Note: Descriptions are shown in the official language in which they were submitted.
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1
PHARMACEUTICAL COMPOSITION
FOR TREATING MOOD DISORDERS
BACKGROUND OF THE INVENTION
Field of the Invention
The present invention relates to a pharmaceutical composition for treating
or preventing mood disorders, comprising theanine. Also, the present invention
relates to a food or beverage for ameliorating or preventing mood disorders,
comprising theanine.
Discussion of the Related Art
Conventionally, mental disorders called "manic-depressive disorders"
have been classified into disorders showing both a manic state and a depressed
state (dipolar disorders) and disorders showing only a depressed state
(monopolar disorders). However, manic-depressive disorders are now called
"mood disorders" as a generic name referring to these two kinds of disorders.
According to the results of epidemiological questionnaires conducted recently
in
Western advanced countries, the proportion of the number of individuals
suffering from mood disorders especially suffering from depression or showing
a
depressed state to the total population (morbidity of individuals suffering
from
depression or showing a depressed state) has been certainly increasing.
Especially with the coming of aging society, it is said that the morbidity
exceeds
10%. Although the causations for mood disorders have not yet been clarified,
it
might be due to "the deficiency of function of a monoamine in the brain." At
present, based on this presumption, a medicament acting on the function of the
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2
monoamine in the brain is used for the treatment of depression in mood
disorders.
The medicament exhibiting an antidepressive action includes an MAO
inhibitor. MAO is an abbreviation standing for a monoamine oxidase, which is
an enzyme acting to oxidize a chemical transmitter such as a monoamine
including norepinephrine, serotonin or dopamine, thereby inactivating the
chemical transmitter. The MAO inhibitor includes iproniazid, phenyprazine,
phenelzine, nialamide, isocarboxyazid, safrazine and the like. However, there
are many limitations upon its use because of problems of severe side effects
such
as hepatic disorders, the risk of the combined use of the inhibitor with a
tricyclic
antidepressant, limitations in the intake of high tyramine-content food, or
the like.
Therefore, all MAO inhibitors are discontinued to be sold at present.
The tricyclic antidepressant is often used as an antidepressant.
Representative examples include imipramine hydrochloride (trade mark:
Tofranil), clomipramine hydrochloride (trade mark: Anafranil), aminotriptin
hydrochloride (trade mark: Tryptanol), desipramine hydrochloride (trade mark:
Pertofrane), amoxapine (trade mark: Amoxan), lofepramine hydrochloride (trade
mark: Amplit) and the like.
The action mechanism of the tricyclic antidepressant is an action of
suppressing reuptake of a monoamine released from a nerve ending. The
medicament having a strong suppressive effect on reuptake of a monoamine
norepinephrine includes desipramine hydrochloride and amoxapine, and the
medicament having a strong suppressive effect on reuptake of serotonin
includes
clomiprane hydrochloride. It is understood that aminotriptin hydrochloride and
imipramine hydrochloride act moderately for suppressing reuptake of
norepinephrine and serotonin.
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A tetracyclic antidepressant has been developed as a medicament having
smaller side effects than those of the tricyclic antidepressant.
Representative
examples include maprotiline hydrochloride (trade mark: Ludiomil), mianserin
hydrochloride (trade mark: Tetramide) and setiptiline maleate (trade mark:
Tecipul). The action of the tetracyclic antidepressant is mainly an effect of
accelerating release of a monoamine from a nerve ending. It is understood that
the tetracyclic antidepressant has an effect of blocking a-2 receptors,
thereby
increasing the amount of a monoamine released.
The tricyclic and tetracyclic antidepressants have been known to have side
effects. One of the side effects is an anti-choline symptom. It has been known
that the tricyclic and tetracyclic therapeutic agents antagonize to an action
of
acetylcholine as a chemical transmitter in the parasympathetic nervous system.
Concrete symptoms of the side effects include an increase in ocular tension by
means of light scattering or the like, dry mouth, suppression of digestive
tracts
such as constipation, difficulty in urination, and the like. Besides the anti-
choline symptom, drowsiness is induced by their suppressive action on the
central nervous system, and further orhostatic hypotension has been also known
as their side effect on the circulatory system. The side effect of the
tetracyclic
antidepressant is smaller than that of the tricyclic antidepressant, but its
antidepressive effect is said to be smaller.
There are therapeutic agents called SSRIs (selective serotonin reuptake
inhibitors) which are antidepressants having smaller side effects than those
of the
tricyclic and tetracyclic antidepressants. SSRIs have the feature of high
selectivity for reuptake of serotonin among monoamines released from a nerve
ending. A representative medicament is fluvoxamine maleate (trade marks:
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Depromel and Luvox). Its side effects include digestive diseases such as
nausea
and emesis at an initial stage of administration, with the side effects being
smaller than those of the tricyclic and tetracyclic antidepressants. In
addition, its
combined use with the MAO inhibitor, an anti-allergic agent such as
terfenadine
(trade mark: Triludan) or astemizole (trade mark: Hismanal), or a digestive
movement improver such as cisapride (trade marks: Acenalin and Risamol) has
been known to be contraindicative.
