A drug composite hydrogel and its preparation method and application

Abstract

The present invention discloses a drug composite hydrogel and its preparation method and application. The drug composite hydrogel of the present invention is prepared by loading analgesics with hydrogel carriers, and the raw materials for preparing the hydrogel carriers include chitosan 0.1-0.2wt%, hydroxypropyl methylcellulose 0.1-0.2wt%, sodium alginate 3-4wt%, acetic acid solution and the remainder of water; the analgesics include analgesics for local infiltration, nerve block or intraspinal anesthesia; the loading ratio of analgesics in the analgesic sustained-release drug composite hydrogel is 5-100mg / ml hydrogel carrier. The present invention is directed to different pH drugs, and the best sustained-release system is obtained by adjusting the raw material ratio. The drug composite hydrogel provided by the present invention has the characteristics of high safety, good fluidity, sustained-release drugs, and no drug burst release, and can be used for local long-term analgesia of pain, and has good application prospects clinically.

Description

Technical Field

[0001] The invention relates to a drug composite hydrogel and a preparation method and application thereof, belonging to the technical field of medical nano biomaterials. Background Art

[0002] Postoperative pain, as one of the perioperative complications, troubles a considerable proportion of the population. About 50% of patients experience postoperative pain within 24 hours after surgery, and postoperative pain can also induce the occurrence of chronic pain, which troubles patients throughout their lives. In order to make up for the defects of short efficacy and strong toxic side effects of clinical analgesics when used in large doses, previous studies have constructed a variety of sustained-release systems, including liposomes, polymer preparations, metal nanoparticles and hydrogels, but there are still problems such as the controlled release of drugs cannot be achieved well, or the biosafety of its carrier needs further evaluation. Even EXPAREL (a bupivacaine liposome injection) currently approved by the FDA cannot avoid the disadvantages of drug burst release caused by liposomes.

[0003] As an organic polymer material with excellent performance, hydrogel has broad application prospects in biomedicine. However, traditional synthetic hydrogels often have complex composition, which leads to the disadvantages of complex preparation process, high cost, and failure to avoid sudden drug release after loading drugs. Although the biosafety of some of them has been verified at the cell and animal levels, there is still a considerable gap from clinical transformation application. However, as a drug carrier, the hydrogel system has the advantages of simple preparation, strong controllability, high strength and good stability. Therefore, it is of great clinical significance to develop an analgesic drug composite hydrogel with good sustained release effect and simple preparation method. Summary of the invention

[0004] The purpose of the present invention is to provide a hydrogel analgesic system loaded with analgesic drugs for sustained-release analgesia including local infiltration, nerve block or intrathecal anesthesia in view of the shortcomings of existing sustained-release analgesics, wherein the loaded drugs include but are not limited to: local anesthetic drugs, including lidocaine, ropivacaine, etc.; general anesthetic analgesics, including sufentanil, dexmedetomidine, etc.

[0005] In order to achieve the above object, the present invention provides an application of a hydrogel carrier in the preparation of an analgesic sustained-release drug composite hydrogel, wherein the raw materials for preparing the hydrogel carrier include chitosan, hydroxypropyl methylcellulose, sodium alginate, acetic acid solution and water;

[0006] The analgesic drugs include those used for local infiltration, nerve block or spinal anesthesia;

[0007] The loading ratio of the analgesic drug in the analgesic sustained-release drug composite hydrogel is 5-100 mg / ml hydrogel carrier.

[0008] Preferably, the raw materials for preparing the hydrogel carrier include 0.1-0.2wt% chitosan, 0.1-0.2wt% hydroxypropyl methylcellulose, 3-4wt% sodium alginate, acetic acid solution and the balance water; the acetic acid solution is 0.8-1.2wt% 0.1M acetic acid solution or acetic acid solution containing equivalent acetic acid (depending on the concentration of the acetic acid solution, the addition ratio is increased or decreased accordingly, so that the actual amount of acetic acid molecules CH3COOH in the system is the same as the acetic acid equivalent of adding 0.8-1.2wt% 0.1M acetic acid solution).

[0009] Preferably, the analgesic drug includes a local anesthetic drug or a general anesthetic analgesic drug, and the local anesthetic drug includes a para-aminobenzoate ester (procaine, benzocaine, tetracaine, etc.), an amide (lidocaine, ropivacaine, bupivacaine, levobupivacaine, etc.), an aminoether or an aminoketone (dyclonine, etc.) local anesthetic drug;

[0010] The general anesthetic analgesic drug includes any one of opioid drugs such as codeine, dihydrocodeine, hydromorphone, oxycodone, methadone, ketamine, morphine, fentanyl, pethidine (meperidine), and dexmedetomidine.

