CN111870806A - A magnetically controlled microneedle robot and its preparation method, use method and application - Google Patents

Abstract

The invention provides a magnetically controlled microneedle robot and a preparation method, use method and application thereof. The magnetically controlled microneedle robot comprises a microneedle structure, and the microneedle structure comprises a microneedle body and a microneedle body located outside the tip of the microneedle body The magnetic layer; wherein, the composition of the magnetic layer includes a magnetic metal organic framework. The magnetically controlled microneedle robot provided by the present invention has high mechanical strength and can realize transdermal drug delivery; meanwhile, the magnetic layer with an organic metal skeleton is separated from the main body of the microneedle, and remains in the body without long-time sticking; Moreover, the active ingredients are adsorbed in the organometallic framework, which can achieve targeted therapy for tumors and other locations. The magnetically controlled microneedle robot provided by the invention can realize targeted therapy, has high utilization rate of active ingredients, and can ensure targeted long-term release of active ingredients in the body.

Description

A magnetically controlled microneedle robot and its preparation method, use method and application

technical field

The invention belongs to the technical field of medicine, and relates to a magnetically controlled microneedle robot and a preparation method, use method and application thereof, in particular to a magnetically controlled microneedle robot for targeted treatment of tumors and its preparation method, use method and application.

Background technique

New cancer cases show an increasing trend every year, so it is necessary to vigorously develop or improve cancer treatment drugs. Malignant lesions of important organs of the human body need to be surgically removed when they become malignant tumors; however, because smaller tumors hide in the corners of the organs or are in very dangerous positions, they cannot be completely removed. One of the important causes of cancer recurrence.

The volume of micro-nano robots is comparable to that of microorganisms, and has the potential to enter the human body for targeted therapy, and can achieve minimally invasive surgery; in order to increase the probability of complete tumor removal, a small wound, convenient and quick micro-needle injection method is used, combined with magnetic field control to achieve The purpose of accelerating the transdermal effect of the robot and the targeted aggregation of the drug in the affected area.

The most obvious advantage of transdermal drug delivery is that it avoids the first-pass effect, and the drug will not be filtered by the liver, which greatly improves the therapeutic effect; Hydrogel Microneedle Arrays for Transdermal Drug Delivery[J].Nano-Micro Letters,2014,6(3 ): 191-199; relates to a hydrogel microneedle array for transdermal drug delivery. In transdermal drug delivery, the stratum corneum is the main obstacle, and the microneedles directly pierce the skin with a short needle array to overcome this obstacle, usually between 25-2000 μm in height; the current microneedles are made of silicon, and the process It is cumbersome and expensive, and the solution of taking out after puncture has problems such as micropores that exist for a short time and are easily broken in the skin, causing inflammation and other problems.

Subsequent research will focus on the above problems from the aspects of structure and material, among which there are many studies on solid microneedles of hydrogels or other polymers. Polymers such as poly(lactic-co-glycolic acid) (PLGA) are used as microneedles, which have widely adjustable mechanical properties and certain biocompatibility, but their hydrophobic properties make it difficult to encapsulate and deliver hydrophilic drugs. Hydrogel microneedles have the advantages of biocompatibility, biodegradability, low cost, easy modification and encapsulation of a variety of drugs, etc., but their mechanical properties are poor and cannot be used for skin puncture. At the same time, the unit drug loading of polymers such as hydrogel or PLGA cannot meet the release requirements of a large dose at one time, and the drug utilization rate is low and the treatment cycle time is long.

Therefore, it is necessary to provide a new microneedle carrying a therapeutic drug, which can achieve higher drug utilization, shorter treatment cycle, and can achieve targeted therapy.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide a magnetically controlled microneedle robot and its preparation method, use method and application. The magnetically controlled microneedle robot provided by the present invention has high mechanical strength and can achieve transdermal drug delivery; The magnetic layer with the organometallic skeleton is separated from the main body of the microneedle and remains in the body without long-term sticking; and the active ingredient is adsorbed in the organometallic skeleton, which can achieve targeted therapy for tumors and other locations. The magnetically controlled microneedle robot provided by the invention can realize targeted therapy, has high utilization rate of active ingredients, and can ensure targeted long-term release of active ingredients in the body.