In addition, a common feature of the antidepressants includes a delayed
exhibition of their effects. It has been known that the antidepressants are
highly
fat-soluble and have a high binding ratio to plasma proteins, so that medical
effectiveness is appeared slowly. Therefore, it is deduced that the effect is
exhibited by some influences caused by continuous stimulation. Also, it has
been reported that the number of receptors is decreased by continuous
stimulation with monoamines released.
SUMMARY OF THE INVENTION
An object of the present invention is to provide a composition for treating
or preventing mood disorders. More specifically, an object of the present
invention is to provide a composition for treating, ameliorating or preventing
mood disorders, wherein the composition is capable of exhibiting its effect at
an
early stage without any side effects.
These and other objects of the present invention will be apparent from the
following description.
As a result of intensive studies on substances effective in the treatment of
mood disorders, the present inventors have found that theanine, an amino acid
CA 02459240 2012-02-17
abundantly contained in green tea, is effective for solving the problems
incurring
in the conventional methods. The present invention has been accomplished
thereby. The present inventors have found for the first time that theanine
gives
the above effect.
5 The present invention relates to:
(1) a pharmaceutical composition for treating or preventing mood disorders,
comprising theanine together with a pharmaceutically acceptable carrier or
diluent;
(2) a food or beverage for ameliorating or preventing mood disorders,
comprising theanine; and
(3) use of theanine for manufacture of the pharmaceutical composition of the
above (1), or manufacture of the food or beverage of the above (2).
In a particular embodiment the present invention provides a
pharmaceutical composition or food or beverage for treating, ameliorating or
preventing symptoms associated with mood disorders, comprising theanine
wherein at least one of the symptoms is selected from the group consisting of
feelings of guilt, suicide and retardation: psychomotor according to the
assessment method by the Hamilton scale.
According to the present invention, the mood disorders of which
symptom is mainly depression or a depressed state can be treated, ameliorated
or
prevented safely and effectively without worrying about side effects.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a graph showing a progressive change in an average score of
the Hamilton scale in each of a group of patients administered with the
theanine
formulated-tablet and a group of patients administered with the control
tablet.
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5a
Figure 2 is a graph showing a progressive change in an average score of
the Hamilton scale in each of a group of patients administered with the
theanine
formulated-tablet and a group of patients administered with the aminotriptin
15 hydrochloride formulated-tablet.
DETAILED DESCRIPTION OF THE INVENTION
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The term "mood disorders" as used herein refers to symptoms given in
International Classification of Diseases, 10th edition, issued by World Health
Organization. According to the classification., the mood disorders are
described
as symptoms showing changes in moods such as depression and elation, and the
fundamental disorder in the mood disorders is defined as follows: "A change in
moods or emotions, which is usually changed to depression or to elation.
Generally, this change in moods is accompanied by a change in whole activity,
and most of other symptoms occur secondarily from this change or can be easily
understood from the relationship therewith." The mood disorders can be
classified into disorders showing both a manic state and a depressed state
(dipolar disorders) and disorders showing only a depressed state (monopolar
disorders). In the mood disorders in both cases, the symptoms of depression or
a
depressed state are mainly observed.
The symptoms observed in patients in a depressed state include depressed
moods, loss of interest and pleasure, an easily increased fatigue and a
decreased
activity due to a loss in vitality, feel of severe fatigue after trying hard,
a
diminished concentration and attentiveness, lowered self-evaluation and self-
confidence, feelings of guilt and sense of worthlessness, hopeless and
pessimistic
views for future, ideas and gestures of self-injury and suicide, sleep
disorders,
loss of appetite and the like. In order to establish the diagnosis according
to the
diagnostic guidelines ICD-10 (World Health Organization; The ICD-10
Classification of Mental and Behavioural Disorders, WHO, Geneva, pp. 181-
191, 1992), at least two items selected from depressed moods, loss of interest
and
pleasure, and easily increased fatigue, and at least two items selected from
diminished concentration and attentiveness, 'Lowered self-evaluation and self-
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confidence, feelings of guilt and sense of worthlessness, hopeless and
pessimistic
view for future, ideas and gestures of self-injury or suicide, sleep disorder,
and
loss of appetite must persist at least 2 weeks.
