U.S. patent application number 10/559731 was filed with the patent office on 2006-06-08 for menthol-containing preparation.
Invention is credited to Tomonori Hamawaki, Takako Isoda, Yosuke Kataoka.
Application Number | 20060121067 10/559731 |
Document ID | / |
Family ID | 33549692 |
Filed Date | 2006-06-08 |
United States Patent
Application |
20060121067 |
Kind Code |
A1 |
Hamawaki; Tomonori ; et
al. |
June 8, 2006 |
Menthol-containing preparation
Abstract
It is known that L-menthol controls smooth muscle contraction.
In order to use L-menthol in practice as a digestive tract
contraction inhibiting agent in digestive tract endoscopy, it is
required to devise means of giving a formulation in which an
L-menthol-containing formulation remains stable and transparent or
little cloudy over a long time after the production and which shows
little foaming at the administration. In the present invention, an
antifoaming agent is further added to a formulation for inhibiting
smooth muscle contraction or a peristaltic contraction in a
digestive tract containing a L-menthol emulsion having an average
particle size of less than 100 nm. Thus, it is possible to obtain a
formulation that remains stable over a long time, has a high light
transmittance, and produces little foam when filled into a
container and sprayed at a target area to inhibit contraction to
facilitate observation of the area in endoscopic examination of the
digestive tract etc.
Inventors: |
Hamawaki; Tomonori;
(Izumisano-shi, JP) ; Kataoka; Yosuke;
(Izumisano-shi, JP) ; Isoda; Takako;
(Izumisano-shi, JP) |
Correspondence
Address: |
WENDEROTH, LIND & PONACK, L.L.P.
2033 K STREET N. W.
SUITE 800
WASHINGTON
DC
20006-1021
US
|
Family ID: |
33549692 |
Appl. No.: |
10/559731 |
Filed: |
June 28, 2004 |
PCT Filed: |
June 28, 2004 |
PCT NO: |
PCT/JP04/09096 |
371 Date: |
December 7, 2005 |
Current U.S.
Class: |
424/400 ;
514/729; 977/906 |
Current CPC
Class: |
A61K 47/24 20130101;
A61K 47/26 20130101; A61B 1/31 20130101; A61K 47/14 20130101; A61K
9/1075 20130101; A61K 31/045 20130101; A61K 49/00 20130101; A61K
47/44 20130101; A61P 1/00 20180101; A61P 43/00 20180101; A61B
1/2736 20130101 |
Class at
Publication: |
424/400 ;
514/729; 977/906 |
International
Class: |
A61K 31/045 20060101
A61K031/045; A61K 9/00 20060101 A61K009/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 30, 2003 |
JP |
2003-186493 |
Claims
1. An L-menthol-containing formulation for inhibiting smooth muscle
contraction, which comprises L-menthol, a surfactant, and an
antifoaming agent and which is an emulsion with an average particle
size of less than 100 nm.
2. The L-menthol-containing formulation according to claim 1, which
further comprises a fat or oil.
3. The L-menthol-containing formulation according to claim 1, which
has a light transmittance of 50% or more.
4. The L-menthol-containing formulation according to claim 1, which
comprises 0.01 to 5.0% by weight of L-menthol, 0.1 to 10% by weight
of a surfactant, and 0.0001 to 0.01% by weight of an antifoaming
agent based on the weight of the whole formulation.
5. The L-menthol-containing formulation according to claim 4,
wherein a content of the fat or oil is far from 0.1 to 10% by
weight.
6. The L-menthol-containing formulation according to claim 1,
wherein the antifoaming agent is at least one agent selected from
silicone antifoaming agents.
7. The L-menthol-containing formulation according to claim 1,
wherein the surfactant is at least one member selected from
polyoxyethylene hydrogenated caster oils and sucrose fatty acid
esters.
8. The L-menthol-containing formulation according to claim 2, which
has a light transmittance of 50% or more.
9. The L-menthol-containing formulation according to claim 2, which
comprises 0.01 to 5.0% by weight of L-menthol, 0.1 to 10% by weight
of a surfactant, and 0.0001 to 0.01% by weight of an antifoaming
agent based on the weight of the whole formulation.
10. The L-menthol-containing formulation according to claim 3,
which comprises 0.01 to 5.0% by weight of L-menthol, 0.1 to 10% by
weight of a surfactant, and 0.0001 to 0.01% by weight of an
antifoaming agent based on the weight of the whole formulation.
11. The L-menthol-containing formulation according to claim 2,
wherein the antifoaming agent is at least one agent selected from
silicone antifoaming agents.
