WO2022048682A1 - 具有多层结构的涂层微针、其制备方法及包含该涂层微针的微针贴片 - Google Patents

具有多层结构的涂层微针、其制备方法及包含该涂层微针的微针贴片 Download PDF

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Publication number
WO2022048682A1
WO2022048682A1 PCT/CN2021/116904 CN2021116904W WO2022048682A1 WO 2022048682 A1 WO2022048682 A1 WO 2022048682A1 CN 2021116904 W CN2021116904 W CN 2021116904W WO 2022048682 A1 WO2022048682 A1 WO 2022048682A1
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Prior art keywords
microneedle
layer structure
sustained
release layer
coated
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PCT/CN2021/116904
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English (en)
French (fr)
Inventor
高云华
周泽荃
张锁慧
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中国科学院理化技术研究所
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Priority to JP2023515182A priority Critical patent/JP2023540769A/ja
Priority to US18/024,585 priority patent/US20230310822A1/en
Publication of WO2022048682A1 publication Critical patent/WO2022048682A1/zh

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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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05D—PROCESSES FOR APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05D7/00—Processes, other than flocking, specially adapted for applying liquids or other fluent materials to particular surfaces or for applying particular liquids or other fluent materials
    • B05D7/50—Multilayers
    • B05D7/56—Three layers or more
    • B05D7/58—No clear coat specified
    • B05D7/586—No clear coat specified each layer being cured, at least partially, separately
    • 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
    • A61M2037/0023—Drug applicators using 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
    • A61M2037/0046—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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05D—PROCESSES FOR APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05D2320/00—Organic additives
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05D—PROCESSES FOR APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05D2520/00—Water-based dispersions

Definitions

  • the present invention relates to the technical field of medicine. More specifically, it relates to a coated microneedle with a multi-layer structure and a preparation method thereof.
  • Transdermal administration is a common mode of administration, with higher bioavailability than oral drug administration, while improving patient compliance with injectable administration.
  • Microneedle is a patch with a needle tip array with a height of micrometer or millimeter.
  • the needle tip is pierced into the skin by pressing to open the skin channel and increase the drug delivery efficiency.
  • the microneedle fabrication process is simple. , low cost, many applicable drugs, patients can self-administration, has received extensive attention in recent years.
  • Microneedles can be divided into the following categories: permeation-enhancing microneedles combined with drug-loaded patches or solutions, drug-loaded coated microneedles, hollow injection microneedles, drug-loaded dissolving microneedles, drug-loaded or swollen microneedles that absorb tissue fluid .
  • the development of microneedles is mostly aimed at one or more specific drugs, and it is necessary to investigate the influencing factors, accelerated stability, long-term stability, bioavailability, bioequivalence, etc.
  • a drug prescription has a long process and high cost.
  • micro-injection formulations of most water-soluble drugs, especially peptide and protein drugs in order to ensure the stability and bioavailability of its active ingredients, there are many excipients in the prescription. It is a water-soluble polymer material and saccharide, which limits the development of this type of drug in the sustained-release micro-injection dosage form.
  • Document 1 Drug Deliv Transl Res. 2019 Feb; 9(1): 192-203.
  • Document 2 Drug Deliv Transl Res. 2016 Oct; 6(5): 486-97.
  • Document 3 Int J Pharm. 2015; 486(1-2): 52-8.
  • the optimal buffer solution system, matrix excipients, surfactants, protective agents for protein drugs, the effects of packaging temperature and humidity on drug activity and different formulations were developed.
  • the experimental period for the optimization of the entire formulation is long, and the cost of raw materials and testing is high.
  • the optimized active substance formulations are all soluble and immediate-release micro-injection dosage forms, which do not have long-acting sustained-release function, and still need to be administered multiple times to achieve effective results. level of immune response.
  • the first object of the present invention is to provide a coated microneedle with a multi-layer structure, which can prevent the drug-containing matrix from rapidly dissolving, prevent the active ingredient from exuding with the tissue of the action site, and increase the drug entry. At the same time, it can also achieve sustained release of water-soluble microneedle active ingredients with immediate release effect, which can reduce the number of administrations and improve patient compliance.
  • the second object of the present invention is to provide the method for preparing the coated microneedles described in the first object above.
  • the third object of the present invention is to provide a microneedle patch.
  • the present invention adopts following technical scheme:
  • a coated microneedle with a multi-layer structure comprising a base, a needle tip on the base, and a functional coating;
  • the functional coating includes content containing water-soluble polymer materials and active ingredients and a sustained-release layer wrapping the content;
  • sustained-release layer is a time-delayed cross-linked sodium alginate system or a near-neutral chitosan system.
  • the raw materials of the delayed cross-linking sodium alginate system include a calcium source, gluconolactone and a carrier.
  • the calcium source is selected from one or more of calcium sodium edetate, calcium carbonate and calcium sulfate.
  • the calcium source is selected from calcium and sodium edetate.
  • the carrier is selected from sodium alginate.
  • the sustained-release layer is a time-delayed cross-linked sodium alginate system
  • the sustained-release layer is a mixed solution formed by mixing the raw materials comprising calcium source, gluconolactone and the carrier in water after drying and cross-linking. linked swollen structure.
  • the viscosity of the mixed solution is 70cps-13000cps.
  • the concentration of the calcium source in the mixed solution is 3mmol/mL ⁇ 0.3mol/mL.
  • the molar concentration of the gluconolactone in the mixed solution is 1-2 times that of the calcium source.
  • the slow-release layer is a near-neutral chitosan system, and the slow-release layer is formed by dissolving the chitosan material in an acidic solution, dialysis in water to near neutrality, and drying and swelling the obtained solution. structure; preferably, the viscosity of the solution is 70cps-13000cps.
  • the raw material of the sustained-release layer further includes a porogen.
  • the porogen is selected from sodium chloride, sodium carbonate, sodium bicarbonate, ammonium bicarbonate, polyvinylpyrrolidone, hyaluronic acid and its sodium salt, cellulose derivatives, trehalose, maltose, cyclodextrin One or more of the fine species.
  • porogen accounts for 0.1-10 wt% of the total weight of the sustained-release layer.
  • the water-soluble polymer material is selected from carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl chitosan, chitosan and its derivatives, polyvinyl alcohol and its derivatives, polyvinylpyrrolidone and its derivatives, sodium hyaluronate, chondroitin sulfate, dextran and its derivatives, sodium alginate, poly-gamma-glutamic acid, pullulan, gelatin, polydopamine , one or more of polyacrylamide.
  • the active ingredient is selected from one or more of water-soluble chemical drugs, polypeptide drugs, protein drugs, and nucleic acid drugs.
  • the active ingredient is selected from leuprolide, recombinant human insulin, thymopentin, recombinant human interferon, glutathione, teriparatide acetate, azelaic acid, goserelin, finasteride
  • water-soluble chemical drugs such as amine, amifostine, tranexamic acid, metformin hydrochloride, polypeptide drugs, protein drugs or nucleic acid drugs.
  • the solid content of the active ingredient does not exceed 2 times the solid content of the water-soluble polymer material.
  • biodegradable and water-insoluble polymer material is selected from one or more of polyanhydrides, polyorthoesters, polyphosphates, aliphatic polyesters and derivatives thereof.
  • polyacid anhydride is selected from one or more of P(CPP-SA), P(FA-SA), and P(FAD-SA).
  • the aliphatic polyester and its derivatives are selected from polyglycolide, polylactide, glycolide-lactide copolymer, polycaprolactone, L-polylactic acid, racemic polylactic acid, poly- One or more of ethylene glycol-polylactic acid copolymer and its derivatives.
  • the content also contains a protective agent; preferably, the protective agent is selected from polyhydroxy compounds, carbohydrate compounds, serum albumin, polyvinylpyrrolidone, chondroitin sulfate, amino acids, and surfactants one or more of them.
  • the protective agent is selected from polyhydroxy compounds, carbohydrate compounds, serum albumin, polyvinylpyrrolidone, chondroitin sulfate, amino acids, and surfactants one or more of them.
  • the protective agent accounts for less than 50% of the total mass of the content, preferably less than 10%.
  • the height of the functional coating does not exceed 1/2 of the overall height of the needle tip, preferably not more than 3/7.
  • the maximum diameter of the functional coating does not exceed 2/3 of the diameter of the bottom of the needle tip, preferably not more than 1/2.
  • microneedle base comprising a base and a tip on the base
  • aqueous solution of the material forming the sustained-release layer is applied to the content and covers the content and combined with the layer structure A, and dried to obtain a swollen layer structure B;
  • the swollen layer structure A and the swollen layer structure B together constitute the sustained-release layer, and the content is encapsulated in the sustained-release layer.
  • the viscosity range of the aqueous solution for forming the content material is 100cps-12000cps.
  • the viscosity range also includes, but is not limited to, 200-10000cps, 200-8000cps, 200-5000cps, 200-1000cps, 200-500cps, 400-10000cps, 400-8000cps, 400-1000cps, and the like.
  • a microneedle patch comprising the coated microneedles having a multi-layered structure as described in the first object above and a backing combined with the coated microneedle substrate.
