High-water-solubility taste masking agent as well as preparation method and application thereof

Abstract

The invention discloses a taste masking agent with high water solubility, the chemical structural formula of the taste masking agent is shown in the specification, and the taste masking agent is cationic ring-opened cucurbituril prepared by taking urea, 1, 3-butanedione, paraformaldehyde and N-methyl piperazine as raw materials; the taste masking agent disclosed by the invention has a good taste masking effect on a bitter drug quinine, is simple and convenient to prepare, has the outstanding advantages of good taste masking effect, high water solubility and the like, and can be developed into an efficient bitter drug taste masking agent; # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a highly water-soluble taste-masking agent and a preparation method thereof, and application of the taste-masking agent in masking the bitter taste of medicines. Background Art

[0002] In order to improve the quality of life, people attach great importance to drug compliance, and the taste of drugs is an important factor affecting patients' compliance. Many oral drugs have unpleasant tastes such as bitterness, which greatly reduces patients' acceptance of the drug. Any formulation prescription will definitely be better than similar competing products if it tastes good. Therefore, improving unpleasant taste is a key issue in the formulation design and development of many drugs. The development of taste masking technology is of great significance to improving patient compliance and its clinical efficacy.

[0003] In recent years, various taste-masking technologies have been widely used in clinical practice. With the development of taste-masking technology, the use of macrocyclic molecules in the form of supramolecular encapsulation to eliminate the bitterness of bitter drugs has gradually become a research hotspot. The combination of macrocyclic molecules and drugs can hinder the interaction between bitter drug molecules and taste receptors, thereby eliminating or reducing bad taste (Pharm. Res. 2014, 31, 2921-2939). At the same time, supramolecular encapsulation is also conducive to the complete release of drugs without being destroyed, and can produce sustained release and controlled release effects through molecular design, so it has greater application potential than other taste-masking technologies. Based on this strategy, a variety of macrocyclic molecules have been studied as taste-masking agents. For example, cyclodextrin is a water-soluble and biocompatible macrocyclic molecule that is used as a taste-masking agent to mask the bitterness of drugs. However, the binding affinity between cyclodextrin and drugs is low, which is not enough to effectively mask the bitter taste (Eur. J. Pharm. Biopharm. 2005, 61, 115-125). Cucurbiturils (CB[n]s), especially CB[7] and CB[8], are widely used in pharmaceutical and biomedical fields (Coord.Chem.Rev.2021,434,213733.). However, the application of CB[n]s in the field of pharmaceutical preparations is limited by its poor water solubility (for CB[8]) and the difficulty of its modification and separation. In 2010, the Isaacs group developed open-ring cucurbiturils (ACBs), which have a large cavity, good water solubility, and can form stable host-guest complexes with drugs (J.Org.Chem.2010,75,4786-4795). However, the existing open-ring cucurbiturils have obvious shortcomings when used as masking agents, such as the inability to better encapsulate typical bitter drugs such as quinine, thereby failing to mask their bitterness (ChemPlusChem.2023,88,e202300465.).

[0004] Quinine is a classic drug used to treat and prevent malaria and can treat pyromaniasis, but it has a very strong bitter taste when taken orally, which has a great negative impact on drug compliance, thus greatly limiting its use. Summary of the invention

[0005] In view of the problems existing in the prior art, the present invention provides a highly water-soluble taste masking agent, the chemical structure of which is as follows:

[0006] The structural formula of taste masking agent Y1 is as follows:

[0007]

[0008] The structural formula of taste masking agent Y2 is as follows:

[0009]

[0010] Another object of the present invention is to provide a method for preparing the above-mentioned taste masking agent:

[0011] 1. Preparation of taste masking agent Y1

[0012] (1) Urea is dissolved in 0.3 mol / L hydrochloric acid, and then 1,3-butanedione is added thereto, and stirred at room temperature for 12 hours. After the reaction is completed, a white crude product is obtained by filtration, and the product is purified to obtain methylated glycoluril, wherein the molar ratio of 1,3-butanedione to urea is 1:2-4;

