CN112023033A - Two-section type micro-needle array medicine patch capable of simultaneously realizing BCG vaccine inoculation and diagnosis and preparation method thereof - Google Patents
Two-section type micro-needle array medicine patch capable of simultaneously realizing BCG vaccine inoculation and diagnosis and preparation method thereof Download PDFInfo
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- CN112023033A CN112023033A CN202010861915.7A CN202010861915A CN112023033A CN 112023033 A CN112023033 A CN 112023033A CN 202010861915 A CN202010861915 A CN 202010861915A CN 112023033 A CN112023033 A CN 112023033A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/02—Bacterial antigens
- A61K39/04—Mycobacterium, e.g. Mycobacterium tuberculosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/48—Other medical applications
- A61B5/4848—Monitoring or testing the effects of treatment, e.g. of medication
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
- A61K49/0006—Skin tests, e.g. intradermal testing, test strips, delayed hypersensitivity
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0046—Solid microneedles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0053—Methods for producing microneedles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0061—Methods for using microneedles
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention discloses a two-section type micro-needle array medicine patch for simultaneously realizing BCG vaccine inoculation and diagnosis, which comprises a micro-needle array and a medicine patch, wherein the micro-needle array is arranged on the medicine patch; the micro-needle comprises a soluble drug-carrying micro-needle tip and an insoluble micro-needle support end, the soluble drug-carrying micro-needle tip is prepared by mixing BCG, tuberculin microspheres and soluble auxiliary materials and freeze-drying the mixture, the tuberculin microspheres are prepared by combining sustained-release auxiliary materials and tuberculin, the BCG and the tuberculin are gathered at the soluble micro-needle drug-carrying tip simultaneously, and the release time of the tuberculin is controlled by the sustained-release microsphere technology, so that two administration purposes of achieving the inoculation of the BCG and diagnosing whether the BCG is successfully inoculated or not by one-time administration are realized. The invention also discloses a preparation method of the medicine patch.
Description
Technical Field
The invention relates to the technical field of biomedical engineering, in particular to a two-section type microneedle array patch for simultaneously realizing BCG vaccine inoculation and diagnosis and a preparation method thereof.
Background
Bcg is currently the only vaccine approved for tuberculosis control. The prevalence of tuberculosis can be well controlled by expanding the range of bcg vaccination of newborns, which is currently performed by intradermal injection of the newborns using a syringe, which usually requires skilled medical personnel to perform, and is often unreliable, and about 5% of bcg vaccination is usually performed subcutaneously, which results in vaccination failure and pyogenic infection, and which is also a risk for the bcg vaccinee or medical personnel. In addition, whether BCG vaccination is successful or not usually requires that tuberculin is injected intradermally for PPD test 3 months after vaccination, and if positive, the vaccination is successful, otherwise, the vaccination fails. It is well known that intradermal injection can cause severe pain, accidental needle sticks, severe skin infections and scarring which can greatly reduce vaccination compliance in vaccinees. In addition, the BCG and tuberculin need to be stored and transported at low temperature, which brings inconvenience to storage and transportation of BCG and tuberculin medicines and increases the circulation cost.
Disclosure of Invention
The invention aims to overcome the defects of difficult pain, high operation difficulty, easy failure, high infection risk, cold chain requirement for storage and transportation and the like of the existing intradermal injection of BCG and tuberculin into human skin, realize two functions of inoculation of BCG and diagnosis of success of inoculation at the same time of one-time administration, and greatly improve the success rate of BCG inoculation and diagnosis.
In order to achieve the purpose, the invention adopts the technical scheme that:
a two-section type micro-needle array medicine patch comprises a micro-needle array and a medicine patch, wherein the micro-needle array is arranged on the medicine patch; microneedle of microneedle array supports the end including soluble medicine carrying microneedle tip and insoluble microneedle, soluble medicine carrying microneedle tip is BCG vaccine, tuberculin microballon, soluble auxiliary material mix and prepare through freeze-drying and obtains, tuberculin microballon adopts slow release auxiliary material and tuberculin combination to make, soluble medicine carrying microneedle tip is arranged in insoluble microneedle supports and serves, microneedle array base is insoluble microneedle array base, insoluble microneedle support the end and is located microneedle array base surface.
According to the technical scheme, the two-section type micro-needle array patch capable of realizing BCG vaccine inoculation and diagnosis can be formed.
