Two-component polyelectrolyte compound drug-loaded gel and preparation method thereof

Abstract

The invention belongs to the technical field of hydrogel, particularly relates to A61K9 / 06, and more particularly relates to bi-component polyelectrolyte compound drug-loaded gel and a preparation method thereof. The bi-component polyelectrolyte compound drug-loaded gel is prepared from the following raw materials: a drug component, positively charged high-molecular polymer polyethyleneimine and negatively charged high-molecular polymer polyacrylic acid. The bi-component polyelectrolyte compound drug-loaded gel provided by the invention can deliver various drugs, including dexamethasone, and the drug-loaded gel can be applied to allergic inflammation and autoimmune inflammatory diseases, and also can be applied to local skin diseases and the like; the product can relieve acute inflammation in a short time, and can also realize a long-term slow release effect.

Description

Technical Field

[0001] The present invention belongs to the technical field of hydrogels, and in particular to A61K9 / 06, and more specifically to a two-component polyelectrolyte complex drug-loaded gel and a preparation method thereof. Background Art

[0002] Polyelectrolyte complex refers to a macromolecular complex network formed by anionic and cationic polymers with opposite charges under the action of electrostatic attraction. This macromolecular complex network has a special adsorption to water. After absorbing water, the wet polyelectrolyte complex is usually gel-like and insoluble in water, so it can maintain its intact shape for a long time, block drug release, and achieve the effect of drug sustained release. Compared with the complex formed by general chemical cross-linking, the polyelectrolyte complex is relatively non-toxic, has good biocompatibility, and is safer in clinical application.

[0003] Dexamethasone sustained-release preparations refer to dexamethasone preparations that can be released slowly and persistently in the human body. Dexamethasone sustained-release preparations are made through a special production process, which allows dexamethasone to be adsorbed inside a special material, and can be released slowly and persistently in the body, continuously exerting a therapeutic effect, reducing fluctuations in blood drug concentrations, reducing the frequency of medication, and improving treatment effects and patient compliance.

[0004] Patent CN112870155A discloses the use of cross-linked polyacrylamide particles to load dexamethasone to prepare an injectable sustained-release preparation of dexamethasone. However, due to suspected adverse events and patient complaints during the use of injectable polyacrylamide hydrogels, the Food and Drug Administration has completely banned the use of polyacrylamide gels; Patent CN106467613A discloses the use of chitosan and different anionic polymers to prepare polyelectrolyte complex hydrogels, achieving the injectability, adhesion and self-healing properties of the hydrogel; Patent CN117771251A discloses the use of hyaluronic acid gel as a carrier of dexamethasone to prepare a dexamethasone sustained-release ophthalmic gel, which delays the sustained release of dexamethasone to a certain extent.

[0005] In order to solve the problems of safety and inability to release slowly in the prior art, the present invention provides an injectable, in-situ curable, long-term sustained-release two-component polyelectrolyte complex drug-loaded gel and a preparation method thereof. Summary of the invention

[0006] In order to solve the above technical problems, the first aspect of the present invention provides a two-component polyelectrolyte complex drug-loaded gel, comprising: a drug component, a positively charged polymer, and a negatively charged polymer.

[0007] When a positively charged polymer meets a negatively charged polymer, a polyelectrolyte complex hydrogel is spontaneously formed due to the electrostatic attraction between them. This polyelectrolyte complex hydrogel is usually nanoscale in size, and due to the neutralization of the charge, the hydrogel can maintain a high relative stability. The drug component can be physically embedded in the polyelectrolyte complex hydrogel, and the embedding can be based on the non-covalent interaction between the drug molecules and the polyelectrolyte complex hydrogel. If the drug molecule itself carries a positive or negative charge, the drug can be adsorbed to the surface or inside of the polyelectrolyte complex hydrogel through electrostatic interaction to form a polyelectrolyte complex drug-loaded gel. The polyelectrolyte complex drug-loaded gel can improve the stability of the drug, and the drug release rate is relatively controllable. Suitable polyelectrolyte complex hydrogels can reduce the stimulation and toxicity of the drug delivery system to the biological matrix. At the same time, by modifying the targeted drug molecules on the polyelectrolyte complex hydrogel, the targeted delivery of the drug can be achieved, the therapeutic effect can be improved, and the side effects can be reduced.

[0008] Preferably, the positively charged high molecular polymer includes: one of polyethyleneimine, chitosan, and chitosan derivatives.

[0009] More preferably, the positively charged high molecular polymer is polyethyleneimine.

[0010] Polyethyleneimine (PEI) molecular chains contain a large number of primary, secondary, and tertiary amine groups, which give PEI a high reactivity, enabling it to react chemically or electrostatically with negatively charged polymers to form a stable hydrogel network; by adjusting the concentration and cross-linking degree of PEI, hydrogels with different physical and chemical properties such as mechanical strength, swelling, and permeability can be prepared to meet different application requirements. At the same time, PEI has low immunogenicity and has a certain degree of biodegradability, thereby reducing the risk of rejection after implantation or injection; in addition, PEI can effectively act on the cell membranes of Gram-positive and Gram-negative bacteria, causing the destruction of bacterial membrane structures, and has high antibacterial properties.

