Thermoreversible supramolecular gels, methods of making and using the same

Abstract

This invention discloses a thermally reversible supramolecular gel, its preparation method, and its applications. The thermally reversible supramolecular gel is obtained by preparing malic acid and sorbitol, micronizing them separately, and then mixing and reacting the malic acid and sorbitol at a molar ratio of 1:3 to 1:4. The thermally reversible supramolecular gel of this invention does not require the addition of an additional cross-linking agent during preparation; it is formed solely through non-covalent bonding between malic acid and sorbitol molecules. This gel can be used to dissolve hydrophobic drugs and, due to its biodegradability, good chemical stability, excellent mechanical properties, good biocompatibility, and strong dissolving ability, is applicable in the biomedical field.

Description

Technical Field

[0001] This invention relates to the field of supramolecular gel technology, and particularly to a thermally reversible supramolecular gel, its preparation method, and its applications. Background Technology

[0002] In the formation of supramolecular gels, the self-assembly of gelling agent molecules, especially the non-covalent interactions between gelling agent molecules such as hydrogen bonding, π-π stacking, electrostatic interaction, van der Waals interaction, dipole-dipole interaction, and coordination interaction, plays a very important role.

[0003] Gels are formed through non-covalent self-assembly, making the gelation process reversible. Through the synergistic effect of non-covalent forces, supramolecular gels form a three-dimensional self-assembled fibrous network structure. This fibrous network structure uses surface tension to prevent the free flow of solvent molecules under gravity. Based on self-assembled supramolecular gels, drugs can be loaded and transported to specific sites in the body.

[0004] Drug delivery technology is crucial for drug therapy and has enabled the successful application of many drugs in disease treatment. Drug delivery technology can solve the challenge of transporting poorly soluble drugs in vivo, enhance targeted drug delivery, minimize off-target effects, and improve patient compliance. However, the current challenge in preparing gel-based drug delivery systems lies in providing a supramolecular gel with excellent mechanical properties, self-healing properties, biosafety, good drug loading capacity, and good in vivo stability. Summary of the Invention

[0005] The purpose of this invention is to provide a thermally reversible supramolecular gel, its preparation method, and its application.

[0006] The technical solution of the present invention is a thermally reversible supramolecular gel, which is formed by mixing and reacting malic acid and sorbitol in a molar ratio of 1:3 to 1:4.

[0007] Preferably, it comprises a molecular structure as shown in Formula I:

[0008]

[0009] The n = 6 to 8.

[0010] Preferably, its hot-melting temperature range is 50℃~60℃.

[0011] Preferably, it is formed by mixing malic acid and sorbitol and simultaneously adding water to react, wherein the molar ratio of malic acid, sorbitol and water is 1:4:0.24 to 1:4:0.48.

[0012] Another technical solution of the present invention is a method for preparing a thermally reversible supramolecular gel, comprising the following steps: preparing solid malic acid and sorbitol, micronizing the solid sorbitol and malic acid respectively by ball milling, microwave, or ultrasonic auxiliary means, and mixing the micronized malic acid and sorbitol at a molar ratio of 1:3 to 1:4 to generate a thermally reversible supramolecular gel.

[0013] Preferably, the steps further include: heating the mixed malic acid and sorbitol to 70°C–85°C under nitrogen protection; homogenizing the mixture for 4–5 hours with the aid of ultrasound until the mixture melts to obtain a clear liquid; and placing the clear liquid in a dry environment at 20–30°C for 8–48 hours to allow it to undergo a self-polymerization reaction, thereby obtaining a thermally reversible supramolecular gel.

[0014] Another technical solution of the present invention is the application of a thermally reversible supramolecular gel as a soluble skin dressing in transdermal drug delivery.

[0015] Another technical solution of the present invention is the application of a thermally reversible supramolecular gel as a delivery medium to dissolve drugs and then apply it to a transdermal drug delivery system.

[0016] Preferably, the drug is a hydrophobic drug.

[0017] Another technical solution of the present invention is the application of a thermally reversible supramolecular gel, which is used as a delivery medium to dissolve an aerosol forming matrix to form a gel for use in an atomizing device. The aerosol forming matrix includes at least one of nicotine, menthol, limonene, linalool, tea polyphenols, and lemon oil.

