Injectable composition comprising anesthetic-loaded hydrogel

Abstract

The present invention relates to an injectable composition comprising a compound capable of forming nanoparticles, an anesthetic, and a hyaluronic acid hydrogel. According to the present invention, the injectable composition is administered in a liquid formulation and undergoes gelation in vivo, thereby preventing rapid degradation, enabling sustained release of the anesthetic over an extended period, and allowing the composition to remain locally in the body for a prolonged time. In addition, it is possible to provide a continuous pain relief effect over a long period of time through stable sustained release of lidocaine.

Description

Injectable composition comprising a hydrogel loaded with an anesthetic

[0001] The present invention relates to an injectable composition comprising a hydrogel loaded with an anesthetic agent and a method for manufacturing the same, etc.

[0002] Lidocaine is a widely used drug for local anesthesia and analgesics, and has been developed into various forms of formulations for pain relief. However, due to lidocaine's short half-life and rapid metabolism in the body, there are limitations in situations requiring continuous drug delivery. To address these issues, there is a demand for drug delivery systems capable of slowly releasing lidocaine, and hydrogel-based drug delivery media are receiving particular attention.

[0003] Hydrogels are polymer networks that maintain a constant structure while containing a large amount of water, and are utilized in various medical applications due to their biocompatibility and ability to control drug release. In particular, lidocaine loading systems using hydrogels improve the sustained-release characteristics of the drug, allowing the effect to be sustained for an extended period with a single administration. This offers the advantages of reducing the inconvenience of repeated administration, maximizing drug efficacy, and minimizing side effects.

[0004] The present invention relates to an injectable composition comprising a hydrogel loaded with lidocaine, and provides a technology that can maximize patient convenience and treatment efficiency by providing a continuous pain relief effect over a long period of time through the stable sustained release of lidocaine.

[0005] The technical problem that the present invention aims to solve is to provide an injectable composition comprising a compound forming nanoparticles; a cross-linked hyaluronic acid hydrogel; and an anesthetic.

[0006] However, the technical problems that the present invention aims to solve are not limited to those mentioned above, and other unmentioned problems will be clearly understood by a person skilled in the art from the description below.

[0007] To solve the above problem, the inventors provide an injectable composition comprising: a compound formed by the following [Chemical Formula 1] and a compound conjugated with CDPL (cyclodextrin-grafted polylysine); a cross-linked hyaluronic acid hydrogel; and an anesthetic.

[0008] [Chemical Formula 1]

[0009]

[0010] According to one aspect, the anesthetic is ambucaine, amolanone, amylocaine, benoxinate, benzocaine, betoxycaine, biphenamine, bupivacaine, butacaine, butamben, butanilicaine, butethamine, butoxycaine, carticaine, chloroprocaine, cocaethylene, cocaine, cyclomethycaine, dibucaine, dimethysoquin, dimethocaine, diperodon, dicyclonine, Ecgonidine, ecgonine, ethyl chloride, etidocaine, beta-eucaine, euprocin, fenalcomine, formocaine, hexylcaine, hydroxytetracaine, isobutyl p-aminobenzoate, leucinocaine mesylate, levoxadrol, lidocaine, mepivacaine, meprylcaine, metabutoxycaine, methyl chloride, myrtecaine, naepaine, Octacaine, orthocaine, oxethazaine, parethoxycaine,It may be one or more selected from the group consisting of phenacaine, phenol, piperocaine, pyridocaine, polidocanol, pramoxine, prilocaine, procaine, propanocaine, proparacaine, propipocaine, propoxycaine, pseudococaine, pyrrocaine, ropivacaine, salicyl alcohol, tetracaine, tolycaine, trimecaine, zolamine, and salts thereof.

[0011] According to one side, the anesthetic may be lidocaine.

[0012] According to one aspect, the composition may be liquid at room temperature and gel at body temperature.

[0013] According to one aspect, the composition may be a sustained-release anesthetic.

[0014] According to one aspect, the cross-linked hyaluronic acid hydrogel may be a hyaluronic acid of 50 to 150 kDa cross-linked to a cross-linking degree of 20%.

