Hydrogel spray for preventing traumatic heterotopic ossification and preparation method and spray device thereof

Abstract

The application discloses a hydrogel spray for preventing traumatic ectopic ossification, a preparation method and a spraying device. The hydrogel spray comprises photocured hydrogel and nano drug-loaded complex loaded with curcumin, the nano drug-loaded complex is uniformly dispersed in the photocured hydrogel to form the hydrogel spray; the preparation method comprises the process of ultrasonic dispersion of the nano drug-loaded complex in the photocured hydrogel; and the spraying device comprises a spray container containing the hydrogel spray and a spraying head. The hydrogel spray has strong penetration capacity, is convenient to operate, does not cause stimulation to human gastrointestinal tract, and can be used for long-term prevention of traumatic ectopic ossification.

Description

Technical Field

[0001] This invention relates to the field of drugs for the prevention of traumatic heterotopic ossification, specifically a hydrogel spray for the prevention of traumatic heterotopic ossification, its preparation method, and a spraying device. Background Technology

[0002] Traumatic heterotopic ossification is the most common type of acquired heterotopic ossification. It is defined as a pathological process in which tissue damage caused by trauma stimulates the ectopic formation of bone in the soft tissue surrounding the injury. Traumatic heterotopic ossification often occurs around large joints such as the elbow and hip, leading to joint pain and swelling, limited range of motion, and even joint stiffness and loss of function, resulting in disability.

[0003] Traumatic heterotopic ossification is currently believed to be related to osteogenic signaling and transduction pathways activated by the inflammatory microenvironment cascade during trauma. Therefore, early control of local tissue inflammation helps prevent traumatic heterotopic ossification. However, traumatic heterotopic ossification is characterized by uncertainty: it is uncertain whether every trauma will trigger it; the specific location of the lesion is uncertain; the specific time of onset is uncertain; and the specific extent of the lesion is uncertain. Once it occurs, surgical resection is the only treatment option, and complete removal is difficult for extensive lesions, placing a heavy burden on patients and society.

[0004] Current methods for preventing traumatic heterotopic ossification include oral nonsteroidal anti-inflammatory drugs (NSAIDs) and prophylactic radiotherapy. While oral NSAIDs are simple to administer, their effectiveness is limited. Oral medications have limited penetration into local tissues, and NSAIDs have significant gastrointestinal irritation and other side effects, making it impossible to maintain a long-term preventative effect. Prophylactic radiotherapy, on the other hand, requires expensive equipment and cannot be routinely performed. Therefore, it can be said that there is currently no ideal preventative method that can intervene locally during surgery and achieve long-term preventative effects. Summary of the Invention

[0005] This invention provides a hydrogel spray for preventing traumatic heterotopic ossification, its preparation method, and a spraying device, in order to solve the problem that it is difficult to have long-term prevention of traumatic heterotopic ossification.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0007] A hydrogel spray for preventing traumatic heterotopic ossification includes a photocurable hydrogel and a nano-drug-loaded complex of curcumin; the nano-drug-loaded complex includes zinc-based zeolite imidazole ester framework nanoparticles that encapsulate curcumin as a drug-loaded scaffold, and nano-cerium oxide as a gating material, the nano-drug-loaded complex being uniformly dispersed in the photocurable hydrogel to form the hydrogel spray.

[0008] Furthermore, the photocurable hydrogel is a methacrylamide hyaluronic acid hydrogel with added photoinitiator.

[0009] A method for preparing the above-mentioned hydrogel spray includes the following steps:

[0010] Step 1: Preparation of drug-loaded nanocomposite;

[0011] Step 2: Add the obtained nano-drug-loaded composite to the photocurable hydrogel and disperse it by ultrasonication to obtain the hydrogel spray.

[0012] Furthermore, step 1 proceeds as follows:

[0013] Step 1.1: Dissolve 2-methylimidazole and curcumin in methanol to form a mixed solution. Add zinc nitrate hexahydrate solution dropwise to the mixed solution and stir for 13-17 minutes to obtain a milky suspension.

[0014] Step 1.2: Disperse the nano-cerium oxide particles and polyvinylpyrrolidone in methanol. Add the methanol containing the nano-cerium oxide particles and polyvinylpyrrolidone to the emulsion suspension and stir the reaction at room temperature for 4-6 minutes. After the stirring reaction is completed, centrifuge the mixture to remove impurities and obtain the final reaction product.

[0015] Step 1.3: After washing and drying the obtained reaction end product, cerium oxide-gated zinc-based zeolite imidazole ester framework nanoparticles loaded with curcumin are obtained, which are the nano-drug-loaded complexes.

