PH response type hydrogel as well as preparation method and application thereof

Abstract

The invention provides pH response type hydrogel as well as a preparation method and application thereof. The pH-responsive hydrogel is prepared from the following raw materials: a hydrophobic monomer, a sensitive monomer, a cross-linking agent, an initiator and an organic solvent, the hydrophobic monomer comprises at least one of methyl acrylate, ethyl acrylate, benzyl acrylate and 2-phenoxyethyl acrylate, and the sensitive monomer comprises at least one of a cross-linking agent, an initiator and an organic solvent. The sensitive monomer comprises a sulfanilamide monomer containing an acryloyl group or a methacryloyl group. According to the pH response type hydrogel disclosed by the invention, the drug release rate difference is obvious under different pH values. Under a low pH value, a slow drug release speed can be maintained, and under a high pH value, rapid drug release can be realized. And the release amount at high pH for 24 hours can reach 150-600% of the release amount at low pH for the same time. The invention further provides a preparation method and application of the pH response type hydrogel.

Description

Technical Field

[0001] The invention belongs to the technical field of hydrogel materials, and in particular relates to a pH responsive hydrogel and a preparation method and application thereof. Background Art

[0002] A hydrogel is a 3D cross-linked polymer network that absorbs and retains large amounts of water while resisting dissolution in aqueous media. Some hydrogels can respond to external stimuli by changing their conformation, solubility, or hydrophilic / lipophilic balance. In the context of drug delivery, pH-responsive hydrogels can exhibit volume phase transitions, swelling / contraction, or assembly / disassembly when exposed to exogenous or endogenous pH changes, thereby achieving responsive drug release.

[0003] Existing hydrogels that release drugs at high pH have the following disadvantages: the difference in drug release rate at different pH is not obvious, that is, the release is still fast at low pH, and the effect of accelerated release at high pH is not significant; the drug release rate is too fast, resulting in no drug component being released after a very short time, and the effective action time is short.

[0004] Therefore, it is necessary to develop a new hydrogel that can maintain a slower drug release rate at low pH and faster drug release at high pH. Summary of the invention

[0005] The present invention aims to solve at least one of the above-mentioned technical problems existing in the prior art. To this end, the present invention provides a pH-responsive hydrogel, which has obvious differences in drug release rates at different pH values. When used for drug delivery, it can increase the drug loading capacity of the drug carrier, optimize the drug response release characteristics, improve the drug bioavailability, and enhance its stability, thereby achieving a more accurate and efficient drug delivery system.

[0006] The invention also provides a method for preparing a pH-responsive hydrogel.

[0007] The invention also provides a pH-responsive drug carrier.

[0008] The invention also provides a method for preparing a pH-responsive drug carrier.

[0009] The first aspect of the present invention provides a pH-responsive hydrogel, wherein the preparation raw materials include a hydrophobic monomer, a sensitive monomer, a crosslinking agent, an initiator and an organic solvent, wherein the hydrophobic monomer includes at least one of methyl acrylate, ethyl acrylate, benzyl acrylate and 2-phenoxyethyl acrylate, and the sensitive monomer includes a sulfonamide monomer containing an acryloyl or methacryloyl group.

[0010] One of the technical solutions of the present invention regarding the pH-responsive hydrogel has at least the following beneficial effects:

[0011] The pH-responsive hydrogel of the present invention has obvious differences in drug release rate at different pH values. At low pH, a slower drug release rate can be maintained, while at high pH, ​​a rapid drug release can be achieved. The release amount at high pH (such as 8.4) in 24 hours can reach 150%-600% of the release amount at low pH (such as 7.4) in the same period of time.

[0012] When the pH-responsive hydrogel of the present invention is used as a drug carrier, the effective action time of the drug is long, and the sustained release of the drug components can still be monitored after 120 hours.

[0013] The pH-responsive hydrogel of the present invention has a constant or reduced volume when accelerating the release of drugs, which is conducive to its adaptability to various environments.

[0014] Low pH mainly refers to 2.0 to 8.0.

[0015] High pH mainly refers to 5.0 to 10.0.

[0016] According to some embodiments of the present invention, the mass ratio of the hydrophobic monomer to the sensitive monomer is 100:1-20.

