A drug-loaded HNTs encapsulation and a preparation method and application thereof

Abstract

This invention provides a drug-loaded halloysite material, its preparation method, and its application. The drug-loaded halloysite material is prepared from halloysite, a drug, and an encapsulation material. Halloysite has good loading and sustained-release effects on drugs such as ciprofloxacin, diclofenac sodium, and nicotinic acid. Encapsulation with the encapsulation material further delays the release of the drug, resulting in slow release in the intestine and stomach, achieving targeted and controlled release. In addition, its preparation method is simple and can achieve rapid encapsulation, further avoiding drug loss during the encapsulation process. It can be used in the biomedical field, especially in the application of sustained-release drugs and intestinal targeted drug delivery, showing good application prospects.

Description

Technical Field

[0001] This invention relates to the field of medical materials, specifically to a drug-loaded HNTs encapsulated with the drug, its preparation method, and its application. Background Technology

[0002] With the continuous development of medical technology, people are paying more and more attention to the control of drug administration. Some drugs may have the following problems during use: (1) They act on other organs before reaching the site where they are supposed to exert their effects, causing certain damage to other organs; (2) Some drugs have poor stability and are degraded and metabolized during transport, failing to achieve good quality effects; (3) Some drugs have poor solubility in the human digestive tract environment and are difficult to be absorbed; (4) Some drugs need to act continuously and be administered without interruption. If the drug dose is too large at one time, it may have a significant impact on the human body and cause other health problems. However, if the drug dose is insufficient, the quality objectives cannot be achieved. The existence of these problems not only imposes certain restrictions on the clinical use of drugs, but also provides a great driving force for the development of new drugs.

[0003] By selecting appropriate carrier materials, loading drugs onto them, and selectively modifying or encapsulating the carrier materials functionally, drug delivery systems can be constructed, effectively addressing issues such as poor drug solubility and low stability. Simultaneously, drugs can be endowed with certain functional responsiveness, enabling them to be smoothly delivered to the desired site and released specifically, maximizing drug utilization and reducing toxic side effects. Numerous studies have demonstrated that the development and selection of drug carriers are of paramount importance for constructing rational and reliable drug systems. Among them, nanomaterials with large specific surface areas show great application potential. Currently, many researchers are using nanomaterials as carriers to encapsulate small molecule drugs, bactericides, nucleic acids, biological enzymes, and detection reagents, applying them to the prevention and diagnosis of medical diseases, as well as anti-inflammatory, bactericidal, and cancer treatment applications.

[0004] Nanoparticles are drug-carrying particles with sizes ranging from 1 to 1000 nm. By utilizing the hydrophilic and hydrophobic groups and hydrogen bonds on the surface of the drug and the carrier, drugs can be bound or adsorbed onto the nanoparticles through covalent bonding, electrostatic adsorption, etc., forming a stable drug delivery system. These forces are not very strong; under certain conditions, drug molecules can detach from the nanoparticles, thus achieving release. Different types of nanoparticles have different properties and functions, and their binding effects with different drugs vary. Therefore, to maximize drug utilization, the rational selection of nanoparticles is essential. Meanwhile, researchers are continuously expanding and deepening their research on nanoparticles, developing more novel nanoparticle drug carrier materials.

[0005] Currently, common nanomedicine carriers are mainly classified into metal nanocarriers, organic nanocarriers, and inorganic nanocarriers based on their properties. Metal nanocarriers include gold nanoparticles and silver nanoparticles; organic nanocarriers include liposomes, polymer micelles, and dendritic macromolecules; and inorganic nanocarriers include silica, carbon nanotubes, and clay minerals. In recent years, research on nanomedicine carriers has mainly focused on liposomes, polymer micelles, mesoporous silica, and clay minerals.

[0006] Halloysite (HNTs) in clay minerals have the characteristics of good biocompatibility, low cytotoxicity, abundant surface groups, different reactions between inner and outer surfaces, and unique hollow tubular structure. In addition, they also have the characteristics of large specific surface area, high porosity, and abundant hydroxyl matrix. They are one of the centrifugal materials for medical drug carriers and have extremely significant advantages in the field of nanomedicine carrier materials.

