Injectable temperature-sensitive hydrogel sustained-release medicinal preparation for in-situ generation of local anesthetic microrod and application of injectable temperature-sensitive hydrogel sustained-release medicinal preparation in long-acting anesthesia and analgesia

Abstract

The invention discloses an injectable temperature-sensitive hydrogel sustained-release medicinal preparation for in-situ generation of local anesthetic microrods and application of the injectable temperature-sensitive hydrogel sustained-release medicinal preparation in long-acting anesthesia and analgesia. The pharmaceutical preparation comprises three parts: injectable hydrogel, local anesthetic soluble salt and an alkaline pH regulator. An alkaline pH regulator is added into a mixed solution of hydrogel and local anesthetic soluble salt, the local anesthetic soluble salt is induced to be self-assembled in the hydrogel to form a micron-sized rod-like structure, and finally the injectable temperature-sensitive hydrogel pharmaceutical preparation containing the local anesthetic microrod is obtained. The preparation has the advantages of simple preparation, low cost, easily available raw materials, good biocompatibility and the like, can effectively delay the release rate of local anesthetics and prolong the local anesthesia and analgesic effects, and shows good application prospects in the aspect of preparation of long-acting local anesthesia and analgesic drugs.

Description

Technical Field

[0001] The present invention relates to an injectable thermosensitive hydrogel sustained-release pharmaceutical preparation capable of in-situ generating local anesthetic microrods and application thereof in long-acting anesthesia and analgesia, belonging to the technical field of biomedicine. Background Art

[0002] Local anesthetics such as bupivacaine, lidocaine, and ropivacaine are commonly used analgesics in clinical practice. Due to their poor water solubility, their soluble salt forms are often used clinically. However, these soluble salt forms are more likely to diffuse into the extracellular space or into the bloodstream, resulting in a shorter duration of effective action and making it difficult to meet patients' needs for long-term analgesia.

[0003] The development of new long-acting local anesthetics requires a lot of time and money. Current research mainly focuses on the use of drug carrier materials (such as bupivacaine liposomes that have been approved for clinical use). ) to encapsulate local anesthetics to achieve sustained or controlled release of the drug. However, due to the inherent physical and chemical characteristics of drug carrier materials, the encapsulation efficiency and total drug loading of local anesthetics are limited, making it difficult to achieve the desired effective analgesic effect. In addition, the synthesis process of most drug carrier materials is complex and costly, and the difficult degradation of the carrier materials can pose a safety hazard to patients. Therefore, the development of a sustained-release local anesthetic drug system with a simple synthesis process, low cost, and good biocompatibility is of great significance for achieving long-term analgesia and local anesthesia. Summary of the Invention

[0004] The purpose of the present invention is to provide a long-term local anesthesia and analgesia drug preparation with good biocompatibility, simple synthesis process and low cost in view of the shortcomings of the prior art.

[0005] In order to achieve the above object, the present invention provides the following technical solutions:

[0006] The invention provides an injectable thermosensitive hydrogel sustained-release pharmaceutical preparation capable of in-situ generating local anesthetic microrods. The raw materials for preparing the pharmaceutical preparation include injectable hydrogel, local anesthetic soluble salt, deionized water and an alkaline pH regulator.

[0007] The present invention also provides a method for preparing an injectable thermosensitive hydrogel sustained-release drug preparation that in situ generates local anesthetic microrods as described above. The preparation method comprises the following steps: dissolving a soluble salt of the local anesthetic and a hydrogel raw material in deionized water until clear and transparent, then adding an alkaline pH regulator to adjust the pH to weak alkalinity, and thoroughly mixing to obtain an injectable hydrogel sustained-release drug preparation containing local anesthetic microrods.

[0008] Preferably, the hydrogel raw material comprises at least one of the amphiphilic polymers PEO-PPO-PEO, PEG-PPG-PEG, PCL-PEG-PCL, PLGA-PEG-PLGA, and PDLLA-PEG-PDLLA;

[0009] Preferably, the soluble salt of the local anesthetic comprises at least one of the soluble salt forms of bupivacaine, ropivacaine, levobupivacaine, tetracaine, lidocaine, prilocaine, mepivacaine, procaine, chloroprocaine, propoxycaine, hexylcaine, cyclomethicone, butoxyprocaine, butacaine, and proparacaine; and the soluble salt form is a pharmaceutically acceptable salt thereof;

[0010] Preferably, the alkaline pH regulator includes any one of sodium hydroxide, sodium bicarbonate and sodium carbonate.

[0011] Preferably, the hydrogel raw material is PEO100-PPO65-PEO100 (Poloxamer 407), and / or the local anesthetic is bupivacaine hydrochloride; and / or the alkaline pH regulator is sodium hydroxide.

[0012] Preferably, the mass ratio of bupivacaine hydrochloride, poloxamer 407 and deionized water is (0.75-4):(20-30):100.