[0011] Preferably, the preparation method of the hydrogel carrier comprises the following steps:

[0012] Step 1: Preparation of chitosan-hydroxypropyl methylcellulose solution: chitosan powder and hydroxypropyl methylcellulose powder are mixed and added into acetic acid solution, and stirred to obtain a uniform chitosan-hydroxypropyl methylcellulose solution;

[0013] Step 2: Preparation of sodium alginate aqueous solution: adding sodium alginate into pure water and stirring evenly to obtain a sodium alginate aqueous solution;

[0014] Step 3: Evenly mix the chitosan-hydroxypropyl methylcellulose solution obtained in step 1 and the sodium alginate aqueous solution obtained in step 2, and stir to react to obtain a hydrogel carrier.

[0015] Preferably, the method comprises the following steps:

[0016] Step 1: Preparation of chitosan-hydroxypropyl methylcellulose solution: chitosan powder and hydroxypropyl methylcellulose powder are mixed, added into acetic acid, and stirred until a uniform chitosan-hydroxypropyl methylcellulose solution is obtained;

[0017] Step 2: Preparation of drug sodium alginate aqueous solution: firstly dissolve the analgesic drug in pure water, adjust the pH of the solution, then add sodium alginate, stir evenly, and obtain the drug sodium alginate aqueous solution, wherein the analgesic drug includes analgesic drugs used for local infiltration, nerve block or spinal anesthesia;

[0018] Step 3: Evenly mix the chitosan-hydroxypropyl methylcellulose solution obtained in step 1 and the drug sodium alginate aqueous solution obtained in step 2, and stir to react to obtain an analgesic sustained-release drug composite hydrogel.

[0019] The present invention also provides a hydrogel carrier, wherein raw materials for preparing the hydrogel carrier include chitosan, hydroxypropyl methylcellulose, sodium alginate, acetic acid solution and water.

[0020] Preferably, the raw materials for preparing the hydrogel carrier include 0.1-0.2wt% chitosan, 0.1-0.2wt% hydroxypropyl methylcellulose, 3-4wt% sodium alginate, acetic acid solution and the balance water; the acetic acid solution is 0.8-1.2wt% 0.1M acetic acid solution or acetic acid solution containing equivalent acetic acid.

[0021] Compared with the prior art, the present invention has the following beneficial effects:

[0022] (1) The present invention can achieve uniform dispersion of drugs and sustained release of drugs in local systems and open environments by adjusting the ratio of raw materials, effectively avoiding adverse events such as sudden drug release; the drug composite hydrogel provided by the present invention has the characteristics of high safety, good fluidity, sustained drug release, and no sudden drug release, and can be used for local long-term analgesia of pain;

[0023] (2) The hydrogel carrier of the present invention is composed of chitosan-hydroxypropyl methylcellulose-sodium alginate, has good fluidity, high biosafety, is self-degradable, can achieve effective drug loading, and can release drugs slowly without burst release. It is applied to local infiltration, nerve block or intrathecal anesthesia to achieve effective slow release of drugs, thereby achieving the purpose of analgesia. Its good biosafety is evaluated to not cause adverse reactions to peripheral nerves, muscles, skin and other tissues after injection. Its good biodegradability ensures that it can be completely degraded in the end without permanent trauma. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 This is a picture of the hydrogel carrier of the present invention;

[0025] Figure 2 is the rheological property of the hydrogel carrier of the present invention;

[0026] Figure 3 The sustained release results of ropivacaine hydrochloride loaded with different concentrations of the hydrogel carrier of the present invention;

[0027] Figure 4 The sustained release results of ropivacaine hydrochloride loaded with 20 mg / ml of hydrogels with different raw material ratios in the embodiments of the present invention are shown;

[0028] Figure 5 The sustained release results of ropivacaine hydrochloride loaded with 20 mg / ml at different raw material ratios of the comparative hydrogel of the present invention;

[0029] Figure 6 This is a statistical diagram of the analgesic effect of the local infiltration of the drug into the hydrogel carrier of the present invention;

[0030] Figure 7 This is a statistical diagram of the sustained-release analgesic effect of the hydrogel carrier nerve blocking drug of the present invention. DETAILED DESCRIPTION

[0031] In order to make the present invention more clearly understood, preferred embodiments are described in detail below with reference to the accompanying drawings.