12. The L-menthol-containing formulation according to claim 3,
wherein the antifoaming agent is at least one agent selected from
silicone antifoaming agents.
13. The L-menthol-containing formulation according to claim 4,
wherein the antifoaming agent is at least one agent selected from
silicone antifoaming agents.
14. The L-menthol-containing formulation according to claim 5,
wherein the antifoaming agent is at least one agent selected from
silicone antifoaming agents.
15. The L-menthol-containing formulation according to claim 2,
wherein the surfactant is at least one member selected from
polyoxyethylene hydrogenated caster oils and sucrose fatty acid
esters.
16. The L-menthol-containing formulation according to claim 3,
wherein the surfactant is at least one member selected from
polyoxyethylene hydrogenated caster oils and sucrose fatty acid
esters.
17. The L-menthol-containing formulation according to claim 4,
wherein the surfactant is at least one member selected from
polyoxyethylene hydrogenated caster oils and sucrose fatty acid
esters.
18. The L-menthol-containing formulation according to claim 5,
wherein the surfactant is at least one member selected from
polyoxyethylene hydrogenated caster oils and sucrose fatty acid
esters.
19. The L-menthol-containing formulation according to claim 6,
wherein the surfactant is at least one member selected from
polyoxyethylene hydrogenated caster oils and sucrose fatty acid
esters.
Description
TECHNICAL FIELD
[0001] The present invention relates to an L-menthol-containing
formulation for inhibiting smooth muscle contraction or
peristalsis, particularly a formulation for inhibiting digestive
tract contraction, which remains stable over a long time, exhibits
high light transmittance, and produces little foam when sprayed at
a target area to inhibit contraction to facilitate observation of
the area in endoscopic examination of the digestive tract etc.
BACKGROUND ART
[0002] Excessive contraction of the digestive tract during
endoscopic examination of the digestive tract such as stomach and
large intestine prevents correct diagnosis and allows a minute
lesion such as a small-sized carcinoma to be missed.
[0003] As a contraction inhibitor for endoscopic examination of the
digestive tract, an anti-cholinergic agent scopolamine butylbromide
(Trade name: Buscopan Injection, Nippon Boehringer Ingelheim Co.,
Ltd.) or glucagon has conventionally been prescribed. However
scopolamine butylbromide is contraindicated in a patient with
glaucoma, prostatic hypertrophy, or arrhythmia, and glucagon has
some problems including its very weak effect in inhibition of
digestive tract contraction. Scopolamine butylbromide has to be
injected immediately before or during the examination because it is
to be injected intravenously or intramuscularly.
[0004] In addition some of the formulations may cause disorder of
accommodation or vertigo after administration, so that the person
who received administration of such a formulation for the
examination should refrain for example from driving a car for a
while after completion of the examination.
[0005] Accordingly, in an attempt to solve the problems mentioned
above, an investigation was made recently to produce a digestive
tract contraction inhibitor formulation using peppermint oil
(Gastrointestinal Endoscopy, Vol.53, No.2, 172-177(2001).
[0006] For production of formulations of such an inhibitor, the
conventional methods disclosed include a method in which peppermint
oil and water are mixed by stirring and allowed to stand at room
temperature for 24 hours and only the transparent portion after
elimination of the oily component floating on the surface of the
water is used, and a method in which after mixing by stirring and
standing at room temperature for 24 hours, an aqueous layer is
filtered to remove an oily component before use. The formulations
produced by these methods, however, have a risk of loss of the
volatile peppermint oil by evaporation while standing at room
temperature for a long time, and thus have a problem that the
content of peppermint oil at the time of administration to a
patient may be inconstant or indefinite. Consequently a constant
amount of a conventionally-formulated product may fail to produce a
constant effect when administered for example by spraying as a
gastric contraction inhibitor onto the wall of stomach, which
results in an insufficient inhibitory effect on contraction.
Furthermore, these products require formulation just before use
because of their difficulty in long-term storage and the quality of
the formulation may be variable from site to site of medical
practice.
DISCLOSURE OF INVENTION
Problem to be Solved by the Invention
[0007] The present inventors succeeded in development of a smooth
muscle contraction inhibitor formulation or a digestive tract
contraction inhibitor formulation containing L-menthol which
remains stable for a long time and transparent by emulsifying
L-menthol and a fat or oil with a surfactant, and filed an
application for patent. This inhibitor formulation, however,
required a relatively high content of the surfactant for
transparency so that foaming occurred during filling the
formulation into a container or during spraying through a tube to
the affected area for endoscopic examination, and the foam made
observation of the affected area difficult. Under these
circumstances, development of an L-menthol-containing digestive
tract contraction inhibitor formulation that has good transparency,
namely high light transmittance, and is less foamy and remains
stable for a long time has ardently been desired.