[0013]

[0014] (2) dissolving the methylated glycoluril in 9 mol / L hydrochloric acid, adding paraformaldehyde, stirring and reacting at room temperature for 24 hours, filtering after the reaction to obtain a white crude product, and purifying to obtain etherified methylated glycoluril, wherein the molar ratio of the methylated glycoluril to the paraformaldehyde is 1:4-6;

[0015]

[0016] (3) dissolving glycoluril in 8 mol / L hydrochloric acid, adding paraformaldehyde, reacting at 50°C for 48 hours, filtering after the reaction, and purifying to obtain a dimer, wherein the molar ratio of glycoluril to paraformaldehyde is 1:1-2;

[0017]

[0018] (4) adding the dimer and etherified methylated glycoluril to anhydrous methane sulfonic acid, reacting at 50° C. for 3 h, cooling the reaction solution to room temperature, and purifying to obtain a tetramer, wherein the molar ratio of the dimer to the etherified methylated glycoluril is 1:4-6;

[0019]

[0020] (5) adding 1,4-di(2-hydroxyethoxy)benzene and triphenylphosphine to anhydrous acetonitrile, adding carbon tetrabromide under ice bath conditions, reacting at room temperature for 4 hours, and purifying after the reaction to obtain 1,4-di(2-bromoethoxy)benzene, wherein the molar ratio of 1,4-di(2-hydroxyethoxy)benzene to triphenylphosphine is 1:2-4, and the molar ratio of carbon tetrabromide to 1,4-di(2-hydroxyethoxy)benzene is 1:0.25-0.5;

[0021]

[0022] (6) adding the tetramer and 1,4-di(2-bromoethoxy)benzene to trifluoroacetic acid, reacting at 70° C. for 3 h, cooling the reaction solution, distilling under reduced pressure, and purifying to obtain tetrabromo-opened cucurbituril X1, wherein the molar ratio of the tetramer to 1,4-di(2-bromoethoxy)benzene is 1:2-4;

[0023]

[0024] (7) adding anhydrous potassium carbonate (or potassium hydroxide), N-methylpiperazine and X1 to dimethyl sulfoxide, reacting at 80° C. for 3 h, cooling the reaction solution to room temperature, filtering, adding 6 mol / L hydrochloric acid to the filtrate to adjust the pH to 1, then counterprecipitating with acetone, and collecting the precipitate by centrifugation to obtain diphenyltetrakis N-methylpiperazine open-ring cucurbituril Y1, wherein the molar ratio of anhydrous potassium carbonate (or potassium hydroxide) to N-methylpiperazine is 1:0.8-1.2, and the molar ratio of X1 to N-methylpiperazine is 1:5-7;

[0025]

[0026] 2. Preparation of taste masking agent Y2

[0027] (1) dissolving 1,4-naphthoquinone in ethyl acetate, adding sodium dithionite solution under stirring, reacting for 3 hours at 30° C. under nitrogen protection, cooling the reaction solution to room temperature, extracting with ethyl acetate, combining the organic phases, and drying them to obtain 1,4-naphthoquinone, wherein the concentration of the sodium dithionite solution is 0.8 mol / L, and the molar ratio of 1,4-naphthoquinone to sodium dithionite is 1:4-6;

[0028]

[0029] (2) adding 1,4-naphthalene diol to 1,2-dibromoethane, adding tetrabutylammonium bromide and sodium hydroxide aqueous solution under stirring, reacting for 12 hours at 80° C. under nitrogen protection, cooling the reaction solution to room temperature, separating the organic phase and the aqueous phase, concentrating the organic phase under reduced pressure, adding the concentrate to acetone for precipitation, filtering and discarding the filtrate, washing the filter cake with acetone and drying to obtain 1,4-bis(2-bromoethoxy)naphthalene, wherein the concentration of the sodium hydroxide aqueous solution is 2 mol / L, the molar ratio of 1,4-naphthalene diol to 1,2-dibromoethane is 1:25-30, the molar ratio of tetrabutylammonium bromide to 1,4-naphthalene diol is 1:15-20, and the molar ratio of 1,4-naphthalene diol to sodium hydroxide is 1:5-7;