[0015] According to another embodiment of the present invention, a method for preparing an injectable composition is provided, comprising the following steps:

[0016] 1) A step of conjugating CDPL with the compound of [Chemical Formula 1] below;

[0017] 2) A step of succinylating and nanoparticleizing the conjugated compound of step 1) above;

[0018] 3) a step of preparing an anesthetic-nanoparticle solution by loading an anesthetic onto nanoparticles prepared through step 2); and

[0019] 4) A step of mixing the anesthetic-nanoparticle solution into the cross-linked hyaluronic acid hydrogel;

[0020] [Chemical Formula 1]

[0021]

[0022] According to one aspect, the anesthetic is ambucaine, amolanone, amylocaine, benoxinate, benzocaine, betoxycaine, biphenamine, bupivacaine, butacaine, butamben, butanilicaine, butethamine, butoxycaine, carticaine, chloroprocaine, cocaethylene, cocaine, cyclomethycaine, dibucaine, dimethysoquin, dimethocaine, diperodon, dicyclonine, Ecgonidine, ecgonine, ethyl chloride, etidocaine, beta-eucaine, euprocin, fenalcomine, formocaine, hexylcaine, hydroxytetracaine, isobutyl p-aminobenzoate, leucinocaine mesylate, levoxadrol, lidocaine, mepivacaine, meprylcaine, metabutoxycaine, methyl chloride, myrtecaine, naepaine, Octacaine, orthocaine, oxethazaine, parethoxycaine,It may be one or more selected from the group consisting of phenacaine, phenol, piperocaine, pyridocaine, polidocanol, pramoxine, prilocaine, procaine, propanocaine, proparacaine, propipocaine, propoxycaine, pseudococaine, pyrrocaine, ropivacaine, salicyl alcohol, tetracaine, tolycaine, trimecaine, zolamine, and salts thereof.

[0023] According to one side, the anesthetic may be lidocaine.

[0024] According to one aspect, step 4) above may further include a step of grinding the cross-linked hyaluronic acid hydrogel into a size suitable for injection.

[0025] According to another embodiment of the present invention, a pre-filled syringe filled with any one of the above-mentioned compositions is provided.

[0026] The injectable composition according to the present invention is injected as a liquid formulation and gels within the body to prevent rapid decomposition and allows for sustained release of an anesthetic for a long time, and can remain locally in the body for a long time.

[0027] The effects of the present invention are not limited to those mentioned above, and other unmentioned effects will be clearly understood by a person skilled in the art from the description below.

[0028] Figure 1 shows the rheological properties of the fabricated hydrogel formulation according to temperature.

[0029] Figure 2 shows the results of confirming the degree of absorption of lidocaine local anesthetic in the body in a rat model.

[0030] Figure 3 evaluates the in vivo safety of the hydrogel formulation and lidocaine-loaded hydrogel.

[0031] Figure 4a confirms the pain control effect of the lidocaine-loaded hydrogel formulation. Figure 4b compares the effects of the lidocaine-loaded hydrogel and the Ropivacaine-hydrogel formulation.

[0032] To solve the above problem, the inventors provide an injectable composition comprising: a compound formed by the following [Chemical Formula 1] and a compound conjugated with CDPL (cyclodextrin-grafted polylysine); a cross-linked hyaluronic acid hydrogel; and an anesthetic.

[0033] [Chemical Formula 1]

[0034]

[0035] In the present invention, the compound represented by [Chemical Formula 1] and the compound conjugated with CDPL can form nanoparticles to carry the drug lidocaine, and after being released from the hydrogel, can act as a drug delivery vehicle for lidocaine.

[0036] It was confirmed that when using a compound conjugated with CDPL and the compound represented by [Chemical Formula 1] above, it affects drug release and rheological properties, making it suitable for sustained drug release in the body for a long time.

[0037] In addition, the composition of the present invention may maintain an injectable liquid formulation at room temperature and then gel within the body temperature range after being injected into the body. The body temperature range refers to 34 to 38 degrees Celsius. By gelling as described above, rapid decomposition is prevented, and the drug can be sustained-released over a long period of time.

