Application of calcium-rich montmorillonite / sodium alginate artificial particles in the preparation of oral drugs

Abstract

The present invention relates to the technical field of drug carriers, specifically an application of calcium-rich montmorillonite / sodium alginate artificial bead particles in the preparation of oral drugs, specifically: calcium-rich montmorillonite / sodium alginate artificial bead particles are used as norfloxacin carriers in the preparation of oral drugs. The present invention optimizes the drug loading within the pH range of 1 to 11, ensures that the artificial particles do not disintegrate, and minimizes drug desorption; the antibacterial study of Escherichia coli is conducted, and positive results are obtained; the clay-based norfloxacin / montmorillonite beads prepared by the present invention exhibit stability, anti-disintegration and minimal drug desorption, making them suitable for use as oral pills.

Description

Technical Field

[0001] The invention relates to the technical field of drug carriers, in particular to application of calcium-rich montmorillonite / sodium alginate artificial bead particles in the preparation of oral drugs. Background Art

[0002] Many studies have explored the use of montmorillonite (MMT) and other materials in various applications. For example, montmorillonite-based composites such as montmorillonite-biochar composites have been studied. In addition, montmorillonite has been used for the absorption of norfloxacin (NF), with the focus on its efficiency, as well as the adsorption of norfloxacin on humic acid and soil. In addition, some studies have explored the use of powdered montmorillonite for the absorption of NF with the aim of potentially treating infections. In contrast, research on artificial beads is relatively limited. Only a few studies have successfully developed Fe-Cu oxide nanocomposite microspheres for NF adsorption without the use of sodium alginate (SA) as a gel. Similarly, modified MMT / SA beads have also been fabricated for NF adsorption, but their adsorption capacity has been limited to 3.85 mg / g.

[0003] Therefore, compared with the NF drug dome matrix tablets currently on the market, there is a lack of research on NF-loaded artificial beads to evaluate their antimicrobial efficacy and potential as oral pills. Although there are studies on drug release from NF / SA artificial beads without montmorillonite, the release rate of NF was too fast, with nine types of beads reaching almost 100% within 15 minutes. This suggests that NF is released in the stomach rather than the gastroduodenal region, thereby reducing the efficacy of the drug. Therefore, the development of clay-based artificial beads is necessary to prevent this undesirable release pattern. Summary of the invention

[0004] In order to solve the above problems, the present invention provides an application of calcium-rich montmorillonite / sodium alginate artificial bead particles in the preparation of oral medicines.

[0005] In order to achieve the above technical objectives, the technical solution adopted by the present invention is:

[0006] Application of calcium-rich montmorillonite / sodium alginate artificial bead particles in the preparation of oral medicines.

[0007] As a possible implementation mode, further, the calcium-rich montmorillonite / sodium alginate artificial bead particles are used as drug carriers in the preparation of oral drugs.

[0008] As a possible implementation manner, further, the calcium-rich montmorillonite / sodium alginate artificial bead particles are used as a norfloxacin carrier in the preparation of oral drugs.

[0009] As a possible implementation mode, further, the specific method of loading norfloxacin on the calcium-rich montmorillonite / sodium alginate artificial bead particles is:

[0010] The calcium-rich montmorillonite / sodium alginate artificial beads are placed in a NF aqueous solution to adsorb NF, and the calcium-rich montmorillonite / sodium alginate artificial beads are separated after the adsorption is completed.

[0011] As a preferred embodiment, preferably, when adsorbing NF, the pH of the NF aqueous solution is adjusted to 1-11.

[0012] As a preferred embodiment, preferably, when adsorbing NF, the adjustment time is to measure the NF adsorption equilibrium time.

[0013] As a possible implementation mode, further, the method for preparing the calcium-rich montmorillonite / sodium alginate artificial beads comprises:

[0014] Step 1: Add SA into deionized water and stir until SA is dissolved to obtain solution A;

[0015] Step 2: Add STx-1b to solution A, stir to dissolve it, and obtain a mixed solution;

[0016] Step 3: Pour the stirred mixed gel solution into a syringe and soak the dripped particles in 4% CaCl2 solution for 6 hours to facilitate molding;

[0017] Step 4: Pour out the 4% CaCl2 solution, wash three times with deionized water, soak in deionized water for 3 hours to remove residual CaCl2, and finally wash three times with deionized water to obtain raw beads with an average particle size of 0.3 mm;

[0018] Step 5: Heat in an oven at 60°C for 12 h to obtain artificial beads with an average size of 0.1 mm.

