A composition for relieving oral dryness suitable for head and neck radiotherapy patients and a preparation method thereof

Abstract

The present invention relates to a composition for relieving oral dryness applicable to head and neck radiotherapy patients, comprising: compound F, citric acid, menthol, vitamin C, xylitol, filler, disintegrant, lubricant; wherein, the compound F is a brand-new compound with M3 PAM activity, which can significantly increase the secretion volume of saliva and can effectively treat xerostomia; in addition, the addition of citric acid and vitamin C in the composition provided by the present invention can not only promote the secretion of saliva, but also accelerate the disintegration rate of tablets and can provide nutrition for patients; and the composition provided by the present invention has few types of excipients, a simple preparation process, and good stability of the prepared tablets.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and particularly relates to a composition for relieving oral dryness applicable to head and neck radiotherapy patients and a preparation method thereof. Background Art

[0002] Head and Neck Cancer is the sixth most common malignant tumor globally, referring to tumors originating from the ear, nose, throat, oral and maxillofacial region, neck and other parts, including nasopharyngeal carcinoma, oropharyngeal carcinoma, hypopharyngeal carcinoma, laryngeal carcinoma, oral cancer, etc. Radiotherapy is one of the main treatment methods. With the improvement of radiotherapy technology, the accuracy of head and neck tumor radiotherapy has been greatly improved: while using higher doses for tumor tissues, the dose received by surrounding normal tissues can also be reduced. However, radiotherapy-related adverse reactions are still inevitable, and dry mouth is one of the most common early complications and long-term sequelae.

[0003] Oral dryness (xerostomia) is defined as an abnormality caused by a reduction in oral saliva flow. After head and neck radiotherapy, the salivary glands are easily damaged, resulting in a decrease in saliva secretion, and the incidence of dry mouth is almost 100%. Dry mouth can affect the patient's speech, is not conducive to eating, induces dental caries, causes a burning sensation in the mouth and other discomforts, seriously affecting the patient's quality of life. Currently, no drug has been proven to be able to repair salivary damage. Although there are some products for relieving oral symptoms on the market, most of them are large-bottle artificial saliva, oral moisturizers, etc., such as patents CN105147818B, CN102085371B, CN110279710A, which cannot meet the needs of patients for convenient use in daily multi-scenario modes.

[0004] Sour taste can stimulate the salivary glands to produce saliva and relieve oral dryness. For example, aged vinegar is added in patent CN114504628A, and the taste is sweet and sour, which can stimulate the taste buds and salivary glands to secrete saliva, effectively improving dry mouth and thirst. Moreover, aged vinegar has good antibacterial and bactericidal effects. Citric acid and vitamin C can not only improve the use effect of oral spray but also effectively provide nutritional supplements for patients.

[0005] Although M cholinergic receptor agonists represented by pilocarpine can improve symptoms, they require long-term medication. For example, patent CN114901283A discloses a dry mouth therapeutic agent with M3 PAM activity;

[0006] In summary, there is an urgent need to provide a preparation with good therapeutic effect on dry mouth, long action time and convenient use to meet the needs of head and neck radiotherapy patients to relieve dry mouth in different daily scenarios, and improve the patient's quality of life and satisfaction. Summary of the Invention

[0007] The object of the present invention is to provide a composition for relieving oral dryness suitable for patients undergoing head and neck radiotherapy and a preparation method thereof, so as to solve the technical problems of poor effect, short action time and inconvenient use existing in the prior art.

