CN110870846A - Rapidly implantable sustained-release microneedle patch and preparation method thereof - Google Patents
Rapidly implantable sustained-release microneedle patch and preparation method thereof Download PDFInfo
- Publication number
- CN110870846A CN110870846A CN201811010762.4A CN201811010762A CN110870846A CN 110870846 A CN110870846 A CN 110870846A CN 201811010762 A CN201811010762 A CN 201811010762A CN 110870846 A CN110870846 A CN 110870846A
- Authority
- CN
- China
- Prior art keywords
- needle
- microneedle
- injection molding
- rapidly
- release
- 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
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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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
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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
- A61M2037/0046—Solid microneedles
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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
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Abstract
The invention discloses a rapidly implantable sustained-release microneedle patch and a preparation method thereof. The invention firstly discloses a rapid implantable slow release microneedle, which comprises a needle point, a middle layer, a needle body and a substrate; the needle tip is formed by a matrix containing biodegradable water-insoluble high polymer materials; the intermediate layer is formed from a matrix comprising a hydrophilic material; the needle body and the base are formed of a matrix comprising a biocompatible polymeric material. The invention also discloses a preparation method of the microneedle. The micro-needle or the micro-needle patch is characterized in that a needle point is made of biodegradable water-insoluble high polymer material, a middle layer is made of hydrophilic material, a needle body and a substrate are made of biocompatible high polymer material to form a multi-layer micro-needle with the needle point difficult to dissolve in water, the multi-layer micro-needle acts on the skin and absorbs water to enable the needle point, the needle body and the substrate to be quickly separated within 1 hour, after the substrate is uncovered, the needle point is remained in the skin, and a user can ensure the long-term release of a medicament in the body without applying the micro-needle.
Description
Technical Field
The invention relates to the technical field of medicines. And more particularly, to a rapidly implantable sustained release microneedle patch and a method for preparing the same.
Background
The transdermal drug delivery preparation is a dosage form of drug delivery through skin, can avoid the interference of gastrointestinal environment on drug effect and liver 'first pass effect', maintain constant optimal blood concentration or physiological effect, prolong effective acting time, reduce drug administration times, enable patients to independently administer drugs, and have better compliance. However, the stratum corneum of the outer layer of the skin can obstruct the absorption of the drug, and the drug is not easy to penetrate into the body, so that the selection of the drug is very limited. In recent years, microneedle technology has been attracting attention, and is one of the physical permeation-promoting methods for transdermal drug delivery, and can achieve painless precise drug delivery.
The traditional micro-needle made of metal, glass and silicon materials can be inevitably broken in the skin when in use due to the performance of the materials, thereby causing damage to human body. In recent years, the used materials of the emerging polymer micro-needle comprise water-soluble high molecules, biocompatible high molecules and biodegradable high molecular materials which can be absorbed by skin, so that the use risk is greatly reduced, meanwhile, the polymer micro-needle has the advantages of low production cost, simple manufacturing process, mass production, environmental friendliness and the like, and the micro-needle can realize the controllable release of the medicine by selecting the water-soluble high molecular materials or the biodegradable high molecular materials with different physicochemical properties. In recent years, a plurality of scientific researchers are dedicated to manufacturing polymer microneedles which are good in biocompatibility, naturally degradable and easy to prepare by using polylactic acid degradable high polymer materials.
Chinese patent (CN104888343A) discloses a polymer solid microneedle and a batch preparation method thereof. The material is a biodegradable polymer material which is insoluble in water, and the preparation method comprises the steps of placing polymer material particles on a microneedle mould, heating the microneedle mould in a closed heating device until the particles are molten, and carrying out compression molding on a melt while the melt is hot through a preparation device. However, the microneedle prepared in the patent cannot load the drug, and only plays a role in pretreating the skin and destroying the stratum corneum barrier of the skin when in use.
International patent publication (WO2007/030477) discloses a solid drug solution perforator (SSPP system) containing drug particles and/or drug-adsorbed or loaded particles and an associated drug reservoir. For drug delivery, the SSPP system includes an active pharmaceutical ingredient in the form of particles or a drug adsorbed to the surface of particles of a matrix material that dissolves upon contact with the patient's body. The inert particles are lactic-glycolic acid copolymer (PLGA) or aluminum hydroxide and aluminum phosphate. The microneedle prepared by the method can load protein and vaccine drugs, but in the method, the drugs are adsorbed on PLGA inert particles, and the slow release effect is basically not existed.
Document 1(Pharmaceutical research.2006May; 23(5):1008-19.) proposes a method for preparing microneedles by using polylactic-co-glycolic acid (PLGA) as a microneedle stent material, in which drug or microspheres of drug-loaded polylactic acid or sodium carboxymethylcellulose are loaded into the microneedles to achieve controlled release of the drug, but in the method, because the main matrix material of the microneedles is PLGA, a user needs to apply the drug for a long time until the PLGA is completely degraded.
Document 2(Biomed microdevices.2007Apr; 9(2):223-34) proposes a method of preparing porous, multilayered biodegradable microneedles using PLA, PGA or PLGA microspheres. The method is characterized in that microspheres made of biodegradable high polymer materials are injected into a mold, and porous or multilayer microneedles are prepared by extrusion and ultrasonic welding or thermal welding technologies, wherein the microneedles are prepared by a spray drying technology or an emulsification method, and the process is complex. The porous, multilayered microneedles are weaker and brittle than single microneedles and are difficult to release from the mold efficiently.
