Preparation method and application of POSS-SH based on trimethoxysilane

Abstract

The invention discloses a preparation method and application of POSS-SH based on trimethoxysilane, and belongs to the technical field of organic-inorganic hybrid materials. The preparation method comprises the following steps: (1) adding (3-mercaptopropyl) trimethoxysilane and a methanol aqueous solution into a round-bottom flask, uniformly mixing, adjusting the pH value to 7 by using hydrochloric acid, and reacting at 30-40 DEG C for 2-3 hours to obtain a mixed solution A; (2) adding (3-aminopropyl) trimethoxysilane into the mixed solution A, uniformly mixing, adjusting the pH value to 6 by using hydrochloric acid, and reacting at 50-60 DEG C for 1-2 hours to obtain a mixed solution B; and (3) adding vinyltriethoxysilane into the mixed solution B, uniformly mixing, adjusting the pH value to 3-5 by using hydrochloric acid, reacting at 80-100 DEG C for 15-24 hours, filtering, washing, extracting and drying to obtain a POSS-SH product. The POSS material prepared by adopting a step-by-step reaction method of three silane raw materials is applied to deaggregation of insoluble organic drug molecules with amino groups / hydroxyl groups, so that the dispersity and the stability of the drug molecules are improved.

Description

Technical Field

[0001] The invention belongs to the technical field of organic-inorganic hybrid materials, and particularly relates to a preparation method of trimethoxysilane-based POSS-SH and application thereof. Background Art

[0002] Poorly soluble organic molecular drugs have a large rigid π-electron conjugated structure, strong dipole-dipole interaction and π-π electron stacking interaction between molecules, charge transfer is very easy to occur between molecules, and H-aggregation or J-aggregation effect is easy to occur in solid condensed state or poor solvents, resulting in poor drug stability and reduced efficacy.

[0003] In order to overcome the instability of material performance caused by the intermolecular aggregation effect, researchers have found that increasing the distance between molecules within a certain range can weaken the intermolecular aggregation effect. When the molecular forces are within 100 nm, charge transfer will occur, leading to the aggregation effect. On this basis, supramolecular cage cyclodextrin, rotaxane and other macrocyclic molecules will encapsulate organic molecules to increase the molecular distance, thereby preventing the aggregation of organic molecules. However, when physical methods are used to trap organic molecules, the forces between the host and the guest are relatively weak, and an irreversible process of deprotection will inevitably occur, which will eventually reduce the stability of organic molecules and fail to fully improve their performance.

[0004] Organic-inorganic hybrid materials have high stability, especially nanocage oligomeric silsesquioxane (Polyhedral Oligomeric Silsequioxane, abbreviated as POSS, chemical formula R x R 8-x Si8O 12 ) was discovered, the unique Si-O-Si cage nanostructure (about 0.53nm) and the 8 active sites around it that can be modified with different structures and properties have become an ideal platform for building organic-inorganic hybrid materials, which are applied in the fields of biomaterials, porous materials, nanomaterials, etc. The organic and inorganic components in the hybrid materials can be connected by covalent bonds at the molecular level to avoid phase separation and make the materials more stable. More importantly, the distance between the adjacent sites of the 8 active sites around POSS is about This distance is very close to the distance when organic molecules aggregate. Therefore, the distance between organic molecules covalently linked by inorganic POSS is expected to reach or exceed the distance between molecules aggregated. This can weaken the strong π-π stacking effect between organic molecules, hinder the charge transfer between molecules, effectively overcome the intermolecular aggregation effect, and improve the performance of organic molecules.

[0005] However, there are still the following disadvantages in using POSS materials to overcome intermolecular aggregation:

[0006] (1) Although the original intention of designing POSS materials is to improve the aggregation effect of insoluble organic molecules, in some cases, the introduction of POSS will lead to new compatibility problems.

[0007] (2) The nanoscale size and rigid structure of POSS molecules mean that they may not be easily dispersed evenly in certain organic molecules. If they are not dispersed evenly, aggregates may form, which not only affects the physical properties of the material but may also aggravate the aggregation problem of poorly soluble organic molecules.

