Drug introduction device and method for animal subcutaneous tissue

Abstract

The invention relates to a drug introduction device for animal subcutaneous tissue. The drug introduction device comprises a horizontally arranged base; the metal guide-in needles comprise needle bodies, the first ends of the needle bodies are fixed to the base, the second ends of the needle bodies vertically extend from the base and are provided with puncture parts used for being inserted into animal subcutaneous tissue, and inward concave structures are formed in the circumferential walls of the needle bodies; the inwards-concave structure is located near the puncture part, a water-soluble polymer material is separably loaded in the inwards-concave structure, and the water-soluble polymer material is loaded with medicine; the water-soluble polymer material is placed in the animal subcutaneous tissue through the puncture part and absorbs tissue fluid to expand, and when the needle body is pulled out, the expanded water-soluble polymer material is separated from the inwards-concave structure under the action of friction force between the water-soluble polymer material and the animal subcutaneous tissue. And thus, the membrane is left in the animal subcutaneous tissue. The invention also relates to a drug introduction method.

Description

Technical Field

[0001] The present invention relates to the technical field of drug subcutaneous implantation, and specifically relates to a drug delivery device for animal subcutaneous tissue and a method thereof. Background Art

[0002] With the rapid development of the global livestock industry, large-scale and intensive farming models have become the mainstream. In China, since the 1980s, the government has actively promoted the industrialization of the livestock industry. Large-scale breeding enterprises have emerged continuously, the industrial chain has gradually improved, and scientific and technological innovation plays a key role in enhancing the production efficiency and competitiveness of the livestock industry. However, the prevention and control of livestock and poultry diseases remains a major challenge for the development of the livestock industry. More than 230 animal diseases have been confirmed to occur in China, among which more than 90 are prevalent for a long time, causing direct and indirect economic losses to the livestock industry of more than 340 billion yuan every year. Moreover, many zoonotic diseases, such as COVID-19 infection, H7N9 avian influenza, etc., not only seriously affect the livestock economy, but also pose a huge threat to public health safety and people's health. Therefore, it is urgent to improve the level of disease prevention and control.

[0003] In the process of animal disease prevention and treatment, drug injection is a common means. At present, syringes are the main tools for farms to administer drugs to livestock. Although they can provide drugs, vaccines, etc. for livestock, there are obvious defects in actual application. It is difficult to achieve the release of high-precision drug doses and cannot meet the needs of long-term drug administration. In recent years, microneedle technology has gradually been applied to the field of livestock drug injection. Microneedles penetrate the skin surface through tiny needles or needle arrays, reducing the pain, bleeding and stress reactions of traditional injections. Its precise control system can accurately inject a specified dose of drug, reducing drug waste. Moreover, most microneedle materials are biodegradable materials, which can be quickly dissolved or absorbed by the body after injection and will not remain in the livestock body for a long time. However, microneedle technology also has limitations. The skin of some livestock (such as adult pigs) is relatively thick, and a large amount of force is required to insert the microneedles. If the operation is improper, the microneedles are prone to excessive bending, stretching and breaking. At the same time, the microneedles are finely designed, and the risk of breakage increases under the action of unstable pressures such as inappropriate injection angles or the movement of livestock during injection. Therefore, it is urgent to develop a drug delivery device for animal subcutaneous tissue that can solve the problems of traditional syringes being unable to administer drugs with high precision and for a long time, and the easy breakage of polymer microneedle injections. Summary of the Invention

[0004] Aiming at the technical problems existing in the prior art, the first object of the present invention is: to provide a drug delivery device for animal subcutaneous tissue, which can achieve the release of high-precision drug doses and long-term drug administration compared with traditional syringes, and at the same time solves the problem of the excessive fragility of polymer microneedle injections, providing a new solution for the long-term and stable drug release in animals.

[0005] The second object of the present invention is to provide a method for drug introduction into the subcutaneous tissue of animals.

[0006] To achieve the above object, the present invention adopts the following technical solutions:

[0007] A drug introduction device for the subcutaneous tissue of animals, comprising: a horizontally arranged base; a metal introduction needle, the metal introduction needle includes a needle body, the first end of the needle body is fixed on the base, the second end of the needle body extends vertically from the base and has a puncture part for inserting into the subcutaneous tissue of animals, an inward concave structure is formed on the circumferential wall of the needle body, the inward concave structure is located near the puncture part, and a water-soluble polymer material is separably loaded inside it, the water-soluble polymer material is loaded with drugs; wherein, the water-soluble polymer material is placed into the subcutaneous tissue of animals through the puncture part and swells by absorbing tissue fluid, when the needle body is pulled out, the swollen water-soluble polymer material is separated from the inward concave structure under the action of friction between it and the subcutaneous tissue of animals, so as to leave it in the subcutaneous tissue of animals.

[0008] Furthermore, the inward concave structure has a plurality of grooves arranged along the circumferential direction of the needle body; the shape of the grooves is wedge-shaped, square or elliptical.

[0009] Furthermore, the groove is wedge-shaped, the upper end of the wedge-shaped groove extends radially towards the central axis of the needle body, and its lower end inclines outwards along the length direction of the needle body towards the puncture part.

