Composition for nasal spray and preparation method therefor

Abstract

The present disclosure relates to a composition for a nasal spray and a preparation method therefor, wherein the composition comprises camostat mesylate as an active ingredient in addition to xanthan gum, thereby having improved mucosal adhesion and film-forming performance.

Description

DESCRIPTION

INVENTION TITLE

Technical Field

Background Art

Disclosure

Technical Problem

Technical Solution

Advantageous Effects

Brief Description of Drawings

[10] FIG. 2 is a process diagram for explaining a method for preparing a composition for nasal spray according to another embodiment of the present disclosure.

[11] FIG. 3 is photographs showing the early stage (0 hr) drying aspects in Experimental Example 1-1.

[12] FIG. 4 is photographs showing the middle stage (3.5 hr) drying aspects in Experimental Example 1-1.

[13] FIG. 5 is photographs showing the final stage (5 hr) drying aspects in Experimental Example 1-1.

[14] FIG. 6 is photographs showing the aspects immediately after application (0 hr) in Experimental Example 1-2.

[15] FIG. 7 is photographs showing the aspects after drying (3 hr) in Experimental Example 1-2.

[16] FIG. 8 is a graph showing results according to Experimental Example 2.

[17] FIG. 9 is a graph showing analysis results by the flow sweep measurement method in Experimental Example 3-1.

[18] FIGS. 10 and 11 are graphs showing analysis results by the step flow measurement method of Experimental Example 3-2.

[19] FIGS. 12 to 14 are graphs showing analysis results by the oscillation frequency sweep measurement method of Experimental Example 3-3. 

Mode for Invention

[20] Hereinafter, the present disclosure will be described in detail with reference to the attached drawings as embodiments of the present disclosure. However, the following embodiments are presented as examples of the present disclosure, and if it is judged that a specific description of a well-known technology or configuration to those skilled in the art may unnecessarily obscure the gist of the present disclosure, the detailed description thereof may be omitted, and the present disclosure is not limited thereby. The present disclosure can be variously modified and applied within the description of the patent claims described later and the equivalent scope interpreted therefrom.

[21] In addition, the terminologies used in this specification are terminologies used to appropriately express the preferred embodiments of the present disclosure, and these may vary depending on the intention of the user or operator or the customs of the field to which the present disclosure belongs. Therefore, the definition of these terminologies should be made based on the contents throughout this specification. Throughout the specification, when a part is said to “include” a certain component, this does not mean that, unless otherwise specifically stated, other components are excluded, but other components may be further included.

[22] Throughout this specification, '%' used to indicate the concentration of a specific substance, unless otherwise stated, is %(w / w) for solid / solid, %(w / v) for solid / liquid, and %(v / v) for liquid / liquid.

[23]

[24] Hereinafter, a composition for nasal spray according to one embodiment of the present disclosure will be described in detail.

[25] The composition for nasal spray according to the present embodiment is a type of adhesive transparent wound dressing used to prevent the penetration of respiratory infection viruses and protect the mucosa by forming a physical film on the nasal mucosa by spraying it into the nasal cavity. It is preferable that such a composition for nasal spray has a viscosity change amount after spraying and application that is equal to or greater than a predetermined value so that it can be attached into the nasal cavity and form a film over a relatively wide range. For example, it is preferable that the viscosity change amount is 4 cP or more. For example, as a rotational rheometer (RHEOMETER(AR)) device analysis result using a 60 mm cone plate, the difference between a viscosity measured under a condition of 103 to 105 shear rate (1 / s) and a viscosity measured under a condition of 1 shear rate (1 / s) may be 4 cP or more. For example, as a rotational rheometer (RHEOMETER(AR)) device analysis result using a 40 mm cone plate, the measured viscosity may be 4 cp or more when changing from a 103 to 105 shear rate (1 / s) condition to a 1 shear rate (1 / s) condition.

[26] The composition for nasal spray contains xanthan gum and camostat mesilate as active ingredients.

