CN112023033B - Two-section micro-needle array patch for simultaneously realizing BCG vaccine inoculation and diagnosis and preparation method thereof - Google Patents
Two-section micro-needle array patch for simultaneously realizing BCG vaccine inoculation and diagnosis and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a two-section micro-needle array patch for simultaneously realizing BCG vaccine inoculation and diagnosis, which comprises a micro-needle array and a patch, wherein the micro-needle array is arranged on the patch; the micro needle comprises a soluble medicine carrying micro needle tip and an insoluble micro needle supporting end, wherein the soluble medicine carrying micro needle tip is prepared by mixing BCG vaccine, tuberculin microsphere and soluble auxiliary materials and freeze drying, the tuberculin microsphere is prepared by combining slow release auxiliary materials and tuberculin, the BCG vaccine and the tuberculin are simultaneously gathered at the soluble micro needle medicine carrying tip, and the release time of the tuberculin is controlled by a slow release microsphere technology, so that two administration purposes of inoculating the BCG vaccine and diagnosing whether the BCG vaccine is successfully inoculated or not can be realized by one administration. The invention also discloses a preparation method of the patch.
Description
Technical Field
The invention relates to the technical field of biomedical engineering, in particular to a two-section micro-needle array patch for simultaneously realizing BCG vaccine inoculation and diagnosis and a preparation method thereof.
Background
BCG vaccine is the only vaccine approved for tuberculosis prevention and treatment at present. The prevalence of tuberculosis is well controlled by expanding the bcg vaccination scope of newborns, which is currently vaccinated by intradermal injections using syringes, which often require skilled medical personnel to operate, and which are often unreliable, with about 5% of bcg vaccinations being injected subcutaneously, resulting in vaccination failure and suppurative infections, which is also a risk for bcg vaccinators or medical personnel. In addition, if BCG vaccination is successful, usually, tuberculin is injected intradermally 3 months after the vaccination for PPD test, if positive, the vaccination is successful, otherwise, the vaccination is failed. It is well known that intradermal injection passes can cause severe pain, accidental needle sticks, severe skin infections, and leaving scars, which can greatly reduce the inoculation compliance of the inoculant. In addition, the bacillus calmette-guerin and tuberculin are stored and transported at low temperature, which brings inconvenience to the storage and transportation of the bacillus calmette-guerin and tuberculin medicines and increases the circulation cost.
Disclosure of Invention
The invention aims to overcome the defects of the prior intradermal injection of BCG vaccine and tuberculin, such as hard pain, high operation difficulty, easy failure, high infection risk, cold chain requirement for storage and transportation, and the like, and simultaneously realizes two functions of inoculating BCG vaccine and diagnosing whether the inoculating is successful or not by one-time administration, thereby greatly improving the success rate of inoculating and diagnosing BCG vaccine.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
the two-section microneedle array patch comprises a microneedle array and a patch body, wherein the microneedle array is arranged on the patch body; the microneedle of the microneedle array comprises a soluble drug-carrying microneedle tip and an insoluble microneedle supporting end, wherein the soluble drug-carrying microneedle tip is prepared by mixing BCG vaccine, tuberculin microspheres and soluble auxiliary materials and freeze-drying, the tuberculin microspheres are prepared by combining slow-release auxiliary materials with tuberculin, the soluble drug-carrying microneedle tip is arranged on the insoluble microneedle supporting end, the microneedle array substrate is an insoluble microneedle array substrate, and the insoluble microneedle supporting end is positioned on the surface of the microneedle array substrate.
According to the technical scheme, the two-section micro-needle array patch capable of simultaneously realizing BCG vaccine inoculation and diagnosis can be formed.
As a preferred embodiment of the microneedle array patch, the tip of the soluble drug-carrying microneedle is a quadrangular pyramid-shaped microneedle tip, and the insoluble microneedle support end is a cylindrical microneedle support end. The micro-needles are required to penetrate the skin to form a micropore array drug delivery channel, and because the tip of the soluble drug carrying micro-needle is a quadrangular pyramid micro-needle tip, the micro-needles are easier to penetrate the skin than a cone type micro-needle tip, and the damage to the skin is small.