[0013] More preferably, the mass ratio of bupivacaine hydrochloride, poloxamer 407 and deionized water is 4:25:100.

[0014] Preferably, an alkaline pH regulator is added to adjust the pH to 7.4±0.1.

[0015] The present invention also provides the use of the above-mentioned injectable thermosensitive hydrogel sustained-release pharmaceutical preparation in the preparation of long-acting local anesthetic and analgesic drugs.

[0016] Compared with the prior art, the present invention has the following beneficial effects:

[0017] The drug preparation provided by the present invention is temperature-sensitive. It is liquid when stored in a refrigerator at 4°C and solidifies at body temperature of 37°C. It can be converted from liquid to solid at the injection site to release the drug at a fixed point, thereby reducing drug diffusion. The local anesthetic in the drug preparation can form a micron-level rod-shaped structure, which has a significant sustained-release effect and effectively prolongs the anesthesia and analgesia time. The drug preparation can be directly injected and can meet the local anesthesia and analgesia needs in various situations. The drug preparation can be rapidly decomposed in the body and has good biocompatibility. After injection, it will not cause adverse reactions in the sciatic nerve, muscles and major organs (heart, liver, spleen, lungs, and kidneys) at the injection site. The drug preparation can be prepared in one step without the need for subsequent processing, and the raw materials are simple and easily available, the cost is low, and the drug effect is long. Therefore, it is a drug sustained-release body with great application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 Schematic diagram of an injectable thermosensitive hydrogel sustained-release drug formulation for in situ generation of local anesthetic microrods;

[0019] Figure 2 is a morphological diagram of the rod-shaped local anesthetic and the hydrogel in the pharmaceutical preparation of the present invention;

[0020] Figure 3 This is a graph showing changes in the morphology of the pharmaceutical preparation of the present invention with temperature;

[0021] Figure 4 is a graph showing the injectability of the pharmaceutical preparation of the present invention;

[0022] Figure 5 is a release profile of the local anesthetic in the pharmaceutical preparation of the present invention;

[0023] Figure 6 This is a diagram showing the nerve blocking effect of the pharmaceutical preparation of the present invention;

[0024] Figure 7 This is a diagram showing the biosafety evaluation of the pharmaceutical preparation of the present invention. DETAILED DESCRIPTION

[0025] To make the present invention more clearly understood, preferred embodiments are described in detail below with reference to the accompanying drawings.

[0026] The experimental methods in the following examples, where specific conditions are not specified, were generally performed under conventional conditions or the conditions recommended by the manufacturers. The materials and reagents used in the following examples, unless otherwise specified, were obtained from commercial sources.

[0027] Example 1: Preparation and characterization of pharmaceutical preparations

[0028] 160 mg of bupivacaine hydrochloride (designated BH) and 1000 mg of poloxamer 407 (designated PF) were dissolved in 4 mL of deionized water to obtain a clear transparent solution. Sodium hydroxide was added under magnetic stirring at 1000 R to adjust the pH to 7.4. The pharmaceutical preparation (designated BMR-PF) was obtained without any subsequent operation. After the addition of sodium hydroxide, the clear solution was observed to gradually turn white. The formation of bupivacaine microrods (designated BMR) was confirmed by centrifuging the product pharmaceutical preparation and taking SEM images ( Figures 1-2 ). Figure 3 The states of the pharmaceutical preparation prepared by the above method at different temperatures; Figure 4 The above-mentioned drug preparations were injected using a 26 G injection needle in air, underwater at 37°C, and on a petri dish.

[0029] Example 2: In vitro release of drug formulations.

[0030] The prepared drug preparation was placed in a dialysis bag, and PBS buffer at pH 7.4 was added and placed in a shaker at 37°C. The release medium was collected at different time points. The total amount of drug released at different time points was detected and calculated using an ultraviolet spectrophotometer. BH solution and bupivacaine hydrochloride gel (named BH-PF) were used as control groups. Figure 5 It can be seen that compared with BH or BH-PF, the BMR-PF group has a significant sustained release effect in vitro, proving that the formed rod-like structure is conducive to sustained release.

[0031] Example 3: Evaluation of the nerve blocking effect of the pharmaceutical preparation.

[0032] Evaluation of the nerve block effect of Example 3 (combined with Figure 5 220-250g Sprague-Dawley rats were randomly divided into four groups (six rats per group): control, BH, BH-PF, and BMR-PF. Each agent (0.5 mL) was injected into the vicinity of the sciatic nerve in the left leg. Sensory and motor blockade was assessed 10 minutes, 30 minutes, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, and 14 hours after injection.

[0033] Sensory blockade was assessed using the hot plate method: the rat was briefly lifted and its left hind paw was placed on a hot plate at 56°C. The paw withdrawal latency (PWL) was measured. To prevent burns, a cutoff time of 12 seconds was set; a latency of at least 6 seconds was considered effective sensory blockade.