As a preferred embodiment of the microneedle array patch of the present invention, the tip of the soluble drug-loaded microneedle is a pyramid-shaped microneedle tip, and the insoluble microneedle support end is a cylindrical microneedle support end. The microneedle needs to penetrate into the skin to form a micropore array drug delivery channel, and the tip of the soluble drug-loaded microneedle is a quadrangular pyramid shaped tip of the microneedle, so that the microneedle is easier to penetrate into the skin than a cone, and has little harm to the skin.
The tip of the soluble drug-carrying micro-needle is used for avoiding the influence of a soluble auxiliary material on a drug, and a material with large irritation or influence on the activity of protein is not suitable to be adopted, and as a preferred embodiment of the micro-needle array patch, the soluble auxiliary material is cane sugar, polyvinyl alcohol or hyaluronic acid, or the soluble auxiliary material is a mixture of cane sugar or hyaluronic acid and polyvinyl alcohol according to the ratio of 1: 2-3: 2.
As a preferred embodiment of the microneedle array patch, the tuberculin microspheres are prepared by combining sustained-release auxiliary materials and tuberculin, preferably, the sustained-release auxiliary materials are a mixture of carboxymethyl chitosan and polylactic acid-polymethyl copolymer in a weight ratio of 2: 1-3: 2, the release time of the sustained-release microspheres is about 90 days, and the time from the beginning to the end of the release is controlled within 6 hours.
The tip of the soluble drug-loaded micro-needle is dissolved in the skin within 15 minutes and separated from the insoluble micro-needle support end to release the BCG drug, and the tuberculin microspheres are degraded in the skin for about 90 days to release tuberculin to generate drug effect.
The insoluble microneedle support end is made of a biological material which is good in biocompatibility of a human body, better in connection with a soluble auxiliary material and sufficient in mechanical strength.
As a preferred embodiment of the micro-needle array patch, the micro-needle array takes 10 x 10 as the best, the height of the micro-needle is not more than 800 micrometers, the height of the tip of the soluble drug-carrying micro-needle is 200 to 400 micrometers, and the height of the support end of the insoluble micro-needle is not more than 400 micrometers, so that the micro-needle can better break the stratum corneum of the skin, the requirements of BCG vaccine inoculation and inspection are met, and in addition, the patch area is not more than 1 square centimeter in order to observe the red rash and induration condition during diagnosis.
As a preferred embodiment of the microneedle array patch of the present invention, the patch includes a pressure sensitive adhesive tape and an absorbent gasket. The pressure sensitive adhesive tape is used for sticking the skin and the microneedle array, and can be directly stuck on the surface of the skin and ensure firmness after being pressed, so that the sticking layer material is required to have good skin biocompatibility and no toxicity, and preferably, the pressure sensitive adhesive is medical pressure sensitive adhesive. The hollow part of the absorption gasket is just embedded into the microneedle array substrate, the thickness of the hollow part of the absorption gasket exceeds the height of the microneedle array substrate and does not exceed the height of the insoluble microneedle support end 2, and the absorption gasket is made of soft materials which are loose and easy to penetrate and harmless to a human body, so that a good liquid absorption effect is achieved.
As a preferred embodiment of the microneedle array patch of the present invention, the patch further comprises a sliced medical sponge, which wraps the microneedles of the microneedle array. The section medical sponge is used for protecting the tip of the soluble drug-loaded micro-needle, and the thickness of the section medical sponge is not shorter than the length of the whole micro-needle so as to ensure the protection of the tip of the micro-needle in the transportation and transfer process.
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 sustained-release auxiliary materials, and performing reduced pressure volatilization at the temperature of 2-8 ℃ to prepare tuberculin microspheres;
step 2: adding a soluble auxiliary material into the tuberculin microspheres prepared in the step 1, adding a BCG vaccine solution, uniformly mixing, pouring into a micro-needle-tip end groove die, centrifuging, removing redundant solution, freeze-drying, and forming a soluble drug-loaded micro-needle tip in the micro-needle-tip end groove die;
and step 3: aligning the microneedle supporting end groove mould above the freeze-dried microneedle tip end 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;
and 4, step 4: the prepared microneedle array is placed in a patch.
As a preferred embodiment of the microneedle array patch of the present invention, the step 1 is specifically: adding tuberculin into a mixture of carboxymethyl chitosan and polylactic acid-polymethyl copolymer in a weight ratio of 2: 1-3: 2, and performing reduced pressure volatilization at the temperature of 2-8 ℃ to prepare the tuberculin microspheres.
