An adjuvant-containing soluble mite allergen microneedle patch

Abstract

The present invention discloses an adjuvant-containing soluble mite allergen microneedle patch, which comprises a needle body and a backing. The needle body comprises a mite allergen, a composite adjuvant and a matrix material. Among them, the composite adjuvant is a mixture of microcrystalline tyrosine and alfalfa polysaccharide, and the content ratio of microcrystalline tyrosine to alfalfa polysaccharide is (2:1) to (1:2). The soluble mite allergen microneedle patch provided by the present invention, by selecting a suitable type and content of the composite adjuvant and the mass ratio of the matrix material in the needle body, makes the prepared soluble mite allergen microneedle patch have appropriate mechanical strength, good therapeutic effect and good safety.

Description

Technical Field

[0001] The present invention relates to the technical field of administration of mite allergens, and particularly relates to a soluble microneedle patch containing an adjuvant and a mite allergen. Background Art

[0002] Allergic asthma is a relatively stubborn disease, mostly occurring in infancy. Long-term repeated attacks of allergic asthma can be complicated by chronic bronchitis, pulmonary interstitial fibrosis, obstructive emphysema, chronic pulmonary heart disease, etc. If treatment is neglected, it can accompany the patient for life. The prevalence rate of asthma in China is about 1%, and can reach 3% in children. It is estimated that there are more than 10 million asthma patients in the country. The main allergens causing allergic asthma include pollen, house dust, mites, animal dander, etc. Among them, mite allergens are one of the most widely distributed and typical allergens in the world.

[0003] Currently, the main desensitization treatments are subcutaneous injection desensitization and sublingual desensitization. Injection treatment requires professional medical personnel to operate, and can cause pain, bleeding, and is likely to result in poor patient compliance; while sublingual treatment requires cooperation with other drug treatments, has a high cost, and its desensitization effect is not as good as that of subcutaneous injection. Therefore, it is necessary to develop a new type of vaccine administration route.

[0004] The skin contains a large number of professional antigen-presenting cells such as Langerhans cells and dendritic cells, making the skin a good vaccine inoculation site. Therefore, the transdermal drug delivery system is a popular new drug delivery technology in recent years. Among them, microneedles have many advantages such as safety, painlessness, convenient administration, and the ability to break through the stratum corneum barrier for delivering biological macromolecule drugs, so the development of microneedles is particularly rapid.

[0005] Many allergen vaccines generally have deficiencies such as weak immunogenicity and difficulty in inducing an effective immune response in the body. Therefore, a certain substance is needed to enhance their immune effect. Under this premise, the research on immune adjuvants is particularly urgent.

[0006] Adjuvants can induce a long-term and highly efficient specific immune response in the body, improve the body's protection ability, and at the same time can reduce the dosage of immune substances and lower the production cost of vaccines. Reasonable selection and use of adjuvants can not only save the amount of antigen used, but also quickly stimulate the immune system, which is particularly significant for people with low immunity. In recent years, to meet the needs of new vaccines, adjuvants have developed from traditional and single forms to new and diversified forms.

[0007] By consulting domestic and foreign literature and patents, no researcher has prepared soluble microneedles that can effectively enhance the treatment effect of mite allergen vaccines.

[0008] A sublingual mite allergen vaccine with chitosan as an adjuvant was prepared according to the Chinese patent with the publication number CN 1733299A. However, the deficiencies of this solution are as follows: ① The preparation methods of sublingual tablets and microneedle preparations are very different and difficult to draw on; ② This patent only mentions in Example 5 that the immunotherapy for asthma has good effects in the chitosan-dermatophagoides farinae allergen treatment group, but there are no experimental data or charts to prove it; ③ The applicant found in the preliminary experiment that the soluble microneedles prepared with chitosan as an adjuvant-loaded mite allergen have the defect of "insufficient mechanical strength and inability to effectively penetrate the skin of experimental animals (pigs)".

