Preparation of anti-chronic pharyngitis microcapsule medicine and application of anti-chronic pharyngitis microcapsule medicine in tipping paper for cigarettes

Abstract

The invention discloses preparation of an anti-chronic pharyngitis microcapsule medicine and application of the anti-chronic pharyngitis microcapsule medicine in tipping paper for cigarettes, the medicine is MF-GA / IL (at) MPN, and the medicine is composed of an ionic liquid (IL) as an internal carrier and a microcapsule carrier with a metal phenol network (MPN) as a shell; wherein the metal phenol network is formed by aluminum ions and mangiferin through a coordination reaction, and the ionic liquid is CAGE ILs formed by vanillin and choline. The combination of mangiferin and glycyrrhizic acid is used as a strategy for treating chronic pharyngitis, it is found that the effective loaded MF-GA / IL-coated MPN microcapsule preparation is obtained by packaging the two drugs including mangiferin and glycyrrhizic acid with the ionic liquid as the core and the metal phenol network as the shell, the tissue permeability of the drugs is improved, a certain slow release effect is achieved, and the effect of treating chronic pharyngitis is achieved. The bioavailability of mangiferin and glycyrrhizic acid is improved, and the anti-inflammatory activity effect is better achieved.

Description

Technical Field

[0001] This invention relates to the fields of pharmaceutical formulation and tobacco technology, and particularly to the preparation of an anti-chronic pharyngitis microcapsule drug and its application in cigarette tipping paper. Background Technology

[0002] Chronic pharyngitis is a common chronic pharyngeal disease with a high incidence rate among smokers. It is characterized by a long course, persistent symptoms, and difficulty in complete cure, severely impacting patients' quality of life. Currently, treatment for chronic pharyngitis mainly relies on topical medications, but existing drugs have limited efficacy and may cause side effects with long-term use. With increasing public health awareness, the market demand for tobacco products with health benefits is growing, prompting the tobacco industry to actively explore innovation and develop new cigarettes incorporating throat-protective ingredients, aiming to reduce the risk of chronic pharyngitis among smokers at its source.

[0003] In recent years, natural plant extracts have attracted much attention in the field of anti-inflammation due to their low toxicity and significant bioactivity. For example, mangiferin and glycyrrhizic acid, derived from mango and licorice respectively, have been widely used in traditional and modern medical research and have shown good potential in regulating inflammatory responses. However, these active ingredients suffer from poor water solubility and low bioavailability, limiting their clinical application. Existing microencapsulation technology has low encapsulation efficiency and insufficient stability for volatile components, and the preparation process is complex. Furthermore, the free drug is difficult to achieve sustained release at the lesion site, further hindering its clinical translation.

[0004] Tipping paper, commonly known as cork paper, is a special paper used to attach the filter to the cigarette using glue. It is an essential packaging material in cigarette manufacturing. Traditionally, tipping paper primarily serves to connect the filter and the cigarette. In recent years, with the continuous optimization and adjustment of cigarette structure, functional tipping paper has been designed and developed to improve the smoking experience and meet consumers' sensory needs. This not only provides cigarettes with a unique sensory experience but also plays a crucial role in stabilizing and enhancing the cigarette's style characteristics. Therefore, developing tipping paper that combines traditional Chinese medicine wisdom with modern tobacco material technology, offering both sensory enjoyment and medicinal value, is of significant practical importance. Summary of the Invention

[0005] The technical problem to be solved by this invention is to provide a preparation of a microcapsule drug for treating chronic pharyngitis and its application in cigarette tipping paper. By using a combination of mangiferin and glycyrrhizic acid as a strategy for treating chronic pharyngitis, it was found that by encapsulating mangiferin and glycyrrhizic acid with an ionic liquid as the core and a metallophenol network as the shell, an effective loaded MF-GA / IL@MPN microcapsule formulation was obtained. This not only improves the tissue permeability of the drug, but also achieves a certain sustained-release effect, improves the bioavailability of mangiferin and glycyrrhizic acid, and better exerts its anti-inflammatory activity.

[0006] The technical problem to be solved by the present invention is achieved through the following technical solution:

[0007] A microcapsule drug for treating chronic pharyngitis, the drug being MF-GA / IL@MPN, is composed of a microcapsule carrier consisting of an ionic liquid (IL) as the internal carrier and a metallophenol network (MPN) as the outer shell; wherein the metallophenol network is formed by the coordination reaction of aluminum ions and mangiferin, and the ionic liquid is CAGEILs formed by geraniol and choline.

[0008] Preferably, in the above technical solution, the average particle size of the microcapsules is 205.31±3.40nm, the polydispersity index (PDI) is 0.117±0.023, and the zeta potential is -54.27±3.25mV.

[0009] Preferably, in the above technical solution, the encapsulation efficiency of mangiferin is 80.58±2.53%, and the drug loading is 0.11±0.02%; the encapsulation efficiency of glycyrrhizic acid is 56.12±10.56%, and the drug loading is 0.08±0.02%.

[0010] A method for preparing a microcapsule drug for chronic pharyngitis includes the following steps:

[0011] (1) Synthesis of CAGEILs: Geranilic acid and choline bicarbonate were mixed with methanol at a molar ratio of 1:1 and stirred at room temperature overnight. Then, the mixture was rotary evaporated and vacuum dried for 48 hours to obtain CAGEILs.