[0008] To solve the above technical problems, the present invention provides the following technical solutions:

[0009] A composition for relieving oral dryness suitable for patients undergoing head and neck radiotherapy, comprising: compound F, citric acid, menthol, vitamin C, xylitol, filler, disintegrant, lubricant;

[0010] The compound F is selected from the following structures: The mass percentage of the compound F in the composition is 5-10%; preferably, the mass percentage of the compound F in the composition is 5%, 6%, 7%, 8%, 9% or 10%;

[0011] The mass percentage of the citric acid in the composition is 1-3%; preferably, the mass percentage of the citric acid in the composition is 1%, 2% or 3%;

[0012] The mass percentage of the vitamin C in the composition is 1-3%; preferably, the mass percentage of the vitamin C in the composition is 1%, 2% or 3%;

[0013] The mass percentage of the menthol in the composition is 1-3%; preferably, the mass percentage of the menthol in the composition is 1%, 2% or 3%;

[0014] The mass percentage of the xylitol in the composition is 1-3%; preferably, the mass percentage of the xylose in the composition is 1%, 2% or 3%;

[0015] The filler is selected from: The mass percentage of the filler in the composition is 60-80%; preferably, the mass percentage of the filler in the composition is 60%, 65%, 70%, 75% or 80%;

[0016] The disintegrant is selected from one or more of sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose or cross-linked polyvinylpyrrolidone; the mass percentage of the disintegrant in the composition is 2%-5%; preferably, the mass percentage of the disintegrant in the preparation is 2%, 2.5%, 3%, 3.5%, 4%, 4.5% or 5%;

[0017] The lubricant is selected from one or more of polyethylene glycol 6000 or polyethylene glycol 4000; the mass percentage of the lubricant in the composition is 1-3%; preferably, the mass percentage of the lubricant in the preparation is 1%, 1.5%, 2%, 2.5% or 3%.

[0018] Furthermore, the present invention also provides a method for preparing a composition for relieving oral dryness suitable for head and neck radiotherapy patients. The composition is prepared by the powder direct compression method, and the specific operation steps are as follows: 1) Weigh the compound F, citric acid, menthol, vitamin C, xylitol, filler and disintegrant according to the prescription amount, and pass them through an 80-mesh sieve respectively, and then add them to a three-dimensional mixer for pre-mixing evenly; 2) Weigh the lubricant according to the prescription amount, pass it through an 80-mesh sieve, and then add it to the premixed powder prepared in step 1), continue to mix evenly and then directly compress the tablets.

[0019] Furthermore, the pre-mixing time in step 1) is 15 - 30 min;

[0020] Furthermore, the mixing time in step 2) is 5 - 10 min;

[0021] Furthermore, the tablet weight in step 2) is 50 mg, and the hardness of the compressed tablets is 15 - 30 N.

[0022] Furthermore, the present invention also provides a synthetic route of compound F:

[0023]

[0024] The synthesis steps are as follows:

[0025] 1) Preparation of compound C: Add compound A, compound B and potassium carbonate to the DMSO solution, heat to 90 - 100 °C, stir for 2 - 6 hours. After the reaction is completed, cool to room temperature, dilute the reaction mixture with saturated ammonium chloride aqueous solution, and extract with ethyl acetate. Wash the organic layer with water and saturated brine, dry with anhydrous magnesium sulfate, and distill off the solvent under reduced pressure. Purify the residue by silica gel column chromatography to obtain compound C;

[0026] 2) Preparation of compound E: Add compound C, compound D and sodium dithionite to the DMF solution, heat to 110 - 120 °C, stir for 3 - 6 hours. After cooling to room temperature, add additional sodium dithionite and stir at 100 - 110 °C for 3 - 6 hours. After the reaction is completed, cool to room temperature, dilute with water and saturated sodium bicarbonate aqueous solution, and extract with ethyl acetate. Wash the organic layer with water and saturated brine, dry with anhydrous magnesium sulfate, and distill off the solvent under reduced pressure. Purify the residue by silica gel column chromatography to obtain compound E;

[0027] 3) Stir at room temperature, add sodium hydroxide aqueous solution to the ethanol solution of compound E, and stir at this temperature for 4 - 6 hours. Dilute the reaction mixture with water, neutralize with hydrochloric acid, filter the precipitated precipitate, wash the precipitate with water, and dry to obtain compound F.

