Transdermal nicotine withdrawal soluble microneedle patch as well as preparation method and application thereof

Abstract

The invention discloses a transdermal nicotine withdrawal soluble microneedle patch and a preparation method and application thereof.According to the transdermal nicotine withdrawal soluble microneedle patch, a drug-loaded compound formed by mixing a water-soluble polymer component, a smoking cessation active component and an auxiliary is added into a microneedle mold, and after low-temperature gradient drying, the transdermal nicotine withdrawal soluble microneedle patch is obtained. A porous target object capable of continuously and stably releasing smoking cessation active ingredients is formed. The soluble microneedle patch disclosed by the invention is obtained by combining a microneedle administration technology and a biocompatible material, so that the harm to the lung caused by smoking can be effectively avoided, and meanwhile, the soluble microneedle patch is directly administrated through the skin, so that a first-pass effect and a side effect possibly caused by an oral administration mode can be further avoided; according to the soluble microneedle patch disclosed by the invention, the cytisine or the analogue thereof is used as a main smoking cessation active ingredient, and the sodium hyaluronate or the analogue thereof is used as a matrix material, so that the soluble microneedle patch not only has enhanced solubility and biocompatibility, but also can help to adjust the release rate of the active ingredient.

Description

Technical Field

[0001] The present invention belongs to the technical field of soluble microneedles, and in particular relates to a transdermal nicotine withdrawal soluble microneedle patch and a preparation method and application thereof. Background Art

[0002] With the improvement of health awareness, quitting smoking has become a health issue of widespread concern around the world. It is an indisputable medical fact that smoking is harmful to health. Due to the harm to health, tobacco causes more than 1 million deaths in my country every year. In addition, about half of smokers in my country currently suffer from tobacco dependence, with a total of about 183.5 million people suffering from the disease. Quitting smoking is recognized as the most effective and cost-effective strategy to reduce the risk of smoking-related diseases and premature death.

[0003] Existing smoking cessation methods mainly include nicotine replacement therapy, psychological behavioral intervention and drug therapy, but there are problems such as high risk of addiction, obvious side effects, high cost or poor effect. In particular, although nicotine substitutes can relieve withdrawal symptoms to a certain extent, their success rate in quitting smoking is limited, and long-term use may produce new dependence. Existing smoking cessation products include nicotine patches, chewing gum, lozenges, etc., but these methods have limitations, such as residual nicotine may be harmful to children or pets, inconvenient to use, or unwelcome in public places. Therefore, it is particularly important to develop a new method for smoking cessation that is efficient, safe, convenient and cost-effective.

[0004] Recently, a medical journal published that the research team set up 27 cooperative units in East my country, South China, North China, Central China, Southwest China, Northwest China, and Northeast China, recruited 2,943 smokers who were willing to quit smoking, observed their smoking cessation and followed up. The results showed that 75.8% of the subjects suffered from tobacco dependence; 32.8% used bupropion hydrochloride sustained-release tablets, 31.8% used psychological and behavioral interventions, 26.4% used varenicline tartrate, 4.6% used other treatments such as acupuncture, and 4.4% used nicotine replacement therapy; after 3 months of treatment and follow-up, 21.74% of the subjects successfully quit smoking. The study shows that the overall smoking cessation effect of the smoking population in my country is not ideal, and there is still a lot of room for improvement in the success rate of smoking cessation.

[0005] Achieve Life Sciences is focused on developing cytisine to solve the global problem of smoking and nicotine addiction. Cytisine is a plant alkaloid that has a high binding affinity to nicotinic acetylcholine receptors. It is believed to reduce the severity of nicotine withdrawal symptoms by interacting with nicotine receptors in the brain and help quit smoking by reducing the reward and euphoria associated with smoking. However, the problem of drug administration has not yet been solved. The traditional inhalation method can cause nausea as a side effect; injections can also greatly reduce the effect due to the first-pass effect of the liver; psychological behavioral interventions are slow and have large individual differences; and electronic cigarettes have safety and addiction transfer issues. Summary of the invention

[0006] In view of the deficiencies of the prior art, the purpose of the present invention is to provide a transdermal nicotine withdrawal soluble microneedle patch that solves the problems of first-pass effect and side effects caused by the current oral or inhalation administration methods.