[0030]

[0031] (3) adding the tetramer and 1,4-di(2-bromoethoxy)naphthalene to trifluoroacetic acid, reacting at 70° C. for 3 h, cooling the reaction solution, distilling under reduced pressure, and purifying to obtain tetrabromo-opened cucurbituril X2, wherein the molar ratio of the tetramer to 1,4-di(2-bromoethoxy)naphthalene is 1:2-4;

[0032]

[0033] (4) adding anhydrous potassium carbonate (or potassium hydroxide), N-methylpiperazine and X2 to dimethyl sulfoxide, reacting at 80° C. for 3 h, cooling the reaction solution to room temperature, filtering, adding 6 mol / L hydrochloric acid to the filtrate to adjust the pH to 1, then counterprecipitating with acetone, and collecting the precipitate by centrifugation to obtain a taste masking agent Y1, wherein the molar ratio of anhydrous potassium carbonate (or potassium hydroxide) to N-methylpiperazine is 1:0.8-1.2, and the molar ratio of X2 to N-methylpiperazine is 1:5-7;

[0034]

[0035] 3. Preparation of Quinine Taste Masking Agent

[0036] (1) dissolving the taste masking agent in water to prepare an aqueous solution at 20 to 40° C., wherein the mass ratio of the taste masking agent to water is 1:10 to 1:15;

[0037] (2) Add quinine to an aqueous solution of a taste-masking agent at 20 to 40° C., stir vigorously for 48 hours, stop the reaction, separate the reaction solution into a solid-liquid solution through a membrane, and freeze-dry the solution in a vacuum to obtain a quinine taste-masking agent; wherein the molar ratio of quinine to the taste-masking agent is 1.5:1 to 3:1.

[0038] Advantages and technical effects of the present invention:

[0039] The reagents used in the invention are all cheap and easily available, the experimental method is simple, the taste-masking agent increases the stability of quinine, and the taste-masking agent of the invention has the advantages of good water solubility, good taste-masking effect, etc., and is expected to improve the use prospects of bitter oral drugs. DETAILED DESCRIPTION

[0040] The method described in the present invention is further described below by examples, but the protection scope of the present invention is not limited by the examples. The reagents used in the present examples are conventional commercially available reagents or reagents prepared by conventional methods unless otherwise specified, and the methods used are conventional methods unless otherwise specified.

[0041] Example 1: Preparation of taste masking agent Y1

[0042] (1) Weigh 10.0 g (170 mmol) of urea and dissolve it in hydrochloric acid (0.3 M, 30 mL), add 5.0 g (58 mmol) of 1,3-butanedione under stirring, stir at room temperature for 12 h, filter the reaction solution to collect the solid, wash the solid with water twice (500 mL × 2), filter the solid, and dry it in a vacuum dryer at 40° C. for 6 h to obtain methylated glycoluril;

[0043] (2) 4.5 g (26 mmol) of methylated glycoluril was dissolved in hydrochloric acid (9 mol / L, 25 mL), and 4.0 g (135 mmol) of paraformaldehyde was slowly added under stirring. The mixture was reacted at room temperature for 24 h. The reaction solution was filtered to collect the solid, and the solid was washed with water 3 times (500 mL × 3). The solid was filtered to obtain the solid, and dried in a vacuum oven at 40°C for 6 h to obtain etherified methylated glycoluril.