[0019] As a preferred implementation manner, preferably, the mass ratio STx-1b:SA=2:1.

[0020] As a preferred embodiment, STx-1b is preferably modified to 200% CEC to enhance the NF loading capacity.

[0021] As a possible implementation mode, further, the cation exchange capacity (CEC) modification method of STx-1b comprises:

[0022] With the modifier being NF, the required amount of modifier is calculated by the following formula to achieve the required number of grams of STx-1b.

[0023] Required NF amount (g) = [(CEC of STx-1b × molecular weight of NF compound × 10 -3) / 100]×weight of STx-1b×[(expected percentage of CEC in organoclay / 100)];

[0024] Wherein, CEC: meq / 100g or cmol(p+) / kg, weight of STx-1b: g.

[0025] In addition, the calcium-rich montmorillonite / sodium alginate artificial bead particles developed by the present invention can also be used as a simple outer coating to prevent the degradation of the artificial particles, such as light-induced decomposition.

[0026] SA is an anionic natural polymer polysaccharide with special solubility in water. The molecular structure of SA is composed of a large number of hydroxyl (-OH) and carboxyl (-COOH) groups, which serve as active adsorption sites and can remove various organic pollutants. Montmorillonite minerals are ideal for granulation, non-toxic to the human body, and have the characteristics of absorbing bacteria, but excessive consumption may cause intestinal blockage. Powdered montmorillonite has the advantages of high adsorption capacity and fast adsorption rate, but when the adsorbent reaches the adsorption saturation state, it will be suspended in the aquatic environment or sewage treatment plant, and the solid and liquid phases are not easy to separate, and water purification cannot be performed. Therefore, montmorillonite and SA are made into artificial granules as oral pills for the treatment of Escherichia coli infection.

[0027] Montmorillonite has a high cation exchange capacity and can be effectively loaded with high concentrations of drugs. Although the granulation process may slightly reduce the loading capacity, the results of this study show that adjusting the pH value can increase the loading capacity. By conducting a thorough market study of drug concentration, it is possible to achieve the desired drug loading in artificial granules. This approach ensures that the artificial granules can achieve the ideal drug loading capacity for their intended application.

[0028] The calcium-rich montmorillonite / sodium alginate artificial beads prepared by the present invention have a high removal efficiency for norfloxacin pollutants in water. The adsorption mechanism is as follows: the adsorption of norfloxacin on the calcium-rich montmorillonite / sodium alginate artificial beads is mainly carried out through cation exchange. The absorption of norfloxacin molecules on the surface of montmorillonite occurs through hydrogen bond interaction, and hydrogen bond interaction exists between two norfloxacin molecules. In addition, the adsorption of norfloxacin in montmorillonite also involves polarization or charge transfer. The polarization process means the charge transfer between the norfloxacin molecules and the montmorillonite surface, thereby causing the occurrence of the adsorption phenomenon.

[0029] By adopting the above technical solution, the present invention has the following beneficial effects compared with the prior art:

[0030] (1) The artificial original beads prepared by adjusting pH in the present invention have an adsorption capacity of 115 mg / g for NF, which is close to the lowest amount of 120 mg / g in the market and is very suitable for antibacterial tests. In addition, the artificial beads prepared have low loss in the acidic environment of the stomach at pH 2, have stability and integrity, and the artificial beads with a loading capacity of 115 mg / g have the advantage of rapid manufacturing.

[0031] (2) The present invention optimizes the drug loading within the pH range of 1 to 11, ensures that the artificial particles do not disintegrate, and minimizes drug desorption; it is studied for antibacterial activity against E. coli, and positive results have been obtained. The prepared clay-based norfloxacin / montmorillonite beads exhibit high stability, resistance to disintegration, and minimal drug desorption in a gastric fluid environment, making them suitable for use as oral pills against E. coli. The findings of the present invention contribute to the development of clay-based artificial beads as potential oral pills. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 A simplified diagram of the research process of clay-based highly stable norfloxacin / montmorillonite beads as oral pills.

[0033] Figure 2 This is the adsorption-desorption isotherm curve of calcium montmorillonite / sodium alginate artificial beads.

