CN115969993A - Traditional Chinese medicine taste-masking compound, preparation and preparation method - Google Patents
Traditional Chinese medicine taste-masking compound, preparation and preparation method Download PDFInfo
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Abstract
The invention belongs to the technical field of traditional Chinese medicines, and particularly relates to a traditional Chinese medicine taste masking compound, a preparation and a preparation method. The compound comprises: bitter Chinese medicine, taste-masking agent and adjuvant, wherein the bitter Chinese medicine is flavone glycoside medicine and/or alkaloid medicine, the taste-masking agent comprises chitosan, and the flavone glycoside medicine is selected from one or more of phillyrin, baicalin, amygdalin, quercetin and rutin; the alkaloid medicine is selected from one or more of berberine, caffeine, quinine and ephedrine, and the adjuvant comprises sodium hydroxide solution or sodium tripolyphosphate solution. The invention provides a taste masking preparation mixed with one or more bitter Chinese medicinal components, which solves the technical problem that the bitter Chinese medicinal components or a plurality of bitter Chinese medicinal composition components are difficult to mask taste; the technology is also suitable for taste masking of children medicine, and solves the problems of poor compliance of children patients in medicine taking and difficulty in medicine taking.
Description
Technical Field
The invention belongs to the technical field of traditional Chinese medicines, and particularly relates to a traditional Chinese medicine taste masking compound, a preparation and a preparation method.
Background
It is known that most of oral medicines, especially traditional Chinese medicine oral medicines, have bitter taste, which causes poor compliance of patients, at present, most of common bitter traditional Chinese medicines are alkaloids (such as berberine, quinine, etc.), terpenes (such as andrographolide, etc.) and ketoflavosides (such as amygdalin, phillyrin, quercetin, etc.), and when the bitter traditional Chinese medicines are taken, the bitter traditional Chinese medicines are combined with bitter receptors TAS2R on the surfaces of taste cells, stimulated taste cell membranes depolarize, and finally, excitation is conducted to taste nerve centers in the center of brain to integrate and generate bitter taste perception.
The taste masking technology of bitter drugs commonly used at present comprises methods such as film coating, flavoring agent addition, cyclodextrin inclusion and the like, but the methods have defects that (1) taste masking is carried out through the film coating, only tablets can be coated, and the method is not applicable to children drugs and drugs with difficult divided doses; (2) taste masking is carried out by adding a flavoring agent, so that the effect on extremely bitter drugs is poor, and particularly, the compliance of people extremely sensitive to bitter is still poor; (3) the high molecular material represented by cyclodextrin is used as a taste masking agent, the high molecular material has extremely high selectivity on the structure of bitter medicaments, only bitter medicaments with proper structures can be successfully included, and the cyclodextrin is used in an excessive dose to cause diarrhea and soft stool.
Chitosan is a cationic polymer which has good biocompatibility and degradability and is almost insoluble in the oral environment, but rapidly dissolves and releases the drug in the gastric acid environment, and these properties make it widely accepted as a very good taste masking material. However, most of the reports of chitosan as a drug taste masking material are as coating material or physical barrier to mask the taste of bitter drugs, while the chitosan as a molecular taste masking material can mask the taste of bitter components of traditional Chinese medicines in terms of molecular structure, and no document or related patent reports are found at present. Therefore, the development of a technology for masking the bitter Chinese medicinal components by adopting chitosan from the molecular level, in particular a technology suitable for mixing various bitter Chinese medicinal components, solves the problem of palatability of patients, particularly children patients, and has a great challenge.
Disclosure of Invention
The first purpose of the invention is to provide a taste masking compound which is suitable for mixing one or more bitter Chinese medicinal ingredients, and solve the technical problem that the bitter Chinese medicinal ingredients or a plurality of bitter Chinese medicinal composition ingredients are difficult to mask taste; the second purpose of the invention is to provide a taste masking preparation suitable for children to take medicine, which solves the problems of poor compliance of children patients to take medicine and difficulty in taking medicine.
In order to realize the purpose of the invention, the invention provides the following technical scheme:
in a first aspect of the present invention, there is provided a taste-masking composition of Chinese herbs, the composition comprising: bitter Chinese medicines, a taste masking agent, an auxiliary agent and a solvent, wherein the bitter Chinese medicines are flavone glycosides and/or alkaloids, and the taste masking agent comprises chitosan.