[0008] (3) The R group in POSS can react with polymers or other molecules, but this reactivity is difficult to control. Excessive reactivity may lead to unnecessary cross-linking and side reactions, affecting the stability and performance of the material. Summary of the invention

[0009] The purpose of the present invention is to provide a method for preparing POSS-SH based on trimethoxysilane, so as to solve the problems that the above-mentioned POSS material is used to overcome the intermolecular aggregation process, such as compatibility, uneven dispersion and difficult control of the reaction process. The present invention not only adjusts the synthesis of the POSS material by controlling parameters such as the type, pH value, temperature and steps of the reaction raw materials, but also improves its stability. When the POSS material is used as a deaggregation process of insoluble organic drug molecules, it can not only improve the dispersibility and solubility of the insoluble organic drug molecules, but also improve its stability.

[0010] To achieve the above object, the present invention provides a method for preparing POSS-SH based on trimethoxysilane, comprising the following steps:

[0011] (1) Add (3-mercaptopropyl)trimethoxysilane and methanol aqueous solution into a round-bottom flask, mix well, adjust the pH to 7 with hydrochloric acid, react at 30-40° C. for 2-3 hours, and obtain a mixed solution A;

[0012] (2) adding (3-aminopropyl)trimethoxysilane to the mixed solution A and mixing them evenly, adjusting the pH to 6 with hydrochloric acid, and reacting at 50 to 60° C. for 1 to 2 hours to obtain a mixed solution B;

[0013] (3) Add vinyl triethoxysilane to the mixed solution B and mix well, adjust the pH to 3-5 with hydrochloric acid, react at 80-100° C. for 15-24 h, filter, wash, extract, and dry to obtain a trimethoxysilane-based POSS-SH product.

[0014] At present, single silane is mostly used for hydrolysis in the preparation process of POSS products. Although the hydrolysis of single-component silane can improve the performance of certain materials, it has the problems of single function, poor environmental adaptability, hydrophobic and hydrophilic balance problems, and lack of controllability in the reaction process. The present invention uses three silanes, namely (3-mercaptopropyl) trimethoxysilane, (3-aminopropyl) trimethoxysilane and vinyl triethoxysilane, as raw materials for hydrolysis reaction, forms a stronger interface bond through covalent bonding of silanols with the surface of inorganic or organic substrates, helps to fix poorly soluble organic molecules, prevents them from falling off or degrading from the material surface, thereby enhancing the interface bond and improving the stability. At the same time, the silane hydrolyzate can form a protective film around the organic molecules, especially the mercapto group in the (3-mercaptopropyl) trimethoxysilane hydrolyzate, has good antioxidant and corrosion resistance, and can effectively isolate the adverse effects of the external environment on the organic molecules. The amino groups provided by (3-aminopropyl)trimethoxysilane can form hydrogen bonds or covalent bonds with many molecules, and the vinyl groups produced by the hydrolysis of vinyltriethoxysilane can be further cross-linked through polymerization reactions. Such a multi-cross-linked network can significantly enhance the stability and durability of organic molecules. The different functional groups in the silane of the present invention may guide poorly soluble organic molecules to arrange in a certain order to form a more stable supramolecular structure, which has a positive effect on maintaining the structural integrity of organic molecules.

[0015] Preferably, the volume ratio of methanol to water in the methanol aqueous solution is (75-90):(10-25).

[0016] Preferably, the mass ratio of (3-mercaptopropyl)trimethoxysilane:(3-aminopropyl)trimethoxysilane:vinyltriethoxysilane is (6-8):(1-2):(0.5-1.5).

[0017] Preferably, the volume ratio of (3-mercaptopropyl)trimethoxysilane: methanol aqueous solution is (1-2): (30-50).

[0018] The hydrolysis of silane is affected by many factors, including pH value, temperature, solvent and concentration. Once the setting is unreasonable, the hydrolysis process will produce unwanted byproducts and the products of the hydrolysis process will be unstable. In the present invention, three silane raw materials are added. In order to control the progress of the reaction, they are added in three steps respectively, and the pH value, temperature and reaction time of each step are controlled so that the reaction rate of each silane is controlled and the generated product is more stable.