[0034] Figure 3 Kinetic adsorption curve of calcium-rich montmorillonite / sodium alginate artificial beads.

[0035] Figure 4 This is a graph showing the effect of the adsorption amount of calcium-rich montmorillonite / sodium alginate artificial beads on cation desorption.

[0036] Figure 5 This is the adsorption trend of calcium-rich montmorillonite / sodium alginate artificial beads at different pH values.

[0037] Figure 6 XRD patterns of calcium-rich montmorillonite / sodium alginate artificial beads before and after adsorption.

[0038] Figure 7 Thermogravimetric analysis and contour plot of artificial beads of calcium-rich montmorillonite / sodium alginate.

[0039] Figure 8 SEM images of calcium-rich montmorillonite / sodium alginate artificial beads before and after adsorption.

[0040] Fig. 9 This is a graph showing the adsorption trend of calcium-rich montmorillonite / sodium alginate artificial beads in a simulated gastric environment and the antibacterial effect in the duodenum.

[0041] Fig.10 This is the adsorption mechanism diagram of calcium-rich montmorillonite / sodium alginate artificial beads before and after adsorption. DETAILED DESCRIPTION

[0042] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention. Therefore, the following detailed description of the embodiments of the present invention provided in the drawings is not intended to limit the scope of the invention claimed for protection, but merely represents the selected embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0043] The present invention provides a calcium-rich montmorillonite / sodium alginate artificial bead particle used as a drug carrier in the preparation of oral drugs, specifically: the calcium-rich montmorillonite / sodium alginate artificial bead particle is used as a norfloxacin carrier in the preparation of oral drugs.

[0044] The specific method of loading norfloxacin on the calcium-rich montmorillonite / sodium alginate artificial bead particles is:

[0045] The calcium-rich montmorillonite / sodium alginate artificial beads are placed in a NF aqueous solution to adsorb NF, and the calcium-rich montmorillonite / sodium alginate artificial beads are separated after the adsorption is completed.

[0046] When adsorbing NF, the pH of the NF aqueous solution was adjusted to 1-11;

[0047] When NF is adsorbed, the adjustment time is the time for determining the NF adsorption equilibrium.

[0048] When adsorbing NFs, STx-1b was modified to 200% CEC to enhance the NF loading capacity.

[0049] The cation exchange capacity (CEC) modification method of STx-1b comprises:

[0050] With the modifier being NF, the required amount of modifier is calculated by the following formula to achieve the required number of grams of STx-1b.

[0051] Required NF amount (g) = [(CEC of STx-1b × molecular weight of NF compound × 10 -3 ) / 100]×weight of STx-1b×[(expected percentage of CEC in organoclay / 100)];

[0052] Wherein, CEC: meq / 100g or cmol(p+) / kg, weight of STx-1b: g.

[0053] The method for preparing calcium-rich montmorillonite / sodium alginate artificial beads comprises:

[0054] Step 1: Take two 250 mL beakers, add 100 mL of deionized water, then add 2 g of SA to each beaker and stir magnetically for several hours until the SA is dissolved;

[0055] Step 2: Add 4 g of STx-1b into a beaker and stir magnetically for 8 h to dissolve it;

[0056] Step 3: Pour the stirred mixed gel solution into a 50 ml syringe and soak the dripped particles in 4% CaCl2 solution for 6 hours to facilitate molding;

[0057] Step 4: Pour out the 4% CaCl2 solution, wash three times with deionized water, soak in deionized water for 3 hours to remove residual CaCl2, and finally wash three times with deionized water to obtain raw beads with an average particle size of 0.3 mm;

[0058] Step 5: Heat in an oven at 60°C for 12 h to obtain artificial beads with an average size of 0.1 mm.

[0059] In the calcium-rich montmorillonite STx-1b of the present invention (purchased from the Clay Mineral Association), a large amount of montmorillonite (73%), an important amount of tridymite (11.6%) and cristobalite (12.8%), a very small amount of quartz (0.12%), and a small amount of amorphous phase (2%) were found.