In order to achieve this object of the invention, the present invention adopts the following technical solutions:

In a first aspect, the present invention provides a magnetically controlled microneedle robot, the magnetically controlled microneedle robot includes a microneedle structure, and the microneedle structure includes a microneedle body and a magnetic layer located outside the tip of the microneedle body;

Wherein, the composition of the magnetic layer includes a magnetic metal organic framework.

The magnetically controlled microneedle robot provided by the present invention has a microneedle structure, and can be administered in a transdermal manner, avoiding the first-pass effect, and the active ingredients will not be filtered by the liver; at the same time, the magnetic properties of the magnetically controlled microneedle robot provided by the present invention The layer can be separated from the microneedle body and remain within the skin, so long-term application of the microneedle is not required.

In the present invention, active ingredients are adsorbed in the magnetic metal organic framework.

The invention utilizes the magnetic metal organic framework to adsorb the active ingredients, can greatly improve the drug loading of the active ingredients, and is suitable for the release of various active ingredients; and avoids cumbersome processes such as encapsulating the active ingredients in microsphere liposomes, and the cost of the process is avoided. Lowering, simple and fast operation, suitable for a wide range of active ingredients.

Preferably, the active ingredients include any one or a combination of at least two of pharmaceutical active ingredients, vaccine active ingredients, cosmetic active ingredients or health care product active ingredients.

Preferably, the length of the microneedle structure is 250-350 μm, such as 260 μm, 270 μm, 280 μm, 290 μm, 300 μm, 310 μm, 320 μm, 330 μm, 340 μm and the like.

Preferably, the length of the needle tip is 25-35% of the length of the microneedle body, such as 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, etc. .

In the present invention, the magnetic layer is a hydrogel layer, and the magnetic metal organic framework is dispersed in the hydrogel layer.

Preferably, the hydrogel is selected from chitosan or polyethylene glycol.

Preferably, the magnetic metal organic framework is selected from a combination of iron-based metal organic frameworks and magnetic nanoparticles.

Preferably, the iron-based metal organic framework contains any one or a combination of at least two of MIL-53(Fe), Fe-MOF-74 or MIL-100(Fe).

Preferably, the magnetic nanoparticles are selected from ferric oxide nanoparticles and/or nickel nanoparticles.

Preferably, based on the total mass of the magnetic layer as 100%, the content of the magnetic metal organic framework is 40-60%, such as 42%, 45%, 48%, 50%, 52%, 55%, 58% %Wait.

In the present invention, the material of the microneedle body is selected from polylactic acid-glycolic acid copolymer.

The material selected for the main body of the microneedle of the present invention has poor water absorption and swelling properties, and the magnetic layer located on the outer side of the needle tip contains a main body material with high water absorption and swelling property. When the magnetically controlled microneedle robot provided by the present invention acts on the skin, the magnetic layer can be Absorb the moisture inside the skin, so that it can quickly absorb water and swell into the skin. When the micro-needle body of the magnetic control micro-needle robot provided by the present invention is removed, the magnetic layer can be left in the skin, so that the magnetic layer can be in the magnetic field and blood. Under the action of circulation, it reaches the target position and plays a role.

At the same time, the microneedle main body material provided by the present invention has good hardness, can achieve the purpose of piercing the stratum corneum (skin) without breaking, and is convenient and safe.

In addition, the magnetic layer provided by the present invention can slowly degrade and gradually release the magnetic metal-organic framework, that is, the active ingredients adsorbed in the magnetic metal-organic framework can be released slowly and long-term.

In a second aspect, the present invention provides a preparation method of the magnetically controlled microneedle robot according to the first aspect, the preparation method comprising the following steps:

The tip of the main body of the microneedle is dipped in a hydrogel solution dispersed with a magnetic metal-organic framework, and then solidified to obtain the magnetically controlled microneedle robot.