In summary, in view of the prior art, taking polylactic acid microneedles as an example, microneedle fabrication can be divided into two categories, one is to fabricate microspheres from polylactic acid degradable polymer materials and drugs, then add the microspheres onto a microneedle mold, and then heat, melt and cool the microspheres to form microneedles with a certain mechanical strength, which can carry drugs, but need to fabricate microspheres first and then form microneedles, which is cumbersome to operate and high in cost; in the other method, polylactic acid powder is directly added on a microneedle mould, heated and melted (higher than 200 ℃) and then cooled to form the microneedle, and the preparation method is difficult to load the drug.
Therefore, it is required to provide a rapidly implantable sustained-release microneedle which is simple in process, high in safety and free from long-term application.
Disclosure of Invention
The first purpose of the invention is to provide a rapid implantable sustained-release microneedle, which can implant a biodegradable needle tip into the skin to achieve the purposes of convenient, safe, biodegradable, sustained-release and efficient drug delivery.
The second purpose of the present invention is to provide a method for preparing the rapidly implantable sustained release microneedle, which has the advantages of simple process and low cost.
A third object of the present invention is to provide a microneedle patch comprising the above rapidly implantable sustained-release microneedle.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a rapid implantable slow release microneedle, which comprises a needle point, a middle layer, a needle body and a substrate; the needle tip is formed by a matrix containing biodegradable water-insoluble high polymer materials; the intermediate layer is formed from a matrix comprising a hydrophilic material; the needle body and the base are formed of a matrix comprising a biocompatible polymeric material.
Further, the needle tip further comprises at least one active ingredient; preferably, the mass ratio of the biodegradable water-insoluble high polymer material to the active ingredient is 0.5: 1-1000: 1, so as to ensure the mechanical strength and the skin puncture property of the microneedle.
In a preferred embodiment of the invention, the needle tip further comprises a pore-forming agent, wherein the pore-forming agent helps intradermal water molecules to enter the interior of the needle tip matrix and regulates the release rate of the drug. The pore-forming agent comprises one or more of sodium chloride, sodium carbonate, sodium bicarbonate, ammonium bicarbonate, trehalose, maltose, polyethylene glycol, cyclodextrin and derivatives thereof, polymethyl pyrrolidone (PVP), low molecular weight hyaluronic acid and sodium salt thereof (molecular weight is 5-100 kDa), and low molecular weight cellulose derivatives (molecular weight is 5-100 kDa).
Preferably, the pore-foaming agent accounts for 0.1-10% of the total mass of the needle tip.
In a preferred embodiment of the present invention, the needle tip further comprises a protective agent, wherein the protective agent includes, but is not limited to, one or more of polyhydroxy compounds (mannitol, sorbitol, xylitol, polyethylene glycol, etc.), sugar compounds (trehalose, dextrin, lactose, sucrose, maltose, etc.), serum albumin, polyvinylpyrrolidone, chondroitin sulfate, and amino acids (proline, tryptophan, glutamic acid, glycine, etc.).
Preferably, the protective agent accounts for 0.1-10% of the total mass of the needle tip.
Further, the hydrophilic material includes, but is not limited to, one or more of monomer polymers or copolymers of polyvinylpyrrolidone and derivatives thereof, poly gamma-glutamic acid, pullulan, hyaluronic acid and sodium salts thereof, trehalose, sucrose, sorbitol, mannitol, xylitol, sodium alginate, and pectin.
The biocompatible polymer materials in the needle body and the substrate comprise one or more of carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl chitosan, polyvinyl alcohol derivatives, polyvinylpyrrolidone derivatives, sodium hyaluronate, chondroitin sulfate, dextran, fibroin and gelatin; preferably, the molecular weight of the biocompatible polymer material is 10-2000 kDa.
Preferably, the needle body and the substrate further comprise small molecular weight saccharides and polyol compounds, specifically one or more of trehalose, sucrose, sorbitol, mannitol, xylitol, and the like, so as to accelerate the dissolution rate of the water-soluble polymer material.
Further, the needle tip is conical or polygonal conical, preferably, the needle tip is conical; the density of the microneedle tips is as follows: 250-1000 per square centimeter of substrate; the total height of the needle tip, the intermediate layer and the needle body is 0.3-2mm, the angle of the needle tip is 10-60 degrees, and the thickness of the substrate is 10-300 mu m; the height of the needle tip is not more than two thirds of the total height of the needle tip, the middle layer and the needle body.
The invention also provides a preparation method of the rapidly implantable sustained-release microneedle, which comprises the following steps:
1) mixing a biodegradable water-insoluble high polymer material with a part of organic solvent, adding or not adding a pore-foaming agent, and adding or not adding a protective agent to prepare a needle tip matrix material solution; mixing the active ingredient with the remaining organic solvent to prepare a pharmaceutical solution; mixing the medicinal solution with the needle point substrate material solution to obtain needle point injection molding liquid;
alternatively, the first and second electrodes may be,
mixing biodegradable water-insoluble high polymer material with organic solvent, adding or not adding pore-forming agent, adding or not adding protective agent, adding active ingredient, and mixing uniformly to obtain needle point injection molding liquid;
2) mixing the hydrophilic material with water to obtain middle layer injection molding liquid; mixing a biocompatible polymer material with water to obtain a needle body and a substrate injection molding liquid;
3) injecting the needle point injection molding liquid into a microneedle mould, heating, removing the organic solvent and cooling; injecting the middle layer injection molding liquid into the microneedle mould, and drying; and injecting the needle body and substrate injection molding liquid into a microneedle mould to prepare the needle body and the substrate, drying and demoulding.