[0017] According to some embodiments of the present invention, the mass ratio of the hydrophobic monomer to the sensitive monomer is 100:2-10.

[0018] According to some embodiments of the present invention, the mass ratio of the hydrophobic monomer to the sensitive monomer is 100:2-8.

[0019] According to some embodiments of the present invention, the mass ratio of the hydrophobic monomer to the sensitive monomer can be any value of 100:2, 100:2.5, 100:3.0, 100:3.5, 100:4.0, 100:4.5, 100:5.0, 100:5.5, 100:6.0, 100:6.5, 100:7.0, 100:7.5 or a range formed by any two of them, such as 100:3.5-6.0.

[0020] According to some embodiments of the present invention, the sensitive monomer includes at least one of acryloyl acetyl sulfonamide, acryloyl sulfadiazine, acryloyl sulfabenzoyl, acryloyl sulfa ketone, acryloyl sulfaguanidine, acryloyl sulfadoxine, acryloyl sulfaquinoxaline, acryloyl sulfinpyrazone, acryloyl sulfa metamethoxine, methacrylic acid sulfabenzoyl, acryloyl sulfamethoxazole, acryloyl sulfa dimethoxazine, methacryloyl acetyl sulfonamide, methacryloyl sulfadiazine and methacryloyl sulfabenzoyl.

[0021] According to some embodiments of the present invention, the cross-linking agent includes at least one of 1,4-butanediol diacrylate and N,N-methylenebisacrylamide.

[0022] According to some embodiments of the invention, the initiator comprises at least one of α-ketoglutaric acid, TPO, TPO-L and cyclohexanone peroxide.

[0023] The second aspect of the present invention provides a method for preparing the pH-responsive hydrogel of the first aspect of the present invention, comprising the steps of mixing various preparation raw materials in an organic solvent and performing a free radical polymerization reaction.

[0024] A technical solution in the method for preparing pH-responsive hydrogel of the present invention has at least the following beneficial effects:

[0025] Simplified synthesis process: The mixed reaction under anaerobic conditions simplifies the synthesis process, avoids possible side reactions or complicated post-processing steps, can improve production efficiency, and reduce unnecessary production costs.

[0026] The preparation method of the present invention does not require expensive equipment and complicated process control, has undemanding reaction conditions, has readily available raw materials, has low production costs, and is easy to industrialize.

[0027] According to some embodiments of the present invention, the organic solvent includes at least one of dimethyl sulfoxide, N-methylpyrrolidone, 1,4-dioxane and N,N-dimethylformamide.

[0028] The third aspect of the present invention provides a pH-responsive drug carrier, which is prepared from the pH-responsive hydrogel of the first aspect of the present invention and a drug.

[0029] One of the technical solutions of the present invention regarding the pH-responsive drug carrier has at least the following beneficial effects:

[0030] Controlled drug release: Since the drug carrier uses a pH-responsive hydrogel, the drug release rate can be adjusted under different pH environments. In a low pH environment (such as normal skin and stomach acid), the drug release is slow, while in a high pH environment (such as the weakly alkaline environment of the small intestine), the drug release rate is fast. This pH sensitivity enables targeted release of drugs in specific parts of the body and in vitro, enhancing the therapeutic effect.

[0031] Prolong the effective duration of drug action: This pH-responsive drug carrier can continuously control the release of drugs while releasing them, thus prolonging the effective duration of the drugs in the body. For example, when using this carrier, the drug can continue to be slowly released after 120 hours, ensuring that the drug can work stably and effectively for a long time and reducing the frequency of administration.

[0032] Improving drug bioavailability: By controlling the release rate of drugs in the body and preventing the drugs from being rapidly metabolized or excreted in a short period of time, the bioavailability of drugs can be improved, allowing the drugs to be more fully absorbed and utilized.

[0033] Adapt to different in vivo environments: Due to the special properties of pH-responsive hydrogels, they can adaptively change in different pH environments of the gastrointestinal tract, maintain good drug release control characteristics, adapt to the physiological conditions of different parts, and enhance the therapeutic effect of drugs. They are particularly suitable for oral drug delivery.