[0011] Preferably, the weight average molecular weight of the polyethyleneimine is 1000-100000.

[0012] More preferably, the weight average molecular weight of the polyethyleneimine is 1800-70000.

[0013] Preferably, the negatively charged high molecular polymer includes one of sodium hyaluronate, hyaluronic acid, carboxymethyl cellulose, polyacrylic acid, and sodium polystyrene sulfonate.

[0014] More preferably, the negatively charged high molecular polymer is polyacrylic acid.

[0015] The polyacrylic acid molecular chain contains a large number of hydrophilic carboxylic acid groups, which can form electrostatic effects with PEI to form polyelectrolyte complex hydrogels. The hydrogels can absorb and retain a large amount of water, and the water absorption rate can usually reach hundreds of times its own weight or even higher. In addition, the composition of polyacrylic acid is similar to human tissue, and can form a stable water molecule barrier with body fluids, which can reduce the occurrence of rejection reactions. The drug-loaded gel is suitable for human injection treatment.

[0016] Preferably, the weight average molecular weight of the polyacrylic acid is 1,000-100,000.

[0017] More preferably, the weight average molecular weight of the polyacrylic acid is 2000-100000.

[0018] Generally speaking, drug-loaded gels with larger molecular weights can absorb more water and expand to a larger volume, which helps to form a more stable release environment and slow down the release rate of the drug. On the contrary, hydrogels with smaller molecular weights have weaker water absorption capacity and limited expansion, which may lead to faster drug release; the diffusion rate of drugs in drug-loaded gels is also affected by molecular weight; drug-loaded gels with larger molecular weights may have more complex pore structures and smaller pore sizes, which will increase the resistance to drug diffusion and reduce the release rate. Drug-loaded gels with smaller molecular weights may have more open pore structures and larger pore sizes, which are conducive to the rapid diffusion and release of drugs. Of course, the slower the release rate of the drug, the better. It should be reasonably selected based on the actual drug needs of the patient. In the present invention, the release rate of the drug components can be reasonably regulated by controlling the weight average molecular weight of polyethyleneimine and polyacrylic acid to meet the needs of different application scenarios.

[0019] Preferably, the drug component includes dexamethasone.

[0020] Preferably, the positively charged high molecular polymer and the negatively charged high molecular polymer are both in the form of solution.

[0021] Further preferably, the solvent of the solution includes water or polyethylene glycol (PEG).

[0022] More preferably, the average molecular weight of the polyethylene glycol is 100-400.

[0023] Preferably, the mass concentration of the positively charged polymer in the positively charged polymer solution is 10-50%.

[0024] Preferably, the mass concentration of the negatively charged polymer in the negatively charged polymer solution is 30-40%.

[0025] Generally speaking, the greater the mass concentration of the drug-loaded gel system, the higher the total amount of drug components released. This is because a higher mass concentration means that more drug molecules can be loaded into the drug-loaded gel; of course, the drug release rate is also affected by the mass concentration of the drug-loaded gel. A higher mass concentration may cause the diffusion path of the drug components in the gel network to become longer, thereby slowing down the release rate.

[0026] The second aspect of the present invention provides a method for preparing a two-component polyelectrolyte complex drug-loaded gel, comprising: using a solvent to configure a positively charged polymer and a negatively charged polymer into a positively charged polymer solution and a negatively charged polymer solution, respectively, and dispersing or dissolving the drug component in the positively charged polymer solution and / or the negatively charged polymer solution.

[0027] The two-component polyelectrolyte complex drug-loaded gel of the present invention can be injected into the body through a dual syringe to complete coagulation and solidification and drug embedding / slow release.

[0028] Beneficial Effects

[0029] (i) The present invention provides an injectable, in-situ curable two-component polyelectrolyte complex drug-loaded gel that can deliver a variety of drugs, including dexamethasone. The drug-loaded gel can be used for allergic inflammation and autoimmune inflammatory diseases, and can also be used for local skin diseases, etc.; the product can relieve acute inflammation in the short term and can also achieve a long-term sustained release effect.

[0030] (ii) The present invention utilizes positively charged polyethyleneimine and negatively charged polyacrylic acid of different molecular weights as raw materials for drug-loaded gel, and injects a two-component solution of polyacrylic acid and polyethyleneimine encapsulating dexamethasone into the body through a double syringe. The polyelectrolyte completes compounding and gelation in the body, thereby achieving physical encapsulation and long-term sustained release of dexamethasone.

[0031] (III) The two-component polyelectrolyte complex drug-loaded gel based on electrostatic interaction provided by the present invention is relatively non-toxic, has good biocompatibility, and is safer in clinical application.

[0032] (iv) In addition to molecular weight, the inventors found that the mass concentration of positively charged polymer solution and negatively charged polymer solution also has a certain influence on the release rate of drug components. A reasonable drug release rate can be set by regulating the mass rate.