  • the coated microneedle provided in the present invention realizes the sustained-release effect of the water-soluble microneedle, is suitable for various existing water-soluble microneedle formulations, reduces the research and development cost of the sustained-release dosage form, and has a simple manufacturing process and is operable Strong sex.
  • the coated microneedle ensures a high level of drug utilization, enables stable and slow release of the drug, prolongs the circulation time of the drug in the body, stabilizes the blood drug concentration, and reduces the side effects of administration.
  • the contents are well wrapped in the slow-release control layer, and the rapid release of the drug in a relatively short period of time is blocked, and the method is simple in process and strong in operability.
  • suitable for the change of sustained-release dosage forms of various immediate-release water-soluble drug formulations, and the change process does not require heating and irradiation.
  • the materials used are non-cytotoxic and have good biocompatibility, which can maximize the retention of the original water-soluble Stability and bioavailability of sexual microneedle formulations.
  • the microneedle patch provided by the present invention also has the effect of the coated microneedle because it contains the above-mentioned coated microneedle.
  • the injection dosage form is less invasive, and is especially suitable for the development of microneedle dosage forms of drugs with obvious first-pass effect and frequent administration.
  • FIG. 1 shows a schematic structural diagram of a coated microneedle in an embodiment of the present invention.
  • FIG. 2 shows a schematic structural diagram of a functional coating in a coated microneedle according to an embodiment of the present invention.
  • FIG. 3 shows a stereomicrograph of the BSA-loaded coated microneedle prepared in Example 1 of the present invention.
  • FIG. 4 shows a side view of the BSA-loaded coated microneedle prepared in Example 1 of the present invention observed under a microscope.
  • Fig. 5 shows the in vitro release chart of the BSA-loaded coated microneedle prepared in Example 1 of the present invention and the microneedle without the cross-linked sodium alginate coating in 0-140 hours.
  • Figure 6 shows the in vitro release chart of the BSA-loaded coated microneedle prepared in Example 1 of the present invention and the microneedle without cross-linked sodium alginate coating in 0-9 hours.
  • FIG. 7 shows the whole needle morphology of the coated microneedle carrying trypan blue prepared in Example 2 of the present invention under a stereo microscope at one time.
  • FIG. 8 shows the local needle morphology of the trypan blue-loaded coated microneedles prepared in Example 2 of the present invention under a triploid stereo microscope.
  • FIG. 9 is a diagram showing the effect of implanting the needle tip of the microneedle patch into pigskin in Example 3 of the present invention.
  • FIG. 10 shows the dissolution diagram of the lower-section integrated base after the microneedle patch pierces the pigskin in Example 3 of the present invention.
  • FIG. 11 shows the trend diagram of drug loading of each formulation in Example 5 of the present invention.
  • FIG. 12 shows the 4-fold microscope observation diagram of the needle tip morphology of the formula 6/10/15/18 in Example 5 of the present invention.
  • FIG. 13 shows a 5x microscope side view and a 4x stereomicroscope observation diagram of each formulation in Example 6 of the present invention.
  • a coated microneedle with a multi-layer structure is provided.
  • the coated microneedle includes a base 1, a needle tip 2 located on the base 1, Functional coating 3;
  • the functional coating 3 includes a content 301 containing water-soluble polymer materials and active ingredients and a sustained-release layer 302 wrapping the content 301;
  • the existence of the sustained release layer 302 realizes the sustained release effect of the dissolved content 301, and can achieve the effect of delayed drug release.
  • the microneedle acts on the skin, it prevents the drug-containing matrix in the content 301 from being released. It dissolves rapidly to prevent the active ingredients from exuding with the tissue of the action site, and increases the amount of drug entering; at the same time, it also has the effect of slow release of the drug, which can reduce the number of administrations and improve the compliance of patients.
  • the sustained release layer 302 has the effect of slowly releasing the dissolved content without reducing the total release amount of the content 301 . At the same time, it is also required that the sustained-release layer has good skin affinity to prevent skin allergies and to have good bonding with the needle tip material.
  • the sustained-release layer 302 is a cross-linked layer structure. Specifically, it can be a swollen layer structure. Exemplary raw materials for forming the sustained-release layer 302 include a time-delayed cross-linked sodium alginate system or near-neutral chitosan.
  • An exemplary delayed cross-linking sodium alginate system includes a calcium source, gluconolactone (GDL) and a carrier in the raw materials; the carrier may preferably be sodium alginate.
  • the calcium source is selected from one or more of calcium sodium edetate, calcium carbonate and calcium sulfate, preferably calcium sodium edetate.
  • the mixed solution formed by mixing calcium source, gluconolactone and the carrier in water can be dried and cross-linked, and the obtained swollen structure is the slow-release layer 302 .
  • the sustained-release layer 302 is obtained by mixing a mixture of calcium source and gluconolactone with an aqueous carrier solution, drying and cross-linking.
  • the calcium source as the calcium source for calcium ion cross-linking, is in a chelated state and has no free calcium ions, so as not to cause cross-linking of a carrier selected from, for example, sodium alginate.
  • Gluconolactone will decompose slowly after encountering water, generate EDTA and gradually release H + ions, H + ions and Ca 2+ compete for chelation and sites on EDTA, and a part of EDTA Ca Na 2 forms EDTA Na 2 H 2 is released Ca 2+ , and a carrier such as selected from sodium alginate forms cross-links.
  • the decomposition of gluconolactone in water is slow, so the release of Ca 2+ is also slow. Therefore, the addition of each raw material is recommended to be added quickly in a short period of time when the slow-release layer needs to be prepared to prevent the premature change of state and the formation of coagulation. glue and can not be well coated with the needle tip.
  • the viscosity of the mixed solution is preferably 70cps-13000cps.
  • the coating of the slow-release layer of the micro-needle tip of the micro-needle is not affected by the capillary phenomenon of the low-viscosity solution, which contaminates the micro-needle substrate, and at the same time ensures that the solution of the slow-release layer has a certain fluidity, which is convenient to stay at the tip of the micro-needle.
  • the concentration of the calcium source and gluconolactone mixed in the mixed solution can be prepared according to the required degree of cross-linking, and the preferred concentration of the calcium source in the mixed solution is 3mmol/mL ⁇ 0.3mol/mL, preferably, the molar concentration of the gluconolactone is 1 ⁇ 2 times of the calcium source.
  • the viscosity of the above mixed solution includes but is not limited to 300-6000cps, 300-5800cps, 300-5700cps, 320-6000cps, 320-5800cps, 320-5700cps, 340-6000cps, 340-5800cps, 340-5700cps, 300 -500cps, 340-3900cps, 410-3850cps, 410-5850cps, 3050-5800cps, etc.
  • the preparation of near-neutral chitosan is that the acid chitosan solution is dialyzed in water to be near-neutral, and the swollen structure obtained after the solution is dried is the slow-release layer 302 .
  • chitosan is an electronegative polymer material and is only soluble in an acidic solution, which can be composed of lactic acid, hydrochloric acid or acetic acid. It is acidic.
  • the solution is dialyzed with ultrapure water to near neutrality, and then concentrated to a certain concentration. After drying, the solution is not redissolved in normal saline/human tissue fluid, and can be used as a sustained-release layer.
  • the viscosity of the above-mentioned near-neutral chitosan solution is preferably 70cps-13000cps.
  • porogen helps the intradermal water molecules to enter the content 301 inside the sustained-release layer 302 to regulate the drug release rate.
  • exemplary porogens include, but are not limited to, sodium chloride, sodium carbonate, sodium bicarbonate, ammonium bicarbonate, polyvinylpyrrolidone, hyaluronic acid and its sodium salts, cellulose derivatives, trehalose, maltose, cyclodextrin One or more of the fine species.
  • the actual addition amount of the porogen may preferably be 0.1-10 wt % of the total weight of the sustained-release layer.
  • the height of the functional coating 3 does not exceed 1/2 of the overall height of the needle tip 2, preferably not more than 3/7; the maximum diameter of the functional coating 3 does not exceed all
  • the diameter of the bottom of the needle tip 2 is 2/3, preferably not more than 1/2.
  • the content 301 in the coated microneedle of the present embodiment can be the formulation of a conventional and existing microneedle containing an active substance, which greatly saves the development cost of the sustained-release microneedle dosage form of the drug.
  • exemplary water-soluble polymer materials include, but are not limited to, carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl chitosan, chitosan and Its derivatives, polyvinyl alcohol and its derivatives, polyvinyl pyrrolidone and its derivatives, sodium hyaluronate, chondroitin sulfate, dextran and its derivatives, sodium alginate, poly-gamma-glutamic acid, pulu One or more of orchid polysaccharide, gelatin, polydopamine and polyacrylamide.
  • the active ingredient refers to the transdermal delivery of the active ingredient through the microneedle or microneedle patch of the present invention, and which has efficacy on animals or humans for diagnosis, treatment, prevention, cosmetic or cosmetic use. Substances for health purposes.
  • the active ingredients include, but are not limited to, pharmaceutical active ingredients, vaccine active ingredients, cosmetic active ingredients, health care product active ingredients, etc., which are specifically selected according to actual needs.
  • the addition amount of the active ingredient can be formulated according to the solubility and stability of the specific active ingredient.
  • the solid content (that is, the mass) of the active ingredient does not exceed 2 times the solid content of the water-soluble polymer material.