[0028] Further, the molar ratio of compound A, compound B and potassium carbonate in step 1) is: 1: 1 - 1.5: 3 - 5; preferably, the molar ratio of compound A, compound B and potassium carbonate in step 1) is: 1: 1.1 - 1.2: 4 - 5; more preferably, the molar ratio of compound A, compound B and potassium carbonate in step 1) is: 1: 1.1: 5;

[0029] Further, the molar ratio of compound C, compound D and sodium dithionite in step 2) is: 1: 1 - 1.5: 4 - 6; preferably, the molar ratio of compound C, compound D and sodium dithionite in step 2) is: 1: 1: 5;

[0030] Further, the concentration of the sodium hydroxide aqueous solution in step 3) is 2M; the concentration of the hydrochloric acid in step 3) is 2M;

[0031] The beneficial effects of the present invention are as follows:

[0032] 1) The present invention provides a composition for relieving oral dryness applicable to head and neck radiotherapy patients. Compound F in the composition is a completely new compound with M3 PAM activity, which can greatly increase the secretion volume of saliva and can effectively treat xerostomia;

[0033] 2) Adding citric acid and vitamin C in the composition provided by the present invention can not only promote the secretion of saliva, but also accelerate the disintegration rate of tablets and can provide nutrition for patients;

[0034] 3) The composition provided by the present invention has few types of excipients, a simple preparation process, and good stability of the prepared tablets. Detailed implementation manners

[0035] The technical solutions of the present invention will be clearly and completely described below in conjunction with the embodiments. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0036] In the following embodiments It is composed of 70% α-lactose monohydrate, 20% microcrystalline cellulose (MCC) and 10% corn starch, and each component meets the requirements of Ph.Eur, USP-NF and JP pharmacopoeias.

[0037] Example 1

[0038] Preparation of compound C:

[0039]

[0040] Weigh 14.25 g of compound A (0.1 mol), 20.49 g of compound B (0.11 mol), and 69.11 g of potassium carbonate (0.5 mol), dissolve them in 500 mL of DMSO solution, heat up to 90 °C, stir for 2 hours. After the reaction is completed, cool to room temperature. Dilute the reaction mixture with saturated ammonium chloride aqueous solution, and extract it with ethyl acetate (300 mL × 3). Combine the organic layers, wash the organic layers with water (300 mL × 1) and saturated brine (300 mL × 1), dry with anhydrous magnesium sulfate, distill off the solvent under reduced pressure, and purify the residue by silica gel column chromatography. The eluent is petroleum ether / ethyl acetate (volume ratio 10 / 1) to obtain 20.7 g of compound C, with a yield of 71%.

[0041] Preparation of compound E:

[0042]

[0043] Take 14.6 g of compound C (0.05 mol), 9.7 g of compound D (0.05 mol) and 21.8 g of sodium dithionite (0.125 mol), dissolve them in 200 mL of DMF solution, heat up to 110 °C, stir for 4 hours. After cooling to room temperature, add an additional 21.8 g of sodium dithionite (0.125 mol), stir at 100 °C for 3 hours. After cooling to room temperature, dilute with water (100 mL × 1) and saturated sodium bicarbonate aqueous solution (200 mL × 1), and extract with ethyl acetate (200 mL × 3). Wash the organic layer with water (200 mL × 1) and saturated brine (200 mL × 1), dry with anhydrous magnesium sulfate, distill off the solvent under reduced pressure, and purify the residue by silica gel column chromatography. The eluent is petroleum ether / ethyl acetate (volume ratio 10 / 1) to obtain 17.3 g of compound E, with a yield of 74%.

[0044] Preparation of compound F:

[0045]

[0046] Take 11.67 g of compound E (0.025 mol) in 60 mL of ethanol solution, add 2 M sodium hydroxide aqueous solution (100 mL) under stirring at room temperature, stir at this temperature for 4 hours. Dilute the reaction mixture with water, then neutralize it with 2 M hydrochloric acid, filter the precipitated precipitate, wash the precipitate with water, and dry to obtain 10.5 g of compound F, with a yield of 96%. MS-ESI: [M+H] + = 439.2, 1H-NMR(400MHz, DMSO-d6): δ(ppm): 13.08 (s, 1H), 12.12 (br, 1H), 8.01 - 8.53 (m, 3H), 7.02 (m, 1H), 3.60 - 3.74 (m, 14H), 3.36 - 3.45 (m, 4H), 2.38 (m, 2H).