Preferably, the flavoketoside drugs are selected from one or more of phillyrin, baicalin, amygdalin, quercetin and rutin; the alkaloid medicine is one or more selected from berberine, caffeine, quinine and ephedrine.
Preferably, the auxiliary agent comprises a sodium hydroxide solution or a sodium tripolyphosphate solution, the mass fraction of the sodium hydroxide solution is 8-10%, and the concentration of the sodium tripolyphosphate solution is 1.0-2.0mg/ml.
Preferably, the compound also comprises a solvent, the solvent comprises 0.5 to 2 volume percent of acetic acid,
preferably, the Chinese medicinal composition is measured by a single bitter Chinese medicament,
single bitter Chinese medicine: and (3) chitosan: the sodium hydroxide solution is 20-80:30-50:5-30, wherein the proportion relationship is mg: mg: mL, preferably, 20-80:30-50:15;
or the like, or a combination thereof,
single bitter Chinese medicine: and (3) chitosan: the sodium tripolyphosphate solution is 20-50:100-500:5, the proportion relation is mg: mg: and (mL).
If the number of the Chinese medicaments is two or more, the taste masking agent, the auxiliary agent and the solution are increased according to multiple proportion, for example, if a single Chinese medicament is 80mg, the chitosan is 30mg and the sodium hydroxide solution is 15mL; the dosage of the two traditional Chinese medicines is 160mg, the dosage of the chitosan is 60mg, and the dosage of the sodium hydroxide solution is 30mL.
In a second aspect of the present invention, a preparation method of a taste-masking Chinese medicine composition is provided, the preparation method comprising:
s1, mixing a taste masking agent with a solvent to prepare a taste masking agent solution;
s2, mixing the bitter Chinese medicine with the taste masking solution to prepare a bitter Chinese medicine-taste masking solution;
and S3, mixing the bitter Chinese medicine-taste masking agent solution and the adjuvant solution to prepare the Chinese medicine taste masking compound.
Preferably, when the adjuvant is sodium hydroxide solution, the specific step of S3 is,
s3, dripping the prepared bitter traditional Chinese medicine-taste masking agent solution into a sodium hydroxide solution to obtain a taste masking compound suspension, and solidifying and drying to prepare a traditional Chinese medicine taste masking compound;
the curing time is 30-90min;
the dripping speed of the bitter Chinese medicinal-taste masking agent solution into the sodium hydroxide solution is 1.0-3.0 mg/mL/min.
Preferably, when the adjuvant is sodium tripolyphosphate solution, the specific steps of S2 and S3 are,
s2, adding glacial acetic acid into the bitter traditional Chinese medicine for dissolving to prepare a bitter traditional Chinese medicine solution, adding the bitter traditional Chinese medicine solution into the taste masking solution, and uniformly mixing to prepare a bitter traditional Chinese medicine-taste masking solution; the dissolving temperature is 40 ℃;
s3, dropwise adding the sodium tripolyphosphate solution into the bitter traditional Chinese medicine-taste masking agent solution, uniformly mixing, and drying to obtain a traditional Chinese medicine taste masking compound; the dropping speed is 1.0-3.0 mg/mL-min.
Preferably, the drying is vacuum drying or spray drying, wherein the inlet temperature of the spray drying is 120 ℃, the diameter of a spray head is 0.7mm, and the pump speed is 30%.
In a third aspect of the present invention, there is provided a taste-masking compound prepared by the preparation method of the second aspect, wherein the compound comprises: bitter Chinese medicine, taste-masking agent, adjuvant and solvent, wherein the bitter Chinese medicine is flavone glycoside medicine and/or alkaloid medicine,
preferably, the taste masking agent comprises chitosan.
Preferably, the flavoketoside drugs are selected from one or more of phillyrin, baicalin, amygdalin, quercetin and rutin; the alkaloid medicine is one or more selected from berberine, caffeine, quinine and ephedrine.
The bitter Chinese medicine can be phillyrin and berberine, or phillyrin, baicalin, amygdalin, or berberine, caffeine, and the bitter Chinese medicine is not limited to one, but not limited to one.
Preferably, the adjuvant comprises sodium hydroxide solution or sodium tripolyphosphate solution, the solvent comprises 0.5-2% acetic acid by volume percentage,
the sodium hydroxide solution or sodium tripolyphosphate solution is classified as an aqueous solution of sodium hydroxide or sodium tripolyphosphate.