[0007] Studies on HNTs as medical drug carriers are not uncommon, but they mainly focus on the surface modification and encapsulation of HNTs. There are relatively few studies on successfully loading drug molecules into the cavity of HNTs, which is undoubtedly a natural loading container for some drugs. Summary of the Invention

[0008] Based on the aforementioned technical background, the inventors made pioneering efforts and discovered that HNTs, as drug carriers, have excellent sustained-release effects on ciprofloxacin, diclofenac sodium, nicotinic acid, and other drugs. Furthermore, these drugs exhibit sensitive pH responsiveness, and encapsulation further delays drug release. In particular, the double-layer encapsulation using pectin and chitosan imparts superior sustained-release performance, resulting in slow release in the intestines and stomach, achieving targeted controlled release. Moreover, the loading and encapsulation process is simple and rapid, significantly shortening the encapsulation time while ensuring a high degree of encapsulation, thus avoiding drug loss during the encapsulation process. This demonstrates great application potential and promising prospects.

[0009] The first aspect of the present invention is to provide a drug-loaded halloysite material for encapsulation, the drug-loaded halloysite material being prepared from halloysite, a drug and an encapsulation material;

[0010] The drug is selected from one or more of ciprofloxacin, diclofenac sodium, nicotinic acid, aspirin, sodium salicylate, and ibuprofen.

[0011] A second aspect of the present invention is to provide a method for preparing the drug-loaded halloysite material described in the first aspect of the present invention, the method comprising the following steps:

[0012] Step 1: Add HNTs to the drug solution, stir, and let stand under vacuum to obtain drug-loaded HNTs;

[0013] Step 2: Add drug-loaded HNTs to the encapsulation material solution and stir to obtain encapsulated drug-loaded HNTs.

[0014] The third aspect of the present invention is to provide an application of the encapsulated drug-loaded halloysite material according to the first aspect of the present invention or the encapsulated drug-loaded halloysite material prepared by the preparation method according to the second aspect of the present invention, which can be applied in the biomedical field, especially for sustained-release drugs and intestinal targeted drug delivery. Attached Figure Description

[0015] Figure 1a , 1b 1c shows transmission electron micrographs of drug-loaded HNTs, respectively;

[0016] Figure 2 The XRD patterns of the drug-loaded HNTs and the raw ore prepared in Examples 1-3 are shown.

[0017] Figure 3 The XRD patterns of the comparative example and the raw ore are shown;

[0018] Figure 4 The infrared spectra of the comparative example and the raw ore are shown;

[0019] Figure 5 The following are line graphs showing the Zeta potentials of the products obtained in Examples 1-9;

[0020] Figure 6a and 6b The sustained-release performance test curves of Examples 1, 4, and 7 in gastric and intestinal fluids are shown respectively.

[0021] Figure 7a and 7b The sustained-release performance test curves of Examples 2, 5, and 8 in gastric and intestinal fluids are shown respectively.

[0022] Figure 8a and 8b The sustained-release performance test curves of Examples 3, 6, and 9 in gastric and intestinal fluids are shown respectively.

[0023] Figure 9 The sustained-release performance curves of the product obtained in Example 8 under different pH conditions are shown. Detailed Implementation

[0024] The present invention will now be described in detail, and its features and advantages will become clearer and more apparent from these descriptions.

[0025] The first aspect of the present invention is to provide a drug-loaded halloysite material, which is made of halloysite, a drug and an encapsulation material.

[0026] The drug is selected from one or more of ciprofloxacin, diclofenac sodium, nicotinic acid, aspirin, sodium salicylate, and ibuprofen; preferably selected from one or more of ciprofloxacin, diclofenac sodium, nicotinic acid, and aspirin, and more preferably selected from one or more of ciprofloxacin, diclofenac sodium, and nicotinic acid.

[0027] HNTs offer significant advantages as sustained-release materials for the aforementioned drugs. The encapsulating material surrounding them can further delay drug release, improving the sustained-release performance of the drug in the target organ. Furthermore, these drugs exhibit highly sensitive pH responsiveness.

[0028] The mass ratio of halloysite to the drug is 1:(30-100), preferably 1:(40-80), and more preferably 1:(50-70).

[0029] The halloysite used in this invention is raw halloysite ore, preferably provided by China Kaolin Co., Ltd., produced in Suzhou, Jiangsu Province. The halloysite tube has a length of about 0.3 to 1.5 μm, an outer diameter of about 70 to 200 nm, and an inner diameter of about 20 to 50 nm.

[0030] The encapsulation material for the drug-loaded halloysite material is selected from one or more of pectin, chitosan, polyvinyl alcohol, and lactic acid-glycolic acid copolymer, preferably from one or more of pectin, chitosan, and polyvinyl alcohol, and more preferably from one or two of pectin and chitosan.

