Technical Field
[0001]
- 1 -
NOVEL INHALANT
The present invention relates to an inhalant
containing cepharanthine.
Background Art
[0002]
KW0329
COVID-19 (Japanese name: novel coronavirus
infectious disease) is an infectious disease caused by a
2019 novel coronavirus (SARS-CoV-2). COVID-19 is an
infectious disease, the outbreak of which was confirmed
in Wuhan, People's Republic of China in November, 2019
and was reported to WHO in December of that year, and
after this, the infection spread worldwide. The symptoms
thereof begin with fever, dry cough, fatigue, spitting,
shortness of breath, sore throat, headache, muscle ache,
arthralgia, dysosmia, dysgeusia, and the like, and in
severe cases, pneumonia becomes severe, leading to
respiratory failure and to the outcome of death.
There are still unclear aspects, such as the
infectability and the aggravation rate when infected,
besides, effective treatments are still being searched
since the virus is a new type. This has been perturbing
people around the world.
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A large number of existing drugs have been screened
so far, and cepharanthine has recently been expected as a
therapeutic agent for COVID-19 (Non Patent Literature 1) .
Citation List
Non Patent Literature
[0003]
Non Patent Literature 1:
https://www.tus.ac.jp/mediarelations/archive/20200422 983
7.html
Summary of the Invention
Technical Problem
[0004]
An object of the present invention is to provide a
novel medication for prevention and/or treatment of
COVID-19, which is a disease based on SARS-CoV-2
infection.
Solution to Problem
[0005]
The above-mentioned cepharanthine is presently used
as an oral administration preparation of a powder or a
tablet, or an injection preparation. The present
inventors conceived to apply cepharanthine, which is
considered as an effective drug for inhibition of
infection by SARS-CoV-2, to a site that is most
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vulnerable to infection by SARS-CoV-2. As a result, it
was found that the purpose can be achieved by forming
cepharanthine into an inhalant that can be directly
applied to the lower respiratory tract, and it was
further found that an inhalant that can efficiently
supply cepharanthine directly to the lower respiratory
tract is obtained by adjusting the particle diameter of
cepharanthine to 0.5 to 10 ~. and the present invention
was accomplished.
[0006]
That is, the present invention provides an inhalant
comprising cepharanthine. In addition, cepharanthine
efficiently reaches the lower respiratory tract by
adjusting the particle diameter of cepharanthine to 0.5
to 10 ~ as the aerodynamic particle diameter and the
aerodynamic mass median diameter of cepharanthine to 0.5
to 10 ~-
Advantageous Effects of the Invention
[0007]
According to the inhalant of the present invention,
cepharanthine, which is considered as an effective drug
for inhibition of infection by SARS-CoV-2, can be
directly supplied to the lower respiratory tract.
Description of Embodiment
[0008]
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The inhalant of the present invention is a
preparation that allows cepharanthine to be inhaled as
aerosol and to be applied to the lower respiratory tract.
[0009]
The cepharanthine used in the present invention is a
chemical substance, the chemical name of which is 6',12'dimethoxy-
2,2'-dimethyl-6,7-
[methylenebis(oxy)]oxyacanthan, and is one of alkaloids
that can be extracted from tamasaki-tsuzurafuji
(Stephania cepharantha Hayata), kohto-tsuzurafuji
(Stephania sasakii Hayata), snake vine (Stephania
japonica), and the like.
Cepharanthine is used for treatment of radiationinduced
leukopenia, alopecia areata/alopecia pityriasis,
secretory otitis media, and pit viper bite. When
cepharanthine is used as an inhalant as in the present
invention, in addition to these indications, the inhalant
is particularly useful as a SARS-CoV-2 infection
inhibitor and a COVID-19 prophylactic and/or therapeutic
agent.
[0010]
In the present invention, cepharanthine can be
either chemically synthesized or extracted from tamasakitsuzurafuji,
kohto-tsuzurafuji, snake vine, and the like.
When cepharanthine is extracted from tamasakitsuzurafuji,
it is possible to use a tamasaki-tsuzurafuji
extract containing, in addition to cepharanthine, an
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alkaloid other than cepharanthine, such as
isotetrandrine, cycleanine, and berbamine. There are
commercial products of cepharanthine and the tamasakitsuzurafuji
extract, and they can be purchased and used.
Alternatively, the tamasaki-tsuzurafuji extract can be
prepared from tamasaki-tsuzurafuji using a known method.
[0011]
In order to apply the cepharanthine used in the
present invention to the lower respiratory tract {the
trachea, bronchi, and lungs), from the viewpoint of
reachability of cepharanthine to the lower respiratory
tract, the particle diameter is preferably adjusted to
0.5 to 10 ~. more preferably 1 to 8 ~. and further more
preferably 2 to 8 ~· Specifically, the aerodynamic mass
median diameter of cepharanthine is preferably adjusted
to 0.5 to 10 ~. more preferably 1 to 8 ~. and further
more preferably 2 to 8 ~· Here, for a powder, the
particle diameter of cepharanthine is the particle
diameter of the cepharanthine-containing powder; and for
a liquid, the diameter is the particle diameter of the
cepharanthine-containing spray droplet. This particle
diameter in the case of a powder can be adjusted by
pulverization, sieving, and the like during the
preparation of the powder. For a spray droplet, the
diameter may be appropriately adjusted according to the
configuration of the nebulizer {such as a jet type, an
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ultrasonic type, and a mesh type) used when the liquid is
inhaled.
