CN113288882A - Rapid separation microneedle patch and preparation method thereof - Google Patents
Rapid separation microneedle patch and preparation method thereof Download PDFInfo
- Publication number
- CN113288882A CN113288882A CN202110390499.1A CN202110390499A CN113288882A CN 113288882 A CN113288882 A CN 113288882A CN 202110390499 A CN202110390499 A CN 202110390499A CN 113288882 A CN113288882 A CN 113288882A
- Authority
- CN
- China
- Prior art keywords
- microneedle patch
- photo
- needle
- microneedle
- thermal material
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000926 separation method Methods 0.000 title claims abstract description 50
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- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims description 23
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 21
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 21
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 10
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- QGKMIGUHVLGJBR-UHFFFAOYSA-M (4z)-1-(3-methylbutyl)-4-[[1-(3-methylbutyl)quinolin-1-ium-4-yl]methylidene]quinoline;iodide Chemical class [I-].C12=CC=CC=C2N(CCC(C)C)C=CC1=CC1=CC=[N+](CCC(C)C)C2=CC=CC=C12 QGKMIGUHVLGJBR-UHFFFAOYSA-M 0.000 claims description 3
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 3
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- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 claims description 3
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- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 claims description 2
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Images
Classifications
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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
- A61K9/70—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
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
- 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
- A61K47/38—Cellulose; Derivatives thereof
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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
- A61K47/40—Cyclodextrins; Derivatives thereof
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- A—HUMAN NECESSITIES
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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- 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
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- 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
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- A—HUMAN NECESSITIES
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- 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
- A61M2037/0023—Drug applicators using microneedles
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
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- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
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- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
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- Dermatology (AREA)
- Engineering & Computer Science (AREA)
- Inorganic Chemistry (AREA)
- Anesthesiology (AREA)
- Biomedical Technology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medical Informatics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Media Introduction/Drainage Providing Device (AREA)
- Medicinal Preparation (AREA)
Abstract
The application discloses a quick-separation microneedle patch and a preparation method thereof. The rapid-separation microneedle patch comprises a base and microneedle bodies, wherein microneedle body arrays are uniformly distributed on the base; the micro needle body comprises a needle point and a middle section, the needle point contains a medicine, and the middle section is used for connecting the needle point and the base; the intermediate section is composed of a water-soluble polymer and a photothermal material, and the photothermal material is dispersed in the water-soluble polymer. The application discloses quick separation micropin paster utilizes the water-soluble polymer that adds the light and heat material as the interlude of micropin needle body, and when using, the interlude is easy to be cracked or is dissolved for the separability of needle point is strong, has realized the quick separation of light-operated condition base and needle point, has widened the application range of polymer micropin paster, has improved the use convenience of micropin paster simultaneously, has improved patient's compliance.
Description
Technical Field
The application relates to the technical field of microneedle drug delivery, in particular to a rapid separation microneedle patch and a preparation method thereof.
Background
With the rapid development of micro-fabrication technology and biomedical technology, microneedle drug delivery systems have come into play and are receiving wide attention. The micro-needle is a novel physical penetration promoting technology and is formed by connecting a plurality of micron-sized fine needle points on a base in an array mode. The length of the micro-needle is 25-1000 μm, and the size and the shape can be individually designed according to the treatment requirement. As a novel transdermal administration mode, the microneedle administration integrates the advantages of a subcutaneous injection administration mode and a transdermal patch administration mode, and has the advantages of no pain, minimal invasion and high drug absorption efficiency. In addition, when the micro-needle is used for drug administration, the patient can self-administer the drug, the operation is convenient and safe, and the compliance of the patient is good. The micro-needle transdermal delivery has wide application, can be used for transdermal delivery of small molecules, biological preparations, vaccines, intracellular DNA/RNA and other medicaments, and covers a plurality of disease fields such as pain, infection, diabetes, skin diseases and the like. The micro-needle has the advantages that other administration modes cannot be replaced by the aid of various body structures and administration characteristics, and clinical application and market development space of the micro-needle are huge. For example, ALZA company carries out clinical research on thyroxine hollow microneedles, and the result shows that the pharmacokinetic curve of microneedle administration is similar to that of subcutaneous injection, and the thyroxine hollow microneedles are expected to be a substitute of injection formulations. Zosano developed a new type of zolmitriptan coated microneedle for the treatment of migraine, which is now approved by FDA for marketing, a pioneer product for microneedle transdermal delivery systems. The polymer micro-needle has the advantages of good biocompatibility, high safety, accurate drug loading, flexible and controllable drug release, low preparation cost and the like, and is the micro-needle which is the most extensive in research and has the greatest application prospect at present.