[0012] (2) Preparation of microcapsules: At room temperature, 1 mg of mangiferin and 1 mg of glycyrrhizic acid were weighed and mixed in the same centrifuge tube. 1 mL of CAGE ILs was added to the centrifuge tube, and the mixture was heated in a 50°C water bath to dissolve the mangiferin and glycyrrhizic acid. 0.1 mL of CAGE ILs containing 0.1 mg of mangiferin and 0.1 mg of glycyrrhizic acid was dispersed in 20 mL of water. After sonication for 60 s, 0.2 mL of AlCl3 solution with a concentration of 10 mg / mL was added, and sonication was continued for 30 s to promote the coordination of aluminum ions with mangiferin at the IL / water interface to form a metallophenol shell, thus obtaining MF-GA / IL@MPN microcapsules.

[0013] Preferably, in the above technical solution, the ultrasonic treatment conditions in step (2) are: ultrasonication at 40% amplitude for 1 min under ice bath, followed by ultrasonication for 30 s after adding aluminum chloride; the concentration of the aluminum chloride solution is 10 mg / mL, and the added volume is twice that of 1L solution.

[0014] Preferably, in the above technical solution, the mass ratio of mangiferin, glycyrrhizic acid, and CAGEILs is 1:1:900, and the mass ratio of CAGEILs to water is 0.9:20.

[0015] Application of a microcapsule drug for chronic pharyngitis in the preparation of cigarette tipping paper with pharyngitis protection function.

[0016] Preferably, in the above technical solution, the application involves dissolving the MF-GA / IL@MPN microcapsules in an aqueous ink and preparing tipping paper using a gravure printing process. The amount of microcapsules added to the tipping paper is 6.42 g / m³. 2 The amount of mangiferin added was 0.70 g / m³. 2 The amount of glycyrrhizic acid added was 0.52 g / m³. 2 .

[0017] A method for preparing cigarette tipping paper includes the following steps:

[0018] (1) Dissolve the MF-GA / IL@MPN microcapsules prepared by the preparation method of claims 4-5 in an aqueous ink oil, stir mechanically for 1-2 hours, and after mixing evenly, obtain a homogeneous solution;

[0019] (2) The homogeneous solution is transferred to the surface of the tipping paper using a gravure printing process, and then dried at a constant temperature of 80-90℃. The dried paper is then hot-stamped, slit, and perforated to obtain the functional cigarette tipping paper. The amount of microcapsules added to the tipping paper is 6.42 g / m³. 2 The amount of mangiferin added was 0.70 g / m³. 2 The amount of glycyrrhizic acid added was 0.52 g / m³. 2 .

[0020] Application of a microcapsule drug for treating chronic pharyngitis in the preparation of products for treating chronic pharyngitis.

[0021] The above-described technical solution of the present invention has the following beneficial effects:

[0022] 1. The microcapsules prepared by this invention not only have good drug encapsulation and loading rates, but the ionic liquid significantly enhances the permeability of drug molecules in biological tissues, enabling the drugs to reach the lesion site more effectively. This effectively improves the bioavailability and in vivo absorption of mangiferin and glycyrrhizic acid.

[0023] 2. This invention innovatively integrates microcapsule technology into the design of cigarette tipping paper, ensuring that when smokers consume tobacco products, the mangiferin and glycyrrhizic acid in the microcapsules—two components with anti-chronic pharyngitis effects—can slowly dissolve in saliva. This not only greatly enriches the sensory experience for consumers but also provides a more convenient and effective treatment method, helping to alleviate symptoms and improve quality of life.

[0024] 3. The preparation method is simple and controllable, and is suitable for large-scale industrial production. Attached Figure Description

[0025] The accompanying drawings, which are incorporated in and form part of this specification, illustrate embodiments of the invention and, together with their description, serve to explain the principles of the invention.

[0026] Figure 1 The 1H and 1F NMR spectra of geranilic acid, choline, and CAGE ionic liquids are shown, including: (A) 1H NMR spectra of geranilic acid, choline, and CAGE ionic liquids; and (B) FTIR spectra of geranilic acid, choline, and CAGE ionic liquids.

[0027] Figure 2 The microstructure and particle size characterization results of MF-GA / IL@MPN microcapsules are shown, including: (A) transmission electron microscopy (TEM) images of nanoparticles; (B) particle size distribution of nanoparticles.

[0028] Figure 3 The changes in (A) particle size, (B) polydispersity index (PDI) and (C) zeta potential of microcapsules stored in pure water at 25°C for 14 days over time are shown.

[0029] Figure 4 The cumulative release curves of MF-GA / IL@MPN microcapsules with free mangiferin (MF) and glycyrrhizic acid (GA) in phosphate-buffered saline (PBS) at 37°C are shown.

[0030] Figure 5 The images show the appearance of the pharynx of rats in each experimental group.

[0031] Figure 6 The effect of MF-GA / IL@MPN on changes in inflammation-related cells such as leukocytes (A), lymphocytes (B), and neutrophils (C) in rats. * indicates p < .05 compared to the blank control group, ** indicates p < .005, *** indicates p < .001; # indicates p < .05 compared to the model group, ## indicates p < .005, ### indicates p < .001.