[0009] Another example is that a soluble microneedle of a pneumococcal polysaccharide vaccine with MF59 (a biodegradable oil emulsion) as an adjuvant was prepared according to the Chinese patent with the publication number CN 110680798A. However, the physicochemical properties of pneumococcal polysaccharide vaccine and mite allergen are different. Different adjuvants or the combined use of adjuvants have different immunological effects on vaccines. Therefore, for different vaccines, it is necessary to screen suitable adjuvants to achieve corresponding therapeutic effects (① Xu Jinjun, Tao Jianping, Peng Jinbiao, etc. Effects of different adjuvants and immunization routes on the immune protection of Eimeria tenella SO7 antigen [J]. Chinese Journal of Preventive Veterinary Medicine, 2007, 29(9): 697-703; ② Tao Li, Duan Jinmei, Shu Xiaoming, etc. Immunopotentiating effect of notoginsenoside R1 on aluminum adjuvant hepatitis A vaccine [J]. Chinese Journal of Biologicals, 2008, 21(3): 197-200.). Therefore, there are still many uncertainties in using the microneedle prescriptions of other existing drugs for reference to develop soluble mite allergen microneedles.

[0010] Furthermore, Kim et al. prepared soluble mite allergen microneedles. (Kim J H, Shin J U, Kim S H et al. Successful transdermal allergen delivery and allergen-specific immunotherapy using biodegradable microneedle patches [J]. Biomaterials, 2017, 150: 38.) However, the researchers used the microdroplet traction method to prepare the microneedles. This method is complex in operation, unable to accurately control the drug loading amount, and difficult to mass-produce on a large scale. There are certain differences in the preparation process from the mold method used in the present invention; moreover, no adjuvant was added to the microneedle prescription, resulting in poor desensitization effects of the prepared soluble mite allergen microneedles. And it is a well-known means in the allergen preparation industry to add adjuvants to increase the desensitization effect.

[0011] The Chinese patent with the publication number CN 109715075A also uses the microdroplet traction method to prepare adjuvant-free mite allergen microneedles as tools for diagnosing and treating allergic diseases, and also has the above-mentioned deficiencies.

[0012] In the patent with the publication number JP 2014156433A, soluble microneedles are used as tools for allergen allergy tests such as mites, but there are no specific examples for preparing soluble microneedles of mite allergens. Therefore, it is difficult to draw on.

[0013] Another example is the literature "Coated microneedle-based cutaneous immunotherapy prevents Der p 1-induced airway allergy in mice". The dust mite allergen Der p1 and the adjuvant CpG are coated on the microneedles. However, the deficiencies of this scheme are as follows: ① The drug loading capacity of the coated microneedles is small, making the amount of vaccine loaded into the microneedles very limited; ② As the coating times of the coated microneedles increase, the microneedles are easily passivated, so there is a risk that the microneedles cannot effectively penetrate into the skin; ③ Although the adjuvant CpG enhances the immunogenicity of Der p1, there is no significant difference. See Figure 1H of this literature (Akhilesh, Kumar, Shakya, et al. Coated microneedle-based cutaneous immunotherapy prevents Der p 1-induced airway allergy in mice. [J]. Journal of Allergy & Clinical Immunology, 2018.).

[0014] At the same time, considering the actual application of microneedles, one of the key factors for the successful development of soluble mite allergen microneedles is that the microneedles can penetrate the skin without breaking to ensure the effective delivery of drugs. Therefore, sufficient mechanical strength is required. (Hiraishi Y, Nakagawa T, Quan Y S, et al. Performance and characteristics evaluation of a sodium hyaluronate-based microneedle patch for a transcutaneous drug delivery system [J]. International Journal of Pharmaceutics, 2013, 441(1-2): 570-579.).

[0015] In summary, how to develop a soluble mite allergen microneedle patch with appropriate mechanical strength, good therapeutic effect and high safety is a technical problem that needs to be urgently solved by those skilled in the art. Summary of the Invention

[0016] The technical problem to be solved by the present invention is to provide a soluble mite allergen microneedle patch and a preparation method thereof, which solve the deficiencies of the above-mentioned prior art by selecting suitable adjuvant types and contents and the content ratio of the matrix material.