[0010] Furthermore, the water-soluble polymer material is a biodegradable water-absorbing and swelling hydrogel, which includes one or more of polyacrylic acid, polyacrylamide, hyaluronic acid, poly(acrylamide-sodium acrylate) or polysialic acid.

[0011] Furthermore, the drugs include antibiotic drugs or anti-parasitic drugs, the antibiotic drugs include oxytetracycline, ampicillin or gentamicin, and the anti-parasitic drugs include ivermectin or niclofolan.

[0012] Furthermore, the metal introduction needles are arranged in an array on the base, and the lengths of each metal introduction needle are the same.

[0013] Furthermore, the puncture part includes a conical section that annularly inclines along the length direction of the needle body from the second end of the needle body, and the end of the conical section defines a puncture tip for inserting into the subcutaneous tissue of animals.

[0014] A method using the above drug delivery device includes the following steps: loading a water-soluble polymer material loaded with a drug in the concave structure of the metal delivery needle; inserting the metal delivery needle into the subcutaneous tissue of an animal and maintaining it for 0.01 - 0.5 minutes, and the water-soluble polymer material absorbs tissue fluid and swells; pulling out the metal delivery needle, so that the swollen water-soluble polymer material separates from the concave structure under the action of friction with the subcutaneous tissue of the animal and remains in the subcutaneous tissue of the animal. Among them, the metal delivery needle can be directly pulled out after being inserted into the subcutaneous tissue of the animal for 0.01 - 0.5 min without remaining in the animal body.

[0015] Further, the preparation method of the water-soluble polymer material includes the following steps: adding a water-soluble polymer monomer, an initiator, a cross-linking agent and an auxiliary agent into a solvent in proportion, stirring and mixing to form a precursor solution; through heat curing or photoinitiation, the precursor solution undergoes a polymerization reaction to form a high molecular hydrogel, and a drug is loaded in the high molecular hydrogel; pouring the high molecular hydrogel into a mold to make it shaped to obtain a water-soluble polymer material.

[0016] Further, the water-soluble polymer monomer includes one or more of acrylic acid, acrylamide, hyaluronic acid, a combination of acrylamide and sodium acrylate, and polysialic acid; the initiator includes one or more of ammonium persulfate and lithium phenyl-2,4,6-trimethylbenzoylphosphinate; the cross-linking agent is N,N'-methylenebisacrylamide; the solvent is deionized water.

[0017] The present invention has the following advantages:

[0018] 1. The drug delivery device of the present invention loads a drug-carrying water-soluble polymer material through a concave structure, and cooperates with the insertion of a metal delivery needle to achieve subcutaneous implantation of a high-precision drug dose. The water-soluble polymer material swells and remains in the subcutaneous tissue after absorbing tissue fluid, and can release the drug slowly for a long time, overcoming the problems that traditional syringes are difficult to achieve high-precision dose release and long-term drug administration, ensuring stable drug concentration in the animal body, and improving the treatment effect.

[0019] 2. The metal delivery needle of the present invention has high strength and is not easy to break. Its puncture part has strong penetration and controllable penetration depth, and can accurately implant the drug in the deep subcutaneous tissue. The metal delivery needles can be used individually or arranged in multiple arrays to improve the drug delivery efficiency, and the length of the metal needle can be customized according to actual needs to enhance the applicability of the device.

[0020] 3. The water-soluble polymer material selected by the present invention is a biodegradable water-absorbing and swelling hydrogel with good biocompatibility, which can be completely degraded after completing the drug slow-release task and will not cause residual harm to the animal body. At the same time, the release rate of the drug can be controlled by adjusting the structure of the polymer material to meet the requirements of different drugs and treatment scenarios.

[0021] 4. The drug delivery device of the present invention is easy to use. The metal delivery needle only needs to be inserted into the subcutaneous tissue of the animal for 0.01 - 0.5 minutes and then can be withdrawn, without complex operations and long waiting times. Compared with the traditional method of subcutaneous implantation of high - molecular sustained - release drugs that requires surgical incision and suture of the skin, it simplifies the operation process, reduces trauma and stress response to the animal, also reduces the risk of infection, and improves the drug - administration efficiency during the breeding process. Brief Description of the Drawings

[0022] Figure 1 is a three - dimensional structural schematic diagram of the drug delivery device of the present invention.

[0023] Figure 2 is a three - dimensional partial schematic diagram of the metal delivery needle and the water - soluble polymer material of the present invention.

[0024] Figure 3 is a three - dimensional partial schematic diagram of the metal delivery needle of the present invention.

[0025] Figure 4 is a sectional view of the drug delivery device of the present invention.

[0026] Figure 5 is a structural schematic diagram when the drug delivery device of the present invention is inserted into the subcutaneous tissue of the animal.

[0027] Figure 6 is a structural schematic diagram when the water - soluble polymer material expands when the drug delivery device of the present invention is inserted into the subcutaneous tissue of the animal.