[0060] During the granulation process, the key role of experimental tools in achieving a successful granulation process was found. It is necessary to pay attention to various aspects of this process. First, choosing a beaker with a large bottom area for preparation is an important factor to ensure uniform mixing by magnetic stirring. This is particularly relevant to the high viscosity of SA. Second, high-viscosity SA should be used, as low-viscosity SA is not suitable for effective granulation with STx-1b. Third, the specified sodium alginate (SA9005-38-3) standard sample must be used, purchased by Aladdin (Shanghai, China) and Fuchen (Tianjin, China) to prevent collapse in the pH range of 1-11, even after 24 hours. It was experimentally observed that in the case of pH>7, the beads gradually collapsed within half an hour. However, according to the artificial gastroduodenal model, the pH of the duodenum is 7. Although the cheaper SA initially seemed suitable for the formation of artificial beads, it decomposed within 0.5 hours, meaning that the beads would collapse and release NF in the stomach instead of the duodenum, resulting in a loss of efficiency.

[0061] In order to verify whether the performance of the artificial beads made of calcium-rich montmorillonite / sodium alginate is improved, the present invention also conducted an adsorption experiment on the calcium-rich montmorillonite STx-1b powder material.

[0062] The adsorption effect of calcium-rich montmorillonite / sodium alginate artificial beads was verified and the adsorption rate was tested under isothermal, kinetic, ion desorption, different pH values ​​and temperature.

[0063] Isothermal adsorption experiment

[0064] Isothermal adsorption experiments were performed using 0.05 g of beads and 40 mL of NF aqueous solution in a 50 mL polypropylene (PP) centrifuge tube. The initial adsorbate concentration was different, and the NF concentration was set to 35, 70, 140, 210, 280, and 350 mg / L, and two sets of parallel samples were made to obtain the maximum adsorption amount.

[0065] The balance (q e ) Adsorption of norfloxacin (NF) under (1)

[0066] q e =(C0-C e )v / m (1)

[0068] In the formula, C0 and C e are the concentrations of NF (mg / L) at time 0 and at equilibrium, respectively; v is the volume of NF solution (mL); and m is the mass of the adsorbent (g). At equilibrium, q e The equilibrium NF adsorption, C e is the equilibrium concentration.

[0069] The NF adsorption data were fitted to the Langmuir isotherm model using linear regression method. The details of the empirical equation are as follows.

[0070] Langmuir isotherm: C L / C S =(1 / K L S m )+C L / S m (2)

[0071] In the formula, C L : NF concentration at equilibrium (mg / L); C S : adsorption capacity at equilibrium (mg / g); K L : adsorption equilibrium constant, which represents the strength of the adsorption surface; S m : Maximum adsorption capacity (mg / g).

[0072] The Langmuir isotherm adsorption curve obtained is as follows: Figure 2 As shown in a, it can be concluded that compared with STx-1b powder, the adsorption amount of original beads A (undried artificial beads with a particle size of 0.3 mm in length) at pH = 6 is 135 mg / g, while the adsorption amount without pH adjustment is 115 mg / g. 115 mg / g is close to the lowest market dosage of 120 mg / g, which is very suitable for antibacterial testing.

[0073] To evaluate the stability of the beads at pH 2, Figure 2 As shown in Fig. 2, the loss of the beads was only 11 mg / g (equivalent to 10% of the total loss) within 24 hours, without any damage to the beads. In addition, if the retention time is limited to 4 hours, the loss of the beads is only 7 mg / g.

[0074] Kinetic experiments

[0075] The adsorption kinetics experiment maintained similar conditions to the isothermal experiment. Under this condition, the initial NF concentration was maintained at 350 mg / L, and the NF adsorption equilibrium time was measured at 0.25 h, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 8.0 h, 16.0 h and 24.0 h.

[0076] The NF adsorption kinetics data were fitted to a pseudo-second-order model using linear regression. The empirical equation is as follows.

[0077] Pseudo second order: t / q t =1 / k1q e 2 +(1 / q e )t(3)

[0078] In the formula, qe is the equilibrium adsorption amount of NF on MMT / SA beads (mg / g); k1 is the equilibrium rate constant of the pseudo-second-order model (g / mg-h).

[0079] The adsorption kinetics curve obtained is as follows Figure 3 As shown, the equilibrium time of artificial beads A and powder STx-1b is 8 hours and 4 hours respectively. Although the equilibrium time of beads is nearly twice that of powder materials, its manufacturing time still has obvious advantages. The pseudo-second-order adsorption kinetic model can fit the experimental data well.

