CN110478612B - Method for preparing bubble type hollow administration microneedle by tip dissolution method - Google Patents

Abstract

The invention discloses a method for preparing a bubble-type hollow drug delivery microneedle by a tip dissolution method. A metal microneedle mold is processed and prepared by using MEMS technology; a layer of 1 mm soluble microneedle solution is cast on the surface of the metal microneedle mold; into the cavity of the microneedle mold, and remove the excess soluble solution on the mold surface; dry the soluble solution to prepare a soluble tip layer; place the PLA sheet on the surface of the metal microneedle mold and heat it to a molten state; The molten PLA was poured into the cavity of the microneedle mold in a vacuum to form a bubble-like structure in the PLA layer; the bubble microneedle with a layered structure was obtained by cooling and demoulding; the microneedle backing layer was polished to make the backing layer The PLA bubbles are exposed; the soluble layer of the microneedle tip layer will dissolve in the skin, and the residual PLA bubble layer will form a hollow microneedle drug delivery channel, achieving the effect of continuous drug delivery of the hollow microneedle. The preparation method of the invention is simple and suitable for wide commercial use.

Description

Method for preparing bubble-type hollow drug delivery microneedle by tip dissolution method

technical field

The invention relates to a process method for preparing a tip-dissolving bubble hollow drug delivery microneedle by using a two-step casting method.

Background technique

Common modes of administration include oral administration, subcutaneous injection, and transdermal administration. Oral administration has the advantages of pre-determined dose, easy portability, and self-administration by patients. However, the rapid degradation of digestive enzymes in the gastrointestinal tract and the first-pass effect of the liver make most therapeutic peptides and protein drugs available. greatly reduced, resulting in a greatly reduced effect of direct oral administration. Another common mode of administration is subcutaneous injection, which has obvious disadvantages, such as pain, discomfort and infection risk. Microneedle transdermal drug delivery technology is a drug delivery technology that applies drugs to the skin for local delivery or through the skin system. Compared with oral administration and subcutaneous injection, it has a good controlled release drug delivery. Or sustained-release administration effect, and the most important thing is that the administration process is safe and painless.

At present, most of the common microneedles are solid drug delivery microneedles. The tip of the microneedle pierces the skin to create a micron-sized channel. The drug directly enters the skin layer through the microneedle channel, thereby increasing the penetration. Then a drug-loaded patch is applied on the channel. Drug delivery by passive diffusion. However, the dosage of solid drug delivery microneedles is small, and the drug penetration effect is time-limited. Compared with solid microneedles, the biggest advantage of hollow microneedles compared to solid microneedles is that, apart from the fact that due to the tiny size of the needle, tissue damage will be limited and pain can be reduced or even completely avoided, the biggest advantage is that hollow microneedles can pierce the skin like a syringe , which can realize continuous administration under micro-control, and greatly improve the administration dose of microneedle. However, the manufacture of hollow microneedles requires higher precision and is easier to break, so the processing and manufacturing costs are relatively expensive.

The traditional hollow microneedle preparation process usually prepares microneedles with hollow structures by chemical reaction etching directly on the substrate of the silicon wafer. It is brittle and easy to break during use, and it will cause harm to the human body if it remains in the human skin. Polylactic acid (PLA) mainly uses corn, cassava, etc. as raw materials, and is a biodegradable material with good biocompatibility. The final products of in vivo hydrolysis of PLA are water and carbon dioxide, which are excreted through the lungs, kidneys and skin. They have good biocompatibility and will not cause obvious inflammatory, immune and cytotoxic reactions.

SUMMARY OF THE INVENTION

In view of the above problems, the purpose of the present invention is to provide a process method for preparing the tip-dissolving bubble hollow drug delivery microneedle by using a two-step casting method. The preparation method has relatively simple operation process and low preparation cost, which is conducive to the efficient preparation of hollow microneedle arrays; and the matrix material of the hollow drug delivery microneedles prepared by this method is PLA, which is a kind of biocompatibility. Degradable material, the degradation time is about a few months, which is sufficient for continuous administration in vivo.

The technical solution adopted in the present invention is a method for preparing a bubble-type hollow drug delivery microneedle by a tip-dissolving method. The soluble tip layer of the microneedle is obtained, and the main body layer of the hollow microneedle with the central bubble is obtained by casting in the second step.