[0032] Figure 7The effect of MF-GA / IL@MPN on the levels of inflammatory cytokines such as tumor necrosis factor-α (A), interleukin-6 (B), and interleukin-1β (C). * indicates p < .05 compared with the blank control group, ** indicates p < .001, *** indicates p < .001; # indicates p < .05 compared with the model group, ## indicates p < .001, ### indicates p < .001.

[0033] Figure 8 The effect of MF-GA / IL@MPN on histopathological changes in the pharynx.

[0034] Figure 9 For in vivo safety evaluation, the following blood routine tests were performed: aspartate aminotransferase (AST) level (A), alanine aminotransferase (ALT) level (B), blood urea nitrogen (BUN) level (C), creatinine (CRE) level (D); and red blood cell (E), hemoglobin (F), and platelet (G) levels. * indicates p < .05 compared with the blank control group, ** indicates p < .005, *** indicates p < .001; # indicates p < .05 compared with the model group, ## indicates p < .005, and ### indicates p < .001.

[0035] Figure 10 The results of hematoxylin-eosin (H&E) staining of liver (A), kidney (B) and lung tissue (C).

[0036] Figure 11 The changes in body weight of rats in each experimental group during the drug administration period are shown. Detailed Implementation

[0037] Various exemplary embodiments of the present invention will now be described in detail with reference to the accompanying drawings. It should be noted that, unless otherwise specifically stated, the relative arrangement, numerical expressions, and values ​​of the components and steps set forth in these embodiments do not limit the scope of the invention.

[0038] Example 1

[0039] Materials and methods

[0040] (1) Materials and animals

[0041] Geranilic acid was purchased from Alfaisa (China) Chemical Co., Ltd.; choline bicarbonate was purchased from Sigma-Aldrich (Shanghai) Trading Co., Ltd.; mangiferin and anhydrous aluminum chloride were purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.; glycyrrhizic acid was purchased from Cool Chemical Technology (Beijing) Co., Ltd.; anhydrous methanol and anhydrous ethanol were purchased from Tianjin Fuyu Fine Chemical Co., Ltd.; acetonitrile (HPLC grade) and methanol (HPLC grade) were purchased from Honeywell Trading (Shanghai) Co., Ltd.; magnesium chloride was purchased from Tianjin Zhiyuan Chemical Reagent Co., Ltd.; manganese chloride tetrahydrate and anhydrous ferric chloride were purchased from Shanghai Maclean Biochemical Technology Co., Ltd. The experimental animals were SPF-grade male / female SD rats, weighing 180–220 g and 10 weeks old, purchased from Shandong Jinan Pengyue Experimental Animal Breeding Co., Ltd.

[0042] (2) Synthesis of CAGE ILs

[0043] Geranilic acid and choline were used to synthesize a typical ionic liquid. The synthesis process was as follows: 1798 μL (0.01 mol) of geranilic acid was mixed with 1 mL of methanol, and 1412 μL (0.01 mol) of choline bicarbonate was mixed with 1 mL of methanol and placed in a 25 mL round-bottom flask. The mixture was magnetically stirred, and then the geranilic acid methanol solution was added dropwise to the 25 mL round-bottom flask. The mixture was stirred overnight at room temperature, and the methanol was removed by rotary evaporation at 40 °C. Then the water was removed by rotary evaporation at 60 °C. Finally, the mixture was vacuum dried for 48 h to obtain the final sample CAGE ILs.

[0044] (3) Characterization of CAGE ILs

[0045] respectively 1 CAGE ILs were characterized by H-NMR and FTIR.

[0046] (4) Preparation of MF-GA / IL@MPN

[0047] An MF-GA / IL@MPN microcapsule was prepared by self-assembly at the ionic liquid-water interface based on the metal-polyphenol coordination principle.

[0048] The first step involves adding 100 μL of CAGE ILs (containing a certain concentration of mangiferin MF and glycyrrhizic acid GA) to 20 mL of pure water. The mixture is then sonicated for 1 min at 40% amplitude using a probe sonicator under ice bath conditions to ensure high dispersion of the ionic liquid (IL) in the 20 mL aqueous solution. The second step is to immediately add 200 μL of anhydrous AlCl3 (10 mg / mL) after sonication. -1 Add to the above mixture and continue ultrasonic treatment for 30 seconds to promote Al 3+Mangiferin dissolved in an ionic liquid undergoes a coordination reaction at the IL / water interface to form a metallophenol shell, yielding MF-GA / IL@MPN microcapsules.

[0049] (5) Characterization of MF-GA / IL@MPN

[0050] 1) Particle size, potential, and morphology: The stability of MF-GA / IL@MPN microcapsules is greatly affected by particle size, polydispersity index (PDI), and zeta potential. Therefore, the particle size, PDI, and zeta potential of MF-GA / IL@MPN were measured using a Nano Brook 90 Plus PALS at 25°C. The shape and surface morphology of the MF-GA / IL@MPN microcapsules were observed using transmission electron microscopy (TEM).