As a preferred embodiment of the microneedle array patch of the present invention, the step 2 is specifically: adding the tuberculin microspheres prepared in the step 1 into a hyaluronic acid solution, adding a bacillus calmette-guerin solution, uniformly mixing, pouring into a micro-needle-tip end groove die, centrifuging, removing redundant solution, freeze-drying, and forming a soluble drug-loaded micro-needle tip in the micro-needle-tip end groove die;
as a preferred embodiment of the microneedle array patch of the present invention, the step 3 is specifically: aligning the microneedle supporting end groove mould above the freeze-dried microneedle tip end groove mould, pouring the prepolymerized PMMA solution into the microneedle supporting end groove mould, and drying at room temperature for 24 hours to obtain a microneedle array;
as a preferred embodiment of the microneedle array patch of the present invention, the step 4 is specifically: the manufactured microneedle array is placed in an absorption washer in a patch paster, microneedles of the microneedle array are wrapped by sliced medical sponges, the patch paster comprises a pressure sensitive adhesive tape, and the pressure sensitive adhesive tape is used for adhering the skin to the microneedle array.
The micro-needle array medicine patch has the main innovation point that the BCG and tuberculin are gathered in the same micro-needle medicine patch, and the inoculation of the BCG and the diagnosis of whether the inoculation is successful or not are simultaneously realized. When the patch is used, the microneedle array patch is integrally and directly adhered to skin by using the patch, proper force is applied to press the bottom of the patch, so that the medicine carrying tip of the soluble microneedle is completely inserted into the skin, the medicine carrying tip of the soluble microneedle is dissolved and separated from the support end of the insoluble microneedle, BCG and tuberculin microspheres in the medicine carrying tip of the soluble microneedle are retained in an immune cell aggregation area at the upper part of the dermal layer of the skin, the BCG directly acts on immune cells to trigger immune reaction, an organism generates anti-tuberculosis antibodies to realize the successful inoculation of the BCG, the tuberculin microspheres do not generate drug effect due to the protection of the surface slow-release layer, the immune action of the BCG in the organism needs about 3 months as time goes on, the surface slow-release layer of the tuberculin microspheres is dissolved, the tuberculin is exposed in the skin and is combined with the antibodies generated by the organism, an antigen-antibody reaction occurs (i.e., PPD assay). If positive erythra and induration appear on the inoculated part, the success of BCG inoculation can be concluded, if not, the BCG inoculation fails, thereby realizing the diagnosis of whether BCG inoculation is successful or not. Therefore, the micro-needle array patch skillfully gathers the BCG and the tuberculin at the tip of the soluble micro-needle drug-loaded needle, and controls the release time of the tuberculin by a slow-release microsphere technology, thereby realizing two drug-delivery purposes of achieving the inoculation of the BCG and diagnosing whether the BCG is successfully inoculated or not by one-time drug delivery. The integrated administration mode of BCG inoculation and diagnosis not only avoids the pain of the traditional intradermal injection, but also greatly simplifies the operation steps of BCG inoculation and diagnosis. Meanwhile, the BCG vaccine and tuberculin are coated in the tip of the micro-needle after freeze drying, and are stable at room temperature, so that the storage and transportation of the medicine are facilitated, and the cost is reduced.
Drawings
Fig. 1 is a schematic structural view of a two-section microneedle array patch according to an embodiment of the present invention.
Detailed Description
To better illustrate the objects, aspects 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 embodiment includes a microneedle array and a patch, the microneedle array is disposed on the patch; the micro-needle of the micro-needle array comprises a soluble drug-loaded micro-needle tip 1 and an insoluble micro-needle support end 2; the soluble drug-loaded micro-needle tip 1 is prepared by mixing BCG, tuberculin microspheres and soluble auxiliary materials and freeze-drying the mixture, the tuberculin microspheres are prepared by combining sustained-release auxiliary materials and tuberculin, the soluble drug-loaded micro-needle tip 1 is arranged on the insoluble micro-needle supporting end 2, the micro-needle array substrate 3 is an insoluble micro-needle array substrate, and the insoluble micro-needle supporting end 2 is arranged on the surface of the micro-needle 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 adhering the skin to the microneedle array; the hollow part of the absorption gasket 5 is placed into the microneedle array substrate 3, and the thickness of the absorption gasket 5 exceeds the height of the microneedle array substrate 3 and does not exceed the height of the insoluble microneedle support end 2; the medical sponge slice 6 is arranged on the plaster patch, and the microneedle of the microneedle array is wrapped by the medical sponge slice 6.
