ORAL RINSE COMPOSITIONS FOR ALLEVIATING XEROSTOMIA
COMPRISING POLYETHYLENE GLYCOL DERIVATIVES
BACKGROUND
1. Field of the Invention
The present invention relates to an oral rinse composition for alleviating
xerostomia comprising a polyethylene glycol derivative as an active
ingredient.
2. Discussion of Related Art
Xerostomia is a disease in which the oral mucosa becomes dry due to a
decrease in saliva secretion due to various causes. Saliva plays an important
role in
maintaining the main function of the oral cavity smoothly and protecting the
oral
mucosa, and therefore, when the amount of saliva secretion is reduced to cause
xerostomia, extremely serious disorders occur, mainly drawing complaints about
abnormalities in chewing function and in speech function, and causing the
generation
of severe bad breath and caries, and depending on the severity, depending on
the
degree, severe pain is experienced, for example, the burning feeling of the
oral mucosa
or the ulceration of oral mucosa.
The causes of xerostomia are congenital malformations such as salivary gland
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Date Recue/Date Received 2022-07-29
agenesis, autoimmune diseases such as Sjogren's syndrome or chronic graft-
versus-
host disease, and psychiatric disorders, diabetes, complications of radiation
therapy,
hepatitis C virus, chronic renal failure, AIDS, primary biliary cirrhosis,
taking other
medications, stress and mental illness, severe fever or diarrhea, dehydration
due to
large amounts of diuresis, when the salivary glands tube was blocked by
calculus or
cancer, body abnormalities such as infectious lesions of salivary glands such
as
epidemic parotitis have become the cause of temporary or long-term xerostomia.
In
addition, as the cause of human aging and menopausal disorders, saliva
secretion is
increased by various stimuli during waking activity, whereas the amount of
saliva
secretion is significantly decreased during sleep, and the proportion of
patients who
complained discomfort due to hypotasis occurring in the sleep reached 23%, and
most
of them were geriatric. (Thie et al., 2002).
For the treatment of xerostomia, among parasympathomimetic drugs,
cholinergic drugs (pilocarpine (Salagen, MGI Pharmaceuticals., Minneapolis),
cevimeline (Evoxac); 3 to 4 times postprandial doses per day, the effect
thereof lasts
2-4 hours) are used to promote the secretion of saliva but also affect other
parts of the
body, thereby increasing the secretion of tears or nasal discharge or
increasing sweat
secretion. It is contraindicated in patients with asthma, acute iritis, narrow
angle
glaucoma, and glaucoma, and may have side effects in the case of
cardiovascular
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Date Regue/Date Received 2022-07-29
disease, chronic bronchitis, and chronic obstructive disease. In addition,
sugar-free
gums and candy containing xylitol, lactoperoxidase, or glucose oxidase that
promote
saliva secretion are on sale. Chewing gum containing a mucosal ingredient
continued
to promote saliva secretion for a long time (Aagaard et al., 1992), and
spraying the
mucosal ingredient had a great effect on geriatric xerostomia (Momm and
Guttenberger, 2002).
In the related arts, there is disclosed an oral rinse composition that can
prevent
and improve oral diseases by including eugenol and bamboo salt (Korea Patent
Publication No. 10-2020-0050801), and there is disclosed a composition that
can
relieve bad breath by including a seaweed extract (Korean Patent No. 10-
2313830).
However, since the related arts suggest that the main purpose is to kill
harmful
bacteria in the oral cavity and eliminate bad breath, there is a problem that
it is difficult
to expect an improvement effect as the duration of the relief of xerostomia is
low
because oral irritation is partially accompanied or a temporary hydration
effect is
exhibited.
In addition, a previous study by the present inventors (Korea Patent
Registration No 10-1526258) discloses the inclusion of active ingredients of
polyethylene glycol derivatives modified with various reactive groups as
compositions
for preventing, treating or ameliorating xerostomia that can bind to oral
mucosa. Based
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Date Recue/Date Received 2022-07-29
on this, for actual commercialization, an oral rinse composition for
alleviating
xerostomia was completed based on the efficacy and safety results of each
derivative
and by confirming whether it can be applied to the human body.
[Related art literature]
[Patent Literature]
Korea Patent Publication No. 10-2020-0050801
Korea Patent Registration No. 10-2313830
Korea Patent Registration No. 10-1526258
SUMMARY OF THE INVENTION
Under the above background, the present inventors have completed an oral
rinse composition for alleviating xerostomia as a granule oral moisturizer
which not
only includes a polyethylene glycol derivative as an active ingredient and
which can
increase oral moisturizing maintenance by covalent bonding of oral mucosa
without
irritation, but also is easy to portable and easy to use.
Accordingly, an object of the present invention is to provide an oral rinse
composition for alleviating xerostomia comprising a polyethylene glycol
derivative as
an active ingredient.
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Date Recue/Date Received 2022-07-29
As a means for solving the above problems, the present invention provides an
oral rinse composition for alleviating xerostomia comprising a polyethylene
glycol
derivative as an active ingredient.
Hereinafter, the configuration of the present invention will be described in
detail.
The present invention relates to an oral rinse composition for alleviating
xerostomia comprising a polyethylene glycol derivative as an active
ingredient.
Polyethylene glycol is well known for its moisturizing effect. However, since
it is applied in the oral mucosa and is easily washed off with water or
saliva, the
durability of the effect of alleviating xerostomia is low.
Therefore, in the present invention, as shown in Chemical Formula 1 below,
this problem has been solved by modifying the terminal reactive group of
polyethylene
glycol to allow covalent bonding with oral mucosa epithelial cells, thereby
allowing
the polyethylene glycol derivative to adhere to oral mucosa epithelial cells
for a long
time.
[Chemical Formula 1]
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Date Recue/Date Received 2022-07-29
0 N 0 ONO
0
0
0
0
00
0 ¨ (CH 2CH 20),
n(0H20H20)-0
0¨(CH2CH20)n
n(01-1201-120)-0
(0)
0
N 0
0 N 0 r
Through the previous studies of the present applicants, among various PEG
derivatives, various PEG derivatives having a reactive group capable of
covalent
bonding with an amine group on oral mucosa epithelial cells have been
developed. In
the process of developing and researching products suitable for oral
application using
various PEG derivatives, the present inventors found that among them, halogen,
amine
(NH2), epoxide and maleimide reactive groups require long time for the amide
coupling reaction with amine group of the cell, and thus, the oral application
time
should be prolonged. In addition, it was also revealed that the use of
toxicants and by-
products may remain in the reactive group synthesis process of the PEG
derivative,
and the odor property of the final finished PEG derivative causes the
remaining
fragrance caused by chemical synthesis and is unsuitable for oral application.
