A highly water-soluble taste-masking agent and its preparation method and application

Abstract

The present invention discloses a highly water-soluble taste-masking agent, the chemical structural formula of which is shown below. The taste-masking agent of the present invention is a cationic open-ring cucurbituril prepared using urea, 1,3-butanedione, paraformaldehyde, and N-methylpiperazine as raw materials. The taste-masking agent of the present invention has a good taste-masking effect on the bitter drug quinine. The taste-masking agent is easy to prepare and has outstanding advantages such as good taste-masking effect and high water solubility. The agent can be developed into a highly effective taste-masking agent for bitter drugs.

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, a preparation method thereof, and application of the taste-masking agent in masking the bitterness of medicines. Background Art

[0002] To improve quality of life, people attach great importance to medication compliance, and drug taste is a key factor influencing patient compliance. Many oral medications produce unpleasant tastes, such as bitterness, which significantly reduces patient acceptance. Any formulation with excellent taste will undoubtedly outperform competing products. Therefore, improving unpleasant taste is a key issue in formulation design and development for many drugs. The development of taste-masking technology is crucial for improving patient compliance and clinical efficacy.

[0003] In recent years, various taste-masking technologies have been widely used in clinical practice. With the development of taste-masking technologies, the use of macrocyclic molecules in supramolecular encapsulation to eliminate the bitterness of bitter drugs has gradually become a research hotspot. The binding of macrocyclic molecules to drugs can hinder the interaction between bitter drug molecules and taste receptors, thereby eliminating or reducing the unpleasant taste (Pharm. Res. 2014, 31, 2921-2939). Furthermore, supramolecular encapsulation facilitates the intact release of drugs without destruction and can achieve sustained and controlled release through molecular design, thus offering 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, a water-soluble and biocompatible macrocyclic molecule, has been used as a taste-masking agent to mask the bitter taste of drugs. However, the binding affinity between cyclodextrin and drugs is low, insufficient 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 taste masking agents, such as the inability to better encapsulate typical bitter drugs such as quinine, thereby failing to mask their bitter taste (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 significant negative impact on drug compliance, greatly limiting its use. Summary of the Invention

[0005] In response to 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 was dissolved in 0.3 mol / L hydrochloric acid, and then 1,3-butanedione was added thereto, and the mixture was stirred at room temperature for 12 h. After the reaction was completed, a white crude product was obtained by filtration, and the crude product was purified to obtain methylated glycoluril, wherein the molar ratio of 1,3-butanedione to urea was 1:2-4;

[0013]

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

[0015]

[0016] (3) dissolving glycoluril in 8 mol / L hydrochloric acid, adding paraformaldehyde, reacting at 50°C for 48 h, 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 methanesulfonic acid, reacting at 50°C for 3 hours, 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-bis(2-hydroxyethoxy)benzene and triphenylphosphine to anhydrous acetonitrile, adding carbon tetrabromide in an ice bath, reacting at room temperature for 4 hours, and purifying after the reaction to obtain 1,4-bis(2-bromoethoxy)benzene, wherein the molar ratio of 1,4-bis(2-hydroxyethoxy)benzene to triphenylphosphine is 1:2-4, and the molar ratio of carbon tetrabromide to 1,4-bis(2-hydroxyethoxy)benzene is 1:0.25-0.5;

[0021]

[0022] (6) The tetramer and 1,4-bis(2-bromoethoxy)benzene were added to trifluoroacetic acid and reacted at 70°C for 3 h. After the reaction, the reaction solution was cooled, distilled under reduced pressure, and purified to obtain tetrabromo-opened cucurbituril X1, wherein the molar ratio of the tetramer to 1,4-bis(2-bromoethoxy)benzene was 1:2-4;

[0023]

[0024] (7) Anhydrous potassium carbonate (or potassium hydroxide), N-methylpiperazine, and X1 are added to dimethyl sulfoxide, reacted at 80°C for 3 hours, the reaction solution is cooled to room temperature, filtered, and the filtrate is added with 6 mol / L hydrochloric acid to adjust the pH to 1, and then reverse precipitation is performed with acetone, and the precipitate is collected by centrifugation to obtain bisphenyltetrakis 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) 1,4-naphthoquinone was dissolved in ethyl acetate, sodium dithionite solution 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-naphthoquinone, wherein the concentration of the sodium dithionite solution was 0.8 mol / L, and the molar ratio of 1,4-naphthoquinone to sodium dithionite was 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 at 80° C. for 12 h 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-bis(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 ring cucurbituril X2, wherein the molar ratio of the tetramer to 1,4-bis(2-bromoethoxy)naphthalene is 1:2-4;

[0032]

[0033] (4) Anhydrous potassium carbonate (or potassium hydroxide), N-methylpiperazine, and X2 are added to dimethyl sulfoxide, reacted at 80°C for 3 hours, the reaction solution is cooled to room temperature, filtered, and the filtrate is adjusted to pH 1 by adding 6 mol / L hydrochloric acid. The filtrate is then precipitated with acetone and the precipitate is collected 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 20-40° C., wherein the mass ratio of the taste masking agent to water is 1:10-1:15;

[0037] (2) Add quinine to an aqueous solution of a taste-masking agent at 20-40° 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 present 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 present invention has the advantages of good water solubility and good taste-masking effect, 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 way of examples, but the scope of protection of the present invention is not limited by the examples. Unless otherwise specified, the reagents used in the examples are conventional commercial reagents or reagents prepared according to conventional methods, 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 with stirring, and stir at room temperature for 12 h. Filter the reaction solution to collect the solid, wash the solid twice with water (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 with stirring. The mixture was reacted at room temperature for 24 h. The solid was collected by filtration and washed with water three times (500 mL × 3). The solid was filtered and dried in a vacuum oven at 40 °C for 6 h to obtain etherified methylated glycoluril.