  • auxiliary agent such as a protective agent
  • exemplary protective agents include, but are not limited to, one or more selected from polyhydroxy compounds, carbohydrate compounds, serum albumin, polyvinyl pyrrolidone, chondroitin sulfate, amino acids, and surfactants; preferably, the The protective agent accounts for less than 10% of the total mass of the content.
  • exemplary polyanhydrides include, but are not limited to, one or more of P(CPP-SA), P(FA-SA), and P(FAD-SA).
  • exemplary aliphatic polyesters and derivatives thereof include, but are not limited to, polyglycolide (PGA, also known as polyglycolic acid or polyglycolic acid), polylactide (PLA, also known as polylactic acid or polyhydroxypropylene). acid), glycolide-lactide copolymer (PLGA or polylactic acid-glycolic acid copolymer), polycaprolactone (PCL), L-polylactic acid (L-PLA), racemic polylactic acid, polyethylene One or more of the diol-polylactic acid copolymer and its derivatives.
  • PGA polyglycolide
  • PLA polylactide
  • PCL polycaprolactone
  • L-PLA L-polylactic acid
  • racemic polylactic acid polyethylene
  • polyethylene One or more of the diol-polylactic acid copo
  • the needle tip 2 is in the shape of a cone or a polygonal pyramid.
  • the needle tip 2 is in the shape of a cone; the distance between the needles is less than or equal to 0.5 mm;
  • microneedle base comprising a base 1 and a needle tip 2 on the base 1;
  • Part of the aqueous solution of the material forming the sustained-release layer 302 is applied to the needle tip 2 and dried to obtain the swollen layer structure A covering the needle tip 2;
  • aqueous solution of the material forming the sustained-release layer 302 is applied to the content 301 and covers the content 301 and combined with the layer structure A, and dried to obtain a swollen layer structure B;
  • the method of application is not specifically limited, as long as the desired combination can be achieved, for example, it can be dipping.
  • the number of times of application can be selected according to the actual situation, and one or more times can be selected.
  • the method of applying the aqueous solution of the material forming the content on the surface of the layer structure A is dipping; the number of dipping is preferably more than 3 times, more preferably 3-10 times.
  • the viscosity of the aqueous solution of the material forming the sustained-release layer 302 is preferably between 70 cps and 13000 cps.
  • the viscosity of the aqueous solution includes, but is not limited to, 300-6000cps, 300-5800cps, 300-5700cps, 320-6000cps, 320-5800cps, 320-5700cps, 340-6000cps, 340-5800cps, 340-5700cps, 3000cps -500cps, 340-3900cps, 410-3850cps, 410-5850cps, 3050-5800cps, etc.
  • the apparent viscosity of the aqueous solution of the material forming the content 301 is preferably 100cps-12000cps.
  • the apparent viscosity of the solution of the material forming the content 301 includes, but is not limited to, 200-7000cps, 250-7000cps, 250-6500cps, 250-600cps, 250-1320cps, 1000-6500cps, 300-600cps, and the like.
  • the above-mentioned method for providing a microneedle substrate comprising a base 1 and a needle tip 2 on the base 1 includes: using a mold, placing the base 1 and/or needle tip 2 material in the corresponding mold, heating , wherein the heating temperature is 50-250° C. and the time is 5-30 minutes; the material is pressed flat, cooled and demolded to obtain the corresponding base 1 and/or needle tip 2 material.
  • the microneedle base is one-piece, the one-piece mold can be used directly; when the microneedle base is split, the base and the needle tip can be combined.
  • a microneedle patch which comprises the above-mentioned coated microneedles having a multi-layer structure, and a backing combined with the coated microneedle substrate 1 .
  • the backing includes but is not limited to one of a pressure-sensitive adhesive backing, a hydrocolloid backing, and a silicone backing.
  • the preparation method of the above-mentioned microneedle patch is to prepare a microneedle array on the basis of preparing the coated microneedles, and further attach a backing to the back of the base.
  • microneedle patch of the present invention can be applied to the fields of disease treatment, prevention, health care and beauty.
  • the drug solution prepared above was placed in a drug-carrying cell with a height of 300 ⁇ m. Take the microneedle that has been equipped with the cross-linked swollen coating, drop the needle tip down into the drug-carrying pool for dipping in the drug solution, and then let the microneedle stand for 3 min to dry the coating. This dip drying process was repeated 4 times.
  • microneedles that have been equipped with the cross-linking swelling coating and the drug-carrying coating are dipped in the cross-linking swelling material solution again, and the microneedles are allowed to stand for 3 minutes to dry the coating.
  • the outer part of the drug-loaded coating of the coated microneedles is coated with a cross-linked swelling coating.
  • a coated microneedle containing a swollen coating with BSA-loaded tip was obtained.
  • the prepared BSA-loaded functional multi-layer structure slow-release coating microneedle is shown in Figure 3, and the side view of the microneedle observed under a microscope is shown in Figure 4.
  • the multi-layer structure microneedle was applied to the newborn pig. On the ear skin, by dissolving the BSA on the base of the microneedles and on the surface of the pig skin, and deducting the total drug load, the average amount of BSA loaded in the microneedles was measured to be 94 wt%; The microneedle was placed in a 500kDa dialysis bag, and an in vitro release experiment was performed to investigate the sustained release effect of the multi-coated microneedle.
  • the drug solution prepared above was placed in a drug-carrying cell with a height of 300 ⁇ m. Take the microneedle that has been equipped with the cross-linked swollen coating, drop the needle tip down into the drug-carrying pool for dipping in the drug solution, and then let the microneedle stand for 3 min to dry the coating. This dip drying process was repeated 4 times.
  • microneedles that have been equipped with the cross-linking swelling coating and the drug-carrying coating are dipped in the cross-linking swelling material solution again, and the microneedles are allowed to stand for 3 minutes to dry the coating.
  • the outer part of the drug-loaded coating of the coated microneedles is coated with a cross-linked swelling coating.
  • Figure 7 shows the whole needle morphology of the prepared trypan blue-loaded functional multi-layer structure slow-release coating microneedle
  • Figure 8 shows the local needle morphology of the microneedle triploid microscope.
  • microneedle patch prepared in Example 2 was applied to the fresh pig skin, pressed with a 30N needle feeder for 40s, placed on the agar hydrogel for moisturizing for 3min, then peeled off the microneedle patch, and observed the inside of the skin. Whether there is an implanted needle tip coating, and whether the pinhole is clearly identifiable; observe the removed microneedle patch under a stereo microscope to see if the coating on the needle tip of the polylactic acid integrated base has fallen off and the base Check if there is any residual dissolved trypan blue at the bottom.
  • Figure 9 shows the pig skin after being acted by microneedles
  • A is the microneedle group wrapped with the cross-linked swollen coating
  • B is the non-cross-linked swollen coating group
  • the needle eye of the pig skin in A is clearer than that in B , indicating that the coating containing trypan blue dissolves more slowly in the skin after being wrapped with a cross-linked coating, and at the same time, it can well prevent the coating from overflowing from the skin and ensure the intradermal entry of the drug.
  • Figure 10 shows the microneedles acting on pigskin
  • A is the microneedle group wrapped with the cross-linked swelling coating
  • B is the non-cross-linking swelling coating group
  • the microneedles in B have There is obvious trypan blue residue, but there is no dissolved trypan blue at the bottom of the one-piece base of the microneedles in A, indicating that in the absence of the delayed release effect of the cross-linked swollen coating, the microneedles of the dissolved coating act on the skin during the process.
  • the coating of the needle tip will overflow from the skin channel due to the rapid dissolution of the needle tip and the resistance between the needle tip and the skin, thereby sticking to the bottom of the one-piece base, reducing the amount of drug entering.
  • the microneedles were subjected to in vitro release experiments, and the trypan blue could be slowly released for up to 15 days.
  • the drug solution prepared above was placed in a drug-carrying cell with a height of 300 ⁇ m. Take the microneedle that has been equipped with the cross-linked swollen coating, drop the needle tip down into the drug-carrying pool for dipping in the drug solution, and then let the microneedle stand for 3 min to dry the coating. This dip drying process was repeated 4 times.
  • microneedles that have been equipped with the cross-linking swelling coating and the drug-carrying coating are dipped in the cross-linking swelling material solution again, and the microneedles are allowed to stand for 3 minutes to dry the coating.
  • the outer part of the drug-loaded coating of the coated microneedles is coated with a cross-linked swelling coating.
  • a coated microneedle containing a swollen coating and the tip of which is loaded with recombinant human interferon is obtained.
  • the multi-layered microneedles were applied to the ear skin of newborn pigs. By dissolving the recombinant human interferon on the base of the microneedles and on the surface of the pig skin, the total drug loading was deducted to measure the amount of recombinant human interferon contained in the microneedles. The average entry amount was 97%; the microneedles were placed in a 300kDa dialysis bag, and an in vitro release experiment was conducted to investigate the sustained release effect of the multi-coated microneedles. The results showed that the microneedles could slowly release 90% of the drug within 12 days.