Preferably, the magnetic metal organic framework is selected from a combination of iron-based metal organic frameworks and magnetic nanoparticles.

Preferably, the preparation method of the iron-based metal organic framework includes a hydrothermal method.

Exemplarily, the present invention enumerates several preparation methods of iron-based metal organic frameworks:

Mix the metal salt solution (metal iron ion source solution such as ferric nitrate, ferric sulfate, ferric acetate) with the organic ligand solution (BDC, DOBDC, BTC, etc.), and react at 120 °C in an autoclave for 24 hours. The powder obtained after drying the solution was washed with methanol for 24 h, and dried to obtain the powder of organometallic framework MOFs.

Specifically: MIL-53(Fe) was prepared by solvothermal method (autogenous pressure) from 1 mmol of Fe ³⁺ (FeCl ₃ , Fe(NO ₃ ) ₃ and Fe ₂ (SO ₄ ) ₃ ), 1 mmol of H ₂ BDC- OH in N,N'-dimethylformamide (DMF, 5 mL); the reaction was stirred for a few minutes, then the resulting suspension was introduced into a Teflon-lined steel autoclave and the temperature set 150°C for three days; the light orange MIL-53(Fe)[DMF] powder was washed first with MeOH and finally, after dispersion in water and drying in air, MIL-53(Fe) was obtained.

Fe-MOF-74 was prepared by solvothermal method (autogenous pressure) from Fe ²⁺ (FeCl ₂ , Fe(NO ₃ ) ₂ and Fe ₂ (SO ₄ ) ₂ ) (80 mg, 0.40 mmol) and H ₄ DOBDC (40 mg, 0.20 mmol) in a solution of N,N-dimethylformamide (3.7 mL), a mixture of 2-propanol (0.2 mL) and water (0.2 mL); sealed in a capped vial and stored at 105°C After filtration, the crystals were washed thoroughly with methanol and then dried in air; the methanol-exchanged samples obtained after soaking once were placed in methanol for 24 hours, and then in vacuum Obtained by heating at 200°C for 6 hours.

MIL-100(Fe) was composed of 2.0 mmol of H ₃ BTC and 2.0 mmol of Fe ³⁺ (FeCl ₃ , Fe(NO ₃ ) ₃ and Fe ₂ (SO ₄ ) ₃ ) by solvothermal method (autogenous pressure) The solution was mixed well with 60 mL of water; the autoclave was then placed in an oven at 200 °C for 8 h; after cooling to room temperature, the light orange solid product was further purified by centrifugation with methanol at 6000 rpm for 8 min; then the highly purified solid was finally Obtained by vacuum drying at 80°C overnight.

The preparation method of the magnetic metal-organic framework includes mixing the metal-organic framework and magnetic nanoparticles in methanol for 6 hours, and then putting it into vacuum drying at 80° C. overnight to obtain the magnetic metal-organic framework.

The magnetic metal-organic framework is mixed into the active ingredient solution, shaken on a shaker, and dried for later use to obtain the magnetic metal-organic framework adsorbed with the active ingredient.

Preferably, an active ingredient is adsorbed in the magnetic metal organic framework.

Preferably, curing can be performed by means of ultraviolet curing or the like.

In the present invention, the main body of the microneedle can be prepared by a common method in the current state of the art. Exemplarily, a polydimethylsiloxane (PDMS) mold is obtained by laser etching or chemical etching. The needle body material, such as polylactic acid-glycolic acid copolymer (PLGA), is configured as a solution (95% (W/V) of PLGA), coated in the mold, used to be lined on the upper part, and placed in a drying oven after curing to obtain Microneedle body.

In a third aspect, the present invention provides a method of using the magnetically controlled microneedle robot according to the second aspect, the using method comprising the following steps:

(1) Implant a magnetic material at the place to be targeted;

(2) after embedding the needle tip of the magnetically controlled microneedle robot into the stratum corneum, remove the magnetically controlled microneedle robot, the magnetic layer is retained in the stratum corneum, and a gradient magnetic field is applied to make the magnetic layer enter the blood circulation;

(3) The magnetic substance attracts the magnetic layer to act on the place to be targeted.

