CN113648528A

CN113648528A - Multiple-administration core-shell microneedle patch and preparation method thereof

Info

Publication number: CN113648528A
Application number: CN202110962916.5A
Authority: CN
Inventors: 郑斌
Original assignee: Tianjin University
Current assignee: Tianjin University
Priority date: 2021-08-20
Filing date: 2021-08-20
Publication date: 2021-11-16

Abstract

The invention relates to a multi-administration core-shell microneedle patch and a preparation method thereof. Core-shell microneedle patches contain a core-shell microstructure, which is created by a 3D manufacturing process that assembles together three different components of a microneedle, including a microneedle shell, a microneedle cap, and a dried drug or vaccine core. The microneedle patch which is inserted once and releases the vaccine antigen in a delayed way at different controllable time points is applied to the skin, the matrix material of the microneedle shell is biodegraded by the human body from several days to several months, and the drug or the vaccine is released to trigger the immune response similar to the repeated injection of the same antigen vaccine. The microneedles are loaded with large amounts of protein antigens and can be easily inserted into the skin in a minimally invasive manner without causing significant skin irritation during long-term implantation, reducing needle/syringe biohazards and the risk of disease transmission. In addition, the obtained microneedle patch delivery system also shows good biocompatibility, showing good potential in the field of transformation medicine.

Description

Multiple-administration core-shell microneedle patch and preparation method thereof

Technical Field

The present invention relates to the field of microneedle patches, and in particular to a housing for a degradable PCL that contains a microneedle patch and can precisely control when the drug is released. The invention also relates to a method for preparing the degradable drug-loaded microneedle patch product.

Background

In order for a treatment to be effective, we must adhere strictly to a particular dosing schedule. Many vaccines and drugs require multiple injections, which can cause problems such as poor patient compliance and economic stress due to the pain associated with the injections, complicated injection procedures and high cost.

This problem becomes even more problematic for patients in countries where development is relatively laggard, due to the limited opportunities for obtaining healthcare services. In these locations, in addition to the difficulty of some parents in remembering the schedule, the repeated journey of the child to the medical center with the child to receive multiple booster doses of vaccine is a challenge to the economic stress of the parents. Global health reports list poor patient compliance and needle and syringe related medical waste issues as key issues for global immunization against deadly infectious diseases such as pneumococcal pneumonia. The World Health Organization (WHO) considers a single-needle vaccine as a better vaccination method, and once the proposal is put forward, the proposal is researched by extensive expert scholars for many years. Furthermore, the medical waste generated by multiple injections also forces us to deal with them, avoiding the development of biohazards and the risk of disease transmission. Therefore, there is a need to develop a new drug and vaccine delivery method that can release multiple times without a syringe and only requires one injection.

Painless and easy-to-use transdermal microneedles have proven to be an advanced method of drug delivery that can be administered in a minimally invasive manner. It has been shown that transdermal microneedles facilitate vaccination because of the presence of a large number of immune cells (i.e., langerhans cells) in the dermal layer of the skin, enhancing immunogenicity. However, to date, most of the relevant functional microneedles can only provide immediate release or sustained release, which limits their use in vaccination. The immediate release microneedles provide burst release of the vaccine only on day 0 after administration, while the vaccine antigens persist in the body, and thus the sustained release microneedles may cause immune tolerance problems in humans to the vaccine. There is also a need for a transdermal microneedle system that can delay burst release for a long period of time to mimic multiple injections during a conventional vaccination procedure.

Disclosure of Invention

The invention provides a core-shell microneedle patch for multiple drug delivery and a preparation method thereof, aiming at solving the problems in the background technology.

In order to realize the purpose of the invention, the advantages of the microneedle patch technology, the advantages of the manufacturing process of the punching assembled polymer layer, the characteristic that the shell matrix material outside the core-shell microneedle can be degraded at different time and further has the advantage of repeated delayed rupture and release are fully utilized, and the microneedle patch product with non-repeated injection and repeated administration is provided, and the vaccine antigen loaded in the hole of the microneedle can be delayed rupture and release through biodegradation of the shell matrix material, so that the novel microneedle administration system can have the characteristics of painless and timely administration under the same administration condition.