The tip of the soluble drug-carrying microneedle is not suitable to be made of a material with large irritation or influence on protein activity in order to avoid the influence of the soluble auxiliary materials on the drug, and the soluble auxiliary materials are sucrose, polyvinyl alcohol or hyaluronic acid or a mixture of sucrose or hyaluronic acid and polyvinyl alcohol according to the proportion of 1:2-3:2 as the preferred implementation mode of the microneedle array patch.
As a preferred embodiment of the microneedle array patch, the tuberculin microspheres are prepared by combining slow-release auxiliary materials and tuberculin, and optimally, the slow-release auxiliary materials are a mixture of carboxymethyl chitosan and polylactic acid-polymethyl copolymer in a weight ratio of 2:1-3:2, the drug release time of the slow-release microspheres is about 90 days, and the time from the beginning of drug release to the end of drug release is controlled within 6 hours.
The tip of the soluble drug-loaded microneedle was dissolved in the skin within 15 minutes and separated from the support end of the insoluble microneedle, releasing the bcg drug, while the tuberculin microsphere was degraded in the skin for about 90 days, releasing tuberculin to take effect.
The insoluble microneedle support end is a biological material which has good biocompatibility for human body, is well connected with soluble auxiliary materials and has enough mechanical strength, and can be PMMA or stainless steel, ceramic and other materials, preferably PMMA materials, as the preferred implementation mode of the microneedle array patch.
As the preferred implementation mode of the microneedle array patch, the microneedle array is 10 x 10, the height of the microneedle is not more than 800 microns, the height of the tip of the soluble drug-carrying microneedle is 200-400 microns, the height of the supporting end of the insoluble microneedle is not more than 400 microns, the microneedle can be ensured to penetrate through the stratum corneum of skin better, the requirements of BCG vaccine inoculation and inspection are met, and in addition, the patch area is not more than 1 square centimeter for the convenience of observing and diagnosing erythema and induration.
As a preferred embodiment of the microneedle array patch of the present invention, the patch includes a pressure-sensitive adhesive tape and an absorbent pad. The pressure-sensitive adhesive tape is used for adhering skin to a microneedle array, and since the pressure-sensitive adhesive tape can be directly adhered to the skin surface and is firm after being pressed, the adhesive layer material is required to have good skin biocompatibility and nontoxicity, and preferably, the pressure-sensitive adhesive is a medical pressure-sensitive adhesive. The hollow part of the absorption gasket is just placed in the micro-needle array substrate, the thickness of the absorption gasket exceeds the height of the micro-needle array substrate and does not exceed the height of the insoluble micro-needle supporting end 2, and the absorption gasket is made of soft materials which are loose and easy to penetrate and harmless to human bodies, so that good liquid absorption effect is achieved.
As a preferred embodiment of the microneedle array patch of the present invention, the patch further includes a sliced medical sponge, which encases the microneedles of the microneedle array. The sliced medical sponge is used for protecting the tip of the soluble drug-loaded microneedle, and the thickness of the sliced medical sponge is not shorter than the whole length of the microneedle so as to ensure the protection of the tip of the microneedle during transportation and transfer.
In addition, the invention also provides a preparation method of the microneedle array patch, which is simple to operate and easy to realize, and comprises the following steps:
step 1: adding tuberculin into the slow release auxiliary materials, and volatilizing at 2-8 ℃ under reduced pressure to prepare tuberculin microspheres;
step 2: adding the tuberculin microspheres prepared in the step 1 into soluble auxiliary materials, adding BCG vaccine solution, uniformly mixing, pouring into a microneedle tip end groove die, centrifuging, removing redundant solution, and freeze-drying to form a soluble drug-carrying microneedle tip in the microneedle tip end groove die;
step 3: then aligning the microneedle supporting end groove mould above the freeze-dried microneedle tip groove mould, pouring a preparation material solution of the prepolymerized insoluble microneedle supporting end into the microneedle supporting end groove mould, and drying at room temperature to obtain a microneedle array;
step 4: placing the prepared microneedle array into a patch.