Specifically include the following steps:

1) The metal microneedle mold is processed and prepared by MEMS technology. The shape and size of the microneedle cavity of the metal microneedle mold are: a conical structure with a bottom diameter of 50 μm and a top diameter of 250 μm; It is composed of 7×7 microcavity arrays, and the thickness of the entire metal microneedle mold is 2mm;

2) Cast a layer of soluble microneedle solution with a thickness of 1 mm on the surface of the metal microneedle mold. The configuration process of the soluble microneedle solution is: using deionized water as a solvent, according to the mass ratio of PVA:PVP=3:1 to configure the total concentration is a 20% (w/w) solution;

3) Under the condition of -0.1MPa, vacuumize for 20min, pour the soluble microneedle solution into the cavity of the metal microneedle mold, and remove the excess soluble microneedle solution on the surface of the metal microneedle mold;

4) heating and drying the soluble microneedle solution at 50° C. for 1 h to form the soluble microneedle tip layer;

5) Place the 8mm thick PLA sheet on the surface of the metal microneedle mold and heat it to 195°C to completely melt the PLA sheet;

6) In a vacuum drying oven, vacuumize the molten PLA on the surface of the metal microneedle mold, and strictly control the vacuuming time for 10 minutes under the condition of -0.1MPa to achieve the effect of incomplete vacuuming. This makes the molten PLA sheet incompletely filled in the cavity, and a central bubble structure is formed while retaining the material at the side walls;

7) Cooling and demoulding to obtain bubble microneedles with a layered structure, the bubble structure is an ellipsoid, one end is a soluble microneedle tip layer, and the other end is a PLA main drug delivery layer;

8) The microneedle backing layer is surface-polished with a plastic polishing and polishing instrument, and the grinding thickness is 2mm, so that the air bubbles of the microneedle backing layer are exposed:

9) During use, the soluble layer at the tip of the microneedle dissolves in the skin, and the residual PLA bubble layer forms the main structure of the hollow microneedle for drug delivery.

Compared with the existing hollow microneedle preparation method, the invention adopts a two-step casting process, the preparation process is relatively simple and convenient, the requirements for preparation equipment and preparation technology are low, and the processing and preparation cost is greatly reduced; the microneedle tip material is PVA, PVP and other biological materials Compatible soluble material, the main drug delivery layer of the bubble hollow structure adopts PLA degradable material, PLA itself has good biocompatibility, even if it breaks in the skin, it can be degraded within a certain period of time; by dissolving the tip to remove After that, the hollow air channel in the middle is opened to become a continuous drug delivery channel, which reduces the difficulty of processing and manufacturing the hollow microneedles.

Description of drawings

Figure 1 is a structural diagram of a tip-dissolving bubble hollow drug delivery microneedle.

Figure 2 is a process flow diagram of preparing a tip-dissolving bubble hollow drug delivery microneedle by a two-step casting method.

Figure 3 is a drawing of a metal microneedle mold.

Figure 4 is a schematic diagram of the drug delivery principle of the bubble hollow drug delivery microneedle.

Fig. 5 is a structural labeling diagram of a tip-dissolving bubble hollow drug delivery microneedle.

Detailed ways

Several preferred embodiments of the present invention will be described in detail below with reference to the accompanying drawings, but the present invention is not limited to the specific equipment and process described below. The present invention covers any alternatives, modifications, equivalent methods and arrangements made within the spirit and scope of the present invention.

In order to give the public a thorough understanding of the present invention, specific details are described in detail in the following preferred embodiments of the present invention, and those skilled in the art can fully understand the present invention without the description of these details.

Figures 1 and 5 show a schematic structural diagram of an implementation case of the two-step casting method of the present invention for preparing the tip-dissolving bubble hollow drug delivery microneedle. The lining polishing removal layer 3 is composed of the soluble microneedle tip layer 1 having a height of 200 μm, the PLA air bubble main structure 2 having a height of 350 μm, and the PLA backing polishing removal layer 3 having a thickness of 2 mm.

The metal microneedle mold includes a soluble microneedle tip layer, a hollow air bubble structure, a PLA main body hollow drug delivery layer and a PLA substrate grinding removal layer;

The process flow diagram of the preparation method is shown in Figure 2, comprising the following steps:

Step 1: Use MEMS technology to fabricate a metal microneedle mold. The structure of the metal microneedle mold is shown in Figure 3. The size of the mold microneedle microcavity: a conical structure with a bottom diameter of 50 μm and a top diameter of 250 μm; the microcavity interval is 2mm, and the mold consists of 7 The thickness of the entire metal microneedle mold is 2mm.

Step 2: Use deionized water as a solvent, configure a solution with a total concentration of 20% (w/w) according to the mass ratio of PVA:PVP=3:1, and pour the configured solution on the surface of the metal microneedle mold to make the mold. The height of the liquid level above is 1mm.

Step 3: place the entire device horizontally in a vacuum drying box, and vacuumize for 20 minutes under the condition of -0.1MPa, so that the soluble microneedle solution is poured into the cavity of the microneedle mold, and the excess solution on the surface of the mold is removed;

Step 4: Set the temperature of the vacuum drying oven to 50°C, heat and dry the soluble microneedle solution for 1 hour, and dry and shape the soluble microneedle tip layer, and the obtained tip layer is about 200 μm high.

Step 5: Place a PLA sheet with a size of 20mmx20mm and a thickness of 8mm on the surface of the metal microneedle mold. The whole device is placed in a vacuum drying oven and heated to 195°C. After 30min, the PLA sheet is completely melted.

Step 6: Vacuum the molten PLA on the surface of the metal mold, and strictly control the vacuuming time for 10 minutes under the condition of -0.1MPa. By incomplete vacuuming, the molten PLA can retain the central bubble and form a side wall structure in the metal mold.