In the present invention, we created a degradable microneedle system that can be fully embedded in the skin, requiring only a single insertion, and that can release vaccine antigens at different time points (ranging from days to months) with delayed rupture. Such microneedles are loaded with large amounts of protein antigens, can be easily inserted into the skin in a minimally invasive manner, do not cause significant skin irritation during long-term implantation, and do not elicit immune responses similar to multiple injections of the same antigen vaccine.

In order to solve the technical problems, the invention provides the following technical scheme: a core-shell microneedle patch for multiple drug delivery, each microneedle has a core-shell microstructure, the microstructure is generated by a 3D manufacturing process, and three different components of the microneedle are assembled together by the process, including a microneedle shell, a microneedle cap and a dry drug or vaccine. The drug or vaccine is encapsulated by the cap layer and the base layer, which are made of the same biodegradable polymer, i.e., Polycaprolactone (PCL). Each microneedle was 600 μm in height, 300 μm in diameter at the base, 200 μm in diameter at the core, and 400 μm in height at the core.

Further, by controlling the degradation of the PCL shell, the patch allows for precise control over when the drug is released. Due to its tiny tip and smooth geometry, the microneedles can be easily inserted and fully embedded in the dermal layer after rapid healing of the skin. In clinical environment, can insert the microneedle of many different PCL shells in principle once only into patient's skin, realize breaking nature release many times after different time periods, reach the effect of similar many injections.

Further, the microneedle mould is synthesized by the following substances: curing agents (Sylgard 184, Dow Corning), silanizing agents (TMCS: trimethylchlorosilane, Sigma Corp. 33014), etc.

Further wherein the core-shell microneedles are synthesized from: PCL, acetone (20% (w/v)), Teflon film, etc.

Further wherein the core drug is synthesized from: polyvinylpyrrolidone, rhodamine B, and the like.

The second technical scheme of the invention is a method for preparing the drug-carrying degradable microneedle patch product, which comprises the following steps:

(1) and (4) fine processing of the microneedle mould. The elastic PDMS substrate used as the microneedle mould is prepared by mixing PDMS (Sylgardl 84, Dow Corning, USA) prepolymer and curing agent at a certain ratio, vacuum degassing, pouring onto glass or silicon substrate, and crosslinking and curing completely to obtain an elastic PDMS substrate.

(2) Preparation of core-shell microneedles PCL was dissolved in acetone (20% (w/v)) and cast as a thin film on Teflon coated dishes. The film was then lyophilized to completely remove the organic solvent. A sufficient number of PCL films were placed between the PDMS mold and the Teflon film, which was placed on two slides. Then compression molding was performed in a vacuum oven under a bonding nip at 60 ℃ for 1-2 hours according to the properties of the polymer.

To create the core-shell structure, made of PLA, an anode mold was made by compressing PLA granules into a PDMS mold under vacuum at 180 ℃ for 2 hours. The PLA mold is then transferred to a glass slide. The second mold, which is smaller in size and the same relative spacing, is aligned using custom alignment devices and then pressed into the pins that have been heated prior to this process. At elevated temperature, the second mold penetrates into the polymer, forming a dimpled structure. And peeling off the second mold to obtain the core-shell structure in the PDMS mold.

(3) Preparation of the core drug. The preparation of the core drug includes the selection of FDA approved drug formulation excipients, and the dissolution or suspension of the therapeutic drug in a suitable polymer solution. In the next step, the solution or suspension is filled into the prepared PDMS negative mold. Depending on the nature of the solution/suspension, repeated solution drop casting and additional centrifugation may be required until the mold is completely filled.