Means for Solving the Problem
[0008] As a result of the inventor's extensive research to obtain
an L-menthol-containing formulation for inhibiting smooth muscle
contraction, especially for inhibiting digestive tract contraction
that remains stable for a long time, exhibits highly light
transmittance, and hardly causes foaming during filling into a
container or administration to a target region, the inventors have
found that an L-menthol-containing formulation that hardly causes
foaming during filling or use of the formulation, is good in
transmittance, and remains stable for a long time can be obtained
by addition of a small amount of an antifoaming agent to a mixture
of L-menthol, a surfactant and water, and making the average
particle size of the emulsion particles less than 100 nm, and
finally have accomplished the present invention.
[0009] Namely the invention relates to:
[0010] (1) An L-menthol-containing formulation for inhibiting
smooth muscle contraction, which comprises L-menthol, a surfactant,
and an antifoaming agent and which is an emulsion with an average
particle size of less than 100 nm;
[0011] (2) The L-menthol-containing formulation according to (1),
which further comprises a fat or oil;
[0012] (3) The L-menthol-containing formulation according to (1) or
(2), which has a light transmittance of 50% or more;
[0013] (4) The L-menthol-containing formulation according to any
one of (1) to (3), which comprises 0.01 to 5.0% by weight of
L-menthol, 0.1 to 10% by weight of a surfactant, and 0.0001 to
0.01% by weight of an antifoaming agent based on the weight of the
whole formulation;
[0014] (5) The L-menthol-containing formulation according to (4),
wherein a content of the fat or oil is from 0.1 to 10% by
weight;
[0015] (6) The L-menthol-containing formulation according to any
one of (1) to (5), wherein the antifoaming agent is at least one
agent selected from silicone antifoaming agents; and
[0016] (7) The L-menthol-containing formulation according to any
one of (1) to (6), wherein the surfactant is at least one member
selected from polyoxyethylene hydrogenated caster oils and sucrose
fatty acid esters.
[0017] The L-menthol employed in the invention is not particularly
limited as to its origin, being generally a main component of
peppermint oil. Peppermint oil is obtained by steam distillation of
a plant for example of Mentha piperita or Mentha arvensis and
contains 30% or more by weight of L-menthol. The
L-menthol-containing material employed may be peppermint oil or
mentha oil as it is, but highly purified L-menthol obtained for
example by fractional distillation of peppermint oil or mentha oil
can also be employed preferably. More preferably L-menthol of a
purity of 90% or more by weight is employed. Recently L-menthol is
produced also by synthesis. In any way the one in compliance with
the Japanese Pharmacopoeia standard of L-menthol is preferable.
[0018] In the present invention, L-menthol is present in an amount
of 0.01 to 5.0% by weight, preferably 0.1 to 3.0% by weight, and
more preferably 0.3 to 1.5% by weight based on the entire weight of
the formulation.
[0019] The antifoaming agent employed in the invention is not
limited particularly as long as it is an antifoaming agent that can
be employed in a pharmaceutical product, and a mixture of two or
more antifoaming agents may be used. Silicone antifoaming agents
are preferable, agents of the polydimethylsiloxane series are
particularly preferable, and polydimethylsiloxane-silicone dioxide
mixture is more preferable.
[0020] The amount of the antifoaming agent employed in the
invention is usually 0.0001 to 0.01% by weight, preferably 0.0005
to 0.007% by weight, and more preferably 0.0007 to 0.005% by weight
based on the entire formulation.
[0021] The surfactant employed in the invention is not limited
particularly as long as it is a surfactant that can be employed in
a pharmaceutical product, and a mixture of two or more surfactants
may be used. The amount of the surfactant is usually 0.1 to 10% by
weight, preferably 0.5 to 5% by weight based on the entire
formulation. The surfactant of the invention preferably contains at
least polyoxyethylene hydrogenated caster oil. The amount of
polyoxyethylene hydrogenated caster oil, when contained, is usually
1 to 3% by weight, preferably 1.5 to 2.5% by weight based on the
entire formulation. Sucrose fatty acid ester and polysorbate may be
used preferably, and polysorbate 80 etc. can be used particularly
preferably.
[0022] In addition to polyoxyethylene hydrogenated caster oil,
other surfactants that can be employed in pharmaceutical products,
such as edible nonionic surfactants and ionic surfactants, may be
employed alone or in combination thereof.