[0018] Compared with the prior art, the advantages of this invention are as follows:

[0019] This invention provides a thermally reversible supramolecular gel, which is prepared without the need for additional crosslinking agents and is formed directly based on the non-covalent bond interaction between malic acid and sorbitol molecules.

[0020] This gel can be used to dissolve hydrophobic drugs and has the characteristics of being non-toxic, biodegradable, chemically stable, and low in preparation cost.

[0021] The gel also has good mechanical properties, injectability, biocompatibility, and drug loading and release capabilities. Attached Figure Description

[0022] Figure 1 The reaction formula for the generation of the thermally reversible supramolecular gel of this invention;

[0023] Figure 2This is a comparison curve of water content and hardness of the thermally reversible supramolecular gel of the present invention.

[0024] Figure 3 This describes the state of the deep eutectic supramolecular gel during the preparation of the thermally reversible supramolecular gel of this invention.

[0025] Figure 4 a is the thermally reversible supramolecular gel of this invention;

[0026] Figure 4 b is a scanning electron microscope image of the thermally reversible supramolecular gel of the present invention;

[0027] Figure 5 This is the result of differential scanning calorimetry for the thermally reversible supramolecular gel of this invention;

[0028] Figure 6 The carbon NMR spectra of malic acid, sorbitol, and the thermally reversible supramolecular gel of this invention are shown.

[0029] Figure 7 The 1H NMR spectrum of malic acid, sorbitol, and the thermally reversible supramolecular gel of this invention;

[0030] Figure 8 Infrared spectra of the thermally reversible supramolecular gel, malic acid, and sorbitol of this invention;

[0031] Figure 9 This is a rheological test diagram of the thermally reversible supramolecular gel of the present invention;

[0032] Figure 10 a is a microneedle patch made from the thermally reversible supramolecular gel substrate of the present invention;

[0033] Figure 10 b is a microneedle patch made by dissolving curcumin in a thermally reversible supramolecular gel;

[0034] Figure 11 The intradermal dissolution rate of the microneedles prepared from the supramolecular gel of this invention;

[0035] Figure 12 This invention relates to a solid e-liquid prepared from a thermally reversible supramolecular gel system and an effective component of an e-cigarette atomizing matrix. Detailed Implementation

[0036] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments:

[0037] This invention discloses a thermally reversible supramolecular gel, formed by the reaction of malic acid and sorbitol in a molar ratio of 1:3 to 1:4, and its components have a molecular structure as shown in Formula I:

[0038]

[0039] Where n = 6 to 8, specifically n = 6, n = 7, or n = 8.

[0040] The thermally reversible supramolecular gel of the present invention has a hot-melting temperature range of 50°C to 60°C, more preferably 55°C to 58°C. The molar ratio of malic acid to sorbitol is more preferably 1:3.5 to 1:4, or 1:4.

[0041] The thermally reversible supramolecular gel of this invention can be formed by reacting a mixture of malic acid and sorbitol with water to enhance its hardness or strength. The molar ratio of malic acid, sorbitol, and water in the reaction is 1:4:0.24 to 1:4:0.48. The water used is purified water.

[0042] The method for preparing the thermally reversible supramolecular gel of the present invention includes the following steps:

[0043] S1. Preparation of solid malic acid and sorbitol;

[0044] S2. Solid sorbitol and malic acid are micronized by ball milling, microwave, or ultrasonic methods respectively;

[0045] S3. The micronized malic acid and sorbitol are mixed at a molar ratio of 1:3 to 1:4 and then reacted to generate a thermally reversible supramolecular gel.

[0046] Another method for preparing the thermally reversible supramolecular gel of the present invention includes the following steps:

[0047] S1. Preparation of solid malic acid and sorbitol;

[0048] S2. Solid sorbitol and malic acid are micronized by ball milling, microwave, or ultrasonic methods respectively;

[0049] S3. Mix the micronized malic acid with sorbitol at a molar ratio of 1:3 to 1:4;

[0050] S4. The mixed malic acid and sorbitol are heated to 70°C to 85°C under nitrogen protection; preferably to 75°C to 80°C, 78°C to 82°C, or 80°C.

