An oral gel and its application

Abstract

The present invention belongs to the field of pharmaceuticals, and particularly relates to an oral gel and its application. The oral gel of the present invention comprises nystatin or nistatin as the active ingredient (API), hydroxyethyl cellulose and sodium carboxymethyl cellulose, and optionally strawberry essence. The oral gel is used for treating oral candidiasis, can effectively mask the earthy smell of the API, and has strong adhesiveness, good spreadability, good palatability and high stability.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceuticals, and particularly relates to an oral gel and its application. Background Art

[0002] Oral candidiasis is an acute, subacute or chronic oral mucosal disease caused by Candida infection. The occurrence of this disease is a continuous process from Candida colonization, infection to onset, and mostly occurs in individuals with high-intensity Candida colonization, accompanied by the destruction of the oral mucosal physiological barrier, or accompanied by underlying diseases and low immune function of the body. In recent years, with the application of broad-spectrum antibacterial drugs, glucocorticoids, immunosuppressants, and the extensive development of organ transplantation and tumor treatment, the prevalence of oral candidiasis has shown an upward trend and has become the most common infectious disease of the oral mucosa. Oral candidiasis is common in the "young, old, and sick" population, and is also known as "the disease of the sick". With the acceleration of the aging process, oral candidiasis will be the focus of the prevention and treatment of future oral mucosal infectious diseases.

[0003] The treatment of oral candidiasis preferably uses topical antifungal drugs, among which nystatin is the first-line drug recommended by domestic and foreign guidelines. As a polyene antifungal drug, nystatin has a strong inhibitory effect on infections caused by Candida albicans, and it is not absorbed through the mucosa. After oral administration, it is not absorbed by the gastrointestinal tract and has high safety. Clinicians often choose it as the treatment drug for thrush (oral fungal infection). Currently, the marketed nystatin preparations for the treatment of thrush mainly include oral tablets, oral suspensions (Mycostatin), and oral gels (Nystaderm Mundgel). However, the currently approved marketed dosage forms of nystatin are not suitable for oral topical administration, especially for young children. For example, for oral tablets, adults need to take them sublingually, while young children, especially infants, cannot do so. Oral suspensions need to be held in the mouth for a long time, otherwise they are easily swallowed and cannot exert local therapeutic effects, and it is difficult for young children to hold them in the mouth for a long time. Oral gels are a more suitable dosage form. They are directly applied in the oral cavity of children and are not quickly swallowed. However, currently only Germany has a related product (Nystaderm), and the adhesion of this product to the oral mucosa is weak. After being coated on the lesion site, it is easy to fall off, resulting in a short residence time of the drug at the lesion site and seriously affecting the drug efficacy.

[0004] On the other hand, nystatin has an extremely bitter and earthy taste. When the drug is directly exposed in the oral cavity, it may cause nausea and vomiting, which are generally difficult for patients to tolerate. As mentioned in the "Diagnosis and Treatment Guidelines for Oral Candidiasis (National Health Commission)" 2022 edition, the local application of nystatin has a poor taste and some patients have difficulty tolerating it. Therefore, masking the taste of nystatin is a major challenge. For example, the prescription of the marketed oral gel (Nystaderm Mundgel) contains a large amount of sucrose (accounting for more than 30%) and raspberry essence, but it only has a certain effect on masking the bitterness of nystatin, and the earthy taste is still relatively strong. There is no suitable solution reported in the development of oral preparations of nystatin. At the same time, no existing report clearly differentiates the masking of the bitterness and earthy taste of nystatin. In the patent application CN106324681A, an oral film-forming gel composition is disclosed, which solves the problem of short retention time of water-soluble gel on the oral mucosa, but does not evaluate the taste masking effect of the drug-containing preparation. In the patent application CN118634191A, an oral gel spray composition is disclosed, which improves patient compliance and treatment effect, but does not evaluate the taste masking effect of the drug-containing preparation. In the literature (DOI: 10.3109 / 03639040903384729), an oral tablet is disclosed, using sodium carboxymethylcellulose and hydroxymethylcellulose as thickeners; sorbitol and sodium saccharin as flavoring agents; after clinical taste tests, the tablet has a very high sweetness, but the taste is still very poor and the taste masking problem is not completely solved.