[0044] (3) 10.0 g (70 mmol) of glycoluril was dissolved in hydrochloric acid (8 mol / L, 30 mL), and 2.1 g (70 mmol) of paraformaldehyde was slowly added under stirring, and the mixture was reacted at 50° C. for 48 h. The reaction solution was filtered to collect the solid, and the solid was washed with water several times until it was neutral. The solid was filtered to obtain the solid, and then dried in a vacuum oven at 40° C. for 6 h to obtain a dimer;

[0045] (4) 2.2 g (7 mmol) of dimer and 7.6 g (30 mmol) of etherified methylated glycoluril were added to 15 mL of anhydrous methane sulfonic acid, and the reaction solution was reacted at 50 °C for 3 h. The reaction solution was cooled to room temperature and dropped into 150 mL of acetone and stirred for 2 h. The solid was collected by filtration, washed twice with acetone (100 mL × 2) and washed twice with water (100 mL × 2). The solid was filtered and dried in a vacuum oven at 40 °C for 6 h to obtain a tetramer.

[0046] (5) 10.0 g (50 mmol) of 1,4-bis(2-hydroxyethoxy)benzene and 31.5 g (120 mmol) of triphenylphosphine were added to 250 mL of anhydrous acetonitrile, and the mixture was stirred in an ice bath at 0°C. 40.0 g (121 mmol) of carbon tetrabromide was added in batches and stirred at room temperature for 4 h. After the reaction was completed, the reaction solution was added to 200 mL of ice water and stirred for 1 h. The solid was collected by filtration, and the solid was washed with methanol-water (3:2, 100 mL×3), and then washed with 100 mL of methanol. The solid was filtered and dried in a vacuum oven at 40°C for 6 h to obtain 1,4-bis(2-bromoethoxy)benzene;

[0047] (6) 3.2 g (4 mmol) of the tetramer was added to 35 mL of trifluoroacetic acid, and 4.6 g (14 mmol) of 1,4-bis(2-bromoethoxy)benzene was added under stirring. The mixture was stirred at 70° C. for 3 h. The reaction solution was cooled to room temperature, and the trifluoroacetic acid was removed by distillation under reduced pressure. The solid was washed with 300 mL of methanol and 300 mL of acetonitrile, respectively. The solid was filtered and dried under vacuum at 40° C. for 6 h to obtain tetrabromo-opened cucurbituril X1.

[0048] (7) 0.3 g (2 mmol) of anhydrous potassium carbonate and 0.245 mL (2 mmol) of N-methylpiperazine were added to 5 mL of dimethyl sulfoxide, and 0.5 g (0.4 mmol) of X1 was added under stirring, and the mixture was reacted at 80°C for 3 h. The reaction solution was cooled to room temperature, filtered, and the filtrate was added with 6 mol / L hydrochloric acid to adjust the pH to 1, and then precipitated with 50 mL of acetone, and the precipitate was collected by centrifugation, dissolved with a minimum amount of water, and precipitated with 20 mL of acetone. After the precipitate was collected by centrifugation, the precipitation step was repeated twice, and the precipitate was dried in a vacuum oven at 40°C for 6 h to obtain the taste masking agent Y1;

[0049] Product hydrogen spectrum: 1 H NMR (600MHz, D2O): δ7.02(s,4H),5.57-5.20(m,14H),4.23-4.09(m,16H),3.24-2.33(m,42H),2.01(s,12H),1.67(d,12H). Carbon spectrum: 13 C NMR (150MHz, D2O): δ160.17, 156.82, 155.90, 150.19, 128.50, 124.58, 155.22, 78.87, 77.63, 71.25, 67.03, 55.75, 52.91, 49.84, 48.62, 42.94, 35.19, 15.93, 14.98. HR-MS: Calcd.forC 70 H 104 N 24 O 12 4+,368.2061; found,368.2061[M-4Cl - ] 4+ ;Calcd.for C 70 H 103 N 24 O 12 3+ ,490.6057; found,490.6044[M-3Cl - ] 3+ ;Calcd.for C 70 H 102 N 24 O 12 2+ ,735.4049; found,735.4046[M-2Cl - ] 2+ .