As a preferred embodiment of the microneedle array patch of the present invention, the step 1 specifically comprises: and adding tuberculin into a mixture formed by carboxymethyl chitosan and polylactic acid-polymethyl copolymer in a weight ratio of 2:1-3:2, and volatilizing at 2-8 ℃ under reduced pressure to prepare tuberculin microspheres.
As a preferred embodiment of the microneedle array patch of the present invention, the step 2 specifically comprises: adding the tuberculin microspheres prepared in the step 1 into a hyaluronic acid solution, adding a BCG vaccine solution, uniformly mixing, pouring into a microneedle tip groove die, centrifuging, removing redundant solution, and freeze-drying to form a soluble drug-loaded microneedle tip in the microneedle tip groove die;
as a preferred embodiment of the microneedle array patch of the present invention, the step 3 specifically comprises: then aligning the microneedle supporting end groove mould above the freeze-dried microneedle tip groove mould, pouring a pre-polymerized PMMA solution into the microneedle supporting end groove mould, and drying for 24 hours at room temperature to obtain a microneedle array;
as a preferred embodiment of the microneedle array patch of the present invention, the step 4 specifically comprises: the manufactured microneedle array is placed in an absorption gasket in a medical patch, the microneedles of the microneedle array are wrapped by a sliced medical sponge, the medical patch comprises a pressure-sensitive adhesive tape, and the pressure-sensitive adhesive tape is used for pasting skin and the microneedle array.
The micro-needle array patch provided by the invention has the main innovation point that BCG vaccine and tuberculin are gathered in the same micro-needle patch, and the inoculation of BCG vaccine and the diagnosis of success or failure of inoculation are realized at the same time. When the patch is used, the whole microneedle array patch is directly stuck on skin, proper force is applied to press the bottom of the patch, so that all the drug carrying tips of the soluble microneedles enter the skin, at the moment, the drug carrying tips of the soluble microneedles are dissolved and separated from the supporting ends of the insoluble microneedles, the BCG vaccine and the tuberculin microspheres in the drug carrying tips are retained in an immune cell aggregation area at the upper part of the dermis of the skin, the BCG vaccine directly acts on immune cells to trigger immune reaction, so that an organism generates anti-tuberculosis antibody, successful inoculation of the BCG vaccine is realized, at the moment, the tuberculin microspheres are prevented from generating drug effect due to the protection of the surface slow release layer, and about 3 months of time is required for the immune action of the BCG vaccine in the organism, at the moment, the surface slow release layer of the tuberculin microspheres is dissolved, the tuberculin is exposed in the skin, combined with the antibody generated by the organism, and antigen-antibody reaction (namely a PPD test) is generated. If positive erythema and induration appear at the previous inoculation position, the success of BCG inoculation can be deduced, and if not, the BCG inoculation fails, so that the diagnosis of whether the BCG inoculation is successful is realized. Therefore, the microneedle array patch of the invention can control the release time of tuberculin by skillfully aggregating BCG vaccine and tuberculin at the drug carrying tip of the soluble microneedle and by the slow release microsphere technology, thereby realizing two drug administration purposes of achieving the inoculation of BCG vaccine and diagnosing whether the BCG vaccine is successfully inoculated or not by one drug administration. The integrated administration mode for BCG vaccine inoculation and diagnosis thereof not only avoids the pain of the traditional intradermal injection, but also greatly simplifies the operation steps of BCG vaccine inoculation and diagnosis. Meanwhile, the bacillus calmette-guerin vaccine and tuberculin are coated in the tip of the microneedle after being freeze-dried and are stable at room temperature, so that the storage and transportation of the medicament are facilitated, and the cost is reduced.
Drawings
Fig. 1 is a schematic structural diagram of a two-stage microneedle array patch according to an embodiment of the present invention.
Detailed Description
For a better description of the objects, technical solutions and advantages of the present invention, the present invention will be further described with reference to the accompanying drawings and specific embodiments.
