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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to an antidiabetic agent containing a
spherical carbon as an active ingredient and a method of treating diabetes
using that antidiabetic agent.
2. Description of the Related Art
The affliction "diabetes" encompasses both (1) primary diabetes, which is
mainly induced by hereditary causes and which primarily causes insulin
deficiency, and (2) secondary diabetes, which is induced by acquired
causes. A common symptom of the two types of diabetes is hyperglycemia,
which causes complications such as neuropathy or retinopathy. As these
complications progress, they result in deuteropathies such as serious
infection, sudden death, blindness, heart failure, cerebral infarction,
myocardial infarction, and the like. Therefore, sufficient care must be
given to chronic complications.
Insulin and internal antidiabetics such as sulfonylurea agents and
biguanide agents are conventionally used as antidiabetics.
However, insulin is completely ineffective when administered internally,
and is nowadays clinically administered only as an injection, which is
painful to the patient. In addition to the pain, there sometimes occur
redness, swelling, induration, itching, and the like at the site of the
injection. Further, repeated subcutaneous injections at the same site
sometimes cause lipodystrophy such as atrophy or hypertrophy of
subcutaneous fat. Hypoglycemia may also occur as a serious side effect of
taking insulin. Specifically, sufficient care should be taken not to cause
hypoglycemia due to over-injection. Careful administration is required for
the patient or the condition which is liable to suffer from hypoglycemia.
The above internal antidiabetics cannot completely be substituted for
insulin. For example, insulin is indispensable for, and the antidiabetics
have no effect on, diabetic conditions such as diabetic coma, juvenile
diabetes, diabetes with ketoacidosis and serious infection.
Medicines of the sulfonylurea agent group include tolbutamide,
chlorpropamide, acetohexamide, tolazamide, glibenclamide, etc., all of
which sometimes cause serious and delayed hypoglycemia and, thus, must be
carefully administered.
Medicines of the biguanide agent group include buformin, metformin, etc.,
which sometimes cause serious lactic acidosis or hypoglycemia and, thus,
must be carefully administered.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide an antidiabetic agent
containing a spherical carbon as an active ingredient.
It is another object of the present invention to provide a method of
treating diabetes that avoids the problems caused by insulin injections
and conventional antidiabetics.
The present inventor thoroughly investigated an active antidiabetic
ingredient different from insulin or conventional internal antidiabetics
such as sulfonylurea agents and biguanide agents. As a result of that
thorough investigation, the present inventor has discovered that the serum
glucose values of diabetic rats are decreased by orally administering a
spherical carbon to the rats. The present invention is based on this
finding.
In order to achieve the objects of the present invention, there is provided
an antidiabetic agent comprising a spherical carbon as an active
ingredient.
The present invention further provides a method of treating diabetes that
avoids the problems caused by insulin injections and conventional
antidiabetics.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The spherical carbon used as an active ingredient in the present invention
is not particularly limited as long as it constitutes an activated carbon
having a spherical shape that can be used for medical treatment. Although
a medical activated carbon powder is generally useful as an antidote, it
is liable to cause constipation as a side effect, particularly when the
carbon powder is used continually. This is a critical problem because
constipation at the time of illness is dangerous.
The spherical carbon used in the present invention has a particle diameter
ranging from 0.05 to 2 mm. When the diameter is less than 0.05 mm, side
effects such as constipation and the like are not sufficiently eliminated.
On the other hand, when the diameter is over 2 mm, oral administration of
the spherical carbon becomes difficult, and the desired pharmacological
effect does not appear quickly.
The shape of the spherical carbon is an important factor for obtaining
satisfactory medical effects of the present invention. It is therefore
necessary that the spherical carbon used in the present invention has a
substantially spherical shape.
Any raw materials used for producing the spherical carbon may be used for
producing the spherical carbon employed in the present invention. Although
examples of such raw materials include sawdust, coals, coconut shells,
petroleum pitches, coal pitches, and synthetic organic high polymers,
petroleum hydrocarbons are preferred. In the present invention, it is
preferred to use an activated spherical carbon and/or a spherical
carbonaceous adsorbent as the spherical carbon.
Particles of an activated spherical carbon that can be used in the present
invention have a diameter of 0.05 to 2 mm. A basic method of producing the
activated spherical carbon used in the present invention involves forming
a raw material into fine spherical particles, carbonizing the spherical
particles, and then activating the carbonized particles.
Various activation methods can be carried out, for example, using steam,
chemicals, air, or carbon dioxide.