[0038] In the present invention, the anesthetic agent is not limited to any commonly used drugs, but examples include the following. Ambucaine, amolanone, amylocaine, benoxinate, benzocaine, betoxycaine, biphenamine, bupivacaine, butacaine, butamben, butanilicaine, butethamine, butoxycaine, carticaine, chloroprocaine, cocaethylene, cocaine, cyclomethycaine, dibucaine, dimethysoquin, dimethocaine, diperodon, dicyclonine, Ecgonidine, ecgonine, ethyl chloride, etidocaine, beta-eucaine, euprocin, fenalcomine, formocaine, hexylcaine, hydroxytetracaine, isobutyl p-aminobenzoate, leucinocaine mesylate, levoxadrol, lidocaine, mepivacaine, meprylcaine, metabutoxycaine, methyl chloride, myrtecaine, naepaine, Octacaine, OrthocaineOxethazaine, parethoxycaine, phenacaine, phenol, piperocaine, pyridocaine, polidocanol, pramoxine, prilocaine, procaine, propanocaine, proparacaine, propipocaine, propoxycaine, pseudococaine, pyrrocaine, ropivacaine, salicyl alcohol, tetracaine, tolycaine, trimecaine, zolamine, and salts thereof. In addition, preferably, the anesthetic may be lidocaine.

[0039] According to one aspect, the composition may be a sustained-release anesthetic.

[0040] According to one aspect, the cross-linked hyaluronic acid hydrogel may be a hyaluronic acid of 50 to 150 kDa cross-linked to a cross-linking degree of 20%.

[0041] According to another embodiment of the present invention, a method for preparing an injectable composition is provided, comprising the following steps:

[0042] 1) A step of conjugating CDPL with the compound of [Chemical Formula 1] below;

[0043] 2) A step of succinylating and nanoparticleizing the conjugated compound of step 1) above;

[0044] 3) a step of preparing an anesthetic-nanoparticle solution by loading an anesthetic onto nanoparticles prepared through step 2); and

[0045] 4) A step of mixing the anesthetic-nanoparticle solution into the cross-linked hyaluronic acid hydrogel;

[0046] [Chemical Formula 1]

[0047]

[0048] According to one aspect, step 4) above may further include a step of grinding or homogenizing the cross-linked hyaluronic acid hydrogel into a size suitable for injection.

[0049] According to another embodiment of the present invention, a pre-filled syringe filled with any one of the above-mentioned compositions is provided.

[0050]

[0051] The terms used in the embodiments are for illustrative purposes only and should not be interpreted as intended to be limiting. Singular expressions include plural expressions unless the context clearly indicates otherwise. In this specification, terms such as "comprising" or "having" are intended to indicate the existence of the features, numbers, steps, actions, components, parts, or combinations thereof described in the specification, and should be understood as not precluding the existence or addition of one or more other features, numbers, steps, actions, components, parts, or combinations thereof.

[0052] Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as generally understood by those skilled in the art to which the embodiments pertain. Terms such as those defined in commonly used dictionaries should be interpreted as having a meaning consistent with their meaning in the context of the relevant technology, and should not be interpreted in an ideal or overly formal sense unless explicitly defined in this application.

[0053] The present invention is capable of various modifications and may have various embodiments. Specific embodiments are illustrated in the drawings and described in detail in the detailed description below. However, this is not intended to limit the present invention to specific embodiments, and it should be understood that it includes all modifications, equivalents, and substitutions that fall within the spirit and scope of the present invention. In describing the present invention, detailed descriptions of related prior art are omitted if it is determined that such detailed descriptions may obscure the essence of the present invention.

[0054]

[0055] Example 1. Experimental Method

[0056] Example 1-1. Preparation of Monoaldehyde β-Cyclodextrin (β-CD)

[0057] To prepare monoaldehyde β-CD (Ald-CD), 30 g of β-CD (26.4 mmol) was dissolved in 300 mL of anhydrous DMSO using a round-bottom flask equipped with a stirring rod. Subsequently, 13.5 g of des-martine iodine (31.8 mmol) was added to the solution and completely dissolved, then stirred at room temperature for 2 hours. Afterward, the solution was precipitated in 3 L of EA / acetone (20% v / v) and stirred overnight at room temperature. The precipitate was recovered by vacuum filtration and dissolved again in a minimal amount of distilled water. This solution was sonicated for 20 minutes and then vacuum filtered again. The filtered solution was frozen at -80°C and then freeze-dried. After freeze-drying, a white solid was obtained as the final product.