[27] Xanthan gum has an ordered and rigid double helix strand structure, and xanthan gum chains form a three-dimensional network, exhibiting gel-like properties and can be cross-linked to form a hydrogel. Cross-linking bonds include hydrogen bonds, ionic bonds, ππ stacking, hydrophobic interactions, host-guest inclusions, etc. As shown in Figure 1, the structure of xanthan gum is a polymer structure with many -OH groups, and as the -OH of xanthan gum and water molecules form strong hydrogen bonds when it is in an aqueous solution, the fluidity of water molecules may be reduced to increase the viscosity. In addition, xanthan gum may form a physical network with cations and form intramolecular cross-linking bonds. Such xanthan gum may be contained in an amount of 0.01 to 0.04% by weight, preferably 0.02 to 0.03% by weight, based on the total weight of the composition. This is not preferable since If xanthan gum is included in an amount of less than 0.01% by weight, the amount of hydrogel is insufficient, and if xanthan gum is included in an amount exceeding 0.04% by weight, the viscosity may increase unnecessarily.

[28] Camostat mesilate plays a role in strengthening the film-forming performance of xanthan gum. As illustrated in FIG. 1, there can be many N, O, and H atoms capable of hydrogen bonding with xanthan gum, with Hydrogen bond donor=2 / Hydrogen bond Acceptor=6 / Rotatable bond=9. In addition to hydrogen bonding, positively charged camostat mesilate may also strengthen the film (gel) network through ionic bonding with negatively charged xanthan gum in a solution state. For example, the pKa of xanthan gum is 3.1, the pKa of camostat mesilate is 19.54 in the acidic phase, and 8.54 in the basic phase. Camostat mesilate and xanthan gum form two types of bonds (hydrogen, ionic bonds) in the liquid phase, exhibit ionicity, have strong electrical interactions, and have the characteristics of allowing ions to move freely. Such camostat mesilate may be contained in an amount of 0.02 to 0.10% by weight, preferably 0.03 to 0.04% by weight, based on the total weight of the composition. If camostat mesilate is included in an amount of less than 0.02% by weight, it may be difficult to form a sufficient film on the hydrogel, and if it is included in an amount exceeding 0.10% by weight, the effect due to excessive use may not be very significant.

[29] For example, camostat mesilate may further strengthen cross-linking with xanthan gum through hydrogen bonding and ionic bonding, and the main action, xanthan gum, may form a physical hydrogel on the nasal mucosa, and the auxiliary action, camostat mesilate, may strengthen film (gel) formation.

[30] Meanwhile, the composition for nasal spray may further include one or more selected from a preservative, an isotonic agent, a fragrance, a pH regulator, and a solvent in addition to xanthan gum and camostat mesilate.

[31] The preservative is a substance added to suppress changes in microbial reproduction, and may include one or more selected from benzoic acid, benzalkonium chloride, phenyl ethyl alcohol, phenoxyethanol, and benzyl alcohol, preferably benzoic acid. Such preservatives may be included in an amount of 0.05 to 0.07% by weight based on the total weight of the composition. If the preservative is included in an amount of less than 0.05% by weight, the antibacterial activity may be reduced to shorten the shelf life, and if it is included in an amount of more than 0.07% by weight, the pH may decrease to cause irritation to the nasal mucosa.

[32] The isotonic agent is a substance added to improve the solubility of other ingredients and increase the adhesiveness to the nasal mucosa, and D-sorbitol may be used. Such an isotonic agent may be contained in an amount of 2 to 5% by weight based on the total weight of the composition. If the isotonic agent is contained in an amount of less than 2% by weight, it may be difficult to maintain the appropriate viscosity required for the spray formulation, and if it is contained in an amount exceeding 5% by weight, the osmotic pressure may increase.

[33] The fragrance is a substance added to improve the user preference by allowing the user to feel the fragrance when spraying, and one or more selected from L-menthol, DL-camphor, eucalyptol, and peppermint oil, preferably L-menthol, may be used. Such fragrances may be contained in an amount of 0.01 to 0.03% by weight based on the total weight of the composition. If the fragrance is contained in an amount of less than 0.01% by weight, the effect of masking each unique fragrance of the composition may be minimal, and if it is contained in an amount exceeding 0.03% by weight, it may have a negative effect on physiological changes due to stimulation of the olfactory sense by the fragrance.

[34] The pH regulator is a substance added to improve the feeling of use by relieving irritation such as a stinging sensation of the nasal mucosa when sprayed into the nasal cavity, and sodium hydroxide may be used. Such a pH regulator may be added in an appropriate amount within a range that satisfies the pH 3 to 5 condition, and preferably, it may be contained in an amount of 0.001 to 0.05% by weight relative to the total weight of the composition. When the above-mentioned range is satisfied, it can provide optimal antibacterial activity and extend the shelf life, and reduce irritation of the nasal mucosa when sprayed into the nasal cavity.