The activated spherical carbon particles can be produced by, for example,
the following three methods: The first method comprises forming a raw
material powder into fine spherical particles using a binder such as
pitch, carbonizing the particles by baking the particles in an inert
atmosphere at 600.degree. to 1000.degree. C., and then activating the
carbonized particles in an atmosphere of steam at 850.degree. to
1000.degree. C. The second method comprises forming melted pitch into fine
spherical particles, oxidizing the particles in an atmosphere containing
oxygen to render the particles infusible, and then carbonizing and
activating the infusible particles under the same conditions as those in
the first method, as disclosed in, for example, Japanese Patent
Publication No. 51-76 (see U.S. Pat. No. 3,917,806). The third method
comprises melt-extruding pitch to form a string-like pitch, breaking the
string-like pitch, casting the broken product into hot water to obtain
spherical particles, oxidizing the particles in an atmosphere containing
oxygen to render the particles infusible, and then carbonizing and
activating the infusible particles under the same conditions as those in
the first method, as disclosed in, for example, Japanese Patent
Publication No. 59-10930 (see U.S. Pat. No. 4,420,443).
The spherical carbonaceous adsorbent used in the present invention
preferably comprises activated carbon particles having a diameter of 0.05
to 2 mm, a pore radius of not more than 80 angstroms in a pore amount of
0.2 to 1.0 ml/g, a total amount of acidic groups (A) of 0.30 to 1.20
meq/g, a total amount of basic groups (B) of 0.20 to 0.70 meq/g, and a
ratio of the total amount of acidic groups (A)/total amount of basic
groups (B) of 0.40 to 2.5. An example of these spherical carbonaceous
adsorbents is disclosed in Japan Patent Publication No. 62-11611 (see the
specification of U.S. Pat. No. 4,681,764).
The spherical carbonaceous adsorbent used in the present invention can be
produced by further oxidizing and reducing, at a high temperature,
activated spherical carbon particles having a diameter of 0.05 to 2 mm and
a pore radius of not more than 80 angstroms in a pore amount of 0.2 to 1.0
ml/g. Oxidation and reduction at a high temperature are preferably
effected so that the total amount of acidic groups (A) and the total
amount of basic groups (B) of the spherical carbonaceous adsorbent
obtained are adjusted within the ranges of 0.30 to 1.20 meq/g and 0.20 to
0.70 meq/g, respectively, and the ratio of the total amount of acidic
groups (A)/total amount of basic groups (B) is adjusted within the range
of 0.40 to 2.5.
The total amount of acidic groups (A) and the total amount of basic groups
(B) are determined by the following usual methods:
(a) Total amount of acidic groups (A)
One gram of a pulverized adsorbent specimen that passed thorough a Taylor
standard sieve of 200 mesh is added to 50 ml of 0.05N aqueous NaOH
solution, followed by shaking for 48 hours. The resultant mixture is
filtered to remove the adsorbent, and the filtrate is neutralized by
titration. The total amount of acidic groups (A) is determined by the
amount of NaOH consumed by the titration and is expressed in units of
meq/g of specimen.
(b) Total amount of basic groups (B)
One gram of a pulverized adsorbent specimen that passed thorough a Taylor
standard sieve of 200 mesh is added to 50 ml of 0.05N aqueous HCl
solution, followed by shaking for 24 hours. The resultant mixture is
filtered to remove the specimen, and the filtrate is neutralized by
titration. The total amount of basic groups (B) is determined by the
amount of HCl consumed by the titration and is expressed in units of meq/g
of specimen.
High temperature oxidation is performed by heating the particles at a high
temperature in an oxidizing atmosphere containing oxygen, which is formed
by using pure oxygen, nitrogen oxides, or air as an oxygen source.
High temperature reduction is performed by heating the particles at a high
temperature in an atmosphere of a gas that is inert to carbon. The
atmosphere of a gas that is inert to carbon is formed by using nitrogen,
argon, helium, or a mixture thereof.
Oxidative heating is preferably carried out at 300.degree. to 700.degree.
C., more preferably at 400.COPYRGT.to 600.degree. C., in an atmosphere
preferably containing 0.5 to 25% by volume of oxygen, more preferably 3 to
10% by volume of oxygen. Reduction is preferably carried out at
700.degree. to 1100.degree. C., more preferably 800.degree. to
1000.degree. C., in an atmosphere of nitrogen.