In
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Date Recue/Date Received 2022-07-29
addition, it was confirmed that the aldehyde (CHO) reactive group requires a
reducing
agent (sodium cyanoborohydride) for the amide coupling reaction, and the
nitrophenyl
carbonate (NPC) reactive group produces harmful by-products (nitrophenol) in
the
amide reaction process, so it was not suitable for oral application.
Accordingly, the present inventors have completed the present invention by
confirming that the use of a branched modified polyethylene glycol derivative
having
a _____________________________________________________________________ NHS (N-
hydroxysuccinimide) reactive group of Chemical Formula 1 results in a
fast amide reaction rate in oral application, no reagents required before and
after the
reaction, and no by-products, and there is no problem with discomfort and
safety when
applied in the oral cavity.
The present invention provides an oral rinse composition for alleviating
xerostomia, comprising a polyethylene glycol derivative of the following
Chemical
Formula (1) as an active ingredient, an acidity adjusting agent and a
flavoring agent;
the polyethylene glycol derivative has a molecular weight of 8,000 to 15,000
Da, and
the composition is the granule formulation.
As can be seen in the Examples below, it was confirmed that the polyethylene
glycol derivative of Chemical Formula 1 had higher moisture absorption
compared to
the linear PEG derivative, which can enhance moisturizing maintenance because
the
polyethylene glycol derivative can trap more water molecules when binding to
the oral
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Date Recue/Date Received 2022-07-29
mucosa.
In addition, the oral rinse composition for alleviating xerostomia according
to
the present invention is prepared in the granule formulation to improve
storage stability
such as moisture absorption and static electricity.
In one embodiment of the present invention, the granules may have a particle
size of 200 to 1500 gm. For example, the granules may have a particle size of
300 to
1000 gm. The particle size of the granules is preferably 200 to 1500 gm for
manufacturing (production) and packet packaging for one-time use and for
stability
during manufacturing and storage.
The composition of the granule formulation of the present invention is
reconstituted in the form of a solution by dissolving it in water when used.
When 1 g of the composition of the granule formulation according to the
present invention is quickly dissolved in 20 ml of water and applied orally,
the dry oral
mucosa is characterized by the formation of a water layer in which the
polyethylene
glycol derivative of formula (1) is tightly bound to the oral mucosa, thereby
maintaining moisture retention for a long time compared to the temporary water
layer
of existing products, thereby maintaining moisture retention for a long time
compared
to the temporary water layer of existing products. Thus, the composition of
the granule
formulation of the present invention is a one-time use product that is mixed
in an
amount of 20 ml of water, then reconstituted into a solution, left in the
mouth for about
30-60 seconds, and spit out, when the mouth feels dry, in particular, for
xerostomia
patients, an elderly person, and a common person before bedtime. Effects
include oral
moisturizing, caries prevention, and cleaning effects.
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Date Recue/Date Received 2022-07-29
In the composition of the present invention, the acidity adjusting agent is
included in an amount of 1 to 10 parts by weight, for example, 2 to 8 parts by
weight,
3 to 7 parts by weight based on 100 parts by weight of the composition.
Preferably,
the acidity adjusting agent is included in an amount of 4 to 6 parts by
weight.
Meanwhile, when the composition is dissolved in water for use and
reconstituted in the form of a solution, the viscosity of the solution may be
0.001 Pa s
to 0.01 Pa. s. The viscosity of the solution can affect the convenience of
users,
application in the oral cavity, feeling of use, and the like, and therefore,
the above
range is suitable. The viscosity can not only improve palatability for oral
application,
but also prevent cytotoxicity and irritation occurring when the granules are
directly
administered. Alternatively, when the composition is dissolved in water in use
and
reconstituted in the form of a solution, the concentration of the solution may
be 4 to
5%.
As the acidity adjusting agent is included, the composition is preferably
dissolved in water for use to exhibit a pH of 7 to 8 when reconstituted in a
solution
form. According to the research results of the present inventors, a pH of 7 to
8 is a
favorable condition for covalent bonding between the PEG derivative according
to the
present invention and an amine in the oral cavity. Furthermore, since the
salivary pH
of xerostomia patients is as low as 6.4 or less, and the xerostomia symptoms
and
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Date Recue/Date Received 2022-07-29
salivary pH show a significant negative correlation, the pH of the composition
for
alleviating xerostomia symptoms is preferably pH 7 to 8.
As the flavoring agent, for example, a powdered food flavor suitable for oral
application such as citrus, fruit, berry, vanilla, mint, etc. may be used, and
the type is
not particularly limited. The flavoring agent may be used in an amount of 1 to
10
parts by weight, for example, 4 to 10 parts by weight, based on 100 parts by
weight of
the composition, but is not limited thereto.
Each of the above ingredients included in the oral rinse composition
according to the present invention may be included in the oral rinse
composition of the
present invention within a range that does not exceed the maximum amount
prescribed
in each country's food safety standards.
The present invention also provides a method of alleviating xerostomia,
including applying the oral rinse composition for alleviating xerostomia to a
subject in
need thereof.
The application includes administering and rinsing an oral rinse composition
for alleviating xerostomia reconstituted in solution form.
For example, when 1 g of the oral rinse composition of the granule formulation
according to the present invention is quickly dissolved in 20 ml of water and
applied
orally, the polyethylene glycol derivative of Chemical Formula 1 is tightly
bound to
the oral mucosa to maintain moisture retention for a long time compared to the
temporary water layer of existing products. Therefore, it can be usefully used
for
Date Recue/Date Received 2022-07-29
subjects or patients with xerostomia. The application may be carried out 1 to
3 times
a day, but is not limited thereto. It can be applied at any time when the
mouth feels
dry, and it is particularly advantageous to apply it before bedtime.
In addition, the present invention provides a method of preparing an oral
rinse
composition for alleviating xerostomia.
Hereinafter, the configuration of the manufacturing method of the present
invention will be described in detail.
The preparation method of the present invention may include preparing a
polyethylene glycol derivative powder of Chemical Formula 1 having a molecular
weight of 8,000 to 15,000 Da; mixing an acidity adjusting agent and a
flavoring agent
with the polyethylene glycol derivative powder, then transferring it to an
airtight
container and liquefying it at a high temperature; when the liquefaction is
completed,
transferring the airtight container to a low temperature to solidify; and when
the
solidification is completed, pulverizing to prepare granules.