The magnetic substance of the present invention needs to have high biocompatibility, for example, magnetic glass-ceramics with high biocompatibility.

In the use method of the present invention, the needle tip of the magnetically controlled microneedle robot needs to be embedded in the skin by transdermal drug delivery. The magnetic layer absorbs water and swells, and it will be separated from the main body of the microneedle and remain in the stratum corneum (skin), and then use The gradient magnetic field sends the magnetic layer into the dermis to enter the blood circulation. In the process of blood circulation, when the magnetic layer reaches the target position, the magnetic substance will attract the magnetic layer to gather near the target position. The layer is gradually degraded, and the metal-organic framework can be released, and the metal-organic framework can release more active ingredients, thereby ensuring a gradual, slow and long-lasting release of the active ingredients at the targeted position.

When considering the actual situation of tumor resection and the actual situation of postoperative medication, it can avoid the problems of drug waste, long cycle, and indiscriminate removal of radiotherapy in chemotherapy, with strong operability and low cost.

In a fourth aspect, the present invention provides a magnetically controlled microneedle robot patch, the magnetically controlled microneedle robot patch includes a lining and the magnetically controlled microneedle robot described in the first aspect, and the microneedle body is fixed on the Said is lined.

Preferably, the magnetically controlled microneedle robot patch includes a microneedle array composed of a lining and the magnetically controlled microneedle robot described in the first aspect, and the microneedle body is fixed on the lining.

In order to ensure that the microneedle body can be well attached to the lining, one end of the microneedle body can have a needle tip, and the other end can be designed with a structure similar to a base, so that it has a good covering plane with the lining , which can achieve strong bonding between the lining and the body of the microneedle.

In a fifth aspect, the present invention provides a magnetically controlled microneedle robot according to the first aspect or a magnetically controlled microneedle robot patch according to the fourth aspect in a disease prevention drug, a disease treatment drug, health care or beauty Applications.

The magnetically controlled microneedle robot provided by the invention carries different active ingredients, and can be used in the fields of preparing medicines for treating diseases, medicines for preventing diseases, cosmetics or health care and the like.

Compared with the prior art, the present invention has the following beneficial effects:

(1) The magnetically controlled microneedle robot provided by the present invention has a microneedle structure, which can be administered through the skin, avoiding the first-pass effect, and the active ingredients will not be filtered by the liver; at the same time, the magnetically controlled microneedle provided by the present invention The magnetic layer of the robot can be separated from the microneedle body and stay in the skin, so it does not need to stick the microneedle for a long time;

(2) The present invention utilizes magnetic metal-organic framework to adsorb active ingredients, which can greatly improve the drug loading of active ingredients, and is suitable for the release of various active ingredients; and avoids cumbersome processes such as wrapping active ingredients in microsphere liposomes , the process cost is reduced, the operation is simple and fast, and the applicable active ingredients are wide;

(3) The hardness of the microneedle main body material provided by the present invention is good, and the purpose of piercing the stratum corneum (skin) can be achieved without breaking, which is convenient and safe;

(4) The needle tip of the magnetically controlled microneedle robot provided by the present invention is embedded in the skin by means of transdermal drug delivery. The magnetic layer absorbs water and swells, detaches from the main body of the microneedle, and remains in the stratum corneum (skin), and then uses a gradient magnetic field to The magnetic layer is sent into the dermis to enter the blood circulation. During the blood circulation, when the magnetic layer reaches the target position, the magnetic substance will attract the magnetic layer to gather near the target position, and the magnetic layer will gradually degrade over time. , the metal-organic framework can be released, and the metal-organic framework can release more active ingredients, thereby ensuring a gradual, slow and long-lasting release of the active ingredients at the targeted position.

Description of drawings

1 is a schematic structural diagram of a magnetically controlled microneedle robot patch provided in Embodiment 1 of the present invention;

Among them, 1-microneedle body; 11-needle tip; 12-magnetic layer; 2-lining.