  • the preparation method is as in Example 1 (needle tip height 500 ⁇ m, needle spacing 500 ⁇ m), wherein in all formulations, in step 4), the drug solution contains 10 mg/mL of BSA; in step 2), the used cross-linked swelling material solution is
  • the composition is the total solid content of 2% sodium alginate solution and 0.3mol/L time delay crosslinking agent, the time delay crosslinking agent is composed of 0.01mol/L calcium sodium edetate and 0.01mol/L gluconolactone, seaweed
  • the mixing volume ratio of sodium solution and time-delayed cross-linking solution is 10:1.
  • the corresponding parameters of the remaining formulas, such as the solid content of PVA (6.0cps) of the drug solution and the dip times of the drug solution, are shown in Table 1.
  • the viscosity of 10wt% PVA solution is 46.8cps, 15% is 251.5cps, 20% is 447.2cps, and 30% is 12020cps.
  • the drug loading test shows that the drug loading of the coated microneedles is related to the apparent viscosity of the drug solution (solid content of the matrix material) and the number of cycles of the drug solution dipping.
  • formula 6, formula 10, formula 15, and formula 18 can approximately reach the drug loading of 10 ⁇ g/tablet.
  • the drug solution was dipped, it was observed that when the apparent viscosity of the drug solution was less than 100cps, capillarity would occur, and the drug loading of the microneedles was too low; when the apparent viscosity of the drug solution exceeded 12000cps, the solution was too viscous. It is too thick to maintain the liquid level during the dipping process, which affects the uniformity of drug loading; therefore, the optimum viscosity of the drug solution is 100-12000cps.
  • FIG 11. A summary of the drug loading trends of each formulation in Example 4 is shown in Figure 11.
  • the 4x microscope observation diagrams of the needle tip shape of formula 6/10/15/18 are shown in a-d in Figure 12 in turn. It can be seen that the shape of the tip of the microneedle remains intact after coating, and it has the ability to pierce the skin.
  • the preparation method is as in Example 1, wherein in all formulations, in step 4), the drug solution contains 10 mg/mL fluorescein scarlet, 15% PVA (6.0cps); in step 2), the used cross-linking swelling material solution
  • the composition of the total solid content is 2% sodium alginate solution and 0.3mol/L delayed crosslinking solution, and the delayed crosslinking solution is composed of 0.01mol/L calcium sodium edetate and 0.01mol/L gluconolactone,
  • the mixing volume ratio of sodium alginate solution and time-delayed cross-linking solution is 10:1.
  • Example 1 The preparation method is as in Example 1, wherein the parameters of each component in Examples 7-12 are shown in Table 3.
  • Example 1 The preparation method is as in Example 1, wherein the parameters of each component in Examples 13-18 are shown in Table 4.
  • Example 1 The preparation method is as in Example 1, wherein the parameters of each component in Examples 19-24 are shown in Table 5.
  • the preparation method is as in Example 1, wherein the parameters of each component in Comparative Example 2 are shown in Table 6.
  • Example 7 The preparation method is as in Example 1, wherein the parameters of each component in Comparative Examples 1-4 are shown in Table 7.

Abstract

本发明公开了一种具有多层结构的涂层微针，其包括基座、位于基座上的针尖、功能性涂层；其中，所述功能性涂层包括含有水溶性高分子材料和活性成分的内容物以及包裹该内容物的缓释层；且所述缓释层包覆在所述针尖上。该涂层微针可阻止含药基质迅速溶解扩散防止活性成分随作用部位的组织渗出，增加药物进入量。本发明还公开了该涂层微针的制备方法及包含其的微针贴片。

Description

具有多层结构的涂层微针、其制备方法及包含该涂层微针的微针贴片 技术领域
本发明涉及医药技术领域。更具体地，涉及一种具有多层结构的涂层微针及其制备方法。
背景技术
经皮给药是一种常见的给药方式，相比口服药物给药具有更高的生物利用度，同时改善了注射给药的患者依从性。随着微加工技术的发展，微针给药的研究进程被快速推进。微针是一种具有微米级或毫米级高度的针尖阵列的贴片，在微针作用于皮肤时，通过按压将针尖刺入皮肤从而打开皮肤通道，增加给药效率，同时微针制作工艺简单，成本低廉，适用药物众多，患者可自主给药，近年来受到了广泛的关注。
对于微针可以分为以下几类：结合载药贴片或溶液的促渗微针、载药涂层微针、空心注射微针、载药溶解微针、载药或吸取组织液的溶胀微针。微针的开发多针对于一种或多种特定的药物，需要对原料药及制剂进行影响因素、加速稳定性、长期稳定性、生物利用度、生物等效性等项目进行考察，从而优选出一种药品处方，其过程漫长，成本高，对于大部分水溶性药物，尤其多肽、蛋白类药物的微针剂型开发，为了保证其活性成分的稳定性和生物利用度，其处方中的辅料多为水溶性高分子材料和糖类，限制了该类药品在缓释微针剂型上的发展。
