Integrated soluble analgesic microneedle patch and preparation method thereof

Abstract

The invention provides an integrated soluble analgesic microneedle patch and a preparation method thereof, and belongs to the technical field of biological medicines. Comprising the following steps: preparing a microneedle female mold; the preparation method comprises the following steps: dissolving a high-molecular polymer material and an analgesic drug in deionized water, and removing bubbles to obtain a microneedle substrate solution; the analgesic drug is one or more of lidocaine, prilocaine, ropivacaine, ibuprofen and pregabalin, the high-molecular polymer material is polyvinylpyrrolidone, or the high-molecular polymer material is a mixture of sodium carboxymethyl cellulose and polyvinylpyrrolidone; injecting the microneedle substrate solution into a microneedle female mold, removing bubbles and drying; and after drying, demolding to obtain the integrated soluble analgesic microneedle patch. The microneedle patch disclosed by the invention can improve the local concentration and bioavailability of the medicine, so that the analgesic effect is enhanced, the side effects of the whole body are reduced, and the microneedle patch can be widely applied to quickly relieving different skin pains.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology, and specifically relates to an integrated soluble analgesic microneedle patch and a preparation method thereof. Background Art

[0002] Skin pain is a common symptom of disease, which may be caused by trauma, inflammation, neurological diseases or other reasons, such as pyoderma gangrenosum, cutaneous vasculitis, erythema nodosum, postherpetic neuralgia, oral ulcers, abnormal pain and pain hypersensitivity caused by chronic inflammation, postoperative or post-traumatic pain, etc., which seriously affect the quality of life of patients. Commonly used treatment methods include injection analgesics, oral analgesics and local skin medications (patches, sprays, local anesthetics, etc.). However, oral medications usually have problems such as slow onset and large side effects; injection administration has problems such as strong injection pain, high professional and technical requirements and poor patient compliance; application administration, such as lidocaine topical patches, may not be able to completely penetrate into the subcutaneous tissue after local application, resulting in poor analgesic effect.

[0003] Microneedles contain several micro needle arrays with a length of 10 to 2000 μm and a width of 10 to 50 μm. They can directly pierce the stratum corneum to release drugs. As a new type of efficient and safe transdermal drug delivery technology, they have attracted widespread attention. Compared with traditional transdermal drug delivery methods, microneedles can pass through the stratum corneum in a directional manner, produce micron-sized mechanical channels, and place drugs directly in the epidermis or upper dermis. They can participate in microcirculation without passing through the stratum corneum, exert pharmacological reactions, and greatly improve delivery efficiency. Moreover, due to their tiny structural characteristics, they can achieve painless and minimally invasive drug delivery and improve patient compliance. At present, the materials used to make microneedles are mostly metals, silicon products and soluble polymer materials. Among them, soluble polymer materials are widely used due to their good biocompatibility and biodegradability.

[0004] For the layered microneedles that are currently widely used, the needle body layer and the backing layer need to be prepared separately during the microneedle preparation process. This preparation method not only increases the preparation cost, but also the presence of cavitation at the needle tip is difficult to resolve, affecting the drug loading and stability of the microneedle body.

[0005] In summary, given that there are currently no clinically available analgesic microneedle patch products on the market, the development of a painless, rapid, transdermal soluble microneedle patch to deliver analgesic drugs has broad application prospects. Summary of the invention

[0006] In order to solve the problems existing in the background technology, the present invention provides an integrated soluble analgesic microneedle patch and a preparation method thereof, which reduces the preparation cost while ensuring that the microneedle matrix is ​​fully filled during the molding process, and the microneedle delivery of analgesics can quickly relieve pain. In addition, a high molecular polymer material with good biocompatibility and biodegradability is used as the microneedle skeleton material to ensure clinical safety. The analgesic microneedle patch provided by the present invention has a simple preparation process, is green and environmentally friendly, has high batch repeatability, and is suitable for industrial production.

[0007] To achieve the above object, the present invention is implemented through the following technical solutions:

[0008] In a first aspect, the present invention discloses a method for preparing an integrated soluble analgesic microneedle patch, comprising:

[0009] 1) preparing a microneedle negative mold;

[0010] 2) dissolving the polymer material and the analgesic drug in deionized water and removing bubbles to obtain a microneedle substrate solution; wherein the mass fraction of the analgesic drug in the microneedle substrate solution is 7% to 16.1%; and the mass fraction of the polymer material in the microneedle substrate solution is 15.4% to 23%;

[0011] 3) injecting the microneedle substrate solution into the microneedle negative mold obtained in step 1), removing bubbles and drying; demoulding after drying to obtain an integrated soluble analgesic microneedle patch;

[0012] Wherein, the polymer material is polyvinyl pyrrolidone, or the polymer material is a mixture of sodium carboxymethyl cellulose and polyvinyl pyrrolidone; the analgesic drug is one or more of lidocaine, prilocaine, ropivacaine, ibuprofen, and pregabalin;

[0013] The chemical name of the ibuprofen is 2-(4-isobutylphenyl) propionic acid, and its molecular formula is C 13 H 18 O 2 The chemical name of pregabalin is (S)-3-aminomethyl-5-methylhexanoic acid, and its molecular formula is C 8 H 17 NO 2 .