[0007] The present invention also aims to provide a method for preparing the above-mentioned transdermal nicotine withdrawal soluble microneedle patch.

[0008] The present invention also aims to provide a use of the above-mentioned transdermal nicotine withdrawal soluble microneedle patch in assisting nicotine withdrawal diseases.

[0009] In order to achieve the above-mentioned purpose, the technical solution of the present invention is implemented as follows: a transdermal nicotine withdrawal soluble microneedle patch, characterized in that a drug-loaded complex formed by mixing a water-soluble polymer component, a smoking cessation active component and an auxiliary agent is added to a microneedle mold, and after low-temperature gradient drying, a porous transdermal nicotine withdrawal soluble microneedle patch that can continuously and stably release the smoking cessation active ingredient is formed.

[0010] Preferably, the mass ratio of the water-soluble polymer, the smoking cessation active component and the auxiliary agent is 1: 0.027-0.349: 0.048-0.069.

[0011] Preferably, the water-soluble polymer component is selected from at least one of sodium hyaluronate, polyvinyl pyrrolidone and polyvinyl alcohol.

[0012] Preferably, the smoking cessation active component is selected from at least one of cytisine, bupropion, nortriptyline, varenicline, or analogs having the same or similar smoking cessation effects.

[0013] Preferably, the auxiliary agent is polyethylene glycol 200 to polyethylene glycol 10000.

[0014] Preferably, every 4.5 cm 2 The concentration of the active ingredient in the microneedle is 2 to 25 mg, and the polyethylene glycol accounts for 5% to 10% of the mass of the hyaluronic acid.

[0015] Another technical solution of the present invention is achieved as follows: a method for preparing a transdermal nicotine withdrawal soluble microneedle patch, the preparation method specifically comprising the following steps:

[0016] S1. Adding water-soluble polymer components, smoking cessation active components and adjuvants into water and adjusting the concentration to a desired concentration to obtain a precursor solution;

[0017] S2. Evenly distribute the precursor solution obtained in S1 in the microneedle negative mold, remove the bubbles in the precursor solution under vacuum conditions, and then perform low-temperature gradient drying to obtain a soluble microneedle patch.

[0018] Preferably, in S1, the concentration of the precursor solution is 0.5-10wt%.

[0019] Preferably, in S2, before using the microneedle negative mold, it is cleaned with ultrasonic waves for 30 minutes and dried.

[0020] Preferably, in S2, the specific method for removing bubbles in the precursor liquid in the microneedle negative mold under vacuum conditions is: placing the microneedle negative mold distributed with the precursor liquid in a vacuum degassing device at a pressure of -0.25MPa to -0.02MPa for degassing treatment for 8 to 12 minutes at room temperature.

[0021] Preferably, in S2, the specific method for low-temperature gradient drying is: placing the microneedle negative mold containing the precursor solution after removing bubbles in an ultra-low temperature refrigerator at -100°C to -60°C for 2h to 6h, and then placing it in a freeze dryer, and gradient drying in sequence under the conditions of -0.02Mba to -0.25Mba, -80°C to 25°C, and each gradient temperature drying time is not less than 2h.

[0022] Preferably, in S2, the microneedle matrix mold area in the PDMS microneedle negative mold is 4.5 cm 2 The corresponding microneedle patch contains 700 to 1000 microneedles, with a needle height of 350 to 1500 μm, a needle base diameter of 100 to 600 μm, and a needle tip spacing of 500 to 800 μm.

[0023] Preferably, in S2, the microneedle negative mold body is obtained by the following method:

[0024] Preferably, after the PDMS and the curing agent are mixed evenly, vacuum bubbles are formed, the de-bubbled mixture is poured into a metal mold to fill it evenly, and then cross-linked and cured at room temperature, and the cured mold is peeled off from the metal mold to obtain a PDMS mold;

[0025] Preferably, the PDMS mold is etched by laser to obtain a PDMS microneedle negative mold.

[0026] The third technical solution of the present invention is achieved as follows: a transdermal nicotine withdrawal soluble microneedle patch is used to assist nicotine withdrawal diseases.

