A two-dimensional mica-based drug delivery system, its preparation method and application

Abstract

This invention belongs to the field of drug delivery system technology, and discloses a two-dimensional vermiculite-based drug delivery system, its preparation method, and its applications. In this invention, expanded vermiculite undergoes ion exchange with NaCl and LiCl, followed by mechanical peeling to obtain a two-dimensional vermiculite nanosheet dispersion through centrifugation. The drug is then dispersed within this dispersion, and a film is formed to obtain a two-dimensional vermiculite-based drug delivery unit. This invention utilizes the synergistic loading of drugs between the vermiculite layers and on its surface: the abundant hydroxyl groups on the vermiculite end faces and the interaction between the drug and the interlayer cations result in a longer drug release time. The vermiculite-based drug delivery system can achieve a gradient release of drugs from the surface to the interlayer based on the pH response of the affected area. Simultaneously, the vermiculite-based drug delivery system provides antibacterial effects through enzyme-like catalytic activity, avoiding the problems of antibiotic overuse and resistance.

Description

Technical Field

[0001] This invention relates to the field of drug delivery system technology, and in particular to a two-dimensional vermiculite-based drug delivery system, its preparation method, and its application. Background Technology

[0002] The conventional clinical treatments for oral mucosal diseases mainly include spraying medications and applying ointments. However, these methods have drawbacks such as short duration of drug use, poor adhesion, and the possibility of local redness and swelling due to improper dosage, resulting in unsatisfactory treatment outcomes. Therefore, there is an urgent need to develop a multifunctional oral "Easy-to-Adhesive" with good adhesion properties to solve these problems.

[0003] Currently, most commercially available oral patches or films are topical plasters for treating skin diseases, and their drug carriers often use organic excipients such as sodium carboxymethyl cellulose, polyvinylpyrrolidone, and glycerin. Although organic drug carriers have good biocompatibility and biodegradability, their drug release effect is poor, and the drug release behavior is difficult to control. At the same time, most existing products contain antibiotics (rukanamycin, gentamicin) and steroids (such as dexamethasone). Long-term use of antibiotics can lead to dysbiosis, increased bacterial resistance, and may cause a series of serious health problems such as tooth development disorders and osteoporosis. Summary of the Invention

[0004] The purpose of this invention is to provide a two-dimensional vermiculite-based drug delivery system, its preparation method, and its application, thereby solving the problems of poor flexibility and adhesion, short efficacy, and antibiotic resistance in existing oral patches.

[0005] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0006] This invention provides a method for preparing a two-dimensional vermiculite-based drug delivery system, comprising the following steps:

[0007] Expanded vermiculite was reacted with NaCl solution to produce Na-bacterial vermiculite;

[0008] A second reaction was carried out between Na-type vermiculite and LiCl solution to obtain Li-type vermiculite;

[0009] Lithium-ionized vermiculite was mechanically crushed with water and then centrifuged to obtain a two-dimensional vermiculite nanosheet dispersion.

[0010] The two-dimensional vermiculite nanosheet dispersion and the drug solution were stirred and dialyzed to remove impurities in sequence to obtain a two-dimensional vermiculite-based drug mixture.

[0011] Two-dimensional vermiculite-based drug mixtures are deposited onto a matrix material through layer-by-layer self-assembly, filtration, or coating, forming a vermiculite-based drug layer with adjustable micron-level thickness on the surface of the matrix material, thus obtaining a two-dimensional vermiculite-based drug delivery system.

[0012] Preferably, the mass ratio of NaCl to expanded vermiculite in the NaCl solution is 40–70:1; and the mass ratio of LiCl to expanded vermiculite in the LiCl solution is 3–7:1.

[0013] Preferably, the temperature of the first reaction is 100–120°C, and the reaction time is 24–48 h.

[0014] Preferably, the temperature of the second reaction is 100–120°C, and the reaction time is 24–48 h.

[0015] Preferably, the mechanical crushing time is 60-100 min; the centrifugation speed is 5000-7500 rpm; and the centrifugation time is 30-60 min.