[0051] 2) Encapsulation efficiency (EE) and drug loading (DL): The encapsulation efficiency (EE) and drug loading (DL) of mangiferin and glycyrrhizic acid in MF-GA / IL@MPN microcapsules were determined by HPLC. The content of mangiferin was determined by HPLC under the following conditions: mobile phase acetonitrile: 0.1% phosphoric acid (17:83, V / V); column temperature 35℃; flow rate 1.0 mL·min⁻¹; detection wavelength 258 nm; injection volume 10 μL; retention time 6 min. Similarly, the content of glycyrrhizic acid was determined by HPLC under the following conditions: mobile phase acetonitrile: 0.1% phosphoric acid (40:60, V / V); column temperature 30℃; flow rate 1.0 mL·min⁻¹. -1 Detection wavelength: 250 nm; injection volume: 10 μL; retention time: 10 min. Drug loading and encapsulation efficiency were calculated using the following formulas:

[0052] EE(%) = (M) package ) / (M package +M free )

[0053] DL(%) = (M) package ) / (M total )

[0054] Among them, M package M represents the mass of MF or GA loaded in the microcapsule. free M represents the mass of free MF or GA. total This represents the weight of the nanoparticles.

[0055] 3) In vitro stability of MF-GA / IL@MPN: The stability of MF-GA / IL@MPN microcapsules at room temperature (25℃) was detected using Nanobrook 90Plus PALS. Specifically, the microcapsules were incubated at 25℃ for 14 days, and the particle size, PDI, and Zeta potential were measured and recorded daily.

[0056] 4) In vitro release performance of MF-GA / IL@MPN: The in vitro release kinetics of the microcapsule formulation were studied using dialysis. The microcapsule formulation (1 mL) and the free mangiferin and glycyrrhizic acid solution (1 mL, 1.0 mg / mL) were sealed separately in dialysis bags (cutoff: 1000 Da). The dialysis bags were immersed in 40 mL of PBS (pH 7.4) containing 0.5% (v / v) Tween-80 at 37 °C. 1 mL of dialysate was collected at 1, 2, 4, 6, 8, 12, and 24 h, and an equal volume of fresh medium was added. The mangiferin and glycyrrhizic acid content in the dialysate was determined by HPLC as described above. The in vitro release rate of the microcapsules was calculated.

[0057] (6) In vivo therapeutic effect of MF-GA / IL@MPN on pharyngitis rats

[0058] 1) Establishment of a pharyngitis model: SPF-grade male / female SD rats were used to establish a chronic pharyngitis model. The model induction drug was 2.5% ammonia water. 2.5% ammonia water was sprayed into the pharynx of the rats twice a day (9:00 AM and 4:00 PM, 8 hours apart), 3 times a day, for 4 weeks. The blank group was given an equal amount of pure water as a normal control.

[0059] 2) Grouping and Management: To evaluate the anti-inflammatory effect of MF-GA / IL@MPN microcapsules on chronic pharyngitis, after establishing a rat model of chronic pharyngitis, rats were randomly divided into nine groups: blank group, model group, positive control group, mangiferin group, glycyrrhizic acid group, mixed group, and low-, medium-, and high-dose microcapsule groups. Each group consisted of eight rats, with an equal number of males and females. All treatment groups received treatment via a spray, administered every other day, with eight sprays administered intermittently for three consecutive weeks. On the second day after each administration, behavioral observations such as weight change and food and water intake were monitored. After treatment, laryngoscopic observation of the rats' pharynx was performed. Rats were euthanized according to institutional guidelines, and serum, heart, liver, spleen, lung, kidney, and larynx tissues were collected for subsequent experiments.

[0060] 3) Laryngoscopy to observe pharyngeal features: Using a rat and mouse laryngoscope, the structure of the pharynx and larynx in rats was observed to assess the health status, inflammation, and pathological changes in the pharynx and larynx. The rat pharyngeal laryngoscopy procedure consists of three steps: First, equipment preparation, i.e., preparing the rat and mouse laryngoscope; second, anesthesia, as the pharynx and larynx are relatively deep in rats, it is necessary to ensure that the rat is under anesthesia to avoid stress or injury; third, observation, after anesthesia, the laryngoscope probe is inserted into the rat's pharynx through the mouth, and the health status of the pharynx and larynx is examined by observing the laryngoscope image, noting any redness, swelling, ulcers, masses, or other pathological changes. During the examination, images are acquired using the laryngoscope camera system.

[0061] 4) Monitoring of inflammatory cells: To assess the anti-inflammatory effect of MF-GA / IL@MPN microcapsules, changes in inflammatory cells can serve as an effective monitoring indicator. The occurrence, development, and control of inflammatory responses in rats were assessed by detecting and analyzing changes in inflammatory cells in rat blood, such as changes in the levels of leukocytes, lymphocytes, and neutrophils.

[0062] 5) Detection of serum inflammatory cytokines: After separating the serum, the levels of TNF-α, IL-6, and IL-1β in rat serum were detected using an ELISA kit according to the instructions.

[0063] 6) Histopathological examination: The laryngeal tissue was fixed overnight with 4% paraformaldehyde, then decalcified with 10% EDTA solution for 30 days, dehydrated, embedded in paraffin, and tissue sections were prepared. The sections were stained with hematoxylin and eosin (H&E, Sigma Aldrich) and observed under an optical microscope.

[0064] 7) In vivo safety assessment: To further investigate the hematologic toxicity of MF-GA / IL@MPN microcapsules, routine blood tests were performed on rats to monitor changes in the levels of red blood cells, hemoglobin, and platelets. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine (CRE), and blood urea nitrogen (BUN) levels were measured using standard kits according to the manufacturer's instructions. Simultaneously, histopathological analysis was performed on liver, kidney, and lung tissues.