Specifically, in this embodiment, the soluble drug-loaded microneedle tip 1 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 sustained-release auxiliary materials and tuberculin, wherein in the embodiment, the sustained-release auxiliary materials are carboxymethyl chitosan and polylactic acid-polymethyl copolymer in a weight ratio of 2: 1-3: 2
Adding tuberculin into the slow-release auxiliary material, and drying at 2-8 ℃ under reduced pressure to obtain the mixture.
Preferably, in the embodiment, the tuberculin microspheres contain 5 doses of tuberculin according to the dose requirement of the inoculation test, and 5IU is taken as a single human dose. The weight ratio of the carboxymethyl chitosan to the polylactic acid-polymethyl copolymer is 2: 1-3: 2, and preferably, the weight ratio is 3:2 within the range of 2: 1-3: 2.
The soluble drug-loaded micro-needle tip 1 is prepared by mixing BCG, tuberculin microspheres and soluble auxiliary materials and freeze-drying the mixture, preferably, in the embodiment, the soluble auxiliary material is hyaluronic acid, the BCG and tuberculin microspheres can be added into a hyaluronic acid solution to be mixed, and the freeze-drying is carried out to prepare the soluble drug-loaded micro-needle tip 1, wherein the BCG is taken by a single person according to the inoculation requirement.
In the present embodiment, the insoluble microneedle support end 2 and the microneedle array substrate 3 are made of PMMA material, and have sufficient toughness and strength. More preferably, the microneedle array is a 10 × 10 array, and comprises 100 microneedles, the microneedle array substrate 3 is a square with an area of 1 square centimeter, the height of the soluble drug-loaded microneedle tip 3 is 400 micrometers, the height of the insoluble microneedle support end 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 medical sponge 6 is made of medical absorbent cotton and has a thickness of more than 800 microns.
The microneedle array patch of this example is prepared by the following method:
(1) adding 5IU of tuberculin into a mixture of carboxymethyl chitosan and polylactic acid-polymethyl copolymer in a weight ratio of 3:2, and performing reduced pressure volatilization at the temperature of 2-8 ℃ to prepare the tuberculin microspheres.
(2) Adding the tuberculin microspheres prepared in the step (1) into a hyaluronic acid solution, adding 0.01 mg of BCG solution, uniformly mixing, pouring into a micro-needle-tip end groove die, centrifuging, removing redundant solution, and forming a soluble drug-loaded micro-needle tip in the micro-needle-tip end groove die.
(3) And aligning the microneedle support end groove mould above the freeze-dried microneedle tip end groove mould, pouring the prepolymerized PMMA solution into the microneedle support end groove mould until the liquid level thickness in the groove is 1 mm (forming a microneedle array substrate after drying), and drying at room temperature for 24 hours to obtain the two-section microneedle array.
(4) And (3) placing the manufactured microneedle array in an absorption washer in the patch paster, and wrapping the microneedles of the microneedle array by the sliced medical sponge to obtain the two-section type microneedle array patch.
Example 2
The microneedle array patch of the invention is used as follows:
firstly, the sliced medical sponge in the microneedle array patch is taken down, the pressure sensitive adhesive tape is pasted on the skin, and the whole microneedle array patch is directly pasted on the skin.
Next, the patch was pressed with the appropriate force (no pain) and the duration of the pressing was stopped for 2 minutes and the microneedle array was affixed 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 dissolvable drug-loaded microneedle tip dissolved in the skin.
Thirdly, the patch is torn off after 15 minutes, at the moment, the tip of the soluble drug-loaded micro needle is completely dissolved and retained in the skin, tiny pores are left in the stratum corneum of the skin, and the skin is completely healed after about 24 hours, thus completing the inoculation of the BCG vaccine.
Finally, PPD test, after 3 months, the hard knot is formed by touching the patch with a hand lightly, the size of the hard knot is measured by a ruler, and the diagnosis of whether the BCG vaccine is successful is completed if the positive reaction of the PPD test is present.
Example 3
Storage stability test of two-stage microneedle array patch of the present invention
The two-section type microneedle array patch prepared in example 1 was placed at room temperature (10-30 ℃) for 12 months, dissolved in buffer solution, and then the activity of bcg and tuberculin contained in the tip of the soluble drug-loaded microneedle was examined.