The above drop casting process results in the formation of a scum layer (or residual film) on the mold. The scum layer is removed by high speed spinning and a suitable solvent is gently dropped on top of the die. The solvent selected should be capable of dissolving the residual material. Spinning depends on the viscosity of the material and the structure of the die. The non-scummed core drug is then transferred to the sacrificial layer. The sacrificial layer is a solid polymer film of PCL, placed on top of a mold and then compressed under vacuum at its glass transition temperature. The entire structure is layered on a solid substrate, such as a glass slide, using heat assisted micro-transfer molding.

(4) And (4) manufacturing a micro-needle cap and a support array. The cap and support array of core-shell microneedles are fabricated according to compression molding and descumming steps. Briefly, PCL or PLA polymer films were compression molded into caps and PDMS molds supporting the arrays, respectively. The support array was transferred to a glass substrate, coated with a solution of PVP K30 in water-soluble polymer in ethanol (0.2g · mL "1), then air dried for 24 hours, the cap made of PLA was aligned with the PVP-coated PLA support array and heat sintered.

(5) Drug loading process and 3D layer-by-layer assembly. First, a previously prepared core drug is aligned using an alignment apparatus and loaded into core-shell microneedles. Next, the scum layer was removed using acetone and water as solvents using the above method. In the final step, the core shell microneedles are transferred to a support array with caps. The mold encasing the core-shell microneedles is then peeled off, creating individual core-shell microneedles on the support array, which can be completely embedded in the skin.

Further, the prepared degradable drug-loaded microneedle patch product is used for in-vitro release research and analysis of in-vitro accumulated release rate of drugs.

Further, in-vivo release research is carried out on the prepared degradable drug-loaded microneedle patch product, and the in-vivo accumulated release rate of the drug is analyzed.

The invention realizes the technical effects that: the invention fully utilizes the advantages of the microneedle patch and the advantages of core-shell biodegradation, provides a microneedle patch product capable of controllably breaking and releasing core drugs or vaccines, and can accurately control when the drugs are released by controlling the degradation of the PCL shell. Due to its tiny tip and smooth geometry, the microneedles can be easily inserted and fully embedded in the dermal layer after rapid healing of the skin. In clinical environment, a plurality of sets of different PCL microneedles can be inserted into the skin of a patient at one time in principle, and multiple rupture release is realized after different time periods, so that the effect similar to multiple times of vaccine injection is achieved. The micro-needle is loaded with a large amount of protein antigens, can be easily inserted into the skin in a minimally invasive mode, cannot cause obvious skin irritation during long-term implantation, can trigger immune reaction similar to multiple injections of the same antigen vaccine, and overcomes the defects of the traditional multiple injections of the vaccine, such as the rush, the side effect, the biohazard caused by a needle head and an injector, and the like.

In particular, the advantages of the invention are:

1. the degradable microneedle patch product can release vaccine antigens for multiple times, plays a role in multiple vaccine injection, and can avoid the problems of high economic pressure, poor compliance and pain caused by injection of a patient during vaccine injection due to the use of microneedles.

2. The degradable microneedle patch product can puncture the stratum corneum which limits drug absorption, can penetrate the stratum corneum and the epidermis without pain and infection, has a large number of immune cells (Langerhans cells) in the dermis layer of the skin, and can supply vaccine antigens in a minimally invasive mode to enhance the immunogenicity.

3. The degradable microneedle patch product disclosed by the invention utilizes the biodegradation of the PCL shell to expose the vaccine antigen, so that the control on the administration time is achieved, and the utilization rate and the treatment effect of the medicine are effectively improved.

4. The degradable microneedle patch product has the advantages of simple method, convenient operation and low price, reduces the biohazard of a needle head/an injector and the risk of disease transmission, does not need high technical requirements, has strong safety and is suitable for popularization.

Drawings

In order to more clearly illustrate the present invention, the following description and drawings of the present invention will be described and illustrated.

It should be apparent that the drawings in the following description illustrate only certain aspects of some exemplary embodiments of the invention, and that other drawings may be derived therefrom by those skilled in the art without the exercise of inventive faculty. It should be noted that the drawings of the present specification are only schematic, and the sizes and the size ratios of the components depicted therein do not represent actual sizes and ratios of products, but are only for schematically representing the positional relationships or the connection relationships between the components. The dimensions of the components may be scaled differently for ease of illustration and understanding.

