Soluble microneedle and preparation method thereof

Abstract

The invention discloses a soluble microneedle and a preparation method thereof, the soluble microneedle comprises a needle tip and a substrate, the substrate comprises an upper surface layer, a hollow layer and a lower surface layer; the needle tip consists of an upper needle and a lower needle; the upper surface layer and the lower surface layer of the substrate are both non-ionic high-molecular compounds; the upper needle of the needle tip is made of a hydrophobic organic silicon material, and the lower needle of the needle tip is made of a charged high polymer material; wherein the upper needle is a hollow cylinder, the lower needle is rhombic, the upper needle and the lower needle are in socket connection, and the medicine is arranged in the hollow layer and the lower needle; according to the soluble microneedle provided by the invention, the drug loading capacity of the microneedle can be adjusted according to the requirement of medication metering, and the applicability is high.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and particularly relates to a soluble microneedle and a preparation method thereof. Background Art

[0002] There have been various physical penetration enhancement technologies for promoting transdermal drug delivery, such as microneedles, iontophoresis, sonophoresis, and magnetic field introduction, etc. Compared with before, it may be difficult to control the administration position and dose for other physical penetration enhancement technologies, while microneedles can control the administration site by changing their length, and for soluble microneedles, the administration dose can be precisely controlled by controlling the drug content at the tip of the cast microneedles. Microneedle administration has unique advantages in these two aspects, so the research in the field of microneedles has been increasing year by year. Microneedles are an array combination with multiple micro needles, and the administration effect breaks through that of traditional transdermal drug delivery preparations. Soluble microneedles can be self-degraded after piercing into the skin without causing harmful residues compared with other types of microneedles, and can achieve sustained and controlled release by screening different matrix material ratios, etc., becoming the most studied type of microneedles currently.

[0003] Hollow microneedles (HMNs) play an important role in drug delivery, but most current HMNs are fabricated based on silicon microfabrication (lithography, etching, etc.). Due to the lack of low-cost, batch, and customized preparation methods, especially for HMNs with flexible substrates. HMNs are based on biocompatible materials such as thermosetting polymers or photocurable resins. The thickness and rigidity / flexibility characteristics of the substrate can be customized according to different applications. However, the existing microneedles have a small drug loading capacity, and most of them need to inject the liquid medicine with the help of external equipment, etc. Summary of the Invention

[0004] The purpose of the present invention is to provide a soluble microneedle and a preparation method thereof. The technical problem to be solved is how to provide a soluble microneedle, which can adjust the drug loading capacity of the microneedle according to the requirements of the medication dosage and has strong applicability.

[0005] To achieve the above purpose, the present invention adopts the following technical solutions;

[0006] The present invention provides a soluble microneedle, including a tip and a base. The base includes an upper surface layer, a hollow layer, and a lower surface layer; the tip consists of an upper needle and a lower needle; both the upper surface layer and the lower surface layer of the base are non-ionic macromolecular compounds; the upper needle of the tip is a hydrophobic organosilicon material, and the lower needle is a charged macromolecular material; wherein the upper needle is a hollow cylinder, the lower needle is rhombic, the upper needle and the lower needle are connected by insertion, and the drug is arranged in the hollow layer and / or the lower needle.

[0007] As a preferred embodiment, the lower needle is divided into a hollow drug-loading part and an inserting hollow needle body fixedly connected to the hollow drug-loading part. The diameter of the cross-section of the hollow needle body is smaller than that of the upper needle. The hollow needle body is connected to the upper needle in an inserting manner. The hollow drug-loading part is divided into an upper triangle and a lower triangle, and the upper triangle and the lower triangle are fixedly connected and communicated. The width of the bottom of the upper triangle is smaller than the diameter of the upper needle, and the width of the top of the lower triangle is larger than the diameter of the upper needle.

[0008] As a preferred embodiment, the non-ionic polymer compound is polyvinylpyrrolidone or / and polyethylene oxide.

[0009] As a preferred embodiment, the hydrophobic organosilicon material is polydimethylsiloxane.

[0010] As a preferred embodiment, the charged polymer material is one or more of chitosan, chitosan oligosaccharide, hyaluronic acid, sodium alginate, sodium carboxymethyl cellulose, collagen, gelatin, and gum arabic.

[0011] As a preferred embodiment, the drug is one or more of nucleic acids and their derivatives, degradation products, macromolecular structure modifiers, polypeptide biochemical drugs, enzymes, cytokines, hormones, antibodies, and vaccines;

[0012] The drug is an antibiotic or an analgesic; the antibiotic is a composition of two or one of piperacillin and tazobactam and / or a chelating agent; wherein the chelating agent is ethylenediaminetetraacetic acid or its salt, or ethylenediamine; the analgesic is fentanyl.

[0013] As a preferred embodiment, the drug is a drug for improving psoriasiform inflammation, and the drug is berberine extracted from the bark of Phellodendron amurense.

[0014] As a preferred embodiment, the length and width of the soluble microneedles are both 10 mm, and the height is 2 - 3 mm; the tips of the needles are distributed in a rectangular array, the distance between adjacent microneedles is 50 - 80 μm, and the diameter of the flow channel is 30 - 50 μm.

[0015] In addition, the present invention also provides a preparation method of the soluble microneedles,

[0016] a: Preparation of solutions:

[0017] Dissolve the charged polymer material, adjust the pH, and prepare a lower needle solution; prepare an upper needle solution from the hydrophobic organosilicon material; dissolve the non-ionic polymer compound to prepare a base solution; prepare a drug solution;

[0018] b: Preparation of microneedles:

[0019] (1) Add the upper needle solution to the first microneedle mold, perform the first centrifugation to fill the micropores of the first microneedle mold with the upper needle solution, recover the excess upper needle solution, and then perform the second centrifugation;

[0020] (2) Add the lower needle solution to the lower half of the second microneedle mold to fabricate the hollow drug-loading part. Perform the first centrifugation to fill the micropores in the lower half of the second microneedle mold with the lower needle solution. After recovering the excess lower needle solution, perform the second centrifugation and drying. Add the drug solution to the hollow drug-loading part of the lower needle, and then combine the upper half and the lower half of the second microneedle mold to fill the micropores in the upper half of the second microneedle mold with the lower needle solution. Herein, steps (1) and (2) are completed simultaneously.