[0065] (7) Statistical Analysis

[0066] All data were analyzed using one-way ANOVA. p < 0.05 was considered statistically significant.

[0067] Results analysis:

[0068] (1) Preparation and characterization of CAGE ILs

[0069] CAGE ILs were synthesized via a metathesis reaction of geranilic acid and choline bicarbonate in a 1:1 molar ratio. The structures of the CAGE ILs were characterized by 1H-NMR and infrared (IR) spectroscopy. Figure 1 The 1H-NMR spectrum showed that the carboxyl peak of geraniol appeared at a chemical shift of 11.90 ppm. In the 1H NMR spectrum of the product CAGE ILs, geraniol-related peaks appeared at chemical shifts of 5.0-5.60 ppm and 1.58-2.64 ppm, while the 11.90 ppm carboxyl peak disappeared, and a bicarbonate-choline-related peak appeared at 3.40-3.86 ppm. The 1634 cm⁻¹ of the geraniol FTIR spectrum... -1 and 1684cm -1 A strong characteristic absorption peak of the carboxyl group is present, which is due to the C=O stretching vibration absorption in the carboxyl group of geranilic acid. However, in the FTIR spectrum of CAGE ILs, the strong absorption of the carboxyl characteristic peak weakens. In the FTIR spectrum of choline bicarbonate, the absorption peak at 3200 cm⁻¹ is also weaker. -1 The peak represents the stretching vibration of the -OH group on the carboxyl group of choline bicarbonate. The -OH peak of choline showed a significant decrease in the FTIR spectrum of CAGE ILs, which is attributed to its participation in the reaction. Based on the combined results of the 1H and 1R spectra, the preliminary assessment indicates successful preparation.

[0070]

[0071] (2) Preparation of MF-GA / IL@MPN

[0072] 1) Primary screening of coordination metals

[0073] MF-GA / IL@MPN microcapsules were prepared via the self-assembly of a metallophenol network at the IL / water interface. In the preparation process, suitable metal ions were first screened from common metals used for metallophenol coordination, including manganese (Mn2). + ), aluminum (Al) 3 +), magnesium (Mg) 2+ ) and iron (Fe2) + or Fe3 + These metal ions can often form coordination compounds with the phenolic hydroxyl groups in drug molecules, thereby affecting the stability and bioavailability of the drug.

[0074] A certain mass of mangiferin and glycyrrhizic acid were dissolved in an ionic liquid. Then, 100 μL of the ionic liquid containing the drug was added to 20 mL of pure water at a volume ratio of 1:200. Next, the drug content was adjusted according to the Fe... 3+ / Mn 2+ / Al 3+ / Mg 2+Metal ions were fed in a ratio of 1:50 (mass ratio), and the particles were ultrasonically sonicated at 40% amplitude for 60 seconds using an ultrasonic probe. The particle size was then measured (Table 1).

[0075] 2) Optimization of coordination metal preparation conditions

[0076] Preliminary screening results indicate that Fe 3+ And Al 3+ It can be used as a coordination metal candidate. Subsequently, conditions were optimized for the two metal ions, and orthogonal experiments were designed to study the effects of various factors, such as metal ion content, pH value, total dosage of MF and GA, and IL / water volume ratio, on the nanocapsule particle size. These four factors are denoted as A, B, C, and D, respectively. Simultaneously, each factor was assigned three levels, thus obtaining Fe... 3+ And Al 3+ The factor level table (Table 2) shows the effect of the four factors on Fe. Based on the orthogonal test results, the four factors affect Fe... 3+ The importance ranking is C>A>D>B (Tables 3 and 4), while Al 3+ The order is A>C>D>B (Tables 4 and 6). Fe 3+ The optimal experimental design is A1B3C3D4, Al 3+ The optimal experimental protocol is A1B1C3D3. This takes into account the neutral environment of the oropharynx and the load Al. 3+ A clear solution of nanocapsules, Al 3+ The A1B1C3D3 scheme, as the coordination metal, is the best choice for preparing nanocapsules.

[0077] Table 1. Particle size results after coordination reaction of various metal ions with mangiferin.

[0078]

[0079]

[0080] Table 2 Factor Level Table

[0081]

[0082] Table 3 uses Fe 3+ Orthogonal design table for coordinating metal ions

[0083]

[0084] Table 4 uses Al 3+ Orthogonal design table for coordinating metal ions

[0085]

[0086] Table 5 uses Fe 3+ Table of orthogonal results for coordinating metal ions

[0087]

[0088]

[0089] Table 6 uses Al 3+ Table of orthogonal results for coordinating metal ions

[0090]

[0091] (3) Characterization of MF-GA / IL@MPN

[0092] MF-GA / IL@MPN microcapsules were prepared using mangiferin, glycyrrhizic acid, CAGE ILs, and AlCl3 as raw materials, based on the principle of metal-polyphenol coordination. The MF-GA / IL@MPN microcapsules exhibited a spherical and uniform morphology. Figure 2 (A). The average diameter of MF-GA / IL@MPN was 205.31±3.40 nm, and the PDI was 0.117±0.023. The narrow particle size distribution further verified the uniformity of the microcapsules. Figure 2 (B). The detected surface potential was -54.27±3.25mV, which to some extent demonstrates the stability of the microcapsule system, as the charge on the particle surface can prevent particle aggregation through electrostatic repulsion. Furthermore, the encapsulation efficiencies of MF and GA in MF-GA / IL@MPN were (80.58±2.53)% and (56.12±10.56)%, respectively, and the drug loadings of mangiferin and glycyrrhizic acid were (0.11±0.02)% and (0.08±0.02)%, respectively.