The polymer microneedle can be structurally divided into two parts, a base and a needle body. In the process of living body application of the polymer microneedle, a professional is often required to press the microneedle patch, so that the microneedle body part is fully contacted with subcutaneous tissue fluid to be dissolved and degraded, and active ingredients in the microneedle body part are released, thereby realizing efficient drug delivery. The application time of the patch is directly influenced by the dissolution performance of the material of the needle body part, and the dissolution time of the water-soluble material in a small amount of subcutaneous tissue fluid is 15 minutes or more. Sustained compression for 15 minutes reduces the ease of use of the microneedles and also results in reduced patient compliance. In addition, some transdermal drug delivery microneedle patches require sustained release for one week or even one month, making polymeric microneedles impractical.
In response to the above problems, Mark r.praussnitz, georgia, has invented a method of forming a bubble between the base of a microneedle and the needle body so that the needle body can be rapidly broken into the subcutaneous tissue during the application process of the microneedle, as described in patent application CN 111465387A. The method has high requirements on the manufacturing process, and the needle breakage is easy to occur in the preparation process, so that the process is unstable. The utility model CN204352374U indicates that the base and the needle body are separated by adding a binder, i.e. a soluble binding substance of starch or protein, between the base and the needle body. The method is time consuming, and the design has insufficient contact with subcutaneous tissue fluid and is less feasible. The invention patent application CN107875115A points out a preparation method of a sectional separable microneedle patch, namely a layer of high-molecular hydrogel with strong water solubility is constructed between a base and a needle body, the method needs long pressing time, and the microneedle application method which is convenient and quick in the true sense is difficult to realize.
In general, the separable microneedle patches reported at present generally have the disadvantages of too long application time, slow microneedle separation speed, high process requirements and the like.
Disclosure of Invention
It is an object of the present application to provide an improved rapidly separable microneedle patch and a method of manufacturing the same.
The following technical scheme is adopted in the application:
one aspect of the application discloses a quick-separation microneedle patch, which comprises a base and microneedle bodies, wherein microneedle body arrays are uniformly distributed on the base; the micro needle body comprises a needle point and a middle section, wherein the needle point contains a medicament or other substances needing slow release, the middle section is used for connecting the needle point and the base, and the middle section is easy to break or dissolve when in use, so that the needle point and the base are separated; the intermediate section is composed of a water-soluble polymer and a photothermal material, and the photothermal material is dispersed in the water-soluble polymer.
The rapid separation microneedle patch refers to a patch which can rapidly separate a needle tip part of a microneedle body from a base when in use; generally, after the microneedle patch is applied to the skin, the separation of all needle tips or at least 95% or more of the needle tips from the base can be achieved within 5 minutes, even within 3 minutes, which is considered to be a quick-release microneedle patch.
In the rapid release microneedle patch of the present application, the intermediate section is made of a water-soluble polymer, and a photothermal material is added thereto to facilitate rapid release of the needle tip and the base by light irradiation. The water-soluble polymer in the middle section of the application can be dissolved, so that the needle tip is separated from the base; and the photo-thermal material is added, so that the photo-thermal material generates heat under the illumination condition, the dissolution of the water-soluble polymer is further promoted by utilizing heat energy, the dissolution speed of the water-soluble polymer is improved, and the rapid separation of the needle point and the base is realized. In an implementation mode of the application, effective separation of the needle points can be realized only in 1-3min, so that the use convenience is greatly improved, the application time is shortened, the convenient and quick microneedle patch application is realized, and the compliance of a patient is improved. In addition, the preparation method of the separable microneedle patch is simple, only the photothermal material is added into the water-soluble polymer in the middle section, and the rest steps can refer to the existing microneedle preparation method.