The viable count of BCG vaccine is detected by cell counter after 4 weeks incubation, the nucleic acid content of tuberculin is detected by ultraviolet-visible spectrophotometry, and the viable count of BCG vaccine and the nucleic acid content of tuberculin in the tip of the two soluble drug-carrying micro-needle are compared by using the two-stage micro-needle array patch prepared just before as a reference.
The result shows that the viable count of BCG vaccine and the nucleic acid content of tuberculin in the two-section type microneedle array patch which is just prepared are basically consistent when the patch is placed at room temperature for 12 months. Indicating that the activity of the BCG vaccine and tuberculin in the two-section type microneedle array patch is not changed after the patch is placed at room temperature for 12 months.
Example 4
Effect test of microneedle array Patch according to the present invention
1. Selection of test animals
18 SPF-grade male and female guinea pigs respectively are selected, and the weight of the guinea pigs is about 300 g. 5IU tuberculin is injected into the skin, and a negative reaction is shown within 72 hours.
2. Test grouping
Guinea pigs negative to the PPD test were randomly divided into three groups as 8 control groups (injection needle group), 8 test groups (microneedle patch group), and 8 blank control groups (no administration), respectively.
3. Test method
(1) Inoculation of BCG vaccine
Microneedle patch test group guinea pigs: the hair on the outer part of the right hind leg of the guinea pig is shaved off, the microneedle array patch of the present invention is stuck on the shaved part, the microneedle array is pressed with moderate force for 2 minutes, and the microneedle patch is torn off after 2 hours.
Injection needle control guinea pigs: the hair on the outer part of the right hind leg of the guinea pig was shaved off and a suitable amount of BCG solution (same dose as the microneedle patch BCG) was drawn up using a 1ml syringe and injected intradermally into the shaved area.
Guinea pigs in the blank control group: hairs on the outer portion of the right hind leg of the guinea pig were shaved, 4 guinea pigs were intradermally injected at the shaved portion by sucking 0.1ml of water for injection with a 1ml syringe, and the other 4 guinea pigs were attached to the shaved portion with a drug-free blank microneedle array patch, and the microneedle array was pressed with a moderate force for 2 minutes, and the microneedle patch was peeled off after 2 hours.
The skin condition of the site to which each guinea pig was applied was observed. Feeding for 3 months.
(2) Diagnosis of success of BCG vaccination
Microneedle patch test group guinea pigs: the hair on the site of the microneedle array patch adhered to the lateral side of the right hind leg of the guinea pig was shaved, the skin was lightly touched with a hand, the edge of the induration was scribed, and the induration diameter of each guinea pig was measured with a ruler and recorded.
Injection needle control guinea pigs: the hair at the original syringe injection site on the outer side of the right hind leg of the guinea pig was shaved off, and a proper amount of tuberculin solution (same dose as the micropin patch tuberculin) was sucked up with a 1ml syringe and injected intradermally into the shaved site. After 72 hours, the size of the eruption and induration at the injection site was measured with a ruler and recorded.
Guinea pigs in the blank control group: hairs on the outer portion of the right hind leg of the guinea pig were shaved, 4 guinea pigs were intradermally injected at the shaved portion by sucking 0.1ml of water for injection with a 1ml syringe, and the other 4 guinea pigs were attached to the shaved portion with a drug-free blank microneedle array patch, and the microneedle array was pressed with a moderate force for 2 minutes, and the microneedle patch was peeled off after 2 hours. After 72 hours, the size of the eruption 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 test results of each group
| Group of | Diameter of induration | Remarks for note |
| Syringe control group | ＋＋ | The red rash infection phenomenon appears |
| Microneedle patch test set | ＋＋ | No obvious infection phenomenon |
| Syringe blank control group | － | No obvious infection phenomenon |
| Microneedle patch blank control group | － | No obvious infection phenomenon |
As can be seen from the results in table 1, the positive PPD test reaction was observed at the guinea pig inoculated portion of the microneedle patch test group and the significant PPD test reaction was observed at the guinea pig inoculated portion of the syringe control group, and the negative PPD test reaction was observed at the guinea pig inoculated portion of the syringe blank control group and the microneedle patch blank control group, which indicated that the vaccination with bcg was successful at both the guinea pigs of the syringe control group and the microneedle patch test group, and particularly, the injection portion of the guinea pig of the syringe control group showed significant erythema infection, while the microneedle patch test group showed no significant infection, and had less side effects. It can be confirmed that the microneedle array patch of the present invention has good therapeutic effects.