[0021] (3) Dry and assemble the microneedles obtained in steps (1) and (2). Connect the first microneedle mold and the second microneedle mold, set the baffle at the top of the first microneedle mold, flip the first microneedle mold and the second microneedle mold, and separate the first microneedle mold and the second microneedle mold from the needle tip.

[0022] (4) Load the defoamed non-ionic polymer compound into the 3D printer cartridge. Under the conditions that the needle aperture is 0.03 mm - 10 mm, the extrusion pressure of the non-ionic polymer compound is 20 Psi - 100 Psi, the lifting speed of the printer needle is 0.5 mm / s - 50 mm / s, and the platform temperature is -15 °C - 50 °C, lift the needle vertically upward, extrude the non-ionic polymer compound to print the upper surface layer and the lower surface layer. With or without adding drugs, print again to seal the upper surface layer and the lower surface layer. Connect the upper needle at the needle tip of step (3) to the lower surface layer and connect it to the lower surface layer of the substrate, and then dry to obtain the soluble microneedles.

[0023] In addition, the present invention also provides another preparation method for the soluble microneedles.

[0024] a: Preparation of solutions:

[0025] Dissolve the charged polymer material, adjust the pH, and prepare the lower needle solution; prepare the upper needle solution from the hydrophobic silicone material; dissolve the non-ionic polymer compound to prepare the substrate solution; and prepare the drug solution into a liquid.

[0026] b: Preparation of microneedles:

[0027] (1) Import the three-dimensional model and print the lower needle

[0028] Load the defoamed lower needle solution into the first cartridge of the 3D printer. Under the conditions that the needle aperture is 0.025 mm - 0.3 mm, the extrusion pressure of the non-ionic polymer compound is 15 Psi - 60 Psi, the lifting speed of the printer needle is 0.5 mm / s - 50 mm / s, and the platform temperature is -15 °C - 50 °C, extrude the lower needle solution to print the lower needle. When printing to 2 / 3 of the lower needle, inject the drug solution, and continue printing the lower needle until the printing is completed. Place it in the second microneedle mold.

[0029] (2) Import the three-dimensional model and print the upper needle;

[0030] Load the degassed upper needle solution into the second cartridge of the 3D printer, and extrude the upper needle solution to print the upper needle under the conditions that the needle aperture is 0.03 mm to 0.3 mm, the extrusion pressure of the non-ionic polymer compound is 20 Psi to 100 Psi, the lifting speed of the printer needle is 0.5 mm / s to 50 mm / s, and the platform temperature is -15 °C to 50 °C; place it in the first microneedle mold;

[0031] (3) Combine the lower needle and the upper needle of steps (1) and (2);

[0032] (4) Load the degassed base solution into the third cartridge of the 3D printer, and under the conditions that the needle aperture is 0.03 mm to 10 mm, the extrusion pressure of the non-ionic polymer compound is 20 Psi to 100 Psi, the lifting speed of the printer needle is 0.5 mm / s to 50 mm / s, and the platform temperature is -15 °C to 50 °C, extrude the base solution to print the upper surface layer and the lower surface layer, with or without adding the medicinal liquid, print again to seal the upper surface layer, connect the upper needle at the tip of step (3) to the lower surface layer, and dry to obtain the soluble microneedles.

[0033] Furthermore, the present invention also provides a microneedle preparation method in which the preparation sequence of the foregoing preparation method of a soluble microneedle is adjusted.

[0034] A preparation method of soluble microneedles, characterized by comprising the following steps:

[0035] a: Preparation of solutions:

[0036] Dissolve the charged polymer material, adjust the pH, and prepare the lower needle solution; prepare the hydrophobic silicone material into the upper needle solution; dissolve the non-ionic polymer compound to prepare the base solution; prepare the drug into the medicinal liquid;

[0037] b: Preparation of microneedles:

[0038] (1) Print the lower surface layer

[0039] Load the degassed base solution into the third cartridge of the 3D printer, and under the conditions that the needle aperture is 0.03 mm to 10 mm, the extrusion pressure of the non-ionic polymer compound is 20 Psi to 100 Psi, the lifting speed of the printer needle is 0.5 mm / s to 50 mm / s, and the platform temperature is -15 °C to 50 °C, extrude the base solution to print the upper surface layer.

[0040] (2) Import the three-dimensional model and print the upper needle;

[0041] Load the degassed upper needle solution into the second cartridge of the 3D printer, and extrude the upper needle solution to print the upper needle under the conditions that the needle aperture is 0.03 mm to 0.3 mm, the extrusion pressure of the non-ionic polymer compound is 20 Psi to 100 Psi, the lifting speed of the printer needle is 0.5 mm / s to 50 mm / s, and the platform temperature is -15°C to 50°C; put it into the first microneedle mold;

[0042] (3) Import the 3D model and print the lower needle

[0043] Load the degassed lower needle solution into the first cartridge of the 3D printer, and extrude the lower needle solution to print the lower needle under the conditions that the needle aperture is 0.025 mm to 0.3 mm, the extrusion pressure of the non-ionic polymer compound is 15 Psi to 60 Psi, the lifting speed of the printer needle is 0.5 mm / s to 50 mm / s, and the platform temperature is -15°C to 50°C. When printing to 2 / 3 of the lower needle, inject the drug solution and continue to print the lower needle until printing is completed; put it into the second microneedle mold;

[0044] Combine the lower needle and the upper needle in steps (2) and (3);

[0045] (4) Print the upper surface layer

[0046] Load the degassed base solution into the third cartridge of the 3D printer, and extrude the base solution to print the upper surface layer under the conditions that the needle aperture is 0.03 mm to 10 mm, the extrusion pressure of the non-ionic polymer compound is 20 Psi to 100 Psi, the lifting speed of the printer needle is 0.5 mm / s to 50 mm / s, and the platform temperature is -15°C to 50°C. Add or do not add the drug solution, and print again to seal the upper surface layer. Connect the upper needle at the tip of step (3) to the lower surface layer, and dry to obtain the soluble microneedle.