[0058]

[0059] Example 1-2. Bonding Ald-CD to EPL

[0060] A solution was prepared by dissolving 20 g (18 mmol) of Ald-CD in 700 mL of PBS (pH 8.0). Then, 7 g (1.8 mmol) of EPL was added, and the mixture was stirred for 24 hours. Afterward, 7 g of sodium borate (180 mmol) was added to the reaction mixture to reduce the Schiff base to a secondary amine, and the mixture was stirred for an additional 24 hours at room temperature. Dynamic dialysis was performed for 72 hours using deionized water with a 6–8 kDa molecular weight barrier. Finally, the dialyzed solution was frozen at -80°C and then freeze-dried.

[0061]

[0062] Examples 1-3. Conjugation of NIR phosphor to CDPL

[0063] First, the ZW800 was manufactured as follows.

[0064]

[0065] 2,3,3-Trimethyl-3H-indole-5-sulfonic acid: Preparation of 4-hydrazinobenzenesulfonic acid (20 g, 97.5 mmol)

[0066] Sodium acetate (16 g, 195 mmol) and 3-methyl-2-butanone (14.9 mL, 139 mmol) were mixed with glacial acetic acid (97 mL) and heated to 110°C in a sealed tube under a nitrogen atmosphere. The resulting product was filtered, washed with methyl tert-butyl ether (MTBE), and precipitated to obtain a brown solid (19.4 g, 83%).

[0067]

[0068] Preparation of 2,3,3-trimethyl-1-[3-(trimethylammonium)propyl]-3H-indoleum-5-sulfonic acid

[0069] Dibromide: 2,3,3-trimethyl-3H-indole-5-sulfonic acid (7.17 g, 36.4 mmol) and (3-bromopropyl)trimethylammonium bromide (10.5 g, 40 mmol) were mixed in toluene (60 mL) and heated at 130°C for 72 hours under a nitrogen atmosphere. After cooling the mixture to room temperature, the solvent was decanted. The product was crystallized in methanol and MTBE to obtain pink crystals (5.11 g, 81%) without further purification in the next step.

[0070]

[0071] Preparation of 2,3,3-trimethyl-1-[3-(trimethylammonium)propyl]-3H-indoleum bromide

[0072] 2,3,3-trimethyl-3H-indole (1.59 g, 10 mmol) and (3-bromopropyl)trimethylammonium bromide (2.87 g, 11 mmol) were mixed in toluene (50 mL) and refluxed in a sealed tube under a nitrogen atmosphere for 72 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain a red residue. The product was crystallized in acetone / methanol (5:1) to obtain a pink solid (2.52 g, 61%).

[0073]

[0074] Preparation of 2-((E)-2-((E)-2-chloro-3-((E)-2-(3,3-dimethyl-5-sulfonato-1-(3-(trimethylammonium)propyl)indoline-2-ylidene) ethylidene) cyclohex-1-en-1-yl) vinyl)-3,3-dimethyl-1-(3-(trimethylammonium)propyl)-3H-indoleum-5-sulfonate disodium bromide

[0075] Bromide salt (1.26 g, 2.41 mmol), Bilsmayr-Hark reagent (0.433 g, 1.5 mmol), and anhydrous sodium acetate (0.37 g, 4.5 mmol) were mixed in absolute ethanol (50 mL) and refluxed for 6 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain a brown residue. The product was washed with dichloromethane to obtain a brown-green solid, which was suspended in methanol (10 mL), filtered, and dried under vacuum to obtain a golden-green solid (1.2 g, 1.1 mmol, 73%).

[0076]

[0077] Preparation of 3-((E)-2-(3,3-dimethyl-1-(3-(trimethylammonium)propyl)indoline-2-ylidene)ethylidene)cyclohex-1-en-1-yl)vinyl)-3,3-dimethyl-1-(3-(trimethylammonium)propyl)-3H-indoleum bromide

[0078] Bromide salt (840 mg, 2 mmol), Bilsmayr-Hark reagent (359 mg, 1 mmol), and anhydrous sodium acetate (492 mg, 6 mmol) were mixed in absolute ethanol (50 mL) and refluxed at 100°C for 5 hours. After cooling the mixture to room temperature, it was concentrated under reduced pressure to obtain a brown residue. After drying the reaction mixture, the brown residue was washed with dichloromethane and MTBE (1:1) to obtain a dye (260 mg, 29%).