[0019] In addition, the hydrolysis reaction of the present invention occurs in a mixed solution of water and methanol, which can increase the solubility of silane and make the reaction more uniform. In addition, the hydrolysis reaction of silane in a specific ratio of methanol and water can better control the reaction process and avoid gelation and precipitation caused by excessive hydrolysis.

[0020] The second aspect of the present invention provides a trimethoxysilane-based POSS-SH, which is prepared by the above-mentioned preparation method.

[0021] The third aspect of the present invention provides an application of POSS-SH based on trimethoxysilane, and the application of POSS-SH in the deaggregation of poorly soluble organic molecules, wherein the poorly soluble organic molecules are poorly soluble organic drug molecules having amino groups and / or hydroxyl groups. It should be noted that the poorly soluble organic molecules are mostly poorly soluble organic drug molecules, and the amino groups or hydroxyl groups contained therein are not their functional groups.

[0022] Preferably, the poorly soluble organic drug molecule is one of KGN and diclofenac.

[0023] KGN: Kartogenin, 2-([1,1-biphenyl]-4-ylcarbamoyl)benzoic acid.

[0024] Preferably, the deaggregation process of poorly soluble organic molecules is:

[0025] Dissolve polyethylene glycol in dichloromethane, then add potassium carbonate, and vigorously stir in a nitrogen atmosphere at an ice-water bath temperature of 0-5°C, then slowly drop a dichloromethane solution of acryloyl chloride, react at room temperature, filter, extract, dry, and spin-dry after the reaction is completed to obtain PEG-Ac;

[0026] Add the poorly soluble organic molecule, NMP and triethylamine into the reaction tube in sequence, seal it, evacuate and pass nitrogen for 3 times, maintain an inert atmosphere, add acryloyl chloride, stir and heat to react, and after the reaction is completed, cool, add water, filter and recrystallize to obtain OM-Ac;

[0027] POSS-SH, PEG-Ac and DMPA were dissolved in tetrahydrofuran, and irradiated with ultraviolet light at room temperature for reaction. Then OM-Ac was dissolved in tetrahydrofuran and added dropwise to the above ultraviolet light irradiation reaction process, and the ultraviolet light was continued to react. After the reaction, the solution was rotary evaporated to obtain POSS-based deaggregated hybrid molecules.

[0028] Preferably, the mass ratio of POSS-SH to PEG-Ac is (15-30):(3-5).

[0029] Preferably, the molar ratio of PEG-Ac to DMPA is (0.6-0.9) mol: (0.05-0.08) mmol.

[0030] Preferably, the molar ratio of DMPA to OM-Ac is (0.6-0.9) mol: (0.1-0.3) mol.

[0031] Therefore, the present invention adopts the above-mentioned preparation method and application of POSS-SH based on trimethoxysilane, which has the following beneficial effects:

[0032] 1. The present invention can introduce a variety of functional groups on the POSS skeleton by sequentially adding (3-mercaptopropyl)trimethoxysilane, (3-aminopropyl)trimethoxysilane and vinyltriethoxysilane. The presence of mercapto, amino and vinyl groups provides rich chemical reactivity, so that the final POSS-SH material can participate in a variety of chemical reactions and has enhanced reactivity.

[0033] 2. In each step of the reaction, the present invention uses hydrochloric acid to adjust the pH value, so as to control the reaction rate and direction and ensure the efficient reaction. The pH value adjustment at different stages helps to optimize the introduction of various functional groups, prevent unnecessary side reactions, and ensure the functionality of the product.

[0034] 3. The entire preparation process of the present invention is carried out at a relatively low temperature, starting from 30-40°C and gradually increasing to 80-100°C, which helps to reduce the side reactions that may be caused by high temperature while maintaining the stability of the reactants and the selectivity of the reaction.

[0035] 4. The POSS-SH material prepared by the present invention is used in the deaggregation process of insoluble organic drug molecules, which effectively improves the dispersibility of insoluble organic drug molecules, weakens the strong π-π stacking effect between organic molecules, hinders the charge transfer between molecules, effectively overcomes the intermolecular aggregation effect, and improves the performance of organic molecules.