It should be understood that the above-described embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.
Claims (10)
1. A two-section type micro-needle array medicine patch is characterized by comprising a micro-needle array and a medicine patch, wherein the micro-needle array is arranged on the medicine patch; microneedle of microneedle array supports the end including soluble medicine carrying microneedle tip and insoluble microneedle, soluble medicine carrying microneedle tip is BCG vaccine, tuberculin microballon, soluble auxiliary material mix and prepare through freeze-drying and obtains, tuberculin microballon adopts slow release auxiliary material and tuberculin combination to make, soluble medicine carrying microneedle tip is arranged in insoluble microneedle supports and serves, microneedle array base is insoluble microneedle array base, insoluble microneedle support the end and is located microneedle array base surface.
2. The microneedle array patch according to claim 1, wherein the soluble drug-loaded microneedle tip is a quadrangular pyramid-shaped microneedle tip, and the insoluble microneedle support end is a cylindrical microneedle support end.
3. The microneedle array patch according to claim 2, wherein the soluble adjuvant is sucrose, polyvinyl alcohol or hyaluronic acid,
or the soluble auxiliary material is a mixture of sucrose or hyaluronic acid and polyvinyl alcohol according to the proportion of 1: 2-3: 2.
4. The microneedle array patch according to claim 3, wherein the slow release adjuvant is a mixture of carboxymethyl chitosan and polylactic acid-polymethyl copolymer in a weight ratio of 2: 1-3: 2.
5. A microneedle array patch according to claim 4, wherein said insoluble microneedle support end can be PMMA or stainless steel, ceramic or the like.
6. The microneedle array patch of claim 5, wherein said microneedle array is arranged at 10 x 10, said dissolvable drug-loaded microneedle tips have a height of 200 to 400 microns, and said non-dissolvable microneedle support tips have a height of no more than 400 microns.
7. A microneedle array patch according to claim 6, wherein said patch comprises a pressure sensitive adhesive tape and an absorbent gasket; the pressure sensitive adhesive tape is used for adhering skin to the microneedle array; the hollow part of the absorption gasket is embedded into the microneedle array substrate, and the thickness of the absorption gasket exceeds the height of the microneedle array substrate and does not exceed the height of the insoluble microneedle support end 2.
8. A microneedle array patch according to claim 7, further comprising a sliced medical sponge, said sliced medical sponge wrapping microneedles of said microneedle array.
9. A preparation method of a two-section type micro-needle array medicine patch, which is characterized in that,
step 1: adding tuberculin into the sustained-release auxiliary materials, and performing reduced pressure volatilization at the temperature of 2-8 ℃ to prepare tuberculin microspheres;
step 2: adding a soluble auxiliary material into the tuberculin microspheres prepared in the step 1, adding a BCG vaccine solution, uniformly mixing, pouring into a micro-needle-tip end groove die, centrifuging, removing redundant solution, freeze-drying, and forming a soluble drug-loaded micro-needle tip in the micro-needle-tip end groove die;
and step 3: aligning the microneedle supporting end groove mould above the freeze-dried microneedle tip end 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;
and 4, step 4: the prepared microneedle array is placed in a patch.