Fig. 1 is a side view schematically illustrating a portion of a drug-degradable microneedle patch article of the present invention.

Detailed Description

The invention and its advantages will be explained in more detail below by means of exemplary embodiments. The description of the exemplary embodiments is merely illustrative and is in no way intended to limit the disclosure, its application, or uses. The present disclosure may be embodied in many different forms and is not limited to the embodiments described herein. These embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the disclosure to those skilled in the art. It should be noted that: unless otherwise indicated, the relative arrangement of parts and steps, the composition of materials, numerical expressions and values, etc., set forth in these embodiments should be construed as merely illustrative, and not a limitation.

Materials and instruments used:

silicone or Polydimethylsiloxane (PDMS), polyvinylpyrrolidone (PVP): purchased from Shanghai Aladdin Biotechnology Ltd;

phosphate Buffered Saline (PBS) solution: the phosphate is self-made, and the phosphate is purchased from Shandong Jining Tianyi GmbH;

scanning Electron Microscope (SEM): from Hitachi, japan;

in Vivo Imaging System (IVIS): purchased from Xenogen corporation, usa;

and (3) rhodamine B: purchased from Beijing Solaibao technologies, Inc.;

polycaprolactone: purchased from Tianjin Yunli chemical Co., Ltd;

microneedle mould: 600 μm in height, 300 μm in base diameter, 200 μm in core diameter, and 400 μm in core height, available from Taizhou micro core pharmaceutical technology.

In a first aspect, the present invention relates to a drug-degradable microneedle patch article. Each of our microneedles has a core-shell structure, which is created by a 3D manufacturing process that assembles three different components of the microneedle together, including the microneedle shell, the microneedle cap, and the dried drug or vaccine core. The drug or vaccine core is surrounded by a cap layer and a base layer, which are made of the same biodegradable polymer, i.e. Polycaprolactone (PCL). Each microneedle was 600 μm in height, 300 μm in diameter at the base, 200 μm in diameter at the core, and 400 μm in height at the core. By controlling the degradation of the PCL shell, we can precisely control when the drug is released. Due to its tiny tip and smooth geometry, the microneedles can be easily inserted and fully embedded in the dermal layer after rapid healing of the skin. In a clinical environment, a plurality of sets of microneedles with different PCL shells can be inserted into the skin of a patient at one time in principle, and multiple times of rupture release can be realized after different time periods, so that the effect similar to multiple times of administration is achieved.

In a second aspect of the invention, the invention also relates to a method for preparing the degradable drug-loaded microneedle patch preparation according to the invention as described above, comprising the following steps 1-7.

Step 1: and (4) fine processing of the microneedle mould. The elastic PDMS substrate used as the microneedle mould is prepared by mixing PDMS (Sylgardl 84, Dow Corning, USA) prepolymer and curing agent at a certain ratio, vacuum degassing, pouring onto glass or silicon substrate, and crosslinking and curing completely to obtain an elastic PDMS substrate.

Step 2: preparation of core-shell microneedles PCL was dissolved in acetone (20% (w/v)) and cast as a thin film on Teflon coated dishes. The film was then lyophilized to completely remove the organic solvent. A sufficient number of PCL films were placed between the PDMS mold and the Teflon film, which was placed on two slides. Then compression molding was performed in a vacuum oven under a bonding nip at 60 ℃ for 1-2 hours according to the properties of the polymer.

And step 3: preparation of the core drug. The preparation of the core drug includes the selection of FDA approved drug formulation excipients, and the dissolution or suspension of the therapeutic drug in a suitable polymer solution. In the next step, the solution or suspension is filled into the prepared PDMS negative mold. Depending on the nature of the solution/suspension, repeated solution drop casting and additional centrifugation may be required until the mold is completely filled.