Example 1
Referring to fig. 1, the microneedle array patch of the present invention includes a microneedle array and a patch, the microneedle array being disposed on the patch; the microneedle of the microneedle array comprises a soluble drug-loaded microneedle tip 1 and an insoluble microneedle support end 2; the soluble drug-carrying microneedle tip 1 is prepared by mixing BCG vaccine, tuberculin microspheres and soluble auxiliary materials and freeze-drying, the tuberculin microspheres are prepared by combining slow-release auxiliary materials and tuberculin, the soluble drug-carrying microneedle tip 1 is arranged on an insoluble microneedle support end 2, the microneedle array substrate 3 is an insoluble microneedle array substrate, and the insoluble microneedle support end 2 is positioned on the surface of the microneedle array substrate 3; the patch comprises a pressure-sensitive adhesive tape 4 and an absorption gasket 5, wherein the pressure-sensitive adhesive tape 4 is used for pasting skin and a microneedle array; the hollow part of the absorption gasket 5 is placed in the microneedle array base 3, and the thickness of the absorption gasket 5 exceeds the height of the microneedle array base 3 and does not exceed the height of the insoluble microneedle supporting end 2; the medical sponge 6 for slicing is arranged on the patch, and the medical sponge 6 for slicing wraps the micro-needles of the micro-needle array.
Specifically, in this embodiment, the tip 1 of the soluble drug-loaded microneedle is a quadrangular pyramid-shaped microneedle tip, and the insoluble microneedle support end 2 is a cylindrical microneedle support end.
The tuberculin microspheres are prepared by combining a slow-release auxiliary material and tuberculin, and in the embodiment, the slow-release auxiliary material is carboxymethyl chitosan and polylactic acid-polymethyl copolymer with the weight ratio of 2:1-3:2
Adding tuberculin into the slow release auxiliary materials, and drying at 2-8 ℃ under reduced pressure to obtain the composition mixture.
Preferably, in this example, tuberculin microspheres comprise tuberculin 5 doses, which are taken as a single dose of 5IU according to the dose requirements of the vaccination test. The weight ratio of the carboxymethyl chitosan to the polylactic acid-polymethyl copolymer is 2:1-3:2, and more preferably, the weight ratio is 3:2 within the range of 2:1-3:2.
The soluble drug-carrying micro needle tip 1 is prepared by mixing BCG vaccine, tuberculin microsphere and soluble auxiliary material and freeze-drying, preferably, in the embodiment, the soluble auxiliary material is hyaluronic acid, and the BCG vaccine and the tuberculin microsphere can be added into a hyaluronic acid solution and mixed and freeze-dried to prepare the soluble drug-carrying micro needle tip 1, wherein the BCG vaccine can be used for obtaining the single human dosage according to the inoculation requirement.
In this embodiment, the insoluble microneedle support end 2 and the microneedle array base 3 are made of PMMA material, having sufficient toughness and strength. More preferably, the microneedle array is a 10 x 10 array, 100 microneedles are all arranged, the microneedle array substrate 3 is square with an area of 1 square centimeter, the height of the soluble drug-loaded microneedle tips 3 is 400 micrometers, the height of the insoluble microneedle support ends 2 is not more than 400 micrometers, the inner diameter of the absorption gasket 5 is 1 centimeter, and the thickness of the absorption gasket 5 is less than 400 micrometers.
The slicing medical sponge 6 is made of medical absorbent cotton, and the thickness of the slicing medical sponge is more than 800 microns.
The microneedle array patch of the embodiment is prepared by the following method:
(1) Adding tuberculin of 5IU into a mixture formed by carboxymethyl chitosan and polylactic acid-polymethyl copolymer in a weight ratio of 3:2, and volatilizing at 2-8 ℃ under reduced pressure to prepare tuberculin microspheres.
(2) Adding the tuberculin microspheres prepared in the step (1) into a hyaluronic acid solution, adding 0.01 mg of BCG vaccine solution, uniformly mixing, pouring into a microneedle tip end groove die, centrifuging, removing the redundant solution, and forming a soluble drug-carrying microneedle tip in the microneedle tip end groove die.