[0027] Compared with the prior art, 1) the soluble microneedle patch of the present invention is obtained by combining microneedle drug delivery technology with biocompatible materials, so that when using the soluble microneedle patch of the present invention, it can effectively avoid the damage to the lungs caused by smoking. At the same time, it is directly administered through the skin, which can further avoid the first-pass effect and side effects that may be caused by oral administration; 2) cytisine or its analogues in the soluble microneedle patch of the present invention are used as the main active ingredient for quitting smoking, and sodium hyaluronate or its analogues are used as the matrix material, which not only has enhanced solubility and biocompatibility, but also helps to regulate the release rate of the active ingredient; 3) The present invention adopts low-temperature gradient drying to prepare a porous structure microneedle patch, which not only expands the contact area between the microneedle and the water after piercing the skin, accelerates the rapid dissolution of the needle body, but also significantly reduces the microneedle. Discomfort after the needle pierces the skin; 4) When the soluble microneedle patch of the present invention is applied to the surface of human skin, the soluble polymer needle body of the microneedle is rapidly dissolved under the action of the dermal tissue fluid, and the smoking cessation active ingredient embedded in the polymer is slowly released. The molecular weight of the smoking cessation active ingredient is small, and it penetrates the dermis from the surface of the skin into the blood circulation system, is absorbed by the capillaries and lymphatic system of the skin, and finally combines with the nicotine receptors in the brain, thereby reducing the desire to smoke; 5) The soluble microneedle patch of the present invention has broad application prospects; with the continuous expansion of the global smoking cessation market and the increasing demand of consumers for health products, the patch will be widely concerned and welcomed as a new and efficient way to quit smoking; at the same time, its advantages such as low cost, simple preparation process and easy use will also provide strong support for market promotion. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] FIG1 is a flow chart of the preparation of a PDMS microneedle negative mold in an embodiment of the present invention; wherein:

[0029] Figure 1A This is a schematic diagram of curing a polydimethylsiloxane mold plate;

[0030] Figure 1B Schematic diagram of the negative mold of laser-etched microneedles;

[0031] FIG2 is a flow chart of the preparation of a soluble microneedle patch in an embodiment of the present invention;

[0032] Figure 2A Schematic diagram of the microneedle negative mold after cleaning and drying;

[0033] Figure 2B Schematic diagram of the negative mold filled with the drug-loaded hyaluronic acid-peeled dry microneedle polyethylene glycol mixed liquid and dried;

[0034] Figure 2C A schematic diagram of peeling off the dried and formed microneedles;

[0035] Figure 3 Schematic diagram of soluble microneedles in an embodiment of the present invention; wherein ① is a porous structure of microneedles; ② is a drug-loaded complex of hyaluronic acid and polyethylene glycol;

[0036] Figure 4 Schematic diagram of the dissolution of the applied soluble microneedle patch;

[0037] Figure 5 This is a schematic diagram of the nicotine addiction conditioned place preference (CCP) test in rats; among them, ① is the tobacco smoke area; ② is the central area; ③ is the area without tobacco smoke. DETAILED DESCRIPTION

[0038] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with specific embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0039] A transdermal nicotine withdrawal soluble microneedle patch provided by an embodiment of the present invention comprises a drug-loaded complex formed by mixing a water-soluble polymer component, a smoking cessation active component and an adjuvant, which is added to a microneedle mold, and after low-temperature gradient drying, a porous transdermal nicotine withdrawal soluble microneedle patch is formed that can continuously and stably release the smoking cessation active ingredient.

[0040] Furthermore, the mass ratio of the water-soluble polymer, the smoking cessation active component and the auxiliary agent is 1: 0.027-0.349: 0.048-0.069; the water-soluble polymer component is selected from at least one of sodium hyaluronate, polyvinyl pyrrolidone and polyvinyl alcohol; the smoking cessation active component is selected from at least one of cytisine, bupropion, nortriptyline and varenicline, or analogs with the same or similar quitting effects; the auxiliary agent is polyethylene glycol; the polyethylene glycol 600 to polyethylene glycol 10000; every 4.5cm 2 The concentration of the active ingredient in the microneedle is 2 to 25 mg, and the polyethylene glycol accounts for 5% to 10% of the mass of the hyaluronic acid.