[0036] 5. The POSS skeleton prepared by the present invention has good thermal stability and chemical stability, and can protect drug molecules from the influence of the external environment, such as oxidation, light or pH change, thereby improving the long-term stability and bioavailability of the drug.

[0037] The technical solution of the present invention is further described in detail below through embodiments. DETAILED DESCRIPTION

[0038] The present invention will be further described below. It should be noted that this embodiment is based on the technical solution and provides a detailed implementation method and a specific operation process, but the present invention is not limited to this embodiment.

[0039] Example 1

[0040] The present embodiment provides a method for preparing POSS-SH based on trimethoxysilane, comprising the following steps:

[0041] (1) Add (3-mercaptopropyl)trimethoxysilane and methanol aqueous solution into a round-bottom flask and mix well, adjust the pH to 7 with hydrochloric acid, and react at 35° C. for 2 h to obtain a mixed solution A;

[0042] (2) adding (3-aminopropyl)trimethoxysilane to the mixed solution A and mixing them evenly, adjusting the pH to 6 with hydrochloric acid, and reacting at 55° C. for 1 h to obtain a mixed solution B;

[0043] (3) Add vinyl triethoxysilane to the mixed solution B and mix well, adjust the pH to 4 with hydrochloric acid, react at 90° C. for 20 h, filter, wash, extract, and dry to obtain the POSS-SH product.

[0044] The volume ratio of methanol to water in the methanol aqueous solution is 80:20.

[0045] The mass ratio of (3-mercaptopropyl)trimethoxysilane, (3-aminopropyl)trimethoxysilane, and vinyltriethoxysilane is 8:1:1.

[0046] The volume ratio of (3-mercaptopropyl)trimethoxysilane to the methanol aqueous solution is 2:40.

[0047] On the other hand, this embodiment further provides an application of POSS-SH based on trimethoxysilane, and the application of POSS-SH in the deaggregation of poorly soluble organic molecules, wherein the poorly soluble organic drug molecule is KGN.

[0048] The deaggregation process of poorly soluble organic molecules is:

[0049] 2.00 mmol polyethylene glycol was dissolved in 30 mL dichloromethane, and then 2.00 mmol potassium carbonate was added, and the mixture was vigorously stirred in a nitrogen atmosphere at an ice-water bath temperature of 0°C, and then 10 mL of a dichloromethane solution of acryloyl chloride was slowly added dropwise, wherein the dichloromethane solution of acryloyl chloride contained 2.00 mmol acryloyl chloride, and the addition was completed over 30 minutes, and the mixture was reacted at room temperature for 24 hours. After the reaction was completed, the mixture was filtered to remove excess potassium carbonate, and extracted with 25.0 mL of distilled water, dried with anhydrous sodium sulfate, and the solvent was spin-dried to obtain PEG-Ac;

[0050] 1.55 mmol (0.44 g) of poorly soluble organic molecules (KGN), 15.0 mL of NMP and 2.32 mmol of triethylamine were added into the reaction tube in sequence, which was sealed and vacuumed and nitrogen was passed through for 3 times, each time for 15 min, while maintaining an inert atmosphere. 2.00 mmol of acryloyl chloride was added, and the mixture was stirred and heated at 50° C. for 12 h. After the reaction was completed, the mixture was cooled, and the reactant was added dropwise into water, filtered, recrystallized, and dried in vacuo to obtain OM-Ac.

[0051] POSS-SH, PEG-Ac and DMPA were dissolved in tetrahydrofuran, and the reaction was carried out under ultraviolet light at room temperature for 2.5 hours. Then, OM-Ac was dissolved in tetrahydrofuran and added dropwise to the above ultraviolet light irradiation reaction process, and the reaction was continued under ultraviolet light for 6 hours. The solvent was removed by rotary evaporation to obtain a POSS-based deaggregated hybrid molecule.

[0052] The mass ratio of POSS-SH and PEG-Ac is 20:3.

[0053] The molar ratio of PEG-Ac to DMPA was 0.8 mol:0.08 mmol.

[0054] The molar ratio of DMPA to OM-Ac was 0.8 mol:0.2 mol.

[0055] Example 2

[0056] The difference between this embodiment and embodiment 1 is that the volume ratio of methanol to water in the methanol aqueous solution is 90:10.