[0047] Compared with the prior art, the present invention has the following beneficial effects.

[0048] 1. The microneedles can adjust the drug loading amount of the microneedles according to the requirements of the drug dosage, and add drugs to the hollow layer and / or the lower needle as needed, with strong applicability.

[0049] 2. The soluble microneedles prepared by the present invention are layered microneedles, which can make it easier to control the drug delivery dose of the microneedles and will not cause drug waste.

[0050] 3. The production of the soluble microneedles of the present invention can be achieved by simple centrifugation, drying or directly using 3D printing technology after adding the liquid. By controlling parameters such as the solution concentration of the material and the centrifugation conditions in the preparation process, the effective drug loading amount and mechanical strength of the microneedles can be further improved.

[0051] Other features and advantages of the present invention will be set forth in the following description, and in part will be obvious from the description, or may be learned by practice of the present invention. The main object and other advantages of the present invention can be achieved and obtained by the means particularly pointed out in the description. Description of the Drawings

[0052] The present invention will be further described in detail below with reference to the accompanying drawings.

[0053] Figure 1 is a side schematic view of the present invention.

[0054] Figure 2 is a top view of the present invention with the connection layer removed.

[0055] Reference numerals: 1 - substrate, 1.1 - upper surface layer, 1.2 - hollow layer, 1.3 - lower surface layer, 2 - needle tip, 2.1 - upper needle, 2.2 - lower needle, 2.3 - connection layer; Detailed Description of the Invention

[0056] The present invention will be described in detail below with reference to specific embodiments. The following embodiments will help those skilled in the art to further understand the present invention, but do not limit the present invention in any form. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can be made. These all belong to the protection scope of the present invention.

[0057] Part I: Pharmaceutical Preparation Part

[0058] Example 1

[0059] This example relates to a soluble microneedle, including a needle tip and a substrate. The substrate includes an upper surface layer, a hollow layer, and a lower surface layer. The needle tip is composed of an upper needle and a lower needle. The upper surface layer and the lower surface layer of the substrate are both polyvinylpyrrolidone. The upper needle of the needle tip is polydimethylsiloxane, and the lower needle is chitosan and sodium alginate. The upper needle is a hollow cylinder, the lower needle is diamond-shaped, and the upper needle and the lower needle are connected by insertion. The drug is arranged in the hollow layer and the lower needle. The drug is berberine extracted from Phellodendron amurense Rupr., and the amount of berberine is 12 g.

[0060] A preparation method of a soluble microneedle is as follows.

[0061] a: Preparation of solutions:

[0062] Dissolve the chitosan and sodium alginate, adjust the pH, and prepare the lower needle solution; prepare the upper needle solution from polydimethylsiloxane; dissolve the polyvinylpyrrolidone and prepare the substrate solution; prepare the medicinal solution from berberine extracted from Phellodendron amurense Rupr.

[0063] b: Preparation of microneedles:

[0064] (1) Add the upper needle solution to the first microneedle mold and centrifuge for the first time to fill the micropores of the first microneedle mold with the upper needle solution. After recovering the excess upper needle solution, perform a second centrifugation.

[0065] (2) Add the lower needle solution to the lower half of the second microneedle mold to fabricate the hollow drug-loading part. Centrifuge for the first time to fill the micropores of the lower half of the second microneedle mold with the lower needle solution. After recovering the excess lower needle solution, perform a second centrifugation and drying. Add the drug solution to the hollow drug-loading part of the lower needle, and then combine the upper half and the lower half of the second microneedle mold to fill the micropores of the upper half of the second microneedle mold with the lower needle solution. Herein, steps (1) and (2) are completed simultaneously.

[0066] (3) Dry and assemble the microneedles obtained in steps (1) and (2). Connect the first microneedle mold and the second microneedle mold, set the baffle at the top of the first microneedle mold, and then turn the first microneedle mold and the second microneedle mold over so that the first microneedle mold and the second microneedle mold are separated from the needle tip.

[0067] (4) Load the defoamed polyvinylpyrrolidone into the 3D printer cartridge. Under the conditions that the needle aperture is 0.03 mm to 10 mm, the extrusion pressure of polyvinylpyrrolidone is 20 Psi to 100 Psi, the lifting speed of the printer needle is 0.5 mm / s to 50 mm / s, and the platform temperature is -15 °C to 50 °C, lift the needle vertically upward. Extrude and print the upper surface layer and the lower surface layer with polyvinylpyrrolidone, with or without adding drugs. Print again to seal the upper surface layer and the lower surface layer. Connect the upper needle of the needle tip obtained in step (3) to the lower surface layer and connect it to the lower surface layer of the substrate, and then dry to obtain the soluble microneedles.