The present inventor orally administered the above spherical carbonaceous
adsorbent to diabetic rats that had already been administered with
streptozotocin. As a result, the inventor found the surprising phenomenon
that serum glucose values of the rats decreased. It was thus found that a
medicine containing as an active ingredient the spherical carbon is useful
as an antidiabetic agent. As a matter of course, this medicine is useful
for treating the chronic complications of diabetes, such as retinopathy or
neuropathy, which are caused by hyperglycemia. In addition, importantly,
when the antidiabetic agent of the present invention was administered to
normal rats, no abnormality was induced, and hypoglycemia did not occur.
The antidiabetic agent of the present invention can preferably be
administered orally. The dosage depends on the subject (animal or human),
the age of the subject, differences among subjects, the conditions of the
disease, etc. For example, the oral dosage of the spherical carbon for a
human patient is generally within the range of 0.2 to 20 g per day. The
dosage may be administered at one time or in 2 to 4 portions. The daily
dosage may be adjusted appropriately according to symptoms.
Thus, the spherical carbon can be administered as it is or in the form of a
pharmaceutical composition as an antidiabetic agent.
When the spherical carbon particles are used as they are, it is most
convenient to ingest a pharmaceutically acceptable aqueous slurry in which
the particles are dispersed in drinking water.
The spherical carbon particles may be administered as a medicine to
patients in any desired form such as granules, tablets, sugar-coated
tablets, capsules, stick packages, divided packages, suspensions, or the
like.
When the particles are administered in the form of capsules, ordinary
gelatin capsules or, if necessary, enteric capsules may be used. When the
carbon particles are used in the form of granules, tablets, or
sugar-coated tablets, the form must be disintegrated into the original
fine spherical particles in the alimentary canal of a patient.
Although the content of the spherical carbon in a pharmaceutical
composition forming part of the present invention may be varied according
to symptoms and other factors, the content is usually 1 to 100% by weight,
preferably 10 to 99% by weight.
A pharmaceutical composition for diabetes may comprise the spherical carbon
as it is in a dosage unit form such as a capsule, a stick package, or a
divided package. That is, the spherical carbon particles as they are may
be enclosed in a capsule or a container such as a stick or a divided bag,
and the adsorbent particles are administered in the form of capsules,
stick packages, or divided packages to a patient suffering from diabetes.
The antidiabetic agent of the present invention can be used for treating
diabetes, preferably by administering the agent internally as an oral
medicine. Therefore, unlike insulin, which has to be injected, the
antidiabetic agent of the present invention will not give a patient pain.
Further, the antidiabetic agent of the present invention will not induce
hypoglycemia and, thus, does not have the problem of conventional
antidiabetics, which are liable to induce hypoglycemia.
Although the present invention will be more precisely explained below with
reference to the following examples, the scope of the present invention is
not limited thereto.
PRODUCTION EXAMPLE 1
Preparation of a Spherical Carbonaceous Adsorbent
An autoclave equipped with a stirrer was charged with 100 g of naphthalene
and 300 g of pitch (H/C=0.55, flow point 220.degree. C.) having an
anisotropic region that was not localized under a polarization microscope.
The resultant mixture was mixed well at 180.degree. C. to form a solution.
Into the resulting solution, 1200 g of 0.5 % aqueous polyvinyl alcohol
solution was added. Then, the mixture was vigorously stirred at
140.degree. C. for 30 minutes and cooled to room temperature under
stirring to form a dispersion of spherical particles. After a large part
of the water was separated from the dispersion, the remaining spherical
particles were treated with hexane in an extractor to remove the
naphthalene contained therein by extraction and then dried by air flow.
The thus-obtained particles were then heated to 300.degree. C. at a rate
of 25.degree. C./h by a flow of heated air in a fluidized bed system, and
were further maintained for 2 hours at 300.degree. C. to obtain infusible
oxygen-containing spherical particles. The particles were then heated to
900.degree. C. in steam and kept at 900.degree. C. for 2 hours in steam so
as to carbonize and activate the particles to obtain porous activated
spherical carbon. The activated spherical carbon had a diameter of 0.05 to
1.0 mm and a pore radius of not more than 80 angstroms in a pore amount of
0.755 ml/g, which was determined by a methanol adsorption method using an
automatic adsorption measuring apparatus.
The thus-obtained activated spherical carbon particles were heated to
600.degree. C. in an atmosphere containing 3% by volume of oxygen, and
were further heated at 600.degree. C. for 3 hours in the same atmosphere
using a fluidized bed. Then, the particles were further heated to
950.degree. C. in an atmosphere of nitrogen and kept at 950.degree. C. for
30 minutes in the same atmosphere to obtain an intended spherical
carbonaceous adsorbent (hereinafter referred to as "Sample 1").