[0016] Preferably, the drug is an analgesic and / or an antibacterial drug; the analgesic is one or more of lidocaine hydrochloride, bupivacaine hydrochloride, and ropivacaine hydrochloride; the antibacterial drug is cetyltrimethylammonium bromide and / or chlorhexidine acetate.

[0017] Preferably, the mass ratio of the two-dimensional vermiculite nanosheets in the two-dimensional vermiculite nanosheet dispersion to the drug in the drug solution is 1:1 to 50.

[0018] The present invention also provides a method for preparing a two-dimensional vermiculite-based drug delivery system, which yields a two-dimensional vermiculite-based drug delivery system.

[0019] The present invention also provides the application of a two-dimensional vermiculite-based drug delivery system in the preparation of drugs for treating oral mucosal diseases.

[0020] As can be seen from the above technical solution, compared with the prior art, the present invention has the following beneficial effects:

[0021] This invention uses two-dimensional vermiculite nanosheets as a delivery system for amide-based local analgesics and amine-based cationic antibacterial drugs. Compared with traditional oral ulcer treatment methods, the two-dimensional vermiculite-based drug delivery system has the following advantages: (1) It makes full use of the abundant hydroxyl groups on the vermiculite end face and the interaction between the interlayer cations and drug molecules, resulting in a longer drug release time; (2) The vermiculite-based drug delivery system can release drugs in a gradient order from the surface to the interlayer by responding to the pH of the affected area; (3) The vermiculite-based drug delivery system provides antibacterial effects through enzyme-like catalytic activity, avoiding the abuse and drug resistance of antibiotics; (4) The vermiculite-based drug delivery system has multiple forms of existence, which can be sprayed onto the affected area as a suspension or made into a drug film, making it widely applicable. Attached Figure Description

[0022] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below.

[0023] Figure 1 The image shown is an atomic force microscope image of two-dimensional vermiculite nanosheets in the two-dimensional vermiculite nanosheet dispersion obtained in step (3) of Example 1; the inset is a longitudinal dimension image.

[0024] Figure 2 This is an appearance diagram of the CA-HL / VMT drug film prepared in Example 1;

[0025] Figure 3 The water contact angle test results are shown for the VMT film prepared in Comparative Example 3.

[0026] Figure 4 The image shows the water contact angle test result of the CA-HL / VMT film prepared in Example 1.

[0027] Figure 5 The curve showing the change in drug release concentration of the CA-HL / VMT drug film prepared in Example 1;

[0028] Figure 6 The drug release concentration change curve of the lidocaine patch for Comparative Example 2 is shown.

[0029] Figure 7 This is a skin adhesion test diagram of the CA-HL / VMT drug film prepared in Example 1;

[0030] Figure 8 The antibacterial performance test diagrams are for the CA-HL / VMT film of Example 1, the HL / VMT film of Example 2, and the VMT film of Comparative Example 3.

[0031] Figure 9 The image shows the catalytic antibacterial performance test results of the VMT film in Comparative Example 3. Detailed Implementation

[0032] This invention provides a method for preparing a two-dimensional vermiculite-based drug delivery system, comprising the following steps:

[0033] Expanded vermiculite was reacted with NaCl solution to produce Na-bacterial vermiculite;

[0034] A second reaction was carried out between Na-type vermiculite and LiCl solution to obtain Li-type vermiculite;

[0035] Lithium-ionized vermiculite was mechanically crushed with water and then centrifuged to obtain a two-dimensional vermiculite nanosheet dispersion.

[0036] The two-dimensional vermiculite nanosheet dispersion and the drug solution were stirred and dialyzed to remove impurities in sequence to obtain a two-dimensional vermiculite-based drug mixture.

[0037] Two-dimensional vermiculite-based drug mixtures are deposited onto a matrix material through layer-by-layer self-assembly, filtration, or coating, forming a vermiculite-based drug layer with adjustable micron-level thickness on the surface of the matrix material, thus obtaining a two-dimensional vermiculite-based drug delivery system.