Step 7: After cooling in a water bath for 10 min, demolding is performed to obtain a bubble hollow microneedle with a layered structure.

Step 8: Use a plastic polishing and polishing instrument to perform plane grinding treatment on the microneedle backing layer, and remove the thickness of 2 mm by grinding, so that the air bubbles in the backing layer are exposed.

Step 9: During use, the soluble layer at the tip of the microneedle dissolves in the skin, and the residual PLA bubble layer forms the main structure of the hollow microneedle for drug delivery. The drug delivery principle diagram of the bubble hollow drug delivery microneedle is shown in Figure 4, and its main structure is composed of a bubble type hollow drug channel 1 and a PLA hollow microneedle main body layer 2.

In the above embodiment, the two-step casting process is adopted, and the preparation process is relatively simple and convenient. The two-step casting process is the first step of casting to obtain the soluble tip layer of the microneedles, and the second step of casting to obtain the hollow microneedles with central bubbles. For the main body layer, this method has low requirements for preparation equipment and preparation technology, and greatly reduces the processing and preparation cost; the microneedle tip material is biocompatible soluble materials such as PVA and PVP, and the theme drug delivery layer of the bubble hollow structure adopts PLA degradable material , PLA itself has good biocompatibility, even if it breaks in the skin, it can be degraded within a certain period of time; after the tip is dissolved and removed, the hollow channel of the bubble in the middle is opened, becoming a continuous drug delivery channel, reducing the hollow micro Difficulty in manufacturing needles.

Embodiments according to the present invention are described above, and the described embodiments do not describe all the details and do not limit the invention to only the described specific embodiments. Obviously, many modifications and variations are possible in light of the above description. The embodiments selected and described in this specification are to better explain the principle and practical application of the present invention, so that those skilled in the art can make good use of the present invention and modifications based on the present invention. The present invention is to be limited only by the claims and their full scope and equivalents.

Claims (3)

1. The method for preparing the bubble type hollow drug delivery microneedle by the tip dissolution method is characterized by comprising the following steps: the method specifically comprises the following steps:

1) the micro-needle micro-cavity of the metal micro-needle mould is processed and prepared by utilizing the MEMS technology, and the shape and the size of the micro-needle micro-cavity of the metal micro-needle mould are as follows: a conical structure with the bottom diameter of 50 mu m and the top diameter of 250 mu m; the micro-cavities of the micro-needles are spaced by 2mm, the metal micro-needle mould consists of a 7 multiplied by 7 micro-cavity array, and the thickness of the whole metal micro-needle mould is 2 mm;

2) pouring a layer of soluble microneedle solution with the thickness of 1mm on the surface of a metal microneedle mould, wherein the preparation process of the soluble microneedle solution is as follows: preparing a solution with a total concentration of 20% (w/w) by using deionized water as a solvent according to a mass ratio of PVA to PVP to 3: 1;

3) horizontally placing the whole device in a vacuum drying box, vacuumizing for 20min under the condition of-0.1 MPa, pouring the soluble microneedle solution into a cavity of a metal microneedle mould, and removing the redundant soluble microneedle solution on the surface of the metal microneedle mould;

4) heating and drying the soluble microneedle solution at 50 ℃ for 1h to form a soluble microneedle tip layer;

5) placing a PLA sheet with the thickness of 8mm on the surface of a metal microneedle mould, heating to 195 ℃ to completely melt the PLA sheet;

6) vacuumizing the molten PLA on the surface of the metal microneedle mould in a vacuum drying oven, and strictly controlling the vacuumizing time for 10min under the condition of-0.1 MPa so as to achieve the effect of incomplete vacuumizing; this results in incomplete filling of the PLA sheet in the molten state in the mould cavity, forming a central bubble structure while retaining material at the side walls;

7) cooling and demolding to obtain the bubble microneedle with a layered structure, wherein the bubble structure is an ellipsoid, one end of the bubble microneedle is a soluble microneedle tip end layer, and the other end of the bubble microneedle is a PLA main body dosing layer;

8) utilize the plastics polishing appearance of polishing to carry out the plane to the micropin back sheet and polish the processing, the thickness of polishing is 2mm, makes the bubble of micropin back sheet expose:

9) when the micro-needle administration main body structure is used, the soluble layer at the tip end of the micro-needle is dissolved in the skin, and the residual PLA bubble layer forms the hollow micro-needle administration main body structure.

2. The method for preparing a bubble type hollow administration microneedle according to the tip dissolution method of claim 1, wherein: the hollow microneedle comprises a soluble microneedle tip layer, a PLA hollow bubble main body structure and a PLA back lining polishing removal layer, wherein the height of the soluble microneedle tip layer is 200 mu m, the height of the PLA hollow bubble main body structure is 350 mu m, and the thickness of the PLA back lining polishing removal layer is 2 mm.

3. The method for preparing a bubble type hollow administration microneedle according to the tip dissolution method of claim 1, wherein: and cooling and demolding by adopting water bath for 10min to obtain the bubble hollow microneedle with the layered structure.

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