[0047] Comparative Example 1

[0048] Preparation of Compound H:

[0049]

[0050] Compound H was prepared according to the method of Patent CN112368282A, and its structure was characterized by mass spectrometry data: MS-ESI: [M+H] + = 708.6.

[0051] Example 2

[0052] Tablet Prescription 1:

[0053] Tablet pressing was carried out according to the material amounts of 20 tablets shown in Table 1, with each tablet containing 5 mg of Compound F;

[0054] Table 1

[0055]

[0056] 1) Weigh Compound F, citric acid, menthol, vitamin C, xylitol, filler, and disintegrant according to the prescription amounts, and pass them through an 80-mesh sieve respectively, then add them to a three-dimensional mixer for pre-mixing for 15 min; 2) Weigh the lubricant according to the prescription amount, pass it through an 80-mesh sieve, and then add it to the premixed powder prepared in step 1), continue to mix for 5 min. After mixing evenly, use a ZP-7A rotary tablet press to directly press the above mixed powder, adjust the tablet weight to 50 mg, and the tablet hardness to 15 - 30 N.

[0057] Example 3

[0058] Tablet Prescription 2:

[0059] Tablet pressing was carried out according to the material amounts of 20 tablets shown in Table 2, with each tablet containing 5 mg of Compound F;

[0060] Table 2

[0061]

[0062]

[0063] 1) Weigh the compound F, citric acid, menthol, vitamin C, xylitol, filler and disintegrant according to the prescription amount, and pass them through an 80-mesh sieve respectively, then add them to a three-dimensional mixer for pre-mixing for 15 min; 2) Weigh the prescription amount of lubricant, pass it through an 80-mesh sieve, then add it to the pre-mixed powder prepared in step 1), continue to mix for 5 min. After mixing evenly, use a ZP-7A rotary tablet press to directly press the above-mentioned mixed powder, adjust the tablet weight to 50 mg, and the tablet hardness to 15 - 30 N.

[0064] Comparative Example 2

[0065] Tablet Comparative Prescription 1:

[0066] Press tablets according to the material amount of 20 tablets shown in Table 3, with each tablet containing 5 mg of compound H;

[0067] Table 3

[0068]

[0069] 1) Weigh the compound H, citric acid, menthol, vitamin C, xylitol, filler and disintegrant according to the prescription amount, and pass them through an 80-mesh sieve respectively, then add them to a three-dimensional mixer for pre-mixing for 15 min; 2) Weigh the prescription amount of lubricant, pass it through an 80-mesh sieve, then add it to the pre-mixed powder prepared in step 1), continue to mix for 5 min. After mixing evenly, use a ZP-7A rotary tablet press to directly press the above-mentioned mixed powder, adjust the tablet weight to 50 mg, and the tablet hardness to 15 - 30 N.

[0070] Comparative Example 3

[0071] Tablet Comparative Prescription 2:

[0072] Press tablets according to the material amount of 20 tablets shown in Table 4, with each tablet containing 5 mg of compound H;

[0073] Table 4

[0074]

[0075] 1) Weigh the compound H, menthol, xylitol, filler and disintegrant according to the prescription amount, and pass them through an 80-mesh sieve respectively, then add them to a three-dimensional mixer for pre-mixing for 15 min; 2) Weigh the prescription amount of lubricant, pass it through an 80-mesh sieve, then add it to the pre-mixed powder prepared in step 1), continue to mix for 5 min. After mixing evenly, use a ZP-7A rotary tablet press to directly press the above-mentioned mixed powder, adjust the tablet weight to 50 mg, and the tablet hardness to 15 - 30 N.