In the assessment of the symptoms of depression as above, a questionnaire
referred to the Hamilton scale is generally used. The Hamilton scale consists
of
21 items, i.e., 1. depressed mood," "2. feelings of guilt," "3. suicide," "4.
insomnia early," "5. insomnia middle," "6. insomnia late," "7. work and
activities," "8. retardation: psychomotor," "9. agitation," "10. anxiety
(psychological)," "11. anxiety (somatic)," "12. somatic symptoms
(gastrointestinal)," "13. somatic symptoms general," "14. genital symptoms,"
"15. hypochondiasis," "16. diminished insight," "17. loss of weight," "18.
diurnal variation, worse in the morning or the evening," "19.
depersonalization
and derealization," "20. paranoid symptoms" and "21. obsessional and
compulsive symptoms." Depending on the extent of the severity of each
symptom, the depression is rated under 5 ranks of "absent," "mild or low,"
"low-moderate," "high-moderate" and "severe," or under 3 ranks "absent,"
"slight or doubtful" and "evident" depending on the kind of symptoms.
As the concrete method of rating the symptoms of depression by the
Hamilton scale, reference can be made to, for instance, Max Hamilton, A Rating
Scale for Depression, J. Neurol. Neurosurg. Psychiat. 23, 56-62 (1960).
The present invention provides a pharmaceutical composition for treating
or preventing mood disorders, and a food or beverage for ameliorating or
preventing mood disorders, wherein each contains theanine. The therapeutic
effect or the like of the pharmaceutical composition or the like on the mood
disorders is attributable to the action of theanine as an active ingredient.
The
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term "treating," "ameliorating" or "preventing" of mood disorders as used
herein
refers to treating, ameliorating or preventing at least one symptom of the
mood
disorders. The therapeutic or ameliorative effect of the pharmaceutical
composition, the food or beverage of the present invention (may be also
collectively referred to herein as "the composition"), or theanine on mood
disorders can be confirmed, for instance, by assessing the symptoms of
patients
suffering from depression or individuals in a depressed state according to the
assessment method by the Hamilton scale, for a case where the patients or
individuals are allowed to take the composition or theanine and a case where
the
patients or individuals are not allowed to take it, and comparing the results
of
both cases. The preventing effect can be confirmed, for instance, by assessing
the symptoms of individuals after the intake of the composition or theanine
according to the assessment method by the Hamilton scale to regularly check
the
absence of incidence of symptoms of depression or a depressed state.
For example, in Test Example 1 set forth below, the therapeutic effect of
the pharmaceutical composition of the present invention on mood disorders was
confirmed in the manner described above. According to the results in Test
Example mentioned above, the composition of the present invention is
considered to be significantly effective for treating or ameliorating the mood
disorders of which symptom is mainly symptom of depression or a depressed
state.
Specifically, it.is found in Test Example mentioned above that the
pharmaceutical composition exhibits a therapeutic effect especially on the
following items in the Hamilton scale: "l. depressed mood," "2. feelings of
guilt," "3. suicide," "8. retardation: psychomotor," and "16. diminished
insight."
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These symptoms are observed characteristically in patients suffering from
depression or showing a depressed state, and the symptoms are different from
those of women in a depressed state caused before and during menstruation.
Therefore, the composition of the present invention is effective especially
when the symptoms of mood disorders are at least one symptom selected from
the group consisting of depressed mood, feelings of guilt, suicide,
retardation:
psychomotor, and diminished insight.
Theanine usable in the present invention is a glutamic acid derivative
contained in tea-leaves, which is the main component of tastiness (umami) of
tea.
It is used as a food additive for seasoning. Processes for preparing theanine
used
in the present invention include, but are not limited to, a process of
extracting
theanine from tea-leaves with any extracting solvent; a process for obtaining
theanine by an organic synthesis reaction [Chem. Pharm. Bull., 19(7), 1301-
1307
(1971)]; a process of treating a mixture of glutamine and ethylamine with
glutaminase to give theanine (Japanese Examined Patent Publication No.
Hei 7-55154); a process comprising culturing cultured cells of tea in a medium
containing ethylamine, thereby achieving growth promotion of the cultured
cells
while increasing the cumulative amount of theanine in the cultured cells
(Japanese Patent Laid-Open No. Hei 5-123166); modification processes in which
ethylamine is substituted by an ethylamine derivative such as ethylamine
hydrochloride in the processes using cultured cells disclosed in Japanese
Examined Patent Publication No. Hei 7-55.154 or Japanese Patent Laid-Open No.
Hei 5-123166; and the like, and any of the processes may be used. The above-
mentioned "tea-leaves" include green tea-leaves, oolong tea-leaves, black tea-
leaves, and the like. Theanine can be used as any of L-theanine, D-theanine
and
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DL-theanine. Among them, the L-form is preferred in the present invention,
because the L-form is approved as a food additive, and is economically
utilizable.
Also, if there is a commercially available product of theanine, such a product
may be used. Incidentally, theanine used in the present invention may be in
any
5 forms, such as purified products, crudely purified products and extracts.