Further, the organic solvent includes, but is not limited to, acetone, ethyl acetate, chloroform, dichloromethane, dimethylsulfoxide, or N-methylpyrrolidone; preferably, the organic solvent is N-methylpyrrolidone.
Further, the mass concentration of the biodegradable water-insoluble high polymer material in the needle tip injection molding liquid matrix material is 5-30%; the mass concentration of the hydrophilic material in the middle layer injection molding liquid is 0.5-10%; the mass concentration of the biocompatible polymer material in the needle body and the substrate injection molding liquid is 10-40%; the mass ratio of the biodegradable water-insoluble high polymer material to the active ingredients is 0.5-1000: 1.
Further, in the step 3), each injection molding liquid is added into the microneedle mold by a pressurization method or a vacuum pumping method, so that bubbles in the microneedles during manufacturing are avoided. If a pressurization method is adopted, the applied pressure is 0.2-0.6MPa, and the time for applying pressure is 1-20 min. If a vacuum pumping method is adopted, the vacuum degree is 0.05-0.1MPa, and the vacuum pumping time is 3-20 min.
Preferably, the temperature of the needle point injection molding liquid after being injected into the microneedle mould is 30-80 ℃, the heating time is 1-24 hours, so that the organic solvent is volatilized, and the microneedle has enough mechanical strength and skin puncture capability after being cooled.
Preferably, the drying condition after the intermediate layer or the needle body and the base injection molding liquid are injected into the microneedle mold is to dry for 0.5 to 6 hours at 20 to 50 ℃ and 10 to 45% humidity.
The invention further provides a rapid implantable sustained release microneedle patch, which comprises a microneedle array and a lining, wherein the microneedle array is composed of the rapid implantable sustained release microneedle; preferably, the lining is a pressure sensitive adhesive lining or a silica gel lining or a hydrocolloid.
The preparation method of the rapidly implantable sustained-release microneedle patch comprises the steps of preparing the microneedle array on the basis of preparing the rapidly implantable sustained-release microneedle, further attaching a lining to the back of the substrate of the microneedle array, and then demoulding.
The microneedle patch can be applied to the fields of disease treatment, prevention, health care and beauty.
The term "active ingredient" refers to a substance that is delivered transdermally by the microneedle or microneedle patch of the present invention and has efficacy for animal or human body for diagnostic, therapeutic, prophylactic, cosmetic or health purposes. According to the present invention, the active ingredients include, but are not limited to, pharmaceutical active ingredients, vaccine active ingredients, cosmetic active ingredients, health care active ingredients, etc., and are selected according to actual needs.
The invention has the following beneficial effects:
the micro-needle or the micro-needle patch of the invention uses biodegradable water-insoluble high molecular material to manufacture the needle point of the micro-needle, uses hydrophilic material to manufacture the middle layer of the micro-needle, uses biocompatible high molecular material to manufacture the needle body and the substrate to form a multi-layer micro-needle with the needle point difficult to dissolve in water, and after the multi-layer micro-needle acts on the skin, the multi-layer micro-needle absorbs the water in the skin to quickly separate the needle point from the needle body and the substrate within 1h, after the patch substrate is removed, the needle point of the micro-needle can be remained in the skin, and a user can ensure the long-. The microneedle patch is not limited by the manufacturing area, can greatly improve the drug loading rate by enlarging the area, and is suitable for intradermal long-acting release of various drugs. In addition, the microneedle preparation process avoids the complex process of wrapping the drug in the microsphere liposome, but uses a low-toxicity organic solvent such as N-methylpyrrolidone to dissolve the biodegradable water-insoluble high polymer material, so that the process cost is reduced, the process is similar to the common dissolving microneedle preparation method, the operation is simple and rapid, high-temperature melting is not needed, and the applicable drug range is wide.
Drawings
The following describes embodiments of the present invention in further detail with reference to the accompanying drawings.
Fig. 1 shows a schematic representation of a microneedle patch structure.
Fig. 2 shows a photograph under a stereomicroscope of the microneedle patch.
Fig. 3 shows a side view under a microscope of a microneedle patch.
Fig. 4 illustrates the skin piercing ability of the microneedle patch.
Fig. 5 shows a fluorescent microscopic photograph of a microneedle patch tip partially implanted with polylactic acid in swine skin.
Detailed Description
In order to more clearly illustrate the invention, the invention is further described below with reference to preferred embodiments and the accompanying drawings. Similar parts in the figures are denoted by the same reference numerals. It is to be understood by persons skilled in the art that the following detailed description is illustrative and not restrictive, and is not to be taken as limiting the scope of the invention.
Example 1 preparation of rapidly implantable sustained-release microneedle
1. Weighing 0.3g of PLGA (80/20) with the molecular weight of 20kDa, adding 0.7ml of N-methylpyrrolidone, and preparing a PLGA solution with the mass fraction of 30%; weighing 100mg of etonogestrel, adding 1ml of N-methyl pyrrolidone, and preparing 100mg/ml of etonogestrel solution; 0.5ml of the etonogestrel solution and 0.5ml of the PLGA solution are uniformly mixed to prepare a 15% PLGA solution containing etonogestrel (50mg/ml) as a needle tip injection molding solution.
2. Weighing 0.25g of polyvinylpyrrolidone with the molecular weight of 10kDa, adding 4.75ml of water, and preparing an aqueous solution of polyvinylpyrrolidone with the mass fraction of 5% as middle layer injection molding liquid; 3.5g of polyvinyl alcohol having a molecular weight of 50kDa was weighed out. Adding 6.5ml of water, heating at 80 ℃ for 2h, and preparing 35% polyvinyl alcohol aqueous solution serving as a needle body and substrate injection molding liquid.