[0057] The mass ratio of (3-mercaptopropyl)trimethoxysilane, (3-aminopropyl)trimethoxysilane and vinyltriethoxysilane is 6:1:0.5.

[0058] The volume ratio of (3-mercaptopropyl)trimethoxysilane to the methanol aqueous solution is 2:50.

[0059] The poorly soluble organic drug molecule is diclofenac (DS).

[0060] Comparative Example 1

[0061] The difference between this comparative example and Example 1 is that vinyltriethoxysilane is replaced by octyltriethoxysilane.

[0062] Comparative Example 2

[0063] The difference between this comparative example and Example 1 is that the mass ratio of (3-mercaptopropyl)trimethoxysilane, (3-aminopropyl)trimethoxysilane and vinyltriethoxysilane is 15:1:1.

[0064] Comparative Example 3

[0065] The difference between this comparative example and Example 1 is that the volume ratio of (3-mercaptopropyl)trimethoxysilane to the methanol aqueous solution is 2:80.

[0066] Comparative Example 4

[0067] The difference between this comparative example and Example 1 is that the mass ratio of POSS-SH to PEG-Ac is 50:3.

[0068] Comparative Example 5

[0069] The difference between this comparative example and Example 1 is that the molar ratio of PEG-Ac to DMPA is 0.8 mol:2 mmol.

[0070] Comparative Example 6

[0071] The difference between this comparative example and Example 1 is that the molar ratio of DMPA to OM-Ac is 0.8:2.

[0072] Comparative Example 7

[0073] The difference between this comparative example and Example 1 is that the pH value is adjusted to 4 in steps (1) to (3).

[0074] Comparative Example 8

[0075] The difference between this comparative example and Example 1 is that the reaction temperature in steps (1) to (3) is 90°C.

[0076] The difference between this comparative example and Example 1 is that (3-mercaptopropyl)trimethoxysilane, (3-aminopropyl)trimethoxysilane and vinyltriethoxysilane are directly mixed and reacted. The specific preparation process is as follows:

[0077] Add (3-mercaptopropyl)trimethoxysilane, (3-aminopropyl)trimethoxysilane, vinyltriethoxysilane and methanol aqueous solution into a round-bottom flask and mix well. Adjust the pH to 4 with hydrochloric acid. React at 90°C for 24h. Filter, wash, extract and dry to obtain POSS-SH product.

[0078] Comparative Example 10

[0079] The difference between this comparative example and Example 1 is that the methanol in step (1) is replaced by ethanol.

[0080] Performance Testing

[0081] 1. Cultivation of Stem Cell Spheroids

[0082] BMSC stem cell spheres were cultured with reference to the literature (Wang W, Li B, Li Y, et al. In vivo restoration of full-thickness cartilage defects by poly (lactide-co-glycolide) sponges filled with fibringel, bone marrow mesenchymal stem cells and DNA complexes [J]. Biomaterials. 2010, 31: 5953-5965), that is, bone marrow was extracted from rabbits, and BMSCs were isolated from the bone marrow by density gradient centrifugation; rabbits (12 kg, 1 month old) were anesthetized with 3 g / L sodium pentobarbital (50 mg / kg), lying on the operating table, hair removal at the ilium, iodine disinfection, and local anesthesia of the joints with 2 g / L lidocaine. 1 mL of sodium heparin (3000 kU / L) was drawn into a 10 mL syringe, and then the syringe was connected to a No. 16 bone marrow puncture needle, punctured into the bone marrow cavity, and 34 mL of bone marrow fluid was drawn. Then, the bone marrow fluid was added to a serum-free medium containing lymphocyte separation fluid and centrifuged at 2000rpm for 30min, and the supernatant containing monocytes was removed. 5mL of serum-free medium was added to resuspend the cells, and the cells were centrifuged at 1500rpm for 5min, and the supernatant was discarded and the cells were washed again. The precipitated cells were resuspended in a low-glucose DMEM medium containing 10% fetal bovine serum, 100mg / mL penicillin and 100U / mL streptomycin, and cultured at 37°C and 5% CO2. The medium was changed every 2 days, and the cells were passaged and expanded after the fusion reached more than 90%.

