CN203736703U - Soluble coaxial-cone multilayer microneedle and microneedle array - Google Patents

Abstract

The utility model discloses a soluble coaxial-cone multilayer microneedle. The microneedle is conical. The internal structure of the microneedle comprises a center layer shaped like a cone or the combination of a cone and a cylinder, and one or more outer layers wrapping the center layer. The microneedle adopts a multilayer structure, and can be dissolved layer by layer and step by step when contacted with body fluid intradermally so as to realize programmable controllability of release time and release amount of one or more drugs. The microneedle is applied to local dermatologic therapy or systemic administration.

Description

Dissolvable coaxial cone multilayer microneedle and microneedle array

technical field

The utility model relates to a biomedical preparation, in particular to a soluble coaxial cone multilayer microneedle and a microneedle array.

Background technique

Protein peptides and nucleic acid biomacromolecular drugs occupy an increasingly important position in the field of medicine and beauty, but due to stability factors, these drugs cannot be administered through the most basic oral route of administration. Drug administration is the most important and reliable route, but injection administration has its disadvantages in safety and compliance that are difficult to overcome. The convenient, reliable and highly compliant route of administration of biopharmaceuticals has become the focus of research in the field of pharmacy.

As the most promising development direction of transdermal drug delivery, microneedle transdermal drug delivery combines the efficacy of injection drug delivery with the safety, convenience and high compliance of transdermal drug delivery. It has attracted widespread attention and is also the most promising biological drug. way of administration. Among them, soluble microneedles avoid the risk of biocompatibility, intradermal fracture and secondary damage of wastes of silicon, metal and other insoluble microneedles, and at the same time do not have the harshness of hollow microneedles in preparation and supporting equipment. It has the characteristics of convenient production and preparation, rapid quantitative drug release, and no secondary damage. It is a very promising microneedle dosage form for transdermal administration of biomacromolecular drugs.

Soluble microneedles were proposed by the Prausnitz team in 2003. According to literature search, the mainstream preparation method of soluble microneedles is mainly divided into three steps: master mold manufacturing, negative mold replication, and microneedle preparation. Among them, the main mold manufacturing mainly includes MEMS technology, LIGA technology, silicon technology, laser, chemical etching, SU-8 photoresist multilayer processing, UV-LIGA technology, etc. These processes all have complex manufacturing processes, many steps, high cost, and the prepared microneedles have a single shape or are difficult to meet the needs of use.

In terms of the types of microneedles, the Prausnitz team has successively developed beveled, conical microneedles, and granular, microbubble microneedles; multi-drug microneedles are mainly axially divided needle tip, middle, and bottom layered drug loading, Or by mixing different drugs and drug particles in the needle. Each layer of these multi-layer multi-drug microneedles is in contact with the intradermal environment, and the release of drugs is simultaneous, which cannot realize the time-sharing, fixed-speed, and sequential programmed release of different drugs.

Utility model content

Based on this, the purpose of this utility model is to provide a kind of dissolvable coaxial cone multi-layer microneedle which can adapt to the efficient and stable release of biomacromolecular drugs and the quantitative program release of multiple drugs.

The specific technical scheme is as follows:

A dissolvable coaxial cone multilayer microneedle is conical in appearance, and its internal structure includes a conical or conical cylindrical central layer and one or more outer layers wrapped around the central layer.

In one of the embodiments, the central layer wraps one or two outer layers.

In one embodiment, the dimensions of the soluble coaxial cone multilayer microneedle are: a height of 300-1000 μm, and a bottom diameter of 50-500 μm.

Another object of the present invention is to provide a dissolvable coaxial cone multilayer microneedle array.

The specific technical scheme is as follows:

A dissolvable coaxial cone multilayer microneedle array, comprising a base layer and two or more dissolvable coaxial cone multilayer microneedles according to any one of claims 1-3 arranged on the base layer, adjacent The needle axis distance between 2 microneedles is 100-5000 μm.