10. The method for preparing a two-stage micro-needle array patch according to claim 9,
the step 1 specifically comprises the following steps: adding tuberculin into a mixture of carboxymethyl chitosan and polylactic acid-polymethyl copolymer in a weight ratio of 2: 1-3: 2, and performing reduced pressure volatilization at the temperature of 2-8 ℃ 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 bacillus calmette-guerin solution, uniformly mixing, pouring into a micro-needle-tip end groove die, centrifuging, removing redundant solution, freeze-drying, and forming a soluble drug-loaded micro-needle tip in the micro-needle-tip end groove die;
the step 3 specifically comprises the following steps: aligning the microneedle supporting end groove mould above the freeze-dried microneedle tip end groove mould, pouring the prepolymerized PMMA solution into the microneedle supporting end groove mould, and drying at room temperature for 24 hours to obtain a microneedle array;
the step 4 specifically comprises the following steps: the manufactured microneedle array is placed in an absorption washer in a patch paster, microneedles of the microneedle array are wrapped by sliced medical sponges, the patch paster comprises a pressure sensitive adhesive tape, and the pressure sensitive adhesive tape is used for adhering the skin to the microneedle array.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112516452A (en) * | 2020-12-18 | 2021-03-19 | 南京鼓楼医院 | Frozen microneedle array and preparation method and application thereof |
| CN114712696A (en) * | 2022-04-08 | 2022-07-08 | 北京化工大学 | Method for preparing three-section type continuous administration polymer microneedle |
| CN115089864A (en) * | 2022-07-14 | 2022-09-23 | 复旦大学 | Method for preparing soluble microneedle patch by using freeze drying technology |
| 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 |
| 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 |
Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110195124A1 (en) * | 2008-10-07 | 2011-08-11 | Tuo Jin | Phase-transition polymeric microneedles |
| CN103893018A (en) * | 2014-04-16 | 2014-07-02 | 华熙福瑞达生物医药有限公司 | Soluble hyaluronic acid micro-needle patch |
| US20140257189A1 (en) * | 2011-10-20 | 2014-09-11 | Ying-shu Quan | Microneedle deposition method |
| CN104707241A (en) * | 2015-03-25 | 2015-06-17 | 北京化工大学 | Two-stage-type micro-needle array and preparation method thereof |
| CN106237318A (en) * | 2016-08-24 | 2016-12-21 | 湖北大学 | A kind of bacillus calmette-guerin vaccine dry powder micropin vaccine and preparation method thereof |
| WO2017043627A1 (en) * | 2015-09-11 | 2017-03-16 | 株式会社バイオセレンタック | Microneedle preparation |
| CN107569447A (en) * | 2017-09-20 | 2018-01-12 | 广州新济薇娜生物科技有限公司 | It is loaded with soluble microneedle patch of purified protein derivative of tuberculin and preparation method thereof |
| CN107823122A (en) * | 2017-11-07 | 2018-03-23 | 湖北大学 | A kind of tuberculin microneedle patch and its preparation method and application |
| CN110840822A (en) * | 2018-07-26 | 2020-02-28 | 华中科技大学 | Method for preparing porous polymer microneedle and application thereof |
-
2020
- 2020-08-25 CN CN202010861915.7A patent/CN112023033B/en active Active
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110195124A1 (en) * | 2008-10-07 | 2011-08-11 | Tuo Jin | Phase-transition polymeric microneedles |
| US20140257189A1 (en) * | 2011-10-20 | 2014-09-11 | Ying-shu Quan | Microneedle deposition method |
| CN103893018A (en) * | 2014-04-16 | 2014-07-02 | 华熙福瑞达生物医药有限公司 | Soluble hyaluronic acid micro-needle patch |
| CN104707241A (en) * | 2015-03-25 | 2015-06-17 | 北京化工大学 | Two-stage-type micro-needle array and preparation method thereof |
| WO2017043627A1 (en) * | 2015-09-11 | 2017-03-16 | 株式会社バイオセレンタック | Microneedle preparation |
| CN106237318A (en) * | 2016-08-24 | 2016-12-21 | 湖北大学 | A kind of bacillus calmette-guerin vaccine dry powder micropin vaccine and preparation method thereof |
| CN107569447A (en) * | 2017-09-20 | 2018-01-12 | 广州新济薇娜生物科技有限公司 | It is loaded with soluble microneedle patch of purified protein derivative of tuberculin and preparation method thereof |
| CN107823122A (en) * | 2017-11-07 | 2018-03-23 | 湖北大学 | A kind of tuberculin microneedle patch and its preparation method and application |
| CN110840822A (en) * | 2018-07-26 | 2020-02-28 | 华中科技大学 | Method for preparing porous polymer microneedle and application thereof |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112516452A (en) * | 2020-12-18 | 2021-03-19 | 南京鼓楼医院 | Frozen microneedle array and preparation method and application thereof |
| CN114712696A (en) * | 2022-04-08 | 2022-07-08 | 北京化工大学 | Method for preparing three-section type continuous administration polymer microneedle |
| CN114712696B (en) * | 2022-04-08 | 2023-06-23 | 北京化工大学 | Method for preparing three-section sustained-administration polymer microneedle |
| 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 |
| CN115089864A (en) * | 2022-07-14 | 2022-09-23 | 复旦大学 | Method for preparing soluble microneedle patch by using freeze drying technology |
| 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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