabolic product in a healthy subject having a
normal pyrimidine metabolic capacity, which is measured in the same
manner. Specifically, when isotope-labeled CO.sub.2 excreted in
expired air is measured as an isotope-labeled metabolic product,
the amount of isotope-labeled CO.sub.2 gas at a predetermined time
after administration of the oral preparation, carbon dioxide gas
.DELTA. (%) value (difference in the isotope-labeled
.sup.13CO.sub.2/.sup.12CO.sub.2 concentration ratio between the
expired air samples collected before and after administration of
the oral preparation), or the initial rate of isotope-labeled
CO.sub.2 gas excreted rate in expired air, can be used as an index
of the excretion behavior of the isotope-labeled metabolic product.
For example, using the carbon dioxide gas .DELTA. (%) value or
initial rate in a healthy subject as a standard, a subject having a
lower carbon dioxide gas .DELTA. (%) value or lower initial rate is
diagnosed as having reduced pyrimidine metabolic capacity.
[0081] Further, in place of or in addition to the excretion
behavior of an isotope-labeled metabolic product, the area under
the curve (AUC), excretion rate (especially the initial excretion
rate), maximum excretion concentration (Cmax), or like parameter,
preferably a pharmacokinetic parameter, in a test subject, can be
compared with the corresponding parameter in a healthy subject.
[0082] The deficiency or existence of a pyrimidine metabolizing
enzyme (at least one of DPD, DHPase, and .beta.-UPase) can be
determined based on the existence or non-existence of the excretion
of the isotope-labeled metabolic product, without comparison with
the excretion behavior of a healthy subject. The existence of a
decrease or increase in pyrimidine metabolic capacity (pyrimidine
metabolic disorder), and the degree thereof (degree of the
disorder) can be determined by comparing the excretion behavior in
the subject or a parameter obtained therefrom, with the
corresponding excretion behavior or parameter in a healthy
subject.
Preparation for Determining Gastric Emptying Capacity
[0083] When using the oral preparation of the present invention for
determining gastric emptying capacity, it is preferable to use as
Component (a) a pyrimidine compound and/or a metabolite thereof
that causes isotope-labeled CO.sub.2 to be excreted in expired air
as a result of metabolism.
[0084] After being orally ingested by a subject, the oral
preparation of the present invention enters the stomach, and is
finally discharged through the pylorus by the
contraction-relaxation and peristalsis of the stomach. After being
discharged from the pylorus, Component (a) is rapidly absorbed in
the duodenum and lower parts of the gastrointestinal tract (the
duodenum, jejunum, ileum, etc.), metabolized, and excreted in
expired air as isotope-labeled CO.sub.2 gas. Component (a) used in
the oral preparation of the present invention is not at all or
hardly absorbed in the stomach, but after being discharged from the
stomach, the component is rapidly absorbed, metabolized, and
excreted in expired air as isotope-labeled CO.sub.2 gas. Therefore,
the excretion behavior of isotope-labeled CO.sub.2 gas in expired
air (expressed as, for example, a ratio of isotope-labeled CO.sub.2
gas relative to .sup.12CO.sub.2 excreted in the expired air
(isotope-labeled CO.sub.2/.sup.12CO.sub.2)) depends on the gastric
emptying rate (gastric emptying time) of Component (a) contained in
the oral preparation of the present invention.
[0085] The dose of the oral preparation of the present invention
may be the same as in the case where the oral preparation of the
present invention is used for determining pyrimidine metabolic
capacity.
[0086] Isotope-labeled CO.sub.2 contained in expired air can be
measured using the same method as in the case where the oral
preparation of the present invention is used for determining
pyrimidine metabolic capacity.
[0087] The gastric emptying capacity in a subject can be assessed
using, as a gastric emptying capacity index, the amount of
isotope-labeled CO.sub.2 gas at a predetermined time after
administration of the oral preparation, the carbon dioxide gas
.DELTA. (%) value (difference in the isotope-labeled
CO.sub.2/.sup.12CO.sub.2 concentration ratio between expired air
samples collected before and after administration of the oral
preparation), or initial rate of isotope-labeled CO.sub.2 gas
excreted rate. For example, using the carbon dioxide gas .DELTA.