It can be understood that the key point of the application is that the photothermal material is added into the water-soluble polymer of the middle section, and the photothermal material is utilized to dissolve the middle section, so that the needle tip is rapidly separated; as to the specific material, specific drug or pharmaceutical composition of the needle tip, reference is made to the prior art; likewise, reference is made to the prior art for the specific composition of the base. In addition, the water-soluble polymer and the photothermal material of the present application may be the existing biocompatible materials, as long as there is no toxic or side effect or damage to the skin and human body, and in principle, the water-soluble polymer and the photothermal material as the intermediate section also cannot have adverse effects on the drug of the needle tip; both of the water-soluble polymer and the photothermal material capable of satisfying the above conditions may be used in the present application, and are not particularly limited herein. However, in consideration of the requirements such as solubility and strength of the intermediate section, the specific selection of the water-soluble polymer and the photothermal material is limited in the preferred embodiment of the present application, and the following technical solutions are described in detail.
In one implementation of the present application, the mass ratio of the photothermal material to the water-soluble polymer is 1:1 to 1:5000, preferably 1:1 to 1:2500, and more preferably 1:1 to 1: 1000.
In the rapid-separation microneedle patch, the water-soluble polymer is a main structural material forming the middle section of the microneedle body, and the photothermal material is dispersed in the middle section formed by the water-soluble polymer to promote the dissolution of the middle section; the dosage of the photo-thermal material directly influences the dissolution speed of the water-soluble polymer; in principle, the more photothermal material is used, the faster the dissolution rate of the intermediate section formed by the water-soluble polymer is; however, particularly, the metal-based photothermal material and the carbon-based photothermal material, the addition of these photothermal materials affects the rigid structure of the intermediate section; therefore, the preferred mass ratio of the photothermal material to the water-soluble polymer herein is 1:1 to 1:5000, more preferably 1:1 to 1:2500, and still more preferably 1:1 to 1: 1000.
In one implementation of the present application, the water-soluble polymer is selected from at least one of chitosan, sodium hyaluronate, sodium alginate, gelatin, polyvinylpyrrolidone, polyvinyl alcohol, sodium carboxymethylcellulose, maltose, and cyclodextrin.
In one embodiment of the present application, the water-soluble polymer has a molecular weight of 10kDa to 1000kDa, preferably 10kDa to 500kDa, more preferably 10kDa to 200 kDa.
In one implementation of the present application, the needle tip is made of a dissolving polymer and/or a degrading polymer.
It is understood that the dissolving polymer and the degrading polymer for preparing the needle tip can be referred to the existing polymer microneedle patch, and the selection of the specific needle tip material can be determined according to the production or use requirements, or according to the drug to be loaded, and is not limited specifically herein.
In one implementation of the present application, the photo-thermal material is a photo-thermal material that can be heated to 45 ℃ or higher by light irradiation for 1 min.
The key point of the application is that the photothermal material is used for illumination and heating to promote the dissolution of the water-soluble polymer in the middle section, so that the needle tip separation speed is improved; therefore, in principle, a photothermal material that can be heated to 45 ℃ or higher by light irradiation for 1min is preferably used. It can be understood that the separable microneedle patch can rapidly separate a needle point within 1-3min, and other photothermal materials can be adopted under the condition of low separation rate requirement; any material that promotes the separation of the needle tip by using a photothermal material is included in the inventive concept of the present application.
In one implementation of the present application, the light irradiation is 650-1000nm infrared light irradiation.
Preferably, the light irradiation is 800-950nm infrared light irradiation.
The wavelength of the infrared light irradiation may be determined according to the photo-thermal material used, as long as the photo-thermal material can generate heat under the irradiation condition to promote the dissolution of the water-soluble polymer, thereby realizing the rapid separation of the needle tip and the base; the application preferably adopts 650-1000nm infrared light irradiation, and more preferably adopts 800-950nm infrared light irradiation.
In one implementation of the present application, the photothermal material is selected from at least one of a metal based photothermal material, a carbon based photothermal material, and an organic compound photothermal material.