[0005] TR201407775A2 provides a composition in the form of an adhesive film, which contains nystatin, at least one corticosteroid and at least one polymer selected from hydroxyethyl cellulose and xanthan gum, and at least one local anesthetic. This composition is effective for the treatment of oral diseases such as oral candidiasis and aphthous ulcers.

[0006] GB2163649B relates to an antifungal suppository, which includes nystatin as an antifungal agent, and a hydrocolloid such as sodium carboxymethylcellulose or hydroxypropyl methylcellulose, and a suppository base with a low melting point. The function of this antifungal suppository is to melt at body temperature to release the hydrocolloid and the antifungal agent, adhere to the vaginal membrane, so that the evenly distributed antifungal agent remains at the infection site.

[0007] Therefore, it is of great significance to develop an oral application preparation of nystatin with a better taste to improve the compliance of clinical medication. In addition, if the adhesion of the preparation to the oral mucosa can be further increased and the retention time of the drug at the lesion site can be prolonged, it will help to improve the drug efficacy and has significant clinical value for patients. Summary of the Invention

[0008] To solve the problem of earthy smell existing in the prior art, the present invention provides an oral gel, which comprises nystatin or nystamycin as the active ingredient (API), hydroxyethyl cellulose (HEC, also known as hydroxyethyl cellulose ether, Natrosol, Natrosol 240JR, Natrosol 250H, Natrosol 250 HHR, Natrosol 250M, NatrosolL 250, Natrosol LR, etc., CAS No. 9004-62-0), and sodium carboxymethyl cellulose (CMC-Na, CAS No. 9004-32-4).

[0009] According to the present invention, the HEC can be selected from HEC 250M (molecular weight 720,000), HEC 250G (molecular weight 300,000), and HEC HX (molecular weight 1,000,000).

[0010] According to the present invention, hydroxypropyl methyl cellulose (HPMC) and acrylic resin are optional rather than essential for the oral gel. That is, the oral gel of the present invention may contain HPMC and / or acrylic resin (such as L100-55), or may not contain HPMC and / or acrylic resin.

[0011] According to the present invention, the oral gel further comprises a flavor, preferably strawberry flavor or raspberry flavor, more preferably strawberry flavor.

[0012] The concentration of the flavor is generally 0.1-1 wt%. The higher the concentration, the stronger the aroma. When it exceeds 1 wt%, the aroma is too strong and it will instead irritate the nose. Therefore, the concentration of the flavor is preferably such that it can maintain a light aroma in the oral gel and cover up the bad earthy smell of the API. According to the present invention, the concentration of the flavor in the oral gel is 0.1-0.8 wt%, preferably 0.1-0.6 wt%, more preferably 0.2-0.5 wt%, and most preferably 0.25 wt%.

[0013] According to the present invention, in the oral gel, the concentration of HEC is 0.5-5 wt%, preferably 1.5-5 wt%, more preferably 2-3 wt%; the concentration of CMC-Na is 0.15-2 wt%, preferably 0.5-2 wt%, more preferably 1-2 wt%.

[0014] As gel polymer materials, as the concentrations of HEC and CMC-Na increase, the viscosity increases and the coatability decreases, and the sum of the concentrations of the two does not exceed 5 wt%, preferably does not exceed 4 wt%.

[0015] On the one hand, the present invention provides the use of a combination of hydroxyethyl cellulose (HEC) and sodium carboxymethyl cellulose (CMC-Na) in masking the earthy smell of nystatin or nystamycin contained in an oral gel.

[0016] On the other hand, the present invention also provides a method for treating oral candidiasis, including administering an effective amount of an oral gel to a patient in need, or the oral gel is used for treating oral candidiasis, or the oral gel is used in the preparation of a medicament for treating oral candidiasis.