[0080] Ion desorption experiment

[0081] Considering the cation exchange capacity (CEC), after modifying STx-1b to 200% CEC, a NF loading capacity of 220 mg / g was obtained without pH adjustment and at pH 6.

[0082] The effect diagram of cation desorption is shown in the figure below: Figure 4 As shown in a and b, for powder STx-1b, the slopes obtained are 0.67 and 0.77, corresponding to unadjusted pH and at pH 6, respectively, indicating that the adsorption of NF on powder STx-1b is related to the cation exchange mechanism. However, since the slope is not close to 1, it indicates that other mechanisms exist for the adsorption of NF by STx-1b powder. Figure 4 As shown in c and d, the slopes of artificial beads A are 0.94 and 1.11, respectively, indicating that the adsorption of NF on the beads is mainly carried out through cation exchange.

[0083] pH effect experiment

[0084] The effect of pH on the adsorption of NF by artificial beads was investigated when the initial NF concentration was 350 mg / L. The initial pH of the water system was 1-11 and was adjusted with 2M NaOH or HCl in increments of 1 unit.

[0085] The effect of pH value on the adsorption Figure 5 As shown, the adsorption capacity of the original artificial beads A can remain relatively stable under conditions of pH values ​​of 1 to 6. In addition, the artificial beads maintain their structural integrity without collapse in the pH range of 1 to 12.

[0086] Refer to the attached Figure 6 As shown in Figure 2, since cation exchange is the main adsorption mechanism, many studies have shown that the interlayer spacing (d value) of MMT changes after adsorption of organic compounds. Since physical grinding cannot break chemical bonds, the original artificial beads and adsorbed samples need to be carefully ground into powder for XRD analysis ( Figure 8a, b, c, d). The XRD spectrum shows that the d value of STx-1b gradually increases with the increase of adsorption amount ( Figure 6 a, b). However, when the initial concentration exceeded 140 mg / L, a combination of peaks or a plateau peak appeared, indicating the presence of a mixed layer ( Figure 6 c, d. The left and right peaks observed in these combined peaks represent the intercalation and non-intercalation of NF, respectively. It is clear that the binding of SA to STx-1b leads to the partial loss of STx-1b adsorption on NF. This information is very important because some types of SA can enhance the stability of artificial beads, but also reduce their adsorption capacity due to cross-linking between materials. Therefore, the choice of SA source plays a crucial role in the quality of the material.

[0087] Thermogravimetric analysis experiment

[0088] The adsorption effects of original NF, SA and artificial beads A, as well as artificial beads A containing 115 mg / g NF in different temperature environments were analyzed. Images of artificial beads A and artificial beads A containing 115 mg / g NF after heating at 900°C were obtained, as well as their profiles.

[0089] Thermogravimetric analysis and profiling Figure 7 As shown in a, the decomposition temperature of SA (T peak ) dropped from 262℃ to 223℃, and the decomposition temperature of NF (T peak ) from 355℃ to 295℃. All t peaks observed in this experiment showed a downward trend. Therefore, the treatment temperature of expired drugs can be reduced from the previous 550℃ to 400℃. Figure 7 b is artificial bead A, Figure 7 cThe left side is gray, Figure 7 cThe left side is black, Figure 7 cThe right side is black, Figure 7 cThe left side is black, Figure 7 cThe left side is gray. Figure 7 d is the profile of these beads. After heating to 900°C, the interior of bead A showed a uniform carbon black color after organic calcination to inorganic, which shows that NF was filled inside artificial bead A. On the other hand, artificial bead A showed a slightly slower black color, which may be due to the conversion of organic SA into inorganic SA on it when heated to 900°C.

[0090] SEM images of samples with different CEC values ​​are shown in the attached figure. Figure 8 As shown. For artificial beads, we observed that SA beads ( Figure 8 a-1, a-2) showed rapid release of NF in previous studies, which suggests that it may not be suitable for oral pills. On the other hand, the flake morphology of STx-1b powder is obvious ( Figure 8 b), after binding with SA, a bead-like structure is formed ( Figure 8 c), surface roughness ( Figure 8 d). After further investigation, the pore structure becomes apparent, e.g. Figure 8 As shown in e-1 to e-3, the scale is 4 μm. Considering that the molecular size of NF is 1.31 nm x 0.75 nm x 0.38 nm, the pore size allows the NF molecules to be inserted, thus filling the porous space. This observation is consistent with the overall black image of the artificial bead ( Figure 7 d) is consistent. In addition, the scanning of F fluorine element on the surface ( Figure 8 f-1, f-2) show separate distributions, supporting the concept of adsorption rather than precipitation at the Langmuir adsorption sites.