In the preparation of the polyethylene glycol derivative of Chemical Formula
1 according to the present invention, -NHS was used as a reactive group, and
it is
suitable for mass production because NHS ester half-life is relatively long,
the number
of production processes is small and simple, and there is low risk in the
production
process.
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Date Recue/Date Received 2022-07-29
In the step of preparing the polyethylene glycol derivative powder of
Chemical Formula 1, the polyethylene glycol derivative preferably has a
molecular
weight of 8,000 to 15,000 Da. When the molecular weight is less than 8,000 Da
or the
molecular weight is more than 15,000 Da, there is a problem that not only
moisture
absorption is lowered, but also the crystallization and powdering processes
are
complicated during the production process, and the production yield is
lowered.
In the step of selecting the polyethylene glycol derivative, the branched
structure of the polyethylene glycol derivative is more advantageous than the
linear
structure. In the case of the branched structure, moisture absorption was
higher, and
since the number of derivative reactive groups that bind to the oral mucosa is
large, it
can retain more moisture for a longer period of time when combined with the
oral
mucosa to keep the oral cavity moist.
In the manufacturing method of the present invention, it may include adding
an acidity adjusting agent according to pH 7 to 8.
The liquefying step may be carried out at 50 C to 70 C for 1 hour. At this
time, when it is less than 50 C, liquefaction is not sufficiently achieved,
and when it
exceeds 70 C, the derivative molecules are partially decomposed and the
effect is
reduced.
The solidifying step may include primary hardening at room temperature for
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Date Recue/Date Received 2022-07-29
1 hour; and secondary hardening at -20 C (freezing).
When the particle size of the granules in the step of preparing the granules
is
200 to 1500 pm, it is preferable for storage stability and to reduce static
electricity
during product packaging.
The present invention also provides a product for relieving xerostomia,
including a container capable of measuring 15 ml to 30 ml of water per use and
a
packet containing a composition for alleviating xerostomia in a granule dosage
form
of 1 g to 1.5 g per use.
The product may include instructions for using a composition for alleviating
xerostomia in a granule formulation packaged for single use including pouring
and
mixing the composition into a container measured an amount of water for single
use
to dissolve the composition, and then applying the composition to a dry mouth
and
spitting out the composition after gargling.
[Effects of the Invention]
As the oral rinse composition for alleviating xerostomia according to the
present invention includes a polyethylene glycol derivative of Chemical
Formula 1 as
an active ingredient, it not only allows covalent bonding of the composition
to the oral
mucosa without irritation to increase oral moisturization duration, but also
allows easy
manufacture and packaging by having a granule formulation, as well as being
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Date Recue/Date Received 2022-07-29
advantageous for storage and use.
BRIEF DESCRIPTION OF THE DRAWINGS
FIGS. lA and 1B show the results of nuclear magnetic resonance (NMR)
analysis of the powder formulation and the granule formulation of the oral
rinse
composition for alleviating xerostomia according to the present invention.
FIG. 2 is a comparison result of surface static electricity according to the
formulation of the oral rinse composition for alleviating xerostomia according
to the
present invention.
DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS
Hereinafter, the present invention will be described in detail by way of
Examples. The following Examples merely illustrate the present invention and
do not
limit the scope of the present invention.
Experimental Example 1. Moisture absorption Confirmation Test of PEG
Derivatives for Oral Moisture Absorption
In order to identify and determine the PEG-OH structure having high oral
moisture absorption, the moisture absorption rates of PEG derivatives having
different
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Date Recue/Date Received 2022-07-29
structures were tested.
Test materials: As a PEG derivative for the moisture absorption test, a dry
powder having a molecular weight of 3,000 Da or more rather than liquid (wax)
PEG
was used, and the test was carried out using powders of a linear structure of
PEG
(Chemical Formula A) having molecular weights of 3,400 Da and 10,000 Da, and a
branched structure of 4arm PEG (Chemical Formula B) and 6arm PEG (Chemical
Formula C) having molecular weights of 10,000 Da as described below.
[Chemical Formula A]
HO_( CH2CH2OH
[Chemical Formula B]
OH
HO
0¨(CH2CH20) n_i
(0H2CH2C)n_p
j
¨\
0¨(0H20H20) n_i
(0H2CH2C)-0
n-1
OH
HO
[Chemical Formula C]
Date Recue/Date Received 2022-07-29
CH2CH20)-H
CH20 fl
H- C- OCH2CH2+H
0H2CH2C)- C-H
H- C- 0-( CH2CH20)-H
H- C- Cr( CH2CH20)-H
cH2oq
kcH2cH2o)¨H
The test materials were purchased from Daechang Chemical, and for the test,
the powder particles were uniformly pretreated by extraction and powdering
processes
using an organic solvent, and then the test was carried out.
Method for Measuring Moisture Absorption: The moisture absorption was
confirmed by the weight of water vapor absorbed per mass of polyethylene
glycol
(PEG). After pretreatment by drying PEG in a desiccator at a temperature of 25
1 C,
it was left for 24 hours under a condition of 60 2% relative humidity at a
temperature
of 25 1 C, which is a moisture absorption condition, and the weight
increase (mg)
per 1 g of PEG was defined as the moisture absorption of the PEG. The moisture
absorption of each PEG was determined by comparing the weight difference
before
and after leaving the moisture absorption condition to be calculated as a
percentage.
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Date Recue/Date Received 2022-07-29
The results are shown in Table 2 below.
[Table 1]
Moisture absorption (%)
Molecular
Molecular Structure
Weight (Da) Numerical
Mean(%)
Value(%)
10.00
Comparative
Di-PEG-OH ; P2OH 3,400 10.74 10.14
Example 1
9.66
13.65
Comparative
Di-PEG-OH ; P2OH 10,000 11.99 12.31
Example 2
11.29
16.46
4-arm PEG-OH;
Example 1 10,000 13.85 15.48
P4011
16.14
14.09
Comparative 11.95
6-arm PEG-OH ; P6OH 10,000 12.59
Example 3
11.72
As shown above, it was confirmed that the linear Di-PEG-OH having a
molecular weight of 3,400 Da (Comparative Example 1) showed the lowest
moisture
absorption rate of 10.14%, and 10,000 Da (Comparative Example 2) showed a rate
of
12.31%, and the branched 4-arm PEG-OH having a molecular weight of 10,000 Da
(Example 1) showed the highest moisture absorption rate of 15.48%.