[0038] In this invention, the preferred method for preparing the expanded vermiculite is as follows: Vermiculite ore (purchased from Weili County, Xinjiang) is repeatedly washed six times with deionized water and anhydrous ethanol to remove dust and organic impurities; after drying, it is mixed with hydrogen peroxide at a ratio of 2:1 and stored in the dark for 24 hours, then placed in a 750W microwave oven for 2 minutes for expansion; finally, the expanded vermiculite is sieved using a 5-mesh (4mm) sieve, and a bulk density of 1 mg / cm³ is selected. 3 Expanded vermiculite.

[0039] In this invention, the NaCl solution is preferably a saturated aqueous solution of NaCl.

[0040] In this invention, the mass ratio of NaCl to expanded vermiculite in the NaCl solution is preferably 40-70:1, more preferably 40-50:1, and even more preferably 40:1.

[0041] In this invention, the concentration of the LiCl solution is preferably 2 mol / L.

[0042] In this invention, the mass ratio of LiCl to expanded vermiculite in the LiCl solution is preferably 3 to 7:1, more preferably 3 to 5:1, and even more preferably 3:1.

[0043] In this invention, the temperature of the first reaction is preferably 100-120°C, more preferably 105-115°C, and even more preferably 110°C; the time of the first reaction is preferably 24-48h, more preferably 24-36h, and even more preferably 24h.

[0044] In this invention, after the first reaction is completed, the process further includes alternating washing with water and anhydrous ethanol.

[0045] In this invention, the temperature of the second reaction is preferably 100-120°C, more preferably 105-115°C, and even more preferably 110°C; the time of the second reaction is preferably 24-48h, more preferably 24-36h, and even more preferably 24h.

[0046] In this invention, after the second reaction is completed, the process further includes alternating washing with water and anhydrous ethanol.

[0047] In this invention, the mechanical crushing time is preferably 60-100 min, more preferably 70-100 min, and even more preferably 90 min.

[0048] In this invention, the instrument for mechanical crushing is preferably a mechanical crusher; the power of the mechanical crusher is preferably 150W; and the working mode of the mechanical crusher is preferably: working for 5 seconds and resting for 5 seconds.

[0049] In this invention, the centrifugation speed is preferably 5000-7500 rpm, more preferably 5000-6000 rpm, and even more preferably 5000 rpm; the centrifugation time is preferably 30-60 min, more preferably 30-40 min, and even more preferably 30 min.

[0050] In this invention, the drug is preferably an analgesic and / or an antibacterial drug, more preferably an analgesic and an antibacterial drug; the analgesic drug is preferably one or more of lidocaine hydrochloride, bupivacaine hydrochloride, and ropivacaine hydrochloride, more preferably lidocaine hydrochloride or bupivacaine hydrochloride, and more preferably lidocaine hydrochloride; the antibacterial drug is preferably cetyltrimethylammonium bromide and / or chlorhexidine acetate, more preferably cetyltrimethylammonium bromide or chlorhexidine acetate, and more preferably chlorhexidine acetate.

[0051] In this invention, the preferred mass ratio of the two-dimensional vermiculite nanosheets in the two-dimensional vermiculite nanosheet dispersion to the drug in the drug solution is 1:1 to 50.

[0052] In this invention, when the drug is lidocaine hydrochloride, the preferred mass ratio of two-dimensional vermiculite nanosheets to lidocaine hydrochloride is 1:1; when the drug is bupivacaine hydrochloride, the preferred mass ratio of two-dimensional vermiculite nanosheets to bupivacaine hydrochloride is 1:10; and when the drug is ropivacaine hydrochloride, the preferred mass ratio of two-dimensional vermiculite nanosheets to ropivacaine hydrochloride is 1:15.

[0053] In this invention, the concentration of the two-dimensional vermiculite nanosheet dispersion is preferably 0.2 mg / mL.

[0054] In this invention, the molecular rejection capacity of the dialysis bag used for dialysis purification is preferably 12-14 KD, more preferably 12-13 KD, and even more preferably 12 KD; the dialysis purification time is preferably 24 hours.