[0023] A formulation of the present invention can be obtained by
stirring water that contains the above-mentioned L-menthol,
surfactant, and antifoaming agent, and, if necessary, also the fat
or oil, with heating, or by heating the mixture after mixing by
stirring.
[0024] Antifoaming effect of the emulsion thus obtained as a smooth
muscle contraction inhibitor formulation of the invention was
evaluated based on the time for disappearance of foam after
1-minute shaking of 20 mL of a sample in a 30-mL glass bottle of 33
mm in diameter in a shaker (170 shakes/min, stroke: 40 mm). The
time for disappearance of foam of the formulation of the invention
is preferably not more than 3 minutes, more preferably not more
than 30 seconds, and particularly preferably not more than 20
seconds.
[0025] The average particle size of the emulsion as a smooth muscle
contraction inhibitor formulation of the invention is less than 100
nm, preferably not more than 70 nm, more preferably not more than
50 nm, and particularly preferably not more than 30 nm.
[0026] The average particle size of the emulsion was determined by
placing a few drops of the sample in a 10-mm cell and adding
distilled water to obtain a sample solution, followed by
measurement using a light scattering photometer (ELS8000, OTSUKA
ELECTRONICS CO., LTD).
[0027] An emulsion having a large average particle size gives a
white turbid formulation, and when such a formulation is sprayed
onto the affected area for endoscopic examination of the digestive
tract etc., observation of the area may be difficult. In contrast,
the emulsion obtained in the invention is a clear or slightly
turbid liquid with foaming suppressed and thus is free of problems
mentioned above.
[0028] The light transmittance of the formulation of the invention
is preferably 50% or more and particularly preferably 70% or
more.
[0029] The light transmittance was measured by placing a sample in
a 10-mm cell using a double beam spectrophotometer Model U-2001
(HITACHI, LTD.) at 900 nm as a measurement wavelength.
[0030] The formulation of the invention can be obtained by means of
a known emulsification or solubilization. A preferred method is one
of those listed below, to which it is not limited.
[0031] i) First, L-menthol is dissolved in a fat or oil. The
dissolution may be conducted at room temperature or with warming.
Then the resultant uniform mixture of the L-menthol and the fat or
oil is added to water containing a surfactant which has been
dispersed well by stirring for example with a stirrer such as
homomixer, and the mixture is stirred thoroughly using a stirrer
such as a homomixer. If necessary, a further ultrasonic treatment
or use of a high-pressure emulsifier may be employed additionally
to ensure uniform and fine particles of the emulsion. Thereafter,
the emulsion thus prepared is autoclaved at 115.degree. C. for 30
minutes.
[0032] ii) In another method, a formulation is prepared by the
method described above, and stored at 60.degree. C. or a higher
temperature for about 1 week instead of the autoclave
sterilization.
[0033] iii) In still another method, a surfactant is added to water
and dispersed using a stirrer such as a homomixer, and thereafter
L-menthol and a fat or oil are added, and the mixture is stirred at
about 80.degree. C. for about 10 minutes with a homomixer.
[0034] For the formulation for inhibiting smooth muscle contraction
of the present invention, a fat or oil can be used. The fat or oil
to be used is not particularly limited as far as it is a
pharmaceutically acceptable fat or oil, but preferably a
middle-chain fatty acid triglyceride (MCT) or a long-chain fatty
acid triglyceride (LCT) such as soybean oil, olive oil, and coconut
oil can be used.
[0035] MCT that can be used includes those with C6- to C12-fatty
acid moiety, and a mixture of those with different carbon numbers
can be used (for example, `Panasate 800` manufactured by NOF
Corporation, `Coconad RK` manufactured by KAO Corporation).
[0036] The fat or oil can be used as a solvent for L-menthol, where
0.5- to 10-fold weight, preferably 1- to 5-fold weight, of the fat
or oil can be used per weight of L-menthol. The fat or oil is used
in an amount usually of 0.1 to 5% by weight, preferably 0.5 to 3%
by weight, based on the weight of the entire emulsion.
[0037] The contraction inhibitory formulation containing a fat or
oil may be prepared by stirring L-menthol, a fat or oil, a
surfactant, and water containing an antifoaming agent, and heating
while stirring, or heating after stirring can produce a more stable
formulation.