[0031] The aforementioned encapsulation material can rapidly encapsulate drug-loaded HNTs. Furthermore, after encapsulation with the aforementioned encapsulation material, the initial burst release rate can be reduced to a certain extent, and the slow release time can be prolonged, exhibiting excellent sustained-release performance. It also has very sensitive pH responsiveness, hardly releasing in the gastric juice environment, and slowly releasing in the intestinal simulated environment, thus achieving targeted controlled release in the intestine.

[0032] The mass ratio of halloysite to encapsulation material is (0.1-3):100, preferably (0.3-2.5):100, and more preferably (0.5-2):100.

[0033] Experiments have shown that the amount of encapsulation material added significantly affects the encapsulation time. When the amount of encapsulation material added is within the above range, the encapsulation of drug-loaded HNTs can be completed quickly.

[0034] In a further preferred embodiment, the encapsulation materials are pectin and chitosan, achieving double-layer encapsulation of halloysite and exhibiting excellent sustained-release properties.

[0035] In the double-layer encapsulation, the mass ratio of pectin to chitosan is 1:(1-3), preferably 1:(1.5-2.5).

[0036] The encapsulated drug-loaded halloysite material of the present invention allows the drug to be loaded inside or outside the halloysite tube. This encapsulated drug-loaded halloysite material has excellent sustained-release performance and pH responsiveness.

[0037] In simulated intestinal fluid, the burst release rate of the encapsulated drug-loaded halloysite material was 10-42% within 5 minutes, while in simulated gastric fluid, the burst release rate was 0-20% within 5 minutes. It exhibits almost no release in the gastric fluid environment but releases slowly in the simulated intestinal environment, with a long release time in the simulated intestinal fluid, continuing to release slowly even after 360 minutes.

[0038] The critical pH for drug release of the encapsulated drug-loaded halloysite material is 3–7, and the drug release rate increases with increasing pH.

[0039] A second aspect of the present invention is to provide a method for preparing the drug-loaded halloysite material described in the first aspect of the present invention, the method comprising the following steps:

[0040] Step 1: Add HNTs to the drug solution, stir, and let stand under vacuum to obtain drug-loaded HNTs;

[0041] Step 2: Add drug-loaded HNTs to the encapsulation material solution and stir to obtain encapsulated drug-loaded HNTs.

[0042] The following is a detailed description and explanation of this step.

[0043] Step 1: Add HNTs to the drug solution, stir, and let stand under vacuum to obtain drug-loaded HNTs.

[0044] The drug solution is prepared by dissolving the drug in a solvent, wherein the solvent is selected from one or more of water and ethanol, preferably water.

[0045] The pH value of the drug solution is 2 to 9, preferably 4 to 7.

[0046] The inventors have discovered that the pH of the drug solution affects the adsorption capacity of the drug on the HNTs carrier. When the pH of the solution is below 4 or above 7, the adsorption effect of HNTs on the drug is poor, the loading capacity is limited, and the adsorption capacity is low.

[0047] The concentration of the drug solution is 1000-2000 mg / mL, preferably 1200-1700 mg / mL, and more preferably 1400-1600 mg / mL.

[0048] The drug is selected from one or more of ciprofloxacin, diclofenac sodium, nicotinic acid, aspirin, sodium salicylate, and ibuprofen; preferably selected from one or more of ciprofloxacin, diclofenac sodium, nicotinic acid, and aspirin, and more preferably selected from one or more of ciprofloxacin, diclofenac sodium, and nicotinic acid.

[0049] The mass ratio of halloysite to the drug is 1:(30-100), preferably 1:(40-80), and more preferably 1:(50-70).

[0050] The stirring time is 1 to 5 hours, preferably 2 to 4 hours. The stirring temperature is 20 to 30°C, preferably 25°C.

[0051] The vacuum pressure is 0.5 to 1 bar, preferably 0.7 to 0.9 bar.

[0052] Experiments have shown that under vacuum conditions, the drug solution can break capillary forces, allowing the drug solution to enter the lumen of HNTs and be loaded within the lumen, which is beneficial for improving the sustained-release performance of HNTs.

[0053] The settling time is 20 to 60 minutes, preferably 30 to 50 minutes.

[0054] After vacuuming and allowing the mixture to stand repeatedly, the loading capacity and loading effect of the drug on HNTs can be improved. The above mixed solution is then centrifuged at 50-70°C and dried.

[0055] Step 2: Add drug-loaded HNTs to the encapsulation material solution and stir to obtain encapsulated drug-loaded HNTs.

[0056] The encapsulation material solution is prepared by placing the encapsulation material in a solvent, wherein the solvent is selected from one or more of water, acetic acid, and ethanol, preferably one or two of water and acetic acid.