[0017] Although carbomer, xanthan gum, HEC, CMC-Na or a combination thereof are commonly used gel polymer materials, the prior art has not clearly taught the application of the combination of HEC and CMC-Na to API nystatin, let alone masking the earthy taste of API.

[0018] The present invention confirms that carbomer, xanthan gum, HEC and CMC-Na alone, and the combinations of HEC with carbomer and xanthan gum respectively, cannot mask the earthy taste of API (nystatin).

[0019] The present invention also confirms that the combination of HEC and CMC-Na can significantly mask the earthy taste of API, the combination of HEC and CMC-Na and strawberry essence can completely mask the earthy taste of API, while raspberry essence cannot completely mask the earthy taste of API. Without being limited to existing or unknown mechanisms, the inventors speculate that the combination of HEC and CMC-Na has a synergistic effect on masking the earthy taste of API.

[0020] In addition, by optimizing the concentrations of HEC and CMC-Na (such as 2-3 wt% of HEC, and 0.5-2 wt% or 1-2 wt% of CMC-Na), while masking the earthy taste of API, the oral gel of the present invention also achieves comparable or even better spreadability and adhesiveness to commercially available products.

[0021] Beneficial effects

[0022] The oral gel of the present invention is used for treating oral candidiasis, can effectively mask the earthy taste of the active ingredient (API) nystatin or nistatin in the oral gel, and has strong adhesiveness, good spreadability, good palatability and high stability. Brief description of the drawings

[0023] In order to more clearly describe the technical solutions of the present invention, a brief introduction will be given below in conjunction with the drawings. These drawings are only some specific embodiments recorded in the present application, and the present invention includes but is not limited to the following drawings.

[0024] Figure 1 Showing the yield stress values of samples of different content batches;

[0025] Figure 2 Showing the normal forces of samples of different content batches;

[0026] Figure 3Show the coatability of samples with different content batches;

[0027] Figure 4 Show the yield stress values of samples with different content batches;

[0028] Figure 5 Show the normal forces of samples with different content batches;

[0029] Figure 6 Show the coatability of samples with different content batches. Detailed implementation

[0030] To further understand the present invention, the technical solutions of the present invention will be clearly and completely described below in conjunction with specific embodiments of the present invention. Obviously, the described embodiments are part of the present invention, not all. All variations obtained by those skilled in the art without creative work based on the embodiments in the present invention fall within the scope of protection required by the present invention. Unless otherwise specified, the percentages in the present invention are wt%.

[0031] Example 1

[0032] The taste masking effect of common sweeteners on API

[0033] Prescription design, see Table 1:

[0034] Table 1

[0035]

[0036] Preparation method

[0037] Mix API with glycerol - water (1:1, M / M) solution, dissolve the gel polymer, sweetener, and bacteriostatic agent in the remaining water, mix the above two parts of the solution evenly, add a pH regulator, make up the remaining purified water, stir evenly, and let it stand overnight for swelling.

[0038] Conclusion

[0039] Existing sweeteners can mask the bitterness of nystatin, but neither alone nor in combination can mask the earthy taste.

[0040] Example 2

[0041] The influence of the combination of HEC and CMC - Na on taste masking of API

[0042] Prescription design, see Table 2:

[0043] Table 2

[0044]

[0045] Preparation method

[0046] Mix the API with a glycerol - water (1:1, M / M) solution. Dissolve the gelling polymer, sweetener, and bacteriostatic agent in the remaining water. After mixing the above two parts of the solution evenly, add a pH regulator, make up the remaining purified water, stir evenly, and let it stand overnight for swelling.

[0047] For the test results, see Table 3.

[0048] Table 3

[0049]

[0050] Conclusion

[0051] Existing sweeteners cannot individually mask the earthy taste of API. The present invention unexpectedly discovers that the combination of HEC and CMC - Na can effectively mask the earthy taste of API, while HEC alone or in combination with other polymers cannot effectively mask the taste, and it has nothing to do with the choice of sweetener.