[0016] In further step 1.2, after the stirring reaction is completed, the mixture is first centrifuged for 8-11 minutes, then washed with methanol to remove impurities, and finally centrifuged for 28-32 minutes to obtain the final reaction product.

[0017] In a further step 2, the nano-drug-carrying composite is added to the photocurable hydrogel and then ultrasonically dispersed at room temperature for 14-17 minutes to obtain the hydrogel spray.

[0018] A spraying device includes a spray container and a spray press head installed on the spray container. The spray container contains a spray liquid, which is the aforementioned hydrogel spray liquid.

[0019] This invention enables intraoperative spraying onto tissues surrounding the wound. After in-situ photocuring, a hydrogel sustained-release film loaded with a nano-drug complex is formed. This film responsively releases the encapsulated curcumin within the inflammatory microenvironment, working synergistically with degradation products to regulate the inflammatory microenvironment of the wound and inhibit inflammatory activation of heterotopic ossification, thereby achieving early and widespread prevention of traumatic heterotopic ossification. Compared to traditional oral drug treatment and prophylactic radiotherapy, the spray of this invention has strong penetrating power, is easy to operate, does not irritate the human gastrointestinal tract, and can be used for long-term prevention of traumatic heterotopic ossification. Attached Figure Description

[0020] Figure 1 This is a scanning cinematography image of the hydrogel after lyophilization by spraying in Embodiment 1 of the present invention.

[0021] Figure 2 This is a transmission electron microscope image of the drug-loaded nanocomposite containing curcumin in Embodiment 1 of the present invention.

[0022] Figure 3 This is a flowchart of the method in Embodiment 2 of the present invention. Detailed Implementation

[0023] The present invention will be further described below with reference to the accompanying drawings and embodiments. Example 1

[0024] This embodiment discloses a hydrogel spray for preventing traumatic heterotopic ossification, comprising a photocurable hydrogel and a curcumin-loaded nano-drug-carrying composite. The curcumin-loaded nano-drug-carrying composite is uniformly dispersed in the photocurable hydrogel to form the hydrogel spray. A scanning cinematographic micrograph of the hydrogel spray after lyophilization is shown below. Figure 1 As shown.

[0025] In this embodiment, the nano-drug-loaded complex uses nano-zinc-based zeolite imidazole ester framework nanoparticles as the drug-loaded scaffold for encapsulating curcumin, and nano-cerium oxide as the gating material, thereby forming a curcumin-loaded nano-drug-loaded complex. A transmission electron microscope image of this nano-drug-loaded complex is shown below. Figure 2 As shown. Wherein:

[0026] The nano-zinc-based zeolite imidazole ester framework (ZIF-8) in this embodiment is composed of zinc ions (Zn... 2+ Zinc-based zeolite imidazole esters are a class of metal-organic frameworks synthesized by microwave-assisted coordination with 2-methylimidazole (2-MiM). These nano-zinc-based zeolite imidazole ester frameworks exhibit good biocompatibility and acid-sensitive environment sensitivity, remaining stable under physiological conditions while degrading under acidic conditions, making them ideal carriers for drug delivery and sustained release.

[0027] The nano-cerium oxide used in this embodiment was purchased from Sinopharm Nanotech Co., Ltd., China, CAS No.: 1306-38-3. The nano-cerium oxide exhibits oxygen free radical responsiveness and scavenging properties.

[0028] The curcumin used in this example was purchased from Sigma-Aldrich, USA, catalog number C7727. Curcumin is a yellow polyphenolic substance extracted from turmeric root, also known as diferoylmethane. It is a symmetrical molecule composed of two aromatic ring-containing o-methoxyphenol groups linked by a seven-carbon chain. Curcumin is synthesized from vanillin and acetylacetone via the Pabon reaction in the presence of boron oxide. It has regulatory effects on inflammatory pathways, anti-inflammatory activity, and immunomodulatory effects.

[0029] In this embodiment, the photocurable hydrogel is a methacrylamide hyaluronic acid hydrogel with added photoinitiator. The methacrylamide hyaluronic acid hydrogel is a hyaluronic acid solution modified with methacrylamide solution. It has the ability to rapidly crosslink from liquid to solid hydrogel in a short time under ultraviolet light. Its porosity meets the requirements for the encapsulation of nanomedicines and has the ability to release drugs in a sustained manner.