[0014] Furthermore, the step 1) is specifically as follows: placing polydimethylsiloxane in a curing agent and stirring and mixing the mixture thoroughly, performing vacuum degassing after mixing, immediately pouring the mixture onto the surface of a stainless steel metal microneedle master template after vacuum degassing for curing and drying, and demolding the mixture after drying to obtain a microneedle negative mold.

[0015] Furthermore, in step 1), the mass ratio of polydimethylsiloxane to curing agent is 10:1; preferably, the preparation system of the microneedle negative mold is DOWSIL TM 184, DOWSIL TM 184 purchased from Dow Corning.

[0016] Furthermore, the microneedle body height of the negative mold of the microneedle prepared in step 1) is 300 to 2000 μm, preferably 300 to 900 μm.

[0017] Furthermore, the shape of the microneedle body of the negative mold of the microneedle prepared in step 1) is a quadrangular pyramid or a cone.

[0018] Furthermore, in step 2), when the polymer material is polyvinyl pyrrolidone, the mass fraction of polyvinyl pyrrolidone in the microneedle substrate solution is 15.4%-21.1%; when the polymer material is a mixture of sodium carboxymethyl cellulose and polyvinyl pyrrolidone, the mass fraction of sodium carboxymethyl cellulose in the microneedle substrate solution is 1.6%-1.9%, and the mass fraction of polyvinyl pyrrolidone is 15.4%-21.1%; the viscosity of sodium carboxymethyl cellulose is 600-1200mPa.s.

[0019] Furthermore, in the step 2), bubbles are removed by repeated vacuuming, the number of vacuuming is 3 to 5 times, the time of each vacuuming is 10 to 15 minutes, and the vacuuming conditions are room temperature and the pressure is 0.1 MPa.

[0020] Furthermore, in the step 3), the drying temperature is 25 to 40° C., and the drying time is 6 to 18 hours.

[0021] Furthermore, in the step 3), the substrate of the microneedle is a circle with a diameter of 10 μm to 50 μm or a square with a side length of 100 μm to 300 μm.

[0022] In a second aspect, the present invention discloses an integrated soluble analgesic microneedle patch prepared by the method.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] (1) The present invention delivers analgesics in the patient's body through microneedles, overcoming the problems of slow onset and poor patient compliance in the clinical application of existing analgesics. The use of this system can improve the patient's treatment compliance and reduce treatment costs.

[0025] (2) The integrated microneedle preparation method provided by the present invention solves the problem of reduced drug loading and unstable needle structure caused by cavitation in layered microneedle preparation, thereby increasing the drug loading while ensuring the mechanical properties and puncture ability of the microneedle.

[0026] (3) The integrated analgesic microneedle patch of the present invention uses a soluble high molecular polymer as the microneedle skeleton, and its overall preparation process is simple, mature and stable, and the preparation cost is low. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 This is a diagram of the analgesic microneedle patch of Example 1;

[0028] Figure 2 This is a diagram of the analgesic microneedle patch of Example 3;

[0029] Figure 3 This is a diagram of the analgesic microneedle patch of Example 4;

[0030] Figure 4 This is a diagram of the analgesic microneedle patch of Example 5;

[0031] Figure 5 This is a diagram of the analgesic microneedle patch of Example 8;

[0032] Figure 6 is a SEM image of the needle body morphology of the analgesic microneedle patch of Example 1;

[0033] Figure 7 is a graph of the mechanical strength of the analgesic microneedle patch of Example 1;

[0034] Figure 8 is a schematic diagram of the dissolution performance of the analgesic microneedle patch of Example 3;

[0035] Fig. 9 is a graph showing the in vitro drug release results of the analgesic microneedles of Examples 1 to 5, Example 7 and Example 8;

[0036] Fig.10 This is the efficacy evaluation of the analgesic microneedle patch in Example 1 in a rat pain model;

[0037] Fig.11 This is a comparison diagram of the needle tips of the double-layer analgesic microneedle patch of Example 1 and the integrated analgesic microneedle patch of Example 1. DETAILED DESCRIPTION

[0038] The present invention is further described and illustrated below in conjunction with specific embodiments. The embodiments are merely exemplary of the present disclosure and do not define the scope of limitation. The technical features of each embodiment of the present invention may be combined accordingly without conflicting with each other.

[0039] Example 1

[0040] This embodiment provides a method for preparing an integrated lidocaine analgesic microneedle patch, comprising the following steps:

[0041] 1) Preparation of a negative microneedle mold: Add polydimethylsiloxane to the curing agent at a mass ratio of polydimethylsiloxane to curing agent of 10:1, stir and mix thoroughly, then vacuum degas under a pressure of 0.1 MPa, and then immediately place it on the surface of a stainless steel metal microneedle master template, cure and dry at 60°C for 0.5 h, and finally peel it off from the stainless steel metal microneedle master template to obtain a polydimethylsiloxane microneedle negative mold.