[0093] (4) Stability of MF-GA / IL@MPN

[0094] The stability of MF-GA / IL@MPN microcapsules at room temperature (25℃) was determined using a particle size potential analyzer. Figure 3 The microcapsules were incubated at 25°C for 14 days, and their particle size, PDI, and zeta potential were measured daily. The results showed that no significant changes in particle size and zeta potential were observed in the microcapsules over the 14 days. The zeta potential remained at a large absolute value of negative charge, indicating that the particles were highly dispersed and had good stability at room temperature.

[0095] (5) Release performance of MF-GA / IL@MPN

[0096] In vitro drug release profiles of MF-GA / IL@MPN and free MF and GA showed that free MF leaked out of the dialysis bag in a burst release manner within 2 hours, while MF-GA / IL@MPN leaked out in a sustained release manner. Figure 4Within 4 hours, the release rate of free MF from the dialysis bag exceeded 95%. Compared with MF-GA / IL@MPN, the release rate of free GA from the dialysis bag was higher at all time points, indicating that the microcapsule formulation has certain sustained-release drug characteristics.

[0097] (6) In vivo therapeutic effect of MF-GA / IL@MPN on pharyngitis rats

[0098] 1) Effects of MF-GA / IL@MPN on the pharyngeal epiphysiology

[0099] The laryngoscopy results showed ( Figure 5 In the control group, the pharyngeal tissue of rats was light red, moist and shiny, with no excessive secretions, and no pathological phenomena such as congestion, swelling, or ulceration. In the model group, large areas of acute congestion, swelling, and ulceration were observed in the pharyngeal tissue of rats. Compared with the model group, all treatment groups showed varying degrees of symptom relief, with the red color lightening, saliva secretion decreasing, and swelling and ulceration alleviating.

[0100] 2) Effects of MF-GA / IL@MPN on inflammatory cells

[0101] By detecting inflammatory cells in rats ( Figure 6 Compared with the control group, the number of white blood cells, lymphocytes, and neutrophils in the model group rats were all increased, indicating that there was an inflammatory infection in the model group rats. Among the drug-treated groups, the MF group and GA group had limited effects on inflammatory cells in pharyngitis rats, while the MF-GA / IL@MPN group at different concentrations had a good anti-inflammatory effect, bringing the inflammatory cells closer to normal levels.

[0102] 3) Effects of MF-GA / IL@MPN on inflammatory factors

[0103] Inflammatory cytokines from pharyngitis are typically present in the bloodstream. Therefore, we validated the inhibitory effect of MF-GA / IL@MPN on the production of inflammatory cytokines by measuring serum levels of TNF-α, IL-6, and IL-1β. Figure 7 Compared with the model group, the serum levels of IL-1β, IL-6 and TNF-α in the MF-GA / IL@MPN group were significantly reduced, and showed a certain dose-dependent effect.

[0104] 4) Effects of MF-GA / IL@MPN on pharyngeal histopathological changes

[0105] Histopathological examination of the pharynx revealed thickened and hyperplastic mucosal epithelium in the model group, with abundant stratified keratinized cells, vasodilation and congestion, minor hemorrhage in the glands, and loose connective tissue, with inflammatory cell infiltration observed. In the control group, the mucosa was normal in morphology, smooth and flat, without obvious differentiation, with compact connective tissue, and basically normal blood vessels and glands, without significant cell infiltration. Compared with the model group, each treatment group showed reduced inflammatory cell infiltration and more compact muscle tissue. The efficacy of MF-GA / IL@MPN at low, medium, and high doses showed an increasing trend. Figure 8 ).

[0106] (7) In vivo safety evaluation

[0107] 1) Hepatotoxicity and nephrotoxicity assay kits: For safety, hepatotoxicity is assessed by detecting serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and nephrotoxicity is assessed by detecting serum creatinine (CRE) and blood urea nitrogen (BUN). Figure 9 The results showed that, compared with the control group, the ALT level in the GA group and the AST level in the MF+GA group showed some liver damage. Among the MF-GA / IL@MPN gradient doses, only the high-dose group showed AST inhibition, while the low and medium-dose groups did not show hepatotoxicity. This indicates that appropriately concentrated MF-GA / IL@MPN can reduce MF and GA-induced liver damage. Creatinine (CRE) and blood urea nitrogen (BUN) levels showed no significant differences between the experimental groups and the control group, indicating that the preparation is harmless or has low toxicity to kidney tissue.

[0108] 2) Complete blood count (CBC) for blood toxicity: A CBC was performed to determine whether MF-GA / IL@MPN would cause adverse blood reactions. Figure 9 The results showed that MF-GA / IL@MPN had no significant effect on the body's red blood cells, platelets, and hemoglobin, indicating that the preparation would not cause adverse blood reactions, which is also a manifestation of its safety.