[0028] Figure 7 is a structural schematic diagram when the water - soluble polymer material remains in the drug delivery device when it is withdrawn from the subcutaneous tissue of the animal.

[0029] Wherein, 1 is the base, 2 is the metal delivery needle, 201 is the needle body, 202 is the puncture part, 202a is the conical section, 202b is the puncture tip, 203 is the concave structure, 203a is the groove, 3 is the water - soluble polymer material, and 4 is the subcutaneous tissue of the animal. Detailed Description of the Invention

[0030] The present invention will be further described in detail below in conjunction with embodiments, but the implementation manners of the present invention are not limited thereto. Unless otherwise specified, the reagents, methods, and equipment used in the present invention are conventional reagents, methods, and equipment in the technical field. The test methods without specific experimental conditions noted in the following embodiments are usually carried out under conventional experimental conditions. Unless otherwise specified, the reagents and raw materials used in the present invention can be obtained commercially. Among them, acrylic acid, ammonium persulfate, sodium dodecyl sulfate, N,N'-methylenebisacrylamide, acrylamide, sodium acrylate, and N,N,N',N'-tetramethylethylenediamine are from Macklin, and lithium phenyl-2,4,6-trimethylbenzoylphosphinate is selected from Bidepharm.

[0031] Referring to Figures 1-4 , which shows one embodiment of a drug delivery device for animal subcutaneous tissue. The device mainly includes a base 1 and a metal delivery needle 2, which together achieve an efficient and precise drug delivery function. The base 1 is arranged horizontally as a whole. The upper part of the base 1 is detachably connected to a carrier, and the carrier can be a handle, a robotic arm, etc. The user can flexibly select and assemble according to specific usage scenarios and requirements. The detachable connection method can be snap connection, buckle connection, bolt connection, magnetic attraction connection, etc.

[0032] The metal delivery needle 2 is fixed to the lower part of the base 1. The metal delivery needle 2 includes a needle body 201. The first end of the needle body 201 is fixed to the base 1, and the second end of the needle body 201 extends vertically from the base 1 and has a puncture part 202 for inserting into the animal subcutaneous tissue 4. The length of the metal delivery needle 2 is 1.5 - 5 cm, and the diameter is 0.2 - 0.5 mm. The relatively small size of the metal delivery needle 2 is suitable for small animals such as pet cats, pet dogs, and poultry, which can reduce the trauma to the animals and accurately deliver the drug to the subcutaneous tissue. The relatively large size is suitable for large animals such as pigs, cows, and horses to ensure that it can penetrate the thicker skin and subcutaneous tissue and accurately deliver the drug to the target position.

[0033] An inward concave structure 203 is formed on the circumferential wall of the needle body 201. The inward concave structure 203 is located near the puncture part 202. Specifically, the distance between the inward concave structure 203 and the puncture part 202 is 0.5 - 1.5 cm, so that when the metal delivery needle 2 is inserted into the animal subcutaneous tissue 4, the water-soluble polymer material 3 in the inward concave structure 203 can quickly contact the tissue fluid. And the water-soluble polymer material 3 can be detachably loaded inside the inward concave structure 203, ensuring that the water-soluble polymer material 3 can be placed in the inward concave structure 203 when not swollen, providing a stable accommodation space, and can be smoothly separated from the inward concave structure 203 after swelling.

[0034] Among them, the water-soluble polymer material 3 is a biodegradable water-absorbing and swelling hydrogel, which includes one or more of polyacrylic acid, polyacrylamide, hyaluronic acid, poly(acrylamide-sodium acrylate), or polysialic acid. For example, polyacrylic acid has strong water absorption and good biocompatibility, can quickly absorb a large amount of tissue fluid and swell into a soft gel-like shape, providing a stable carrier for the loading and release of drugs; polyacrylamide has high mechanical strength and stability, can maintain a certain shape after swelling and is not easy to break, which helps to retain the drug intact in the subcutaneous tissue and achieve slow release; hyaluronic acid itself is a natural substance existing in animals, has excellent biocompatibility and moisturizing properties, can reduce the stimulation to animal tissues, and at the same time promote tissue repair and regeneration, improving the therapeutic effect of drugs. The above water-soluble polymer material 3 can be selected as a single component or a combination of multiple components according to the specific drug properties, treatment needs and physiological characteristics of the animal to achieve the best therapeutic effect.

[0035] The water-soluble polymer material 3 is loaded with drugs. Among them, the drugs include antibiotic drugs, anti-parasitic drugs or glucocorticoid drugs. The antibiotic drugs include oxytetracycline, ampicillin or gentamicin. Oxytetracycline is used to treat diseases such as respiratory tract infections and intestinal infections. Ampicillin is used to treat infectious diseases such as pneumonia and urethritis in animals. Gentamicin is used to treat serious infectious diseases such as septicemia and peritonitis in animals. The anti-parasitic drugs include ivermectin or niclofolan. Ivermectin is used to prevent and treat parasite infections such as roundworms and scab mites in livestock. Niclofolan is used to treat animal fasciola hepatica infections. By loading the drug in the water-soluble polymer material 3 and introducing it into the subcutaneous tissue 4 of the animal by using the concave structure 203, the slow release of the drug can be achieved, the action time of the drug in the animal body can be prolonged, the therapeutic effect of the drug can be improved, and at the same time the frequency and dose of drug use can be reduced, and the side effects of the drug on the animal can be reduced.