(3) And then aligning the microneedle supporting end groove mould above the freeze-dried microneedle tip groove mould, pouring a pre-polymerized PMMA solution into the microneedle supporting end groove mould until the liquid level thickness in the groove is 1 mm (the microneedle array substrate is formed after drying), and drying for 24 hours at room temperature to obtain the two-section microneedle array.
(4) And placing the manufactured microneedle array in an absorption gasket in the patch, and wrapping the microneedles of the microneedle array by the sliced medical sponge to obtain the two-section microneedle array patch.
Example 2
The microneedle array patch provided by the invention is used as follows:
firstly, taking down the slice medical sponge in the microneedle array patch, pasting the pressure-sensitive adhesive tape on the skin, and directly pasting the whole microneedle array patch on the skin.
Next, the patch is pressed with a proper force (preferably without pain) for 2 minutes, and the microneedle array is stuck with a pressure-sensitive tape of the microneedle array patch to fix the depth of penetration of the microneedle array into the skin, and the soluble drug-loaded microneedle tips dissolve intradermally.
And tearing off the medicine patch after 15 minutes, wherein the tip of the soluble medicine carrying micro needle is completely dissolved and retained in the skin, and the skin cuticle leaves a micro-pore canal, and the medicine patch is completely healed after about 24 hours, so that the BCG vaccine inoculation is completed.
Finally, after 3 months of PPD test, the hard nodule is formed at the place where the medicine is stuck by hand, the size of the hard nodule is measured by a ruler, and whether the hard nodule is in positive reaction of PPD test is judged, namely, whether the BCG vaccine is successful is finished.
Example 3
Storage stability test of the two-stage microneedle array patch of the invention
The two-stage microneedle array patch prepared in example 1 was placed at room temperature (10-30 ℃) for 12 months, dissolved in a buffer solution, and the activity of bcg vaccine and tuberculin contained in the tip of the soluble drug-loaded microneedle was detected.
Wherein the bacillus calmette-guerin is cultured for 4 weeks by incubation, the viable count is detected by a cell counter, the tuberculin is detected by an ultraviolet-visible spectrophotometry, the two-section microneedle array drug patches prepared just before are used as a control, and the viable count of the bacillus calmette-guerin contained in the tips of the two soluble drug-carrying micronet and the nucleic acid content of the tuberculin are compared.
The results show that the viable count of BCG and the nucleic acid content of tuberculin in the two-stage microneedle array patch which is just prepared are basically consistent after the patch is placed at room temperature for 12 months. Indicating that the bacillus calmette-guerin activity in the two-stage microneedle array patch is unchanged after being placed for 12 months at room temperature.
Example 4
Effect test of the microneedle array patch of the invention
1. Selection of test animals
18 SPF-grade female and male half guinea pigs are selected and used, and the weight is about 300 g. The tuberculin is injected into the skin for 5IU, and the tuberculin has negative reaction within 72 hours.
2. Test group
Guinea pigs negative for PPD test were randomly divided into three groups, which were 8 control groups (injection needle group), 8 test groups (microneedle patch group) and 8 blank control groups (no drug administration), respectively.
3. Test method
(1) BCG vaccine inoculation
Microneedle patch test group guinea pigs: the hair on the outer side of the right hind leg of the guinea pig is shaved, the microneedle array patch is stuck on the shaved part, the microneedle array is pressed for 2 minutes by moderate force, and the microneedle patch is torn off after 2 hours.
Injection needle control group guinea pigs: the hair of the outer part of the right hindleg of the guinea pig is shaved off, and a proper amount of BCG vaccine solution (the same as the dosage of the microneedle medicine BCG vaccine) is sucked by a 1ml syringe and is injected intradermally at the shaved part.
Blank group guinea pigs: the hair of the outer side part of the right hind leg of the guinea pig is shaved, 4 guinea pigs are sucked by a 1ml syringe to inject 0.1ml injection water into the shaved part, the other 4 guinea pigs are pasted on the shaved part by a blank microneedle array medicine without medicine, the microneedle array is pressed for 2 minutes by moderate force, and the microneedle medicine is torn off after 2 hours.