[0091] Refer to the attached Fig. 9 The aim of this study was to evaluate the different antimicrobial efficacy of oral pellets. Two formulations were compared: beads A, where STx-1b / SA was first granulated and NF was then adsorbed onto the beads; and beads B, where STx-1b powder was first adsorbed and then granulated with SA. First, the desorption rates of beads A and B were evaluated in a simulated gastric environment at pH 2. The results showed that the difference in drug release between the two formulations was negligible ( Fig. 9 a). Subsequently, the sample and the control group of pure bacteria were immersed in a culture medium containing E. coli to detect its antibacterial effect in the gastrointestinal tract. The bacterial concentration was evaluated by measuring the OD600 value. The higher the OD600 value, the higher the corresponding bacterial concentration ( Fig. 9 b). It is noteworthy that within 25 hours, the OD600 values ​​of raw beads A and the control sample gradually increased, indicating that raw beads A (referring to artificial beads that have not yet been loaded with NF) have no antibacterial properties. In contrast, within 25 hours, the OD600 values ​​of beads A and beads B were both low and comparable, indicating that they have similar antibacterial efficacy due to the presence of NF. In addition, turbidity, as an indicator of bacterial growth, showed a similar trend ( Fig. 9 c). Among them, the culture medium containing A beads and B beads appeared clear after 25 hours of culture, while the culture medium containing raw A beads and the control group appeared turbid ( Fig. 9 c). This observation is consistent with the bacterial growth curve ( Fig. 9 b) Although the differences between the two groups in terms of separation and antibacterial effects were limited, it is worth noting that the drug loading capacity of beads B may be higher. However, considering the costs associated with drug loading, the present invention recommends the method of granulation first and then drug loading.

[0092] Refer to the attached Fig.10 As shown, molecular dynamics simulation revealed the formation of hydrogen bonds between the montmorillonite (MMT) surface and functional groups in the norfloxacin molecule and between two norfloxacin molecules.

[0093] In the first system, a norfloxacin molecule ( Fig.10 c-3) interacts with MMT, initially without hydrogen bonding ( Fig.10 a-1). During the AIMD simulation, it was observed that hydrogen bonds were formed between the hydrogen atoms in the -CH2 group of norfloxacin (which is on the same ring as the -NH2 group) and the oxygen atoms in the T layer of the MMT surface ( Fig.10 a-2). In addition, hydrogen bonds are formed between the hydrogen atoms in the -CH3 group of norfloxacin and the oxygen atoms in the MMTT layer ( Fig.10 a-3). These results indicate that the absorption of norfloxacin molecules on the montmorillonite surface occurs via hydrogen bonding interactions.

[0094] In the second system, which involves two norfloxacin molecules with MMT, no hydrogen bonds exist in the initial configuration of the AIMD simulation ( Fig.10 b-1). In the AIMD simulation, a hydrogen bond is formed between the hydrogen atom on the -COOH group of one norfloxacin molecule and the oxygen atom on the -COOH group of another norfloxacin molecule ( Fig.10 b-2). In addition, there is a hydrogen bond between the hydrogen atom on the -NH2 group of one norfloxacin molecule and the oxygen atom on the -COOH group of another norfloxacin molecule ( Fig.10 b-3). These findings suggest the presence of hydrogen bonding interactions between the two norfloxacin molecules. In addition to hydrogen bonding, the adsorption of norfloxacin in montmorillonite also involves polarization or charge transfer. This polarization leads to the generation of an induced dipole moment, which contributes to the intermolecular diffusion forces and further enhances the adsorption process.