[35] The solvent is a liquid medium, and one or more of purified water and ethanol may be selected, and preferably, purified water may be used. Such a solvent may be contained in an amount of 95 to 97% by weight relative to the total weight of the composition. If the solvent is contained in an amount of less than 95% by weight, the appropriate viscosity required for the spray formulation is not secured, so the spray amount is small and the composition has difficulty reaching the nasal mucosa, and the efficacy may be somewhat reduced. If it is contained in an amount exceeding 97% by weight, it may not adhere to the nasal mucosa and may easily flow outward.

[36]

[37] Hereinafter, a method for preparing a composition for nasal spray according to another embodiment of the present disclosure will be described in detail with reference to the drawings. Since each component has been described in detail above, redundant descriptions will be omitted.

[38] FIG. 2 is a process diagram for explaining a method for preparing a composition for nasal spray according to another embodiment of the present disclosure.

[39] Referring to FIG. 2, first, a solvent is heated and sterilized (S10).

[40] The solvent may be sterilized by heating it to 80 to 100°C. Sterilization is preferably performed at 200 to 600 rpm for 20 to 40 minutes. If the temperature and time are exceeded, microorganisms may easily multiply since microorganisms exist in the solvent.

[41]

[42] In addition, after the sterilized solvent is cooled to 45 to 55°C, a fragrance and a preservative are added to perform first mixing (S20).

[43] After the solvent sterilized in the step S10 is cooled to 45 to 55°C, a fragrance and a preservative may be added and primarily mixed at 200 to 600rpm for 30 to 90 minutes. If the temperature range mentioned above is exceeded, the fragrance may volatilize, so it is preferable to check the temperature before adding the fragrance. If the mixing time mentioned above is exceeded, it may be difficult for the fragrance and preservative to be evenly mixed in the composition.

[44]

[45] After that, the isotonic agent is added to the primarily mixed mixture to perform second mixing (S30).

[46] The isotonic agent may be added to the mixture that has been primarily mixed in the step S20 to perform second mixing at 200 to 600 rpm for 10 to 60 minutes.

[47]

[48] Thereafter, the secondly mixed mixture is cooled to 20 to 30°C, and then camostat mesilate is added to perform third mixing (S40).

[49] After the secondly mixed mixture is cooled to 20 to 30°C in the step S30, camostat mesilate is added to perform third mixing at 200 to 600 rpm for 10 to 60 minutes.

[50]

[51] In addition, the pH is adjusted to 3 to 5 while adding a pH regulator to the thirdly mixed mixture (S50).

[52] The pH regulator may be adjusted to 3 to 5 while adding the pH regulator in the mixture thirdly mixed in the step S40, and it may be fine to carry out the pH adjustment while performing stirring at 200 to 300 rpm for 10 to 60 minutes.

[53]

[54] Thereafter, solvent sterilized after mixing xanthan gum in the pH-adjusted solution is added (S60).

[55] While slowing adding xanthan gum to a solution of which pH has been adjusted in the step S50 so that it does not clump with the raw material, the sterilized solvent may be added after dissolving it at 200 to 600 rpm for 90 to 150 minutes. Since xanthan gum easily clumps with the raw material and is not well mixed, it is preferable to mix them for a longer time than the mixing time in the primary to third mixing mentioned above.

[56]

[57] Finally, the mixture to which the sterilized solvent is added is filtered (S70).

[58] The mixture to which the sterilized solvent is added in the step S60 may be filtered using a 5 to 10 μm filter.

[59]

[60] Hereinafter, the present disclosure will be described in more detail using Examples. These examples are only intended to more specifically explain the present disclosure, and it is obvious to those skilled in the art that the scope of the present disclosure is not limited by them.

[61]

[62] Example 1. Preparation of composition for nasal spray

[63] After 150 kg of purified water was sterilized by heating it to 90°C, only 30 kg of purified water was cooled to 50°C. Thereafter, 0.030 kg of L-menthol and 0.090 kg of benzoic acid were added thereto, and the mixture was mixed at 500 rpm for 1 hour while maintaining the temperature to 50°C. In addition, 5.250 kg of D-sorbitol solution was added to mix the mixture at 500 rpm for 1 hour while maintaining the temperature to 50°C. Thereafter, after cooling the mixture to 25°C, 0.0525 kg (0.035% by weight (0.35 mg / mL) of camostat mesilate was added to mix the mixture at 500 rpm for 1 hour, and sodium hydroxide was added to mix the mixture for 20 minutes to adjust the pH to 4. After 0.0375 kg of xanthan gum was dissolved therein at 500 rpm for 1 hour, the remaining purified water was added, mixed, and filtered through a 5 to 10 μm filter.