[0041] The present invention also provides a method for preparing the above-mentioned transdermal nicotine withdrawal soluble microneedle patch, which specifically comprises the following steps:

[0042] S1. Adding a water-soluble polymer component, a smoking cessation active component, and an adjuvant into water, adjusting the concentration to a desired concentration of 0.5-10 wt %, and obtaining a precursor solution with a concentration of 0.5-10 wt %;

[0043] S2. After ultrasonic cleaning of the microneedle negative mold for 30 minutes and drying, the precursor solution obtained in S1 is evenly distributed in the microneedle negative mold, and bubbles in the precursor solution are removed under vacuum conditions, followed by low-temperature gradient drying to obtain a soluble microneedle patch.

[0044] The specific method for removing bubbles in the precursor solution in the microneedle negative mold under vacuum conditions is:

[0045] At room temperature, placing the microneedle negative mold with the precursor solution distributed thereon in a vacuum degassing device at a pressure of -0.10 MPa to -0.06 MPa for degassing treatment for 8 to 12 minutes;

[0046] The microneedle matrix mold area in the PDMS microneedle negative mold is 4.5 cm 2 The corresponding microneedle patch contains 700 to 1000 microneedles, with a needle height of 350 to 1500 μm, a needle base diameter of 100 to 600 μm, and a needle tip spacing of 500 to 800 μm.

[0047] The specific method for low temperature gradient drying is:

[0048] The negative microneedle mold containing the precursor solution after the bubbles are removed is placed in an ultra-low temperature refrigerator at -100℃ to -60℃ for 2h to 6h, and then placed in a freeze dryer and dried in a gradient manner at 0.02Mba-0.08Mba and -80℃ to 25℃, with each gradient temperature drying time being no less than 2h;

[0049] The microneedle negative mold body is obtained by the following method:

[0050] After the PDMS and curing agent are mixed evenly, vacuum bubbles are formed, and the de-bubbled mixture is poured into a metal mold to fill it evenly, and then cross-linked and cured at room temperature, and the cured mold is peeled off from the metal mold to obtain a PDMS mold;

[0051] The PDMS mold was etched by laser to obtain a PDMS microneedle negative mold.

[0052] The embodiments of the present invention further provide the use of the above-mentioned transdermal nicotine withdrawal soluble microneedle patch in assisting nicotine withdrawal diseases.

[0053] The following are specific embodiments

[0054] Example 1

[0055] The soluble microneedle patch obtained in Example 1 of the present invention is obtained by the following steps:

[0056] (1) Prepare a polydimethylsiloxane (PDMS) mold (plate), the specific method is as follows:

[0057] As shown in FIG1 , PDMS and curing agent are poured into a beaker at a mass ratio of 10:1, stirred for about 5 minutes, placed in a vacuum device for about 10 minutes to remove bubbles, and then the mixture is poured into a metal mold to fill the metal mold; the metal mold is placed horizontally at room temperature, and the filler is cross-linked and cured, and the cured PDMS is peeled off from the metal mold to obtain a PDMS mold.

[0058] The PDMS mold was etched using laser marking machine parameters to prepare a PDMS microneedle negative mold; the microneedle matrix mold area in the microneedle negative mold was 4.5 cm 2 The corresponding microneedle patch contains 700 to 1000 microneedles, with a needle height of 350 to 1500 μm, a needle base diameter of 100 to 600 μm, and a needle tip spacing of 500 to 800 μm.

[0059] Before use, the PDMS microneedle negative mold was treated with an ultrasonic cleaner for 30 minutes and then dried for standby use.