[0036] During actual use, when the puncturing part 202 of the metal introducing needle 2 is inserted into the subcutaneous tissue 4 of an animal, the water-soluble polymer material 3 contacts the tissue fluid in the animal body through the puncturing part 202. Due to its good water absorbency, it will quickly absorb the tissue fluid and expand. After being placed for a certain period of time, the operator pulls out the needle body 201. A relatively large frictional force will be generated between the expanded water-soluble polymer material 3 and the subcutaneous tissue 4 of the animal. Under the action of this frictional force, the water-soluble polymer material 3 is smoothly separated from the concave structure 203 and then remains in the subcutaneous tissue 4 of the animal. As time goes by, the water-soluble polymer material 3 remaining in the subcutaneous tissue will gradually degrade, and at the same time, the loaded drug will be slowly and continuously released into the animal body to achieve the long-acting therapeutic effect of the drug. The metal introducing needle 2 is inserted deeper into the tissue, and after the water-soluble polymer material 3 expands, the resistance of the tissue fluid can be used to overcome the adhesion between the polymer material and the metal needle.

[0037] Referring to Figure 2 and Figure 3 , the concave structure 203 has a plurality of grooves 203a arranged along the circumferential direction of the needle body 201. The shape of the grooves 203a is wedge-shaped, square, elliptical or the like. In this embodiment, the groove 203a is wedge-shaped. The cross-section of the wedge-shaped groove 203a is a right triangle. The upper end of the wedge-shaped groove 203a extends radially towards the central axis of the needle body 201 to form a structure that blocks the unexpanded water-soluble polymer material 3, and its lower end inclines outwards along the length direction of the needle body 201 towards the puncturing part 202. This inclined surface effectively balances the requirements for fixing and separating the water-soluble polymer material 3.

[0038] Referring to Figures 5-7 , before expansion, the water-soluble polymer material 3 is accommodated in the groove 203a, and its surface is flush with the side wall of the needle body 201. When the metal introducing needle 2 is inserted into the subcutaneous tissue 4 of an animal, the frictional resistance with the surrounding tissue can be reduced, which not only reduces the risk of damage to the animal tissue but also ensures the smoothness of the insertion process, and further ensures that the water-soluble polymer material 3 can be accurately delivered to the target position.

[0039] During the whole process from the initial state of the device until it is inserted into the subcutaneous tissue 4 of the animal, due to the certain blocking force at the upper end where the wedge-shaped groove 203a extends radially to the central axis of the needle body 201, the water-soluble polymer material 3 can be relatively stably fixed in the groove 203a, effectively preventing it from accidentally detaching during the insertion process.

[0040] After the needle body 201 is inserted into the subcutaneous tissue 4 of the animal, the water-soluble polymer material 3 contacts the tissue fluid, quickly absorbs water and starts to expand. As the expansion process progresses, the water-soluble polymer material 3 will protrude from the groove 203a to the outside of the needle body 201.

[0041] When the metal introduction needle 2 needs to be pulled out, the inclined surface of the wedge-shaped groove 203a forms a smooth transition with the water-soluble polymer material 3, without hindering the expanded water-soluble polymer material 3. At the same time, a certain resistance is generated between the protruding part of the water-soluble polymer material 3 and the animal subcutaneous tissue 4. Under the action of this resistance, the water-soluble polymer material 3 can stay in the subcutaneous tissue smoothly, while the metal introduction needle 2 can be smoothly pulled out from the subcutaneous tissue, thus completing the separation process of the water-soluble polymer material 3 and the groove 203a, and leaving the water-soluble polymer material 3 loaded with drugs in the animal subcutaneous tissue 4, avoiding problems such as material residue or damage to the subcutaneous tissue. Finally, the drug water detaches from the water-soluble polymer material 3 and is gradually released into the tissue.

[0042] Among them, the number of the metal introduction needles 2 can be one or more, that is, they can be used alone or multiple needles can be used synchronously. In this embodiment, the number of the metal introduction needles 2 is eight. The eight metal introduction needles 2 are arranged in an array on the base 1, and the length of each metal introduction needle 2 is the same, and the insertion depth is kept consistent, so that the water-soluble polymer material 3 carried by each needle body 201 can be delivered to the same subcutaneous depth position, ensuring the uniformity and effectiveness of drug introduction.

[0043] In an embodiment not shown, the concave structure 203 has a plurality of grooves 203a arranged along the circumferential direction of the needle body 201. The plurality of grooves 203a are connected in series to define an annular groove. The shape of the annular groove can also be wedge-shaped, square or elliptical, etc., so that the water-soluble polymer material 3 can be integrally filled in the annular groove.