[0052] Example 3

[0053] The effect of other polymers alone or in combination on masking the earthy taste of API

[0054] For the formulation design, see Table 4.

[0055] Table 4

[0056]

[0057] Preparation method

[0058] Mix the API with a glycerol - water (1:1, M / M) solution. Dissolve the gelling polymer, sweetener, and bacteriostatic agent in the remaining water. After mixing the above two parts of the solution evenly, add a pH regulator, make up the remaining purified water, stir evenly, and let it stand overnight for swelling.

[0059] Conclusion

[0060] Common gelling matrices such as carbomer and xanthan gum, whether alone or in combination, and CMC - Na alone, cannot mask the earthy taste of nystatin API.

[0061] Example 4

[0062] The masking effect of flavor on the earthy taste of API

[0063] Although the combination of gelling polymers can significantly reduce the earthy taste of API, it cannot completely mask the taste. Further addition of flavor for seasoning is investigated.

[0064] For the formulation design, see Table 5.

[0065] Table 5

[0066]

[0067] Conclusion

[0068] Among the existing flavors, strawberry flavor and raspberry flavor can well cover up the earthy smell of API; considering that children have a relatively high acceptance of the sour and sweet strawberry flavor, strawberry flavor can be used as the object of investigation.

[0069] Example 5

[0070] Effect of different ratios of HEC + CMC-Na on the quality of the gel (1)

[0071] Experimental design

[0072] Select the combination of HEC 250M and CMC-Na, investigate the gel properties after preparing the gel with different ratios of the two, and compare with the marketed product Nystaderm.

[0073] Prescription design, see Table 6.

[0074] Table 6

[0075]

[0076] Preparation method

[0077] Mix API with glycerol-water (1:1, M / M) solution, dissolve the gel polymer, sweetener, and bacteriostatic agent in the remaining water, mix the above two parts of the solution evenly, add the pH regulator, make up the remaining purified water, stir evenly, and let it stand overnight for swelling.

[0078] Test results - compare the yield stress values of samples with different contents

[0079] Definition of yield stress value: the stress corresponding to a 300% deformation of the sample

[0080] Detection equipment: rheometer HAAKE Mars iQ AIR

[0081] For general topical preparation samples, when extruding the sample from the tube, the deformation of the sample is about 300% or so. This value can judge the internal structure stability of the sample. The higher the YS value, the better the internal structure stability of the sample.

[0082] The results suggest that the gel prepared with HEC + CMC-Na has a more stable internal structure than the gel prepared with HEC alone and the control drug (Nystaderm) ( Figure 1 )

[0083] Test results - compare the normal force of samples with different contents

[0084] Definition of normal force value: The force perpendicular to the surface of an object, pointing towards the surface in contact with the object surface, reflecting the mechanical behavior of the gel in the vertical direction during the shearing process.

[0085] Detection equipment: Rheometer HAAKE Mars iQ AIR

[0086] Place the sample on the sample plate. After the rotor is in close contact with the sample plate, lift it up and observe the adhesion of the sample; the greater the normal force, the better the adhesion.

[0087] The samples when HEC and CMC-Na are used in combination have a greater normal force and better adhesion than when HEC is used alone and the control drug Nystaderm. Figure 2 ).

[0088] Test results - Comparison of the spreadability of samples with different content batches

[0089] Definition of spreadability: It refers to the property of a liquid or paste-like substance to be evenly coated on the surface of a solid substrate (or skin) to form a thin film or coating.

[0090] Detection equipment: Rheometer HAAKE Mars iQ AIR

[0091] Place the sample under low-shear to high-shear and high-shear to low-shear cyclic conditions, and observe the spreadability of the sample. The greater ΔA, the better the spreadability. Figure 3 ).

[0092] The samples when HEC and CMC-Na are used in combination have better spreadability than when HEC is used alone and the control drug Nystaderm.

[0093] Test summary

[0094] The gel matrix combination of HEC + CMC-Na has better gel characteristics.