[0068] Example 2

[0069] This example relates to a soluble microneedle, which includes a needle tip and a substrate. The substrate includes an upper surface layer, a hollow layer, and a lower surface layer; the needle tip is composed of an upper needle and a lower needle; the upper surface layer and the lower surface layer of the substrate are both polyethylene oxide; the upper needle of the needle tip is polydimethylsiloxane, and the lower needle is sodium carboxymethylcellulose and gelatin; wherein the upper needle is a hollow cylinder, the lower needle is diamond-shaped, the upper needle and the lower needle are connected by socket connection, and the drug is arranged in the hollow layer and the lower needle; the drug is berberine extracted from Phellodendron amurense bark, and the amount of berberine is 8 g.

[0070] A preparation method of the soluble microneedle is as follows.

[0071] a: Preparation of solutions:

[0072] Dissolve the sodium carboxymethylcellulose and gelatin, adjust the pH to prepare the lower needle solution; prepare the upper needle solution with polydimethylsiloxane; dissolve the polyethylene oxide to prepare the substrate solution; prepare the drug solution with berberine extracted from Phellodendron amurense bark.

[0073] b: Preparation of microneedles:

[0074] (1) Import a 3D model and print the lower needle

[0075] Load the degassed lower needle solution into the first cartridge of the 3D printer, and extrude the lower needle solution to print the lower needle under the conditions that the needle aperture is 0.025 mm to 0.3 mm, the polyethylene oxide extrusion pressure is 15 Psi to 60 Psi, the printer needle lifting speed is 0.5 mm / s to 50 mm / s, and the platform temperature is -15°C to 50°C. When printing to 2 / 3 of the lower needle, inject the medicinal liquid, and continue printing the lower needle until printing is completed; place it in the second microneedle mold;

[0076] (2) Import a 3D model and print the upper needle;

[0077] Load the degassed upper needle solution into the second cartridge of the 3D printer, and extrude the upper needle solution to print the upper needle under the conditions that the needle aperture is 0.03 mm to 0.3 mm, the polyethylene oxide extrusion pressure is 20 Psi to 100 Psi, the printer needle lifting speed is 0.5 mm / s to 50 mm / s, and the platform temperature is -15°C to 50°C; place it in the first microneedle mold;

[0078] (3) Combine the lower needle and the upper needle in steps (1) and (2);

[0079] (4) Load the degassed base solution into the third cartridge of the 3D printer, and under the conditions that the needle aperture is 0.03 mm to 10 mm, the polyethylene oxide extrusion pressure is 20 Psi to 100 Psi, the printer needle lifting speed is 0.5 mm / s to 50 mm / s, and the platform temperature is -15°C to 50°C, extrude the base solution to print the upper surface layer and the lower surface layer, with or without adding the medicinal liquid, and print again to seal the upper surface layer. Connect the upper needle at the tip of step (3) to the lower surface layer, and dry to obtain the soluble microneedle.

[0080] In addition, the preparation steps of the microneedles can also be carried out in the following order: first prepare the lower surface layer and the upper needle, then prepare the lower needle, and finally prepare the upper surface layer. The rest is the same as the foregoing preparation methods in Example 1 and Example 2, only the order of the preparation steps is adjusted.

[0081] Example 3

[0082] This example relates to a soluble microneedle, including a tip and a base. The base includes an upper surface layer, a hollow layer, and a lower surface layer; the tip is composed of an upper needle and a lower needle; the upper surface layer and the lower surface layer of the base are both polyvinylpyrrolidone; the upper needle of the tip is a hydrophobic silicone material, and the lower needle is chitosan and sodium alginate; among them, the upper needle is a hollow cylinder, the lower needle is diamond-shaped, the upper needle and the lower needle are connected by socket connection, and the drug is arranged in the hollow layer and the lower needle; the drug is a Japanese encephalitis vaccine microneedle;

[0083] A preparation method of soluble microneedles is as follows.

[0084] a: Preparation of solutions:

[0085] Dissolve the chitosan and sodium alginate, adjust the pH, and prepare the lower needle solution; prepare the upper needle solution from the hydrophobic organosilicon material; dissolve the polyvinylpyrrolidone to prepare the base solution; prepare the drug into a liquid medicine.

[0086] b: Preparation of microneedles:

[0087] (1) Add the upper needle solution to the first microneedle mold, centrifuge for the first time to fill the micropores of the first microneedle mold with the upper needle solution, recover the excess upper needle solution, and then centrifuge for the second time.

[0088] (2) Add the lower needle solution to the lower half of the second microneedle mold to make a hollow drug-loading part, centrifuge for the first time to fill the micropores of the lower half of the second microneedle mold with the lower needle solution, recover the excess lower needle solution, and then centrifuge for the second time and dry; add the liquid medicine to the hollow drug-loading part of the lower needle, and then combine the upper half and the lower half of the second microneedle mold to fill the micropores of the upper half of the second microneedle mold with the lower needle solution. Among them, steps (1) and (2) are completed simultaneously.

[0089] (3) Dry and assemble the microneedles in steps (1) and (2); connect the first microneedle mold and the second microneedle mold, set the baffle at the top of the first microneedle mold, turn over the first microneedle mold and the second microneedle mold, and separate the first microneedle mold and the second microneedle mold from the needle tip.

[0090] (4) Load the defoamed polyvinylpyrrolidone into the 3D printer cartridge. Under the conditions of a needle aperture of 0.03 mm to 10 mm, a polyvinylpyrrolidone extrusion pressure of 20 Psi to 100 Psi, a printer needle lifting speed of 0.5 mm / s to 50 mm / s, and a platform temperature of -15°C to 50°C, lift the needle vertically upward, extrude and print the upper surface layer and the lower surface layer with polyvinylpyrrolidone, with or without adding drugs, and print again to seal the upper surface layer and the lower surface layer. Connect the upper needle of the needle tip in step (3) to the lower surface layer and connect it to the lower surface layer of the base, and dry to obtain the soluble microneedles.