[0038] Heat treatment can be accomplished by a method which is not
limited specifically, and it is acceptable to heat an
L-menthol-containing emulsion, which contains L-menthol, a fat or
oil, a surfactant, and an antifoaming agent, at any stage during
the course of manufacturing. Examples of the heat treatment may be
a procedure in which emulsification of the mixture is performed for
example with a homomixer under a heating condition, in which
emulsification of the mixture is performed using a high pressure
emulsifier under a heating condition, in which the emulsion is
filled in a container which is then sterilized by heating, in which
the emulsion is filled in a container which is then stored at a
high temperature, or in which the emulsification is performed under
a heating condition followed by sterilization also under a heating
condition. Heating time may vary depending on the stirring
condition, and it is desirable to maintain the heating condition
for 1 minute to 14 days, preferably for 5 minutes to 6 hours.
[0039] The heating temperature may be 60.degree. C. or higher,
preferably 70.degree. C. to 130.degree. C., especially preferably
80.degree. C. to 121.degree. C. A satisfactory result is obtained
when heating sterilization is performed under the heating condition
usually employed for an ordinary fat emulsion (110 to 121.degree.
C.).
[0040] Another active ingredient, a thickening agent, a stabilizer,
a preservative, etc. may be added appropriately as needed.
[0041] The thickening agent may be carrageenan, methyl cellulose,
carboxymethyl cellulose, guar gum, pectin, or the like. Addition of
the thickening agent can adjust the falling-down rate of the
formulation sprayed inside the digestive tract to a desirable
rate.
[0042] The amount of the thickening agent to be added may vary
according to the type of the thickening agent and is usually
selected from the range from 0.01 to 5% by weight.
[0043] The stabilizer may be sodium edetate and the preservative
may be sorbic acid, benzalkonium chloride, a parabene, or the like,
in a suitable amount.
[0044] The L-menthol-containing formulation of the invention is
sprayed directly onto the target area, for example the inner side
of the digestive tract, via a sprayer or an endoscopic forceps
guide, in laparotomic or endoscopic surgery of the digestive tract,
in endoscopic examination of the digestive tract, or in any medical
care that requires inhibition of the digestive tract contraction.
For direct administration of a constant amount of emulsion via a
sprayer or an endoscopic forceps guide, it is desirable to fill the
unit dose of the emulsion that has been prepared as described above
into an extrusive vessel such as a pre-filled syringe. It is a
matter of course that the product of the invention can be filled
and stored in a container such as a vial or ampoule.
[0045] The formulation of the invention remains stable even after
storage for a long term. For example, the average particle size of
the emulsion does not exceed 100 nm and the light transmittance
does not become below 50% after storage at 25.degree. C. for 1
month.
Effect of the Invention
[0046] The formulation for inhibiting smooth muscle contraction,
the emulsion of the invention remains stable over a long time,
exhibits a high light transmittance, and causes little foam during
filling in a container or in use, namely in administration.
Therefore the formulation is useful as a contraction inhibitor to
be used particularly in endoscopic examination of the digestive
tract.
BRIEF DESCRIPTION OF THE DRAWINGS
[0047] FIG. 1 shows the percent change of peristaltic contraction
wave area of the body of stomach of dog in Experimental Example
2.
[0048] FIG. 2 shows the percent change of peristaltic contraction
wave area of the pyloric part of stomach of dog in Experimental
Example 2.
DESCRIPTION OF REFERENCE NUMERALS
[0049] The solid line with the marks .circle-solid. indicates a
graph for the composition in Example 7, and the dotted line with
the marks X indicates a graph of the untreated case.
BEST MODE FOR CARRYING OUT THE INVENTION
[0050] The invention is described in more detail in the following
Examples, Comparative Examples, and Experimental Examples.
EXAMPLE 1
[0051] To 200 mL of water were added 4.0 g of polysorbate 80 (Tween
80, Rheodol TW-O120V, KAO Corporation) and 0.02 g of a
polydimethylsiloxane-silicone dioxide mixture (KS-69, Shin-Etsu
Chemical Co., Ltd.), followed by emulsification with a homomixer
(liquid temperature: 60.degree. C.) to give a
polydimethylsiloxane-silicone dioxide mixture fluid. To 1600 mL of
water were added 20.0 g of a sucrose fatty acid ester (Surfhope
J1616, Mitsubishi-Kagaku Foods Corporation), 36.0 g of
polyoxyethylene hydrogenated caster oil 60, (NIKKOL HCO-60, Nikko
Chemicals Co., Ltd.), and 30.0 g of MCT (Coconad RK, Kao
Corporation) were added and dispersed with a homomixer. To this
liquid were added 16.0 g of L-menthol that was in compliance with
the Japanese Pharmacopoeia standard (L-Menthol, The SUZUKI Menthol
CO., LTD.) and the polydimethylsiloxane-silicone dioxide mixture
fluid, followed by emulsification with a homomixer at a liquid
temperature of 80.degree. C. Water was added to this liquid to make
the entire volume 2000 mL to give a desired emulsion. The average
particle size of this emulsion was 28.5 nm with the light
transmittance of 96.09%.
