Artificial saliva spray and preparation method thereof

Abstract

The invention provides an artificial saliva spray. The artificial saliva spray is prepared from the following components in percentage by mass: 0.001 to 0.003 percent of hydrogenated castor oil, 0.02 to 0.07 percent of xanthan gum, 0.01 to 0.03 percent of cyclodextrin, 0.01 to 0.02 percent of calcium chloride, 0.01 to 0.05 percent of dipotassium phosphate, 0.1 to 0.15 percent of potassium chloride, 0.05 to 0.1 percent of sodium chloride, 0.004 to 0.006 percent of magnesium chloride and the balance of water. The artificial saliva suitable for the spray is provided, the dosage is accurate, the good oral cavity adhesion capacity is achieved, and the effect maintaining time is long.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, and particularly relates to an artificial saliva for treating xerostomia. BACKGROUND

[0002] Saliva is a body fluid secreted by oral mucosa and is one of the most important components in the oral cavity. The total amount of saliva secretion of a normal person is about 1000-1500 ml per day. The composition thereof includes more than 99% of water; organic matters mainly are salivary amylase, mucin, lysozyme and mucopolysaccharide; and inorganic ions mainly are potassium, sodium and calcium, etc. Saliva has three major functions of tissue covering, nutrition and regulation of oral flora.

[0003] Xerostomia, i.e. dry mouth, is a subjective feeling of dry mouth and objective reduction of saliva secretion, including reduction of saliva flow and change of saliva composition. The prevalence of xerostomia is about 5.5%-46%, and the prevalence increases with age. The causes of xerostomia are many, and generally include drugs, aging, radiotherapy, chemotherapy and systemic diseases such as rheumatoid, endocrine, nervous, genetic, metabolic and infectious diseases. The qualitative and quantitative saliva secretion dysfunction leads to the feeling of dry mouth, which brings great discomfort and even pain to patients, and long-term reaction of severe patients even causes difficulty in swallowing and conversation, sleep disorders, loss of taste, occurrence of dental caries and oral fungal infection, etc., which seriously affects the quality of life of patients.

[0004] In the prior art, there are some reports on artificial saliva with dissolved inorganic salts, thickening agents, flavoring agents and other components. The spray has the advantages of convenient application and good tolerance, but the spray requires a relatively low viscosity to avoid the disadvantages of spray head blockage, inaccurate spray dose and the like. However, the artificial saliva with low viscosity has the defects of poor oral adhesion and short effect maintenance time, and the clinical application is limited. For example, CN101524363A adds hydroxypropyl methyl cellulose to enhance the bioadhesion of the prepared artificial saliva. A small amount of the artificial saliva can maintain the oral moist feeling for a limited time, and a large amount of the artificial saliva will be unsuitable for preparation of a spray due to too large viscosity. SUMMARY

[0005] The present application provides an artificial saliva suitable for a spray, which has accurate dose, good oral adhesion and long effect maintenance time.

[0006] The present application discloses an artificial saliva spray, which comprises the following components in mass percentage: 0.001%-0.003% of hydrogenated castor oil, 0.02%-0.07% of xanthan gum, 0.01%-0.03% of cyclodextrin, 0.01%-0.02% of calcium chloride, 0.01%-0.05% of dipotassium hydrogen phosphate, 0.1%-0.15% of potassium chloride, 0.05%-0.1% of sodium chloride, 0.004%-0.006% of magnesium chloride and the balance of water.

[0007] In some embodiments, the xanthan gum is XANTURAL 75.

[0008] In some embodiments, the cyclodextrin is a-cyclodextrin or β-cyclodextrin.

[0009] In some embodiments, the artificial saliva spray further contains a flavoring agent, which is one or more of xylitol, mannitol, and peppermint oil.

[0010] In some embodiments, the artificial saliva spray contains the following components in the following mass percentages: hydrogenated castor oil 0.002%, xanthan gum 0.05%, cyclodextrin 0.02%, calcium chloride 0.0146%, dipotassium hydrogen phosphate 0.0342%, potassium chloride 0.12%, sodium chloride 0.0844%, magnesium chloride 0.0052%, peppermint oil 0.001%, and the balance being water.

[0011] In some embodiments, the artificial saliva spray has a liquid volume of 0.4 g per spray.

[0012] The artificial saliva spray can be prepared by the following steps: a) 1 / 3 of the water is heated to 80°C, and xanthan gum is added and mixed evenly; b) The liquid prepared in step a) is cooled to 25°C, and is left to stand for half an hour, and cyclodextrin and hydrogenated castor oil are added and stirred; c) 1 / 3 of the water is added to calcium chloride, dipotassium hydrogen phosphate, potassium chloride, sodium chloride, and magnesium chloride, and is dissolved; d) Steps b) and c) are mixed, the remaining water is added, and the product is filled, sterilized, and obtained.