The skin condition of each guinea pig at the site of application was observed. Feeding for 3 months.
(2) Diagnosis of successful BCG vaccination
Microneedle patch test group guinea pigs: the hair was shaved off from the outside of the right hind leg of the guinea pig at the site where the patch was attached, the skin was gently touched with a hand, streaked along the edge of the induration, and the induration diameter of each guinea pig was measured with a ruler and recorded.
Injection needle control group guinea pigs: the hair of the external side of the right hind leg of the guinea pig was shaved off and a proper amount of tuberculin solution (the same dose as the microneedle patch tuberculin) was sucked by a 1ml syringe and injected intradermally at the shaved place. After 72 hours, the size of the rash and induration at the injection site was measured with a ruler and recorded.
Blank group guinea pigs: the hair of the outer side part of the right hind leg of the guinea pig is shaved, 4 guinea pigs are sucked by a 1ml syringe to inject 0.1ml injection water into the shaved part, the other 4 guinea pigs are pasted on the shaved part by a blank microneedle array medicine without medicine, the microneedle array is pressed for 2 minutes by moderate force, and the microneedle medicine is torn off after 2 hours. After 72 hours, the size of the rash and induration at the injection site was measured with a ruler and recorded.
(3) Test results
The test results are shown in Table 1.
Table 1 results of the various tests
| Group of | Diameter of hard knot | Remarks |
| Syringe control group | ＋＋ | The occurrence of erythema infection |
| Microneedle patch test set | ＋＋ | No obvious infection phenomenon |
| Blank control group of injector | － | No obvious infection phenomenon |
| Microneedle patch blank control group | － | No obvious infection phenomenon |
As can be seen from the results in Table 1, the guinea pig inoculation sites of the microneedle patch test group and the syringe control group showed obvious PPD test positive reaction, while the guinea pig inoculation sites of the syringe control group and the microneedle patch control group showed PPD test negative reaction, which indicates that the BCG vaccine of the syringe control group and the guinea pigs of the microneedle patch test group were successfully inoculated, and in particular, the syringe control group and the injection site of the guinea pigs showed obvious erythema infection, while the microneedle patch test group showed no obvious infection and less side effects. Therefore, the microneedle array patch of the invention can be confirmed to have good curative effect.
It is to be understood that the above examples of the present invention are provided by way of illustration only and are not intended to limit the scope of the invention. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. It is not necessary here nor is it exhaustive of all embodiments. Any modification, equivalent replacement, improvement, etc. which come within the spirit and principles of the invention are desired to be protected by the following claims.
Claims (9)
1. The two-section microneedle array patch is characterized by comprising a microneedle array and a patch, wherein the microneedle array is arranged on the patch; the microneedle of the microneedle array comprises a soluble drug-carrying microneedle tip and an insoluble microneedle supporting end, wherein the soluble drug-carrying microneedle tip is prepared by mixing BCG vaccine, tuberculin microspheres and soluble auxiliary materials and freeze-drying, the tuberculin microspheres are prepared by combining slow release auxiliary materials with tuberculin, the soluble drug-carrying microneedle tip is arranged on the insoluble microneedle supporting end, the microneedle array substrate is an insoluble microneedle array substrate, and the insoluble microneedle supporting end is positioned on the surface of the microneedle array substrate;
the soluble auxiliary materials are sucrose, polyvinyl alcohol or hyaluronic acid;
the slow release auxiliary material is a mixture formed by carboxymethyl chitosan and polylactic acid-polymethyl copolymer in a weight ratio of 2:1-3:2.
2. The microneedle array patch of claim 1, wherein the soluble drug-loaded microneedle tips are quadrangular pyramid shaped microneedle tips and the insoluble microneedle support ends are cylindrical microneedle support ends.
3. The microneedle array patch of claim 2,
the soluble auxiliary material is a mixture of sucrose or hyaluronic acid and polyvinyl alcohol according to a ratio of 1:2-3:2.