[0060] (2) Preparation of soluble microneedle patch, the specific method is as follows:

[0061] Sodium hyaluronate (0.48 g of low molecular weight sodium hyaluronate and 0.12 g of enzyme-cleaved oligomeric sodium hyaluronate) was dissolved in 5.94 mL of ultrapure water, and 60 μL of polyethylene glycol and 18 mg of cytisine were added in sequence, and stirred evenly to obtain a sodium hyaluronate solution containing cytisine, wherein the mass proportion of the sodium hyaluronate was 10%, and the average molecular weights of the sodium hyaluronate (low molecular weight sodium hyaluronate and enzyme-cleaved oligomeric sodium hyaluronate) were 30000 Da and 8000 Da, respectively; the molecular weight of the polyethylene glycol was 600;

[0062] As shown in Figure 2, a sodium hyaluronate solution containing cytisine is poured onto the surface of the cleaned PDMS microneedle negative mold to make the solution evenly distributed on the PDMS microneedle negative mold; at room temperature, the pressure of the vacuum debubbling device is adjusted to -0.08 MPa, and the bubbles in the solution on the mold are removed for 10 minutes. The mold is then taken out and freeze-dried for 12 hours. The microneedle patch is then peeled off from the microneedle negative mold to obtain a soluble microneedle patch loaded with cytisine.

[0063] According to the method of Example 1, cytisine microneedles with different drug loading concentrations, curing process conditions, different microneedle lengths and microneedle morphologies were prepared. The results are shown in Table 1 below:

[0064] Table 1 Comparison results of different microneedle lengths and microneedle morphologies

[0065]

[0066]

[0067] Example 2

[0068] The soluble microneedle patch obtained in Example 2 of the present invention is obtained by the following steps:

[0069] (1) First, prepare a PDMS microneedle negative mold according to the method of Example 1.

[0070] (2) Preparation of soluble microneedle patch, the specific method is as follows:

[0071] Dissolve 0.6 g of polyvinyl alcohol in 5.94 mL of ultrapure water, add 60 μL of polyethylene glycol and 18 mg of bupropion in sequence, and stir evenly to obtain a polyvinyl alcohol solution containing bupropion, wherein the mass proportion of the polyvinyl alcohol is 10%, and the average molecular weight of the polyvinyl alcohol is 40,000 Da; the molecular weight of the polyethylene glycol is 1,000.

[0072] Pour the polyvinyl alcohol solution containing bupropion onto the surface of the cleaned PDMS microneedle negative mold to evenly distribute the solution on the PDMS microneedle negative mold; at room temperature, adjust the pressure of the vacuum debubbling device to -0.08 MPa, treat for 10 minutes to remove the bubbles in the solution on the mold, take out the mold, and then freeze-dry it at low temperature for 12 hours, then peel off the microneedle patch from the microneedle negative mold to obtain a soluble microneedle patch loaded with bupropion.

[0073] Example 3

[0074] The soluble microneedle patch obtained in Example 3 of the present invention is obtained by the following steps:

[0075] (1) First, prepare a PDMS microneedle negative mold according to the method of Example 1.

[0076] (2) Preparation of soluble microneedle patch, the specific method is as follows:

[0077] Dissolve 0.6 g of polyvinyl pyrrolidone in 5.94 mL of ultrapure water, add 60 μL of polyethylene glycol and 18 mg of nortriptyline in sequence, and stir evenly to obtain a polyvinyl pyrrolidone solution containing nortriptyline, wherein the mass proportion of the polyvinyl pyrrolidone is 10%, the average molecular weight of the polyvinyl pyrrolidone is 50,000 Da, and the molecular weight of the polyethylene glycol is 2,000.

[0078] Pour the polyvinyl pyrrolidone solution containing nortriptyline into the cleaned PDMS microneedle negative mold to evenly distribute the solution on the PDMS microneedle negative mold; at room temperature, adjust the pressure of the vacuum debubbling device to -0.08 MPa, treat for 10 minutes to remove the bubbles in the solution on the mold, take out the mold, and then freeze-dry it at low temperature for 12 hours, then peel off the microneedle patch from the microneedle negative mold to obtain a soluble microneedle patch loaded with nortriptyline.

[0079] Example 4

[0080] The soluble microneedle patch obtained in Example 4 of the present invention is obtained by the following steps:

[0081] (1) First, prepare a PDMS microneedle negative mold according to the method of Example 1.