[64]

[65] Examples 2 to 5. Preparation of composition for nasal spray

[66] A composition for nasal spray was prepared in the same manner as in Example 1 except that camostat mesilate was applied at the ratio described in Table 1 below.

[67] [Table 1]ClassificationCamostat mesilate content (% by weight)Example 20.02 (0.2 mg / mL)Example 30.07 (0.7 mg / mL)Example 40.10 (1.0 mg / mL)

[68]

[69] Comparative Example 1. Preparation of Composition for Nasal Spray

[70] A nasal spray was prepared in the same manner as in Example 1 except that camostat mesilate was not used.

[71]

[72] Experimental Example 1: Drying aspectevaluation

[73] 1-1. Drying aspect test depending on whether there is camostat mesilate or not

[74] Compositions for nasal spray according to Example 1 and Comparative Example 1 were applied in an amount of 1 ml each to a 3.5 cm diameter plate, and then dried in a dry oven at 60°C. In addition, the drying aspect was checked at each of the early (0 hr), middle (3.5 hr), and last (5 hr) stages, and the results are shown in FIGS. 3 to 5.

[75] The experimental group on the left was applied to the plate considering surface tension, and the experimental group on the right was applied with physical vibration and adhered to the plate as much as possible, and then it was dried.

[76] Referring to FIG. 3, it could be confirmed in the case of the initial stage that Comparative Example 1 had strong surface tension, so it did not adhere to the plate and clumped up as it was, and there was no significant difference from Example 1. Referring to FIG. 4, it could be confirmed in the case of the middle stage that Comparative Example 1 was attached to the surface and existed in an undried liquid state, whereas Example 1 was attached to a relatively wide range and dried. Referring to FIG. 5, it could be confirmed in the case of the final stage that Comparative Example 1 was dried as is at the applied location, whereas Example 1 was attached to a wide range and dried. As a result, it could be found that the difference in area depending on the presence or absence of camostat mesilate was approximately 4 times on the left side and approximately 10.3 times on the right side.

[77]

[78] 1-2. Drying aspect test depending on the content of camostat mesilate

[79] The compositions for nasal spray according to Examples 1 to 4 were applied in an amount of 1 ml each to a 3.5 cm diameter plate while physically vibrating, and then dried in a dry oven at 37°C. In addition, the aspects immediately after application (0 hr) and after drying (3.0 hr) were checked, and the results are shown in FIGS. 6 and 7.

[80] Referring to FIGS. 6 and 7, it could be confirmed immediately after application (0 hr) that they were applied by being attached to the entire plate surface regardless of the content of camostat mesilate. After drying (3 hr), although there was some difference (white arrow) in the drying area of ​​Examples 1 and 2 with a low content of camostat mesilate, it could be confirmed that a film was formed at all contents and that it was attached to a relatively wide range and dried. In particular, it could be confirmed that Examples 3 and 4 with a high content of camostat mesilate were attached and dried over a relatively wide range compared to Examples 1 and 2.

[81]

[82] Experimental Example 2: Viscosity evaluation depending on the content of camostat mesilate

[83] In order to determine the physical properties depending on the content of camostat mesilate, the viscosities of Examples 1 to 4 were measured using a Brookfield viscometer, and the results are shown in FIG. 8.

[84] The Brookfield viscometer was set to zero point and the rotation speed to 1.0 RPM to measure the viscosity of the sample. The sample was about 20 mL, and the rotation speed was 1.0 RPM, which may have a speed of 1.223 s-1 when converted to a shear rate.

[85] Referring to FIG. 8, as the content of camostat mesilate increased, the viscosity tended to increase, and the viscosities were shown to be higher in the order of Example 4 (9.00 cp), Example 3 (8.40 cp), Example 1 (7.80 cp), and Example 2 (7.20 cp).

[86]

[87] Experimental Example 3: Evaluation of viscoelastic behavior

[88] Viscosity and viscoelasticity were measured sequentially using a rotational rheometer (RHEOMETER(AR)) according to (1) flow sweep, (2) step flow, and (3) oscillation frequency sweep measurement methods. In order to clearly confirm the experimental values, the ones using a 60 mm cone plate and the ones using a 40 mm cone plate were distinguished.