[0083] 2. BMSC differentiation function test

[0084] The effects of KGN, Example 1 and POSS-based deaggregation hybrid molecules prepared by Comparative Examples 1 to 10 on BMSC cell spheroids were investigated. Taking Example 1 as an example, the POSS-based deaggregation hybrid molecules (based on the amount of KGN added therein, the amount of KGN added was 0.5 mg) were uniformly dispersed in a PBS solution, and the BMSC cell spheroids were also dispersed in a PBS solution. The two solutions were quickly and uniformly mixed to obtain a mixed solution, which was injected into a 48-well plate through a 16G needle syringe, and then the culture medium was added for culture, and the solution was changed every two days; the comparative example and KGN were also carried out with reference to the above method, and the secretion of GAG and the content of Col II were tested after 14 days. The secretion of GAG was measured by the dimethyl methylene blue (DMMB) method; the content of Col II was determined by the Col II ELISA kit. The test results are shown in Table 1.

[0085] Table 1 Performance test results

[0086]

[0087] It can be seen from the above performance test results that the POSS-based deaggregated hybrid molecule prepared in Example 1 has a good effect of promoting cell proliferation. This is mainly because the POSS-SH material prepared in Example 1 has multiple multifunctional groups, which increases the connection between the POSS-SH material and the poorly soluble organic drug molecules, thereby increasing the dispersibility, solubility and cell proliferation effect of the poorly soluble organic drug molecules.

[0088] However, the comparative examples are significantly worse than the embodiments in terms of corresponding performance tests because they do not adopt the necessary technical solutions. In comparative example 1, the proportion of methanol in the reaction solvent is changed, which affects the preparation of the POSS material. It can be seen that its effect of promoting cell proliferation decreases, proving that the reaction solvent and its volume ratio have an important influence on the cell proliferation effect. The three silane mass ratios defined in comparative example 2 were not used, which affected the preparation process of the POSS material, and thus affected the cell proliferation promoting effect of the poorly soluble organic drug molecule KGN. Comparative example 3 changes the ratio of silane to methanol-water mixed solution, and the reaction concentration of silane changes, which affects the preparation process of the POSS material, and the reaction product changes, resulting in a decrease in the effect of promoting cell proliferation after it is applied to the poorly soluble organic drug molecules. Comparative documents 4 to 6 respectively change the proportion of raw materials in the process of grafting the poorly soluble organic drug molecules on the POSS material, which will also have a certain impact on the effect of the final poorly soluble organic drug molecules. Comparative Example 7 changes the pH value in the POSS material preparation process, and three steps are all carried out at pH value 4. Under the condition that pH value is relatively low, silane hydrolysis reaction is very fast, and reaction process cannot be controlled, and by-products and precipitation are easily generated, causing the POSS material prepared to be used in the deaggregation process of insoluble organic drug molecules, the dispersibility and solubility of insoluble organic drug molecules are not high, and the cell proliferation effect is poor. Comparative Example 8 changes the reaction temperature of three steps, and is all carried out at 90 degrees Celsius. The reaction temperature of each step is all higher, and the reaction rate cannot be effectively controlled, and the reaction produces by-products, and the POSS material prepared is applied to the deaggregation process of insoluble organic drug molecules, and the cell proliferation effect declines. Comparative Example 9 adds three kinds of silane raw materials to methanol-water mixed solution simultaneously to react, and hydrolysis reaction is difficult to control, and reaction easily produces by-products, and the product obtained is also prone to unstable problems, and the POSS material prepared is applied to the deaggregation of insoluble organic drug molecules, and the cell proliferation effect declines equally. In Comparative Example 10, methanol in the reaction solvent is replaced with ethanol. Due to the complexity of the silane hydrolysis reaction, the reaction solvent has a greater impact on the hydrolysis reaction, resulting in a reaction product that is different from that in Example 1, and a decreased cell proliferation effect. The above experimental results further demonstrate the importance of the technical solution defined in the present invention for its technical effect.