[0057] The encapsulation material is selected from one or more of pectin, chitosan, polyvinyl alcohol, and lactic acid-glycolic acid copolymer, preferably from one or more of pectin, chitosan, and polyvinyl alcohol, and more preferably from one or two of pectin and chitosan.

[0058] The mass ratio of halloysite to encapsulation material is (0.1-3):100, preferably (0.3-2.5):100, and more preferably (0.5-2):100.

[0059] Experiments have shown that if too little encapsulation material is added, the encapsulation time is long and the encapsulation effect is poor. As the amount of encapsulation material added increases, the encapsulation time gradually decreases, enabling rapid encapsulation and preventing excessive release of drugs during the encapsulation process.

[0060] In a preferred embodiment of the present invention, the encapsulation material is pectin and chitosan. The mass ratio of pectin to chitosan is 1:(1-3), preferably 1:(1.5-2.5).

[0061] The inventors have discovered that the double encapsulation of halloysite with pectin and chitosan can endow it with superior sustained-release properties and prolong the duration of slow release. Specifically, in the sustained-release process simulating intestinal fluid, pectin plays the main role in sustained-release performance, while chitosan plays the main role in inhibiting drug release. In gastric fluid, chitosan plays the main role in sustained-release performance.

[0062] The stirring speed is 300-800 r / min, preferably 400-600 r / min.

[0063] The stirring time is 0.5 to 60 minutes, preferably 0.5 to 5 minutes. The encapsulation material described in this application can encapsulate drug-loaded HNTs in a relatively short time.

[0064] After stirring, the above mixed solution is centrifuged to disperse it, and excess encapsulation material is washed away to obtain encapsulated drug-loaded HNTs.

[0065] The third aspect of the present invention is to provide an application of the encapsulated drug-loaded halloysite material according to the first aspect of the present invention or the encapsulated drug-loaded halloysite material prepared by the preparation method according to the second aspect of the present invention, which can be applied in the biomedical field, especially for sustained-release drugs and intestinal targeted drug delivery.

[0066] This encapsulated drug-loaded halloysite material is a pH-responsive intestinal targeted controlled-release drug delivery system. The drug is essentially not released in the stomach, which can effectively reduce the side effects of the drug on the stomach and improve the drug utilization rate. It has positive significance for the utilization and development of medical drugs.

[0067] The beneficial effects of this invention are as follows:

[0068] (1) The encapsulated drug-loaded halloysite material of the present invention is made of halloysite, drug and encapsulation material. The encapsulated drug-loaded halloysite material can achieve rapid encapsulation and effectively avoid excessive release of drug during the encapsulation process.

[0069] (2) The drug described in this invention is loaded inside and outside the tube of halloysite, and loaded inside the lumen, which is beneficial to further improve the sustained release performance of HNTs on the drug.

[0070] (3) The encapsulated drug-loaded halloysite material described in this invention has excellent sustained-release performance and sensitive pH response. It hardly releases in the gastric juice environment and slowly releases in the intestinal simulated environment, thereby achieving targeted controlled release in the intestine.

[0071] (4) The preparation method of the encapsulated drug-loaded halloysite material is simple, which can achieve rapid encapsulation, effectively reduce the excessive release of drugs during the encapsulation process, reduce the side effects of drugs on the stomach and other organs, and improve drug utilization.

[0072] Example

[0073] The present invention is further illustrated by specific examples below. These embodiments are only for illustrating the present invention and are not intended to limit the scope of the present invention.

[0074] Example 1

[0075] 250 mg of HNTs (China Kaolin Co., Ltd.) was added to 10 mL of a drug solution with a concentration of 1500 mg / mL. The solvent was water, and the pH of the ciprofloxacin (CIP) solution was 4. The solution was stirred at room temperature for 3 h while maintaining a constant pH during stirring. The solution was then placed in a vacuum drying oven and evacuated to 0.8 bar. After maintaining the vacuum for 40 min, the pressure was restored to normal. This vacuum cycle was repeated 3 times. Finally, the solution was centrifuged and dried overnight at 60 °C to obtain the drug-loaded HNTs.

[0076] Add 100 mg of CS (pectin) powder to 5 mL of 2% acetic acid solution, stir the suspension to form a transparent CS solution, add 100 mg of drug-loaded HNTs to 5 mL of CS solution, stir at 500 r / min for 1 min, centrifuge to disperse, rinse off excess CS polyelectrolyte with distilled water, and dry at 60 °C overnight to obtain CS-encapsulated drug-loaded HNTs.

[0077] Example 2

[0078] The preparation of drug-loaded HNTs was carried out in a manner similar to that in Example 1, except that the pH of the diclofenac sodium solution was 7.