[0095] Example 6

[0096] Effect of different ratios of HEC+CMC-Na on the gel quality (2)

[0097] Test design

[0098] Select the combination of HEC 250M and CMC-Na, investigate the gel properties after preparation at different ratios of the two, and compare with the marketed product Nystaderm.

[0099] Prescription design, see Table 7.

[0100] Table 7

[0101]

[0102] Preparation method

[0103] Mix the API with a glycerol - water (1:1, M / M) solution. Dissolve the gel polymer, sweetener, and bacteriostatic agent in the remaining water. After mixing the above two parts of the solution evenly, add a pH regulator, make up the remaining purified water, stir evenly, and let it stand overnight for swelling.

[0104] Test results - Comparing the yield stress values of samples with different contents

[0105] Definition of yield stress value: The stress corresponding to a 300% deformation of the sample

[0106] Detection equipment: Rheometer HAAKE Mars iQ AIR

[0107] For general topical preparation samples, when extruding the sample from the tube, the deformation of the sample is approximately around 300%. This value can be used to judge the internal structural stability of the sample. The higher the YS value, the better the internal structural stability of the sample.

[0108] The results suggest that the combination of HEC 3% + CMCNa 2% is better than the combination of HEC 3% + CMCNa 1%. These two combinations are far better than other combinations, including commercial products ( Figure 4 )

[0109] Test results - Comparing the normal force of samples with different contents

[0110] Definition of normal force value: The force perpendicular to the surface of an object, pointing towards the surface in contact with the object surface, which reflects the mechanical behavior of the gel in the vertical direction during shear.

[0111] Detection equipment: Rheometer HAAKE Mars iQ AIR

[0112] Place the sample on the sample plate. After the rotor is in close contact with the sample plate, lift it up and observe the adhesion force of the sample; the greater the normal force, the better the adhesion.

[0113] The normal force of the combination of HEC + CMC - Na is better than that of the control drug Nystaderm, and the higher the dosage, the greater the normal force ( Figure 5 )

[0114] Test results - Comparing the spreadability of samples with different contents

[0115] Definition of spreadability: It refers to the property of a liquid or paste - like substance to be evenly coated on the surface of a solid substrate (or skin) to form a thin film or coating.

[0116] Detection equipment: Rheometer HAAKE Mars iQ AIR

[0117] Place the sample under low-shear to high-shear and high-shear to low-shear cyclic conditions, observe the spreadability of the sample. The larger the ΔA, the better the spreadability.

[0118] Conclusion

[0119] The spreadability when HEC and CMC-Na are used in combination is better than that of the control drug Nystaderm, and the spreadability of HEC 2% + CMC-Na 2% is the best ( Figure 6 )

[0120] Example 7

[0121] Optimal ratio of HEC+CMC-Na for taste masking

[0122] Experimental design

[0123] Select the optimized combination of HEC 250M and CMC-Na, and investigate the difference in taste after preparing the gel at different ratios of the two.

[0124] For the prescription design, see Table 8.

[0125] Table 8

[0126]

[0127] Preparation method

[0128] Mix API with glycerol-water (1:1, M / M) solution. Dissolve the gel polymer, sweetener, and bacteriostatic agent in the remaining water. After mixing the above two parts of the solution evenly, add the pH regulator, make up the remaining purified water, stir evenly, and let it stand overnight for swelling.

[0129] Scoring criteria

[0130] Ten healthy volunteers each take the gel of each prescription with a quantitative spoon, apply it in the mouth, and score the taste, smoothness of spreading, and the retention time of the gel in the mouth respectively.

[0131] Conclusion

[0132] The taste of the three prescriptions in Table 8 is significantly better than that of the commercial product, and the spreadability and adhesion are at least equivalent to those of the commercial product, and even better.

[0133] Example 8

[0134] Stability of oral gel

[0135] For the prescription design, see Table 9.