[0076] Example 4

[0077] Disintegration experiment:

[0078] Add about 2 mL of purified water into a flat-bottom test tube with a diameter of about 1.5 cm, control the water temperature at about 37 °C, then add 1 tablet prepared in Example 2-3 and Comparative Example 2-3, let it stand for 60 S, observe and record the time from adding the tablet into the test tube to complete disintegration into powder. A total of 4 batches of samples were tested, and 6 tablets were measured in parallel for each batch of samples. The results are shown in Table 5.

[0079] Table 5 Results of Disintegration Experiment of Tablet Preparations

[0080] Batch number Disintegration time (S) Example 2 34±2S Example 3 26±2S Comparative Example 2 38±2S Comparative Example 3 66±2S

[0081] According to the results in Table 5, it can be seen that the disintegration time limit of the tablets prepared by the present invention is shorter, fully meeting the requirements of the disintegration time limit of orally disintegrating tablets. Without adding citric acid and vitamin C, the disintegration time limit is significantly prolonged, indicating that citric acid and vitamin C can promote the disintegration of tablets.

[0082] Example 5

[0083] Study on Saliva Secretion Volume:

[0084] Healthy male Wistar rats (200 ± 20 g) were used to establish an animal model of radiation-induced xerostomia according to the literature method (Li Bixia, Chen Qianyi, Dai Zhenhui, Ye Jingyun, Wang Wenjing, Chen Shan, Zhang Jiapeng, Chen Peiyi. Establishment of an animal model of radiation-induced xerostomia and biological effects of radioactive tissue injury in submandibular glands. Chinese Journal of Tissue Engineering Research 2017, 21(32): 5164-5169). Eighteen successfully modeled rats were randomly divided into 3 groups, with 6 rats in each group. Equal-volume gavage administration was carried out respectively: the control group was gavaged with a water suspension of the tablets in Comparative Example 2 at 5 mg / rat (calculated by compound H, the same below), and the experimental groups were respectively gavaged with a water suspension of the tablets in Example 2 and 3 at 5 mg / rat (calculated by compound F, the same below). The rats in each group were gavaged for 14 days, once a day. Four hours after the administration ended, a dry cotton ball was placed under the tongue of the rats, and the saliva was absorbed with the cotton ball. Calculate the weight difference of the cotton ball before and after absorbing saliva as the saliva secretion volume data (mg). Compare the differences in saliva secretion volume among the rats in each group. The results are shown in Table 6:

[0085] Table 6 Saliva Secretion Volume

[0086] Group Saliva secretion amount (mg) Control group (Comparative Example 2) 230.46±28.46 Experimental group (Example 2) 348.72±33.28 Experimental group (Example 3) 373.84±40.14

[0087] According to the results in Table 6, it can be seen that the tablets prepared by the present invention can effectively promote saliva secretion, and the effect is significantly better than that of the control group, indicating that the compound F of the present invention has a good effect of promoting saliva secretion.

[0088] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principle of the present invention shall be equivalent replacement methods and are all included in the protection scope of the present invention.

Claims

1. A composition for relieving oral dryness suitable for head and neck radiotherapy patients, comprising: Compound F, citric acid, menthol, vitamin C, xylitol, filler, disintegrant, lubricant; The compound F is selected from the following structures: The mass percentage of the compound F in the composition is 5-10%; The mass percentage of the citric acid in the composition is 1-3%; The mass percentage of the vitamin C in the composition is 1-3%; The mass percentage of the menthol in the composition is 1-3%; The mass percentage of the xylitol in the composition is 1-3%; The filler is selected from: The mass percentage of the filler in the composition is 60-80%; The disintegrant is selected from one or more of sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose or cross-linked polyvinylpyrrolidone; the mass percentage of the disintegrant in the composition is 2%-5%; The lubricant is selected from one or more of polyethylene glycol 6000 or polyethylene glycol 4000; the mass percentage of the lubricant in the composition is 1-3%.