The theanine used in the present invention has high safety. For instance,
in an acute toxic test using a mouse, there are no cases of death with an oral
administration at 5 g/kg weight, and there are found no abnormalities in the
general states, weight and the like. Also, especially L-theanine is known as a
10 main component of umami (tastiness) of the green tea, and is also used as a
food
additive giving umami, without the limitation of its added amount under the
regulation for food hygiene. Moreover, contrary to the conventional drugs,
since
there is no side effect by theanine at all, the mood disorders can be safely
and
effectively treated, ameliorated or the like according to the composition of
the
present invention.
The composition of the present invention includes, for instance, a
medicament in the forms of tablets, capsules, powders, granules, beverages,
and
the like; foods such as dry foods and supplements; and beverages such as
refreshing beverages, mineral waters, luxury beverages and alcoholic
beverages,
wherein each composition contains theanine. Incidentally, the same effects can
be obtained as those of the composition of the present invention by using the
theanine per se.
The pharmaceutical composition of the present invention is obtained by
forming a preparation by combining theanine with a known pharmaceutical
carrier. For instance, a preparation which is suitable for oral administration
can
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be obtained by combining theanine with a pharmacologically acceptable liquid
or
solid carrier suitable for oral administration. Also, a solvent, a dispersant,
an
emulsifier, a buffer, a stabilizer, an excipient, a binder, a disintegrant, a
lubricant,
or the like is optionally added thereto, so that a solid agent such as a
tablet, a
capsule, a powder, a fine powder, or a granule, or a liquid agent such as a
healthcare drink, a suspension agent or an emulsion agent can be formed.
Furthermore, there can be also made into a dry product which can be made
liquid
by adding an appropriate liquid carrier before use.
The pharmaceutical carrier can be selected depending upon the
administration form and preparation form of the pharmaceutical composition. In
the case of an orally administered preparation comprising a solid composition,
there can be utilized as a carrier, for instance, starch, lactose, saccharose,
mannitol, carboxymethyl cellulose, cornstarch, an inorganic salt or the like.
In
addition, during the preparation of the orally administered preparation, a
binder,
a disintegrant, a surfactant, a lubricant, a fluidity accelerator, a flavor, a
colorant,
a perfume, or the like can be further formulated. In the case of forming into
a
tablet, for instance, the tablet may be covered with a sugar-coating made of
sucrose, gelatin or hydroxypropyl cellulose, or with a film made of a
substance
soluble in the stomach or intestine as desired. In the case of an orally
administered preparation comprising a liquid composition, for instance,
purified
water, ethanol or the like is utilized as a carrier. Furthermore, an auxiliary
agent
such as a wetting agent or a suspending agent, a sweetener, a flavor, an
antiseptic,
or the like may be added as desired.
The food or beverage of the present invention is obtained by formulating
theanine during the preparation of a known food or beverage. During the
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preparation, optional ingredients as those listed below may be added in proper
amounts so long as the exhibition of the desired effects of the present
invention
would not be hindered. The food and beverage as used herein are not strictly
distinguishable, and also referred to as "foodstuff' from the above viewpoint.
For instance, the beverage of the present invention includes, but is not
particularly limited to, teas such as green tea, oolong tea, black tea and
herb tea,
fruit juice concentrates, reconstituted juice concentrates, fresh juices,
mixed fruit
juices, fruit grain-containing fruit juice, fruit juice-containing beverages,
mixed
fruit/vegetable juice, vegetable juice, carbonated beverages, soft drinks,
milk
beverage, Japanese sake, beer, wine, cocktails, shochu, whiskey, and the like,
wherein the beverage contains theanine.
Also, in the foodstuff of the present invention, crude medicines, herbs,
amino acids, vitamins, and other materials and raw materials which are
acceptable in foods and beverages may also be used together.
The above crude medicine includes, but are not particularly limited to,
Common valerian, Angelica acutiloba, Paeonia lactiflora, peony, Panax ginseng
and the like, which are effective for maintaining hormonal balance in women.
The above herbs include, but is not particularly limited to, anise, carrot
seed, clove, coriander, cypress, cinnamon, juniper, ginger, sweet orange, pine
needle, basil, patchouli, bitter orange, fennel, black pepper, bay,
peppermint,
bergamot, mandarin, myrrh, lemongrass, rosemary, grapefruit, cedarwood,
citronella, sage, thyme, tea tree, violet leaf, vanilla, hyssop, eucalyptus,
lime,
lemon, ylang-ylang, cardamon, clary sage, jasmine, geranium, chamomile,
Bulgarian rose, rose, olibanum, lavender, chamomile, geranium, sandalwood
neroli, verbena, petigrain, vetiver, majoram, lemon balm (Melissa
officinalis),
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rosewood, Hypericum, St. John's wort, and kawakawa, with preference given to
peppermint, bergamot, ylang-ylang, geranium, chamomile, lavender, St. John's
wort, and kawakawa, which have sedative and relaxation effects. The forms of
these herbs include, but are not particularly limited to, extract, essential
oil, dry
powder, and the like.