Preferably, the single medicine proportion of the traditional Chinese medicine taste masking compound is as follows:
single bitter Chinese medicine: and (3) chitosan: the sodium hydroxide solution is 4: mg: the total volume of the mixture is mL,
the mass fraction of the sodium hydroxide solution is 8-10%,
or the like, or, alternatively,
single bitter Chinese medicine: and (3) chitosan: the sodium tripolyphosphate solution is 4: mg: and (mL).
If the medicine is two or more traditional Chinese medicines, the taste masking agent, the adjuvant and the solution are increased according to multiple proportion.
The invention provides a taste-masking traditional Chinese medicine preparation, wherein the effective component of the taste-masking traditional Chinese medicine preparation is the suspension of the taste-masking traditional Chinese medicine compound, the solvent of the preparation suspension comprises but is not limited to purified water, and the administration dose of the taste-masking traditional Chinese medicine preparation SD rat (200 +/-10 g) is 20-30mg/kg.
The invention has the beneficial effects that:
1. the invention uses chitosan to mask taste, overcomes the defect that chitosan is not used to mask taste of bitter traditional Chinese medicine in the prior art, further verifies that the taste masking mechanism of chitosan to bitter traditional Chinese medicine is weak hydrogen bond action among components to realize taste masking from molecular level through experiments, and overcomes the defects that coating only can mask taste of tablets, cyclodextrin inclusion has higher requirements on medicine molecular structure, physical encapsulation is difficult to realize taste masking of various bitter medicine components, taste masking of flavoring agents is difficult to mask taste of extremely bitter medicines and the like in the existing taste masking technology.
2. The taste masking agent chitosan can mask the taste of various bitter traditional Chinese medicine components at the same time, which cannot be realized by the existing taste masking technology.
3. The chitosan taste-masking compound is suspended in purified water to be further prepared into the traditional Chinese medicine oral liquid, so that the effective taste masking of a single extremely bitter medicine or mixed components of a plurality of bitter medicines can be realized, and the problem of poor compliance of patients taking extremely bitter traditional Chinese medicines, especially children patients with extremely sensitive bitter taste, is solved.
Drawings
FIG. 1 is an analysis and processing chart of the major components of the forsythin-chitosan complex and the forsythin bulk drug in the electronic tongue test, wherein the major components are distinguished on the X axis (the farther the distance is away, the better the taste masking effect is), which represents that the taste masking effect is good;
FIG. 2 shows the results of human taste evaluation of phillyrin-chitosan complex and phillyrin drug substances in the present invention;
FIG. 3 is an analysis and processing diagram of main components of an electronic tongue test of a berberine-chitosan complex and a berberine bulk drug in the invention, wherein the main components are distinguished on an X axis (the farther the distance is, the better the taste masking effect is), which represents that the taste masking effect is good;
FIG. 4 shows the results of human taste evaluation of berberine-chitosan complex and berberine drug substances according to the present invention;
FIG. 5 is an analysis and processing diagram of major components of the phillyrin-berberine-chitosan complex and phillyrin-berberine bulk drug in an electronic tongue test, wherein the major components are distinguished on an X axis (the farther the distance is apart, the better the taste masking effect is), which represents that the taste masking effect is good;
FIG. 6 shows the evaluation results of phillyrin berberine-chitosan complex and phillyrin berberine bulk drugs in human taste sense;
FIG. 7 shows the results of human taste evaluation of quinine-chitosan complexes and quinine drug substances in accordance with the present invention;
FIG. 8 shows the results of human taste evaluation of quercetin-chitosan complexes and quercetin-based drug substances of the present invention;
FIG. 9 shows the combination of chitosan and bitter herbs simulated by Materials Studio software of the present invention, and the circled part is the hydrogen bond formed by the bitter herbs and chitosan: a) Phillyrin; b) Berberine; c) Rutin; d) Quercetin; e) Baicalin; f) Amygdalin;
FIG. 10 is a Fourier transform infrared spectrogram of the forsythin-chitosan taste-masking composition of the present invention, which comprises, from top to bottom, a forsythin-chitosan composition, a blank composition, chitosan, forsythin and a blank composition 1:1 physical mixture, and a forsythin spectrogram in this order;
FIG. 11 is a Fourier transform infrared spectrum of the berberine-chitosan taste-masking composition of the invention, from top to bottom, the berberine-chitosan composition, the blank composition, chitosan, the berberine and blank composition 1:1 physical mixture and the berberine spectrogram are shown in sequence;
FIG. 12 is a graph showing how chitosan/bitter drugs bind to bitter receptor proteins using Discovery Studio software in the present invention: a) Phillyrin; b) Berberine; c) Chitosan;
FIG. 13 is the in vitro release profile of phillyrin-chitosan complex of the present invention;
FIG. 14 is the in vitro release curve of berberine-chitosan complex of the present invention.