And 4, step 4: and (4) manufacturing a micro-needle cap and a support array. The cap and support array of core-shell microneedles are fabricated according to compression molding and descumming steps. Briefly, PCL or PLA polymer films were compression molded into caps and PDMS molds supporting the arrays, respectively. The support array was transferred to a glass substrate, coated with a solution of PVP K30 in water-soluble polymer in ethanol (0.2g · mL "1), then air dried for 24 hours, the cap made of PLA was aligned with the PVP-coated PLA support array and heat sintered.

And 5: drug loading process and 3D layer-by-layer assembly. First, a previously prepared core drug is aligned using an alignment apparatus and loaded into core-shell microneedles. Next, the scum layer was removed using acetone and water as solvents using the above method. In the final step, the core shell microneedles are transferred to a support array with caps. The mold encasing the core-shell microneedles is then peeled off, creating individual core-shell microneedles on the support array, which can be completely embedded in the skin.

In a third aspect of the invention, the invention relates to a drug degradable microneedle patch product as described in the first aspect above or prepared according to the method of preparing the drug degradable microneedle patch product as described in the second aspect above, using fluorescent staining for in vitro release studies to analyze the cumulative in vitro release rate of the drug.

In a fourth aspect of the invention, the invention relates to the drug-degradable microneedle patch product as described in the first aspect above or prepared according to the method for preparing the drug-degradable microneedle patch product as described in the second aspect above, using fluorescent staining for in vivo release studies, analyzing the rate of cumulative release of the drug in vivo. In vivo release studies the animal is preferably a mouse.

Also, in the third and fourth aspects described above, the technical features described in the degradable drug-loaded microneedle patch preparation of the present invention and the preparation method thereof as described above and the preferred ranges thereof are still applicable here.

Preparation examples 1 to 5:

the degradable drug-loaded microneedle patch preparations 1 to 5 of the present invention were prepared in the following general preparation procedure. The general preparation method comprises the following steps:

the micro-needle shell and the micro-needle cap are made of biodegradable polymer, namely Polycaprolactone (PCL). Preparing PCL biodegradable polymer core-shell microneedles with different molecular weights.

Preparation of control sample:

the control sample was prepared using the same general procedure as described above.

Table 1: control sample and preparation of preparation examples 1 to 5

In vitro delayed burst Release examples of core-Shell microneedles

The specific operation steps are as follows: PCL biodegradable polymer core-shell microneedles with different molecular weights are prepared. We placed these microneedles containing the fluorescent dye as a vaccine model in a Phosphate Buffered Saline (PBS) solution at 37 ℃, record the amount of released fluorescent dye daily, and calculate the cumulative vaccine antigen penetration at each time point. When the dye is confined in the core, there is no visible fluorescence signal due to quenching. When the dye begins to leak from the microneedle, a signal becomes visible indicating the time of release.

The measurement results are shown in table 2:

TABLE 2 in vitro cumulative release rate of vaccine antigen versus time for samples of microneedle preparations of control examples 1, 2, 3, 4 and 5

As can be seen from the data in table 2, PCLs of different molecular weights can provide different delayed release times, from days to months, and the core-shell microneedles of example 5 have higher molecular masses, providing longer degradation times, up to 40 days for longer delay times.

Examples of therapeutic effects

Establishing a mouse model, applying the control sample and the microneedle products of preparation examples 1, 2, 3, 4 and 5 to a mouse, loading the microneedle with the fluorescent dye as a model for researching the in vivo release of the vaccine antigen, and evaluating the effectiveness of the microneedle in multiple dosing through the release of the fluorescent dye in the mouse through animal behavior experiments.

The specific operation steps are as follows: microneedles were inserted into the skin of mice using commercially available microneedle applicators, which were completely embedded in the skin of mice without causing infection or irritation, and placed into the dermal layer. We observed the release of the fluorochrome daily using an In Vivo Imaging System (IVIS), recorded the amount of fluorochrome released, and calculated the cumulative vaccine antigen penetration at each time point. When the dye is confined in the core, there is no visible fluorescence signal due to quenching. When the dye begins to leak from the microneedle, a signal becomes visible indicating the time of release.