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Date Regue/Date Received 2022-07-29
As a result of confirming the moisture absorption of PEG-OH of linear and
branched structures, the higher the molecular weight of the linear PEG-OH of
the solid
powder, the higher the moisture absorption (that is, the moisture absorption
of the
molecular weight of 10,000 Da (Comparative Example 2) is higher than that of
3,400
Da (Comparative Example 1)), and the moisture absorption of the branched PEG
was
higher when comparing the moisture absorption between the linear and branched
PEG
structures based on the same molecular weight of 10,000 Da. In particular,
compared
to the 6-arm PEG-OH (Comparative Example 3), the 4-arm PEG-OH (Example 1)
structure exhibited the highest moisture absorption, so the 4 arm-PEG-OH
(Example
1) was selected as the main ingredient of the present invention.
In addition to the branched 4arm-PEG-OH, 6arm-PEG-OH and 8arm-PEG-
OH can be used for oral moisturizing, but no superiority to 4arm-PEG-OH could
be
confirmed in the synthesis/manufacturing process and moisturizing effect for
PEG
derivatives.
Experimental Example 2. Moisture Content Confirmation Test By 4arm-
Peg-OH Molecular Weight for Oral Moisture Absorption
According to the results of Experimental Example 1, it was confirmed that the
branched 4arm-PEG-OH structure had high moisture absorption, and in order to
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Date Regue/Date Received 2022-07-29
confirm the moisture absorption according to the molecular weight of the same
structure, a moisture content confirmation test according to 4arm PEG-OH of
10,000
Da, 20,000 Da, and 30,000 Da molecular weights was carried out. The test
method
was carried out by exposing 4arm-PEG-OH test materials for each molecular
weight
to a temperature of 25 1 C and a relative humidity of 60 2% under moisture
absorption conditions for 4 hours, and then analyzing the moisture content
contained
in each test material using a moisture meter (MS-70; METTLER TOLEDO, 400 W
straight halogen lamp heating system with SRA filter and SHS weighting
technology).
That is, moisture absorption was confirmed using the difference in moisture
content
before and after exposure to moisture absorption conditions.
As shown in the table below, the moisture content and moisture absorption
were measured according to the 4arm-PEG-OH structure having the molecular
weights
of 10,000 Da, 20,000 Da, and 30,000 Da. 4arm-PEG-OH PEG derivatives with a
molecular weight of 5,000 Da or less (for example, 2,000 Da and 5,000 Da) were
excluded from this test material because powdering was not easy in the
production/synthesis process. 4arm-PEG-OH of each molecular weight was
purchased
from Daechang Chemical, and for the test, the powder particles were uniformly
pretreated by extraction and powdering processes using an organic solvent, and
then
the test was carried out. The results are shown in Table 2 below.
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Date Recue/Date Received 2022-07-29
[Table 2]
Moisture Content (%)
Molecular
Molecular
Weight Before After
Structure
(Da) exposure exposure A - B AVR
(B) (A)
4-arm 0.707 1.638 0.931
Example 1 PEG-OH 10,000 0.753 1.400 0.647 0.750
; P4011
0.807 1.480 0.673
4-arm PEG- 0.783 1.398 0.615
Comparative OH
20,000 0.724 1.368 0.644 0.558
Example 4 ; P4OH
0.764 1.180 0.416
4-arm PEG- 0.708 0.857 0.149
OH
Comparative ; P4OH 0.691 0.811 0.12
30,000 0.136
Example 5
0.695 0.834 0.139
As shown in the above results, the smaller the molecular weight, the greater
the difference in moisture content before and after 4 hours of exposure at 60%
relative
humidity. That is, it was found that the higher the molecular weight of 4arm-
PEG-OH,
the lower the moisture absorption.
That is, 4arm-PEG-OH (Example 1) of 10,000 Da among molecular weights
10,000 Da, 20,000 Da, and 30,000 Da of 4arm-PEG-OH showed the greatest
difference
(A-B) in moisture content before and after exposure to 60% relative humidity
and was
Date Regue/Date Received 2022-07-29
found to absorb a lot of moisture.
As described above, a 4arm-PEG-OH molecular weight 2,000 Da or 5,000 Da
was excluded due to the difficulty of the final powder manufacturing process
for the
PEG derivative and the resulting low production yield. In the overall reaction
process
for PEG derivatization, the crystallization and powder manufacturing process
affect
the production yield in the chemical reaction process and the crystallization
and
recrystallization process using an organic solvent after
filtration/concentration. In
addition, it is an essential consideration because the production yield is
lowered in the
washing/recrystallization process to remove impurities with an organic solvent
and the
powdering process of the final even particles after drying. According to the
results
of Experimental Example 2, of 4arm-PEG-OH molecular weights 20,000 Da and
30,000 Da were not suitable for oral moisturizing because the moisturizing
effect
according to the increase in molecular weight was low.
For this reason, (Example 1) a 4arm-PEG-OH structure having a molecular
weight of 10,000 Da was used as a main raw material for the synthesis and
preparation
of the PEG derivative, which is the main ingredient for oral moisturizing of
the present
invention.
Experimental Example 3. Selection of PEG Derivative Reactive Group
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Date Recue/Date Received 2022-07-29
In order to select a reactive group of a PEG derivative that forms a covalent
bond with an amine group present in the oral mucosa, the half-life according
to the
reactive group of the PEG derivative and the number of production processes
(number
of steps) required for the synthesis of the reactive group were comparatively
analyzed.
When the half-life is short, the covalent bond with the amine group of the
oral mucosa
cannot occur because hydrolysis occurs quickly during dissolution of the
composition
in water. Therefore, it is difficult to use a reactive group with a short half-
life for
preparing an oral rinse composition for alleviating xerostomia.
The half-life was measured based on the UV absorbance of the N-hydroxy
succinimide (NHS) group hydrolyzed in a buffer condition of 25 C and pH 8. The
results are shown in Table 3 below.