[0017] To this end, the present invention adopts the following technical solutions:

[0018] A soluble mite allergen microneedle patch containing an adjuvant, comprising a needle body and a backing. The needle body comprises a mite allergen, a composite adjuvant and a matrix material. Among them, the composite adjuvant is a mixture of microcrystalline tyrosine and alfalfa polysaccharide, and the content ratio of microcrystalline tyrosine to alfalfa polysaccharide is (2:1) to (1:2).

[0019] More preferably, the content ratio of microcrystalline tyrosine to alfalfa polysaccharide in the composite adjuvant is (2:1).

[0020] Preferably, the content ratio of the composite adjuvant to the mite allergen is (8:1) to (2:1).

[0021] More preferably, the content ratio of the composite adjuvant to the mite allergen is 4:1.

[0022] Preferably, the mass ratio of the matrix material in the needle body is 50-60%.

[0023] More preferably, the mass ratio of the matrix material in the needle body is 50%.

[0024] Preferably, in a soluble mite allergen microneedle patch containing an adjuvant, the components and their contents in the needle body are: the mass ratio of the mite allergen is 10%, the mass ratio of the matrix material is 50%, the mass ratio of microcrystalline tyrosine is 26.67%, and the mass ratio of alfalfa polysaccharide is 13.33%.

[0025] In the present invention, the matrix material is a pharmaceutically acceptable material, including but not limited to: ductile or brittle materials, monosaccharide, oligosaccharide or polysaccharide materials, synthetic polymer materials, etc., as long as the formability, moisture absorption and piercing property of the soluble microneedle are satisfied.

[0026] Compared with the prior art, the soluble mite allergen microneedle patch provided by the present invention has the following beneficial effects:

[0027] The present invention screens suitable types and contents of composite adjuvants (microcrystalline tyrosine + alfalfa polysaccharide) and the mass ratio of the matrix material in the needle body (50-60%), so that the prepared mite allergen soluble microneedle patch has appropriate mechanical strength, good therapeutic effect and good safety. Detailed implementation manners

[0028] The following are specific embodiments of the present invention to further describe the technical solutions of the present invention, but the protection scope of the present invention is not limited to these embodiments. Any change or equivalent substitution that does not deviate from the concept of the present invention is included in the protection scope of the present invention.

[0029] Example 1 Preparation of mite allergen soluble microneedles

[0030] The polydimethylsiloxane negative mold required for preparing mite allergen soluble microneedles is prepared by the inverse molding method. The mite allergen soluble microneedles are prepared by centrifuging into the mold in two steps, and the microneedles are dried in an experimental box at 10°C and then demolded to obtain the finished soluble microneedle patch.

[0031] Example 2 Screening of adjuvant types

[0032] Set the proportion of the adjuvant in the total mass of the needle body to a certain value of 40%, the content of the mite allergen to 10%, and the content of the microneedle matrix material Gantrez AN to 50%. Only change the type of adjuvant, and select microcrystalline tyrosine (MCT), oil emulsion (MF59), chitosan (CS), and alfalfa polysaccharide (MSP) to investigate the effects of different combinations of adjuvants on the therapeutic effect of microneedles as shown in Table 1. The soluble microneedles involved in this example are prepared by referring to Example 1 of the present invention.

[0033] Table 1. Prescriptions of soluble microneedles containing different types of adjuvants

[0034] NO. MCT MF59 CS MSP 1 - - - - 2 40％ - - - 3 - 40％ - - 4 - - 40％ - 5 - - - 40％ 6 20％ 20％ - - 7 20％ - 20％ - 8 20％ - - 20％ 9 - 20％ 20％ - 10 - 20％ - 20％ 11 - 20％ - 20％ 12 - - 20％ 20％

[0035] Prepare soluble microneedles according to the prescriptions in Table 1. Among them, Group NO.1 refers to adding no adjuvant, and Groups NO.2-NO.12 refer to adding a single adjuvant or a composite adjuvant in a ratio of 1:1, and measure the mechanical strength of the microneedles and the therapeutic effect of the mite allergen.