2 is a schematic structural diagram of a needle tip in Embodiment 1 of the present invention;

Among them, 121-magnetic metal organic framework; 122-hydrogel.

FIG. 3 is a schematic diagram of a treatment process using the magnetically controlled microneedle robot patch provided in Embodiment 1 of the present invention.

Detailed ways

The technical solutions of the present invention are further described below through specific embodiments. It should be understood by those skilled in the art that the embodiments are only for helping the understanding of the present invention, and should not be regarded as a specific limitation of the present invention.

Preparation Example 1

A magnetic iron-based metal organic framework, the preparation method is as follows:

(1) Mix ferric nitrate with (trichloromethyl) carbonate (BTC), and react at 120° C. in an autoclave for 24 hours. The powder obtained after drying the solution was washed with methanol for 24 h, and dried to obtain the powder of organometallic framework MOFs;

(2) Organometallic framework MOFs powder, ferric oxide nanoparticles and nickel nanoparticles (mass ratio of 19:4:1) were mixed and stirred in methanol for 6 h, and then vacuum-dried at 80 °C to obtain magnetic iron-based metal organic skeleton.

Preparation Example 2

A magnetic iron-based metal organic framework, the preparation method is as follows:

(1) Composed of 1 mmol of Fe ³⁺ (FeCl ₃ , Fe(NO ₃ ) ₃ and Fe ₂ (SO ₄ ) ₃ , mass ratio 1:1:1), 1 mmol of H ₂ BDC-OH, in N,N '-dimethylformamide (DMF, 5 mL); the reactants were stirred for 5 min, then the resulting suspension was introduced into a Teflon-lined steel autoclave and the temperature was set at 150°C for three days; shallow The orange MIL-53(Fe)[DMF] powder was first washed with MeOH, and finally, MIL-53(Fe) was obtained after dispersing in water and drying in air.

(2) MIL-53(Fe) powder and Fe3O4 nanoparticles (mass ratio of 19:3) were mixed and stirred in methanol for 6 h, and then vacuum-dried at 80 °C to obtain a magnetic iron-based metal-organic framework.

Preparation Example 3

A magnetic iron-based metal organic framework, the preparation method is as follows:

(1) Composed of Fe ²⁺ (FeCl ₂ , Fe(NO ₃ ) ₂ and Fe ₂ (SO ₄ ) ₂ , mass ratio 1:1:1) (80 mg, 0.40 mmol) and H ₄ DOBDC (40 mg, 0.20 mmol) Dissolve in solution a mixture of N,N-dimethylformamide (3.7 mL), 2-propanol (0.2 mL) and water (0.2 mL); seal in a capped vial and heat oven at 105°C Left for 24 hours, dark brown needle-like crystals were obtained; after filtration, the crystals were washed thoroughly with methanol, and then dried in air; the methanol-exchanged samples obtained after soaking for 1 time were placed in methanol for 24 hours, and then under vacuum at 200 The iron-based metal organic framework was obtained by heating at ℃ for 6 hours.

(2) The iron-based metal-organic framework powder and nickel nanoparticles (mass ratio of 19:1) were mixed and stirred in methanol for 6 h, and then vacuum-dried at 80 °C to obtain a magnetic iron-based metal-organic framework.

Example 1

A magnetically controlled microneedle robot patch, as shown in Figure 1, is composed of a microneedle array composed of a lining 2 and a magnetically controlled microneedle robot.

The magnetically controlled microneedle robot is composed of a microneedle body 1 and a magnetic layer 12 located outside the tip portion 11 of the microneedle body.

As shown in FIG. 2 , the outer side of the needle tip portion 11 has a magnetic layer 12 , and the components of the magnetic layer 12 include a magnetic metal organic framework 121 and a hydrogel 122 .