[Table 3]
Number of
Production
Half-life
Molecular Structure Reactive Group
Reaction
(minutes)*
Processes
(Steps)
PEG-
Comparative Succinimidyl
CH2CH2CH2CH2- 33.6 4
Example 6 Valerate (SVA)
CO2-NHS
Comparative Succinimidyl
PEG-0-0O2-NHS 20.4 1
Example 7 Carbonate (SC)
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Date Recue/Date Received 2022-07-29
PEG-02C-
Succinimidyl
Example 2 CH2CH2CH2- 17.6 2
Glutarate (SG)
CO2-NHS
PEG-02C-
Comparative Succinimidyl
CH2CH2-0O2- 9.8 2
Example 8 Succinate (SS)
NHS
Succinimidyl
Comparative PEG-0-CH2-0O2-
Carboxymethylated 0.75 3
Example 9 NHS
(SCM)
Comparative PEG-0-CH2 CH2-- Succinimidyl
23.3 4
Example 10 CO2- NHS Butanoate (SBA)
Comparative PEG-0-CH2 CH2- Succinimidyl
16.5 5
Example 11 CO2-NHS Propionate (SPA)
As shown in the above results, succinimidyl carbonate (SC) ester
(Comparative Example 7) had a simple production process of 1 step and a
relatively
long half-life, but there was risks and environmental risks of using phosgene
gas in the
manufacturing process. On the other hand, in the case of the derivative
(Example 2)
modified with succinimidyl glutarate (SG) according to the present invention,
the
amide reaction rate in oral application is fast, there are no reagents
required before and
after the reaction, and no by-products, and there is no problem with
discomfort and
safety in oral application. In addition, compared with other reactive groups,
the half-
life of Example 2 is relatively long, the number of production processes is
small and
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Date Regue/Date Received 2022-07-29
simple, and the risk in the production process is low. Accordingly, a
derivative
(Chemical Formula 1) modified with succinimidyl glutarate (SG) was prepared
through Preparation Example 1 below and used in subsequent experiments.
<Preparation Example 1. Preparation of Polyethylene Glycol Derivatives
of Chemical Formula 1>
[Chemical Formula 1]
0 N
ONO
0
0
0
0
¨(CH 2CH 20)n
n(OH2CH2C)-0
\_j_\
0¨(C1-12CH20)n
n(OH2CH2C)-0
0 1
0
0 N 0
[Reaction Formula 1]
24
Date Regue/Date Received 2022-07-29
OH OR
HO RO
0 --- 0112CH2C),-- (CH2C1120L-1 Glutaric anhydride, TEA
(0112CH2C) 0 ¨ icH2C1120)õ_1
( 0 1-0\_ H
70-
---- (CH2C1120) Methylene chloride 0 2C 2 Xi-1
20-24hrs., RT
foH2cH2c),¨ (oH2cH2c)._I¨o
OH OR
HO RO
Chemical Formula 2
Chemical Formula 3
O 0
N 0
0
0 0
0
0
0
0 ¨(CH2CH20 n
n OH2CH2C 0
NHS, DCC
n
MC, RT n 0H2c1-12c)-0-- ¨CH2C1-120
15-20hrs
0 0
o I
NcIN R
OH
Chemical Formula 1
After dissolving the compound of Chemical Formula 2 in methylene chloride
at room temperature, triethylamine was added. After adding glutaric anhydride
to the
reaction solution, stirring was performed at room temperature for 20 to 24
hours. The
reaction solution was washed with a 14% ammonium chloride aqueous solution,
and
when the layers were separated, the lower organic solution layer was
collected. The
aqueous solution layer was extracted using methylene chloride. The combined
organic
solution layer was precipitated in diethyl ether after moisture was removed
using
magnesium sulfate and the solvent was concentrated. The precipitate was
filtered and
dried under vacuum at room temperature for 24 hours to obtain a compound of
Chemical Formula 3.
The compound of Chemical Formula 3 was dissolved in methylene chloride,
Date Recue/Date Received 2022-07-29
and N-hydroxy succinimide (NHS) and dicyclohexyl carbodiimide (DCC) were added
thereto. The reaction solution was stirred at room temperature for 15 to 20
hours. After
the reaction, dicyclohexyl urea (DCU) as a by-product was filtered using a
glass filter,
and the filtered solution was precipitated in diethyl ether after
concentrating the solvent.
After filtering the precipitate, it was dissolved in ethyl acetate at 55 5 C
and
recrystallized at 0-5 C for 15-17 hours. The recrystallized product was
filtered,
washed 3 times with diethyl ether, and dried under vacuum at room temperature
for 24
hours to obtain a compound (n=57) of Chemical Formula 1 having a weight
average
molecular weight of 10,000.
Experimental Example 4: Composition test using a pH adjusting agent
As a result of research by the present inventors, it was found that the
conditions for forming a covalent bond between the amine group of the oral
mucosa
and the reactive group of the PEG-SG derivative of Chemical Formula 1 were pH
6.0
to 8Ø
However, when the PEG-SG derivative of Chemical Formula lused as a main
ingredient for oral moisturizing and the flavoring agent were dissolved in
water, weak
acidity (pH4.5), which was not suitable for the above pH conditions, was
exhibited.
In order to adjust the composition of the present invention to a pH condition
suitable for covalent bonding in the oral cavity, an acidity adjusting agent
(sodium
26
Date Recue/Date Received 2022-07-29
bicarbonate) used as a food additive was added to determine the amount of the
acidity
adjusting agent so that the pH was 6.0 to 8.0".
Test Materials: As shown in Table 4 below, the acidity adjusting agent
(sodium bicarbonate) was prepared by adding 0 (control), 1, 5, and 10% of the
product
content (1.5 g). A pH test was carried out using three lg samples for each
composition.
[Table 4]
Polyethylene
Glycol Derivative Acidity
Flavoring
of Chemical Adjusting Total
Agent
Formula 1 Agent
Comparative 93.3% 6.7% 0% 100%
Example 12 (1.4g) (0.1g) (0.000g) (1.5g)
92.3% 6.7% 1% 100%
Example 3
(1.385g) (0.1g) (0.015g) (1.5g)
88.3% 6.7% 5% 100%
Example 4
(1.325g) (0.1g) (0.075g) (1.5g)
83.3% 6.7% 10% 100%
Example 5
(1.25g) (0.1g) (0.150g) (1.5g)
Test Methods: To accurately measure the pH of the prepared samples, pH
meter calibration was carried out in 3 sections (pH 4.0, 7.0, 10.0 standard
buffer), and
27
Date Regue/Date Received 2022-07-29
the allowable parameter pH gradient was 90 to 105% and 0 30 mV (0.5 at 25 C
pH
units) were checked. After completely dissolving 1 g of each test material in
20 ml
of distilled water, the pH was checked.