[0079]

[0080] Synthesis of CC-linked ZW800 analogues: 3-((E)-2-(3,3-dimethyl-1-(3-(trimethylammonium)propyl)indoline-2-ylidene)ethylidene)cyclohex-1-en-1-yl)vinyl)-3,3-dimethyl-1-(3-(trimethylammonium)propyl)-3H-indolium bromide (1.0 mmol) and 3-(4-voronophenyl)propionic acid (1.8 mmol) were added to H2O and refluxed for 72 hours in the presence of Pd(PPh3)4 (0.065 mmol). The reaction progress was monitored by visible / near-infrared spectroscopy using samples diluted with methanol and continued until the absorption of the starting material disappeared. After cooling the mixture to room temperature, the H2O was removed under reduced pressure. The solid was separated by precipitation with methanol / acetone, and the precipitate was further washed with acetone. Final fluorescent material of analytical purity was obtained using open-reverse-phase column chromatography (eluting with acetonitrile / water).

[0081]

[0082] After synthesizing ZW800-1C as described above, a solution of ZW800-1C-NHS ester was prepared by dissolving 22.9 mg (22.38 μmol) of NIR phosphor in 1 mL of DMSO. A CDPL solution was prepared by dissolving 250 mg (18.65 μmol, MW 13,403) of CDPL in 25 mL of PBS (pH 9.0) in a round-bottom flask equipped with a stirring rod. The ZW800-1C-NHS ester solution was slowly added dropwise to the CDPL solution with vigorous stirring. The reaction mixture was stirred for 3 hours, and 0.6 M sodium hydroxide was added as needed while maintaining the pH at 9.0. After 3 hours, the product was precipitated in 250 mL of EA / acetone (20% v / v) and centrifuged at 3000 rpm for 15 minutes. After discarding the supernatant, the process of dissolving ZW800-CDPL in DIW and precipitating it again in EA / acetone was repeated two more times. The product was vacuum dried to obtain a green solid.

[0083]

[0084] Examples 1-4. Succinylation of ZW800-CDPL

[0085] To prepare amphoteric nanoparticles (NP), 2 g (143 μmol) of ZW800-CDPL was dissolved in PBS (pH 9.0; 10 mg / mL). Then, a solution of 300 mg of succinic anhydride (3 mmol) dissolved in DMSO (250 mg / mL) was added. The mixture was stirred at room temperature for 1 hour, and 0.6 M sodium hydroxide was added as needed to maintain the pH at 9.0. After confirming partial succinylation by the ninhydrin test, the product was dialyzed with DIW for 72 hours. After dialyzing, the solution was frozen at -80°C and then freeze-dried.

[0086]

[0087] Examples 1-5. Preparation of Lidocaine Nanoparticles (Lid-NP)

[0088] To prepare Lid-NP, 90 mg of lidocaine was dissolved in DIW. Then, 500 mg of NP powder was dissolved in DIW, and 90 mg of lidocaine was dissolved in the NP solution. The mixture was shaken at room temperature for 2 hours. Afterward, the solution was centrifuged at 14,000 rcf for 10 minutes to precipitate impurities, and the product complex was obtained from the supernatant by filtering through a spin column (MWCO 10K). The molar ratio of lidocaine to NP was measured using a UV spectrophotometer.

[0089]

[0090] Examples 1-6. Preparation of Cross-linked Hyaluronic Acid (HA)

[0091] 100 mg of HA was dissolved in 600 μL of 0.3 M NaOH solution. 20 μL of 1,4-butanediol diglycidyl ether (BDDE) was added to the HA solution. The mixture was shaken for 1 minute and reacted at 40°C for 2 hours. Afterward, the mixture was neutralized to pH 7.0 with 0.1 M HCl. The neutralized reaction mixture was dialyzed with deionized water (DW) using a 6–8 kDa molecular weight barrier to remove any remaining BDDE. After dialysis, the HA hydrogel was broken down into injectable particle sizes using a syringe with an 18–23 G needle. The injectable HA hydrogel particles (xHA) were lyophilized.