[0082] (2) Preparation of soluble microneedle patch, the specific method is as follows:

[0083] Polyvinyl alcohol (0.3 g) and polyvinyl pyrrolidone (0.3 g) were dissolved in 5.94 mL of ultrapure water, and 60 μL of polyethylene glycol and 18 mg of varenicline were added in sequence, and the mixture was stirred evenly to obtain a polyvinyl alcohol / polyvinyl pyrrolidone solution containing varenicline, wherein the mass proportion of the polyvinyl alcohol / polyvinyl pyrrolidone was 10%, and the average molecular weights of the polyvinyl alcohol / polyvinyl pyrrolidone were 40,000 Da and 50,000 Da, respectively; the molecular weight of polyethylene glycol was 1000.

[0084] Pour the polyvinyl alcohol / polyvinyl pyrrolidone solution containing varenicline into the cleaned PDMS microneedle negative mold to evenly distribute the solution on the PDMS microneedle negative mold; at room temperature, adjust the pressure of the vacuum debubbling device to -0.08MPa, treat for 10 minutes to remove the bubbles in the solution on the mold, take out the mold, and then freeze-dry it at low temperature for 12 hours, then peel off the microneedle patch from the microneedle negative mold to obtain a soluble microneedle patch containing varenicline.

[0085] Example 5

[0086] Taking the soluble microneedle patch loaded with cytisine prepared in Example 1 as an example, three microneedle in vitro dissolution rate analysis experiments were carried out respectively. The specific experimental steps are as follows:

[0087] After the soluble microneedle patch of cytisine was moistened with water, it was placed under a microscope to observe the dissolution process of the needle tip within 30 seconds. A 20% (w / v) gelatin gel was prepared to simulate the wet mucosa, and the soluble microneedle patch of cytisine labeled with methylene blue was inserted into the gelatin gel. After 1 minute, the microneedle was removed with tweezers, and the dissolution performance of the microneedle was evaluated by the blue dye remaining on the gelatin. The results are shown in Table 2:

[0088] Table 2 Dissolution of the needle tip of the soluble microneedle patch of cytisine after wetting with water

[0089] serial number Test samples Needle tip dissolution time (seconds) 1 Cytisine Microneedle Patch 18 2 Cytisine Microneedle Patch 20 3 Cytisine Microneedle Patch 25

[0090] Table 3 Residual blue dye after inserting the soluble microneedle patch of cytisine into gelatin gel

[0091]

[0092] Note: The evaluation criteria for dissolution performance are as follows:

[0093] High: The needle tip is almost completely dissolved within 60 seconds, and there is no significant blue dye residue on the gelatin;

[0094] Middle: The needle tip partially dissolved within 60 seconds, with slight blue dye residue on the gelatin;

[0095] Low: The needle tip dissolves less within 60 seconds, and there is obvious blue dye residue on the gelatin.

[0096] By analyzing the data in Table 2 and Table 3 above, it can be seen that the porous microneedle patch of the present invention completely dissolves quickly, which is conducive to quickly eliminating the foreign body sensation and discomfort during the use of the microneedle; the blue mark left on the gelatin film after the needle tip is removed indicates that the prepared microneedle dissolves and releases the blue dye rate, and the blue dye diffusion rate of the hyaluronic acid-polyethylene glycol as the matrix microneedle is slower than that of the hyaluronic acid as the matrix microneedle. Therefore, the prepared cytisine microneedle slowly releases the drug after contacting with the moist environment, exerting a continuous curative effect on cigarette addiction.

[0097] Example 6

[0098] Taking the soluble microneedle patch loaded with cytisine prepared in Example 1 as an example, a mouse experiment was carried out to verify its beneficial effect as a medical microneedle patch for smoking cessation.

[0099] Design a Conditioned Place Preference (CPP) Experiment to evaluate:

[0100] A mouse cigarette addiction model was established. The mice were divided into an experimental group (cytisine microneedle treatment) and a control group (placebo microneedle treatment). Each group of mice freely explored two different environments, one containing tobacco smoke and the other without tobacco smoke. The degree of preference of mice for the environment containing tobacco smoke was used as an indicator to assess addiction.