The soluble coaxial cone multilayer microneedle of the utility model has the following characteristics:

1. The soluble coaxial cone multilayer microneedle of the present utility model comprises a conical or conical cylindrical central layer and one or more outer layers wrapped in the central layer, and the central layer and the outer layer are composed of active drugs and /or made of structural materials, that is, it can be a pure drug layer composed of only drugs or a drug-free layer with only structural materials or a combination of structural materials and active drugs. The soluble coaxial cone multilayer microneedle can be applied to high-efficiency and stable drug release of biomacromolecular drugs and cosmetics, and painless/minor pain intradermal/subcutaneous drug delivery of multi-drug quantitative program release. The microneedle has a coaxial double-layer or multi-layer structure, and each layer can be loaded with different drugs or not loaded as an isolation layer to stabilize the drug. After the microneedle is applied to the skin, it can be dissolved layer by layer and step by step in contact with body fluids in the skin. , so as to realize the program controllable release time and release amount of one or more drugs, which is used for local skin treatment and systemic administration.

2. The structural materials of each layer can be the same or different, and the concentrations of the prepared structural material solutions can be the same or different. Different structural materials can adjust the speed of drug release, pack drugs with different properties, adjust the mechanical properties of microneedles, and adjust the combination between layers. Different concentrations of structural materials can adjust the drug release rate, adjust the thickness of each layer, and adjust the drug loading. The drugs loaded on each layer can be the same or different, and can be a single drug or a mixture of multiple drugs. Microneedles with multiple layers of different structural materials containing the same drug can realize the adjustment of the release rate in different time periods; microneedles containing different drugs in each layer can realize the programmed release of drugs in each layer.

3. The active drug is directly prepared in the form of a homogeneous solution or dissolved in a water-soluble polymer structure material to prepare a microneedle, so as to realize the rapid release of the drug. Active drugs can also be loaded into nanoparticles of specific carrier materials, and then dissolved in a structured solution to prepare microneedles to achieve controlled release of drugs. The drug solution and the drug nanoparticles are carried in the same layer or in different layers to realize the rapid release and controlled release of the same drug or different drugs in a microneedle.

4. Select materials that are inert to the external environment and specifically respond to the intradermal environment to prepare the drug-free outer layer, which can protect the drug that is sensitive to the environment and prevent the inactivation of the drug during storage. A drug-free isolation layer can be used to avoid the interaction between different drugs that are easy to interact with each other.

Description of drawings

Figure 1 is a side view of a soluble coaxial cone multilayer microneedle array;

2-11 are cross-sectional views of various structures of soluble coaxial cone multilayer microneedles;

Figures 12-15 are schematic diagrams of the master model of the soluble coaxial cone multilayer microneedle;

Figure 16-Figure 19 is a schematic diagram of the negative mold of the soluble coaxial cone multilayer microneedle;

Figure 20 is a top view of the soluble coaxial cone multilayer microneedle array;

Fig. 21 is the physical figure of the soluble coaxial cone double-layer microneedle;

Fig. 22 is a physical diagram of a soluble coaxial cone double-layer microneedle array.

Explanation of reference signs:

101, conical central layer; 102, outer layer; 103, soluble coaxial cone double-layer microneedle; 104, conical cylindrical central layer; 105, first outer layer; 106, second outer layer; 107, soluble coaxial Cone three-layer microneedle.

Detailed ways

The utility model discloses a dissolvable coaxial cone multi-layer microneedle, which has a conical shape in appearance and dimensions: the height is 300-1000 μm, the bottom surface diameter is 50-500 μm, and its internal structure includes a conical or conical column-shaped central layer. and one or more outer layers wrapped in the central layer (refer to Figure 2-11), the central layer and the outer layer are both prepared from active drugs and/or structural materials, the active drug and structural materials The mass ratio of the two is 10:1˜1:100 (preferably 10:1˜1:10, more preferably 5:1˜1:5).

The active drug is selected from one or more of protein biological drugs, vaccines or gene drugs; the protein drug is selected from polypeptide biochemical drugs, cell growth factors, antibody drugs, antibacterial peptides or enzyme drugs; The vaccine is selected from toxoid vaccines, virus vaccines, therapeutic vaccines, DNA therapeutic vaccines, cell therapeutic vaccines or genetically engineered protein vaccines; the genetic drug is selected from nucleic acid and its degradation products or derivatives.