[0034] Motor block was assessed using a 4-point scale: at predetermined times, the rat's tail was lifted and the left hind paw's appearance was observed. Specifically, a score of 1 indicated a normal appearance of the foot when the rat was lifted by the tail; a score of 2 indicated complete dorsiflexion of the foot and impaired toe splay; a score of 3 indicated plantar flexion with inability to splay the toes; and a score of 4 indicated complete loss of dorsiflexion and plantar flexion, with impaired gait. The duration of motor block with a score of 2 or greater was defined as the motor block duration.

[0035] Combine Figure 6 It can be seen that the BMR-PF group has the longest-lasting nerve block effect and can be used to prepare long-acting analgesic or local anesthetic drugs.

[0036] Example 4: Biosafety evaluation of pharmaceutical preparations.

[0037] On the 7th day after the injection of the drug preparation, the rats were euthanized with an overdose of sevoflurane and perfused intracardially with 300 mL of 0.9% saline. The heart, liver, spleen, lungs, and kidneys were collected, fixed with 4% paraformaldehyde, embedded in paraffin, sectioned, and stained with H&E. The left sciatic nerve and muscle tissue were collected, fixed with 4% (w / v) paraformaldehyde solution, embedded in paraffin, and stained with H&E, TBO, and FLB. Figure 7 It can be seen that muscles and nerves remained intact after injection treatment, and the drug formulation did not induce local tissue toxicity. In addition, almost no inflammation or other pathological changes were observed in the heart, liver, spleen, lungs, and kidneys in any group, indicating that the composite material has satisfactory biosafety and biocompatibility.

[0038] In summary, the present invention provides a new pharmaceutical preparation and its use in the preparation of long-acting analgesics and / or long-acting local anesthesia drugs. Experimental results show that the pharmaceutical preparation can significantly prolong the analgesic and / or local anesthesia time of nerve block, has an excellent sustained-release effect, and can be used for the treatment of preoperative, intraoperative or postoperative pain, or intraoperative local anesthesia, and has no obvious side effects after treatment. The raw materials of the pharmaceutical preparation provided by the present invention are easy to obtain, the preparation method is simple, and it has good application prospects in the preparation of long-acting analgesics and / or long-acting local anesthesia drugs.

[0039] The above description is only a preferred embodiment of the present invention and does not constitute any formal or substantial limitation to the present invention. It should be noted 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. An injectable thermosensitive hydrogel sustained-release pharmaceutical preparation that generates in situ local anesthetic microrods, characterized in that: The raw materials for preparing the pharmaceutical preparation include: injectable hydrogel, soluble salt of local anesthetic, deionized water and alkaline pH regulator.

2. The method for preparing an injectable thermosensitive hydrogel sustained-release pharmaceutical preparation for in situ generation of local anesthetic microrods according to claim 1, characterized in that: The preparation method comprises the following steps: dissolving a soluble salt of a local anesthetic and a hydrogel raw material in deionized water until the solution is clear and transparent, adding an alkaline pH regulator to adjust the pH to a weakly alkaline state, and thoroughly mixing to obtain an injectable hydrogel sustained-release drug preparation containing local anesthetic microrods.

3. The preparation method according to claim 2, wherein The hydrogel raw material includes at least one of amphiphilic polymers PEO-PPO-PEO, PEG-PPG-PEG, PCL-PEG-PCL, PLGA-PEG-PLGA, and PDLLA-PEG-PDLLA; and / or, the soluble salt of the local anesthetic comprises at least one of the soluble salt forms of bupivacaine, ropivacaine, levobupivacaine, tetracaine, lidocaine, prilocaine, mepivacaine, procaine, chloroprocaine, propoxycaine, hexylcaine, cyclomethicone, butoxyprocaine, butacaine, and proparacaine; and the soluble salt form is a pharmaceutically acceptable salt thereof; And / or, the alkaline pH regulator includes any one of sodium hydroxide, sodium bicarbonate and sodium carbonate.

4. The preparation method according to claim 3, wherein The hydrogel raw material is PEO100-PPO65-PEO100 (Poloxamer 407), and / or the local anesthetic is bupivacaine hydrochloride; and / or the alkaline pH regulator is sodium hydroxide.

5. The preparation method according to claim 4, wherein The mass ratio of bupivacaine hydrochloride, poloxamer 407 and deionized water is (0.75-4): (20-30):

100.

6. The preparation method according to claim 5, wherein The mass ratio of bupivacaine hydrochloride, poloxamer 407 and deionized water is 4:25:

100.

7. The preparation method according to claim 2, wherein An alkaline pH adjuster was added to adjust the pH to 7.4 ± 0.

1.

8. Use of the injectable thermosensitive hydrogel sustained-release pharmaceutical preparation according to claim 1 in the preparation of long-acting local anesthetic and analgesic drugs.

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