[0051] S5. Homogenize the mixture for 4-5 hours, preferably 4.5 hours, with the aid of ultrasound, until the mixture melts and a clear liquid is obtained;

[0052] S6. Place the clarified liquid in a dry environment at 20-30°C for 8-48 hours, preferably 12-36 hours, or 16-24 hours, to allow it to undergo a self-polymerization reaction, thereby obtaining a thermally reversible supramolecular gel.

[0053] The present invention relates to the application of a thermally reversible supramolecular gel, which can be used as a soluble skin dressing for transdermal drug delivery.

[0054] Another application of the thermally reversible supramolecular gel of the present invention is that it can be used as a delivery medium to dissolve drugs and then applied to transdermal drug delivery systems. The aforementioned drugs can be hydrophobic.

[0055] Another application of the thermally reversible supramolecular gel of the present invention is to use the gel formed by dissolving the aerosol forming matrix as a delivery medium in an atomizing device. The aerosol forming matrix includes at least one of nicotine, menthol, limonene, linalool, tea polyphenols, and lemon oil.

[0056] Example 1

[0057] Malic acid and sorbitol were prepared and micronized using ball milling. The corresponding weights of malic acid and sorbitol were weighed and mixed according to molar ratios of 1:1, 1:2, 1:3, 1:4, and 1:5. The gelation results and curing times are shown in the table below.

[0058] Group reagents Malic acid / sorbitol molar ratio Does it form a gel? Gel formation time (h) Ⅰ 1：1 × × Ⅱ 1：2 × × Ⅲ 1：3 √ 12-48 Ⅳ 1：4 √ 8-36 Ⅴ 1：5 × ×

[0059] The data obtained from the table above shows that when the molar ratio of malic acid to sorbitol is in the range of 1:3 to 1:4, the micronized malic acid and sorbitol mixture can form a gel. This indicates that within a certain range, the molar ratio of malic acid to sorbitol in the reagent can produce similar effects through their synergistic interaction. Furthermore, at a specific gelling ratio, the curing time decreases with increasing ratio. These results demonstrate that only sorbitol-based solutions at specific ratios can form a gel state and eventually solidify into a solid gel.

[0060] In this embodiment, when the molar ratio of malic acid to sorbitol is in the range of 1:3 to 1:4, the reaction formula for the formation of a gel from the mixed solution of malic acid and sorbitol is as follows: Figure 1 As shown.

[0061] Example 2

[0062] When micronized malic acid and sorbitol were mixed in a molar ratio of 1:4, different proportions of water were added to induce hydrogen bonding cross-linking between gels. The gelation time and hardness were tested under the following conditions: molar ratios of malic acid, sorbitol, and water were 1:4:0, 1:4:0.24, 1:4:0.48, 1:4:0.96, 1:4:1.92, and 1:4:2.88. The results are shown in the table below.

[0063]

[0064] It can be seen that aqueous solutions of malic acid, sorbitol and water in molar ratios of 1:4:0, 1:4:0.24 to 1:4:1.92 can form gels with relatively consistent curing times.

[0065] like Figure 2 As shown, the gels obtained in the above experiments, when tested by a texture analyzer, showed that the molar ratio of malic acid, sorbitol and water in the range of 1:4:0.24 to 1:4:0.48 exhibited better hardness. Therefore, this molar ratio range can be selected to enhance the gel strength.

[0066] Example 3

[0067] Preparation of thermally reversible supramolecular gels according to the present invention

[0068] Malic acid and sorbitol were micronized using ball milling. The malic acid and sorbitol were then mixed at specific molar ratios of 1:1, 1:2, 1:3, 1:4, and 1:5. Under a non-aqueous nitrogen atmosphere, the mixture was homogenized at 70–85°C for 4–5 hours using methods such as ultrasound. After heating until the mixture melted, a clear, viscous liquid was obtained. This liquid was dried and cooled to a solid state in a desiccator to obtain a thermally reversible supramolecular gel. The morphology of the thermally reversible supramolecular gel is as follows: Figure 4 As shown in (a).

[0069] Scanning electron microscopy (SEM) images were taken of the thermally reversible supramolecular gel obtained in this embodiment, and the results are as follows: Figure 4 As shown in (b), the microstructure of the thermally reversible supramolecular gel reveals the cross-linked network structure of the gel.