The structural material is selected from: carbopol, vinylpyrrolidone and monomeric polymers or copolymers of its derivatives, dextran, polyvinyl alcohol, Soluplus (BASF), hypromellose, hyaluronic acid, bovine Serum albumin, one or more of maltose.

A soluble coaxial cone multilayer microneedle array, comprising a base layer and 2 or more of the above-mentioned soluble coaxial cone multilayer microneedles arranged on the base layer, the needle axis distance between two adjacent microneedles 100-5000μm.

The microneedle array of the utility model is prepared through the following technical process:

The preparation method of the above-mentioned soluble coaxial cone multilayer microneedle array comprises the following steps:

(1) Duplicate the PDMS negative mold according to the specific size mold;

(2) Using the negative mold prepared in step (1) to prepare the central layer of the soluble coaxial cone multilayer microneedles by one-step method or step-by-step method;

(3) Utilize the female mold obtained in step (1) to wrap one or more outer layers on the center layer obtained in step (2) by mold layering method or spraying layering method to obtain the soluble coaxial Conical multilayer microneedles.

The preparation steps of the one-step method described in step (2) are as follows: prepare the active drug and/or structural material into the center layer injection solution, then pour it into the center layer female mold, centrifuge at 2000-5000rpm for 1-20min, dry and demould. The central layer arranged on the base layer is obtained; the preparation steps of the step-by-step method are as follows: the active drug and/or structural material is prepared into the central layer injection liquid, then poured into the central layer female mold, and centrifuged at 2000-5000rpm for 1- 20min, concentrated and solidified, and finally poured into the base material, centrifuged at 2000-5000rpm for 1-20min, dried and demolded to obtain the center layer arranged on the base.

The preparation steps of the mold layering method described in step (3) are as follows: prepare the active drug and/or structural material into the outer injection liquid, then pour it into the outer female mold, centrifuge at 2000-5000rpm for 1-20min, and then Put the central layer into the outer female mold, centrifuge at 2000-5000rpm for 1-20min, form an outer layer wrapped around the central layer, and dry it.

The preparation steps of the spraying and layering method described in step (3) are as follows: prepare the active drug and/or structural material into the outer injection liquid, and then spray the outer injection liquid evenly on the central layer to form a layer wrapped in the central layer. The outer layer is ready to dry.

The utility model is further elaborated below by specific examples.

Example 1

Methylene blue dyed soluble coaxial cone multilayer microneedles (coaxial biconical)

Mold fabrication: Duplicate the negative PDMS mold with a 10×10 rectangular microneedle array master mold (see Figure 1 and Figure 20). The microneedles in the inner mold A1 of the main mold are conical (see Figure 12): the bottom diameter is 300 μm, the length is 600 μm, and the axial distance is 1 mm; the microneedles in the outer mold B1 of the main mold are conical (see Figure 13): the bottom diameter is 225 μm, the length 600μm, axial distance 1mm; frustum-shaped superimposed layer in main mold C1 (see Figure 14): bottom diameter 300μm, top diameter 225μm, length 200μm, axial distance 1mm. The corresponding female molds a1, b1 and c1 are copied (see Figure 16-18 for the shape of the microhole).

In this embodiment, a dissolvable conical multi-layer microneedle array containing 100 microneedles, wherein the appearance of the microneedles is cone-shaped, the external dimensions are: the height is 800 μm, the diameter of the bottom surface is 300 μm, and its internal structure includes conical A central layer and an outer layer wrapped around the central layer.