(%) value or initial rate in a healthy subject as a standard, a
subject having a lower carbon dioxide gas .DELTA. (%) value or
initial rate can be diagnosed as having reduced gastric emptying
capacity.
[0088] The oral preparation of the present invention can be
administered singly, or may be administered at the same time as or
immediately before or after ingestion of a test meal. Preferably,
the gastric emptying capacity-determining composition of the
present invention is administered immediately after ingestion of a
test meal. The test meal is not limited as long as it does not
impair the effects of the gastric emptying capacity determination
using the preparation of the present invention, and may be a solid
food, fluid food, or liquid food.
[0089] The main cause of dyspepsia (non-ulcer upper
gastrointestinal tract syndrome) is a gastrointestinal motility
disorder, and in particular reduction of gastric emptying capacity.
Therefore, the oral preparation of the present invention can be
effectively used as a preparation for a diagnostic test for
dyspepsia, and in particular dyspepsia caused mainly by
insufficient gastric emptying capacity (e.g., dysmotility-like
dyspepsia).
[0090] Further, use of the oral preparation of the present
invention for determining gastric emptying capacity makes it
possible to determine the efficacy, or the therapeutic effects on
individual subjects, of gastrointestinal drugs, and in particular
drugs associated with gastrointestinal motor functions.
Specifically, the determination can be performed by measuring the
gastric emptying capacity using the oral preparation of the present
invention before and after administration of a gastrointestinal
drug, and in particular a drug associated with gastric mobility
function, and comparing the two measurements. This assesses the
efficacy of the drug itself. In addition, since therapeutic effects
of a drug on individual subjects can also be assessed, the oral
preparation can also be used for selecting drugs that are suitable
for individual subjects. Examples of drugs associated with
gastrointestinal motor functions include drugs that control the
peristalsis of the stomach by enhancement or suppression, such as
gastrointestinal motor function improving agents, gastrointestinal
motor function enhancers, and gastrointestinal motor function
activators (specifically, acetylcholine agonists, dopamine receptor
antagonists, dopamine D.sub.2 receptor antagonists, serotonin
receptor agonists, opiate agonists, and Chinese medicines (Liu Jun
Zi Tang, Ban Xia Xie Xin Tang, and An Zhong San), and
gastrointestinal motor function suppressants (anticholinergic
drugs, muscarinic receptor antagonists, etc.), and the like. Such
determination can also be performed on a dyspeptic patient, and in
particular a patient with dyspepsia caused mainly by insufficient
gastric motor functions (a patient with dysmotility-like
dyspepsia), as a test subject. In this case, the
pharmacotherapeutic effects on individual dyspepsia patients can be
determined, thereby making it possible to select a suitable drug
associated with gastrointestinal motor functions (a
gastrointestinal motor function improving agent, gastrointestinal
motor function enhancer, or gastrointestinal motor function
activator as mentioned above).
EXAMPLES
[0091] The present invention is described below with reference to
Examples and Test Examples, which show production examples and
evaluations of the properties of preparations. However, the scope
of the present invention is not limited to these Examples and Test
Examples.
Production Examples of Preparations
Example 1
[0092] Twenty grams of .sup.13C uracil and 380 g of D-mannitol
(Mannit, a product of Kyowa Hakko Kogyo Co., Ltd.) were mixed,
placed into a sample mill (KIIWG-1F, a product of Fuji Paudal Co.,
Ltd.), and mixed and pulverized (pulverization conditions: at a
pulverization rotor speed of 12800 rpm and a sample feed motor
speed of about 10 rpm, using a screen with 1-mm diameter punched
holes), to prepare a powder material. A 200-g quantity of the
obtained powder material was weighed out into a speed kneader
(NSK-150, a product of Okada Seiko Co., Ltd.), and 20 g of purified
water was added, followed by kneading. The resulting wet powder was
extruded through an extrusion granulator (Dome Gran DG-L, a product
of Fuji Paudal Co., Ltd.) equipped with a dome-shaped die with 1-mm
diameter holes, and dried using an air-blow dryer (SPHH-200, a
product of Espec Corp.) set at 60.degree. C. Among the particles of
the dried preparation, those that passed through a sieve having a
mesh size of 1400 .mu.m and did not pass through a sieve having a
mesh size of 355 m were obtained as a granular preparation
containing 5 wt. % of .sup.13C uracil.