[0013] The sterilization in step d) is performed by steam sterilization at 121°C for 30 minutes.

[0014] The present application has the following beneficial effects: 1) Among various oral mucosa administration dosage forms, oral spray has a simple preparation process, can deliver drugs to the oral mucosa or oropharynx, and can exert local effects, and is particularly suitable for the treatment of xerostomia that requires rapid effects, and is particularly suitable for patients who are unable to swallow and the elderly.

[0015] 2) The use of xanthan gum achieves the unexpected technical effect that only a small amount is needed to obtain artificial saliva with appropriate viscosity and good water loss effect, and xanthan gum has pseudoplasticity, and the viscosity decreases under high shear (such as filling and spray release); the filling amount difference is small, and the delivered dose is uniform; and the influence of electrolytes and high temperature is small. It can be subjected to high-temperature sterilization, does not need process cleaning control, and reduces production costs.

[0016] 3) Hydrogenated castor oil, xanthan gum, cyclodextrin combination, solubilization, improve stability, mask bad smell, used for mucosal preparations, further prolong the onset time, and can play a certain antibacterial effect. DETAILED DESCRIPTION

[0017] The following detailed description of the embodiments of the present application, must be noted that the following examples are used to illustrate the present application rather than limiting the present application.

[0018] Example 1 Prescription composition: Hydrogenated castor oil 0.002%, xanthan gum 0.05%, cyclodextrin 0.02%, calcium chloride 0.0146%, dipotassium hydrogen phosphate 0.0342%, potassium chloride 0.12%, sodium chloride 0.0844%, magnesium chloride 0.0052%, menthol 0.001%, the rest of the water.

[0019] Preparation method: a) 1 / 3 of the water is heated to 80℃, xanthan gum is added, and mixed uniformly; b) The liquid prepared in step a) is cooled to 25℃, placed for half an hour, cyclodextrin, hydrogenated castor oil and menthol are added, and stirred; c) 1 / 3 of the water is added to calcium chloride, dipotassium hydrogen phosphate, potassium chloride, sodium chloride, magnesium chloride, and dissolved; d) Step b) and step c) are mixed, the remaining water is added, mixed uniformly, 80g / bottle is filled, and 121℃ / 30min steam sterilization is sterilized, and the product is obtained.

[0020] Example 2 Prescription composition: Hydrogenated castor oil 0.002%, xanthan gum 0.05%, cyclodextrin 0.02%, calcium chloride 0.0146%, dipotassium hydrogen phosphate 0.0342%, potassium chloride 0.12%, sodium chloride 0.0844%, magnesium chloride 0.0052%, the rest of the water.

[0021] Preparation method: a) 1 / 3 of the water is heated to 80℃, xanthan gum is added, and mixed uniformly; b) The liquid prepared in step a) is cooled to 25℃, placed for half an hour, cyclodextrin, hydrogenated castor oil and menthol are added, and stirred; c) 1 / 3 of the water is added to calcium chloride, dipotassium hydrogen phosphate, potassium chloride, sodium chloride, magnesium chloride, and dissolved; d) Step b) and step c) are mixed, the remaining water is added, mixed uniformly, 80g / bottle is filled, and 121℃ / 30min steam sterilization is sterilized, and the product is obtained.

[0022] Example 3 Prescription composition: Hydrogenated castor oil 0.001%, xanthan gum 0.02%, cyclodextrin 0.03%, calcium chloride 0.0146%, dipotassium hydrogen phosphate 0.0342%, potassium chloride 0.12%, sodium chloride 0.0844%, magnesium chloride 0.0052%, peppermint oil 0.001%, balance water.

[0023] Preparation method: Same as in Example 1.

[0024] Example 4 Prescription composition: Hydrogenated castor oil 0.003%, xanthan gum 0.07%, cyclodextrin 0.01%, calcium chloride 0.0146%, dipotassium hydrogen phosphate 0.0342%, potassium chloride 0.12%, sodium chloride 0.0844%, magnesium chloride 0.0052%, balance water.

[0025] Preparation method: Same as in Example 2.

[0026] Example 5 Prescription composition: Hydrogenated castor oil 0.002%, xanthan gum 0.05%, cyclodextrin 0.01%, calcium chloride 0.0146%, dipotassium hydrogen phosphate 0.0342%, potassium chloride 0.12%, sodium chloride 0.0844%, magnesium chloride 0.0052%, peppermint oil 0.001%, balance water.

[0027] Preparation method: Same as in Example 1.