[0044] Refer to Figure 2 and Figure 3 , the puncture part 202 includes a conical section 202a that is annularly inclined along the length direction of the needle body 201 from the second end of the needle body 201, and is annularly symmetrically inclined with respect to the central axis of the needle body 201. The end of the conical section 202a defines a puncture tip 202b for inserting into the animal subcutaneous tissue 4.

[0045] The following is a specific embodiment description of using the drug introduction device for different animals.

[0046] Embodiment 1

[0047] The animal is selected from a domestic chicken. A metal introduction needle 2 with a length of 1.5 cm and a diameter of 0.2 mm is made through a mold, and the distance between the concave structure 203 and the puncture part 202 is 0.5 cm.

[0048] The concave structure 203 is loaded with polyacrylic acid hydrogel. The specific preparation method of polyacrylic acid hydrogel is as follows: a one-pot method is used to prepare PAA resin emulsion, 2g of acrylic acid monomer is weighed, 0.15g of initiator ammonium persulfate (APS), 0.01g of emulsifier sodium dodecyl sulfate (SDS) are added, and 0.5mL of deionized water is added to react to obtain PAA resin emulsion. Subsequently, 0.02g of crosslinking agent N,N'-methylenebisacrylamide (MBA) is added to the prepared PAA resin emulsion, and heat curing treatment is performed for 2h to finally obtain polyacrylic acid (PAA) hydrogel.

[0049] 0.02 g of antibiotic oxytetracycline was uniformly loaded into the prepared polyacrylic acid hydrogel.

[0050] The prepared metal introduction needle 2 loaded with oxytetracycline-loaded polyacrylic acid hydrogel was inserted into the subcutaneous tissue of the domestic chicken and kept for 0.5 minutes after insertion to ensure that the polyacrylic acid hydrogel had enough time to absorb tissue fluid and fully swell. After that, the metal introduction needle 2 was slowly removed.

[0051] During the insertion of the metal introduction needle 2, the polyacrylic acid hydrogel loaded in the concave structure 203 fully contacts the subcutaneous tissue fluid of the domestic chicken and absorbs water, and expands rapidly. When the metal introduction needle 2 is pulled out, the expanded polyacrylic acid hydrogel is smoothly detached from the surface of the metal introduction needle 2 due to the resistance of the tissue fluid and the friction between the polyacrylic acid hydrogel and the subcutaneous tissue, and is successfully retained in the subcutaneous tissue of the domestic chicken.

[0052] Example 2

[0053] The animal is selected from a domestic pig, and a metal introduction needle 2 with a length of 2 cm and a diameter of 0.3 mm is manufactured by a mold, and the distance between the concave structure 203 and the puncture part 202 is 0.5 cm.

[0054] The concave structure 203 is loaded with polyacrylamide hydrogel. The specific preparation method of polyacrylamide hydrogel is as follows: first, accurately weigh 2g acrylamide (AM), 0.15g ammonium persulfate (APS) and 0.05g N,N'-methylenebisacrylamide (MBA), and add these substances to 9.9mL deionized water in turn, and mix them evenly by stirring them thoroughly. After being completely mixed, add 0.1mL N,N,N',N'-tetramethylethylenediamine (TMEDA) and continue stirring to ensure that all ingredients react fully. Subsequently, in order to ensure the reaction effect and the quality of hydrogel molding, the obtained precursor solution is quickly transferred to the corresponding customized mold prepared in advance, and finally the polyacrylamide hydrogel is obtained.

[0055] 0.05 g of the antiparasitic drug ivermectin was uniformly loaded into the prepared polyacrylamide hydrogel.

[0056] Insert the metal introduction needle 2 prepared and loaded with ivermectin-loaded polyacrylamide hydrogel into the subcutaneous tissue of a domestic pig, and keep it for 0.5 min after insertion to ensure that the polyacrylamide hydrogel has enough time to absorb tissue fluid and fully expand. Then, slowly remove the metal introduction needle 2.

[0057] During the insertion of the metal introduction needle 2, the polyacrylamide hydrogel loaded in the concave structure 203 is in full contact with the subcutaneous tissue fluid of the domestic pig and absorbs water, expanding rapidly. When the metal introduction needle 2 is pulled out, the expanded polyacrylamide hydrogel is subjected to the resistance of the tissue fluid and the frictional force between it and the subcutaneous tissue, and smoothly detaches from the surface of the metal introduction needle 2 and is successfully retained in the subcutaneous tissue of the domestic pig.

[0058] Example 3

[0059] The animals were selected from domestic pigs, and a metal introduction needle 2 with a length of 3 cm and a diameter of 0.3 mm was made through a mold. The distance between the concave structure 203 and the puncture part 202 was 0.5 cm.

[0060] The concave structure 203 was loaded with hyaluronic acid hydrogel. The specific preparation method of the hyaluronic acid hydrogel was as follows: Weigh 1 g of methacrylated hyaluronic acid (HAMA) and add it to 10 mL of deionized water containing 0.01 g of photoinitiator lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP). Stir well to completely dissolve and uniformly mix HAMA and LAP in deionized water, and then use photoinitiated free radical copolymerization reaction to obtain hyaluronic acid hydrogel.