[0093] The particle diameter of the thus obtained granular
preparation containing 5 wt. % of .sup.13C uracil was measured by a
vibration sieve method (specifically, using a Robot Shifter RPS-85
measurement apparatus (a product of Seishin Enterprise Co., Ltd.)
at a vibration level of 5, a shift time of 5 minutes, and a pulse
interval of 1 second). Table 1 shows the results.
TABLE-US-00001 TABLE 1 Proportion Particle Diameter (wt. %) 1400
.mu.m or more 2.09 Not less than 1000 .mu.m and less than 1400
.mu.m 7.29 Not less than 850 .mu.m and less than 1000 .mu.m 22.07
Not less than 710 .mu.m and less than 850 .mu.m 59.04 Not less than
500 .mu.m and less than 710 .mu.m 8.99 Not less than 355 .mu.m and
less than 500 .mu.m 0.09 Not less than 250 .mu.m and less than 355
.mu.m 0.00 Not less than 150 .mu.m and less than 250 .mu.m 0.09
Less than 150 .mu.m 0.34 Total 100.0
Comparative Example 1
[0094] Ten grams of .sup.13C uracil and 190 g of D-mannitol
(Mannit, a product of Kyowa Hakko Kogyo Co., Ltd.) were placed into
a speed kneader (NSK-150, a product of Okada Seiko Co., Ltd.) and
mixed, and then, without pulverization, 20 g of purified water was
added, followed by kneading. Thereafter, granulation, drying, and
particle size regulation by sieving were carried out under the same
conditions as in Example 1 to obtain a granular preparation
containing 5 wt. % of .sup.13C uracil. The particle diameter of the
thus obtained granular preparation containing 5 wt. % of .sup.13C
uracil was measured using the same method as in Example 1. Table 2
shows the results.
TABLE-US-00002 TABLE 2 Proportion Particle Diameter (wt. %) 1400
.mu.m or more 1.24 Not less than 1000 .mu.m and less than 1400
.mu.m 5.80 Not less than 850 .mu.m and less than 1000 .mu.m 30.39
Not less than 710 .mu.m and less than 850 .mu.m 54.87 Not less than
500 .mu.m and less than 710 .mu.m 6.01 Not less than 355 .mu.m and
less than 500 .mu.m 0.20 Not less than 250 .mu.m and less than 355
.mu.m 0.10 Not less than 150 .mu.m and less than 250 .mu.m 0.20
Less than 150 .mu.m 1.19 Total 100.0
Example 2
[0095] Twenty grams of .sup.13C uracil and 180 g of D-mannitol
(Mannit, a product of Kyowa Hakko Kogyo Co., Ltd.) were mixed,
placed into a sample mill (KIIWG-1F, a product of Fuji Paudal Co.,
Ltd.), and mixed and pulverized (at a pulverization rotor speed of
12800 rpm and a sample feed motor speed of about 10 rpm, using a
screen with 1-mm diameter punched holes), to prepare a powder
material. A 144-g quantity of the obtained powder material was
weighed out into a speed kneader (NSK-150, a product of Okada Seiko
Co., Ltd.), and 14.4 g of purified water was added, followed by
kneading. The resulting wet powder was extruded through an
extrusion granulator (Dome Gran DG-L, a product of Fuji Paudal Co.,
Ltd.) equipped with a dome-shaped die with 1-mm diameter holes, and
dried using an air-blow dryer (SPHH-201, a product of Espec Corp.)
set at 60.degree. C. Among the particles of the dried preparation,
those that passed through a sieve having a mesh size of 1400 .mu.m
and did not pass through a sieve having a mesh of 355 .mu.m were
obtained as a granular preparation containing 10 wt. % of .sup.13C
uracil.
Comparative Example 2
[0096] Twenty grams of .sup.13C uracil and 180 g of D-mannitol
(Mannit, a product of Kyowa Hakko Kogyo Co., Ltd.) were thoroughly
mixed, and placed into a speed kneader (NSK-150, a product of Okada
Seiko Co., Ltd.). Twenty grams of purified water was added,
followed by kneading. Subsequently, granulation, drying, and
particle size regulation by sieving were carried out under the same
conditions as in Example 2 to obtain a granular preparation
containing 10 wt. % of .sup.13C uracil.