[0042] 2) Prepare the materials required for the microneedle patch substrate: prepare the materials according to the mass ratio of sodium carboxymethyl cellulose: polyvinyl pyrrolidone: lidocaine: deionized water of 2.5:30:10:100, the polyvinyl pyrrolidone is K30 grade, and the viscosity of sodium carboxymethyl cellulose is 600-1000 mPa.s;

[0043] The prepared sodium carboxymethyl cellulose, polyvinyl pyrrolidone and lidocaine were added into deionized water, dissolved under magnetic stirring at 4°C for 4 h, and the bubbles were removed by ultrasound to obtain a microneedle substrate solution.

[0044] 3) pouring the microneedle substrate solution obtained in step 2) into the polydimethylsiloxane microneedle negative mold obtained in step 1), and evacuating the solution to allow the solution to fill the needle tip of the microneedle negative mold well, while retaining a solution height of 2 to 3 mm;

[0045] The filled microneedle female mold was placed in an oven and dried at 35° C. for 18 hours. After drying, the integrated lidocaine analgesic microneedle patch of Example 1 was obtained by demoulding. Figure 1 shown.

[0046] Example 2

[0047] This embodiment provides a method for preparing an integrated lidocaine analgesic microneedle patch, comprising:

[0048] 1) Preparation of negative microneedle mold: adding polydimethylsiloxane to the curing agent at a mass ratio of 10:1, stirring and mixing, then vacuum degassing at a pressure of 0.1 MPa, and immediately placing it on the surface of the stainless steel metal microneedle master template, curing and drying at 60°C for 0.5h, and finally peeling it off from the metal microneedle to obtain the negative polydimethylsiloxane microneedle mold.

[0049] 2) Prepare the materials required for the microneedle patch substrate: prepare the materials according to the mass ratio of polyvinyl pyrrolidone: lidocaine: deionized water of 20:10:100, and the polyvinyl pyrrolidone is K30 grade;

[0050] The prepared polyvinyl pyrrolidone and lidocaine were added into deionized water, heated and stirred for 3 h to dissolve, and the bubbles were removed by ultrasound to obtain a microneedle substrate solution.

[0051] 3) pouring the microneedle substrate solution obtained in step 2) into the polydimethylsiloxane microneedle negative mold obtained in step 1), and evacuating the solution to allow the solution to fill the needle tip of the microneedle negative mold well, while retaining a solution height of 2 to 3 mm;

[0052] The filled microneedle female mold is placed in an oven and dried at 37° C. for 10 hours. After drying, the integrated lidocaine analgesic microneedle patch of Example 2 is obtained by demoulding.

[0053] Example 3

[0054] This embodiment provides a method for preparing an integrated lidocaine analgesic microneedle patch, comprising:

[0055] 1) Preparation of negative microneedle mold: adding polydimethylsiloxane to the curing agent at a mass ratio of 10:1, stirring and mixing, then vacuum degassing at a pressure of 0.1 MPa, and immediately placing it on the surface of the stainless steel metal microneedle master template, curing and drying at 60°C for 0.5h, and finally peeling it off from the metal microneedle to obtain the negative polydimethylsiloxane microneedle mold.

[0056] 2) Prepare the materials required for the microneedle patch substrate: prepare the materials according to the mass volume ratio (M / V) of polyvinyl pyrrolidone: sodium carboxymethyl cellulose: lidocaine: deionized water of 30:2.5:10:100, wherein the polyvinyl pyrrolidone is K30 grade and the sodium carboxymethyl cellulose has a viscosity of 800-1200 mPa.s;

[0057] The prepared sodium carboxymethyl cellulose, polyvinyl pyrrolidone and lidocaine were added into deionized water, and dissolved under magnetic stirring at 4°C for 6 h. The bubbles were removed by ultrasound to obtain a microneedle substrate solution.

[0058] 3) pouring the microneedle substrate solution obtained in step 2) into the polydimethylsiloxane microneedle negative mold obtained in step 1), and evacuating the solution to allow the solution to fill the needle tip of the microneedle negative mold well, while retaining a solution height of 2 to 3 mm;

[0059] The filled microneedle female mold was placed in an oven and dried at 37° C. for 10 hours. After drying, the integrated lidocaine analgesic microneedle patch of Example 3 was obtained by demoulding. Figure 2 shown.

[0060] Example 4

[0061] This embodiment provides a method for preparing an integrated lidocaine and ropivacaine analgesic microneedle patch, comprising:

[0062] 1) Preparation of negative microneedle mold: adding polydimethylsiloxane to the curing agent at a mass ratio of 10:1, stirring and mixing, then vacuum degassing at a pressure of 0.1 MPa, and immediately placing it on the surface of the stainless steel metal microneedle master template, curing and drying at 60°C for 0.5h, and finally peeling it off from the metal microneedle to obtain the negative polydimethylsiloxane microneedle mold.