文献1(Drug Deliv Transl Res.2019Feb；9(1):192-203.)、文献2(Drug Deliv Transl Res.2016 Oct；6(5):486-97.)、文献3(Int J Pharm.2015；486(1-2):52-8.)等一系列文章中分别详细说明了对于脊髓灰质炎病毒疫苗、甲型流感疫苗病毒、AsnB蛋白的长期稳定性处方筛选，单因素控制变量优选出适应蛋白药物的最佳缓冲溶液体系、基质辅料、表面活性剂、保护剂，包装温湿度对药物活性的影响和不同配方。整个配方优化的实验周期长，原料药和检测消耗成本高，优选出的活性物质配方均为可溶解速释微针剂型，不具有长效缓释功能，仍需进行多次给药达到有效的免疫响应水平。
文献4(Eur J Pharm Biopharm.2019 Mar；136:259-266.)、文献5(J Control Release.2012 Sep 28；162(3):529-37.)中，分别描述了载有重组流感病毒血凝素(HA)溶解涂层微针和载有HIV-1 CN54gp140的一体式溶解微针的研究，二者的载药微针和药物皮下注射作所产生的的免疫学反应结果显示，微针用于BALB/c小鼠所产生的特异性血清IgG和各抗体滴度均略低于同等剂量的皮下注射所产生的量，说明速释处方的涂层微针和一体式微针在作用于活体皮肤时，发生了活性成分在微针内残留、刺入皮肤时随组织液流出等情况，影响了活性成分的利用率。
发明内容
基于以上事实，本发明的第一个目的在于提供一种具有多层结构的涂层微针，该微针可阻止含药基质迅速溶解，防止活性成分随作用部位的组织渗出，增加药物进入量；同时，其还可实现缓释具有速释效果的水溶性微针活性成分，在给患者用药时可以减少 给药次数，提升患者的依从性。
本发明的第二个目的在于提供上述第一个目的所述的涂层微针的制备方法。
本发明的第三个目的在于提供一种微针贴片。
为达到上述第一个目的，本发明采用下述技术方案：
一种具有多层结构的涂层微针，其包括基座、位于基座上的针尖、功能性涂层；
其中，所述功能性涂层包括含有水溶性高分子材料和活性成分的内容物以及包裹该内容物的缓释层；且
所述缓释层包覆在所述针尖上。
进一步地，所述缓释层为延时交联海藻酸钠体系或近中性壳聚糖体系。
进一步地，所述延时交联海藻酸钠体系的原料中包含钙源、葡萄糖酸内酯和载体。
进一步地，所述钙源选自依地酸钙钠、碳酸钙、硫酸钙中的一种或几种。
进一步地，所述钙源选自依地酸钙钠。
进一步地，所述载体选自海藻酸钠。
进一步地，所述缓释层为延时交联海藻酸钠体系，所述缓释层为将包含钙源、葡萄糖酸内酯与所述载体的原料于水中混合形成的混合溶液经干燥、交联而成的溶胀结构。
进一步地，所述混合溶液的粘度为70cps-13000cps。
进一步地，所述钙源在混合溶液中浓度为3mmol/mL～0.3mol/mL。
进一步地，所述葡萄糖酸内酯在混合溶液中的摩尔浓度为钙源的1～2倍。
进一步地，所述缓释层为近中性壳聚糖体系，所述缓释层为将壳聚糖材料溶于酸性溶液中，在水中透析至近中性，得到的溶液经干燥、溶胀而成的结构；优选地，所述溶液的粘度为70cps-13000cps。
进一步地，所述缓释层的原料中还包含致孔剂。
进一步地，所述致孔剂选自氯化钠、碳酸钠、碳酸氢钠、碳酸氢铵、聚乙烯吡咯烷酮、透明质酸及其钠盐、纤维素类衍生物、海藻糖、麦芽糖、环糊精类中的一种或几种。
进一步地，所述致孔剂占所述缓释层总重量的0.1-10wt％。
进一步地，所述水溶性高分子材料选自羧甲基纤维素、羟丙基甲基纤维素、羟乙基纤维素、羧甲基壳聚糖、壳聚糖及其衍生物、聚乙烯醇及其衍生物、聚乙烯吡咯烷酮及其衍生物、透明质酸钠、硫酸软骨素、葡聚糖及其衍生物、海藻酸钠、聚γ-谷氨酸、普鲁兰多糖、明胶、聚多巴胺、聚丙烯酰胺中的一种或几种。
进一步地，所述活性成分选自水溶性化学药物、多肽类药物、蛋白类药物、核酸类药物中的一种或几种。
进一步地，所述活性成分选自亮丙瑞林、重组人胰岛素、胸腺五肽、重组人干扰素、谷胱甘肽、醋酸特立帕肽、壬二酸、戈舍瑞林、非那雄胺、氨磷汀、氨甲环酸、盐酸二甲双胍等水溶性化学药物、多肽药物、蛋白质药物或核酸类药物中的一种或几种。
进一步地，所述活性成分的固含量不超过所述水溶性高分子材料固含量的2倍。
进一步地，形成所述基座和/或针尖的材料包括生物可降解且不溶于水的高分子材料。
进一步地，所述生物可降解且不溶于水的高分子材料选自聚酸酐、聚原酸酯、聚磷酸酯、脂肪族聚酯及其衍生物中的一种或几种
进一步地，所述聚酸酐选自P(CPP-SA)、P(FA-SA)、P(FAD-SA)中的一种或几种。
进一步地，所述脂肪族聚酯及其衍生物选自聚乙交酯、聚丙交酯、乙交酯-丙交酯共聚物、聚己内酯、左旋聚乳酸、外消旋聚乳酸、聚乙二醇-聚乳酸共聚物及其衍生物中的一种或几种。
进一步地，所述内容物中还包含有保护剂；优选地，所述保护剂选自多羟基化合物、糖类化合物、血清白蛋白、聚乙烯基吡咯烷酮、硫酸软骨素、氨基酸、表面活性剂中的一种或几种。
进一步地，所述保护剂占内容物总质量的50％以下，优选为10％以下。
进一步地，所述功能性涂层的高度不超过所述针尖整体高度的1/2，优选不超过3/7。
进一步地，所述功能性涂层的直径最大处不超过所述针尖底部直径的2/3，优选不超过1/2。
为达到上述第二个目的，本发明采用下述技术方案：
一种具有多层结构的涂层微针的制备方法，包括如下步骤：
提供包含基座和位于基座上的针尖的微针基底；
将部分形成所述缓释层的材料的水溶液施加到所述针尖上，干燥，得包覆针尖的溶胀的层结构A；
将形成所述内容物的材料的水溶液施加在所述层结构A的表面，干燥，得位于所述层结构A表面的内容物；
将另一部分形成所述缓释层的材料的水溶液施加到所述内容物上并覆盖所述内容物且与所述层结构A结合，干燥，得溶胀的层结构B；
其中，溶胀的层结构A与溶胀的层结构B一起构成所述缓释层，且所述内容物被包裹在该缓释层中。
进一步地，将形成所述内容物的材料的水溶液施加在所述层结构A的表面的方法为蘸取；蘸取的次数优选为3次以上，更优选为3-10次，最优选为3-7次。
进一步地，所述形成所述内容物材料的水溶液的粘度范围为100cps-12000cps。示例性的，该粘度范围还包括但不限于为200-10000cps、200-8000cps、200-5000cps、200-1000cps、200-500cps、400-10000cps、400-8000cps、400-1000cps等。
为达到上述第三个目的，本发明采用下述技术方案：
一种微针贴片，其包含如上第一个目的所述的具有多层结构的涂层微针以及与所述涂层微针基底相结合的被衬。
本发明的有益效果如下：
本发明中提供的涂层微针实现了水溶性微针的缓释效果，且其适用于现有的各种水溶性微针配方，减少了缓释剂型的研发成本，制作过程简便，可操作性强。同时，该涂层微针保证高水平药物利用率、可使药物平稳、缓慢释放，延长药物在体内的循环时间，使血药浓度平稳，减小给药副作用。
本发明提供的涂层微针的制备方法中，很好的实现了将内容物包裹在缓释控制层中，阻滞药物在较短时间内的快速释放，该方法工艺简单，可操作性强，适用于多种速释水溶性药物配方的缓释剂型的改变，且改变过程无需加热、辐照，所使用的材料无细胞毒性，生物相容性好，可以对大限度地保留原有水溶性微针制剂的稳定性和生物利用度。
本发明提供的微针贴片因为包含如上所述的涂层微针，从而也具有该涂层微针所具 有的效果，该微针贴片皮肤穿刺性良好，所载药物利用度高，相对注射剂型入侵性小，尤其适用于首过效应明显，给药频繁的药物的微针剂型开发。
附图说明
下面结合附图对本发明的具体实施方式作进一步详细的说明。
图1示出本发明实施方式中涂层微针的结构示意图。
图2示出本发明实施方式中涂层微针中功能性涂层的结构示意图。
图3示出本发明实施例1制得的载BSA的涂层微针的体视显微镜图。
图4示出本发明实施例1制得的载BSA的涂层微针在显微镜下观察的侧视图。
图5示出本发明实施例1制得的载BSA的涂层微针与未加交联海藻酸钠涂层的微针在0-140小时间的体外释放图。
图6示出本发明实施例1制得的载BSA的涂层微针与未加交联海藻酸钠涂层的微针在0-9小时间的体外释放图。
图7示出本发明实施例2制得的载台盼蓝的涂层微针的一倍体视显微镜整针形态。
图8示出本发明实施例2制得的载台盼蓝的涂层微针三倍体视显微镜局部针形态。
图9示出本发明实施例3中微针贴片的针尖植入猪皮效果图。
图10示出本发明实施例3中微针贴片穿刺猪皮后下段一体式基座的溶解图。
图11示出本发明实施例5中各配方的载药量趋势图。
图12示出本发明实施例5中配方6/10/15/18的针尖形态4倍体式显微镜观察图。
图13示出本发明实施例6中各配方的5倍显微镜侧视图及4倍体视显微镜观察图。
具体实施方式
为了更清楚地说明本发明，下面结合优选实施例和附图对本发明做进一步的说明。附图中相似的部件以相同的附图标记进行表示。本领域技术人员应当理解，下面所具体描述的内容是说明性的而非限制性的，不应以此限制本发明的保护范围。
根据本发明的一个具体实施方式，提供一种具有多层结构的涂层微针，如图1和图2所示，该涂层微针包括基座1、位于基座1上的针尖2、功能性涂层3；