[0092]

[0093] Examples 1-7. Preparation of injectable hydrogels loaded with Lid-NP

[0094] Lid-NP was dissolved in distilled water at a concentration of 1 g mL⁻¹. 70 mg of xHA was added to 300 μL of the Lid-NP solution to prepare Lid-NP loaded xHA. The Lid-NP loaded xHA was lyophilized. Prior to use, the lyophilized Lid-NP loaded xHA was added to a 10 wt% Pluronic F127 solution over ice. The composition of the Lid-NP loaded injectable hydrogel is shown in Table 1 below.

[0095] Lid-NP Hydrogel-Loaded Drug Lidocaine Composition 7% xHA 10% F1271-5% Lid-NP

[0096] Example 2. Confirmation of changes in rheological properties of lidocaine-loaded hydrogel

[0097] The rheological properties of the fabricated hydrogel formulation according to temperature were confirmed and are shown in Figure 1. Rheological changes involving gelation were confirmed in an environment of 34°C to 36°C. As a result, it was confirmed that the hydrogel fabricated through this study could change from a liquid state to a gel form upon contact with an environment similar to body temperature and maintain that change.

[0098]

[0099] Example 3. Pharmacokinetic evaluation of lidocaine-loaded hydrogel

[0100] The degree of in vivo absorption of lidocaine local anesthetic was confirmed through serum from rat models injected with lidocaine alone and rat models injected with a lidocaine-loaded hydrogel, and the results are shown in Figure 2. As a result, lidocaine measurements were confirmed in the serum of animals treated with lidocaine alone from 1 hr to 6 hr, whereas in animals injected with the lidocaine-loaded hydrogel, it was confirmed that the serum lidocaine concentration was not detected in excess within a short period after injection, but remained at a low concentration over the long term (1 hr to 14 days). This demonstrates that the lidocaine-loaded hydrogel invented in this study allows for the slow, sustained release of lidocaine in vivo.

[0101]

[0102] Example 4. Evaluation of the in vivo safety of the hydrogel formulation and lidocaine-loaded hydrogel

[0103] The effects of injecting hydrogels without lidocaine and hydrogels containing lidocaine on major organs in vivo were histologically confirmed, and at the same time, the scales of liver damage and myocardial damage detectable at the blood level were confirmed through hematopathological confirmation and are shown in Figure 3.

[0104] Consequently, pathological analysis of major organs in rat models injected with hydrogel and lidocaine-loaded hydrogel confirmed that there was no effect on tissue damage or pathological safety compared to the control group. In addition, analysis of blood collected after hydrogel injection confirmed that no significant changes were observed compared to the control group when checking indicators of liver and myocardial damage.

[0105]

[0106] Example 5. Evaluation of the pain control effect of lidocaine-loaded hydrogel

[0107] Figure 4 shows the results confirming the pain control effect of the lidocaine-loaded hydrogel formulation. The animal model used was the rat CCI (chronic constriction injury) model, which is commonly used for pain sensitivity experiments. As shown in the graph in Figure 4a, after constructing a pain model through rat nerve ligation, lidocaine alone was injected into the surrounding nerve tissue at a concentration of 1.6 mg / kg to 5 mg / kg, and a hydrogel loaded with lidocaine at the same concentration was injected in the same manner. Consequently, it was confirmed that the pain control effect was significantly increased in the group injected with the lidocaine-loaded hydrogel compared to the animal model injected with lidocaine alone. In addition, through the experiment in Fig. 4b, the pain control effect was compared with that of a Ropivacaine-hydrogel formulation that has already been developed and is currently being used in clinical practice. It was confirmed that the injection of the lidocaine-loaded hydrogel invented in this invention could stably maintain the pain control effect in a pain model for up to 14 days, compared to the Ropivacaine-hydrogel which can maintain the pain control effect for up to 3 days.

[0108]

[0109] Although the embodiments have been described above with reference to the limited drawings, those skilled in the art can apply various technical modifications and variations based on the above. For example, suitable results may be achieved even if the described techniques are performed in a different order than described, and / or if the components of the described system, structure, device, circuit, etc. are combined or assembled in a form different from described, or replaced or substituted by other components or equivalents.