[0028] Comparative Example 1 Prescription composition: HPMC K4M 0.05%, Calcium chloride 0.0146%, Dipotassium hydrogen phosphate 0.0342%, Potassium chloride 0.12%, Sodium chloride 0.0844%, Magnesium chloride 0.0052%, Peppermint oil 0.001%, Balance: Water.

[0029] Preparation method: Take all components except HPMC, dissolve them in water and stir until homogeneous. While stirring, add HPMC K4M. After complete dissolution, add sodium hydroxide to adjust the pH to 6.0. Fill 80g / bottle into spray bottles to obtain the final product.

[0030] Comparative Example 2 Prescription composition: HPMC K4M 0.45%, calcium chloride 0.0146%, dipotassium hydrogen phosphate 0.0342%, potassium chloride 0.12%, sodium chloride 0.0844%, magnesium chloride 0.0052%, balance water.

[0031] Preparation method: Take all components except HPMC, dissolve them in water and stir until homogeneous. While stirring, add HPMC K4M. After complete dissolution, add sodium hydroxide to adjust the pH to 6.0. Fill 80g / bottle into spray bottles and sterilize by steam at 121℃ for 30 minutes.

[0032] Comparative Example 3 Prescription composition: HPMC K15M 0.02%, calcium chloride 0.0146%, dipotassium hydrogen phosphate 0.0342%, potassium chloride 0.12%, sodium chloride 0.0844%, magnesium chloride 0.0052%, peppermint oil 0.001%, balance water.

[0033] Preparation method: Take all components except HPMC, dissolve them in water and stir until homogeneous. While stirring, add HPMC K15M. After complete dissolution, add sodium hydroxide to adjust the pH to 6.0. Fill 80g / bottle into spray bottles and sterilize by steam at 121℃ for 30 minutes.

[0034] Comparative Example 4 Prescription composition: HPMC K15M 0.29%, calcium chloride 0.0146%, dipotassium hydrogen phosphate 0.0342%, potassium chloride 0.12%, sodium chloride 0.0844%, magnesium chloride 0.0052%, peppermint oil 0.001%, balance water.

[0035] Preparation method: Take all components except HPMC, dissolve them in water and stir until homogeneous. While stirring, add HPMC K15M. After complete dissolution, add sodium hydroxide to adjust the pH to 6.0. Fill 80g / bottle into spray bottles to obtain the final product.

[0036] Experimental Example 1: Effect of Steam Sterilization at 121℃ for 30 minutes on Samples Samples from the examples and comparative examples before filling were compared with samples after steam sterilization at 121℃ for 30 minutes, and their pH value and viscosity were measured respectively. The results showed that the changes before and after sterilization in Examples 1-5 were small and relatively stable, as detailed in Table 1.

[0037] Table 1. Effect of steam sterilization at 121℃ for 30 minutes on the samples

[0038] Experimental Example 2: Detection of the effect of slowing down water loss Moisture loss was measured as follows: The oral mucosa of rabbits was carefully peeled off, removing as much other tissue as possible. A portion of the mucosa, approximately 4 square centimeters in area, was taken. 0.15 g of physiological saline, Examples 1-4, and Comparative Examples 1-4 were evenly applied to the mucosa surface, respectively. The mucosa was then placed in an infrared moisture meter at a temperature of 37°C to allow moisture evaporation. Weights were recorded at 5, 10, 15, 20, 25, and 30 minutes, and the cumulative percentage of moisture loss was calculated. The results showed that Examples 1-5 effectively mitigated moisture loss; specific results are shown in Table 2.

[0039] Table 2. Detection of the effect of slowing down water loss

[0040] Experimental Example 3: Detection of spray dosage variation, spray volume per spray, and drug (calcium chloride) content per spray Method for detecting the difference in filling volume: For each example and comparative example, 20 bottles of test sample were taken, and the weight after filling and the weight of empty bottles were weighed respectively to obtain the filling volume of each contents and the average filling volume, and the difference in filling volume was calculated. Method for testing spray volume per spray: For each example and comparative example, take 4 bottles of test sample, spray them several times, wipe them clean, weigh them accurately, and then spray them 3 times continuously. After each spray, wipe them clean and weigh them accurately. Calculate the spray volume for each spray. Spray them 10 times continuously, wipe them clean, weigh them accurately, and then measure the spray volume 3 times in the same way. Continue to spray them 10 times continuously, and then measure the spray volume 4 times in the same way. Calculate the average value of the spray volume of 10 sprays for each bottle, compare it with the labeled spray volume (0.4g), and calculate the RSD (%).

[0041] Content testing of each spray of drug (calcium chloride): Preparation of standard substance solution: Accurately measure the national standard substance solution of calcium (1000 μg / ml), dilute with water to prepare a solution containing 50 μg per ml.