其中，所述功能性涂层3包括含有水溶性高分子材料和活性成分的内容物301以及包裹该内容物301的缓释层302；且
所述缓释层302包覆在所述针尖2上。
该涂层微针中，缓释层302的存在实现了溶解型内容物301的缓释效果，且可以达到药物迟释的效果，在微针作用于皮肤时，阻止内容物301中含药基质迅速溶解，防止活性成分随作用部位的组织渗出，增加药物进入量；同时还具有使药物缓释的作用，在给患者用药时可以减少给药次数，提升患者的依从性。
也即，本实施方式中，缓释层302起到在不降低内容物301总的释放量的前提下，缓释溶解型内容物的效果。同时，还需要缓释层具有较好的亲肤性，以防止皮肤过敏以及与针尖材料较好的结合性。在一个优选示例中，所述缓释层302为交联的层结构。具体地，可为溶胀的层结构。示例性的形成缓释层302的原料中包含延时交联海藻酸钠体系或近中性壳聚糖。示例性的延时交联海藻酸钠体系的原料中包含钙源、葡萄糖酸内酯 (GDL)和载体；所述载体可优选为海藻酸钠。可选地，所述钙源选自依地酸钙钠、碳酸钙、硫酸钙中的一种或几种，优选为依地酸钙钠。
具体地，延时交联海藻酸钠体系可将钙源、葡萄糖酸内酯与所述载体于水中混合形成的混合溶液经干燥、交联，得到的溶胀结构即为所述缓释层302。优选为，将钙源与葡萄糖酸内酯的混合液与载体水溶液混合，经干燥、交联，得所述缓释层302。
上述示例中，钙源作为钙离子交联的钙源，为螯合状态，没有游离钙离子，从而不会导致例如选自海藻酸钠的载体交联。葡萄糖酸内酯在遇水后会缓慢分解，生成EDTA并逐渐释放出H +离子，H +离子和Ca 2+竞争EDTA上的螯和位点，一部分EDTA Ca Na 2形成EDTA Na 2H 2释放出Ca 2+，和例如选自海藻酸钠的载体形成交联。葡萄糖酸内酯在水中的分解是缓慢的，所以Ca 2+的释放也是缓慢的，因此，各原料的添加，建议在需要制备缓释层时短时间内迅速添加，防止状态过早变化形成凝胶而无法与针尖很好的包覆结合。
上述钙源、葡萄糖酸内酯与所述载体海藻酸钠溶于水中混合形成的混合溶液中，混合溶液的粘度优选为70cps-13000cps。以保证微针的微针针尖缓释层的涂载不受低粘度溶液毛细现象的影响，污染微针基底，同时保证缓释层溶液具有一定流动性，便于留在微针针尖处。在又一个优选示例中，上述混合液中，钙源与葡萄糖酸内酯的混合在该混合溶液中的浓度可依据所需交联度进行配制，优选的所述钙源在混合溶液中浓度为3mmol/mL～0.3mol/mL，优选地，所述葡萄糖酸内酯的摩尔浓度为钙源的1～2倍。
示例性的，上述混合溶液的粘度包括但不限于300-6000cps、300-5800cps、300-5700cps、320-6000cps、320-5800cps、320-5700cps、340-6000cps、340-5800cps、340-5700cps、300-500cps、340-3900cps、410-3850cps、410-5850cps、3050-5800cps等。
具体地，近中性壳聚糖的制备为酸性壳聚糖溶液在水中透析为近中性，该溶液干燥后得到的溶胀结构即为所述缓释层302。
上述示例中，壳聚糖为电负性高分子材料，仅溶于酸性溶液，该酸性溶液可以由乳酸、盐酸或醋酸等组成，将壳聚糖溶于酸性溶液中，该壳聚糖溶液整体呈酸性，将该溶液用超纯水透析成近中性，再浓缩至一定浓度，该溶液在干燥后不复溶于生理盐水/人体组织液，可用作缓释层制作。
上述近中性壳聚糖溶液的粘度优选为70cps-13000cps。以保证微针的微针针尖缓释层的涂载不受低粘度溶液毛细现象的影响，同时保证缓释层溶液具有一定流动性。
本实施方式中，包覆有内容物301的缓释层302中，可根据实际需要选择是否添加致孔剂。致孔剂有助于皮内水分子进入缓释层302内部的内容物301中，调控药物释放速率。示例性的致孔剂包括但不限于氯化钠、碳酸钠、碳酸氢钠、碳酸氢铵、聚乙烯吡咯烷酮、透明质酸及其钠盐、纤维素类衍生物、海藻糖、麦芽糖、环糊精类中的一种或几种。致孔剂的实际添加量可优选为占缓释层总重量的0.1-10wt％。
在又一个优选示例中，所述功能性涂层3的高度不超过所述针尖2整体高度的1/2，优选不超过3/7；所述功能性涂层3的直径最大处不超过所述针尖2底部直径的2/3，优选不超过1/2。这种方案能够使微针保持良好的针尖形态，具有足够的皮肤穿刺能力，在穿刺皮肤时功能性涂层部分不易被皮肤挤出，提高功能性涂层部分的皮肤进入量，从而提高药物的利用率。
另外，本实施方式的涂层微针中的内容物301可为常规现有的含活性物质的微针的 配方，极大程度地节省了药物的缓释微针剂型的开发成本。该内容物中，示例性的水溶性高分子材料包括但不限于选自羧甲基纤维素、羟丙基甲基纤维素、羟乙基纤维素、羧甲基壳聚糖、壳聚糖及其衍生物、聚乙烯醇及其衍生物、聚乙烯吡咯烷酮及其衍生物、透明质酸钠、硫酸软骨素、葡聚糖及其衍生物、海藻酸钠、聚γ-谷氨酸、普鲁兰多糖、明胶、聚多巴胺、聚丙烯酰胺中的一种或几种。
在又一个优选示例中，所述活性成分指通过本发明的微针或微针贴片以透皮方式传递、且具有对动物或人体起作用的效能的用于诊断、治疗、预防、化妆或保健目的的物质。依据本实施方式，所述活性成分包括但不限于医药活性成分、疫苗活性成分、化妆品活性成分、保健品活性成分等，具体根据实际需要进行选择。活性成分的添加量可根据具体活性成分的溶解度、稳定性进行配制。优选地，所述活性成分的固含量(也即质量)不超过所述水溶性高分子材料固含量的2倍。
内容物中，还可根据实际情况选择是否添加助剂，例如保护剂。示例性的保护剂包括但不限于选自多羟基化合物、糖类化合物、血清白蛋白、聚乙烯基吡咯烷酮、硫酸软骨素、氨基酸、表面活性剂中的一种或几种；优选地，所述保护剂占内容物总质量的10％以下。
该涂层微针中，基座1及位于基座1上的针尖2可以一体成型或分层成型。形成基座1及针尖2的材料可以相同也可以不同。在一个优选示例中，形成所述基座1和/或针尖2的材料包括生物可降解且不溶于水的高分子材料。其中，示例性的生物可降解且不溶于水的高分子材料包括但不限于选自聚酸酐、聚原酸酯(poly(orthoesters)，POE)、聚磷酸酯(Polyphosphoesters，PPEs)、脂肪族聚酯(aliphatic polyesters)及其衍生物中的一种或几种。进一步地，示例性的聚酸酐包括但不限于P(CPP-SA)、P(FA-SA)、P(FAD-SA)中的一种或几种。示例性的脂肪族聚酯及其衍生物包括但不限于选自聚乙交酯(PGA，也称为聚羟基乙酸或聚乙醇酸)、聚丙交酯(PLA，也称聚乳酸或聚羟基丙酸)、乙交酯-丙交酯共聚物(PLGA或称聚乳酸-乙醇酸共聚物)、聚己内酯(PCL)、左旋聚乳酸(L-PLA)、外消旋聚乳酸、聚乙二醇-聚乳酸共聚物及其衍生物中的一种或几种。
在一个优选示例中，所述针尖2为圆锥状或多角锥状，优选地，针尖2为圆锥状；针间距小于等于0.5毫米；所述高度在0.2-0.7毫米。
本发明的又一个具体实施方式提供如上所述的具有多层结构的涂层微针的制备方法，该方法包括：
提供包含基座1和位于基座1上的针尖2的微针基底；
将部分形成所述缓释层302的材料的水溶液施加到所述针尖2上，干燥，得包覆针尖2的溶胀的层结构A；
将形成所述内容物301的材料的水溶液施加在所述层结构A的表面，干燥，得位于所述层结构A表面的内容物301；
将另一部分形成所述缓释层302的材料的水溶液施加到所述内容物301上并覆盖所述内容物301且与所述层结构A结合，干燥，得溶胀的层结构B；
其中，溶胀的层结构A与溶胀的层结构B一起构成所述缓释层302，且所述内容物301被包裹在该缓释层302中。
上述制备方法中，对施加的方式不做具体限制，能够实现所需结合即可，例如，可 为蘸取。另外，施加的次数可根据实际情况来选择，可以选择一次或多次。优选地，将形成所述内容物的材料的水溶液施加在所述层结构A的表面的方法为蘸取；蘸取的次数优选为3次以上，更优选为3-10次。
为了保证微针的微针针尖缓释层的涂载不受低粘度溶液毛细现象的影响，污染微针基底，同时保证交缓释层溶液具有一定流动性，便于留在微针针尖处，形成交联溶胀的缓释涂层，所述形成所述缓释层302的材料的水溶液的粘度优选在70cps-13000cps之间。示例性的，所述水溶液的粘度包括但不限于300-6000cps、300-5800cps、300-5700cps、320-6000cps、320-5800cps、320-5700cps、340-6000cps、340-5800cps、340-5700cps、300-500cps、340-3900cps、410-3850cps、410-5850cps、3050-5800cps等。
为了保证内容物301能够很好的位于层结构A表面，所述形成所述内容物301的材料的水溶液的表观粘度优选为100cps-12000cps。示例性的，形成内容物301的材料的溶液的表观粘度包括但不限于为200-7000cps、250-7000cps、250-6500cps、250-600cps、250-1320cps、1000-6500cps、300-600cps等。
在一个优选示例中，上述提供包含基座1和位于基座1上的针尖2的微针基底的方法包括：利用模具，将基座1和/或针尖2材料置于相应的模具中，加热，其中加热温度为50-250℃，时间为5-30分钟；将材料按压平整，冷却脱模，得到相应的基座1和/或针尖2材料。当微针基底为一体式时，直接采用一体式模具即可；当该微针基底为分体式时，再结合基座和针尖即可。