Comparative Example 3
Tablets
[0097] One hundred grams of .sup.13C uracil, 60 g of lactose (a
product of H.M.S), 25 g of corn starch (a product of Nihon Shokuhin
Kako Co., Ltd.), 10 g of crystalline cellulose (Ceolus PH301, a
product of Asahi Kasei Co.), and 4 g of hydroxypropylcellulose
(HPC-L fine powder, a product of Nippon Soda Co., Ltd.) were placed
into a speed kneader (NSK-150, a product of Okada Seiko Co., Ltd.)
and mixed. Forty grams of purified water was then added, followed
by kneading. Subsequently, the resulting kneaded powder was
granulated using a speed mill (ND-02, a product of Okada Seiko Co.,
Ltd.) equipped with a screen with 3-mm diameter punched holes, and
dried using an air-blow dryer (SPHH-200, a product of Espec Corp.)
set at 70.degree. C. The dried granules were sieved through a No.
16 sieve for particle size regulation, and 1 g of magnesium
stearate (a product of Taihei Chemical Industrial Co., Ltd.) was
added to 199 g of the granules after particle size regulation to
obtain granules for tablets. The granules for tablets were
compressed into tablets each weighing 200 mg using a single-punch
tabletting machine (No. 2B, a product of Kikusui Seisakusho Ltd.)
equipped with punches and dies with a diameter of 8 mm and rounded
corners.
Example 3
[0098] Twenty grams of .sup.13C uracil and 180 g of D-mannitol
(Mannit, a product of Kyowa Hakko Kogyo Co., Ltd.) were thoroughly
mixed, placed into a sample mill (SAM, a product of Nara Machinery
Co., Ltd.), and mixed and pulverized (shape of grinding blades:
pin-type; rotor speed: 4000 rpm, screen: a screen with 3-mm
diameter punched holes), to obtain a powder preparation.
Comparative Example 4
[0099] Twenty grams of .sup.13C uracil was sieved through a No. 30
sieve to prepare a powder preparation.
Comparative Example 5
[0100] Two hundred grams of .sup.13C uracil was placed into a
sample mill (SAM, a product of Nara Machinery Co., Ltd.) and
pulverized under the same conditions as in Example 3, to obtain a
powder preparation.
Evaluation of Properties of Preparations
Test Example 1
Particle Size Distribution Measurement
[0101] The particle size distribution of the powder preparations of
Example 3 and Comparative Examples 4 and 5 was measured using a dry
particle size distribution measuring apparatus (LDSA-1500A, a
product of Tohnichi Computer) under the following conditions: a
focal distance of 100 mm, a number of averaging processes of 10, an
averaging interval of 5 milliseconds, and an air pressure of 0.4
MPa. From the particle size distribution measured, the particle
diameter at 10% (10% D), particle diameter at 50% (50% D), and
particle diameter at 90% (90% D) were calculated. Table 3 shows the
results.
TABLE-US-00003 TABLE 3 10% D (.mu.m) 50% D (.mu.m) 90% D (.mu.m)
Ex. 3 5.74 14.95 56.58 Comp. Ex. 4 6.46 75.58 235.00 Comp. Ex. 5
6.01 52.60 260.57
[0102] As shown in Table 3, in the powder preparation of
Comparative Example 4, which was obtained by sieving .sup.13C
uracil alone, and the powder preparation of Comparative Example 5,
which was obtained by pulverizing .sup.13C uracil alone, the
particle diameter was not reduced, indicating an insufficient
pulverization effect, whereas in the powder preparation of Example
3, which was obtained by mixing and pulverization, the particle
diameter was reduced, demonstrating a sufficient pulverization
effect.
Test Example 2
Evaluation of Solubility of Preparations
[0103] One hundred milliliters of tap water was added to each of
200-ml beakers at room temperature. Then, while stirring with a
magnetic stirrer (RCN-7D, a product of EYELA) at 200 rpm, 2000 mg
each of the granular preparations of Example 1 and Comparative
Example 1 was added to each beakers, and the time required for the
preparations to dissolve was measured by visual observation.
[0104] Further, three minutes after addition of the granular
preparations, the amounts of undissolved residues of the
preparations were visually evaluated.