[0089] Stability test

[0090] The POSS materials prepared in Example 1 and Comparative Examples 1 to 10 were dissolved in a hydrochloric acid solution with a pH of 1, and after standing for three days, the acid-treated POSS materials were evaporated to obtain acid-treated POSS materials, which were then applied to poorly soluble organic drug molecules for preparation.

[0091] The POSS-based deaggregated hybrid molecules prepared by KGN, Example 1 and Comparative Examples 1 to 10 were placed at 60° C. for three days to obtain the POSS-based deaggregated hybrid molecules after high temperature treatment.

[0092] The BMSC differentiation function test was performed on the above-treated materials. The test results are shown in Table 2.

[0093] Table 2 Stability test results

[0094]

[0095] It can be seen from Table 2 that the cell proliferation effect of the POSS material prepared in Example 1 after acidification treatment and then applied to the deaggregation of KGN insoluble organic drug molecules, or the prepared POSS-based deaggregation hybrid molecules after high-temperature treatment, was not significantly decreased, while the cell proliferation effect of the POSS materials prepared in Comparative Examples 1 to 10 after acidification treatment and then applied to the deaggregation of KGN insoluble organic drug molecules, or the POSS-based deaggregation hybrid molecules after high-temperature treatment was significantly decreased, which indicates that the POSS material prepared in the present invention and the POSS-based deaggregation hybrid molecules formed by the insoluble organic drug molecules have good stability.

[0096] The effects of the POSS-based deaggregated hybrid molecule and pure diclofenac prepared in Example 2 on the treatment of rheumatoid arthritis were tested. The POSS-based deaggregated hybrid molecule and pure diclofenac prepared in Example 2 were subjected to an accelerated test at a high temperature of 40° C. and a relative humidity of 75%±5% for 6 months for stability testing, and the treated materials were tested again for the effect of treating rheumatoid arthritis.

[0097] The test method is:

[0098] 40 SD male rats were randomly divided into 4 groups according to body weight, with 10 rats in each group, namely, blank control group (ig physiological saline 10ml / kg), model group (ig physiological saline 10ml / kg), diclofenac group, and POSS-based deaggregation hybrid molecule group. Except for the blank group, 0.1ml of Freund's complete adjuvant was injected intradermally into the right hind toe of each rat to induce inflammation.

[0099] The dose of diclofenac was set at 10 mg / kg (3.14 × 10 -2 mmol / kg), which is calculated from the human dose. The dosage of the POSS-based deaggregation hybrid molecule prepared in Example 2 is the same as the dosage of diclofenac, and the specific dosage is calculated according to the amount of DS in the POSS-based deaggregation hybrid molecule.

[0100] Observation indicators: A: Body weight observation: Starting from the first day of the experiment, the rats were weighed once a week thereafter; B: Swelling rate measurement: The volume change (Δml) below the right hind ankle joint of the rats was measured, and the difference between post-inflammation and pre-inflammation was used to express the swelling degree, and the measurement was carried out before and after inflammation for 21 consecutive days.

[0101] Compared with the blank control group, the overall body weight of the diclofenac group decreased, and the body weight of the rats in the POSS-based deaggregation hybrid molecule group increased at 3 weeks, indicating that the POSS-based deaggregation hybrid molecule group had a significant improvement on the slow weight gain of adjuvant arthritis rats.

[0102] The swelling rate test results are shown in Table 3.

[0103] Table 3 Swelling rate test results

[0104]

[0105]

[0106] It can be seen from Table 3 that the POSS-based deaggregation hybrid molecule prepared in Example 2 has a significantly reduced swelling value of the right toe of the rat after 21 days compared with the model group and the diclofenac group, indicating that the present invention has a more significant effect after treating diclofenac. At the same time, it can also be seen in Table 3 that the POSS-based deaggregation hybrid molecule prepared in Example 2 is subjected to accelerated aging, and the foot swelling degree is tested again after 21 days. Compared with the effect before accelerated aging, the swelling value of the right toe of the rat is still significantly reduced, indicating that the POSS-based deaggregation hybrid molecule prepared in the present invention has good stability and efficacy.