[0079] Example 3

[0080] The preparation of drug-loaded HNTs was carried out in a similar manner to that in Example 1, except that the pH of the nicotinic acid solution was 7.

[0081] Example 4

[0082] The preparation of drug-loaded HNTs was carried out in a similar manner to that in Example 1, except that 200 mg of PCN powder was dissolved in 5 mL of distilled water, the suspension was stirred to form a transparent PCN solution, and 100 mg of drug-loaded HNTs was added to 5 mL of PCN solution.

[0083] Example 5

[0084] The preparation of drug-loaded HNTs was carried out in a similar manner to that in Example 2, except that 200 mg of PCN powder was dissolved in 5 mL of distilled water, the suspension was stirred to form a transparent PCN solution, and 100 mg of drug-loaded HNTs was added to 5 mL of PCN solution.

[0085] Example 6

[0086] The preparation of drug-loaded HNTs was carried out in a similar manner to that in Example 3, except that 200 mg of PCN powder was dissolved in 5 mL of distilled water, the suspension was stirred to form a transparent PCN solution, and 100 mg of drug-loaded HNTs was added to 5 mL of PCN solution.

[0087] Example 7

[0088] The preparation of drug-loaded HNTs was carried out in a similar manner to that in Example 1, except that: 100 mg of drug-loaded HNTs were added to 5 mL of CS acetic acid solution with a concentration of 20 mg / mL (acetic acid concentration of 2%), stirred at 500 r / min for 1 min, centrifuged, and excess CS polyelectrolyte was rinsed off with distilled water. Then, 5 mL of PCN solution with a concentration of 40 mg / mL was introduced into the solution, stirred at 500 r / min for 1 min, centrifuged, and excess PCN polyelectrolyte was rinsed off with distilled water.

[0089] Example 8

[0090] The preparation of drug-loaded HNTs was carried out in a similar manner to that in Example 2, except that: 100 mg of drug-loaded HNTs were added to 5 mL of CS acetic acid solution with a concentration of 20 mg / mL (acetic acid concentration of 2%), stirred at 500 r / min for 1 min, centrifuged, and excess CS polyelectrolyte was rinsed off with distilled water. Then, 5 mL of PCN solution with a concentration of 40 mg / mL was introduced into the solution, stirred at 500 r / min for 1 min, centrifuged, and excess PCN polyelectrolyte was rinsed off with distilled water.

[0091] Example 9

[0092] The preparation of drug-loaded HNTs was carried out in a similar manner to that in Example 3, except that: 100 mg of drug-loaded HNTs were added to 5 mL of CS acetic acid solution with a concentration of 20 mg / mL (acetic acid concentration of 2%), stirred at 500 r / min for 1 min, centrifuged, and excess CS polyelectrolyte was rinsed off with distilled water. Then, 5 mL of PCN solution with a concentration of 40 mg / mL was introduced into the solution, stirred at 500 r / min for 1 min, centrifuged, and excess PCN polyelectrolyte was rinsed off with distilled water.

[0093] Comparative Example

[0094] Add 100 mg HNTs to 5 mL of CS acetic acid solution with a concentration of 20 mg / mL (acetic acid concentration of 2%), stir at 500 r / min for 1 min, centrifuge, and rinse off excess CS polyelectrolyte with distilled water. Then introduce 5 mL of PCN solution with a concentration of 40 mg / mL, stir at 500 r / min for 1 min, centrifuge, and rinse off excess PCN polyelectrolyte with distilled water.

[0095] Experimental Example

[0096] Experiment Example 1: Transmission Electron Microscopy and EDS Testing

[0097] The drug-loaded HNTs prepared in Examples 1-3 were uniformly dispersed by sonication in ethanol for 30 min. The uniformly dispersed solution was then dropped onto a silicon wafer using a capillary pipette. After the ethanol evaporated, the wafer was placed under a JEM-2010 transmission electron microscope for testing. EDS analysis was performed on the drug-loaded HNTs prepared in Example 1, and the test results are shown below. Figure 1a , Figure 1b and Figure 1c As shown.

[0098] Figure 1a In the EDS spectrum, the F element unique to ciprofloxacin is uniformly distributed on the surface of HNTs, indicating that ciprofloxacin can be well adsorbed on the outer surface of HNTs. The transmission electron microscope shows that the gray scale increases and the resolution decreases at the lumen position, indicating that a certain amount of ciprofloxacin is loaded in the lumen of HNTs.

[0099] from Figure 1b As can be seen, diclofenac sodium is loaded in the lumen of HNTs, and the loading amount in the lumen is relatively large.