[0063] 2) Prepare the materials required for the microneedle patch substrate: prepare the materials according to the mass ratio of sodium carboxymethyl cellulose: polyvinyl pyrrolidone: lidocaine: ropivacaine: deionized water of 2.5:30:10:10:100, the polyvinyl pyrrolidone is K30 grade, and the sodium carboxymethyl cellulose has a viscosity of 600-1000 mPa.s.

[0064] The prepared sodium carboxymethyl cellulose, polyvinyl pyrrolidone, lidocaine and ropivacaine were added into deionized water, dissolved under magnetic stirring at 4°C for 4 h, and the bubbles were removed by ultrasound to obtain a microneedle substrate solution.

[0065] 3) pouring the microneedle substrate solution obtained in step 2) into the polydimethylsiloxane microneedle negative mold obtained in step 1), and evacuating the solution to allow the solution to fill the needle tip of the microneedle negative mold well, while retaining a solution height of 2 to 3 mm;

[0066] The filled microneedle female mold is placed in an oven and dried at 37° C. for 9 hours. After drying, the integrated lidocaine and ropivacaine analgesic microneedle patch of Example 4 is obtained by demoulding. Figure 3 shown.

[0067] Example 5

[0068] This embodiment provides a method for preparing an integrated leprocaine composite analgesic microneedle patch, comprising:

[0069] 1) Preparation of negative microneedle mold: adding polydimethylsiloxane to the curing agent at a mass ratio of 10:1, stirring and mixing, then vacuum degassing at a pressure of 0.1 MPa, and immediately placing it on the surface of the stainless steel metal microneedle master template, curing and drying at 60°C for 0.5h, and finally peeling it off from the metal microneedle to obtain the negative polydimethylsiloxane microneedle mold.

[0070] 2) preparing the materials required for the microneedle patch substrate: preparing the materials according to the mass volume ratio (M / V) of polyvinyl pyrrolidone: sodium carboxymethyl cellulose: lidocaine: prilocaine: deionized water of 30:2.5:10:10:100, wherein the polyvinyl pyrrolidone is K30 grade and the sodium carboxymethyl cellulose has a viscosity of 600-1000 mPa.s;

[0071] The prepared sodium carboxymethyl cellulose, polyvinyl pyrrolidone, lidocaine and prilocaine were added into deionized water, magnetically stirred for 5 h at 4°C to dissolve, and the bubbles were removed by ultrasound to obtain a microneedle substrate solution.

[0072] 3) pouring the microneedle substrate solution obtained in step 2) into the polydimethylsiloxane microneedle negative mold obtained in step 1), and evacuating the solution to allow the solution to fill the needle tip of the microneedle negative mold well, while retaining a solution height of 2 to 3 mm;

[0073] The filled microneedle female mold was placed in an oven and dried at 37° C. for 10 hours. After drying, the integrated leprocaine composite analgesic microneedle patch of Example 5 was obtained by demoulding. Figure 4 shown.

[0074] Example 6

[0075] This embodiment provides a method for preparing an integrated lidocaine and pregabalin composite analgesic microneedle patch, comprising:

[0076] 1) Preparation of negative microneedle mold: adding polydimethylsiloxane to the curing agent at a mass ratio of 10:1, stirring and mixing, then vacuum degassing at a pressure of 0.1 MPa, and immediately placing it on the surface of the stainless steel metal microneedle master template, curing and drying at 60°C for 0.5h, and finally peeling it off from the metal microneedle to obtain the negative polydimethylsiloxane microneedle mold.

[0077] 2) Prepare the materials required for the microneedle patch substrate: prepare the materials according to the mass ratio of polyvinyl pyrrolidone: lidocaine: pregabalin: deionized water of 30:10:15:100, wherein the polyvinyl pyrrolidone is K30 grade;

[0078] The prepared polyvinyl pyrrolidone, lidocaine and pregabalin were added into deionized water, heated and stirred for 3 h to dissolve, and the bubbles were removed by ultrasound to obtain a microneedle substrate solution.

[0079] 3) pouring the microneedle substrate solution obtained in step 2) into the polydimethylsiloxane microneedle negative mold obtained in step 1), and evacuating the solution to allow the solution to fill the needle tip of the microneedle negative mold well, while retaining a solution height of 2 to 3 mm;

[0080] The filled microneedle female mold is placed in an oven and dried at 37° C. for 10 hours. After drying, the integrated lidocaine and pregabalin composite analgesic microneedle patch of Example 6 is obtained by demoulding.