The above amino acid includes, but are also not particularly limited to, for
example, glutamine, glutamic acid, inosinic acid, alanine, arginine, aspartic
acid,
threonine, serine, y-aminobutyric acid, taurine, thiotaurine, hypotaurine and
the
like.
The above vitamin includes, but is not limited to, vitamin A, vitamin B1,
vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin
K,
folic acid, nicotinic acid, lipoic acid, pantothenic acid, biotin, ubiquinone
and
prostaglandin, as well as derivatives of these vitamins.
The above mineral includes, but is not limited to, calcium, iron,
magnesium, copper, zinc, selenium, potassium, and the like.
In addition, in the preparation of the foodstuff of the present invention,
there can be used aloe, royal jelly, melatonin, placenta, propolis,
isoflavone,
soybean lecithin, egg yolk lecithin, egg yolk oil, chondroitin, cacao mass,
collagen, vinegar, cholera, spirulina, ginkgo leaves, green tea, tochu tea
(Eucommia ulmoides), Chinese wolfberry tea, oolong tea, mulberry leaf, Rubus
suavissimus (tencha), banaba tea, unsaturated fatty acids, saccharides such as
oligosaccharides, bacteria such as bifidobacteria and red koji, mushrooms such
as agaricus (Agaricus blazei), Agaricus blazei Murrill, reisi (ganoderma) and
Grifloa frondosa, fruits such as blueberry, prune, grape, olive, Japanese
apricot
and citruses, seeds such as peanut, almond, sesame and pepper, vegetables such
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as green pepper, chili, Welsh onion, pumpkin, gourd, carrot, burdock, jute
leaf
(Corchorus capsularis), garlic, perilla, Japanese horseradish (wasabi),
tomato,
(pickled) shallot, leaf vegetables, tubers and beans, seaweeds such as wakame,
fishes and shells, meat, poultry and whale meat, cereals and the like.
Further,
extracts, dried products, crudely purified products, purified products,
processed
products, fermentation products and the like of the above-mentioned components
can be also used.
The foodstuff of the present invention is not particularly limited so long as
the foodstuff is in the form that is orally administrable such as solution,
suspension, powder, or molded solid product. Specifically, pasty products,
processed soybean products, seasonings, mousses, jelly, frozen
confectionaries,
candies, chocolates, chewing gums, crackers, cakes, breads, soups, coffees,
cocoas, teas, green tea, juices, milk beverages, dairy products, liquors, and
the
like.
The process for preparing the composition of the present invention
includes, but is not particularly limited to, general processes of producing
foodstuffs and pharmaceuticals, such as a process of mixing theanine with
other
starting materials in a powdery form, a process of dissolving theanine and
other
starting materials in a solvent to give a mixed solution, a process of
lyophilizing
the mixed solution, and the like.
The composition of the present invention is completed by realizing an
inventive idea of use of theanine in the treatment or the like of mood
disorders
on the basis of a newly found pharmacological effect of theanine. From this
viewpoint, in one embodiment of the present invention, there can be also
provided use of theanine for manufacture of the composition of the present
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invention.
The content of theanine in the composition of the present invention is not
particularly limited as long as theanine can be administered preferably in the
following range of dose in view of the administration form, use and the like.
In
5 consideration of the effective dose of theanine, the content of theanine is
usually
preferably 0.00025% by weight or more, more preferably from 0.0025 to 100%
by weight: Additionally, in consideration of usual forms of the composition of
the present invention (for example, the forms of the above solid foods, liquid
foods and pharmaceuticals), the content is more preferably from 0.08 to 99% by
10 weight.
The dose of the composition of the present invention, especially the
pharmaceutical composition, can be varied and determined suitably depending
upon the administration form, administration style, the purpose of use, age,
weight and symptoms of an individual to be administered. Generally, the
15 composition of the present invention maybe administered such that the dose
of
theanine in the present invention is preferably from 0.2 to 200 mg/kg body
weight, more preferably from 0.5 to 50 mg/kg body weight to human (for
example, adults) per day. Since the effects can be sufficiently exhibited by
administering theanine in this range, the above dose range of theanine can be
said to be an effective dose range of theanine. However, since there are
individual differences in the kind and extent of symptoms listed above, the
dose
of the composition of the present invention or theanine is not limited to the
above
range.
The pharmaceutical composition of the present invention can be
administered in a single dose or in dose of several divided portions within
one
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day in an amount in the desired dose range, and a dose period can be
arbitrary.
EXAMPLES
The present invention will be describe hereinbelow by means of the
following Examples and Test Examples, without intending to limit the present
invention thereto.