In one implementation manner of the application, the metal photothermal material comprises gold nanorods, gold nanocages, ferroferric oxide nanoparticles, copper sulfide and silver sulfide; the carbon material photo-thermal material comprises a carbon nano tube, graphene and carbon quantum dots; the organic compound photo-thermal material comprises polycaprolactone, porphyrin and cyanine compounds.
Therefore, the photo-thermal material specifically adopted in the application is at least one selected from gold nanorods, gold nanocages, ferroferric oxide nanoparticles, copper sulfide, silver sulfide, carbon nanotubes, graphene, carbon quantum dots, polycaprolactone, porphyrin and cyanine compounds.
Another aspect of the application discloses a method for preparing a rapidly separated microneedle patch of the application, comprising pouring a solution of a needle tip into a mold, centrifuging to deposit the solution at the bottom of a groove of the mold, removing the excess solution, and drying to solidify the needle tip in the mold; dispersing the photo-thermal material in a water-soluble polymer, pouring the photo-thermal material into a mould with a solidified needle point, centrifuging the photo-thermal material to deposit the photo-thermal material into a groove of the mould, removing the redundant water-soluble polymer, drying the photo-thermal material to solidify the middle section, and connecting the middle section with the needle point; and adding the polymer of the base into the surface of a mold with a solidified middle section and a needle point, drying, and demolding to obtain the quick-separation microneedle patch.
The preparation method is characterized in that the middle section is made of a water-soluble polymer added with a photo-thermal material, the middle section is poured after the needle point is solidified, and the base is poured after the middle section is solidified; the rest can be prepared by referring to the existing microneedle.
In one implementation of the present application, the main component of the mold is PDMS or other silane-based materials.
The beneficial effect of this application lies in:
the application discloses quick separation micropin paster utilizes the water-soluble polymer that adds the light and heat material as the interlude of micropin needle body, and the separable ability of reinforcing needle point has realized the quick separation of light-operated condition base and needle point, has widened the application range of polymer micropin paster, has improved the use convenience of micropin paster simultaneously, has improved patient's compliance.
Drawings
Fig. 1 is a schematic structural view of a rapid-release microneedle patch in an embodiment of the present application;
fig. 2 is a schematic flow chart illustrating the preparation of a rapid release microneedle patch in an embodiment of the present application;
fig. 3 is Scanning Electron Microscope (SEM) images of a rapidly separating microneedle patch prepared in an example of the present application, wherein, a, b, and c are SEM images of a rapidly separating microneedle patch prepared using polyvinylpyrrolidone (PVP) as a needle tip at different magnifications, d, e, and f are SEM images of a rapidly separating microneedle patch prepared using polyvinyl alcohol (PVA) as a needle tip at different magnifications, and g, h, and i are SEM images of a rapidly separating microneedle patch prepared using polylactic-co-glycolic acid (PLGA) as a needle tip at different magnifications, respectively;
fig. 4 is a graph showing a result of a mechanical property test of a rapidly separated microneedle patch prepared in an embodiment of the present application, in which PVP denotes a PVP needle point rapidly separated microneedle patch, PVA denotes a PVA needle point rapidly separated microneedle patch, PLGA denotes a PLGA needle point rapidly separated microneedle patch, a negative control denotes a microneedle patch prepared without adding a photo-thermal material to a middle section, and a gold nanorod microneedle denotes a microneedle patch prepared with adding a gold nanorod as a photo-thermal material to a middle section;
fig. 5 is a result diagram of a test result of in vitro separation capability of a rapidly separated microneedle patch prepared in an embodiment of the present application, where a negative control refers to a microneedle patch prepared without adding a photo-thermal material to a middle section, a gold nanorod microneedle refers to a microneedle patch prepared with adding a gold nanorod to the middle section as a photo-thermal material, no illumination refers to a result diagram of tearing off the patch immediately after the microneedle patch is attached, illumination for 30s refers to a result diagram of tearing off the patch after illumination for 30 seconds after the microneedle patch is attached, and illumination for 1min refers to a result diagram of tearing off the patch after illumination for 1 minute after the microneedle patch is attached.