[0036] (1) Measurement of the mechanical strength of microneedles:

[0037] The mechanical strength of the soluble microneedles is measured by the skin puncture staining method. The higher the perforation success rate, the higher the mechanical strength of the microneedles.

[0038] The measurement method is as follows: Use a dispenser to insert the prepared microneedles into the skin of neonatal pigs, pull them out after 30S, stain with methylene blue solution, and finally use a digital camera to take pictures of the stained pig skin surface. Calculate and determine the number of stained channels, and calculate the microneedle perforation success rate. The perforation success rate = the number of stained holes / the number of microneedles (n = 6).

[0039] (2) Determination of the therapeutic effect of mite allergens:

[0040] Randomly divide healthy Balb / c mice into 14 groups, with 6 mice in each group, namely the microneedle treatment group (NO.1 - NO.12), the normal group (NO.13), and the asthma group (NO.14). Sensitize the mice on days 0, 7, and 14 respectively. The normal group is intraperitoneally injected with 150 μL of PBS, and the other groups are intraperitoneally injected with 50 μg of house dust mite extract and 2 mg of Al(OH)3 adjuvant (both in accordance with the industry specifications for mouse sensitization and modeling), diluted with PBS to a final volume of 150 μL. One week after sensitization, the asthma group is given PBS solution, and the treatment group is treated with microneedle patches. Treat once every 3 days for a total of 5 times. One week after the last treatment, except for the normal group, each group is stimulated by aerosol inhalation of dust mite extract for 7 consecutive days. 24 h after the last stimulation, the specific IgE level in the serum of each group of mice is detected by ELISA. Measure the absorbance (OD value) at a wavelength of 450 nm. The larger the OD value, the more IgE content.

[0041] During the sensitization stage, when the body first comes into contact with the allergen, an immune response occurs, resulting in the production of a large number of type 2 T helper lymphocytes and IgE antibodies specific to the allergen. The IgE antibodies bind to the receptors on the surface of mast cells and basophils in the respiratory mucosa and skin. After the body is sensitized, when it encounters the same allergen again, an allergic reaction will occur. During the allergic reaction stage, the allergen molecule binds to the IgE antibody on the surface of mast cells and basophils, triggering the degranulation process, that is, these cells release histamine and other inflammatory chemical mediators into the surrounding tissues and blood, thus causing local or systemic reactions. Therefore, the lower the IgE content, the better the therapeutic effect.

[0042] When the perforation success rate of the microneedle is greater than 80%, and the OD difference = OD value (asthma group) - OD value (microneedle treatment group) > 0.50, it is considered qualified. The test results and the calculation results of the OD difference are shown in Table 2.

[0043] Table 2. Effects of different types of adjuvants on the mechanical strength of microneedles and the therapeutic effect of mite allergens (mean ± SD, n = 6)

[0044] NO. OD value Perforation success rate % OD difference 1 1.83±0.11 97.1±2.2 0.10 2 0.76±0.03 74.2±0.5 1.17 3 1.57±0.10 62.0±0.7 0.36 4 1.44±0.04 78.2±1.3 0.49 5 1.56±0.07 94.2±1.8 0.37 6 0.92±0.01 69.5±1.1 1.01 7 1.52±0.13 80.3±1.6 0.41 8 0.59±0.05 87.3±1.3 1.34 9 1.48±0.03 74.9±1.0 0.45 10 0.88±0.06 77.2±1.2 1.05 11 1.41±0.08 73.6±0.2 0.52 12 1.47±0.10 85.6±2.1 0.46 13 0.11±0.01 / / 14 1.93±0.16 / /

[0045] As can be seen from Table 2:

[0046] ① Compared with the normal group (NO.13), the IgE level in the asthma group (NO.14) was significantly increased, indicating successful modeling; compared with the asthma group (NO.14), the IgE levels in the treatment groups (NO.1-12) were all decreased to varying degrees, indicating that the microneedle patches loaded with mite allergens had a certain degree of immune improvement effect.