[0055] In this invention, the matrix material is preferably a mixed cellulose ester membrane; the pore size of the mixed cellulose ester membrane is preferably 0.45 μm, and the diameter is preferably 25 mm.

[0056] The present invention also provides a method for preparing a two-dimensional vermiculite-based drug delivery system, which yields a two-dimensional vermiculite-based drug delivery system.

[0057] The present invention also provides the application of a two-dimensional vermiculite-based drug delivery system in the preparation of drugs for treating oral mucosal diseases.

[0058] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0059] Example 1

[0060] This embodiment provides a method for preparing a two-dimensional vermiculite-based drug delivery system, including the following steps:

[0061] (1) Expanded vermiculite (VMT) and a saturated aqueous solution of NaCl (mass ratio of NaCl to expanded vermiculite 40:1) were heated at 110℃ for 24 h. After the reaction was completed, the mixture was washed alternately with water and anhydrous ethanol until Cl was undetectable. - Na-based vermiculite was obtained;

[0062] (2) Na-modified vermiculite was heated with a 2 mol / L LiCl solution (LiCl and expanded vermiculite in a mass ratio of 3:1) at 110 °C for 24 h. After the reaction, the mixture was washed alternately with water and anhydrous ethanol until Cl was undetectable. - Lithium-based vermiculite was obtained;

[0063] (3) Li-bacterial vermiculite was mixed with water and mechanically exfoliated using a mechanical crusher at 150W. The mechanical crusher worked for 5 seconds and rested for 5 seconds, with a total working time of 90 minutes. Then, it was centrifuged at 5000 rpm for 30 minutes, and the supernatant was collected to obtain a 0.2 mg / mL two-dimensional vermiculite nanosheet dispersion.

[0064] (4) 10 mL of 0.2 mg / mL two-dimensional vermiculite nanosheet dispersion was added dropwise at a rate of 20 μL / time to 10 mg / mL lidocaine hydrochloride (HL), with a total addition of 1 mL; then 5 mg / mL chlorhexidine acetate (CA) was added dropwise, with a total addition of 4 mL, and the mixture was magnetically stirred for 24 h; then the mixture was dialyzed for 24 h using a dialysis bag with a molecular cutoff of 12 KD to remove impurities, with water exchanged every 2 h to obtain a two-dimensional vermiculite-based drug mixture;

[0065] (5) Place a microporous filter membrane with a diameter of 25 mm and a pore size of 0.45 μm on a sand core solvent filter, and then add a two-dimensional vermiculite-based drug mixture to prepare a two-dimensional vermiculite-based drug membrane on the surface of the microporous filter membrane through layer-by-layer self-assembly. After removing the microporous filter membrane, a two-dimensional vermiculite-based drug delivery system is obtained, denoted as CA-HL / VMT drug membrane.

[0066] Example 2

[0067] This embodiment provides a method for preparing a two-dimensional vermiculite-based drug delivery system, specifically referring to Embodiment 1, except that chlorhexidine acetate is not added in step (4), and it is denoted as HL / VMT drug film.

[0068] Example 3

[0069] This embodiment provides a method for preparing a two-dimensional vermiculite-based drug delivery system, specifically referring to Embodiment 1, except that lidocaine hydrochloride is not added in step (4), and it is referred to as CA / VMT drug film.

[0070] Example 4

[0071] This embodiment provides a method for preparing a two-dimensional vermiculite-based drug delivery system. See Example 2 for details. The difference is that in step (4), lidocaine hydrochloride is replaced with bupivacaine hydrochloride (HB), denoted as HB / VMT drug film.

[0072] Example 5

[0073] This embodiment provides a method for preparing a two-dimensional vermiculite-based drug delivery system. See Example 2 for details. The difference is that in step (4), lidocaine hydrochloride is replaced with ropivacaine hydrochloride (HR), denoted as HR / VMT drug film.

[0074] Comparative Example 1

[0075] This comparative example provides a method for preparing a two-dimensional vermiculite-based drug delivery system, specifically referring to Example 2. The difference is that in step (4), lidocaine hydrochloride is replaced with sodium 3-hydroxybutyrate (3HB) (an anti-inflammatory drug), denoted as 3HB / VMT drug film.