[0081] Example 7

[0082] This embodiment provides a method for preparing an integrated prilocaine analgesic microneedle patch, comprising:

[0083] 1) Preparation of negative microneedle mold: adding polydimethylsiloxane to the curing agent at a mass ratio of 10:1, stirring and mixing, then vacuum degassing at a pressure of 0.1 MPa, and immediately placing it on the surface of the stainless steel metal microneedle master template, curing and drying at 60°C for 0.5h, and finally peeling it off from the metal microneedle to obtain the negative polydimethylsiloxane microneedle mold.

[0084] 2) Prepare the materials required for the microneedle patch substrate: prepare the materials according to the mass ratio of polyvinyl pyrrolidone: sodium carboxymethyl cellulose: prilocaine: deionized water of 30:3:25:100, wherein the polyvinyl pyrrolidone is K30 grade and the sodium carboxymethyl cellulose has a viscosity of 800-1200 mPa.s;

[0085] The prepared sodium carboxymethyl cellulose, polyvinyl pyrrolidone and prilocaine were added into deionized water, and dissolved under magnetic stirring at 4°C for 5 h. The bubbles were removed by ultrasound to obtain a microneedle substrate solution.

[0086] 3) pouring the microneedle substrate solution obtained in step 2) into the polydimethylsiloxane microneedle negative mold obtained in step 1), and evacuating the solution to allow the solution to fill the needle tip of the microneedle negative mold well, while retaining a solution height of 2 to 3 mm;

[0087] The filled microneedle female mold is placed in an oven and dried at 37° C. for 8 hours. After drying, the integrated prilocaine analgesic microneedle patch of Example 7 is obtained by demoulding.

[0088] Example 8

[0089] This embodiment provides a method for preparing an integrated ibuprofen analgesic microneedle patch, comprising:

[0090] 1) Preparation of negative microneedle mold: adding polydimethylsiloxane to the curing agent at a mass ratio of 10:1, stirring and mixing, then vacuum degassing at a pressure of 0.1 MPa, and immediately placing it on the surface of the stainless steel metal microneedle master template, curing and drying at 60°C for 0.5h, and finally peeling it off from the metal microneedle to obtain the negative polydimethylsiloxane microneedle mold.

[0091] 2) preparing materials required for the microneedle patch substrate: preparing various materials according to the mass ratio of polyvinyl pyrrolidone: ibuprofen: deionized water of 30:25:100, wherein the polyvinyl pyrrolidone is K30 grade;

[0092] The prepared polyvinyl pyrrolidone and ibuprofen were added into deionized water, and dissolved under magnetic stirring for 4 h at room temperature. The bubbles were removed by ultrasound to obtain a microneedle substrate solution.

[0093] 3) pouring the microneedle substrate solution obtained in step 2) into the polydimethylsiloxane microneedle negative mold obtained in step 1), and evacuating the solution to allow the solution to fill the needle tip of the microneedle negative mold well, while retaining a solution height of 2 to 3 mm;

[0094] The filled microneedle female mold was placed in an oven and dried at 37° C. for 7 hours. After drying, the integrated ibuprofen analgesic microneedle patch of Example 8 was obtained by demoulding. Figure 5 shown.

[0095] The microneedle patches of Examples 1 to 8 have substantially the same morphology, mechanical properties and dissolution properties.

[0096] Example 9

[0097] This example is a scanning electron microscope experiment of the integrated lidocaine analgesic microneedle patch of Example 1. The experimental method is as follows: the prepared microneedles are fixed on a V-shaped copper sheet with conductive tape, and after gold spraying, an electron scanning microscope (Scanning Electron Microscope, SEM) is used to set the working voltage to 5kV, observe the morphology of the microneedle patch, and collect images.

[0098] like Figure 6 As shown, the microneedle patch has a flat base, a complete needle tip, a quadrangular pyramid shape, a height of 900 μm, and is neatly arranged.

[0099] Example 10

[0100] This example is a mechanical strength test experiment of the integrated lidocaine analgesic microneedle patch of Example 1, and the measurement method is as follows:

[0101] Cut the patch part with a certain number of pins and fix it on the base of the electronic universal testing machine (Xinsans, 5000 series). Press it down at a constant pressing rate. Use a mechanical sensor to detect the force and draw a force-displacement curve, such as Figure 7 shown.

[0102] according to Figure 7 It can be seen that the force applied to each needle can reach 1.4N, which is much higher than the force required for the microneedle to pierce the skin (0.2N), and the hardness is enough to pierce the skin.

[0103] Embodiment 11

[0104] This example is a dissolution performance test experiment of the integrated lidocaine analgesic microneedle patch of Example 2, and the measurement method is as follows:

[0105] The microneedle patch was manually inserted into the skin, and pressure was applied for 20 seconds before keeping it inserted. After 30 minutes, the dissolution was observed under a microscope. Figure 8 As shown, the microneedle has good solubility.

[0106] Example 12

[0107] This example is a drug in vitro release curve determination of the integrated analgesic microneedle patch of Examples 1 to 5, Example 7, and Example 8. The control groups of Examples 1 to 3 are commercially available lidocaine creams, the control group of Example 5 is commercially available prilocaine gel, the control group of Example 7 is 25% prilocaine solution, and the control group of Example 8 is commercially available ibuprofen gel.