4. A microneedle array patch as in claim 3, wherein the insoluble microneedle support end is PMMA or stainless steel, ceramic material.
5. The microneedle array patch of claim 4, wherein the microneedle array is arranged at 10 x 10, the soluble drug loaded microneedle tip height is 200 to 400 microns, and the insoluble microneedle support tip height is no more than 400 microns.
6. The microneedle array patch of claim 5, wherein the patch includes a pressure sensitive adhesive tape and an absorbent pad; the pressure-sensitive adhesive tape is used for pasting skin and the microneedle array; the hollow portion of the absorption gasket is placed in the microneedle array base, and the thickness of the absorption gasket exceeds the height of the microneedle array base and does not exceed the height of the insoluble microneedle supporting end.
7. The microneedle array patch of claim 6, further comprising a sliced medical sponge, the sliced medical sponge encasing the microneedles of the microneedle array.
8. A method for preparing the two-section micro-needle array patch according to claim 1, wherein,
step 1: adding tuberculin into the slow release auxiliary materials, and volatilizing at 2-8 ℃ under reduced pressure to prepare tuberculin microspheres;
step 2: adding the tuberculin microspheres prepared in the step 1 into soluble auxiliary materials, adding BCG vaccine solution, uniformly mixing, pouring into a microneedle tip end groove die, centrifuging, removing redundant solution, and freeze-drying to form a soluble drug-carrying microneedle tip in the microneedle tip end groove die;
step 3: then aligning the microneedle supporting end groove mould above the freeze-dried microneedle tip groove mould, pouring a preparation material solution of the prepolymerized insoluble microneedle supporting end into the microneedle supporting end groove mould, and drying at room temperature to obtain a microneedle array;
step 4: placing the prepared microneedle array into a patch.
9. The method for preparing the two-stage microneedle array patch of claim 8, wherein,
the step 1 specifically comprises the following steps: adding tuberculin into a mixture formed by carboxymethyl chitosan and polylactic acid-polymethyl copolymer in a weight ratio of 2:1-3:2, and volatilizing at 2-8 ℃ under reduced pressure to prepare tuberculin microspheres;
the step 2 specifically comprises the following steps: adding the tuberculin microspheres prepared in the step 1 into a hyaluronic acid solution, adding a BCG vaccine solution, uniformly mixing, pouring into a microneedle tip groove die, centrifuging, removing redundant solution, and freeze-drying to form a soluble drug-loaded microneedle tip in the microneedle tip groove die;
the step 3 specifically comprises the following steps: then aligning the microneedle supporting end groove mould above the freeze-dried microneedle tip groove mould, pouring a pre-polymerized PMMA solution into the microneedle supporting end groove mould, and drying for 24 hours at room temperature to obtain a microneedle array;
the step 4 specifically comprises the following steps: the manufactured microneedle array is placed in an absorption gasket in a medical patch, the microneedles of the microneedle array are wrapped by a sliced medical sponge, the medical patch comprises a pressure-sensitive adhesive tape, and the pressure-sensitive adhesive tape is used for pasting skin and the microneedle array.
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| CN112516452A (en) * | 2020-12-18 | 2021-03-19 | 南京鼓楼医院 | Frozen microneedle array and preparation method and application thereof |
| CN114712696B (en) * | 2022-04-08 | 2023-06-23 | 北京化工大学 | A method for preparing three-stage continuous drug delivery polymer microneedles |
| CN115300783A (en) * | 2022-07-03 | 2022-11-08 | 湖北迈科泰克生物医药有限公司 | Double-phase microneedle patch capable of improving drug delivery efficiency and preparation method |
| CN115089864B (en) * | 2022-07-14 | 2023-12-29 | 复旦大学 | Method for preparing soluble microneedle patch by using freeze drying technology |
| CN115501474A (en) * | 2022-09-16 | 2022-12-23 | 深圳高性能医疗器械国家研究院有限公司 | Preparation method of soluble microneedle adhesive film |
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