Detailed Description
For the convenience of understanding, the chitosan taste masking preparation of the present invention will be described in detail below by way of specific examples and the accompanying drawings. The features and advantages of the present invention will become more apparent from the exemplary descriptions. It is specifically noted that the specific examples and figures are for illustrative purposes only and it will be apparent to those skilled in the art that, in light of the description herein, various modifications and changes can be made in the invention which are within the scope of the invention.
Applicant lists the following examples to illustrate the inventive work product of the present invention
Example 1 preparation of Forsythiaside-Chitosan taste masking Complex and bitterness evaluation
The preparation method comprises the following specific steps:
s1, weighing 30-50mg of chitosan according to the table 1, dissolving the chitosan in 3mL of acetic acid solution with the volume percentage of 1%, and magnetically stirring the chitosan solution for 30min at room temperature to dissolve the chitosan to obtain chitosan solution;
s2, mixing 20-80mg of phillyrin with 3mL of chitosan solution, and magnetically stirring at room temperature for 30min to obtain the chitosan solution containing phillyrin;
and S3, dripping a chitosan solution containing phillyrin from an injector at the flow rate of 1.5mL/min into 5-30mL of a sodium hydroxide solution with the mass fraction of 10% through magnetic stirring, performing magnetic stirring to solidify the generated compound for 60min, centrifuging for 5min at 2500r/min, and drying for 96 hours in a vacuum drier to prepare the phillyrin shell taste-masking compound.
And (3) determining the binding rate: weighing forsythin-chitosan compound powder equivalent to 18mg forsythin in a 10mL volumetric flask, adding methanol to scale and fixing volume to obtain suspension. 2mL of suspension is measured, the suspension is centrifuged on a centrifuge at the rotating speed of 8000r/min for 10min, after the centrifugation is finished, 100 mu L of supernatant is sucked, and methanol is diluted to 1mL. Measuring the amount of unbound free drug in the supernatant by HPLC, calculating the binding rate, and showing the binding rate of phillyrin-taste-masking complex in Table 1 and Table 1
Evaluation of bitterness of electronic tongue: weighing 18mg of phillyrin and a compound (based on the principle that the amount of the taste-masking auxiliary materials is the minimum and the amount of the bitter taste-masked medicines is the maximum, selecting a sample 6 as a taste-masking evaluation object to perform taste-masking evaluation, and parallelly sampling 3 parts) which are equivalent to 18mg of phillyrin in 40mL of purified water respectively, and starting testing for 120 seconds after the sensor reaches the equilibrium condition. The sensor was then washed in purified water, 1-6 times according to the wash time signal curve, and three replicates were measured. The taste-masking result of electronic tongue measurement shows (figure 1) that the prepared chitosan taste-masking compound has a good taste-masking effect on phillyrin compared with free drugs.
Human taste evaluation: 8 healthy male and female volunteers aged 20-35 years were selected and informed of the purpose and significance of the test, but no specific sample information was disclosed. Volunteers were provided with 6.75mg phillyrin and a chitosan taste-masking complex (sample 6) equivalent to 6.75mg phillyrin dispersed in 10mL water for 15 seconds. Immediately after preparation, each volunteer placed about 1mL of the dispersion on the tongue for 30 seconds and then spitted out. After the mouthfeel was rapidly recorded, the mouth was rinsed three times with purified water, and after 15 minutes until the taste had disappeared completely, the bitterness of the next sample was evaluated. The bitterness level was recorded using the following values: 0 no smell; 1, slightly bitter; 2, moderate bitterness; 3 strong bitter taste; 4 very strong bitter taste. The taste masking evaluations were performed on each sample by the volunteers scoring the degree of bitterness. Human taste evaluation results show (fig. 2), that the forsythin-chitosan complex masked by chitosan has a significant difference with the forsythin taste, which is consistent with the electronic tongue results.