3. Adding the needle point injection molding liquid into the microneedle mould, enabling the needle point injection molding liquid to enter a needle hole of the microneedle mould in a vacuumizing mode, removing redundant solution on the mould, and heating for 3 hours at 70 ℃; adding 30 mul of the middle layer injection molding liquid into a mold, enabling the middle layer injection molding liquid to enter the cooled microneedle mold pin holes in a vacuumizing mode, removing the redundant solution on the mold, and drying for 10 minutes at the temperature of 25 ℃ and the humidity of 20%; adding 150 mul of the needle body and the substrate injection molding liquid to the microneedle mould, and vacuumizing to avoid bubbles; the microneedle mould was dried at 25 ℃ and 10% humidity for 6 hours.
4. And demolding the dried microneedle.
The prepared microneedle is shown in figure 1, and the microneedle has 300 needles per 0.5 square centimeter and the length of 0.5 mm.
After the microneedle patch is used, the separation time of a needle point, a needle body and a substrate is 0.5h, and an in vitro release experiment shows that the sustained-release time of etonogestrel is 30 days.
Etonogestrel in this example can be substituted with other active ingredients that are heat resistant 80 degrees small molecule compounds, including but not limited to active ingredients such as ethinylestradiol, levonorgestrel, norgestrel, gestodene, desogestrel, artemisinin derivatives, paclitaxel derivatives, etc., and the resulting microneedle patches have similar sustained release effects.
The polyvinylpyrrolidone in the middle layer injection molding liquid of the present embodiment may be substituted by polyvinylpyrrolidone derivatives, poly-gamma-glutamic acid, pullulan, hyaluronic acid and its sodium salt, trehalose, sucrose, sorbitol, mannitol, xylitol, sodium alginate, pectin, gelatin, etc., and the obtained microneedle patch has a similar sustained release effect.
In the needle body and the base injection molding liquid of the present embodiment, the polyvinyl alcohol may be substituted by one or more of carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl chitosan, polyvinyl alcohol, polyvinyl pyrrolidone, sodium hyaluronate, and chondroitin sulfate, and the obtained microneedle patch has similar slow release effect.
Pore-forming agents such as 0.1-5% of sodium chloride, 0.1-5% of sodium carbonate, 0.1-3% of sodium bicarbonate, 0.1-3% of ammonium bicarbonate, 1-10% of trehalose, 1-10% of maltose, 1-10% of cyclodextrin and derivatives thereof, 1-10% of polymethyl pyrrolidone, 1-10% of sodium hyaluronate and 1-10% of carboxymethyl cellulose can be added into the injection molding liquid of the needle tip of the embodiment, and the obtained microneedle patch can slowly release for 5-20 days.
Example 2 preparation of rapidly implantable sustained-release microneedle
1. Weighing 0.4g of polylactic acid (PLA) with the molecular weight of 10kDa, adding 0.6ml of N-methyl pyrrolidone, and preparing a PLA solution with the mass fraction of 40%; weighing 10mg of red fluorescent dye, adding 1ml of N-methyl pyrrolidone, and preparing into a fat-soluble simulated medicine red fluorescent dye solution with the mass fraction of 10 mg/ml; 0.5ml of red fluorescent dye solution and 0.5ml of PLA solution are mixed evenly to prepare 20 percent PLA solution containing 5mg/ml of red fluorescent dye as injection molding liquid for the needle point.
2. Weighing 0.05g of pullulan, adding 9.95ml of water, and preparing a pullulan aqueous solution with the mass fraction of 0.5% as middle-layer injection molding liquid; 2.5g of sodium carboxymethylcellulose with the molecular weight of 200kDa is weighed, 7.5ml of water is added to prepare an aqueous solution of the sodium carboxymethylcellulose with the mass fraction of 25 percent, and the aqueous solution is used as a needle body and a base injection molding liquid.
3. Adding the needle point injection molding liquid into the microneedle mould, enabling the needle point injection molding liquid to enter a needle hole of the microneedle mould in a vacuumizing mode, removing redundant solution on the mould, and heating for 2 hours at 80 ℃; adding 50 mul of middle layer injection molding liquid into the cooled microneedle mould, enabling the middle layer injection molding liquid to enter a pinhole of the microneedle mould in a pressure applying mode, and drying for 10 minutes at the temperature of 25 ℃ and the humidity of 30%; adding 150 mul of the needle body and the substrate injection molding liquid to the microneedle mould, and vacuumizing to avoid bubbles; the microneedle mould was dried at 25 ℃ and 35% humidity for 0.5 hour.
4. And demolding the dried microneedle.
The prepared microneedle is shown in fig. 1, and the stereomicroscope images are shown in fig. 2 and 3, the microneedle is 400 needles per square centimeter, and the length of the microneedle is 0.7 mm.
After the microneedle patch is used, the separation time of the needle tip, the needle body and the substrate is 1 h.
In the embodiment, the fluorescent scarlet can be replaced by active ingredients of other heat-resistant 80-degree small molecular compounds, and the obtained microneedle patch has similar slow release effect.