The test results are shown in table 3:

table 3 cumulative release rate of vaccine antigen in vivo versus time for samples of microneedle preparations of examples 1, 2, 3, 4 and 5

As can be seen from the data in table 3, the delayed release time of the PCL shells of the samples of the microneedle articles of the preparation examples 1, 2, 3, 4 and 5 according to the present invention is one day to one month, and has a good correlation with the degradation time; PCL with microneedles having higher molecular weights can provide longer delayed release times (i.e., longer degradation times).

It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein, and any reference signs in the claims are not intended to be construed as limiting the claim concerned.

Furthermore, it should be understood that although the present description refers to embodiments, not every embodiment may contain only a single embodiment, and such description is for clarity only, and those skilled in the art should integrate the description, and the embodiments may be combined as appropriate to form other embodiments understood by those skilled in the art. These other embodiments are also covered by the scope of the present invention.

It should be understood that the above-mentioned embodiments are only for explaining the present invention, and the protection scope of the present invention is not limited thereto, and any person skilled in the art should be able to cover the technical scope of the present invention and the equivalent replacement or change of the technical solution and the inventive concept thereof in the technical scope of the present invention.

The use of the word "comprising" or "comprises" and the like in the present invention means that the element preceding the word covers the element listed after the word and does not exclude the possibility of also covering other elements. The terms "inner", "outer", "upper", "lower", and the like indicate orientations or positional relationships based on those shown in the drawings, and are only for convenience in describing the present invention and simplifying the description, but do not indicate or imply that the referred devices or elements must have a specific orientation, be constructed and operated in a specific orientation, and thus are not to be construed as limiting the present invention, and when the absolute position of the described object is changed, the relative positional relationships may be changed accordingly. In the present invention, unless otherwise expressly stated or limited, the terms "attached" and the like are to be construed broadly, e.g., as meaning a fixed connection, a removable connection, or an integral part; either directly or indirectly through intervening media, either internally or in any other relationship. The specific meanings of the above terms in the present invention can be understood by those skilled in the art according to specific situations. The term "about" as used herein has the meaning well known to those skilled in the art, and preferably means that the term modifies a value within the range of ± 50%, ± 40%, ± 30%, ± 20%, ± 10%, ± 5% or ± 1% thereof.

All terms (including technical or scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs unless specifically defined otherwise. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.

Techniques, methods, and apparatus known to those of ordinary skill in the relevant art may not be discussed in detail but are intended to be part of the specification where appropriate.

The disclosures of the prior art documents cited in the present description are incorporated by reference in their entirety and are therefore part of the present disclosure.

Claims

1. The core-shell microneedle patch for multiple drug delivery is characterized in that a microneedle is provided with at least one core-shell microstructure, and three different components including a microneedle shell, a microneedle cap and a dried drug or vaccine are assembled together by each core-shell microstructure through a 3D manufacturing process;

the patch has a tiny tip and a smooth geometry;

the drug or vaccine is wrapped by the cap layer and the base layer and is made of the same biodegradable polymer, namely Polycaprolactone (PCL).

2. The multiple drug delivery core-shell microneedle patch according to claim 1, wherein the patch precisely controls when the drug is released by controlling degradation of the PCL housing, and the microneedles are inserted and completely embedded in the dermal layer after the skin is rapidly healed;

in a clinical setting, multiple sets of microneedles of different PCL housings can in principle be inserted into the skin of a patient at one time, achieving multiple burst release after different periods of time, similar to multiple injections.

3. The multiple drug delivery core-shell microneedle patch according to claim 1, wherein said microneedle mould is synthesized from a substance comprising: curing agent (Sylgard 184), silylating agent (TMCS: trimethylchlorosilane).

4. The multiple drug delivery core-shell microneedle patch according to claim 1, wherein the core-shell microneedle is synthesized from a substance comprising: PCL, acetone (20% (w/v)), Teflon film.