[0101] A rat nicotine addiction model was established, and rats with smoking addiction were selected and divided into an experimental group (cytisine microneedle treatment) and a control group (placebo microneedle treatment); during the adaptation period, the rats were placed in a conditioned preference device (CCP) to adapt to the environment and eliminate the position preference; during the training period, the treatment group and the control group were treated with cytisine microneedle and placebo microneedle respectively when entering the tobacco smoke area, and did not receive any treatment when entering the tobacco smoke-free area; during the test period, the treatment group and the control group were not given any treatment, and the rats were tested for their position preference residence time in the tobacco smoke area and the tobacco smoke-free area. The results are shown in Table 4 below:

[0102] Table 4 Comparison of the location preference residence time of rats in the tobacco smoke area and the non-tobacco smoke area

[0103]

[0104]

[0105] Note: Preference index (preference for tobacco smoke area) = (time in tobacco smoke area during test period - time in non-tobacco smoke area during test period) / (time in tobacco smoke area during test period + time in non-tobacco smoke area during test period) * 100%

[0106] The data in Table 4 above show that the addiction of the mice in the experimental group is significantly lower than that of the mice in the control group, confirming the beneficial effect of the soluble microneedle patch provided by the present invention in nicotine withdrawal.

[0107] In summary, 1) the soluble microneedle patch of the present invention is obtained by combining microneedle drug delivery technology with biocompatible materials, so that when using the soluble microneedle patch of the present invention, it can effectively prevent the damage to the lungs caused by smoking, and at the same time, it is directly administered through the skin, which can further avoid the first-pass effect and side effects that may be caused by oral administration; 2) cytisine or its analogs in the soluble microneedle patch of the present invention are used as the main active ingredient for quitting smoking, and sodium hyaluronate or its analogs are used as the matrix material, which not only has enhanced solubility and biocompatibility, but also helps to regulate the release rate of the active ingredient; 3) The present invention prepares a porous structure microneedle patch by adopting low-temperature gradient drying, which not only expands the contact area between the microneedle and water after piercing the skin, accelerates the rapid dissolution of the needle body, but also significantly reduces the discomfort after the microneedle pierces the skin; 4) The needle body of the soluble microneedle patch of the present invention is exquisitely designed to ensure that it can easily penetrate the stratum corneum of the skin for drug delivery. An adhesive layer is attached to the back of the patch for firmly attaching to the skin surface to ensure that the patch remains in place during the dissolution process; 5) When the soluble microneedle patch of the present invention is applied to the surface of human skin, the soluble polymer needle body of the microneedle is rapidly dissolved under the action of the dermal tissue fluid, and the smoking cessation active ingredient embedded in the polymer is slowly released. The molecular weight of the smoking cessation active ingredient is small, and it penetrates the dermis from the surface of the skin into the blood circulation system, is absorbed by the capillaries and lymphatic system of the skin, and finally binds to the nicotine receptors in the brain, thereby reducing the desire to smoke; 6) The soluble microneedle patch of the present invention has broad application prospects; with the continuous expansion of the global smoking cessation market and the increasing demand of consumers for health products, the patch will be widely concerned and welcomed as a new and efficient way to quit smoking; at the same time, its advantages such as low cost, simple preparation process and easy use will also provide strong support for market promotion.

[0108] According to the degree of addiction of smokers, patches of different doses, such as 42mg, 21mg and 10mg, can be provided to ensure that the amount of nicotine replacement during the smoking cessation process is neither excessive nor insufficient, which helps to make a smooth transition. The patch is attached to the skin without complicated operation steps, and generally can maintain stable release for a certain period of time, reducing the trouble of frequent use. The patch is small and light, and can be attached to hidden places such as arms without affecting daily life and work. The patch form is relatively stable during storage and is not easily affected by the external environment and deteriorated. It can be carried in independent packaging or a small storage box. Therefore, it can be foreseen that the patch will occupy an important position in the future smoking cessation market and produce significant economic and social benefits.

[0109] The above is only a preferred specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any changes or substitutions that can be easily thought of by a person skilled in the art within the technical scope disclosed by the present invention should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention should be based on the protection scope of the claims.