[0110] Therefore, other embodiments, other manufacturing examples, and equivalents to the claims also fall within the scope of the claims set forth below.

Claims

1. A compound conjugated with CDPL (cyclodextrin-grafted polylysine) and a compound comprising the following [Chemical Formula 1]; a cross-linked hyaluronic acid hydrogel; and an anesthetic; comprising an injectable composition. [Chemical Formula 1] 2. In claim 1, the anesthetic is ambucaine, amolanone, amylocaine, benoxinate, benzocaine, betoxycaine, biphenamine, bupivacaine, butacaine, butamben, butanilicaine, butethamine, butoxycaine, carticaine, chloroprocaine, cocaethylene, cocaine, cyclomethycaine, dibucaine, dimethysoquin, dimethocaine, diperodon, Dicyclonine, ecgonidine, ecgonine, ethyl chloride, etidocaine, beta-eucaine, euprocin, fenalcomine, formocaine, hexylcaine, hydroxytetracaine, isobutyl p-aminobenzoate, leucinocaine mesylate, levoxadrol, lidocaine, mepivacaine, meprylcaine, metabutoxycaine, methyl chloride, myrtecaine, Naepaine, octacaine, orthocaine, oxethazaine, parethoxycaine,An injectable composition comprising one or more selected from the group consisting of phenacaine, phenol, piperocaine, pyridocaine, polidocanol, pramoxine, prilocaine, procaine, propanocaine, proparacaine, propipocaine, propoxycaine, pseudococaine, pyrrocaine, ropivacaine, salicyl alcohol, tetracaine, tolycaine, trimecaine, zolamine, and salts thereof.

3. An injectable composition according to claim 2, wherein the anesthetic is lidocaine.

4. An injectable composition according to claim 1, wherein the composition is liquid at room temperature and gels within the body temperature range.

5. An injectable composition according to claim 1, wherein the composition sustainably releases an anesthetic.

6. A composition according to claim 1, wherein the cross-linked hyaluronic acid hydrogel is a hyaluronic acid of 50 to 150 kDa cross-linked to a cross-linking degree of 20%.

7. A method for manufacturing an injectable composition, comprising the following steps: 1) A step of conjugating CDPL with the compound of [Chemical Formula 1] below; 2) A step of succinylating and nanoparticleizing the conjugated compound of step 1) above; 3) a step of preparing an anesthetic-nanoparticle solution by loading an anesthetic onto nanoparticles prepared through step 2); and 4) A step of mixing the anesthetic-nanoparticle solution into the cross-linked hyaluronic acid hydrogel; [Chemical Formula 1] 8. In claim 7, the anesthetic is ambucaine, amolanone, amylocaine, benoxinate, benzocaine, betoxycaine, biphenamine, bupivacaine, butacaine, butamben, butanilicaine, butethamine, butoxycaine, carticaine, chloroprocaine, cocaethylene, cocaine, cyclomethycaine, dibucaine, dimethysoquin, dimethocaine, diperodon, Dicyclonine, ecgonidine, ecgonine, ethyl chloride, etidocaine, beta-eucaine, euprocin, fenalcomine, formocaine, hexylcaine, hydroxytetracaine, isobutyl p-aminobenzoate, leucinocaine mesylate, levoxadrol, lidocaine, mepivacaine, meprylcaine, metabutoxycaine, methyl chloride, myrtecaine, Naepaine, octacaine, orthocaine, oxethazaine, parethoxycaine,A method of manufacturing comprising one or more selected from the group consisting of phenacaine, phenol, piperocaine, pyridocaine, polidocanol, pramoxine, prilocaine, procaine, propanocaine, proparacaine, propipocaine, propoxycaine, pseudococaine, pyrrocaine, ropivacaine, salicyl alcohol, tetracaine, tolycaine, trimecaine, zolamine, and salts thereof.

9. A method of manufacturing in which the anesthetic in Clause 8 is lidocaine.

10. A method of manufacturing according to claim 7, further comprising, in step 4), a step of grinding the cross-linked hyaluronic acid hydrogel into a size suitable for injection.

11. A pre-filled syringe filled with the composition of any one of claims 1 to 6.

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