Example 2 preparation of Berberine-Chitosan taste-masking Complex and bitterness evaluation
The preparation method comprises the following specific steps:
s1, weighing 30-50mg of chitosan according to the table 2, dissolving the chitosan in 3mL of acetic acid solution with the volume percentage of 1%, and magnetically stirring the chitosan solution at room temperature for 30min to dissolve the chitosan to obtain chitosan solution;
s2, mixing 20-80mg of berberine with 3mL of chitosan solution, and magnetically stirring at room temperature for 30min to obtain chitosan solution containing berberine;
s3, dripping the chitosan solution containing berberine from the injector at the flow rate of 1.5mL/min into 5-30mL of sodium hydroxide solution with the mass fraction of 10 percent by magnetic stirring to prepare the compound. The resulting composite was allowed to cure for 60 minutes with gentle stirring by a magnetic stirrer. Centrifuging at 2500r/min for 5min, and drying in vacuum drier for 96 hr to obtain berberine taste-masking compound.
And (3) determining the binding rate: weighing berberine-chitosan complex powder equivalent to 16.67mg berberine into a 10mL volumetric flask, adding methanol to scale and fixing volume. 2mL of suspension is measured, the suspension is centrifuged on a centrifuge at the rotating speed of 8000r/min for 10min, after the centrifugation is finished, 100 mu L of supernatant is sucked, and methanol is diluted to 1mL. The amount of unbound free drug in the supernatant was determined by HPLC and the binding rate was calculated and the results are shown in table 2.
TABLE 2 Berberine-Chitosan Complex binding Rate
Evaluation of bitterness of electronic tongue: 40mg of berberine and a chitosan taste-masking compound (sample 15 is selected as a taste-masking evaluation object to carry out taste-masking evaluation according to the principle that the amount of taste-masking auxiliary materials is the minimum and the amount of taste-masked bitter drugs is the maximum, and 3 samples are parallelly sampled) which is equivalent to 40mg of berberine are weighed and respectively put in 40mL of purified water, and the taste is parallelly measured for three times according to the measurement conditions of the example 1. The taste masking result of electronic tongue measurement (figure 3) shows that chitosan has good taste masking effect on berberine compared with free drug.
Human taste evaluation: the same volunteers as in example 1 were selected and provided with 50mg of berberine and a chitosan taste-masking complex equivalent to 50mg of berberine (sample 15) dispersed in 20mL of water for 15 seconds. After working according to example 1, the results of human taste evaluation (fig. 4) show that berberine-chitosan complex with masked chitosan can significantly reduce or eliminate the bitter taste of berberine, which is consistent with the results of electronic tongue.
Example 3 preparation of taste-masked composition from berberine and phillyrin, respectively, and chitosan and bitterness evaluation the detailed preparation process:
s1: weighing 60mg of chitosan, dissolving in 6mL of acetic acid solution with volume percentage of 1%, magnetically stirring at room temperature for 30min to dissolve the chitosan to obtain chitosan solution,
s2: dispersing 80mg of phillyrin and 80mg of berberine, mixing with 6mL of chitosan solution, and magnetically stirring at room temperature for 30min to obtain chitosan solution containing phillyrin and berberine;
s3: dripping chitosan solution containing phillyrin and berberine from a syringe at a flow rate of 1.5mL/min into 30mL of sodium hydroxide solution with a mass fraction of 10% by magnetic stirring, and gently stirring by a magnetic stirrer to solidify the generated taste-masking compound for 60 minutes. Centrifuge at 2500r/min for 5min and dry in a vacuum desiccator for 96 h. Preparing the forsythin and berberine taste-masking compound.
Evaluation of bitterness of electronic tongue: weighing 40mg of berberine and 40mg of phillyrin, mixing, weighing the chitosan taste-masking compound equivalent to 40mg of berberine and 40mg of phillyrin simultaneously, respectively placing in 40mL of purified water, and performing parallel determination for three times according to the method of example 1. The taste masking result of the electronic tongue test shows (figure 5), compared with the composition medicine of free bitter medicines phillyrin and berberine, the chitosan has good taste masking effect on the bitter combined medicine of phillyrin and berberine.
Human taste evaluation: the same volunteers as in example 1 were selected and given a mixture of 20mg berberine and 20mg phillyrin and a complex equivalent to 20mg berberine and 20mg phillyrin dispersed in 20mL water for 15 seconds, and after working as in example 1, the human taste evaluation results showed (fig. 6) that chitosan can mask the bitter taste of the bitter composition of phillyrin and berberine, consistent with the electronic tongue results.