[0108] The measurement steps are as follows:

[0109] (1) Immediately after the Bama Xiang pig was killed, the abdominal skin was cut, the subcutaneous fat layer and connective tissue were carefully peeled off, and the skin was rinsed with saline. The skin was placed in saline and stored in a low-temperature refrigerator for later use. Before the experiment, the skin was naturally thawed and soaked in 0.9% saline for 30 minutes, and then dried with filter paper for later use.

[0110] (2) The transdermal diffusion device was a modified Franz diffusion device, and the exposed skin area in the diffusion cell was 1.77 cm 2 , the volume of the receiving chamber is 8mL. Take the microneedle patches prepared in Examples 1 to 5, Example 7, and Example 8 above, press them vertically into the skin surface, add 8.5mL of receiving liquid into the receiving pool (the absorption liquid is controlled, and the level of the absorption liquid is accurately about 1mm higher than the ex vivo skin surface to ensure stable contact between the liquid surface and the skin during the sampling process), and place it in a 32±0.5℃ constant temperature water bath. During this period, the receiving liquid is continuously stirred with a magnetic stirrer to release the drug naturally, and the stirring speed is 300rpm / min.

[0111] (3) Sampling: 0.2 mL of the receiving solution was taken at 0h, 0.5h, 1h, 2h, 4h, 6h, 8h, and 12h after coating. Six samples were prepared at each time point. After sampling, 0.2 mL of the receiving solution was added to the receiving chamber, filtered through a 0.22 μm microporous filter membrane, and stored in the freezer for testing. The skin was taken after the transdermal absorption experiment was completed at 0h, 0.5h, 1h, 2h, 4h, 6h, 8h, and 12h, and the absorption solution was absorbed with filter paper. The microneedles were removed (wiped 3 times with 3 alcohol cotton balls), the skin was cut into pieces, 2 mL of pH = 7.4 phosphate buffer was added to the grinding tank, and the skin was ground with an adjustable speed homogenizer. After centrifugation, 0.5 mL of the supernatant was taken and stored in the freezer for testing.

[0112] (4) The contents of lidocaine, prilocaine, and ibuprofen were measured by liquid chromatography. The chromatographic conditions were as follows: octadecylsilane bonded silica gel was used as the filler; phosphate buffer (1.3 ml of 1 mol / L sodium dihydrogen phosphate solution and 32.5 ml of 0.5 mol / L sodium dihydrogen phosphate solution were placed in a 1000 ml volumetric flask, diluted to the mark with water, and shaken)-acetonitrile (50:50) (pH adjusted to 8.0 with phosphoric acid) was used as the mobile phase; the detection wavelengths were 254 nm for lidocaine, 290 nm for prilocaine, and 264 nm for ibuprofen.

[0113] (5) Draw a microneedle in vitro release curve, such as Fig. 9 shown.

[0114] like Fig. 9 As shown in a, taking commercially available lidocaine cream as a control, the release amount of the analgesic microneedles of Examples 1, 2 and 3 within 8 hours is statistically shown (wherein the microneedle patch obtained in Example 1 is microneedle 1, the microneedle patch obtained in Example 2 is microneedle 2, and the microneedle patch obtained in Example 3 is microneedle 3). The microneedles significantly increase the release rate of lidocaine, and 73 to 91 μg can be released in 0.5 hours, and the release amount in 12 hours can reach more than 1 mg.

[0115] like Fig. 9 As shown in b, with commercially available prilocaine gel as a control, the release amount of prilocaine analgesic microneedles of Example 5 within 12 hours is statistically displayed (wherein the microneedle patch obtained in Example 5 is microneedle 5). It can be clearly seen that the microneedles have a faster and higher release rate than prilocaine gel, can release higher levels of lidocaine and prilocaine in a short time, can take effect in a short time and provide long-lasting analgesia.

[0116] like Fig. 9 As shown in c, with 25% prilocaine solution as a control, the release statistics of the analgesic microneedles containing 25% prilocaine in Example 7 within 12 hours show that (wherein, the microneedle patch obtained in Example 7 is microneedle 7) under the same drug content conditions, microneedle administration can take effect quickly.

[0117] like Fig. 9 As shown in d, with commercially available ibuprofen gel as a control, the release amount of ibuprofen analgesic microneedles in Example 8 within 12 hours is statistically displayed (wherein the microneedle patch obtained in Example 8 is microneedle 8). It can be seen that the microneedles have a faster release rate than the gel.