EXAMPLE 2
[0052] To 200 mL of water were added 4.0 g of Tween 80 (Rheodol
TW-O120V, KAO Corporation) and 0.06 g of a
polydimethylsiloxane-silicone dioxide mixture (KS-69, Shin-Etsu
Chemical Co., Ltd.), followed by emulsification with a homomixer
(liquid temperature: 60.degree. C.) to give a
polydimethylsiloxane-silicone dioxide mixture fluid. To 1600 mL of
water were added 20.0 g of a sucrose fatty acid ester (Surfhope
J1616, Mitsubishi-Kagaku Foods Corporation), 36.0 g of HCO-60
(NIKKOL HCO-60, Nikko Chemicals Co., Ltd.), and 30.0 g of MCT
(Coconad RK, Kao Corporation) and dispersed with a homomixer. To
this liquid were added 16.0 g of L-menthol that was in compliance
with the Japanese Pharmacopoeia standard (L-Menthol, The SUZUKI
Menthol CO., LTD.) and the polydimethylsiloxane-silicone dioxide
mixture fluid, followed by emulsification with a homomixer at a
liquid temperature of 80.degree. C. Water was added to this liquid
to make the entire volume 2000 mL to give a desired emulsion. The
average particle size of this emulsion was 28.8 nm with the light
transmittance of 94.68%.
EXAMPLE 3
[0053] To 200 mL of water were added 4.0 g of Tween 80 (Rheodol
TW-O120V, KAO Corporation) and 0.10 g of a
polydimethylsiloxane-silicone dioxide mixture (KS-69, Shin-Etsu
Chemical Co., Ltd.), followed by emulsification with a homomixer
(liquid temperature: 60.degree. C.) to give a
polydimethylsiloxane-silicone dioxide mixture fluid. To 1600 mL of
water were added 20.0 g of a sucrose fatty acid ester (Surfhope
J1616, Mitsubishi-Kagaku Foods Corporation), 36.0 g of HCO-60
(NIKKOL HCO-60, Nikko Chemicals Co., Ltd.), and 30.0 g of MCT
(Coconad RK, Kao Corporation) and dispersed with a homomixer. To
this liquid were added 16.0 g of L-menthol that was in compliance
with the Japanese Pharmacopoeia standard (L-Menthol, The SUZUKI
Menthol CO., LTD.) and the polydimethylsiloxane-silicone dioxide
mixture fluid, followed by emulsification with a homomixer at a
liquid temperature of 80.degree. C. Water was added to this liquid
to make the entire volume 2000 mL to give a desired emulsion. The
average particle size of this emulsion was 27.7 nm with the light
transmittance of 93.72%.
EXAMPLE 4
[0054] To 200 mL of water were added 4.0 g of Tween 80 (Rheodol
TW-O120V, KAO Corporation) and 0.02 g of a
polydimethylsiloxane-silicone dioxide mixture (KS-66, Shin-Etsu
Chemical Co., Ltd.), followed by emulsification with a homomixer
(liquid temperature: 60.degree. C.) to give a
polydimethylsiloxane-silicone dioxide mixture fluid. To 1600 mL of
water were added 20.0 g of a sucrose fatty acid ester (Surfhope
J1616, Mitsubishi-Kagaku Foods Corporation), 36.0 g of HCO-60
(NIKKOL HCO-60, Nikko Chemicals Co., Ltd.), and 30.0 g of MCT
(Coconad RK, Kao Corporation) and dispersed with a homomixer. To
this liquid were added 16.0 g of L-menthol that was in compliance.
with the Japanese Pharmacopoeia standard (L-Menthol, The SUZUKI
Menthol CO., LTD.) and the polydimethylsiloxane-silicone dioxide
mixture fluid, followed by emulsification with a homomixer at a
liquid temperature of 80.degree. C. Water was added to this liquid
to make the entire volume 2000 mL to give a desired emulsion. The
average particle size of this emulsion was 27.6 nm with the light
transmittance of 95.75%.