[0033] (V) The polyelectrolyte complex drug-loaded gel provided by the present invention is degradable and can be completely degraded into non-toxic and harmless small molecules at 37°C for more than 6-8 weeks, thereby avoiding long-term toxicity or side effects to organisms and being safe and environmentally friendly. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 It is the drug sustained release curve diagram of Example 1, Example 3, Example 4, Example 6, Example 9 and Example 10.

[0035] Figure 2 Schematic diagram of the injectability of the two-component polyelectrolyte complex drug-loaded gel prepared in Example 1. DETAILED DESCRIPTION

[0036] In the following examples, PAA and PEI were purchased from Titan.

[0037] Experimental group 1 Polyelectrolyte complex hydrogel degradation experiment

[0038] The raw materials of the polyelectrolyte complex hydrogel include positively charged high molecular polymer polyethyleneimine and negatively charged high molecular polymer polyacrylic acid, wherein the volume ratio of the PAA solution to the PEI solution is 1:1.

[0039] The specific component information is shown in Table 1.

[0040] Table 1

[0041]

[0042]

[0043] The degradation test results of Examples 1-10 are shown in Table 2.

[0044] Table 2

[0045] serial number Degradation time at 37℃ Test 1 More than 56 days Test 2 More than 56 days Test 3 More than 56 days Test 4 More than 56 days Test 5 More than 56 days Test 6 More than 56 days Test 7 More than 56 days Test 8 More than 56 days Test 9 More than 42 days Test 10 More than 42 days

[0046] Drug sustained release test of two-component polyelectrolyte complex drug-loaded gel in the experimental group

[0047] The above-mentioned Test 1, Test 3, Test 4, Test 6, Test 9 and Test 10 were selected, and different concentrations of the drug component dexamethasone were dispersed with a polyacrylic acid solution as Examples 1, Example 3, Example 4, Example 6, Example 9 and Example 10; the sustained-release effect of dexamethasone was tested; wherein the volume ratio of the PAA solution to the PEI solution was 1:1.

[0048] The test results are shown in Table 2.

[0049] The drug sustained release curves of Examples 1, 3, 4, 6, 9 and 10 are shown in FIG. Figure 1 shown.

[0050] Example 1 Schematic diagram of injectability of a two-component polyelectrolyte complex drug-loaded gel Figure 2 shown.

[0051] Table 2

[0052]

[0053] Data discussion: Comparing Example 1 with Example 4, and Example 6 with Example 10, increasing the weight average molecular weight of either polyacrylic acid or polyethyleneimine will slow down the release of dexamethasone. This may be because as the weight average molecular weight increases, the hydrogel formed by polyacrylic acid and polyethyleneimine becomes denser, which reduces the diffusion coefficient of the drug in the composite gel, thereby delaying the release of dexamethasone. Comparing Example 4 with Example 6, reducing the mass concentration of polyethyleneimine is also beneficial to slowing down the release of dexamethasone, but the burst release in Example 6 is more severe than that in Example 4. It can be seen that the reduction of polyethyleneimine in Example 6 is not conducive to the complete formation of the polyelectrolyte complex, and there are some uncured areas in the drug-loaded gel, resulting in an increase in the burst release of dexamethasone.

Claims

1. A two-component polyelectrolyte complex drug-loaded gel, characterized in that: Ingredients include: Drug components, positively charged polymers, negatively charged polymers.

2. The two-component polyelectrolyte complex drug-loaded gel according to claim 1, characterized in that: The positively charged polymer comprises: one of polyethyleneimine, chitosan and chitosan derivatives.

3. The two-component polyelectrolyte complex drug-loaded gel according to claim 2, characterized in that: The weight average molecular weight of the polyethyleneimine is 1000-100000.

4. The two-component polyelectrolyte complex drug-loaded gel according to claim 1, characterized in that: The negatively charged high molecular polymer includes: sodium hyaluronate, hyaluronic acid, carboxymethyl cellulose, polyacrylic acid, and sodium polystyrene sulfonate.

5. The two-component polyelectrolyte complex drug-loaded gel according to claim 4, characterized in that: The weight average molecular weight of the polyacrylic acid is 1000-100000.

6. The two-component polyelectrolyte complex drug-loaded gel according to claim 1, characterized in that: The drug component includes dexamethasone.

7. The two-component polyelectrolyte complex drug-loaded gel according to claim 1, characterized in that: The positively charged high molecular polymer and the negatively charged high molecular polymer are both in the form of solution.

8. The two-component polyelectrolyte complex drug-loaded gel according to claim 7, characterized in that: The solvent used in the solution includes water or polyethylene glycol.

9. The two-component polyelectrolyte complex drug-loaded gel according to claim 8, characterized in that: The average molecular weight of the polyethylene glycol is 100-400.

10. A method for preparing the two-component polyelectrolyte complex drug-loaded gel according to claim 9, characterized in that: The following steps are involved: The positively charged polymer and the negatively charged polymer are respectively dissolved into a positively charged polymer solution and a negatively charged polymer solution using a solvent, and the drug component is dispersed or dissolved in the positively charged polymer solution and / or the negatively charged polymer solution.

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