[0034] Volume change characteristics: When the drug is released at an accelerated rate, the volume of the drug carrier remains unchanged or decreases, which is conducive to the rapid penetration and release of the drug in the body. The volume change of the carrier during drug release (such as decrease) also helps the carrier contact the target site, further enhancing the accuracy of drug release and local efficacy.

[0035] Enhanced targeting: The pH response properties of drug carriers enable them to change in specific environments in the body (such as acidic or alkaline areas), thereby improving the targeting of drugs. In this way, drugs can be delivered more accurately to the lesion area or the area that needs treatment, reducing the impact on healthy tissues.

[0036] Reduced side effects: By achieving precise drug release in the body, drug carriers can reduce over-release of drugs and unwanted side effects. This makes drug therapy safer and more effective, especially for long-term treatment or high-dose drugs.

[0037] Therefore, the pH-responsive drug carrier of the present invention utilizes the pH-sensitive properties of the hydrogel to effectively control the release rate of the drug, prolong the drug action time, and improve the targeting and bioavailability of the drug. It is a carrier system that is very suitable for precision drug delivery and has significant clinical application value.

[0038] The fourth aspect of the present invention provides a method for preparing the pH-responsive drug carrier of the third aspect of the present invention, the preparation method comprising soaking the pH-responsive hydrogel in an organic solution of the drug and in water in sequence.

[0039] A technical solution in the preparation method of a pH-responsive drug carrier of the present invention has at least the following beneficial effects:

[0040] Improving the loading efficiency of drug carriers: By soaking in a drug solution, drugs can be loaded more efficiently. The porous structure of the hydrogel helps to absorb and store drug molecules, and this soaking treatment ensures that the drug is evenly distributed in the hydrogel network, thereby increasing the drug loading.

[0041] Enhance the controllability of drug release: The soaking step in water helps the hydrogel to further adjust its swelling state after absorbing the drug solution, affecting the rate of drug release. This step can optimize the structure of the hydrogel, ensure that the difference in drug release under different pH conditions is more obvious, and thus achieve precise release control.

[0042] Optimize the initial release of drugs: Pre-immersion of drug carriers in drug solution can help control the release rate of drugs in the initial stage. During the drug release process, the hydrogel will first absorb water and swell, and adjust its swelling degree under different pH environments, thereby affecting the release behavior of the drug.

[0043] Enhance the stability of hydrogels: By soaking the hydrogels, their internal network structure can be adjusted and their stability in the body environment can be improved. In particular, when soaking in liquid medicine, it helps the hydrogels to fully absorb the drugs and remove some possible solvent residues during the soaking process in water, avoiding adverse effects on the stability of the drugs or carriers themselves.

[0044] Optimizing the precision and bioavailability of drug release: By controlling the immersion process of the hydrogel, the loading and release characteristics of the drug can be optimized, allowing the drug to be released at a more precise rate in the body, thereby improving the bioavailability and therapeutic effect of the drug.

[0045] Reduce side effects: Due to the enhanced controllability of drug release, rapid or excessive release of drugs in the body can be avoided, thereby reducing drug side effects. This gradual drug release can ensure that the drug has a better therapeutic effect at the target site while reducing the impact on healthy tissues.

[0046] Simplified preparation process: Compared with other complex drug loading processes (such as high pressure, high temperature treatment, etc.), the soaking treatment step is simple in process and low in cost, which is conducive to industrial production and large-scale application.

[0047] The organic solution of the drug, wherein the organic solvent comprises at least one of dimethyl sulfoxide, N-methylpyrrolidone, 1,4-dioxane and N,N-dimethylformamide.

[0048] Therefore, by soaking the pH-responsive hydrogel in an organic solution of the drug and water in turn, the drug loading capacity of the drug carrier can be increased, the drug release characteristics can be optimized, the drug bioavailability can be improved, and its stability can be enhanced, thereby achieving a more precise and efficient drug delivery system.

[0049] According to some embodiments of the present invention, the soaking time in water is 8 hours to 36 hours.

[0050] According to some embodiments of the present invention, the soaking time in water is 12 hours to 36 hours.

[0051] According to some embodiments of the present invention, the soaking time in water is 20 hours to 30 hours.