EXAMPLE 5
[0055] To 200 mL of water were added 4.0 g of Tween 80 (Rheodol
TW-O120V, KAO Corporation) and 0.06 g of a
polydimethylsiloxane-silicone dioxide mixture (KS-66, Shin-Etsu
Chemical Co., Ltd.), followed by emulsification with a homomixer
(liquid temperature: 60.degree. C.) to give a
polydimethylsiloxane-silicone dioxide mixture fluid. To 1600 mL of
water were added 20.0 g of a sucrose fatty acid ester (Surfhope
J1616, Mitsubishi-Kagaku Foods Corporation), 36.0 g of HCO-60
(NIKKOL HCO-60, Nikko Chemicals Co., Ltd.), and 30.0 g of MCT
(Coconad RK, Kao Corporation) and dispersed with a homomixer. To
this liquid were added 16.0 g of L-menthol that was in compliance
with the Japanese Pharmacopoeia standard (L-Menthol, The SUZUKI
Menthol CO., LTD.) and the polydimethylsiloxane-silicone dioxide
mixture fluid, followed by emulsification with a homomixer at a
liquid temperature of 80.degree. C. Water was added to this liquid
to make the entire volume 2000 mL to give a desired emulsion. The
average particle size of this emulsion was 26.3 nm with the light
transmittance of 94.16%.
EXAMPLE 6
[0056] A mixture of 4.0 g of Tween 80 (Rheodol TW-O120V, KAO
Corporation) and 0.10 g of a polydimethylsiloxane-silicone dioxide
(KS-66, Shin-Etsu Chemical Co., Ltd.) were added to 200 mL of
water, followed by emulsification with a homomixer (liquid
temperature: 60.degree. C.) to give a polydimethylsiloxane-silicone
dioxide mixture fluid. To 1600 mL of water were added 20.0 g of a
sucrose fatty acid ester (Surfhope J1616, Mitsubishi-Kagaku Foods
Corporation), 36.0 g of HCO-60 (NIKKOL HCO-60, Nikko Chemicals Co.,
Ltd.), and 30.0 g of MCT (Coconad RK, Kao Corporation) and
dispersed with a homomixer. To this liquid were added 16.0 g of
L-menthol that was in compliance with the Japanese Pharmacopoeia
standard (L-Menthol, The SUZUKI Menthol CO., LTD.) and the
polydimethylsiloxane-silicone dioxide mixture fluid, followed by
emulsification with a homomixer at a liquid temperature of
80.degree. C. Water was added to this liquid to make the entire
volume 2000 mL to give the desired emulsion. The average particle
size of this emulsion was 27.2 nm with the light transmittance of
92.58%.
EXAMPLE 7
[0057] To 200 mL of water were added 4.0 g of Tween 80 (Rheodol
TW-O120V, KAO Corporation) and 0.02 g of a
polydimethylsiloxane-silicone dioxide mixture (KS-66, Shin-Etsu
Chemical Co., Ltd.), followed by emulsification with a homomixer
(liquid temperature: 60.degree. C.) to give a
polydimethylsiloxane-silicone dioxide mixture fluid. To 1600 mL of
water were added 20.0 g of a sucrose fatty acid ester (Surfhope
J1616, Mitsubishi-Kagaku Foods Corporation), 36.0 g of HCO-60
(NIKKOL HCO-60, Nikko Chemicals Co., Ltd.), and 24.0 g of MCT
(Coconad RK, Kao Corporation) and dispersed with a homomixer. To
this liquid were added 16.0 g of L-menthol that was in compliance
with the Japanese Pharmacopoeia standard (L-Menthol, The SUZUKI
Menthol CO., LTD.) and the polydimethylsiloxane-silicone dioxide
mixture fluid, followed by emulsification with a homomixer at the
liquid temperature of 80.degree. C. Water was added to this liquid
to make the entire volume 2000 mL to give a desired emulsion. The
average particle size of this emulsion was 23.2 nm with the light
transmittance of 97.34%.
COMPARATIVE EXAMPLE 1
[0058] 1.12 g of L-menthol that was in compliance with the Japanese
Pharmacopoeia standard (L-menthol, The SUZUKI Menthol CO., LTD.)
and 2.8 g of MCT (Coconad RK, Kao Corporation) were mixed and
dissolved in a water bath at 60.degree. C. to give an L-menthol
solution. Water, 60 mL was added to 0.28 g of Tween 80 (Rheodol
TW-O120V, KAO Corporation), 1.68 g of a sucrose fatty acid ester
(Surfhope J1616, Mitsubishi-Kagaku Foods Corporation), and 2.8 g of
HCO-60 (NIKKOL HCO-60, Nikko Chemicals Co., Ltd.), followed by
dispersion with a homomixer (60.degree. C. in a water bath). To
this liquid was added the L-menthol solution, followed by
emulsification with a homomixer (60.degree. C. in a water bath).