本发明的又一个具体实施方式中提供一种微针贴片，其包含如上所述的具有多层结构的涂层微针，以及与所述涂层微针基底1相结合的被衬。
其中，所述背衬包括但不限于压敏胶背衬、水胶体背衬、硅胶背衬中的一种。
上述微针贴片的制备方法，是在制备所述涂层微针的基础上，制备微针阵列，进一步在基座背面贴上背衬后即可。
本发明所述微针贴片可应用于疾病治疗、预防、保健、美容领域。
以下结合一些具体实施例对本发明的技术方案进行说明：
实施例1
一种含牛血清白蛋白(BSA)的海藻酸钠缓释层的多层微针的制备
1)将适量左旋聚乳酸放置于微针一体式基质模具(也即，基座、针尖一体式)上，模具下方抽真空，并对模具进行高温加热，加热温度为190℃，加热时间为5分钟，将高分子材料按压平整，冷却脱模后得到聚乳酸一体式微针基座(针尖高度700μm，针间距500μm)。
2)以水为溶剂，配制海藻酸钠固含量为2％的水溶液，加入固含量为0.5％的海藻糖作为致孔剂；以水为溶剂，配制0.3mol/L的延时交联液，其组成为0.3mol/L依地酸钙钠和0.3mol/L葡萄糖酸内酯；将含有致孔剂的海藻酸钠水溶液与延时交联液按照体积比v:v＝10:1的比例进行混合，制备成交联溶胀材料溶液，其粘度为3700cps。4000rmp涡旋混匀30s，5000rmp离心1分钟静置待用。
3)将上述制备的交联溶胀材料溶液放置在300μm高的载药池中，取一片聚乳酸一体式微针基座，针尖向下落入载药池中进行蘸取，然后将微针静置3min进行涂层干燥。
4)以水为溶剂，聚乙烯醇(33.4cps)为基质，加热溶胀配制成10％水溶液，加入 2％海藻糖作为保护剂，制备水溶性涂层材料溶液；将BSA配制成16mg/mL水溶液，与上述涂层材料溶液以体积比v:v＝1:1进行混合。最终形成含有5％聚乙烯醇、1％海藻糖、6mg/mL BSA的药物溶液(也即内容物溶液，下同其他实施例)，该药物溶液的粘度为512cps。2000rmp涡旋混匀5min，5000rmp离心1min静置待用。
5)将上述制备的药物溶液放置在300μm高的载药池中。取已经搭载了交联溶胀涂层的微针，针尖向下落入载药池中进行药液蘸取，然后将微针静置3min使涂层干燥。该蘸液干燥过程重复4次。
6)将上述已经搭载了交联溶胀涂层、载药涂层的微针，再一次蘸取交联溶胀材料溶液，将微针静置3min进行涂层干燥。使该涂层微针的载药涂层的外部包裹上交联溶胀涂层。得到含有溶胀涂层包裹的，针尖载BSA的涂层微针。
所制得的载BSA的功能性多层结构缓释涂层微针如图3所示，微针在显微镜下观察的侧视图如图4所示，将多层结构微针作用于新生猪的耳部皮肤上，通过溶解微针基底上和猪皮肤表面的BSA，用总载药量扣除，测得微针所载BSA的平均进入量为94wt％；将该微针分别和水溶性涂层微针对照放置在500kDa的透析袋中，进行体外释放实验，考察该多涂层微针的缓释效果，该微针与水溶性涂层微针的等剂量微针的体外释放图如图5和图6所示(其中，图5和图6中，“水溶性涂层微针”是指未加交联海藻酸钠制备得到的不含交联涂层的微针；“多层结构涂层微针”是指本实施例制备得到的含有溶胀涂层包裹的，针尖载BSA的涂层微针)，在该图中可以明显看出交联溶胀包裹涂层(也即缓释层)对载药溶解涂层(也即内容物)的迟释、缓释作用。
实施例2
含台盼蓝的海藻酸钠缓释层的多层微针贴片的制备
1)将适量左旋聚乳酸放置于微针一体式基质模具上，模具下方抽真空，并对模具进行高温加热，加热温度为190℃，加热时间为5分钟，将高分子材料按压平整，冷却脱模后得到聚乳酸一体式微针基座(针尖高度700μm，针间距500μm)。
2)以水为溶剂，配制海藻酸钠固含量为2％的水溶液，加入固含量为0.01mol/L的氯化钠作为致孔剂；以水为溶剂，配制0.01mol/L的延时交联液，其组成为0.01mol/L依地酸钙钠和0.01mol/L葡萄糖酸内酯；将含有致孔剂的海藻酸钠水溶液与延时交联液按照体积比v:v＝10:1的比例进行混合，制备成交联溶胀材料溶液，其粘度为3700cps。4000rmp涡旋混匀30s，5000rmp离心1分钟静置待用。
3)将上述制备的交联溶胀材料溶液放置在300μm高的载药池中，取一片聚乳酸一体式微针基座，针尖向下落入载药池中进行蘸取，然后将微针静置3min进行涂层干燥。
4)以水为溶剂，聚乙烯醇(33.4cps)为基质，加热溶胀配制成10％水溶液，制备水溶性涂层材料溶液；将台盼蓝配制成2％水溶液，与上述涂层材料溶液以体积比v:v＝1:1进行混合。最终形成含有5％聚乙烯醇、1％台盼蓝的染料药物溶液，粘度为435cps。2000rmp涡旋混匀5min，5000rmp离心1min静置待用。
5)将上述制备的药物溶液放置在300μm高的载药池中。取已经搭载了交联溶胀涂层的微针，针尖向下落入载药池中进行药液蘸取，然后将微针静置3min使涂层干燥。该蘸液干燥过程重复4次。
6)将上述已经搭载了交联溶胀涂层、载药涂层的微针，再一次蘸取交联溶胀材料溶液，将微针静置3min进行涂层干燥。使该涂层微针的载药涂层的外部包裹上交联溶胀涂层。
7)在制作完成的涂层微针的一体式基座背部贴上压敏胶背衬，得到含有有溶胀涂层包裹的针尖载台盼蓝的涂层微针贴片。
所制得的载台盼蓝的功能性多层结构缓释涂层微针的一倍体视显微镜整针形态如图7所示，微针三倍体视显微镜局部针形态如图8所示。
实施例3
涂层微针贴片的皮肤穿刺性及涂层植入实验
将实施例2中制作好的微针贴片，作用于新鲜猪皮上，用30N进针器按压40s后，置于琼脂水凝胶上保湿3min，然后揭下微针贴片，观察皮肤内是否有植入的针尖涂层，针孔是否清晰可辨；将揭下来的微针贴片在体视显微镜下观察聚乳酸一体式基座的针尖上的涂层是否都已掉落，基座的底部是否有残留溶解的台盼蓝。
图9中所示为被微针作用后的猪皮，A为有交联溶胀涂层包裹的微针组，B为无交联溶胀涂层组，A中猪皮的针眼相较B更加清晰，说明载台盼蓝的涂层在有交联涂层的包裹后在皮内溶出得更慢，同时很好地防止涂层从皮内溢出，保证了药物的皮内进入量。具体地，用棉签轻轻擦拭猪皮表面，然后将棉签泡在生理盐水中涡旋震荡2h，测量溶液吸光度得知A表皮渗出的药物占微针载药量的2wt％，B表皮渗出的药物占微针载药量的10wt％，说明该多层结构可以保障微针作用皮肤于后药物不从针孔渗出。图10中所示为作用在猪皮后的微针，A为有交联溶胀涂层包裹的微针组，B为无交联溶胀涂层组，B中的微针的一体式基底上有明显的台盼蓝残余，而A中微针的一体式基座底部无溶出的台盼蓝，说明在没有交联溶胀涂层的迟释作用时，在溶解涂层微针作用于皮肤过程中，会因为针尖溶解迅速、针尖与皮肤作用产生阻力而使针尖涂层从皮肤孔道溢出，从而粘在一体式基座底部，降低了药物进入量。具体地：将作用于皮肤后的微针泡在生理盐水中，涡旋震荡10min，测量溶液吸光度得知微针A一体式基座上残留的药物占微针载药量的3wt％，微针B一体式基座上残留的药物为占整体载药量的24wt％，说明该多层结构可以保障微针的药物进入量，从给药角度提高药物的生物利用度。将该微针进行体外释放实验，可缓慢释放台盼蓝长达15天。
实施例4
一种含重组人干扰素的近中性壳聚糖缓释层的多层微针的制备
1)将适量左旋聚乳酸放置于微针一体式基质模具上，模具下方抽真空，并对模具进行高温加热，加热温度为190℃，加热时间为5分钟，将高分子材料按压平整，冷却脱模后得到聚乳酸一体式微针基座(针尖高度700μm，针间距500μm)。
2)以1％乳酸水溶液为溶剂，配制壳聚糖固含量为1.5％的酸性水溶液，加入固含量为1％的海藻糖作为致孔剂；溶解完全后放置于3500截留分子量的透析袋中，在超纯水中透析3天，直至壳聚糖溶液的pH为6.0～6.5时停止透析，将该近中性壳聚糖溶液轻微加热，直至壳聚糖固含量为1.5％(通过称重确认)，平衡至室温，离心1分钟静置待用。
3)将上述制备的交联溶胀材料溶液放置在300μm高的载药池中，取一片聚乳酸一体式微针基座，针尖向下落入载药池中进行蘸取，然后将微针静置3min进行涂层干燥。
4)以水为溶剂，聚乙烯吡咯烷酮(K120)为基质，溶解于超纯水中配制成5％水溶液，加入2％海藻糖作为保护剂，制备水溶性涂层材料溶液；将重组人干扰素冻干粉配制成20mg/mL水溶液，与上述涂层材料溶液以体积比v:v＝1:1进行混合。最终形成含有2.5％聚乙烯吡咯烷酮、1％海藻糖、10mg/mL重组人干扰素的药物溶液。2000rmp涡旋混匀5min，5000rmp离心1min静置待用。
5)将上述制备的药物溶液放置在300μm高的载药池中。取已经搭载了交联溶胀涂层的微针，针尖向下落入载药池中进行药液蘸取，然后将微针静置3min使涂层干燥。该蘸液干燥过程重复4次。
6)将上述已经搭载了交联溶胀涂层、载药涂层的微针，再一次蘸取交联溶胀材料溶液，将微针静置3min进行涂层干燥。使该涂层微针的载药涂层的外部包裹上交联溶胀涂层。得到含有有溶胀涂层包裹的，针尖载重组人干扰素的涂层微针。
将多层结构微针作用于新生猪的耳部皮肤上，通过溶解微针基底上和猪皮肤表面的重组人干扰素，用总载药量扣除，测得微针所载重组人干扰素的平均进入量为97％；将该微针放置在300kDa的透析袋中，进行体外释放实验，考察该多涂层微针的缓释效果，结果显示该微针12天可缓慢释放药物90％。
实施例5
药物溶液固含量/黏度和载药次数对微针载药量的影响