[0095] In the first system, which consists of a norfloxacin molecule and montmorillonite, polarization or charge transfer occurs between the norfloxacin molecule and the montmorillonite surface ( Fig.10 c-1). The yellow isosurface indicates the accumulation of charge, and the blue isosurface indicates the consumption of charge. This polarization process means that there is a charge transfer between the norfloxacin molecule and the montmorillonite surface, which leads to the adsorption phenomenon. Similarly, in the second system, two norfloxacin molecules are bound to montmorillonite, and there is a strong polarization or charge transfer between the two norfloxacin molecules ( Fig.10 c-2). The polarization between the two norfloxacin molecules was observed to be even stronger than that between the norfloxacin molecule and the MMT surface. This indicates that significant charge transfer occurred between the two norfloxacin molecules, further improving the overall adsorption capacity. According to the AIMD simulation results, both hydrogen bonding and polarization effects contribute to the adsorption of norfloxacin on the MMT surface. It is worth noting that the polarization effect between the two norfloxacin molecules is significantly greater than that between the norfloxacin molecule and the MMT surface.

[0096] This finding suggests a possible mechanism for the adsorption process: during the adsorption process, a single norfloxacin molecule is initially adsorbed by the montmorillonite surface. As more norfloxacin molecules are introduced, they are adsorbed by the existing adsorbed norfloxacin molecules, resulting in the gradual accumulation of norfloxacin on the montmorillonite surface. This process continues until the maximum adsorption of norfloxacin by montmorillonite. The combination of hydrogen bonding and polarization has given people a comprehensive understanding of its adsorption mechanism, indicating that intermolecular interactions play a vital role in the study of norfloxacin adsorption on the montmorillonite surface.

[0097] Before oral administration of artificial granules, it is necessary to determine (1) whether the drug is easily desorbed by the strong acid in gastric juice, (2) the stability and anti-disintegration ability of the artificial granules, (3) the time required to prepare drug-loaded artificial granules, and (4) the need to optimize the drug loading within the pH range of 1 to 11. This allows the drug loading experiment to be adjusted according to market research to achieve the ideal drug loading according to the drug concentration. (5) Understanding the drug loading mechanism requires the use of the cation exchange capacity of minerals. By calculation, different proportions of market research can obtain 50% or 200% drug loading. This makes it possible to conduct preliminary studies on other drug loading using clay-based artificial beads.

[0098] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. Application of calcium-rich montmorillonite / sodium alginate artificial bead particles in the preparation of oral medicines, characterized in that: The calcium-rich montmorillonite / sodium alginate artificial bead particles are used as a norfloxacin carrier in the preparation of oral drugs; The method for preparing the calcium-rich montmorillonite / sodium alginate artificial beads comprises: Step 1: Add SA into deionized water and stir until SA is dissolved to obtain solution A; Step 2: Add STx-1b to solution A, stir to dissolve it, and obtain a mixed solution; Step 3: Pour the stirred mixed gel solution into a syringe and soak the dripped particles in 4% CaCl2 solution for 6 hours to facilitate molding; Step 4: Pour out the 4% CaCl2 solution, wash three times with deionized water, soak in deionized water for 3 hours to remove residual CaCl2, and finally wash three times with deionized water to obtain raw beads with an average particle size of 0.3 mm; Step 5: Heat in an oven at 60°C for 12 h to obtain artificial beads with an average size of 0.1 mm; The specific method of loading norfloxacin on the calcium-rich montmorillonite / sodium alginate artificial bead particles is: The calcium-rich montmorillonite / sodium alginate artificial beads are placed in a NF aqueous solution to adsorb NF, and the calcium-rich montmorillonite / sodium alginate artificial beads are separated after the adsorption is completed.

2. The use according to claim 1, characterized in that: When adsorbing NF, the pH of the NF aqueous solution is adjusted to 1-11.

3. The use according to claim 1, characterized in that: When NF is adsorbed, the adjustment time is the time for determining the NF adsorption equilibrium.

4. The use according to claim 1, characterized in that: Mass ratio STx-1b:SA = 2:

1.

5. The use according to claim 4, characterized in that: Modification of STx-1b to 200% CEC enhanced the NF loading capacity.

6. The use according to claim 5, characterized in that: The CEC modification method of STx-1b comprises: With the modifier as NF, the required amount of modifier is calculated by the following formula to achieve the required number of grams of STx-1b; Required NF amount: g = [(CEC of STx-1b × molecular weight of NF compound × 10 -3 ) / 100] × weight of STx-1b × [(expected percentage of CEC in organoclay / 100)]; Where, CEC: meq / 100 g or cmol (p+) / kg, weight of STx-1b: g.

Images