Example 3 preparation of rapidly implantable sustained-release microneedle
1. Weighing 0.3g of PLGA (75/25) with the molecular weight of 10kDa, adding 0.7ml of N-methylpyrrolidone, and preparing a PLGA solution with the mass fraction of 30%; weighing 15mg of interferon a-2b, dissolving in sterile water for injection, adding micronized and sterilized 35mg of zinc hydroxide, and vortex mixing for 10min to form 1g of zinc salt interferon a-2b solution; 1g of zinc salt interferon a-2b solution is added into the 30 percent PLGA solution, and a sol system containing drug loading is formed by stirring and is used as a needle point injection molding solution.
2. Weighing 0.25g of trehalose, adding 4.75ml of water to prepare a trehalose aqueous solution with the mass fraction of 5% as middle-layer injection molding liquid; weighing 3g of polyvinyl alcohol with the molecular weight of 70kDa, adding 7ml of water, heating at 85 ℃ for 2h, and preparing a polyvinyl alcohol aqueous solution with the mass fraction of 30% as a needle body and substrate injection molding liquid.
3. Adding the needle point injection molding liquid into a microneedle mould, enabling the needle point injection molding liquid to enter a needle hole of the microneedle mould in a vacuumizing mode, removing redundant solution on the mould, and heating at 30 ℃ for 12 hours; adding 20 μ l of the middle layer injection molding liquid into the cooled mold, allowing the middle layer injection molding liquid to enter the pinholes of the microneedle mold by applying pressure, removing the excess solution on the mold, and drying at 25 deg.C and 30% humidity for 20 min; adding 200 μ l of the needle body and the substrate injection molding liquid into the microneedle mold, vacuumizing to avoid generation of bubbles, and drying the microneedle mold at 25 deg.C and 10% humidity for 6 hr.
4. And demolding the dried microneedle.
The prepared microneedles are shown in fig. 1.
After the microneedle patch is used, the separation time of the needle tip, the needle body and the substrate is 0.75 h. The in vitro release experiment result shows that the slow release time of the interferon a-2b is about 30 days.
In this embodiment, interferon a-2b may be substituted with other types of active ingredients, particularly, proteins or polypeptides having poor heat resistance, such as insulin, growth hormone, nerve growth factor, etc., to obtain microneedle patches having similar sustained release effects.
The trehalose of the middle layer injection molding liquid of the present embodiment may be substituted by polyvinylpyrrolidone derivatives, poly-gamma-glutamic acid, pullulan, hyaluronic acid and sodium salts thereof, trehalose, sucrose, sorbitol, mannitol, xylitol, sodium alginate, pectin, gelatin, etc., and the obtained microneedle patch has a similar sustained release effect.
In the needle body and the base injection molding liquid of the present embodiment, the polyvinyl alcohol may be substituted by one or more of carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl chitosan, polyvinyl alcohol, polyvinyl pyrrolidone, sodium hyaluronate, chondroitin sulfate, and dextran, and the obtained microneedle patch has similar slow release effect.
In the injection molding liquid for the needle tip of the embodiment, a pore-forming agent, such as 0.1-5% of sodium chloride, 0.1-5% of sodium carbonate, 0.1-3% of sodium bicarbonate, 0.1-3% of ammonium bicarbonate, 1-10% of trehalose, 1-10% of maltose, 1-10% of cyclodextrin and its derivatives, 1-10% of polymethyl pyrrolidone, 1-10% of sodium hyaluronate, and 1-10% of carboxymethyl cellulose, may be added, and the sustained release time of the obtained microneedle patch may be controlled within 5 days-20 days.
The needle point injection molding liquid of the embodiment can be added with a protective agent, such as one or more of 1-10% of polyhydroxy compounds (such as 1% of glycerol, 3% of butanediol, 1-5% of xylitol, 1-10% of mannitol), 1-10% of carbohydrate compounds (1-10% of trehalose, 1-5% of sucrose), 0.1-5% of serum albumin, 1-10% of polyvinylpyrrolidone and 1-10% of amino acids, and the slow release time of the obtained microneedle patch can be controlled within 5-20 days.
Example 4 preparation of rapidly implantable sustained-release microneedle
1. Weighing 0.3g of PLGA (50/50) with the molecular weight of 15kDa, adding 0.7ml of N-methylpyrrolidone to prepare PLGA solution with the mass fraction of 30%; weighing 40mg of granisetron hydrochloride, adding 1ml of N-methylpyrrolidone, and preparing a granisetron hydrochloride solution with the mass fraction of 40 mg/ml; 0.5ml of granisetron hydrochloride solution and 0.5ml of PLGA solution are uniformly mixed to prepare 15% PLGA solution containing 20mg/ml of granisetron hydrochloride, and the 15% PLGA solution is used as the needle tip injection molding solution.
2. Weighing 1g of gelatin, adding 9ml of water, and preparing a gelatin water solution with the mass fraction of 10% as middle layer injection molding liquid; weighing 4g of chondroitin sulfate with the molecular weight of 40kDa, adding 6ml of water, and preparing a chondroitin sulfate aqueous solution with the mass fraction of 40% as injection molding liquid of the needle body substrate.
3. Adding the needle point injection molding liquid into the microneedle mould, enabling the needle point injection molding liquid to enter the needle hole of the microneedle mould in a vacuumizing mode, removing the redundant solution on the mould, and heating for 2 hours at 60 ℃; adding 20 mul of the middle layer injection molding liquid into the cooled mould, enabling the middle layer injection molding liquid to enter a micro-needle mould pinhole in a pressure applying mode, and drying for 15 minutes under the conditions of 25 ℃ and 30% humidity; adding 150 mul of the needle body and the substrate injection molding liquid to a microneedle mould, and vacuumizing to avoid bubbles; the microneedle mould was dried at 25 ℃ and 35% humidity for 4 hours.