[0100] Figure 1c In the HNTs, a relatively large proportion showed nicotinic acid loading within the lumen.

[0101] Experiment Example 2: XRD Test

[0102] The drug-loaded HNTs prepared in Examples 1-3 were subjected to XRD analysis using a Rigako D / MAX-PC2005 diffractometer (Japan). A Cu target X-ray tube was used, equipped with a bent graphite monochromator. The tube voltage was set to 40 kW, the tube current to 100 mA, the scan rate to 9° / min, and the step size to 0.02°. The test results are as follows: Figure 2 As shown. The XRD test results of the comparative example and the raw ore are as follows. Figure 3 As shown.

[0103] from Figure 2 As can be seen, the XRD patterns of drug-loaded HNTs are almost identical to those of the original HNTs, indicating that the drug-loaded HNTs still retain the original crystal structure of HNTs, and the drug loading has no effect on the structure of HNTs themselves.

[0104] Figure 3 In the study, the XRD pattern of the encapsulated HNTs was consistent with that of the raw HNTs, indicating that the double encapsulation of pectin / chitosan did not affect the structure of HNTs, and HNTs still maintained their original crystal structure.

[0105] Experiment Example 3 Infrared Spectroscopy Test

[0106] The comparative sample and HNTs ore were tested using a Spectrum 100 Fourier transform infrared spectrometer manufactured by Platinum Elmer, Inc. KBr was dried at 150℃ for 4 hours, and the test material was dried at 60℃ for 5 hours before being used. 0.08 g of KBr was weighed, ground, and pressed into a pellet for testing as the test background. Then, 0.08 g of KBr and 0.02 g of the test material were ground and pressed into pellets, which were then placed in the instrument for testing. The measurement wavelength range was 4000–400 cm⁻¹. -1 The test results are as follows: Figure 4 As shown.

[0107] Figure 4 In the comparative study, the product obtained was at 1743 cm⁻¹. -1 and 1744cm -1 It exhibits a weak vibrational peak, corresponding to the carbonyl group in PCN, at 1566 cm⁻¹. -1 The amide group characteristic peak at the point is very weak, corresponding to the amide group in CS, indicating that PCN and CS were successfully loaded onto HNTs.

[0108] Experimental Example 4: Zeta Potential Test

[0109] Zeta potential testing was performed using a Zetasizer Nano ZS90 Zeta potential analyzer manufactured by Malvern Instruments Ltd., UK. The products obtained in Examples 1-9 were dispersed in water by sonication for 5 minutes to form colloidal systems, which were then dropped into the Zeta potential analyzer for testing. The test results are as follows: Figure 5 As shown.

[0110] from Figure 5 As can be seen, during the CS encapsulation process, the Zeta potential changes in the positive direction. After further PCN encapsulation, the Zeta potential changes from positive to negative. The drug-loaded PNTs after double-layer encapsulation become -23.8mV, -19.3mV and -22.1mV respectively. The changes in Zeta potential during the encapsulation process indicate the success of the encapsulation.

[0111] Experimental Example 5: Sustained-release performance test

[0112] Sustained-release performance test in gastric juice: 100g of the products prepared in Examples 1-9 were weighed and added to 200mL of gastric simulated buffer solution with pH=1.2 (simulated gastric juice was prepared by mixing 0.2M dilute hydrochloric acid and 0.2M KCl solution at a volume ratio of 250:147). The entire sustained-release system was stirred at 37°C with a magnetic stirring speed of 50r / min. 4mL of supernatant was pipetted at 5min, 10min, 20min, 30min, 60min, 120min, 240min, and 360min. The supernatant was filtered through a 0.22μm polyethersulfone aqueous filter membrane to remove HNTs in the solution. The drug content in the filtered supernatant was measured by ultraviolet spectrophotometry, and the drug release amount in the simulated gastric juice was calculated.

[0113] The formula for cumulative release is:

[0114] q t = (Ce*V) / m.

[0115] Where, q t -The cumulative release of halloysite per unit mass at time t, in mg / g;

[0116] The Ce-t time simulates the concentration of the drug in the solution, in mg / L;

[0117] V - Simulated solution volume, L;

[0118] m - Mass of drug-loaded halloysite, in g.

[0119] Cumulative release rate formula:

[0120] R(%)=(qt / Qe)*%.

[0121] The cumulative release of halloysite at time Rt, %;

[0122] The cumulative release of halloysite per unit mass at time qt-t, in mg / g;

[0123] Qe - the unit loading of the drug on halloysite, mg / g.