[0030] The hydrogel spray for preventing traumatic heterotopic ossification described in this embodiment is placed in a dark brown container and stored in a refrigerator at 4 degrees Celsius, protected from light. When used, it is rapidly sprayed onto the wound site and simultaneously cured with a 405nm blue light flashlight. Upon reaching the tissue surrounding the wound, the hydrogel spray rapidly cross-links and solidifies in situ within 20 seconds under 405nm ultraviolet light irradiation, forming a drug-loaded composite solid hydrogel film that adheres to the interstitial spaces. This allows for the rapid formation of a sustained-release drug-eluting composite hydrogel film at the wound site. The oxygen free radical-responsive degradation of nano-cerium oxide and the acid-responsive degradation of the nano-zinc-based zeolite imidazole ester framework promote the degradation of the nano-drug-loaded composite in the inflammatory environment of the wound and the release of the encapsulated curcumin. The released curcumin, along with the zinc ions generated from the degradation, and cerium oxide, together promote the mildening of the local microenvironment of the wound, regulate the immune system, restore homeostasis, and prevent the occurrence of traumatic heterotopic ossification. Example 2

[0031] This embodiment discloses a method for preparing the aforementioned hydrogel spray liquid, such as... Figure 3 As shown, it includes the following steps:

[0032] Step 1: Preparation of the drug-loaded nanocomposite, the process is as follows:

[0033] Step 1.1: Take 2-methylimidazole, curcumin, methanol, and zinc nitrate hexahydrate solution. 2-methylimidazole is a product manufactured by Aladdin Company of China, curcumin is a product manufactured by Sigma-Aldrich Company of the United States, and zinc nitrate hexahydrate solution is a product manufactured by Aladdin Company of China.

[0034] In this embodiment, each 18.7 mL of methanol corresponds to 7 mL of 2-methylimidazole (35.84 mM), 44.5 mg of curcumin, and 7 mL of zinc nitrate hexahydrate solution. First, 2-methylimidazole and curcumin are ultrasonically dissolved in methanol to form a mixed solution. The mixed solution is then magnetically stirred for 20 min at room temperature (15-25°C) to ensure thorough dispersion of the substrate. Next, zinc nitrate hexahydrate solution is added dropwise to the mixed solution at a uniform rate, with continuous stirring for 13-17 minutes during the addition process, resulting in a milky suspension. In this embodiment, the preferred stirring time is 15 minutes.

[0035] Step 1.2: Using nano-cerium oxide particles and polyvinylpyrrolidone (PVP), wherein the nano-cerium oxide particles are products manufactured by China Xianfeng Nanotechnology Co., Ltd., and the polyvinylpyrrolidone (PVP) is a product manufactured by China Aladdin Co., Ltd. In this embodiment, 10 mg of nano-cerium oxide particles and 300 mg of polyvinylpyrrolidone are used per 15 mL of methanol, and the nano-cerium oxide particles and polyvinylpyrrolidone are ultrasonically dispersed in methanol.

[0036] Take the emulsified suspension obtained from 44.5 mg of curcumin in step 1.1, add methanol containing nano-cerium oxide particles and polyvinylpyrrolidone to the emulsified suspension obtained in step 1.1, and stir the mixture at room temperature for 4-6 minutes. In this embodiment, the stirring reaction time is preferably 5 minutes.

[0037] After the stirring reaction is complete, a first centrifugation is performed for 8-11 minutes, followed by washing three times with methanol to remove unloaded drug and unreacted impurities. Finally, a second centrifugation is performed for 28-32 minutes, yielding an orange-yellow final product. In this embodiment, the rotation speed for both the first and second centrifugation is 12,000 rpm, and the preferred centrifugation time for the first centrifugation is 10 minutes, while the preferred centrifugation time for the second centrifugation is 30 minutes.

[0038] Step 1.3: After washing the obtained reaction end product three times with deionized water by centrifugation, it is then freeze-dried under vacuum to obtain cerium oxide-gated zinc zeolite imidazole ester framework nanoparticles loaded with curcumin (Cur@ZIF@CeO2), which is the nano-drug-loaded complex.

[0039] Step 2: Take the nano-drug-loaded composite Cur@ZIF@CeO2 obtained in Step 1, as well as the methacrylamide hyaluronic acid hydrogel and the photoinitiator. The methacrylamide hyaluronic acid hydrogel is a product manufactured by China Yongqinquan Intelligent Equipment Co., Ltd., and the photoinitiator is LAP ((phenyl(2,4,6-trimethylbenzoyl)lithium phosphate) manufactured by China Yongqinquan Intelligent Equipment Co., Ltd.