4. Demolding of dried microneedles
The prepared microneedle is shown in figure 1, and the microneedle has 1000 needles per square centimeter and the length of 0.3 mm.
After the microneedle patch is used, the separation time of the needle tip, the needle body and the substrate is 0.5 h. The in vitro release result shows that the slow release time of the granisetron hydrochloride is about 15 days.
In this embodiment, granisetron hydrochloride may be substituted with other active ingredients, for example, leuprolide acetate, octreotide acetate, amlodipine besylate/ketoprofen, cyclosporine, controlled release of diclofenac sodium, everolimus, methylphenidate, clarithromycin, mycophenolic acid, griseofulvin, mariron (mabilone), tacrolimus (tacrolimus), and other drugs, and the obtained microneedle patch has similar slow release effect.
Example 5 preparation of rapidly implantable sustained-release microneedle
1. 0.2g of PLGA (80/20) with the molecular weight of 15kDa is weighed, 0.8ml of N-methyl pyrrolidone is added to prepare PLGA solution with the mass fraction of 20 percent, and the PLGA solution is used as injection molding liquid for the needle tip.
2. 0.05g of glucan with the molecular weight of 70kDa is weighed, 4.95ml of water is added, and a glucan water solution with the mass fraction of 1% is prepared to be used as middle layer injection molding liquid. Weighing 3.5g of sodium alginate with molecular weight of 50 kDa. 6.5ml of water is added to prepare 35 percent sodium alginate aqueous solution serving as a needle body and base injection molding liquid.
3. Adding the needle point injection molding liquid into a microneedle mould, enabling the needle point injection molding liquid to enter a needle hole of the microneedle mould in a vacuumizing mode, removing redundant solution on the mould, and heating for 1 hour at 60 ℃; adding 10 mul of middle layer injection molding liquid into the cooled mould, enabling the middle layer injection molding liquid to enter a microneedle mould pinhole in a vacuumizing mode, removing redundant solution on the mould, and drying for 10 minutes at 25 ℃ and 20% humidity; adding 150 mul of the needle body and the substrate injection molding liquid to the microneedle mould, and vacuumizing to avoid bubbles; drying the microneedle mould for 6 hours at 25 ℃ and 10% humidity;
4. and demolding the dried microneedle.
The prepared microneedle is shown in figure 1, and the microneedle has a needle length of 600 needles/square centimeter and a needle length of 0.4 mm.
After the microneedle patch is used, the separation time of the needle tip, the needle body and the substrate is 1.5 h.
The polylactic acid-PLGA of the embodiment can be replaced by other biodegradable water-insoluble high polymer materials, so that the microneedle patch has a slow-release effect.
Example 6 preparation of rapidly implantable sustained-release microneedles
1. Weighing 0.20 of polyorthoester (t-CDM: 1,6-HD 35:65), adding 0.80ml of N-methylpyrrolidone to prepare a polyorthoester solution with the mass fraction of 20%, weighing 20mg of levonorgestrel, adding 1ml of N-methylpyrrolidone to prepare an estradiol solution with the mass fraction of 20 mg/ml; a solution of levonorgestrel (1 ml) was mixed with a solution of polyorthoester (1 ml) to prepare a needle tip injection molding fluid containing estradiol.
2. Weighing 0.5g of sodium hyaluronate with the molecular weight of 100kDa, adding 4.5ml of water, and preparing 10% by mass of sodium hyaluronate aqueous solution to be used as middle layer injection molding liquid; 2.0g of hydroxypropyl methyl cellulose with the molecular weight of 200kDa is weighed, 8.0ml of water is added to prepare 20 percent hydroxypropyl methyl cellulose aqueous solution serving as a needle body and a base injection molding liquid.
3. Adding the needle point injection molding liquid into a microneedle mould, enabling the needle point injection molding liquid to enter a needle hole of the microneedle mould in a vacuumizing mode, removing redundant solution on the mould, and heating for 3 hours at 70 ℃; adding 20 mul of the middle layer injection molding liquid into a mold, enabling the middle layer injection molding liquid to enter a microneedle mold pinhole in a vacuumizing mode, and drying for 10 minutes at the temperature of 25 ℃ and under the humidity of 30%; adding 200 mul of the needle body and the substrate injection molding liquid to the cooled microneedle mould, and vacuumizing to avoid bubbles; drying the microneedle mould for 6 hours at 25 ℃ and 30% humidity;
4. and demolding the dried microneedle.
The prepared microneedle is shown in figure 1, and the microneedle has 200 needles per square centimeter and the length of 0.8 mm.
After the microneedle patch is used, the separation time of the needle point and the substrate is 1.0 h; in vitro release showed a sustained release time of 14 days for estradiol.
The embodiment can be replaced by other small-molecule active ingredients to obtain the sustained-release effect of the microneedle patch.
Example 7 preparation of rapidly implantable sustained-release microneedle in which pore-forming agent was added to the tip of needle
1. Weighing 3g of PLGA (80/20) with the molecular weight of 20kDa, adding 7ml of N-methyl pyrrolidone, and then adding 0.15g of PVP K30 as a pore-foaming agent to prepare PLGA solution containing PVP K30; weighing 50mg of vinpocetine, adding 1ml of N-methyl pyrrolidone, and preparing a 50mg/ml vinpocetine solution; 1ml of vinpocetine solution and 1ml of PLGA solution containing PVP K30 were mixed to prepare a tip injection containing vinpocetine.