Detailed Description
In order to enable the drug in the microneedle to better play a sustained release role, a microneedle structure which can enable the needle point of the microneedle to be broken and left in a body is designed in the prior art; for example, microneedles are designed to be constructed of a base, an intermediate section, and a needle tip, wherein, in use, the intermediate section dissolves or breaks, leaving the drug-containing needle tip in the body. However, the conventional microneedles having similar structures generally have a problem of low microneedle separation speed. Patent application CN111465387A mentions that the middle section is designed into a bubble structure, which has a good separation effect and a good separation rate; however, the bubble structure has high process requirements on one hand, and on the other hand, the needle is easily broken in the preparation process, so that the process is unstable, and the product consistency is poor.
Based on the research and the recognition, the middle section is creatively prepared from the water-soluble polymer, the photo-thermal material is added into the middle section, and the photo-thermal material is used for promoting the dissolution of the water-soluble polymer, so that the needle tip separation speed is greatly improved; and because a bubble structure is not required to be designed in the middle section, the stability of the water-soluble polymer is better, and the problem of needle breakage in the preparation process can be avoided.
The present application is described in further detail below with reference to specific embodiments and the attached drawings. The following examples are intended to be illustrative of the present application only and should not be construed as limiting the present application.
Example one
Preparation and performance of microneedle patch
The quick-separation microneedle patch of the embodiment, as shown in fig. 1, comprises a base 1 and microneedle bodies 2, wherein the microneedle bodies 2 are uniformly arranged on the base 1 in an array manner; the microneedle body 2 comprises a needle point 21 and an intermediate section 22, wherein the needle point 21 contains a medicament, the intermediate section 22 is used for connecting the needle point 21 and the base 1, and the intermediate section 22 is easy to break or dissolve when in use, so that the needle point 21 and the base 1 can be quickly separated; the intermediate section 22 is composed of a water-soluble polymer and a photothermal material dispersed in the water-soluble polymer. In this embodiment, polyvinylpyrrolidone (PVP) is used as the base; the middle section adopts gold nanorods as a photo-thermal material, and the water-soluble polymer of the middle section adopts Hyaluronic Acid (HA); the needle tip has strong universality, and in the embodiment, polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA) and polylactic-co-glycolic acid (PLGA) are respectively selected as the needle tip.
The method for preparing the quick-release microneedle patch of this example is as follows:
as shown in fig. 2, solutions of 800mg/mL PVP aqueous solution, 300mg/mL PVA aqueous solution, and 400mg/mL PLGA dissolved in ethylene glycol diethyl ether are prepared respectively as a tip solution, and various drugs can be added to the tip solution as required, in this example, only the structure of the separable microneedle patch is designed, and the specific drugs are not limited; taking three PDMS molds, wherein the PDMS molds are of a groove array structure of 10 multiplied by 10; pouring 100 mu L of PVP aqueous solution into one PDMS mold, pouring 100 mu L of PVA aqueous solution into the other PDMS mold, and pouring 100 mu L of PLGA solution into the other PDMS mold; after pouring of the three molds is completed, centrifuging at the room temperature of 3000rpm for 5min, depositing the needle point solution at the bottom of the groove, scraping the redundant needle point solution on the surface, putting the needle point solution into a blast oven, drying at the temperature of 40-50 ℃ for 0.5-2h, and taking out the PDMS mold; preparing a water-soluble polymer of the middle section, dispersing gold nanorods in 200mg/mL HA water solution to make the concentration of the gold nanorods be 0.5mg/mL, and preparing a solution of the middle section; pouring 100 mu L of middle section solution into each of the three PDMS molds, centrifuging at 3000rpm for 5min at room temperature to make the middle section solution enter the groove part as much as possible, scraping the excessive middle section solution on the surface, placing the groove part into a blast oven, drying at 40 ℃ for 0.5h, and taking out the PDMS molds; preparing a base solution, namely preparing polyvinylpyrrolidone (PVP) into a PVP aqueous solution with the concentration of 800mg/mL to be used as the base solution; and pouring 100 mu L of base solution into the surfaces of the three PDMS molds respectively, putting the three PDMS molds into a blast oven, drying the three PDMS molds for 10 hours at 40 ℃, taking out the molds, and demolding to obtain the quick-separation microneedle patches of the embodiment.