Example 4 quinine-Chitosan taste-masking Complex preparation and bitterness assessment
The preparation method comprises the following specific steps:
s1: weighing 30mg of chitosan, dissolving in 3mL of acetic acid solution with volume percentage of 1%, magnetically stirring at room temperature for 30min to dissolve to obtain chitosan solution,
s2: dispersing 80mg of quinine, mixing with 3mL of chitosan solution, and magnetically stirring at room temperature for 30min for fully mixing to obtain a chitosan solution containing quinine;
s3: the chitosan solution containing quinine is dropped into 15mL of sodium hydroxide solution with the mass fraction of 10 percent and magnetic stirring from a syringe at the flow rate of 1.5mL/min to prepare the taste masking compound. The resulting taste-masking compound was allowed to cure for 60 minutes with magnetic stirring. Centrifuging at 2500r/min for 5min, and drying in a vacuum drier for 96 h to prepare the quinine taste-masking complex.
Human taste evaluation: the same volunteers as in example 1 were selected and provided with 40mg of quinine and the complex corresponding to 40mg of quinine dispersed in 20mL of water for 15 seconds. Human taste evaluation according to the assay of example 1 (FIG. 7) shows that the quinine-chitosan taste-masking complex significantly reduces or eliminates the bitter taste of quinine.
Example 5 preparation of Quercetin-Chitosan taste masking Complex and bitterness assessment
The preparation method comprises the following specific steps:
s1, weighing 30mg of chitosan, dissolving the chitosan in 3mL of acetic acid solution with volume percentage of 1%, magnetically stirring the chitosan solution at room temperature for 30min to dissolve the chitosan to obtain chitosan solution,
s2, dispersing 80mg of quercetin, mixing with 3mL of chitosan solution, and magnetically stirring at room temperature for 30min for fully mixing to obtain a chitosan solution containing quercetin;
and S3, dripping the chitosan solution containing the quercetin into 15mL of sodium hydroxide solution with the mass fraction of 10% which is subjected to magnetic stirring from an injector at the flow rate of 1.5mL/min, and slowly and magnetically stirring to solidify the generated taste-masking compound for 60 minutes. Centrifuging at 2500r/min for 5min, and drying in vacuum desiccator for 96 hr to obtain quercetin taste-masking compound.
Human taste evaluation: the same volunteers as in example 1 were selected and provided with 30mg of quercetin and a chitosan taste-masking complex equivalent to 30mg of quercetin dispersed in 20mL of water for 15 seconds. The results of human taste evaluation according to the measurement method of example 1 (fig. 8) show that the quercetin-chitosan taste-masking complex has a good effect of masking the bitterness of quercetin.
Example 6 Forsythiaside-Chitosan taste masking Complex preparation (TPP crosslinker)
The preparation method comprises the following specific steps:
s1, dissolving a proper amount of chitosan into 50mL of acetic acid aqueous solution with the volume percentage of 1%, and continuously stirring for 30min to obtain a chitosan solution with the mass fraction of 0.2% -0.8%;
s2, weighing 25-50mg of phillyrin according to the table 3, adding 500 mu L of glacial acetic acid, and completely dissolving the phillyrin in water bath at 40 ℃ for 5 min; dissolving 5-10mg of sodium tripolyphosphate in 5mL of purified water to form a solution with the concentration of 1.0-2.0mg/mL, slowly adding the phillyrin solution into the chitosan solution to obtain a phillyrin-chitosan solution mixed solution, and magnetically stirring to uniformly mix the phillyrin-chitosan solution mixed solution.
And S3, dropwise adding the solution of sodium tripolyphosphate into the phillyrin-chitosan mixed solution at a rate of 1mL/min, magnetically stirring at room temperature for 15min after dropwise adding, and spray-drying by a spray-drying method to prepare the taste-masking preparation of the chitosan-phillyrin, wherein the inlet temperature is 120 ℃, the nozzle diameter is 0.7mm, and the pump speed is 30%. The ratio of the medicinal materials in table 3 refers to the mass ratio of the bitter Chinese medicine to the taste-masking agent.
TABLE 3 Forsythiaside-Chitosan Complex binding Rate
The result shows that the sodium tripolyphosphate adopted by the invention as the auxiliary agent of the taste-masking compound can also play a certain taste-masking effect on the ribulose glycoside drugs.
The applicant further verifies the taste-masking mechanism of the traditional Chinese medicine taste-masking compound.