[0052] According to some embodiments of the present invention, the soaking time in water can be any one of 22h, 23h, 24h, 25h, 26h, 27h, 28h or a range formed by any two of them, such as 24h to 28h. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] Figure 1 This is the test result of the release effect of the rhein-loaded gel in Example 1.

[0054] Figure 2 This is the test result of the release effect of naproxen-loaded gel in Example 1.

[0055] Figure 3 This is the test result of the release effect of the quercetin-loaded gel in Example 2.

[0056] Figure 4 This is the test result of the release effect of the ciprofloxacin-loaded gel in Example 3.

[0057] Figure 5 This is the test result of the release effect of the quercetin-loaded gel in Example 4.

[0058] Figure 6 This is the test result of the release effect of the berberine hydrochloride gel in Example 5. DETAILED DESCRIPTION

[0059] The following will be combined with the embodiments to clearly and completely describe the concept of the present invention and the technical effects produced, so as to fully understand the purpose, characteristics and effects of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, other embodiments obtained by those skilled in the art without creative work are all within the scope of protection of the present invention.

[0060] In the description of the present invention, the description with reference to the terms "one embodiment", "some embodiments", "illustrative embodiments", "examples", "specific examples", or "some examples" means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representation of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner.

[0061] Unless otherwise specified, "room temperature" in the present invention means 25°C±5°C.

[0062] Unless otherwise specified, "about" in the present invention means that the allowable error is within ±2%.

[0063] If the specific conditions are not specified in the examples, the experiments were carried out under conventional conditions or conditions recommended by the manufacturer. If the manufacturers of the reagents or instruments are not specified, they are all conventional products that can be purchased commercially.

[0064] The raw material information used in some examples is shown in Table 1.

[0065] Table 1

[0066]

[0067]

[0068]

[0069]

[0070] Example 1

[0071] First, a pH-responsive hydrogel was prepared, and then a pH-responsive drug carrier was prepared. The specific process is as follows:

[0072] The hydrophobic monomer methyl acrylate, the sensitive monomer acrylamide, the crosslinking agent 1,4-butanediol diacrylate, the initiator α-ketoglutaric acid, and the solvent dimethyl sulfoxide were weighed separately and mixed to fully dissolve.

[0073] in:

[0074] The amount of dimethyl sulfoxide solvent used was 76.5 wt%.

[0075] The amount of methyl acrylate used was 20 wt%.

[0076] The sensitive monomer is prepared by reacting acryloyl chloride with acetyl sulfonamide to obtain the corresponding acryloyl acetyl sulfonamide monomer, wherein acryloyl chloride and acetyl sulfonamide are mixed, heated to 50° C., reacted for 4 hours, and filtered to obtain the product. The amount of the sensitive monomer is 2 wt %.

[0077] The amount of 1,4-butanediol diacrylate used was 1 wt%.

[0078] The amount of α-ketoglutaric acid used was 0.5 wt%.

[0079] In an oxygen-free environment, pH-responsive hydrogel was obtained after photoinitiation by irradiation with ultraviolet light for 8 h.

[0080] The pH-responsive hydrogel was immersed in the organic solution of the drug for 12 h.

[0081] The gel was transferred into pure water and soaked for 24 hours to obtain a pH-responsive drug carrier.

[0082] Example 2

[0083] First, a pH-responsive hydrogel was prepared, and then a pH-responsive drug carrier was prepared. The specific process is as follows:

[0084] The hydrophobic monomer methyl acrylate, the sensitive monomer acrylamide sulfadiazine, the cross-linking agent polyethylene glycol diacrylate, the initiator Irgacure 2959, and the solvent dimethylformamide were weighed respectively, mixed evenly, and fully dissolved.

[0085] in:

[0086] The amount of dimethylformamide used as solvent is 67.5 wt%.

[0087] The amount of methyl acrylate used is 30 wt%.

[0088] The sensitive monomer is prepared by reacting acryloyl chloride and sulfadiazine to obtain the corresponding acryloylsulfadiazine monomer, wherein acryloyl chloride and sulfadiazine are mixed, heated to 50° C., reacted for 4 hours, and filtered to obtain the product. The amount of the sensitive monomer is 1 wt %.

[0089] The amount of polyethylene glycol diacrylate used is 1 wt %.