In this example, rapidly separating microneedle patches with PVP, PVA and PLGA tips were prepared, respectively. As a control, in this example, no gold nanorods were added to the middle section solution, the same HA aqueous solution was used to prepare the middle section, and the remaining steps and conditions for microneedle patch preparation were the same as those described above, to prepare a negative control microneedle patch; similarly, the tips of the negative control microneedle patches were PVP, PVA, and PLGA, respectively, and the middle section and the base were the same as the quick-release microneedle patch of this example.
The Scanning Electron Microscope (SEM) was used to observe the rapidly separating microneedle patches prepared in this example, in which the tips of the microneedles were PVP, PVA, and PLGA, respectively, and the results are shown in fig. 3, in which a, b, and c are SEM images of the rapidly separating microneedle patch prepared using polyvinylpyrrolidone (PVP) as the tip at different magnifications, d, e, and f are SEM images of the rapidly separating microneedle patch prepared using polyvinyl alcohol (PVA) as the tip at different magnifications, and g, h, and i are SEM images of the rapidly separating microneedle patch prepared using polylactic-co-glycolic acid (PLGA) as the tip at different magnifications, respectively.
The results of fig. 3 show that the rapidly separating microneedle patch prepared in this example has a complete and uniform shape of each microneedle, a tip diameter of less than 10 μm, a base diameter of 300 μm and a height of 700 μm, and 100 needles (10 × 10) in the entire array and a size of 1cm × 1 cm; consistent with the expected results.
Second, mechanical property of micro-needle patch
The three rapidly separated microneedle patches and the three negative control microneedle patches prepared in this example were subjected to mechanical property testing using a tensile machine. Specifically, first, the microneedle patch was linked to a horizontal stainless steel holder; moving vertically downwards at a speed of 0.5 mm/mim; when a microneedle body of the microneedle patch contacts the horizontal platform, the sensor records the stress condition and the displacement condition of the microneedle body until the microneedle body is completely damaged; and comparing the change curve of the stress of the microneedle body with and without the photo-thermal material along with the displacement. The test results are shown in fig. 4. In fig. 4, PVP represents the PVP needle point rapid separation microneedle patch, PVA represents the PVA needle point rapid separation microneedle patch, PLGA represents the PLGA needle point rapid separation microneedle patch, negative control means a microneedle patch prepared without adding a photothermal material to the middle section, and gold nanorod microneedles means a microneedle patch prepared by adding a gold nanorod as a photothermal material to the middle section.
The results of fig. 4 show that the microneedle patch with Gold Nanorods (GNRs) added to the middle section has stronger mechanical properties than the negative control microneedle patch without any material, indicating that the three rapidly separated microneedle patches prepared in this example have stronger mechanical properties, and can penetrate into the skin and efficiently deliver drugs to the subcutaneous tissue.
Third, in vitro separation ability of microneedle patch
In the test, the PVP needlepoint rapid separation microneedle patch is prepared according to the method of 'preparation and performance of a microneedle patch', the preparation method is the same as that of 'preparation and performance of a microneedle patch', and a negative control microneedle patch of the PVP needlepoint with a middle section not added with a gold nanorod is also prepared; the difference is that the test adds nile red dye into the tip solution to make the tip red, so as to observe the separation of the tip.
A piece of flat 2% agarose gel is manufactured as bionic skin in the test, the prepared PVP needlepoint containing nile red dye is quickly separated from the microneedle patch and the negative control microneedle patch of the PVP needlepoint are applied to the gel, and the test is respectively provided with the following test groups:
in the first group, after the microneedle patch is applied to the gel, the patch is immediately torn off without illumination, and the retention condition of the needle tip in the gel is observed so as to represent the separation capability of the needle tip of the microneedle patch;
in the second group, after the microneedle patch is applied to the gel, the gel is irradiated for 30s, then the patch is torn off, and the retention condition of the needle point in the gel is observed so as to represent the separation capability of the needle point of the microneedle patch;
in the third group, after the microneedle patch is applied on the gel, the gel is irradiated for 1min, then the patch is torn off, and the retention condition of the needle point in the gel is observed so as to represent the separation capability of the needle point of the microneedle patch;
wherein, the illumination refers to 850nm infrared light vertical illumination.