[0050] Example 2: Preparation of taste masking agent Y2

[0051] (1) 10.0 g (63 mmol) of 1,4-naphthoquinone was dissolved in 250 mL of ethyl acetate solution, and sodium dithionite solution (50.0 g (287 mmol) dissolved in 350 mL of water) was added under stirring, and the mixture was reacted at 30° C. for 3 h under nitrogen protection. The reaction solution was cooled to room temperature, extracted with ethyl acetate, and the organic phases were combined and dried to obtain 1,4-naphthalenediol;

[0052] (2) 10.0 g (63 mmol) of 1,4-naphthalenediol was added to 150 mL of 1,2-dibromoethane, and an aqueous sodium hydroxide solution (15.0 g (375 mmol), 1.2 g (3.72 mmol) of tetrabutylammonium bromide, dissolved in 160 mL of water) was added under stirring, and the mixture was reacted at 80° C. under nitrogen protection for 12 h. The reaction solution was cooled to room temperature, and the organic phase and the aqueous phase were separated. The organic phase was concentrated under reduced pressure, and the concentrated solution was added to 100 mL of acetone for precipitation. The filtrate was filtered and discarded. The filter cake was washed with acetone and dried in a vacuum oven at 40° C. for 6 h to obtain 1,4-bis(2-bromoethoxy)naphthalene;

[0053] (3) 3.0 g (4 mmol) of the tetramer was added to 35 mL of trifluoroacetic acid, and 5.0 g (13 mmol) of 1,4-bis(2-bromoethoxy)naphthalene was added under stirring. The mixture was stirred at 70° C. for 3 h. The reaction solution was cooled to room temperature, and the trifluoroacetic acid was removed by distillation under reduced pressure. The solid was washed with 300 mL of methanol and 300 mL of acetonitrile, respectively, and the solid was filtered and dried under vacuum at 40° C. for 6 h to obtain tetrabromo-opened cucurbituril X2.

[0054] (4) 0.3 g (2 mmol) of anhydrous potassium carbonate and 0.225 mL (2 mmol) of N-methylpiperazine were added to 5 mL of dimethyl sulfoxide, and 0.5 g (0.3 mmol) of X2 was added under stirring. The reaction was carried out at 80°C for 3 h. The reaction solution was cooled to room temperature and filtered. 6 mol / L hydrochloric acid was added to the filtrate to adjust the pH to 1. The precipitate was then precipitated with 50 mL of acetone, and the precipitate was collected by centrifugation. The precipitate was dissolved with a minimum amount of water, and precipitated with 20 mL of acetone. After the precipitate was collected by centrifugation, the above steps were repeated twice. The precipitate was dried in a vacuum oven at 40°C for 6 h to obtain a taste masking agent Y2.

[0055] Product hydrogen spectrum: 1 H NMR (600MHz, D2O): δ7.91(m,4H),7.63(s,4H),5.45-5.19(m,14H),4.26-3.78(m,22H),3.50-2.34(m,44H),2.04(s,4H),1.68(d,12H). Carbon spectrum: 13 C NMR (150MHz, D2O): δ160.19, 156.80, 155.87, 148.34, 127.84, 127.47, 124.58, 122.82, 78.80, 77.63, 71.27, 57.40, 56.15, 53.04, 49.60, 48.62, 42.69, 36.21, 14.71. HR-MS: Calcd. for C 70 H 104 N 24 O 12 4+ ,393.2139; found,393.2135[M-4Cl - ] 4+ ;Calcd.For C 70 H 103 N 24 O 12 3 + ,523.9495; found,523.9491[M-3Cl - ] 3+ ;Calcd.for C 70 H 102 N 24 O 12 2+ ,785.4206; found,785.4200[M-2Cl - ] 2+ .

[0056] Example 3: Preparation of Quinine Taste Masking Agent

[0057] (8) Dissolve 40.0 mg (0.02 mmol) of Y1 in 0.5 mL of water, add 16.0 mg (0.05 mmol) of quinine under stirring, react at room temperature for 48 h, filter, collect the filtrate, and lyophilize in vacuo to obtain quinine inclusion complex Q / Y1.