[89]

[90] 3-1. Flow sweep: Evaluation of the relationship between shear rate and viscosity

[91] The shear rate was sequentially changed using a 60 mm cone plate, the flow curve data was measured while taking a certain rest time, and the results are shown in FIG. 9.

[92] Referring to FIG. 9, when the shear rate was low (white arrow), the viscosity difference between Comparative Example 1 and Example 1 was shown to be large, but it could be confirmed that the viscosity difference decreased as the shear rate increased (black arrow). As a result, it could be found that Example 1 had a greater viscosity decrease than Comparative Example 1 so that Example 1 had molecules that were more oriented than Comparative Example 1.

[93]

[94] 3-2. Step flow: Viscosity evaluation after spray injection and application

[95] Step flow is a method of measuring the viscosity of a sample by simulating a specific process intended for each phase by setting the shear rate, which determines the rotation speed of the rheometer, step by step. The phase was set in such a manner that maintains the shear rate at a high speed and then changes it to a low speed, thereby comparing the physical properties by assuming the situations after the spray injection and application.

[96] The spray injection situation was set to a 103 to 105 shear rate (1 / s) condition, and the stationary situation, i.e. the application number situation, was set to a 1 shear rate (1 / s) condition. After about 1 to 2 mL of sample was dispensed into the device based on this, the average value of the viscosity for each phase was measured while changing from 1000 s-1 (Phase 1) to 1 s-1 (Phase 2), and the results using a 60 mm cone plate are shown in FIG. 10, and the results using a 40 mm cone plate are shown in FIG. 11.

[97] Referring to FIG. 10, the viscosity of Example 1 under spray injection conditions was 1.57 cps and that of Comparative Example 1 was 1.51 cps, which were shown to be similar, but it could be confirmed that, after application, the viscosity of Example 1 was 7.69 cps and that of Comparative Example 1 was 5.18 cps, which showed a relatively large difference. As a result, it could be confirmed that the viscosity increase of Example 1 was higher than that of Comparative Example 1, and specifically, it could be confirmed that the viscosity change amount after spray injection and application of Example 1 was 6.12 cps, whereas it was 3.66 cps in Comparative Example 1. That is, it could be found that Example 1 and Comparative Example 1 had a viscosity difference of about 1.7 times. That is, as a result of rotational rheometer (RHEOMETER(AR)) device analysis using a 60 mm cone plate, it could be confirmed that the viscosity of the composition for nasal spray according to the present disclosure significantly increased after application, with a difference of 4 cps or more in viscosity measured under conditions of 103 to 105 shear rate (1 / s) and viscosity measured under conditions of 1 shear rate (1 / s).

[98] Referring to FIG. 11, under spray injection conditions, the viscosity was all shown to be 2 cp or less regardless of the content of camostat mesilate (black arrow), but after application, the viscosity of Example 1 containing 0.35% by weight of camostat mesilate was shown to be the highest at 31.49 cp. Then, Example 4 (9.43 cp), Example 2 (4.96 cp), and Example 3 (4.86 cp) were shown to be high in that order. That is, As the results of the rotational rheometer (RHEOMETER(AR)) device analysis using a 40 mm cone plate, it could be confirmed that the viscosity of the composition for nasal spray according to the present disclosure was shown to be 4 cp or more when the condition was changed from 103 to 105 shear rate (1 / s) to 1 shear rate (1 / s), and the viscosity after application significantly increased in all Examples.

[99]

[100] 3-3. Oscillation frequency sweep: Viscoelasticity evaluation

[101] Oscillation frequency sweep is a measurement method that evaluates the viscoelasticity of a sample while changing the angular frequency, and the viscoelasticity evaluation depending on the frequency of the sample was conducted in order to check the physical properties of the sample by assuming the environment after application. The degree of oscillation was severe, and the values ​​were compared at a relatively low oscillation of angular frequency 100 or less, which is the situation after injection, except for the situation immediately after spray injection. In order to clearly check the experimental values, the experimental values ​​using a 60 mm cone plate are shown in FIG. 12, and the experimental values ​​using a 40 mm cone plate are shown in FIGS. 13 and 14.

[102] The spray injection is in the middle section between 100 and 101 (white arrow), and the section after application is the black dotted arrow section. Storage modulus (G') is the elastic coefficient, which is a numerical value (blue) indicating how much it changes in response to an external force (stress), i.e., which means the elasticity inherently possessed by the sample as the storage modulus. In general, a high G' may mean a high force to return to its original state. Complex viscosity(η) represents a numerical value (red) for resistance as a complex viscosity, and tan delta (tan delta=G' / G'') is a loss tangent, which represents the relative ratio (red-brown) between viscosity and elasticity as properties of the material itself.