[0061] Uniformly load 1 g of the antibiotic ampicillin into the prepared hyaluronic acid hydrogel.

[0062] Insert the metal introduction needle 2 prepared and loaded with ampicillin-loaded hyaluronic acid hydrogel into the subcutaneous tissue of a domestic pig, and keep it for 0.5 min after insertion to ensure that the hyaluronic acid hydrogel has enough time to absorb tissue fluid and fully expand. Then, slowly remove the metal introduction needle 2.

[0063] During the insertion of the metal introduction needle 2, the hyaluronic acid hydrogel loaded in the concave structure 203 is in full contact with the subcutaneous tissue fluid of the domestic pig and absorbs water, expanding rapidly. When the metal introduction needle 2 is pulled out, the expanded hyaluronic acid hydrogel is subjected to the resistance of the tissue fluid and the frictional force between it and the subcutaneous tissue, and smoothly detaches from the surface of the metal introduction needle 2 and is successfully retained in the subcutaneous tissue of the domestic pig.

[0064] Example 4

[0065] The animal is selected from domestic cattle, and a metal introduction needle 2 with a length of 5 cm and a diameter of 0.5 mm is manufactured by a mold, and the distance between the concave structure 203 and the puncture part 202 is 0.5 cm.

[0066] The concave structure 203 is loaded with polyacrylamide hydrogel. The specific preparation method of polyacrylamide hydrogel is as follows: first, accurately weigh 2g acrylamide (AM), 0.15g ammonium persulfate (APS) and 0.05g N,N'-methylenebisacrylamide (MBA), and add these substances to 9.9mL deionized water in turn, and mix them evenly by stirring them thoroughly. After being completely mixed, add 0.1mL N,N,N',N'-tetramethylethylenediamine (TMEDA) and continue stirring to ensure that all ingredients react fully. Subsequently, in order to ensure the reaction effect and the quality of hydrogel molding, the obtained precursor solution is quickly transferred to the corresponding customized mold prepared in advance, and finally the polyacrylamide hydrogel is obtained.

[0067] 0.05 g of antibiotic gentamicin was uniformly loaded into the prepared polyacrylamide hydrogel.

[0068] The prepared metal introduction needle 2 loaded with gentamicin-loaded polyacrylamide hydrogel was inserted into the subcutaneous tissue of the domestic cattle and kept for 0.5 minutes after insertion to ensure that the polyacrylamide hydrogel had enough time to absorb tissue fluid and fully swell. Afterwards, the metal introduction needle 2 was slowly removed.

[0069] During the insertion of the metal introduction needle 2, the polyacrylamide hydrogel loaded in the concave structure 203 fully contacts the subcutaneous tissue fluid of the domestic cattle and absorbs water, and expands rapidly. When the metal introduction needle 2 is pulled out, the expanded polyacrylamide hydrogel is smoothly detached from the surface of the metal introduction needle 2 due to the resistance of the tissue fluid and the friction between the subcutaneous tissue and the subcutaneous tissue, and is successfully retained in the subcutaneous tissue of the domestic cattle.

[0070] Example 5

[0071] The animal is selected from domestic cattle, and a metal introduction needle 2 with a length of 2 cm and a diameter of 0.5 mm is manufactured by a mold, and the distance between the concave structure 203 and the puncture part 202 is 0.5 cm.

[0072] The concave structure 203 is loaded with polysialic acid hydrogel, and the specific preparation method of the polysialic acid hydrogel is as follows: 1g of methacryloyl polysialic acid (PSAMA) is weighed and added to 10mL of deionized water containing 0.01g of photoinitiator phenyl-2,4,6-trimethylbenzoyl lithium phosphinate (LAP). The PSAMA and LAP are fully stirred to completely dissolve and evenly mix in the deionized water, and then a free radical copolymerization reaction is initiated by light to cause polymerization and cross-linking between PSAMA molecules to obtain the polysialic acid hydrogel.

[0073] 0.05 g of the glucocorticoid drug dexamethasone was evenly loaded into the prepared poly(sialic acid) hydrogel.

[0074] The metal introduction needle 2 loaded with the poly(sialic acid) hydrogel loaded with dexamethasone was inserted into the subcutaneous tissue of a domestic cow and kept for 0.5 min after insertion to ensure that the poly(sialic acid) hydrogel had enough time to absorb tissue fluid and fully expand. Then, the metal introduction needle 2 was slowly removed.

[0075] During the insertion of the metal introduction needle 2, the poly(sialic acid) hydrogel loaded in the concave structure 203 was in full contact with the subcutaneous tissue fluid of the domestic cow and absorbed water, swelling rapidly. When the metal introduction needle 2 was pulled out, the swollen poly(sialic acid) hydrogel was subjected to the resistance of the tissue fluid and the frictional force with the subcutaneous tissue, smoothly detached from the surface of the metal introduction needle 2, and successfully retained in the subcutaneous tissue of the domestic cow.

[0076] Example 6

[0077] The animal was selected from domestic sheep. A metal introduction needle 2 with a length of 2 cm and a diameter of 0.3 mm was fabricated through a mold, and the distance between the concave structure 203 and the puncture part 202 was 0.5 cm.