2. Weighing 0.05g of poly-gamma-glutamic acid, adding 4.95ml of water, and preparing 1% of poly-gamma-glutamic acid aqueous solution serving as middle-layer injection molding liquid; 3.5g of polyvinyl alcohol with the molecular weight of 50kDa is weighed, 6.5ml of water is added, the mixture is placed at 85 ℃ for heating for 2 hours, and a polyvinyl alcohol aqueous solution with the mass fraction of 35% is prepared and used as a needle body and base injection molding liquid.
3. Adding the needle point injection molding liquid into a microneedle mould, enabling the needle point injection molding liquid to enter a needle hole of the microneedle mould in a vacuumizing mode, removing redundant solution on the mould, and heating for 3 hours at 70 ℃; adding 10 mul of the middle layer injection molding liquid into a mold, enabling the middle layer injection molding liquid to enter a microneedle mold pinhole in a vacuumizing mode, and drying for 10 minutes at the temperature of 25 ℃ and under the humidity condition of 20%; adding 150 mul of the needle body and the substrate injection molding liquid to the cooled microneedle mould, and vacuumizing to avoid bubbles; drying the microneedle mould for 6 hours at 25 ℃ and 10% humidity;
4. and demolding the dried microneedle.
The prepared microneedle is shown in figure 1, and the microneedle has 500 needles per square centimeter and the length of 1.0 mm.
After the microneedle patch is used, the separation time of the needle point and the substrate is 1.5 h; the in vitro release showed a sustained release of vinpocetine of 10 days.
The vinpocetine can be replaced by other small-molecule active ingredients to obtain the slow-release effect of the microneedle patch.
Examples 8 to 19
According to the preparation method of example 5, the rapid implantable sustained release microneedles containing the pore-forming agent are respectively prepared, and the specific formula is shown in table 1.
TABLE 1 preparation of polylactic acid sustained-release microneedle patch containing pore-forming agent
Examples 20-30 preparation of Small molecule drug-implanted polylactic acid sustained-Release microneedle Patch
Examples 20-30 were prepared as in example 1, with the specific parameters for the components of examples 20-30 shown in Table 2.
TABLE 2 preparation of micro-needle patch for small molecule drugs
EXAMPLES 31-37 preparation of implantable polylactic acid-based sustained-Release microneedle Patches for macromolecular drugs
Examples 31-37 were prepared as in example 3, with the specific parameters for the components of examples 31-37 shown in Table 3.
TABLE 3 preparation of microneedle patches of macromolecular drugs
Examples 31-37 are also applicable to the preparation of other biomacromolecule drugs or vaccine microneedle patches.
Example 38 preparation of an implantable polylactic acid-based sustained-release microneedle patch of asiaticoside
1. Weighing 0.05g of sodium hyaluronate with the molecular weight of 50kDa, adding 4.95ml of water, heating at 85 ℃ for 1h, and preparing 1% by mass of sodium hyaluronate aqueous solution as middle layer injection molding liquid. 3.5g of polyvinyl alcohol with the molecular weight of 50kDa and 0.35g of trehalose are weighed, 6.5ml of water is added, the mixture is heated for 2 hours at 85 ℃, and a polyvinyl alcohol-trehalose aqueous solution with the mass fraction of 35% is prepared to be used as a needle body and base injection molding liquid.
2. Weighing 0.3g of PLGA (75/25) with the molecular weight of 20kDa, and adding 0.7ml of N-methylpyrrolidone to prepare a 30% PLGA solution; dispersing 20mg of asiaticoside in the 30% PLGA solution to obtain a tip injection molding solution;
3. adding the needle point injection molding liquid into a microneedle mould, enabling the needle point injection molding liquid to enter a needle hole of the microneedle mould in a vacuumizing mode, removing redundant solution on the mould, and heating for 6 hours at 60 ℃; adding 10 mul of the middle layer injection molding liquid into a mold, enabling the middle layer injection molding liquid to enter a microneedle mold pinhole in a vacuumizing mode, and drying for 10 minutes at the temperature of 25 ℃ and under the humidity condition of 20%; adding 150 mul of the needle body and the substrate injection molding liquid to the cooled microneedle mould, and vacuumizing to avoid bubbles; drying the microneedle mould for 6 hours at 25 ℃ and 10% humidity;
4. attaching a pressure-sensitive adhesive lining to the back of the dried microneedle substrate; and (6) demolding.
The prepared microneedle patch is shown in figure 1, and has 49 needles per square centimeter, and the needle point and the needle body are 1.5mm in height.
When the microneedle patch is applied to the pigskin, the substrate can be completely peeled off after 50 minutes, and the slow release time can reach 15 days.
Examples 39 to 44 preparation of implantable polylactic acid-based sustained-release microneedle patch containing cosmetic ingredients
Examples 39-44 were prepared as in example 38, with the specific parameters for each component as shown in Table 4.
Table 4 preparation of cosmetic microneedle patch
Example 45 skin penetration test of rapidly implantable sustained Release microneedles
The microneedle patches prepared in examples 1 to 44 (except example 19) were applied to fresh pig skin, pressed with a finger for 1min, stained with 1% trypan blue for 20min, and excess trypan blue was wiped off with a cotton swab, and then the skin was observed for the presence of pinholes, as shown in fig. 4 (example 1) which is a photograph of trypan blue-stained pig skin, so that the microneedle pinholes were clearly seen. The effects of the other examples are the same as those of example 1.