[0032] Example 1

[0033] Preparation of ropivacaine composite hydrogel:

[0034] The raw material ratio is as follows: chitosan 0.1-0.2wt%, hydroxypropyl methylcellulose 0.1-0.2wt%, sodium alginate 3-4wt%, 0.1M acetic acid solution 0.8-1.2wt% and the rest of water are added; the loading ratio of analgesic drug ropivacaine in the drug composite hydrogel is 5-100mg / ml; chitosan powder and hydroxypropyl methylcellulose powder are mixed, and then the mixture is gradually added into 0.1M acetic acid solution, and stirred until a chitosan-hydroxypropyl methylcellulose solution is obtained. The drug sodium alginate aqueous solution is prepared by the following process: firstly, ropivacaine is dissolved in pure water, the pH of the ropivacaine solution is adjusted to 7.0, sodium alginate is dissolved in the drug solution, and a predetermined amount of sodium alginate is added into the drug solution under constant magnetic stirring, and stirred evenly to obtain a drug sodium alginate aqueous solution with a final concentration. The chitosan-hydroxypropyl methylcellulose solution and the sodium alginate solution are mixed evenly, stirred for reaction, and then placed in a pure water bath to obtain a drug composite hydrogel.

[0035] Figure 1 This is an image of the hydrogel prepared by the above method.

[0036] Comparative Example 1

[0037] The materials are added according to 0.2-0.3wt% of chitosan, 0.3-0.4wt% of hydroxypropyl methylcellulose, 5-6wt% of sodium alginate, 0.8-1.2wt% of 0.1M acetic acid solution and the rest of water; the loading ratio of the analgesic drug ropivacaine in the drug composite hydrogel is 5-100mg / ml; chitosan powder and hydroxypropyl methylcellulose powder are mixed, and then the mixture is gradually added into 0.1M acetic acid, and stirred until a chitosan-hydroxypropyl methylcellulose solution is obtained. The drug sodium alginate aqueous solution is prepared by the following process: firstly, ropivacaine is dissolved in pure water, the pH of the ropivacaine solution is adjusted to 7, sodium alginate is dissolved in the drug solution, and a predetermined amount of sodium alginate is added into the drug solution under constant magnetic stirring, and stirred evenly to obtain a drug sodium alginate aqueous solution with a final concentration. The chitosan-hydroxypropyl methylcellulose solution and the sodium alginate solution were mixed evenly, stirred for reaction, and then placed in a pure water bath at 30°C to obtain a drug composite hydrogel. The raw material ratio was inappropriate, and the prepared ropivacaine composite hydrogel had a burst release ( Figure 5 ).

[0038] Example 2 Analysis of rheological properties of drug composite hydrogel

[0039] The gelation temperature (Tgel) of the gel was determined by rheological method. The gelation temperature Tgel is the temperature corresponding to the inflection point between the liquid state and the gel state G' and G". Each sample was measured in parallel 3 times and the average value was taken. Select the "Temperature ramptrigger.rsep" method in Favorites on the left side of the software, set the oscillation frequency to 0.01Hz, and double-click to test. Start measuring the changes in the elastic modulus G' of the sample in the range of 10 to 40°C. After the test, save the data.

[0040] Figure 2 This is the rheological property analysis of the drug composite hydrogel measured by the above method.

[0041] Example 3 Sustained release results of composite hydrogel carriers loaded with different concentrations of ropivacaine hydrochloride

[0042] 3 ml of hydrogel loaded with different concentrations of drugs was placed in a glass bottle, and PBS buffer with pH 7.4 was added. The total amount of drug released at different time points was detected and calculated using an ultraviolet spectrophotometer.

[0043] Figure 3 The sustained release results of the hydrogel carrier of Example 1 of the present invention (the raw material ratio of the hydrogel is: chitosan 0.15wt%, hydroxypropyl methylcellulose 0.15wt%, sodium alginate 3.6wt%, 0.1M acetic acid solution 1wt% and the balance water) loaded with different concentrations of ropivacaine hydrochloride (0-30mg / ml); from Figure 3It can be seen that under this hydrogel system, the drug has a good sustained-release effect.

[0044] Example 4 Sustained release results of hydrogels with different raw material ratios loaded with 30 mg / ml ropivacaine hydrochloride

[0045] The hydrogel formulations with different raw material ratios were used to load 30 mg / ml of ropivacaine hydrochloride. According to the detection method in Example 3, the sustained release results of the drug composite hydrogel were detected.

[0046] Figure 4 The sustained release results of 30 mg / ml ropivacaine hydrochloride loaded on the hydrogel prepared according to the ratio of Example 1; wherein, the raw material ratio of sample No. 1 hydrogel is: chitosan 0.12wt%, hydroxypropyl methylcellulose 0.15wt%, sodium alginate 3wt%, 0.1M acetic acid solution 1wt% and the balance water, and the raw material ratio of sample No. 2 hydrogel is: chitosan 0.18wt%, hydroxypropyl methylcellulose 0.18wt%, sodium alginate 4wt%, 0.1M acetic acid solution 1wt% and the balance water; it can be seen from the figure that under this system, the drug has a good sustained release effect.