[0091] Example 4

[0092] This example relates to a soluble microneedle, including a needle tip and a base. The base includes an upper surface layer, a hollow layer, and a lower surface layer; the needle tip is composed of an upper needle and a lower needle; the upper surface layer and the lower surface layer of the base are both polyethylene oxide; the upper needle of the needle tip is a hydrophobic organosilicon material, and the lower needle is sodium carboxymethylcellulose and gelatin; among them, the upper needle is a hollow cylinder, the lower needle is rhombic, the upper needle and the lower needle are connected by socket connection, and the drug is arranged in the hollow layer and the lower needle; the drug is a Japanese encephalitis vaccine microneedle.

[0093] A preparation method of soluble microneedles is as follows.

[0094] a: Preparation of solutions:

[0095] Dissolve the sodium carboxymethylcellulose and gelatin, adjust the pH, and prepare the lower needle solution; prepare the upper needle solution from the hydrophobic silicone material; dissolve the polyethylene oxide to prepare the base solution; prepare the drug into a liquid medicine.

[0096] b: Preparation of microneedles:

[0097] (1) Add the upper needle solution to the first microneedle mold, centrifuge for the first time to fill the micropores of the first microneedle mold with the upper needle solution, recover the excess upper needle solution, and then centrifuge for the second time.

[0098] (2) Add the lower needle solution to the lower half of the second microneedle mold to make a hollow drug-loading part. Centrifuge for the first time to fill the micropores of the lower half of the second microneedle mold with the lower needle solution. Recover the excess lower needle solution, then centrifuge for the second time and dry. Add the liquid medicine to the hollow drug-loading part of the lower needle, and then combine the upper half and the lower half of the second microneedle mold to fill the micropores of the upper half of the second microneedle mold with the lower needle solution. Among them, steps (1) and (2) are completed simultaneously.

[0099] (3) Dry and assemble the microneedles in steps (1) and (2); connect the first microneedle mold and the second microneedle mold, set the baffle at the top of the first microneedle mold, turn the first microneedle mold and the second microneedle mold over, and separate the first microneedle mold and the second microneedle mold from the needle tip.

[0100] (4) Load the degassed polyethylene oxide into the 3D printer cartridge. Under the conditions of a needle tip diameter of 0.03 mm to 10 mm, a polyethylene oxide extrusion pressure of 20 Psi to 100 Psi, a printer needle lifting speed of 0.5 mm / s to 50 mm / s, and a platform temperature of -15 °C to 50 °C, lift the needle vertically upward, extrude and print the upper surface layer and the lower surface layer with polyethylene oxide, with or without adding drugs, and print again to seal the upper surface layer and the lower surface layer. Connect the upper needle of the needle tip in step (3) to the lower surface layer and connect it to the lower surface layer of the base, and dry to obtain the soluble microneedles.

[0101] Control group 1

[0102] This embodiment relates to a soluble microneedle, including a needle tip and a base. The base includes an upper surface layer, a hollow layer, and a lower surface layer; the needle tip is composed of an upper needle and a lower needle; the upper surface layer and the lower surface layer of the base are both polyvinylpyrrolidone; the upper needle of the needle tip is a hydrophobic silicone material, and the lower needle is sodium alginate; among them, the upper needle is a hollow cylinder, the lower needle is diamond-shaped, the upper needle and the lower needle are connected by socket connection, and the drug is arranged in the hollow layer and the lower needle; the drug is an antibiotic, piperacillin and tazobactam

[0103] A preparation method of soluble microneedles is as follows.

[0104] a: Preparation of solutions:

[0105] Dissolve the sodium alginate, adjust the pH, and prepare the lower needle solution; prepare the upper needle solution from the hydrophobic silicone material; dissolve the polyvinylpyrrolidone to prepare the base solution; and prepare the drug into a liquid medicine.

[0106] b: Preparation of microneedles:

[0107] (1) Add the upper needle solution to the first microneedle mold, centrifuge for the first time to fill the microchannels of the first microneedle mold with the upper needle solution, recover the excess upper needle solution, and then centrifuge for the second time.

[0108] (2) Add the lower needle solution to the lower half of the second microneedle mold to make a hollow drug-loading part, centrifuge for the first time to fill the microchannels of the lower half of the second microneedle mold with the lower needle solution, recover the excess lower needle solution, and then centrifuge for the second time and dry; add the liquid medicine to the hollow drug-loading part of the lower needle, and then combine the upper half and the lower half of the second microneedle mold to fill the microchannels of the upper half of the second microneedle mold with the lower needle solution. Among them, steps (1) and (2) are completed simultaneously.

[0109] (3) Dry and assemble the microneedles in steps (1) and (2); connect the first microneedle mold and the second microneedle mold, set the baffle at the top of the first microneedle mold, turn over the first microneedle mold and the second microneedle mold, and separate the first microneedle mold and the second microneedle mold from the needle tip.

[0110] (4) Load the degassed polyvinylpyrrolidone into the 3D printer cartridge. Under the conditions that the needle aperture is 0.03 mm to 10 mm, the extrusion pressure of polyvinylpyrrolidone is 20 Psi to 100 Psi, the lifting speed of the printer needle is 0.5 mm / s to 50 mm / s, and the platform temperature is -15°C to 50°C, lift the needle vertically upward, extrude and print the upper surface layer and the lower surface layer with polyvinylpyrrolidone, with or without adding drugs, print again to seal the upper surface layer and the lower surface layer, connect the upper needle of the needle tip in step (3) with the lower surface layer, and connect it with the lower surface layer of the base, and dry to obtain the soluble microneedles.

[0111] Control group 2

[0112] This embodiment relates to a soluble microneedle, comprising a needle tip and a base. The base includes an upper surface layer, a hollow layer, and a lower surface layer; the needle tip consists of an upper needle and a lower needle; the upper surface layer and the lower surface layer of the base are both polyethylene oxide; the upper needle of the needle tip is a hydrophobic silicone material, and the lower needle is gelatin; wherein the upper needle is a hollow cylinder, the lower needle is rhombic, the upper needle and the lower needle are inserted and connected, and the drug is disposed in the hollow layer and the lower needle; the drug is an antibiotic, namely piperacillin and tazobactam.