The results are shown in Table 5 below.
[Table 5]
pH Mean pH
Comparative
4.5 4.4 4.5 4.5
Example 12
Example 3 7.0 7.1 7.0 7.0
Example 4 7.4 7.5 7.5 7.5
Example 5 7.8 7.8 7.9 7.8
As shown in the above results, the mean pH of each sample to which 1, 5, and
10% of the acidity adjusting agent was added was 7.0, 7.5, and 7.8. As a
result, it
was confirmed that 1 to 10% of the addition amount of the acidity adjusting
agent was
in an amount range suitable for covalent pH 6.0 to 8.0 conditions.
However, as a result of sensory evaluation, the composition in which the
acidity adjusting agent was added in an amount of 10% or more (Example 5) was
excluded because it caused a bitter taste and irritation to the tongue when
applied orally.
28
Date Regue/Date Received 2022-07-29
In subsequent experiments, a composition (Example 4) having an acidity
adjusting
agent addition amount of 5% was prepared and used according to Preparation
Example
2 below.
<Preparation Example 2. Preparation of Oral Rinse Composition for
Alleviating Xerostomia>
An oral rinse composition for alleviating xerostomia, including the
polyethylene glycol derivative of Chemical Formula 1, an acidity adjusting
agent and
a flavoring agent, was prepared in various formulations, and cytotoxicity
(human
safety), human applicability such as moisturizing effect (functionality), and
ease of
handling in a commercialization process, product stability, etc. were
evaluated through
the following Experimental Examples.
<Preparation Example 2-1. Preparation of Oral Rinse Composition for
Alleviating Xerostomia in Powder Formation>
Each of 89 parts by weight of a polyethylene glycol derivative, 5 parts by
weight of sodium hydrogen carbonate as an acidity adjusting agent, and 6 parts
by
weight of mint as a flavoring agent was added to a V-type mixer, and mixed at
20 to
25rpm for 15 minutes to prepare a finished composition in powder form.
<Preparation Example 2-2. Preparation of Oral Rinse Composition for
Alleviating Xerostomia in Liquid Formation>
1.5g of the powder composition of Preparation Example 2-1 was dissolved in
29
Date Recue/Date Received 2022-07-29
30m1 of water to prepare a liquid composition.
<Preparation Example 2-3. Preparation of Oral Rinse Composition for
Alleviating Xerostomia in Granular Formation>
An airtight container accommodating the powder composition prepared in
Preparation Example 2-1 was liquefied at 60 C for 1 hour. When the
liquefaction was
completed, the airtight container was transferred to room temperature and
primarily
hardened for 1 hour, and then secondarily hardened at -20 C to solidify. When
the
solidification was completed, the solidified product was pulverized to a
particle size
of 355 to 1400ttm.
Experimental Example 5. Cytotoxicity Test
The cytotoxicity test is a test to confirm the safety of the composition
according to the present invention, and the presence and degree of a cytotoxic
reaction
in cultured cells (L-929) was evaluated. A good laboratory practice (GLP)
institution
was commissioned to perform the test according to each test method presented
in ISO
10993.
Test Materials:
As shown in Table 6 below, each test solution was prepared using a powder
Date Recue/Date Received 2022-07-29
formulation (A) without an acidity adjusting agent, a powder formulation (B,
Preparation Example 2-1) containing an acidity adjusting agent, and a liquid
formulation test material (C, Preparation Example 2-2) in which a powder
formulation
(B) was dissolved in 30 ml of water.
[Table 6]
Powder formulation Powder formulation Liquid formulation
(A) (B) (C)
Classification Comparative Comparative
Example 13 Example 14
(Same as Example 6
(Same as Example
Comparative
4)
Example 12)
Polyethylene
Glycol
1.4 g 1.325 g 1.325 g
Derivative
(4arm-PEG-SG)
Flavoring Agent 0.1 g 0.1 g 0.1 g
Acidity
0.075 g 0.075 g
Adjusting Agent
1.5 gin
Total 1.5g 1.5g
10z(30m1) DW
Cytotoxicity Test Method
5-1. Test Method of Powder Sample: In the extract (E-MEM +5% FBS), the
powder test material and the control were dissolved at a concentration of 0.2
g/ml, and
dissolved for 24 2 hours to prepare a test solution. The culture medium of
cell L-929
31
Date Regue/Date Received 2022-07-29
was removed from the plate well, replaced with 1 mL of test solution and
control
medium (extract solution), and then the cells were cultured. During culturing,
microscopic examinations were carried out every 24, 48, 72 4 hours to
evaluate
cytotoxicity. Positive and negative controls were also used in the test.
5-2. Test Method of Liquid Sample: A liquid test solution was prepared in
which a dilution solution (2X E-MEM + 10% FBS) and the liquid test material
were
combined/diluted in a 1:1 ratio. The culture medium of cell L-929 was removed
from
the plate well, replaced with 1 mL of test solution and control medium
(diluent), and
then the cells were cultured. During culturing, microscopic examinations were
carried
out every 24, 48, 72 4 hours to evaluate cytotoxicity. Cadmium chloride
(100uM
CdC12) as a positive control and E-MEM + 5% I-BS as a negative control were
also
used in the test.
As the evaluation criteria of the cytotoxicity test, a score of 0 to 4 was
recorded
by evaluating the morphological change of cells and the degree of change in
viable
cells according to lysis or separation. Scores 3 and 4 were judged to be
cytotoxic,
and scores of 1 and 2 were judged to be non-cytotoxic.
The results are shown in Tables 7 and 8 below.
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Date Regue/Date Received 2022-07-29
[Table 7]
Cytotoxicity Score
Comparative Comparative Example 6
Classification
Example 13 Example 14
24hr 48hr 72hr 24hr 48hr 72hr 24hr 48hr 72hr
Test Material 4/4/4 4/4/4 4/4/4 4/4/4 4/4/4 4/4/4 0/0/0 0/0/0 0/0/0
Positive
4/4/4 4/4/4 4/4/4 4/4/4 4/4/4 4/4/4 0/0/0 0/0/0 0/0/0
Control
Negative
0/0/0 0/0/0 0/0/0 0/0/0 0/0/0 0/0/0 0/0/0 0/0/0 0/0/0
Control
Cell Control 0/0/0 0/0/0 0/0/0 0/0/0 0/0/0 0/0/0 0/0/0 0/0/0 0/0/0
As shown in the above results, as a result of confirming the cytotoxicity test
for each composition and both formulations, for Comparative Examples 13 and
14, a
cytotoxicity score of '4' was recorded and strong cytotoxicity was exhibited,
and
Example 6 did not exhibit any cytotoxicity with a cytotoxicity score of '0'.