[0047] ② For the groups with the piercing success rate meeting the test requirements, they were NO.1, NO.5, NO.7, NO.8, and NO.12 groups; for the groups with the OD difference meeting the test requirements, they were NO.2, NO.6, NO.8, NO.10, and NO.11 groups; considering both the piercing success rate and the OD difference must meet the test requirements, only the NO.8 group.

[0048] Therefore, choosing the combination of microcrystalline tyrosine (MCT) and alfalfa polysaccharide (MSP) as the composite adjuvant to develop soluble microneedles of mite allergens can take into account both the mechanical strength of the microneedles and the therapeutic effect of the mite allergens.

[0049] Example 3 Screening of the content ratio of each component in the composite adjuvant

[0050] On the basis of Example 2, further investigate the differences in the effects of the content ratio of each component in the composite adjuvant on the microneedle performance and therapeutic effect.

[0051] Set the proportion of the immune adjuvant in the total mass of the needle body to a fixed value of 40%, the components of the composite adjuvant are fixed as MCT and MSP, the content of the mite allergen is 10%; the content of the microneedle matrix material is 50%. Only change the content ratio of MCT and MSP, and investigate the effects of composite adjuvants with different content ratios on the mechanical strength of the microneedles and the therapeutic effect of the mite allergens as shown in Table 3.

[0052] The preparation method of the soluble microneedles involved in this example refers to Example 1 of the present invention. The detection methods and standards for the mechanical strength of the microneedles and the therapeutic effect of the mite allergens prepared by the prescriptions shown in Table 3 refer to Example 2 of the present invention. The test results and the calculation results of the OD difference are shown in Table 3.

[0053] Table 3. Effects of the content ratio of each component of the composite immune adjuvant on the mechanical properties of the microneedles and the therapeutic effect of the mite allergens (mean±SD, n = 6)

[0054] MCT:MSP OD value Perforation success rate % OD difference 4:1 0.61±0.04 75.2±0.7 1.32 2:1 0.23±0.02 83.9±0.3 1.70 1:1 0.59±0.05 87.3±1.3 1.34 1:2 0.78±0.03 90.1±2.0 1.15 1:4 1.45±0.04 93.2±0.5 0.48

[0055] As can be seen from Table 3:

[0056] ① Within a certain range, as the proportion of MSP increases, the OD value shows a trend of first decreasing and then increasing, and the mechanical strength of the microneedles shows a gradually increasing trend.

[0057] ② Considering both the perforation success rate and OD difference must meet the test requirements, the content ratio of MCT to MSP is (2:1) to (1:2).

[0058] ③ The smaller the OD value, the more IgE content. Therefore, only when MCT:MSP = 2:1, the therapeutic effect of mite allergen is the best, and the mechanical strength of the microneedles also meets the test requirements.

[0059] Example 4 Screening of the mass ratio of the composite adjuvant to the mite allergen

[0060] On the basis of Example 3, further investigate the differences in the effects of the mass ratio of the composite adjuvant to the mite allergen on the performance and therapeutic effect of the microneedles.

[0061] Set the proportion of the microneedle matrix material to 50%, the components and ratio of the composite adjuvant are fixed as MCT:MSP = 2:1, and only change the content ratio of the composite adjuvant to the mite allergen. Investigate the effects of different content ratios of the composite adjuvant to the mite allergen on the mechanical strength of the microneedles and the therapeutic effect of the mite allergen as shown in Table 4.

[0062] The preparation method of the soluble microneedles involved in this example refers to Example 1 of the present invention. The detection methods and standards for the mechanical strength of the microneedles and the therapeutic effect of the mite allergen prepared by the prescriptions shown in Table 4 refer to Example 2 of the present invention. The test results and the calculation results of the OD difference are shown in Table 4.