5. The multiple drug delivery core-shell microneedle patch according to claim 1, wherein the core drug is synthesized from materials including: polyvinylpyrrolidone and rhodamine B.

6. The multiple drug delivery core-shell microneedle patch according to claim 1, wherein each microneedle has a height of 600 μm, a base diameter of 300 μm, a core diameter of 200 μm, and a core height of 400 μm.

7. A method of making a multiple drug delivery core-shell microneedle patch according to any one of claims 1 to 6, comprising the steps of:

1) fine processing of the microneedle mould:

the elastic PDMS substrate used as the microneedle mould is prepared by fully and uniformly mixing a PDMS prepolymer and a curing agent, vacuum degassing, pouring onto a glass or silicon substrate, and completely crosslinking and curing to form an elastic PDMS substrate;

2) preparation of core-shell microneedles PCL:

dissolved in acetone (20% (w/v)) and cast as a thin film on Teflon coated petri dishes;

the film was then lyophilized to completely remove the organic solvent;

placing enough PCL films between the PDMS mold and the Teflon film, wherein the Teflon film is positioned on the two glass slides; then, according to the performance of the polymer, the polymer is compressed and molded for 1 to 2 hours in a vacuum oven under a bonding clamp at 60 ℃;

3) preparation of core drug:

the preparation of the core drug includes selecting FDA approved drug formulation excipients, dissolving or suspending the therapeutic drug in a suitable polymer solution;

in the next step, the solution or suspension is filled into the PDMS negative mold prepared, which may need to be repeated for the solution/suspension depending on the nature, and additional centrifugation is performed until the mold is completely filled;

the above drop casting process results in the formation of a scum layer (or residual film) on the mold;

removing the scum layer by high speed spinning and gently dropping a suitable solvent on top of the die, the solvent selected should be capable of dissolving the residual material, the spinning being dependent on the viscosity of the material and the structure of the die;

then transferring the scum-free core drug to a sacrificial layer, which is a solid polymer film of PCL, placed on top of a mold and then compressed at its glass transition temperature under vacuum;

the entire structure is divided on a solid substrate using heat assisted micro-transfer molding;

4) manufacturing a micro-needle cap and a support array:

the cap and the support array of the core-shell micro-needle are manufactured according to the steps of compression molding and scum removal, namely PCL or PLA polymer films are respectively compression molded into PDMS molds of the cap and the support array;

the support array was transferred to a glass substrate, coated with a solution of PVP K30 in water-soluble polymer in ethanol (0.2g · mL "1), then air-dried for 24 hours, the cap made of PLA was aligned with the PVP-coated PLA support array and heat sintered;

5) drug loading process and 3D layer-by-layer assembly:

firstly, aligning a previously prepared core drug by using an alignment device, and loading the core drug into a core-shell microneedle;

secondly, removing the scum layer by using acetone and water as solvents by using the method;

in the last step, the core-shell microneedles are transferred to a support array with a cover, then the mold wrapping the core-shell microneedles is peeled off, and the independent core-shell microneedles are generated on the support array and can be completely embedded into the skin.

8. The method of multiple drug delivery core-shell microneedle patch according to claim 7, wherein a core-shell structure is created, made of PLA, and an anode mold is made by compressing PLA particles into a PDMS mold under vacuum at 180 ℃ for 2 hours; the PLA mold is then transferred to a glass slide;

the second mold, which is smaller in size and the same in relative spacing, is aligned using custom alignment devices and then pressed into the pins that have been heated prior to this process;

at elevated temperature, the second mold penetrates into the polymer to form a dimpled structure; and peeling off the second mold to obtain the core-shell structure in the PDMS mold.

9. The method for multi-time drug delivery core-shell microneedle patch according to claim 7, wherein the prepared drug-degradable microneedle patch product is used for in vitro release research to analyze the in vitro cumulative release rate of drugs.

10. The method for multi-time drug delivery of the core-shell microneedle patch according to claim 7, wherein the prepared degradable drug-loaded microneedle patch product is subjected to in vivo release study, and the in vivo cumulative release rate of the drug is analyzed.