Preparation Example 1 Preparation of Theanine by Enzymatic Method
The amount 21.9 g of glutamine and 28.5 g of ethylamine hydrochloride
were allowed to react at 30 C for 22 hours in 0.5 L of 0.05 M borate buffer
(pH 9.5) in the presence of 0.3 U glutaminase (manufactured by Amano Enzyme
Inc.). Thereafter, the reaction mixture was subjected to column chromatography
TM
using Dowex 50 x 8 column and Dowex 1 x 2 column (both manufactured by
Muromachi Kagaku Kogyo K.K.), and thereafter the resulting product was
treated with ethanol, thereby isolating a desired product from the reaction
mixture.
The identification of the obtained substance as L-theanine was carried out
by subjecting the isolated substance to amino acid analyzer and paper
chromatography, whereby confirming that the isolated substance exhibits the
same behaviors as the standard substance. Moreover, when the isolated
substance was subjected to hydrolysis treatment with hydrochloric acid or
glutaminase, glutamic acid and ethylamine were generated at a molar ratio of
1:1.
Since the isolated substance was hydrolyzed by glutaminase, it was shown that
ethylamine was bonded at the y-position of glutamic acid. In addition, it was
also confirmed by using the glutamic acid dehydrogenase that glutamic acid
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generated by hydrolysis had an L-form. From the above, the resulting isolated
substance was finally confirmed to be L-theanine. By the above procedure, 8.5
g
of L-theanine was obtained.
Preparation Example 2 Extraction of L-Theanine from Tea Leaves
Ten kilograms of tea leaves (Camellia sinensis L.) were subjected to
extraction with boiling water. The resulting extract was then applied to a
cationic exchange resin ("Dowex HCR W-2," manufactured by Muromachi
Kagaku Kogyo K.K.), and the component adsorbed to the resin was eluted with
1 N NaOH. The eluted fraction was applied to an activated carbon ("Taiko
Kasseitan SG" manufactured by Futamura Kagaku Kogyo K.K.), and eluted with
15% ethanol. The resulting eluted fraction was concentrated with an RO
membrane ("NTR 729 HF" manufactured by NITTO DENKO
CORPORATION). Thereafter, the concentrate was purified by column
chromatography in the same manner as in Preparation Example 1. Furthermore,
the purified product was recrystallized, to give 24.8 g of L-theanine.
Here, in the preparation of each composition described hereinbelow,
L-theanine [trade mark: Suntheanine, manufactured by Taiyo Kagaku Co., Ltd.]
was used.
Example 1 Preparation of Theanine-Formulated Tablet
As one example of the composition of the present invention, a theanine-
formulated tablet was prepared by mixing the raw materials given below, and
tabletting the resulting mixture.
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Frosted Sugar 71.67% by (0.5375 g)
weight
Trehalose 10% by (0.075 g)
weight
L-Theanine 13.33% by (0.1 g)
weight
Sucrose Fatty Acid Ester 1% by (0.0075 g)
weight
Flavor (Lemon Flavor) 4% by (0.03 g)
weight
Total 100% by (0.75 g)
weight
Specifically, each of the raw materials was mixed in accordance with the
above composition, and the mixture was granulated to give a tablet of 0.75 g.
Comparative Example 1 Preparation of Control Tablet
A control tablet was prepared by mixing the raw materials given below,
and tabletting the resulting mixture.
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Frosted Sugar 85% by (0.6375 g)
weight
Trehalose 10% by (0.075 g)
weight
Sucrose Fatty Acid Ester 1% by (0.0075 g)
weight
Flavor (Lemon Flavor) 4% by (0.03 g)
weight
Total 100% by (0.75 g)
weight
Specifically, each of the raw materials was mixed in accordance with the
above composition, and the mixture was granulated to give a tablet of 0.75 g.
Example 2 Preparation of Theanine-Formulated Candy
As one example of the composition of the present invention, a theanine-
formulated candy was prepared using the following raw materials.
Granulated Sugar 64 kg
Malt Syrup 23 kg
L-Theanine 10 kg
Flavor (Lemon Flavor) 0.05 kg
50% Tartaric Acid 1 kg
Water 30 kg
The granulated sugar was dissolved in 20 kg of water with heating to
110 C. Ten kilograms of the remaining water in which L-theanine was
CA 02459240 2004-02-27
previously dissolved, and malt syrup were added thereto, and the temperature
was raised to 145 C. After heating was stopped, the flavor and 50% tartaric
acid
were added thereto and mixed. The mixture was cooled to 75 to 80 C, and
formed with a molding roller, to give a theanine-formulated candy (1.2 g per
5 drop). The content of L-theanine in the candy was determined by HPLC. As a
result, its content was 89.6 mg/g (7.47% by weight) per drop of 1.2 g.
Example 3 Preparation of Theanine-Formulated Blueberry Beverage
As one example of the composition of the present invention, a theanine-
10 formulated blueberry beverage was prepared using the following raw
materials.