[0063] Table 4. Effects of the mass ratio of the composite adjuvant to the mite allergen on the mechanical properties of the microneedles and the therapeutic effect of the mite allergen (mean ± SD, n = 6)

[0064] Compound adjuvant: mite allergen OD value Perforation success rate % OD difference 16:1 1.58±0.17 93.2±2.1 0.35 8:1 0.84±0.06 87.6±1.7 1.09 4:1 0.23±0.02 83.9±0.3 1.70 2:1 0.57±0.07 81.2±1.1 1.36 1:1 1.47±0.11 75.8±1.4 0.46

[0065] As can be seen from Table 4,

[0066] ① As the proportion of the mite allergen increases, the mechanical strength of the microneedles and the therapeutic effect of the vaccine show a downward trend.

[0067] ② Considering both the perforation success rate and OD difference must meet the test requirements, the content ratio of the composite adjuvant to the mite allergen is (8:1) to (2:1).

[0068] ③ Only when the composite adjuvant:mite allergen = 4:1, the therapeutic effect of the mite allergen is the best, and the mechanical strength of the microneedles also meets the test requirements.

[0069] Example 5 Screening of the mass proportion of the matrix material

[0070] On the basis of Example 4, further investigate the differences in the effects of the mass proportion of the matrix material in the needle body on the performance and therapeutic effect of the microneedles.

[0071] The components and ratios of the composite adjuvant were fixed as MCT:MSP = 2:1, and the content ratio of the composite adjuvant to the mite allergen was fixed as 4:1. Only the content of the matrix material was changed, and the effects of different contents of the matrix material on the performance and therapeutic effect of the microneedles were investigated as shown in Table 5.

[0072] The preparation method of the soluble microneedles involved in this example referred to Example 1 of the present invention. The detection methods and standards for the mechanical strength and mite allergen therapeutic effect of the microneedles prepared according to the prescriptions shown in Table 5 referred to Example 2 of the present invention.

[0073] Table 5. Effects of the mass ratio of the matrix material on the mechanical properties of the microneedles and the therapeutic effect of the mite allergen (mean±SD, n = 6)

[0074] Matrix material content (%) OD value Perforation success rate % OD difference 40 0.64±0.04 70.4±0.1 1.29 50 0.23±0.02 83.9±0.3 1.70 60 0.98±0.10 88.4±1.5 0.95 70 1.73±0.13 96.2±1.7 0.20

[0075] As can be seen from Table 5,

[0076] ① When the content of the matrix material of the microneedles was 40%, the mechanical strength of the microneedles was weak and not sufficient to penetrate into the skin of mice, resulting in a poor therapeutic effect of the mite allergen.

[0077] ② As the mass ratio of the matrix material gradually increased from 50% to 70%, the mechanical strength of the microneedles increased accordingly, but the drug loading capacity of the microneedles decreased, resulting in a weakened therapeutic effect of the mite allergen.

[0078] ③ Considering comprehensively that the perforation success rate and OD difference must meet the test requirements, the mass ratio of the matrix material was 50 - 60%.

[0079] ④ Only when the mass ratio of the matrix material was 50%, the therapeutic effect of the mite allergen was the best, and the mechanical strength of the microneedles also met the test requirements.

[0080] In summary, in the mite allergen soluble microneedles provided by the present invention, the optimal prescription for the needle body is: the mass ratio of the matrix material is 50%, the mass ratio of the mite allergen is 10%, the mass ratio of the composite adjuvant is 40%, the mass ratio of microcrystalline tyrosine (MCT) in the composite adjuvant is 26.67%, and the mass ratio of alfalfa polysaccharide (MSP) is 13.33%.

[0081] In the mite allergen soluble microneedles provided by the present invention, the suitable prescription for the needle body is: the mass ratio of the matrix material is 50 - 60%, the content ratio of the composite adjuvant to the mite allergen is (8:1) - (2:1), and the content ratio of microcrystalline tyrosine (MCT) to alfalfa polysaccharide (MSP) in the composite adjuvant is (2:1) - (1:2).