Example 6
includes an acidity adjusting agent, and by dissolving the composition in 30
ml of
water and applying it to the cells as a liquid, it was confirmed as a safe
composition
and formulation that did not affect the morphological change and survival of L-
929
cells.
[Table 8]
33
Date Recue/Date Received 2022-07-29
Powder Formulation Powder Liquid Formulation
(a) Formulation (b) (c)
Classification
Comparative Comparative
Example 6
Example 13 Example 14
0.05 g/ml
Amount of
1.5g 1.5g
test material (1.5 g/30m1 in DW)
Test Material
Cytotoxic Test Material Extraction Type
Dilution Type*
sample
concentration 0.2g/m1 in media 0.2g/m1 in media 0.025g/m1 in
media
Cytotoxicity
Cytotoxicity. Cytotoxicity. No Cytotoxicity.
result
As shown in the above results, since the powder compositions (Comparative
Examples 13 and 14) exhibit cytotoxicity, it is not suitable to directly apply
the dry
powder formulation to a xerostomia patient with a small amount of saliva
secretion.
Therefore, after changing to a liquid formulation by adding water to the
powder formulation of the present invention, no toxicity was observed as the
concentration of the test material for the cytotoxicity test was reduced from
0.2 g/ml
to 0.025 g/ml (1.5 g/30 ml x 1/2). In addition, unlike applying a powder
composition
to the dry oral mucosa, which gives irritation to the sensitive mucous
membrane, when
the powder was reconstituted into a liquid formulation, moisture that the oral
cavity
lacked was additionally supplied, and the expected effect of increasing the
moisturizing effect was exhibited by allowing the patient to easily apply the
product
34
Date Recue/Date Received 2022-07-29
in the oral cavity.
Experimental Example 6. Moisturizing Effect Confirmation Test
According to Cell Viability
By applying the composition of the present invention to human epithelial
cells,
a moisturizing layer is formed by covalent bonding of the main ingredient PEG
derivative to the cell surface, and an in vitro test was carried out to
confirm cell
viability by exposing the cells to a dry environment.
Test Materials:
Example 6 of the present invention, in which cytotoxicity safety was
confirmed in Experimental Example 5, and Hydris Oral Rinse, a product for
relieving
xerostomia manufactured by Colgate, were used as test materials. Both test
materials
are liquids in the same formulation. As a negative control, PBS (phosphate-
buffered
saline; Gibco) was used.
[Table 9]
HydrisIN1 Oral Rinse Example
6 I
Alain Ingredient Glycerin, Polyethylene Glycol PEG
Aloisturizer
Derivative
(Main Ingredient)
(4arm-PEG-
SG)
Sorbitol, Sodium Saccharin, None
Other
Sucralose/Cellulose Gum, Xanthan
Date Recue/Date Received 2022-07-29
(Sw eetenei; Thickener, Gum, Carbomer/Poloxamer
407/Cetylpyridinium Chloride,
Surfactant,
Sodium Benzoate
Preservative)
Disodium Phosphate, Sodium Sodium
Buffer Phosphate
Bicarbonate
Coloring Agent, FD&C Blue 1, Mint Mint
L. Flavoring Agent ad
Test Method:
Using human pharynx epithelial cells, the composition of the present
invention, HydrisTM Oral Rinse of Colgate, and phosphate-buffered saline (PBS)
were
applied to the cells at 37 C for 15 minutes and cultured, then the test
material was
removed and washed with PBS, the cells were exposed to dry conditions of 30%
humidity at 25 C, and cell viability was measured. The effect of the treated
test
materials to protect cells by reducing apoptosis due to drying was confirmed
by cell
viability. Cells were treated with PBS as a positive control, and the
viability of cells
not exposed to dry conditions was set to 1 (100%), and cell viability
according to
treatment with a test material was expressed as a percentage. Cell viability
was
analyzed using Cell Counting Kit 8 (CCK8; Dojindo Molecular Technologies,
Inc.,
Rockville, MD, USA). This kit is used to quantify the number of living cells
by
generating orange formazan dye during bioreduction in the presence of electron
36
Date Regue/Date Received 2022-07-29
carriers using a water-soluble tetrazolium salt.
The results are shown in Table 10 below.
[Table 10]
Non-Dry
Condition
Dry Condition
(Positive
Classification Control)
PBS PBS HydrisTM Example
6
(N = 8) (N = 16) (N = 8) (N = 8)
Mean 100 11.6 12.0 71.9
Median 101.9 4.6 11.5 81.5
SD 7.34 17.06 3.38 47.26
As shown above, the mean value of the cell viability of Example 6 of the
present invention based on the cell viability (%) of the positive control was
71.9%
(median: 81.5%), showing the highest cell viability, and the Hydris product of
GSK
showed a relatively low viability with a mean value of 12.0% (median: 11.5%).
Because the moisturizing ingredient remained in the cells even after cell
washing by covalent bonding of the main ingredient PEG derivative of Example 6
and
oral cells to maintain the effect of the moisturizing coating, cells are
washed and then
exposed to a dry environment to minimize cell death due to drying to maintain
cell
37
Date Regue/Date Received 2022-07-29
viability. In other words, the composition including the existing moisturizer
is washed
off by talking or ingestion of drinks/food after oral application, so it has a
limited role
as a moisturizer, but the moisturizing effect is temporary, and therefore, it
must be
frequently applied intraorally. However, the main ingredient of the PEG
derivative of
the present invention is for maintaining a moisturizing effect for a long time
without
being washed away by physical stimulation by covalent bonding with cells.
Experimental Example 7. Reactive Group Activity and Electrostatic Test
of the Main Ingredient 4arm-Peg-Sg Derivative
Common PEG derivatives are prepared in the form of final powder (powder
type) through chemical reaction, synthesis, a manufacturing process, and a
recrystallization process after crystallization and washing. These powdered
PEG
derivatives are mixed with additives, and the recovered mixture is filled into
the hopper
of the equipment for fixed quantity (1 g) packet packaging, and then the
powder is
supplied to the scale (load cell) from the vibrating plate and the weight is
measured,
and the fixed quantity is filled in aluminum packets. However, in the case of
a powder
formulation such as Preparation Example 2-1, a loss due to static electricity
occurs
during the weighing, mixing and recovery of the mixture at the beginning of
the
production process, and for the same reason, it was found that the recovery
rate was
38
Date Recue/Date Received 2022-07-29
lowered.