[0012]
Examples of the form of the inhalant of the present
invention include an inhalation powder, an inhalation
liquid, and an inhalation aerosol but it is not
particularly limited. When the inhalant of the present
invention is used, a tool or device suitable for
inhalation administration is used, or a container
combined with a tool for inhalation may be filled with
the inhalant.
[0013]
The inhalation powder is a preparation for
inhalation as an aerosol of a cepharanthine-containing
powder prepared such that the inhalation amount may be
constant. The cepharanthine-containing powder may be
prepared as a powder having a particle diameter of
preferably 0.5 to 10 ~' more preferably 1 to 8 ~' and
further more preferably 2 to 8 ~' specifically, may be
prepared as a powder having an aerodynamic mass median
diameter of preferably 0.5 to 10 ~' more preferably 1 to
8 ~' and further more preferably 2 to 8 ~·
In the cepharanthine-containing powder, sugar and
sugar alcohol can also be used as additives. Here,
examples of the sugar include lactose hydrate, sucrose,
and glucose. Examples of the sugar alcohol include
- 7 -
erythritol, isomalt, lactitol, maltitol, mannitol,
sorbitol, and xylitol.
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Specific examples of the inhalation powder include a
dry power inhaler {hereinafter, abbreviated to DPI). As
the device used for the inhalation powder of the present
invention, a device that is commonly used as a DPI can be
used. For example, examples of the device using capsules
include Monohaler, HandiHaler, Breezhaler, and FlowCap.
In addition, Diskhaler, Diskus, and Ellipta using
aluminum blisters are mentioned.
Examples of a reservoir-type device filled with a
powder in a container include Turbuhaler, Clickhaler,
Swinghaler, and Twisthaler.
[0014]
The inhalation liquid is an inhalation preparation
in a liquid form that is inhaled with a nebulizer or the
like. Cepharanthine may be dissolved or suspended in an
appropriate solvent to prepare a solution or suspension.
An isotonizing agent, a pH adjuster, and the like can be
added during the preparation.
The droplet of the inhalation liquid may be
controlled to a droplet of preferably 0.5 to 10 ~. more
preferably 1 to 8 ~. and further more preferably 2 to 8
~ according to the configuration of the nebulizer {such
as a jet type, an ultrasonic type, and a mesh type),
specifically, may be controlled to a droplet having an
aerodynamic mass median diameter of preferably 0.5 to 10
- 8 -
~. more preferably 1 to 8 ~. and further more
preferably 2 to 8 ~·
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As the cepharanthine according to the inhalation
liquid of the present invention, a Cepharanthin {R)
injection, which is manufactured and sold by Medisa
Shinyaku Inc., can be used. Specifically, a Cepharanthin
{R) injection may be inhaled using a nebulizer directly
or after dilution with an appropriate solvent.
A device commonly used as a nebulizer can be used as
the device used for the inhalation liquid of the present
invention. Examples thereof include a type of nebulizing
a drug solution with compressed air {a jet type), a type
of nebulizing a drug solution using vibration of
ultrasonic transducer {a jet type), and a type of
nebulizing a drug solution by extruding the drug solution
through mesh holes by vibration or the like {a mesh
type) .
[0015]
The inhalation aerosol is a metered-dose spray
inhalant that facilitates to spray a certain amount of
cepharanthine together with a propellant filled in the
container.
The spray droplet to be sprayed by the inhalation
aerosol may be adjusted to a spray droplet of preferably
0.5 to 10 ~. more preferably 1 to 8 ~. and further more
preferably 2 to 8 ~ by adjusting the composition of the
solution or suspension of cepharanthine, the propellant
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to be filled, the shape of the nozzle as a member of the
container, and the like. Specifically, the spray droplet
may be adjusted to a droplet having an aerodynamic mass
median diameter of preferably 0.5 to 10 ~' more
preferably 1 to 8 ~' and further more preferably 2 to 8
~·
The inhalation aerosol can be produced by dissolving
or suspending cepharanthine in an appropriate solvent to
prepare a solution or suspension, filling a pressure
proof container with the solution or suspension together
with a propellant liquid, and attaching a metering valve
thereto. A dispersant, a stabilizer, and the like can be
added during the preparation of the solution or
suspension.
Example of the inhalation aerosol include a
pressurized metered dose inhaler.
[0016]
The inhalant of the present invention can be used as
a SARS-CoV-2 infection inhibitor or a COVID-19
prophylactic and/or therapeutic agent, in addition to
alopecia areata/alopecia pityriasis, secretory otitis
media, and pit viper bite which are indications of
cepharanthine. Although the dosage thereof varies
depending on the weight, age, sex, symptoms, and the like
of the patient, the dosage for adults is usually in a
range of 1 to 20 mg of cepharanthine per day. In
addition, when the inhalant of the present invention is
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used as a SARS-CoV-2 infection inhibitor or a COVID-19
prophylactic and/or therapeutic agent, an anti-HIV agent,
such as Nelfinavir, can also be used in combination.