[0076] Comparative Example 2

[0077] This comparative example provides a Debai Ning lidocaine patch, which is a commercially available product.

[0078] Comparative Example 3

[0079] This comparative example provides a method for preparing a two-dimensional vermiculite-based thin film, specifically referring to Example 1. The difference is that step (4) is omitted, and the two-dimensional vermiculite nanosheet dispersion from step (3) is subjected to layer-by-layer self-assembly in step (5), which is referred to as VMT film.

[0080] Drug release tests were conducted on the drug films from Examples 1-5 and Comparative Examples 1-2. The specific method was as follows: the drug film was added to PBS buffer solution at pH 4.5 for drug release. To prevent swelling and breakage of the drug film during release, a dialysis bag was used to hold the drug film and PBS buffer solution together as a single unit, placed in a beaker. Then, 3 mL of the liquid outside the bag was taken at regular intervals and placed in a quartz dish for absorbance testing to obtain the drug release concentration at that moment. The results are shown in Table 1. The cumulative drug release was calculated according to the following formula (1).

[0081]

[0082] In the formula:

[0083] M t —Cumulative drug release (mg),

[0084] V—The total volume of the medium solution in the beaker (mL),

[0085] C n —The solution concentration (mg / mL) corresponding to the nth extraction.

[0086] C i —The solution concentration (mL) corresponding to the i-th extraction.

[0087] V i —Volume (mL) of solution extracted each time.

[0088] Table 1. Drug release concentration of the drug film

[0089]

[0090]

[0091] Table 1 shows that HL, HB, and HR all exhibit good sustained-release capabilities, demonstrating the excellent compatibility of vermiculite nanosheet structures with amide drugs. It also reveals the size-dependent drug loading characteristics of the two-dimensional confined interlayer channels in vermiculite. The smaller lidocaine hydrochloride exhibits the most sustained-release effect. Example 1 demonstrates the dual analgesic and antibacterial functions of vermiculite-based delivery units. Comparative Example 1 shows a larger sustained-release amount of 3-hydroxybutyric acid due to its smaller size, which allows for easier entry and exit from the vermiculite space.

[0092] Atomic force microscopy was performed on the two-dimensional vermiculite nanosheets in the dispersion obtained in step (3) of Example 1. The results are as follows: Figure 1 As shown. By Figure 1 It is known that the radial dimension of the two-dimensional vermiculite nanosheets is approximately 650 nm. Figure 1 The vertical dimension is approximately 4 nm. Figure 1 illustration).

[0093] The appearance of the CA-HL / VMT drug film prepared in Example 1 is shown in the figure below. Figure 2 As shown.

[0094] The water contact angle of the CA-HL / VMT film prepared in Example 1 and the VMT film prepared in Comparative Example 3 were tested, and the results are as follows: Figure 3 , Figure 4 As shown. From Figure 3 , Figure 4 It can be seen that the contact angle of the CA-HL / VMT drug film is increased by 35.87° compared to the pure vermiculite film. This indicates that compared to the pure vermiculite film, the surface adhesion of the drug film is both beneficial to oral adhesion and not particularly hydrophilic.

[0095] The drug release concentration change curve of the CA-HL / VMT drug film prepared in Example 1 is shown in Figure 1. Figure 5 As shown. By Figure 5 It can be seen that 0–8h is the rapid drug release mode. During this stage, lidocaine hydrochloride and chlorhexidine acetate, which are linked to drug molecules on the vermiculite surface by van der Waals forces, are released first under acidic conditions. 9–24h is the sustained drug release mode. During this stage, lidocaine hydrochloride molecules and chlorhexidine acetate molecules that have entered the vermiculite interlayer are gradually released into the environment.

[0096] The drug release concentration change curve of the lidocaine patch in Comparative Example 2 is shown below. Figure 6 As shown. By Figure 6 It can be seen that the concentration change of the CA-HL / VMT drug release curve in this invention is significantly different from that of the drug release curve of the CA-HL / VMT drug film in this invention.