[0042] Preparation of lanthanum solution: Weigh 23.45g of lanthanum oxide, add 20ml of water, slowly add 75ml of hydrochloric acid to dissolve, dilute with water to 1000ml, and shake well.

[0043] Preparation of the standard curve: Accurately measure 0, 0.5, 1.0, 1.5, 2.0, and 2.5 ml of the standard substance solution and place them in separate 25 ml volumetric flasks. Dilute to the mark with lanthanum solution and mix well. Using the first flask as a blank solution, measure the absorbance at a wavelength of 422.7 nm using atomic absorption spectrophotometry (General Chapter 0406, Part IV, Chinese Pharmacopoeia 2015). Perform linear regression between absorbance and concentration to obtain the regression equation.

[0044] Preparation and determination of the test solution: Take one bottle of test solution, remove the cap, spray several times until a normal mist spray volume is achieved, then wash the nozzle with water. Place a small beaker obliquely over the nozzle and spray continuously 10 times. Transfer the solution in the beaker to a 25 ml volumetric flask with lanthanum solution, dilute to the mark, and shake well. Use the first bottle of solution under the standard curve section as the blank solution, and determine the solution using the same method as under the standard curve preparation section. Calculate the calcium concentration from the regression equation, calculate the calcium chloride content per spray, and compare it with the labeled content.

[0045] The results showed that the sprays prepared in Examples 1-5 had small variations in dosage and good uniformity in delivery. Comparative Example 4, however, experienced nozzle clogging and poor spraying after multiple consecutive sprays. Details are shown in Table 3.

[0046] Table 3. Variation in spray dosage and test results per spray volume

[0047] Experiment 4: Evaluation of antibacterial ability Referring to the antibacterial efficacy test method in General Chapter 1121 of the Chinese Pharmacopoeia, the antibacterial ability of the artificial saliva prepared in the examples and comparative examples was tested. The results showed that the artificial saliva prepared in Examples 1-5 had a certain antibacterial ability. Details are shown in Table 4.

[0048] Table 4. Antibacterial ability test

[0049] Experimental Example 5: Stability Evaluation Artificial saliva prepared in the examples was placed at a temperature of 40℃±2℃ and a relative humidity of 75%±5% for 6 months. Samples were taken at the end of the 1st, 2nd, 3rd and 6th months, and the appearance was compared and the pH, viscosity and spray volume were tested. The results showed that the artificial saliva prepared in Examples 1-5 did not show significant changes in any of the indicators after six months of accelerated testing, and had good stability.

Claims

1. An artificial saliva spray, characterized in that, It contains the following components by weight percentage: hydrogenated castor oil 0.001%–0.003%, xanthan gum 0.02%–0.07%, cyclodextrin 0.01%–0.03%, calcium chloride 0.01%–0.02%, dipotassium hydrogen phosphate 0.01%–0.05%, potassium chloride 0.1%–0.15%, sodium chloride 0.05%–0.1%, magnesium chloride 0.004%–0.006%, and the balance being water.

2. The artificial saliva spray as described in claim 1, characterized in that, The xanthan gum is xanthan gum XANTURAL 75.

3. The artificial saliva spray as described in claim 1, characterized in that, The cyclodextrin is α-cyclodextrin or β-cyclodextrin.

4. The artificial saliva spray as described in claim 1, characterized in that, The artificial saliva spray also contains a flavoring agent, which is one or more of xylitol, mannitol, and peppermint oil.

5. The artificial saliva spray as described in claim 1, characterized in that, Each spray of the artificial saliva spray contains 0.4g of liquid.

6. The artificial saliva spray as described in any one of claims 1 or 5, characterized in that, It contains the following components by weight percentage: 0.002% hydrogenated castor oil, 0.05% xanthan gum, 0.02% cyclodextrin, 0.0146% calcium chloride, 0.0342% dipotassium hydrogen phosphate, 0.12% potassium chloride, 0.0844% sodium chloride, 0.0052% magnesium chloride, 0.001% peppermint oil, and the balance being water.

7. The method for preparing the artificial saliva spray as described in claim 1, characterized in that, Includes the following steps: a) Heat 1 / 3 of the water to 80°C, add xanthan gum, and mix well; b) Cool the liquid prepared in step a) to 25°C, let it stand for half an hour, add cyclodextrin and hydrogenated castor oil, and stir. c) Add calcium chloride, dipotassium hydrogen phosphate, potassium chloride, sodium chloride, and magnesium chloride to 1 / 3 of the water and dissolve them; d) Mix steps b) and c), add the remaining water, fill, and sterilize to obtain the final product.

8. The method for preparing the artificial saliva spray as described in claim 7, characterized in that, The sterilization in step d) is performed by steam sterilization at 121°C for 30 minutes.

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