[0124] Sustained-release performance test in intestinal fluid: 100g of the products prepared in Examples 1-9 were weighed and added to 200mL of intestinal simulation buffer solution with pH=7.4 (simulated intestinal fluid was obtained by diluting 10x PBS phosphate buffer solution 10 times). The entire sustained-release system was kept at 37°C with stirring at a magnetic stirring speed of 50r / min. 4mL of supernatant was pipetted at 5min, 10min, 20min, 30min, 60min, 120min, 240min and 360min respectively. The supernatant was filtered through a 0.22μm polyethersulfone aqueous filter membrane to remove HNTs in the solution. The drug content in the filtered supernatant was measured by ultraviolet spectrophotometry, and the amount of drug released in the simulated intestinal fluid was calculated.

[0125] The test results of Examples 1, 4, and 7 in gastric juice and intestinal juice are as follows: Figure 6a and 6b As shown, the test results of Examples 2, 5, and 8 in gastric and intestinal fluids are as follows: Figure 7a and 7b As shown, the test results of Examples 3, 6, and 9 in gastric and intestinal fluids are as follows: Figure 8a and 8b As shown.

[0126] Figure 6a and 6b In simulated gastric fluid, the sustained-release effect of the drug-loaded HNTs prepared in Example 1 was poor, with an initial burst release of about 77%. In contrast, the release of the double-encapsulated drug-loaded HNTs prepared in Example 7 was not much different from its release in the simulated intestinal solution, at about 20%. Compared with the unencapsulated drug-loaded HNTs, the burst release and sustained-release amounts were significantly reduced. Both pectin and chitosan encapsulation reduced the release of CIP from HNTs to some extent, and the sustained-release effect of chitosan was better than that of pectin. This indicates that in gastric fluid, chitosan is the main agent responsible for the sustained-release effect of the double-encapsulated drug-loaded HNTs.

[0127] In simulated intestinal fluid, drug-loaded HNTs with double-layer encapsulation exhibited the best sustained-release performance, with a low burst release rate of only about 14% at 5 minutes, showing a clear sustained-release trend that continued to release slowly even after 360 minutes. The sustained-release performance of single-layer encapsulation with pectin and chitosan was second best, with pectin encapsulation showing a better sustained-release effect than chitosan encapsulation. This indicates that during the sustained-release process in simulated intestinal fluid, pectin has a better sustained-release effect than chitosan. Unencapsulated HNTs showed the worst sustained-release effect, but a clear sustained-release trend was still observed within 120 minutes, demonstrating that HNTs have significant advantages as natural sustained-release materials for CIP drugs.

[0128] Figure 7a and 7bIn simulated gastric fluid, the double-layer encapsulated HNTs did not release DS until 360 min later, but showed significant release in simulated intestinal fluid. This indicates that the double-layer encapsulated HNTs have a pH-responsive effect, releasing only in the neutral intestinal environment and not in the acidic gastric environment. Chitosan-encapsulated drug-loaded HNTs did not release DS within 240 min, only releasing trace amounts of DS into the solution after 240 min. This suggests that chitosan effectively prevents drug release in the acidic gastric environment. Although pectin-encapsulated HNTs continuously released DS, the release rate was not high, and its effect was not as significant as that of chitosan-encapsulated HNTs. This indicates that in simulated gastric fluid, the chitosan coating layer in the double-layer encapsulated product plays a more significant role in sustained release.

[0129] In simulated intestinal fluid, the double-layer encapsulated HNTs exhibited the best sustained-release performance and the lowest burst release rate of approximately 42%, showing a very clear sustained-release trend. Similar to CIP, pectin showed better sustained-release effects than chitosan in intestinal fluid, while unencapsulated drug-loaded HNTs showed poor sustained-release effects. This indicates that HNTs have limited sustained-release effects on DS, making encapsulation essential. The pectin and chitosan encapsulated on the outer surface can further delay the release of DS to some extent, improving its sustained-release performance in the intestine.

[0130] Figure 8a and Figure 8b In simulated intestinal fluid, the sustained-release effects of drug-loaded HNTs encapsulated in double layers and those encapsulated in pectin were not significantly different, with relatively low burst release rates of approximately 27% and 26% at 5 minutes, respectively. However, the release time of NA encapsulated in double layers was longer, continuing even after 360 minutes. The sustained-release effect of chitosan encapsulation was moderate, indicating that pectin played a major role in sustained release in simulated intestinal fluid.