[0090] The amount of Irgacure 2959 used was 0.5 wt%.

[0091] In an oxygen-free environment, the corresponding organogel was obtained after irradiation with ultraviolet light for 6 hours.

[0092] The gel was transferred into pure water and soaked for 24 hours to obtain the drug-loaded hydrogel.

[0093] Example 3

[0094] First, a pH-responsive hydrogel was prepared, and then a pH-responsive drug carrier was prepared. The specific process is as follows:

[0095] The hydrophobic monomer ethyl acrylate, the sensitive monomer acrylamide sulfonamide, the crosslinking agent N,N-methylenebisacrylamide, the initiator α-ketoglutaric acid, and the solvent N-methylpyrrolidone were weighed separately and mixed to fully dissolve.

[0096] in:

[0097] The amount of solvent N-methylpyrrolidone used was 46.5 wt%.

[0098] The amount of ethyl acrylate used was 50 wt%.

[0099] The sensitive monomer is prepared by reacting acryloyl chloride with sulfabenzoyl to obtain the corresponding acryloylsulfabenzoyl monomer, wherein acryloyl chloride and sulfabenzoyl are mixed, heated to 50° C., reacted for 4 hours, and filtered to obtain the product. The amount of the sensitive monomer is 1 wt %.

[0100] The amount of N,N-methylenebisacrylamide used is 2 wt%.

[0101] The amount of α-ketoglutaric acid used was 0.5 wt%.

[0102] In an oxygen-free environment, pH-responsive hydrogel was obtained after photoinitiation by irradiation with ultraviolet light for 8 h.

[0103] Example 4

[0104] First, a pH-responsive hydrogel was prepared, and then a pH-responsive drug carrier was prepared. The specific process is as follows:

[0105] The hydrophobic monomer benzyl acrylate, the sensitive monomer methacryloyl acetylsulfonamide, the cross-linking agent N,N-methylenebisacrylamide, the initiator α-ketoglutaric acid, and the solvent 1,4-dioxane were weighed separately and mixed to fully dissolve.

[0106] in:

[0107] The amount of the solvent 1,4-dioxane used was 68 wt%.

[0108] The amount of benzyl acrylate used was 25 wt%.

[0109] The sensitive monomer is prepared by reacting methacryloyl chloride and acetyl sulfonamide to obtain the corresponding methacryloyl acetyl sulfonamide monomer, wherein methacryloyl chloride and acetyl sulfonamide are mixed, heated to 50° C., reacted for 4 hours, and filtered to obtain the product. The amount of the sensitive monomer is 5 wt %.

[0110] The amount of N,N-methylenebisacrylamide used was 1 wt%.

[0111] The amount of α-ketoglutaric acid used was 1 wt%.

[0112] In an oxygen-free environment, pH-responsive hydrogel was obtained after photoinitiation by irradiation with ultraviolet light for 8 h.

[0113] Example 5

[0114] First, a pH-responsive hydrogel was prepared, and then a pH-responsive drug carrier was prepared. The specific process is as follows:

[0115] The hydrophobic monomer 2-phenoxyethyl acrylate, the sensitive monomer methacryloyl sulfadiazine, the cross-linking agent N,N-methylenebisacrylamide, and the solvent N,N-dimethylformamide were weighed separately and mixed to fully dissolve.

[0116] in:

[0117] The amount of solvent N,N-dimethylformamide used is 64 wt%.

[0118] The amount of 2-phenoxyethyl acrylate used was 30 wt%.

[0119] The sensitive monomer is prepared by reacting methacryloyl chloride and sulfadiazine to obtain the corresponding methacryloyl sulfadiazine monomer, wherein methacryloyl chloride and sulfadiazine are mixed, heated to 50° C., reacted for 4 hours, and filtered to obtain the product. The amount of the sensitive monomer is 3 wt %.

[0120] The amount of N,N-methylenebisacrylamide used is 2 wt%.

[0121] The amount of cyclohexanone peroxide used was 1 wt%.

[0122] In an oxygen-free environment, cyclohexanone peroxide as an initiator is added and mixed thoroughly, and a pH-responsive hydrogel is obtained after initiation.