[0136] Table 9

[0137]

[0138] (1) Preparation of gel matrix

[0139] Set the temperature of the water pot to 75 ± 5 °C, add about 90.38% of the prescription amount of purified water to the water pot, then add the prescription amounts of methylparaben and propylparaben, stir in the main tank of the vacuum emulsifying mixer, with the fast stirring frequency set to 300 Hz (100 - 700 Hz) and the slow stirring frequency set to 25 Hz (20 - 30 Hz), stir for about 30 min. After methylparaben and propylparaben are completely dissolved, stop heating. After the temperature of the main tank cools below 30 °C, continue to add the prescription amounts of stevioside, dipotassium hydrogen phosphate, and potassium dihydrogen phosphate, and stir until completely dissolved. Subsequently, add sodium carboxymethylcellulose and hydroxyethyl cellulose in sequence, and continue to stir until completely swollen, with the fast stirring speed at 1000 HZ (500 - 1200 HZ) for 120 min and the slow stirring speed at 25 HZ (20 - 30 HZ) for 120 min.

[0140] (2) Preparation of liquid medicine

[0141] Add glycerol and an equal amount of purified water (about 5.1% of the prescription amount of purified water) to a beaker, stir (stirring speed: 50 - 500 rpm) evenly, then add API, continue to stir, and set aside after sufficient wetting.

[0142] (3) Preparation of gel sample

[0143] Pour the liquid medicine in the beaker into the main pot containing the gel matrix (rinse the beaker once with the remaining purified water and then transfer it to the main pot), then add the prescription amount of strawberry essence, set the slow stirring speed to 20 ± 5 Hz, do not turn on the fast stirring, and stir for at least 10 h until the product is completely gelled.

[0144] (4) Sample filling

[0145] Fill the above gel sample into aluminum medicinal ointment tubes, seal the tails, and set aside.

[0146] (5) Stability test

[0147] pH determination method:

[0148] Take 0.5 g of the gel sample, add 2.5 g of purified water, stir evenly, and measure the pH value with a pH meter.

[0149] Content determination method: Refer to the high performance liquid chromatography method (General Principles 0512, Volume IV of Chinese Pharmacopoeia 2020 Edition) for determination.

[0150] Chromatographic conditions: Octadecylsilyl silica gel was used as the filler (Agilent, OmniSpher 150 mm×4.6 mm, 5 μm or equivalent chromatographic column); pH 6.0 phosphate buffer solution (weigh 0.4 g of disodium hydrogen phosphate dihydrate and 1.4 g of sodium dihydrogen phosphate (dihydrate), dissolve in 1000 mL of water, adjust the pH value to 6.0 with 8.5% phosphoric acid, filter, and degas) was used as mobile phase A, and methanol was used as mobile phase B. Isocratic elution was carried out according to mobile phase A: mobile phase B = 35:65 (V:V), and the running time was 30 min. The flow rate was 0.8 mL per minute; the detection wavelength was 305 nm; the column temperature was 30 °C, and the sample tray temperature was 4 °C.

[0151] Solution preparation:

[0152] Reference substance solution: Take about 10 mg of nystatin reference substance, accurately weigh it, place it in a 100 mL volumetric flask, add about 40 mL of N,N-dimethylformamide, ultrasonically dissolve it for 2 min, add about 10 mL of mobile phase A, and make up the volume to the mark with methanol, shake well, and you will get it.

[0153] Test solution: Take about 300 mg of the test sample, accurately weigh it, place it in a 50 mL volumetric flask, add about 5 mL of mobile phase A, vortex for 5 min until the sample is completely dispersed, add about 20 mL of N,N-dimethylformamide, and after the temperature reaches room temperature, make up the volume to the mark with methanol, shake well, and filter through a 0.45 μm nylon filter membrane to get it.

[0154] Potency determination method, refer to USP <81> ANTIBIOTIC-MICROBIAL ASSAYS Cylinder-Plate Assay, and the specific steps are as follows:

[0155] (1) Preparation of bacteria-containing medium

[0156] Add 1 mL of the test bacterial suspension to every 100 mL of the medium (temperature not higher than 45 °C), shake well and set aside.