The preparation method of the above-mentioned soluble coaxial cone multilayer microneedle array comprises the following steps:

(1) Dissolve 40 mg of Carbopol in 200 μL of deionized water under stirring at 800 rpm, adjust the pH to 6 with 10 M NaOH, pour the formed uniform glue into the female mold a1 (see Figure 16), centrifuge at 4000 rpm for 20 min, and dry After 24 hours, the conical central layer 101 arranged on the base layer was obtained after demoulding;

(2) Dissolve 1 mg of methylene blue in 50 μL of deionized water, add 20 mg of dextran, swell into a homogeneous solution, pour it into the female mold b1 (see Figure 17), centrifuge at 5000 rpm for 5 minutes, and recover the excess solution outside the micropores of the female mold ; Place the negative mold c1 on the negative mold b1 (see Figure 18), place the center layer on the negative mold c1, centrifuge at 2000 rpm for 5 minutes, dry for 24 hours, and demould, the outer layer contains methylene blue, and the inner and outer layers are conical The soluble coaxial cone double-layer microneedle 103 (as shown in Fig. 2, Fig. 21, Fig. 22).

Example 2

Methylene blue stained soluble coaxial cone multilayer microneedles (coaxial cone cylinder)

Mold manufacturing: a 15×20 rectangular microneedle array master mold was used to replicate the PDMS negative mold. The microneedle in the inner mold A2 of the main mold is conical and cylindrical (see Figure 15): the diameter of the bottom cylindrical part is 75 μm, the length is 200 μm, the diameter of the top conical part is 75 μm, the length is 100 μm, and the axial distance is 500 μm. The microneedles in the outer mold B2 of the main mold are conical (see Figure 13), with a bottom diameter of 150 μm, a length of 400 μm, and an axial distance of 500 μm. The corresponding female molds a2 and b2 are copied (refer to Figure 19 and 17 for the shape of the microhole).

In this embodiment, a dissolvable coaxial cone multilayer microneedle array containing 300 microneedles, wherein the appearance of the microneedles is cone-shaped, the external dimensions are: the height is 400 μm, the diameter of the bottom surface is 150 μm, and its internal structure includes a conical cylinder A central layer and an outer layer wrapped around the central layer.

The preparation method of the above-mentioned soluble coaxial cone multilayer microneedle array comprises the following steps:

(1) Dissolve 40 mg of Carbopol in 200 μL of deionized water under stirring at 800 rpm, adjust the pH to 6 with 10 M NaOH, pour the formed uniform glue into the female mold a2 (see Figure 19), centrifuge at 4000 rpm for 20 min, and dry After 24 hours, the conical cylindrical central layer 104 arranged on the base layer was obtained after demoulding;

(2) Dissolve 1 mg of methylene blue in 50 μL of deionized water, add 20 mg of polyvinylpyrrolidone, swell into a homogeneous solution, pour it into the female mold b2 (see Figure 17), centrifuge at 5000 rpm for 3 minutes, and recover excess from the micropores of the female mold solution, dry and concentrate for 1 hour; place the center layer on the female mold b2, centrifuge at 3000rpm for 5 minutes, dry for 24 hours, and demould, the inner layer is a conical column, and the outer layer is a conical soluble coaxial cone double layer containing methylene blue Microneedles (as shown in Figure 4).

Example 3

Soluble coaxial cone multilayer microneedles (three layers) containing methylene blue

Mold fabrication: Duplicate the negative PDMS mold with a 10×10 rectangular microneedle array master mold (see Figure 1). The microneedle in the inner mold A3 of the main mold is conical and cylindrical (see Figure 15): the diameter of the bottom cylindrical part is 125 μm, the length is 400 μm, the diameter of the bottom of the top conical part is 125 μm, the length is 200 μm, and the axial distance is 1 mm. The copy corresponds to the female mold a3 (see Figure 19 for the micropore shape), and the outer molds of the female mold are b1 and c1 prepared in Example 1 (see Figures 17 and 18 for the micropore shape).

In this example, a dissolvable coaxial cone multilayer microneedle array containing 100 microneedles, wherein the appearance of the microneedles is cone-shaped, the external dimensions are: the height is 800 μm, the diameter of the bottom surface is 300 μm, and its internal structure includes a conical cylinder The center layer and the two outer layers wrapped around the center layer.