Claims

1. A transdermal nicotine withdrawal soluble microneedle patch, characterized in that: A drug-loaded complex formed by mixing a water-soluble polymer component, a smoking cessation active component and an auxiliary agent is added to a microneedle mold. After low-temperature gradient drying, a porous transdermal nicotine withdrawal soluble microneedle patch is formed that can continuously and stably release the smoking cessation active ingredient.

2. The transdermal nicotine withdrawal soluble microneedle patch according to claim 1, characterized in that: The mass ratio of the water-soluble polymer, the smoking cessation active component and the auxiliary agent is 1: 0.027-0.349: 0.048-0.069; 2 The concentration of the active ingredient in the microneedle is 2 to 25 mg, and the polyethylene glycol accounts for 5% to 10% of the mass of the hyaluronic acid.

3. The transdermal nicotine withdrawal soluble microneedle patch according to claim 1 or 2, characterized in that: The water-soluble polymer component is selected from at least one of sodium hyaluronate, polyvinyl pyrrolidone, and polyvinyl alcohol; the smoking cessation active component is selected from at least one of cytisine, bupropion, nortriptyline, and varenicline, or analogs with the same or similar smoking cessation effects; the auxiliary agent is polyethylene glycol 200 to polyethylene glycol 10000.

4. A method for preparing a transdermal nicotine withdrawal soluble microneedle patch, characterized in that: The preparation method specifically comprises the following steps: S1. Adding water-soluble polymer components, smoking cessation active components and adjuvants into water and adjusting the concentration to a desired concentration to obtain a precursor solution; S2. Evenly distribute the precursor solution obtained in S1 in the microneedle negative mold, remove the bubbles in the precursor solution under vacuum conditions, and then perform low-temperature gradient drying to obtain a soluble microneedle patch.

5. The method for preparing the transdermal nicotine withdrawal soluble microneedle patch according to claim 4, characterized in that: In S1, the concentration of the precursor solution is 0.5-10wt%.

6. The method for preparing the transdermal nicotine withdrawal soluble microneedle patch according to claim 4, characterized in that: In S2, before using the microneedle negative mold, it is cleaned with ultrasonic waves for 30 minutes and dried.

7. The method for preparing the transdermal nicotine withdrawal soluble microneedle patch according to claim 6, characterized in that: In S2, the specific method of removing bubbles in the precursor solution in the microneedle negative mold under vacuum conditions is: placing the microneedle negative mold with the precursor solution distributed thereon in a vacuum degassing device at a pressure of -0.25 MPa to -0.02 MPa for degassing treatment for 8 to 12 minutes at room temperature; The specific method for low-temperature gradient drying is: place the microneedle negative mold containing the precursor liquid after removing bubbles in an ultra-low temperature refrigerator at -100℃~-60℃ for 2h~6h, then place it in a freeze dryer, and gradient dry it in sequence under the conditions of -0.02Mba~-0.25Mba, -80℃~25℃, and each gradient temperature drying time is not less than 2h.

8. The method for preparing the transdermal nicotine withdrawal soluble microneedle patch according to claim 7, characterized in that: In S2, the microneedle matrix mold area in the microneedle negative mold is 4.5 cm 2 The corresponding microneedle patch contains 700 to 1000 microneedles, with a needle height of 350 to 1500 μm, a needle base diameter of 100 to 600 μm, and a needle tip spacing of 500 to 800 μm.

9. The method for preparing the transdermal nicotine withdrawal soluble microneedle patch according to any one of claims 4 to 8, characterized in that: In S2, the microneedle negative mold body is obtained by the following method: After the PDMS and curing agent are mixed evenly, vacuum bubbles are formed, the de-bubbled mixture is poured into a metal mold to fill it evenly, and then cross-linked and cured at room temperature, and the cured mold is peeled off from the metal mold to obtain a PDMS mold; The PDMS mold was etched by laser to obtain a PDMS microneedle negative mold.

10. Use of the transdermal nicotine withdrawal soluble microneedle patch according to claims 1-3 or the transdermal nicotine withdrawal soluble microneedle patch obtained by the preparation method according to any one of claims 4-9 in assisting nicotine withdrawal diseases.

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