The gels of the above three groups were observed and photographed to obtain the separation of the needle tip and the base of the microneedle patch, and the results are shown in fig. 5. In fig. 5, negative control refers to a microneedle patch prepared without adding a photothermal material to the middle section, gold nanorod microneedles refer to a microneedle patch prepared with adding gold nanorods to the middle section as a photothermal material, no illumination refers to a result graph obtained by tearing off the patch immediately after the microneedle patch is pasted, illumination for 30s refers to a result graph obtained by tearing off the patch after illumination for 30 seconds after the microneedle patch is pasted, and illumination for 1min refers to a result graph obtained by tearing off the patch after illumination for 1 minute after the microneedle patch is pasted.
The results of fig. 5 show that rapid separation of microneedles can be achieved with 1min illumination based on the addition of gold nanorods.
Fourth, capability of separating microneedle patch on skin
In the test, a negative control microneedle patch with a PVP (polyvinyl pyrrolidone) needle point and a Nile red dye-containing needle point for quickly separating the microneedle patch from the PVP needle point and a negative control microneedle patch with a PVA needle point and a Nile red dye-containing needle point for quickly separating the microneedle patch from the PLGA needle point are prepared according to the ' in-vitro separation capability of the microneedle patch ' and the ' III ' and the negative control microneedle patch ' and used for testing.
First, the pigskin is degreased, depilated and disinfected. Then, the microneedle patch loaded with the dye is punctured into the pigskin, the microneedle patch is pressed on the skin by a thumb and a finger for 1min, infrared light is used for vertically irradiating the microneedle patch and irradiating for 1min, the torn patch is observed by using a handheld magnifying lens, and the torn patch is photographed by using a digital camera; and analyzing the separation of the needle tip and the base.
The result shows that on the basis of adding the gold nanorods, the rapid separation of various microneedle patches, such as PVP (polyvinyl pyrrolidone), PVA (polyvinyl alcohol) and PLGA (polylactic-co-glycolic acid) microneedle patches on the skin can be realized by pressing the fingers for 1min and illuminating for 1 min.
Example two
In the embodiment, on the basis of the first embodiment, different water-soluble polymers and photo-thermal materials are respectively adopted to prepare the middle section, the needle tip is prepared by polyvinylpyrrolidone (PVP), and Nile red dye is added into a needle tip solution to enable the needle tip to be red, and the rest is the same as the first embodiment. The specific components and concentrations of the middle stage solutions are shown in table 1.
TABLE 1 middle section solution formulation
| Numbering | Middle section solution |
| Test 1 | Chitosan with concentration of 1mg/mL and ferroferric oxide nano-particles with concentration of 1mg/ |
| Test | |
| 2 | Sodium alginate with concentration of 1mg/mL and copper sulfide with concentration of 0.1mg/mL |
| Test 3 | Gelatin with a concentration of 10mg/mL + silver sulfide with a concentration of 0.7mg/mL |
| Test 4 | Polyvinylpyrrolidone with a concentration of 500mg/mL and carbon nanotubes with a concentration of 0.2mg/mL |
| Test 5 | Polyvinyl alcohol with concentration of 200mg/mL and graphene with concentration of 0.1mg/mL |
| Test 6 | Carboxymethyl cellulose sodium with concentration of 80mg/mL and carbon quantum dots with concentration of 0.05mg/mL |
| Test 7 | Maltose concentration of 100mg/mL + polycaprolactone concentration of 0.1mg/ |
| Test | |
| 8 | Cyclodextrin at 5mg/mL + porphyrin at 0.1mg/mL |
| Test 9 | Cyclodextrin at a concentration of 10mg/mL + indocyanine green at a concentration of 0.1mg/mL |
In the example, nine middle section solutions are prepared according to the formula in table 1, nine rapid separation microneedle patches are prepared by respectively adopting the nine middle section solutions, the needle point separation capability of the nine rapid separation microneedle patches is tested by adopting the method of the first embodiment, "the third embodiment," the in vitro separation capability of the microneedle patches ", and the test result shows that the microneedle patches can realize effective separation of the microneedle needle point part and the base under the condition of 850nm infrared illumination for 0.5-2 min. According to the method of the fourth embodiment, the separation capability of the microneedle patch on the skin is tested, and the test result shows that the microneedle patch can realize effective separation of the microneedle tip part and the base under the conditions of continuous vertical pressing for 1min and then 850nm infrared illumination for 0.5-2 min.