[0113] A preparation method of a soluble microneedle is as follows in specific steps.

[0114] a: Preparation of solutions:

[0115] Dissolve the gelatin, adjust the pH, and prepare the lower needle solution; prepare the upper needle solution from the hydrophobic silicone material; dissolve the polyethylene oxide to prepare the base solution; and prepare the drug into a liquid medicine.

[0116] b: Preparation of microneedles:

[0117] (1) Add the upper needle solution to the first microneedle mold, perform the first centrifugation to fill the micropores of the first microneedle mold with the upper needle solution, recover the excess upper needle solution, and then perform the second centrifugation.

[0118] (2) Add the lower needle solution to the lower half of the second microneedle mold to make a hollow drug-loading part, perform the first centrifugation to fill the micropores of the lower half of the second microneedle mold with the lower needle solution, recover the excess lower needle solution, and then perform the second centrifugation and drying; add the liquid medicine to the hollow drug-loading part of the lower needle, and then combine the upper half and the lower half of the second microneedle mold to fill the micropores of the upper half of the second microneedle mold with the lower needle solution. Among them, steps (1) and (2) are completed simultaneously.

[0119] (3) Dry and assemble the microneedles in steps (1) and (2); connect the first microneedle mold and the second microneedle mold, set the baffle at the top of the first microneedle mold, turn over the first microneedle mold and the second microneedle mold, and separate the first microneedle mold and the second microneedle mold from the needle tip.

[0120] (4) Load the degassed polyethylene oxide into the 3D printer cartridge. Under the conditions that the needle aperture is 0.03 mm to 10 mm, the polyethylene oxide extrusion pressure is 20 Psi to 100 Psi, the printer needle lifting speed is 0.5 mm / s to 50 mm / s, and the platform temperature is -15°C to 50°C, lift the needle vertically upward, extrude and print the upper surface layer and the lower surface layer with polyethylene oxide, with or without adding the drug, and print again to seal the upper surface layer and the lower surface layer. Connect the upper needle of the needle tip in step (3) to the lower surface layer, and connect it to the lower surface layer of the base, and then dry to obtain the soluble microneedle.

[0121] In addition, for Examples 1-4 and Control Groups 1 and 2, a connection layer can be provided below the widest part in the shape of a rhombus for connecting the lower needles, or the connection layer can be omitted.

[0122] Part II: Pharmacodynamics Part

[0123] 2.1 Experimental animals: Aged Kunming mice (10 months old), weighing 18-22 g, male, laboratory temperature (25±1)°C, relative humidity 65%.

[0124] 2..2 Test samples:

[0125] The test samples are mainly Examples 1-4 and Control Groups 1-2.

[0126] 2..3 Transdermal performance test:

[0127] Puncture the excised mouse skin. Press the microneedles (prepared in Examples 1 and 3) on the healthy and intact excised mouse skin with a thumb force of 5 N. After staying for 30 s, fix the microneedles with medical adhesive tape. After 10 min, pull out the microneedles, stain the skin surface with 0.4% trypan blue solution, and remove the stain on the skin surface after 10 min. Observe the situation of the stained pores on the skin surface. The result shows that blue dot matrices appear on the mouse skin surface, which are consistent with the arrangement and spacing of the microneedle matrix. Trypan blue is a cell viability dye that cannot penetrate the stratum corneum but can stain the internal tissues through the damaged parts of the stratum corneum. Therefore, only the areas penetrated by the microneedles on the skin surface can show blue dots. The blue dot matrices on the mouse skin surface after the experiment prove that the berberine microneedles of Phellodendron amurense extract and the Japanese encephalitis vaccine microneedles can successfully penetrate the mouse skin.

[0128] 2..4 Skin penetration test:

[0129] 1) Preparation of excised skin: Take healthy mice, euthanize the mice by ether euthanasia method, cut off the abdominal hair with scissors, carefully scrape off the hair with a blade, quickly peel off the abdominal skin, wipe off the subcutaneous fat and other subcutaneous tissues with absorbent cotton, and store it in a sealed freezer at -80°C for standby.

[0130] 2) Preparation of the test ointment: Weigh 8 g of berberine of Phellodendron amurense extract, 50 g of white vaseline, and 10 g of lanolin, heat to melt, stir until dissolved, and obtain a 10% (g / g) berberine ointment of Phellodendron amurense extract after cooling to room temperature.

[0131] 3) Transdermal test: The in vitro permeation experiment was carried out using a Franz horizontal diffusion cell (effective diffusion area of 3 square centimeters). Three tests were conducted in parallel, and 40% PEG 400 was used as the receiving medium. A magnetic stirrer was maintained at 500 rpm in the receiving cell at all times. The microneedle preparations of Example 1 and Example 2 were respectively pressed against the abdominal skin of mice with a thumb at 5 N, and the closed state was maintained to prevent evaporation of the solution and change of components. (Another 10% (g / g) berberine ointment preparation of Phellodendron amurense bark extract was used as Control 3 and evenly applied to the abdominal skin of mice of the same size as the skin treatment group with ointment. Three tests were conducted in parallel, and the closed state was maintained to prevent evaporation of the solution and change of components) During the experiment, samples were taken at 3, 6, 9, 12, 24, 36, and 48 h. After sampling at each sampling point, fresh receiving fluid was replenished so that the lower surface of the skin was always in contact with the receiving phase throughout the experiment. High performance liquid chromatography was used to examine the drug content in the receiving fluid, and the transdermal absorption rate was calculated.