[0047] Figure 5 The sustained release results of ropivacaine hydrochloride loaded with different concentrations of the hydrogel carrier prepared according to the ratio of Comparative Example 1; wherein, the raw material ratio of sample No. 1 (No. 1) hydrogel is: chitosan 0.22wt%, hydroxypropyl methylcellulose 0.32wt%, sodium alginate 5wt%, 0.1M acetic acid solution 1.1wt% and the balance water, and the raw material ratio of sample No. 2 (No. 2) hydrogel is: chitosan 0.25wt%, hydroxypropyl methylcellulose 0.35wt%, sodium alginate 5.5wt%, 0.1M acetic acid solution 1.2wt% and the balance water. As can be seen from the figure, there is a burst release phenomenon of the drug.

[0048] Example 5 Evaluation of the analgesic effect of local infiltration drug sustained release

[0049] The in vivo experiment was conducted using a mouse plantar incision pain model. The ropivacaine composite hydrogel prepared in Example 1 was injected around the plantar incision of mice (6 mice per group) for local infiltration anesthesia. The mice in different groups were tested for mechanical pain threshold at different time points. For details, see Figure 5 Compared with the 0.5% concentration of the drug alone group (ropivacaine aqueous solution), Figure 5 As shown, the drug-loaded hydrogel treatment group can achieve a prolonged effective analgesia time.

[0050] Figure 5 This is an evaluation of the analgesic effect of local infiltration drug sustained release measured by the above method.

[0051] Example 7 Evaluation of the sustained-release analgesic effect of nerve block drugs

[0052] The in vivo experiment was conducted using a mouse plantar incision pain model. The ropivacaine composite hydrogel prepared in Example 1 was injected around the sciatic nerve of mice (6 mice per group), and the mice in different groups were tested for mechanical pain threshold at different time points. Figure 6 .like Figure 6 As shown, treatment with a hydrogel loaded with ropivacaine injected around the sciatic nerve resulted in a prolonged period of effective analgesia.

[0053] Figure 6 This is the sustained-release analgesic effect of nerve blocking drugs measured by the above method.

[0054] The above embodiments are only preferred embodiments of the present invention and are not any formal or substantial limitations of the present invention. It should be pointed out that ordinary technicians in this technical field can make several improvements and supplements without departing from the present invention, and these improvements and supplements should also be regarded as the scope of protection of the present invention.

Claims

1. Application of a hydrogel carrier in the preparation of analgesic sustained-release drug composite hydrogel, characterized in that: The raw materials for preparing the hydrogel carrier include 0.1-0.2wt% chitosan, 0.1-0.2wt% hydroxypropyl methylcellulose, 3-4wt% sodium alginate, acetic acid solution and the balance water; the acetic acid solution is 0.8-1.2wt% 0.1M acetic acid solution or acetic acid solution containing the above equivalent acetic acid; The analgesic sustained-release drug composite hydrogel is loaded with an analgesic drug, and the analgesic drug is an amide local anesthetic drug such as lidocaine, ropivacaine, bupivacaine or levobupivacaine; The loading ratio of the analgesic drug in the analgesic sustained-release drug composite hydrogel is 5-100 mg / ml hydrogel carrier.

2. The use according to claim 1, characterized in that The preparation method of the hydrogel carrier comprises the following steps: Step 1: Preparation of chitosan-hydroxypropyl methylcellulose solution: chitosan powder and hydroxypropyl methylcellulose powder are mixed and added into acetic acid solution, and stirred to obtain a uniform chitosan-hydroxypropyl methylcellulose solution; Step 2: Preparation of sodium alginate aqueous solution: adding sodium alginate into pure water and stirring evenly to obtain a sodium alginate aqueous solution; Step 3: Evenly mix the chitosan-hydroxypropyl methylcellulose solution obtained in step 1 and the sodium alginate aqueous solution obtained in step 2, and stir to react to obtain a hydrogel carrier.

3. The use according to claim 1, characterized in that The preparation method of the analgesic sustained-release drug composite hydrogel comprises the following steps: Step 1: Preparation of chitosan-hydroxypropyl methylcellulose solution: chitosan powder and hydroxypropyl methylcellulose powder are mixed, added into acetic acid, and stirred until a uniform chitosan-hydroxypropyl methylcellulose solution is obtained; Step 2: Preparation of drug sodium alginate aqueous solution: firstly, dissolve the analgesic drug in pure water, adjust the pH of the solution, then add sodium alginate, stir evenly, and obtain a drug sodium alginate aqueous solution; Step 3: Evenly mix the chitosan-hydroxypropyl methylcellulose solution obtained in step 1 and the drug sodium alginate aqueous solution obtained in step 2, and stir to react to obtain an analgesic sustained-release drug composite hydrogel.

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