Firstly, the applicant selects forsythin, baicalin, amygdalin, quercetin and rutin from flavone glycosides drugs, and selects berberine and quinine from alkaloid drugs as representative drugs, wherein the forsythin and the berberine are common drugs in the flavone glycosides drugs and the alkaloid drugs, so that the taste masking mechanism of chitosan on the drugs is explored.
The experimental steps are as follows: the combination mode of phillyrin, berberine and other flavoketoside bitter Chinese medicines and chitosan is inspected by utilizing material Studio molecular simulation software, the bitter Chinese medicine structure and chitosan structure file is imported into the software, a force field is applied to simulate the combination mode of the bitter Chinese medicines and the chitosan, the intermolecular acting force existing between the bitter Chinese medicines and the chitosan is judged, and whether hydrogen bonds are contained is calculated.
As a result: as shown in figure 9, the circled part in the figure represents that hydrogen bonds are formed between chitosan and bitter traditional Chinese medicine molecules, which indicates that the chitosan can form hydrogen bonds with hydrogen or oxygen atoms on six-membered rings of flavone glycosides or alkaloid drugs through self hydroxyl groups, so as to prevent the combination between bitter molecules and bitter receptors in oral cavity, thereby achieving the purpose of taste masking.
Subsequently, forsythin is selected from flavone glycosides drugs, berberine is selected from alkaloids drugs as a representative drug, and the taste masking mechanism of chitosan on bitter traditional Chinese medicines is further explored through an infrared spectrogram.
The experimental steps are as follows: taking about 2mg bitter Chinese medicine or chitosan-bitter medicine compound and 100mg potassium bromide, grinding uniformly, pressurizing to 20MPa, tabletting and carrying out infrared test. Wave number range is 400-4000cm -1 Resolution of spectrometer 4cm -1 The signal-to-noise ratio is 50000.
As a result: as shown in FIG. 10, the characteristic peaks of phillyrin, mainly included in the region of 3479cm -1 Two nearby hydroxyl stretching vibration peaks, an asymmetric stretching vibration peak of C-O-C and some peaks belonging to benzene rings. Comparing the forsythin and forsythin-chitosan taste masking compound with infrared spectrum to find that the characteristic peak of forsythin in the compound disappears or moves, and the compound is 1775cm -1 A peak belonging to carbonyl is added nearby, indicating thatChitosan may form amide bonds with forsythin.
As shown in FIG. 11, characteristic peak of berberine is mainly included at 1455cm -1 Nearby stretching vibration peaks belonging to C-N bonds and some peaks belonging to benzene rings. The compound is also at 1775cm -1 A peak belonging to carbonyl groups is increased nearby, which indicates that chitosan may form amide bonds with berberine.
Subsequently, the applicant also verifies the combination simulation of bitter Chinese medicine and receptor, and selects phillyrin and berberine as examples.
The experimental steps are as follows: a docking mode of phillyrin, berberine and chitosan and a human bitter receptor TAS2R 10 is simulated by using Discovery Studio simulation docking software. Introducing phillyrin, berberine, chitosan and human body bitter receptor TAS2R 10 structure into software, applying force field to simulate bitter drug and chitosan binding process with bitter receptor, and calculating binding energy by software to determine the binding tightness of compound and receptor.
TABLE 4 binding energy of Chitosan/bitter Chinese herbs with bitter receptor protein
As a result: the docking results are shown in fig. 12. The binding energy of chitosan and human bitter taste receptor TAS2R 10 is significantly lower than that of phillyrin and berberine molecules and bitter taste receptor TAS2R 10 (as shown in Table 4), so as to conclude that phillyrin and berberine are more tightly bound with bitter taste receptor and have more heavy bitter taste
Forsythiaside-chitosan taste-masking compound and berberine-chitosan taste-masking compound in-vitro release experiment verification
The experimental steps are as follows: weighing 20mg of phillyrin or berberine and a compound equivalent to 20mg of phillyrin or berberine into a 500mL conical flask, adding 250mL of a release medium with the pH value of 1.2, inspecting the release of phillyrin/berberine and the taste-masking compound thereof under the conditions of 37 ℃ and 120rpm, respectively taking 1mL of sample solution at 10min, 30min, 1h, 1.5h, 2h and 3h, supplementing 1mL of the release medium, and measuring the cumulative release amount of the medicament by HPLC.