Examples
[0017]
The present invention will now be described
specifically by Examples below but the present invention
is not limited by these Examples.
[0018]
Example 1
Lactose hydrate (98.5 g) was added to cepharanthine
(particle diameter: 1.2 ~= measured by a laser
diffraction method, 1.5 g) pulverized with a jet mill,
followed by mixing with High Flex Gral (manufactured by
EARTHTECHNICA Co., Ltd., HF-GS-2J). The resulting powder
(0.1 g) was filled in a capsule to prepare an inhalation
powder.
[0019]
Comparative Example 1
Lactose hydrate (98.5 g) was added to unpulverized
cepharanthine (particle diameter: 50 ~= measured by a
laser diffraction method, 1.5 g), followed by mixing with
High Flex Gral (manufactured by EARTHTECHNICA Co., Ltd.,
HF-GS-2J). The resulting powder (0.1 g) was filled in a
capsule to prepare an inhalation powder.
[0020]
Test Example 1
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The inhalation powders obtained in Example 1 and
Comparative Example 1 were each measured for the Stage 2
expression rate (%) and the fine particle dose (FPD) (%)
using Monohaler as a device. The results are shown in
Table 1.
(1) Stage 2 expression rate (%)
The Stage 2 expression rate, which is a rate of
reaching the respiratory tract, was determined using Twin
Impinger, which is an in vitro evaluation apparatus for
inhalants.
(2) Fine particle dose (FPD) (%)
The evaluation was performed in accordance with the
aerodynamic particle size measurement method for
inhalants described in The Japanese Pharmacopoeia 17th
Edition 2nd Supplement using a multi-stage liquid
impinger of the apparatus 1.
[0021]
[Table 1]
Raw material name Example 1 Comparative Example 1
Cepharanthine (pulverized) 1.5
Cepharanthine (unpulverized) 1.5
Lactose 98.5 98.5
Tl Stage2 expression rate (%) 29 3
MSLI fine particle dose (FPD) (%) 29 3
[0022]
As is evident from the results of Table 1, in the
inhalation powder of Example 1, the Stage 2 expression
rate (%) and the fine particle dose (FPD) (%) were each
as high as about 30%. It was considered to be possible
to deliver cepharanthine to the deep part of the lung.
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In contrast, as to unpulverized cepharanthine of
Comparative Example 1, the Stage 2 expression rate {%)
and the fine particle dose {FPD) {%) were each as low as
about 3%. It was considered to be difficult to deliver
cepharanthine to the deep part of the lung.
[0023]
Example 2
Cepharanthine {1.5 g) was suspended in 100 g of
sterile purified water with a stirrer, thereto trometamol
{0.1 g) and ethanol {0.1 g) were added and dissolved, and
sodium chloride {0.7 g) was added and dissolved to
prepare an inhalant.
[0024]
Example 3
Cepharanthin {R) injection was used as an inhalation
liquid. The composition of Cepharanthin {R) injection 10
mg {2 mL) contains cepharanthine {10 mg) as an active
ingredient and benzyl alcohol {40 mg), sodium chloride
{20 mg), and hydrochloric acid {appropriate amount) as
additives {see the package insert of Cepharanthin {R)
injection 10 mg).
[0025]
Test Example 2
The inhalation liquids obtained in Examples 2 and 3
were each verified visually whether the agent was sprayed
in a mist form using a nebulizer as a device.
Furthermore, the agent in a mist form was collected, and
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the particle diameter thereof was measured with a
microscope. The results are shown in Table 2. A liquid
sprayed in a mist form is indicated as Good in the Table.
[0026]
[Table 2]
Example 2 Example 3
Cepharanthine 1.5 10
Purified water 100 2
Trometamol 0.1
Ethanol 0.1
Benzyl alcohol 40
Hydrochloric acid Q.S.
Sodium chloride 0.7 20
Visual verification (mist form) Good Good
Particle diameter (urn) 4 5
[0027]
Both the drug solutions of Examples 2 and 3 were
sprayed in a mist form, and the particle diameter was
about 4 ~in Example 2 and about 5 ~in Example 3. The
drug solutions of Examples 2 and 3 were judged to be
suitable as inhalation liquids.
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Claims
1. An inhalant comprising cepharanthine.
2. The inhalant according to claim 1, wherein the
cepharanthine has a particle diameter of 0.5 to 10 ~-
3. An inhalation powder comprising cepharanthine.
4. The inhalation powder according to claim 3, wherein
the cepharanthine has a particle diameter of 0.5 to 10
~-
5. An inhalation liquid comprising cepharanthine.
6. An inhalant comprising cepharanthine having an
aerodynamic mass median diameter of 0.5 to 10 ~-
7. An inhalation powder comprising cepharanthine having
an aerodynamic mass median diameter of 0.5 to 10