Therefore, changes in reactive group activity and whether static electricity
was
generated were analyzed by changing the physical form of the granule
formulation of
Preparation Example 2-3 to solve the static electricity problem in the
manufacturing
process caused by the physical form, that is, powder, of 4arm-PEG-SG, which is
the
main ingredient of the PEG derivative of the present invention.
Test materials: As in the previous experimental examples, 4arm-PEG-SG, a
PEG derivative in powder form, and a sample in the form of granules were
prepared.
Test Method:
Prior to the electrostatic test, it was confirmed by nuclear magnetic
resonance
(NMR) analysis that there was no problem in the reactive group activity and
stability
of the PEG derivative even after the physical state change of melting and
solidifying
4arm-PEG-SG in powder form. FIGS. lA and 1B are the results of nuclear
magnetic
resonance (NMR) analysis of the powder formulation and the granule formulation
of
the oral rinse composition for alleviating xerostomia according to the present
invention,
confirming that there is no problem in the activity and stability of the
reactive group
regardless of the change in physical state.
The electrostatic test was measured using an electrostatic meter (EYE-02)
capable of measuring the surface electrostatic force of the main ingredient
PEG
39
Date Recue/Date Received 2022-07-29
derivatives of the two formulations. 50 g and 100 g of each of the PEG
derivatives, the
main ingredient of the powders and granules, were placed in a PET storage pack
(vinyl
pack) used for weighing in the manufacturing process, and the surface
electrostatic
force was measured and compared.
As shown in Figure 2, as a result of confirming and comparing the surface
electrostatic force generated depending on the physical form, that is, powders
and
granules of the PEG derivative 4arm-PEG-SG, it was confirmed that the surface
static
electricity of the powder decreases by about 50% or more when the morphology
changes into granules.
As a result, in the case of the granule formulation of Preparation Example 2-
3, the loss in the hopper due to static electricity was reduced and packet
filling was
facilitated, unlike the powder formulation of Preparation Example 2-1.
Experimental Example 8. Stability Confirmation Test According to the
formulation of the Final Finished Composition
A test to confirm product stability according to the formulation was carried
out as follows.
Test Materials: An oral rinse composition of the powder formulation of
Preparation Example 2-1 (Comparative Example 15) and the granule formulation
of
Date Recue/Date Received 2022-07-29
Preparation Example 2-3 (Example 7) of the present invention was prepared, and
1 g
of each was packaged in an aluminum packet.
Stability Test Method: lg of the finished composition in powder and granule
form was filled in an aluminum packet (9cm x 2cm), sealed with a heat
adhesive, and
stored in a thermo-hygrostat chamber with a relative humidity of 60% 5% at
25
2 C. Stability test analysis was performed on days 0, 1, 2, 3, 4, 5, 6, 7, 8
and 10 of
storing the sample, 10mg of the analyzed sample was weighed, put into an NMR
tube
and dissolved in 0.62mL of CDCb, and analyzed by 1H-NMR (400 MHz). The
analysis method confirmed the reactive group activity of the main ingredient
4arm-
PEG-SG derivative by the succinimidyl group peak of 2.80-2.90ppm (parts per
million;
proton) of the NMR spectrum. That is, since 4arm-PEG-SG is the main ingredient
that binds to the oral mucosa and provides a moisturizing effect, the
functional group
(succinimidyl group) activity of 4arm-PEG-SG, which covalently bonds with the
amine (NH2) group of the oral mucosa, was analyzed by 1H-NMR, and the
stability of
the finished composition was confirmed. The stability of the finished
composition was
judged as "Stable" when the NMR activity value of the main ingredient 4arm-PEG-
SG was 90% or more, and "Not stable" when it was less than 90%.
The results are shown in Table 11 below.
[Table 11]
41
Date Regue/Date Received 2022-07-29
Result of NWIR (%) Analysis According to the Test Period
Test
Material Day Day Day Day Day Day Day Day Day Day
0 1 2 3 4 5 6 7 8 10
96.0 95.9 95.4 92.1 88.1
N/A N/A N/A N/A N/A
3 7 4 5 4
Comparat
96.0 95.9 95.0 92.1 87.0
ive N/A N/A N/A N/A N/A
Example 7 5 0 8 1
15 96.0 95.9 95.3 92.2 87.0
N/A N/A N/A N/A N/A
4 6 4 5 4
(Powder)
Stable Not stable
96.5 96.3 96.2 95.5 93.9 93.6 90.2 *90.2 89.2
86.88
1 6 1 0 6 3 6 1 5
Example
96.4 96.4 95.8 95.4 94.0 92.2 90.2 86.9
7 88.81 80.84
1 0 1 8 8 8 9 4
(Granule 96.3 96.3 95.9 94.5 93.8 92.6 92.6 87.9
88.22 83.94
) 3 2 7 5 5 6 8 5
Stable Not stable
*On day 7, one batch among the three batches satisfies the standard (90% or
more),
but the mean value of the three batches is below the standard, so it is judged
as Not
stable.
As shown in the above results, as a result of confirming the stability test
under
severe conditions (25 2 C, relative humidity 60% 5%) according to the
formulation
of the finished composition, the reactive group activity of the main
ingredient 4arm-
PEG-SG derivative showed stable results of 92.15%, 92.19%, and 92.25% on day 3
for composition in the form of a powder (Comparative Example 15), and 90.26%,
42
Date Regue/Date Received 2022-07-29
90.29%, and 92.68% on day 6 for composition in the form of a granule (Example
7).
When the formulation of the finished composition was in the form of powder
(Comparative Example 15), the granule finished composition (Example 7) showed
stable results for 6 days compared to the results stable for 3 days under
severe
conditions, and it was confirmed that the stability was improved. The
formulation of
the composition is changed to a granule form, and compared to a powder form,
the
exposure area to the air is reduced, and it appears that the absorption of
moisture in the
air according to the decrease in exposure is reduced and the stability is
increased.
Therefore, the formulation of the final finished composition was determined
to be granule. A product for alleviating xerostomia including a container
capable of
measuring the amount of water per use and a packet packaged with a composition
for
alleviating xerostomia in the form of granules per use was developed as a
final product.
43
Date Recue/Date Received 2022-07-29