[0058] (5) 40.0 mg (0.02 mmol) of Y2 was dissolved in 0.5 mL of water, and 15.0 mg (0.05 mmol) of quinine was added under stirring. The reaction solution was reacted at room temperature for 48 h, filtered, and the filtrate was collected and freeze-dried in vacuo to obtain quinine inclusion complex Q / Y2.

[0059] Example 4: Determination of water solubility of taste masking agents

[0060] In this example, the saturated aqueous solution method was used to determine the water solubility of the taste masking agent, i.e., the cationic open-ring cucurbituril.

[0061] 3 mL of ultrapure water was added to the reaction bottle, and an excess of cationic open-ring cucurbituril Y1 or Y2 was added to ensure that it could not be completely dissolved, and stirred at room temperature for 72 h. The mixture was filtered using a 0.22 μm microporous membrane, and 1 mL of the filtrate was freeze-dried to obtain a solid powder. The mass of the solid powder was weighed to obtain the water solubility of the cationic open-ring cucurbituril. The test results are shown in Table 1.

[0062] Table 1

[0063]

[0064] Example 5: Electronic tongue experiment

[0065] The analysis system used in this analysis is the bitter drug analysis system ANO and BTO, which has 2 sensors and 1 standard electrode. The sensors are activated and calibrated before testing.

[0066] 1. Test fluid:

[0067] Reference solution (reference saliva): 30 mM potassium chloride + 0.3 mM tartaric acid;

[0068] Negative electrode cleaning solution: 100mM hydrochloric acid + 30% volume ethanol;

[0069] Positive electrode cleaning solution: 10 mM potassium hydroxide + 100 mM potassium chloride + 30% volume ethanol;

[0070] Sample solution preparation: Prepare the sample to be tested into 50 mL of a solution with a concentration of 50 μM;

[0071] 2. SA402B electronic tongue test:

[0072] Balance: The sensor is first cleaned in the cleaning solution for 90 seconds, then in the reference solution for 120 seconds, and then in another reference solution for 120 seconds. The sensor is reset to zero at the equilibrium position for 30 seconds. Test: The test time is 30 seconds, and the first taste value is output. After the reference solution is cleaned for 3 seconds, the sensor is inserted into the new reference solution to test the aftertaste for 30 seconds. Drug bitter sensor ANO and BTO test;

[0073] The test results are shown in Table 2. The data include two types of bitterness: base salt bitterness and alkaline bitterness. The data size indicates the degree of bitterness. The larger the data, the greater the bitterness. It can be seen from the table that the data of taste masking agent Y1 and taste masking agent Y2 are close to 0 or negative values, indicating that they have no bitterness and are good taste masking agents. The data of quinine inclusion complex (Q / Y1, Q / Y2) are close to 0 or negative values, confirming that the two cationic open-ring cucurbiturils have good taste masking effects.

[0074] Table 2

[0075]

Claims

1. A highly water-soluble taste masking agent, whose chemical structural formula is as follows:

2. The method for preparing the taste masking agent according to claim 1, characterized in that: At room temperature, an inorganic base and N-methylpiperazine are dissolved in dimethyl sulfoxide to prepare a mixed solution; tetrabromo-opened cucurbituril is added to the mixed solution, stirred at 70-90° C. for 3 hours, cooled to room temperature, and filtered; the filtrate is added to acetone, centrifuged to obtain a precipitate; the precipitate is dissolved in water, and then placed in acetone for precipitation, and the precipitation step is repeated twice, and the precipitate is vacuum dried to obtain a taste masking agent; The tetrabromo-opened cucurbituril structural formula is as follows:

3. The method for preparing the taste masking agent according to claim 2, characterized in that: The inorganic base is one of potassium hydroxide and anhydrous potassium carbonate; the molar ratio of the inorganic base to N-methylpiperazine is 1:0.8-1.

2.

4. The method for preparing the taste masking agent according to claim 2, characterized in that: The molar ratio of N-methylpiperazine to tetrabromo-opened ring cucurbituril is 5:1-7:

1.

5. Use of the highly water-soluble taste-masking agent according to claim 1 in masking the bitter taste of medicines.

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