[0132] 4) Detection method:

[0133] Chromatographic column: Thermo OSD-2HYPERSIL (4.6 mm × 150 mm, 5 μm); Mobile phase: acetonitrile: water = 70:30 (v / v); Detection wavelength: 220 nm; Flow rate: 0.8 mL; Column temperature: 30 °C; Injection volume: 10 μL.

[0134] 5) Data analysis:

[0135] The diffusion of the drug in the ointment through the semi-permeable membrane follows the Higuchi formula, that is, the cumulative drug release amount Q is proportional to the square root of time t. That is, Q = Kt 1 / 2 , therefore, the slope K can reflect the rate of drug release in the ointment.

[0136] Table 1 Results of percutaneous penetration test at 48 h

[0137] Test sample <![CDATA[Q / μg / cm 2 > <![CDATA[K / μg / (cm 2. h)]]> Control 3 10.5±0.32 1.62±0.03 Example 1 992±21.73 97.44±6.23 Example 2 694±25.33 87.32±5.12

[0138] The results showed that the microneedle permeation rate was significantly higher than that of the ointment.

[0139] 2.5 Determination of microneedle drug loading

[0140] The tips of the microneedles prepared in Example 1, 3 and Control Group 1 were separated from the substrate with a blade, and then the separated tips of Example 1 and 3 were dissolved in 1% acetic acid; the separated tips of Example 2, 4 and Control Group 2 were dissolved in deionized water, and the Coomassie brilliant blue method was used to determine the content of PD-L1 antibody, and the microneedle drug loading was calculated.

[0141] The outer layer of the microneedles prepared from chitosan and sodium alginate increased the drug loading capacity of the microneedles for PD-L1 antibody compared with the outer layer of the microneedles prepared from sodium alginate alone; the outer layer of the carboxymethyl cellulose sodium and gelatin microneedles increased the drug loading capacity of the microneedles for berberine, an extract of Phellodendron bark, compared with the use of gelatin alone.

[0142] In summary, the above are only the preferred embodiments of the present invention, and are not used to limit the scope of implementation of the present invention. All equivalent changes and modifications made according to the shape, structure, features and spirit described in the scope of the claims of the present invention shall be included in the scope of the claims of the present invention.

Claims

1. A soluble microneedle, characterized in that, It includes a tip and a base, and the base includes an upper surface layer, a hollow layer, and a lower surface layer; the tip consists of an upper needle and a lower needle; both the upper surface layer and the lower surface layer of the base are non-ionic high-molecular compounds; the upper needle of the tip is a hydrophobic silicone material, and the lower needle is a charged high-molecular material; wherein the upper needle is a hollow cylinder, the lower needle is diamond-shaped, the upper needle and the lower needle are connected by socket connection, and the drug is arranged in the hollow layer and / or the lower needle.

2. The soluble microneedle according to claim 1, characterized in that, The lower needle is divided into a hollow drug-loading part and a socket hollow needle body fixedly connected to the hollow drug-loading part. The diameter of the cross-section of the socket hollow needle body is smaller than the diameter of the upper needle. The socket hollow needle body is connected to the upper needle by socket connection. The hollow drug-loading part is divided into an upper triangle and a lower triangle, and the upper triangle and the lower triangle are fixedly connected and communicated. The width of the bottom of the upper triangle is smaller than the diameter of the upper needle, and the width of the top of the lower triangle is larger than the diameter of the upper needle.

3. A soluble microneedle according to claim 2, wherein The non-ionic high-molecular compound is polyvinylpyrrolidone or / and polyethylene oxide, and the hydrophobic silicone material is polydimethylsiloxane.

4. The soluble microneedle according to claim 3, wherein The charged high-molecular material is one or several of chitosan, chitosan oligosaccharide, hyaluronic acid, sodium alginate, sodium carboxymethylcellulose, collagen, gelatin, and arabic gum.

5. A soluble microneedle according to claim 4, characterized in that, The drug is one or several of nucleic acids and their derivatives, degradation products, macromolecular structure modifiers, polypeptide biochemical drugs, enzymes, cytokines, hormones, antibodies, and vaccines; The drug is an antibiotic or an analgesic; the antibiotic is a combination of two or one of piperacillin and tazobactam and / or a chelating agent; wherein the chelating agent is ethylenediaminetetraacetic acid or its salt, or ethylenediamine; the analgesic is fentanyl.

6. The soluble microneedle according to claim 4, wherein The drug is a drug for improving psoriasiform inflammation, and the drug is berberine extracted from the bark of Phellodendron amurense.

7. A soluble microneedle according to claim 4, wherein The length and width of the soluble microneedle are both 10 mm, and the height is 2 - 3 mm; the tips are distributed in a rectangular array, the distance between adjacent microneedles is 50 - 80 μm, and the diameter of the flow channel is 30 - 50 μm.