[0157] (2) Preparation of double dishes

[0158] Take a sterile petri dish, place it on a horizontal table, add 16 mL of bacteria-containing medium to each petri dish. After cooling, place 6 steel tubes equidistantly with a steel tube placer, and cover it with a sterile tile cover for standby.

[0159] (3) Sample addition

[0160] ① Standard curve double plates: Take one double plate, and add 300 uL of standard solution dropwise at intervals. Among them, add standard solution S3 to 3 steel tubes, and add standard solution S1 to the other 3 steel tubes. Prepare at least 3 double plates in parallel (usually 3 - 5), which are the double plates of S1 concentration. Prepare double plates of S2, S4, and S5 concentrations in the same way.

[0161] ② Test sample double plates: Take one double plate, and add 300 μL of standard solution and test sample solution dropwise at intervals. Among them, add standard solution S3 to 3 steel tubes, and add test sample solution U3 to the other 3 steel tubes. Prepare at least 3 double plates in parallel (usually 3 - 5), which are the test sample double plates.

[0162] (4) Incubation

[0163] Place the double plates in an incubator at 29 - 31 °C for 16 - 18 hours.

[0164] (5) Calculation

[0165] Take the incubated double plates, remove the steel tubes, place them on an antibacterial zone measuring instrument to measure the diameters of each antibacterial zone. Calculate the average value of the diameters of the antibacterial zones of all S3, and correct the average values of the diameters of the antibacterial zones of S1, S2, S4, and S5. Use the natural logarithm of the concentration of each standard solution as the abscissa and the corrected antibacterial zone diameter as the ordinate to make a standard curve, and directly substitute the antibacterial zone of the test sample into the curve to calculate the concentration of the test sample.

[0166] For the stability results, see Table 10.

[0167] Table 10

[0168]

[0169] Note: In the table, M is month, and ND is not determined.

[0170] The data shows that there is no significant change in the pH value of the accelerated and long - term 6M samples; there is no significant difference in the content of the upper, middle, and lower (i.e., front, middle, and back) parts of the sample, and no obvious stratification occurs; the content and titer IU are both within the qualified range, indicating that the preparation has good stability.

Claims

1. An oral gel for masking the earthy smell of nystatin or nystatin, which comprises nystatin or nystatin as an active ingredient, hydroxyethyl cellulose (HEC) and sodium carboxymethyl cellulose (CMC-Na), does not contain acrylic resin, wherein the concentration of HEC is 0.5 - 5 wt%, and the concentration of CMC-Na is 0.15 - 2 wt%.

2. The oral gel according to claim 1, wherein the concentration of HEC is 1.5 - 5 wt%, and the concentration of CMC-Na is 0.5 - 2 wt%.

3. The oral gel according to claim 2, wherein the concentration of HEC is 2 - 3 wt%, and the concentration of CMC-Na is 1 - 2 wt%.

4. The oral gel according to any one of claims 1 - 3, which further comprises a flavoring agent selected from strawberry flavor and / or raspberry flavor.

5. The oral gel according to claim 4, wherein the flavoring agent is strawberry flavor.

6. The oral gel according to claim 4, wherein the concentration of the flavoring agent is 0.1 - 0.8 wt%.

7. The oral gel according to claim 4, wherein the concentration of the flavoring agent is 0.1 - 0.6 wt%.

8. The oral gel according to claim 4, wherein the concentration of the flavoring agent is 0.2 - 0.5 wt%.

9. The oral gel according to claim 1, wherein the sum of the concentrations of HEC and CMC-Na does not exceed 5 wt%.

10. The oral gel according to claim 9, wherein the sum of the concentrations of HEC and CMC-Na does not exceed 4 wt%.

11. Use of a combination of hydroxyethyl cellulose and sodium carboxymethyl cellulose in the preparation of a drug for inhibiting the earthy smell of nystatin or nystatin contained in an oral gel.

12. Application of the oral gel according to any one of claims 1 - 10 in the preparation of a drug for treating oral candidiasis.

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