[0123] Gel performance test

[0124] The pH-responsive hydrogels of Examples 1 to 5 were immersed in organic solutions of drugs such as rhein, naproxen, berberine hydrochloride, quercetin and ciprofloxacin for 12 hours. The gels were then transferred to pure water and immersed for 24 hours to obtain the corresponding pH-responsive drug carriers. The drug release effect was tested. The results are shown in FIG. Figures 1 to 6 shown.

[0125] Figure 1 This is the test result of the release effect of the rhein-loaded gel in Example 1.

[0126] Figure 2 This is the test result of the release effect of naproxen-loaded gel in Example 1.

[0127] Figure 3 This is the test result of the release effect of the quercetin-loaded gel in Example 2.

[0128] Figure 4 This is the test result of the release effect of the ciprofloxacin-loaded gel in Example 3.

[0129] Figure 5 This is the test result of the release effect of the quercetin-loaded gel in Example 4.

[0130] Figure 6 This is the test result of the release effect of the berberine hydrochloride gel in Example 5.

[0131] from Figures 1 to 6 It can be seen that the drug release rate at high pH is significantly higher than that at low pH.

[0132] It should be noted that it is not possible to first polymerize methyl acrylate to prepare a chain polymer and then use acryloyl chloride to modify the chain polymer, because acryloyl chloride will not react with the linear polymer. The scheme of the present invention is to react acyl chloride with a certain sulfonamide, and the reaction product is used as a monomer to copolymerize with methyl acrylate to obtain a gel.

[0133] The present invention has been described in detail above in conjunction with the embodiments, but the present invention is not limited to the above embodiments, and various changes can be made within the knowledge scope of ordinary technicians in the relevant technical field without departing from the purpose of the present invention.

Claims

1. A pH-responsive hydrogel, characterized in that: The preparation raw materials include hydrophobic monomers, sensitive monomers, crosslinking agents, initiators and organic solvents. The hydrophobic monomers include at least one of methyl acrylate, ethyl acrylate, benzyl acrylate and 2-phenoxyethyl acrylate. The sensitive monomers include sulfonamide monomers containing acryloyl or methacryloyl groups.

2. The pH-responsive hydrogel according to claim 1, characterized in that The mass ratio of the hydrophobic monomer to the sensitive monomer is 100:1-20.

3. The pH-responsive hydrogel according to claim 1, characterized in that The sensitive monomer includes at least one of acryloyl acetyl sulfonamide, acryloyl sulfapyridine, acryloyl sulfabenzoyl, acryloyl sulfa ketone, acryloyl sulfaguanidine, acryloyl sulfadoxine, acryloyl sulfaquinoxaline, acryloyl sulfinpyrazone, acryloyl sulfa metamethoxine, methacrylic acid sulfabenzoyl, acryloyl sulfamethoxazole, acryloyl sulfa dimethoxazine, methacryloyl acetyl sulfonamide, methacryloyl sulfamethoxazine and methacryloyl sulfabenzoyl.

4. The pH-responsive hydrogel according to any one of claims 1 to 3, characterized in that The crosslinking agent includes at least one of 1,4-butanediol diacrylate and N,N-methylenebisacrylamide.

5. The pH-responsive hydrogel according to any one of claims 1 to 3, characterized in that The initiator includes at least one of α-ketoglutaric acid, TPO, TPO-L and cyclohexanone peroxide.

6. A method for preparing a pH-responsive hydrogel according to any one of claims 1 to 5, characterized in that: The method comprises the steps of mixing various preparation raw materials in an organic solvent and carrying out a free radical polymerization reaction.

7. A pH-responsive drug carrier, characterized in that: The hydrogel is prepared from the pH-responsive hydrogel according to any one of claims 1 to 5 and a drug.

8. A method for preparing the pH-responsive drug carrier according to claim 7, characterized in that: The preparation method comprises soaking the pH-responsive hydrogel in an organic solution of a drug and in water in sequence.

9. The method according to claim 8, characterized in that In the organic solution of the drug, the organic solvent includes at least one of dimethyl sulfoxide, N-methylpyrrolidone, 1,4-dioxane and N,N-dimethylformamide.

10. The method according to claim 8, characterized in that The soaking time in water is 8h to 36h.

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