[0109] 3) Histopathological assessment of toxicity: Histopathological analysis was conducted to investigate whether MF-GA / IL@MPN had any adverse effects on the liver, kidneys, and lung tissues of rats with pharyngitis. Figure 10The results showed that in all groups of liver tissue, HE staining revealed that hepatocytes were arranged regularly and uniformly, with clear cell structure and no obvious inflammation or lesions. This indicates that MF-GA / IL@MPN is non-toxic or low-toxic to liver tissue. In all groups of kidney tissue, HE staining revealed clear cell arrangement in the renal tubules and glomeruli, with no obvious lesions. The cytoplasm of the renal tubules was pink, the capillary network structure of the glomeruli was clear, and there was no edema or inflammatory reaction in the interstitial tissue. This indicates that MF-GA / IL@MPN is non-toxic or low-toxic to kidney tissue. In all groups of lung tissue, HE staining showed that, compared with the experimental groups, the blank group showed clear cells, thin alveolar walls, intact vascular structure, no fluid or exudate in the alveoli, neatly arranged alveolar wall cells, and no inflammatory cells in the alveolar cavities. The fibrous tissue of the lung interstitium was uniform, with no obvious hyperplasia. The pulmonary vascular walls were clear, without thrombosis or abnormal hyperplasia, indicating that MF-GA / IL@MPN is non-toxic or low-toxic to lung tissue.

[0110] 4) Effects of MF-GA / IL@MPN on organ coefficients and body weight in rats

[0111] In the later stages of the experiment, the organ coefficients of rats in each experimental group (Table 6) and changes in body weight during the drug administration period were compared. Figure 11 As can be seen, the organ coefficients of the experimental group did not change abnormally compared with the blank group, and the weight changes of rats in each group were relatively stable, indicating that the preparation is safe or low in toxicity.

[0112] Table 6. Organ coefficients of rats in each group

[0113]

[0114] In summary, we have successfully prepared a microcapsule drug MF-GA / IL@MPN based on the metal-polyphenol coordination principle. This system consists of an ionic liquid (IL) as the internal carrier and a metallophenol network (MPN) as the microcapsule shell. The formation of the MPN shell improves the stability of the IL droplets in water, while the encapsulated IL core effectively loads the drug and enhances its tissue permeability, thereby improving drug bioavailability. Furthermore, MF-GA / IL@MPN can downregulate the levels of IL-1β, IL-6, and TNF-α, exerting an anti-chronic pharyngitis therapeutic effect.

[0115] Application Examples 1-3

[0116] Application Example 1

[0117] A certain amount of the microcapsules of this invention are weighed and dissolved in an aqueous ink, mechanically stirred for 1-2 hours, and mixed evenly to obtain a homogeneous solution A. The homogeneous solution A is then transferred to the surface of 10kg tipping paper using a gravure printing process, and then dried at a constant temperature of 80-90℃. The dried paper undergoes further processes such as hot stamping, slitting, and perforation to obtain functional cigarette tipping paper. The amount of microcapsules added to this tipping paper is 4.26g / m³. 2 The amount of mangiferin added was 0.46 g / m³. 2 The amount of glycyrrhizic acid added was 0.34 g / m³. 2 .

[0118] Application Example 2

[0119] A certain amount of the microcapsules of this invention are weighed and dissolved in an aqueous ink, mechanically stirred for 1-2 hours, and mixed evenly to obtain a homogeneous solution A. The homogeneous solution A is then transferred to the surface of 10kg tipping paper using a gravure printing process, and then dried at a constant temperature of 80-90℃. The dried paper undergoes further processes such as hot stamping, slitting, and perforation to obtain functional cigarette tipping paper. The amount of microcapsules added to this tipping paper is 4.98g / m³. 2 The amount of mangiferin added was 0.54 g / m³. 2 The amount of glycyrrhizic acid added was 0.40 g / m³. 2 .

[0120] Application Example 3

[0121] A certain amount of the microcapsules of this invention are weighed and dissolved in an aqueous ink, mechanically stirred for 1-2 hours, and mixed evenly to obtain a homogeneous solution A. The homogeneous solution A is then transferred to the surface of 10kg tipping paper using a gravure printing process, and then dried at a constant temperature of 80-90℃. The dried paper undergoes further processes such as hot stamping, slitting, and perforation to obtain functional cigarette tipping paper. The amount of microcapsules added to this tipping paper is 6.42g / m³. 2 The amount of mangiferin added was 0.70 g / m³. 2 The amount of glycyrrhizic acid added was 0.52 g / m³. 2 .

[0122] Comparative Example

[0123] A certain amount of blank microcapsules of the present invention were weighed and dissolved in an aqueous ink, mechanically stirred for 1-2 hours, and mixed evenly to obtain a homogeneous solution A. The homogeneous solution A was then transferred to the surface of 10kg tipping paper using a gravure printing process, and then dried at a constant temperature of 80-90℃. The dried paper underwent further processes such as hot stamping, slitting, and perforation to obtain functional cigarette tipping paper. The amount of microcapsules added to this tipping paper was 4.86g / m³. 2 The amount of mangiferin added was 0 g / m³. 2The amount of glycyrrhizic acid added was 0 g / m³. 2 .