[0097] The skin adhesion test was performed on the CA-HL / VMT drug film prepared in Example 1, and the results are as follows: Figure 7 As shown. By Figure 7 It is evident that the medicated film possesses excellent adhesion, which can largely solve the problems of short adhesion time and easy detachment of oral medications. Furthermore, the medicated film releases lidocaine hydrochloride and chlorhexidine acetate in a gradient manner, thereby exerting analgesic and bactericidal effects, respectively.

[0098] The antibacterial properties of the CA-HL / VMT film of Example 1, the HL / VMT film of Example 2, and the VMT film of Comparative Example 3 were tested, and the results are as follows: Figure 8 As shown. By Figure 8 It is known that the medicated film of the present invention has an inhibition rate of more than 95% against both Escherichia coli and Staphylococcus aureus.

[0099] In addition, to evaluate the catalytic antibacterial performance of vermiculite, the VMT film of Comparative Example 3 was tested for antibacterial performance and designated as the H2O2+VMT group. Near-infrared irradiation was added to the H2O2+VMT group, designated as the H2O2+VMT+NIR group. The group containing only H2O2 and no VMT film as in Comparative Example 3 was designated as the H2O2 group, and the group containing neither VMT film nor H2O2 as in the Control group. The results are as follows: Figure 9 As shown. By Figure 9 It is known that the iron element in the vermiculite octahedral structure has an enhancing effect on the catalysis of H2O2 (a metabolite of oral streptococci) under 808nm near-infrared irradiation, and also exhibits enhanced antibacterial properties.

[0100] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method of preparing a two-dimensional vermiculite-based drug delivery system, characterized by, Includes the following steps: Expanded vermiculite was reacted with NaCl solution to produce Na-bacterial vermiculite; A second reaction was carried out between Na-type vermiculite and LiCl solution to obtain Li-type vermiculite; Lithium-ionized vermiculite was mechanically crushed with water and then centrifuged to obtain a two-dimensional vermiculite nanosheet dispersion. The two-dimensional vermiculite nanosheet dispersion and the drug solution were stirred and dialyzed to remove impurities in sequence to obtain a two-dimensional vermiculite-based drug mixture. Two-dimensional vermiculite-based drug mixtures are deposited onto a matrix material through layer-by-layer self-assembly, filtration, or coating, forming a vermiculite-based drug layer with adjustable micron-level thickness on the surface of the matrix material, thus obtaining a two-dimensional vermiculite-based drug delivery system. The mechanical crushing conditions are as follows: the mechanical crushing time is 60~100min, the power is 150W, and the working mode is: 5s working and 5s resting. The drug is an analgesic and / or antibacterial; the analgesic is one or more of lidocaine hydrochloride, bupivacaine hydrochloride, and ropivacaine hydrochloride; the antibacterial is cetyltrimethylammonium bromide and / or chlorhexidine acetate; the mass ratio of the two-dimensional vermiculite nanosheets in the two-dimensional vermiculite nanosheet dispersion to the drug in the drug solution is 1:1~50.

2. A method of preparing a two-dimensional mica-based drug delivery system according to claim 1, characterized by, The mass ratio of NaCl to expanded vermiculite in the NaCl solution is 40~70:1; the mass ratio of LiCl to expanded vermiculite in the LiCl solution is 3~7:

1.

3. A method of preparing a two-dimensional vermiculite-based drug delivery system according to claim 2, characterized in that, The temperature of the first reaction is 100~120℃; the reaction time is 24~48h.

4. The method for preparing a two-dimensional vermiculite-based drug delivery system according to claim 3, characterized in that, The temperature of the second reaction is 100~120℃; the time of the second reaction is 24~48h.

5. A method for preparing a two-dimensional vermiculite-based drug delivery system according to claim 3 or 4, characterized in that, The centrifugation speed is 5000~7500 rpm; the centrifugation time is 30~60 min.

6. A two-dimensional vermiculite-based drug delivery system prepared by the preparation method of any one of claims 1 to 5.

7. The use of the two-dimensional vermiculite-based drug delivery system of claim 6 in the preparation of a medicament for treating oral ulcers.

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