[0118] Embodiment 14

[0119] This example is a drug efficacy test of the integrated lidocaine analgesic microneedle patch of Example 1 in a rat pain model, and the test method is as follows:

[0120] The hot plate method was used, and the hot plate temperature was 52℃±2℃. The rats had their basal pain latency measured before the experiment, and were observed on the hot plate for 60 seconds to observe the licking behavior. The time when the rats first started licking their hind feet was recorded as the pain latency. The rats were measured again every 10 minutes, for a total of 3 measurements, and the average value was taken. Rats with a basal pain latency of less than 30 seconds were selected for the experiment. Blank patches or lidocaine patches were attached to the two hind feet of the rats, and the pain latency was measured by the hot plate method 2 hours later. If the rats did not lick their feet for more than 60 seconds, they were transferred to prevent burns.

[0121] like Fig.10 As shown, the pain latency of rats before administration was 24.9±5.6 seconds, and the pain latency after administration was 38.7±11.0 seconds, which was significantly different ( Fig.10 The * in the figure indicates significant difference).

[0122] Comparative Example 1

[0123] This comparative example provides a comparison between a double-layer analgesic microneedle patch and the integrated analgesic microneedle patch of the present invention. Comparative Example 1 The preparation method of the double-layer lidocaine analgesic microneedle patch is as follows:

[0124] 1) Preparation of negative microneedle mold: adding polydimethylsiloxane to the curing agent at a mass ratio of 10:1, stirring and mixing, then vacuum degassing at a pressure of 0.1 MPa, and immediately placing it on the surface of the stainless steel metal microneedle master template, curing and drying at 60°C for 0.5h, and finally peeling it off from the metal microneedle to obtain the negative polydimethylsiloxane microneedle mold.

[0125] 2) Prepare the materials required for the needle body layer and the backing layer: prepare the materials according to the mass ratio of sodium carboxymethyl cellulose: polyvinyl pyrrolidone: lidocaine: deionized water of 2.5:30:10:100 for the needle body layer, and prepare the materials according to the mass ratio of sodium carboxymethyl cellulose: polyvinyl pyrrolidone: deionized water of 2.5:30:100 for the backing layer. The polyvinyl pyrrolidone is K30 grade, and the viscosity of sodium carboxymethyl cellulose is 600-1000 mPa.s;

[0126] The prepared needle body layer and backing layer materials were dissolved under magnetic stirring at 4°C for 4 hours, and bubbles were removed by ultrasound to obtain microneedle body solution and microneedle backing solution;

[0127] Preparation of needle body layer: pouring needle body solution into microneedle negative mold, adding appropriate amount of needle body solution after vacuum degassing, and repeating vacuum degassing for 5 times; then removing excess solution above the needle body in the negative mold, drying at 37°C for 9h, and obtaining microneedle body;

[0128] Preparation of backing layer: Take out the dried microneedle mold, pour the backing layer solution on the top of the needle body, and dry it at 37°C for 8h after vacuum degassing;

[0129] After demolding, a double-layer lidocaine analgesic microneedle patch was obtained.

[0130] like Fig.11 As shown, Fig.11 The left picture in the figure is the tip microscope picture of comparative example 1. Fig.11 The right figure in the figure is a microscope image of the needle tip of Example 1. It can be seen from the figure that despite multiple replenishment of the needle tip solution, bubbles still exist in the double-layer microneedle, and the needle tip of the double-layer microneedle is bent, which affects its structural stability and drug loading. The integrated microneedle does not have the above problems.

[0131] Comparative Examples 2 to 20

[0132] The following comparative examples 2 to 20 provide the screening of the formula ratio of the integrated lidocaine analgesic microneedle patch, and the optimal formula is determined through a large number of experiments. Specifically, one or two of the polymer materials polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), small molecule sodium hyaluronate (small molecule HA), and large molecule sodium hyaluronate (large molecule HA) are used as microneedle skeleton materials, and then 10% lidocaine is added, and compared with Examples 1 and 2 of the present invention.

[0133] Comparative Examples 1 to 12 use polyvinyl pyrrolidone and polyvinyl alcohol as microneedle skeleton materials, and are compared with Examples 1 and 2, wherein the mass fraction of lidocaine in the microneedle base solution is 10%, the drying temperature is 35°C, and the drying time is 18h, as shown in Table 1 below. As can be seen from Table 1, the one-piece lidocaine analgesic microneedle patch prepared by selecting the currently commonly used polyvinyl pyrrolidone and polyvinyl alcohol as skeleton materials, when the mass fraction of the analgesic drug in the microneedle base solution is 10%, a variety of ratios have been tried and no microneedles can be formed, while the formulas of Examples 1 and 2 of the present invention can form one-piece lidocaine analgesic microneedle patches with both mechanical properties and puncture ability.

[0134] Table 1 Formulation screening 1

[0135]

[0136] Comparative Examples 13 and 14 use macromolecular sodium hyaluronate and small molecule sodium hyaluronate as microneedle skeleton materials, and are compared with Examples 1 and 2, wherein the mass fraction of lidocaine in the microneedle base solution is 10%, the drying temperature is 35°C, and the drying time is 18h, as shown in Table 2. As can be seen from Table 2, it is also difficult to prepare an integrated lidocaine analgesic microneedle patch by selecting macromolecular sodium hyaluronate and small molecule sodium hyaluronate as skeleton materials, while the formulas of Examples 1 and 2 of the present invention can form an integrated lidocaine analgesic microneedle patch having both mechanical properties and puncture ability.