[0124] Sensory evaluation

[0125] Based on a certain specification of slim cigarette currently in production by the company (cigarette length 97mm, circumference 17mm, filter length 30mm); benchmark auxiliary material parameters: cigarette paper basis weight 28g / m³ 2 The cigarette paper has an air permeability of 50 CU, is a regular forming paper, uses the same formula of tobacco, and employs the tipping paper prepared according to this invention. Four cigarette samples are rolled on the same machine. The cigarette samples are equilibrated under the conditions specified in GB / T 16447-2004, and then smoked according to the method specified in GB / T 19609-2004.

[0126] Table 7 Sensory evaluation results of conventional cigarettes with added microcapsules

[0127]

[0128] As can be seen from Table 1, the overall sensory quality of cigarettes with added tea mangiferin-glycyrrhizic acid ionic liquid microcapsules is better than that of cigarettes with added blank ionic liquid microcapsules. Specifically, the cigarettes with added tea mangiferin-glycyrrhizic acid ionic liquid microcapsules have a significantly enhanced fruity aroma: they have a stronger sweet and green aroma, and the consistency between the first and last puffs is better, showing good application prospects.

[0129] Although the present invention has been disclosed above with reference to embodiments, it is not intended to limit the present invention. Any person skilled in the art can make various different choices and modifications without departing from the spirit and scope of the present invention. Therefore, the scope of protection of the present invention is defined by the claims and their equivalents.

Claims

1. A microcapsule drug for treating chronic pharyngitis, characterized in that, The drug is MF-GA / IL@MPN, which is a microcapsule carrier consisting of an ionic liquid (IL) as the core and a metallophenol network (MPN) as the shell; wherein, the metallophenol network is formed by the coordination reaction of aluminum ions with mangiferin and glycyrrhizic acid, and the ionic liquid is CAGEILs formed by geraniol and choline.

2. The anti-chronic pharyngitis microcapsule drug according to claim 1, characterized in that, The microcapsules have an average particle size of 205.31±3.40 nm, a polydispersity index (PDI) of 0.117±0.023, and a zeta potential of -54.27±3.25 mV.

3. The anti-chronic pharyngitis microcapsule drug according to claim 1, characterized in that, The encapsulation efficiency of mangiferin was 80.58±2.53%, and the drug loading was 0.11±0.02%; the encapsulation efficiency of glycyrrhizic acid was 56.12±10.56%, and the drug loading was 0.08±0.02%.

4. The method for preparing the anti-chronic pharyngitis microcapsule drug according to any one of claims 1-3, characterized in that, Includes the following steps: (1) Synthesis of CAGEILs: Geranilic acid and choline bicarbonate were mixed with methanol at a molar ratio of 1:1 and stirred at room temperature overnight. Then, the mixture was rotary evaporated and vacuum dried for 48 hours to obtain CAGEILs. (2) Preparation of microcapsules: At room temperature, weigh 1 mg of mangiferin and 1 mg of glycyrrhizic acid and mix them in the same centrifuge tube. Add 1 mL of CAGE ILs to the centrifuge tube and heat in a 50°C water bath to dissolve mangiferin and glycyrrhizic acid. Disperse 0.1 mL of CAGE ILs containing 0.1 mg of mangiferin and 0.1 mg of glycyrrhizic acid in 20 mL of water. After sonication for 60 s, add 0.2 mL of AlCl3 solution with a concentration of 10 mg / mL and continue sonication for 30 s to promote the coordination of aluminum ions with mangiferin at the IL / water interface to form a metallophenol shell, thus obtaining MF-GA / IL@MPN microcapsules.

5. The preparation method according to claim 4, characterized in that, The ultrasonic treatment conditions in step (2) are as follows: ultrasonication at 40% amplitude for 1 min in an ice bath, followed by the addition of AlCl3 and continued ultrasonication for 30 s; the concentration of the aluminum chloride solution is 10 mg / mL, and the added volume is twice that of the IL solution.

6. The preparation method according to claim 4, characterized in that, The mass ratio of mangiferin, glycyrrhizic acid, and chloroforms is 1:1:900, and the mass ratio of chloroforms to water is 0.9:

20.

7. The use of the anti-chronic pharyngitis microcapsule drug according to any one of claims 1-3 in the preparation of cigarette tipping paper with pharyngitis protection function.

8. The application according to claim 7, characterized in that, The application involves dissolving the MF-GA / IL@MPN microcapsules in an aqueous ink and preparing tipping paper using a gravure printing process. The amount of microcapsules added to the tipping paper is 6.42 g / m³. 2 The amount of mangiferin added was 0.70 g / m³. 2 The amount of glycyrrhizic acid added was 0.52 g / m³. 2 .

9. A method for preparing cigarette tipping paper, characterized in that, Includes the following steps: (1) Dissolve the microcapsules according to any one of claims 1-3 in an aqueous ink oil, stir mechanically for 1-2 hours, and after mixing evenly, obtain a homogeneous solution; (2) The homogeneous solution is transferred to the surface of the tipping paper using a gravure printing process, and then dried at a constant temperature of 80-90℃. The dried paper is then hot-stamped, slit, and perforated to obtain the functional cigarette tipping paper. The amount of microcapsules added to the tipping paper is 6.42 g / m³. 2 The amount of mangiferin added was 0.70 g / m³. 2 The amount of glycyrrhizic acid added was 0.52 g / m³. 2 .

10. The use of the anti-chronic pharyngitis microcapsule drug according to any one of claims 1-3 in the preparation of products for treating chronic pharyngitis.

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