The preparation method is as follows:

(1) Preparation of magnetic iron-based metal-organic frameworks adsorbed with doxorubicin

The magnetic iron-based metal-organic framework powder provided in Preparation Example 1 was mixed into 10 mL of DOX solution, shaken on a shaker, and dried;

Among them, the addition amount of the magnetic iron-based metal organic framework is 20% of the mass of the solution, and the concentration of the DOX solution is 10 mg/mL;

(2) Preparation of magnetic layer solution

Mix the organometallic framework MOFs powder with DOX adsorbed in step (1) and PEG-400, and the mixing ratio of the two is 4:6;

(3) Preparation of microneedle body patch

Polylactic acid-glycolic acid copolymer (PLGA, purchased from Aladdin, trade name P136522) was configured into a 95% (W/V) solution, coated in the mold, lined with silica gel on the upper part, and demolded after curing for 2 hours , placed in a drying box to obtain the microneedle body patch;

Among them, the length of the main body of the microneedle is 300±5 μm;

(4) Preparation of magnetically controlled microneedle robot patch

The microneedles were placed upside down on a precise displacement platform, immersed in the magnetic layer solution at a depth of 80 μm, taken out for ultraviolet (UV) light curing for 10 s, and then placed in a drying oven at 60 °C to dry to obtain a magnetically controlled microneedle robot patch.

As shown in Figure 3, the usage method is as follows:

The needle tip of the magnetically controlled microneedle robot patch is embedded in the skin by means of transdermal drug delivery. The magnetic layer absorbs water and swells, and it will be separated from the microneedle body and stay in the stratum corneum (skin), and then the magnetic layer will be sent into the stratum corneum (skin) using a gradient magnetic field. The dermis enters the blood circulation. In the process of blood circulation, when the magnetic layer reaches the target position, the magnetic material will attract the magnetic layer to gather near the target position. As time goes by, the magnetic layer gradually degrades, which can release metal Organic frameworks and metal-organic frameworks can release more active ingredients, which can ensure a gradual, slow and long-lasting release of active ingredients at targeted locations.

Example 2

A magnetically controlled microneedle robot patch, the difference from Example 1 is that the preparation method is as follows:

(1) Preparation of magnetic iron-based metal-organic frameworks adsorbed with doxorubicin

The magnetic iron-based metal-organic framework powder provided in Preparation Example 2 was mixed into 10 mL of DOX solution, shaken on a shaker, and dried;

Among them, the addition amount of the magnetic iron-based metal organic framework is 20% of the mass of the solution, and the concentration of the DOX solution is 10 mg/mL;

(2) Preparation of magnetic layer solution

Mix the organometallic framework MOFs powder with DOX adsorbed in step (1) and PEG-600, and the mixing ratio of the two is 6:4;

(3) Preparation of microneedle body patch

Polylactic acid-glycolic acid copolymer (PLGA, purchased from Aladdin, trade name P136522) was configured into a 95% (W/V) solution, coated in the mold, lined with silica gel on the upper part, and demolded after curing for 2 hours , placed in a drying box to obtain the microneedle body patch;

Among them, the length of the main body of the microneedle is 260±5μm;

(4) Preparation of magnetically controlled microneedle robot patch

The microneedles were placed upside down on a precise displacement platform, immersed in the magnetic layer solution with a depth of 65 μm, taken out for ultraviolet (UV) light curing for 10 s, and then placed in a drying oven at 60 °C to dry to obtain a magnetically controlled microneedle robot patch.

The usage method is the same as that of Example 1.

Example 3

A magnetically controlled microneedle robot patch, the difference from Example 1 is that the preparation method is as follows:

(1) Preparation of magnetic iron-based metal-organic frameworks adsorbed with doxorubicin

The magnetic iron-based metal-organic framework powder provided in Preparation Example 3 was mixed into 10 mL of DOX solution, shaken on a shaker, and dried;

Among them, the addition amount of the magnetic iron-based metal organic framework is 20% of the mass of the solution, and the concentration of the DOX solution is 10 mg/mL;

(2) Preparation of magnetic layer solution

Mix the DOX-adsorbed organometallic framework MOFs powder in step (1) with chitosan, and the mixing ratio of the two is 5:5;