EXAMPLE 46 intradermal Implantation of rapidly implantable sustained Release microneedles
The microneedles fabricated in examples 1 to 44 (except example 19) were applied to fresh pig skin, pressed with fingers for 1min, and the microneedle patch was left on the skin for 1 hour, and then the intradermal implantation of the needle tip was observed under a fluorescent microscope. As shown in fig. 5 (taking example 2 as an example), a photograph of the polylactic acid microneedle tip loaded with the fluorescent dye implanted in the skin after being implanted in the skin is shown, and the array implantation of the fluorescent dye can be clearly seen. The effects of the other examples are the same as those of example 1.
It should be understood that the above-mentioned embodiments of the present invention are only examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention, and it will be obvious to those skilled in the art that other variations or modifications may be made on the basis of the above description, and all embodiments may not be exhaustive, and all obvious variations or modifications may be included within the scope of the present invention.
Claims (10)
1. A rapid implantable sustained-release microneedle is characterized by comprising a needle point, a middle layer, a needle body and a substrate; the needle tip is formed by a matrix containing biodegradable water-insoluble high polymer materials; the intermediate layer is formed from a matrix comprising a hydrophilic material; the needle body and the base are formed of a matrix comprising a biocompatible polymeric material.
2. The rapidly implantable sustained-release microneedle according to claim 1, wherein the needle tip contains at least one active ingredient; preferably, the mass ratio of the biodegradable water-insoluble high polymer material to the active ingredient is 0.5: 1-1000: 1.
3. The rapidly implantable sustained-release microneedle according to claim 1, wherein the biodegradable water-insoluble polymer material is one or more of polyanhydride, polyorthoester, polyphosphoester, aliphatic polyester, polytrimethylene carbonate, polydioxanone and its derivatives.
4. The rapidly implantable sustained-release microneedle according to claim 1, wherein the needle tip further comprises a pore-forming agent; wherein the pore-forming agent is one or more of sodium chloride, sodium carbonate, sodium bicarbonate, ammonium bicarbonate, trehalose, maltose, cyclodextrin and derivatives thereof, polymethyl pyrrolidone, hyaluronic acid and sodium salts thereof, and cellulose derivatives; preferably, the pore-foaming agent accounts for 0.1-10% of the total mass of the needle tip; more preferably, the needle tip further comprises a protective agent; wherein the protective agent is one or more of polyhydroxy compound, carbohydrate, serum albumin, polyvinylpyrrolidone, chondroitin sulfate and amino acid; more preferably, the protective agent accounts for 0.1-10% of the total mass of the needle tip.
5. The rapidly implantable sustained-release microneedle according to claim 1, wherein the hydrophilic material comprises one or more of monomer polymers or copolymers of polyvinylpyrrolidone and derivatives thereof, poly-gamma-glutamic acid, pullulan, hyaluronic acid and sodium salts thereof, trehalose, sucrose, sorbitol, mannitol, xylitol, sodium alginate, and pectin.
6. The rapidly implantable sustained-release microneedle according to claim 1, wherein the biocompatible polymer material comprises one or more of carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl chitosan, polyvinyl alcohol derivatives, polyvinylpyrrolidone derivatives, sodium hyaluronate, chondroitin sulfate, dextran, fibroin, and gelatin; preferably, the molecular weight of the biocompatible polymer material is 10-2000 kDa.
7. The rapidly implantable sustained-release microneedle according to claim 1, wherein the height of the needle tip is equal to or less than two thirds of the total height of the needle tip, the intermediate layer and the needle body.
8. A method of preparing a rapidly implantable sustained release microneedle according to any one of claims 1 to 7, comprising the steps of:
mixing a biodegradable water-insoluble high polymer material with a part of organic solvent, adding or not adding a pore-foaming agent, and adding or not adding a protective agent to prepare a needle tip matrix material solution; mixing the active ingredient with the remaining organic solvent to prepare a pharmaceutical solution; mixing the medicinal solution with the needle point substrate material solution to obtain needle point injection molding liquid;
alternatively, the first and second electrodes may be,
mixing biodegradable water-insoluble high polymer material with organic solvent, adding or not adding pore-forming agent, adding or not adding protective agent, adding active ingredient, and mixing uniformly to obtain needle point injection molding liquid;
mixing the hydrophilic material with water to obtain middle layer injection molding liquid; mixing a biocompatible polymer material with water to obtain a needle body and a substrate injection molding liquid;
injecting the needle point injection molding liquid into a microneedle mould, heating, removing the organic solvent and cooling; injecting the middle layer injection molding liquid into the microneedle mould, and drying; and injecting the needle body and substrate injection molding liquid into a microneedle mould to prepare the needle body and the substrate, drying and demoulding.
9. A rapidly implantable sustained release microneedle patch comprising a microneedle array comprising the rapidly implantable sustained release microneedles of any one of claims 1 to 7 and a backing.
10. The rapidly implantable sustained-release microneedle patch according to claim 9, wherein the microneedle patch is applied to the fields of disease treatment, prevention, health care, and beauty.
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| CN201811010762.4A CN110870846A (en) | 2018-08-31 | 2018-08-31 | Rapidly implantable sustained-release microneedle patch and preparation method thereof |
| PCT/CN2019/103331 WO2020043167A1 (en) | 2018-08-31 | 2019-08-29 | Quick implantable slow-release microneedle patch and preparation method therefor |
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| CN115581770A (en) * | 2022-10-10 | 2023-01-10 | 江苏集萃新型药物制剂技术研究所有限公司 | Microneedle patch and method for producing same |
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