The foregoing is a more detailed description of the present application in connection with specific embodiments thereof, and it is not intended that the present application be limited to the specific embodiments thereof. It will be apparent to those skilled in the art from this disclosure that many more simple derivations or substitutions can be made without departing from the spirit of the disclosure.
Claims (10)
1. A quick-release microneedle patch characterized by: the micro-needle assembly comprises a base (1) and micro-needle bodies (2), wherein the micro-needle bodies (2) are arranged on the base (1) in an array manner;
the microneedle body (2) comprises a needle tip (21) and a middle section (22), wherein the middle section (22) is used for connecting the needle tip (21) and the base (1);
the intermediate section (22) is composed of a water-soluble polymer and a photothermal material, and the photothermal material is dispersed in the water-soluble polymer.
2. A quick release microneedle patch according to claim 1, wherein: the mass ratio of the photo-thermal material to the water-soluble polymer is 1:1-1:5000, preferably 1:1-1:2500, and more preferably 1:1-1: 1000.
3. A quick release microneedle patch according to claim 1, wherein: the water-soluble polymer is at least one selected from chitosan, sodium hyaluronate, sodium alginate, gelatin, polyvinylpyrrolidone, polyvinyl alcohol, sodium carboxymethylcellulose, maltose and cyclodextrin.
4. A quick release microneedle patch according to claim 3, wherein: the molecular weight of the water-soluble polymer is 10kDa to 1000kDa, preferably 10kDa to 500kDa, more preferably 10kDa to 200 kDa.
5. A quick release microneedle patch according to claim 1, wherein: the needle tip (21) is made of a dissolving polymer and/or a degrading polymer.
6. A quick detach microneedle patch according to any one of claims 1 to 5, characterized in that: the photo-thermal material is a photo-thermal material which can be heated to be more than or equal to 45 ℃ after being irradiated for 1 min.
7. A quick release microneedle patch according to claim 6, wherein: the light irradiation is 650-1000nm infrared light irradiation, and preferably, the light irradiation is 800-950nm infrared light irradiation.
8. A quick release microneedle patch according to claim 6, wherein: the photo-thermal material is at least one selected from a metal photo-thermal material, a carbon material photo-thermal material and an organic compound photo-thermal material.
9. A quick release microneedle patch according to claim 8, wherein: the metal photo-thermal material comprises gold nanorods, gold nanocages, ferroferric oxide nanoparticles, copper sulfide and silver sulfide;
the carbon material photo-thermal material comprises a carbon nano tube, graphene and carbon quantum dots;
the organic compound photo-thermal material comprises polycaprolactone, porphyrin and cyanine compounds.
10. A method of manufacturing a quick-release microneedle patch according to any one of claims 1 to 9, wherein: pouring a solution of the needle point (21) into a mold, centrifuging to deposit the solution at the bottom of a groove of the mold, removing redundant solution, drying, and solidifying the needle point (21) in the mold; dispersing the photo-thermal material in a water-soluble polymer, pouring the photo-thermal material into a mould with a solidified needle point (21), centrifuging the photo-thermal material to deposit the photo-thermal material in a groove of the mould, removing the redundant water-soluble polymer, and drying the photo-thermal material to solidify the middle section (22); and adding the polymer of the base (1) into the surface of a mould coagulated with the middle section (22) and the needle point (21), drying, and demoulding to obtain the rapid-separation microneedle patch.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110390499.1A CN113288882A (en) | 2021-04-12 | 2021-04-12 | Rapid separation microneedle patch and preparation method thereof |
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| CN114917182A (en) * | 2022-06-13 | 2022-08-19 | 南京大学 | Sustained-release microneedle patch capable of being separated immediately and preparation method thereof |
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| US11642506B1 (en) | 2021-12-02 | 2023-05-09 | Win Coat Corporation | Multi-layered microneedle patch and method of manufacturing the same |
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