(3) Preparation of microneedle body patch

Polylactic acid-glycolic acid copolymer (PLGA, purchased from Aladdin, trade name P136522) was configured into a 95% (W/V) solution, coated in the mold, lined with silica gel on the upper part, and demolded after curing for 2 hours , placed in a drying box to obtain the microneedle body patch;

Among them, the length of the main body of the microneedle is 340±5 μm;

(4) Preparation of magnetically controlled microneedle robot patch

The microneedle was placed upside down on a precise displacement platform to be immersed in the magnetic layer solution with a depth of 110 μm, taken out for ultraviolet (UV) light curing for 10 s, and then placed in a drying oven at 60 °C to dry to obtain a magnetically controlled microneedle robot patch.

The usage method is the same as that of Example 1.

Comparative Example 1

The difference from Example 1 is that in this comparative example, the PEG-400 in step (2) was replaced with a 95% (W/V) PLGA solution.

Comparative Example 2

The difference from Example 1 is that, in this comparative example, PLGA in step (3) was replaced by PEG-400.

Performance Testing

The magnetic control microneedle robot patch provided by Example 1-3 and Comparative Example 1-2 was tested for performance, and the method was as follows:

(1) Transdermal test: Using pigskin as the skin puncture object, apply a load of 0.07N to the magnetically controlled microneedle robot patch for puncture, and then observe the appearance of the sample, where:

Qualified: The morphology of the magnetic layer has not changed significantly, and the main body of the microneedle is not bent;

Unqualified: the magnetic layer is damaged or the needle tip is bent or broken;

(2) Magnetic layer detachment test: place the sample in phosphate buffer for 0.5h, and observe whether the magnetic layer is separated from the main body of the microneedle;

(3) Drug release ability test: use PBS containing 0.1% Tween 8 solubilizer pH=7.4 as buffer1 (interstitial fluid stability); PBS containing 10% fetal bovine serum FBS as buffer2 (serum stability test); containing 0.1% Tween 8 Solubilizer pH=6.5 PBS as buffer3 (drug release efficiency test in tumor). Doxorubicin DOX was pre-packaged in MOFs as a drug substitute. Add the same concentration of DOX-MOFs-GH to different buffers, incubate at 37℃, 200rpm incubator, at different time points (PBS: 0/2/4/6/12/24/48/72h (according to the tracer data) Determined); FBS: 0/4/6/8/12/24/36/72h (determined according to the tracer data)) Take the solution and transfer it to a 96-well plate to test the UV absorption value at 480nm with a microplate reader (note that each After the solution is taken, an equal volume of buffer should be added, and the drug release efficiency is calculated by comparing the standard solution curve of DOX in buffer 1/2/3, and the stability is checked, wherein:

In buffer1 and buffer2, the ratio of drug release within 48h is judged:

If the drug release ratio within 48h is less than 1%, it is excellent;

If the drug release ratio within 48h is 1-10%, it is good;

If the ratio of drug release within 48h is more than 10%, it is unqualified;

In buffer3, it is judged by the drug release curve within 72h:

If the curve is close to a linear equation, that is, the drug is released slowly, it is qualified;

If the curve is close to an exponential equation, that is, a burst of drug release occurs, it is unqualified.

(4) Targeting ability test: establish a mouse tumor-bearing model, place the magnetic glass-ceramic on the tumor after tumor resection, and then leave the magnetic layer on the exposed skin of the mouse by transdermal administration In the stratum corneum, a gradient magnetic field perpendicular to the skin was applied, and magnetic resonance imaging was performed on the tumor site before administration and 9 hours after administration to observe the aggregation of the magnetic layer at the tumor site, including:

The MR signal of the tumor site is the strongest, and the signal of other organs is weak or almost no MR signal is qualified;

If there is no significant difference in the MR signals of the tumor site and other organs, it is considered unqualified.