[0044] (3) Dissolve 10.0 g (70 mmol) of glycoluril in hydrochloric acid (8 mol / L, 30 mL), slowly add 2.1 g (70 mmol) of paraformaldehyde with stirring, and react at 50°C for 48 h. Filter the reaction solution to collect the solid, wash the solid several times with water until neutral, filter the solid, and dry it in a vacuum dryer 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 methanesulfonic acid. The reaction solution was reacted at 50 °C for 3 h. The reaction solution was cooled to room temperature and added dropwise to 150 mL of acetone and stirred for 2 h. The solid was collected by filtration and washed twice with acetone (100 mL × 2) and twice with water (100 mL × 2). The solid was filtered and dried in a vacuum oven at 40 °C for 6 h to obtain the 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, the reaction solution was added to 200 mL of ice water and stirred for 1 h. The solid was collected by filtration and washed with methanol-water (3:2, 100 mL × 3) and then 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 in a vacuum oven 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 with stirring. The mixture was reacted at 80°C for 3 h. The reaction solution was cooled to room temperature and filtered. The filtrate was adjusted to pH 1 by adding 6 mol / L hydrochloric acid. The precipitate was then collected by centrifugation, dissolved in a minimum amount of water, and precipitated with 20 mL of acetone. The precipitate was collected by centrifugation and the precipitation step was repeated twice. 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 (150 MHz, 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. High resolution mass spectrometry HR-MS: Calcd. for C 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 with stirring. The mixture was reacted at 30° C. under nitrogen protection for 3 h. The reaction solution was cooled to room temperature and extracted with ethyl acetate. The organic phases were combined and dried to obtain 1,4-naphthodiol.

[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. 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 concentrate 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 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 in a vacuum oven 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 mixture was reacted at 80°C for 3 h. The reaction solution was cooled to room temperature and filtered. The filtrate was added with 6 mol / L hydrochloric acid to adjust the pH to 1. The mixture was then precipitated with 50 mL of acetone, and the precipitate was collected by centrifugation. The mixture was dissolved with a minimum amount of water, and precipitated with 20 mL of acetone. The precipitate was collected by centrifugation and the above steps were repeated twice. The precipitate was dried in a vacuum oven at 40°C for 6 h to obtain the 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 (150 MHz, 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. High resolution mass spectrometry 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 with stirring, and react at room temperature for 48 h. Filter, collect the filtrate, and lyophilize in vacuo to obtain quinine inclusion complex Q / Y1.

[0058] (5) Dissolve 40.0 mg (0.02 mmol) of Y2 in 0.5 mL of water, add 15.0 mg (0.05 mmol) of quinine with stirring, and react at room temperature for 48 h. Filter, collect the filtrate, and lyophilize 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, namely the cationic open-ring cucurbituril.

[0061] 3 mL of ultrapure water was added to a reaction flask, and an excess of cationic open-ring cucurbituril Y1 or Y2 was added to ensure that it could not be completely dissolved. The mixture was stirred at room temperature for 72 h, filtered using a 0.22 μm microporous filter membrane, and 1 mL of the filtrate was lyophilized 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 two sensors and one 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 50 mL of the sample to be tested into a solution with a concentration of 50 μM;

[0071] 2. SA402B electronic tongue test:

[0072] Balance: The sensor is first cleaned in cleaning solution for 90 seconds, then in reference solution for 120 seconds, and then in another reference solution for another 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 a new reference solution to test the aftertaste for 30 seconds. Drug bitterness sensor ANO and BTO tests are also performed.

[0073] The test results are shown in Table 2. The data include both basic salt bitterness and alkaline bitterness. The data size indicates the degree of bitterness; larger data values ​​indicate greater bitterness. The table shows that the data for taste masking agents Y1 and Y2 are close to 0 or negative, indicating they lack bitterness and are excellent taste masking agents. The data for quinine inclusion complexes (Q / Y1 and Q / Y2) are close to 0 or negative, confirming that the two cationic open-ring cucurbiturils have excellent taste masking effects.

[0074] Table 2

[0075]

Claims

1. A highly water-soluble taste masking agent, the chemical structure of which is as follows:

2. The method for preparing the taste masking agent according to claim 1, wherein: 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 and centrifuged to obtain a precipitate; the precipitate is dissolved in water, then precipitated in acetone, and the precipitation step is repeated twice. The precipitate is vacuum dried to obtain a taste masking agent; The tetrabromo-opened ring cucurbituril structural formula is as follows:

3. The method for preparing the taste masking agent according to claim 2, wherein: The inorganic base is one of potassium hydroxide and anhydrous potassium carbonate; and 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, wherein: The molar ratio of N-methylpiperazine to tetrabromo-opened ring cucurbituril is 5:1 to 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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