[0131] In simulated gastric fluid, the sustained-release curves of the double-layer encapsulation and chitosan encapsulation largely overlapped, and both exhibited very low burst release rates, around 8% at 5 minutes. Subsequent release rates for all three encapsulation methods remained low, indicating that all three methods effectively prevented NA release in simulated gastric fluid. In contrast, the unencapsulated drug-loaded HNTs showed a higher burst release rate, suggesting that loading alone is insufficient to effectively prevent NA release in simulated gastric fluid. All the products exhibited pH-responsive characteristics, showing reduced release in the acidic gastric environment but slow release in the neutral intestinal environment. The double-layer encapsulated drug-loaded HNTs demonstrated the best pH responsiveness and sustained-release performance.

[0132] Experimental Example 6: pH Response Test

[0133] The product obtained in Example 8 was weighed and added to 200 mL of aqueous solutions with pH values ​​of 1.2, 3, 4, 5, 6, 7.4, 9, and 10 (pH adjusted by dilute HCl and NaOH). The entire sustained-release system was kept at 37°C with constant stirring at a magnetic stirrer speed of 50 rpm, maintaining a constant pH. At 5 min, 10 min, 20 min, 30 min, 60 min, 120 min, 240 min, and 360 min, 4 mL of the supernatant was pipetted. The supernatant was filtered through a 0.22 μm polyethersulfone aqueous filter membrane to remove halloysite from the solution. The drug content in the filtered supernatant was measured by ultraviolet spectrophotometry, and the drug release in the simulated intestinal fluid was calculated. The test results are as follows: Figure 9 As shown.

[0134] Figure 9 In the study, when the pH was 1.2 and 3, the product prepared in Example 8 did not release any DS within 360 minutes. Starting from pH 4, DS began to be released, with a burst release rate of 9% at 5 minutes. As the pH increased, the release rate of the drug gradually increased at the same time. When the pH reached 9, the increase in the release rate gradually slowed down, and the release curve did not change much. This indicates that the critical release pH of DS is around 3 to 4, that is, the pH switch for controlling the release is 3 to 4. When pH < 4, the switch is closed, and when pH ≥ 4, the switch is open. The release rate of DS increases with the increase of pH, and there is a clear sustained release trend within 360 minutes. This shows that the double-layer encapsulated drug-loaded HNTs prepared in Example 8 is a pH-responsive sustained-release material with excellent sustained-release performance for DS.

[0135] The present invention has been described in detail above with reference to specific embodiments and exemplary examples; however, these descriptions should not be construed as limiting the present invention. Those skilled in the art will understand that various equivalent substitutions, modifications, or improvements can be made to the technical solutions and embodiments of the present invention without departing from the spirit and scope of the invention, and all such modifications and improvements fall within the scope of the present invention. The scope of protection of the present invention is defined by the appended claims.

Claims

1. A drug-loaded halloysite material for encapsulation, the drug-loaded halloysite material being prepared from halloysite, a drug, and an encapsulation material; The drug is selected from one or more of ciprofloxacin, diclofenac sodium, nicotinic acid, and aspirin; The encapsulation materials are pectin and chitosan, achieving a double-layer encapsulation of halloysite; In the double-layer encapsulation, the mass ratio of pectin to chitosan is 1:(1-3). In simulated intestinal fluid, the burst release rate of the encapsulated drug-loaded halloysite material was 10-42% within 5 minutes, while in simulated gastric fluid, the burst release rate was 0-20% within 5 minutes. The critical pH for drug release from the encapsulated drug-loaded halloysite material is 3–7.

2. The encapsulating drug-loaded halloysite material according to claim 1, characterized in that, The mass ratio of halloysite to the drug is 1:(30-100).

3. The encapsulating drug-loaded halloysite material according to claim 1, characterized in that, The mass ratio of halloysite to encapsulation material is (0.1-3):

100.

4. A process for the preparation of an encapsulated drug-loaded halloysite material according to one of claims 1 to 3, characterized in that, The method includes the following steps: Step 1: Add halloysite to the drug solution, stir, and let stand under vacuum to obtain drug-loaded halloysite; Step 2: Add drug-loaded halloysite to the encapsulation material solution and stir to obtain the encapsulated drug-loaded halloysite material; In step 1, the pH value of the drug solution is 2-9, and the concentration of the drug solution is 1000-2000 mg / mL; In step 1, the vacuum pressure is 0.5–1 bar, and the settling time is 20–60 min; In step 2, the stirring speed is 300-800 r / min and the stirring time is 0.5-60 min.

5. The use of a drug-loaded halloysite material according to any one of claims 1 to 3 or a drug-loaded halloysite material prepared by the preparation method according to claim 4 in the preparation of a medicament for sustained-release and / or intestinal targeted administration.

Images