[0105] Table 4 shows the results. As is apparent from the results,
the preparation of Comparative Example 1 took a long time to
dissolve, and a large amount of the preparation remained
undissolved; whereas the preparation of Example 1 dissolved in a
short time, and only a small amount of the preparation remained
undissolved.
TABLE-US-00004 TABLE 4 Time Until Dissolution Undissoved Residue
Ex. 1 1 min 10 sec Very small amount Comp. Ex. 1 3 min or longer
Larde amount
Test Example 3
Evaluation of Solubility of Preparations
[0106] Six tablets obtained in Comparative Example 3 were subjected
to a disintegration test according to Japanese pharmacopoeia, 14th
Edition, General Test Procedures, Disintegration Test. As a result,
all the tablets had a disintegration time of 15 minutes or
longer.
Test Example 4
Evaluation of Accuracy of Diagnosis of Pyridine Metabolic Capacity
Disorder
[0107] After orally administering the preparations of Example 2 and
Comparative Example 2 to three healthy subjects (Subjects A, B, and
C), air expired from the subjects was collected over time and the
.sup.13C carbon dioxide gas concentration in the expired air was
measured using a GC-MS analyzer (ABCA-G, a product of Europa
Scientific).
[0108] FIG. 2 shows the change in .sup.13C carbon dioxide gas
concentration in the expired air after administration of the
preparation of Example 2; and FIG. 3 shows the change in .sup.13C
carbon dioxide gas concentration after administration of the
preparation of Comparative Example 2. In FIGS. 2 and 3, the
ordinate indicates A.sup.13C values (%), which are differences
between the .delta. .sup.13C value (%)
(.sup.13CO.sub.2/.sup.12CO.sub.2 concentration ratio) of the
expired air collected before administration of the preparation for
determining pyrimidine metabolic capacity, and the .delta. .sup.13C
values (h) of the expired air collected at various periods of time
after administration of the preparation. The abscissa indicates the
periods (minutes) at which the expired air was collected after
administration of the preparation. When the preparation of
Comparative Example 2 was administered, the change in .sup.13C
carbon dioxide gas concentration was small in one of the three
subjects, showing variation among the subjects (see FIG. 3). In
contrast, when the preparation of Example 2 was administered to the
same three subjects, the changes in .sup.13C carbon dioxide gas
concentration in the subjects were similar to each other, showing
only small variation among individuals. These results demonstrate
that a pyridine metabolic capacity disorder can be diagnosed
rapidly, highly accurately, and with only small variation among
individuals, by administering the preparation of Example 2 and
diagnosing a pyridine metabolic capacity disorder using, as an
index, the .sup.13C carbon dioxide gas concentration in the expired
air collected 20 to 30 minutes after administration of the
preparation (see FIG. 2).
Test Example 5
Diagnosis of Gastric Emptying Capacity
[0109] The preparation of Example 1 was orally administered, at a
dose corresponding to 100 mg of 2-.sup.13C uracil, to human
patients (20 cases) suspected of postoperative gastroparesis,
within 20 days after the patients had undergone stomach extraction
operations. Air expired from the patients was collected 10, 20, 30,
40, 50, and 60 minutes after administration, and the
.sup.13CO.sub.2 concentrations of the obtained expired air samples,
together with those of expired air samples (pre) collected in the
same manner before administration, were measured using GC/MS.
Subsequently, the amount of change in .sup.13CO.sub.2 concentration
(.DELTA. .sup.13C (%)) in the expired air was calculated. FIG. 4
shows the results.
[0110] As shown in FIG. 4, the expired air test using the
preparation of the present invention was able to classify the human
patients (20 cases) into those with normal gastric emptying
capacity (normal type: solid line), those with reduced gastric
emptying capacity (delayed gastric emptying type: broken line), and
those with insufficient gastric emptying capacity (insufficient
type: dotted line). When the plasma 2-.sup.13C uracil
concentrations of these patients were measured 20 minutes after
administration of the preparation, a reduction in plasma 2-.sup.13C
uracil concentration was observed in accordance with the gastric
emptying capacity, in the patients with reduced gastric emptying
capacity (delayed gastric emptying) and in the patients with
gastric emptying capacity insufficiency. This demonstrates that the
expired air test using the oral preparation of the present
invention effectively reflects the gastric emptying capacity.
* * * * *