As a result: from fig. 13 and fig. 14, it can be seen that the taste-masking complex of forsythin-chitosan and berberine-chitosan is not released in the simulated oral environment, but the forsythin-chitosan in the taste-masking complex of forsythin-chitosan in the simulated gastric acid environment is released up to 70% in vitro, and the berberine-chitosan taste-masking complex is released more than 50% in vitro in the simulated gastric acid environment and can be released rapidly, which indicates that the taste-masking complex of the present invention has a good taste-masking effect on bitter drugs, and does not affect the drug release in vivo.
Claims (10)
1. A taste-masking composition of traditional Chinese medicine, said composition comprising: the bitter traditional Chinese medicine comprises a bitter traditional Chinese medicine, a taste masking agent and an auxiliary agent, wherein the bitter traditional Chinese medicine is a flavone glycoside medicine and an alkaloid medicine, and the taste masking agent comprises chitosan.
2. The traditional Chinese medicine taste-masking composition of claim 1, wherein the flavoketoside drug is selected from one or more of phillyrin, baicalin, amygdalin, quercetin and rutin; the alkaloid medicine is one or more selected from berberine, caffeine, quinine and ephedrine.
3. The traditional Chinese medicine taste-masking compound according to claim 1, wherein the auxiliary agent comprises 8-10% by mass of sodium hydroxide solution or sodium tripolyphosphate solution, and the concentration of the sodium tripolyphosphate solution is 1.0-2.0mg/ml.
4. The traditional Chinese medicine taste-masking compound according to claim 1, further comprising a solvent, wherein the solvent is 0.5-2% by volume of acetic acid.
5. The traditional Chinese medicine taste-masking compound according to claim 1, wherein the single medicine proportion of the traditional Chinese medicine taste-masking compound is as follows:
single bitter Chinese medicine: and (3) chitosan: the sodium hydroxide solution is 20-80:30-50:5-30, wherein the proportion relationship is mg: mg: mL, preferably, 20-80:30-50:15;
or the like, or, alternatively,
single bitter Chinese medicine: and (3) chitosan: the sodium tripolyphosphate solution is 20-50:100-500:5, the proportion relation is mg: mg: and (mL).
6. A preparation method of a traditional Chinese medicine taste-masking compound is characterized by comprising the following steps:
s1, mixing a taste masking agent with a solvent to prepare a taste masking agent solution;
s2, mixing the bitter Chinese medicine with the taste masking solution to prepare a bitter Chinese medicine-taste masking solution;
and S3, mixing the bitter Chinese medicine-taste masking agent solution and the adjuvant solution to prepare the Chinese medicine taste masking compound.
7. The method for preparing the taste-masking traditional Chinese medicine composition according to claim 6, wherein when the adjuvant is sodium hydroxide solution, S3 comprises the following steps,
s3, dripping the prepared bitter Chinese medicine-taste masking agent solution into a sodium hydroxide solution to obtain a taste masking compound suspension, and curing and drying to prepare a Chinese medicine taste masking compound;
the curing time is 30-90min;
the dripping speed of the bitter Chinese medicinal-taste masking agent solution into the sodium hydroxide solution is 1.0-3.0 mg/mL/min.
8. The method for preparing the taste-masking traditional Chinese medicine composition according to claim 6, wherein when the adjuvant is a sodium tripolyphosphate solution, the specific steps of S2 and S3 are,
s2, adding glacial acetic acid into the bitter traditional Chinese medicine for dissolving to prepare a bitter traditional Chinese medicine solution, adding the bitter traditional Chinese medicine solution into the taste masking solution, and uniformly mixing to prepare a bitter traditional Chinese medicine-taste masking solution; the dissolving temperature is 40 ℃;
s3, dropwise adding the sodium tripolyphosphate solution into the bitter traditional Chinese medicine-taste masking agent solution, uniformly mixing, and drying to obtain a traditional Chinese medicine taste masking compound; the dropping speed is 1.0-3.0 mg/mL-min.
9. The method for preparing the taste-masking traditional Chinese medicine composition according to any one of claims 7 or 8, wherein the drying is vacuum drying or spray drying, the inlet temperature of the spray drying is 120 ℃, the diameter of a spray head is 0.7mm, and the pump speed is 30%.
10. A taste-masking preparation of a Chinese medicine characterized in that the effective ingredient is a suspension of the taste-masking compound of a Chinese medicine according to claims 1 to 5.
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