制备方法如实施例1(针尖高度500μm，针间距500μm)，其中所有配方中，步骤4)中，药物溶液中均含有10mg/mL的BSA；步骤2)中，所用的交联溶胀材料溶液的组成均为总固含量2％海藻酸钠溶液和0.3mol/L延时交联剂，延时交联剂组成为0.01mol/L依地酸钙钠和0.01mol/L葡萄糖酸内酯，海藻酸钠溶液与延时交联液的混合体积比为10:1。其余配方的相应的参数，如药物溶液的PVA(6.0cps)固含量与药物溶液的蘸液次数见表1。
表1 各配方制作参数及载药量
Figure PCTCN2021116904-appb-000001
Figure PCTCN2021116904-appb-000002
经测量，10wt％PVA溶液黏度为46.8cps、15％为251.5cps、20％为447.2cps、30％为12020cps。
经载药量测试可知，该涂层微针的载药量与药物溶液的表观粘度(基质材料固含量)和药物溶液蘸液循环次数相关。在相同药物浓度条件下，配方6、配方10、配方15、配方18均可近似达到10μg/片的载药量。同时，在蘸取药物溶液时，观察到当药物溶液表观粘度小于100cps时，会产生毛细现象，且微针载药量过低；当药物溶液表观粘度超过12000cps时，溶液因太过粘稠而无法在蘸取过程中保持液面水平，影响载药均一性；故药物溶液的最适黏度为100-12000cps。
实施例4中各配方的载药量趋势总结如图11所示。配方6/10/15/18的针尖形态4倍体式显微镜观察图依次如图12中a-d所示，可知，微针在进行涂层之后针尖形状保持完整，具有穿刺皮肤的能力。
实施例6
不同针间距和针尖高度、涂层高度的涂层微针制作
制备方法如实施例1，其中所有配方中，步骤4)中，药物溶液中均含有10mg/mL的荧光素大红，15％PVA(6.0cps)；步骤2)中，所用的交联溶胀材料溶液的组成均为总固含量2％海藻酸钠溶液和0.3mol/L延时交联液，延时交联液组成为0.01mol/L依地酸钙钠和0.01mol/L葡萄糖酸内酯，海藻酸钠溶液与延时交联液的混合体积比为10:1。
所使用的针形参数和各实施例的载药量如下表2所示。
表2 各对比例制作参数及载药量
Figure PCTCN2021116904-appb-000003
各配方的5倍显微镜侧视图及4倍体视显微镜观察图依次如图13中a-e所示，可知，该本申请中的微针可具有多种不同的型号，且涂层厚度均一性好。
实施例7-12
制备方法如实施例1，其中实施例7-12中各组分的参数见表3。
表3 各组分的配比及工艺参数
Figure PCTCN2021116904-appb-000004
实施例13-18
制备方法如实施例1，其中实施例13-18中各组分的参数见表4。
表4 各组分的配比及工艺参数
Figure PCTCN2021116904-appb-000005
Figure PCTCN2021116904-appb-000006
实施例19-24
制备方法如实施例1，其中实施例19-24中各组分的参数见表5。
表5 各组分的配比及工艺参数
Figure PCTCN2021116904-appb-000007
Figure PCTCN2021116904-appb-000008
实施例25-26
制备方法如实施例1，其中对比例2中各组分的参数见表6。
表6 各组分的配比及工艺参数
Figure PCTCN2021116904-appb-000009
对比例1-4
制备方法如实施例1，其中对比例1-4中各组分的参数见表7。
表7 各组分的配比及工艺参数
Figure PCTCN2021116904-appb-000010
Figure PCTCN2021116904-appb-000011
显然，本发明的上述实施例仅仅是为清楚地说明本发明所作的举例，而并非是对本发明的实施方式的限定，对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动，这里无法对所有的实施方式予以穷举，凡是属于本发明的技术方案所引伸出的显而易见的变化或变动仍处于本发明的保护范围之列。

Claims (10)

  1. 一种具有多层结构的涂层微针，其特征在于，其包括基座、位于基座上的针尖、功能性涂层；
    其中，所述功能性涂层中包括含有水溶性高分子材料和活性成分的内容物以及包裹该内容物的缓释层；且
    所述缓释层包覆在所述针尖上。
  2. 根据权利要求1所述的具有多层结构的涂层微针，其特征在于，所述缓释层为延时交联海藻酸钠体系或近中性壳聚糖体系；
    优选地，所述延时交联海藻酸钠体系的原料中包含钙源、葡萄糖酸内酯和载体；
    优选地，所述钙源选自依地酸钙钠、碳酸钙、硫酸钙中的一种或几种，更优选为依地酸钙钠；
    优选地，所述载体为海藻酸钠。
  3. 根据权利要求2所述的具有多层结构的涂层微针，其特征在于，当所述缓释层为延时交联海藻酸钠体系时，所述缓释层为将包含钙源、葡萄糖酸内酯与所述载体的原料于水中混合形成的混合溶液经干燥、交联而成的溶胀结构；优选地，所述混合溶液的粘度为70cps-13000cps；优选地，所述钙源在混合溶液中浓度为3mmol/mL～0.3mol/mL；优选地，所述葡萄糖酸内酯在混合溶液中的摩尔浓度为钙源的1～2倍；或
    当所述缓释层为近中性壳聚糖体系时，所述缓释层为将壳聚糖材料溶于酸性溶液中，在水中透析至近中性，得到的溶液经干燥、溶胀而成的结构；优选地，所述溶液的粘度为70cps-13000cps。
  4. 根据权利要求2所述的具有多层结构的涂层微针，其特征在于，所述缓释层的原料中还包含致孔剂；优选地，所述致孔剂选自氯化钠、碳酸钠、碳酸氢钠、碳酸氢铵、聚乙烯吡咯烷酮、透明质酸及其钠盐、纤维素类衍生物、海藻糖、麦芽糖、环糊精类中的一种或几种；优选地，所述致孔剂占所述缓释层总重量的0.1-10wt％。
  5. 根据权利要求1所述的具有多层结构的涂层微针，其特征在于，所述水溶性高分子材料选自羧甲基纤维素、羟丙基甲基纤维素、羟乙基纤维素、羧甲基壳聚糖、壳聚糖及其衍生物、聚乙烯醇及其衍生物、聚乙烯吡咯烷酮及其衍生物、透明质酸钠、硫酸软骨素、葡聚糖及其衍生物、海藻酸钠、聚γ-谷氨酸、普鲁兰多糖、明胶、聚多巴胺、聚丙烯酰胺中的一种或几种；
    优选地，所述活性成分选自水溶性化学药物、多肽类药物、蛋白类药物、核酸类药物中的一种或几种；
    优选地，所述活性成分的固含量不超过所述水溶性高分子材料固含量的2倍。
  6. 根据权利要求1所述的具有多层结构的涂层微针，其特征在于，形成所述基座和/或针尖的材料包括生物可降解且不溶于水的高分子材料；优选地，所述生物可降解且不溶于水的高分子材料选自聚酸酐、聚原酸酯、聚磷酸酯、脂肪族聚酯及其衍生物中的一种或几种；
    优选地，所述聚酸酐选自P(CPP-SA)、P(FA-SA)、P(FAD-SA)中的一种或几种；
    优选地，所述脂肪族聚酯及其衍生物选自聚乙交酯、聚丙交酯、乙交酯-丙交酯共聚物、聚己内酯、左旋聚乳酸、外消旋聚乳酸、聚乙二醇-聚乳酸共聚物及其衍生物中的一种或几种。
  7. 根据权利要求1所述的具有多层结构的涂层微针，其特征在于，所述内容物中还包含有保护剂；优选地，所述保护剂选自多羟基化合物、糖类化合物、血清白蛋白、聚乙烯基吡咯烷酮、硫酸软骨素、氨基酸、表面活性剂中的一种或几种；优选地，所述保护剂占内容物总质量的50％以下。
  8. 根据权利要求1所述的具有多层结构的涂层微针，其特征在于，所述功能性涂层的高度不超过所述针尖整体高度的1/2，优选不超过3/7；所述功能性涂层的直径最大处不超过所述针尖底部直径的2/3，优选不超过1/2。
  9. 如权利要求1-8任一项所述的具有多层结构的涂层微针的制备方法，其特征在于，包括如下步骤：
    提供包含基座和位于基座上的针尖的微针基底；
    将部分形成所述缓释层的材料的水溶液施加到所述针尖上，干燥，得包覆针尖的溶胀的层结构A；
    将形成所述内容物的材料的水溶液施加在所述层结构A的表面，干燥，得位于所述层结构A表面的内容物；
    将另一部分形成所述缓释层的材料的水溶液施加到所述内容物上并覆盖所述内容物且与所述层结构A结合，干燥，得溶胀的层结构B；
    其中，溶胀的层结构A与溶胀的层结构B一起构成所述缓释层，且所述内容物被包裹在该缓释层中。
  10. 一种微针贴片，其特征在于，包含如权利要求1-8任一项所述的具有多层结构的涂层微针，以及与所述涂层微针基底相结合的被衬。
PCT/CN2021/116904 2020-09-07 2021-09-07 具有多层结构的涂层微针、其制备方法及包含该涂层微针的微针贴片 WO2022048682A1 (zh)

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US18/024,585 US20230310822A1 (en) 2020-09-07 2021-09-07 Coated microneedle with multilayer structure, method for preparing the same and microneedle patch comprising coated microneedle

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