[0078] The concave structure 203 was loaded with poly(acrylic acid) hydrogel. The specific preparation method of the poly(acrylic acid) hydrogel was as follows: The PAA resin emulsion was prepared by the one-pot method. 2 g of acrylic acid monomer was weighed, and 0.15 g of initiator ammonium persulfate (APS), 0.01 g of emulsifier sodium dodecyl sulfate (SDS) were added simultaneously, and 0.5 mL of deionized water was added for reaction to obtain the PAA resin emulsion. Subsequently, 0.02 g of crosslinking agent N,N'-methylenebisacrylamide (MBA) was added to the obtained PAA resin emulsion, and heat curing treatment was carried out for 2 h to finally obtain poly(acrylic acid) (PAA) hydrogel.

[0079] 0.02 g of the antibiotic ampicillin was evenly loaded into the prepared poly(acrylic acid) hydrogel.

[0080] The metal introduction needle 2 loaded with the poly(acrylic acid) hydrogel loaded with ampicillin was inserted into the subcutaneous tissue of a domestic sheep and kept for 0.5 min after insertion to ensure that the poly(acrylic acid) hydrogel had enough time to absorb tissue fluid and fully expand. Then, the metal introduction needle 2 was slowly removed.

[0081] During the insertion of the metal introduction needle 2, the polyacrylic acid hydrogel loaded in the concave structure 203 comes into full contact with the subcutaneous tissue fluid of the domestic sheep and absorbs water, swelling rapidly. When the metal introduction needle 2 is withdrawn, the swollen polyacrylic acid hydrogel is subjected to the resistance of the tissue fluid and the frictional force between it and the subcutaneous tissue, and smoothly detaches from the surface of the metal introduction needle 2 and is successfully retained in the subcutaneous tissue of the domestic sheep.

[0082] Example 7

[0083] The animal was selected from domestic sheep, and a metal introduction needle 2 with a length of 3 cm and a diameter of 0.3 mm was fabricated through a mold. The distance between the concave structure 203 and the puncture part 202 was 0.5 cm.

[0084] The poly(acrylamide-sodium acrylate) hydrogel was loaded in the concave structure 203. The specific preparation method of the poly(acrylamide-sodium acrylate) hydrogel was as follows: First, 0.9 g of acrylamide (AM) and 0.6 g of sodium acrylate (SAA) were weighed and added to 8.5 mL of deionized water, and continuously stirred for 30 min until completely miscible to form a uniform mixed solution. Then, 18 mg of crosslinking agent N,N'-methylenebisacrylamide (MBA) and 15 mg of photoinitiator lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP) were added to the mixed solution. To avoid the interference of light on the reaction, it was stirred for 30 min under dark conditions to completely dissolve each component. Subsequently, the solution was irradiated under a UV lamp with a wavelength of 405 nm for 3 min to initiate the polymerization reaction, and finally the poly(acrylamide-sodium acrylate) hydrogel was obtained.

[0085] 0.5 g of anthelmintic niclofolan was uniformly loaded into the prepared poly(acrylamide-sodium acrylate) hydrogel.

[0086] The metal introduction needle 2 loaded with the poly(acrylamide-sodium acrylate) hydrogel loaded with niclofolan was inserted into the subcutaneous tissue of the domestic sheep and kept for 0.5 min after insertion to ensure that the poly(acrylamide-sodium acrylate) hydrogel had enough time to absorb the tissue fluid and swell fully. Then, the metal introduction needle 2 was slowly removed.

[0087] During the insertion of the metal introduction needle 2, the poly(acrylamide-sodium acrylate) hydrogel loaded in the concave structure 203 comes into full contact with the subcutaneous tissue fluid of the domestic sheep and absorbs water, swelling rapidly. When the metal introduction needle 2 is withdrawn, the swollen poly(acrylamide-sodium acrylate) hydrogel is subjected to the resistance of the tissue fluid and the frictional force between it and the subcutaneous tissue, and smoothly detaches from the surface of the metal introduction needle 2 and is successfully retained in the subcutaneous tissue of the domestic sheep.

[0088] Effect verification

[0089] In vitro porcine skin penetration test

[0090] Select a complete piece of pigskin, clean the impurities, hair, etc. on its surface to ensure that the surface of the pigskin is clean and flat, simulating the natural state of animal skin. Prepare the metal introduction needle 2 prepared in Example 2, as well as a traditional syringe and polymer microneedles. Vertically align these three instruments with the same area of the pigskin and perform puncture operations in sequence. When puncturing, apply the same force to each instrument, and keep pressing for about 5 s and then pull out. After the puncture is completed, observe the situation on the surface of the pigskin. It can be seen that the metal introduction needle 2 of Example 2 punctured clear and fine holes on the pigskin, indicating that the metal introduction needle 2 has good puncture performance and can penetrate with a smaller wound; although the traditional syringe can also pierce the pigskin, the resulting wound is significantly larger, which may bring more trauma and infection risks to the animal; while the polymer microneedles are difficult to penetrate deep into the pigskin during the puncture process, indicating that there are certain limitations in penetrating thicker skin.