The preparation method of the above-mentioned soluble coaxial cone multilayer microneedle array comprises the following steps:

(1) Dissolve 80mg of polyvinylpyrrolidone in 200μL of deionized water, swell and dissolve into a homogeneous solution, pour this solution into the female mold a3 (see Figure 19), centrifuge at 5000rpm for 10min, and dry for 24 hours. Conical cylindrical center layer 104 on the base layer;

(2) Dissolve 2 mg of Eudragit (Evonik) in 20 μL of 95% ethanol to prepare a spray solution. The microneedle array is arranged inside the rotatable cylindrical spray pot. After drying, the first outer layer 105 wrapped in the central layer is obtained.

(3) Dissolve 1 mg of methylene blue in 50 μL of deionized water, add 20 mg of Soluplus, swell into a homogeneous solution, pour it into the female mold b1 (see Figure 17), centrifuge at 5000 rpm for 10 minutes, and recover the excess solution outside the micropores of the female mold; Place the female mold c1 on the mold b1 (see Figure 18), place the microneedles obtained in step (2) on the female mold c1, centrifuge at 5000 rpm for 20 minutes, dry for 24 hours, and demold, that is, wrap the second outer layer on the first outer layer. For the outer layer 106, a soluble coaxial cone multilayer microneedle 107 (three layers) containing methylene blue in the outer layer is obtained (as shown in FIG. 11 ).

Example 4

Methylene blue/FITC-silk protein nanoparticles soluble coaxial cone multilayer microneedles

In this example, a dissolvable coaxial cone multilayer microneedle array containing 100 microneedles, wherein the appearance of the microneedles is cone-shaped, the external dimensions are: the height is 800 μm, the diameter of the bottom surface is 300 μm, and its internal structure includes a conical cylinder The central layer and the outer layer wrapped around the central layer.

The preparation method of the above-mentioned soluble coaxial cone multilayer microneedle array comprises the following steps:

(1) To prepare FITC-labeled silk protein nanoparticles with a particle size of 200nm, take 1mg and disperse in 20μL deionized water, add 10mg of polyvinylpyrrolidone, swell and dissolve into a uniform solution, and pour this solution into the female mold a3 (see Figure 19), centrifuge at 3000rpm for 8min, and recover the excess solution outside the micropores in the female mold a3; dissolve 80mg of polyvinylpyrrolidone in 200μL deionized water, pour it into the female mold a3 containing the drug as the base layer, centrifuge at 1000rpm for 2min, and dry for 24 hours, demoulding to obtain a central layer containing silk protein nanoparticles arranged on the base layer;

(2) Dissolve 1 mg of methylene blue in 50 μL of deionized water, add 20 mg of polyvinylpyrrolidone, swell into a homogeneous solution, pour it into the female mold b1 (see Figure 17), centrifuge at 4000 rpm for 5 minutes, and recover excess from the micropores of the female mold Solution; place the female mold c1 on the female mold b1 (see Figure 18), place the above-mentioned silk protein nanoparticle inner layer microneedles on the female mold c1, centrifuge at 4000rpm for 5min, dry for 24h, and demould to obtain methylene blue/FITC -Silk protein nanoparticles soluble coaxial cone multilayer microneedles.

The above-mentioned embodiments only express several implementations of the utility model, and the description thereof is relatively specific and detailed, but it should not be construed as limiting the patent scope of the utility model. It should be noted that those skilled in the art can make several modifications and improvements without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the scope of protection of the utility model patent should be based on the appended claims.

Claims (4)

1. A kind of dissolvable coaxial cone multilayer microneedle, its outward appearance is conical shape, it is characterized in that, its inner structure comprises the central layer of conical shape or conical cylinder and one or more layers are wrapped in the outer layer of central layer . 2. The dissolvable coaxial cone multilayer microneedle according to claim 1, characterized in that, the central layer is wrapped with one or two outer layers. 3. The dissolvable coaxial cone multilayer microneedle according to claim 1 or 2, characterized in that, the external dimensions of the dissolvable coaxial cone multilayer microneedle are: a height of 300-1000 μm and a bottom diameter of 50-500 μm . 4. A dissolvable coaxial cone multilayer microneedle array, characterized in that it comprises a base layer and 2 or more dissolvable coaxial cone multilayer microneedles according to any one of claims 1-3 arranged on the base layer. Layer microneedles, the needle axis distance between two adjacent microneedles is 100-5000 μm.