Then water was added to this liquid to make the entire volume 140
mL, followed by ultrasonic emulsification for 10 minutes to give an
emulsion. Then the emulsion was autoclaved at 115.degree. C. for 20
minutes to give a desired emulsion. The average particle size of
this emulsion was 30.3 nm with the light transmittance of
97.48%.
EXPERIMENTAL EXAMPLE 1
[0059] Into a 30-mL bottle, 20 mL of a sample was placed and the
bottle was shaken for 1 minute in a shaker SR-IIW (Taiyo Kagaku
Kogyo Co., Ltd., 170 shakes/min, 40 nm stroke).
[0060] After 1-minute shaking, the time for disappearance of foam
was measured. The results of the measurement are shown together
with average particle sizes and light transmittance in Table 1.
TABLE-US-00001 TABLE 1 Average particle Average particle size Light
transmittance Example or size at initial Light transmittance after
storage for 1 month at after storage for 1 month Time for
disappearing Comparative Example (nm) at initial (%) 25.degree.
C.(nm) at 25.degree. C.(%) of foams Example 1 28.5 96.09 33.7 93.80
4 sec. Example 2 28.8 94.68 34.4 92.46 4 sec. Example 3 27.7 93.72
37.6 90.11 4 sec. Example 4 27.6 95.75 31.0 94.11 3 sec. Example 5
26.3 94.16 30.7 91.82 3 sec. Example 6 27.2 92.58 32.5 98.62 3 sec.
Example 7 23.2 97.34 25.9 96.16 6 sec. Comparative 30.3 97.48 -- --
6.5 hr Example 1
As evident from Table 1, all of the formulations obtained in
Examples of the invention had an average particle size as about
1.2-fold large as the initial particle size not only immediately
after formulation but also even after storage at 25.degree. C. for
1 month, with a light transmittance of 95% or more of the initial
value, and foam disappeared in a very short time, the time for
disappearance being 6 seconds or less. In contrast the average
particle size and the initial light transmittance of the emulsion
obtained in Comparative Example 1 were not very different from
those of the emulsions obtained in Examples, but 6 hours and 30
minutes was required for disappearance of foam.
EXPERIMENTAL EXAMPLE 2
Inhibitory Effect on Stomach Contraction of Anesthetized Dog
Materials and methods
[0061] To a dog (about 10 kg) which had been kept fasting over day
and night, atropine sulfate as a pre-anesthetic medication was
intravenously injected followed by intravenous injection of
thiopental sodium for induction of anesthesia. An intratracheal
tube was inserted and fixed. A mixture gas of nitrous oxide and
oxygen was blown into. Isoflurane was sent via the isoflurane
vaporizer. The concentration of isoflurane was elevated gradually
from 0.5% for maintenance anesthesia. The anesthetized dog was
laparotomized at the median line, and a strain gauge force
transducer (SGT) was fixed in the body of stomach and at the
pyloric part of stomach according to the conventional
procedure.
[0062] Ten minutes after completion of IMC (inter-digestive
migrating contraction), erythromycin at 6 mg/animal was
intravenously administered to induce peristaltic movement of the
stomach. Ten more minutes later, 10 ml of the formulation of
Example 7 which had been stored at 25.degree. C. for 1 month was
administered via a stomach catheter into the body of stomach or to
the pyloric part of stomach, and contraction was recorded.
Contraction-inhibiting effect was evaluated from the percent change
of the wave area at every 10 minutes after administration of the
formulation. The results are shown in FIG. 1 and FIG. 2. As a
control, the percent change of the wave area without treatment was
also determined.
[0063] As shown in FIG. 1 and FIG. 2, the contraction inhibitor
formulation of the invention, when sprayed on the body or the
pyloric part of the stomach after induction of contraction by
administration of erythromycin, inhibited significantly more
strongly as compared with the untreated stomach. No foam appeared
in endoscopy after spraying of the contraction inhibitor
formulation, with no disturbance for observation of the area.
INDUSTRIAL APPLICABILITY
[0064] The L-menthol-containing formulation for inhibiting smooth
muscle contraction of the invention remains stable for a long time
after preparation, exhibits a high light transmittance, and hardly
causes foaming when administered into the digestive tract, and thus
can be used favorably for endoscopic examination of the digestive
tract such as esophagus, stomach, small intestine, large intestine,
and rectum.
* * * * *