[0091] Long-acting drug release test

[0092] In order to accurately test the long-acting drug release performance, in vivo degradation tests were carried out on various hydrogels prepared in Examples 1-7, and during the test, the degradation conditions of different hydrogels in vivo were monitored. The results showed that the degradation rate of the polyacrylic acid hydrogel was relatively fast and was basically completed within four weeks; the degradation rate of the hyaluronic acid hydrogel was slow and only partial degradation was completed; for the polysialic acid hydrogel, during the 21-day test period, although its degradation rate increased, it was always less than 0.1%, enabling it to achieve long-acting drug release. In addition, the degradation rates of the polyacrylamide hydrogel and the poly(acrylamide-sodium acrylate) hydrogel were also slow, and they also had the potential to achieve long-acting drug release. This fully demonstrates that the hydrogels prepared in each example of the present invention have excellent performance in long-acting drug release.

[0093] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principle of the present invention shall be equivalent replacement methods and are all included in the protection scope of the present invention.

Claims

1. A drug introduction device for animal subcutaneous tissue, characterized in that, Comprising: A horizontally arranged base; A metal introduction needle, the metal introduction needle includes a needle body, the first end of the needle body is fixed on the base, the second end of the needle body extends vertically from the base and has a puncture part for inserting into the subcutaneous tissue of an animal, and a concave structure is formed on the circumferential wall of the needle body, the concave structure is located near the puncture part, and a water-soluble polymer material is detachably loaded inside it, and the water-soluble polymer material is loaded with a drug; Wherein, the water-soluble polymer material is placed into the subcutaneous tissue of the animal through the puncture part and absorbs tissue fluid to expand. When the needle body is withdrawn, the expanded water-soluble polymer material is separated from the concave structure under the action of the frictional force between it and the subcutaneous tissue of the animal, so as to be retained in the subcutaneous tissue of the animal.

2. The drug delivery device for animal subcutaneous tissue according to claim 1, characterized in that, The concave structure has a plurality of grooves arranged along the circumferential direction of the needle body; the shape of the grooves is wedge-shaped, square or elliptical.

3. The drug introduction device for animal subcutaneous tissue according to claim 2, characterized in that, The groove is wedge-shaped, the upper end of the wedge-shaped groove extends radially towards the central axis of the needle body, and its lower end inclines outwards along the length direction of the needle body towards the puncture part.

4. The drug introduction device for animal subcutaneous tissue according to claim 1, wherein, The water-soluble polymer material is a biodegradable water-absorbing and swelling hydrogel, which includes one or more of polyacrylic acid, polyacrylamide, hyaluronic acid, poly(acrylamide-sodium acrylate) or polysialic acid.

5. A drug introduction device for animal subcutaneous tissue according to claim 1, characterized in that, The drug includes an antibiotic drug or an anti-parasitic drug, the antibiotic drug includes oxytetracycline, ampicillin or gentamicin, and the anti-parasitic drug includes ivermectin or niclofolan.

6. The drug delivery device for animal subcutaneous tissue according to claim 1, wherein, The metal introduction needles are arranged in an array on the base, and the length of each metal introduction needle is the same.

7. The drug introduction device for animal subcutaneous tissue according to claim 1, characterized in that, The puncture part includes a conical section that annularly inclines along the length direction of the needle body from the second end of the needle body, and the end of the conical section defines a puncture tip for inserting into the subcutaneous tissue of the animal.

8. A method of using a drug delivery device according to any one of claims 1 to 7, characterized in that, Including the following steps: Loading a water-soluble polymer material loaded with a drug into the concave structure of the metal introduction needle; Inserting the metal introduction needle into the subcutaneous tissue of the animal and maintaining for 0.01 - 0.5 minutes, and the water-soluble polymer material absorbs tissue fluid and expands; Withdrawing the metal introduction needle, so that the expanded water-soluble polymer material is separated from the concave structure under the action of the frictional force between it and the subcutaneous tissue of the animal, and is retained in the subcutaneous tissue of the animal.

9. The import method according to claim 8, characterized in that The preparation method of the water-soluble polymer material includes the following steps: Adding a water-soluble polymer monomer, an initiator, a cross-linking agent and an auxiliary agent into a solvent in proportion, and stirring and mixing to form a precursor solution; Through thermal curing or photo-initiation, the precursor solution undergoes a polymerization reaction to form a polymer hydrogel, and a drug is loaded in the polymer hydrogel; Pouring the polymer hydrogel into a mold to make it molded to obtain a water-soluble polymer material.

10. The import method according to claim 9, wherein, The water-soluble polymer monomers include one or more of acrylic acid, acrylamide, hyaluronic acid, a combination of acrylamide and sodium acrylate, and polysialic acid; the initiators include one or more of ammonium persulfate and lithium phenyl-2,4,6-trimethylbenzoylphosphinate; the crosslinking agent is N,N'-methylenebisacrylamide; and the solvent is deionized water.

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