Fructose Sucrose Solution 12 kg
Blueberry Concentrate Juice 1 kg
1/5 Transparent Lemon Juice 0.4 kg
Sodium Citrate 0.05 kg
50% Sodium Citrate (Crystals) for pH
adjustment
L-Theanine 0.1 kg
Flavor (Blueberry Flavor) 0.05 kg
Water Proper
amount Total 100 kg
Fructose glucose solution, blueberry concentrate juice, 1/5 transparent
lemon juice, sodium citrate and L-theanine were added to water to dissolve the
components with stirring. The solution was adjusted to pH 3.1 with 50% sodium
15 citrate (crystals) and heated to 95 C, and the flavor was added thereto,
and the
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21
mixture was filled into a 100-ml can and then cooled to produce a theanine-
formulated blueberry beverage. The L-theanine in the blueberry beverage was
quantified. As a result, the content was 98.3 mg/100 ml (0.098 % by weight).
Example 4 Preparation of Theanine-Formulated Grapefruit Beverage
As one example of the composition of the present invention, a theanine-
formulated grapefruit beverage was prepared using the following raw materials.
Fructose Sucrose Solution 6 kg
L-Theanine 0.1 kg
Ferric Pyrophosphate 0.06 kg
Placenta Extract 0.01 kg
100% Grapefruit Juice 30 kg
Sodium Citrate for pH
adjustment
Flavor (Grapefruit Flavor) 0.05 kg
Water Proper
amount
Total 100 kg
Fructose sucrose solution, L-theanine, ferric pyrophosphate, placenta
extract and 100% grapefruit juice were added to water with stirring to
dissolve
the components. The pH of the resulting solution was adjusted to 3.1 by using
sodium citrate. After the temperature was raised to 95 C, the flavor was added
thereto. The resulting solution was filled and then cooled to produce a
theanine-
formulated grapefruit beverage. The L-theanine in the grapefruit beverage was
quantified. As a result, its content was 96.4 mg/100 ml (0.096% by weight).
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Test Example 1 Evaluation Test for Therapeutic Effects on Mood Disorders
The therapeutic effects of the pharmaceutical composition of the present
invention on mood disorders were examined for a group of 24 normofolatemic
patients (average age: 42-year old). The normofolatemic patients refer to
those
individuals showing a normal folate plasma level (3 to 17 ng/ml), who are not
patients with neural tube defect caused by lack of folate.
In diagnosis, the patients were assessed to be mild to severe according to
the diagnostic criteria of DMS III R (Diagnostic and Statistical Manual of
Mental
Disorders, 3rd Ed. Rev American Psychiatric Association, Washington DC, pp.
235-253, 1987). The test was conducted in double blind, and the test period
was
3 weeks. The 24 patients (average body weight: 61 kg) were divided into two
even groups according to the above diagnostic results. One group was
administered with the theanine-formulated tablet prepared in Example 1 (group
administered with the theanine-formulated tablet), and the other group was
administered with the control tablet prepared in Comparative Example 1 (group
administered with the control tablet). Each patient was administered with one
tablet twice a day, at 10 am and 4 pm (amount of theanine intake: 200 mg). The
therapeutic effects were assessed according to the Hamilton scale consisting
of
21 items regarding the assessment for depression. The assessment was made
before the intake of each tablet (i.e. before the beginning of the test) and
on
Day 7, Day 14 and Day 21 from the intake, during each of the days,
respectively.
A progressive change in the average score of the Hamilton scale for each
of the group of the patients administered with the theanine-formulated tablet
of
Example 1 and the group administered with the control tablet of Comparative
CA 02459240 2004-02-27
23
Example 1 is shown in Figure 1. The average score of the Hamilton scale was
significantly decreased from "24" before the intake to "15" after 3 weeks of
the
intake in the group administered with the theanine-formulated tablet of
Example
1 (p < 0.01), while a reduction in the score in the group administered with
the
control tablet of Comparative Example 1 was hardly recognized. By the intake
of the theanine-formulated tablet of Example 1, the therapeutic effects were
observed as early as after 1 week from the intake.
The average score for each symptom item of the Hamilton scale in each
group of patients before the intake and on Day 7, Day 14 and Day 21 from the
intake is shown in Table 1. The average score was subjected to Student paired
t-test against the score before the intake.
Image
CA 02459240 2004-02-27
As shown in Table 1, significant amelioration in the symptoms "1.
depressed mood," "2. feelings of guilt," "3. suicide," "8. retardation:
psychomotor," and "16. diminished insight" were recognized on Day 7, Day 14
and Day 21 in the group administered with the theanine-formulated tablet.
These
5 symptoms are characteristics of the patients with depression or in a
depressed
mood. On the other hand, no amelioration in every symptom was observed in
the group administered with the control tablet.
According to the above test results, the therapeutic effects of the
pharmaceutical composition of the present invention on mood disorders were
10 recognized. During the period of intake, records were also taken for
occurrence
of any side effects. However, no side effects were observed.