[103] Referring to FIG. 12, in the case of storage modulus (G'), Example 1 showed a slightly lower value than Comparative Example 1, indicating that Example 1 had relatively lower elasticity than Comparative Example 1. Accordingly, it was possible to numerically identify the cause of the tendency of Comparative Example 1 to allow the injection solutions to clump together with each other rather than adhere to the surface, as in the tendency shown from the results of Experimental Example 1.

[104] In the case of complex viscosity (η) and tan delta, Example 1 showed higher values ​​than Comparative Example 1, indicating that there was a significant difference in viscosity compared to the elasticity modulus, which did not show a significant difference. Accordingly, it was possible to numerically confirm that Example 1 had a high resistance to external physical stimulation after application and a high viscosity.

[105] Referring to FIG. 13, in the case of storage modulus (G'), Example 3 showed the highest elasticity, followed by Example 2, Example 4, and Example 1. This indicated that the formulation elasticity was affected depending on the content of camostat mesilate. Referring to FIG. 14, in the case of complex viscosity (η), the highest complex viscosity was shown in Example 3, in the same manner as the elastic modulus, followed by Example 2, Example 4, and Example 1. This indicates that the content of camostat mesilate also affects the complex viscosity.

[106] The above-described results could confirm that differences occurred depending on the content of camostat mesilate, and it could be found that camostat mesilate improved surface adhesion and viscosity.

[107]

[108] Although the exemplary embodiments of the present disclosure have been described in detail above, the scope of rights of the present disclosure is not limited thereto, and various modifications and improved forms made by those skilled in the art using the basic concept of the present disclosure defined in the following claims also fall within the scope of rights of the present disclosure.

[109] All technical terms used in the present disclosure, unless otherwise defined, are used with the same meaning as generally understood by those skilled in the art in the relevant field of the present disclosure. The contents of all publications described as reference documents in this specification are introduced into the present disclosure.  

Claims

 

1. A composition for nasal spray comprising xanthan gum and camostat mesilate as active ingredients. 

2. The composition for nasal spray of claim 1, wherein as a rotational rheometer (RHEOMETER(AR)) device analysis result using a 60 mm cone plate, the difference between a viscosity measured under a condition of 103 to 105 shear rate (1 / s) and a viscosity measured under a condition of 1 shear rate (1 / s) is 4 cP or more. 

3. The composition for nasal spray of claim 1, wherein as a rotational rheometer (RHEOMETER(AR)) device analysis result using a 40 mm cone plate, the measured viscosity is 4cPor more when changing from a 103 to 105 shear rate (1 / s) condition to a 1 shear rate (1 / s) condition. 

4. The composition for nasal spray of claim 1, wherein xanthan gum is contained in an amount of 0.01 to 0.04% by weight based on the total weight of the composition. 

5. The composition for nasal spray of claim 1, wherein camostat mesilate is contained in an amount of 0.02 to 0.10% by weight based on the total weight of the composition. 

6. The composition for nasal spray of claim 1, further comprising one or more selected from a preservative, an isotonic agent, a fragrance, a pH regulator, and a solvent. 

7. A method for preparing a composition for nasal spray, comprising the steps of:(a) sterilizing a solvent by heating it;(b) cooling the sterilized solvent to 45 to 55°C, and then adding a fragrance and a preservative thereto to perform first mixing;(c) adding an isotonic agent to the primarily mixed mixture to perform second mixing;(d) cooling the secondarily mixed mixture to 20 to 30°C, and then adding camostat mesilate thereto to perform third mixing;(e) adjusting the pH to 3 to 5 while adding a pH adjuster to the thirdly mixed mixture;(f) mixing xanthan gum into the pH-adjusted solution, and then adding the sterilized solvent thereto; and(g) filtering the mixture to which the sterilized solvent has been added. 

8. The method of claim 7, wherein the first mixing is performed at 200 to 600 rpm for 30 to 90 minutes, and the second mixing and the third mixing are performed at 200 to 600 rpm for 10 to 60 minutes. 

9. The method of claim 7, wherein the mixing in the step (f) is performed at 200 to 600 rpm for 90 to 150 minutes. 

10. The method of claim 7, wherein the filtration in the step (g) is performed using a 5 to 10 μm filter. 

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