The test results are shown in Table 1:

Table 1

It can be seen from the examples and performance tests that the magnetic layer of the magnetically controlled microneedle robot provided by the present invention can be separated from the main body of the microneedle and remain in the skin. The main body will not be broken; and the magnetically controlled microneedle robot provided by the present invention can achieve targeted drug delivery and ensure that the active ingredient is gradually, slowly and long-actingly released at the targeted position.

It can be seen from the comparison between the examples and the comparative examples that both the microneedle body and the magnetic layer in the present invention are indispensable, and the magnetic layer cannot be left in the skin without any one to achieve the purpose of targeting.

The applicant declares that the present invention is to illustrate the magnetic control microneedle robot of the present invention and its preparation method, use method and application through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned process steps, that is to say, it does not mean that the present invention must rely on the above-mentioned process steps. process steps can be implemented. Those skilled in the art should understand that any improvement of the present invention, the equivalent replacement of the selected raw materials of the present invention, the addition of auxiliary components, the selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims (10)

1. A magnetic control microneedle robot is characterized by comprising a microneedle structure, wherein the microneedle structure comprises a microneedle main body and a magnetic layer positioned on the outer side of the needle tip part of the microneedle main body;

wherein the composition of the magnetic layer comprises a magnetic metal organic framework.

2. The magnetically controlled microneedle robot according to claim 1, wherein an active ingredient is adsorbed within said magnetic metal organic skeleton;

preferably, the active ingredient comprises any one or a combination of at least two of a pharmaceutical active ingredient, a cosmetic active ingredient or a health care active ingredient.

3. The magnetically controlled microneedle robot according to claim 1 or 2, wherein the length of said microneedle structure is 250-350 μm;

preferably, the length of the needle tip portion is 25-35% of the length of the microneedle body.

4. The magnetically controlled microneedle robot according to any one of claims 1-3, wherein said magnetic layer is a hydrogel layer having said magnetic metal-organic framework dispersed therein;

preferably, the hydrogel is selected from chitosan or polyethylene glycol;

preferably, the magnetic metal-organic framework is selected from the group consisting of iron-based metal-organic frameworks and magnetic nanoparticles;

preferably, the content of the magnetic metal organic framework is 40-60% based on 100% of the total mass of the magnetic layer.

5. The magnetically controlled microneedle robot according to any one of claims 1-4, wherein the material of said microneedle body is selected from polylactic-co-glycolic acid.

6. The method for preparing a magnetically controlled microneedle robot according to any one of claims 1-5, comprising the steps of:

and dipping the needle tip part of the microneedle main body into the hydrogel solution dispersed with the magnetic metal organic framework, and then curing to obtain the magnetic control microneedle robot.

7. The method of claim 6, wherein the magnetic metal-organic framework is selected from the group consisting of an iron-based metal-organic framework and a combination of magnetic nanoparticles;

preferably, the preparation method of the iron-based metal organic framework comprises a hydrothermal method;

preferably, the active ingredient is adsorbed within the magnetic metal organic framework.

8. Use of a magnetically controlled microneedle robot according to any of claims 1-5, characterized in that it comprises the following steps:

(1) implanting a magnetic object at a position to be targeted;

(2) after the needle tip part of the magnetic control micro-needle robot is embedded into the horny layer, the magnetic control micro-needle robot is removed, the magnetic layer is retained in the horny layer, and a gradient magnetic field is applied to enable the magnetic layer to enter blood circulation;

(3) the magnetic substance attracts the magnetic layer to act on the target.

9. A magnetically controlled microneedle robot patch, characterized in that it comprises a backing and a magnetically controlled microneedle robot according to any one of claims 1 to 5, said microneedle body being fixed to said backing;

preferably, the magnetically controlled microneedle robot patch comprises a microneedle array composed of a backing and the magnetically controlled microneedle robot of any one of claims 1 to 5, the microneedle body being fixed to the backing.

10. Use of the magnetically controlled microneedle robot of any one of claims 1-5 or the magnetically controlled microneedle robot patch of claim 9 in disease prevention medicine, disease treatment medicine, healthcare or cosmetology.

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