[0082] Example 6 Safety evaluation of the mite allergen vaccine soluble microneedles

[0083] To investigate whether there are potential risks of toxic and side effects after the adjuvant is added to the soluble mite allergen microneedles, this example intends to take the optimal formulation of the present invention (see Example 5) as an example to preliminarily evaluate the safety of the soluble mite allergen microneedles provided by the present invention.

[0084] Test method: Six 6-week-old Balb / c mice were selected. All of them were sensitized to asthma for 1 week. After that, the treatment group was given microneedle patches once every 3 days for a total of 5 times. Before each vaccination with microneedles, the mice were first anesthetized, then their backs were depilated, and then the vaccination was carried out. One week after the last treatment, they were challenged by aerosol inhalation of dust mite extract for 7 consecutive days. During this period, the local reactions of the mice to the application of microneedles, weight changes, mental status, and body temperature changes were observed. The results are shown in Table 6.

[0085] Table 6. Safety test results of soluble mite allergen microneedle patches

[0086]

[0087]

[0088] As can be seen from Table 6, all safety indicators of the mice were normal after vaccination, and no adverse reactions occurred, indicating that the soluble mite allergen microneedles provided by the present invention have good safety for mice.

Claims

1. An adjuvant-containing soluble mite allergen microneedle patch, comprising a needle body and a backing, characterized in that, The described needle body comprises mite allergen, compound adjuvant and matrix material, wherein the compound adjuvant is a mixture of microcrystalline tyrosine and alfalfa polysaccharide, and the content ratio of microcrystalline tyrosine to alfalfa polysaccharide is (2:1) to (1:2); the content ratio of the compound adjuvant to the mite allergen is (8:1) to (2:1); the mass proportion of the matrix material in the needle body is 50 to 60%.

2. The adjuvant-containing soluble mite allergen microneedle patch according to claim 1, characterized in that, In the described compound adjuvant, the content ratio of microcrystalline tyrosine to alfalfa polysaccharide is 2:

1.

3. The adjuvant-containing soluble mite allergen microneedle patch according to claim 1, characterized in that, In the described compound adjuvant, the content ratio of microcrystalline tyrosine to alfalfa polysaccharide is 1:

2.

4. The adjuvant-containing soluble mite allergen microneedle patch according to claim 1, characterized in that, In the described compound adjuvant, the content ratio of the compound adjuvant to the mite allergen is 8:

1.

5. The adjuvant-containing soluble mite allergen microneedle patch according to claim 1, characterized in that, In the described compound adjuvant, the content ratio of the compound adjuvant to the mite allergen is 4:

1.

6. The adjuvant-containing soluble mite allergen microneedle patch according to claim 1, characterized in that, In the described compound adjuvant, the content ratio of the compound adjuvant to the mite allergen is 2:

1.

7. The adjuvant-containing soluble mite allergen microneedle patch according to claim 1, characterized in that, In the described needle body, the mass proportion of the matrix material is 60%.

8. The adjuvant-containing soluble mite allergen microneedle patch according to claim 1, characterized in that, In the described needle body, the mass proportion of the matrix material is 50%.

9. The adjuvant-containing soluble mite allergen microneedle patch according to any one of claims 1 to 8, characterized in that, In the described needle body, the components and their contents are as follows: the mass proportion of the mite allergen is 10%, the mass proportion of the matrix material is 50%, the mass proportion of microcrystalline tyrosine is 26.67%, and the mass proportion of alfalfa polysaccharide is 13.33%.

10. The adjuvant-containing soluble mite allergen microneedle patch according to any one of claims 1 to 8, characterized in that, In the described needle body, the components and their contents are as follows: the mass proportion of the mite allergen is 10%, the mass proportion of the matrix material is 50%, the mass proportion of microcrystalline tyrosine is 20%, and the mass proportion of alfalfa polysaccharide is 20%.

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