[0070] Differential scanning calorimetry was performed on the thermally reversible supramolecular gel obtained in this embodiment, and the results are as follows: Figure 5 As shown, curve a indicates that the melting point of malic acid is 130℃~140℃, curve b indicates that the melting point of sorbitol is 95℃~100℃, and curve c shows that the mixture has only one melting peak, with a melting point lower than that of the individual monomers. Curve d shows that the gel melting temperature is 50℃~60℃, meaning that heating the supramolecular gel at 50℃~60℃ restores it to a clear, viscous liquid state. Placing the clear liquid in a drying environment at 20℃~30℃ for 8~48 hours yields a supramolecular gel again.

[0071] The thermally reversible supramolecular gel obtained in this embodiment was characterized by nuclear magnetic resonance, and the results are as follows: Figure 6 , Figure 7 As shown, where Figure 6 The carbon NMR spectra of malic acid, sorbitol, and the thermally reversible supramolecular gel of this invention are as follows: Figure 7 The NMR spectra of malic acid, sorbitol, and the thermally reversible supramolecular gel of this invention are shown. The NMR analysis results show that the spectrum of the thermally reversible supramolecular gel does not have any new chemical shifts compared to the monomers. Combined with the results of differential scanning calorimetry, it is concluded that the thermally reversible supramolecular gel of this invention is a physical reaction of non-covalent linkage between malic acid and sorbitol, rather than a chemical reaction.

[0072] Infrared spectroscopy was performed on the thermally reversible supramolecular gel obtained in this embodiment, and the results were compared with the characteristic peaks of the raw material. The infrared spectra are shown below. Figure 8 As shown, the absorption peak of the C=O stretching vibration of malic acid appears at 1710 cm⁻¹. -1 Theoretically, the absorption peak of a free carboxylic acid group is at 1760 cm⁻¹. -1 This is because carboxylic acids often exist as dimers, which lowers the original chemical bond force constants for forming hydrogen bonds, causing the absorption peak to shift to lower wavenumbers. After the formation of a thermally reversible supramolecular gel, the dimer breaks down, and the peak shape becomes clearer. This is because the formation of the hydrogen bond network lowers the original chemical bond force constants for forming hydrogen bonds, shifting the absorption peak to lower wavenumbers, and also increases the change in dipole moment during vibration, leading to an increase in absorption peak intensity. Therefore, it can be determined that a hydrogen bond network has formed between malic acid and sorbitol.

[0073] Rheological tests were performed on the thermally reversible supramolecular gel obtained in this embodiment, using flow-temperature scanning as follows: Figure 9 As shown, the viscosity of the thermally reversible supramolecular gel of this invention gradually decreases with increasing temperature. This is because hydrogen bonds are broken with increasing temperature, resulting in poor adhesion. When the temperature returns to room temperature, hydrogen bonds re-form, maintaining the same thermally reversible property.

[0074] This invention provides a thermally reversible supramolecular hydrogel, which is a supramolecular hydrogel with viscous properties. It is a thermally reversible supramolecular hydrogel formed through a non-covalent physical reaction of fruit acid and sorbitol.

[0075] Example 4

[0076] Malic acid and sorbitol were prepared and micronized separately. The corresponding weights of malic acid and sorbitol were weighed in a molar ratio of 1:4 and mixed. Under non-aqueous nitrogen protection, the mixture was homogenized at 70℃~85℃ for 4~5 hours with the aid of ultrasound. Then, the mixture was heated until it melted to obtain a clear viscous liquid with a refractive index of 1.4960~1.4970 Nd.

[0077] The obtained viscous liquid was uniformly spread on the surface of the microneedle mold. A thermally reversible supramolecular gel (800 μm needle length, 410 μm base width, and 11 × 11 array) was added to the surface of the microneedle mold, and the mixture was centrifuged (4000 rpm, 10 min) to fill the needle cavity. After drying at 25 °C for 48 hours, the MSNs-MNs were carefully removed from the mold. The morphology of the prepared microneedles is as follows. Figure 10 As shown.

[0078] This invention involves mixing a thermally reversible supramolecular gel with polyvinylpyrrolidone (PVP), a microneedle substrate material, to improve the toughness and hardness of the microneedles. This mixture is used to dissolve hydrophobic drugs such as curcumin, and the resulting morphology is as follows: Figure 10 As shown.