Test Example 2 Comparison to Tricyclic Antidepressant
Comparison of the therapeutic effects on mood disorders between a
15 tricyclic antidepressant and the pharmaceutical composition of the present
invention was made in a group of 10 normofolatemic patients (average age:
48-year old). In diagnosis, the patients were judged to be mild to severe
according to the diagnostic criteria of DMS III R. The test was conducted in
double blind, and the test period was 4 weeks. The 10 patients (average body
20 weight: 55 kg) were divided into two even groups. One group was
administered
with the theanine-formulated tablet prepared in Example 1 (group administered
with the theanine-formulated tablet), and the other group was administered
with
a tricyclic antidepressant aminotriptin hydrochloride-formulated tablet (group
administered with the aminotriptin hydrochloride-formulated tablet). Each
25 patient was administered with one tablet twice a day, at 10 am and 4 pm
(amount
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26
of theanine intake: 200 mg; amount of aminotriptin hydrochloride intake: 50
mg).
The therapeutic effects were evaluated according to the Hamilton scale
consisting of 21 items regarding assessment for depression. The assessment was
made before the intake of each tablet and on Day 14 and Day 28 after the
intake,
during each of the days. In addition to the Hamilton scale, side effects were
recorded in a questionnaire.
A progressive change in the average score of the Hamilton scale for each
of the group of patients administered with the theanine-formulated tablet of
Example 1 and the group administered with the aminotriptin hydrochloride-
formulated tablet is shown in Figure 2. The average score in the Hamilton
scale
was significantly decreased from "29" before the intake to "23" on Day 14 or
to
"20" on Day 27 in the group administered with the theanine-formulated tablet
in
Example 1. In the group administered with the aminotriptin hydrochloride-
formulated tablet, on the other hand, the score was decreased to "27" on Day
14
so that the effects were hardly recognized, but the score was then decreased
to
"20" on Day 27. As described above, it was confirmed that the therapeutic
effects of the pharmaceutical composition of the present invention were
exhibited more rapidly.
The records of side effects in each tested individual during the test period
are as follows.
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Theanine-Formulated Tablet of Example 1
Patient. No. Side Effects (Day 14) Side Effects (Day 28)
A None None
B None None
C None None
D None None
E None None
Aminotriptin Hydrochloride-Formulated Tablet
Patient No. Side Effects (Day 14) Side Effects (Day 28)
F Drowsiness Drowsiness, Constipation
G Dry Mouth Dry Mouth
H None None
I Constipation Constipation
J Palpitations, Constipation Palpitations, Constipation
During the test period, no side effects were recognized in all the
individuals administered with the theanine-formulated tablet of Example 1, but
side effects were recognized in 4 out of 5 individuals administered with the
aminotriptin hydrochloride-formulated tablet.
Test Example 3 Evaluation Test for Ameliorative Effects on Mood Disorders
The evaluation test for ameliorative effects on mood disorders was
conducted with the theanine-formulated candy of Example 2, the theanine-
formulated blueberry beverage of Example 3 and the theanine-formulated
grapefruit beverage of Example 4.
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The test was conducted for a group of 9 normofolatemic patients (average
age: 51-year old). In the diagnosis, the patients were judged to be mild to
severe
according to the diagnostic criteria of DMS III R. The test period was 4
weeks.
The 9 patients (average body weight: 63 kg) were divided into groups, each
consisting of 3 patients. Each patient was administered with one theanine-
formulated candy of Example 2, one can of the theanine-formulated blueberry
beverage of Example 3, or one can of the theanine-formulated grapefruit
beverage of Example 4, twice a day, at 10 am and 4 pm (amount of theanine
intake: about 200 mg). The therapeutic effects were evaluated according to the
Hamilton depression scale consisting of 21 items regarding assessment for
depression. The assessment was made before the intake of each composition and
on Day 28 after the intake, during each of the days.
A progressive change of the score of the Hamilton scale for each patient
during the test period is as follows:
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Theanine-Formulated Candy of Example 2
Patient No. Before Intake Day 28
A 30 21
B 24 19
C 26 24
Theanine-Formulated Blueberry Beverage of Example 3
Patient No. Before Intake Day 28
D 38 30
E 22 20
F 35 33
Theanine-Formulated Grapefruit Beverage of Example 4
Patient No. Before Intake Day 28
D 38 30
E 22 20
F 35 33
It can be seen that the score in each patient is decreased by all of the food
and beverages in Examples 2 to 4, thereby revealing that mood disorders are
ameliorated. Accordingly, the ameliorative effects of the food and beverage of
the present invention on mood disorders were confirmed by this test.
According to the present invention, there are provided a safe
pharmaceutical composition, and food and beverage, each having a significant
suppressive effect on the depression in a mood disorder.
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The present invention being thus described, it will be obvious that the
same may be varied in many ways. The scope of the claims should not be
limited by the preferred embodiments set forth, but should be given the
broadest
interpretation consistent with the description as a whole.