[0040] In this embodiment, 10 mg of the drug-loaded nanocomposite Cur@ZIF@CeO2 corresponds to 10 ml of methacrylamide hyaluronic acid hydrogel and 0.025 g of photoinitiator. The drug-loaded nanocomposite Cur@ZIF@CeO2 is dissolved in the methacrylamide hyaluronic acid hydrogel, and the photoinitiator is added. Then, it is ultrasonically dispersed at room temperature to obtain the hydrogel spray described in Example 1. The ultrasonic dispersion power is 30 W, and the ultrasonic dispersion time is 14-17 minutes. In this embodiment, the ultrasonic dispersion time is preferably 15 minutes.

[0041] The hydrogel spray prepared in this embodiment is placed in a brown-black spray bottle and stored in a refrigerator at 4 degrees Celsius away from light. When using it, it is quickly sprayed onto the wound site and simultaneously cured with a 405nm blue light flashlight. Within 20 seconds, a composite hydrogel film with sustained-release drug can be quickly formed at the wound site. Example 3

[0042] This embodiment discloses a spraying device, which includes a spray bottle as a spray container. The top of the spray bottle is the bottle opening, and a spray head is screwed onto the bottle opening. The spray bottle contains the hydrogel spray liquid described in Embodiment 1.

[0043] To use, aim the spray nozzle at the tissue around the wound, then press the nozzle to spray the hydrogel solution onto the tissue around the wound.

[0044] The preferred embodiments of the present invention have been described in detail above with reference to the accompanying drawings. These embodiments are merely descriptions of preferred embodiments and are not intended to limit the scope or concept of the invention. The specific technical features described in the above embodiments can be combined in any suitable manner without contradiction. Such combinations, as long as they do not violate the spirit of the present invention, should also be considered as part of this disclosure. To avoid unnecessary repetition, the present invention will not further describe the various possible combinations.

[0045] This invention is not limited to the specific details of the above embodiments. Within the scope of the technical concept of this invention and without departing from the design idea of ​​this invention, all modifications and improvements made by those skilled in the art to the technical solutions of this invention should fall within the protection scope of this invention. The technical content for which protection is sought in this invention has been fully described in the claims.

Claims

1. A hydrogel spray for preventing traumatic heterotopic ossification, characterized in that, The invention includes a photocurable hydrogel and a nano-drug-loaded composite containing curcumin. The nano-drug-loaded composite comprises zinc-based zeolite imidazole ester framework nanoparticles that encapsulate curcumin as a drug-loaded scaffold, and nano-cerium oxide as a gating material. The nano-drug-loaded composite is uniformly dispersed in the photocurable hydrogel to form the hydrogel spray. The photocurable hydrogel is a methacrylamide hyaluronic acid hydrogel with added photoinitiator.

2. A method for preparing the hydrogel spray as described in claim 1, characterized in that, Includes the following steps: Step 1: Preparation of drug-loaded nanocomposite; Step 2: Add the obtained nano-drug-loaded composite to the photocurable hydrogel and disperse it by ultrasonication to obtain the hydrogel spray.

3. The method for preparing the hydrogel spray according to claim 2, characterized in that, Step 1 is as follows: Step 1.1: Dissolve 2-methylimidazole and curcumin in methanol to form a mixed solution. Add zinc nitrate hexahydrate solution dropwise to the mixed solution and stir for 13-17 minutes to obtain a milky suspension. Step 1.2: Disperse cerium oxide nanoparticles and polyvinylpyrrolidone in methanol. Add methanol containing cerium oxide nanoparticles and polyvinylpyrrolidone to the milky suspension and stir for 4-6 minutes at room temperature. After the stirring reaction is completed, centrifuge and remove impurities to obtain the final reaction product. Step 1.3: Wash and dry the obtained final reaction product to obtain cerium oxide-gated zinc-based zeolite imidazole ester framework nanoparticles loaded with curcumin, which is the nano-drug-loaded complex.

4. The method for preparing the hydrogel spray according to claim 3, characterized in that, In step 1.2, after the stirring reaction is completed, the mixture is first centrifuged for 8-11 minutes, then washed with methanol to remove impurities, and finally centrifuged for 28-32 minutes to obtain the final reaction product.

5. The method for preparing the hydrogel spray according to claim 2, characterized in that, In step 2, the nano-drug-loaded composite is added to the photocurable hydrogel and then ultrasonically dispersed at room temperature for 14-17 minutes to obtain the hydrogel spray.

6. A spraying device, comprising a spray container and a spray press head installed on the spray container, the spray container containing spray liquid, characterized in that, The spray liquid is the hydrogel spray liquid as described in claim 1.

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