[0079] Example 5

[0080] Rats were anesthetized to study the intradermal dissolution capacity of thermally reversible supramolecular gel microneedles. The microneedles were then inserted into the skin of isolated rats for a series of time intervals. The height of the microneedles and the dissolution trend were then observed under a microscope. The dissolution effect of the microneedles was as follows: Figure 11 As shown.

[0081] Example 6

[0082] The present invention relates to a thermally reversible supramolecular gel, which can be used as a delivery medium to dissolve an aerosol-forming matrix to form a gel for use in atomizing devices. The aerosol-forming matrix includes at least one of nicotine, menthol, limonene, linalool, tea polyphenols, and lemon oil.

[0083] Specifically, in this embodiment, a thermally reversible supramolecular gel is prepared by mixing one or more of the active ingredients in e-cigarette oil, such as menthol or DL-limonene, nicotine, linalool, tea polyphenols, and lemon oil, to form an aerosol gel, i.e., a solid e-cigarette oil. The morphology of the prepared gel is as follows: Figure 12 As shown. After solid e-liquid is loaded into the atomizing device, it is heated by the atomizing device. When heated to 50℃-60℃, the surface of the solid e-liquid melts into liquid e-liquid. When further heated to a higher temperature, the liquid e-liquid can be atomized into an aerosol, that is, e-cigarette vapor.

[0084] In summary, this invention provides a thermally reversible supramolecular hydrogel with excellent mechanical properties, injectability, biocompatibility, and drug loading and release capabilities. Furthermore, this thermally reversible supramolecular hydrogel exhibits excellent in vivo stability. This hydrogel can serve as a drug delivery system for encapsulating various drugs, particularly hydrophobic drugs (with good sustained-release effects), demonstrating promising application prospects.

[0085] The technical solutions described above in the embodiments and experimental methods of this invention are complete and clear. Obviously, the described embodiments are only a part of the embodiments of this invention, not all of them. The above embodiments are only used to explain this invention and do not constitute a limitation on the scope of protection of this invention.

[0086] The above description is only a preferred embodiment of the present invention. All equivalent changes and modifications made within the scope of the claims of the present invention should be covered by the claims of the present invention.

Claims

1. A thermally reversible supramolecular gel, characterized in that, Solid malic acid and sorbitol are mixed in a molar ratio of 1:3 to 1:4 after micronization. The mixture is heated to 70°C to 85°C under nitrogen protection. Homogenization is achieved by ultrasonication for 4 to 5 hours until the mixture melts, resulting in a clear liquid. The clear liquid is then placed in a dry environment at 20 to 30°C for 8 to 48 hours to allow it to undergo a self-polymerization reaction, thus obtaining a thermally reversible supramolecular gel.

2. The thermally reversible supramolecular gel according to claim 1, characterized in that, It is formed by reacting malic acid and sorbitol with water, wherein the molar ratio of malic acid, sorbitol and water is 1:4:0.24 to 1:4:0.

48.

3. A method for preparing the thermally reversible supramolecular gel as described in claim 1, characterized in that, The process includes the following steps: preparing solid malic acid and sorbitol; micronizing the solid sorbitol and malic acid separately using ball milling, microwave, or ultrasonic-assisted methods; mixing the micronized malic acid and sorbitol at a molar ratio of 1:3 to 1:4; heating to 70°C to 85°C under nitrogen protection; homogenizing the mixture for 4 to 5 hours with ultrasonic assistance until the mixture melts to obtain a clear liquid; and placing the clear liquid in a dry environment at 20 to 30°C for 8 to 48 hours to allow it to undergo a self-polymerization reaction, thus obtaining a thermally reversible supramolecular gel.

4. An application of the thermally reversible supramolecular gel as described in claim 1, characterized in that, It is used as a soluble skin dressing for transdermal drug delivery.

5. An application of the thermally reversible supramolecular gel as described in claim 1, characterized in that, After being dissolved, the drug is used as a delivery medium in a transdermal drug delivery system.

6. The application of the thermally reversible supramolecular gel according to claim 5, characterized in that, The drug is a hydrophobic drug.

7. An application of the thermally reversible supramolecular gel as described in claim 1, characterized in that, The gel formed by dissolving the aerosol forming matrix as a delivery medium is used in an atomizing device. The aerosol forming matrix includes at least one of nicotine, menthol, limonene, linalool, tea polyphenols, and lemon oil.

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