[0137] Table 2 Formulation screening 2

[0138]

[0139] Comparative Examples 16 to 20 use one or two of polyvinyl pyrrolidone and sodium carboxymethyl cellulose in a certain ratio as microneedle skeleton materials, and are compared with Examples 1 and 2, wherein the mass fraction of lidocaine in the microneedle substrate solution is 10%, the drying temperature is 35°C, and the drying time is 18h, as shown in Table 3. As can be seen from Table 3, 2.5% to 3% sodium carboxymethyl cellulose and 20% to 30% polyvinyl pyrrolidone are mixed, and when the lidocaine content is 10%, an integrated lidocaine analgesic microneedle patch with similar mechanical properties and puncture ability as Examples 1 and 2 of the present invention can be formed.

[0140] Table 3 Formulation screening 3

[0141]

[0142] Therefore, the integrated soluble analgesic microneedle patch of the present invention has a soft and waterproof backing and good skin puncture ability, which can deliver drugs directly to the vicinity of the pain nerve endings under the epidermis or in the dermis through the microneedle transdermal drug delivery system to improve the local concentration and bioavailability of the drug, thereby enhancing the analgesic effect and reducing systemic side effects, and can be widely used for the rapid relief of different skin pains. The integrated soluble analgesic microneedle patch of the present invention has the following characteristics: (1) integrated molding, easy to manufacture, good mechanical properties and puncture ability; (2) the microneedle skeleton is made of water-soluble biodegradable materials, including polyvinyl pyrrolidone and sodium carboxymethyl cellulose; (3) high-content analgesic drugs such as lidocaine and ropivacaine are loaded.

[0143] The above-mentioned embodiments only express several implementation modes of the present invention, and the description is relatively specific and detailed, but it cannot be understood as limiting the scope of the present invention. For those skilled in the art, several modifications and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention.

Claims

1. A method for preparing an integrated soluble analgesic microneedle patch, characterized in that: include: 1) preparing a microneedle negative mold; 2) dissolving the polymer material and the analgesic drug in deionized water and removing bubbles to obtain a microneedle substrate solution; wherein the mass fraction of the analgesic drug in the microneedle substrate solution is 7% to 16.1%; and the mass fraction of the polymer material in the microneedle substrate solution is 15.4% to 23%; 3) injecting the microneedle substrate solution into the microneedle negative mold obtained in step 1), removing bubbles and drying; demoulding after drying to obtain an integrated soluble analgesic microneedle patch; Wherein, the polymer material is polyvinyl pyrrolidone, or the polymer material is a mixture of sodium carboxymethyl cellulose and polyvinyl pyrrolidone; the analgesic drug is one or more of lidocaine, prilocaine, ropivacaine, ibuprofen, and pregabalin.

2. The preparation method according to claim 1, characterized in that: The step 1) is specifically as follows: placing polydimethylsiloxane in a curing agent and stirring and mixing thoroughly, performing vacuum degassing after mixing, immediately pouring the mixture onto the surface of a stainless steel metal microneedle master template after vacuum degassing for curing and drying, and demolding after drying to obtain a microneedle negative mold.

3. The preparation method according to claim 2, characterized in that: In the step 1), the mass ratio of polydimethylsiloxane to curing agent is 10:

1.

4. The preparation method according to claim 1, characterized in that: The microneedle negative mold prepared in step 1) has a needle body height of 300 to 2000 μm.

5. The preparation method according to claim 1, characterized in that: The microneedle negative mold prepared in step 1) has a needle body in the shape of a quadrangular pyramid or a cone.

6. The preparation method according to claim 1, characterized in that: In step 2), when the polymer material is polyvinyl pyrrolidone, the mass fraction of polyvinyl pyrrolidone in the microneedle substrate solution is 15.4%-21.1%; when the polymer material is a mixture of sodium carboxymethyl cellulose and polyvinyl pyrrolidone, the mass fraction of sodium carboxymethyl cellulose in the microneedle substrate solution is 1.6%-1.9%, and the mass fraction of polyvinyl pyrrolidone is 15.4%-21.1%.

7. The preparation method according to claim 1, characterized in that: In the step 2), the bubbles are removed by repeated vacuuming, the number of vacuuming is 3 to 5 times, and the time of each vacuuming is 10 to 15 minutes.

8. The preparation method according to claim 1, characterized in that: In the step 3), the drying temperature is 25 to 40° C., and the drying time is 6 to 18 hours.

9. The preparation method according to claim 1, characterized in that: In the step 3), the base of the microneedle is a circle with a diameter of 10 μm to 50 μm or a square with a side length of 100 μm to 300 μm.

10. An integrated soluble analgesic microneedle patch prepared by the method according to any one of claims 1 to 9.

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