2. The composition according to claim 1, wherein, The mass percentage of the compound F in the composition is 5%, 6%, 7%, 8%, 9% or 10%; The mass percentage of the citric acid in the composition is 1%, 2% or 3%; The mass percentage of the vitamin C in the composition is 1%, 2% or 3%; The mass percentage of the menthol in the composition is 1%, 2% or 3%; The mass percentage of the xylitol in the composition is 1%, 2% or 3%; The mass percentage of the filler in the composition is 60%, 65%, 70%, 75% or 80%; The mass percentage of the disintegrant in the composition is 2%, 2.5%, 3%, 3.5%, 4%, 4.5% or 5%; The mass percentage of the lubricant in the composition is 1%, 1.5%, 2%, 2.5% or 3%.

3. The composition according to claim 1 or 2, wherein, The mass percentage of the compound F in the composition is 10%; The mass percentage of the citric acid in the composition is 1%; The mass percentage of the vitamin C in the composition is 1%; The mass percentage of the menthol in the composition is 1%; The mass percentage of the xylitol in the composition is 2%; The mass percentage of the filler in the composition is 80%; The mass percentage of the disintegrant in the composition is 3%; The mass percentage of the lubricant in the composition is 2%.

4. The composition according to any one of claims 1 or 2, wherein, The disintegrant is selected from: cross-linked sodium carboxymethyl cellulose; The lubricant is selected from: polyethylene glycol 4000.

5. The preparation method of the composition according to any one of claims 1-4, wherein, comprises the following steps: 1) Weigh compound F, citric acid, menthol, vitamin C, xylitol, filler and disintegrant according to the prescription amount, and pass through an 80-mesh sieve respectively, and then add them to a three-dimensional mixer for pre-mixing evenly; 2) Weigh the prescription amount of lubricant, pass through an 80-mesh sieve, and then add it to the premixed powder prepared in step 1), continue to mix evenly and then directly press tablets.

6. The preparation method according to claim 5, wherein, The pre-mixing time in the step 1) is 15-30 min; The mixing time in step 2) is 5 - 10 min; the tablet weight in step 2) is 50 mg, and the hardness of the tablet is 15 - 30 N.

7. A method for preparing compound F, characterized in that the synthesis route is: The specific synthesis steps are as follows: 1) Preparation of compound C: Add compound A, compound B and potassium carbonate to DMSO solution, heat to 90 - 100 °C, stir for 2 - 6 hours. After the reaction is completed, cool to room temperature, dilute the reaction mixture with saturated ammonium chloride aqueous solution, and extract with ethyl acetate; wash the organic layer with water and saturated brine, dry with anhydrous magnesium sulfate, and distill off the solvent under reduced pressure; purify the residue by silica gel column chromatography to obtain compound C; 2) Preparation of compound E: Add compound C, compound D and sodium dithionite to DMF solution, heat to 110 - 120 °C, stir for 3 - 6 hours. After cooling to room temperature, add additional sodium dithionite and stir at 100 - 110 °C for 3 - 6 hours. After the reaction is completed, cool to room temperature, dilute with water and saturated sodium bicarbonate aqueous solution, and extract with ethyl acetate. Wash the organic layer with water and saturated brine, dry with anhydrous magnesium sulfate, distill off the solvent under reduced pressure, and purify the residue by silica gel column chromatography to obtain compound E; 3) Stir at room temperature, add aqueous sodium hydroxide solution to the ethanol solution of compound E, and stir at this temperature for 4 - 6 hours; Dilute the reaction mixture with water, neutralize with hydrochloric acid, filter the precipitated precipitate, wash the precipitate with water, and dry to obtain compound F.

8. The preparation method according to claim 7, characterized in that: The molar ratio of compound A, compound B and potassium carbonate in step 1) is: 1:1 - 1.5:3 - 5; the molar ratio of compound C, compound D and sodium dithionite in step 2) is: 1:1 - 1.5:4 - 6; the concentration of the aqueous sodium hydroxide solution in step 3) is 2 M; the concentration of hydrochloric acid in step 3) is 2 M.

9. The preparation method according to claim 8, characterized in that: The molar ratio of compound A, compound B and potassium carbonate in step 1) is: 1:1.1:5; the molar ratio of compound C, compound D and sodium dithionite in step 2) is: 1:1:5.

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