8. A method for preparing a soluble microneedle according to any one of claims 4-7, characterized in that, It includes the following steps: a: Preparation of solutions: Dissolve the charged high-molecular material, adjust the pH, and prepare the lower needle solution; prepare the upper needle solution from the hydrophobic silicone material; dissolve the non-ionic high-molecular compound to prepare the base solution; Prepare the drug into a liquid medicine; b: Preparation of microneedles: (1) Add the upper needle solution to the first microneedle mold, centrifuge for the first time to make the upper needle solution fill the microchannels of the first microneedle mold, recover the excess upper needle solution, and then centrifuge for the second time; (2) Add the lower needle solution to the lower half of the second microneedle mold to make the hollow drug-loading part, centrifuge for the first time to make the lower needle solution fill the microchannels of the lower half of the second microneedle mold, recover the excess lower needle solution, and then centrifuge for the second time and dry; add the liquid medicine to the hollow drug-loading part of the lower needle, and then combine the upper half and the lower half of the second microneedle mold to make the lower needle solution fill the microchannels of the upper half of the second microneedle mold. Among them, steps (1) and (2) are completed simultaneously; (3) Dry and assemble the microneedles in steps (1) and (2); connect the first microneedle mold and the second microneedle mold, set the baffle at the top of the first microneedle mold, turn the first microneedle mold and the second microneedle mold over, and separate the first microneedle mold and the second microneedle mold from the tip; (4) Load the degassed non-ionic polymer compound into the 3D printer cartridge. Under the conditions that the needle aperture is 0.03 mm to 10 mm, the extrusion pressure of the non-ionic polymer compound is 20 Psi to 100 Psi, the lifting speed of the printer needle is 0.5 mm / s to 50 mm / s, and the platform temperature is -15 °C to 50 °C, lift the needle vertically upward. Extrude the non-ionic polymer compound to print the upper surface layer and the lower surface layer, with or without adding drugs. Print again to seal the upper surface layer and the lower surface layer. Connect the upper needle of the tip in step (3) to the lower surface layer and connect it to the lower surface layer of the substrate. Dry to obtain the soluble microneedles.

9. A method for preparing a soluble microneedle according to any one of claims 4-7, characterized in that, It includes the following steps: a: Preparation of solutions: Dissolve the charged polymer material, adjust the pH, and prepare the lower needle solution; prepare the upper needle solution from the hydrophobic silicone material; dissolve the non-ionic polymer compound to prepare the substrate solution; prepare the drug into a liquid medicine. b: Preparation of microneedles: (1) Import the 3D model and print the lower needle Load the degassed lower needle solution into the first cartridge of the 3D printer. Under the conditions that the needle aperture is 0.025 mm to 0.3 mm, the extrusion pressure of the non-ionic polymer compound is 15 Psi to 60 Psi, the lifting speed of the printer needle is 0.5 mm / s to 50 mm / s, and the platform temperature is -15 °C to 50 °C, extrude the lower needle solution to print the lower needle. When printing to 2 / 3 of the lower needle, inject the liquid medicine and continue printing the lower needle until printing is completed; place it in the second microneedle mold. (2) Import the 3D model and print the upper needle; Load the degassed upper needle solution into the second cartridge of the 3D printer. Under the conditions that the needle aperture is 0.03 mm to 0.3 mm, the extrusion pressure of the non-ionic polymer compound is 20 Psi to 100 Psi, the lifting speed of the printer needle is 0.5 mm / s to 50 mm / s, and the platform temperature is -15 °C to 50 °C, extrude the upper needle solution to print the upper needle; place it in the first microneedle mold. (3) Combine the lower needle and the upper needle in steps (1) and (2); (4) Load the degassed substrate solution into the third cartridge of the 3D printer. Under the conditions that the needle aperture is 0.03 mm to 10 mm, the extrusion pressure of the non-ionic polymer compound is 20 Psi to 100 Psi, the lifting speed of the printer needle is 0.5 mm / s to 50 mm / s, and the platform temperature is -15 °C to 50 °C, extrude the substrate solution to print the upper surface layer and the lower surface layer, with or without adding the liquid medicine. Print again to seal the upper surface layer. Connect the upper needle of the tip in step (3) to the lower surface layer and dry to obtain the soluble microneedles.

10. A method for preparing a soluble microneedle according to any one of claims 4-7, characterized in that, It includes the following steps: a: Preparation of solutions: Dissolve the charged polymer material, adjust the pH, and prepare the lower needle solution; prepare the upper needle solution from the hydrophobic silicone material; dissolve the non-ionic polymer compound to prepare the substrate solution; Prepare the drug into a liquid medicine; b: Preparation of microneedles: (1) Print the lower surface layer Load the degassed base solution into the third cartridge of the 3D printer. Under the conditions that the needle aperture is 0.03 mm to 10 mm, the extrusion pressure of the non-ionic polymer compound is 20 Psi to 100 Psi, the lifting speed of the printer needle is 0.5 mm / s to 50 mm / s, and the platform temperature is -15°C to 50°C, extrude the base solution to print the upper surface layer; (2) Import the 3D model and print the upper needle; Load the degassed upper needle solution into the second cartridge of the 3D printer. Under the conditions that the needle aperture is 0.03 mm to 0.3 mm, the extrusion pressure of the non-ionic polymer compound is 20 Psi to 100 Psi, the lifting speed of the printer needle is 0.5 mm / s to 50 mm / s, and the platform temperature is -15°C to 50°C, extrude the upper needle solution to print the upper needle; Place it in the first microneedle mold; (3) Import the 3D model and print the lower needle Load the degassed lower needle solution into the first cartridge of the 3D printer. Under the conditions that the needle aperture is 0.025 mm to 0.3 mm, the extrusion pressure of the non-ionic polymer compound is 15 Psi to 60 Psi, the lifting speed of the printer needle is 0.5 mm / s to 50 mm / s, and the platform temperature is -15°C to 50°C, extrude the lower needle solution to print the lower needle. When printing to 2 / 3 of the lower needle, inject the drug solution and continue printing the lower needle until printing is completed; Place it in the second microneedle mold; Combine the lower needle and the upper needle in steps (2) and (3); (4) Print the upper surface layer Load the degassed base solution into the third cartridge of the 3D printer. Under the conditions that the needle aperture is 0.03 mm to 10 mm, the extrusion pressure of the non-ionic polymer compound is 20 Psi to 100 Psi, the lifting speed of the printer needle is 0.5 mm / s to 50 mm / s, and the platform temperature is -15°C to 50°C, extrude the base solution to print the upper surface layer. Add or do not add the drug solution, and print again to seal the upper surface layer. Connect the upper needle at the tip of step (3) to the lower surface layer, and dry to obtain the soluble microneedles.

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