[0107] Therefore, the present invention adopts the above-mentioned preparation method and application of POSS-SH based on trimethoxysilane, adopts a method of stepwise reaction of three silane raw materials, and utilizes pH value, temperature and reaction time to accurately control the preparation process of POSS material. The prepared POSS material has multiple functional groups and is applied to the deaggregation of poorly soluble organic drug molecules with amino / hydroxyl groups, which can not only improve the dispersibility of the drug molecules, but also improve their stability.

[0108] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that they can still modify or replace the technical solution of the present invention with equivalents, and these modifications or equivalent replacements cannot cause the modified technical solution to deviate from the spirit and scope of the technical solution of the present invention.

Claims

1. A method for preparing POSS-SH based on trimethoxysilane, characterized in that, The following steps are involved: (1) Add (3-mercaptopropyl)trimethoxysilane and methanol aqueous solution into a round-bottom flask, mix well, adjust the pH to 7 with hydrochloric acid, react at 30-40° C. for 2-3 hours, and obtain a mixed solution A; (2) adding (3-aminopropyl)trimethoxysilane to the mixed solution A and mixing them evenly, adjusting the pH to 6 with hydrochloric acid, and reacting at 50 to 60° C. for 1 to 2 hours to obtain a mixed solution B; (3) Add vinyl triethoxysilane to the mixed solution B and mix well, adjust the pH to 3-5 with hydrochloric acid, react at 80-100° C. for 15-24 h, filter, wash, extract, and dry to obtain a trimethoxysilane-based POSS-SH product.

2. A method for preparing POSS-SH based on trimethoxysilane according to claim 1, characterized in that, The volume ratio of methanol to water in the methanol aqueous solution is (75-90):(10-25).

3. A method for preparing POSS-SH based on trimethoxysilane according to claim 1, characterized in that, The mass ratio of (3-mercaptopropyl)trimethoxysilane:(3-aminopropyl)trimethoxysilane:vinyltriethoxysilane is (6-8):(1-2):(0.5-1.5).

4. A method for preparing POSS-SH based on trimethoxysilane according to claim 1, characterized in that, The volume ratio of (3-mercaptopropyl)trimethoxysilane:methanol aqueous solution is (1-2):(30-50).

5. A POSS-SH based on trimethoxysilane, characterized in that, The method is prepared according to any one of claims 1 to 4.

6. Use of a trimethoxysilane-based POSS-SH in the deaggregation of poorly soluble organic molecules according to claim 5, wherein the poorly soluble organic molecules are poorly soluble organic drug molecules having amino and / or hydroxyl groups.

7. The application of POSS-SH based on trimethoxysilane according to claim 6, characterized in that, The deaggregation process of poorly soluble organic molecules is: Dissolve polyethylene glycol in dichloromethane, then add potassium carbonate, and vigorously stir in a nitrogen atmosphere at an ice-water bath temperature of 0-5°C, then slowly drop a dichloromethane solution of acryloyl chloride, react at room temperature, filter, extract, dry, and spin-dry after the reaction is completed to obtain PEG-Ac; Add the poorly soluble organic molecule, NMP and triethylamine into the reaction tube in sequence, seal it, evacuate and pass nitrogen for 3 times, maintain an inert atmosphere, add acryloyl chloride, stir and heat to react, and after the reaction is completed, cool, add water, filter and recrystallize to obtain OM-Ac; POSS-SH, PEG-Ac and DMPA were dissolved in tetrahydrofuran, and irradiated with ultraviolet light at room temperature for reaction. Then OM-Ac was dissolved in tetrahydrofuran and added dropwise to the above ultraviolet light irradiation reaction process, and the ultraviolet light was continued to react. After the reaction, the solution was rotary evaporated to obtain POSS-based deaggregated hybrid molecules.

8. The application of POSS-SH based on trimethoxysilane according to claim 7, characterized in that, The mass ratio of POSS-SH:PEG-Ac is (15-30):(3-5).

9. The use of a trimethoxysilane-based POSS-SH according to claim 7, characterized in that: The molar ratio of PEG-Ac:DMPA is (0.6~0.9)mol:(0.05~0.08)mmol.

10. The use of a trimethoxysilane-based POSS-SH according to claim 7, characterized in that: The molar ratio of DMPA:OM-Ac is (0.6~0.9) mol:(0.1~0.3) mol.

Images