The spherical carbonaceous adsorbent particles had a diameter of 0.05 to 1
mm, a pore radius of not more than 80 angstroms in a pore amount of 0.751
ml/g, which was determined by the methanol adsorption method using an
automatic adsorption measuring apparatus, a total amount of acidic groups
(A) of 0,542 meg/g, a total amount of basic groups (B) of 0.525 meq/g, and
a ratio of the total amount of acid groups (A)/total amount of basic
groups (B) of 1.03.
In acute toxicity tests of the spherical carbonaceous adsorbent, which was
orally administered to male and female rats (Cpb: WU: Wistar Random), no
abnormality was observed even at the maximum dosage (5000 mg/kg for male
and female rats>based on the Guidelines for Toxicity Studies of Drugs
(Notification No. 118 of the Pharmaceutical Affairs Bureau, Ministry of
Health and Welfare, Japanese Government, February 15, 1984).
EXAMPLE 1
Effect of Antidiabetic Agent on Diabetic Rats
Sample 1 obtained in Production Example 1 was used as the spherical
carbonaceous adsorbent functioning as an active ingredient of the
antidiabetic agent.
According to the ordinary method of preparing a diabetic model,
streptozotocin (41 mg/kg (rat body weight)) was administered to the caudal
veins of male JCL-SD rats (body weight ranging from 200 to 230 g) to
prepare diabetic model rats. After ten days had elapsed following the
administration of streptozotocin, blood was collected from the jugular
vein of each rat in the morning, serum was separated, and the serum
glucose value was measured. The rats were then divided into two groups (a
control group and an administration group; 6 rats each) so that there was
no deviation between the groups.
The control group and the administration group were freely fed on rat feed
(produced by Japan CLEA) and rat feed (produced by Japan CLEA) having
added thereto 5% spherical carbonaceous adsorbent, respectively, for 6
weeks.
After 4 and 6 weeks had passed, blood was collected from the jugular vein
of each rat in the morning, serum was separated, and the serum glucose
value was measured. The results are shown in Table 1. As seen from Table
1, although the serum glucose values of the rats in the control group
increased, all serum glucose values of the rats in the administration
group decreased. This decrease in the serum glucose value suggests that
abnormal metabolism is corrected.
TABLE 1
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After an After an
At the elapse of elapse of
Start 4 weeks 6 weeks
Serum Serum Serum
glucose body glucose glucose
value weight value value
(mg/dl) (g) (mg/dl) (mg/dl)
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Control group
454 .+-. 47
297 .+-. 7
573 .+-. 81
558 .+-. 68
Administration
468 .+-. 35
297 .+-. 12
341 .+-. 124
344 .+-. 142
group
Significant p < 0.01 p < 0.01
difference
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Value: Mean .+-. Standard deviation (n = 6)
Significant difference test: Nonpair ttest
EXAMPLE 2
Effect of Antidiabetic Agent on Normal Rats
Sample 1 was used as the spherical carbonaceous adsorbent as in Example 1.
Male JCL-SD rats were weighed and divided into two groups (a control group
and an administration group; 8 rats each) so that there was no deviation
in body weight between the groups.
The control group and the administration group were freely fed on rat feed
(produced by Japan CLEA) and rat feed (produced by Japan CLEA) having
added thereto 5% spherical carbonaceous adsorbent, respectively, for 4
weeks.
After 4 weeks had passed, blood was collected from the jugular vein of each
rat in the morning, and the serum glucose value was measured. The results
are shown in Table 2. As seen from Table 2, the spherical carbonaceous
adsorbent did not induce hypoglycemia in the normal rats.
TABLE 2
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Serum glucose value
(mg/dl)
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Control group 213 .+-. 8
Administration group
215 .+-. 11
Significant difference
NS
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Value: Mean .+-. Standard deviation (n = 8)
Significant difference test: Nonpair ttest
FORMULATION EXAMPLE 1
Capsule
Two hundred milligrams of spherical carbonaceous adsorbent obtained in
Production Example 1 were enclosed in a gelatin capsule to form a capsule.
FORMULATION EXAMPLE 2
Stick Package
Two grams of spherical carbonaceous adsorbent obtained in Production
Example 1 were put into a stick made of a laminated film
(constitution=glassine paper/polyethylene/aluminum
foil/polyethylene/polyvinylidene chloride; thickness=74.+-.8 .mu.m) and
was heat-sealed to produce a stick package.
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